Outcome of Surgical Repair of Complete Rupture of Distal Biceps Tendon: A Clinical Series

Abstract

Complete distal biceps rupture is a rare injury as compared to proximal biceps tendon rupture. It is usually caused by an eccentric contraction of the muscle, often seen with a sudden unintentional pull or jerk. An epidemiological study showed an incidence of 1.2 ruptures per 100,000 patients per year with an average age of 47 years. It is important not to miss the diagnosis initially, since delay in surgery does affect the outcome. In low-demand patients with complete distal biceps tendon tears, non-operative treatment may be entertained provided the patient understands the potential for residual weakness, particularly of forearm supination. The surgical repair is the treatment of choice especially in high demand male patients. There are a variety of fixation methods including bone anchors, suspension techniques, bone tunnels with interference screws, and transosseus sutures. No one technique has emerged as the gold standard and the choice remains that of surgeon. In this case series we present couple of patients with distal biceps tendon rupture one with acute rupture and another with chronic rupture treated surgically. We conclude patients do benefit from surgical repair.

Keywords: Distal biceps tendon; Acute; Chronic; Tendon tear; Elbow; Repair

Abbreviations: USG: Ultra Sono Gram; MRI: Magnetic Resonance imaging ; ASES: American Shoulder and Elbow Surgeons; LABC: Lateral Ante Brachial Cutaneous; PREE: Patient-Rated Elbow Evaluation

Introduction

Nearly 90% of biceps tendon ruptures occur in the proximal biceps and involve the long head of biceps. The remaining ruptures occur in the distal biceps tendon representing only 3% of biceps muscle injuries. The mechanism of injury in distal rupture involves a strong eccentric contraction of the biceps tendon against unanticipated resistance. The injury is most common in the dominant arm of middle-aged men. Symptoms include weakness in elbow flexion (by 30%) and forearm supination (by 40%) [1].

Some individuals may maintain reasonable function after non-operative treatment of a ruptured distal biceps tendon, biomechanical and clinical studies suggest that most individuals benefit from surgical repair or reconstruction [2]. The surgical treatment of distal biceps tendon tears has been studied extensively. The techniques available for repair involve a three-level distinction: anatomic versus non-anatomic repair, single-incision versus double-incision exposure and fixation method (most commonly the use of cortical button, interference screws, transosseous sutures or suture anchors) [2,3].

The number of reported distal biceps tendon tears seems to have increased over the last few years, likely related to better understanding and improved diagnostic methods [4] However in a number of instances, the diagnosis is initially missed. In this case series we present couple of patients with complete distal biceps tendon rupture; one with acute rupture and another with chronic rupture. We discuss the diagnosis, treatment, outcome and complications of surgical repair of the tendon using suture anchor.

Clinical Series

Case 1

63 year old left dominant handed male patient sustained injury to left elbow at work site one month before he presented to us,- while he was trying to cut a banana tree it was about to fall on his feet, while he tried to catch the tree before it fell. He had a painful ‘pop’ at the time of injury. He noticed painful range of movement of left elbow and difficulty in using left elbow. Initially he consulted an orthopaedic surgeon and was managed with a sling and analgesics, when he presented to us he had developed painful restriction of range of movement and was so unhappy about the initial treatment. On inspection there was flattening of the distal contour of the arm as compared to opposite arm (Figure 1), mild tenderness at anticubital fossa. He had weakness of flexion and supination.

On ‘hook test’ (Figure 2) we could not hook finger around any anterior structures with elbow in flexed and supinated position. Pre operative quick DASH score was 57. X-ray showed no bony abnormality and an MRI confirmed complete rupture (Figure 3) and marked retraction of distal biceps tendon from bicipital tuberosity of the radius. Since the duration of injury was just one month we planned for reinsertion of tendon to bicipital tuberosity using fibre wire and an anchor screw. After pre anaesthesia evaluation patient was taken up for surgery. We went through anterior approach using a curved single incision over antecubital fossa without a tourniquet, and retrieved the tendon from the superior part of the incision (Figure 4).

Figure 2: The hook test for distal biceps tendon, as described by O’Driscoll [6]. a. The normal test in which the examiner’s fingers can be hooked under the biceps tendon. b. The abnormal test, in which the examiner is unable to hook the distal biceps tendon. c. Demonstration of a normal hook test. As shown, a cord-like structure is felt under the index finger. d. Clinical picture demonstrating an abnormal hook test. The examiner is unable to feel the cord-like structure corresponding to the distal biceps tendon.

Figure 3: MRI showing complete rupture and marked retraction of distal beceps tendon from bicipital tuberosity of radius.

Figure 4: Retrieval of the ruptured tendon from the proximal part of incision.

On the distal part of the incision further dissection was done and recurrent branch of radial artery was ligated (Figure 5) to avoid injury to it. Bicepital tuberosity on radius was identified and bed prepared (Figure 6). An anchor screw was passed into it and with the fibre wire, tendon was re attached (Figure 7), as we expected there was enormous tension on tendon and hence a long arm slab in 1100 of flexion and supination was given. Patient was discharged on second post op day and at one month follow up slab and sutures were removed, elbow mobilisation started (Figure 8). Wound was healed well and at 2 months post of he had near normal range of movement and without any pain and quick DASH score improved to 11 at 2 months post op and it is improving further.

Figure 8: At 1 month follow up POP slab was removed and sutures removed wound healed well.

Case 2

A 44 year old right hand dominant male farmer patient sustained distal bicepital tendon rupture following a fall from tree while he was trying to cut a branch of tree and he lost control and fell down and tried to catch another branch of the tree to save himself and he heard a painful pop at that time and finally he fell on the ground. Fortunately he did not have any major fractures but noticed pain and swelling around the elbow. On the same day he presented to us. On examination swelling and ecchymosis in the distal arm and proximal forearm. Severe tenderness was noted. X ray of right elbow was normal and an MRI showed complete tear of distal biceps tendon. He was treated similarly as described in case one and biceps was reattached using fibre wire and suture anchor. Post operative protocol was also similar as case one and at 3 months follows up his quick DASH score improved to zero and he returned back to work.

Discussion

Distal biceps rupture is a rare injury as compared to proximal biceps tendon rupture usually caused by an eccentric contraction of the muscle, often seen with a sudden unintentional pull or jerk. An epidemiological study showed an incidence of 1.2 ruptures per 100,000 patients per year with an average age of 47 years [5]. Unlike proximal biceps tendon rupture which leave only a cosmetic deformity (with little or no functional disability), the distal biceps tendon injury affects functional outcome of elbow resulting in stiffness, chronic pain, weakness of flexion and supination. Unfortunately, the implications of this injury are high, in demanding male labourers. In a number of instances, the diagnosis is initially missed. In such situations patients are extremely unhappy. As seen in our patient (case one) his diagnosis was missed initially and when he presented to us at one month post injury he was very unhappy about initial treatment and outcome.

The diagnosis of complete distal biceps tendon tears can be established based on patient history and physical examination. X ray elbow may be normal; Ultra sonogram (USG) and magnetic resonance imaging (MRI) provide more valuable information. Patients may report a painful ‘pop’ at the time of injury. A useful clinical test was described by O’Driscoll et al. [6,7], the so-called ‘hook test’. The patient is asked to look at the palm of his hand on the affected side with the shoulder elevated, the elbow flexed at 90° and the forearm in supination. An intact distal biceps tendon allows the examiner to hook his fingers around the cord-like structure. If the bicep is torn, since the distal brachial is is flat, the examiner will not be able to hook his finger around any anterior structures. This test was elicited in patient with chronic distal biceps tendon rupture (case 1) We did not try this test in other patient with acute tendon rupture because it was painful (Figure 2).

Nonoperative treatment in symptomatic patients has been shown to result in a 30–50% loss in supination strength and 20% loss in elbow flexion strength [8]. Thus the surgical repair is the treatment of choice especially in high demand male patients. So, the consensus of opinion is that acute ruptures should be repaired primarily if possible, and there are a variety of fixation methods including bone anchors, suspension techniques, bone tunnels with interference screws, and transosseus sutures [9]. No one technique has emerged as the gold standard and the choice remains that of surgeon.

The techniques available for repair involve a three-level distinction: anatomic versus non-anatomic repair, single-incision versus double-incision exposure and various fixation methods. Randomised controlled trial was conducted to compare acute DBT tears treated surgically with a single-incision technique (fixation with two suture anchors) or double-incision technique (fixation with transosseous bone tunnels) [10]. The authors found that both techniques provided similar results in terms of pain, American Shoulder and Elbow Surgeons (ASES) elbow scores, and functional sub-scores, DASH score, patient-rated elbow evaluation (PREE) score, and isometric extension, pronation or supination strength.

However, the double-incision technique resulted in significantly higher strength for elbow flexion when compared to the singleincision technique (104% Vs 94%, respectively). We have used single incision technique in both cases and used anchor screw for fixation. In acute cases this approach gives excellent exposure for retrieval, preparation and fixation at radial tuberosity. In chronic cases if there is associated lacertus fibrosus tear, tendon retracts so much and generates lot of tension when it is brought down and hence it requires immobilisation in flexion and supination. In situation where severe retraction of tendon requires reconstruction this is best done with auto graft. Outcome of our patients is excellent. Quick DASH score improved from 57 to 11 at 2 months post op and it is improving further in patient with chronic rupture and quick DASH score improved to 0 at 3 months post-op in patient with acute rupture (Figures 9 & 10).

Figure 9: At 2 months follow up.

Figure 10: At 2 months follow up.

Injuries to posterior interosseous nerve and the lateral ante brachial cutaneous (LABC) nerve have been reported in 5% to 40% of elbows respectively, more commonly with a single anterior incision [10,11]. Heterotrophic ossification may be seen on radiographs after distal biceps tendon repair using any exposure or fixation technique, but it seems to be more common and tends to interfere more with forearm rotation using a two-incision technique. Care should be taken not to expose the ulna to prevent cross union [3]. We don’t have such complication in either case.

Conclusion

Distal biceps tendon rupture is a relatively rare injury usually caused by an eccentric contraction of the muscle in middle aged men. It is common on the dominant side. It is important not to miss the diagnosis initially, since delay in surgery does affect the outcome. In low-demand individuals acute complete tears are occasionally treated non-operatively, but most patients benefit from surgical repair.

For More Articles: Biomedical Journal Impact Factor : https://biomedres.us

Ewing’s Sarcoma/Pnet Presenting as Breast Mass

Abstract

Introduction: Ewing’s sarcoma family of tumours (ESFT) are uncommon, aggressive malignant tumours that usually arise in soft tissues or bones in children and young adults. Long bones of the lower limbs are most commonly involved. Occurrence at atypical sites can pose a diagnostic challenge. We report an exceptional case of this tumour presenting as a breast mass in a male patient.

Case Report: A 23-year-old male patient was referred to our centre with complaint of a progressively enlarging breast lump. This was initially suspected to be carcinoma, breast. On re-evaluation at our centre, FNAC yielded a diagnosis of small round cell malignancy and a possibility of Ewing’s/PNET was suggested which was confirmed on trucut biopsy and immune histochemistry. Chest CT scan subsequently performed revealed a left sided heterogeneous soft tissue mass involving a large part of thorax, causing contra lateral meditational shift. Understanding the nature and extent of disease and expecting a dismal outcome the patient refused any further investigation and treatment.

Discussion: ESFT are aggressive fast growing tumours which require urgent diagnosis for swift commencement of therapy. Occurrence at unusual sites or uncommon presentations can lead to consideration of alternative clinical diagnoses and make the evaluation challenging. This case highlights the need for careful evaluation of cytology smears, keeping in mind the unexpected, avoiding the unnecessary diagnostic delay.

