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HLA (HLA) alleles are risk factors for CD8+ T-cell-mediated drug hypersensitivity reactions. However, as most HLA associations are incompletely predictive and/or involve risk alleles at low frequency, costly sequence-based typing can elude an economically productive cost: benefit ratio for clinical validation studies and diagnostic and/or preventative screening. Hence rapid and low-cost detection assays are now required, both for single alleles but also across risk loci associated with broader multi-disease risk; exemplified by associations with diverse alleles in HLA-B*35, including HLA-B*35:01 and green tea- or co-trimoxazole-induced liver injury. Here, we developed a cost-effective ($10USD) qPCR assay for rapid (2.5 h) clinical detection of HLA-B*35 alleles. The assay was validated using 430 DNA samples with previous American society for histocompatibility and immunogenetics-accredited sequence-based high-resolution HLA typing, positively detecting all HLA-B*35 allelic variants in our cohort, and as expected by primer design, the six samples that expressed low-frequency B*78:01. The assay did not result in positive detection for any negative control allele. With expected detection of B*35 and B*78, our assay sensitivity (95% CI, 95.07%-100.00%) and specificity (95% CI, 98.97%-100.00%) of 100% using as low as 10 ng of DNA provides a reliable HLA-B*35 screening tool for clinical validation and HLA-risk-based prevention and diagnostics.

Delayed drug hypersensitivities are CD8+ T-cell mediated reactions associated with up to 50% mortality. Human leukocyte antigen (HLA) alleles are known to predispose disease, specific to drug, reaction, and patient ethnicity, with pre-treatment screening recommended for a handful of the strongest associations to identify and prevent drug use in high-risk patients. However, an incomplete predictive value implicates other HLA-imposed risk factors, and low carriage of many identified HLA-risk alleles combined with the high cost of sequence-based typing has limited economic viability for similar recommendation of screening across drugs and healthcare systems. To mitigate, an expanding armoury of low-cost polymerase chain reaction-based screens is being developed, and HLA-imposed risk factors are being discovered. These include (1) polymorphic variants of metabolic and endoplasmic reticulum aminopeptidase enzymes, towards multi-allelic screening with increased predictivity, (2) regulation by immune checkpoint inhibitors, enabling de-tolerised animal models of human disease, and (3) immunodominant T-cell receptors (TCR) on clonally expanded CD8+ T-cells. For the latter, HLA-risk restricted TCR provides immunogenomic strategies and samples from a single patient to identify novel HLA-risk associations in underserved minority populations, tissue-relevant effector biomarkers towards earlier diagnosis and treatment, and HLA-TCR-presented immunogenic structures to aid future drug development.

A systematic investigation of the electrocatalytic Methanol Oxidation Reaction (MOR) was carried out using a model Co:Pt alloy system with different compositions and structural arrangements of the ...

Evidence of autoimmune disease associated with hepatitis C virus (HCV)-infection has important clinical implications. A systematic profile of these autoantibodies in relevant clinical cohorts relative to healthy controls is needed to better inform current standard of care for chronic hepatitis C. Samples from an Australian cohort of chronic HCV-infected subjects (n=127) were tested for the presence of 19 diagnostic autoantibodies and compared with data available from a control cohort representing a general Caucasian population (n=198). Chronic HCV-infected individuals had a greater number of autoantibodies than controls (p

Abacavir hypersensitivity syndrome (ABC HSS) is strongly associated with carriage of human leukocyte antigen (HLA)-B*57:01, which has a 100% negative predictive value for the development of ABC HSS. However, 45% of individuals who carry HLA-B*57:01 can tolerate ABC. We investigated immune and non-immune related genes in ABC HSS (n = 95) and ABC tolerant (n = 43) HLA-B*57:01 + patients to determine other factors required for the development of ABC HSS. Assignment of phenotype showed that ABC HSS subjects were significantly less likely than tolerants to carry only ERAP1 hypoactive trimming allotypes (p = 0.02). An altered self-peptide repertoire model by which abacavir activates T cells is in keeping with observation that endoplasmic reticulum aminopeptidase 1 (ERAP1) allotypes that favour efficient peptide trimming are more common in ABC HSS patients compared to patients who tolerate ABC. Independently, non-specific immune activation via soluble cluster of differentiation antigen 14 (sCD14) may also influence susceptibility to ABC HSS.

