Pyrone-based inhibitors of metalloproteinase types 2 and 3 may work as conformation-selective inhibitors.

Matrix metalloproteinases are zinc-containing enzymes capable of degrading all components of the extracellular matrix. Owing to their role in human disease, matrix metalloproteinase have been the subject of extensive study. A bioinorganic approach was recently used to identify novel inhibitors based on a maltol zinc-binding group, but accompanying molecular-docking studies failed to explain why one of these inhibitors, AM-6, had approximately 2500-fold selectivity for MMP-3 over MMP-2. A number of studies have suggested that the matrix-metalloproteinase active site is highly flexible, leading some to speculate that differences in active-site flexibility may explain inhibitor selectivity. To extend the bioinorganic approach in a way that accounts for MMP-2 and MMP-3 dynamics, we here investigate the predicted binding modes and energies of AM-6 docked into multiple structures extracted from matrix-metalloproteinase molecular dynamics simulations. Our findings suggest that accounting for protein dynamics is essential for the accurate prediction of binding affinity and selectivity. Additionally, AM-6 and other similar inhibitors likely select for and stabilize only a subpopulation of all matrix-metalloproteinase conformations sampled by the apo protein. Consequently, when attempting to predict ligand affinity and selectivity using an ensemble of protein structures, it may be wise to disregard protein conformations that cannot accommodate the ligand

Distinct load dependence of relaxation rate and diastolic function in Oryctolagus cuniculus and Ratus norvegicus

This study investigated potential differences on load dependence of relaxation rate and diastolic function between Oryctolagus cuniculus and Ratus norvegicus, which have constitutive differences in the mechanisms involved in myocardial inactivation. Load dependence of relaxation rate and diastolic function were evaluated with the response of left ventricular time constant tau and diastolic pressure-dimension relation to beat-to-beat aortic constrictions in open-chest rabbits and rats. Afterload levels were normalized, being expressed as a percentage of peak isovolumetric pressure (relative load). In control heartbeats, relaxation rate and diastolic function were similar in the two animal species. They presented, however, distinct responses to afterload elevations. In rabbits, time constant decreased similar to7% and diastolic pressure-dimension relation remained unchanged when afterload was elevated to a relative load of 73-76%. Above this afterload level, a significant deceleration of relaxation rate (increase of time constant) and an upward shift of diastolic pressure-dimension relation were observed. In rats, afterload elevations accelerated pressure fall up to a relative load of 97-100% and no afterload-induced shift of the diastolic pressure-dimension relation was observed. This study provides, therefore, evidence that Oryctolagus cuniculus has lower afterload reserve of myocardial relaxation and diastolic function than Ratus norvegicus

What Has Changed During the COVID-19 Pandemic? - The Effect on an Academic Breast Department in Portugal

Introduction: One year ago, Portugal entered its first lockdown because of the coronavirus disease-2019 (COVID-19) pandemic. The impact of this on delays in cancer diagnosis and treatment is a major concern, which may negatively affect the outcomes of these patients. Materials and methods: This retrospective, single-center analysis compared the clinical and pathological characteristics of breast cancer (BC) patients referred to a medical oncology first appointment between March 2020 and 2021, with the same period in the previous year. Results: Strikingly, there was a 40% reduction in the number of BC patients during lockdown. However, there was a statistically significant increase in the proportion of metastatic BC patients admitted for the first time for systemic therapy (13.6% vs. 28.9%, p = 0.003). Additionally, a statistically significant increase in the number of patients with bilateral early BC at diagnosis after March 2020 was found (7.2% vs. 1.9%, p = 0.043). Conclusion: These findings support international recommendations for an accelerated restoration of BC screening, to reduce incidence of advanced breast cancer at diagnosis and mitigate the expected impact of the COVID-19 pandemic on patients with cancer. Further work is needed to examine in detail the impact of measures to manage the COVID-19 pandemic on breast cancer outcomes.info:eu-repo/semantics/publishedVersio

Mycobacterium Tuberculosis Prosthesis Joint Infection

info:eu-repo/semantics/publishedVersio

Dynapenia, abdominal obesity or both: which accelerates the gait speed decline most?

OBJECTIVE: to investigate whether the combination of dynapenia and abdominal obesity is worse than these two conditions separately regarding gait speed decline over time. METHODS: a longitudinal study was conducted involving 2,294 individuals aged 60 years or older free of mobility limitation at baseline (gait speed >0.8 m/s) who participated in the English Longitudinal Study of Ageing. Dynapenia was determined as a grip strength 102 cm for men and >88 cm for women. The participants were divided into four groups: non-dynapenic/non-abdominal obese (ND/NAO); only abdominal obese (AO); only dynapenic (D) and dynapenic/abdominal obese (D/AO). Generalised linear mixed models were used to analyse gait speed decline (m/s) as a function of dynapenia and abdominal obesity status over an 8-year follow-up period. RESULTS: over time, only the D/AO individuals had a greater gait speed decline (-0.013 m/s per year, 95% CI: -0.024 to -0.002; P < 0.05) compared to ND/NAO individuals. Neither dynapenia nor abdominal obesity only was associated with gait speed decline. CONCLUSION: dynapenic abdominal obesity is associated with accelerated gait speed decline and is, therefore, an important modifiable condition that should be addressed in clinical practice through aerobic and strength training for the prevention of physical disability in older adults

Association of Serum 25-Hydroxyvitamin D Deficiency with Risk of Incidence of Disability in Basic Activities of Daily Living in Adults >50 Years of Age.

