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Examination on Refurbishing the Design of Mechanical Products Such as Enclosure System in the Refrigerator Fabricated on Quantum-Dispatched Life-Stress Model and Sample Size
Introduction
The system performed by machine conveys (built) power to hold a planned effect which demands forces & motion, acquiring mechanical advantages through fairly completing some mechanisms. For instance, by accomplishing the vapor-compression refrigerating cycle, refrigerator lets cooled air from heat exchanger to freezer & refrigerator section. So, reserved foods in the refrigerator can be kept for some perioded time under the happenings really deployed by the end-user. That is, if there are constructional defects on the structure, it will not quickly function within its presumed lifetime (Figure 1). As unexpectedly observing it by some tests in the laboratory, an engineer shall conceive it by the most satisfactory method [1]. It keeps:
1) ALT program, 2) Load inquiry, 3) ALTs with diverse improvements, and 4) Judgment if system achieves the objective BX life. For a demonstration inquiry, the mechanical product such as enclosure system in the refrigerator will be studied.
Figure 1
Parametric ALT in Product Performed by Machine
Replying on the time independent Schrodinger’s equation shall be stated:
Linear transport can be stated:
For a certain happening in the semi-conduct, solid-state diffusion may be abbreviated
As junction function in Equation (3) sets the reverse, the lifestress (LS) protype can be expressed:
To stretch out the acceleration factor, signified by the association between the upraised stress and routine stress, AF can be expressed:
To secure the allotted time for objective lifetime – B1 lifetime of ten years, sample size coalesced with Equation (6) shall be expressed [2]:
Case Study
Enhancing the design life of cooling enclosure in the household refrigerator pitted in the market. As the maximum amount contained in the refrigerator, end-user wants to utilize the refrigerator to keep the reserved food fresh. To satisfy these suppositions, the enclosure system in a household refrigerator is invented to clasp the absolutely necessary food over forecasted customer circumstances in its system life. The main components in the cooling enclosure comprises of the following:
Because refrigerators cost-downed are required in the market, the newly devised aluminum (1070 Al) tubing in the enclosure was embraced and redevised from the earliest copper tubing (Figure 2). From the market, as corrosive load is repeatedly exposed, some components in the cooling enclosure had been pitting because of not revealed system defects. As an outcome, customer appeals the troublesome product to replace it. To function it for expected lifetime, the design defects of cooling enclosure in the refrigerator might be recognized and altered by parametric ALT (Figure 3). The parts of the enclosure for Aquarius pitting/crevice corrosion cover a cathode, anode, water solution (hydrolysis), and conductor (metal). That is, they are as follows:
(1) As straightly attacked by chloride of the cotton tape, Cl− on the tube, passive film breakdowns, (2) At the evaporator temperature, water condensation on the tube,
Figure 3
Figure 4
The hydrolysis reaction in the pitted crevice of aluminum metal may be expressed as:
For the refrigerator, the usual ranges of conditions range from 0–50 oC ambient temperture, 0–85% humidity and 0.2–0.24 G vibration. The life target for a compressor in the refrigerator is set to be B1 life of ten years. The compressor functions on daily on/off cycles of between 22 and 98. With system life cycles of ten years, LB, the compressor is anticipated to experience up to 357,700 use time. To rapidly replicate the pitting corrosion on the tubing, the concentration of chlorine was increased, compared with 0.35% chlorine concentration because the saline water solution. The time-to-failure cycles for pitting corrosion were raised at a stress level of 3.5% saline solution (concentration load of chlorine for ALT). For an cumulative factor, λ, of 2, AF could be computed to have 100.0 from Equation (10). To fulfil the lifetime objective – B1 life of ten years, if the shape parameter, β, was presumed to be 2.0, the mission time for eighteen samples determined from Equation (7) were 8,500 cycles. As a consequence, the annoying design of enclosure can be replicated and adjusted.
Results and Conclusion
In first ALT, the refrigerators put in the 3.5% saline solution were fitted at 1130 cycles (one), 1160 cycles (two), 1680 cycles (four) (Figure 5). As the troublesome enclosure from the first ALT and the market were carefully inquired, there carefully inquired, there were constructional flaws — no contraction tube which can be protected from the chloride attack. That is, the evaporator tubing could directly contact with the cotton adhesive tape which contained chloride in polyvinyl chloride (PVC) coating. To stop the pitting of enclosure in the refrigerator, designs were modified: enlarging the length of contraction tube with a non-metallic coating that can protect the direct chloride attack, C1, from 50 mm to 200 mm; (2) altering the tape, C2, from cotton to polyethylene; (3) attaching polyethylene foam pads that can prevent galvanic corrosion, C3 (Figure 6). In 2nd ALT, because of no concerns till 4,700 cycles, the enclosure in the household refrigerator can fulfil the aimed lifetime – B1 lifetime of ten years.
A Small WIN: A Case Review on Amniotic Grafting for Wound Healing
Introduction
Wound healing is a complex process influenced by various factors, including patient-specific conditions and wound etiology. Chronic wounds, such as diabetic foot ulcers, venous leg ulcers, and post-MOHS surgery wounds, pose significant challenges to patients’ quality of life and healthcare systems. In recent years, amniotic grafts have emerged as a promising therapeutic option due to their unique properties and potential to enhance wound healing.
Human Amniotic Membrane Allografts (HAMA)
The human amniotic membrane, derived from the placenta, possesses several remarkable qualities that make it an attractive wound healing material. These include:
1) Rich Milieu of Bioactive Factors: The amniotic membrane contains amino acids, growth factors, and other nutrients essential for tissue repair. These components facilitate its intrauterine function and contribute to its healing properties [1].
2) Cell Migration and Repair: Human Amniotic Allograft Membrane (HAMA) supports wound healing by promoting cell migration and tissue repair. It acts as a scaffold, facilitating the regeneration of damaged tissues [1].
3) The Acesso Biologics product line encompasses single-layer, double-layer, and triple-layer allografts. These allografts consist of dehydrated, terminally irradiated membranes and are available in various configurations and sizes, catering to diverse physician preferences. Notably, the product line includes NeoStim TL (Triple Layer)
4) In this specific utilization case study, the triple-layer HAMA (regulated under Section 361 of the Public Health Service Act) was employed. This particular allograft is intended for homologous use.
Diabetic Foot Ulcers
Diabetic foot ulcers are a common complication in individuals with diabetes. HAMA has been studied extensively in this context. Here are key findings:
• Clinical Studies: Randomized controlled trials (RCTs) and observational studies have evaluated HAMA’s effectiveness in diabetic foot ulcer treatment. Most RCTs reported significantly higher wound closure rates compared to conventional treatments. Additionally, large chronic ulcers resistant to standard therapy achieved closure with amniotic membrane allografts [1].
• Reduction in Healing Time: Despite study heterogeneity, current evidence suggests that amniotic membrane allografts reduce healing time compared to conventional methods [1].
Venous Insufficiency
Venous leg ulcers (VLUs) are a common manifestation of venous insufficiency. Recent clinical data highlights the efficacy of dehydrated human amnion/chorion allografts (dHACA) in treating diabetic wounds. These grafts contain endogenous growth factors that facilitate wound healing. In a prospective, multi-center trial, dHACA demonstrated superior healing rates compared to other bioengineered skin substitutes [2,3].
MOHS Surgery Treatment
MOHS surgery, commonly used for skin cancer removal, often leaves sizable wounds. Amniotic grafts have shown promise in this context:
• Wound Closure: Studies employing different preparation methods of amniotic membranes have reported successful wound closure in MOHS surgery patients. The unique properties of HAMA contribute to tissue regeneration and expedited healing [1].
Summary
Amniotic grafting represents a valuable addition to wound healing strategies. While further research is needed to standardize protocols and assess long-term outcomes, current evidence supports its use in diabetic foot ulcers, venous insufficiency, and MOHS surgery treatment. Clinicians should consider individual patient factors and tailor treatment plans accordingly. In summary, the amniotic membrane’s regenerative potential holds great promise for improving wound healing outcomes across diverse patient populations.
Case Review
55-year-old diabetic patient with primary complain of ulcer on the right foot. Past medical history includes diabetes and high blood pressure. For appropriation of this comparison we are reviewing the treatment of two Right Foot DFU on the same patient; first wound treated with standard of care and the second wound treated with a triple layer allograft from Acesso Biologics a human amniotic membrane allograft (HAMA) (Figures 1-3) (Tables 1 & 2).
Figure 1
Figure 2
Figure 3
Table 1:
Table 2:
Note: **Pt feels “good” and not available for follow up.
Conclusion
In this study, we compared conservative treatment with the established standard of care (SOC) for both wounds. Our focus was on treatment efficacy and patient response, particularly considering the psychosocial aspects. For wound #1, during the period from Week 15 to Week 22 (8 weeks of SOC therapy), there were no missed events, and wound closure was achieved. This was in contrast to the initial 6 weeks (Week 1 to Week 6), which involved two consecutive weeks of advanced treatment followed by one SOC session to achieve closure. Since both wounds were located on the patient’s right foot and successfully closed, we must also consider the patient’s overall well-being. Notably, the patient healed in half the time when comparing SOC to TL HAMA treatment. Despite multiple breaks in treatment, wound closure was still achieved. In modern medicine, recognizing the importance of a “happy patient” as a crucial component of health management is essential. If HAMA treatments can be more actively utilized, we can anticipate shorter therapy durations and, most importantly, improved patient satisfaction. However, further research is necessary to validate these healing rates and document any psychosocial changes resulting from expedited treatment methodologies. As poet Amanda Gorman aptly puts it, “We are moving in the right direction.”
Epidemiology, Phylogeny and Drug Resistance Against Human Immuno-Deficiency Virus in Pakistan
Introduction
The virus known as human immunodeficiency virus (HIV) targets immune system cells, increasing a person’s susceptibility tovarious maladies and diseases. (MEHMOOD, et al. [1,2]) The human immunodeficiency virus (HIV) is a member of the retroviral family Orthoretrovirinae and belongs to the genus Lentivirus. (Mozhi [3]). HIV is divided into types 1 and 2 according to genetic attributes and variations in the viral proteins (HIV-1, HIV-2). HIV-1 is divided into three classes: group M (main), group O (outlier), and group N. (Dubey [4]) The far more varied group, Group M, is made up of nine subtypes (A-D, F-H, J, and K) and many circulating recombinant forms (CRFs) (He, et al. [5,6]). The prevalence of the subtypes geographically and demographically is varied, including one or more variants dominate infection in certain geographical regions; for instance, subtype C predominates in Southern and Eastern Africa, as well as China. (Daw, et al. [7,8]. The incidence of non-B subtypes and infection is expected to rise in the industrialized western world, along with the US, because of increased rates of mobility and interaction with people from non-B endemic areas. (Stella [9]) Regarding this tendency, most research-based efforts have been focused on the geographically prevalent subtype B in North America and Europe. (SS Wang, et al. [10]). According to recent studies, subtypes C and A together account for more than 70% of all new infections, whereas HIV-1 subtype B only accounts for 12% of the approximated 40 million HIV-infected people globally. (Yuan, et al. [11]).
The prevalence and epidemiology of HIV in Pakistan, when compared to other nations in the region, is comparatively low. According to the Joint United Nations Program on HIV/AIDS (UNAIDS), the approximated number of HIV-positive individuals in Pakistan is 150,000 as of 2019, representing around 0.1% of the population. (Paul [12]) According to estimates, 183,705 persons in Pakistan are HIV positive (PLHIV). Individuals who inject drugs (PWID), male, female, and transgender sex workers (MSW, FSW, & TGSW), men who have sex with men (MSM), and transgenders are among the primary demographics where the HIV pandemic in the nation is centered. (Anwar, et al. [13]). HIV can cause AIDS if not properly treated by sharing injecting equipment or coming into touch with certain bodily fluids of an HIV-positive person, most commonly during unprotected sexual activity. (Anwar, et al. [13]) Antiretroviral treatment (ART) advancements have led to notable successes, among them the significant reductions in morbidity and death seen in HIV-infected individuals. The virus’s main survival strategy, which derives from its enormous ability to produce variation, is antiretroviral (ARV) medication or drug resistance. (Kharsany, et al. [14,15]) An evaluation of 117 sources has provided information on the general frequency of ARV resistance in the developing world, with an emphasis on treatment-naive individuals, the effects of prevention of mother-to-child transmission (PMTCT) drug regimens on resistance, and the connection between medication adherence and resistance.
(Hamers, et al. [16]) Global treatment-naive populations’ patterns of ARV resistance seem to match regional patterns in the use of ARV drugs. The frequency of resistance (to any medicine) among people who have never had treatment was reported to be 5.5% in Africa, 7.4% in East Asia, 5.7% in Southeast Asia, and 6.4% in Latin America, lower than the rates in North America (11.4%) and Europe (10.6%). (Abubakari [17]). Pre-exposure prophylaxis, a medicine that people who are at risk for catching HIV use to prevent contracting HIV through sex or injecting drugs, is one of the efficient ways to prevent contracting HIV through sex or drug use, and post-exposure prophylaxis (PEP), a medication that HIV-positive patients must take within 72 hours of an increased risk to cease the virus from taking hold. Learn more about additional HIV prevention strategies. (Auerbach, et al. [18,19]).
Materials & Methods
Statement
No cross-sectional survey of HIV-1 has been done to date to provide a true depiction of the epidemiology in the nation especially targeting Punjab because it is needed to develop better public health policies related to the prevention and therapies, despite the fact that it may seem exhausting to invest in a disease that typically presents its fate, improperly tapping into the source of the disease can lead to its spread to high-risk groups. Additionally, it is necessary to alleviate the disease’s morbidities, and genotyping can show which principal vector the virus used to propagate.
Ethics Statement
Study Group: 40 specimens in total were included in the research to conduct the whole experimentation. This number of 40 totally satisfied the calculation for the cross-sectional epidemiological study of HIV-1.
Whereas,
Z=Standard normal variate (for 5% error =1.96, (p<0.05)), p= expected proportion of population’s disease in previous research; In Pakistan for HIV-1 it’s 0.01. d= absolute error/precision.
If we put the values in the given formula with 5% error rate (p<0.05), we got 12 & we got higher number of samples than this to strengthen this study. To conduct this cross-sectional study a certain group of patients comprised in this research, All the patients were HIV-1 positive and got their treatment from the Punjab AIDS control program, inclusion criteria is simple as this study mainly focus on DRMs, so this study includes that patients of HIV-1 who were on the treatment of HIV-1. Sanger sequencing done for the identification of DRMs in HIV-1 positive samples, following steps done for this experimentation.
