Search

SUMMARY In order to identify T cell epitopes within the Mycobacterium leprae 45-kD serine-rich antigen, we analysed responses to overlapping 17-mer peptides encompassing the whole antigen in non-exposed UK controls, Pakistani leprosy patients and tuberculosis patients in both the United Kingdom and Pakistan. This antigen has been described as M. leprae -specific, although it has a hypothetical homologue in M. tuberculosis . Human peripheral blood mononuclear cells were stimulated with peptide for 5 days and IFN-γ measured in supernatants by ELISA. Some peptides were recognized more frequently by T cells from tuberculoid leprosy patients than those from UK controls, suggesting that such T cell epitopes might have diagnostic potential, while other peptides induced greater responses among UK control subjects. Short-term cell lines confirmed that these assays detected specific T cell recognition of these peptides. However, many tuberculosis patients also recognized these potentially specific peptides suggesting that there could be a true homologue present in M. tuberculosis . [ABSTRACT FROM AUTHOR]

Cachexia is one of the prominent features of advanced tuberculosis (TB) seen in association with increased expression of the monokine TNF-α. Several mycobacterial proteins, including PPD, stimulate TNF-α secretion from monocytes. Host factors that may play a role in cytokine expression from monocytes remain largely unknown. One such factor is the opsonizing antibodies. Monocytes have high-affinity receptors (FcγI and FcγIII) for IgG1 and IgG3 antibodies that mediate antigen uptake. We have reported selective up-regulation of IgG1 (which bind to Fcγ receptors) in advanced TB and have recently shown the ability of PPD-specific IgG1 antibodies to augment TNF-α expression in PPD-stimulated monocytes. These observations have now been extended to other cytokines with semipurified fractions from secreted antigens of Mycobacterium tuberculosis (containing 30 kD and 58 kD) that were devoid of lipids, glycolipids and carbohydrates. In the presence of heat-inactivated TB plasma containing known amounts of antigen-specific IgG1 antibodies, these fractions induced significantly increased TNF-α, IL-6 and IL-10 secretion. Absorption of IgG1 with Protein ‘A’ removed the augmenting activity for TNF-α and IL-6 secretion from the TB plasma samples. In the case of IL-10, removal of IgG1 resulted in increased rather than decreased IL-10 secretion. These results suggest a possible pathogenic role for antibodies in TB by enhancing proinflammatory and blocking down-regulatory cytokines such as IL-10 cytokines during the chronic phase of TB. [ABSTRACT FROM AUTHOR]

Examines the role of immunoglobulin G1 antibody subclass in the upregulation of tumor necrosis factor (TNF) expression in PPD-stimulated monocytes. Possible link with disease pathogenesis in tuberculosis; Role of opsonizing antibodies in modulating TNF alpha expression.

Background Clinical severity of coronavirus disease 2019 (COVID-19) may vary over time; trends in clinical severity at admission during the pandemic among hospitalized patients in the United States have been incompletely described, so a historical record of severity over time is lacking. Methods We classified 466677 hospital admissions for COVID-19 from April 2020 to April 2021 into 4 mutually exclusive severity grades based on indicators present on admission (from most to least severe): Grade 4 included intensive care unit (ICU) admission and invasive mechanical ventilation (IMV); grade 3 included non-IMV ICU and/or noninvasive positive pressure ventilation; grade 2 included diagnosis of acute respiratory failure; and grade 1 included none of the above indicators. Trends were stratified by sex, age, race/ethnicity, and comorbid conditions. We also examined severity in states with high vs low Alpha (B.1.1.7) variant burden. Results Severity tended to be lower among women, younger adults, and those with fewer comorbidities compared to their counterparts. The proportion of admissions classified as grade 1 or 2 fluctuated over time, but these less-severe grades comprised a majority (75%–85%) of admissions every month. Grades 3 and 4 consistently made up a minority of admissions (15%–25%), and grade 4 showed consistent decreases in all subgroups, including states with high Alpha variant burden. Conclusions Clinical severity among hospitalized patients with COVID-19 has varied over time but has not consistently or markedly worsened over time. The proportion of admissions classified as grade 4 decreased in all subgroups. There was no consistent evidence of worsening severity in states with higher vs lower Alpha prevalence. [ABSTRACT FROM AUTHOR]

Chronic inflammation associated with cachexia, weight loss, fever and arthralgia is the hallmark of advanced mycobacterial diseases. These symptoms are attributed to the chronic stimulation of tumour necrosis factor (TNF)- α. Mycobacterial components directly stimulate adherent cells to secrete TNF- α. We have shown recently that IgG1 antimycobacterial antibodies play a role in augmenting TNF- α in purified protein derivative (PPD)-stimulated adherent cells from non-BCG-vaccinated donors. We now show that IgG1 antibodies can also augment TNF- α expression in stimulated adherent cells obtained from BCG-vaccinated donors and this augmentation is not linked to interleukin (IL)-10 secretion. In addition IgG1 antimycobacterial antibodies can reverse the effect of TNF- α blockers such as pentoxifylline and thalidomide. These studies therefore have clinical implications for anti-inflammatory drug treatments which are used increasingly to alleviate symptoms associated with chronic inflammation. [ABSTRACT FROM AUTHOR]

