Mechanical assessment of proprietary and improvised pelvic binders for use in the prehospital environment.

INTRODUCTION: Pelvic fractures often result from high-energy trauma and are associated with a 10% mortality rate and significant morbidity. Pelvic binders are applied in suspected pelvic injury to stabilise fractured bone, decrease bleeding and potentiate tamponade. A binder must hold the pelvis with sufficient force for this effect to be achieved. This study aims to quantify the ability of proprietary and improvised pelvic binders to hold a target tensile force over time. METHODS: The ability of three proprietary and three improvised binders to hold a binding force for 2 hours was tested. A uniaxial materials testing machine was used to tension each binder to 150 N and then hold the displacement for 2 hours; the drop in tension over time was recorded for each binder. The ability to hold tension above 130 N after 2 hours was set as the metric of binder performance. RESULTS: The median tension at 2 hours was above 130 N for the SAM Pelvic Sling II and T-POD Pelvic Stabilisation Device and was below 130 N for the Prometheus Pelvic Splint, field-expedient pelvic splint (FES) and the Personal Clothing System-Multi-Terrain Pattern Combat Trousers binders. The tension in the improvised FES after 2 hours was approximately at the target 130 N; however, in 40% of the tests, it held above 130 N. CONCLUSIONS: Binders varied in their ability to maintain sufficient tension to treat a pelvic fracture over the 2-hour testing period. The FES performed well under our testing regime; with relatively low cost and weight, it represents a good alternative to proprietary binders for the austere environment.

Longitudinal in vivo metabolic labeling reveals tissue-specific mitochondrial proteome turnover rates and proteins selectively altered by parkin deficiency.

Our study utilizes a longitudinal isotopic metabolic labeling approach in vivo in combination with organelle fraction proteomics to address the role of parkin in mitochondrial protein turnover in mice. The use of metabolic labeling provides a method to quantitatively determine the global changes in protein half-lives whilst simultaneously assessing protein expression. Studying two diverse mitochondrial populations, we demonstrated the median half-life of brain striatal synaptic mitochondrial proteins is significantly greater than that of hepatic mitochondrial proteins (25.7 vs. 3.5 days). Furthermore, loss of parkin resulted in an overall, albeit modest, increase in both mitochondrial protein abundance and half-life. Pathway and functional analysis of our proteomics data identified both known and novel pathways affected by loss of parkin that are consistent with its role in both mitochondrial quality control and neurodegeneration. Our study therefore adds to a growing body of evidence suggesting dependence on parkin is low for basal mitophagy in vivo and provides a foundation for the investigation of novel parkin targets.

Deprenyl reduces inflammation during acute SIV infection.

In the era of antiretroviral therapy, inflammation is a central factor in numerous HIV-associated comorbidities, such as cardiovascular disease, cognitive impairment, and neuropsychiatric disorders. This highlights the value of developing therapeutics that both reduce HIV-associated inflammation and treat associated comorbidities. Previous research on monoamine oxidase inhibitors (MAOIs) suggests this class of drugs has anti-inflammatory properties in addition to neuropsychiatric effects. Therefore, we examined the impact of deprenyl, an MAOI, on SIV-associated inflammation during acute SIV infection using the rhesus macaque model of HIV infection. Our results show deprenyl decreased both peripheral and CNS inflammation but had no effect on viral load in either the periphery or CNS. These data show that the MAOI deprenyl may have broad anti-inflammatory effects when given during the acute stage of SIV infection, suggesting more research into the anti-inflammatory effects of this drug could result in a beneficial adjuvant for antiretroviral therapy.

Routine use of salivary bypass tubes in laryngectomy patients: systematic review.