BackgroundPrecise prediction of residual tumour size following neoadjuvant systemic therapy for breast cancer is crucial in assessing response and surgical decision making. Our study is aimed at assessing the performance of conventional imaging modalities like ultrasound and mammography in predicting the residual tumour size after neoadjuvant systemic therapy and in evaluating the impact of imaging on the surgical outcomes.MethodsWe retrospectively compared the tumour size measured by ultrasonography and mammography and the residual tumour size on final histopathology in 109 patients. Concordance was defined as a size difference within 25% of the histopathology size. We also looked at the distribution of concordance between different T status and molecular subtypes, accuracy of USG in predicting pathological complete response and axillary lymph nodal metastasis and also surgical outcomes in the discordant cases.ResultsThe concordance rates of mammography and ultrasonography were 68.2% and 52.3% respectively without statistically significant difference between the two modalities (p = 0.081). Combination of both the modalities had a concordance rate of 57.8%. Ultrasonography had accuracy of 81.7% for predicting pathological complete response and 79.8% for predicting axillary nodal metastasis. We did not identify any influence of histologic subtype on the associations between preoperative measurements and pathology size or the accuracy for detecting pathological complete response (p values 0.43 and 0.46 respectively). In 12 cases, the radiology-pathology discordance could have led to large excision volume surgeries. In the overall cohort, recurrence free survival and overall survival rates at median follow up of 19.1 month were 87.2% and 95.4% respectively.ConclusionsUltrasound and mammography showed moderate concordance with pathology for estimation of the residual tumour size without any significant difference in the performance between the two. Despite the moderate concordance, surgical outcomes were fairly well managed in the discordant cases with the oncoplastic surgical techniques. Our study highlights the usefulness of the cheaper and widely available conventional imaging modalities in the developing countries where the cost of treatment is to be contained.

Purpose of review An update of the pharmacogenetic risk factors associated with T-cell-mediated delayed hypersensitivity reactions. Recent findings Recent HLA associations relevant to our understanding of immunopathogenesis and clinical practice include HLA-B∗13:01 with co-trimoxazole-induced SCAR, and HLA-A∗32:01 with vancomycin-DRESS, for which an extended HLA class II haplotype is implicated in glycopeptide antibiotic cross-reactivity. Hypoactive variants of ERAP1, an enzyme-trimming peptide prior to HLA loading, are now associated with protection from abacavir-hypersensitivity in HLA-B∗57:01+ patients, and single-cell sequencing has defined the skin-restricted expansion of a single, public and drug-reactive dominant TCR across patients with HLA-B∗15:02-restricted carbamazepine-induced SJS/TEN. More recent strategies for the use of HLA and other risk factors may include risk-stratification, early diagnosis, and diagnosis in addition to screening. Summary HLA is necessary but insufficient as a risk factor for the development of most T-cell-mediated reactions. Newly emerged genetic and ecological risk factors, combined with HLA-restricted response, align with underlying immunopathogenesis and drive towards enhanced strategies to improve positive-predictive and negative-predictive values. With large population-matched cohorts, genetic studies typically focus on populations that have been readily accessible to research studies, but it is now imperative to address similar risk in globally relevant and understudied populations.

All fifteen patients with HLA-A*32:01 restricted vancomycin-induced DRESS, showed negative ex vivo responses to dalbavancin however two showed cross-reactivity to teicoplanin and telavancin. Adjunctive diagnostic testing should be considered to detect potential cross-reactivity amongst glycopeptides.

Development of a method is crucial for discovery, development, and analysis of medicines in the pharmaceutical formulation. Method validation could also be thought to be one in all the foremost well-known areas in analytical chemistry as is reproduced within the substantial variety of articles submitted and presented in peer review journals every year. Validation of an analytical procedure is to demonstrate that it's appropriate for its intended purpose. Results from method validation are often wont to decide the quality, reliability and consistency of analytical results. Analytical methods need to be validated or revalidated. This review describes general approach towards validation process and validation parameters to be considered during validation of an analytical method. It also refers to various regulatory requirements like WHO, USFDA, EMEA, ICH, ISO/IEC. The parameters described here are according to ICH guidelines which include accuracy, precision, specificity, limit of detection, limit of quantification, linearity range and robustness.

