Casting a wider net: Immunosurveillance by nonclassical MHC molecules.

Most studies of T lymphocytes focus on recognition of classical major histocompatibility complex (MHC) class I or II molecules presenting oligopeptides, yet there are numerous variations and exceptions of biological significance based on recognition of a wide variety of nonclassical MHC molecules. These include αß and γδ T cells that recognize different class Ib molecules (CD1, MR-1, HLA-E, G, F, et al.) that are nearly monomorphic within a given species. Collectively, these T cells can be considered "unconventional," in part because they recognize lipids, metabolites, and modified peptides. Unlike classical MHC-specific cells, unconventional T cells generally exhibit limited T-cell antigen receptor (TCR) repertoires and often produce innate immune cell-like rapid effector responses. Exploiting this system in new generation vaccines for human immunodeficiency virus (HIV), tuberculosis (TB), other infectious agents, and cancer was the focus of a recent workshop, "Immune Surveillance by Non-classical MHC Molecules: Improving Diversity for Antigens," sponsored by the National Institute of Allergy and Infectious Diseases. Here, we summarize salient points presented regarding the basic immunobiology of unconventional T cells, recent advances in methodologies to measure unconventional T-cell activity in diseases, and approaches to harness their considerable clinical potential.

Young-onset type 2 diabetes and younger current age: increased susceptibility to retinopathy in contrast to other complications.

BACKGROUND: Type 2 diabetes diagnosed during youth and early adulthood is aggressive and associated with a high burden of vascular complications. The increase in complications is often attributed to long disease duration and poor metabolic control. Whether people with young-onset type 2 diabetes are inherently more susceptible to long-term complications than those diagnosed in later adulthood is unclear. METHODS: Prospective data from 3322 individuals, diagnosed between the age of 15 and 70 years and collected 10-25 years after diabetes diagnosis, were analysed. The cross-sectional associations between age at diagnosis and microvascular and macrovascular complications were analysed using logistic regression models, adjusted for duration of diabetes exposure and metabolic risk factors including blood pressure, cholesterol and updated mean HbA1c . RESULTS: The prevalence of retinopathy was highest in those with young-onset type 2 diabetes (diagnosed at age 15 to <40 years). After 10-15 years' diabetes duration, the adjusted odds ratio for retinopathy in this population was 2.8 (95% CI 1.9-4.1; reference group those diagnosed at 60 to <70 years of age). The odds of retinopathy remained higher in people with young-onset type 2 diabetes after longer durations of diabetes exposure; the odds decreased with increasing age at diagnosis. This pattern was not observed in models of other complications: after 10-15 years' diabetes exposure, the adjusted odds ratios for albuminuria, peripheral neuropathy and macrovascular disease in people with young-onset type 2 diabetes were 0.5 (95% CI 0.4-0.8), 0.7 (95% CI 0.5-1.1) and 0.2 (95% CI 0.1-0.3), respectively. CONCLUSION: After accounting for disease duration and other important confounders, people with type 2 diabetes diagnosed in youth and early adulthood (or with a younger current age) appeared to be inherently more susceptible to retinopathy. For other complications, adjusted risk appears highest in the oldest age of diagnosis group. These data have screening and treatment target implications.

Development and validation of a real-time PCR assay for the glassy-winged sharpshooter Homalodisca vitripennis (Hemiptera: Cicadellidae).

The glassy-winged sharpshooter (Homalodisca vitripennis) is an invasive pest organism, which is found throughout Central America and has recently invaded a few countries in the Pacific Islands. As a carrier of the highly virulent plant pathogenic bacterium Xylella fastidiosa, it is of great economic significance to horticulture and is estimated to cost Californian vineyards over US$100 million per year in control and losses. New Zealand is currently free from this pest, but its recent spread through the Pacific has raised concerns of it establishing in New Zealand, potentially as a result of introduction through human travel. We report here a real-time polymerase chain reaction assay for the rapid identification of H. vitripennis. The assay was extensively validated in silico then optimized and tested against a range of Cicadellidae species, both internationally collected and local to New Zealand. This assay was able to correctly identify H. vitripennis samples, and distinguish between H. vitripennis and close relatives, such as the smoke-tree sharpshooter (Homalodisca liturata) and will be of great benefit to New Zealand biosecurity.

