Objectives The aim of this study was to determine the incidence of and risk factors for community-associated Clostridium difficile infection (CDI). Methods Prospective surveillance of ...community-derived faecal samples for C. difficile cytotoxin, followed by a questionnaire-based case–control study in two distinct patient cohorts (one semi-rural and the other urban). Results The proportion of randomly selected faecal samples positive for C. difficile cytotoxin was 2.1% in both patient cohorts (median ages 73 and 45 years for the urban and semi-rural cohorts, respectively). Exposure to antibiotics in the previous 4 weeks, particularly multiple agents (P < 0.001), aminopenicillins (P < 0.05) and oral cephalosporins (P < 0.05), was significantly more frequent among cases than controls. Hospitalization in the preceding 6 months was significantly associated with CDI (45% versus 23%; P = 0.022). However, almost half the cases had not received antibiotic therapy in the month before C. difficile detection, and approximately one-third neither had exposure to antibiotics nor recent hospitalization. Contact with infants aged ≤2 years was significantly associated with CDI (14% versus 2%; P = 0.02). Prior exposure to gastrointestinal-acting drugs (proton pump inhibitor, H2 antagonist or non-steroidal anti-inflammatory) was not significantly more common in CDI cases. C. difficile PCR ribotype 001 caused 60% and 13% of urban and semi-rural community-associated CDI cases, respectively. Conclusions Reliance on antibiotic history and age (≥65 years) will contribute to missed diagnoses of community-associated CDI. Potential risk factors for community-associated CDI should be explored further to explain the large proportion of cases not linked to recent antibiotic therapy or hospitalization.
Highlights • Glioblastoma multiforme (GBM) is the most common and deadly primary brain tumor. • CD44 is a transmembrane molecule overexpressed in GBM. • Processes involving CD44 promote GBM invasion, ...proliferation and therapy resistance. • Targeting CD44 is a promising GBM therapy.
Alveolar rhabdomyosarcoma (RMS) is associated with an underlying pathogenic translocation involving either PAX3 or PAX7 and FOXO1. The presence or absence of this fusion defines the biology and ...clinical behavior of this subtype of RMS and its identification in tumors is relevant to prognostication and treatment planning. To further explore the unique characteristics of fusion-driven RMS, we leveraged a published gene expression data set to perform an unbiased comparison of 33 fusion-positive and 25 fusion-negative RMS cases. Our analyses revealed 1790 expressed loci with more than two-fold differential expression at a threshold of P < .05. Genes with increased expression in fusion-positive relative to fusion-negative RMS were significantly enriched for those involved in “nervous system development,” “neuron differentiation,” and “neurogenesis,” highlighting a neurodevelopmental gene expression signature driven by the alveolar RMS-associated fusion protein. We show that neurodevelopmental genes are enriched near PAX3-FOXO1 fusion protein binding sites, suggesting a genome-wide fusion protein-mediated activation of cis regulatory elements. Among the genes with differential expression in fusion-positive versus fusion-negative RMS, we identified expression of the transcriptional regulator of motor neuron and oligodendrocyte development, OLIG2, as a marker of the fusion protein-dependent neurodevelopmental signature. Immunohistochemical analysis of a cohort of 73 RMS specimens revealed OLIG2 expression in 96.4% of fusion-positive RMS (N = 27/28), but only in 6.7% of fusion-negative RMS (N = 3/45; P < .001). The proportion of OLIG2-expressing cells in fusion-negative cases did not exceed 5%, while 92.9% of fusion-positive cases showed expression in at least 5% of cells. Our findings identify OLIG2 expression as a unique manifestation of a neurodevelopmental gene expression signature driven by the oncogenic fusion protein characteristic of alveolar RMS, which may aid in the diagnostic and prognostic distinction of fusion-positive cases.
•The PAX3/7-FOXO1 fusion gene defines a prognostically distinct subset of rhabdomyosarcoma with alveolar morphology.•A neurodevelopmental gene expression signature characterizes fusion-positive rhabdomyosarcoma.•OLIG2 is a neurodevelopmental gene with increased expression in fusion-positive rhabdomyosarcoma relative to its fusion-negative counterparts.•Detection of OLIG2 expression by immunohistochemistry correlates with the presence of an underlying PAX3/7-FOXO1 fusion in rhabdomyosarcoma.
Lung cancer is the leading cause of cancer death. Radiotherapy given in the curative setting is associated with a 3% risk of death from Pneumocystis jirovecii pneumonia (PJP). Prolonged courses of ...high-dose steroids also increase the risk of PJP. International guidelines recommend the use of chemoprophylaxis with trimethoprim-sulfamethoxazole for patients at high risk. We assessed the effect of an intervention designed to reduce the impact of PJP.
Prophylaxis guidelines were introduced in 2016. Case records of patients treated with radical radiotherapy were examined for the periods 2014 to 2015 (pre-intervention) and 2017 to 2018 (post-intervention). In total, 247 patients were treated pre-intervention and 334 post-intervention.
Freedom from PJP death at 1 year was 96% before intervention and 99% after (hazard ratio 0.3, 95% confidence interval 0.1–0.9, P = 0.029). Although the rate of use of chemoprophylaxis according to the guideline rose from 1% to 13% (P = 0.003), the use of high-dose steroids also fell from 35% to 16% (P < 0.00001).