Tribulus terristries belongs to family zygophyllaceae and commonly known as Puncture vine, Tribulus including goat's-head, bindii, bullhead, burra gokharu, bhakhdi, caltrop, small caltrops, cat's-head, devil's eyelashes, devil's-thorn, devil's-weed, puncture vine, and tackweed. Found widely distributed warmer regions of the world, throughout in India, srilanka, west Tibet, consists of dried fully ripen fruits of plant. Fruits are used as Diuretics tonics and also in the treatment of calculous affections and painful micturation, they are also used as aphrodiasic and in gout. Standardization is a system ensuring predefined set of the quantity, quality and therapeutic effect of the constituents in each dose. It is an imperative stride in establishing a quality assurance plan for production and manufacturing thereby, curtailing batch to batch variation and reassuring acceptability, safety, quality and efficacy of the drug , Thin layer chromatography (TLC) and high performance thin layer chromatography (HPTLC) fingerprint profiles are used for ensuring the identity, transparency and potency of herbal formulations.

The human leukocyte antigen (HLA) system is the most polymorphic in the human genome that has been associated with protection and predisposition to a broad array of infectious, autoimmune, and malignant diseases. More recently over the last two decades, HLA class I alleles have been strongly associated with T-cell mediated drug hypersensitivity reactions. In the case of abacavir hypersensitivity and HLA-B*57:01, the 100% negative predictive value and low number needed to test to prevent a single case has led to a durable and effective global pre-prescription screening strategy. However, HLA associations are still undefined for most drugs clinically-associated with different delayed drug hypersensitivity phenotypes, and an HLA association relevant to one population is not generalizable across ethnicities. Furthermore, while a specific risk HLA allele is necessary for drug-induced T-cell activation, it is not sufficient. The low and incomplete positive predictive value has hindered efforts at clinical implementation for many drugs, however, has provided the impetus to understand the mechanisms of HLA class I restricted T-cell mediated drug hypersensitivity reactions. Current research has focused on defining the contribution of additional elements of the adaptive immune response and other genetic and ecologic risk factors that contribute to drug hypersensitivity risk. In this review we focus on new insights into immunological, pharmacological, and genetic mechanisms underpinning HLA associated drug reactions and the implications for future translation into clinical care.

Adverse drug reactions (ADRs) remain associated with significant mortality. Delayed hypersensitivity reactions (DHRs) that occur greater than 6 h following drug administration are T-cell mediated with many severe DHRs now associated with human leukocyte antigen (HLA) risk alleles, opening pathways for clinical prediction and prevention. However, incomplete negative predictive value (NPV), low positive predictive value (PPV), and a large number needed to test (NNT) to prevent one case have practically prevented large-scale and cost-effective screening implementation. Additional factors outside of HLA contributing to risk of severe T-cell-mediated DHRs include variation in drug metabolism, T-cell receptor (TCR) specificity, and, most recently, HLA-presented immunopeptidome-processing efficiencies via endoplasmic reticulum aminopeptidase (ERAP). Active research continues toward identification of other highly polymorphic factors likely to impose risk. These include those previously associated with T-cell-mediated HLA-associated infectious or auto-immune disease such as Killer cell immunoglobulin-like receptors (KIR), epistatically linked with HLA class I to regulate NK- and T-cell-mediated cytotoxic degranulation, and co-inhibitory signaling pathways for which therapeutic blockade in cancer immunotherapy is now associated with an increased incidence of DHRs. As such, the field now recognizes that susceptibility is not simply a static product of genetics but that individuals may experience dynamic risk, skewed toward immune activation through therapeutic interventions and epigenetic modifications driven by ecological exposures. This review provides an updated overview of current and proposed genetic factors thought to predispose risk for severe T-cell-mediated DHRs.

250 words Background A breast cancer biobank with retrospectively collected patient data and FFPE tissue samples was established in 2018 at Prashanti Cancer Care Mission, Pune, India. It runs a cancer care clinic with support from a single surgeon's breast cancer practice. The clinical data and tissue sample collection is undertaken with appropriate patient consent following ethical approval and guidelines. Methods The biobank holds clinical history, diagnostic reports, treatment and follow-up information along with FFPE tumor tissue specimens, adjacent normal and, in few cases, contralateral normal breast tissue. Detailed family history and germline mutational profiles of eligible and consenting patients and their relatives are also deposited in the biobank. Results Here, we report the first audit of the biobank. A total number of 994 patients with breast disease have deposited consented clinical records in the biobank. The majority of the records (80%, n = 799) are of patients with infiltrating ductal carcinoma (IDC). Of 799 IDC patients, 434 (55%) have deposited tumor tissue in the biobank with consent. In addition, germline mutation profiles of 84 patients and their family members are deposited. Follow-up information is available for 85% of the 434 IDC patients with an average follow-up of 3 years. Conclusion The biobank has aided the initiation of translational research at our center in collaboration with eminent institutes like IISER Pune and SJRI Bangalore to evaluate profiles of breast cancer in an Indian cohort. The biobank will be a valuable resource to the breast cancer research community, especially to understand South Asian profiles of breast cancer.