Abbreviations: ESFT: Ewing Sarcoma Family of Tumours; PNET: Peripheral Neuro Ectodermal Tumour; FNAC: Fine Needle Aspiration Cytology; CT: Computed Tomography

Introduction

Ewing Sarcoma Family of Tumours (ESFT) is uncommon, aggressive, malignant tumours that usually arise in soft tissue or bones in children and young adults. The term ESFT includes typical Ewing’s Sarcoma, the Peripheral Neuro ectodermal tumour (PNET) or Askin’stumor of the chest wall [1]. It is the second most malignant tumour in the 10-20 year age group [2]. ESFTs arise from migrating embryonic cells of the neural crest showing variable neuro ectodermal differentiation. The differentiation pattern forms the basis of differentiating each individual type of ESFT though these features commonly overlap. This tumour family most commonly involves long bones of lower limbs, however, atypical presentations have been studied, which can present a diagnostic challenge [3,4]. Here we present an exceptional case of Ewing’s Sarcoma presenting as a breast mass in a male patient.

Case Report

A 23 year old male presented with a four month history of a progressively enlarging lump in his left breast. Physical examination revealed a firm, fixed and non tender mass measuring approximately 8X7 centimetres in his left breast. It was unattached to the overlying skin. The contra lateral breast and both axilla were normal. A Fine Needle Aspiration Cytology (FNAC) performed at another tertiary centre concluded in the diagnosis of breast carcinoma and the patient was referred to our centre for further management. With a clinical suspicion of breast carcinoma in mind, a repeat FNAC was performed at our centre. Cytology smears showed loosely cohesive clusters of small to medium sized monomorphic round cells which were, at places arranged around blood vessels, against a background of necrotic debris. Cells had pale, vacuolated, fragile cytoplasm, round nuclei with opened up chromatin and 2-3 conspicuous nucleoli (Figures 1a & 1b).

Figure 1A: Loosely cohesive clusters of small to medium sized monomorphic round cells against a necrotic background.

Figure 1B: These cells have pale, vacuolated, round nuclei with opened up chromatin and 2-3 conspicuous nucleoli.

Based on these features a diagnosis of small round cell malignancy with a possibility of Ewing’s Sarcoma/PNET was suspected. Trucut biopsy was performed and showed small round tumour cells arranged around blood vessels with occasional rosette formation and areas of necrosis (Figure 2a). On immune histochemistry cells stained positive for CD 99, NSE and vimentin (Figures 2b-2d) while they were negative for LCA, synaptophysin, cytokeratin and desmin. This confirmed the diagnosis of Ewing’s Sarcoma/ PNET. Computed tomography (CT) scan showed a large, heterogeneously enhancing, solid left chest wall mass with internal necrosis arising from anterior fourth rib, with extension into left breast, mediastinal shift and complete atelectasis of the left lung (Figure 3).

Figure 2a: Small round tumor cells arranged around blood vessels with occasional rosette formation and areas of necrosis.

Figure 2b: Positivity for CD99.

Figure 2c: Positivity for vimentin.

Figure 2d: Positivity for NSE.

Figure 3: Computed tomography(CT) Scan showed a large, heterogeneously enhancing, solid left chest wall mass with internal necrosis arising from anterior fourth rib, with extension into left breast, mediastinal shift and complete atelectasis of the left lung.

Discussion

ESFTs form a single group of bone and soft tissue tumours with undifferentiated Ewing’s at one end of the spectrum and Peripheral neuro ectodermal tumour (PNET) showing clear signs of neural differentiation at the other [5]. The most common sites of Ewing’s sarcoma are chest wall, Para vertebral region, retroperitoneal space, lower extremities, and gluteal region. However, few cases have been reported in the kidney, breast, gastrointestinal tract, prostate, endometrium, the adrenal glands, brain, and lung [6]. The breast is uncommonly involved and only 5-6 cases have been reported inEnglish literature, all of them in females [7]. This case is probably the first case of this tumour presenting as a breast mass in a male patient. Occurrence at unusual sites or uncommon presentations can lead to consideration of alternative clinical diagnoses and make the evaluation challenging. The index case had a tumorprobably arising from a rib, extending into thorax posteriorly and presenting as a breast mass anteriorly. This resulted in an initial confounding diagnosis of carcinoma breast.

A delay in the correct diagnosis resulted in expansion of the tumour into the mediastinum, thus upstaging the disease. It has been reported that those with localized non pelvic disease treated with multimodal therapeutic modalities including concomitant chemoradiation, have a5-year disease-free survival rate of approximately 70%. This, however, comes down significantly when the tumour spreads into the body cavities, as was seen in this case. The patient belonged to a low socio economic background and understanding the poor prognosis, he refused any further investigations and treatment. On FNAC, the differential diagnoses consists of other small round cell tumours like lymphoma, plasmacytoma, as well as small cell variants of the various epithelial and soft tissue tumours. Careful evaluation of the cytology smears, keeping in mind the unexpected, and supplementing it with immune histochemical marker studies, is, therefore, of utmost importance.

This group of tumours is characterized by the presence of the typical translocation t (11; 22) (q24; q12), the EWS-FLI1 chimeric transcript on molecular analysis and the expression of CD99 antigen (MIC-2) at immune histochemistry [8]. Other markers, like vimentin and NSE, show variable positivity. Imaging modalities usually present findings that are non specific. The diagnosis is usually made on histopathology, immunohistochemistry and the characteristic translocation t (11;22) found on molecular analysis. This case, however, highlights the importance of thorough evaluation of FNAC smears in guiding towards diagnosis and also the need for an early diagnosis in such cases.

Conclusion

ESFTs are aggressive, fast growing tumours which require urgent diagnosis for swift commencement of therapy. Occurrence at unusual sites or uncommon clinical presentations can lead to consideration of alternate clinical diagnosis, making the management challenging. The delay in diagnosis in the index case might have led to the spread of disease and a dismal prognosis, which should be avoided.

For More Articles: Biomedical Journal Impact Factor : https://biomedres.us

FLT3 Receptor Heterogeneity Strictly Specifies the Dimensions of Malignant Transformation Events in Acute Myeloid Leukemia

Abstract

Qualitative mutational events act synergistically with increases in mutated FLT3 receptors in the plasma-membrane in inducing constitutive activation of the receptors in terms of such indices as auto phosphorylation of the tyrosine kinase domains. Dimerization of the FLT3 sub-units and diminished “repulsive” dysfunctions of the juxtamembrane domain allow for permissive receptor activation. Incremental numbers of mutated receptors may strictly characterize the nature of origin of the malignant transformation event in terms of both synergic and compensatory mechanisms that directly modulate and further impact the hematopoietic progenitor cell subpopulations and also renewal of the hematopoietic stem populations in the bone marrow. Blast cell generation proliferation and impaired differentiation programs come to account for a great degree of heterogeneity in hematopoietic ally-related cell types in response to agents with tyrosine kinase inhibitory action.

Abbreviations: AML: Acute Myeloid Leukemia; ITDs: Internal Tandem Duplications; TKIs: Tyrosine kinase inhibitors; WT: Wild Type; GFI: Growth Factor Independence; SKY: Spleen Tyrosine kinase

Introduction

Stem cell hematopoietic replacement or renewal, and inhibitory effects on proliferation or contrasting maturation of progenitor cells are distinct stages and essentially highly distinctive process mechanisms in leukemogenesis. As such, the development of Internal Tandem Duplications (ITDs) in the FLT3 mutant cell juxtamembrane domain, in a large subset of Acute Myeloid Leukemia (AML) patients, has to be considered within such a differential context that is reflected in complete remission, disease-free survival, relapse rate and overall survival of AML patients with ITDs. FLT3- ITDs account for up to 25% of AML cases; the transcription factor ATF4 in these patients is essential for FLT3-ITD-induced autophagy [1]. The development of FLT3-targeted inhibitors constitutes an important paradigm shift in managing patients with very aggressive FLT3-mutated AML [2]. AML is highly heterogeneous and involves immature myeloid cell proliferation and bone marrow failure [3]. Allogeneic stem-cell transplantation decreases the risk of AML recurrence compared to standard chemotherapy but is associated with the risk of serious complications [4]. AML is the most common acute leukemia in adults, and treatment options, particularly in the elderly, are limited [5].

Autophosphorylation

Oncogenic forms of FLT3 are important therapeutic targets in AML but clinical responses to small-molecule kinase inhibitors are short-lived due to rapid emergence of resistance arising from point mutations or compensatory increases in FLT3 expression [6]. The complexity of autophosphorylation events in the two intra-cellular tyrosine kinase domains implicates both FLT3-ITD mutant cells and also cells with wild-type FLT3 in the development of constitutive activation of the FLT3 receptors. It is hypothesized that FLT3-ITD leukemia cells exhibit mechanisms of intrinsic signaling adaptation to TKI treatment that are related to an incomplete response [7]. It is further to such considerations that various different adaptor proteins are also involved in the activation of different cellular pathways and activators that lead to impaired maturation and increased proliferation of progenitor cells.

The ITDs are associated with preserved reading frame and involve non-ligand activation of the FLT3 receptors in a contextual referential system that involves often groups of three or more duplicated head-to-tail insertions of tandem duplications withthe stabilization of phosphorylation or open configuration of the tyrosine kinase domains. The ITDs are located to the juxtamembrane domain of the individual receptor in a manner that also implicates Dimerization of FLT3 receptor homodimers.

Constitutional Activation

The prognosis in AML patients could be further stratified by different mutation combinations and hence the value of nextgeneration sequencing for genomic classification [8]. Dimensions of constitutive activation of the FLT3-ITDs are also reflected in other tyrosine-kinase receptor type III family in a manner that wellillustrates the high levels of homology between various members of this large receptor family. Such high degrees of mechanistic variability in down-stream pathway effects indicate a range of nonspecific targeting of mediators within the potential scope of biologic and clinical consequences of tyrosine kinase activation modulation.

Systems of therapeutic intervention with tyrosine kinase inhibitors (TKIs) indicate that FLT3-WT (wild-type), as constitutively activated, is highly significant in terms comparable to FLT3-ITDs mutant receptors. As such, concepts of constitutive activation of the FLT3 receptors in general and of FLT3-WT/ITD receptors, in particular, also include excessive numbers of these receptors traversing the plasma-membrane of the cells. Within further realization model systems, the signal transmutations of the FLT3 receptors are profoundly influenced by numerous potential parameters of control and modulation in signal transduction. FLT3- ITD AML usually responds poorly to conventional therapies and may become resistant to TKIs due to molecular bypass mechanisms [9].

Tyrosine Kinase Domains

The tyrosine kinase domains that are autophosphorylated and activated lead to an essential stage model that mechanistically can affect proliferation, maturation and even apoptosis of blast cells in both the bone marrow and peripheral blood of AML patients. Degrees of synergism may also include FLT3-ITD and FLT3-TKD (where mutations are present in the tyrosine kinase domains) and are generally exclusive phenomena and appear not generally applicable to the biology of FLT3-mutant AML cells. TKI treatment increases the surface expression through up-regulation of FLT3 and glycosylation of FLT3-ITD and FLT3-D935 Y mutants [10].

FLT3-ITDs are a negative prognostic factor in AML patients particularly in patients over 60 years of age; such a modulated series of effects is reflected in results of studies examining the potential therapeutic benefits of administered TKIs as single agents or when combined with standard chemotherapy. The use of allogeneic stem cell transplantation has improved outcome in FLT3- ITDs patients especially in terms of relapse rates, including also AML patients treated immediately after first relapse. Growth Factor Independence 1 (GFI1) is a negative indicator of AML progression and high levels of GFI1 expression are paralleled by higher FLT3 expression and exhibit a FLT3-ITD signature of gene expression; knock-down of GFI1 expression in vitro leads to decreased FLT3 RNA and down-regulation of FLT3-ITD signaturegenes [11].