An Integrated DAIDS Laboratory Oversight Framework: Application of the DAIDS GCLP Guidelines.

The Division of AIDS (DAIDS) Good Clinical Laboratory Practice (GCLP) Guidelines establish a framework to guide the oversight of laboratories supporting DAIDS-sponsored clinical research or trials. Compliance with these guidelines promotes data reliability, consistency, validity, and the safety of the clinical research or trial participants and laboratory staff, as well as ensures adherence to regulatory requirements. This article describes the application of the DAIDS GCLP Guidelines, the DAIDS Integrated Laboratory Oversight Framework, and the coordinated efforts of the collaborative oversight team of laboratory experts to support and monitor the performance of over 175 participating laboratories worldwide. Data from two self-administered online surveys conducted in 2017 and 2023 assessed the laboratory staff's experience implementing the GCLP Guidelines. The results of the 2017 survey were instrumental in informing changes to GCLP audit activities and promoting harmonization in the approach to laboratory oversight. A key finding from the 2023 survey results is the preference for hybrid GCLP training encompassing face-to-face and online modules. Overall, both surveys acknowledged satisfaction with applying and implementing GCLP Guidelines. The need to effectively disseminate information about DAIDS laboratory oversight requirements to support the improved implementation of GCLP Guidelines was notable from both survey results. The collaborative team of laboratory experts and the integrated oversight approach promote knowledge-sharing and accountability to support the application of the GCLP Guidelines and compliance monitoring. The systematic implementation of the integrated laboratory oversight activities helped identify valuable lessons for improving laboratory performance and opportunities to strengthen quality oversight for laboratories participating in clinical research or trials. .

Incidences and Clinical Implications of Communications between Musculocutaneous Nerve and Median Nerve in the Arm - A Cadaveric Study.

OBJECTIVES: Variations such as communications between median nerve and musculocutaneous nerve or in their abnormal branching pattern constitute a major concern in clinical and surgical field. Knowledge of these variations not only provides the clinician with a proper interpretation of the case, but also minimizes the complication in surgical approaches in this region. METHOD: We examined 50 isolated upper limbs to investigate the possible incidences of various types of communications between these two neighbouring peripheral nerves. RESULT: Twenty-eight per cent of limbs were found to have communication between these two nerves. When categorized according to Venieratos and Anagnostopoulou's classification method, 11 out of 14 cases (79%) showed type I communications, two out of 14 (14%) showed type II and the remaining one (7%) showed type III communication pattern. CONCLUSION: Prior knowledge of communications between these two neighbouring nerves, both in terms of their incidences and pattern of communications, may be of considerable significance to neurologists and orthopaedic surgeons in dealing with nerve entrapment syndromes in the upper limb of patients.

Micro RNA expression profiles as adjunctive data to assess the risk of hepatocellular carcinoma recurrence after liver transplantation.

Donor livers are precious resources and it is, therefore, ethically imperative that we employ optimally sensitive and specific transplant selection criteria. Current selection criteria, the Milan criteria, for liver transplant candidates with hepatocellular carcinoma (HCC) are primarily based on radiographic characteristics of the tumor. Although the Milan criteria result in reasonably high survival and low-recurrence rates, they do not assess an individual patient's tumor biology and recurrence risk. Consequently, it is difficult to predict on an individual basis the risk for recurrent disease. To address this, we employed microarray profiling of microRNA (miRNA) expression from formalin fixed paraffin embedded tissues to define a biomarker that distinguishes between patients with and without HCC recurrence after liver transplant. In our cohort of 64 patients, this biomarker outperforms the Milan criteria in that it identifies patients outside of Milan who did not have recurrent disease and patients within Milan who had recurrence. We also describe a method to account for multifocal tumors in biomarker signature discovery.

Prediction of long-term disability in multiple sclerosis.