RNA Extraction and cDNA Synthesis
Collect the serum sample and centrifuge it to pellet the cells. The viral RNA extraction was performed by using the Qiagen viral RNA extraction kit (catalog no. 52904). After the extraction of RNA from samples cDNA synthesized with the reverse primer (D). For this experimentation many primers were used for the maximum coverage of the pol region. A list of primers was given in the given table which were used in this experimentation. For this purpose, Qiagen One step rt-PCR kit used where cDNA and desired Round 1 product is being amplified by using pair of primers forward primer (A) & reverse primer (D) 10uM/ug (Table 1).
Table 1: This Table 1 shows the primers used in this experimentation (cDNA synthesis, round 1 & 2 PCR, and cycle sequencing PCR).
Note: All these 11 primers are used to amplify the maximum region of pol region in HIV-1 which is the most vulnerable region for DRMs.
Table 1: This Table 1 shows the primers used in this experimentation (cDNA synthesis, round 1 & 2 PCR, and cycle sequencing PCR).
Note: All these 11 primers are used to amplify the maximum region of pol region in HIV-1 which is the most vulnerable region for DRMs.
Cycle Sequencing PCR
As the PCR products were purified by using HighPrep PCR clean up, These products served as the cycle sequencing PCR template (Table 2). For each PCR product a specific combination of primers was used for sequence that region. The following table shows the primers which were used to sequence that region.
Table 2:
Capillary Electrophoresis
Purified cycle sequencing product was now ready for capillary electrophoresis, where in the end extracted sequence can be seen in the form of chromatograms. 40 ul of purified product poured in the 96-well plate &sealed with septa. The plate was now ready for the 3500XL Genetic Analyzer which was used for this procedure.
Data Analysis
Sequence Editing: Sequencing files produced by 3500xl in the form of ABI files. This is the raw data which was trimmed by the Sequencher software to make a final FASTA file.
• Launch Sequencher and open the ABI files by going to File > Open > ABI File. • Select the ABI files that you want to edit and click Open. • The ABI files will be displayed in the Sequencher window. • Use the trimming and editing tools in Sequencher to remove any low-quality or incorrect bases from the sequences. You can use the Trim tool to remove bases from the ends of sequences, or the Edit tool to make changes to the sequences. • Once you have finished editing the sequences, you can export them as a consensus FASTA file by going to File > Export > Consensus FASTA. • In the Export Consensus FASTA dialog box, select the sequences that you want to include in the FASTA file, and state the output file name and location. • Click Save to export the consensus FASTA file.
DRMs can be find by submitting sequences (FASTA file) in the “Stanford University HIV Drug resistance Database” https://hivdb. stanford.edu/. Where it’s not only detects the DRMs but also characterize into its subtype & also finds the drugs that are resistance to the HIV virus.
Results
Gel Electrophoresis
For tracking the PCR progress agarose gel was made for the visualizing of amplicons through gel electrophoresis experiment. 1.5% agarose gel made for this experiment, and it run on the Voltage of 110 for 45 minutes. To judge the exact size of amplicon 100bp Ladder run as a control (Figures 1-3).
Figure 1
Figure 2
Figure 3
Sequence Alignment & Phylogenetic Tree
Sequences of additional HIV-1 subtypes were acquired in FASTA format from NCBI in order to evaluate the phylogenetic context of the sequenced samples. The additional sequences which were extracted from NCBI were: KC203330.1-KC203332.1(China), KT581450.1(- Germany), JX227940.1(Senegal), JX227940.1, KF890251.1, KF890250.1(India), MT240851.1, MT240850.1, MT223668.1, MT223667.1, MT223665.1(Pakistan), AY010480.1, FM164924.1 HIV- 1(France), L23102.1, FM164931.1(Taiwan). These all sequences include different subtypes which make a tree to validate previous study and it also strengthens this study. A rooted tree construct for this study with HBX2 as a reference sequence (Figures 4 & 5).
Figure 4
Figure 5
Detection of Drug Resistance Mutations (DRMs)
The Stanford HIV Drug Resistance Database (HIVDB) is an important tool for public health workers who are keeping track of ADR and TDR, scientists who are making new ARV drugs, and HIV care providers who are taking care of HIVDR patients. HIVDR researchers also use HIVDB to compare their findings to those of other studies and to do meta-analyses, which require data from many studies and make it possible to learn new things that can’t be learned from just one survey. To summarize the outcome in sequenced samples that makes a relation between drug resistance mutations with drugs can be seen in the gplot given below (Figures 6 & 7).
Interpretation of Above Plot
In the above plot out of 10 sequenced samples 4 samples were resistance towards the following drugs as shown in the y-axis of the graph. All the drugs are the inhibitors for reverse transcriptase region in HIV-1. Relation of each mutation with its drug described below. Sample Ids 226 and 229 are resistance to Rilpivirine (RPV) and Etravirine (ETR) also has 138A mutation inHIV-1. Sample Id 231 have resistance to Lamivudine (3TC), emtricitabine (FTC) and abacavir (ABC) also has M184V mutation in HIV-1. Sample Id 232 have resistance to Lamivudine (3TC), emtricitabine (FTC) and abacavir (ABC) also has M184V Nevirapine (NVP) and efavirenz(EFV) mutation in HIV-1.
Figure 6
Figure 7
Discussion
In this century the main problem is drug resistance in viruses. HIV known as fast evolving virus, treatment were only effective for a ew months because of drug resistance mechanism. (Bloch [20]) The Present study investigated the drug resistance against HIV-1 in pakistan. These strains might enter the population as a result of the emigration of HIV-positive people, such as labourers and sex workers, from countries including India, Iran, and Afghanistan. (Zahid [21]) The Middle East, and Africa. 2017’s analysis of the virus’s geographic distribution in Pakistan revealed that sequences entered into the database up until that point were tightly associated with sequences from Afghanistan, India, South Africa, Kenya, and Rwanda. (Zahid, et al. [21]) Our findings were in line with this, showing that sequences were grouping with nations like Yemen, South Africa, and Uganda in the Middle East, as well as with African nations like Uganda and South Africa. (Klotz [22]). However, 18.75% of the sequences are new subtypes and are grouped with Tanzania, Afghanistan, and Sweden. These connections between HIV strains that are proliferating in other nations might be the result of infected people entering and leaving Pakistan without a medical clearance or surveillance. As a result, it is necessary to update immigration regulations in order to stop future contagious spread. Drug resistance is rising along with the trend of genetic variation, and the virus is developing high-level resistance due to vulnerability to ART medications.
The RPV and ETR are non-nucleoside reverse transcriptase inhibitors (NNRTIs) that are utilised to treat HIV-1. The E138A mutation in HIV-1 is a resistance-associated mutation that can occur in the reverse transcriptase (RT) enzyme of the virus. (Himmel [23,24]) This mutation can confer resistance to NNRTIs like RPV and ETR. This means that if a person’s HIV-1 strain has the E138A mutation, it may be less susceptible to the antiviral effects of RPV and ETR, making these drugs less effective in treating the virus. 3TC, FTC and ABC are nucleoside reverse transcriptase inhibitors (NRTIs) that are utilised to treat HIV-1. The M184V mutation in HIV-1 is a resistance-associated mutation that can occur in the reverse transcriptase (RT) enzyme of the virus. (Cilento, et al. [25-27]) This mutation can confer resistance to NRTIs like 3TC, FTC and ABC, meaning that if a person’s HIV-1 strain has the M184V mutation, it may be less susceptible to the antiviral effects of these drugs, making them less effective in treating the virus. This is one of the most common mutations that happen in HIV-1 and is considered as a significant genetic marker for NRTI resistance. NVP and EFV are non-nucleoside reverse transcriptase inhibitors (NNRTIs) that are utilized to treat HIV-1. The K103N mutation in HIV- 1 is a resistance-associated mutation that can occur in the reverse transcriptase (RT) enzyme of the virus. (Huang, et al. [24,28,29]) This mutation can confer resistance to NNRTIs like NVP and EFV, meaning that if a person’s HIV-1 strain has the K103N mutation, it may be less susceptible to the antiviral effects of these drugs, making them less effective in treating the virus.
The K103N mutation is considered as among most common NNRTI resistance mutations and it is often associated with cross-resistance to other NNRTIs Drug resistance for HIV has not yet been resolved. In actuality, patients with coexisting conditions are more likely to have treatment resistance. For instance, a pregnant HIV-positive woman who lacks access to appropriate care might receive therapy with sdNVP to stop mother-to-child transmission. (Nguyen [30]) Because sdNVP use can result in NNRTI resistance, if she later receives regular medication, it could not be effective. Additionally, if she stays on the ineffective treatment and picks up more drug-resistance mutations, which can jeo pardise second-line therapies, and if she doesn’t live in a region where viral load monitoring is possible. Drugs and monitoring need to be much more widely available in order to address the issue of drug resistance.
Conclusion
These connections between HIV strains that are proliferating in other nations might be the result of infected people entering and leaving Pakistan without a medical clearance or surveillance. As a result, it is necessary to update immigration regulations in order to stop future contagious spread. Drug resistance is rising along with the trend of genetic variation, and the virus is developing high-level resistance due to vulnerability to ART medications.
Declarations
Go to
Data Availability Statement
The data generated during this study has been included in the manuscript.
Google Trends Analysis of Nigerian Public Interest in Common Health Issues
Introduction
In recent times, internet has become more accessible such that many people are obtaining information from internet sources [1]. The nature of information sourced from the internet is dependent on the nature os searches done on the search engine. Among the available search engines, Google is currently most popular. It has become an important source of information for many people [2]. Lately, researchers have been capitalizing on this trend to obtain data on topics of interest, ranging from deep learning to currency exchange rate [1], trip information and others. Similarly, the Google search has become a source of health information to lay persons and healthcare personnel alike [2]. By analysing the trend of Google search, the public interest in various medical problems can be assessed, giving valuable information for proper planning and funding allocation in healthcare [3]. Google Trends is a tool that allows users to freely access Google search data. It provides an in-depth analysis of billions of daily Google search results and provides information on geographical and temporal patterns in search volumes for user-specific terms. Recently, the analysis of Google Trends has been utilised with success in different fields relating to, which ranges from the analysis of COVID-19 to chronic health issues [4]. By comparing the search volume index (SVI), a geographical difference can be determined, making funding allocation much easier [5,6] Despite the fact that Google Trends is being utilised throughout the health-related fields, thus far there is no Google Trends analysis that investigates the Google search of common health issues in Nigeria. Based on literatures surveyed, there was no study conducted on Google Trends analysis of public interest of common health issues in Nigeria. This study aims to examine the public interest of common health issues in Nigeria, using Google search of ten major health issues as search terms.
Methods
Google Trends is a freely accessible tool that uses periodic search volume to offer information on the temporal patterns of search queries that the general population have entered into the Google search engine. For this study, monthly search volume (MSV) was used. MSV represents the total number of searches made during a given month in a particular nation using Google. Google Trends for the period of eight years which is equivalent to ninety-six months (2015-2022) for searches specifically related to ten common health issues in Nigeria. The rationale for the selection of ten common health issues was to gain a better perspective on the trending health issues inflicting Nigerians. The summation of trends in different year were compared, spatial pattern of trends was conducted, and the correlation analysis of trends were conducted using the data for each search terms. These will enhance more robust inference to be drawn. For the purpose of validating the search terms, the authors validated the search terms using Google Trends. In the situation whereby the searches generated for the search term is very low, such search term was removed. A total of ten search terms were retained from January 2015 to December 2022 and they were analysed using Google Trends. The year 2015 was chosen because it was a period when Google unveils a top search list for Nigeria [7]. In order to evaluate the trend of Google searches in Nigeria, we had extracted the score of monthly search volume for each of the selected search term. The scores were tabulated and inserted into SPSS version 23, the periodical and the aggregate scores were compared with each search terms. The search terms were summarized in Table 1 below.
Table 1: Summary of search terms.
Results
Trend in Google Search for Common Health Issues
The summary of monthly search volume of all the ten search terms from January 2015 to December 2022 is provided in Table 2. Also, the spatial pattern of searches across the entire states in Nigeria for each of the search terms are provided in (Figures 1-10)
Table 2: Summary of monthly search volume of search terms from 2015 to 2022.
Note: V = Vomit; D = Diarrhea; Ap = Abdominal pain; Hy = Hypertension; Bp = Back pain; I = Insomnia; Cp = Chest pain; Hd = Headache; Np: = Neck pain; C = Cough
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Table 3: Intercorrelation Analysis between the Entire Search Terms.
Note: **Correlation is significant at the 0.01 level (2-tailed)
Kelman and Tanis [14] found a relationship between that abdominal pain and vomiting. In addition, a strong and positive relationship between Diarrhea, Insomnia, Headache, and Back pain was found. This corroborates the findings of Hartvigsen, Hancock and Kongsted [15] which found a positive relationship between back pain, Insomnia and Headache. Furthermore, there is a strong and positive relationship between Abdominal pain, Back pain, Headache, Insomnia, and Chest pain. This agrees with the findings of Yoon, et al. [16] which found the relationship between headache, back pain and headache. It found a strong and positive relationship between Hypertension and Cough. This agrees with the findings of Rachel, et al. [17] which found a positive relationship between cough and increased risk of hypertension. Finally, there is a strong and positive relationship between Chest pain, Headache and Neck pain. This agrees with the study of Roldan [18] which found a relationship between Chest pain, Headache and Neck pain. There is a strong and positive relationship between Back pain Headache, Insomnia, Chest pain. This agrees with the study of Korabelnikova, et al. [19] which found a complex relationship between Headache and Insomnia disorders.
Discussion
As the internet has become increasingly accessible in Nigeria, people turn to the web to seek information regarding their health challenges. In this study, the increasing popularity of Google search as a tool to obtain information on common health challenges in Nigeria were captured. The values shown in Table 2 revealed the trend of search terms on Google for vomit, diarrhea, and abdominal pain, hypertension, back pain and insomnia, and chest pain, headache, neck pain, and cough between January 2015 and December, 2022. On the graph, it was shown that there were flunctuations for all the ten search terms. All the searches for the entire search terms increased between March and April 2020, and between February and March 2022. It is pertinent to note that the increase in searches for the period of March and July 2020 can be linked to the heat of COVID-19 pandemic. Given the increased worldwide media coverage of the pandemic, Starcevic, et al. [8,9] noted that it is not unexpected that Google searches related to health issues during the COVID-19 pandemic rose in March and April 2020; this is because the heat of the COVID-19 pandemic was evidenced by travel restrictions, social distancing, and economic lockdown which negatively affected human health conditions, finances and mobility.