Multi-Components

Considered response of FLT3-mutated hematopoietic cells to small molecule inhibitors is, hence, an overall index of participation of multiple pathways that originate from autophosphorylation of the tyrosine kinase domains and that are reflected in such pathways as inhibited apoptosis and in the activation of intra-nuclear catenin. The multi-component systems of adaptor proteins in particular allow for signal response in the evolutionary course of AML cell proliferation and of impaired maturation beyond the hematopoietic blast stage. Spleen tyrosine kinase (SYK) is activated and increases in FLT3-ITD-positive AML patients and is critical for transformation and maintenance of the leukemia clone in these patients [12].

A critical stage of differentiation appears to be the transition of (CD34+/CD33-) subpopulations of progenitor cells to the (CD34+/CD33+) cell population when considering FLT3 precursor cells in AML patients. The three main groups of mutated FLT3 hematopoietic cells include FLT3-ITDs, and also FLT3-point mutations in the juxtamembrane domain, and the tyrosine kinase domain mutations. FLT3-TKD-mutated AML patients have a more favorable prognosis clinically when compared with patients with FLT3-ITD mutations [13]. As such, an essentially significant degree of heterogeneity is found within the complex phenomenon of FLT3- mutated hematopoietic progenitor cell populations considered and is contributory to AML leukemogenesis. The complex heterogeneity of AML has seriously hampered the development of a curative treatment; mono-therapy is associated with resistance due to the parallel signaling circuitry involving also MAPK and mTOR [14]. Whereas FLT3-ITD cells tend to target myeloid-type cells, FLT3- TKDs are associated with a preferential selection of lymphoid-type precursor cells.

Autophosphorylation

The essential absence of stop-codons in both FLT3-ITD and FLT3-TKD cells affecting especially the internal tandem duplications in the former group of mutated receptors is fully consistent with excessive signaling as a hallmark of the constitutive receptor activation and tyrosine kinase autophosphorylation. Dynamics of constitutive phosphorylation of the FLT3-mutated receptors are reflected within contexts of auto-stimulation that primarily include excessive suppression of the “repulsive forces” that affect the juxtamembrane domain of the receptor in patients with FLT3-ITDs. Also, glycosylation of the extra-cellular domain of the FLT3 cells, whether FLT3-ITD or WT, may possibly be implicated not only in the trans-membrane insertion of the FLT3 receptors but also as implemented component in response to extra-cellular stimuli that may synergistically cooperate with constitutive receptor activation and phosphorylation of the tyrosine kinase domains.

Andrographolide (an active component of Andrographis paniculata) suppresses MV4-11 cell proliferation through inhibition of FLT3 signaling with also inhibition of fatty acid synthesis and cellular iron uptake [15]. FLT3 LIGAND The FLT3 receptor ligand FL functionality is mechanistically homologous to the KIT receptor and dynamics of each ligand type and is projected towards thefurther creation of established states of autophosphorylation of the tyrosine kinase domain. In this sense, TKIs may be expected to impact the constitutive activation of the blast cells in terms of ongoing dimensions of proliferation and impaired maturation of the hematopoietic progenitor cells in patients with AML.

Results of the non-responsive sub-populations of hematopoietic progenitor cells may in part arise from the marked heterogeneity of pathway response and inclusion as terms of effect arising from constitutive activation and autophosphorylation of the FLT3 receptors. High expression of proviral integration site for Moloney murine leukemia virus-1 (PIM-1), a serine/threonine kinase, is a high risk independent prognostic factor in AML [16]. The SOX4 transcription factor is not only an independent prognostic factor in AML but also an important molecular oncogenic agent in leukemogenesis [17].

High expression of Inhibin-Beta A (a ligand of the transforming growth factor Beta super family) is an adverse prognostic marker for de novo AML [18]. As such, incremental numbers of FLT3 receptors that traverse the cell membrane may potentially prove a dynamic interplay with tyrosine kinase activation in further oncogenesis and synergistically potentiate ongoing progression of the AML cell subpopulations. Indeed, further synergistic compensatory increases in FLT3-ITDs may prove instrumental in augmenting dimensions of malignant transformation events that include stem cell subpopulations generating mutated progenitor hematopoietic cells.

or More Articles: Biomedical Journal Impact Factor : https://biomedres.us

An Alternative Technique for Treating Complex Ureteral Strictures and Defects using A Peritoneal Graft

Abstract

Purpose: To describe a new technique of ureteral reconstruction using a free peritoneal graft.

Methods: Between 2006 and 2015 we identified 8 patients with complex ureteral strictures involving in 7 cases the middle ureter. Stricture length ranged from 4 to 12 cm. Two cases were secondary to long strictures from retroperitoneal fibrosis after vascular surgical, 3 cases followed an extensive resection, required for large intraureteral masses, 2 cases were secondary to repeated endoscopic procedures for urinary stones and 1 case followed repeated pyeloplastics. After ureteral incision a free peritoneal graft was harvested from nearby healthy peritoneum. An onlay patch was fixed with running suture to the remaining ureteral plate after placement of an ureteral catheter. The ureter was wrapped with omentum.

Results: Follow-up has ranged from 14 to 76 months. Five patients were free from recurrence after 6, 30, 36, 54 and 60 months, showing good passage of the contrast without dilatation of the upper urinary tract on the uro-CT/urography. In 2 patients occurred a recurrence below the reconstructed ureter after 6 and 60 months without symptoms and with mild hydronephrosis. The last patient showed asymptomatic obstruction of the reconstructed segment with hydronephrosis of the upper pole system 6 months after the procedure. The limitation of this study is the small sample series, due to the selective indications.

Conclusion: This technique allows for preservation of any remaining vascular supply of the ureter and can be a feasible and use full alternative to nephrectomy, ileal ureter and autotransplantation in highly selected cases.

Keywords: Peritoneal Graft; Complex Ureteral Stricture; Middle Ureter; Ureter Reconstruction

Introduction

Mid-ureteral strictures and defects with or without involvement of the upper urinary tract represent one of the most serious reconstructive challenges for urologists and might require more complex treatment like bowel replacement or auto transplantation. These procedures are of considerable magnitude and associated with high rates of complications and long term morbidity [1-3]. Based on the evidence that atonic ureters affected by schistosomiasis can drain well by gravity [4-6] and on the success of buccal mucosal graft in the repair of complicated hypospadias [7,8] in 1999 Naude described a new technique using buccal mucosal graft for treating complicated ureteral strictures with good results [9]. Starting from our experience in urethral reconstruction with buccal mucosal graft, we describe a new alternative technique of ureteral reconstruction using a free peritoneal graft in 8 highly selected cases. Written informed consent was collected from all patients before intervention.

Materials and Methods

Between January 2006 and December 2015, 8 patients with mid-ureteral narrowing and obstruction and/or with complex ureteral stricture were treated using a peritoneal graft. Stricture/ defect length ranged from 4 to 12 cm. Due to their length, all cases would have otherwise required an ileal ureter, nephrectomy or auto transplantation. Two cases were secondary to long strictures from retroperitoneal fibrosis after vascular surgical procedures, three cases followed an extensive resection, required for large intraureteral masses (2 papillomas and 1 pTaG1) resulting in insufficient ureteral width for closure, 2 cases was secondary to repeated endoscopic procedures for urinary stones and 1 case followed repeated open pyeloplastics (with involvement of a long part of proximal ureter). The surgical procedure was performed with extraperitoneal exposure of strictured ureter in 7 patients while in 1 was performed transperitoneally.

After identification of the strictured ureteric segment, the narrow segment was opened longitudinally and the incision was extended for 1 cm in both directions into healthy ureter, preserving the longitudinal ureteral adventizial vessels to support the vascularization of the graft; a free peritoneal graft of appropriate dimension was harvested from nearby healthy peritoneum, shaped to appropriate size and fixed with running 5/0 Monocryl suture to the remaining ureteral plate after placement of an indwelling ureteral catheter (Figures 1 & 2). Finally, the greater omentum was mobilized to cover completely the reconstructed area and secured with absorbable interrupted suture (Table 1). The wound was drained with a 24 Chavier drain and a transurethral catheter was inserted into the urinary bladder for 10 days to ensure a zero degree pressure system. A cystography was performed after 10 days to show the patency of the ureter and the absence of extravasation: if the suture line was watertight, the transurethral catheter was removed; otherwise it remained in place for an additional week or more. The ureteral catheter was removed after 6 weeks or 3 months, depending on the length of the stricture and on the presence of extravasation, and an intravenous pyelography was done after removal to show the patency of the reconstructed ureter.

Table 1: Characteristics of the operated ureteral strictures.

Results

A total of 8 ureteral reconstructions with peritoneal graft were successfully performed in 8 patients. All postoperative courses were uneventful without any major complications. The urethral catheter was removed after cystography on the 10th postoperative day in 3 patients, after 3 weeks in 4 patients and after 6 weeks in the other one. The ureteral stent was removed six weeks postoperatively in 3 patients and after 3 months in the other 5 patients.After removal of the ureteral catheter all patients became an intravenous pyelography, which showed the patency of all ureteral reconstructions except in one patient, who became symptomatic and required the insertion of another stent. Patient follow-up has ranged from 14 to 76 months (average 42.1 months). Five patients (62.5%) were free from stricture recurrence after 14, 36, 54, 56 and 60 months, showing free passage of the contrast through the operated ureter without dilatation of the upper urinary tract on the uro-CT or urography and normal renal function (Figures 3 & 4). A stricture recurrence below the reconstructed ureter occurred 60 and 6 months after the procedure in 2 patients (25%). The first of these was operated for a large intraureteral mass and the length of patch was 5 cm.

After 60 months the patient developed a recurrence below the reconstructed ureter without symptoms, with mild hydronephrosis at the urography and with minimal worsening of the renal function: he didn’t required surgery and died 16 months later with stable disease at 92 years. The second patient was operated for a long double stricture of a length of 12 cm after repeated endoscopic operations for urinary stones and after radiotherapy and robotic radical prostatectomy for a prostate tumor. For the persistence of extravasation he needed the urethral catheter for 6 weeks; after the removal of the stent, 3 months after the operation, he became symptomatic and after temporary stenting, also this patient became asymptomatic with narrowing of the ureter below the reconstructed patent ureteric segment and hydronephrosis at the urography. A reoperation was not an option for this patient, who refused other attempts to save the kidney. In the last patient (12.5%), who had a partial duplicated ureter, the intravenous urography showed obstruction of the reconstructed segment of the upper pol ureter with hydronephrosis of the upper pole system 3 months after removal of the ureteral catheter (6 months after the surgical procedure); the patient was completely asymptomatic and the obstruction was occasionally found during the control examination; the lower pol system showed a good drainage and the patient didn’t required surgery.

Discussion

The ureteric strictures can be caused by several factors like stones, infections, fibrosis, malignancy, radiotherapy or in most cases by iatrogenic surgical trauma occurred during gynecological, colorectal and vascular surgery or after endourological surgery [10- 12]. The strictures, that are too long or not suitable for treatment with end to end anastomosis, Boari flap or Psoas hitch technique, may require an ileal ureter, autotransplantation or nephrectomy. These procedures are complex and associated with high risk of complications specially in unprepared patients in emergency situations. Further more, if the stricture involves the middle ureter, the risk of ischemic necrosis, due to the reduced vascular supply of this segment, can be high even for shorter lesions and an end to end anastomosis is not recommended even if feasible, As alternative to these complex procedures, based on the evidence that atonic ureters affected by schistosomiasis can drain well by gravity and on the success of buccal mucosal graft in the repair of complicated hypospadias, Naude and other Authors [13-15] have reported the successfull use of buccal mucosal patch graft for the reconstruction of a variety of ureteric lesions without major complications. [16- 18] Animal experiments have showed, that a free peritoneal graft, used as bladder substitute, works like a multipotent matrix for urethelialization of the reconstructed area, supporting the migration of the smooth muscle cells from the edges of the defects in a centripetal direction [19-21].