BACKGROUND: Pharyngocutaneous fistula is a cause of significant morbidity following laryngectomy. Routine use of salivary bypass tubes during laryngectomy has been proposed to reduce the incidence of fistulae and neopharyngeal strictures. METHOD: Following a systematic search of Embase, Medline and Cochrane databases (1946 - current), included articles were assessed for bias according to the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: Three case-control trials showed reduced pharyngocutaneous fistula rates with the use of salivary bypass tubes; six case series reported widely varied fistula rates. With regards to stricture rates, the largest case-control trial found no improvement with salivary bypass tube use. No fatal adverse events were observed among the 204 patients who received a salivary bypass tube. CONCLUSION: Low-level evidence suggests salivary bypass tubes may reduce the incidence of fistula in high-risk patient groups. A robust randomised controlled trial, or large, multicentre cohort studies, are needed to further examine this intervention.

Tranexamic acid in epistaxis: a systematic review.

BACKGROUND: The role of tranexamic acid in the management of epistaxis remains unclear. There is uncertainty about its safety and about the contraindications for its use. We performed a systematic review of the use of systemic and topical tranexamic acid in epistaxis and a comparative review of its use in other specialties. OBJECTIVE OF REVIEW: This review assesses and summarises the existing evidence for the efficacy and safety of tranexamic acid in the management of epistaxis. TYPE OF REVIEW: Systematic review. SEARCH STRATEGY: MEDLINE and EMBASE were searched for 'epistaxis' and equivalent MESH terms, combined with the Boolean operator 'OR' and 'tranexamic acid'. The Cochrane library and society guidelines were reviewed for evidence regarding the use of tranexamic acid in other specialties. EVALUATION METHOD: All five relevant RCTs were included in the review and were evaluated according to the recommendations of the Cochrane Handbook for Systematic Reviews. RESULTS: Three RCTS pertained to spontaneous epistaxis; of these, one trial found no benefit of oral tranexamic acid in acute epistaxis, one trial found no significant benefit of topical tranexamic acid, but the largest of the trials showed significant benefit of topical tranexamic acid in acute epistaxis management. Two RCTs examined oral tranexamic acid for prophylaxis of recurrent epistaxes in patients with hereditary haemorrhagic telangiectasia; both showed significant reduction in severity and frequency. CONCLUSIONS: Tranexamic acid, as a WHO 'essential medicine', is a powerful, readily available tool, the use of which in epistaxis has been limited by uncertainty over its efficacy and its safety profile. This systematic review summarises the existing evidence and extrapolates from the wealth of data for other specialties to address the clinical question - does TXA have a role in epistaxis management?

Chronic mucocutaneous candidiasis: characterization of a family with STAT-1 gain-of-function and development of an ex-vivo assay for Th17 deficiency of diagnostic utility.

Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent and persistent superficial infections, with Candida albicans affecting the mucous membranes, skin and nails. It can be acquired or caused by primary immune deficiencies, particularly those that impair interleukin (IL)-17 and IL-22 immunity. We describe a single kindred with CMC and the identification of a STAT1 GOF mutation by whole exome sequencing (WES). We show how detailed clinical and immunological phenotyping of this family in the context of WES has enabled revision of disease status and clinical management. Together with analysis of other CMC cases within our cohort of patients, we used knowledge arising from the characterization of this family to develop a rapid ex-vivo screening assay for the detection of T helper type 17 (Th17) deficiency better suited to the routine diagnostic setting than established in-vitro techniques, such as intracellular cytokine staining and enzyme-linked immunosorbent assay (ELISA) using cell culture supernatants. We demonstrate that cell surface staining of unstimulated whole blood for CCR6⁺ CXCR3⁻ CCR4⁺ CD161⁺ T helper cells generates results that correlate with intracellular cytokine staining for IL-17A, and is able to discriminate between patients with molecularly defined CMC and healthy controls with 100% sensitivity and specificity within the cohort tested. Furthermore, removal of CCR4 and CD161 from the antibody staining panel did not affect assay performance, suggesting that the enumeration of CCR6⁺ CXCR3⁻ CD4⁺ T cells is sufficient for screening for Th17 deficiency in patients with CMC and could be used to guide further investigation aimed at identifying the underlying molecular cause.

Delayed recovery from Cheyne-Stokes respiration in heart failure after successful cardiac transplantation: a case report.

