From exercise intolerance to functional improvement: The second wind phenomenon in the identification of McArdle disease

McArdle disease is the most common of the glycogen storage diseases. Onset of symptoms is usually in childhood with muscle pain and restricted exercise capacity. Signs and symptoms are often ignored in children or put down to 'growing pains' and thus diagnosis is often delayed. Misdiagnosis is not uncommon because several other conditions such as muscular dystrophy and muscle channelopathies can manifest with similar symptoms. A simple exercise test performed in the clinic can however help to identify patients by revealing the second wind phenomenon which is pathognomonic of the condition. Here a patient is reported illustrating the value of using a simple 12 minute walk test.RSS is funded by Ciências sem Fronteiras/CAPES Foundation. The authors would like to thank the Association for Glycogen Storage Disease (UK), the EUROMAC Registry funded by the European Union, the Muscular Dystrophy Campaign, the NHS National Specialist Commissioning Group and the Myositis Support Group for funding

Extremely high He isotope ratios in MORB-source mantle from the proto-Iceland plume

The high <sup>3</sup>He/<sup>4</sup>He ratio of volcanic rocks thought to be derived from mantle plumes is taken as evidence for the existence of a mantle reservoir that has remained largely undegassed since the Earth's accretion. The helium isotope composition of this reservoir places constraints on the origin of volatiles within the Earth and on the evolution and structure of the Earth's mantle. Here we show that olivine phenocrysts in picritic basalts presumably derived from the proto-Iceland plume at Baffin Island, Canada, have the highest magmatic <sup>3</sup>He/<sup>4</sup>He ratios yet recorded. A strong correlation between <sup>3</sup>He/<sup>4</sup>He and <sup>87</sup>Sr/<sup>86</sup>Sr, <sup>143</sup>Nd/<sup>144</sup>Nd and trace element ratios demonstrate that the <sup>3</sup>He-rich end-member is present in basalts that are derived from large-volume melts of depleted upper-mantle rocks. This reservoir is consistent with the recharging of depleted upper-mantle rocks by small volumes of primordial volatile-rich lower-mantle material at a thermal boundary layer between convectively isolated reservoirs. The highest <sup>3</sup>He/<sup>4</sup>He basalts from Hawaii and Iceland plot on the observed mixing trend. This indicates that a <sup>3</sup>He-recharged depleted mantle (HRDM) reservoir may be the principal source of high <sup>3</sup>He/<sup>4</sup>He in mantle plumes, and may explain why the helium concentration of the 'plume' component in ocean island basalts is lower than that predicted for a two-layer, steady-state model of mantle structure

Altered thymic differentiation and modulation of arthritis by invariant NKT cells expressing mutant ZAP70

Various subsets of invariant natural killer T (iNKT) cells with different cytokine productions develop in the mouse thymus, but the factors driving their differentiation remain unclear. Here we show that hypomorphic alleles of Zap70 or chemical inhibition of Zap70 catalysis leads to an increase of IFN-gamma-producing iNKT cells (NKT1 cells), suggesting that NKT1 cells may require a lower TCR signal threshold. Zap70 mutant mice develop IL-17-dependent arthritis. In a mouse experimental arthritis model, NKT17 cells are increased as the disease progresses, while NKT1 numbers negatively correlates with disease severity, with this protective effect of NKT1 linked to their IFN-gamma expression. NKT1 cells are also present in the synovial fluid of arthritis patients. Our data therefore suggest that TCR signal strength during thymic differentiation may influence not only IFN-gamma production, but also the protective function of iNKT cells in arthritis

DNA restriction fragment length polymorphism analysis of Mycobacterium tuberculosis isolates from HIV-seropositive and HIV-seronegative patients in Kampala, Uganda