A free peritoneal graft was already successfully used in cardiovascular surgery and in gastrointestinal surgery [22-23]. In urology a pediculated peritoneal graft was initially used for cistoplasty and closure of vesicovaginal fistulae [24] but a free peritoneal graft was used for the first time in animal experiments for bladder repair with good results from Hutschenreiter [25]. Thueroff [26] used a free peritoneal graft to cover defects of the renal pelvis not suitable for primary closure or to envelope renal pelvis and/or ureter to reduce the risk of extrinsec obstruction, due to scarring in 31 patients, with good results in 25. Stadie et al. had good results in 29 out of 30 patients in a similar study. Encouraged from these studies, we have treated these 8 selected patients with long mid-ureteral strictures and with complex ureteral strictures, using a free peritoneal patch graft, wrapped with greater omentum. In five patients we achieved good urographic results and actually they are still free from recurrence. One patient developed a stricture recurrence after 5 years but during all this period he maintained normal renal function without complications related to the procedure.

In the other patient with recurrence, the multiple operations for urinary stones and especially the preceding radiotherapy have probably caused the persistence of extravasat and favoured the stricture below the reconstructed ureter. The last patient with partial double district, who developed the obstruction of the reconstructed segment of the upper pol ureter, was admitted to the hospital some months before with hydronephrosis of the upper pol and reduction of parenchima, due to a 2,5 cm stone in theproximal duplicated ureter: He underwent to repeated endoscopic procedures without success and with persistence of the stone. We attempted to remove the stone with open surgery and the ureter was closed with a peritoneal graft. The poor urinary drainage of the upper pol has failed to maintain the patency of the reconstructed ureter and so, probably, in this case no type of reconstruction was indicated. The advantage of this technique is the unlimited availability of the material, which can be simply harvested from nearby healthy peritoneum without related complications.

Furthermore this technique of reconstruction is simple and associated with a lower rates of complications and long term morbidity; it allows a good drainage of the upper tract and patency of the ureter, preserving as much as possible the vascular supply and reducing the risk of ischemic necrosis. In addition it can be used in unprepared patients in emergency situation to avoid more complex procedure. The limitations of this study are the small sample series and its retrospective nature. Our results are however encouraging and to our knowledge, this is the first paper which describes the use of a free peritoneal patch graft for the treatment of strictures of the middle segment of the ureter.We think, that this approach should be considered in all patients, who would need ureteric replacement for long mid-ureteral strictures, and specially in those with renal impairment, to avoid metabolic problems or increasing morbidity.

Conclusion

Mid-ureteral strictures and defects represent one of the most serious reconstructive challenges for urologists. We describe a novel technique for treating long mid-ureteral strictures or defects using a peritoneal graft with Omental wrapping. This technique allows for preservation of any remaining vascular supply of the ureter and can be a feasible and useful alternative to nephrectomy, ileal ureter and auto transplantation in highly selected cases.

For More Articles: Biomedical Journal Impact Factor : https://biomedres.us

Evaluation of the Effect of Propolis on Implant Stability by Resonance Frequency Analysis and Removal Torque Test

Abstract

Purpose: Osseointegration is the structural and functional connection without fibrous tissue, between the bone and the implant surface under load. Free radicals are among the factors that affect bone healing and osseointegration. Recently, researchers have begun to show interest in the idea that implant-related complications may occur due to free radical-induced tissue damage. Hence use of a material with antioxidant properties may be a useful tool on implantology. This study is planned presuming propolis could have positive effects on osseointegration and implant stability due to its antioxidant nature, its effect accelerating the bone formation, wound healing and increasing the bone density.

Methods: Study consisted of three groups. At all groups, implants were placed on proximal metaphyseal region of the rabbit tibia. Only dental implants were placed on the Control Group. Propolis solution was applied to slots before placing the implants on Local Group and propolis was applied systemically for 28 days after implantation on Systemic Group. Resonance frequency analysis (RFA) was performed on the day implants are placed and both RFA and removal torque test were performed on the 28th day.

Results: The study was composed of 24 rabbits grouped as follows: Control (n = 8), local (n = 8), and systemic (n = 8) for application of propolis. Systemic group showed statistically lower results of RFA at baseline (p<0.05). Propolis application resulted in a significant increase in RFA in each group: local (baseline RFA, 46,8 vs RFA after Propolis 56.0; P< 0.05), systemic (baseline RFA, 44.8 vs RFA after propolis, 58.8, P< 0,05); while the control group showed no significant difference (baseline RFA, 51.5 vs RFA after waiting period, 57.8 P> 0.05). Removal torque test showed statistically significant difference between the groups (systemic group 58,7; local, 49,8 and control, 45,1; P<0.05).

Conclusion: These results suggest that the propolis may have a positive effect on implant stability, especially if administered systemically.

Introduction

Propolis is a natural product bees prepare by enzymatically changing secretions they gathered from the buds and barks of plants. Nowadays, propolis has syrup, spray, throat lozenge, cream and lotion preparations which are formulated to prevent and treat upper respiratory tract infections like cold and flu, for use in cosmetic purposes and in dermatological problems such as wounds and burns, also infections like acne, Herpes Simplex 1 and 2. In addition, there are toothpaste and mouthwash preparations used in the caries prevention and treatment of oral infections such as gingivitis and stomatitis [1]. Investigations have shown that propolis has antimicrobial, antiviral, antifungal, antiprotozoal, antiparasitic, antiinflammatory, anti-ulcer antitumor and antioxidant effects and protective effects on liver, heart and brain [2].

Propolis has been shown to regulate the blood glucose level and the blood pressure, to affect the amount of lipid in blood and to cleanse lipid peroxidation products and free radicals [3]. In addition, propolis has immunostimulant, antimutagenic [4], anesthetic [5,6] and analgesic [7] effects. Osseointegration is the structural and functional connection without fibrous tissue, between the bone and the implant surface under load [8]. There are many factors that affect osseointegration. Primer stability, implant surface characteristics, anatomical state of implant area, prosthesis design, occlusion pattern on healing phase and bone metabolism constitute some of these factors [9]. Free radicals are among the factors that affect bone healing and osseointegration. Recently, researchers started to show interest in the idea that implantrelated complications may occur due to free radical-induced tissue damage [9-10].

On healing process after implantation, granulation tissue is minimal and well-organized bone formation is observed [11]. Following the placement of the implant, with the necrosis and resorption of the traumatized bone, new bone formation and a series of healing events occur in the area around the titanium body [11,12]. Following the implantation, the amount of contact between the implant and the surrounding bone increases due to bone healing. Treatment may fail if implants are loaded before this contact reaches a certain level. For this reason, loading time should be decided based on the implant stability [13].

Based on the literature review, we thought that propolis may shorten the consolidation phase after implantation and have a positive impact on implant stability. In this study, we aimed to investigate the effects of propolis on stability and to help to develop new agents that will support the osseointegration and bone healing process.

Methods

This study was approved by the Cumhuriyet University IRB and the animal care and use committee.

Animals

For our study, 24 male New Zealand rabbits (Oryctolagus Cunilus L), approximately 6 months old and weighing about 2.5- 3 kg, were obtained from Cumhuriyet University Experimental Animals. Food and water requirements of all animals were met without limit. Standard conditions were applied in the animal room (22-24 °C, 55-70% humidity, 1 atm, 12 hours light / dark room). During the study period, animals were placed in stainless steel cages measuring 50 x 80 x 50 cm, with each cage containing a single rabbit. All animals were brought to the laboratory one month prior to surgical procedure and monitored to ensure optimal health conditions, protection from infections, and adaptation to their new location. Animals were divided into 3 groups, each consisting of 8 rabbits.

Implantation of the Biomaterials

Animals went under anesthesia by intramuscular injection of 10-20 mg / kg Xylazine (Rompun 2%, Bayer, Istanbul, Turkey) and 50 mg / kg Ketamine HCl (Ketalar, Eczacıbaşı-Warner Lambert, İstanbul, Turkey) before the surgical procedure. 3.5 x 10 mm sized dental implants with external hexagonal platform, were obtained from ADIN Dental Implant Systems (SLA Surface, Toureg-NP, Afula, Israel). The unilateral tibia proximal region was shaved and cleaned with antiseptic solution on each rabbit. Surgical area was prepared by coating with sterile surgical drapes and sterile film. A 2-3 cm incision was made from the proximal to distal metaphyseal region of the tibia. Subcutaneous tissues and muscle layers were dissected with blunt dissection to reach tibia surface. Implant slots were prepared using burs at the rate of 600-1000 rpm, under sufficient isotonic solution irrigation, according to the company’s recommendations (Table 1).

Table 1: Difference of surgical procedures on groups.

Dental implants were placed in the slots using a ratchet and attention was paid to have adequate primary stabilization. After implantation, RFA measurements were made with Ostell (Integration Diagnostics AB, Göteborg, and Sweeden). After the operation, elevated epidermal flap was sutured to its original position with 5-0 polyglactine 910 (Vikril Jonson & Johnson / Ethicon) attaching the muscle, subcutaneous fascia and skin. Postoperatively, 50 mg / kg Ceftaxon (Cephaxon-Toprak) IM and 4 mg / kg Carprofen (Rimadyl-Pfizer) were administered subcutaneously for 3 days. 200 mg / kg / day of the propolis was given to the rabbits in Systemic Group by oral gavage for 28 days. All the rabbits were taken to a 28-day rest period under pre-prepared, appropriate ambient conditions. At the end of the 28-day follow-up period, animals were sacrificed via 200 mg / kg i.p. sodium pentobarbital injection.

Preparation of the Propolis

1g of propolis (Eğriçayır Organic Bee Products / Mersin) was added to 1 ml dimethyl sulfoxide (DMSO) and vortexed for 1 minute (Jeio Tech, Vortex Mixer VM-96T). The prepared mixture was put in an ultrasonic bath (Kudos HP Heating Series ultrasonic cleaner) and stirred at 25 °C and 53 kHz, for 15 minutes. After filtering via sterile filters with 0.22 μm pore size, prepared solution was diluted with saline (1: 4; DMSO: saline) and got ready to use.

Resonance Frequency Analysis

Osstell® was used to measure the resonance frequency. The measurements were made by placing the Smart Peg on implants. After inserting the implants and at the end of follow-up period, resonance frequency analysis was performed and the procedure was repeated 5 times for each implant. At each measurement, the most repeated result was accepted as correct.

Removal Torque Test

All rabbits were subjected to removal torque test after RFA measurement at the end of follow-up period. The probe of the digital torque meter (Lutron TQ-8800; Lutron Electronics Enterprise, Taipei, Taiwan) was attached to the implant, and force was applied in a controlled and increasing way reverse clockwise. The moment implant began to rotate within its slot, force was stopped. Highest value on the digital display was recorded in N / cm.

Statistical Analysis

The data obtained from our study were uploaded to the SPSS (ver: 22.0) program and evaluated. When the parametric test assumptions are fulfilled (Kolmogorov-Simirnov) Variance Analysis and Tukey Test; when the parametric test assumptions were not met, the Kruskal – Wallis Test was applied and the P-values was taken as 0.05.

Results

One of the animals in control group died due to diarrhea. None of the other subjects had a pathology caused by the device or method that affected their general health. Findings in the study were analyzed in two parts as resonance frequency analysis and removal torque test. Measurements were performed separately foreach group (Figure 1). When the operation day measurements of resonance frequency analysis in all three groups were compared, the difference was significant (P <0.05). When the measurements were compared in pairs, difference between the control group and the systemic group was significant, but no significant difference was found between the control group and the local group or the local group and the systemic group (P> 0.05). When the resonance frequency measurements were compared on the 28th day in all three groups, the difference between the groups was not significant (P> 0.05) (Figure 2).