This increasing trend is consistent with other studies in the literature [10,11]. As shown in Figure 1, the search term for “Vomit” is mostly searched on Google in Abia and Imo states. This implies that vomit is a serious health condition in Abia and Imo states such that people in the two states do consider “vomit” as a serious health issue. As shown in Figure 2, the search term for “Diarrhea” is mostly searched on Google in Niger and Eboyi states. This implies that diarrhea is a serious health issue in Niger and Eboyi states. As shown in Figure 3, the search term for “Abdominal pain” is mostly searched on Google in Plateau state. This implies that abdominal pain is usually a serious health issue in Plateau state. As shown in Figure 4, the search term for “Hypertension” is mostly searched on Google in Sokoto and Eboyi states. Unlike Table 2 which has many states that does not have representation of people Google searched for the search terms, the case of hypertension is different because it was virtually searched in most of the states in Nigeria except Zamfara, Jigawa, Kebbi, and Yobe. Aside from these four states, the search term of hypertension has representatives of Google search from the remaining states in Nigeria. As shown in 5, the search term for “Back pain” is mostly searched on Google in Plateau and Oyo states.
This implies that back pain is usually a serious health issue in Plateau and Oyo states. As shown in Figure 6, the search term for “Insomnia” is mostly searched on Google in Eboyi state. This implies that insomnia is a serious health issue in Eboyi state. As shown in Figure 7, the search term for “Chest pain” is mostly searched on Google in Ekiti and Oyo states which are situated in the southwestern part of Nigeria. This implies that chest pain is a serious health issue in Ekiti and Oyo states. As shown in Figure 8, the search term for “Headache” is mostly searched on Google in Ekiti state. This implies that headache is usually a serious health issue in Ekiti state such that people in the state do consider it as a serious health issue which demand searching Google for its nature, causes, and treatment.
As shown in Figure 9, the search term for “Neck pain” is mostly searched on Google in Oyo state, which implies that neck pain is a serious health issue in Oyo state. As shown in Figure 10, the search term for “Cough” is mostly searched on Google in Eboyi state. This implies that cough is usually a serious health issue in Eboyi state. Based on the intercorrelation analysis shown in Table 3, all the variables were significant at p-values less than 0.01 and correlated between 0.299 and 0.943, except Chest pain and Hypertension. From the analysis, Vomit is correlated with Headache (r = 0.812), Back pain (r = 0.810), and Insomnia (r = 0.807). Diarrhea is correlated with Insomnia (0.787), Headache (r = 0.774), and Back pain (r = 0.774). Abdominal pain is correlated with Back pain (r = 0.886), Headache (r = 0.884), Insomnia (r = 0.863), and Chest pain (r = 0.850). Hypertension is correlated with Cough (r = 0.514). Back pain is correlated with Headache (r = 0.943), Chest pain (r = 0.927), and Insomnia (r = 0.923). Insomnia is correlated with Headache (r = 0.922) and Chest pain (r = 0.858). Chest pain is correlated with Headache (r = 0.925) and Neck pain (r = 0.813). Headache is correlated with Neck pain (r = 0.798). This study found strong and positive relationship between Vomit and Headache, Back pain and Insomnia. This corroborates the findings of Mainyar, et al. [12] which found a relationship between Vomit and Headache. Sheena, et al. [13] found a relationship between abdominal pain and headache.
Conclusions and Recommendations
It is concluded from the findings that the entire search terms increased between March and April 2020, which can be linked to the heat of COVID-19 pandemic that was evidenced by travel restrictions, social distancing, and economic lockdown which negatively affected human health conditions, finances and mobility. Furthermore, based on the spatial data, it is pertinent to note that pivot programmes and health initiatives to address specific health challenges in Nigeria are usually carried in Lagos which has the population and cultural strengths, and Abuja which is the seat of federal power; however, there is need to include more states that has major hit of specific health issues. Such as Abie and Imo states for vomit, Niger and Eboyi states for diarrhea, Plateau state for abdominal pain, Sokoto and Eboyi states for hypertension, Plateau and Oyo states for back pain, Eboyi state for insomnia, cough, Ekiti and Oyo states for chest pain, and Oyo state for neck pain, and Ekiti state for head ache.
Modern Process of Social Adaptation and Integration of Women Athletes in Public Life
Introduction
The conditions of modern society provide women with enormous opportunities for sports self-realization. The feminization of sports, as an objective social phenomenon, is spreading not only in our country, but throughout the whole world. Women are mastering traditionally male sports. The reasons for this are: changes in the socio-economic role of women in society, the general process of feminization of all aspects of social life. Today, women do not want to concede to men in anything: it is not surprising to see a woman leader in all high-ranking positions in various fields of science, culture, education, economics, politics, business, not to mention sports. This position of a woman in society places corresponding demands on her personal qualities and, importantly, on her external and internal form. This implies a healthy lifestyle, a high level of performance, both mental and physical, strengthening, preserving and maintaining a woman’s health, her spiritual and moral standards. However, it is not only the position in society that forces a woman to be active and healthy. We must not forget that regardless of the functions performed by a woman in the social environment, she performs one of the most important missions for the human race – the childbearing/reproductive one. This classifies the female half of humanity as a certain group of people who, in addition to being aware of their expressed gender identity, understand their significance and necessity. This process contributes to the formation of a woman’s social and group identity (the individual’s entry into various communities and awareness of unity with the group environment: [1,2]). This way, an important factor in a woman’s social viability is health, not only bodily, physical, but, importantly, mental, psychosocial well-being, determined by the adaptation and integration of the individual in the modern medium.
The Purpose of the Study
Is to identify factors of psychosocial maladaptation of female athletes in order to establish the conditions for their habilitation.
Research Results and Discussions
However, the rapid pace of technogenic transformation of the biosphere and disruption of the body’s adaptation against the background of a catastrophic decline in overall health lead to ecological- generative dissonance [3]. In this case, first of all, adaptation mechanisms that can protect reproductive function are damaged. It is known that the main feature of adaptation in sports, unlike many other areas of human activity, is the multi-stage nature of adaptation to extreme conditions: each subsequent stage of many years of improvement, each competition requires another adaptation leap from the athlete. All this predetermines special requirements for the phenogenetic characteristics of the body, and therefore women’s sports and increasing physical activity can be considered as one of the factors influencing the surrounding eco-social environment on health in general and on reproductive function in particular. The mechanisms of suppression of the function of the reproductive system during high physical activity include the following processes: weight loss and energy deficiency. Poor nutrition leads to a decrease in body weight and, more importantly, the percentage of fatty tissue in the body. This, in turn, leads to a decrease in the activity of the process of extragonadal aromatization of androgens into estrogens, as a result of which feedback with the hypothalamus and/or pituitary gland is being disrupted [4,5].
Another negative factor associated with intense training, competitions, eating disorders (anorexia – dietary restriction as part of an inferiority complex in relation to one’s appearance; and bulimia – a neuropsychic desire to constantly eat and chew: [6]) is represented by. The psychological stress, which may be one of the reasons that can cause amenorrhea (lack of menstrual bleeding: [7]). The negative impact of excessively intense physical activity on the development of the reproductive function of female athletes in the future can lead to disturbances in the neuroendocrine regulation of the reproductive system [8]. In this case, a special place in the pathogenesis of reproductive dysfunction is given to hyperandrogenism. According to many authors [9] etc, it is the increased level of androgens that causes masculinization, represented by:
• Athletic (male or intersex) morphotype, characterized by tall stature, narrowed pelvis and broad shoulders/ • Hypoplasia of the mammary gland and uterus; • A rough voice; • External masculine appearance.
The athletic morphotype in the subpopulation of female athletes is registered in around 66-84.7% of cases, and among highly qualified female athletes – in 70-90%. In turn, insufficiency of ovarian function causes various disorders of the menstrual cycle and infertility, as well as systemic consequences for the body, playing a significant role in the development of osteoporosis and oncological diseases of the female reproductive system [10].
All of the above mentioned often meets with a disapproving reaction associated with the possible negative consequences of professional sports: a negative impact on the female body, reproductive function, the impact of competition on the psyche, on the ability to create a normal family. That is why the issues of socialization, social adaptation of a female athlete, the development of her normal family life, and the formation of her gender-role behaviour are especially acute today. This is especially true for female athletes who have achieved great success in their sports careers. They are the most vulnerable category of athletes, spoiled by fame, recognition and material reinforcement.
Oblivion, if we keep in mind the short memory of fans, admirers, supporters, can still be experienced. It is more difficult to endure the transition from glory to infamy, from the ranks of celestial beings to the class of mere mortals, from dazzling, healthy youth to frail old age. Not everyone is able to afford a new life, the life after fame. Someone drowns the grief and misunderstanding of others in wine, others suffer while receiving meager disability and old-age pensions. And the more a professional athlete was once favoured, the louder his name was, the bitterer his resentment, the more hopeless his subsequent path in life, when he is already forgotten and no one needs him. There is a certain pattern/conditionality in the fact that athletes who have not achieved significant results are quite successful in realizing themselves as coaches and judges. The process of social adaptation occurs smoothly for them, without any stressful deviations. Athletes who, in parallel with active participation in competitions, received an education at a university, also did not suffer any inconvenience in the social world, since they prudently took care of their future. Many of them could continue their sports careers in veteran teams, which again softened their exit from the world of sports.
The above mentioned can apply to both male and female athletes. However, there are some features of adaptation of a female athlete in modern society. As studies show [11,12], primary socialization carried out by the family is of decisive importance for the upbringing of a girl athlete. The source of influence is the family’s personal interest in their child’s successful sports activities. Primary socialization contributes to the process of personality development of a girl athlete and gives it a different direction. The child forms his personal “I” through the perception of culture and communication with his family/relatives. The family functions as a link between the child and other systems around him; it helps both the perception of the world in general and the building of relationships in a school or team. In the family, the type of structure for the future behaviour, character, and integration of the girl athlete into her own life, this way, is laid down. However, the sports career of a young female athlete does not always develop successfully and is often very short-lived depending on the type of sport and early specialization, often even in older preschool age (swimming, figure skating, artistic and rhythmic gymnastics, diving). On average, the duration of a sports career is around 10.5 years [13]. Longer sports careers can be observed among athletes, skiers, sports players, and also wrestlers. Conducted sociological studies [12,14] have identified a number of reasons why female athletes leave sports early. It can be the following: injuries, age, health status, mental fatigue, sports failures, inability to withstand high sports loads, disappointment in sports activities, a desire to try oneself in another activity, including getting an education, getting married, etc.
As practice shows, it is very difficult for female athletes, who already in childhood learned the joy of great sports victories, to adapt to social life. A significant role in psychosocial maladjustment is played by the life characteristics of a female athlete in her microsociety, focused exclusively on elite sports. At the same time, a significant part of female athletes begins to engage in sports so that they could to achieve high athletic results. Sports failures in some cases are caused by psychosocial dissonance, the development of mental maladjustment, which ultimately leads to general psychophysical disorders/ maladaptation [15]. There is an assumption that playing sports influences the formation of such character traits in female athletes as aggressiveness and cruelty, due to the fact that competitive activity provokes those involved in the manifestation of negative character traits. However, in the course of sociological research conducted by L.I. Lubysheva [12], 45% of the respondents denied the presence of such traits. At the same time, 5% of the female athletes surveyed claim that sports activity contributed to the development of aggressiveness in them, and 7.8% talk about the appearance of cruelty in their behaviours and also associate this with playing sports. At the same time, most women note the positive impact of sports on the formation of their character. Sports, according to the athletes, contributed to the development of communication skills, the formation of determination, concentration and discipline.
In the mentioned studies, special attention was paid to one of the character traits of female athletes – the desire for leadership, since, as practice shows, this quality has a negative impact on the strength of the family life of an athlete. The majority of respondents claim that it was sports activity that shaped their desire for leadership. At the same time, only half of the respondents wanted to be a leader in family life; the other half would not want to occupy a leading position in the family. The same leadership trend already can be observed in the families of married female athletes.
Any study of the female contingent always presupposes their self-assessment of their external and internal state. In this regard, as part of a questionnaire survey [12], the opinions of female athletes about the influence of sports on their appearance and femininity were analysed. Figure 1 shows the self-assessment of female athletes about the influence of sports on their appearance. The majority of women surveyed note the positive impact of sports on their appearance (63.8%). They say they are slimmer and look great. However, sports can also negatively affect the appearance of an athlete, as evidenced by 14.2% of respondents who claim that their weight has become higher than normal due to sports activities. This is especially true for basketball players, swimmers and speed skaters.
Figure 1
To analyse the athletes’ self-esteem of their femininity, a preliminary study was conducted on what they consider to be indicators of femininity (Figure 2). From Figure 2 it can be observed that the concept of femininity for female athletes is associated, first of all, with friendliness and politeness (62.1%), pleasant body shape comes in second place (47.2%), sexuality takes third place (44.0%) and in fourth place – a beautiful gait (42.2%). At the same time, 66.0% of the surveyed athletes were satisfied with their femininity; a third of them believe that their femininity needs correction; and only 3.5% of respondents are convinced that they do not possess such a quality as femininity. At the same time, according to the results of correlation analysis, self-esteem of femininity is closely interconnected with the indicator of self-esteem of one’s attractiveness: 87.2% of the female athletes surveyed claim that men like them, a very small part of respondents (0.7%) answered that they rather dislike than like, 11% of respondents found it difficult to answer this question. Summarizing the above analysis of self-esteem of appearance and attractiveness, it can be affirmed that female athletes rate their femininity and attractiveness quite highly. They do not show any complexes about their height or excess weight and believe that it is sports that help them look good. They believe that they are in no way inferior to their peers in attractiveness, that men like them, and, therefore, playing sports can only contributes to the structure of their female destiny.
Figure 2
Most often, problems for female athletes arise at the moment when they leave big-time sports, because the issues of readaptation and resocialization, adaptation to new living conditions become acute. The results of medical and social studies conducted with former athletes show that their personal lives and the implementation of their reproductive program are less successful than those of women who did not engage in sports. Female athletes have many health problems associated with suffering injuries, osteoporosis, which in particularly advanced cases can make a young woman disabled; they are more likely to suffer from endometriosis (invasion of the mucous membrane of the uterine body/endometrium into various tissues and organs: the muscles of the uterus, ovaries, lungs, brain, etc., which leads to pain during menstruation, menorrhagia – increased and prolonged menstrual bleeding); they have an increased incidence of pathological menopause and severe menopausal syndrome [16].
