Emerging technology: electrical stimulation in obstructive sleep apnoea

Electrical stimulation (ES) of the upper airway (UAW) dilator muscles for patients with obstructive sleep apnoea (OSA) has been used for several decades, but in recent years research in this field has experienced a renaissance; the results of several studies have triggered a steady rise in the interest in this topic. Prospective trials, although still lacking a sham-controlled and randomised approach, have revealed the potential of ES. Hypoglossal nerve stimulation (HNS) leads to a significant reduction in the apnoea-hypopnoea index and the oxygen desaturation index (ODI). There are similar results published from feasibility studies for transcutaneous ES. A limitation of HNS remains the invasive procedure, the costs involved and severe adverse events, while for the non-invasive approach complications are rare and limited. The limiting step for transcutaneous ES is to deliver a sufficient current without causing arousal from sleep. Despite the progress up to date, numerous variables including optimal stimulation settings, different devices and procedures remain to be further defined for the invasive and the non-invasive method. Further studies are required to identify which patients respond to this treatment. ES of the UAW dilator muscles in OSA has the potential to develop into a clinical alternative to continuous positive airway pressure (CPAP) therapy. It could benefit selected patients who fail standard therapy due to poor long-term compliance. It is likely that international societies will need to review and update their existing guidance on the use of ES in OSA.     

Stabilization and formulation of a recombinant Human Cytomegalovirus vector for use as a candidate HIV-1 vaccine

Live attenuated viral vaccine/vector candidates are inherently unstable and infectivity titer losses can readily occur without defining appropriate formulations, storage conditions and clinical handling practices. During initial process development of a candidate vaccine against HIV-1 using a recombinant Human Cytomegalovirus vector (rHCMV-1), large vector titer losses were observed after storage at 4 °C and after undergoing freeze-thaw. Thus, the goal of this work was to develop candidate frozen liquid formulations of rHCMV-1 with improved freeze-thaw and short-term liquid stability for potential use in early clinical trials. To this end, a virus stability screening protocol was developed including use of a rapid, in vitro cell-based immunofluorescence focus assay to quantitate viral titers. A library of ∼50 pharmaceutical excipients (from various known classes of additives) were evaluated for their effect on vector stability after freeze-thaw cycling or incubation at 4 °C for several days. Certain additives including sugars and polymers (e.g., trehalose, sucrose, sorbitol, hydrolyzed gelatin, dextran 40) as well as removal of NaCl (lower ionic strength) protected rHCMV-1 against freeze-thaw mediated losses in viral titers. Optimized solution conditions (e.g., solution pH, buffers and sugar type) slowed the rate of rHCMV-1 titer losses in the liquid state at 4 °C. After evaluating various excipient combinations, three new candidate formulations were designed and rHCMV-1 stability was benchmarked against both the currently-used and a previously reported formulation. The new candidate formulations were significantly more stable in terms of reducing rHCMV-1 titer losses after 5 freeze-thaw cycles or incubation at 4 °C for 30 days. This case study highlights the utility of semi-empirical design of frozen liquid formulations of a live viral vaccine candidate, where protection against infectivity titer losses due to freeze-thaw and short-term liquid storage are sufficient to enable more rapid initiation of early clinical trials.     

Enkephalin immunoreactivity in synaptoid elements on glial cells in the rat neural lobe

Opioid peptides were localized in fibres of the rat neural lobe using various immunocytochemical methods at the light- and electron-microscopical level. Leu-enkephalin immunoreactivity was present in beaded fibres distributed throughout the neural lobe. These fibres surround the neurohypophyseal glial cells (pituicytes) and make synaptoid contacts upon their soma and processes. The reaction product was localized both in dense-core vesicles of about 100 nm in diameter and diffusely spread over the cytoplasm. No arguments in support of the co-existence of enkephalins and the neurohypophyseal hormones vasopressin and oxytocin in the same terminal were found.It is suggested that pituicytes might mediate the inhibitory effect of opiod peptides on vasopressin and oxytocin release from the neural lobe.     

家庭营养支持的应用

家庭营养支持分为家庭肠外营养（HPN）和家庭肠内营养（HEN）,在改善患者营养状况,提高生活质量方面具有很大优越性。现从HPN和HEN两方面介绍了国内外家庭营养支持的历史发展与现状、应用指征、并发症以及转归、评价,并简单总结了目前尚存在的问题和今后的发展趋势。     

Intrathecal delivery of protein therapeutics to the brain: A critical reassessment

Disorders of the central nervous system (CNS), including stroke, neurodegenerative diseases, and brain tumors, are the world’s leading causes of disability. Delivery of drugs to the CNS is complicated by the blood–brain barriers that protect the brain from the unregulated leakage and entry of substances, including proteins, from the blood. Yet proteins represent one of the most promising classes of therapeutics for the treatment of CNS diseases. Many strategies for overcoming these obstacles are in development, but the relatively straightforward approach of bypassing these barriers through direct intrathecal administration has been largely overlooked. Originally discounted because of its lack of usefulness for delivering small, lipid-soluble drugs to the brain, the intrathecal route has emerged as a useful, in some cases perhaps the ideal, route of administration for certain therapeutic protein and targeted disease combinations. Here, we review blood–brain barrier functions and cerebrospinal fluid dynamics and their relevance to drug delivery via the intrathecal route, discuss animal and human studies that have investigated intrathecal delivery of protein therapeutics, and outline several characteristics of protein therapeutics that can allow them to be successfully delivered intrathecally.     