Summary Background Germ cell tumors of the ovary constitute less than one percent of ovarian tumors worldwide. Choriocarcinoma arising de novo from the ovary is very rare and only occasionally reported in the literature. Herein, we report a case of bilateral non-gestational pure primary ovarian choriocarcinoma that was confirmed by beta human chorionic gonadotropin (β-HCG) levels and histopathology. Case Report Our case is of a middle-aged multiparous female who presented with amenorrhea for three months. She underwent an evaluation with ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI), which revealed bilateral bulky solid adnexal masses. Based on an increased blood level of the beta human chorionic gonadotropin and a histopathological examination, the diagnosis of bilateral non-gestational pure primary ovarian choriocarcinoma was made. Conclusions The imaging findings were found to be specific for bilateral non-gestational pure primary ovarian choriocarcinoma.

VANET is the largest wireless communications research area. VANETs of rapidly moving vehicles can be inefficient or unreliable. With the passing of time, VANET technology advances via inter vehicle interaction, but many problems need to be resolved in order to strengthen the network. This paper simulates road traffic simulators in a way that ensures safe communication between different types vehicles and prevents traffic based congestion in the cities of India. Ms. Pooja Deshpande | Mrs. Vrushali Uttarwar | Ms. Ekta Choudhari "Implementing Secured and Comport Transportation using Vehicular Ad-Hoc Network for Realistic City Scenario" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-4 | Issue-1 , December 2019, URL: https://www.ijtsrd.com/papers/ijtsrd29771.pdf

Primary angiosarcoma of the breast is a rare (0.04% of all malignant breast tumors) and potentially life-threatening disease. Given its variable and non-specific clinical, radiological and pathological presentation, accurate diagnosis is a challenge. Primary angiosarcoma of the breast predominantly occurs in younger patients and it is often overlooked and misdiagnosed at radiology and pathology. To ensure that this aggressive malignancy is not overlooked, radiologists need to be aware of the fact that such tumors may present with non-specific imaging features. We report a case of a 32-year-old female with primary angiosarcoma of the breast presenting with non-specific imaging features. It was initially interpreted as a capillary cavernous hemangioma at histopathology following an ultrasound-guided biopsy. This eventually turned out to be angiosarcoma after a second histopathology opinion was sought in light of the radiology-pathology discordance.

The detection of hazardous carcinogenic heavy metals in aqueous solutions is important for biological health and environmental protection. There are various techniques to ascertain these oncogenic chemicals in an aqueous solution, like a potentiometric electrochemical sensor, spectrophotometer sensor, colorimeter sensor, and chemical sensors. As compared to other available methods, the colorimeter sensor has advantages such as low-cost instrument, qualitative sample detection, and higher precision. In this paper, the colorimeter is developed in the lab to detect hexavalent chromium [Cr (VI)] in the aqueous solution. Moreover, the absorbance principle is used to calibrate and measure the known sample concentration using amplified optical power light-emitting diodes (OP-LED). The estimation of Cr (VI) concentration in an aqueous solution is evaluated and programmed in a low-cost Arduino UNO development board. The concentration value is displayed on the touch screen. The readings displayed on the lab developed instrument annotates that the concentration percentage of the known sample can be used to determine the unknown concentration. The concentration of the known solution is determined and compared with commercially available colorimeters concerning the lab-developed colorimeter.