If leaving sports in men is more often associated with objective circumstances (decrease in results, lack of prospects, injuries, incompatibility with a coach or partner), then the reasons for women are the desire to have a family, friends, profession, entertainment, that is, the emergence of other interests. This process is preceded by a socalled “transition period”, which can last several years. About a third of male athletes experience some discomfort about this: on the one hand, athletes do not want to part with their usual way of life, with everyone’s attention, with material incentives; on the other hand, a new field of activity either frightens them or seems less attractive, grey, and mundane compared to sports activities that are rich in emotions. The athlete finds himself in a kind of information vacuum, which can lead to isolation, irritability, and aggressiveness. This determines for most athletes the desire to remain in the field of sports, the world of which allows them to feel comfortable, and also to use the accumulated experience of a sports career in their future activities. The profession of trainer is mainly chosen (38.7% of respondents: according to [12]; see Figure 3). According to the study, 17.4% would choose the profession of a physical education instructor, 16.3% – an organizer of physical education and sports work. Only 4.6% of the surveyed athletes associate their professional interests with the profession of physical education teachers.
Figure 3
However, female athletes, in comparison with male athletes, realize themselves more successfully in professional activities, especially in modern conditions that require determination, perseverance in achieving goals, and high performance. “It is much easier for women than for men to translate the mental experiences into the physical ones” [[17], p.251]. Among women who were involved in professional sports, there are many successful managers, which is confirmed by sociological research data, where 20.2% of respondents stated that they want to become a manager (Figure 3). Today we can observe a lot of women leaders, both in sports as well in business.
Therefore, the above mentioned allows us to summarize what has been said and determine that a significant role in psychosocial maladaptation is played by the features of the life of a female athlete in her microsociety, focused exclusively on elite sports, namely:
• A sharp rejuvenation of women’s sports (most female athletes begin to engage in sports in childhood, before the age of 10). • Emancipation of sports, the development by female athletes of non-traditional, new and purely “male” sports, which is associated with the general trend of feminization of society; • The confidence of female athletes regarding the positive impact of sports on their health, appearance, attractiveness and femininity; • Value attitudes of female athletes to sports activities, which are manifested in the awareness of its high importance for the formation of character: sociability, determination, concentration in some cases, sport can also develop negative character traits in women – aggressiveness and cruelty; • The leading motivation of female athletes is determined by their desire to improve their health and find themselves in a new social circle.
This, in turn, puts forward a number of provisions providing for the improvement of the system of sports competitions, softening the conditions of wrestling, it is necessary to develop special rules for competitions, humanize women’s sports, protect women, taking into account the special biosocial role that she plays in society. At the same time, the task of sports medicine doctors is to ensure that, within the framework of the slogan “Sports achievements!” to be on the side of the girl not as a mechanism for setting records, but as a woman – a future mother, since health should always and everywhere occupy a prevailing position [18]. Here it is also necessary to take into account conflicts that arise between the trainer and the sports doctor. In this case, only a clear understanding of the doctor about the possible negative consequences of adaptation disorders and his stable professional and public position on protecting the health and the woman’s fulfilment of her main sociobiological role will make it possible to defeat common sense and save the female athlete for motherhood.
Conclusion
Summarizing the above, it should be noted that a comprehensive adaptive approach to the problem of a female athlete involving the entire arsenal of pedagogical, psychological, sociological and medical measures is the only correct one in achieving the highest goal of society: preserving the gene pool, harmonizing the personal and social life of a woman, and therefore a harmonious development of society.
Polymeric Network of Amines, Chemical Modifications, Conformational Analysis of Nanoparticle Interaction, and Orientation of DNA
Opinion
Nanostructures are used as biomarkers, therapeutics, catalysts, and structural reinforcements. They have a wide range of chemical characteristics. It has a long history and is essential to include specific functionality when using surfactants to embellish. Here, a broad range of surface-active substances, including surface-active chemicals, polymers, standard alkyl modifiers, and biological ligands, are referred to as “surfactants.” This opinion provides a thorough analysis of the covalent and non-covalent interactions of these surfactants with several types of nanomaterials, including layered materials, metals, polymers, and oxides. [1] The degree of surface regularity and defects in the nanoparticle cores and the surfactant shell, as well as surface energy, pH sensitivity, and surface chemistry, are significant factors that contribute to differentiation. The authors discuss a wide range of surface modification sensors, applications in biological recognition and therapeutics, nanomaterials for catalysis, energy storage, and conversion, the dispersion properties of nanoparticles in structural composites and cement, and traditional detergents. [2] Design guidelines for surfactants are presented in order to enhance the functionality of certain nanostructures.
In the field of nanoscale architecture, a notable phenomenon that occurs in topologically preset superstructures is the interaction and orientation of the polymeric network of amines on the surface of colloids. The completion of such techniques requires a general change in manufacturing practices towards biological systems, which is accomplished via physical and chemical stereochemical manipulation. Through the amino groups on their surfaces, the amino groups of a polymeric network of amines assist with nanoparticle surfaces (Figure 1). This interaction event also entails a modification in the protonation state that forms at the end of the functional group (amino or amine) and enhances the length of the sequence of the molecule. Designing, assembling, and using DNA for biological purposes has a lot of potential if we understand how DNA interacts with nanoparticles. [3] There has been an increase in knowledge and use of the processes behind the DNA-nanoparticle interfacial phenomenon. Despite the reporting of some prior reviews, systematic and comprehensive reviews are uncommon. Here, we have summarized the most recent developments in the fundamental theories relating to DNA-nanoparticle interactions and their applications in biosensing in order to gain a better understanding of the processes involved in the interaction between DNA and nanoparticles [4].
Figure 1
Inorganic nanoparticles such as metal nanoparticles, carbon- based compounds, metal oxides, and quantum dots received particular attention. The surface characteristics, interacting processes, kinetics, and spatial control of DNA adsorption for each material were listed and addressed. We also highlighted a few of the most modern biomolecule detection systems based on DNA-NP interactions. Finally, the difficulties and suggested directions for the future were discussed. The comprehensive knowledge of the mechanics behind DNA-nanoparticle interactions provided by this research may provide fresh ideas for creating biosensors with enhanced capabilities. [5] Off-lattice Monte Carlo simulations are used to examine the interfacial characteristics of polymer chains on spherical nanoparticles. Results reveal that as the polymer-nanoparticle interaction strength increases, the number of adsorbed monomers grows while the number of adsorbed polymers drops. The chain length and nanoparticle size have no effect on the interfacial layer thickness. Three unique levels of stacking behaviour are displayed by the interfacial monomers. [6] The polymer-nanoparticle interaction intensity has a significant impact on the mobility of monomers in the topmost layer.
There is never a glassy coating around the nanoparticle because the interfacial monomers are always in motion. Finally, our findings demonstrate that while nanoparticle motion can weaken polymer adsorption, it does not affect the conformational characteristics of adsorbed polymers. Following the aforementioned information, the design of metal-based nanostructure nanoparticles that can act as carriers for cellular transfection has been a prominent objective in bioorganic and medicinal chemistry. [7] Thus, the DNA molecules function as counter ions and block the repellent interactions between positively charged Au/Ag nanoparticles, allowing them to assemble into densely packed superstructures. Enlarged structural and interaction revisions in detail can draw attention to the significance of the colloids/DNA complex. [8] Although these approaches rely on the massive electromagnetic field increase that transpires around metallic nanoparticles, primarily Ag/Au. The conformation of both macromolecules was altered, because of the two polymeric networks of amines adhering to the nanoparticles, which suggests a charge transfer effect on the surface. [9] By using DNA as a template, it is possible to construct nanoparticles with more complex geometries and get insight into the effectiveness of these particles as vectors for delivering genes and drugs [10].
In this research opinion, the primary goal of the author was to comprehend their chemical and biological efficacy during nucleic acid interactions in cellular transfection. Making high-performance polymer nanocomposites (PNCs) requires a thorough knowledge of the process through which nanoparticles (NPs) fortify polymer matrices. Here, the reinforcing impact of an NP network was specifically investigated using coarse-grained molecular dynamics simulations. According to our findings, NPs self-assembled formed a three-dimensional (3D) network that strengthened the polymer matrix when NP-NP interactions were increased. [11] In contrast to NP-polymer interactions, NP-NP interactions have a very distinct reinforcing mechanism. While the former evenly distributed the stress throughout the NP network, the latter encouraged polymer chains’ orientation in order to transfer the external stress. [12] This research disclosed the chemical mechanism by which the NP network strengthened the polymer matrix and offered directions for creating high-performance PNCs by interfacial modification. This perspective was divided into different sections, with a focus on the biophysical methods used for the synthesis and analysis of polymeric networks of amines and their interactions with metal nanoparticles employed as carriers of medicines and genes.
Introduction
In the fields of cellular transfection and medicinal chemistry, bottom- up approaches for the synthesis and depiction of various stereochemistry consisting of polymeric networks of amines play a significant role. Examining the adsorption mechanism of diverse polymeric networks of amines on Ag/Au nanoparticles has been done previously using a variety of physiochemical approaches. [13] The structure of artificial polyamine analogs and their conjugates, which serve as perfect vectors, has biological relevance in the transfection process, the development of molecular mechanisms, and therapeutic uses in a variety of biological therapies. [14] Lipopolyamines’ ability to condense DNA was originally noted more than ten years ago. Three years later, it was shown that the DNA/lipid multiplexes have been formed and employed for cellular transfection. [15] When the plasmid interacts with a polymeric network of amines, the plasmid changes structurally from an A-DNA assembly to a B-DNA structure and alters its superhelicity which results in an auxiliary linear form. [16] These molecules conflict with one another due to the high-intermolecular positive charge, which outspreads the molecules and optimizes counter-ion collapse upon interaction with polyanionic DNA because of conformational stabilization.
Nanostructures offer enormous promise for use in many industrial applications, including quantum dot lasers and biomacromolecules sensing technology. [17] One of the most intriguing study areas is the conjugation of biomacromolecules, where noble metal nanoparticles and their interactions have been studied. Most research has been done on Ag/Au nanoparticles concerning biomacromolecules conjugated to chemistry (Figure 2) [18]. These nanoparticles have also undergone additional analysis to comprehend their biochemical efficacy in gene/drug administration. [19] Understanding their fundamental function and determining their binding capacity with the target showed their utmost importance. For example, biosensors for DNA hybridization, for instance, DNA-labeled gold and CdSe nanoparticles with special colorimetric and fluorescent features, have been employed to explore the hidden clues. [20] As well, the gold nanoparticle has drawn a lot of interest. [21]
Figure 2
The utilization of DNA/Au nanoparticles was demonstrated as another alluring method for raising the sensitivity of numerous significant procedures.
For instance, Zhou, et al. [22] and Willner and coworkers [23], had developed a dendritic assembly having nanoparticles, respectively, to intensify the fragile quartz crystal microbalance extra precisely, the thickness-shear mode sensor (TSM) [24] signals in-built in a traditional assembly that can attack hybridization-based HS-ss- OSNs. [25] The electrostatic interfaces among the stimulating DNA/ vector complexes with positive charges and the glycosaminoglycans of the cell membranes that carry negative charges result in an overall, positive charge. These findings have been revealed during in vitro investigations with lipids and polymers that carry a cationic charge. [26] Nowadays, the main goal of the researchers is to discover how to demonstrate other analytical “figures of merit” including selectivity and dynamic range for Ag/Au nanoparticle conjugation in a better way. [27] Using a variety of physiochemical and spectroscopic characterization approaches, most of the researchers examine the significance and newer possibilities that influence the creation of gene-drug delivery systems. In this opinion, the author aims to build following the synthetic procedures that are now in use, with the necessary adjustments made to ensure that linear PA analogs and their conjugates are prepared properly [28].
The investigation of interfacial phenomena and the conformational alterations of PAs that hold various nanoparticles can be conducted successfully using physiochemical characterization techniques that have a wide range of analytical applications and are frequently used in vibrant fields. Despite these developments, general guidelines governing the design of synthetic vectors, as well as their design and synthesis, have not yet been fully realized. [29] The rational modulation of vector designs necessitates a more quantitative examination of the cellular uptake and intracellular processing of these vectors. More theoretically designed mathematical frameworks for PAs will make it easier to evaluate these problematic systems from an assimilated viewpoint. Chemical manipulation in stereochemistry, and conformational analysis of interaction Because of their importance in the pharmaceutical industry, safety, and accessibility in use, the synthetic vector PAs, whether in their free polycationic form or linearly conjugated to other biomacromolecules, transpire naturally and exhibit fascinating biological activities.
However, a profile of their potential benefits and drawbacks has emerged, including a description of their efficiency in some viral systems. Pour cette raison, several methods for determining their structural analysis should be used, and a greater comprehension of their mechanism of action is required to prepare a wide range of synthetic PAs analogues and conjugates. [30] Therefore, the current medical science requires modeling as a necessity that depends on the biological systems of potential gene delivery vehicles. We need to create novel polymeric networks of amines for nucleic acid delivery systems, considering all these developments in science, particularly in the field of gene-related biomacromolecules. Only these carrier systems (Figure 3) can offer the nanoparticles adequate support and keep them from aggregating. Thus, in this view, the author explores the growth of such delivery methods, which may have greater benefits. Additionally, the author emphasizes mostly simple, modifiable synthetic procedures that enable the effective manufacture of linear PA analogs and conjugates for a given purpose. The phenomenon of adsorption and conformational changes occurring on the surface of nanoparticles/ biomacromolecules is being explored. Thus, the 3D conformation of biomolecules is essential for biological features to explore the route of action and efficiency of these discussed networks. Henceforth, the aiming scheme addresses the following points:
Figure 3
A. Design, Synthesis, and Characterization of Polyamines
How will it play a major and appealing function in developing suitable gene delivery vectors as drug carriers for treating diseases? By taking this into account, the various stereochemistry of polymeric networks of amines that alter the contact and orientation capabilities of these cation/colloid complexes is proposed. This is the primary objective of this opinion. These methodologies either entail selective functionalization of the amino functionalities, the use of appropriate- guarding assemblies or acylating mediators, or protocols for fragment creation. Branched hexamines (Ia-b) [31], derivatives of polyamine (III and IVa-f) [32], and tris(2-aminoethyl)amine (IIa-b), as well as other PA analogs with their derivatives, can be studied, the elucidation and analysis of their performance can be further studied (Figure 4). To further investigate synthetic PA analogues and conjugates in the quest to produce PA-based molecules with potential pharmacological or technical applications and gene delivery vehicles, it is essential to better understand their structure and mode of action. [33] These methods will likely be widely applied soon to hasten the process of identifying the strongest synthetic PA analogs and conjugates and to make it easier to develop PA-based drugs or molecules with agrochemical or technical interest.