Figure 1: Distribution of RFA 1st day values of groups.

Figure 2: Distribution of RFA 28th day values of groups.

Table 2: Comparison of RFA 1st day and 28th day differences between groups.

When comparing the removal torque test measurements in all three groups, the difference was significant (P <0.05). When the removal torque test measurements were compared in pairs difference between the control group and the systemic group was found to be significant, but no significant difference was found between the control group and the local group, the local group and the systemic group (P> 0.05) (Figure 3). There was no significant difference between the RFA measurements of Control Group on day 1 and day 28 (P> 0.05). In the Local Group and Systemic Group, the differences were significant when comparing RFA 1st and 28th day measurements (P <0.05). The most important difference is seen in the systemic group (Table 2). When improvement of RFA from 1st to 28th day in all three groups was compared, the difference between the groups was found to be statistically insignificant. But the biggest difference is seen in the systemic group. This result may be due to the low number of subjects.

Figure 3: Distribution of RFA 28th day values of groups.

Discussion

There are defensive mechanisms in the organism which prevent reactive oxygen species from forming and damaging them. These are called antioxidant defense systems or antioxidants. Studies show that antioxidants play a protective role against free radicals [14]. Propolis is a very complex natural compound that has been in use since ancient times for treatment and is still in use today. In-vitro antioxidant activity of propolis has been shown in many studies conducted with different methods. Benzyl caffeate, the high amount of phenolic component and caffeic acid phenyl ester which is the active component of propolis has been suggested to be responsible for its antioxidant activity [15].

Propolis has antibacterial, anti-inflammatory, antitumor, analgesic and anesthetic effects [15,16]. Anti-inflammatory, hepatoprotective, cardio protective and radio protective effects of propolis are associated with its high antioxidant activity [17]. There are many studies investigating the effects of propolis on bone. In a study by Altan et al., effect of systemically applied propolis on the expanded premaxillary suture was studied and it was thought that bone formation in this region could be accelerated [18]. In a study by Guney et al., effects of propolis on fracture healing were examined and the time-dependent, beneficial effects of propolis were discussed. Toker et al. [19] investigated the effects of systemic propolis on morphometric and histopathological changes in experimental periodontitis induced in rats and found propolis to prevent alveolar bone loss [20].

Based on these studies, we suggest that the propolis may shorten the consolidation phase after implantation and have a positive effect on implant stability. In addition, due to its antiinflammatory and anesthetic effect, propolis may reduce postoperative stress. There is no standard for the extraction procedure or thecomposition of propolis-containing extracts [21]. Traditionally, the dissolved fraction of propolis in 70% ethanol is extracted and is called propolis balsam [22]. However, DMSO has been shown to be less toxic than ethanol [23,24]. In a study investigating the antimicrobial activity of propolis, DMSO extracts showed higher antimicrobial activity than acetone extracts [25]. In another study using DMSO, experimental periodontitis was induced in rats and systemic propolis administration decreased alveolar bone loss [20]. Taking these studies into consideration, we decided to use DMSO in the preparation of the propolis solution.

An official dose limit for propolis has not been established. However, in rats LD50 was found to be 2-7.34 g / kg. The recommended daily dose is 1.4 mg / kg [26,27]. Studies have indicated that propolis is toxic when administered over a concentration of 2000 mg / kg [16]. In a study on rats, propolis administered via oral gavage at 500 mg / kg / day following intraperitoneal implant placement was found to have mitigating effects on inflammation, angiogenesis and fibrogenesis [27]. In a study conducted by Bereket et al., effect of propolis on the consolidation phase was investigated after distraction osteogenesis was performed on rabbits and the applications at oral doses of 100 mg / kg / day and 200 mg / kg / day were compared. It was observed that the 200 mg application was more effective in accelerating new bone formation [28]. We did not encounter any experimental or clinical study investigating the effect of propolis on implant stability. Therefore, the duration, dosage and regimen for propolis after implantation was determined for the first time in this study but studies investigating effects of propolis on bone healing constitutes a basis for our research. Therefore, systemic propolis administration course was selected as 200 mg / kg / day.

There are many studies in which propolis is applied locally. In a rabbit study, the intraarticular administration of propolis in the experimental septic arthritis model yielded beneficial results [29]. Another study showed that a layer of propolis application with allograft enhanced and accelerated osseointegration and shortened the consolidation phase [30]. In addition, the ability to obtain a dense form of propolis that is homogeneously dissolved, has no toxic effect and can be easily applied to the implant cavity, allowed us to plan the study in this way. During the experiment, the surgical procedure and placement of implants were performed by a single operator, aiming to standardize.

The selection of rabbits as experimental animals in our study is due to the fact that physiological bone healing in rabbits is similar to humans, and at the same time the rate of healing is three times higher than that of humans [31]. Physiologically, an 8-week healing period in rabbits is equal of 6 to 8 months of healing in humans [32]. The 4-week recovery period for rabbits is thought to be sufficient for monitoring new bone formation and angiogenesis [33]. Therefore, we opted to perform the measurements on the 28th day to achieve appropriate osseointegration, bone healing and implant stability. One of the major problems faced by dentists is the assessment of the osseointegration of the dental implant. The amount of osseointegration between the implant surface and the bone supporting the implant is used to measure the stability of the implant [34]. This measurement can be made with many different techniques [34,35]. Most important methods are percussion test, Periotest, resonance frequency analysis and removal torque test.

The use of percussion sounds to measure implant stability is a highly subjective method and is not reliable enough. One of the first devices used to provide an objective stability measurement was the Periotest, initially designed for measuring the stability of the teeth, but also for implant stability [36,37]. However, reproducibility of the results obtained with Periotest is affected by many factors such as the vertical position of the measuring point on the abutment, the angulations, and the distance between the hand piece and abutment [38]. The removal torque test is one of the in vivo mechanical tests used to evaluate the strength of the connection between the bone and the implant surface [31,39,40]. When removal torque is tested, it is assumed that the implant’s high resistance to the extraction indicates that there is a high amount of bone formation and contact between the bone and the implant surface. Ivanoff et al. [40] have shown that the removal torque value is closely related to the bone implant contact and the amount of bone entering the grooves.

They reported that the need for higher torque forces to remove implants can be interpreted as an increase in bone implant contact and an increase in osseointegration strength [41]. However, removal torque test may not be the most effective method for measuring the amount of bone around the implant or the fixation. The underlying biomechanical principles in torque tests are quite complex. Shear force in the bone implant interface is the most important component. The removal torque tests are invasive biomechanical tests that give information about the rigidity of the implant within the bone [42]. The removal torque test shows resistance to shear forces at the bone implant interface, but the results do not always show a direct correlation with bone response or surface hardness.

Therefore, it is also necessary to measure the amount of bone implant contact [43]. On the other hand, it is possible to measure implant stability by resonance frequency analysis in terms of the implant stability quotient (ISQ) at every moment of treatment and loading [44,45]. It is believed that the measurements made by resonance frequency analysis have eliminated the observer dependent errors. Because the transducer is inserted onto the implant and the measurement is automated. It has been reported that the torque used during the insertion of the transducer (Smart Peg) on implant does not affect the test results and that the results obtained with this method are highly reproducible [46]. Studies have shown that bone height supporting implants significantly affects the RFA values [44,47,48]. If the rigidity of the bone implant interface is assessed by RFA, the results are expected to relate to bone density and bone implant contact, as well as changes occurring during healing at the bone implant interface or parallel to the resorption of the peri-implant bone [49].

Although there are many methods to assess implant stability, resonance frequency analysis, a non-invasive method introduced by Meredith et al. [44,50,51], allows monitoring of changes in stability and stiffness at the bone implant interface to allow clinically successful and failed implant differentiation [44]. In addition to the non-invasive use of ISQ values in evaluating implant stability, thismethod has been reported to provide reliable and accurate results regarding the bone-implant interface in early evaluation of implant stability [39, 52]. Meredith et al. [50] have shown that implants with high initial ISQ values have shown that stability can reach a peak plateau with shorter recovery periods and that resonance frequency analysis can be a valuable method for monitoring the connection between the implants and the surrounding bone. Considering these investigations, we decided to combine resonance frequency analysis and removal torque test to measure implant stability in our study.

Primer stability plays an important role in the clinical success of implants. Therefore, the results of resonance frequency analysis performed during surgical application can help physicians to predict the prognosis of the implant. Because of this and because it is possible to observe the amount of change in stability as a numerical value, in our study, resonance frequency analysis was performed twice, one immediately after the implant placement and one on the 28th day. In our study, effects of propolis which is known to have a high antioxidant effect, has been experimentally investigated with local and systemic applications on the implant stability in rabbits. After completing the measurements on day 28, the results of the applied stability tests were evaluated.

Numerous modifications have been made to the implant design or surgical technique to improve implant stability and osseointegration. There are many factors that influence osseointegration. Primer stability, implant surface characteristics, anatomic state of the implant site, prosthesis design, occlusion pattern on healing phase and bone metabolism constitute some of these factors [9]. Recently, researchers have begun to show interest in the idea that implant-related complications may occur due to the free radical-induced tissue damage [9-10]. The results of our work have led us to believe that propolis may have positive effects on implant stability and the application of propolis when primer stability is lower, may be an effective support in achieving the desired level of osseointegration and stability within the same duration. These effects are thought to be more pronounced when propolis is administered systemically.

Conclusion

In order to support osseointegration and increase implant stability, propolis application may have positive effects, especially with systemic administration. However, more studies are needed in this area and our work may form a baseline to find alternative ways of supporting osseointegration, to have a clear understanding of the effects of propolis on implant stability, and to determine the effective dosage and administration pattern to help with bone healing.

For More Articles: Biomedical Journal Impact Factor : https://biomedres.us

Spatial and Temporal Variations of Climatic Parameters under Changing Climate of Hindu Kush Himalayan Region of India

Mini Review

Climate change can severely threat India’s water security. India’s hydro-climatic regime is expected to alter significantly over the course of the 21st century. If the current pattern of demand and usage continues, it is predicted that by 2030 about half the demand for water will be unmet. Growing population, rapid industrialization and urbanization, and climate change will further affect water availability. In this context, it is important for India to consolidate water resource management through rational estimates and regulation. The vulnerability of the Indian subcontinent to the impact of changing climate is of vital importance because the major impact of climate change in this continent would be on the hydrology, affecting water resources and agricultural economy. Water resource has become a prime concern for development and planning, including food production and flood control. The impact of climate change may be relatively severe with the reduction in the water availability over different parts of the globe. Hindu Kush Himalayan region of Jammu and Kashmir is a hill state having varied topography and great diversity in cultural, social and economic practices of its different regions.

However, agriculture remains the backbone of the economy of Jammu and Kashmir with over 65 percent of its population depends on agriculture and allied sectors. These sectors contribute around 27 percent to the State’s income. The diversity in physiographic features, agro-climatic variations at macro and micro level, existence of cold arid, temperate, inter-mediate and sub-tropical zones. Over the years, the agriculturists and farmers have adopted several area specific and time specific cultivation practices to meet the requirement of their staple food crops. Dwindling water resources too is a major challenge as only 42 percent of the cultivated area is under irrigation. Fragile soil in hilly areas is susceptible to soil erosion and a single cropping season is available in temperate and high altitude areas. Net irrigated area in the region is just 24 percent Irrigation is an essential input of agriculture and is practiced in all parts of the world where rainfall does not provide enough ground moisture.