Rationale Allergic contact dermatitis (ACD) is a classic delayed hypersensitivity reaction commonly associated with corticosteroids that can rarely manifest as a delayed rash following systemic administration. Methods A 50-year old woman developed local edema and delayed spreading rash following interarticular injection with dexamethasone and methylprednisolone acetate (MA). 6-months following this intradermal skin testing (IDST) was positive to MA and methylprednisolone sodium succinate, and IDST and patch test negative to other corticosteroids. She tolerated dexamethasone challenge. Cells were isolated from 4-mm punch biopsies from 48-hour positive IDST and unaffected skin with liberase digestion and sorted on CD3. scTCR and scRNA-seq were performed using plate-based assays (Smart-seq-2). Data was filtered using Seurat and analysed with Visual Genomics Analysis Studio (VGAS) software. Results Histopathology showed a superficial perivascular dermatitis with epidermal spongiosis in keeping with ACD. T-cells were 18x more prevalent in affected skin and those from both affected and unaffected sites were predominantly CD8+ T-cells that expressed CD45RO and polyclonal TCR alpha beta. Differentially expressed genes (DEG) in T-cells from affected skin reflected homing (CCR7,S1PR1), T-cell activation and proliferation (TNFRS9, GRAP2, ZYG11A, ZHX1), T-cell effector differentiation (IL-21R), and stress survival (EEF1A1, IFI6) without representation of markers of T-cell residency (ITGAE) or regulation. Conclusions We demonstrate insights into the immunopathogenesis of drug-induced ACD by showing that IDST+ methylprednisolone associated ACD is corticosteroid-specific and associated with a polyclonal population of primarily CD45RO+ memory CD8+ T-cells showing upregulation of markers of homing, T-cell activation, proliferation and differentiation but lacking markers of T-cell residency and regulation.

Summary The aim of this study was to determine the prevalence and type of autoantibodies in a general Australian population cohort. Samples collected from 198 individuals included in a cross sectional Busselton Health Study were tested using autoantibody assays routinely performed at Clinical Immunology, PathWest Laboratory Medicine, Western Australia. At least one autoantibody was detected in 51.5% of individuals (males = 45.1%, females = 58.3%). The most frequently detected serum autoantibodies were anti-beta-2-glycoprotein I (12.1%) followed by anti-smooth muscle (11.6%) and anti-thyroid peroxidase (8.6%). Vasculitis associated anti-neutrophil cytoplasmic antibodies were present in 5.1%, while anti-nuclear antibodies were detected in 8.6% of individuals. Notably, 65% of positive results were detected at low levels with the exception of anti-myeloperoxidase and anti-beta 2 glycoprotein I IgG antibodies. Autoantibodies are commonly detected at low levels in a predominantly Australian or European population cohort. No large Australian study has yet provided these data for contemporary routine tests. This paper gives important information on the background frequency of autoantibodies in the general population. Due to the nature of this study we are unaware of whether these individuals have subsequently developed an autoimmune disease, however this was not clinically diagnosed at the time of sample collection.

Hepatitis C virus (HCV)-specific T cell responses are critical for immune control of infection. Viral adaptation to these responses, via mutations within regions of the virus targeted by CD8+ T cells, is associated with viral persistence. However, identifying viral adaptation to HCV-specific CD4+ T cell responses has been difficult although key to understanding anti-HCV immunity. In this context, HCV sequence and host genotype from a single source HCV genotype 1B cohort (n = 63) were analyzed to identify viral changes associated with specific human leucocyte antigen (HLA) class II alleles, as these variable host molecules determine the set of viral peptides presented to CD4+ T cells. Eight sites across the HCV genome were associated with HLA class II alleles implicated in infection outcome in this cohort (p ≤ 0.01; Fisher’s exact test). We extended this analysis to chronic HCV infection (n = 351) for the common genotypes 1A and 3A. Variation at 38 sites across the HCV genome were associated with specific HLA class II alleles with no overlap between genotypes, suggestive of genotype-specific T cell targets, which has important implications for vaccine design. Here we show evidence of HCV adaptation to HLA class II-restricted CD4+ T cell pressure across the HCV genome in chronic HCV infection without a priori knowledge of CD4+ T cell epitopes.

Host hepatitis C virus (HCV)-specific T cell responses and the ability of the virus to escape this response are important correlates of infection outcome. Understanding this host-viral interplay has been difficult given the often asymptomatic nature of acute HCV infection. We studied a recent transmission case to determine whether adapted viral strains can be transmitted and influence the recipient's anti-HCV T cell response. The diversity of viral populations was examined using next-generation sequencing, and HCV-specific T cell interferon (IFN)-γ responses were assessed using a peptide panel representing the autologous viruses. HCV-specific T cell responses in the source were directed against peptides that did not match the dominant autologous virus but rather low-frequency variants, implying existing viral adaptation in the source strain. Most HCV T cell epitopes that elicited an IFN-γ response in the source did not in the recipient, despite the pair sharing human leukocyte antigen alleles that govern antigen presentation and similar autologous viruses. Intrahost HCV variation in the recipient fell within predicted T cell epitopes, suggesting alternative targets of the immune response. These data suggest that transmission of adapted viral species can direct the host's HCV-specific immune response profile during acute infection.