Figure 4
Because of this, researchers will try to have a detailed description of the structural variety as well as their synthetic analogues and the biological importance of these compounds. [34] With the effects of these factors in mind, this discussion also focuses on the physical and chemical characteristics of PAs. With the help of fragment-synthesis- related methods and selective alterations of PA’s functional groups, the PA skeleton is put together to the necessary length for nanoparticles and DNA.
On the number of differently functionalized nitrogen atoms.
1. By using relatively simple amino building blocks.
2. By using conjugates that can perform either by selecting the amino features of PAs or the assembly of the PA skeleton. Based on the above important characteristics, the author explores the importance of the polyamine network for gene-drug delivery. B. In structure–activity relationship studies of biologically active molecules bearing PAs, how does the chain also try to give an understanding of their mode of action and the development of potent analogs with important medicinal applications? The author can build the necessary and effective vector for gene/drug delivery, as well as their more practical handling, thanks to the systematic synthesis of metallic nanoparticles embedded in a polymeric network coupled to a colloidal core particle. The key goal of this study was to create such inventive drug delivery methods.
a. Preparation of gold nanoparticles [35]: Citrate solutions By creating aqueous stock solutions of the requisite percent HAu- Cl4.3H2O and required percent sodium citrate, reduced gold nanoparticles have been created. The sodium citrate solution will be added in the necessary amount after the HAuCl4.3H2O solution has been heated to a boil while being stirred. Before making wine red, the reaction mixture underwent a sequence of color changes. After the last color change, the boiling went on for another 30 minutes. The gold nanoparticle solution will be diluted to the necessary volume using DI water after cooling to room temperature. Most gold solutions’ isolated, almost spherical particles have varied sizes before salt or analysis are added.
b. Preparation of silver nanoparticles [36]: When the hydrated solution of AgNO3 is heated to its boiling point, the necessary concentration of trisodium citrate solution is added. The combination is then heated to the proper reaction temperature. This creates silver colloids. All of the solutions have been prepared using triple-distilled water. The average diameter of the silver colloids is a defining characteristic.
C. Since the release and integration of DNA by the cell depend on the polymeric network of PAs/DNA complexes adhering to a negative surface, the analysis of structural alterations caused by this adsorption is also essential in determining the efficacy of the vector. The key goal to be identified, according to the author, is to characterize the gene delivery vector to examine conformational changes that occurred because of PA adsorption on the surface of a metal. Another objective is to investigate its interaction with DNA. Because of the protonation state and how it will affect the chemical and physical features of the ethylene functional groups in the skeleton of the polymer and their function in the creation of bonds with the metal, PAs will experience significant conformational changes. [37] The charge transfer that resulted from this contact between the surface and the PA accounts for the resonance phenomenon seen with various spectral techniques. [38] How are scientists able to use various biophysical characterization techniques to show that structural alterations are obvious at various molecular levels? On the one hand, it appears that after interacting with PAs, the DNA takes on a more linear form.
Results
The current study has assessed target definition for vaginal cuff SBRT with comparative analysis of CT and MRI. Stereotactic irradiation procedures have been performed at our Radiation Oncology Department of Gulhane Medical Faculty at University of Health Sciences. Prior to vaginal cuff SBRT, all included patients have been individually evaluated by a multidisciplinary team of experts from surgical oncology, radiation oncology, and medical oncology. Critical goal of vaginal cuff SBRT planning has been to achieve optimal target coverage without violation of critical organ dose constraints. IGRT techniques such as kilovoltage cone beam CT was used, and vaginal cuff SBRT has been delivered by Synergy (Elekta, UK) LINAC. We found that CT and MRI defined target definition resulted in differences. Thus, we utilized fused CT and MRI for ground truth target volume definition for vaginal cuff SBRT.
Discussion
Endometrial cancer is a significant public health concern for women with its critical incidence around the globe [1]. Surgery, radiation therapy (RT), and systemic treatments may be used alone or in combination for management of endometrial cancer with respect to patient, disease, and treatment characteristics [2-7]. Recently, SBRT has emerged as a viable irradiation technique for management of a variety of cancers throughout the human body. Admittedly, recent years have witnessed critical advances in technology. Automatic segmentation techniques, molecular imaging methods, IGRT, IMRT, stereotactic RT, and ART techniques have been introduced for improved radiotherapeutic management of patients [8-49]. With improved stereotactic localization of well-defined targets under image guidance, SBRT offers a highly precise radiotherapeutic modality. High doses of radiation may be delivered in a single fraction or with a limited number of fractions, and highly conformal treatment with steep dose gradients around the target may allow for optimal irradiation with an acceptable toxicity profile. More recently, SBRT has been used for vaginal cuff boost as an alternative to brachytherapy [7]. The utilization of a vaginal cuff boost may be considered for patients deemed to be at a higher risk of vaginal recurrence. Cervical stromal invasion along with other factors including age, margin status, grade, extent of invasion, histology, and lower external beam RT doses may be regarded as critical issue to consider for optimal patient selection.
In the context of radiation oncology, improved target definition and critical organ sparing should be considered among the pertinent aspects of optimal stereotactic irradiation. Determination of larger target volumes may lead to radiation induced toxicity, and definition of smaller than actual target volumes may result in decreased local control of the disease. It should be mentioned that adaptive irradiation approaches and multimodality imaging-based target definition may be suggested to improve radiotherapeutic results [50-106]. The current study has assessed target definition for vaginal cuff SBRT with comparative analysis of CT and MRI. Stereotactic irradiation procedures have been performed at our Radiation Oncology Department of Gulhane Medical Faculty at the University of Health Sciences. Prior to vaginal cuff SBRT, all included patients have been individually evaluated by a multidisciplinary team of experts from surgical oncology, radiation oncology, and medical oncology. The critical goal of vaginal cuff SBRT planning has been to achieve optimal target coverage without violation of critical organ dose constraints. IGRT techniques such as kilovoltage cone beam CT were used, and vaginal cuff SBRT has been delivered by Synergy (Elekta, UK) LINAC. We found that CT and MRI defined target definition resulted in differences. Thus, we utilized fused CT and MRI for ground truth target volume definition for vaginal cuff SBRT. From a radiation oncology perspective, our results may have implications for increased adoption of multimodality imaging- based target definition for vaginal cuff SBRT, nevertheless, the need for future studies to shed light on this critical issue may not be neglected.
Figure 5
Because of the interaction with the polymer and how it relates to the poorer thermodynamic stability of the bonding section of DNA, this shift in the superhelicity of the DNA resulted in noticeable modifications in different DNAs. [39] Due to the great significance of procedures of biological importance, i.e., gene transport, the early research findings can provide very favourable and essential evidence in the elucidation of recognition complications existing between massive chains of polymers (Figure 5). By combining the necessary amount of PAs’ aqueous solution with the necessary amount of the plasmid’s aqueous solution, samples were obtained for biophysical characterization procedure measurements. The complex was stored for at least one hour before the measurement to guarantee that the DNA completely interacted with PEI and that the percentage of nitrogen/phosphorus in the chain of PAs and DNA was 9:1. Furthermore,
1. To collect samples for PAs and DNA characterization measurements, add the same amount of water as the other ingredient that was used to construct the complex. Before being included in the complex, the Ag/Au colloid had been activated [40].
2. To observe a robust characterization spectrum, this activation involved the colloid aggregation achieved by the addition of potassium nitrate solution prepared in water at the requisite concentration.
3. To get the spectra at various excitation wavelengths, the stimulated Ag/Au colloid was then mixed with the aforementioned solution of complex using glass capillaries.
Route of Investigation
Polymer networks are intricate structures made up of molecules. While most chemists have a good understanding of the properties of individual parts, the statistical and ill-defined nature of network structures makes it difficult to translate that chemical understanding into polymer networks. As a result, extrapolating from the molecular behaviour of components to the complete spectrum of performance and attributes of the entire polymer network is difficult, if not now impossible. [41] Therefore, polymer networks offer an untapped, significant, and interdisciplinary opportunity to exert chemical control at the molecular level over material macroscopic properties. [42] The fact that many scientists are typically inexperienced with the methods for characterizing the molecular structure of networks is a hurdle to advanced molecular approaches to polymer networks. In the absence of further fillers, we provide a critical evaluation of the existing characterization methods available to comprehend the relationship between molecular characteristics and the performance and behaviour of polymer networks [34].
We emphasise methods for characterizing the chemistry and molecular characteristics of individual polymer strands and junctions, the gelation process by which strands create networks, the topology of the resultant network, and the dynamics and mechanics of the finished product. Instead of acting as a comprehensive guide for carrying out these measurements, the aim is to harmonize the underlying concepts, identify unresolved issues, and offer chemists a succinct summary by which they may develop characterization procedures that are appropriate for their research goals. [43] Strategic pairings of several approaches are frequently needed for the molecular characterization of polymer networks since these networks are frequently difficult to properly characterize using a single technique. It has been investigated using biophysical characterization approaches to determine how to create an effective drug delivery system and how well it binds to biomacromolecules. On the one hand, it enables the spectroscopic spectral investigation of biomacromolecules at extremely low concentrations to investigate the physiological environment [44].
Contrarily, metals are substrates on which polymeric networks of amines are strongly attached in heterogeneous systems, such as the case of the proposed complexes, where multiple interactions are possible; as a result, the synthesis and design of novel polymeric networks of amines and their metal nanoparticles are discussed here. Structural investigations of PAs have been followed by some spectroscopic studies i.e. C, H, and N, electron impact mass spectra, 1H and 13C NMR spectra, and IR spectra. Circular dichroism (CD) spectroscopy has been used to conduct comprehensive research on the conformational properties of several optically active substances, from small molecules to natural (proteins, DNA, and RNA) or synthetically occurring macromolecules. Using biophysical characterization techniques, it has been determined that the chemical state of the discussed cationic polymers is on the ionic surfaces of cells, where equivalent adoption and contact processes may also occur. [45] Spectroscopic analysis can be performed by carefully observing the particular modifications that occur in the polymeric network of the amines and the plasmid after adsorption and complexation. When examining DNA/ nanoparticle systems, these techniques can be twice as helpful.
Different techniques, including circular dichroism, differential scanning calorimetry, potential measurements, atomic force microscopy, temperature-dependent UV, and light scattering, will be used to characterize the stability of the DNA in the cationic complexes, various altered features of the cationic complexes, conformational alterations, physical and chemical features of the cationic complexes. Isothermal titration calorimetry has been used to track the general thermodynamical characteristics of the binding event of these cationic complexes (ITC). These cationic complexes bind to DNA and strengthen the base-pair-stacking interactions, increasing the enthalpy occurring during the helix–coil transition. [46] The ability to bind is related to minor exothermic enthalpy modifications. Therefore, the binding route as a whole is entropically advantageous. A comparison of the thermodynamic parameters can help in understanding this.
Future Outlook
With the help of this scientific foundation, the fields of gene therapy and drug delivery systems have evolved quickly and are today recognized as the most promising areas of medical study. Researchers will study the biophysical characterization of novel gene delivery systems that depend on the interaction of nanoparticles and biomacromolecules with the target tissue. [47] This research, will be studied how to detect the interaction between cationic complexes using biophysical technologies, which is a significant issue connected to gene therapy. To fully realize the promise and potential of gene therapeutics, the effective and targeted delivery of therapeutic genes to a target site must be addressed. By strategically using intracellular mechanisms, it may be necessary to analyze the binding affinity of enhanced synthetic vector designs and to look into innovative avenues for overcoming challenges in the field’s actual implementation. [48] However, what scientists now require is the creation and implementation of drug delivery systems essential for the building of efficient gene therapy methods using gene-related medicinal supplies. Despite this widespread understanding, there will be a lot of pressure to develop the vector to maximize the efficiency of gene expression, but the pharmacokinetics of its use have been overlooked.
Acknowledgment
The author (Rajiv Kumar) expresses gratitude to his younger brother, Bitto, for inspiring him.
Availability of Data and Materials
Where applicable, the reference section contains pertinent citations.
Competing Interests
The author has stated that they have no conflicting interests.
Are an increasing number of individuals opting for plant-based milk alternatives like oats, soy, or almonds? And do these plant-based products provide equivalent nutritional value compared to cow milk? Certainly, this does not apply universally. In low-income countries where diets heavily rely on cereals and staples with over 75% of calories coming from staples and protein intake is insufficient, switching from cow’s milk to oat milk could be il-advised. A glass of cow’s milk might be the sole source of high-quality protein for the day. However, for many individuals plant-based milks serve as a suitable replacement, particularly benefiting those who are suffering from lactose intolerance. Indeed, it is not the sole reason for people to opt for plant derived milks over dairy milk. Authoritative bodies such as the (FDA) Food and Drug Administration, advise against consuming low-quality raw milk. Additionally, research indicates that higher consumption of saturated fats correlates with elevated cholesterol levels heightening the risk of stroke and heart diseases. Obesity indeed poses a significant risk for stroke, heart diseases and various cancers. However, if consuming a diet high in saturated fat is the only means for someone to maintain a healthy body weight it may be considered more advantageous in their particular circumstances. Nevertheless, numerous countries currently advocate for reducing saturated fat consumption, emphasizing monounsaturated fats found in foods like nuts, seeds, fish, and avocados [1]. Furthermore, the quality of raw milk directly influences the quality of dairy products.
Only raw milk of high quality produced under stringent hygiene standards can yield superior dairy products. Dairy production significantly contributes to the greenhouse gas emissions (GHG) and constitutes slightly over one quarter of the carbon footprint. Increasing awareness of this negative impact on the environment has led many individuals to explore plant-based alternatives. Surveys in the UK indicate that approximately one quarter of adults now incorporate some non-dairy milks into their diets. This trend is more pronounced among younger demographics (16- 23 years) opting for plant-based alternatives. Due to animal-based product production having a larger water footprint compared to plant-based products with equivalent nutritional value, when we analyze various environmental metrics for milk production such as use of land, GHGs, water utilization, and eutrophication intensity are estimated per liter of milk produced. Cow’s milk production exhibits considerably higher environmental impacts when compared to production of plant-based alternatives across all standard metrics. It generates approximately three times more greenhouse gases, utilizes around ten times more land and consumes two to twenty times more fresh water. Additionally, it results in significantly higher levels of eutrophication.
