Open Access Journal on General Practice

Successful Treatment of Extranodal Natural Killer T Cell Lymphoma Nasal Type Complicated by Severe Hemophagocytic Syndrome A Case Report

Introduction

Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type(ENKL), is a rare malignancy of Non-Hodgkin lymphoma characterized by an aggressive clinical course and poor prognosis [1]. It is mostly endemic to East Asia and is associated with Epstein–Barr Virus (EBV) infection [2]. Its lesions are predominantly present in the Upper Aerodigestive Tract (UADT) such as the nasal cavity, nasopharynx, paranasal sinuses or palate. Less commonly, ENKL can manifest at extra nasal locations like the lung, skin, soft tissue, gastrointestinal tract, and testis. Since the neoplasm can destroy the midline facial structures, the disease used to be known as lethal midline granuloma [3,4].The presentation of the disease at extra nasal locations is nonspecific and may mimic many other benign or malignant lesions. Patients with extra nasal presentation often have more adverse clinical features such as an advanced stage, elevated LDH and poor performance status, and the survival rate is inferior compared with the nasal sites [5-7]. Hemophagocytic Syndrome (HPS), also known as Hemophagocytic Lymphohistiocytosis (HLH), is highly heterogeneous and comprises primary and secondary types.
Secondary HPS is associated with a variety of underlying conditions such as infection, malignancy, and autoimmune diseases. ENKL is frequently complicated with HPS, and survival is discouraging in this circumstance [8]. However, no standard treatment has been established based on the results of randomized controlled trials because of the rarity of the disease [9]. Here, we report a case of ENKL complicated by severe Lymphoma- Associated Hemophagocytic Syndrome (LAHS). The patient was treated according to the R-DEP (ruxolitinib, liposomal doxorubicin,VP-16,dexamethasone) chemotherapeutic regimen, and the hemophagocytic lymphohistocytosis gradually improved during chemotherapy. Then P-Gemox (pegaspargase, gemcitabine, oxaliplatin) chemotherapy in combination with the use of anti- PD1 antibody (Sintilimab Injection ) were performed and achieved PR(partial remission). For personal reasons, the patient chose a different hospital to continue the treatment. He achieved CR (Complete Remission) with the therapy of anti-PD1 antibody and Chidamide. Unit now the patient has received the therapy for almost one year and follow up regularly in outpatient department.

Case Report

A 32-year-old non-smoking man was emergently transferred to our hospital on June 30, 2019, because of a month-long highgrade fever, cough, left-sided chest pain and blood in phlegm. Prior to this, the patient had a history of trauma to the right lower limb and the wound healed itself. About ten days later he presented to a local hospital with the above-mentioned chief complaint and a chest computed tomography scan showed multiple nodules, ground-glass opacities and patchy infiltration scattered in both lung fields. Then he had been treated as for pneumonia. However, his clinical condition did not improve. The patient was therefore admitted to our hospital for further evaluation and treatment. There was no relevant personal or family medical history for this patient. The physical examination upon admission revealed a palpable mass(3cm)on the left dorsal side and the lower margin of the right 9th rib, respectively. Fine rales were heard in the lower left lung. Hematologic examination showed a white blood cell count of 2.67×109/L, a hemoglobin concentration of 11.6 g/ dL, and a platelet count of 77×109/L. Serum chemistry showed abnormal results as follows: aspartate aminotransferase (AST)115 IU/L, alanine aminotransferase (ALT)133 IU/L, fibrinogen 1.13g/L, lactate dehydrogenase 966IU/L (normally 114–240 IU/L),Creactive protein 25.53 mg/L (normally less than 10mg/L),the procalcitonin level 0.17ng/ml(normally<0.05ng/ml),triglyceride 2.96mmol/L (normally 0.33-1.7 mmmol/L), serum ferritin8141.3 ㎍/L (normally 20–200 ㎍/L), soluble interleukin (IL)- 2 receptor>7500U/mL (normally 223–710U/mL) and natural killer (NK) cell activity 1.75%.In addition, his plasma EBV DNA level was 4300copies/ml. A bone marrow aspiration did not show lymphoma involvement (Figure 1).

Figure 1:

a) PET/CT revealing heterogeneous hypermetabolic masses in both lung fields, as well as hepatic, splenic, osseous, soft tissue, and multiple lymph node metastases that involved the mediastinum, porta hepatis, bilateral hilum of lung.
b) Chest CT scan showing multiple nodules, ground-glass opacities and patchy infiltration in both lungs.

The patient was HIV negative. Two sets of blood cultures, and tumor markers, including CEA,SCC, CFRA21-1,Pro-GRP, and NSE were all normal. The G test and GM test were both negative. Antinuclear antibody, anti-ENA antibodies, and anti-neutrophil cytoplasmic antibodies were all negative. Administration of broadspectrum antibiotics did not resolve hissymptoms. Bronchoscopic examination did not give a definite diagnosis. Lung nodules increased and grew larger, and hypoxia progressed. A CT-guided transthoracic needle biopsy of the left lower lung was performed (Figure 2). During the course of treatment, FDG PET/CT was conducted and revealed heterogeneous hypermetabolic masses in both lung fields, as well as hepatic, splenic, osseous, soft tissue on the left dorsal side and the lower margin of the right 9th rib, and multiple lymph node metastases that involved the mediastinum, porta hepatis, bilateral hilum of lung. Then we also performed a ultrasound-guided percutaneous puncture biopsy of soft tissue at the lower margin of the right 9th rib. Immunohistochemical staining of these two specimens both yielded positive results for CD56, CD3, CD2,and the Ki-67 proliferation index was 80%;in situ hybridization for EBV-encoded early small RNAs (EBER) was also positive; however, results were negative for CD79a,CD20.

Figure 2: PET-CT on December 24, 2019, showing that the lesions almost disappeared.

Moreover, Hemophagocytic lymphohistiocytosis was confirmed by cytopenia, fever, splenomegaly, hyperserotonemia, hypertriglyceridemia, low natural killer (NK) cell activity and increased circulating soluble IL-2 receptor. A diagnosis of ENKL complicated by LAHS was made. The markedly elevated circulating plasma EBV-DNA level supported the diagnosis. R-DEP(ruxolitinib, liposomal doxorubicin,VP-16,dexamethasone) chemotherapeutic regimen was performed to control the LAHS and it gradually improved during chemotherapy. Then six cycles of P-GEMOX(pegaspargase, gemcitabine, oxaliplatin) chemotherapy in combination with the use of anti-PD1 antibody(Sintilimab Injection) were performed and achieved PR(partial remission) after the treatment. Although the patient suffered from septic shock caused by Klebsiella pneumoniae in the neutropenic period, he was cured by broad-spectrum antibiotics when neutrophil improved. For personal reasons, the patient chose a different hospital to continue the treatment. He achieved CR(complete remission) confirmed by using positron emission tomography-computed tomography (PETCT) with the therapy of anti-PD1 antibody(Tislelizumab Injection) and Chidamide. Until now the patient has received the therapy for more than one year and follow up regularly in outpatient department (Figure 3).

Figure 3: Pathologic findings in CT-guided transthoracic needle biopsy specimens.
a) Histologically, a small number of nuclear hyperchromatic cells presented with large areas of observable necrosis(HEstaining;magnification,×400).
b) Immunohistochemical staining positive for the expression of CD2(magnification,×400).
c) Immunohistochemical staining positive for CD3 expression (magnification,×400).
d) Immunohistochemical staining positive for the expression of CD56 (magnification,×400).
e) Immunohistochemical staining positive for the expression of TIA-1(magnification,×400).
f) In situ hybridization positive for EBV-encoded RNA (magnification,×400).

Discussion

To our knowledge, there have been only a few reports documenting long-term remission in patients with ENKL complicated by severe LAHS. Han et al conducted a study comparing NK/T-LAHS with LAHS associated with other T cell lymphomas, which indicated that both had poor prognosis with a median survival time of 28 and 33 days, respectively [10]. Chang, et al. [11] identified that a long diagnosis time was a poor prognostic factor for patients with LAHS. So the early identification of lymphoma-associated HPS is essential to improve patient, prognosis. However it is challenging since misdiagnosis often occurs as fever and pancytopenia may also be caused by severe infection. The CT findings of pulmonary non-Hodgkin’s lymphoma are varied and nonspecific. Patchy consolidations, nodules, and masses are the most frequent CT findings and infiltrations can also be seen [12]. It is reported that PET-CT may act as a significant tool to assess patients with LAHS, as it is highly sensitive in detecting neoplasms of the majority of histologic subtypes of lymphoma, and also demonstrates extensive 18‑fluorodeoxyglucose (FDG) uptake in tumor tissues [13]. Anyhow there is no non-invasive test specific enough to make a correct diagnosis of ENKL. So lymphoma complicated with HPS should be considered in patients presenting with fever, cough, dyspnea and pancytopenia, associated with unilateral or bilateral pulmonary consolidation and pleural effusion, when combination therapy involving numerous antimicrobial agents has failed. A proper diagnosis may be established by a histopathological examination.
The International Peripheral T-cell Lymphoma Project demonstrated that extranasal NK/T-cell lymphoma (nasal type) has worse clinical features and survival rate, even in cases with apparently localised disease, than nasal NK/T-cell lymphoma in extranodal NK/T cell lymphoma [14].In this report, the tumor involved multiple organs throughout the patient’s body. As with the progressive disease courses and poor prognosis, effective therapeutic strategies are urgently needed. As for HPS, the patient was treated according to the R-DEP(ruxolitinib, liposomal doxorubicin,VP-16,dexamethasone) chemotherapeutic regimen, and the overall condition of the patient gradually improved during chemotherapy. Nevertheless, it was equally important to treat primary diseases as well as treating HPS [11]. Regarding ENKL, no standard treatment has been established based on the results of randomized controlled trials because of the rarity of the disease [9]. ENKL cells are associated with a high expression of P-glycoprotein, leading to multidrug resistance that is likely responsible for the poor response to conventional anthracycline-based chemotherapy [15]. P-GEMOX is a modification of the Gemcitabine, L-Asparaginase, and Oxaliplatin (GELOX) regimen in which L-asparaginase is switched to pegaspargase and was also included as a suggested treatment regimen for ENKL in the NCCN guidelines [16]. In a retrospective analysis of 117 patients with ENKL (96 with newly diagnosed ENKL and 21 with relapsed/refractory(R/R) disease), the P-GEMOX regimen resulted in an ORR of 88% and responses were similar for patients with newly diagnosed and R/R ENKL [17].
Recently, newer agents for ENKL, including immune checkpoint inhibitors and histone deacetylase inhibitor, have been shown to exhibit promising efficacy. Tislelizumab is an anti-human programmed death receptor-1 (PD-1) monoclonal IgG4 antibody that is being developed by Bei Gene as an immunotherapeutic, anti-neoplastic drug. Tislelizumab has been investigated in haematological cancers and advanced solid tumours, leading to its approval in December 2019 in China for patients with relapsed or refractory classical Hodgkin’s lymphoma after at least secondline chemotherapy [18].The registration of tislelizumab for other indications is currently underway. Chidamide (CS055, HBI-8000),a novel oral benzamide class of subtype-selective inhibitor of HDAC 1,2,3 and10,inhibited cell proliferation and interfered withPI3KAkt- mTOR and MAPK signaling. A prospective phase II trial in China illustrated that chidamide monotherapy was effective in 15 patients (detailed disease stages not reported) with relapsed/refractory extranodal NK/T-cell lymphoma [19]. In our case the patient has already received the therapy of anti-PD1 antibody with Chidamide for more than one year, showing that this treatment is effective and safe. As randomized trials comparing different regimens have not yet been conducted and standard therapy has not yet been established for these patients, treatment should be individualized based on patient, tolerance and comorbidities.

Conclusion

At this moment, there is no recommended treatment for ENKL complicated with HPS because of the extreme rarity of this entity. It was equally important to treat primary diseases as well as treating HPS. L-asparaginase-containing regimens are the cornerstone for treating ENKL. In this modern ENKL treatment era, newer agents are being investigated for treating ENKL and prospective multicenter trials need to be performed to establish an optimal treatment for this rare and dismal disease.

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Journal on Electrical Engineering and Computer Science

Fast GPU Interpolation for Medical Robotics Using the Conformal Geometric Algebra Framework

Introduction

Generating trajectories for 3D objects is a fundamental problem in areas of robotics, image processing, and others. There are few mathematical algorithms for the interpolation of points that use vector calculus, quaternions, dual-quaternions, and linear algebra. Geometric algebra is a powerful mathematical framework for solving problems using basic geometry entities (circles, points, spheres, planes, and lines), and can represent Euclidean geometry, quaternions, and dual quaternions. For this reason, it can be used for interpolating geometric entities for applications in medical robotics, graphic engineering, robotics, and aeronautics. In this work, a GPU implementation for interpolating geometric entities of conformal geometric algebra is proposed. The design is based on an interpolation algorithm that maps rotations and translations of motors as 8D vectors in the Study manifold.

The paper is organized as follows: section ?? reports on related work, section 2 gives a brief introduction to geometric algebra, with special emphasis on conformal geometric algebra. Section 3 presents the motor interpolation algorithm based on geometric algebra for interpolating entities in different dimensions, while section 4 describes the optimization and implementation of the interpolation algorithm in GPU and section 5 shows the experimental results. Finally, section 7 presents our conclusions and future work. Due to the easy representation of complex problems in robotics and image processing, several works have been proposed to accelerate geometric algebra operations. Most related techniques for accelerating geometric algebra algorithms are based on speeding up basic operations (inner, outer and geometric product, etc) with FPGA Co-processors [1-4] and GPU parallelization [5,6]. More complex architectures have been developed for applications on computational vision. In [7] the authors present an algorithm of Clifford convolution and Clifford Fourier transforms for color edge detection, and an alternative algorithm based on rotor edge detection is proposed in [8].

Gerardo Soria-Garc´ıa et al. introduce an FPGA implementation of Conformal Geometric Algebra Voting Scheme for Geometric Entities Extraction, such as lines, and circles on images of edges [9]. A GPU implementation for conformal geometric algebra interpolation application based on GPU is presented in [10]. The algorithm presented in this work is a modification using motors of the dual-quaternion method to interpolate rotation, translation, and dilation of the geometric entities like points, lines, circles, pair of points, planes, and spheres.

Geometric Algebra

In an n-dimensional real vector space Rn, we can introduce an orthonormal basis of vectors { }, i = 1, …, n. This leads to a basis for the entire geometric algebra.

The Geometric Algebra (GA) of the real n-dimensional quadratic vector space (V, Q) is denoted as Gn. In the case Gp,q,r (n = p + q + r) denotes the GA of (V, Q) where p, q, r correspond the number of the basis vectors which square in GA to 1,-1,and 0, respectively. The geometric product of two vectors a and b is written as ab and can be expressed as a sum of its symmetric and antisymmetric parts:

where the inner product a · b and the outer product a ∧ b is defined by and

Gn = Gp,q,r when n = p + q + r with p-unit vectors, q-unit vectors and r-unit vectors which square to 1,-1 and zero respectively. Gn is a graded linear space

where the elements of ∧n are referred to as (homogeneous) multivectors of grad k for k = 0,1, 2,…..,n. In the following, for short, elements of ∧1 V are called vectors. Thus, any M ∈ Gn can be uniquely decomposed into a sum Σk < M >k where < M >k∈ ∧k V. Furthermore, Gn is a Z2-graded algebra in the following sense:

Where

Then,

is called the even (resp. the odd) part pf Gn. Note that due to equation (4), is a subalgebra of Gn. Later in this paper, the even subalgebra of Gn will be denoted by .

The dimension of Gn is 2n. The multivector basis of Gn has 2n bases for scalars, bivectors, trivectors and k-vectors. A k-blade is either the identity element 1 of Gn (when k = 0 or, when k > 0), it is defined as the wedge product A linear combination of k-vectors is called a homogeneous multivector. Consider two homogeneous multivectors Ar and Bs ∈ G n of grades r and s, respectively. The geometric product of Ar and Bs can be written as

Conformal Geometric Algebra

In Conformal Geometric Algebra G4,1 (CGA), the Euclidean vector space R3 is represented in R4,1. The space for G4,1 has an orthonormal vector basis given by {e1, e2, e2, e4, e5} with the properties

The null basis {e0 ,e∞ } (origin and point at infinity) is defined as

These null vectors satisfy the relations

Let be E = e∞ ∧ e 0 the Minkowski plane. The unit Euclidean pseudo-scalar is Ie:= e1∧e2∧e3, and the conformal pseudoscalar Ic = Ie E is used for computing the inverse and duals of multivectors. Given a nonsingular k-vector Ak ∈ G4,1 ≡ G4,1,0, the dual and its inverse are respectively.

where A+ stands for the reversion of A and |A| its magnitude. (Table 1) where IPNS and OPNS stand for Inner Product Null Space and Outer Product Null Space respectively.

Table 1: Representation of entities in conformal geometric algebra.

Points, Lines, Planes, and Spheres

The representation of a 3D Euclidean point x = [ x, y, z ]T in R3 in the geometric algebra G4,1 is given by

Given two conformal points xc and yc, their difference in Euclidean space can be defined as

and, consequently, the following equality

is fulfilled as well. The line is formulated as a form in the Inner Product Null Space (IPNS) as follows

where n (bivector) is the orientation and the vector m the moment of the line. The plane is formulated as a form in IPNS

where the n (bivector) for the plane orientation and d is the distance from origin orthogonal to the plane.