BACKGROUND: Sleep-disordered breathing (SDB), especially central sleep apnea with Cheyne-Stokes respiration (CSA-CSR), is highly prevalent in patients with severe heart failure (HF). SDB, and predominantly CSR, may improve after recovery of cardiac function, but available data are limited and inconclusive, particularly in patients who have undergone heart transplantation (HTX). CASE REPORT: The case of a 59-year-old man with dilated cardiomyopathy and advanced chronic HF, plus CSA-CSR, is reported. The patient showed normalization of cardiac function after successful HTX, with delayed but gradual stepwise improvements in CSA-CSR over time. CONCLUSIONS: Although there is a close relationship between cardiac function and manifestations of SDB and CSA-CSR, stabilization of nocturnal respiration after improvement in cardiac function may be delayed rather than immediate.

[Detection and therapy of respiratory dysfunction by implantable (cardiac) devices]. / Detektion und Therapie respiratorischer Störungen durch implantierbare (kardiale) Devices.

Sleep-disordered breathing (SDB) represents a common comorbidity in cardiac patients. The prevalence of obstructive sleep apnea (OSA) and central sleep apnea (CSA) is very high, particularly in patients with heart rhythm disorders and heart failure (HF). Patients with pacemakers (PM) and implantable defibrillators (ICD) including cardiac resynchronization therapy (CRT) show SDB prevalences up to 75%. However, some modern PM, ICD and CRT devices allow the detection of SDB via transthoracic impedance analysis with high sensitivity compared to polysomnographic (PSG) controls. Thus, this method could be of relevance in screening and monitoring SDB in patients with implantable cardiac devices. Preliminary studies demonstrated the possibility to treat OSA in selected patients by stimulation of the cranial nerves, especially the hypoglossal nerve. However, this requires extensive diagnostics and advanced surgical approaches including many medical disciplines and is not part of this review article. However, unilateral and transvenous stimulation of the phrenic nerve to treat central sleep apnea and Cheyne-Stokes respiration in HF patients in particular can be performed by cardiologists. This article summarizes preliminary data on the results of this promising therapy.

[Sleep-related breathing disorders and (resulting) cardiovascular diseases]. / Schlafbezogene Atmungsstörungen und kardiovaskuläre (Folge-)Erkrankungen.

Sleep-related breathing disorders occur in cardiology patients mostly as obstructive or central sleep apnea with Cheyne-Stokes respiration. The prevalence and incidence are clearly increased in comparison to the general population. Depending on the underlying cardiac disease up to 75% of patients can have obstructive or central sleep apnea and up to 50% have indications for therapy according to the current guidelines. Obstructive sleep apnea is considered to be an independent and well treatable risk factor for the development and deterioration of many cardiovascular diseases. This review briefly describes examples of prevalence, pathophysiology and current study situation with respect to the association between sleep-related breathing disorders and arterial hypertension, atrial fibrillation, arteriosclerosis with coronary heart disease, myocardial infarction and heart failure. Although the role of obstructive sleep apnea as a risk factor for the development of these diseases is well documented, central sleep apnea is less of a risk factor per se but is considered to mirror an underlying cardiac disease with then further negative consequences for this disease. It is not the sleep apnea per se but the subsequent cardiovascular diseases which limit the prognosis of these patients and therefore bring them into the focus of cardiology. Obstructive and central sleep apnea can be successfully and sustainably treated by various forms of nocturnal positive airway pressure therapy. Furthermore, there are several therapeutic procedures which are currently being tested and the significance will be investigated in the coming years.

The evolutionary young miR-1290 favors mitotic exit and differentiation of human neural progenitors through altering the cell cycle proteins.