BACKGROUND: Little is known about the predictive value of neurophysiological measures for the long-term course of multiple sclerosis (MS). OBJECTIVE: To prospectively investigate whether combined visual (VEP) and motor evoked potentials (MEP) allow prediction of disability over 14 years. METHODS: A total of 30 patients with relapsing-remitting and secondary progressive MS were prospectively investigated with VEPs, MEPs and the Expanded Disability Status Scale (EDSS) at entry (T0) and after 6, 12 and 24 months, and with cranial MRI scans at entry (T2-weighted and gadolinium-enhanced T1-weighted images). EDSS was again assessed at year 14 (T4). The association between evoked potential (EP), magnetic resonance (MR) data and EDSS was measured using Spearman's rank correlation. Multivariable linear regression was performed to predict EDSS(T4) as a function of z-transformed EP-latencies(T0). The model was validated using a jack-knife procedure and the potential for improving it by inclusion of additional baseline variables was examined. RESULTS: EDSS values(T4) correlated with the sum of z-transformed EP-latencies(T0) (rho = 0.68, p < 0.0001), but not with MR-parameters(T0). EDSS(T4) as predicted by the formula EDSS(T4) = 4.194 + 0.088 * z-score P100(T0) + 0.071 * z-score CMCT(UE, T0) correlated with the observed values (rho = 0.69, p < 0.0001). CONCLUSION: Combined EPs allow prediction of long-term disability in small groups of patients with MS. This may have implications for the choice of monitoring methods in clinical trials and for daily practice decisions.

Ovarian development in Wistar rat treated prenatally with single dose diisobutyl phthalate.

Phthalates are a class of industrial compounds with an array of toxicological properties used in day to day life. Diisobutyl phthalate on (DIBP) is used as an additive to keep the plastics soft or flexible (plasticizer) in nitrocellulose plastic, nail polish, explosives, lacquer manufacturing etc. Although DIBP exposure in humans is generally low, people in adhesive industries and pharmaceutical industries are exposed to higher levels. The aim of this study was to determine the effect of single dose of DIBP on developing ovary of Wistar rat. One hundred and eight adult pregnant Wistar rats were divided into control and experimental groups. Rats in experimental group were given DIBP on day 10, 12 and 14 of gestation at 0.375, 0.75 and 1.25 ml/kg body weight dose intraperitoneally in a single dose. Sections of ovaries collected on day 21 of gestation were stained with hematoxylin and eosin and examined and Masson's trichrome histologically. Sections belonging to the control group showed the presence of oocytes in clusters separated by thin fibrous septa. Degeneration oocytes, empty follicles surrounded by follicular cells without gonocytes in the center were observed in ovarian stroma. Blood vessels in the ovarian stroma were prominent and congested. Around a bunch of follicles total architectural disarray was observed although on special staining fibrosis was not evident. As pregnant women are constantly exposed, effect of DIBP on ovary of a developing fetus would denote the long term consequence in future generations (Fig. 5, Ref. 39).

Leveraging lessons learned from the COVID-19 pandemic for HIV.

The rapid development of COVID-19 vaccines and their deployment in less than a year is an unprecedented scientific, medical, and public health achievement. This rapid development leveraged knowledge from decades of HIV/AIDS research and advances. However, the search for an HIV vaccine that would contribute to a durable end to the HIV pandemic remains elusive. Here, we draw from the US government experience and highlight lessons learned from COVID-19 vaccine development, which include the importance of public-private partnerships, equitable inclusion of populations impacted by the infectious pathogen, and continued investment in basic research. We summarize key considerations for an accelerated and re-energized framework for developing a safe and efficacious HIV vaccine.

Formulation, pharmacokinetics and biodistribution of Ofloxacin-loaded albumin microparticles and nanoparticles.