The sphere is formulated as a form in IPNS

A poin is a sphere with zero radius. Considering the dual equation for the sphere, we can write the constraint for a point lying on a sphere

The sphere can be directly computed by the wedge of four conformal points in the Outer Product Null Space (OPNS)

Replacing any of these points with the point at infinity, we obtain the OPNS plane equation

Similar to Eq. (17), the OPNS line equation can be formulated as a circle passing through the point at infinity

Rigid Transformations

In CGA many of the transformations can be formulated in terms of successive reflections between planes.

Reflection: The equation of a point x reflected with respect to a plane π is

Translation: The transformation of geometric entity O formulated as two successive reflections w.r.t. the parallel planes π1 and π2 is given by

where a = 2dn, d is the distance of translation, and n is the direction of translation

Rotation: Similarly, we can formulate a rotation as the product of two reflections between non-parallel planes π1 and π2 which cross the origin.

The geometric product of the unit normal vectors of these planes n1 and n2 yields the equation for the rotor

where the unit bivector n = n1 ∧n2, and teh angle θ is twice the angle between π1 and π2

Screw Motion: The operator for screw motion or motor M is a composition of a translator T and a rotor R, both w.r.t. to an arbitrary axis L. The equation for a motor is as follows

where the screw line is n and m stand for the orientation and momentum of the screw line and the dual angle angle . Finally, the motor transformation for any object O ∈ G4,1 reads

Interpolation Algorithm Using the Study Quadric Manifold

where SE (3) is the special Lie group for 3D Euclidean rigid transformations, α represents any Euclidean rigid transformation and the vector X containing homogeneous coordinates X ∈ M6. Note that the motor algebra is a sub-algebra of the 3D conformal geometric algebra G4,1, thus the interpolation uses motors depending upon which algebra is used one can use I for motors of or e∞ for motors of G4,1 which both square to zero and are acting similarly as the isotropic operator of the dual quaternions which use ε which squares to zero as well. Given the set X ∈ M6 containing three homogeneous points X1, X2, X3 ∈ P7, the interpolation curve X ∈ M6 is generated by interpolating the given homogeneous points X1, X2, Xn ∈ P7which satisfy the set X computed as follows

The interpolation polynomials f0(t), f1(t), and f2(t) are formulated as follows

where t, t0, t1, and t2 are interpolation values between 0 and 1. t represents the segment of curve where the point is calculated, t0, t1 and t2 are values that represent the section of curve where interpolated and control points meeting. The Study-quadric bilinear form is given by the following matrix G,

If one wishes to interpolate more points, the above-explained interpolation equation can be extended and adapted as De Casteljou algorithm [12]. This is shown on Algorithm 1. This algorithm calculates a homogeneous point for the given set X that contains the control points (X1,··· , XN) and the interpolation values (t, t0,t1,t2) and the the Study quadric bilinear matrix Q. Here t, t0, t1, t2 are interpolation variables. t is the position interval variable and allows to determine the position within the curve of the interpolation point, the value t goes from 0 to 1. To calculate all the points of the curve, all the values of t are traversed. (t0, t1,t2) are values that indicate at which point the interpolation points, in the functions that came in Klawiter library [12], the values t0 = 0,t1 = 0.5,t2 = 1 are proposed so that the interpolated points correspond to the initial control point, the mid-control point and the endpoint respectively. These are fixed for each curve, only t is what can change when calculating a point within a specific curve.

Algorithm 1: Study quadric interpolation.

First, the algorithm checks the number of elements in X. If there is only one point, this is returned as the solution. Otherwise, X is used to get intermediate control points via equation (26) and saved in M. M is used to call the algorithm recurrently until we get only one interpolation point and returned it. Figure 1 shows the algorithm interpolation for five control points. See that in each interpolation step, for N control points, we get N−2 interpolation points and N −1 repeats are required. Since in the last step, equation (26) required 3 points, an odd number of control points are needed. where X is the set of control homogeneous points (X1, ·, XN) that describe the curve trajectory, G is the quadric matrix, t0, t1, and t2 are global constant values, in this case,0, 0.5, and 1 respectively. where G is the quadric matrix, and X the array of homogeneous points that contains the points X1 to Xn, t0, t1, and t2 are constant values, in this case, 0.5, and 1 respectively. As is seen int the algorithm, is required that the array X have an odd number of homogeneous points to get an interpolation curve. Note that the solution is in fact a rational motion utilizing a interpolating spline which in turn involves rational sub-spline motions, see [13].

Figure 1: Interpolation of five control points with algorithm 1.

In general, the Study quadric interpolation algorithm uses homogeneous points represented by dual-quaternions or by homogenous matrices. As we know, motors are isomorphic to dualquaternions and a motor can be represented as a homogeneous point as well. This motor represented as a vector Lies on the Study Manifold, see Table 2. In this regard, we propose a modified interpolation algorithm. For that, the homogeneous points are replaced by motors and substitute matrix operations with GA operations. Since the matrix multiplications in (26) with form , which result is a constant value expressed as:

Table 2: Study quadric homogeneous point represented in dualquaternion and its equivalences as motor in G⁺_3,0,1 and as motor in G_4,1

Changing the homogeneous points with their respective motor representation in CGA and analyzing the motor multiplication, is shown that the coefficient of the blade e123∞ (α3) from the motor multiplication is the double value of (29). This coefficient (α3) can be extracted from any motor using the partial derivative:

or via inner product with the Ie and e0:

Using GA, the equation (26) is reformulated for a motor based interpolation algorithm. It uses 3 control motors as follows

In the same manner as Algorithm 1, for more control points, equation (32) can be rewritten using the De Casteljou algorithm as described on Algorithm 2. This algorithm calculates one motor gave the set M of control motors (m1,··· ,mN) and the interpolation constants (t,t0,t1,t2). Similar to Algorithm 1, the interpolation function is called recursively with the calculated motors from the last step as input until we get only one motor. Since the last step needs three motors to calculate the last one, M must contain an odd number of motors. (Algorithm 2)

Algorithm 2: Motor Interpolation on CGA.

Speeding up the Algorithms Using a GPU Accelerator

The algorithmic complexity using the framework Gn ∈ R 2n is: for binary operations O(22N); for unary operations O(2N), and for M interpolated motors using K motors O(MK). To accelerate the motor interpolation algorithm for real-time applications, one can utilize arithmetic accelerators based on FPGA, ASIC, and GPU. We utilize an accelerator based on CPU-GPU co-design, where the GPU is the GTX-970 by Nvidia, which has a computing capability of 5.2 and it can be implemented on any GPU using CUDA. The algorithm was developed to compute in parallel single or multiple interpolation curves. For the computing of a single interpolation curve, the default GPU was implemented, where each motor is computed in one thread launched in a Stream. For the case of multiple curves, the multi-streaming implementation was selected to overlap the streams. GTX-970 GPU does not support recursive algorithms, due to hardware limitations. To implement the motor interpolation, we translated the Algorithm 2 into an equivalent-iterative version given by the Algorithm 3.

Algorithm 3: Motor Interpolation on CGA (iterative).

The versatile Compute Unified Device Architecture (CUDA), is a platform for parallel computing, which was developed by NVIDIA for highly parallel implementations and uses its GPUs. CUDA is based on C/C++ programming languages, however other languages like Python or Fortran can be used as well. Our accelerator was written with CUDA C++ for the GPU acceleration and C++ for the CPU interface. The GTX-970 GPU does not support recursive algorithms; thus the Algorithm 2 has to be translated into an equivalent iterative version as presented in Algorithm 3. In this regard, the algorithm uses one stream for one curve of interpolation and multi-stream for multiple curves. Here, the GPU global memory is the largest in GPU, it has the highest latency, and it can be accessed from any stream for multi-stream applications. This is very helpful, if the number of motors to be computed is large, or if we compute multiple curves, or launch many algorithms employing the same GPU via multistreaming. The GPU and CPU have different architectures.
The CPU has a few sets of cores for sequential applications. In contrast, the GPU has many cores for highly parallel computing. Figure 2 compares the CPU and GPU architectures. Note that GPU cores run asynchronously using threads. Each core is limited to 32, 64, 128, 256, or 512 threads. If a parallel GPU implementation is launched, it is required a certain number of cores. These are figured out as a direct function of the selected threads per block. In the case of the motor interpolation, each thread launches a copy of the algorithm.
All GPU operations run explicitly or implicitly on a stream. If a kernel is launched in GPU, it runs explicitly or implicitly on a stream. A stream is a sequence of asynchronous operations which are executed on a device following an order ruled by the host code. A stream involves these operations to maintain order, to permit operations to be queued in the stream, and to be executed after all preceding operations. It cares for querying the status of queued operations. These operations include data transfer and kernel launches. Recent GPUs allow a parallel technique known as multi-streaming, where multiple streams are launched, and the transference data and kernel launch can be overlapped as shown in Figure 3. For the case of parallel calculation of multiple curves, the multi-streaming implementation is used, and each curve is computed in an independent stream.

Figure 2: Architecture comparison of
a) CPU and
b) GPU.

Figure 3: Different streams used for a concurrent implementa- tion
a) 1-stream,
b) Concurrent approach for device-to-host asynchronous memory copy,
c) Concurrent approach for host-to-device asynchronous memory copy,
d) Concurrent approach for host-to- device and device-to-host asynchronous memory copy.

Experiments

The Study’s quadric and the motor interpolation are compared to analyze which of the algorithms has the best speed performance. Many motors were calculated using 15 test groups of 5 motors considering following amount of points 20, 50, 100, 200, 500, 1000, 2000, 5000, 10000, and 20000. The test was programmed using MATLAB on a Desktop with Intel core I7 microprocessor at 2.4 GHz, 32 GB of RAM, and a GTX-970 GPU by NVIDIA. The results are presented in Figure 4. The execution time of both algorithms grew linearly while the number of points increases, thus the algorithm complexity is O(n). We see that the motor interpolation version is faster than the Study quadric interpolation, namely for 20000 points, it is 28× times faster. Figure 4 shows that the motor interpolation algorithm selected for sequential and parallel implementation utilizes same hardware parameters. The sequential implementation was programmed using C++ language and CUDA C++ for the parallel approach using 32 threads per block in the kernel. The interpolated motors were computed using single and double-precision floating-point representation. All the measures consider only the algorithm execution, but data transference, file writing, and reading are excluded. Results are shown in Figure 5.

Figure 4: Comparison of Study’s quadric and Motor interpola tion speed-up.

Figure 5: CPU and GPU speed-up analysis.

It was confirmed that the GPU has the best time performance for calculating the interpolation algorithm. When the time execution in CPU increases linearly, the time in GPU for 500 or fewer points remains almost constant. For the case of 20000 motors, the GPU implementation runs 79× and 60× times faster than the CPU for single and double floating-point respectively. The different multi-streaming implementations were analyzed; 16 different interpolation curves were calculated using the concurrent approach for host-to-device and device-to-host asynchronous memory copy with 4 configurations (1, 2, 4, and 8 streams) with 32 threads per block. The measure times include data transference. Figure 6 depicts that the use of multi-streaming reduces the execution time considerably, i.e. for 20000 points, 8 streams version is 2.7×, 1.9× and 1.6× times faster than 1, 2 and 4 streams respectively.

Figure 6: Comparison of the Multi-Stream speed-up.

Interpolation of Surgery Motion

This Study’s quadric-based motor interpolation was used to interpolate trajectories in medical robotics for kidney surgery, see Figure 7. The robot manipulator hast to follow a path for suture around a certain region on the kidney phantom. We design to tasks follow an Ultrasound (US)-probe trajectory and the interpolation of a given 3D points sequence. One gives the point coordinates and their desired orientations, these are interpolated by the motor algorithm, see Figures 7b-7d. Afterward, we check the precision error using inverse kinematics. The inverse kinematics was also formulated in conformal geometric algebra, the algorithm was reported in [14 -17].

Figure 7:

a) Robot; views:
b) X-Y,
c) X-Z,
d) Y-Z.

Conclusion

In this work, an optimized version of the Study quadric interpolation algorithm is presented using the conformal geometric algebra framework. A Matlab implementation confirms that conformal geometric algebra interpolation is 28x times faster than a Study quadric interpolation for 20000 motors. The performance of CPU and GPU approaches of motor interpolation algorithm were contrasted for the cases of single and double floating-point precision. The comparison shows that the GPU is 79x and 60 times faster than the CPU implementation for single and double precision respectively. Furthermore, 16 interpolation curves were calculated via multi-streaming. These results confirm that multi streaming reduces the execution time for multiple curves interpolation. We show an application of the motor algorithm for suture by kidney surgery. In near future, we will pursue to implement the interpolation algorithm using multiple GPUs and reduce the data dependency. Also, we will build an OpenCL library of the algorithms using Python.

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Open Access Journal on public and environmental health

Awareness and Utilization of Emergency Contraception Among Female High School Students in Southeast Ethiopia

ABSTRACT

Background: Despite the existence of sound contraceptive methods including emergency contraception, there are huge numbers (84 million) of unplanned pregnancies occurring globally. Fifty percent of these pregnancies ended up in induced abortion out of which, 21 million are unsafely manipulated. Teen age girls are at double risk of the situation. The situation is worse in the developing countries like Ethiopia and much worse in rural and sub urban areas. The paucity of information in most rural part limits interventions that fit to the local situation.Objective: To assess awareness and utilization of emergency contraception and associated factors among female high school students in Dodola town, Oromia regional state, Ethiopia.Methods: A cross- sectional quantitative study was conducted using stratified random sampling technique. Data were entered, cleaned and analyzed using SPSS version 20. Bivariate and multivariate logistic regression analyses were conducted to examine the factors associated with the awareness and utilization of emergency contraceptives.Result: From a total of 773 female students 719 completed the questioners correctly; making the response rate of 93.02%. Four hundred fifty-three (63%) of the respondents were aged between 13-15 years with the mean age of 15.46(SD +/-1.76). Majority 578(80.4%) of the study participants were from Oromo ethnic group. About 304 (42.3%) had ever heard the existence of EC and about 9.8% of sexually active respondents had used it. Awareness of EC was associated with age greater than 15 years (AOR= 2.92(95% CI (1.99,4.26)], having radio (AOR= 4.43(95%CI (2.64,7.38)], having TV (AOR= 1.99(95% CI(1.19,3.30)] and chewing chat (AOR=3.08(95%CI (1.39, 6.82)]. Utilization of EC was associated with age, mothers’ educational status and having constant pocket money.Conclusion and Recommendations: The study revealed that awareness and utilization of emergency contraceptives is low. This leads to increased risk of unintended pregnancy and unsafe abortion. Therefore, the study recommends all concerned bodies should take parts in designing programs which increase the awareness and utilization of EC among high school students.

Plain English Summary

The long-established contraceptive methods including emergency contraception have not contributed adequately to stop the occurrence of huge numbers of unplanned pregnancies globally. Close to half of these pregnancies ended up in induced abortion and significant proportions of it are manipulated unsafely. Teen age girls in developing nations including Ethiopia are at increased risks. The situation is worse in the developing countries like Ethiopia and much worse in rural and sub urban areas. However, the gap in information has been affecting the interventions. Therefore, this study is conducted with the aim to assess the awareness and utilization of emergency contraception and associated factors among female high school students’ south-east of the Oromia region, Ethiopia. The study employed a cross- sectional quantitative using stratified random sampling technique. The overall data management and processing used sound statistical software for this purpose. Appropriate statistics were used to reveal statistical associations of related variables to the emergence contraception awareness and utilization. Ninety three percent of the study participants completed the questioners correctly. More than half of the respondent were in the age range between 13-15 years with the mean age of 15.46(SD +/-Majority of the study participants were from Oromo ethnic group. Less than half of the respondents had ever heard the existence of emergency contraceptives. Small proportions of sexually active respondents had used it. The study indicated that awareness and use of emergency contraceptives increase with age and level of education both the students and that of the mothers. The study revealed that awareness and utilization of emergency contraceptives is low. This leads to increased risk of unintended pregnancy and unsafe abortion. Therefore, the study recommends all concerned bodies should take parts in designing programs which increase the awareness and utilization of EC among high school students.

