Low hazard small-scale synthesis and chemical analysis of high purity nitroglycerine (NG)

A previously reported two-phase (99.5% fuming nitric acid/dichloromethane) batch method to prepare high purity 1,2,3-propanetriyl trinitrate (nitroglycerine, NG) was evaluated, simplified and adapted specifically for low hazard small-scale synthesis. The purity of the product, as determined by NMR spectroscopy, HPLC and IR spectroscopic analysis was found to be greater than 99%. The quick synthetic method is highly recommended when small amounts of highly pure NG are required for analytical and related purposes in the absence of a microreactor

Cutaneous cervical metastasis from an esophageal adenocarcinoma mimicking a dental cervical cellulitis: A case report

Cutaneous metastases occur in 0.5 to 9% of all cancers. Esophageal cancer is one of the most aggressive cancers worldwide. Most cutaneous metastases from esophageal cancer were related to squamous cell carcinomas. Few cases have been described about cutaneous metastases related to esophageal adenocarcinomas. These metastases mostly affect patients over 60 years-old, and present as cutaneous asymptomatic nodules. A 69-year-old male presented with a painless and extensive left neck cutaneous induration and erythema. The lesion that was initially diagnosed as a dental cervical cellulitis by his dental practitioner. The patient was known since 2019 to suffer from a esophageal adenocarcinoma whose first treatment was surgery. The patient was currently under immunotherapy for a local recurrence. We firstly assessed the uncommon cervical cellulitis by carrying out an injected head and neck computed tomography (CT) scan which showed an unspecific skin, dermal and muscular infiltration of the left cervical region. The 18-FDG PET/CT demonstrated a suspicious fixation of the neck that was followed by a skin biopsy. The histological and immunohistochemical examination showed the metastatic adenocarcinomatous origin of the cervical skin lesion. The patient was upstaged to a stage IV of his esophageal cancer and started palliative chemotherapy. Special attention must be paid in case of diffuse cervical skin infiltrations, even in the presence of a dental infection, in patients with cancer, in order to perform the correct diagnosis.Cutaneous metastases occur in 0.5 to 9% of all cancers. Esophageal cancer is one of the most aggressive cancers worldwide. Most cutaneous metastases from esophageal cancer were related to squamous cell carcinomas. Few cases have been described about cutaneous metastases related to esophageal adenocarcinomas. These metastases mostly affect patients over 60 years-old, and present as cutaneous asymptomatic nodules. A 69-year-old male presented with a painless and extensive left neck cutaneous induration and erythema. The lesion that was initially diagnosed as a dental cervical cellulitis by his dental practitioner. The patient was known since 2019 to suffer from a esophageal adenocarcinoma whose first treatment was surgery. The patient was currently under immunotherapy for a local recurrence. We firstly assessed the uncommon cervical cellulitis by carrying out an injected head and neck computed tomography (CT) scan which showed an unspecific skin, dermal and muscular infiltration of the left cervical region. The 18-FDG PET/CT demonstrated a suspicious fixation of the neck that was followed by a skin biopsy. The histological and immunohistochemical examination showed the metastatic adenocarcinomatous origin of the cervical skin lesion. The patient was upstaged to a stage IV of his esophageal cancer and started palliative chemotherapy. Special attention must be paid in case of diffuse cervical skin infiltrations, even in the presence of a dental infection, in patients with cancer, in order to perform the correct diagnosis

Early initiation of antiretroviral therapy and associated reduction in mortality, morbidity and defaulting in a nurse-managed, community cohort in Lesotho.

INTRODUCTION: The latest WHO guidelines recommend initiating antiretroviral therapy (ART) at CD4 cell counts less than 350 cells/μl. However, donors and national governments are reluctant to support implementation owing to uncertainty regarding feasibility and relative benefit. Lesotho has supported earlier initiation since 2008. We assessed outcomes comparing early (CD4 cell counts >200 cells/μl) and late (CD4 cell counts ≤200 cells/μl) initiation. METHODS: We describe survival probability among patients initiating ART at CD4 cell counts 200 or less and more than 200 cells/μl and assess associations between baseline CD4 cell counts and mortality, morbidity, loss to follow-up and hospitalization using Cox regression adjusting for confounders identified a priori. RESULTS: Our analysis included 1177 patients; median age was 38 years and the majority (67%) were women. Median time on ART for the overall cohort was 506 days (interquartile range 396-608). Five hundred and thirty eight patients initiated ART at a CD4 cell count 200 cells/μl or less (interquartile range 54-160) and 639 patients initiated at CD4 cell count more than 200 cells/μl (interquartile range 238-321). In multivariate analysis, we found that patients initiating at CD4 cell count more than 200 cells/μl were 68% less likely to die (adjusted hazard ratio 0.32, 95% confidence interval 0.20-0.50), and 39% less likely to be lost to follow-up (adjusted hazard ratio 0.61, 95% confidence interval 0.43-0.87). Initiating ART at CD4 cell count more than 200 cells/μl was also associated with a 27% reduction in the rate of incident morbidity (adjusted hazard ratio 0.73, 95% confidence interval 0.65-0.82) and a 63% decreased rate of hospitalization (adjusted hazard ratio 0.37, 95% confidence interval 0.19-0.73). CONCLUSION: Earlier initiation is feasible in a low resource, high HIV prevalence setting, and provides important benefits in terms of reduced mortality, morbidity, retention and hospitalization. Donors should fully support the implementation of the latest WHO recommendations