Albumin microparticles containing Ofloxacin (Fluoroquinolone derivative commonly used in hospitals) were formulated by the spray dry method. By decreasing the pump feed rate or the total polymer concentration, a mixture of albumin/hypromellose acetate succinate (HPMCAS) microparticles and nanoparticles (MP/NP), containing Ofloxacin, were formulated. MP/NP were characterized, in vitro (particle size, zeta potential, and encapsulation efficiency). A comparison of the pharmacokinetics and biodistribution of aqueous Ofloxacin and Ofloxacin-loaded MP/NP, in Balb/c mice, revealed that peak concentrations were reduced in the serum, liver, spleen and brain, and a more sustained release was observed in serum and all of the organs tested for Ofloxacin MP/NP, compared to aqueous Ofloxacin. The MP/NP formulation allowed extended release by 24 h in the liver and more than 48 h in the brain. In serum, the elimination rate of Ofloxacin MP/NP is slower, the half life is longer, area under the plasma concentration time curve is decreased and volume of distribution is increased.

Acute HIV-1 infection: what's new? Where are we going?

This supplemental issue of the Journal of Infectious Diseases is devoted to the important topic of primary human immunodeficiency virus type 1 (HIV-1) infection. It was prompted by the planning of the Acute HIV-1 Infection Meeting in Boston in September 2009, at which leading scientists and practitioners gathered to discuss new insights into the early, critical events of HIV-1 infection. The reviews that follow underline the current state of the field with regard to transmission biology of HIV-1; the clinical presentation, diagnosis, and management of primary HIV-1 infection; the pathogenesis of primary HIV-1 infection; and innate and adaptive immune responses to the virus. We trust that these findings have the potential to influence the development of effective vaccine strategies.

Challenges for rapid molecular HIV diagnostics.

The introduction of serological point-of-care assays 10 years ago dramatically changed the way that human immunodeficiency virus (HIV) infection was identified and diagnosed. Testing at the point of care has lead to a dramatic increase in the number of individuals who are screened and, most importantly, receive their HIV test result. As the AIDS epidemic continues to mature and scientific advances in prevention and treatment are evaluated and implemented, there is a need to identify acute (viremic preseroconversion) infections and to discriminate "window phase" infections from those that are serologically positive, especially in resource-limited settings, where the majority of vulnerable populations reside and where the incidence of HIV infection is highest. Rapid testing methods are now at a crossroads. There is opportunity to implement and evaluate the incremental diagnostic usefulness of new test modalities that are based on sophisticated molecular diagnostic technologies and that can be performed in settings where laboratory infrastructure is minimal. The way forward requires sound scientific judgment and an ability to further develop and implement these tests despite a variety of technical, social, and operational hurdles, to declare success.

Research productivity and collaboration of the NIH-funded HIV vaccine trials network: A bibliometric analysis.

The HIV Vaccine Trials Network (HVTN) is the world's largest publicly funded, multi-disciplinary international collaboration facilitating the development of vaccines to prevent HIV/AIDS and has conducted the vast majority of HIV/AIDS clinical trials since its inception in 1999. Although scientific findings from the program have been published in scholarly journals, the impact of a large scientific research network such as the HVTN on the HIV/AIDS vaccine field has not been assessed. This paper describes and elucidates the productivity, influence, and collaboration among HVTN researchers over the last two decades. Our analyses indicate that the HVTN has funded a large number of HIV/AIDS vaccine safety and efficacy clinical trials through a strong global network of clinical sites. In addition, several metrics indicate HVTN researchers also published original research articles that are influential in the HIV vaccine field. Scientific research collaboration is critically important in a complex and multidisciplinary field such as HIV vaccine development as it allows improved sharing of knowledge and expertise as well as the pooling of resources and data. We found that collaboration in the HIV vaccine field increased during this time period and collaboration among HVTN authors increased even more. Combining these productivity, influence, and collaboration metrics with research outcomes can provide a comprehensive assessment of large complex programs such as the HVTN.

Mind the gap from research laboratory to clinic: Challenges and opportunities for next-generation assays in human diseases.