Keywords: Emergency Contraceptive; Awareness; Utilization; Adolescent

Abbreviations: CI: Confidence Interval; EDHS: Ethiopian Demographic Health Survey; EC: Emergency Contraceptive; ECPs: Emergency Contraceptive Pills; IRB: Institutional Reviewing Board; IUCD: Intra Uterine Contraceptive Device; KAP: Knowledge, Attitude and Practice; SPSS: Statistical Package for Social Science

Introduction

Background

Emergency contraception (EC) is contraceptive methods that can be used by women within five days following unprotected intercourse to prevent an unplanned pregnancy.EC provide a unique opportunity for preventing pregnancy after unprotected sex that no other contraceptive method can provide. It is as effective as 75-99% if taken within recommended time frame [1]. The capability of EC addressing the problems of unintended pregnancy in adolescent and young people posits the service one of the most crucial remedies in contraceptive arena for the fact that the sexual activity during adolescence is usually infrequent, unplanned and unprotected [1,2]. Moreover, the steady increase in school attendance rates in developing countries has given the chance for large proportion of young people to become sexually mature while they are at secondary school or earlier. When unintended pregnancy occurred to young girls they forced to dropout from school or goes for unsafe abortion [3]. In connection to the magnitude of the problems, nearly 210 million pregnancies occur each year globally. About 40% of these pregnancies were unintended. Of these unintended pregnancies 50% ended in abortion. About 42 million induced abortions each year, nearly 20 million abortions are unsafe. This represents 13% of maternal death. More than 95% of unsafe abortions occur in developing countries and nearly half of maternal deaths in sub-Saharan Africa were due to unsafe abortion [4,5]. In most developing countries complication of pregnancy and childbirth are a leading cause of death and disability among women of reproductive age. Teenage girls are at double risk of dying from pregnancy and birth complication than women over 20 years. This risk is five times higher for those girls under 15. In sub-Saharan Africa nearly 60 % of women who have unsafe abortion are younger than 25years of age, and 25% are teenagers [5,6].
The magnitude of abortion related morbidity and mortality are highest among young unmarried women in developing nations. For instance, in Uganda among women hospitalized with abortion-related complications, about two-thirds were 15 to 19 years old, two-thirds were students, and 80 % of them had never been married. In Nigeria Hospital-based studies have shown that up to 80% of patients with abortion-related complications are adolescents. In Ethiopia abortion accounts 60% 0f gynecological admission and girls under age 15 are three times more likely to end their pregnancies in abortion as compared to those ages 20-24. According to the 2011 Ethiopian Health and Demographic Survey (EDHS), 12% of young women age 15–19 have already begun childbearing [1,6,7]. Study conducted in Nepal among youths of 15-24 years in higher secondary and undergraduate students, the level of awareness of EC found to be 47%. But, only few mentioned the correct definition (17.02%) and consuming time (9.58%) of emergency contraceptive pills (ECP). Similarly, a study done in Dar Es Salaam, Tanzania, revealed that 57% of the respondents aware of ECP and only 14% had used it. A study conducted in Dessie, Ethiopia, on knowledge, attitude and practice (KAP) of emergency contraception among female college students disclosed that among those who had history of having sexual intercourse 78.3% of them faced unwanted pregnancies and 43.3% of these unwanted pregnancies resulted in abortion.
Of the respondents who had heard about emergency contraception only 15.4% of them made use of it. A study conducted in Jimma town, south west Ethiopia among female high school students revealed that (40.5%) had heard about EC. From those who heard of EC, 27% of the respondents mentioned the correct recommended timing for oral pills of emergency contraception [8- 11]. Currently, there are more adolescent girls in school than ever in our country. It is imperative that these girls have to complete their secondary education and beyond without any risk of unwanted pregnancies. EC is one of the known contraceptive methods to avert such problem. Knowing the level of awareness and utilization of EC by school adolescents is the first step of all the intervention to be implemented to protect adolescents from unintended pregnancy. Though few studies have been conducted on EC, they were focused only on students of higher institutions in big cities of the country. However, there are few or no scientific based research has been conducted so far in a district town like Dodola in which students come from both the town and rural areas around it. Thus, this study was conducted with an intention to determine awareness and utilization of EC and factors affecting the awareness and utilization of EC among Dodola female high school students. The study finding aimed to shape the local intervention by equipping district and zonal health leaders and service providers. Furthermore, the finding of the study will enable the comparison of service utilization within the region and outside; hence area specific interventions can be planned.

Methods and Materials

Study Setting

Dodola is located in southern part of Ethiopia, Oromia national regional state, west Arsi Zone at distance of 320km from the capital city Addis Ababa and 75km from Shashemene, the zonal center. According to 2014\15 woreda base plan, Dodola has total population 30,238 of which 14,917 males and 15,321 females. There are two administrative kebeles. With respect to some social services, the town has one district hospital and two health posts owned by the government. Moreover, it has one higher, four medium, six lower clinics, one pharmacy and eleven drug stores owned privately. There are three elementary, one high school and one preparatory public school.

Study Design

The study employed an institutional based cross-sectional quantitative study design with internal comparison carried out among female high school students in Dodola town, Oromia regional state in January 2016.

Population

Source Population: The source population of the study includes all high school female students in Dodola town who were enrolled in 2015/16 academic year.Study Population: The Study populations were female high school students which were randomly selected for the study from both high schools in the town.

Sample Size

The sample size was determined using the following assumptions: for the first study objective, expected prevalence of level of awareness of EC (64.48%) [12], Level of confidence 95%, and 5% margin of error (d=0.05). Formula for calculating the sample size n= [(Ζ 2) ×P (1 – P)/D2]. Considering design effect of 1.5 and using correction formula for finite population (N=1123female students) by adding nonresponse rate of 10% the final sample size=395. Following similar assumption and formula by taking the prevalence of EC utilization to be (25%) [11] sample size for the second objective was 344. However, when adjusted for sexually active students, the sample size increased to 773. By comparing two sample sizes, the largest 773 was taken as final sample size to ensure the maximum sample size (Figure 1).

Figure 1: Conceptual framework for EC. Note: Berhanu Desta and Nigatu Regassa 2011.

Sampling Technique

The schools were stratified in grade levels (9th& 10th). Respondents from each section were selected by simple random sampling using school enrollment list as sampling frame. Proportional distribution of sample was assigned to the respective schools, grades and sections based on the enrolment data for the academic year (Figure 2).

Figure 2: Schematic Presentation of Sampling Technique.

Data Collection Procedure & Quality Management

The data collection instrument was an anonymous selfadministered structured questionnaire. The questionnaires initially prepared in English and translated to Afan Oromo, and again back to English to ensure consistency and validity by language experts. Five percent of the samples were pretested before the actual data collection and some questions were amended. Training was given for data collection facilitators and supervisors for two days before the pretest and for a day after the pretest. The questionnaires were distributed to randomly selected students. Once the students finished filling the self-administered questionnaires, they had deposited them in a designated box, as informed earlier, to assure their anonymity. The overall data collection process was supervised by Principal investigator.

Operational Definition

Utilization of Emergency Contraceptives: Ever practice of emergency contraceptives.Awareness of Emergency Contraceptive: Ever heard the existence of emergency contraceptive.Unprotected Sexual Intercourse: Sexual intercourse that may result in unintended pregnancy.

Data Processing and Analysis

The collected data ware checked for their completeness and consistency and entered into SPSS version 20 for analysis. Data was summarized and organized using appropriate descriptive measures; frequencies and percentages of the responses were calculated. Associations between variables were assessed by using Odds Ratio with 95% Confidence Interval. First all variables were analyzed with bivariate analysis, then variables with p-value less than 0.25 were considered in Multivariate logistic- regression. Statistical association was declared at p-value less than 0.05 both in Bivariate and Multivariate logistic-regression.

Results

Socio-Demographic Characteristics of the Study Population

Seven hundred nineteen of the total 773 school adolescents were completed the survey questionnaire. Fifty four (6.98%) of the questionnaire were discarded due to incompleteness. Majority of the respondents 452(62.9%) were aged between 13-15 years with the mean age of 15.46 year with standard deviation (SD) of 1.76. About (51.6%) were attending grade nine and most of the respondents (96.2%) were single during the survey. The dominant religion was Islam (73.3%) followed by Orthodox (18.8%) and the majority were from Oromo ethnic group 578(80.4%).

Majority of the respondents 692(96.2%) had ever heard about modern contraceptives but only 304(42.3%) had ever heard the existence of EC before the survey. From those who ever heard of EC, 65.8% of them said oral pill should be used within 72hrs (3days) and 20.4% of them said Intra uterine Contraceptive Device (IUCD) should be used within 120hrs (5days) after unprotected sex to prevent unintended pregnancy. Of those who heard of EC, 207(68.1%) respondents said EC should be used after unprotected sex whereas 90(29.6%) of them said it should be used after unwanted pregnancy (Table1).

Table 1: Socio demographic characteristics of female high schools students of Dodola town, January 2016.

Utilization of Emergency Contraceptive

From the total 275 sexually active students only 27(9.8%) of them had used EC. Oral pill was the only methods utilized as EC. About 21(77.8%) of users took the first dose within 72hours after unprotected sexual intercourse and 17(63%) of them were recommended to use EC by their female friends. More than eighty five percent of EC users had used it two and more times. (Table 2).

Table 2: Awareness and utilization of female high schools students towards emergency contraception in Dodola town, January 2016.

Determinant Factors Related to the Awareness and Practice of Emergency Contraceptives

During bivariate logistic regression, age of respondent, having TV, having radio, having constant pocket money, drinking alcoholic beverage, chewing chat, mothers’ educational status and place of primary education showed significant association with the awareness of EC. Similarly, age of respondent, grade level, having TV, having constant pocket money, drinking alcoholic beverage and mothers’ educational status showed association with utilization of EC when analyzed using bivariate logistic regression. However, multivariate logistic regression analysis indicated that, age >15years (AOR= 2.92(95% CI(1.99,4.26)], having radio(AOR= 4.42 (95% CI(2.64,7.38)], having TV(AOR= 1.99(95% CI(1.19,3.30)] and chewing chat(AOR= 3.08 (95% CI(1.39,6.82)]showed statistically significant association with the awareness of EC (Table 3). Likewise, only age >15years (AOR= 3.52(95% CI(1.04,1.92)], having constant pocket money(AOR= 3.52(95% CI(1.15,10.75)] and mothers’ educational status(AOR= 4(95% CI(1.32,12.09)] were remained the real predictors of EC utilization when adjusted to the confounders with multivariate analysis (Tables 3 & 4).

Table 3: Bivariate and multivariate logistic regressions of selected variables in relation to awareness of EC among female high school students in Dodola town; January 2016.

Table 4: Bivariate and multivariate logistic regressions of selected variables in relation to Utilization of EC among female high school students in Dodola town; January 2016.

Discussion

Unintended pregnancy that usually followed by unsafe abortion is a major reproductive health challenge in developing countries. This RH risk is higher among young females than adult women(4). Nevertheless, unwanted pregnancy resulting from unprotected sex can be prevented by the proper use of EC. The result of this study showed that 38.2% of the respondents were sexually active. Forty percent of sexually active students had history of pregnancy, which 83.6% of those pregnancies were unwanted and 58.7% of unwanted pregnancy resulted in unsafe abortion. Similar studies in Dessie and Mekele cities have showen lower prevalence of unintended pregnancy and unsafe abortion. High rate of unwanted pregnancy and unsafe abortion in this study than the above two studies may be due to high awareness and utilization of EC in those studies than current one which is 70% for Dessie and 90.3% for Mekele [9,13]. When compared to Dodola, the small rural town, the former two cities are with relative better positions both in health service accessibilities and information dissemination. This is more or less similar with studies of Addis Ababa University students 43.5% and high school students of Jimma town 40.5% [11,14]. But it is lower than those studies conducted among tertiary students in Nigeria, college students of Dessie town and Adewa preparatory students 65.3%,69.9%&64.48% respectively [9,13,15]. This discrepancy could be due to socio-demographic and difference in the education status of the study population.
This study revealed that, out of sexually active respondents only 9.8% of them were utilized emergency contraceptive methods. It is more or less similar with research done among youths of Parbat district, Nepal 8.34% [10]. The finding of this study found to be lower than study conducted among Tertiary Students in Osun State, Southwestern Nigeria 32.6%, Mekele preparatory school 53.5% and Debre Markos University 18.4% [13,15,16]. This might be due to the age and knowledge difference between university and high school students. Regarding determinant factors for the awareness and utilization of EC, the present study found that respondents whose age is greater than 15 years were about three times more likely to be aware and utilize EC compared to the age group of fifteen or less years. The finding is consistent with previous studies conducted in Addis Ababa, Mekele, Haramaya and Dessie which reported older age groups were more likely to be aware and practice EC when compared to younger age groups [9,17,13-14]. This might be due to younger youth may be less concerned about unwanted pregnancy and EC as they have not yet started or newly joining to sexual activity. The other possible explanation for this could be as age increases the education level and knowledge of sexual matters may increase.
This study found that respondents who had constant pocket money were more than three times more likely to practice EC than those who had no pocket money. This may be explained by having constant pocket money may help students to decide by themselves to buy and use EC if they faced unprotected sexual intercourse without the consent of others. Moreover, the more they are financial sufficient, the more that they have freedom to practice sex. This is in agreement with the study conducted in Hawassa University about the patterns of risky sexual practice among students [18].

Conclusion and Recommendation

The study finding showed low awareness and utilization of emergency contraceptive among female high school students. This may be among the reasons for high rate of unintended pregnancy and unsafe abortion among the study population. Awareness and utilization of female high school students on EC are affected by a range of circumstances. Given the high rate of unintended pregnancy and unsafe abortion reported by the study participants; the academic institution with the health sector should take measures that can increase awareness of students and ensure easy availability of EC at school level or adolescent and youth friendly clinic in the nearby.

Acknowledgement

We would like to thank school of public and environmental health, College of medicine and health sciences, Hawassa University for technical and financial support. We also would like to extend our gratitude to Dodola town education office, school principals, teachers, data collection facilitators, supervisors and study participants for their invaluable assistance and participation during the study period.

Declaration

Ethical Considerations

Ethical clearance was obtained from Hawassa University, College of Medicine and Health sciences Institutional Review Board (IRB). Official letter from Hawassa University was submitted to Dodola town educational office and high school’s administrators. Informed verbal consent was obtained from the study participants after detail explanation of the purpose and the benefit of the study. Participants were informed that they have full right to discontinue or refuse to participate in the study at any time in the continuum of the data collection. They were also informed the anonymity of the study that by any means their participation in the study and response shall remain confidential.

Consent for the Publication

This manuscript is an extract from the MPH thesis. All ethical issues including communication of the finding to various stakeholders were properly communicated and their consents were obtained verbally.

Data Availability

The data for this study will be available when needed from the SPSS data pool.

Declaration of Funding

As mentioned earlier, this study was part of the fulfillment for the requirement for the master’s degree in public health; small proportion of fund received from Hawassa University and the other portions of expenses were covered by me in support from my family and friend.

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Open Access Journal of Maxillofacial Surgery

Oral Manifestations of Behcet’s Syndrome: Case Report

Introduction

Systemic diseases may be preceded or spread, with oral manifestations. The lesions of the oral cavity are attended, for the most part, by Stomatology Specialists, so that knowledge of the oral manifestations of systemic diseases contributes to correct behavior in the face of these conditions that, finally, must be referred to the specialist in the attention of each one of them [1]. Behcet’s syndrome is an autoimmune disease of the seronegative vasculitic type, with a disease of vessels of variable caliber [2]. Although the etiology of Behcet’s Syndrome is unknown, there are numerous investigations that indicate the participation of genetic, infectious (viral and bacterial) and immunological factors. Among the most important are the association with the HLA genotype of the patients, the cross-reactivity with human peptides and the activation of the vascular endothelium [3]. This disease is more common and severe along the old “silk road”, which extended from East Asia to the Mediterranean, Turkey’s current territory. 80 to 370 cases are reported per 100,000 inhabitants in Turkey, while the prevalence ranges from 13.5 to 35 per 100,000 in Japan, Korea, China, Iran, Iraq and Saudi Arabia; being a more severe manifestation in Japan [4]. In relation to sex, a predominance of female sex in countries of America and male sex in Asia is described, mainly between the ages of 20 and 40 [5]. In Cuba there are no prevalence studies of this entity [3]. The first description made of this pathology arises may have been described by Hippocrates in his third book of endemic diseases [4]. In 1930, the Greek ophthalmologist Benediktos Adamantiades reported to a patient with arthritis, oral and genital ulcers, phlebitis, and iritis but it was not until 1936 that the Turkish dermatologist Hulsui Behcet determined the description of this disease of more accurate way [6]. The clinical spectrum of this disease, characterized by a symptomatic triad (recurrent oral and genital ulcers with uveitis and hypotension) in addition to the fact that the histopathological study of the affected organs and the analytical data are nonspecific, makes its diagnosis based on the clinical method of description and grouping of signs and symptoms [7]. In 1990, the criteria for the diagnosis of this entity were established for the first time by the International Study Group for Behçet’s Disease [8].
In 2006, new diagnostic criteria of the International Group for the study of Behcet’s disease were established [9], which declared a major or mandatory criterion: recurrent oral ulcers and minor criteria: recurrent genital ulcers, eye lesions, skin lesions, vascular lesions and positive patergia test [10]. In 2013, the international criteria for the diagnosis of the disease were reviewed, as a result of the analysis they proposed to award 2 points to ocular lesions and oral and genital aphthous lesions and assign 1 point to skin lesions, of the Central Nervous System, vascular manifestations and the positive patergia test. According to these criteria, a patient with a score ≥ 4 points is classified as a Behcet disease [3]. At present it is known that it is not curable, but treatable [4]. The goals of therapy are to: suppress inflammation, reduce the frequency and severity of recurrences. To be effective, treatment must be implemented early [11]. Objective: Describe the oral manifestations and therapeutic behavior to be followed before a patient with Behcet syndrome.

Case Presentation

Patient of 20 years of age, female sex, black race, urban origin, who comes to the emergency services of Maxillofacial Surgery of the body of guard of the Dr. Gustavo Aldereguía Lima Hospital in Cienfuegos, Cuba referred by the specialist in Stomatology General Comprehensive that provided services in the area of health corresponding to the patient for presenting multiple ulcerated lesions throughout the oral cavity and lips Figure 1.

Figure 1: Ulcerated lesions on lips.

Anamnesis

During the interrogation, the patient was referred to as inflammation of the entire oral cavity, pain during food intake and difficulty swallowing (dysphagia), burning sensation and burning of the mouth, halitosis, recurrent episodes (7 to 8 times a year) ulcerated bleeding lesions, which previously healed spontaneously until their total disappearance but during the last episode the lesions persist. It also refers to the presence of genital ulcers, skin rash in the frontal region and persistent joint pain.