The drug and vaccine landscape for neglected diseases (2000–11): a systematic assessment

Background In 1975–99, only 1·1% of new therapeutic products had been developed for neglected diseases. Since then, several public and private initiatives have attempted to mitigate this imbalance. We analysed the research and development pipeline of drugs and vaccines for neglected diseases from 2000 to 2011. Methods We searched databases of drug regulatory authorities, WHO, and clinical trial registries for entries made between Jan 1, 2000, and Dec 31, 2011. We defi ned neglected diseases as malaria, tuberculosis, diarrhoeal diseases, neglected tropical diseases (NTDs; WHO defi nition), and other diseases of poverty according to common defi nitions. Findings Of the 850 new therapeutic products registered in 2000–11, 37 (4%) were indicated for neglected diseases, comprising 25 products with a new indication or formulation and eight vaccines or biological products. Only four new chemical entities were approved for neglected diseases (three for malaria, one for diarrhoeal disease), accounting for 1% of the 336 new chemical entities approved during the study period. Of 148 445 clinical trials registered in Dec 31, 2011, only 2016 (1%) were for neglected diseases. Interpretation Our fi ndings show a persistent insuffi ciency in drug and vaccine development for neglected diseases. Nevertheless, these and other data show a slight improvement during the past 12 years in new therapeutics development and registration. However, for many neglected diseases, new therapeutic products urgently need to be developed and delivered to improve control and potentially achieve elimination

Impact of Dietary Resistant Starch on the Human Gut Microbiome, Metaproteome, and Metabolome

Diet can influence the composition of the human microbiome, and yet relatively few dietary ingredients have been systematically investigated with respect to their impact on the functional potential of the microbiome. Dietary resistant starch (RS) has been shown to have health benefits, but we lack a mechanistic understanding of the metabolic processes that occur in the gut during digestion of RS. Here, we collected samples during a dietary crossover study with diets containing large or small amounts of RS. We determined the impact of RS on the gut microbiome and metabolic pathways in the gut, using a combination of “omics” approaches, including 16S rRNA gene sequencing, metaproteomics, and metabolomics. This multiomics approach captured changes in the abundance of specific bacterial species, proteins, and metabolites after a diet high in resistant starch (HRS), providing key insights into the influence of dietary interventions on the gut microbiome. The combined data showed that a high-RS diet caused an increase in the ratio of Firmicutes to Bacteroidetes, including increases in relative abundances of some specific members of the Firmicutes and concurrent increases in enzymatic pathways and metabolites involved in lipid metabolism in the gut

Identifying genetic networks underlying myometrial transition to labor

BACKGROUND: Early transition to labor remains a major cause of infant mortality, yet the causes are largely unknown. Although several marker genes have been identified, little is known about the underlying global gene expression patterns and pathways that orchestrate these striking changes. RESULTS: We performed a detailed time-course study of over 9,000 genes in mouse myometrium at defined physiological states: non-pregnant, mid-gestation, late gestation, and postpartum. This dataset allowed us to identify distinct patterns of gene expression that correspond to phases of myometrial 'quiescence', 'term activation', and 'postpartum involution'. Using recently developed functional mapping tools (HOPACH (hierarchical ordered partitioning and collapsing hybrid) and GenMAPP 2.0), we have identified new potential transcriptional regulatory gene networks mediating the transition from quiescence to term activation. CONCLUSIONS: These results implicate the myometrium as an essential regulator of endocrine hormone (cortisol and progesterone synthesis) and signaling pathways (cyclic AMP and cyclic GMP stimulation) that direct quiescence via the transcripitional upregulation of both novel and previously associated regulators. With term activation, we observe the upregulation of cytoskeletal remodeling mediators (intermediate filaments), cell junctions, transcriptional regulators, and the coordinate downregulation of negative control checkpoints of smooth muscle contractile signaling. This analysis provides new evidence of multiple parallel mechanisms of uterine contractile regulation and presents new putative targets for regulating myometrial transformation and contraction

Extracellular vesicles in hematological malignancies: EV-dence for reshaping the tumoral microenvironment