<p>Abstract</p> <p>Background</p> <p>The identification and differentiation of strains of <it>Mycobacterium tuberculosis </it>by DNA fingerprinting has provided a better understanding of the epidemiology and tracing the transmission of tuberculosis. We set out to determine if there was a relationship between the risk of belonging to a group of tuberculosis patients with identical mycobacterial DNA fingerprint patterns and the HIV sero-status of the individuals in a high TB incidence peri-urban setting of Kampala, Uganda.</p> <p>Methods</p> <p>One hundred eighty three isolates of <it>Mycobacterium tuberculosis </it>from 80 HIV seropositive and 103 HIV seronegative patients were fingerprinted by standard IS<it>6110</it>-RFLP. Using the BioNumerics software, strains were considered to be clustered if at least one other patient had an isolate with identical RFLP pattern.</p> <p>Results</p> <p>One hundred and eighteen different fingerprint patterns were obtained from the 183 isolates. There were 34 clusters containing 54% (99/183) of the patients (average cluster size of 2.9), and a majority (96.2%) of the strains possessed a high copy number (≥ 5 copies) of the IS<it>6110 </it>element. When strains with <5 bands were excluded from the analysis, 50.3% (92/183) were clustered, and there was no difference in the level of diversity of DNA fingerprints observed in the two sero-groups (adjusted odds ratio [aOR] 0.85, 95%CI 0.46–1.56, <it>P </it>= 0.615), patients aged <40 years (aOR 0.53, 95%CI 0.25–1.12, <it>P </it>= 0.100), and sex (aOR 1.12, 95%CI 0.60–2.06, <it>P </it>= 0.715).</p> <p>Conclusion</p> <p>The sample showed evidence of a high prevalence of recent transmission with a high average cluster size, but infection with an isolate with a fingerprint found to be part of a cluster was not associated with any demographic or clinical characteristics, including HIV status.</p

Search for direct pair production of the top squark in all-hadronic final states in proton-proton collisions at s√=8 TeV with the ATLAS detector

The results of a search for direct pair production of the scalar partner to the top quark using an integrated luminosity of 20.1fb−1 of proton–proton collision data at √s = 8 TeV recorded with the ATLAS detector at the LHC are reported. The top squark is assumed to decay via t˜→tχ˜01 or t˜→ bχ˜±1 →bW(∗)χ˜01 , where χ˜01 (χ˜±1 ) denotes the lightest neutralino (chargino) in supersymmetric models. The search targets a fully-hadronic final state in events with four or more jets and large missing transverse momentum. No significant excess over the Standard Model background prediction is observed, and exclusion limits are reported in terms of the top squark and neutralino masses and as a function of the branching fraction of t˜ → tχ˜01 . For a branching fraction of 100%, top squark masses in the range 270–645 GeV are excluded for χ˜01 masses below 30 GeV. For a branching fraction of 50% to either t˜ → tχ˜01 or t˜ → bχ˜±1 , and assuming the χ˜±1 mass to be twice the χ˜01 mass, top squark masses in the range 250–550 GeV are excluded for χ˜01 masses below 60 GeV

Molecular epidemiology and evolutionary genetics of Mycobacterium tuberculosis in Taipei

<p>Abstract</p> <p>Background</p> <p>The control of tuberculosis in densely populated cities is complicated by close human-to-human contacts and potential transmission of pathogens from multiple sources. We conducted a molecular epidemiologic analysis of 356 <it>Mycobacterium tuberculosis </it>(MTB) isolates from patients presenting pulmonary tuberculosis in metropolitan Taipei. Classical antibiogram studies and genetic characterization, using mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MIRU-VNTR) typing and spoligotyping, were applied after culture.</p> <p>Methods</p> <p>A total of 356 isolates were genotyped by standard spoligotyping and the strains were compared with in the international spoligotyping database (SpolDB4). All isolates were also categorized using the 15 loci MIRU-VNTR typing method and combin with <it>NTF </it>locus and RD deletion analyses.</p> <p>Results</p> <p>Of 356 isolates spoligotyped, 290 (81.4%) displayed known spoligotypes and 66 were not identified in the database. Major spoligotypes found were Beijing lineages (52.5%), followed by Haarlem lineages (13.5%) and EAI plus EAI-like lineages (11%). When MIRU-VNTR was employed, 140 patterns were identified, including 36 clusters by 252 isolates and 104 unique patterns, and the largest cluster comprised 95 isolates from the Beijing family. The combination of spoligotyping and MIRU-VNTR revealed that 236 (67%) of the 356 isolates were clustered in 43 genotypes. Strains of the Beijing family was more likely to be of modern strain and a higher percentage of multiple drug resistance than other families combined (P = 0.08). Patients infected with Beijing strains were younger than those with other strains (mean 58.7 vs. 64.2, p = 0.02). Moreover, 85.3% of infected persons younger than 25 years had Beijing modern strain, suggesting a possible recent spread in the young population by this family of TB strain in Taipei.</p> <p>Conclusion</p> <p>Our data on MTB genotype in Taipei suggest that MTB infection has not been optimally controlled. Control efforts should be reinforced in view of the high prevalence of the Beijing strain in young population and association with drug resistance.</p