Regulation of cellular proliferation and differentiation during brain development results from processes requiring several regulatory networks to function in synchrony. MicroRNAs are part of this regulatory system. Although many microRNAs are evolutionarily conserved, recent evolution of such regulatory molecules can enable the acquisition of new means of attaining specialized functions. Here we identify and report the novel expression and functions of a human and higher primate-specific microRNA, miR-1290, in neurons. Using human fetal-derived neural progenitors, SH-SY5Y neuroblastoma cell line and H9-ESC-derived neural progenitors (H9-NPC), we found miR-1290 to be upregulated during neuronal differentiation, using microarray, northern blotting and qRT-PCR. We then conducted knockdown and overexpression experiments to look at the functional consequences of perturbed miR-1290 levels. Knockdown of miR-1290 inhibited differentiation and induced proliferation in differentiated neurons; correspondingly, miR-1290 overexpression in progenitors led to a slowing down of the cell cycle and differentiation to neuronal phenotypes. Consequently, we identified that crucial cell cycle proteins were aberrantly changed in expression level. Therefore, we conclude that miR-1290 is required for maintaining neurons in a differentiated state.

A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing.

Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549 692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual's cognitive changes were constructed. One SNP--rs2075650, located in TOMM40 (translocase of the outer mitochondrial membrane 40 homolog)--had a genome-wide significant association with cognitive ageing (P=2.5 × 10(-8)). This result was replicated in a meta-analysis of three independent Swedish cohorts (P=2.41 × 10(-6)). An Apolipoprotein E (APOE) haplotype (adjacent to TOMM40), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample (P=2.18 × 10(-8); females, P=1.66 × 10(-11); males, P=0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P=3.66 × 10(-11)) and TOMM40 (rs11556505; P=2.45 × 10(-8)) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to APOE (rs429358). Functional genomic analysis indicated that SNPs in the TOMM40/APOE region have a functional, regulatory non-protein-coding effect. The APOE region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear.

Exosome-mediated shuttling of microRNA-29 regulates HIV Tat and morphine-mediated neuronal dysfunction.

Neuronal damage is a hallmark feature of HIV-associated neurological disorders (HANDs). Opiate drug abuse accelerates the incidence and progression of HAND; however, the mechanisms underlying the potentiation of neuropathogenesis by these drugs remain elusive. Opiates such as morphine have been shown to enhance HIV transactivation protein Tat-mediated toxicity in both human neurons and neuroblastoma cells. In the present study, we demonstrate reduced expression of the tropic factor platelet-derived growth factor (PDGF)-B with a concomitant increase in miR-29b in the basal ganglia region of the brains of morphine-dependent simian immunodeficiency virus (SIV)-infected macaques compared with the SIV-infected controls. In vitro relevance of these findings was corroborated in cultures of astrocytes exposed to morphine and HIV Tat that led to increased release of miR-29b in exosomes. Subsequent treatment of neuronal SH-SY5Y cell line with exosomes from treated astrocytes resulted in decreased expression of PDGF-B, with a concomitant decrease in viability of neurons. Furthermore, it was shown that PDGF-B was a target for miR-29b as evidenced by the fact that binding of miR-29 to the 3'-untranslated region of PDGF-B mRNA resulted in its translational repression in SH-SY5Y cells. Understanding the regulation of PDGF-B expression may provide insights into the development of potential therapeutic targets for neuronal loss in HIV-1-infected opiate abusers.

Plasma gelsolin accumulates in macrophage nodules in brains of simian immunodeficiency virus infected rhesus macaques.

Plasma gelsolin (pGSN), an isoform 1, is secreted by various types of cells in the central nervous system (CNS) and periphery, but not by the liver. pGSN circulates in blood and cerebrospinal fluid (CSF); however, its concentration in CSF is approximately twenty times lower than in plasma. It has been shown that several types of cells such as oligodendrocytes, neurons, and/or astrocytes contribute to the overall pool of pGSN in the CNS. Further, it has been postulated that pGSN plays multiple roles during microbial infection and modulates inflammatory responses; however, the exact mechanism of regulation is not known. We previously showed that levels of pGSN in CSF of individuals with advanced neurocognitive impairment due to HIV infection of the brain are decreased. Here, we show that macrophages express significant amounts of pGSN in response to HIV infection in vitro. Using immunohistochemistry of simian immunodeficiency virus infected rhesus monkey brains, we show that increased levels of pGSN are present in macrophage nodules creating locally a high level of this protein within the brain. This may not be reflected by the overall decreased level in the distinct CSF compartment.