In areas of irregular rainfall, irrigation is used during dry spells to ensure harvests and to increase crop yields. A major constraint to the development of agriculture in Jammu and Kashmir is the fact that only 50 per cent of the ultimate irrigation potential of the state has been harnessed. The ultimate irrigation potential in Jammu and Kashmir has been assessed at 1358 thousand hectare, which includes 250 thousand hectare to be developed through major and medium irrigation and 1108 thousand hectare through minor irrigation. The impact of climate change on annual air temperature and precipitation and crop water requirement is great concern in present context. The present paper focused on detecting trends in maximum temperature, minimum temperature, precipitation, reference evapotranspiration, evaporation and relative humidity at monthly, seasonal and annual basis for different regions of HKH.

Reference evapotranspiration (RET) plays a critical role in irrigation planning and is needed for the determination of water demands of crops. The widely used Mann-Kendall test was used at 5% and 10% significance level on time series data of 20 year (1995-2015) for Srinagar Kashmir region and 15 year data of Leh (2001-2015). The magnitude of the identified trends in the meteorological parameters was obtained through the parametric linear regression test. In order to identify the dominant variables among the independent variables associated with changes in dependent variable, a stepwise regression method was used. The results on monthly basis, annually and seasonal basis were carried out. In case of Srinagar on annual basis only RET (ETo) witnessed statistically significant increasing trend at 5% significance level.

Trend analysis on seasonal basis revealed that ET0 in autumn season at the rate of 8.32 mm/decade and in winter season at the rate of 8.63 mm/decade and precipitation in autumn season at the rate of 19.21 mm/decade witnessed statistically significant increasing trends only at 5% level of significance and no trends were observed in other seasons. No significant trends were witnessed in maximum temperature, minimum temperature, relative humidity and evaporation at 5% or 10% significance level. In case of Leh region, it is witnessed that statistically significant falling trends are witnessed in maximum temperature in the month of July at the rate of 1.70°C/decade, at 5% level of significance.

In case of minimum temperature statistically significant falling trend at 5% level of significance as the values of Z (Test Statistics) obtained through the MK test are more than -1.96 was witnessed in month of August at the rate of 1.31°C/decade. Statistically significant falling trend was witnessed in the month of December at the rate of 1.74°C/decade at 10 % significance level. It is witnessed that statistically significant falling trends are witnessed in relative humidity in the month of March to December (at 5% level of significance. On examining the results of stepwise regression to determine the meteorological parameters responsible for the observed ETO changes, wind speed followed by sunshine duration, and temperature were found to be the main causative variables of the observed changes in the ETO over Srinagar in the annual time scale.

It is understood that the global warming and its impact on the hydrological cycle and the nature of hydrological events would pose an additional threat to the Himalayan region. To harness this potential, India needs to invest soon in increasing storage capacity, improving water-use efficiency, and managing surface-water and groundwater resources in a sustainable way to avoid problems of soil Stalinization and water logging. In order to minimize the adverse impacts of climate change on country’s water resources and attaining its sustainable development and management, there are needs of developing rational adaptation strategies. Thus, due consideration is required to be given to the effect of climate change while planning, designing and operation of the water resources projects.

These would be reflected in proper assessment of water resources, developing suitable hydrological design practices and operational policies for water projects, putting in place effective flood and drought management strategies, developing water efficient irrigation practices, etc. believes in a future in which the region’s mountain people can experience enhanced livelihoods, equity, and social and environmental security in which they can adapt to environmental, socioeconomic, and climate change and in which generations of mountain and downstream populations can enjoy the benefits and opportunities afforded by the region’s natural endowment.

For More Articles: Biomedical Journal Impact Factor : https://biomedres.us

Amniotic Membrane in the Treatment of Spinal Cord Injuries

Mini Review
Spinal cord injury (SCI) is one of the most common and devastating injuries found in the neurological clinic [1,2]. It is defined as damage to the spinal cord that causes temporary or permanent changes in its function, resulting in significant neurological dysfunction and disability [3,4]. SCI has physical, social and occupational consequences for patients and their families, resulting in loss of independence and an increase in the mortality rate [3]. In addition, studies show that expenses for care of patients with SCI can reach US$1.1-4.6 million per patient throughout life. Thus, it is extremely important to develop effective treatments [5]. This type of injury can cause many disorders, depending on his localization and severity. According to Castro, the number of people with some type of physical disability has increased in the past few years [6]. A partial spinal cord injury is sufficient to cause permanent disabilities, such as the Brown-Sequard syndrome, often observed after spinal cord hemisection [7]. Currently, surgical treatment for mechanical stabilization and decompression has been performed in cases of unstable fractures with spinal cord injury and the use of drugs to treat such lesions has been extensively studied [8].

In the last three decades, numerous neuroprotective and neuroregenerative therapies have been transferred from preclinical studies to clinical trials [3]. However, it is still not possible to find standard therapy universally accepted and new therapeutic approaches are needed [4]. Experimental and clinical studies evidenced that spinal cord suffers primary and secondary damages after acute injury [9]. Primary injury occurs with the initial traumatic event that produces immediate mechanical disruption and displacement of the spine, which causes compression or transection of the spinal cord [3]. There are rupture of meninges, hemorrhage and massive death of neurons, oligodendrocytes and astrocytes [10]. Together, these events immediately initiate a cascade of secondary lesions, which cyclically results in the death of neurons and glial cells, ischemia and inflammation, resulting in further damage to the spinal cord and neurological dysfunction [3]. After these secondary damages, changes in the organization and structural architecture of the spinal cord occur, including the formation of cystic cavities and a glial scar, causing a physical barrier to axonal regeneration [3,10,11]. The glial scar and cystic cavities, in combination with poor endogenous remyelination and axonal growth, prove that the spinal cord has a low potential for intrinsic recovery, thus SCI causes permanent neurological deficits [3].

The treatment and functional reconstruction of an injury in the central nervous system constitute a challenge for health areas. A growing number of researchers have attempted to apply neural stem cells combined with artificial materials for nerve repair. However, these approaches are challenged by ethical and practical issues. Amniotic tissue, on the other hand, is a clinical product of discard and amniotic epithelial cells are pluripotent, with low immunogenicity and are not the subject of ethical debate [12]. Amniotic membrane (AM), innermost layer of the fetal membranes, is composed of three histologically distinct layers: the epithelial layer, the basement membrane and avascular mesenchymal/ stromal layer. The epithelial layer comprises a flat, cuboidal and columnar cells uniformly disposed on the basement membrane, which consists mainly of collagen IV, elastin, fibronectin, laminin and proteoglycans. The mesenchymal layer in turn consists of three regions: an acellular compact layer, that forms the main fibrous skeleton of the AM composed of collagens I, III and fibronectin; a network of dispersed fibroblast-like mesenchymal cells; and a spongy layer of loosely arranged collagen fibers that separates the amniotic membrane from the chorion [13].

Both cell types isolated from AM, amniotic epithelial cells (AECs) and amniotic mesenchymal stromal cells (AMSC), express stem cell markers and have the ability to differentiate toward all three germ layers [14]. AECs have been used in several researches to study the damaged tissues repair and experimental evidence has demonstrated its great regenerative potential for various tissues [14-16]. In addition, AECs have some properties similar to neural and glial cells and ability to secrete neurotransmitters [17-19]. Thus, these cells have great potential in the treatment of SCI. Sankar demonstrated in his study that AECs survive in the transplanted environment, support the growth of axons through them, preventing glial scar formation at the site of injury and the death of damaged neurons. These results are similar to those found in neural transplantation studies. Thus, it is believed that AECs may exhibit the same properties of neural tissue, regarding the beneficial effects on repair of SCI [20]. Roh also obtained good results when applying AECs in SCI induced in rats. His results demonstrated that transplantation of AECs has a beneficial effect on SCI-induced neuropathic pain [21]. Gao investigate the synergistic effects of anti-inflammatory drug administration and transplantation of AECs following SCI in rats. He stated that this combination reduced the secondary damage and promoted functional recovery after SCI [1].

However, in order to improve the results obtained in the treatment of this type of lesion, studies have used AECs combined with scaffolds. They stated that this combination resulted in a lower glial scar in the damaged region when compared to animals that received only AECs. These animals also had lower inflammatory infiltrate and improved motor function. Scaffolding provided a more favorable environment for regeneration of the central nervous system, ensuring that transplanted cells had a growth surface and promoted cell adhesion [12]. In this context, several studies have chosen to use the AM as a fragment, rather than isolated AECs. This protocol allows to preserve the micro-environment with all the growth factors and differentiation factors present, providing action of these chemical mediators in the injured tissue repair process. In addition, it also facilitates the processing and use of AM. AM patching provides to the injured tissue mechanical protection, anti-adhesive effect, wound protection and migration and adhesion of basal epithelial cells. In addition, studies show that AM has several useful properties for the proper development of the repair process: reduction of fibrosis, prevention of apoptosis, restoration of the epithelial phenotype, antibacterial action, anti-inflammatory action, protease inhibitor, low immunogenicity and does not induce rejection after transplantation [22-24].

Other studies have demonstrated the great potential of using AM fragments on the treatment of other tissue injuries. Cargnoni [25] applied AM as a patch to reduce the induced necrosis in rat hearts and Sant’Anna [26] demonstrated that AM application reduced liver fibrosis induced by bile duct ligation when it was applied around the rat liver. Furthermore, Nicodemo demonstrated in her study that human amniotic membrane fragment application on acute lesion in the Achilles tendon of rats favored the evolution of tissue repair, reduced the inflammatory response, induced the proliferation of fibroblasts and collagen fibers, and allowed a reduction in healing process time [27]. In clinical practice, it has also been applied in ophthalmology since 1997 [28]. It is used therapeutically for defects of the cornea and conjunctiva [29]; prevention of postoperative adhesions [30]; reconstruction of defects of the pharynx and oral mucosa [31] and in bone defects [32]. In general, AM patching has shown interesting results when applied in injured tissue, with low incidence of side effects, encouraging the development of new experimental research aimed at the treatment of SCI. Further studies are needed to determine the effects of this treatment protocol on the development of the SCI repair process.

For More Articles: Biomedical Journal Impact Factor : https://biomedres.us

The Effect of 6 Weeks versus 3 Weeks Post Partum Visit On Short Interval Delivery Rate

Abstract

The Effect of 6 Weeks versus 3 Weeks Post Partum Visit on Short Interval Delivery Rate.

Objective: To evaluate the effect of postpartum visit timing on short interval delivery rates.

Methods: Retrospective chart review was conducted on all patients who had two deliveries at a large community hospital resident’s clinic between May of 2011 to January 2013. Patient demographics, breast feeding, economic status, and postpartum visit attendance were compared to patients that had only one delivery during that time period. From May 2015 to January 2017, 18 months after altering the timing of postpartum visit from 6 to 3 weeks, the short interval delivery and attendance at postpartum visit were compared between the two time periods at the same clinic. Univariate analysis using Chi square or t -test were used as appropriate.

Results: During the initial study phase 72 (7.3%) out of 991 patients had a short interval delivery. Only age (25.4 ± 6.4, 27.9 ± 5.1, p=0.001) and attendance at the postpartum visit (49.6% vs. 63.6, p=0.02) differed between the short interval delivery and the non-short interval delivery groups. In the follow up period (May 2015 to January 2017), 53 (5%) out of 1056 deliveries were short interval deliveries. Postpartum visit attendance was 752 (71.2%). Significant decrease in short interval pregnancy was noted when comparing the two time periods (7.3% vs. 5%, p=0.04). In addition an increase in PPV attendance was noted (62.1% vs. 71.2%, p=0.001).

Conclusion: Changing the timing of the postpartum visit from 6 weeks to 3 weeks may decrease short interval delivery rate and increase postpartum visit attendance.