Following their discovery at the end of the 20th century, extracellular vesicles (EVs) ranging from 50-1,000 nm have proven to be paramount in the progression of many cancers, including hematological malignancies. EVs are a heterogeneous group of cell-derived membranous structures that include small EVs (commonly called exosomes) and large EVs (microparticles). They have been demonstrated to participate in multiple physiological and pathological processes by allowing exchange of biological material (including among others proteins, DNA and RNA) between cells. They are therefore a crucial way of intercellular communication. In this context, malignant cells can release these extracellular vesicles that can influence their microenvironment, induce the formation of a tumorigenic niche, and prepare and establish distant niches facilitating metastasis by significantly impacting the phenotypes of surrounding cells and turning them toward supportive roles. In addition, EVs are also able to manipulate the immune response and to establish an immunosuppressive microenvironment. This in turn allows for ideal conditions for heightened chemoresistance and increased disease burden. Here, we review the latest findings and reports studying the effects and therapeutic potential of extracellular vesicles in various hematological malignancies. The study of extracellular vesicles remains in its infancy; however, rapid advances in the analysis of these vesicles in the context of disease allow us to envision prospects to improve the detection and treatment of hematological malignancies

MEK1/2 inhibition in murine heart and aorta after oral administration of refametinib supplemented drinking water

Upregulation of the RAS-RAF-MEK-ERK-MAPK pathway is involved in the development of several human tumors, aortic aneurysms, atherosclerosis, and cardiomyopathy. Refametinib, a highly selective MEK-inhibitor, has already shown antineoplastic activity in phase II trials. Furthermore, it showed potency to attenuate aortic root growth in murine models. Current formulations of this drug however necessitate oral gavage as a delivery method for long-term studies, which is labor-intensive and induces stress and occasional injury, potentially confounding results. Therefore, we developed a novel oral administration method for refametinib. A 2-hydroxypropyl-beta-cyclodextrin (HPBCD) based drinking water preparation of refametinib was formulated, for which a selective, analytical UHPLC-UV method was developed to assess the in-use stability. Next, 16 week old male wild-type C57Bl/6J mice received either a daily dose of 50 or 75 mg/kg/day refametinib or were given regular drinking water during 7 days. In both dosage groups the refametinib plasma levels were measured (n = 10 or 7, respectively). Furthermore, pERK/total ERK protein levels were calculated in the myocardial and aortic tissue of mice receiving a daily dose of 50 mg/kg/day refametinib and untreated mice (n = 4/group). After 7 days no significant degradation of refametinib was observed when dissolved in drinking water provided that drinking bottles were protected from UV/visible light. Furthermore, a dose-dependent increase in refametinib plasma levels was found whereby active plasma levels (> 1.2 mu g/mL) were obtained even in the lowest dose-group of 50 mg/kg/day. A significant reduction of pERK/total ERK protein levels compared to untreated mice was observed in aortic and myocardial tissue of mice receiving a daily dose of 50 mg/kg/day refametinib. Importantly, a relatively high mortality rate was noted in the highest dose group (n = 5). This approach provides a valid alternative oral administration method for refametinib with a reduced risk of complications due to animal manipulation and without loss of functionality, which can be implemented in future research regarding the malignant upregulation of the RAS-RAF-MEK-ERK-MAPK pathway. However, care must be taken not to exceed the toxic dose

The impact of the COVID-19 lockdown on human psychology and physical activity; a space analogue research perspective

Introduction Astronauts will encounter isolated, confined and extreme (ICE) conditions during future missions, and will have to be able to adapt. Until recently, however, few places on Earth could serve as acceptable space analogues (i.e., submarine and polar regions). The coronavirus disease-2019 (COVID-19)-related lockdowns around the globe provided a good opportunity to obtain more comprehensive datasets on the impact of prolonged isolation on human functioning in a very large sample. Methods Seven hundred forty-eight individuals (Belgium 442, Spain 183, Germany 50, Italy 50, US 23; Mean age +/- SD: 41 +/- 14 years, with an age range of 18-83 years; 66% women) filled out an online survey assessing the impact of the COVID-lockdown on psychological, exercise and general health variables a first time near the beginning of the initial lockdown (hereafter 'T1'; 24 +/- 13 days after the start of the first lockdown; i.e., 3 weeks after the start of the first lockdown) and a second time a couple of weeks thereafter (hereafter 'T2'; 17 +/- 5 days after the first online survey; i.e., 6 weeks after the start of the first lockdown). Results From T1 to T2 an improvement of subjective sleep quality was observed (P = 0.003), that was related to an increase in subjective sleep efficiency and a decrease in sleep latency and disturbance (P <= 0.013). Weekly sitting time decreased, and the weekly amount of moderate and vigorous physical activity increased from T1 to T2 (P <= 0.049). No differences from T1 to T2 were observed in terms of mood, loneliness and state anxiety. A lower amount of sitting time was significantly correlated with improved subjective sleep quality (r = 0.096, P = 0.035) and with an increased amount of moderate (r = -0.126, P = 0.005) and vigorous (r = -0.110, P = 0.015) physical activity. Conclusion Compared to 3 weeks into the first COVID-imposed lockdown, 6-weeks after the start of the first COVID-imposed lockdown, physical activity and subjective sleep scores were positively impacted. The present, large sample size study further confirms exercise as a worthwhile countermeasure to psycho-physiological deconditioning during confinement