Systemic aminoglycosides are trafficked via endolymph into cochlear hair cells

Aminoglycoside antibiotics rapidly enter and kill cochlear hair cells via apical mechanoelectrical transduction (MET) channels in vitro. In vivo, it remains unknown whether systemically-administered aminoglycosides cross the blood-labyrinth barrier into endolymph and enter hair cells. Here we show, for the first time, that systemic aminoglycosides are trafficked across the blood-endolymph barrier and preferentially enter hair cells across their apical membranes. This trafficking route is predominant compared to uptake via hair cell basolateral membranes during perilymph infusion

Small but crucial : the novel small heat shock protein Hsp21 mediates stress adaptation and virulence in Candida albicans

Peer reviewedPublisher PD

Comparison of gastrointestinal pH in cystic fibrosis and healthy subjects

The primary objective of this study was to define the pH conditions under which supplemental pancreatic enzyme preparations must function in the upper gastrointestinal tract. The hypothesis was that normal or greater gastric acid output in patients with cystic fibrosis (CF), combined with low pancreatic bicarbonate output, results in an acidic duodenal pH, compromising both dosage-form performance and enzyme activity. Gastrointestinal pH profiles were obtained in 10 CF and 10 healthy volunteers under fasting and postprandial conditions. A radiotelemetric monitoring method, the Heidelberg capsule, was used to continuously monitor pH. Postprandial duodenal pH was lower in CF than in healthy subjects, especially in the first postprandial hour (mean time greater than pH 6 was 5 min in CF, 11 min in healthy subjects, P <0.05). Based on the dissolution pH profiles of current enteric-coated pancreatic enzyme products, the duodenal postprandial pH in CF subjects may be too acidic to permit rapid dissolution of current enteric-coated dosage forms. However, the pH was above 4 more than 90% of the time on the average, suggesting that irreversible lipase inactivation in the duodenum is not likely to be a significant limitation to enzyme efficacy. Overall results suggest that slow dissolution of pH-sensitive coatings, rather than enzyme inactivation, may contribute to the failure of enteric-coated enzyme supplements to normalize fat absorption.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44403/1/10620_2005_Article_BF01296029.pd

Vitamin d status predicts 30 day mortality in hospitalised cats

Vitamin D insufficiency, defined as low serum concentrations of the major circulating form of vitamin D, 25 hydroxyvitamin D (25(OH)D), has been associated with the development of numerous infectious, inflammatory, and neoplastic disorders in humans. In addition, vitamin D insufficiency has been found to be predictive of mortality for many disorders. However, interpretation of human studies is difficult since vitamin D status is influenced by many factors, including diet, season, latitude, and exposure to UV radiation. In contrast, domesticated cats do not produce vitamin D cutaneously, and most cats are fed a commercial diet containing a relatively standard amount of vitamin D. Consequently, domesticated cats are an attractive model system in which to examine the relationship between serum 25(OH)D and health outcomes. The hypothesis of this study was that vitamin D status would predict short term, all-cause mortality in domesticated cats. Serum concentrations of 25(OH)D, together with a wide range of other clinical, hematological, and biochemical parameters, were measured in 99 consecutively hospitalised cats. Cats which died within 30 days of initial assessment had significantly lower serum 25(OH)D concentrations than cats which survived. In a linear regression model including 12 clinical variables, serum 25(OH)D concentration in the lower tertile was significantly predictive of mortality. The odds ratio of mortality within 30 days was 8.27 (95% confidence interval 2.54-31.52) for cats with a serum 25(OH)D concentration in the lower tertile. In conclusion, this study demonstrates that low serum 25(OH)D concentration status is an independent predictor of short term mortality in cats

Outcome following emergency laparotomy in 33 UK donkeys: A retrospective multicentre study