A diverse array of plant-based milk alternative exists, sourced from various plants. The majority of plant-based milks can be classified into five main groups derived from legumes, cereals, pseudo-cereals, nuts and seeds. Products include soya, peanuts, rice, corn, quinoa, almonds, coconut, pistachios, flax seeds and sunflower seed milk. Milk alternatives like soy, almond and others are often compared to cow’s milk due to the recognized distinction in composition between animal and plant derived foods. Plant derived proteins do not match the nutritional quality of those from animal sources. In addition to protein content significant differences exist in the natural nutrients found in cow’s milk compared to plant-based alternatives, such as vitamin B12, calcium, fiber, and fat content and concentration (vanga and Raghavan,2018). Presently according to American Dietary Guidelines fortified soy beverages are categorized in milk group due to their essential nutrients profile resembling that of cow’s milk. Similarly fortified soy milk is considered as a healthy dietary pattern because it provides numerous minerals (calcium, potassium, phosphorus, magnesium, zinc, selenium) and vitamins (A, D B12). When shopping for plant-based foods it’s crucial for consumers to check the Nutrition Facts label and opt for products high in proteins, calcium, potassium and vitamins while being low in saturated fatty acids and sugar contents. Regulations regarding the labelling of plant-based milks or beverages vary from one country to another. Currently many countries such as India and China, freely use the term dairy for plant-based beverages.
However, in the United States and the UAE the term Soya preceding milk label shows that beverage is not cow milk and is subjected to documented specific non-dairy standards. (FDA,2018). Countries like Australia and New Zealand include soya milk among legally marketed brands [2]. However, European countries do not use the term milk for plant-based alternatives and label them as drink(Soya Drink). Cow milk offers a unique combination of nutrients, including high quality proteins, minerals and vitamins which are essential for bone and muscle development and overall well-being. Additionally, cow’s milk naturally contains important fatty acids like omega-3s. Its rich taste and cream-like texture makes a versatile ingredient in different culinary creations from creamy sauces to decadent desserts. Moreover, cow’s milk has been a dietary staple for centuries providing a culturally and historically significant source of nourishment for many communities around the world [3]. The dairy industry has shown resilience and adaptability in responding to the rise of plant-based milk alternatives. Through innovation by introducing new products including lactose-free milk, fortified milk, and flavored varieties, to meet evolving consumer preferences. Additionally, partnerships with plant-based companies and investments in sustainable practices demonstrate the industry’s commitment to remaining competitive while addressing environmental concerns. This proactive approach not only ensures the longevity of traditional dairy products but also fosters greater choice and accessibility for consumers seeking dairy and plant-based options alike.
Evaluation of Multimodality Imaging Based Vaginal Cuff Boost with Stereotactic Body Radiation Therapy (SBRT) for Endometrial Cancer: An Original Article
Introduction
Endometrial cancer is a significant public health concern for women with its critical incidence around the globe [1]. Surgery, radiation therapy (RT), and systemic treatments may be used alone or in combination for management of endometrial cancer with respect to patient, disease, and treatment characteristics [2-7]. Recently, Stereotactic Body Radiation Therapy (SBRT) has emerged as a viable irradiation technique for management of a variety of cancers throughout the human body. The utilization of a vaginal cuff boost may be considered for patients deemed to be at a higher risk of vaginal recurrence. Cervical stromal invasion along with other factors including age, margin status, grade, extent of invasion, histology, and lower external beam RT doses may be regarded as critical issues to consider for optimal patient selection. Admittedly, recent years have witnessed critical advances in technology. Automatic segmentation techniques, molecular imaging methods, Image Guided RT (IGRT), Intensity Modulated RT (IMRT), stereotactic RT, and adaptive RT (ART) techniques have been introduced for improved radiotherapeutic management of patients [8-49]. With improved stereotactic localization of well-defined targets under image guidance, SBRT offers a highly precise radiotherapeutic modality. High doses of radiation may be delivered in a single fraction or with a limited number of fractions, and highly conformal treatment with steep dose gradients around the target may allow for optimal irradiation with an acceptable toxicity profile. More recently, SBRT has been used for vaginal cuff boost as an alternative to brachytherapy [7]. Herein, we assess target definition for vaginal cuff SBRT with comparative analysis of Computed Tomography (CT) and Magnetic Resonance Imaging (MRI).
Materials and Methods
Department of Radiation Oncology at University of Health Sciences serves a tertiary cancer center for patients from Turkey and abroad. By using state of the art irradiation techniques, a plethora of benign and malignant tumors are irradiated here. In the context of this study, the endpoint has been target definition for vaginal cuff SBRT with comparative analysis of CT and MRI. All included patients were referred to the Department of Radiation Oncology at Gulhane Medical Faculty, University of Health Sciences for vaginal cuff SBRT. We undertook a comparative analysis of target definition by CT simulation images for SBRT planning and with MRI. CT simulations of the patients were carried out at CT-simulator (GE Lightspeed RT, GE Healthcare, Chalfont St. Giles, UK) available at our department. Also, MRI of patients were acquired and used for comparative evaluation. The Linear Accelerator (LINAC) with the capability of sophisticated IGRT techniques has been utilized for stereotactic irradiation. After rigid patient immobilization, planning CT images were acquired at CT-simulator for vaginal cuff SBRT planning. Thereafter, acquired SBRT planning images have been transferred to the delineation workstation via the network. Target volumes and normal tissues were contoured on these images and structure sets were generated. Also, target definition has also been performed on MRI for comparison purposes. All patients underwent vaginal cuff SBRT at Department of Radiation Oncology at Gulhane Medical Faculty, University of Health Sciences.
Results
The current study has assessed target definition for vaginal cuff SBRT with comparative analysis of CT and MRI. Stereotactic irradiation procedures have been performed at our Radiation Oncology Department of Gulhane Medical Faculty at University of Health Sciences. Prior to vaginal cuff SBRT, all included patients have been individually evaluated by a multidisciplinary team of experts from surgical oncology, radiation oncology, and medical oncology. Critical goal of vaginal cuff SBRT planning has been to achieve optimal target coverage without violation of critical organ dose constraints. IGRT techniques such as kilovoltage cone beam CT was used, and vaginal cuff SBRT has been delivered by Synergy (Elekta, UK) LINAC. We found that CT and MRI defined target definition resulted in differences. Thus, we utilized fused CT and MRI for ground truth target volume definition for vaginal cuff SBRT.
Discussion
Endometrial cancer is a significant public health concern for women with its critical incidence around the globe [1]. Surgery, radiation therapy (RT), and systemic treatments may be used alone or in combination for management of endometrial cancer with respect to patient, disease, and treatment characteristics [2-7]. Recently, SBRT has emerged as a viable irradiation technique for management of a variety of cancers throughout the human body. Admittedly, recent years have witnessed critical advances in technology. Automatic segmentation techniques, molecular imaging methods, IGRT, IMRT, stereotactic RT, and ART techniques have been introduced for improved radiotherapeutic management of patients [8-49]. With improved stereotactic localization of well-defined targets under image guidance, SBRT offers a highly precise radiotherapeutic modality. High doses of radiation may be delivered in a single fraction or with a limited number of fractions, and highly conformal treatment with steep dose gradients around the target may allow for optimal irradiation with an acceptable toxicity profile. More recently, SBRT has been used for vaginal cuff boost as an alternative to brachytherapy [7]. The utilization of a vaginal cuff boost may be considered for patients deemed to be at a higher risk of vaginal recurrence. Cervical stromal invasion along with other factors including age, margin status, grade, extent of invasion, histology, and lower external beam RT doses may be regarded as critical issue to consider for optimal patient selection.
In the context of radiation oncology, improved target definition and critical organ sparing should be considered among the pertinent aspects of optimal stereotactic irradiation. Determination of larger target volumes may lead to radiation induced toxicity, and definition of smaller than actual target volumes may result in decreased local control of the disease. It should be mentioned that adaptive irradiation approaches and multimodality imaging-based target definition may be suggested to improve radiotherapeutic results [50-106]. The current study has assessed target definition for vaginal cuff SBRT with comparative analysis of CT and MRI. Stereotactic irradiation procedures have been performed at our Radiation Oncology Department of Gulhane Medical Faculty at the University of Health Sciences. Prior to vaginal cuff SBRT, all included patients have been individually evaluated by a multidisciplinary team of experts from surgical oncology, radiation oncology, and medical oncology. The critical goal of vaginal cuff SBRT planning has been to achieve optimal target coverage without violation of critical organ dose constraints. IGRT techniques such as kilovoltage cone beam CT were used, and vaginal cuff SBRT has been delivered by Synergy (Elekta, UK) LINAC. We found that CT and MRI defined target definition resulted in differences. Thus, we utilized fused CT and MRI for ground truth target volume definition for vaginal cuff SBRT. From a radiation oncology perspective, our results may have implications for increased adoption of multimodality imaging- based target definition for vaginal cuff SBRT, nevertheless, the need for future studies to shed light on this critical issue may not be neglected.
Novel Aryl Substituted Alkenol (Ladimejol) from the Chemical Modifications of Caffeic Acid and Prospection for its Potential Biological Activities
Introduction
Over time, the harmful effects of reactive oxygen species (ROS) and free radicals (FR) have drawn increasing attention from man and the scientific world because the debilitations they cause in cellular injury and the aging process [1,2]. These reactive oxygen species easily initiate the per-oxidation of membrane lipids leading to the accumulation of lipid peroxides in the body while under pathological conditions and an imbalance is created between these reactive oxygen species and antioxidant defense mechanism. This eventually leads to oxidative stress due to modification in cellular membrane [3]. In an attempt to remedy this malady, antioxidants are routinely employed. Caffeic acid is a naturally occurring plant-based poly-phenolic compound found in coffee, turmeric, thyme, oregano, cauliflower, mushrooms, vegetables and fruits such as berries, and pears [4]. This acid can also be obtained via the Shikimic acid pathway [5], from Escherichia coli on tyrosine substrate and by the conversion of p-coumaric acid to caffeic acid by the fungal isolate Pycnoporus cinnabarinus [6]. Caffeic acid is a phenolic hydroxycinnamic acid. The trans isomer is more common and active and its IUPAC nomenclature is (E)-3-(3,4-dihydroxyphenyl) prop-2-enoic acid [7,8]. The hydroxyl groups in caffeic acid enable the donation of hydrogen atoms to the stabilization of the resultant phenoxyl radical. The unsaturated side chain’s double bond (2, 3 double bond) further enhances the stability of the phenoxylradical.
Additionally, studies suggest that caffeic acid can form chelates with divalent metals further contributing to its multifaceted antioxidant capabilities [9,10]. These comprehensive explorations of the caffeic acid underscore its intricate bio-functionalities and potential therapeutic applications making it a worthy candidate chemical or drug for more investigations. Other biological applications of caffeic acid are found in anti-diabetic therapy [11] anti-inflammation [12,13], anti-carcinogenicity [14], cardio-protection [15], antithrombotic therapy [16] and anti-aging properties [17]. The obvious and incontrovertible gamut of the multifaceted uses of this acid necessitated the present research. Consequently, this research was designed firstly to chemically modify caffeic acid via esterification, acetylation and reduction reactions. Secondly, it was also envisaged if new and potentially more active drug templates could result from this study. Furthermore, the acid and the obtained derivatives were to be screened for antioxidant activity (IC50) using the rapid bench-top bioassay employing the DPPH reagent while the agar-diffusion method was to be used in evaluating the anti-bacterial and antifungal sensitivity properties employing the use of typed clinical isolates of gram (+) (Staphylococcus aureus), gram (-) (E. coli) bacteria and a fungal strain (Candida albicans). In addition, comparison of results obtained will be done with values obtained with acid, the chemically modified derivatives, Vitamin C (antioxidant drug), chloramphenicol (antibiotic) and fluconazole (antifungal drug) all clinical positive controls with a view to determining if any improvements could be observed in the biological activities of the synthesized compounds Table 1.
Table 1: Calibration curve for DPPH reagent at λmax 516 nm.
Note: Blank Absorbance of 0.004%w/v DPPH reagent: (0.869)
Experimental
Reagents/Solvents
The following reagents and solvents were so obtained viz DPPH (2, 2-diphenyl-1-picryl hydrazyl hydrate) was purchased from Tianjin Kernel Chemical Reagent Company, China, Caffeic acid from Kamel Chemical Company, China and vitamin C was obtained from Fidson Pharmaceuticals, Nigeria respectively. Solvents and reagents namely, acetic acid, acetic anhydride, di-ethyl ether, ethanol, ethyl acetate, hydrochloric acid, iodine, magnesium sulphate, methanol, n-hexane, liquid paraffin, petroleum-ether, pyridine HCl, sodium borohydride, sodium hydroxide, sulphuric acid and tetrahydrofuran were sourced as AnaLAR Grade Chemicals from the British Drug House Chemicals Limited, Poole, England.
Solubility Tests for Caffeic Acid
The solubility profiles of caffeic acid were determined by adding separately between five (5) and eight (8) mL of different solvents namely, acetic acid, ethanol, ethyl acetate, dilute hydrochloric acid, dilute sulphuric acid, methanol, n-hexane, petroleum ether, dilute hydrochloric acid, dilute sulphuric acid and water (hot) to caffeic acid (0.05 g) in different test tubes and observation was made for solubility (dissolution) or otherwise.
Determination of Melting Point of Caffeic Acid
A small quantity of caffeic acid (0.02 g) was carefully transferred to capillary tube whose one end has been previously sealed by a laboratory gas flame. The capillary tube was attached to an electro- thermal thermometer using a thin wire thread. A beaker (50 mL) containing quantity of liquid paraffin (25 mL) was placed on a wire gauze (mesh) on a tripod stand. The thermometer with the attached capillary tube was clamped onto a retort stand and immersed in the liquid paraffin bath. The beaker was gradually heated with constant stirring to ensure uniformity of temperature throughout the bath. The temperature at which the caffeic acid started melting and the temperature at which the acid completely melted were recorded and the melting point was subsequently obtained.
Synthesis of Ester product of Caffeic Acid Caffeic Acid
(0.65 g) was weighed into a conical flask (250 mL). Ethanol (50 mL) was added and the mixture was gently stirred with a glass rod until the particles were completely dissolved to obtain a clear solution. Another ethanol (50 mL) was measured and added to the solution in the flask to ensure complete dissolution of the particles. Concentrated sulphuric acid (5 mL) was added to the solution to serve as a catalyst. The flask containing the solution was corked with aluminum foil to prevent air from passing through. It was left for two (2) weeks to ensure that complete synthetic reaction was affected in the refrigerator at a temperature of between -3 °C and 5 °C (Figure 1).