Physical Exam

Multiple ulcers were detected in the oral cavity of approximately 1cm and more, covered by a yellowish-green pseudo membrane and with fetidity due to the over-added infection of the lesions, with irregular, undefined, elevated, rounded, hyperemic edges, bleeding to the minimum stimulus, painful on palpation, located in the region of the oropharynx, tongue, palate, gum, floor of mouth, mucosa of cheeks and lips Figure 2a. In addition, irregular and rough surface was detected upon palpation of the frontal cutaneous region Figure 2b and in the left axillary and subaxillary region Figure 2c. The case of the patient was consulted with the Internal Medicine services for a better treatment of genital lesions and joint pain.

Figure 2:(a) yellowish-green pseudo membrane located in the tongue and oropharynx;
(b) Skin rash in the frontal region;
(c) Irregular and rough surface in the left axillary and subaxillary region.

Complementary Exams

The following complements were indicated:
a) Blood count
b) Leukogram
c) Blood chemistry
d) Hepatic Profile
e) HIV serology
f) Rheumatoid Factor
g) C-reactive protein
h) LE cells
i) Immunoglobulins Serum
j) Patergia test
k) Surface antigen
l) Hepatitis C antibody
The results of the complementary examinations were within the normal parameters except the Leukogram in which there was a considerable increase in segmented leukocytes (neutrophils) with a value of 80%, which showed that the over-added infection of the lesions was bacterial. During the patergia test, a small sterile needle was inserted into the skin of the forearm, causing a small red papule to appear at the needle insertion site one or two days after the test was performed, which indicated hyperreactivity of the immune system to minor trauma or damage Figure 3. It is not 100% specific, only a proportion of patients with Behcet syndrome have a positive response.

Figure 3: Red papule on forearm skin two days after the patergia test.

Diagnosis

With these results, some possible diagnoses were ruled out: Human Immunodeficiency Syndrome, Rheumatoid Arthritis, Hepatitis B and C, Herpes Simplex type 1, Recurrent Aphthous Stomatitis, Parvovirus, Discoid Lupus Erythematosus. Finally, the patient was diagnosed with Behcet Syndrome with a scientific basis in the criteria for the diagnosis of this syndrome of 2013, complying with the mandatory or major requirement: recurrent oral ulcers in oral mucosa with a minimum of 3 episodes during a year (2 points ) and with three minor criteria: genital ulcers (2 points), erythema nodosum (1 point) in this case in the left frontal, axillary and subaxillary region and positive patergia test (1 point). According to this current classification criterion it is only necessary to accumulate a score ≥ 4 points, in this case the patient added a total of 6 points.

Treatment

As part of the Stomatological treatment, the patient was indicated a series of hygienic dietary measures such as: eliminating or reducing acidic foods from the diet (lemon, orange, tangerine, pineapple, guava, tomato, natural yogurt); avoid ingesting foods with artificial condiments and at elevated temperatures and instead use natural condiments and ingesting food and drinks that are refreshing but not gaseous; Eliminate local irritants such as coffee, cigar and alcohol. In addition, local topical anesthetics such as 0.2% lidocaine were indicated half an hour before eating food to relieve the pain caused by chewing and swallowing in these cases. In this case, the indication of mouthwash with saline solution or 20% chamomile tincture was very effective, 20 drops in 200 milliliters of boiled water 3 times a day for 7 days, the use of chamomile was preferred as part of the natural medicine treatment and traditional for its properties: anti-inflammatory, analgesic, antibacterial, antiulcer, antiviral and antifungal.
The Internal Medicine services treated the patient with a prednisone in a 20-milligram bulb intravenously every 8 hours, then gradually reduced to a maintenance dose of 10 milligrams orally in tablets, this corticosteroid was very effective in the treatment of inflammatory component of oral, genital and arthropathic lesions of the patient and as an immunomodulator. In addition, colchicine (0.5 mg) was given one tablet every 8 hours; methotrexate (2.5 mg) four tablets in weekly dose; folic acid (5 mg) one tablet daily, except on the day of Metrotexate, all in order to control the rheumatologic component. Currently, the patient is compensated for the disease.

Discussion

Systemic diseases are those morbid processes that affect more than one organic system. The etiopathogenesis of many of these diseases is still not completely clear, but it is well known that, in large part of them, inflammatory processes and immune system disorders that give rise to the various manifestations are involved. The majority of patients with recurrent oral aphthous ulcers have no other involvement, but in others the presence of chronic aphthous stomatitis lesions is associated with systemic processes [1]. Behcet’s syndrome is a very rare autoimmune disease condition in these latitudes [4]. The most accepted concept so far defines it as: in a chronic, multisystemic, recurrent inflammatory process whose main alteration lies in a vasculitis that involves the arteries and veins of any caliber. It is characterized in the clinic by presenting patients with inflammation of the mucous membranes, translated by oral and genital ulcers; in addition to uveitis; digestive symptoms, skin lesions, arthritis and occasional neurological intake.
The etiology of Behcet’s disease is unknown and although the majority of cases are sporadic, some studies support the possible genetic origin with evidence of autosomal recessive inheritance as it is reported that in 1 in 10 families there is another member with the disease or other autoimmune diseases in first-degree relatives such as hypothyroidism, scleroderma, discoid lupus erythematosus and juvenile idiopathic arthritis. Another of the arguments described in defense of this genesis is the increased risk of suffering from Behcet’s disease when it is associated with the presence of the HLA-B51 main histocompatibility system antigen [12]. It is believed as for many autoimmune or auto-inflammatory syndromes, that certain infectious factors (in particular, Streptococcus antigens) and / or environmental factors are capable of triggering symptoms in individuals with certain genetic variants [13]. In some investigations, the herpes simplex virus type 1 and parvovirus B 19, among the triggers of Behcet’s syndrome, other research reports that in this syndrome there is an alteration in the number and activation of lymphocytes, so the CD4 + / CD8 + index inversion has been observed.
The syndrome is usually more serious and frequent in men [3], however the case presented corresponds to a female patient. The white skin color shows a predominance, although there is a great miscegenation in Cuba [12], this ailment is uncommon in the black population but when it appears they present greater complications and worse prognosis [14]. Over the years different criteria have been used to diagnose the disease, the International Study Group for Behçet’s Disease in 1990 considers the existence of recurrent oral ulceration with at least two of the following clinical manifestations: recurrent genital ulceration, ocular involvement, involvement cutaneous or positive patergia test to make the diagnosis [8]. In 2006 the International Group declares it necessary to present: Mandatory Criteria or major criteria: recurrent oral ulcers (minor canker sores, major canker sores or herpetiform ulcers, in oral mucosa with a minimum of 3 episodes for a year). Minor criteria: recurrent genital ulcers (ulcers or aphthous scars in genital areas observed by the doctor or the patient) (2 points). Eye lesions (anterior or posterior uveitis, or the presence of vitreous cells in the examination with slit lamp or vasculitis retinal diagnosis by an ophthalmologist) (1point).
Skin lesions (erythema nodosum, folliculitis, papulopustular lesions, acneiform nodules, observed by the doctor in postadolescent patients not treated with corticosteroids) (2 points). Patergia test: positive (cutaneous hypersensitivity characterized by the appearance of a sterile pustule, 24 to 48 h after needle puncture, observed by a doctor) (1 point). Vascular lesions (arterial, venous thrombosis or aneurysms) (1 point). The diagnosis is made with the mandatory criterion plus 3 points [10]. In 2013, an international group, composed of representatives from 27 countries, reviewed the international criteria, according to these criteria, a patient with a score ≥ 4 points is classified as a Behcet disease [3]. The presence of recurrent, painful, variable-sized canker sores that heal in 1-3 weeks usually without scarring in most cases are the first manifestation, as occurred in this case. The genital canker sores present in 72-94% of cases are morphologically similar to oral ones, usually heal at 2-4 weeks, but they do leave a scar [7]. There are no typical laboratory alterations of Behcet Syndrome. Erythrosedimentation and C-reactive protein levels are often moderately high but do not correlate well with disease activity, in this case these values were kept within normal parameters.
Acute phase reactants may be elevated, mainly in patients with vasculitis of large vessels. Serum immunoglobulins are sometimes elevated and immunocomplex levels may be elevated, but autoantibodies such as rheumatoid factor, antinuclear antibodies, anticardiolipin and neutrophil antithoplasm (ANCA) are negative [3]. The patergia test is not 100% specific, only a proportion of patients with Behcet Syndrome have a positive response and the positivity in patients with the syndrome vary in different geographical areas (60-70% in Turkey and Japan, but rare in America and Europe) [11], however, the case presented is of a patient born in Cuba who is part of the American continent in which the test was positive, not coinciding with world statistics, where positivity is rare in the Americas. The differential diagnosis should be made with: Reiter’s disease, Steven-Johnson syndrome, aphthous stomatitis, recurrent Mollaret meningitis, Whipple’s disease, multiple sclerosis, Harada’s disease, inflammatory bowel diseases, sarcoidosis and ankylosing spondylitis. The diagnosis is based on detailed medical history and long-term clinical observation. There is no way to predict whether a patient with recurrent oral ulcerations will develop the disease even if frequent outbreaks constitute an alarm sign, as confirmed in this case. The choice of treatment depends on the clinical manifestations and their severity.
An early diagnosis followed by a treatment with corticosteroids, medication used in this patient, could prevent the fearful neurological complications in the opinion of several authors, although more recent studies report highly positive results with immunosuppressants [7]. It is described that all patients should use colchicine and steroids, with Metrotexate being the diseasemodifying drug most used in the treatment of this [5]. The majority of patients diagnosed with Behcet syndrome have a productive life. The symptoms are controlled with a healthy diet, rest, physical exercises and drug treatment and the prognosis varies according to the affected organs [7]. Behcet’s disease has a chronic course with exacerbations and unpredictable remissions, the frequency and severity of which may decrease over time. After the first five years, the disease acquires a stable course or towards improvement; after the fourth decade, clinical severity is decreased, with longer intervals of recurrence between exacerbations. The prognosis is good, unless there is commitment of vital organs. The presentation at the age of early onset (before age 25) has been associated with more severe manifestations of the disease and increased mortality [13].

Conclusion

While it is true that multiple systemic diseases present with aphthous oral manifestations, oral ulcers in Behcet’s disease are the first clinical manifestation, which in most cases, lead the patient to seek medical help and constitute for countless authors the cornerstone to reach the diagnosis of this disease, so it is considered vital that the Comprehensive General Stomatologist putting into practice the knowledge acquired about the syndrome, consider it a possible differential diagnosis more before a patient with recurrent oral ulcerations. The timely management of a patient with an unusual and exceptional pathology can have an optimal evolution and reduction of complications in the quality of life. It is recommended to expand coverage and health education to be able to detect these cases in the first instance, thus avoiding underdiagnosis.

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Open Access Journals on Surgery

Oral Manifestations of Behcet’s Syndrome: Case Report

Introduction

Case Presentation

Anamnesis

Physical Exam

Complementary Exams

Diagnosis

Treatment

Discussion

Conclusion

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Open Access Journal on Chemistry

Mechanistic Role of Egyptian Propolis Against Ehrlich Ascites Carcinoma and Methotrexate Limitations

ABSTRACT

Although several conventional anti-cancer drugs are available, most of them are toxic and intolerable after long-term use. Therefore, there has been a global increased interest to identify novel agents that can possess anti-tumor effects by it or maximize the anti-tumor effects of low doses of conventional anti-cancer drugs. Egyptian propolis is a powerful antioxidant and free radical scavenger produced by bee. The current review was designed to characterize Egyptian propolis, investigate its anticancer effect and a potential protective role against methotrexate (MTX) toxicity.

Keywords: Cancer; Propolis; Methotrexate; Ehrlich Ascites Carcinoma

Abbreviations: EAC: Ehrlich Ascites Carcinoma; TSTA: Tumor Specific Transplantation Antigen; ALL: Acute Lymphatic Leukemia; DHFR: Dihydrofolate Reductase; PMNs: Polymorphonuclear Neutrophils; ROS: Reactive Oxygen Species; CZE: Capillary Zone Electrophoresis; INFs: Induce the Production of Interferon’s; PEE: Propolis Ethanolic Extract; CAPE: Caffeic Acid Phenyl Ester

Cancer and Its Incidence

Cancer is characterized by the uncontrolled growth of abnormal cells which disrupt body tissue, metabolism. It tends to spread locally to various parts of the body. The genetic and environmental factors are crucial for cancer formation and progression. Among the environmental factors are the lifestyle of people that include tobacco, alcohol, and physical activity. Industry, microbial factors (radiation, pollution, infection) and diet are also important reasons for cancer development [1]. About 18 million cancer cases and 10 million cancer deaths were estimated in 2018. One of the most diagnosed cancers is the lung cancer that leads to death. It is followed by breast cancer, prostate cancer, colorectal cancer stomach cancer, and liver cancer for mortality. Lung cancer is the most frequent and leads to death among males, followed by prostate and colorectal cancer. Breast cancer is also the most diagnosed cancer that causes cancer death followed by colorectal and lung cancer. Cervical cancer ranks the fourth for both incidence and mortality.
In Egypt, the commonest sites of cancer in Egyptian males are liver, bladder, non-Hodgkin’s lymphoma, lung and prostate. These sites represent 60.2% of all cancer in males. The commonest sites in Egyptian females are breast, liver, non-Hodgkin’s lymphoma, colorectal and ovary. These represent61% of cancer in females as in Figure 1.

Ehrlich Ascites Carcinoma (EAC)

Experimental tumors are important for modeling, where EAC is one of the commonest. Initially it appears as a spontaneous breast cancer in the female mouse. It is used as an experimental tumor by transplanting tumor tissues subcutaneously from mouse to another [2,3]. The liquid form in the peritoneum of the mouse and called it as “Ehrlich ascites carcinoma” owing to the ascites liquid with the carcinoma cells. EAC is an undifferentiated carcinoma. It is originally hyperdiploid that has high transplantable capability, rapid proliferation and shorter life span. It has 100% malignancy and has no tumor specific transplantation antigen (TSTA). EAC likes human tumors. The tumors are most sensitive to chemotherapy because they are undifferentiated and have rapid growth rate. The rate of proliferating of EAC cells was characterized in four phases.
The phases are
(1) A logarithmic phase for four or five days, after 107 tumor cells transplantation intraperitoneal (i.p.),
(2) A plateau phase where the number of cells stayed constant on the 5th to 13th day,
(3) A transitory proliferating phase on the 13th to15th day,
(4) A second plateau phase on the 15th to 18th day [4].
In general, the EAC model could be applied owing to its assessment of the cancer biology. Also, the cellular and molecular mechanisms of novel anti-proliferation, anti-angiogenic, antimetastatic effects of compounds against cancer could be assessment.

Cancer Treatment

The treatment of cancer is a multidisciplinary therapy that consists of radiotherapy, surgery, chemotherapy and immunotherapy [5]. The treatment depends on the cancer type, its state of advancement and its location. The first treatment is surgery. It is useful in removing of solid tumors. It may be necessary for the early stage of cancers and benign tumors. It may leave residual cancer cells and has undesirable side effect. It changes the rate of growth of the remained cancer cells via triggering a faster metastatic process. The multimodal therapy such as immunotherapy, radiotherapy, chemotherapy and other forms of treatments come after surgery in order to provide a good chance to kill the metastatic cancer cells or keeping them in the remission state [6]. The radiotherapy may cure cancer in different sites of the body. This technique destroys cancer cells by using high-energy X-rays targeted directly to the tumor. During the radiotherapy treatment, the water molecules in the body form what is called free radicals. The free radicals destroy the cell’s DNA by oxidation while preventing its replication.
They kill the cancer cells which rapidly divide. Location, type, stage of cancer, person’s age and general health are all factors affect the radiotherapy. Radiotherapy may be the only treatment with chemotherapy before surgery to shrink the tumor. It is used after surgery to kill off any remaining cancer cells and to ease symptoms such as bleeding. The common side effects of radiotherapy are the killing of dividing healthy cells near by the cancer cells including the fatigue and the skin itchiness and color changes [7].

Chemotherapy

Chemotherapy is considered as one of cancer treatment that involves the use of therapeutic agents which have direct tumorkilling properties. It is the most effective for cancers that divide rapidly and have good blood supply. The treatment by chemotherapy cures maintains long term remission (free of disease) increases the effectiveness of surgery or radiotherapy and helps to control pain and other symptoms. The effective drugs in treating cancer interfere with the cancer cells activity. This takes place by going directly into the sabotage of a specific phase of cell development or by sending messages that confuse the cells to destroy themselves. It is well known that not all drugs are effective against all cancers but various groups of drugs act in different way [8]. Nowadays, the antitumor chemotherapy is very limited although there are many advances in the research and development of different cancer drugs [9]. A major problem of chemotherapy drugs is that the drugs are not specifically selective for neoplastic cells but can eliminate the normal healthy cells too particularly those often divide. If multiple cell lines have destroyed the organ toxicity occurs. Patients with cancer receiving chemotherapy are commonly suffered from anemia, proneness to infections and hair loss. Examples for different chemotherapies are 5-flurouracil, cisplatin and methotrexate (MTX) and their side effects.

Methotrexate

Methotrexate, (2,4-diamino-N10-methyl propyl glutamic acid) is an analog of folic acid in which the groups bonded to the C4 carbon and N10 hydrogen are NH2 and CH3. The structure of the molecule consists of three parts as in Figure 2. MTX has received intensive studies and proved effective therapeutics agents. It treats many solid tumors, autoimmune diseases, and hematologic malignancies [10]. It is a folate antimetabolite with antineoplastic and antirheumatic properties which play a great role in treatment of breast cancer, osteogenic sarcoma, lung cancer, choriocarcinoma, bladder carcinoma, acute lymphatic leukemia (ALL), brain medulloblastoma, primary lymphoma psoriasis, chronic myeloid leukemia and rheumatoid arthritis [11]. The mechanism by which the MTX acts as a cancer chemotherapeutic agent is the inhibition of the dihydrofolate reductase (DHFR) with high affinity giving rise to a depletion of tetrahydrofolates that are needed for the synthesis of both the purines and thymidine. Thus, the synthesis of RNA, DNA and other metabolic reactions is interrupted by MTX. It interferes with mitotic cell division as described in Figure 3 [12].