Objective: To assess the effect of vitamin D administration on the skin blood flow response to occlusion and heat. Design: Cross-sectional study. Methods: Twenty age matched subjects; 10 who had diabetes and 10 who were controls were administered 4,000 IU of vitamin D3 for 3 weeks at breakfast. The function of the endothelial cells was evaluated in 2 ways; first, the response to 4 minutes of vascular occlusion of the skin was measured with a laser Doppler flow meter. Second, the skin blood flow response to local heat at 42 degrees C for 6 minutes was examined. Results: The results of the experiments showed that the blood flow response to heat was reduced after 3 weeks administration of vitamin D in the subjects with diabetes and in the control subjects (p

Infection is the leading cause of death in rheumatoid arthritis (RA). Corticosteroid (CS) use is a known and important risk factor for serious infections (SIs). Mannose binding lectin (MBL) is a genetically determined component of the innate immune system implicated in neonatal infections.Our aim was to determine whether MBL deficiency is a risk factor for SIs in RA and to compare it with CS use and also synthetic and biologic disease-modifying antirheumatic drug (DMARD) therapy.Data on 228 patients with RA were collected for up to 7 years (median = 5.9 years). Serum MBL concentrations were determined in all patients receiving synthetic (n = 96) or biologic (n = 132) DMARD therapy.High rates of SIs were observed in RA irrespective of treatment (17%). Similar rates of SIs were observed in synthetic and biologic DMARD users. The rates of single and multiple SIs were similar, irrespective of the use of a biologic agent. Undetectable MBL (56 ng/mL) concentrations and maintenance prednisolone at 10 mg per day or higher were associated with an increased risk for an SI, with incident risk ratio of 4.67 (P = .001) and 4.70 (P.001), respectively.Undetectable MBL and prednisolone confer a high risk for an SI. The use of biologic DMARDs did not confer substantial SI risk in this observational study. MBL deficiency is hitherto an unrecognized risk factor for an SI in RA.

Balance is sensed through peripheral and central receptors and mediated by central control through the brain and spinal cord. Although some evidence exists as to the areas of the brain involved and how processing of data occurs in young individuals, nothing has been published on people with diabetes. The purpose of this study was to examine the electroencephalogram (EEG) during common sensorimotor and balance training tasks and to relate these to task difficulty.Postural sway and EEG change of alpha, beta, and sigma wave bands were measured in 17 young subjects, 10 older subjects, and 10 subjects with diabetes during eight progressively more difficult balance tasks with eyes open and closed, feet in tandem or apart, and on foam or a firm surface.EEG power of beta and sigma wave bands showed significant increases on the cortical and parietal areas of the brain relative to the control tasks when eyes were open (P0.05). The cortical involvement decreased as the task became more difficult with vision and somatosensory information reduced, whereas that of the parietal area increased with task difficulty. The greatest increase was in subjects with diabetes, and the least was in younger people. Individuals with diabetes had increased sigma and beta EEG power in all regions of the brain examined with increased complexity of the balance task.This study demonstrated cortical and parietal involvement in static balance tasks commonly used in sensorimotor training. The results support the proposal that there was increased subcortical control with increase in task difficulty in the young subjects, but in subjects with diabetes, there was a major increase in activity across the brain.

Epigenetic regulations are heritable changes in gene expression that occur in the absence of alterations in DNA sequences. Various epigenetic mechanisms include histone modifications and DNA methylations. In this review, we examine methods to study DNA methylations and their contribution to degenerative diseases by mediating the complex gene-by-environment interactions. Such epigenetic modifications despite being heritable and stably maintained are also potentially reversible and there is scope for the development of epigenetic therapies for this disease.