Modern vaccinology has experienced major conceptual and technological advances over the past 30 years. These include atomic-level structures driving immunogen design, new vaccine delivery methods, powerful adjuvants, and novel animal models. In addition, utilizing advanced assays to learn how the immune system senses a pathogen and orchestrates protective immunity has been critical in the design of effective vaccines and therapeutics. The National Institute of Allergy and Infectious Diseases of the National Institutes of Health convened a workshop in September 2020 focused on next generation assays for vaccine development (Table 1). The workshop focused on four critical pathogens: severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and human immunodeficiency virus (HIV)-which have no licensed vaccines-and tuberculosis (TB) and influenza-both of which are in critical need of improved vaccines. The goal was to share progress and lessons learned, and to identify any commonalities that can be leveraged to design vaccines and therapeutics.

Short term methylphenidate treatment does not increase myocardial injury in the ischemic rat heart.

Methylphenidate is commonly used for the treatment of attention deficit hyperactivity disorder. The cardiovascular safety of methylphenidate has been a subject of debate with some studies indicating that methylphenidate increases the likelihood of experiencing a myocardial infarction. However, it is unknown whether methylphenidate worsens the extent of injury during an ischemic insult. The purpose of this study was to determine whether short term exposure to methylphenidate increases the extent of myocardial injury during an ischemic insult. Male and female rats received methylphenidate (5 mg/kg/day) or saline for 10 days by oral gavage. Hearts were subjected to 20 min of ischemia and 2 h of reperfusion on a Langendorff isolated heart apparatus on day 11. Cardiac contractile function was monitored via an intraventricular balloon and myocardial injury was assessed by triphenyltetrazolium chloride staining. Methylphenidate significantly increased locomotor activity in male and female rats, confirming absorption of this psychostimulant into the central nervous system. Male hearts had significantly larger infarcts than female hearts, but methylphenidate had no impact on infarct size or postischemic recovery of contractile function in hearts of either sex. These data indicate that methylphenidate does not increase the extent of injury induced by an ischemic insult.

Engineering immunity for next generation HIV vaccines: The intersection of bioengineering and immunology.

Bioengineering approaches grounded in immunology have the potential for the discovery and development of a successful HIV vaccine. The overarching goal is to engineer immunity through a fusion of immunology with bioengineering to create novel strategies for the design, development and delivery of vaccines based on the controlled modulation of the immune system. To foster these collaborations, the National Institute of Allergy and Infectious Diseases (NIAID) and National Institute of Biomedical Imaging and Bioengineering (NIBIB) brought together a group of experts (see Table 1) from these diverse fields for a workshop in September 2018 to: (1) engage the engineering, immunology, and HIV vaccinology communities to dialogue on the topic of an HIV vaccine and; (2) generate a framework of new and innovative research avenues to explore in HIV vaccinology between knowledge stakeholders and problem solvers.

Airborne contact dermatitis induced by parthenium: a study of 50 cases in South India.

Airborne contact dermatitis (ABCD) is a commonly occurring form of allergic contact dermatitis with varied aetiology, often posing a diagnostic challenge in management. A study was carried out on patients with a clinical picture and history consistent with ABCD due to exposure to Parthenium hysterophorus (parthenium weed), who were patch tested. There were 50 patients with parthenium-induced ABCD (36 men and 14 women; age range 24-75 years). The majority (90%) of the patients were farmers and most of the patients (74.5%) had exacerbations during summer. The most common type of dermatitis was the classic pattern (46%) followed by the mixed pattern (30%), erythroderma (14%) and chronic actinic dermatitis (10%). Of the 40 cases patch tested with the Indian standard series of antigens, 36 (90%) cases had patch-test results positive for parthenium.

Disseminated rhinosporidiosis with unusual involvement of the nail apparatus.

Rhinosporidiosis is an uncommon chronic granulomatous disease caused by Rhinosporidium seeberi. It primarily affects the nasal mucosa and the nasopharynx. The disease may disseminate to the skin, larynx, trachea, genitalia, bones and even the internal organs. Although simultaneous onset of nasal and disseminated lesions has been reported, dissemination usually occurs several years after the onset of nasal lesions. We report a rare case of disseminated rhinosporidiosis involving both nares, the nasal mucosa, nasopharynx, oral cavity and oropharynx, as well as widespread cutaneous lesions over the trunk and the limbs with nail involvement. This last feature has not, to our knowledge, been previously reported.