The dihydrofolate reductase enzyme is the initial cellular target of MTX and other antifolates. It catalyzes the reduction of folate and 7,8 dihydrofolate to 5,6,7,8 tetrahydrofolate. Primary MTX enters the cell by an active carrier transport mechanism and shared by the reduced folates and mediated by the reduced folate carrier (RFC) [13]. MTX is modified inside the cell and retained in it. This is established by the addition of glutamate residues (up to 5) catalyzed by the folylpolyglutamate synthetase enzyme [14,15]. MTX and its polyglutamylated forms are tightly binding inhibitors for DHFR. They interfere with pyrimidine and thymidylate biosynthesis. MTX polyglutamates together with dihydrofolate polyglutamates are inhibitors for enzymes involved in the purine biosynthesis including the aminoimidazole carboxamide ribonucleotide transformylase and phosphoribosylglycinamide transformylase. The enzymatic removal of glutamyl groups from the polyglutamylated forms of folates and MTX is efficiently catalyzed by gamma glutamyl hydrolase [16, 17].
The life threatening may be due to the side effect of high dose of MTX (MTX-HD). However the various doses of oral MTX are variable because of the inter-individual variability of gastrointestinal absorption of MTX. Bone marrow, gastrointestinal mucosa and hair are vulnerable to the effect of MTX. Their high rate of cellular turnover and because the MTX concentration is inversely proportional to renal clearance, the renal toxicity is frequent with MTX-HD [18]. MTX-HD is normally used as a cytotoxic chemotherapeutic agent in many malignancies treatment. This treatment is acute lymphoblastic leukaemia and the treatment of various inflammatory diseases treatment [19]. The efficiency of this agent is limited by its toxicity that causes severe side effects and leads to liver cirrhosis, liver fibrosis, hypertrophy of the hepatocytes, hepatocellular necrosis, hepatitis, and death. In general, MTX toxicity has severe side effects on the haematopoietic system as well as liver enzymes [20]. MTX also increases the amount of H2O2 and free radicals generated by the stimulated polymorphonuclear neutrophils (PMNs). PMNs lead to toxicity and consequently increase the cellular damage rate.
MTX interferes with the homocysteine metabolism via decreasing the levels of 5-methyltetrahydrofolate, homocysteine levels and S-adenosylmethionine (SAM) [21]. In addition, MTX leads to methionine synthesis and reduction in antioxidant enzymes which are catalase, superoxide dismutase, glutathione peroxidase and SAM (SAM acts as an antioxidant) in cerebrospinal fluid of patients on MTX treatment [21]. The deficiency of SAM caused by MTX could be a reason for increasing the reactive oxygen species (ROS). Administration of SAM also caused lipid peroxidation inhibition in a rat model [22]. The undesirable side effects of antitumor drugs could be overcome with compounds able to discriminate the tumor cells from normal proliferative cells. The resistance can be minimized using modality approach combined with different complementary mechanism of action. At this stage, the use of natural sources is belived to have a great value for cancer control and programs destruction [23].
Natural products are rich with chemical compounds having antitumor and cytotoxic activities due to their enormous propensity. This propensity synthesizes a various structural diverse bioactive compounds [24]. Natural products have made significant achievements over 60% of the clinical use of anti-cancer drugs originated from natural products such as plants, marine organisms and bee products [25]. Antioxidant-rich foods are used to assess the human body to reduce the oxidative damage caused by free radicals [26]. There are many synthetic antioxidants used in the pharmaceutical and food industry has toxic and mutagenic effects [27]. The isolation and progressing of natural antioxidants such as polyphenols and flavonoids have attracted the researchers interest everywhere [28].

Propolis

Propolis is a bee product containing resins and other materials that collected by certain species of bees from buds and exudates of plants [29]. This product is also known as bee glue. It is usually sticky in nature and some are dry and gel-like in texture. Bees form the propolis by mixing their own waxes with the resins that previously collected. Certain types of bee use the propolis as glue material for building their hive while some kind of bees like Trigona sp. cover the whole hive with a mass of the propolis [30]. Bees synthesize the propolis in order to protect the bee community. The hive covered with propolis is protected from any possible enemies. It also keeps the inner temperature of the hive at around 35 ℃. Propolis mixed with the bee hive hardens the cell walls and makes it stronger against any physical stress. Some bee’s varieties cover the carcasses of intruders killed in the hive for the attainment of internal aseptic environment. Propolis can defensed the bees against infections, bacteria and fungi [31,32].

Chemical Constituents of Propolis

Propolis is usually creamy to dark brown in color. Some varieties are green and red. The contents of propolis vary according to the environment of the bees and depend initially on the plants around it [32,33]. The compounds present in the propolis are also dependent on the substances that secreted by different plants. Some of these substances are lipophilic materials on the leaves, gums and lattices aside from the resin [33]. Propolis contains esters of phenolic acid (58%), bees wax (24%), flavonoid aglycones (6%), triterpenes (0.5%) and lipids and wax (8%). It also contains minerals and micronutrients such as zinc, manganese, copper and pollen [34]. The buds of black poplar trees in some reigons (Populus nigra) are the main source of propolis that contains high amount of phenolic acids, flavonoid aglycones (flavones and flavonones) and esters [33].

Capillary zone electrophoresis (CZE) technique is normally used for the determination of Twelve different flavonoids as acacetin, pinocembrin, rutin, chrysin, catechin, naringenin, luteolin, kaempferol, galangin, apigenin, myricetin, and quercetin. Two phenolic acids, cinnamic acid and caffeic acid and one stilbene derivative, resveratrol in propolis extracts as shown in Figures 4 & 5 [35]. Biological activity and medicinal use of Propolis

Antimicrobial Properties

Antiviral Activity

Flavonoids of propolis induce the production of interferon’s (INFs). Interferon’s have several antiviral effects. These effects are strengthening of cell membrane and induction of nucleases which destroy the viral genome and the modification of the initiation factor phosphorylation pattern Eukaryotic. This factors affects the transduction of proteins and stops all their biosynthesis including that of viruses [36]. Isopentyl ferulated isolated from propolis was found to inhibit greatly the infectious activity of influenza virus A1 Honey Kong (H3N2) in vitro [37]. Administration of aqueous extract of Propolis decreases the mortality and increases the mean survival length in mice infection with influenza virus A/PR8/ 34 (HONI) [38]. Melliferone, moronic acid, and betulonic acid and four known aromatic compounds were successfully isolated from Brazilian Propolis and tested for anti-HIV activity in H9 lymphocytes. It was found that moronic acid has significant anti-HIV activity [39].

Antibacterial Capacity

The antibacterial activity of propolis against the gram-positive bacteria is due to the presence of aromatic acids, flavonoids, esters, flavone, flavonol, volatile fractions of phenols, caffeic acid and its esters, cinnamic acid, terpenoids, and chrysin that are present in propolis resins. These bioactive compounds can further contribute to antibacterial activity through a mechanism based on two parts, which described in Figure 6. It is known that, propolis represses the bacterial movement and enzyme activity. It exhibits bacteriostatic action towards different bacterial genera. It can also be bactericidal with high concentrations and is able to affect cytoplasmic membrane. The effect of propolis ethanolic extract (PEE) on the physiology of Bacillus subtilis, Escherichia coli, and Rhodobacter sphaeroides, was investigated [40]. H. pylori, is an important factor for gastrointestinal illnesses. This bacterium has the enzyme of peptide deformylase which catalyses the elimination of formyl group from the N-terminus of polypeptide chains. As the activity of this enzyme is fundamental for H. pylori existence, it is viewed as a promising helpful medication target. Caffeic acid phenyl ester (CAPE) is a competitive inhibitor of peptide deformylase.
Propolis combination with synthetic antibiotics allows dose reduction of the selected antibiotics and potentiates their effect. Italian PEE greatly increases the effect of gentamycin, ampicillin and streptomycin. It also moderates the action of vancomycin, chloramphenicol and ceftriaxone. No effect was observed when the PEE was used simultaneously with erythromycin. Furthermore, the PEE which comes from Australian bee suppresses the s. aureus growth although it has a low activity towards p. aeruginosa. The synergism among Bulgarian, Brazilian propolis and the antibiotics (ciprofloxacin and norfloxacin) that dealing with DNA and the metabolism in salmonella typhi was investigated.

Anti-Fungal Activity

The antifungal activity is a function of the chemical variation of propolis [41]. A Poland PEE sample showed high fungicidal activity towards C. albicans, C. krusei and C. glabrata. French Propolis extracts were effective against C. glabrata and C. albicans but less effective towards the A. fumigates. Brazilian PEE proved activity against different Candida strains (C. guilliermondii, C. albicans, C. krusei, and, C. tropicalis [42]. Red and green Brazilian propolis exhibits reasonable activity against various fungal species of Trichophyton. The Argentina propolis microparticles (PMs) and PEE have a good antifungal activity towards clinical yeast isolates, C. albicans and non-C. albicans. The action of different propolis extracts (PEE and propolis water extract (PWE)) as Fungicide was studied against three C. albicans morphotypes. It was shown that the PEE is the most effective.

Antiprotozoal and Antiparastic Activity

The ethanolic and dimethyl-sulphoxide extracts of propolis, were active against Trypanosoma cruzi [43].

Antioxidant and Anti-Inflammatory Activity

The mediators such as vasoactive amines, eicosanoids, platelet aggregation factors, cytokines, kinins and free oxygen radicals are released through injured tissue during the inflammation process. The cytokines which are released from the active macrophages lead to vessel dilatation. During this stage, the phospholiases, cyclooxygenase (COX) and lipoxygenase (LOX) are activated by the phospholipids in cytoplasmic membrane. The activation of these enzymes affects the eicosanoid, arachidonic acid metabolism and generates the main inflammatory mediators. In addition, the reactive oxygen species (ROS) produced during the inflammatory process attacks the cellular components, thus destruct lipids, proteins, and DNA [44]. Also, ROS catalyzes NF-κB translocation in the nucleus and causes transcription of cyclooxygenase- 2 (COX-2), cytokines, nitric oxide synthase (NOS), phospholipase A2, superoxide dismutase. Therefore, it leads to the damage of the tissue. The anti-inflammatory activity of both the flavonoids and phenolic acids that found in the propolis comes from their antioxidative properties.

These bioactive compounds inhibit the activity of lipoxygenase, cyclooxygenase, NADPH-oxidase, tyrosine-protein kinase, ornithine decarboxylase, myeloperoxidase, decrease the levels of prostaglandins (PGE2) and leukotrienes [45]. Propolis overcomes the phosphorylation of inhibitor of κB binding protein (IκBα) and activator protein-1 (AP-1). Propolis is also capable to block the NF- κB activation. The mechanism of propolis protective effect during the oxidative stress is discribed in Figure 7. Flavonoids and phenolic acids can be characterized by their strong antioxidant activity. This activity is related to the chemical structure of these compounds that can inhibit the activity of xanthine oxidase, ascorbic acid oxidase, protein kinase C, cyclooxygenase, cAMP phosphodiesterase, lipoxygenase and, Na+/K+ ATPase. These forbid the generation of ROS through scavenging, disturbing the reactions that result in lipid peroxidation, chelating metal ions, and potentiating the action of other antioxidants.

In Cuban propolis nemorosone is the most abundant compound that shows a good antioxidant capacity as reported by Cuesta-Rubio et al. Kangaroo island propolis ethyl acetate extract is rich with stilbenes that have a powerful antioxidant activity. The propolis of Anhui, China shows powerful scavenging activity due to the presence of caffeic acid and caffeate derivatives. The methanolic extracts of Algerian propolis were found to contain large amounts of flavanones, caffeic acid esters, galangin and kaempferol. They possess powerful scavenging action. The Romanian PEE decreased the concentration of malondialdehyde (MDA) and increased the activity of glutathione peroxidase. Turkish PEE has a good antioxidant activity that increases the catalase (CAT) activity and decreases the MDA levels. The compounds isolated from propolis have also revealed anti-inflammatory activity. Major flavonoids as galangin, chrysin and quercetin have reduced the PGE2 levels. This action occurred by reduction of COX and lipoxygenase expression. The quercetin, kaempferol, genistein, and daidzein inhibits activation of STAT-1 (signal transducer and activator of transcription 1) and NF-κΒ (nuclear factor kappa-light-chain-enhancer of activated B cells) that are important transcription factors for inducible NO synthase [46] (Figure 8). Caffeic acid inhibits the arachidonic acid production as well as COX-1 and -2 activities and many oxidases such as myeloperoxidase, lipoxygenase, ornithine decarboxylase and tyrosine kinase. The artepillin C found in Brazilian propolis inhibits the production of PGE2 [44].

Anti-Proliferative Activity

Propolis possesses an antitumor activity in animal models and cell cultures. This activity result from the propolis ability to inhibit the DNA synthesis in tumor cells, capacity to induce apoptosis and the ability in activating the macrophages to give factors capable of regulating the function of B, T and NK cells. The flavonoids of propolis play a protective role towards the toxicity of the chemotherapeutic agents and radiation in mice. They are promising to have similar protection effect in humans. Combination with an adjuvant antioxidant therapy can increase the effectiveness of chemotherapy via ameliorating the side effect on leukocytes, kidneys and liver and therefore enable the dose escalation. Aqueous extracts from Croatian and Brazilian propolis inhibit the growth of human cervical carcinoma. The chinese hamster lung fibroblast lines, decreased the number of lung tumor nodules in mice [47]. On the other hand, water extract of Japanese propolis inhibited murine S-180 sarcoma cells and the growth of transplanted tumors in mice [48]. Ethanolic extract of Brazilian propolis prevents colon cancer development in rats induced by 1,2-dimethylhydrazine (DMH) [49], reduce human prostate cell proliferation [50]and the growth rate of colon cancer lines as CaCo2, HT-29, HCT116, and SW480. The activity of the anti-colon cancer of Chinese propolis ethanolic extract was reported by Karapetsas et al.
Methanolic extract of Brazilian propolis has cytotoxic effect against human pancreatic cancer line PANC-1 [51].
Chrysin flavonoid constituent of temperate Propolis was found to disturb the cell cycle progression and cancerous cell division. It also decreases in expression of telomerase reverse transcriptase in human [52]. Beside chrysin the caffeic acid and quercetin have exhibited powerful cytotoxic effect on leukaemia cell lines [53]. Chrysin reduces the size and the number of preneoplasmic hepatic nodules that induced by diethylnitrosamine in rats. It also reduced the expression of COX-2, NF-κB [54]. A large number of flavonoids have antineoplastic activity. A flavanol from Mexican propolis showed action towards the A549 lung cancer. The HT- 1080 fibrosarcoma cell line is stronger than 5-fluorouracil. Some terpenes from propolis have proved anticancer potential effect. Two cycloartanes from Burmese Propolis demonstrated strong cytotoxicity against A549, HT-1080, PANC-1 and HeLa. Manool and diterpene of the Greek propolis evidenced specific antiproliferative activity against the colon HT-29 cancer line [55].
Most of studied compounds of propolis against cancer are CAPE. Various studies have illustrated that CAPE has cytostatic and cytotoxic action against several cancer cell lines in both animal and human [56]. CAPE has specific antioxidant activity. It prevents the carcinogenesis by oxidative stress. It has been suggested to be template for the design of anticancer drug within this area [57,58]. Various cinnamic acid derivatives from Brazilian propolis investigated for anticancer activity included artepillin C, drupanin and baccharin [59]. These compounds showed cytostatic effect at low concentration on human gastric, colon cancer and leukemia cell lines [59]. In addition, artepillin C has wide apoptotic antineoplastic activity on human cancer cell lines and in vivo as reported by Kimoto et al.; Bhargava et al; Ferreira and Negri.

Other Important Activities of Propolis

Many investigations revealed useful results in diabetes with propolis. Application on encapsulation of propolis in type-2 diabetes mellitus has been reported to minimize the level of glucose in blood during fasting and also to increase the endogenous activity of insulin [60]. CAPE has also been proposed as an anti-diabetic agent. It greatly stimulates glucose uptake in cultured skeletal muscle cells [61]. Green Propolis of Brazil possesses anti-ulcer action in stomach and diabetic ulcers. It increases the epithelialization rates and reduces the ingress of pro-inflammatory neutrophils and macrophages [44,62]. Propolis of Australia has protective activity against sunburn and skin cancers. It reduces the cutaneous inflammation, immunosuppression and lipid peroxidation induced by UV exposure [63]. Other skin protection activity has been found by CAPE in several melanoma cell lines [64].

Figure 1: Incidence of cancer in Egypt.

Figure 2: Chemical structure of methotrexate.

Figure 3: Mode of action of MTX in cancer.

Figure 4: Major flavonoids found in propolis [35].

Figure 5: Major phenolics and their derivatives found in propolis[35].

Figure 6: The mechanism of propolis as anti-bacterial agent.

Figure 7: Signal transduction pathways.

Figure 8: Major biological activities of Propolis.