I Editor i We read with interest the article by Spinelli and Pellino[1] describing the impact of the COVID-19 pandemic on outpatient clinics, elective surgery, emergency surgery, and how this burden translates to patients. The current COVID-19 pandemic will act as a significant stressor to surgeons and may exacerbate these issues. Future research is required across a wider sample of junior surgeons to understand causality, monitor trends, and aid implementation of national and local-level support and guidance to safeguard the mental wellbeing of our future surgeons. [Extracted from the article]

Introduction: Congenital heart disease (CHD) is the most common congenital abnormality, affecting approximately 7 in 1,000 live births. Transposition of the great arteries (TGA) is the most commonly diagnosed cyanotic heart defect in neonates. We propose that TGA has a genetic cause, likely to be de novo or in genes causing heterotaxy syndrome.Purpose: Exomes of 9 subjects diagnosed with TGA with no family history of CHD and their unaffected parents (trios) were subject to sequencing. The project aims were to: implement the exome bioinformatic analysis pipeline to identify de novo mutations (DNMs) and validate variants called by the pipeline. This is the first study investigating de novo changes in TGA patients.Methods: Bioinformatic pipeline was set up to analyse sequencing performed on Illumina GAIIX following exon capture. Programs used included Casava-Gerald after base calling, NovoAlign/BWA for alignment, SAMtools for variant calling. Integrated Genomics Viewer was used to inspect the variants. Polymerase chain reactions were performed prior to sending off for validation by Sanger sequencing.Results: Bioinformatic pipeline identified on average 188 DNMs per trio. 17 variants were chosen for validation. 1 trio had 2 de novo mutations: 1 nonsense in ZNF227 and 1 missense in PHLPP2. 1 trio had a de novo change in RBP5 gene. 1 trio had an inherited splice site change in RTTN, a candidate gene.Conclusions: The presence of de novo and inherited mutations suggests a complex polygenic cause of TGA. [ABSTRACT FROM PUBLISHER]

Background: To date, relatively few representative data have been available to health planners and advocacy groups on the life expectancy of people with intellectual disability. A study of trends in the survival profiles of people with intellectual disability was undertaken to assist in the planning of appropriate medical and support services.Methods: Since 1953, the Disability Services Commission of Western Australia has maintained a database of persons diagnosed with intellectual disability. The database was used to calculate survival probabilities on a total of 8724 individuals, 7562 of whom were still alive at the time of sampling in December 2000.Results: Kaplan-Meier survival plots showed a strong negative association between severity of intellectual disability and survival, with median life expectancies of 74.0, 67.6, and 58.6 years for people with mild, moderate, and severe levels of handicap. Significant negative associations also were observed with male gender, Indigenous Australian parentage, and individuals diagnosed with a specific genetic disorder.Conclusions: The findings indicate a major and expanding increase in the service requirements of this aging, intellectually disabled population during the past two generations. [ABSTRACT FROM AUTHOR]

To evaluate the economic impact of the current 2-dose measles-mumps-rubella (MMR) vaccination program in the United States, a decision tree-based analysis was conducted with population-based vaccination coverage and disease incidence data. All costs were estimated for a hypothetical US birth cohort of 3,803,295 infants born in 2001. The 2-dose MMR vaccination program was cost-saving from both the direct cost and societal perspectives compared with the absence of MMR vaccination, with net savings (net present value) from the direct cost and societal perspectives of $3.5 billion and $7.6 billion, respectively. The direct and societal benefit- cost ratios for the MMR vaccination program were 14.2 and 26.0. Analysis of the incremental benefit-cost of the second dose showed that direct and societal benefit-cost ratios were 0.31 and 0.49, respectively. Varying the proportion of vaccines purchased and administered in the public versus the private sector had little effect on the results. From both perspectives under even the most conservative assumptions, the national 2-dose MMR vaccination program is highly cost-beneficial and results in substantial cost savings. [ABSTRACT FROM AUTHOR]

Erythema nodosum leprosum (ENL) is a serious complication of lepromatous (L) disease in leprosy. We have previously shown that of the four IgG subclasses, IgGl and IgG3 Mycobacterium leprae-specific antibodies are significantly lower in leprosy patients during ENL reaction compared with untreated L patients. To see if this decrease results from a down-regulation of antibody synthesis during ENL, the frequency of antibody-secreting B cells (ABSC) in the blood compartment was determined by ELISPOT and related to serum immunoglobulin concentrations (μg/ABSC). Control groups consisted of 16 patients with stable L disease and 32 healthy endemic controls (EC). Paired samples were analysed during acute ENLS (n=13) and after the reaction had subsided to identify changes associated with ENL. Polyclonal (PC) IgGl was elevated in L patients compared with EC (325μg versus 180 μg). Interestingly, patients during acute ENL showed concentrations higher than L patients (419μg), which decreased after the reaction had subsided (260μg), indicating the transient nature of the antibody response. IgG2 antibodies showed the reverse trend and were lower during ENL and increased after the reaction had subsided. The mean concentrations for PC IgG3 and IgG4 antibodies were similar during ENL and after the reaction had subsided. Thus, decrease in M. leprae-specific IgGl and IgG3 antibodies is not related to down-regulation of B cell responses. Identification of factors which regulate PC IgGl antibody synthesis may provide additional insights into determinants of ENL reactions. [ABSTRACT FROM AUTHOR]

Focuses on a study which examined life expectancy of persons with intellectual disability in Perth, Western Australia. Measurements and statistical assessment; Distribution and age profile of cases with intellectual disability; Results and discussion.