With aging, the detrimental effects of stress can impair a person's ability to learn and sustain memory. Humor and its associated mirthful laughter can reduce stress by decreasing the hormone cortisol. Chronic release of cortisol can damage hippocampal neurons, leading to impairment of learning and memory. Objectives • The study intended to examine the effect of watching a humor video on short-term memory in older adults. Design • The research team designed a randomized, controlled trial.The study took place at Loma Linda University in Loma Linda, CA, USA.The study included 30 participants: 20 normal, healthy, older adults-11 males and 9 females-and 10 older adults with type 2 diabetes mellitus (T2DM)-6 males and 4 females.The study included 2 intervention groups of older adults who viewed humorous videos, a healthy group (humor group), aged 69.9 ± 3.7 y, and the diabetic group, aged 67.1 ± 3.8 y. Each participant selected 1 of 2 humorous videos that were 20 min in length, either a Red Skeleton comedy or a montage of America's Funniest Home Videos. The control group, aged 68.7 ± 5.5 y, did not watch a humor video and sat in quiescence.A standardized, neuropsychological, memory-assessment tool, the Rey Auditory Verbal Learning Test (RAVLT), was used to assess the following abilities: (1) learning, (2) recall, and (3) visual recognition. The testing occurred twice, once before (RAVLT1) and once after (RAVLT2) the humorous video for the humor and diabetic groups, and once before (RAVLT1) and once after (RAVLT2) the period of quiescence for the control group. At 5 time points, measurements of salivary cortisol were also obtained. The Kruskal-Wallis test was used to measure significance of the data based on the 3 groups.In the humor, diabetic, and control groups, (1) learning ability improved by 38.5%, 33.4%, and 24.0%, respectively (P = .025); (2) delayed recall improved by 43.6%, 48.1%, and 20.3%, respectively (P = .064); and (3) visual recognition increased by 12.6%, 16.7%, and 8.3%, respectively (P = .321). For levels of salivary cortisol, the research team found significant and borderline decreases for the humor group between baseline and (1) post-RAVLT1 (P = .047), (2) postvideo (P = .046), and (3) post-RAVLT2 (P = .062). The diabetic group showed significant decreases between baseline and (1) post-RAVLT1 (P = .047), (2) postvideo (P = .025), and (3) post-RAVLT2 (P = .034). The study found no significant changes for the control group.The research findings supported potential clinical and rehabilitative benefits for humor that can be applied to whole-person wellness programs for older adults. The cognitive components-learning ability and delayed recall-become more challenging as individuals age and are essential to older adults for providing a high quality of life: mind, body, and spirit. Because older adults can experience age-related memory deficits, complementary, enjoyable, and beneficial humor therapies should be implemented for them.

The interaction between hepatitis C virus (HCV) and cellular immune responses during very early infection is critical for disease outcome. To date, the impact of antigen-specific cellular immune responses on the evolution of the viral population establishing infection and on potential escape has not been studied. Understanding these early host-virus dynamics is important for the development of a preventative vaccine. Three subjects who were followed longitudinally from the detection of viremia preseroconversion until disease outcome were analyzed. The evolution of transmitted/founder (T/F) viruses was undertaken using deep sequencing. CD8 + T cell responses were measured via enzyme-linked immunosorbent spot (ELISpot) assay using HLA class I-restricted T/F epitopes. T/F viruses were rapidly extinguished in all subjects associated with either viral clearance ( n = 1) or replacement with viral variants leading to establishment of chronic infection ( n = 2). CD8 + T cell responses against 11 T/F epitopes were detectable by 33 to 44 days postinfection, and 5 of these epitopes had not previously been reported. These responses declined rapidly in those who became chronically infected and were maintained in the subject who cleared infection. Higher-magnitude CD8 + T cell responses were associated with rapid development of immune escape variants at a rate of up to 0.1 per day. Rapid escape from CD8 + T cell responses has been quantified for the first time in the early phase of primary HCV infection. These rapid escape dynamics were associated with higher-magnitude CD8 + T cell responses. These findings raise questions regarding optimal selection of immunogens for HCV vaccine development and suggest that detailed analysis of individual epitopes may be required. IMPORTANCE A major limitation in our detailed understanding of the role of immune response in HCV clearance has been the lack of data on very early primary infection when the transmitted viral variants successfully establish the acute infection. This study was made possible through the availability of specimens from a unique cohort of asymptomatic primary infection cases in whom the first available viremic samples were collected approximately 3 weeks postinfection and at regular intervals thereafter. The study included detailed examination of both the evolution of the viral population and the host cellular immune responses against the T/F viruses. The findings here provide the first evidence of host cellular responses targeting T/F variants and imposing a strong selective force toward viral escape. The results of this study provide useful insight on how virus escapes the host response and consequently on future analysis of vaccine-induced immunity.