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Open Access Journal on Pathology

Experience of Indian National Biobank in COVID-19 Pandemic and Future Directions

Introduction

The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) [1]. SARS-CoV-2 was first reported in China and till date accounted for 169 597 415 confirmed global cases of COVID-19, including 3 530 582 deaths. Worldwide [2]. On March 11th 2020, WHO declared public health emergency [3]. High transmissibility of this virus rapidly surged number of cases and many countries around the globe announced regionalnational lockdowns [4]. The lockdown situations adversely affected businesses, slow down of scientific activities and operational activities of several sectors including biobanks [5]. The National Liver Disease Biobank (NLDB), India is an advanced open resource sharing liver disease biobank for liver and associated disease research established with the joint efforts of the Department of Biotechnology (DBT) and Institute of Liver & Biliary Sciences (ILBS), New Delhi, Government of India [6]. NDLB is India’s first liver disease biobank with a storage capacity of more than 5.4 million biosamples and certified by Tissue Repository Network (CTR. Net) in 2020 [7]. NLDB has been set up in an institute dedicated to patient care and research in liver diseases.
The biobank collects high quality biosamples across the country with clinical data. A total of 73,831 aliquots of serum, plasma, PBMC, urine, tissue, stool, and whole blood from 12,607 patients have been collected and stored at NLDB as of Dec 31st 2020. Biosample and access to the advance analytical facility openly available under one roof for all researchers. In order to deliver cutting edge services for collaborative liver disease research NLDB acquired a non-profitable business and financial model, charging only the cost for utilization of services, NLDB engaged trained and highly competent staff with world class storage and advanced analytical infrastructure, aiming to become a nodal centre for providing the clinical and basic researchers to reliably store biosamples and carry out their research at one platform. The national sudden lockdown was placed on 24 March 2020 in India for 68 days in different phases when the number of confirmed coronavirus cases were approximately 500 [8]. The lockdown restricted people to stay in their homes [9] and all transport services were suspended with exceptions for essential emergency services [10].

Impacts

The sudden lockdown brought both the opportunities and challenges to the biobank. Although, the National Liver Disease Biobank (NLDB) is a liver and related diseases biobank, the government of India designated it as an add-on COVID biobank permitting for collection and storage of COVID-19 biosamples for research, developing diagnostics and vaccines. NLDB faced tri-directional challenges based on financial, operational and sustainability, but were accepted positively with changing in the processes and management.

Crisis Management

The storage facility and associated equipment are one of the key elements in operations of biobank. As per best practices published by International Society for Biological and Environmental Repositories [11], telephone numbers for professional assistance should be clearly posted in the repository and accompanying administrative areas (e.g., engineering or facilities personnel, power companies, fuel supply companies, transportation services). The emergency planning was focused to maintain cryopreservation of biosamples from various possible events that may breakdown the freezers. NLDB has 10 % of the total storage capacity as backup, maintained at operating temperature at all times. Safe guarded by 24×7 CCTV surveillance and a security personal and all mechanical freezers connected with datalogger equipped with SMS alert system. Three biobank personnel are trained and even prepared for 24×7 shifts in case of emergency. Contact numbers of emergency response team (engineering, electricity and security office) are posted on all storage units. Earlier the emergency plan was only focused for natural calamities. Learning from the current situation, an upgraded emergency plan based on management and transportation of sample at satellite center, business strategy, financial planning and operations of biobank is under review. Moreover, NLDB also started to develop contingency plan to keep operating in pandemic positions. There were difficulties in taking consent with COVID infected patients. Leftover diagnostic samples stored at biobank without consent will be utilised for research after approval from ethics board.

Sample Collection

The NLDB follows the “decentralized collection, centralized storage, distribution and informatics” model. (Figure 1). It has collaboration with 18 hospitals for collection of biosamples and supports many research projects by providing biosamples along with associated data. Biosamples are collected with necessary precautions, however, in this pandemic, the need of PPE kit, sanitizer, and establishment of BSL2/BSL3 facility was critical, considering all samples as highly infectious.

Figure 1: NLDB Model for biosample collection, transportation and distribution.

The challenges confronted while functioning in this pandemic:
1. There has been a significant decline in the number of samples collected from both host institute and the satellite centres because Outpatient Department and surgeries are only limited for emergency cases (Figure 2). 2. Co-ordination with satellite centers and maintenance of samples became difficult because of limited staff.
2. At initial period, hospitals were not prepared to screen for COVID-19 for all patients, leading to high chances of collecting COVID-19 contaminated samples from asymptomatic patients. Sample processing protocols were revised and precautions were made even for handling samples apparently COVID negative.
3. Biobank was instructed to collect COVID-19 biosamples but processing and storage area was not designed to handle highly infectious samples. To avoid cross contamination, urgent requirements for separate space for processing and storage of COVID and non-COVID samples was flagged.
4. Dedicated routes to transport cryoshippers containing aliquoted COVID biosamples were made from patient ward to BSL2+ facility and then to the storage area.

Figure 2: Effect of biosample collection during lockdown.

Logistics and Supply of LN2 Gas

The surging Covid-19 in March, 2020 and the Indian government’s decision to contain the disease outbreak through lockdown adversely affected the domestic logistics sector, especially road transportation, production and supply of essential goods [12]. With increasing number of active cases of Covid-19, the consumption and demand of oxygen was increased throughout the country [13]. Some LN2 industries directed to produce more oxygen in comparison to LN2 gas. The resource management for consumables, refilling of LN2 in cryoshippers, transient storage and transportation of biosamples are managed from main centre established at New Delhi, India. The sudden nationwide lockdown almost got NLDB in a standstill affecting the operational chain such as managing the collection, storage, transportation of biosamples from satellite centres. Biobank has consumption of 100 litres/day to maintain temperature of two LN2 tank. NLDB does not have LN2 plant and dependents only on LN2 supply from outside. Closedown of LN2 factories due to movement of labours, local shortage/limited access to liquid nitrogen, shortage of drivers, made it difficult to get the LN2 tanks refilled. Moreover, the market price of LN2 was hiked up to three times in comparison to the previous routine rate. The pandemic taught that biobank should have inhouse plant for LN2 supply. To avoid such problem in future, NLDB processed to establish an LN2 plant in ILBS premises with capacity to produce approx. 250 litres of LN2/ day (Figure 3).

Figure 3: Elements which affected the LN2 supply in the pandemic.

Operations

The ban and restrictions on public transport effected the employees resulting in only 40% attendance of the staff. Biobank staff were seconded in COVID-19 testing lab and the sudden focus and orders to quickly set up procedures to test covid-19 samples, and two-technicians infected with COVID-19 at different time periods and others quarantined for coming in close contact, were big challenges faced. IT experts were not able to resolve the technical issues in the biobank software from home due to nonavailability of remote access for the software. There was temporary interruption of collection and distribution activities as hospitals redirected to treat critical cases and COVID -19 patients only. During lockdown, one of the -80⁰C freezers stopped working, consequently the samples were shifted to the backup freezer. Repair was delayed due to restricted movement and limited supply of spare parts and backup LN2 freezer was being utilised for storage of COVID-19 samples. Biobank samples were on complete risk in case of any failure in storage system as the backup freezers were already in use. Emergency purchase of two -80 freezers was done to accommodate more COVID samples as left over covid-19 samples from hospital diagnostic centers were directed to store in biobank for future research. SOPs were revised as per the knowledge gained in the pandemic. A separate SOP is developed as per guidelines of Indian Council for Medical Research/ Government of India for collection, storage and distribution of COVID-19 samples for research.

Personnel Wellbeing

Commuting for the personnel was big issue in lockdown. However, staff working in COVID lab were provided accommodation in hospital. The safety guidelines issued by Ministry of Health and Family Welfare Government of India to maintain social distancing at work place and transport were followed with necessary compliance [14,15]. Routine test, thermal scanning, sanitizing machine, touch free mechanism installed at all entry and exit points and common areas. Complete ban on non-necessary visit and emergency visits were allowed only after negative rapid antigen test. Two biobank technical staff resigned from their job because their family not allowed them to work on COVID-19 samples.

Management Related Issues

a. Finance: A project for add-on COIVD biobank facility was submitted to the Government of India which was approved and funds released on priority basis in December, 2020.
b. Biobank Information Management System (BIMS): IT related issues were impediment for biobank due to no remote access of clinical databases, biobank systems, slow adaptation and update of software. BIMS was updated with annotation for COVID-19 as per recommendations of ICMR, GOI.
c. HAZARD Management: The primary and basic requirement of biobank is safety of its staff and of the environment against biological and chemical hazards. There were no specific guidelines available for storage, collection, distribution and QMS of highly infectious samples in ISO20387, NCI and ISBER best practices. Sharing of COVID biosamples are not as easy as non-COVID samples thus National Oversight Committee was constituted by ICMR to review the same. NLDB has provision to share the sample after approval of Biosample release committee (BRC). Sample are released after signing MTA and undertaking by recipient to handle COVID-19 and it is informed that any violation or misuse would be dealt with strict action as per laws of Government of India.

Work Culture & Infection

Work culture of biobank has been totally changed due to COVID fright and implementation of new rule and SOPs. Handling the informed consent, annotation forms duly signed by COVID patients was a big issue. WHO and ICMR guidelines are being followed by NLDB to prevention from any infection, Intensive communication and training on good hygiene practices, PPE kit donning and doffing has been provided to biobank personnel. Technicians are equally divided for COVID and non-COVID related work. It is compulsory to wear N95-type masks, use of hand sanitizer, disinfect all documents coming through patents in Ultraviolet (UV) light, and to sanitize work area daily and disinfect the storage area twice a week.

Research Support

The government of India has released huge funds for research focused on Diagnostics, Vaccines, Novel Therapeutics, Repurposing of Drugs or any other intervention for control of COVID-19 as most of the research institutes were closed or had limited access to maintain necessary equipment during lockdown.

Discussion

The sudden lockdown consequent to the COVID-19 pandemic brought both the opportunities and challenges to the biobank. NLDB handled the tri-directional challenges that were operational, financial and sustainability. Sudden changes in operations, supply chain disruptions, manpower presence and remote access of software were major difficulties along with the Handling of Covid-19 biosamples, inaccessibility of donors and challenges in obtaining informed consent. Although, there was neither biobank practices and standards included any plan to run a biobank in a pandemic, NLDB followed the available national [15] and international standards [16] and guidelines [11,17,18] to handle the infectious samples. Though, biobank had an emergency plan for backup storage though there were no thoughts to have an emergency plan for LN2 supply and to work with limited man power. Flexibility in purchase rules, monitoring of efficient utilization, stock management for every one month can be a great help to run biobank in emergency. Biobank must have inhouse LN2 plant along with a rate contract with suppliers to supply LN2 in emergency at equivalent prices. All SOPs revised to treat all sample as infectious Remote monitoring and access of software during emergencies is a must. However, development of remote monitoring software is only possible after the contribution of key stakeholders, such as hospital administration, IT team, privacy legal expert and biobank operations team. In conclusion, NLDB used this pandemic as a learning experience and modifying its operational, emergency and business plans for future crisis and pandemics.

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Open Access Journal on Graduate and Professional Studies in Business

Tai Chi, Qigong, and the Treatment of Hypertension

Introduction

Tai chi, also referred to as taiji or taijiquan, is considered both a martial art and a kind of low-impact exercise. Its origins are unclear, but it apparently dates back at least to the thirteenth century. The oldest style is the Chen style, which originated in the Chen village in China [1,2]. The second oldest style, and also the most popular style, practiced by more people than any other style, is the Yang style [3]. The other main styles are the Wu and Wu Hao styles [4], and the Sun style [5], which is the youngest of the five main styles. The various styles of tai chi have much in common, although there are some differences, which we need not discuss in this article. One of the main common features of all styles of tai chi is that they generate healing life energy (qi, pronounced chee), which serves to boost the body’s immune system and prevent the onset of illness and disease. Qi energy also has a beneficial effect on treating existing illness. Many articles and books have been written about the health benefits of tai chi [6-7], so we need not go into the details here. Suffice it to say that many medical studies have found that the regular practice of tai chi can lead to many health benefits, including the treatment of existing diseases and illnesses.
Qigong has been around a lot longer than tai chi, perhaps thousands of years [8]. Many books and articles have been written about this traditional Chinese medicine tool as well [9-74]. It is also a set of gentle exercises that generate qi, which has beneficial healing effects for a wide variety of ailments, including, but not limited to ankylosing spondylitis [75-76], anxiety and stress reduction [77-82], arthritis [83-89], autism [90], back pain [91-92], cancer [93-115], cognitive impairment [116-119], COPD [120-121], COVID-19 [122-123], depression [124-134], elder care [135-138], fibromyalgia [139-141], longevity [142-144], Parkinson’s Disease [145-146], and traumatic brain injury [147], to name a few. The present article focuses on the beneficial effects of tai chi and qigong exercises on hypertension and blood pressure. It reviews a few studies that have found beneficial effects and cites a number of other studies for further reading and research.

Methodology

The PubMed.gov database [148] was searched to find studies that had been done to determine the effectiveness of tai chi and qigong exercises on blood pressure and hypertension.

Findings

The findings reported upon in this article are representative of the numerous studies that have been done examining the effects of tai chi and qigong on blood pressure and hypertension. Additional studies on this topic are cited in the reference section below Liu et al. [149] conducted a meta-analysis to determine the effectiveness of tai chi and qigong exercises in the treatment of essential hypertension (EH). Specifically, they looked at blood pressure (BP), levels of nitric oxide (NO), and endothelin-1 (ET-1). Exercises were performed from 1.5 to 6 months. Nine randomized controlled tests (RCTs) of 516 EH patients in China found that those who did the exercises were able to reduce both systolic and diastolic blood pressure. The exercises also contributed to higher NO blood levels and lower ET-1 blood levels. Although the difference in treatment outcomes using tai chi and qigong exercises versus antihypertensive drugs was statistically insignificant, combining the two therapies resulted in significantly better outcomes than what would occur using only tai chi and qigong or drug therapy. Thus, tai chi and qigong exercises were equally effective as drug therapy in the treatment of hypertension, only without the side-effects that may be present with drug therapy. Liu et al. concluded that tai chi and qigong exercises could be an effective complementary and alternative therapy for EH patients.
The tai chi exercises varied by study, and included the Yang- 24 form, Yang-8, and Chen-style tai chi. The qigong exercises also varied by study, and included Mawangdui Daoyinshu and Baduanjin, among others. Subgroup analyses were performed for the different types of tai chi and qigong, and some were found to be more effective than others. One subgroup analysis of changes in systolic blood pressure ranked the effectiveness of the various exercises as follows, from most to least effective:
a) Chen-style tai chi
b) Mawangdui Daoyinshu Qigong
c) Self-compiled qigong
d) Yang-style tai chi
An examination of different subgroups found that some tai chi and qigong exercises were more effective than others in lowering diastolic blood pressure. The ranking, from most to least effective, was:
a. Chen-style tai chi
b. Self-compiled qigong
c. Mawangdui Daoyinshu Qigong
d. Yang-style tai chi
Liu et al. concluded that Chen-style tai chi might be most effective in reducing blood pressure, while Yang-style tai chi might be the least effective. The authors also compared the effectiveness of the various tai chi and qigong exercises on improving NO levels. The ranking from most to least effective was:
a. Yang-style tai chi
b. Baduanjin Qigong
c. Mawangdui Daoyinshu Qigong
Chen-style tai chi and self-compiled qigong were not statistically significant in improving NO levels. The authors also analyzed subgroup data on the effectiveness of tai chi and qigong in reducing ET-1. The ranking from most to least effective was:
a. Baduanjin Qigong
b. Yang-style tai chi
c. Mawangdui Daoyinshu Qigong
Self-compiled qigong was found not to be statistically significant in lowering ET-1 levels. Thus, it appears that Baduanjin and Yangstyle tai chi may be more effective than other exercises in improving NO and ET-1 scores.
If one were to interpret the findings of this study, one might conclude that choosing qigong and or tai chi therapy might be superior to drug therapy for the treatment of EH for two reasons. Although the study found that qigong/tai chi therapy and drug therapy are equally effective in treating EH, qigong/tai chi therapy has two distinct advantages over drug therapy: qigong/tai chi therapy has no adverse side-effects, and it does not cost anything. Drug therapy, on the other hand, sometimes has adverse sideeffects, and it is not free. The study also found that combining qigong/tai chi therapy with drugs might be superior to choosing just one of the two options.
Pan et al. [150] conducted a systematic review of randomized controlled trials on the effects of tai chi on blood pressure, body mass index (BMI), and quality of life (QOL) on patients suffering from hypertension. Their meta-analysis of 24 studies containing 2,095 patients (1,074 in the treatment group and 1,021 in the control group) found that the intervention group had significantly better outcomes for systolic blood pressure (SBP) [p ≤ 0.001], diastolic blood pressure (DBP) [p ≤ 0.001], physical functioning [ p ≤ 0.001], role-physical [p ≤ 0.001], general health [p = 0.001], bodily pain [p ≤ 0.001], vitality [p ≤ 0.001], social functioning [p = 0.027], role-emotional [p = 0.003], and mental health [p = 0.001] compared to the control group. However, the differences in BMI between the groups were insignificant. Pan et al. concluded that tai chi is an effective therapy to improve SBP and DBP for patients suffering from essential hypertension. Zou et al. [151] found that the practice of baduanjin was beneficial for quality of life (p = 0.004), sleep quality (p = 0.001), balance (p = 0.004), handgrip strength (p = 0.007), trunk flexibility (p = 0.006), systolic (p = 0.0004) and diastolic (p = 0.005) blood pressure, and resting heart rate (p = 0.0005). They examined the results of various studies on each of these topics. In the case of the effect of baduanjin on blood pressure, they examined 9 studies having a total of 743 participants.
Ladawan et al. [152] investigated the effects of qigong exercise on cognitive function, blood pressure and cardiorespiratory fitness in 12 healthy middle-aged subjects who performed qigong exercises in 60-minute sessions, three times a week for eight weeks. They found that the exercises resulted in significant improvements in Trail Making Tests Part A (p = 0.04), systolic blood pressure (p = 0.0001), diastolic blood pressure (p = 0.005), mean arterial pressure (p < 0.001) and maximal workload (p = 0.032). Twelve weeks after cessation of the exercises, they had all returned to the baseline. The authors concluded that it is necessary to perform qigong regularly to maintain the improved health effects.
Ching et al. [153] examined data on 370 subjects from seven randomized controlled trials (RCTs). The following six types of qigong exercises were used:
a) Conventional Qigong
b) Guolin Qigong
c) Shuxinpingxue Gong
d) Dongeui Qigong
e) Ba Duan Jin Qigong
f) Mawangdui Daoyinshu Qigong
They found that the practice of qigong exercises had a significant effect on reducing systolic (p < 0.001) and diastolic (p < 0.001) blood pressure. The above studies are representative of the studies that have been done in recent years on the effectiveness of tai chi and qigong on reducing high blood pressure. Some other recent studies are listed in the reference section at the end of this article [154-188].

