11Beta-hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics

In aging humans and rodents, inter-individual differences in cognitive function have been ascribed to variations in long-term glucocorticoid exposure. 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) regenerates the active glucocorticoid cortisol from circulating inert cortisone, thus amplifying intracellular glucocorticoid levels in some tissues. We show that 11beta-HSD1, but not 11beta-HSD2, mRNA is expressed in the human hippocampus, frontal cortex, and cerebellum. In two randomized, double-blind, placebo-controlled crossover studies, administration of the 11beta-HSD inhibitor carbenoxolone (100 mg three times per day) improved verbal fluency (P < 0.01) after 4 weeks in 10 healthy elderly men (aged 55-75 y) and improved verbal memory (P < 0.01) after 6 weeks in 12 patients with type 2 diabetes (52-70 y). Although carbenoxolone has been reported to enhance hepatic insulin sensitivity in short-term studies, there were no changes in glycemic control or serum lipid profile, nor was plasma cortisol altered. 11beta-HSD1 inhibition may be a new approach to prevent/ameliorate cognitive decline.     

Early PREdiction of sepsis using leukocyte surface biomarkers: the ExPRES-sepsis cohort study

Purpose

Reliable biomarkers for predicting subsequent sepsis among patients with suspected acute infection are lacking. In patients presenting to emergency departments (EDs) with suspected acute infection, we aimed to evaluate the reliability and discriminant ability of 47 leukocyte biomarkers as predictors of sepsis (Sequential Organ Failure Assessment score?≥?2 at 24 h and/or 72 h following ED presentation).

Methods

In a multi-centre cohort study in four EDs and intensive care units (ICUs), we standardised flow-cytometric leukocyte biomarker measurement and compared patients with suspected acute infection (cohort-1) with two comparator cohorts: ICU patients with established sepsis (cohort-2), and ED patients without infection or systemic inflammation but requiring hospitalization (cohort-3).

Results

Between January 2014 and February 2016, we recruited 272, 59 and 75 patients to cohorts 1, 2, and 3, respectively. Of 47 leukocyte biomarkers, 14 were non-reliable, and 17 did not discriminate between the three cohorts. Discriminant analyses for predicting sepsis within cohort-1 were undertaken for eight neutrophil (cluster of differentiation antigens (CD) CD15; CD24; CD35; CD64; CD312; CD11b; CD274; CD279), seven monocyte (CD35; CD64; CD312; CD11b; HLA-DR; CD274; CD279) and a CD8 T-lymphocyte biomarker (CD279). Individually, only higher neutrophil CD279 [OR 1.78 (95% CI 1.23–2.57); P?=?0.002], higher monocyte CD279 [1.32 (1.03–1.70); P?=?0.03], and lower monocyte HLA-DR [0.73 (0.55–0.97); P?=?0.03] expression were associated with subsequent sepsis. With logistic regression the optimum biomarker combination was increased neutrophil CD24 and neutrophil CD279, and reduced monocyte HLA-DR expression, but no combination had clinically relevant predictive validity.

Conclusions

From a large panel of leukocyte biomarkers, immunosuppression biomarkers were associated with subsequent sepsis in ED patients with suspected acute infection.

Clinical trial registration

NCT02188992.

     

Subdomain organization of the Acanthamoeba myosin IC tail from cryo-electron microscopy