BACKGROUND: Vitamin D deficiency compromises muscle function and is related to the etiology of several clinical conditions that can contribute to the development of disability. However, there are few epidemiological studies investigating the association between vitamin D deficiency and the incidence of disability. OBJECTIVES: We aimed to assess whether vitamin D deficiency is associated with the incidence of disability in basic activities of daily living (BADL) and to verify whether there are sex differences in this association. METHODS: A 4-y follow-up study was conducted involving individuals aged 50 y or older who participated in ELSA (English Longitudinal Study of Ageing). The sample consisted of 4814 participants free of disability at baseline according to the modified Katz Index. Vitamin D was assessed by serum 25-hydroxyvitamin D [25(OH)D] concentrations and the participants were classified as sufficient (>50 nmol/L), insufficient (>30 to ≤50 nmol/L), or deficient (≤30 nmol/L). Sociodemographic, behavioral, and clinical characteristics were also investigated. BADL were re-evaluated after 2 and 4 y of follow-up. The report of any difficulty to perform ≥1 BADL was considered as an incident case of disability. Poisson models stratified by sex and controlled for sociodemographic, behavioral, and clinical characteristics were carried out. RESULTS: After 4-y follow-up, deficient serum 25(OH)D was a risk factor for the incidence of BADL disability in both women (IRR: 1.53; 95% CI: 1.16, 2.03) and men (IRR: 1.44; 95% CI: 1.02, 2.02). However, insufficient serum 25(OH)D was not a risk factor for the incidence of BADL disability in either men or women. CONCLUSIONS: Independently of sex, deficient serum 25(OH)D concentrations were associated with increased risk of incidence of BADL disability in adults >50 y old and should be an additional target of clinical strategies to prevent disability in these populations

Aspectos da mortalidade atribuível ao tabaco: revisão sistemática

O artigo teve por objetivo analisar as metodologias publicadas e empregadas no cálculo da mortalidade atribuível ao fumo. Foram pesquisadas as bases de dados eletrônicas MEDLINE, LILACS entre 1990 e 2006. Foram encontrados 186 estudos que apresentaram a mensuração de mortalidade a partir do cálculo da fração atribuível ao fumo. Desses, foram selecionados 41 artigos. Os estudos realizados nos Estados Unidos e Canadá apresentaram metodologia uniformizada e taxas de mortalidade entre 18%-23%; 25%-29% no sexo masculino e 14%-17% no feminino. As variações metodológicas podem justificar as diferenças da mortalidade entre os estudos e nas estimativas para as principais doenças tabaco-relacionadas.The objective of the article was to assess methodologies published and applied in calculating mortality attributable to smoking. A review of the literature was made for the period 1990 to 2006, in the electronic databases MEDLINE and LILACS. A total of 186 studies were found, which measured mortality based on calculating the smoking-attributable risk. Of these, a total of 41 were selected. The studies that were carried out in the United States and Canada presented a more standard methodology and reported smoking attributable mortality to be 18%-23%, with male mortality being 25%-29% and female mortality 14%-17%. The variations can be attributed to methodological differences and to different estimates of the main tobacco-related illnesses

Thermal Adaptation and Diversity in Tropical Ecosystems: Evidence from Cicadas (Hemiptera, Cicadidae)

The latitudinal gradient in species diversity is a central problem in ecology. Expeditions covering approximately 16°54′ of longitude and 21°4′ of latitude and eight Argentine phytogeographic regions provided thermal adaptation data for 64 species of cicadas. We test whether species diversity relates to the diversity of thermal environments within a habitat. There are general patterns of the thermal response values decreasing in cooler floristic provinces and decreasing maximum potential temperature within a habitat except in tropical forest ecosystems. Vertical stratification of the plant communities leads to stratification in species using specific layers of the habitat. There is a decrease in thermal tolerances in species from the understory communities in comparison to middle level or canopy fauna. The understory Herrera umbraphila Sanborn & Heath is the first diurnally active cicada identified as a thermoconforming species. The body temperature for activity in H. umbraphila is less than and significantly different from active body temperatures of all other studied species regardless of habitat affiliation. These data suggest that variability in thermal niches within the heterogeneous plant community of the tropical forest environments permits species diversification as species adapt their physiology to function more efficiently at temperatures different from their potential competitors