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Open Access Journal on parkinsons disease

Use of Anti-Inflammatory Drugs in the Treatment of Parkinson’s Disease: A Systematic Review of Perimental Studies

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopamine neurons (AD) in the substance nigra pars compacta (CNS) and accumulation of insoluble cytoplasmic protein inclusions called Lewy and Lewy neurites bodies [1]. The precise mechanism underlying the pathogenesis of PD is not yet fully understood. The accumulation of evidence suggests that soluble α-synuclein aggregates, known as oligomers, play a significant role in PD where the neurodegenerative process culminates in impairing several subcellular functions [1]. Thus, clinically, PD presents as muscle stiffness, tremor at rest, bradykinesia (abnormal slowness of voluntary movements), postural instability; some patients also have symptoms related to psychiatric and cognitive disorders. In this context, intraneuronal accumulation and aggregation of alpha-synuclein can start from several sites such as the intestinal tract, where this altered protein (alpha-synuclein) can be transported through the enteric route to the CNS through the parasympathetic pathway [2]. In addition to this hypothesis, there is genetic influence in the functional roles of genes identified as monogenic forms of PD. Mutations in SNCA, LRRK2 and VPS35 genes have been highly penetrating and cause autosomal dominant forms of PD [1]. Thus, showing the existence of multifactorial processes to support the underlying cause of this aberrant protein accumulation. Therefore, what most of these studies show is that when alpha-synuclein is lodged in the CNS itself, it is directly linked to damage triggered by the activation of microglia, which, by releasing inflammatory factors, causes an oxidative burst affecting neuronal cells leading to death [3].
Thus, since there is a pattern of inflammatory characteristics after the beginning of the accumulation of these proteins, this tangle of interleukins, TNF-α, TNF-γ, CCL2, ROS and NO may increase such accumulation and aggregation already in force, thus determining an even more cumulative and oxidative neurodegenerative picture, exponentially affecting the patient’s condition, becoming a real “Parkinson’s snowball”. Thus, this hypothesis suggests a clinical applicability of treatment with anti-parkinsonian drugs of antiinflammatory nature and drugs properly anti-inflammatory drugs (IANES and corticosteroids), where the anti-inflammatory action may provide a therapeutic resource for patients with the purpose of promoting a decrease in levels of dopaminergic cell lesions and lowering of alpha-synuclein accumulation. This study, therefore, aims to correlate the use of these two types of drugs with antiinflammatory attributes to the treatment of PD, observing whether there is an anti-inflammatory or neuroprotective response (via dopaminergic markers) and which group of drugs is better than the other.

Methodology

This study consisted of a systematic review prepared according to the Preferred reporting items for systematic review and metaanalysis protocols (PRISMA-P). The eligibility criteria defined for the inclusion of an article in this review were human and animal studies, contain relevant information regarding the neuroprotective action of the drug in PD, applicability of anti-inflammatory drugs, csf analysis, use of in-silico computational method and clinical results and be indexed in the electronic databases MEDLINE/ Pubmed, LILACS, EMBASE, Scopus and Web of Science. Using the PECOS strategy, the descriptors used in the searches were chosen based on the technical-scientific terms MeSH (Medical Subjective Heading) and DeCS (Descriptors in Health Sciences), combined by the Boolean operator “AND” or “OR” (Table 1). MEDLINE/ PubMed research strategy: “Idiopathic Parkinson’s Disease” OR “Lewy Body Parkinson’s Disease” OR “Parkinson’s Disease, Idiopathic” OR “Parkinson Disease, Idiopathic “ OR “Parkinson’s Disease, Lewy Body” OR “Parkinson’s Disease” OR “Idiopathic Parkinson Disease” OR “Lewy Body Parkinson Disease” OR “Primary Parkinsonism” OR “Parkinsonism, Primary” OR “Paralysis Agitans” AND “Neuroinflammation” OR “Inflammations” OR “Innate Inflammatory Response” OR “Inflammatory Response, Innate” OR “Innate Inflammatory Responses” AND “Anti Inflammatory Agents” OR “Agents, Anti-inflammatory” OR “Anti-inflammatories” OR “Anti-inflammatory Agents” OR “Agents, Anti-Inflammatory” OR “Agents, Anti Inflammatory” OR “Anti-Inflammatories” OR “Anti Inflammatories” OR “Anti-inflammatory Agents, Non-Steroidal” OR “NSAIDs” OR “Non-Steroidal Anti-Inflammatory Agents” OR “Non-Steroidal Anti Inflammatory Agents” OR “Nonsteroidal Anti-Inflammatory Agents” OR “Nonsteroidal Anti Inflammatory Agents” OR “Anti Inflammatory Agents, Nonsteroidal” OR “Antiinflammatory Agents, Nonsteroidal” OR “Nonsteroidal Antiinflammatory Agents” OR “Corticosteroids” OR “Corticoids” OR “Inhibitors, Cyclo-Oxygenase” OR “Inhibitors, Cyclo Oxygenase” OR “Inhibitors, Cyclooxygenase” OR “Prostaglandin Synthesis Antagonists” OR “Antagonists, Prostaglandin Synthesis” OR “Inhibitors, Prostaglandin-Endoperoxide Synthase” OR “Inhibitors, Prostaglandin Endoperoxide Synthase” OR “Prostaglandin Endoperoxide Synthase Inhibitors” OR “Prostaglandin Synthase Inhibitors” OR “Cyclo-Oxygenase Inhibitors” OR “Cyclo Oxygenase Inhibitors” OR “Inhibitors, Prostaglandin Synthase” OR “Inhibitors, Cyclooxygenase 2” OR “Cyclooxygenase-2 Inhibitors” OR “Inhibitors, Cyclooxygenase-2” OR “Coxibs” OR “COX-2 Inhibitors” OR “COX 2 Inhibitors” OR “Inhibitors, COX-2” OR “COX2 Inhibitors” OR “Inhibitors, COX2”.

Table 1: PECOS Strategy.

EMBASE research strategy: (‘parkinson disease’/exp/mj OR ‘parkinson disease’/mj OR ‘parkinson`s disease’/mj OR ‘parkinsons disease’/mj OR ‘paralysis agitans’/mj OR ‘parkinson disease, symptomatic’/mj) AND (‘anti-inflammatory agent’/exp/mj OR ‘antiinflammatory agent’/mj OR ‘anti-inflammatory agents’/mj OR ‘antiinflammatory agents, steroidal’/mj OR ‘anti-inflammatory agents, topical’/mj OR ‘anti-inflammatory drug’/mj OR ‘anti-inflammatory agent’/mj OR ‘anti-inflammatory agents’/mj OR ‘anti-inflammatory agents, steroidal’/mj OR ‘anti-inflammatory agents, topical’/mj OR ‘antiflogistic agent’/mj OR ‘antiinflammation agent’/mj OR ‘anti inflammatory agent’/mj OR ‘anti-inflammatory drug’/mj OR ‘antiinflammatory steroid’/mj OR ‘anti-inflammatory activity’/exp/mj OR ‘anti-inflammatory action’/mj OR ‘anti-inflammatory activity’/ mj OR ‘anti-inflammatory effect’/mj OR ‘anti-inflammatory action’/ mj OR ‘anti-inflammatory activity’/mj OR ‘anti-inflammatory effect’/mj OR ‘antiphlogistic action’/mj OR ‘antiphlogistic activity’/ mj OR ‘antiphlogistic effect’/mj OR ‘nonsteroid anti-inflammatory agent’/exp/mj OR ‘nsaid’/mj OR ‘anti-inflammatory agents, nonsteroidal’/ mj OR ‘anti-inflammatory agents, non-steroidal’/mj OR ‘anti-inflammatory agent, nonsteroid’/mj OR ‘non steroid antiinflammatory agent’/mj OR ‘non steroid anti-inflammatory drug’/ mj OR ‘non-steroidal anti-inflammatory agent’/mj OR ‘non-steroidal anti-inflammatory drug’/mj OR ‘non-steroidal anti-inflammatory agent’/mj OR ‘non-steroidal anti-inflammatory drug’/mj OR ‘nonsteroid anti-inflammatory agent’/mj OR ‘nonsteroid antiinflammatory drug’/mj OR ‘nonsteroid antirheumatic agent’/mj OR ‘nonsteroidal anti-inflammatory drug’/mj OR ‘nonsteroidal anti-inflammatory drugs’/mj OR ‘nonsteroidal anti-inflammatory drugs’/mj OR ‘nonsteroidal anti-inflammatory agent’/mj OR ‘nonsteroidal anti-inflammatory drug’/mj OR ‘prostaglandin synthase inhibitor’/exp/mj OR ‘cyclooxygenase inhibitor’/mj OR ‘cyclooxygenase inhibitors’/mj OR ‘prostaglandin synthase inhibitor’/mj OR ‘prostaglandin synthetase inhibitor’/mj OR ‘cyclooxygenase 2 inhibitor’/exp/mj OR ‘cox 2 inhibitor’/mj OR ‘cox 2 specific inhibitor’/mj OR ‘cox 2 specific inhibitors’/mj OR ‘cox- 2 inhibitor’/mj OR ‘cox-2 specific inhibitor’/mj OR ‘cox-2 specific inhibitors’/mj OR ‘cox2 inhibitor’/mj OR ‘cox2 specific inhibitor’/ mj OR ‘coxib’/mj OR ‘coxibs’/mj OR ‘cyclooxygenase 2 inhibitor’/ mj OR ‘cyclooxygenase 2 inhibitors’/mj) AND (‘modulation’/exp/ mj OR ‘modulation’/mj OR ‘protection’/exp/mj OR ‘protection’/ mj OR ‘protective factors’/mj OR ‘treatment outcome’/exp/mj OR ‘medical futility’/mj OR ‘outcome and process assessment (health care)’/mj OR ‘outcome and process assessment, health care’/ mj OR ‘outcome management’/mj OR ‘patient outcome’/mj OR ‘therapeutic outcome’/mj OR ‘therapy outcome’/mj OR ‘treatment outcome’/mj OR ‘disease management’/exp/mj)
LILACS Research Strategy: “Idiopathic Parkinson’s Disease” OR “Lewy Body Parkinson’s Disease” OR “Parkinson’s Disease, Idiopathic” OR “Parkinson Disease, Idiopathic “ OR “Parkinson’s Disease, Lewy Body” OR “Parkinson’s Disease” OR “Idiopathic Parkinson Disease” OR “Lewy Body Parkinson Disease” OR “Primary Parkinsonism” OR “Parkinsonism, Primary” OR “Paralysis Agitans” AND “Neuroinflammation” OR “Inflammations” OR “Innate Inflammatory Response” OR “Inflammatory Response, Innate” OR “Innate Inflammatory Responses” AND “Anti Inflammatory Agents” OR “Agents, Anti-inflammatory” OR “Anti-inflammatories” OR “Anti-inflammatory Agents” OR “Agents, Anti-Inflammatory” OR “Agents, Anti Inflammatory” OR “Anti-Inflammatories” OR “Anti Inflammatories” OR “Anti-inflammatory Agents, Non-Steroidal” OR “NSAIDs” OR “Non-Steroidal Anti-Inflammatory Agents” OR “Non-Steroidal Anti Inflammatory Agents” OR “Nonsteroidal Anti-Inflammatory Agents” OR “Nonsteroidal Anti Inflammatory Agents” OR “Anti Inflammatory Agents, Nonsteroidal” OR “Antiinflammatory Agents, Nonsteroidal” OR “Nonsteroidal Antiinflammatory Agents” OR “Corticosteroids” OR “Corticoids” OR “Inhibitors, Cyclo-Oxygenase” OR “Inhibitors, Cyclo Oxygenase” OR “Inhibitors, Cyclooxygenase” OR “Prostaglandin Synthesis Antagonists” OR “Antagonists, Prostaglandin Synthesis” OR “Inhibitors, Prostaglandin-Endoperoxide Synthase” OR “Inhibitors, Prostaglandin Endoperoxide Synthase” OR “Prostaglandin Endoperoxide Synthase Inhibitors” OR “Prostaglandin Synthase Inhibitors” OR “Cyclo-Oxygenase Inhibitors” OR “Cyclo Oxygenase Inhibitors” OR “Inhibitors, Prostaglandin Synthase” OR “Inhibitors, Cyclooxygenase 2” OR “Cyclooxygenase-2 Inhibitors” OR “Inhibitors, Cyclooxygenase-2” OR “Coxibs” OR “COX-2 Inhibitors” OR “COX 2 Inhibitors” OR “Inhibitors, COX-2” OR “COX2 Inhibitors” OR “Inhibitors, COX2” .

Web of Science Search Strategy

TÓPICO (Parkinson disease*) AND TÓPICO (inflammation*) AND TÓPICO (anti-inflammatory*).

Scopus Search Strategy

(TITLE-ABS-KEY (Parkinson AND disease) AND TITLE-ABSKEY ( inflammation ) AND TITLE ( anti-inflammatory ) ) .
The selection of articles was performed by two researchers blindly and independently through reading the titles, reading the abstracts and, finally, full reading of the articles. Any disagreement in the selection was resolved in consensus meetings. Articles that fully met the eligibility criteria were included in this study. The selection process is described in Flowchart 1 adapted from PRISMA (Figure 1). In order to analyze the methodological quality of the included studies, each article was evaluated by a researcher based on the items of the ACROBAT-NRSI (A Cochrane Risk of Bias Assessment Tool for Non-Randomized Studies) [4]. Acrobat-NRSI scores were used to exclude articles that did not present hardhitting information to the research, besides serving as a basis for discussing the methodological quality of the articles and the possible viruses in the generalization of their results (Figures 2 & 3). From each article included, data related to the objectives of this review were extracted, such as author, title, type of study, population, PD induction drug, drugs used applied, positive results. These data were computed and compared using the t-Student test for independent samples, with the purpose of comparing the percentage s percentages of the and effects on PD between NCAs and other anti-inflammatory drugs (Table 2).

Table 2: Characteristic of selected experimental clinical trials.

Figure 1: Adapted from PRISMA.

Figure 2.

Figure 3.

Findings

Twenty-one articles were analyzed, separated between two groups according to the drug used for pre-clinical study, antiparkinsonian drugs of anti-inflammatory nature and drugs properly anti-inflammatory drugs (IINES and corticosteroids). Improvement in motor function, decreased movement patriotization, increased levels of striatal dopamine, decreased interleukins and blockage of inflammatory pathways, such as those participating in MPP+ and COX-2, as well as increased and/or decreased loss of neurons armed with tyrosine hydroxylase (TH) enzyme, an important marker of neuroprotection, were identified.