Acanthamoeba myosin IC (AMIC) is a single-headed myosin comprised of one heavy chain (129 kDa) and one light chain (17 kDa). The heavy chain has head, neck (light chain-binding), and tail domains. The tail consists of four subdomains: a basic region (BR) (23 kDa) and two Gly/Pro/Ala-rich (GPA) regions, GPA1 (6 kDa) and GPA2 (15 kDa), flanking an Src homology 3 region (6 kDa). Although the AMIC head is similar in sequence, structure, and function (ATPase motor) to other myosin heads, the organization of the tail has been less clear as has its function beyond an assumed role in binding interaction partners, e.g., the BR has a membrane affinity and the GPA components bind F-actin in an ATP-independent manner. To investigate the spatial arrangement of subdomains in the tail, we have used cryo-electron microscopy and image reconstruction to compare actin filaments decorated with WT AMIC and tail-truncated mutants of various lengths. The BR forms an oval-shaped feature, approximately 40 A long, that diverges obliquely from the head, extending azimuthally around the actin filament and toward its barbed end. GPA2 and GPA1 are located together on the inner (actin-proximal) side of the tail, close enough to act in concert in binding the same or another actin filament. The outer face of the BR is strategically exposed for membrane or vesicle binding.     

Risk factors for enterococcal urinary tract infections: a multinational,retrospective cohort study

European Journal of Clinical Microbiology & Infectious Diseases - Complicated urinary tract infection (cUTI) is a frequent cause of morbidity. In this multinational retrospective cohort study,...     

Impact of early life exposure to antiepileptic drugs on neurobehavioral outcomes based on laboratory animal and clinical research

Epilepsy affects approximately 1% of children under the age of 15, making it a very common neurological disorder in the pediatric population (Russ et al., 2012 [1]). In addition, ~ 0.4–0.8% of all pregnant women have some form of epilepsy (Hauser et al., 1996a,b; Borthen et al., 2009; Krishnamurthy, 2012 [2], [3], [4], [5]). Despite the potential deleterious effects of antiepileptic drugs (AEDs) on the developing brain, their use is still required for seizure control in pregnant women (Krishnamurthy, 2012 [5]), and they represent the standard approach for treating children with epilepsy (Chu-Shore and Thiele, 2010; Quach et al., 2010; Verrotti et al., 2011 [6], [7], [8]). Even when AEDs are effective, there are potential side effects, including cognitive and affective changes or altered sleep and appetite. The consequences of AED exposure in development have been studied extensively (Canger et al., 1999; Modi et al., 2011a,b; Oguni, 2011 [9], [10], [11], [12]). Despite intensive study, there is still debate about the long-term consequences of early life AED exposure. Here, we consider the evidence to date that AED exposure, either prenatally or in early postnatal life, has significant adverse effects on the developing brain and incorporate studies of laboratory animals as well as those of patients. We also note the areas of research where greater clarity seems critical in order to make significant advances. A greater understanding of the impact of AEDs on somatic, cognitive and behavioral development has substantial value because it has the potential to inform clinical practice and guide studies aimed at understanding the genetic and molecular bases of comorbid pathologies associated with common treatment regimens. Understanding these effects has the potential to lead to AEDs with fewer side effects. Such advances would expand treatment options, diminish the risk associated with AED exposure in susceptible populations, and improve the quality of life and health outcomes of children with epilepsy and children born to women who took AEDs during pregnancy.This article is part of a Special Issue entitled “The Future of Translational Epilepsy Research”.     

Access to dental services for head and neck cancer patients

Dental assessment is important for patients with cancer of the head and neck who are to have radiotherapy, as many of these patients have poor dental health before they start treatment. This, compounded by the fact that radiotherapy to the head and neck has a detrimental effect on oral health, has led the National Institute for Clinical Excellence (NICE) to issue guidance that the dental health of these patients should be assessed before treatment. Unfortunately some multidisciplinary teams, such as the one at United Lincolnshire Hospitals, do not have access to a restorative dentist or a dental hygienist. In a retrospective survey we investigated access to general dental services by patients with head and neck cancer who were to have radiotherapy at our hospital and found that 37/71 (52%) had not been reviewed by a dentist within the past 12 months. A secondary national survey that investigated the availability of restorative dental and dental hygienic services showed that of the 56 multidisciplinary teams that deal with head and neck cancer in England, 19 (34%) do not have access to a restorative dentist and 23 (41%) do not have access to a dental hygienist, suggesting that this problem may be countrywide.