Natural products in drug discovery: advances and opportunities

Natural products and their structural analogues have historically made a major contribution to pharmacotherapy, especially for cancer and infectious diseases. Nevertheless, natural products also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization, which contributed to a decline in their pursuit by the pharmaceutical industry from the 1990s onwards. In recent years, several technological and scientific developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances — are addressing such challenges and opening up new opportunities. Consequently, interest in natural products as drug leads is being revitalized, particularly for tackling antimicrobial resistance. Here, we summarize recent technological developments that are enabling natural product-based drug discovery, highlight selected applications and discuss key opportunities

Global, regional, and national sex-specific burden and control of the HIV epidemic, 1990-2019, for 204 countries and territories: the Global Burden of Diseases Study 2019

Background: The sustainable development goals (SDGs) aim to end HIV/AIDS as a public health threat by 2030. Understanding the current state of the HIV epidemic and its change over time is essential to this effort. This study assesses the current sex-specific HIV burden in 204 countries and territories and measures progress in the control of the epidemic. Methods: To estimate age-specific and sex-specific trends in 48 of 204 countries, we extended the Estimation and Projection Package Age-Sex Model to also implement the spectrum paediatric model. We used this model in cases where age and sex specific HIV-seroprevalence surveys and antenatal care-clinic sentinel surveillance data were available. For the remaining 156 of 204 locations, we developed a cohort-incidence bias adjustment to derive incidence as a function of cause-of-death data from vital registration systems. The incidence was input to a custom Spectrum model. To assess progress, we measured the percentage change in incident cases and deaths between 2010 and 2019 (threshold >75% decline), the ratio of incident cases to number of people living with HIV (incidence-to-prevalence ratio threshold <0·03), and the ratio of incident cases to deaths (incidence-to-mortality ratio threshold <1·0). Findings: In 2019, there were 36·8 million (95% uncertainty interval [UI] 35·1–38·9) people living with HIV worldwide. There were 0·84 males (95% UI 0·78–0·91) per female living with HIV in 2019, 0·99 male infections (0·91–1·10) for every female infection, and 1·02 male deaths (0·95–1·10) per female death. Global progress in incident cases and deaths between 2010 and 2019 was driven by sub-Saharan Africa (with a 28·52% decrease in incident cases, 95% UI 19·58–35·43, and a 39·66% decrease in deaths, 36·49–42·36). Elsewhere, the incidence remained stable or increased, whereas deaths generally decreased. In 2019, the global incidence-to-prevalence ratio was 0·05 (95% UI 0·05–0·06) and the global incidence-to-mortality ratio was 1·94 (1·76–2·12). No regions met suggested thresholds for progress. Interpretation: Sub-Saharan Africa had both the highest HIV burden and the greatest progress between 1990 and 2019. The number of incident cases and deaths in males and females approached parity in 2019, although there remained more females with HIV than males with HIV. Globally, the HIV epidemic is far from the UNAIDS benchmarks on progress metrics. Funding: The Bill & Melinda Gates Foundation, the National Institute of Mental Health of the US National Institutes of Health (NIH), and the National Institute on Aging of the NIH