BackgroundEmergency laparotomies in donkeys are infrequently performed and there is limited literature on the subject.ObjectivesTo determine findings and associated outcomes of exploratory laparotomies in donkeys.Study designDescriptive retrospective study.MethodsDonkeys undergoing emergency exploratory laparotomy for investigation and treatment of colic at seven UK referral hospitals between 2005-2017 were included. Data were retrieved from available hospital records. Descriptive statistics and inferential statistical analysis of outcomes of interest was performed in three steps.ResultsThirty-three cases fulfilled the inclusion criteria. Clinical signs on presentation were available for 32 donkeys, of which 53.1% (17/32) presented for investigation of colic while in 46.9% (15/32) the presenting complaint was non-specific. Primary lesion location included small intestine (42.4%, 14/33), large colon (39.3%, 13/33), caecum (6.1%, 2/33), stomach (6.1%, 2/33) and 6.1% (2/33) had multiple abnormal findings without a clear primary lesion. Overall survival to discharge was 54.5% (18/33). Five donkeys (15.2%, 5/33) were euthanased at surgery and of those recovering from general anaesthesia a further 35.7% (10/28) were euthanased or died prior to discharge. Six donkeys (21.4%, 6/28) required a second laparotomy of which 4 (66.7%, 4/6) survived. Post-operative complications occurred in 82.1% (23/28) of cases and included hyperlipaemia (42.9%, 12/28), incisional complications (21.4%, 6/28), ileus (21.4%, 6/28) and persistent colic (17.9%, 5/28). When adjusted for other complications, donkeys with primary gastric lesions were less likely to have presented with severe colic compared with those with primary small intestinal lesions (OR: 0.07, 95% CI 0.01-0.95, p = 0.05). Only age was positively associated with death prior to discharge (OR: 1.18, 95% CI 1.03-1.36, p = 0.02).Main limitationsSmall sample size and retrospective design.ConclusionDonkeys with abdominal lesions may present with a range of signs often not including colic. Surgical findings were diverse and survival to discharge appears to be lower than in horses

LIF receptor signaling limits immune-mediated demyelination by enhancing oligodendrocyte survival

Multiple sclerosis (MS) is a disabling inflammatory demyelinating disease of the central nervous system (CNS) that primarily affects young adults. Available therapies can inhibit the inflammatory component of MS but do not suppress progressive clinical disability. An alternative approach would be to inhibit mechanisms that drive the neuropathology of MS, which often includes the death of oligodendrocytes, the cells responsible for myelinating the CNS. Identification of molecular mechanisms that mediate the stress response of oligodendrocytes to optimize their survival would serve this need. This study shows that the neurotrophic cytokine leukemia inhibitory factor (LIF) directly prevents oligodendrocyte death in animal models of MS. We also demonstrate that this therapeutic effect complements endogenous LIF receptor signaling, which already serves to limit oligodendrocyte loss during immune attack. Our results provide a novel approach for the treatment of MS

Dual transcriptome of the immediate neutrophil and Candida albicans interplay

Background: Neutrophils are traditionally considered transcriptionally inactive. Compared to other immune cells, little is known about their transcriptional profile during interaction with pathogens. Methods: We analyzed the meta-transcriptome of the neutrophil-Candida albicans interplay and the transcriptome of C. albicans challenged with neutrophil extracellular traps (NETs) by RNA-Seq, considering yeast and hypha individually in each approach. Results: The neutrophil response to C. albicans yeast and hyphae was dominated by a morphotype-independent core response. However, 11 % of all differentially expressed genes were regulated in a specific manner when neutrophils encountered the hyphal form of C. albicans. While involving genes for transcriptional regulators, receptors, and cytokines, the neutrophil core response lacked typical antimicrobial effectors genes. Genes of the NOD-like receptor pathway, including NLRP3, were enriched. Neutrophil-and NET-provoked responses in C. albicans differed. At the same time, the Candida transcriptome upon neutrophil encounter and upon NET challenge included genes from various metabolic processes and indicate a mutual role of the regulators Tup1p, Efg1p, Hap43p, and Cap1p. Upon challenge with neutrophils and NETs, the overall Candida response was partially morphotype-specific. Yet again, actual oppositional regulation in yeasts and hyphae was only detected for the arginine metabolism in neutrophil-infecting C. albicans. Conclusions: Taken together, our study provides a comprehensive and quantitative transcript profile of the neutrophil-C. albicans interaction. By considering the two major appearances of both, neutrophils and C. albicans, our study reveals yet undescribed insights into this medically relevant encounter. Hence, our findings will facilitate future research and potentially inspire novel therapy developments.Originally published in manuscript form with title [RNA-Seq transcription profile of the neutrophil: Candida albicans in vitro interaction]Errata BMC Genomics (2017) 18:696 DOI: 10.1186/s12864-017-4097-4</p