Discussion

In view of these findings, this systematic review demonstrated that there is an effective therapeutic relationship in the use of anti-inflammatory drugs in PD through findings such as, mainly, quantitative increase or decrease in the loss of tyrosine hydroxylase enzyme [5-9]and improvement of motor function or prevention of motor decline [5,10-16]. However, since these are experimental studies in animals where clinical failures are commonly recorded in this methodology, caution should be exercised in the face of these findings, even if it shows clinical relevance. In addition, the importance of the therapeutic look is emphasized, especially in pathophysiological terms elapsed by the articles, observing in most of them that this disease, which affects the nicrostriatal region harboring the substantia nigra and quite rich in microglia, has the cumulative character of alpha synuclein in its altered form, which leads to the formation of a highly fibrillar aggregate by very little known pathways, thus, there is the beginning of a cascade of events that lead to the release of inflammatory toxic factors and a progressive dopaminergic neurodegeneration [17,18]. It is identified, therefore, that within this pathophysiological mechanism there is linked an inflammatory response, so there is a target to be investigated and possibly treated, demonstrating possible therapeutic purposes against PD.
In parallel, this review was able to investigate some other parameters found in experimental animal studies. Some motor tests showed improvement in the face of performance tests, applicability of previous training or open field observation, in addition, motor improvement of the forelimbs and later [5], significant decrease in cataleptic behavior [10], improvement of ambulation and immobilization time [7]and reduction of hypokinesia [15]. These results reinforce the hypothesis of a neuroinflammatory cause of Parkinson’s and once again the application of anti-inflammatory drugs for a possible therapy. It can be observed that characteristics that are found in patients such as muscle stiffness, tremor at rest, bradykinesia and postural instability could be solved or attenuated by a drug with function, absorption and mechanisms similar to what were found in this review. Therefore, there is a vast ness of possibilities for anti-inflammatory pharmacological use, in which, however, there is still a need to weigh the pros and cons, the latter being something of changeable capacity within the pharmaceutical industry, in which with investments in research and advanced technology can be achieved a less deleterious profile to the body, such as raising blood pressure, interaction with anti-hypertensive drugs, reduction of renal perfusion and gastrointestinal symptoms [16].
Within this context, it was also possible to identify an increase, then neuroprotection from levels of dopamine, TH enzyme and dopaminergic neurons in some animals. These results can be explained by the fact that the neuroinflammatory process, in its characteristic of exponential cascading lesion of dopaminergic neurons [8,19], was blocked and there was no more decrease in degenerative character. All this was observed from immunohistochemical analyses of TH (Tyrosine Hydroxylase) levels, an enzyme involved in dopamine synthesis through a series of biochemical reactions that has the amino acid tyrosine as a precursor and a molecular marker of dopaminergic neurons, along with dopamine dosage [5-9,18,19]. Thus, it was demonstrated what can occur in a neural system previously healthy, but with microglia activated by the pathophysiology of PD, in this case by mimetic drugs of PD such as rotenone and 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP). Thus, it is envisaged, once again, the use of these drugs or something more advanced both in patients already diagnosed and living with the disease chronically, as well as in patients at the beginning of diagnosis and mild clinical picture, promoting neuroprotection and, consequently, a greater defense and increased quality of life.
Some drugs in the studies acted directly on microglia and other inflammatory foci, some of them are very common, such as ibuprofen, meloxicam, piroxicam, AAS, Valdecoxib and Parecoxib (NHEMS, which act by inhibiting COX-2, prostaglandin and ultimately reducing cytokines), dimethazone (Corticosteroid that reduces the gene expression of pro-inflammatory cytokines). All of them obtained good results regarding the lowering of glial hyperactivation and intracellular inflammatory, in addition to stimulating the recovery and regeneration phase, avoiding in some cases the toxicity of MPTP [20], which shows that even having extensive knowledge and applicability of these drugs, they can still be key parts for the advancement of neural therapy in PD. Similarly, oxymatrine, an alkaloid compound found at the root of a Chinese herb (Sophora flavescent), promoted relief of motor deficits induced by MPTP and conferred significant neuroprotection, in addition to inhibiting the activation of microglia and exacerbated release of pro-inflammatory as cytokines [13]. This shows that within the vastness of drugs known and disseminated by the pharmaceutical industry, there are still a gigantic number of other substances that can be used in the treatment of this disease [20-27].

Conclusion

Our study has concluded that there is a need for investment in quality, more robust, broad-spectrum preclinical studies, with minimal view to achieve the ideal pharmacological therapeutic for this target. Thus, it is necessary more clinic trials to confirm this relationship between an inflammatory profile and use of antiinflammatory drugs which possible therapeutic agents to treatment of PD.

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Open Access Journal of Obesity and Diabetes

Type 2 Diabetes Mellitus and COVID-19 in Mexico. A comprehensive Assessment

Introduction

On February 11, 2020, the International Committee for Taxonomy in Viruses named SARS-CoV-2. Composed of a genome of 30,000 base pairs, belonging to the Coronaviridae family of the order Nidovirales. Phylogenetically coronaviruses are classified into alpha, beta, gamma and delta. Coronaviruses were identified 50 years ago as pathogens responsible for the common cold, mainly HCoV-OC43, HCoV-229E among other variants. At the beginning of 2002, coronaviruses were considered exclusively veterinary pathogens, however, by 2019 they were identified in biological samples from patients diagnosed with pneumonia [1-4]. Showing an age trend initially with geriatric patients, it has been shown that the risk of mortality increases after 75 years [5]. However, today age is no longer a dependent factor for infection. It is important to mention this since it may be due to multiple etiologies in addition to infection, such as: comorbidities, lack of metabolic control, suspension of work in the outpatient clinic due to hospital oversaturation derived from the pandemic, sedentary lifestyle, among others.
Hence it is important to emphasize the lack of metabolic control derived from all those cardiometabolic diseases, such as: obesity, hypertension, dyslipidemias and mainly diabetes mellitus, which turns out to be the first pandemic that has not been adequately controlled since ancient times [6]. All these factors are directly and proportionally related to the risk of severe progression and poor prognosis due to the chronic inflammatory state that generate more the acute systemic inflammatory response derived from COVID-19. In the case of obesity, another factor shared by both pathologies increased even more derived from confinement due to the forced closure of sports centers, favoring a sedentary lifestyle. The anxiety derived from the pandemic favors a greater consumption of foods with low nutritional power, again favoring obesity and lack of metabolic control. Therefore, in the context of a controlled diabetic patient, the measures that had to be implemented as a strategy to reduce the rate of infections are one of the factors to generate lack of control. The percentage of uncontrolled diabetics since the beginning of the pandemic is more and more common and continues to rise, which entails greater spending on health, greater generation of medical supplies and resources. There is an excess of mortality in the Mexican Republic derived from the pandemic, not only due to COVID-19, but also due to other causes [7,8] without forgetting to mention the possibility of under- registration that exists, for example, in marginalized areas or those who could not have hospital access derived from the same scenario. That is why the relevance of this article where a comprehensive scenario is proposed for the knowledge and management of COVID-19 in those patients who already have a chronic damage such as Diabetes Mellitus.

Pathophysiology

The incubation period for SARS-CoV-2 is 5 days with a range of 2 to 14 days [9]. The spectrum of diseases generated by coronavirus infection is mainly acute respiratory, chronic, enteric, hematological, endothelial and of the central nervous system. The mechanism of transmission of the disease by SARS-CoV-2 is from person to person through the airway by the drops of Flügge that are exhaled when coughing, sneezing or speaking and are inhaled or deposited in the mouth and ocular conjunctiva, as well as surfaces, which can function as fomites [10]. The main structural proteins found on the membrane surface of the SARS-CoV-2 viral particles participate within the pathophysiology, which are: Spike (S), membrane (M) and envelope (E). Among other, these are responsible for the anchorage and entry of these microorganisms to the host’s cells. It should be noted the type 2 angiotensin converting enzyme (ACE 2) which is a type I membrane protein that contains receptors in the lung, heart, kidney and intestine, endothelium, nervous system, mainly. The ACE 2 receptors that are located in the lower respiratory tract of humans are the cellular receptors for SARS CoV-2. Since the virion has the S-glycoprotein or Spike protein, which projects through the viral envelope and forms the spicules of the crown, this is glycosylated and is responsible for mediating the binding of the receptor (protein S + ACE 2), as well as its fusion with the host cell [11,12].
This strong bond unites the entire SARS-CoV-2 membrane with the host cell membrane, entering it through endocytosis. Viral particles release their RNA that binds to viral DNA, initiating the viral replication cycle, which leave the host cell through exocytosis. Once the RNA of the SARS-CoV-2 particles begins its translation and transcription, two processes are generated: the first related to the high demand for manufacturing viral proteins causing cellular stress that ends in apoptosis of the target cells; while in the second, the viral RNA acts in a molecular pattern associated with pathogens, which leads it to be recognized by the cells of the immune system, initiating the activation of the cytokine cascade and the migration of neutrophils. Hypercoagulability, venous stasis and endothelial damage is another of the main characteristics mediated by the ACE 2 receptors that SARS-CoV-2 particles possess, being observed in the endothelium of the veins, arteries and arterial smooth muscle cells of the brain; This produces dysfunction and inflammation of the microvasculature that alters vascular flow and initiates platelet activation, increasing risk for macrovascular and microvascular thrombosis, pulmonary thromboembolism, deep vein thrombosis, catheter-related thrombosis, ischemic cerebrovascular disease, acrosyndromes, and capillary leak syndrome. in organs such as lungs, kidneys and heart, increasing mortality, one of the main complications [13] (Figure 1).

Image 1: Physcopathogenesis of COVID-19.

SARS-COV2 as a Diabetogenic Agent

Diabetes is associated with a chronic low-grade inflammatory state that favors the development of an exaggerated and constant inflammatory response. At the molecular level, there is an increase in the levels of IL-6 and C-reactive protein (CRP), so the proinflammatory state typical of diabetes can favor the cytokine storm and the systemic inflammatory response that accompanies the acute respiratory distress syndrome (ARDS) in patients with COVID 19 [14]. This is why diabetics infected with SARS-CoV-2 have a higher rate of hospital admission, severe pneumonia, and higher mortality compared to non-diabetic subjects [15]. SARS-CoV-2 is considered diabetogenic since it is also capable of causing direct damage to the pancreas, due to the expression of ACE 2 (mainly in islet cells) even in a higher proportion than at the lung level, which could worsen hyperglycemia and even induce the onset of diabetes in previously non- diabetic subjects [16]. It should be noted that only 1-2% of patients with mild COVID-19 infection present pancreatic lesions, while 17% of patients with severe cases present with lesions of the pancreas, which can accentuate the systemic inflammatory response and, therefore, Therefore, accelerate the appearance of ARDS [17]. On the other hand, the current scenario of the pandemic even in uninfected subjects may favor the deterioration of metabolic control due to difficulties in accessing the health system, lack of physical activity and increased stress associated with confinement.
Therapeutic strategies should be aimed at facilitating access to the health system through telemedicine to advise the patient on the adaptation of treatment or any other remotely manageable medical situation and guide patients and caregivers in the control of diabetes in order to prevent hospitalization [18]. Clinical symptoms. Different stages of SARS-CoV-2 disease have been described in humans depending on the clinical severity, which can range from mild symptoms such as: fever, myalgia, headache, cough, anosmia. Up to severe symptoms characteristic of pneumonia with severe respiratory impairment [19,20-25]. Table 1 Mild and moderate infections comprise 80.9% of the registered cases; the severe ones, 13.8% and the critical ones, 4.7%. In the adult population it is 1.2%; while in pediatric population it is 15.8% [26]. The prevalence of asymptomatic patients differs according to the age group and can be reported by up to 40% [27]. Due to the high percentage of asymptomatic patients not only in Mexico, but also worldwide, it is vitally important to continue using a facial mask in our daily lives in order to reduce the risk of contagion. Even people with a full vaccination schedule are not exempt from COVID-19 infection.

Table 1: Clinical symptoms of COVID-19 severity.

Prognostic factors for serious and severe disease are considered: cardiovascular disease, diabetes mellitus, hypertension, chronic lung disease, cerebrovascular disease, cancer, chronic kidney disease, obesity and smoking [28,29]. Some alterations in laboratory parameters associated with a pro-inflammatory and procoagulant state are indicative of a poor prognosis, such as multiorgan failure [30]:
• Lymphopenia.
• Elevated liver enzymes.
• Elevated LDH.
• Elevation of acute inflammation markers (CRP, ferritin, procalcitonin).
• D-dimer elevation.
• Prothrombin time lengthening.
• Elevation of troponins.
• CPK elevation.
• Markers of kidney damage (elevated creatinine, anuria). Diagnosis. There are different detection techniques for SARSCoV- 2, each with different sensitivity and specificity. We currently have three types of diagnostic tests [17,18]:
a) Nucleic acid detection tests (PCR). In the case of the gold standard. Being its high cost the main limitation for its application.
b) Antigen (Ag) detection tests.
c) Antibody detection tests (Ab): IgM / A and IgG.

We must emphasize that a negative result does not exclude infection, therefore, if the clinical suspicion is high (clinical data, epidemiological context, radiological findings, sometimes earlier in computed tomography than the positivity of the PCR and analytical studies), it is recommends repeating the same sample in 48-72 hours or trying to obtain it from the lower respiratory tract, especially in severe or progressive disease [16]. Throughout the pandemic, a high percentage of false negatives has been observed in the practice of antigenic tests, the most used in Mexico due to the difference in cost between PCR, which has perpetuated in the patient the uncertainty of being or not with the infection, which means that they do not follow the medical indications and finally contribute to continue perpetuating the contagion. Educating the patient about what a negative result implies despite high clinical suspicion is part of our work in this pandemic and therefore, as health professionals, we should not base our treatment on a laboratory test and the recommended measures should be initiated in the context of isolation, symptomatic treatment and continuous monitoring of associated comorbidities in order to avoid complications as explained in detail.
Treatment of diabetes mellitus in patients with COVID-19. Treatment depends on the clinical characteristics of each patient, risk of complications, age, ease of access to the health area, socioeconomic status, risk of drug interactions especially in patients with polypharmacy, etc. Treatment for COVID-19 infection should be symptomatic, that is, based on the clinical picture presented by each patient, which can be: antihistamines, cough suppressants, thromboprophylaxis, analgesics and anti-inflammatories, educate for self-monitoring of vital signs and provide all the necessary alarm data. As outpatient management in non-serious patients and mild symptoms, the following should be taken into account: prevention of infection, healthy lifestyle, general measures to improve diabetes control, treatment of hyperglycemia, treatment of comorbidities and support doctor (Figure 2). For the treatment of asymptomatic or non-severe patients, the following is recommended: home management, follow usual treatment for diabetes control, goal of fasting glucose 70-130 mg / dL, HbA1c <6.5%, use of telemedicine to clarify doubts and education, indicate alarm and isolation measures, adjust the medication only if there is lack of control. Speaking of telemedicine, Mexico is not fully prepared, since it has a technological development of around 25%, however, thanks to portable technology such as a cell phone that facilitates the use of telemedicine, it can favor the medical attachment of chronic degenerative diseases and likewise surveillance of the clinical evolution of COVID-19 in those patients with a high risk of complications. Up to 70% of the population could benefit from these programs [22,24,30].

Image 2: Measures to be implemented in diabetic patients with COVID-19 taken with modified from M.M. Lima-Martínez et al.

In the case of patients with mild-moderate infection: home management with close monitoring, assess risk of progression and assess the need for in-hospital management, medication adjustments according to glycemic control, fasting blood glucose target of 72-144 mg / dL, HbA1c <7%, close medical contact. For those with severecritical infection: use insulin in continuous intravenous infusion or basal-bolus-correction regimen, fasting glycemic goal of 72-180 mg / dL, HbA1c <8%, strict monitoring of plasma glucose, electrolytes, ketone bodies, renal and cardiovascular function, procoagulant markers among others. Always in-hospital (22,30). (Figure 3). With the above mentioned, the need for extra medication should be taken into account depending on the symptoms of COVID-19 according to the evidence reported so far. It is intended to exemplify the treatment of these two entities together, since if we only dedicate ourselves to treating the patient based exclusively on the diagnosis of COVID-19, forgetting about their underlying pathology, in this case diabetes mellitus, we increase the risk of complications and mortality. Special considerations for drugs for diabetes mellitus in COVID-19 should be taken into account, such as: Metformin, SGLT2-i, GLP-1 analogs, DPP-4 inhibitors, sulfonylureas, and insulin. Each one with specific indications, making the appropriate dose adjustments according to the patient’s needs, to optimize therapeutic goals, but it is important to emphasize that for those who require hospitalization derived from COVID-19, the drug of choice for glycemic control will be insulin [22].

Image 3: Indication in the management of covid 19 according to the clinical severity of diabetic patients. Takane and modified from M.M. Lime Martinez, et al. & Medina – Chavez JH, et al.

In diabetics hospitalized for COVID-19, the use of prophylactic doses of low molecular weight heparin, such as Enoxaparin, is suggested in the absence of contraindications (active bleeding or platelet count <25 × 109 / l, and others), with dose adjustment for patients with frank elevation of D-dimer and those that present severity criteria [15]. It is important to individualize the prothrombotic risk according to the age and associated comorbidities of each patient, even in patients with mild symptoms thromboprophylaxis is indicated, the duration of this measure will also depend on how many associated risk factors present and the clinical severity, which requires a minimum of 2 weeks in those asymptomatic or mild symptoms and up to 6 weeks in severe conditions. Even with the resolution of the symptoms and / or the hospital discharged, this measure must continue for a minimum of 7 days [30].

Conclusions

The union of protein S with ACE 2 is the most important point within the pathophysiology since it culminates in a systemic inflammatory response and endothelial damage, which opens the door for a wide panorama of complications in the organism, even that a patient debut as diabetic from infection. At the beginning of 2020, when the first case of COVID-19 was registered, to date, the Mexican population presents data of exhaustion derived from isolation. Despite this, the vaccination program that was established in Mexico has not been fast enough, placing itself practically in the last place in Latin America for complete coverage of vaccines and reducing the rate of infections to be able to restore daily activities in a greater proportion and better still reduce morbidity and mortality in vulnerable groups. In addition to this, the lack of supplies and medical personnel in the health sector remains constant, which does not favor the scenario of both pandemics since it also worsens the medical adherence required by patients with chronic degenerative diseases, leading to a greater risk of complications, greater risk of contagion and finally higher mortality; thus, generating a vicious circle. Offering a broad panorama as a comprehensive evaluation of what COVID-19 implies in a patient with Diabetes Mellitus offers us new opportunities to reduce complications and serious progression of the disease, emphasizing the need to establish strategies such as telemedicine if necessary for better medical surveillance, promote pharmacological adherence and provide timely help in case of seriousness, always treating together.
We are in a century where two pandemics converge with each other, increasingly diabetic patients with lack of metabolic control, generating catastrophic damage to health, psychosocial and the economy. It is necessary to control both, starting with preventive measures to be able to modify the impact that has been generated so far. The points to follow in the context of DM2 and COVID-19 will be prevention measures where isolation is the most important, educating the patient, surveillance of comorbidities and glucose self-monitoring to be able to adjust the dose or change the medication in case of lack of control, monitor alarm signs and offer symptomatic treatment according to the needs of the patient, without forgetting the necessary use of telemedicine as a support tool.

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