Figure 1
Synthesis of Acetyl Derivative
[18,19] These methods were employed with some modifications. Caffeic acid (0.60 g) was dissolved in a mixture of acetic anhydride (15 mL) and acetic acid (15 mL) in a beaker. The solution was heated for thirty (30) minutes and allowed to cool. Concentrated sulphuric acid (7 mL) was added as catalyst. Further heating was done for a few more minutes. The mixture was covered with aluminum foil and kept in the refrigerator at a temperature of between -4 °C and 5 °C. After two (2) weeks, a yellow liquid was formed in the beaker. A moderately warmed diethyl ether (7 mL) was added and the mixture warmed again for some minutes and allowed to cool before further use (Figure 2).
Figure 2
Synthesis of the Reduction Product of Caffeic Acid
[20] This method was adopted with some modifications. A solution of caffeic acid (1.80 g) in diethyl ether was slowly added to a suspension of sodium borohydride (0.60 g) in diethyl ether (220 mL) at room temperature and left for fifteen (15) minutes. The mixture was then stirred until evolution of gas ceased. Iodine (0.65 g) and diethyl ether (25 mL) were added slowly to the mixture at a temperature of 0 °C (in ice) with further evolution of hydrogen gas. The contents were further stirred for an hour and half. Dilute hydrochloric acid (8 mL) was added carefully and the mixture extracted with diethyl ether. The combined ethereal extract was washed with 3M sodium hydroxide (37 mL), brine and dried over silica gel. Evaporation of the organic layer gave the reduced product (Figure 3).
Figure 3
Determination of Specific Optical Rotation of Caffeic Acid and its Derivatives
The quartz tube in the polarimeter (ADP-220, Bellingham Stanley, England) was filled with distilled water and the machine subsequently zeroed. It was then emptied and refilled with a small quantity of caffeic acid solution (3 mL) in water and the value recorded. Similarly, the procedure was separately repeated for derivatives in their liquid states and likewise their values were recorded.
Determination of Refractive Index of Caffeic acid and Its Derivatives
The refractometer (WAY-15, Abbe, England) is operated at the wavelength (λ) of sodium D line (589.3 nm) at 20.5 oC. The machine was switched on and allowed for fifteen (15) minutes to attain equilibrium. The refractive prism assembly was opened and the mirror was removed. A syringe was used to deliver a clear aqueous solution of caffeic acid (4 m L) onto the prism. The prism assembly was closed and its refractive index taken. This procedure was separately repeated for the three derivatives.
Thin-layer Chromatography of Caffeic Acid and Derivatives
A portion of caffeic acid (0.04 g) dissolved in methanol (2 mL) or 2 mL of liquid samples (derivatives) was applied on a 15 cm x 10 cm silica gel analytical plate (Merck, Germany) and then developed in a toluene: acetone: water (10:20:1) mixture in a chromatographic tank until optimal separation and resolution was observed. The retardation factor (RF) was then computed
thus:
RF = distance moved by spot distance moved by solvent front
Infra-Red Spectroscopy of Caffeic Acid and Derivatives
Caffeic acid (0.25 g) or 2.5 mL (liquid derivatives) each was analyzed for IR characteristics using the FTIR 84005 Spectrophotometer (Shimadzu, Japan).
Ultra-Violet/Visible Spectroscopy of Samples
Caffeic acid (0.2 g) dissolved in methanol or 2 mL of liquid derivative was analyzed for UV/VS absorption characteristics using the Jenway 6405 UV/VS Spectrophotometer.
Antioxidant Activity
Spectrophotometric Determination of Antioxidant Activity using DPPH Reagent: The determination of antioxidant activity of a substance is premised on donation and acceptance of electrons by reacting chemical species. Hence, chemical reagents or species which are capable of donating electrons or hydrogen atoms can convert the purple-coloured DPPH radical (2, 2-diphenyl-1-picrylhydrazyl hydrate) to its yellow-coloured non-radical form; 1, 1-diphenyl-2-picryl hydrazine [21,22]. Hence, the antioxidant activity of a compound can be evaluated by spectrophotometry.
Preparation of Calibration Curve for DPPH Reagent
This experiment was carried out as described by both [23,24] with some modifications. DPPH (4 mg) was weighed and dissolved in methanol (100 mL) to produce the stock solution (0.004 % w/v). Serial dilutions of the prepared stock solution were then carried out to obtain the following concentrations viz, 0.0004, 0.0008, 0.0012, 0.0016, 0.0020, 0.0024, 0.0028, 0.0032 and 0.0036 % w/v. The absorbance of each of the sample was taken at λm 516 nm using the Ultra- Violet Spectrophotometer (Jenway 6405, USA). This machine was zeroed after an absorbance had been taken with a solution of methanol without DPPH which served as the blank.
Determination of the Antioxidant Activity of Caffeic Acid, Derivatives and Vitamin C
4 mg of sample was mixed with 100 mL of methanol. Serial dilutions were carried out to obtain the following concentrations; 0.0004 mg mL-1, 0.0008 mg mL-1, 0.0012 mg mL-1, 0.0016 mg mL-1 and 0.0020 mg mL-1 using methanol. 6 mL of each concentration was incubated with 7 mL of 0.004 % w/v methanolic DPPH solution for optimal analytical accuracy. After an incubation period of thirty (30) minutes in the dark at room temperature (25 ± 2 0C). An observation was then made for a change in the color of the mixture from purple to yellow. The absorbance of each of the samples was taken at λm 516 nm. The Radical Scavenging Activity (RSA %) or
Percentage Inhibition (PI %) of free radical DPPH was thus computed:
Ablank is the absorbance of the control reaction (DPPH solution without the test sample and Asample is the absorbance of DPPH incubated with the sample. Caffeic acid /synthesized derivative / Vitamin C concentration providing 50 % inhibition (IC50) was calculated from a graph of inhibition percentage against the concentration of the caffeic acid/ synthesized derivative / Vitamin C [25-27]. Vitamin C was used as a standard antioxidant drug.
Antimicrobial Tests
The micro-organisms used in this study, namely, Staphylococcus aureus (NCTC 4598), Escherichia coli (NCTC 5463) and Candida albicans (NCYC 56) were clinically isolated from specimens of diarrheal stool, urine, wounds and vaginal swabs obtained from the University of Uyo Health Centre, Uyo. The clinical isolates were collected in sterile bottles, identified and typed by convectional biochemical tests [28,29]. Preservation by refrigeration was done at 5 0C at the Department of Pharmaceutical Microbiology and Biotechnology, Faculty of Pharmacy prior to further use. The hole-in-plate agar diffusion method was used observing standard operating procedures for bacteria and fungi respectively. The inoculum of each micro-organism was introduced into each petri-dish (Pyrex, England). Cylindrical plugs were removed from the agar plates by means of a sterile cork borer (Pyrex, England) to produce wells with diameter of approximately six (6.00) mm. The wells were equidistant from each other and the edge of the plate [30,31]. Concentrations of 10 mg mL-1 and 20 mg mL-1 of caffeic acid, 7.5 mg mL-1 and 15 mg mL-1 of derivatives were introduced into the wells. Also, different concentrations of 5 mg mL-1 chloramphenicol (Gemini Chemicals, Nigeria), 1mg mL-1 of Nystatin (Diamond Healthcare Chemicals, Nigeria) and aqueous methanol (1:1) were introduced into separate wells as positive and negative controls respectively [32-35]. The determinations were carried out in triplicates. The plates were left at room temperature for two (2) h to allow for diffusion. The plates were then incubated at 37 ± 2 0C for twenty-four (24) h. Zones of inhibition were measured in millimeters (mm).
Caffeic acid, an odourless brownish yellow substance is also described as tanned yellow compound. It is a hydroxy-cinnamic acid which is a major sub-group in phenolic compounds with the phenyl ring substituted by hydroxyl groups at positions C-3 and C-4. Some monographic studies were carried out to determine its identity, purity, integrity and suitability for the present research. It was observed to be soluble in acetic acid, ethanol, methanol and hot water. However, it was insoluble in ethyl acetate, diethyl ether, dilute HCl, dilute H2 SO4, n-hexane and petroleum ether. The determined values of melting point and refractive index both fall within stated limits in literature. The UV λmax (246 nm) absorption is indicative of the presence of electron densities dispersed over -Ar-C=C, -Ar-OH, acyclic -C=C and alcoholic -OH chemical species while retardation factor RF (0.58) shows that the acid is moderately polar and hence likewise retarded on the silica gel. The IR spectral matrix of caffeic acid shows stretchings at 1589, 1614, 1723, 2885, 3130 and 347 cm-1 which are diagnostically characteristic of – Ar-C=C, acyclic -C=C,.-C=O, -CH bending modes, alcoholic -OH in carboxylic acid and -Ar-OH groups respectively. Ethyl caffeate (CE), an aromatic phenol ester was synthesized as an odourless colourless liquid compound. The UV λmax (326 nm) absorption which is comparatively higher than that of the pro-drug (caffeic acid) indicates the presence of electron clouds over -C-O-C, -Ar-C=C, acyclic -C=C, -C=O and -Ar-OH chromophores.
The retardation factor RF (0.69) indicates that the ester derivative is comparably non-polar and hence weakly retarded on the silica gel plate. Its IR spectrum shows peaks at 987, 1202, 1586, 1612, 1694, 2887 and 3471 cm-1 which are diagnostic of alkyl bending modes, hence accounting for the disappearance of the alcoholic OH peak at 3130, -C-O-C, -Ar-C=C, acyclic -C=C, -C=O, -CH and -Ar-OH respectively. It is instructive to note that the peak representing -C-O-C is diagnostically elucidative indicating that the hydrogen atom in the alcoholic -OH had been replaced with an ethyl group (-CH2CH3) showing that esterification of caffeic acid had been effected. Ethyl caffeate has been obtained via Co-A acylytransferase expression on E. coli [36] and is naturally occurring in diverse plants such as Prunus yedensis, Polygonum amplexicale and Bidens piloso from where it has been separately isolated [37]. Its radio-sensitizing effects have been studied and documented [38]. Furthermore, it is used as an anti-aging agent in cosmetology, treat inflammatory disorders and suppresses NF-Kappa B activation. The acetyl product (CA) was obtained as a pale yellow liquid. In addition, the UV λmax (352 nm) absorption which is also higher than that of caffeic acid suggests that electrons are found delocalized over -Ar-C=C, acyclic -C=C, -OCOCH3 and -Ar-OH chromophoric species. The retardation factor RF (0.66) indicating some level of lipophilic character ensures it is comparably less hindered on the silica plate.
The IR spectral matrix of the acetyl derivative is replete with peaks at 1607, 1676, 1717, 1736 and 3375 cm-1 accounting for -Ar-C=C, acyclic C=C, -C=O in OCOCH3 -C=O and -Ar-OH chemical species. It is noteworthy that the hydrogen atom in the alcoholic -OH was replaced with the acetyl group in the acetylation process hence ensuring the disappearance of the alcohol peak at 3130 cm-1 inherent in the parent caffeic acid. The reduced product, 1-(3,4-dihydroxy phenyl)-2-propen-3-ol (3,4-benzenediol-2-propen-3-ol) (Ladimejol) (CR) was synthesized as a highly viscous dark yellow liquid. The UV λmax (332 nm) absorption is indicative of presence of electrons moieties in -Ar-C=C, acyclic -C=C, -OH and -Ar-OH chemical species while RF (0.88) shows that this derivative is inherently non-polar because of the increased presence of non-polarity occasioned by the conversion of the -C=O to a -CH2 thereby enhancing its relatively free movement on the silica-coated plate. The IR spectrum of the (CR) is characterized by stretchings at 1587, 1612, 2933, 3125 and 3429 cm-1 which are indicative of the presence of -Ar-C=C, acyclic C=C, -CH, alcoholic -OH and -Ar-OH species.
It noteworthy to highlight that the reduction reagent (NaBH4 /I2) selectively reduces the -C=O to -CH2 [20] while the -C=C whether acyclic or aromatic is untouched. Surprisingly, in previous studies by this lead author and other co-workers, the three (3) endocyclic -Ar-C=C bonds were also reduced in vanillin and gallic acid [23] [24] because the -C=O specie was directly attached to the aromatic phenyl ring in the compounds. This translated to losses of the aromatic character in both vanillin and gallic acid respectively. However, if the -C=O is far from the aromatic ring (when not found attached to the aromatic ring), only the -C=O will be selectively reduced and not the -Ar-C=C bonds as observed in [20] and this present investigation. Comprehensive literature search of organic chemistry data libraries indicates that this reduced derivative (CR) whose IUPAC nomenclature is 1-(3,4-dihydroxy phenyl)-2-propen-3-ol (3,4-benzenediol-2-propen-3-ol) is new and hereby given the trivial identity of Ladimejol. It was observed that caffeic acid, CE , CA, and CR showed optical rotation [α]D20 of +0.267, +0.262, +0.386 and 0 0 respectively indicating that the pro-drug and the derivatives are optically active except the reduced product. Hence, the reduced derivative, 1-(3,4-dihydroxy phenyl)-2-propen-3-ol) (3,4-benzenediol-2-propen-3-ol (Ladimejol) will demonstrate neither laevorotation (-) (ability of a compound to rotate plane of light in anticlockwise direction) nor dextro-rotation (+) (ability of a compound to rotate plane of light in clockwise direction). However, caffeic acid, ester and acetyl derivatives will elicit dextro-rotation (+) (ability of a compound to rotate plane of light in clockwise direction) [39,40]. This reduced derivative belongs to the class of compounds known as phenyl-propenoids which are related to catechols because of the attachment of the aryl component to an allyl alcohol.