Keywords: Short; Interval; Delivery; Pregnancy; Postpartum; Visit

Introduction

The World Health Organization recommends ideal pregnancy spacing between 18 and 60 months [1]. In the United States the recommended interval between pregnancies has not yet reached a consensus. However, in the literature, short interval pregnancy (SIP) has been defined between 6 and 18 months from live birth to conception of a subsequent pregnancy [2]. SIP has been associated with multiple maternal and neonatal complications. Preterm premature rupture of membranes, preterm birth, placental abruption, congenital anomalies, low birth weight, autism, schizophrenia, fetal and maternal death have all been noted to increase with SIP [3].

Interestingly, in the United States, risk factors for SIP include college education, childbearing after 30 yrs of age, and private insurance benefits [2]. This indicates a group that may have a wish for a SIP. From the literature, those that have a SIP of less than 6 months are at the highest risk of poor pregnancy outcomes and as such may benefit most from intervention [4]. It has been reported that SIP (less than 6 months) is more common in lower social economic groups, younger ages, lower educational levels and in those receiving suboptimal prenatal care [5,6]. The National Survey of Family Growth, reports that in the United States, unintended pregnancy rates are as high as 50% with a third of them meeting criteria for SIP [2].

The economic burden of these unintended pregnancies is estimated at 11billion dollars per year [7]. The postpartum period or puerperium, defined as the time between the delivery of theplacenta and generally considered to end six weeks postpartum, is critical for the prevention of SIP. Immediate initiation of postpartum contraception at the postpartum visit (PPV) is the intervention that has had the greatest impact in reducing SIP [8]. The convention of the six week PPV is based on older non evidence based expert opinion [9]. Most women resume sexual activity before 6 weeks after delivery and, in the non-breastfeeding woman, ovulation can happen as early as 25 days postpartum [10]. Interestingly, many providers counsel their patients to schedule their postpartum visit 6 weeks after delivery, thus loosing valuable time for the timely initiation of birth control. We chose to use two deliveries in an 18 months time frame as short interval deliveries. Based on this information we hypothesized that women with short interval delivery (SID) would be more likely to miss their postpartum visit (PPV). Furthermore, techniques to increase attendance at the PPV would in turn decrease SID. The following study was designed to answer these questions.

Methods

Charts were reviewed of all patients that had 2 deliveries during an 18 month period (May 2011 to January 2013) from a residency clinic at a community hospital. The study was approved by St. Luke’s institutional review board. The short interval deliveries (SID) were compared to patients who only had one delivery during this time period (non-SID). We compared the following variables; age, parity, employment status, insurance coverage, race, breastfeeding, attendance at postpartum visit (PPV) and Depo-Provera post delivery all related to first pregnancy. Separate univariant analyses on the above variables were performed comparing SID to non-SID patients. The information obtained from this analysis was used to develop a protocol to apply prospectively to our clinic population to decrease SID. In a follow up time period, May 2015 to January 2017, we compared SID to the above previous study period. The proportion of SID as well as the percentage of all patients that attended their PPV was compared to the previous time period. Chi square and t- test were used as appropriate. A p value of 0.05 or less was considered significant. Correction for multiple measurements was not performed. Statistical calculations were done utilizing Sigma Stat software (Systat Software, San Jose, CA)

Results

During the initial study phase 991 deliveries were performed, of which 72 (7.3%) were SID. PPV attendance was 616 (62.1%). Only younger age (25.4 ± 6.4, 27.9 ± 5.1, p=0.001) and attendance at the PPV (43.1% vs. 63.6, p=0.02) differed between the SID and the non SID group (Table 1). The only modifiable variable was attendance at the PPV. Based on these finding, a PPV program was developed that included moving the PPV from 6 weeks to 3 weeks in attempt to increase PPV attendance. In the follow up period of the 1056 deliveries, 53 (5%) were SID and PPV attendance was 71.2% (n=752). Significant decrease in SID was noted when comparing the two time periods (7.3% vs. 5%, p=0.04). In addition an increase in PPV attendance was noted (62.1% vs. 71.2%, p=0.001).

Table 1: Comparison of Characteristics of Short Interval Delivery to Non -Short Interval Delivery during Initial Phase of Study.

Discussion

We noted that a younger age and failure to attend their PPV after first pregnancy were increased in SID as compared to non-SID in our population. From this information, we altered the timing of the PPV from traditional 6 weeks to 3 weeks, in an attempt to increase PPV attendance. In the second phase of our study we noted, an increase in our PPV attendance and a decrease in SID. Thus, suggesting a 3 week PPV as a possible intervention to decreasing SID. Previous studies have shown that the initiating of contraception in the postpartum period is an effective tool in decreasing SIP [11]. National data has demonstrated that up to 40 % of patients fail to attend their postpartum visit [12]. Novel approaches to increase PPV attendance can provide a timely venue to discuss and prescribe contraception. This in turn will decrease the SIP. Another approach to increase prenatal care is the offering of incentives, such as coupons, cash, and merchandise. Although some of these studies noted an increase in attendance at prenatal care visits, they were no more likely to return for a PPV than the non- incentivized controls [13]. Furthermore, short interval pregnancy was not an outcome measure in these incentivizingstudies. We chose to use two deliveries in an 18 months time frame. We employed these criteria for several reasons. It was a definable end point that could be obtained from our current databases (Table 2).

Table 2: Comparison of Attendance of Postpartum Visit (PPV) at First Pregnancy and Short Interval Delivery (SID) Between Phase 1 (6 Week PPV) and Phase 2 (3 Week PPV) of Study.

Trying to determine if an individual had a positive pregnancy test or a termination after a live birth was fraught with validity difficulties. Lastly, this endpoint of 2 deliveries in 18 months may identify the greatest risk group for potential pregnancy complications and hence the appropriate subset of SIP that would benefit from an intervention [1]. Although we have noted no adverse clinical outcomes since altering the timing of our PPVs, our study was underpowered to look at improvement in detection or failure to identify problems as a result of altering PPV timing. The 6 week PPV is based on the physiology to allow for sufficient time for involution of pregnancy. This timing of the PPV is based on no discernable evidence [14]. The traditional timing of PPV may relate to a time when less effective contraception was available. Studies have shown that between 20 and 60% of women has had intercourse by 6 weeks postpartum [15]. The return of ovulation can occur as early as 26 days postpartum and 78% of women have ovulated before their “first post partum” menses [16]. For these reason, the starting of contraception prior to 6 weeks seems prudent.

Although we encourage long acting reversible contraception (LARC) in appropriate individuals, estrogen containing contraception was also prescribed at the 3 week PPV. These medications were avoided in breast feeding patients and in those that may be at higher risk of venous thrombosis. This includes obesity, smokers, difficulty in ambulation and other medical complications. If these individuals were not amenable to other forms of birth control, then combined contraception was started after 6 weeks. There are several strengths of our study. It was performed on a stable population that is not transient. Although minor deviation from individualizations can occur, major counseling, treatments, and follow up are protocol driven, ensuring evidence proven standard of care. We chose two time periods to allow for adequate implementation of our revised PPV protocol and decreasing the chance of overlapping study participants. As noted earlier, we defined our SIP as two deliveries in the dedicated time periods. This ensured validity in our measurements and also identified those pregnancies at highest risk for poor outcomes. Lastly, during the both study phases the only immediate postpartum contraception available was medroxy progesterone.

This eliminates the bias of immediate postpartum LARC on the incidence of SID. There are some noted weaknesses to our study. A randomized study design would have allowed for a more effective method to control potential biases that may occur over time. Although our definition of SIP has its value, it could be considered a weakness, because it fails to identify a large population that maybe at risk for subtle outcome concerns. The time period was considerable for this project. Thus, different clinician and changes in patient population may have occurred. The difference we found in attendance at PPV and decrease in SID were statistically significant in our two cohorts, but our study was underpowered to analyze more clinically important outcomes, such as preterm labor, preeclampsia, LBW, or other morbidities. SIP can lead to poor pregnancy outcomes. Postpartum contraception is a proven intervention that has decreased SIP rate. However, to implement postpartum contraception novel approaches are needed to ensure the patient can receive it. Changing the PPV from the standard 6 to 3 weeks may be one technique to provide clinician-patient interaction to educated and prescript postpartum contraception in a timely fashion.

For More Articles: Biomedical Journal Impact Factor : https://biomedres.us

Desmocollin-3 and Cancer

Abstract

Desmocollin-3 [DSC3] is a transmembrane glycoprotein belonging to cadherin family of homophilic adhesion molecules, and is produced by the endoplasmic reticulum. DSC3 expression is seen in the suprabasal layer of stratified epithelium. DSC3 is a p53 responsive gene and can be detected by microarray. DSC3 protein expression is associated with expression of wild type p53 expression and can be detected by immune histochemistry. DSC3 protein is expressed on the surface of normal tissues. In proliferative tissues like, fetal and cancer, DSC3 protein is also seen in cytoplasm besides on cell surface. Expression of DSC3 is used as a diagnostic biomarker to differentiate squamous NSCLC from adenocarcinoma of lung. DSC3 expression is also seen in ovarian cancer, melanoma, colorectal cancer, cervical cancer, and meningioma cancer arising from oral cavity.

Expression of wild type p53 is associated with expression of DSC3. Chemotherapy, radiotherapy, targeted therapy [tyrosine kinase inhibitors], hypo methylating agents are known to induce expression of DSC3 in DSC3 negative cancers. As a homophilic adhesion molecule, it provides a unique opportunity for active immunotherapy by inducing DSC3 on surface of immune cells. CADI-05 is one such immunotherapy. It is found useful in management of squamous NSCLC and ovarian cancer when used with chemotherapy. It improves response rate and survival. As a mono therapy, it induces remission in melanoma and bladder cancer.

Keywords: Desmocollin- NSCLC; Cancer; CADI-05; Biomarker; Immunotherapy

Abbreviations: DSC3: Desmocollin-3; NSCLC: Non-small cell lung cancer

Introduction

Desmocollin-3[DSC3] is one of the adhesion molecules of cadher in super family found in desmosome and is a major adhesive force of epithelial cells [1-6]. DSC3 is a transmembrane calcium-dependent glycoprotein produced by the endoplasmic reticulum,encoded by the DSC3 gene. DSC3 is expressed, mainly in basal and immediate suprabasal layers of the stratified squamous epithelia [7] like buccal mucosa, esophagus, cervix, fore skin tongue, trachea etc. [3,8]. As an adhesion molecule, DSC3 provides homophilic adhesion i.e. cells expressing DSC3 will adhere to each other at the site of expression but not with others; it also works as a receptor as well as ligand to participate in cell signaling [9].

P53 and Desmocollin-3

DSC3 is one of the p53-responsive gene [1-11]. p53 is reported to be an upstream to DSC3. Expression of DSC3 gene is associated with expression of wild type of p53 and depends on the methylation status of the DSC3 DNA in the p53 binding site [10,11]. p53 expression in cancer is known to be altered by mutation or deletion of the p53 gene, with mutation of p53 being the most common event in human cancer [12]. Besides deletion and mutation of p53, p53 target genes are also silenced by epigenetic silencing like DNA methylation [1-11]. Mutant p53 inactivates p63 and is also associated with down regulation of DSC3 [10]. p63 is a master regulator of epidermal gene transcription and plays an essential function in controlling epidermal development , cell proliferation, stratification and cell–matrix adhesion [13]. There are two main isoforms of p63, Tap63 and Delta Np63. Delta Np63 alpha isoform is the most abundantly expressed p63 isoform. Both p63 and delta Np63 are activator for desmocollin-3 gene [13]. Knockdown of p63 and delta Np63 results in marked reduction in expression of DSC3 without any effect on expression of another adhesion molecule E-cadherin [13].