Characterisation of Hepatitis C virus (HCV)-specific CD8+ T-cell responses in the context of multiple HCV exposures is critical to identify broadly protective immune responses necessary for an effective HCV vaccine against the different HCV genotypes. However, host and viral genetic diversity complicates vaccine development. To compensate for the observed variation in circulating autologous viruses and host molecules that restrict antigen presentation (human leucocyte antigens; HLA), this study used a reverse genomics approach that identified sites of viral adaptation to HLA-restricted T-cell immune pressure to predict genotype-specific HCV CD8+ T-cell targets. Peptides representing these putative HCV CD8+ T-cell targets, and their adapted form, were used in individualised IFN-γ ELISpot assays to screen for HCV-specific T-cell responses in 133 HCV-seropositive subjects with high-risk of multiple HCV exposures. The data obtained from this study i) confirmed that genetic studies of viral evolution is an effective approach to detect novel in vivo HCV T-cell targets, ii) showed that HCV-specific T-cell epitopes can be recognised in their adapted form and would not have been detected using wild-type peptides and iii) showed that HCV-specific T-cell (but not antibody) responses against alternate genotypes in chronic HCV-infected subjects are readily found, implying clearance of previous alternate genotype infection. In summary, HCV adaptation to HLA Class I-restricted T-cell responses plays a central role in anti-HCV immunity and multiple HCV genotype exposure is highly prevalent in at-risk exposure populations, which are important considerations for future vaccine design.

For older adults, the damaging effects of aging and stress can impair the ability to learn and sustain memory. Humor, with its associated mirthful laughter, can reduce stress and cortisol, a stress hormone. Chronic release of cortisol can damage hippocampus neurons, leading to impairment of learning and memory.The primary goal of this study was to determine whether watching a humorous video had an effect on short-term memory in an older population.The research team designed a randomized, controlled trial.The study took place at Loma Linda University in Loma Linda, California.The research team recruited 20 normal, healthy, older adults, 11 males and 9 females.The humor group (n = 10, mean = 69.3 ± 3.7 y) self-selected 1 of 2 humorous videos--a Red Skelton comedy or a montage of America's Funniest Home Videos--and watched it for 20 min. A control group (n = 10, mean = 68.7 ± 5.5 y) sat calmly for 20 min and were not allowed to read, sleep, or talk on a cell phone.The Rey Auditory Verbal Learning Test was used to assess short-term memory--learning ability, delayed recall, and visual recognition. Salivary cortisol levels were measured at predetermined times.Learning ability improved by 38.5% and 24.0% in the humor and control groups, respectively (P = .014). Delayed recall improved by 43.6% and 20.3% in the humor and control groups, respectively (P =.029). Within the humor group, delayed recall (43.6%) was significant compared with learning ability (38.5%) (P = .002). At 3 predetermined time points, significant decreases in salivary cortisol were observed in the humor group (P = .047, P = .046, and P = .062, respectively).The study's findings suggest that humor can have clinical benefits and rehabilitative implications and can be implemented in programs that support whole-person wellness for older adults. Learning ability and delayed recall are important to these individuals for a better quality of life--considering mind, body, spirit, social, and economic aspects. Older adults may have age-associated memory deficiencies. However, medical practitioners now can offer positive, enjoyable, and beneficial humor therapies to improve these deficiencies.

With ageing, the damaging effects of stress can impair the ability to learn and sustain memory. The purpose was to examine the effect of watching a humor video on short term memory in 3 age matched...

Background It is well established that there is a reduction in the skin blood flow (SBF) in response to heat with age and diabetes. While it is known that high BMI creates a stress on the cardiovascular system and increases the risk of all cause of morbidity and mortality, little is known of the effect of high BMI on SBF response to heat. Since diabetes is associated with age and a higher BMI, the interrelationship between age, BMI and SBF needs to be investigated to better understand the contribution diabetes alone has to endothelial impairment. Material/Methods This study examined the SBF to heat in young and old people with low and high BMI and people with diabetes with high BMI to determine the contribution these variables have on SBF. Subjects were ten young and older people with BMI 20 and ten subjects with diabetes with BMI >20. The SBF response, above the quadriceps, was determined during a 6 minutes exposure to heat at 44°C. Results Even in young people, SBF after the stress of heat exposure was reduced in subjects with a high BMI. The effect of BMI was greatest in young people and lowest in older people and people with diabetes; in people with diabetes, BMI was a more significant variable than diabetes in causing impairment of blood flow to heat. BMI, for example, was responsible for 49% of the reduction in blood flow after stress heat exposure (R=−0.7) while ageing only accounted for 16% of the blood flow reduction (R=−0.397). Conclusions These results would suggest the importance of keeping BMI low not only in people with diabetes to minimize further circulatory vascular damage, but also in young people to diminish long term circulatory vascular compromise.