The AAO–HNS Committee on Hearing and Equilibrium Guidelines for the diagnosis and evaluation of therapy in Menière's disease: have they been applied in the published literature of the last decade?

The AAO–HNS Committee on Hearing and Equilibrium Guidelines for the diagnosis and evaluation of therapy in Menière's disease: have they been applied in the published literature of the last decade? To assess how effectively the American Academy of Otolaryngology–Head and Neck Surgery Committee on Hearing and Equilibrium (AAO–HNS CHE) guidelines for the diagnosis and evaluation of therapy in Menière's disease have been applied in the last 11 years of published literature. This was a MedLine‐based review. Some 79.7% of papers attempted to use the AAO–HNS CHE guidelines. However, only 50% of these publications managed to use the AAO–HNS CHE criteria in the diagnosis and evaluation of therapy correctly. In order to advance our understanding of this condition, improved application of the AAO–HNS CHE guidelines by authors and editors alike is required in the reporting of results of the therapy of Menière's disease.     

A Review of HNS‐32: A Novel Azulene‐l‐Carboxamidine Derivative with Multiple Cardiovascular Protective Actions

HNS‐32 [N¹,N¹‐dimethyl‐N²‐(2‐pyridylmethyl)‐5‐isopropyl‐3,8‐dimethylazulene‐1‐carboxamidine] (CAS Registry Number: 186086‐10‐2) is a newly synthesized azulene derivative. Computer simulation showed that its three dimensional structure is similar to that of the class Ib antiarrhythmic drugs, e.g., lidocaine or mexiletine. HNS‐32 potently suppressed ventricular arrhythmias induced by ischemia due to coronary ligation and/or ischemia‐reperfusion in dogs and rats. In the isolated dog and guinea pig cardiac tissues, HNS‐32 had negative inotropic and chronotropic actions, prolonged atrial‐His and His‐ventricular conduction time and increased coronary blood flow. In the isolated guinea pig ventricular papillary muscle, HNS‐32 decreased maximal rate of action potential upstroke (V?_max) and shortened action potential duration (APD). These findings suggest that HNS‐32 inhibits inward Na⁺ and Ca²⁺ channel currents. In the isolated pig coronary and rabbit conduit arteries, HNS‐32 inhibited both Ca²⁺ channel‐dependent and ‐independent contractions induced by a wide variety of chemical stimuli. HNS‐32 is a potent inhibitor of protein kinase C (PKC)‐mediated constriction of cerebral arteries. It is likely to block both, Na⁺ and Ca²⁺ channels expressed in cardiac and vascular smooth muscles. These multiple ion channel blocking effects are largely responsible for the antiarrhythmic and vasorelaxant actions of HNS‐32. This drug may represent a novel approach to the treatment of arrhythmias.     

Acute toxic effect of typical chemicals and ecological risk assessment based on two marine microalgae,Phaeodactylum tricornutum and Platymonas subcordiformis

With the increasing demand for typical hazardous and noxious substances (HNS) in chemical industry, there is an increased leakage risk of these HNS during transportation by vessel and storage nearby seashore. In this study, the acute toxicity of nonylphenol, butyl acrylate and 1, 2-dichloroethane to Phaeodactylum tricornutum (P. tricornutum) and Platymonas subcordiformis (P. subcordiformis), was investigated to assess their ecological risk. The results showed that the three kinds of HNS showed significant time- and dose-dependent patterns on the growth inhibition of two marine microalgae. The 96 h-EC₅₀ of nonylphenol, butyl acrylate and 1, 2-dichloroethane on P. tricornutum was 1.088, 45.908 and 396 mg L⁻¹, respectively, and the 96 h-EC₅₀ of that on P. subcordiformis was 0.851, 52.621 and 389 mg L⁻¹, respectively. It was a common method to evaluate the harm of pollutants to organisms by calculating HC₅ value (the minimum pollutant concentration value harmful to 95 % of the studied species, which was no-effect concentration) with Species Sensitivity Distribution (SSD). On the basis of EC₅₀, the ecological risk assessment was further carried out, and HC₅ value of nonylphenol and 1, 2-dichloroethane to aquatic organism was 0.079 and 44 mg L⁻¹, respectively.