Desmocollin-3 and Cancer:

Desmosomal abnormalities are seen in cancer, as are alterations in DCS3 expression. In many epithelial cancers, DSC3 expression either over expressed or absent. DSC3 expression is not seen in many cancers e.g. adenocarcinoma of lung, breast, prostate cancer wherein there is mutation of P53 or hyper methylation. DSC3 was first cloned from human bladder cancer cell line [14]. Its presence can be detected by microarray (gene) or immunehistochemistry (protein)

a. Lung Cancer:DSC3 is not seen in normal lung tissue [15]. DSC-3 gene is over expressed 58 fold compared to adenocarcinoma [16]. Immunohistochemistry reveals in lung cancer expression of DSC3 is seen at basal layers of tumor. DSC3expression is seen in around 30% of cases [17]. DSC 3 expression is seen in squamous NSCLC and not in adenocarcinoma of lung. It is closely associated with p63 expression which is another marker used for differentiation of Squamous NSCLC from other varieties [18-20].

b. OvarianCancer: DSC3 is seen in around 85% of ovarian caners. Its expression seems to be dependent on FSH.

c. Melanoma: DSC3 is expressed in melanoma [21-24]. Its expression decreases with increased thickness and progression to metastatic melanoma [22].

c. Melanoma: DSC3 expression is seen in 60% colon cancer and also seen in 40% of colorectal lesion metastatic to the liver [10,25,26].

e. Bladder Cancer: DSC3 was first cloned from a bladder cancer cell line [14]. We have documented DSC3 expression in around 60% of bladder cancer irrespective of grade and stage of tumor.

f. Meningioma: DSC3 expression is described in around 60% of meningioma [21,27].

g. Chondrosarcoma: DSC3 gene expression is detected in 4 of the 5 chondrosarcoma cell lines [28].

h. Pediatric Acute Lymphoblastic Leukemia: DSC3 gene is described to be over expressed in all TEL-AML1 subtype of paediatric acute lymphoblastic leukemia [29].

i. Skin Tumors: Loss of DSC3 is seen with tumour development and progression [30] and is associated with increase in K-Ras induced skin tumors [31].

j. Oral squamous cell carcinoma: Oral mucosa normally expresses DSC3. However development of oral Squamous cell carcinoma is associated with reduction or absence of DSC3 expression. This reduction/absence of DSC3 expression was associated with higher histological grade (moderately or poorly differentiated) [32].

k. Breastcancer: DSC3 is expressed in a normal breast but is down-regulated in breast cancer cell lines and primary breast tumors at protein as well as gene level [3,33]. The loss of DSC3protein expression is more likely to be aberrant methylation of rather than gene deletion or gross rearrangement of the gene [3].

l. Prostatecancer: DSC3 is expressed in normalprostate as well asbenign prostate tumors but is absent in prostate cancer due to hyper methylation [34].

Table 1: Sensitivity of DSC3 for squamous NSCLC.

Desmocollin-3 as a diagnostic biomarker:

a. Squamous NSCLC: DSC3 is used as a diagnostic biomarker to differentiate Squamous NSCLC from adenocarcinoma of lung [35-42]. DSC3 is more specific for squamous NSCLC compared to p63 as p63 is also expressed in Adenocarcinoma. DSC3 gene is up-regulated in squamous NSCLC and down regulated in adenocarcinoma [43]. Specificity of DSC3 is 100% while sensitivity is variable [18-20, 44,45] and varies with differentiation of tumor. Maximum sensitivity is seen in highly differentiated tumors and is lowest for poorly differentiated Squamous NSCLC. Sensitivity of DSC3 for squamous NSCLC is 93.2% in large cohort of 426 but drops to 59% in poorly differentiated squamous NSCLC (Table 1). DSC3 expression in NSCLC is also not related to stage or histologic grade [17] of a disease [46].

b. Paediatric Acute Lymphoblastic Leukaemia: DSC3 gene expression can be used to differentiate TEL-AML1 from other subtypes of paediatricacute lymphoblastic leukaemia [29].

a) NSCLC: In spite of squamous NSCLC having poor prognosis,smaller clinical trials suggest that DSC3 expressing tumors are likely to have better survival compared to DSC3 negative tumors and may serve as a potential prognostic marker [1,17].

b) Colorectalcancer: Tumors with methylated DSC3 DNA were significantly correlated to a worse clinical outcome than unmethylated tumors. The methylation status of DSC3 DNA was not linked to any of clinical pathological parameters includingage, gender, size of tumor, tumor grading, and tumor stage in these patients [10].

c) Prostatecancer: Loss of DSC3 predicts poor prognosis.

Effect of therapeutic intervention on DSC3 expression:

a. DNA damaging agents: Expression of wild type of p53 can also be increased or induced by DNA damaging agents like radiotherapy, doxorubicin, cisplatin, paclitaxel, gemcitabine etc. Expressionof wild type p53 is sufficient to induce expression of DSC3 in breast, colorectal and lung cancers in absence of DSC3 DNA methylation [1,10,11]. Expression of wild typep53 converts DSC3 negative tumors in to DSC3 positive.

b. Tyrosine Kinase inhibitors: DSC3 expression has reciprocal relationship with ERK of MAPK family.Decreased ERK is seen following successful treatment with tyrosine kinase inhibitors. EGFR inhibitor like gefitinib converts DSC3 negative EGFR mutant adenocarcinoma of lung in to DSC3 positive.

c. Hypomethylating/Demethylating agents: DSC3 hypermethylation is seen in prostate and breast cancerleading to lack of DSC3 expression by this tumors [3, 6, 33]. Hypomethylating/Demethylating agents like azacytidine convert DSC3 negative tumors to DSC3 Cadi-05[3,47].

Desmocollin-3 and immunotherapy:

DSC3 is a homophilic adhesion molecule, which works as a receptor as well as a ligand. This provides an opportunity to develop an active immunotherapy for DSC3 expressing tumors by inducing DSC3 on surface of tumor targeting activated immune cells. CADI- 05 is one such active immunotherapy. It induces DSC3 expression on immune cells and also induces Th1 type of immune response through TLR2 agonist activity [48]. Cadi-05 increases tumor infiltrating immune cells [49] and found useful in management of cancers as a monotherapy for small size tumors [49,50]. As combination therapy with checkpoint modulators, radiotherapy as well as chemotherapy, Cadi-05 improves outcome of large size tumors [51].

Cadi-05 achieves and maintains remission in melanoma as well as in bladder cancer as a systemic monotherapy [52, 53]. In combination with chemotherapy, it improves response rate. Responses achieved are durable and results in improved survival. Identical results are seen when combined with radiotherapy. It is expected that combination with anti PD-L1 therapy will result in significant improvement in no. of durable responses.

For More Articles: Biomedical Journal Impact Factor : https://biomedres.us

Trigger of All Fingers in an 80 Years Old Male: A Case Report

Introduction

Trigger finger is a common condition with a reported prevalence of 2% to 20% [1,2]. Generally, trigger finger affects women more than men and the age distribution is bimodal with one group below six years of age and the other in their fifth and sixth decade of lif. It is a disorder which is associated with entrapment of the flexor digitorum superficialis or flexor digitorum profundus tendon along its course through fibro-osseous tunnels of the wrist, palm and digits of the hand [1]. Onset is usually gradual, associated with repetitive tasks, unaccustomed activity or compression of the pulley against hard objects. Snapping, clicking, locking, stiffness, and difficulty extending a flexed digit, often with discomfort or pain, are the most prominent symptoms [3,4]. Several studies suggest that individuals with type 1 diabetes, rheumatoid arthritis, carpal tunnel syndrome, arthritic changes in the wrist, hypothyroidism, mucopolysaccharidoses, amyloidosis, and congestive heart failure may be predisposed to flexor tendon entrapment [1].

The research on patients with trigger finger indicates various methods of treating patients including splinting, nonsteroidal antiinflammatory agents, percutaneous injection of corticosteroids, and surgical releas [1,2,5]. Very small, uncontrolled case series have shown in their results that only about half of patients are satisfied with their symptoms after a period of splint immobilization [6-8]. Triggering may resolve after one or two corticosteroid injections, but the results vary substantially between studies (35 % and 87 % for one and 72 % to 92 % for two injections) [9-13]. Various literatures suggest that patients should be informed about 50% success rates when offering a corticosteroid injection for trigger finger and that the chances of patients landing to surgical release still remains [14-16]. Percutaneous release has a success rate of 94% according to a recent systematic review of 2114 procedures but is accompanied by relatively high rates of complications like injury to nerves, injury to A2 pulley and bowstringing [17]. Open surgical release has a high success rate with few adverse events and is supposed to be the final treatment for trigger fingers [18,19]. We here present a case of trigger finger which has unique presentation but is successfully treated with open release.

Case Report

Figure 1: Release of A1 pulley of right thumb.

Figure 2: Release of A1 pulley of right thumb.

An 80 years old male patient presented to our OPD with triggering of both thumbs and middle finger of left hand. The patient had no co morbidities like diabetes, hypertension, or hypothyroidism and hence was advised percutaneous steroid injections along with analgesics and relative splinting. 2 weeks after the injection he was relieved of his symptoms in left thumb and middle finger but right thumb was still affected. The patient was advised 2nd dose of subcutaneous steroid injection along the flexor tendon sheath and A1 pulley of right thumb but his symptoms still persisted. As the patient was still reluctant to undergo surgical release he was offered splinting and relative rest to the thumb. After 2 months of initial presentation he again present to our OPD with triggering and pain at A1 pulleys of all fingers in right hand and remaining 3 fingers in the left hand. He was finally operated with release of A1 pulley of all fingers in right hand and steroid injections in left hand. After 3 months of surgery the patient was doing well with good finger grip and no pain or restriction of movements. The operative pictures and surgical approach has been shown in (Figures 1 & 2).

Discussion

The present case is unique in itself with only one case reported till date as triggering of 10 fingers [20]. Although the presentation was gradual and the treatment was staged with physiotherapy, steroid injection and finally with surgical open release but eventually all the fingers were involved in a period of 3 months and they needed some form of intervention. Two out of three fingers which were initially treated by steroid injections were cured with no symptoms after 3 months of presentation. This result is similar to the published data about the efficacy of steroid injections in treatment of trigger fingers [9-11]. Patients who have recurrence or treatment failure with steroid injections are usually seen to opt for surgery in the first place, if other fingers are involved. Similar is the situation in our case where the patient opted for surgical release when remaining fingers were involved.

Trezies et al. investigated the occupational histories of 178 patients with idiopathic trigger fingers and they demonstrated no significant difference between the occupational distribution of patients with trigger digits and that of the general population [21]. They concluded that occupation may have a role to play in triggering of digits but many patients develop trigger for reasons other than occupation. Weilby concluded that anatomic and intrinsic factors, contribute to a predisposition for the development of tendon entrapment of the hand [22]. Our patient was a male who did not have any predisposing factors such as thyroid disease, diabetes, renal disease, connective tissue disorders, gout or rheumatoid arthritis. The unusual presentation of this patient at the age of 80 years with no positive family history and with no occupational predisposition for trigger finger makes this case unique in itself.

Conclusion

Trigger finger is a condition characterized by fibrocartilagenous metaplasia and hypertrophy of the surrounding structures of the flexor tendon resulting in a painful and debilitating restriction of motion. Flexor tendinopathy could be multi-factorial including anatomical variations of the pulley system and biomechanical etiologies. This could be exposure to shear forces and unaccustomed activity. Conventional treatment aims at decreasing inflammation through corticosteroid injection or surgically removing imposing tissue. Steroids although serve as a non surgical means to relieve the patient of symptoms, but have a limited role in multiple trigger digits presenting at one setting.

For More Articles: Biomedical Journal Impact Factor : https://biomedres.us