Antioxidant Activity
A calibration curve was prepared for DPPH (2, 2-diphenyl-1-picryl hydrazyl hydrate) reagent with the aim of ascertaining its purity and suitability for use in the antioxidant evaluations. The Beer-Lambert’s Law remains the basis of all absorption spectrophotometry [22]. The calibration curve obtained confirms that the underlying principles behind the Law were obeyed as the curve (Graph 1) shows a straight line which passed through the origin. The reduction of the DPPH radical was determined by taking its absorption at a wavelength of λm 516 nm. It was observed that the absorbance of DPPH decreased as the concentration of added free radical scavenger (caffeic acid /derivative/vitamin C) increased which suggested that the DPPH reagent was being reduced (Table 2). It was observed that as the radical scavengers were being introduced separately into the different beakers containing the DPPH reagent, a colour change from purple to yellow occurred for all except the reduced product (CR) which gave a very dark brownish yellow colour probably because of its very viscous characteristics. Furthermore, Table 3 displays radical scavenging activity (RSA %) or percentage inhibition (PI %) and the computed IC50 values of caffeic acid /derivative / vitamin C. The RSA % is an indicator of the antioxidant activity of a compound. Interestingly, caffeic acid, ester derivative (CE) and acetyl product (CA) all demonstrated significantly remarkable antioxidant activity (IC50) of 0.22, 0.19 and 0.16 μg mL-1 respectively. These values compare favourably with that of a standard antioxidant drug (Vitamin C) at 0.18 μg mL-1. The ester and acetyl products both essentially contain chemical species such as -CH2 CH3 and -COCH3 which confer some lipophilic character on them thereby enabling the compounds to get to the allosteric sites where the pharmacological action of anti-oxidation is to be effectuated in living organisms. Furthermore, the acetyl derivative gave the most significant antioxidant activity (0.16 μg mL-1) amongst all the compounds tested including being even more antioxidant than Vitamin C in this study. From the foregoing, it can be inferred that both esterification and acetylation separately enhances the antioxidant activity of caffeic acid. However, the activity of the reduced product could not be regressed in this present study. It is somewhat necessary to point out that the ester and acetyl derivatives of gallic acid and cinnamic acid also demonstrated equally remarkable antioxidant activities in previous studies by the lead author and co-workers [24,41].
Figure 1
Table 2: Absorbance of samples incubated with DPPH at different concentration at λmax 516 nm (Blank absorbance of 0.004% DPPH reagent: 0.869) (± 0.002).
Table 3: Radical scavenging activity (percentage inhibition %) of samples at different concentrations and IC50 of samples (±0.02).
Note: Refer to Table 2, • RSA % (PI %) = Radical Scavenging Activity (Percentage Inhibition %) • IC50 = Concentration at which 50 % of DPPH is scavenged or inhibited • NR = Not regressed
Antibacterial Tests
The microbes used in the sensitivity tests attested to the antibacterial spectrum encompassing one (1) gram positive bacterium namely, S. aureus (NCTC 4598) and one (1) gram negative bacterial species, E. coli (NCTC 5463). The results as presented in the Table 4 show that the antibacterial activity was concentration-dependent. The higher the concentration of the antibacterial compound applied the higher the antibacterial activity. Caffeic acid and acetyl derivative were bacteriostatic at both concentrations (10 and 20 mg m L-1) employed. Furthermore, the acetyl derivative (CA) was more active than the prodrug even at comparably lower concentrations (7.5 and 15 mg m L-1) as can be seen in the Table 4. However, both the ester (CE) and reduced (CR) (Ladimejol) derivatives recorded no growths on the agar plates. The acetyl derivative was more suppressive of the S. aureus than E. coli. It is safe to imply that acetylation of caffeic acid enhances its antibacterial activity. Furthermore, it can be inferred from these results that acetyl derivative (CA) could be a promising lead compound in the search for newer antibacterial agents for treatment and management infections of bacterial origins.
Table 4: Antibacterial screening of caffeic acid and its derivatives at different concentrations on test microbes in aqueous methanol (1:1) (± 0.01 mm).
Note: The zone diameter recorded is zone of inhibition + size of cup (zone of inhibition +6.00) mm Refer to Table 2. • NCTC – National Collection of Type Cultures, Central Public Health Laboratory, • Colindale Avenue, London NW9, UK. • ATCC- American Type Culture Collection, Washington, DC. • NG- No Growth
Antifungal Screening
The antifungal screening was done with C. albicans (NCYC 56). Similarly, the antifungal activity demonstrated by caffeic acid and derivatives with the exception of the reduced derivative (CR) (Ladimejol) are equally concentration-dependent as displayed in Table 5. Furthermore, it was noticed that both caffeic acid and ester derivative (CE) demonstrated some levels of anti-candidal activity but are somewhat inferior in comparison to the significantly remarkable activity demonstrated the acetyl derivative (CA). The reduced derivative as observed in the antibacterial sensitivity tests also showed a no growth situation in the antifungal screening. It is probable that its viscous nature could be factor which this worker and fellow co-workers are interested in investigating in the subsequent stages of the studies on caffeic acid. However, it is convenient to infer that the acetyl derivative (CA) may be a potential lead compound in the discovery of new antifungal drug templates especially in the treatment of candida-resistant infections.
Table 5: Antifungal sensitivity screening of caffeic acid and synthesized derivatives at different concentrations on a fungal strain in Me-OH/H2O (1:1) (± 0.01 mm).
Note: The zone diameter recorded is zone of inhibition + size of cup (zone of inhibition +6.00) mm Refer to Table 2. • NCYC- National Collection of Yeast Cultures, UK. • NG–No Growth
Conclusion
This study reports for the first time the synthesis of 1-(3,4-dihydro phenyl)-2-peopen-3-ol (3,4- benzenediol-2-propen-3-ol) (CR), a new aryl substituted alkenol from the reduction of caffeic acid’s nucleus. It has been assigned the trivial name Ladimejol. This compound has demonstrated no antioxidant activity (IC50), antibacterial and antifungal activities in this present study. Potential activities such as anti-inflammatory and anti-cancer amongst many others are to be worked on the reduced derivative in subsequent researches. However, the acetyl derivative did demonstrate more excellent antioxidant, antibacterial and antifungal activities than the derivatives and even caffeic acid. It is noteworthy that the acetyl derivative (CA) could be further studied in more expanded structural activity relationship studies (SARS), drug design development and formulation studies.
Consent for Publication
None.
Funding
None.
Conflict of Interest
The authors declare no conflict of interest financial or otherwise.
Acknowledgements
The authors heartily acknowledge the Department of Pharmaceutical and Medicinal Chemistry, University of Uyo, Nigeria for the use of its Jenway 6405UV/VS. The assistance of Pharm. (Mrs) M. Alozie of the Department of Pharmaceutical Microbiology and Biotechnology, University of Uyo, Nigeria is warmly appreciated. We are also grateful to the University of Ibadan, Nigeria for its IR-FTIR 8400 Spectrophotometer (Shimadzu, Japan) in obtaining the IR spectra of compounds.
Prophecy and Doomsday: Reconsideration of a Likelihood
Opinion
As said by Freud, an important mental need in some neurotic patients is the need for uncertainty in their life, or for doubt, which may prepare the background for drawing the patient away from reality, isolate him from the world, organize the person’s perspective for magical fantasizing, and turn their thoughts to those subjects upon which all mankind is uncertain, like life and its continual after death [1]. In this regard, ‘Animism’ (magical thinking) may be considered a system of thought that allows us to grasp the whole universe as a single unity from a single point of view, and myths, as well, are based on animistic premises, which are not devoid of an essential need for controlling humans’ surroundings. So, hand in hand with the animistic scheme, there came a body of guidelines for how to achieve mastery over men, monsters, animals, and things—or rather, over their spirits. These formulations may be named ‘sorcery’ and ‘magic’, as the ‘strategy of animism’ [2]. Accordingly, since magic should protect the person from his foes and threats, it must give him the power to hurt his nemeses, and it must subject natural phenomena to the will of man, while the element of distance was ignored and telepathy was taken for granted. Therefore, it is easy to comprehend the drives that lead men to practice magic: they are human wishes, like children, that, in the beginning, satisfy their aspirations in a hallucinatory manner by generating a satisfying status quo (kids’ play). As a result, as stated by Schopenhauer, the problem of death stands at the outset of every philosophy [3,4].
On the other hand, eschatology refers to expectations of the end of the present age, human history, or the world itself. While the ‘End- Time’, ‘End of the World’, or ‘Judgement Day’ is foreseen by several religious convictions (like Judaism, Christianity, Islam, Hinduism, and Buddhism) or Armageddon sects, the belief that the end of the world is forthcoming is known as ‘Apocalypticism’. Then again, while signs of environmental hazards like wars, conflicts, and increasing levels of crimes and wickedness in the world, which have not been rare during different epochs, may signal that the ‘End-Time’ is near, the term usually refers, allegorically and transcendentally, to the end of ordinary reality, reunion with the divine, transformation, and redemption. The Oxford English Dictionary defines eschatology as “the part of theology concerned with death, judgment, and the final destiny of the soul and of humankind.” On the other hand, people are drawn to the idea of an apocalypse for a variety of reasons. For example, while some may find the concept of a dramatic world-changing event to be electrifying or exhilarating, others may feel that an apocalypse would provide a sense of purpose or meaning in a world that can sometimes feel messy or worthless [5,6]. On the other hand, ‘End of Life’ may be accounted for, matter-of-factly, as a natural distress, which may encompass every Tom, Dick, and Harry in the world over, and, also, may occur personally or collectively, naturally or oddly, timely or untimely, and fairly or unfairly, depending on the subject’s demographic physiognomies, attitude, mentality, understanding, dogma, wishes, and surroundings.
Therefore, it may not be formulated homogenously or systematically, though it may be classified metaphorically. Ontogenetically, ‘End of Life’ for every individual may be determined as his or her last moments of life, just before death. Phylogenetically, ‘End-Time’ of every colony, group, or nation may symbolize the demise of their last survivals. Accordingly, while ‘End of Life’ is, factually, a repeatable and acceptable expiration of a human being due to imaginable maladies, catastrophes, or tragedies, universal ‘End of Life’ may have supernatural, spiritualistic, or, possibly, political implications. Currently, in many folklores, global ‘End-Time’, has been designated as an aftermath of war between superpowers, which may happen due to hegemonic rivalries or retaliations [7]. On the other hand, while from usual spiritualistic outlooks, ‘End of Life’ may be the commencement of a resurrection and new beginning, from some radical outlooks, it may be analyzed as a gizmo for new schema, sovereignty, or setting because, politically, ‘End-Time’ may not simply mean ‘End of Life’ of creatures, and it may allude to ‘End of Life’ of nemeses, too. For example, while some scholars in the last decades believed that the end of collectivism could be acknowledged, symbolically, as the ‘End of History’ and substantiation of ‘Liberal Democracy’ [8-10], the subsequent conflicts or mishaps showed that neither history may be ended philosophically nor democracy may be implemented painlessly or correctly.
Similarly, neither globalization, which has been labeled, correctly or incorrectly, as ‘democratic imperialism’ by leftists, nor neoliberalism, which has promoted fiscal complications, oligarchy, or monopoly in some realms, was efficacious with respect to their pledged purposes and fortunes. On the other hand, in an epoch when everything should be analyzed, first politically and then socially, fiscally, or philosophically, the doctrine of ‘End of Life’, too, may not be considered only transcendentally, especially when it is being discussed too widely. Anyhow, while Freud formulated telepathy as a longitudinal and unconscious passage towards innate unconscious drives [11], it is not impossible for politics to misuse, consciously and methodically, insensible or topsy-turvy foretelling. In this regard, the prediction of Armageddon and related circumstances has, at all times and in all places, its explicit patrons. So, while, for example, vague and antique predictions of Nostradamus, as a real or fictional foreteller [12], who belonged to a few centuries ago (a process that is not essentially, logically, and scientifically approvable) are being promoted and publicized, time after time and massively, they may have some real implications or intentions, which should be analyzed politically, not transcendentally. Similarly, more meticulous and truthful foresees may have more chance to involve a political memo instead of a mere prophecy. Though sociological, political, or financial analysis, which is usually based on real proofs and statistics, may predict to some degree present or future deviances on related grounds, the gap between associated facts and predictions is usually tighter and more rational than awkward and boundless breaks in magical forewarnings.
On the other hand, while unworldly prophecies are usually around revitalization and celestial judgment, recompense, or sentence, politically indorsed or devised forewarnings are commonly about worldly matters. Similarly, some sociopolitical theories, like ‘Class Struggle’, ‘Historical Materialism’, ‘Materialism Dialectic’, etc., may be regarded as hypothetical formulations, not unbreakable prophecies, because, while they may or may not be true, their application on behalf of revolutionary modifications is not conceivable without the materialization of a series of parameters [13]. So, they may not be accounted for as automatic deterministic forecasts and may be regarded more as conditional, conceivable restructurings. But why do deep states’ doctrinaires or proposers resort to concrete or contrived forecasts? Because they, as elites and realist organizers, may prefer to prepare the mindset of their people, who do not have analogous mentalities, for upcoming unexpected schemas that are not habitually favorable. Therefore, they generate psychological links between present, but intolerant, people and bygone, ambiguous, and mystical figures who may have whispered some lyrics or decrees to transmit a series of desired repercussions for present or upcoming plans. Anyway, control of public minds and desensitization of people’s emotions, which was, at all times and in all places, a never-ending wish of different ruling classes, may have eventually found beneficial tools in mystical, paranormal, or abstruse phenomena because, when masses are bewildered, the systems may become immunized against genuine estimates and scrupulous critiques, at least provisionally [14,15].
Moreover, such psychological maneuvers may prevent possible embracement or failure in unpredicted happenings and may increase their ability to manage circumstances through unhurried decoration of settings, though they do that disguisedly, clandestinely, and prematurely, in spite of plausible domino effects. Likewise, such an intention may become more effective when there are shared elements between the covert objectives of decision-makers and the overt wishes of the masses. On the other hand, they may persuade, concurrently, other people, even their adversaries, to move unconsciously towards the said objectives, though in a different way, based on the aforementioned conjoint clues—a process that is similar to the defense mechanism of projective identification in borderline personality structure. Therefore, mysticism, forecasting, and traditional beliefs may construct, bit by bit, a milieu that may not be generable explicitly and effortlessly by mass media, reasoning, or yearnings. Though, ethically, misuse of cultural or holy beliefs on behalf of political purposes is not acceptable, Machiavellianism may theoretically enable it, at least for politically aware tacticians [16]. Anyhow, while the intention of the present paper is neither denial of hilarious, supportive, or methodical predictions nor devaluation of spirituality in the psychological life of human beings, it signifies the analysis of every plausible phenomenon that may captivate unaware people who don’t like to become fooled, bamboozled, or exploited, though the infiniteness of mysticism seems to be so prevailing that almost not a soul may disregard fully its mesmerism, joy, or vigor.
On the other hand, while many people, especially pacifists, may believe that it is unlikely that any person plans, politically and calculatedly, for Armageddon, isolation of affect, egocentrism, bizarreness, or superego lacuna in every planner with obsessive-compulsive, narcissistic, schizotypal, or antisocial personality trait or disorder, respectively, or even conditional inescapability, may eventually prepare some mindsets for such merciless resolutions. Unfortunately, the constant supremacy of rationality over irrationality is not continually guaranteed.
Biomedical Journal of Scientific & Technical Research (BJSTR) 