Reducing radiotherapy-associated infections is an important component of radical treatment in lung cancer. Highlighting chemoprophylaxis guidelines reduced the death rate from PJP, with an associated more judicious use of steroids. Advocating prophylaxis in patients with lymphocyte count <0.6 × 109/l is the next intervention to be studied.
•Radical radiotherapy has a 3% risk of death from Pneumocystis jirovecii pneumonia (PJP).•Prolonged courses of high-dose steroids also increase the risk of PJP.•Guidelines recommend the chemoprophylaxis for patients at high risk.•Local education reduced deaths from PJP and reduced steroid use.
Catalytic promiscuity is a useful, but accidental, enzyme property, so finding catalytically promiscuous enzymes in nature is inefficient. Some ancestral enzymes were branch points in the evolution ...of new enzymes and are hypothesized to have been promiscuous. To test the hypothesis that ancestral enzymes were more promiscuous than their modern descendants, we reconstructed ancestral enzymes at four branch points in the divergence hydroxynitrile lyases (HNL’s) from esterases ∼100 million years ago. Both enzyme types are α/β-hydrolase-fold enzymes and have the same catalytic triad, but differ in reaction type and mechanism. Esterases catalyze hydrolysis via an acyl enzyme intermediate, while lyases catalyze an elimination without an intermediate. Screening ancestral enzymes and their modern descendants with six esterase substrates and six lyase substrates found higher catalytic promiscuity among the ancestral enzymes (P < 0.01). Ancestral esterases were more likely to catalyze a lyase reaction than modern esterases, and the ancestral HNL was more likely to catalyze ester hydrolysis than modern HNL’s. One ancestral enzyme (HNL1) along the path from esterase to hydroxynitrile lyases was especially promiscuous and catalyzed both hydrolysis and lyase reactions with many substrates. A broader screen tested mechanistically related reactions that were not selected for by evolution: decarboxylation, Michael addition, γ-lactam hydrolysis and 1,5-diketone hydrolysis. The ancestral enzymes were more promiscuous than their modern descendants (P = 0.04). Thus, these reconstructed ancestral enzymes are catalytically promiscuous, but HNL1 is especially so.
Background and Purpose
Calcium/calmodulin‐dependent protein kinase IIδ (CaMKIIδ) is an important regulator of cardiac contractile function and dysfunction and may be an unwanted secondary target for ...anti‐cancer drugs such as sunitinib and imatinib that have been reported to alter cardiac performance. This study aimed to determine whether anti‐cancer kinase inhibitors may affect CaMKII activity and expression when administered in vivo.
Experimental Approach
Cardiovascular haemodynamics in response to acute and chronic sunitinib treatment, and chronic imatinib treatment, were assessed in guinea pigs and the effects compared with those of the known positive and negative inotropes, isoprenaline and verapamil. Parallel studies from the same animals assessed CaMKIIδ expression and CaMKII activity following drug treatments.
Key Results
Acute administration of sunitinib decreased left ventricular (LV) dP/dtmax. Acute administration of isoprenaline increased LVdP/dtmax dose‐dependently, while LVdP/dtmax was decreased by verapamil. CaMKII activity was decreased by acute administration of sunitinib and was increased by acute administration of isoprenaline, and decreased by acute administration of verapamil. CaMKIIδ expression following all acute treatments remained unchanged. Chronic imatinib and sunitinib treatments did not alter fractional shortening; however, both CaMKIIδ expression and CaMKII activity were significantly increased. Chronic administration of isoprenaline and verapamil decreased LV fractional shortening with parallel increases in CaMKIIδ expression and CaMKII activity.
Conclusions and Implications
Chronic sunitinib and imatinib treatment increased CaMKIIδ expression and CaMKII activity. As these compounds are associated with cardiac dysfunction, increased CaMKII expression could be an early indication of cellular cardiotoxicity marking potential progression of cardiac contractile dysfunction.
SETTING: Pharmacies in 19 cities in Angola, Brazil, China, Democratic Republic of Congo, Egypt, Ethiopia, Ghana, India (n = 3), Kenya, Nigeria, Russia, Rwanda, Thailand, Turkey, Uganda, United ...Republic of Tanzania and Zambia.OBJECTIVE: To assess the quality of the two main
first-line anti-tuberculosis medicines, isoniazid and rifampicin, procured from private-sector pharmacies, to determine if substandard and falsified medicines are available and if they potentially contribute to drug resistance in cities in low- and middle-income countries.DESIGN: Local
nationals procured 713 treatment packs from a selection of pharmacies in 19 cities. These samples were tested for quality using 1) thin-layer chromatography to analyze levels of active pharmaceutical ingredient (API), and 2) disintegration testing.RESULTS: Of 713 samples tested, 9.1% failed
basic quality testing for requisite levels of API or disintegration. The failure rate was 16.6% in Africa, 10.1% in India, and 3.9% in other middle-income countries.CONCLUSIONS: Substandard and falsified drugs are readily available in the private marketplace and probably contribute to
anti-tuberculosis drug resistance in low- and middle-income countries. This issue warrants further investigation through large-scale studies of drug quality in all markets.
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