Spindle oscillations are generated in the dorsal thalamus and modulated by the thalamic reticular nucleus

Spindle waves occur during the early stage of slow wave sleep and are thought to arise in the thalamic reticular nucleus (TRN), causing inhibitory postsynaptic potential spindle-like oscillations in the dorsal thalamus that are propagated to the cortex. We have found that thalamocortical neurons exhibit membrane oscillations that have spindle frequencies, consist of excitatory postsynaptic potentials, and co-occur with electroencephalographic spindles. TRN lesioning prolonged oscillations in the medial geniculate body (MGB) and auditory cortex (AC). Injection of GABA~A~ antagonist into the MGB decreased oscillation frequency, while injection of GABA~B~ antagonist increased spindle oscillations in the MGB and cortex. Thus, spindles originate in the dorsal thalamus and TRN inhibitory inputs modulate this process, with fast inhibition facilitating the internal frequency and slow inhibition limiting spindle occurrence

Cell-Based Assays in High-Throughput Screening for Drug Discovery

Drug screening is a long and costly process confronted with low productivity and challenges in using animals, which limit the discovery of new drugs.  To improve drug screening efficacy and minimize animal testing, recent efforts have been dedicated to developing cell-based high throughput screening (HTS) platforms that can provide more relevant in vivo biological information than biochemical assays and thus reduce the number of animal tests and accelerate the drug discovery process. Today, cell-based assays are used in more than half of all high-throughput drug screenings for target validation and ADMET (absorption, distribution, metabolism, elimination and toxicity) in the early stage of drug discovery. In this review, we discuss the uses of different types of cells and cell culture systems, including 2D, 3D and perfusion cell cultures, in cell-based HTS for drug discovery. Optical and electrochemical methods for online, non-invasive detection and quantification of cells or cellular activities are discussed. Recent progresses and applications of 3D cultures and microfluidic systems for cell-based HTS are also discussed, followed with several successful examples of using cell-based HTS in commercial development of new drugs. Finally, a brief discussion on potential applications of cell-based HTS for screening phytochemicals and herbal medicines is provided in this review

Quality of life in rectal cancer patients with permanent colostomy in Xi’an

Purposes: The aim of this study was to observe the quality of life (QOL) in rectal cancer patients with permanent colostomy in different periods after operation. Methods: A 1-,3-,6-month prospective study of QOL in 51 rectal cancer patients with permanent colostomy and 50 ones without permanent colostomy was assessed by using European Organization for Research and Treatment of Cancer (EORTC) QOL-30 and CR38 questionnaires. Results: The variation of QOL in different periods was “v” type. In the 1st postoperative month, these patients had the lowest quality of life scores, accompanied significantly varied functions and severe symptoms. Almost of all indexes of these patients had improved consistently in postoperative periods. The scores of global QOL even better than pre-operative level at 6th months post-operation, but the social function, body image, chemotherapy side effects and financial difficulties had not restored to the baseline level. Patients without permanent colostomy had a better score in most of categories of QOL-30 and CR38. Conclusions: The 1st postoperative month was crucial for patients’ recovery, in which we should pay great attention to these problems which relate to the recovery of rectal cancer patients with permanent colostomy.Keywords: Quality of life, Rectal cancer, Permanent colostomy, EORTC QOL-30 and CR38 questionnairesAfrican Health sciences Vol 14 No. 1 March 201

Nonsurgical molding of congenital auricular deformities and analysis of the correction outcomes: A single-center, retrospective study in east China

ObjectiveOur research was carried out to provide a clinical reference for the application of nonsurgical therapy in newborns with congenital auricular deformities in east China.MethodsA retrospective study of consecutive newborns using noninvasive ear molding was conducted in Hangzhou in east China's Zhejiang Province. The demographic and clinical information and photographs of the ear before and after treatment were taken. The diagnosis of each auricular deformity was identified, and the treatment outcome was evaluated.ResultsA total of 224 patients including 356 congenital ear anomalies received noninvasive ear molding. The median age of infants to initiate treatment was 39.5 days. The median treatment duration was 42.5 days. The median follow-up time was 137.0 days. The overall treatment effective rate of all infants with nonoperative ear molding was 92.1%, and mild skin irritation and ulceration occurred in 34 ear deformities (9.6%). It confirmed that the treatment efficiency was satisfactory and the complication rate was still acceptable despite the late initiation treatment of neonates in east China. Further analysis of treatment outcomes among three subgroups of infants (the ages to initiate the ear molding were respectively less than or equal to 28, 29–56, and more than 57 days) revealed that initiation treatment was significantly related to the treatment results and the earlier the initiation treatment, the higher the effective rate and the lower the complication incidence.ConclusionOur study hints that newborns in east China may have a longer period for correction. What is more, although our study affirmed a longer period for noninvasive molding, early diagnosis and treatment are still recommended to improve therapy efficiency and reduce treatment duration and complications

At-home disposal practices of used insulin needles among patients with diabetes in China: A single-center, cross-sectional study

BackgroundMost insulin injections for people with diabetes are administered at home, thus generating many used needles. Unsafe disposal of these at-home needles can lead to needle stick injuries, blood-borne disease transmission, and environmental contamination. Previous studies have shown varying results on the prevalence of and factors associated with safe sharps disposal practices of people with diabetes.ObjectiveTo assess the prevalence of and the factors associated with the safe disposal of used insulin needles among patients with diabetes.MethodsWe collected data from 271 insulin-using patients at a tertiary care hospital in China. A self-designed instrument was used to assess sociodemographic data, disease- and treatment-related characteristics, sharps disposal practices, education on diabetes self-management and sharps disposal, and awareness of the potential risks associated with unsafe sharps disposal. Multivariate logistic regression analysis was used to explore factors associated with safe sharps disposal practices.ResultsOnly 10.3% (28/271) of participants disposed of used at-home insulin needles in a safe manner, and 14.8% (45/271) of participants had received previous instruction on sharps disposal. Previous sharps disposal instruction (AOR = 4.143, 95% CI = 1.642–10.450) and awareness of the risk of blood-borne pathogen transmission (AOR = 3.064, 95% CI = 1.332–7.046) were associated with safe disposal of used insulin needles.ConclusionIn our study, the prevalence of safe sharps disposal practices was low, and a minority of respondents had received previous instruction on sharps disposal. Participants who had previously received instruction and were aware of the risk of blood-borne pathogen transmission were more likely to handle sharps safely. Our study findings suggest that health care professionals should pay attention to sharps disposal practices of patients with diabetes and conduct diabetes education programs that include information on safe sharps disposal methods and potential hazards of unsafe sharps disposal

Effects of Different Freezing Methods on the Quality of Sea Bass

In this study, the effects of different freezing methods namely air freezing, cryogenic freezing, freezing after dipping in a refrigerating medium consisting of 20% ethanol (V/V), 20% propylene glycol (V/V), 5 g/100 mL trehalose aqueous solution and freezing after dipping in anhydrous ethanol on the quality of sea bass were investigated. The results showed that the freezing rates of refrigerating medium freezing and anhydrous ethanol freezing were 8.20 and 6.25 cm/h, which were 32.80 and 25.00 times as high as that of air freezing, respectively. The microstructure of frozen sea bass showed that the small ice crystals formed between muscle tissues were small, and the muscle fibers were closely arranged. Refrigerating medium freezing was more conducive to maintaining the water-holding capacity (WHC) of muscle tissues and slowing down the migration of immobilized water, and had a significant effect on maintaining the freshness, texture properties and protein thermostability of fish fillets. In summary, refrigerating medium freezing can effectively slow down the quality deterioration of frozen sea bass. The results of this study will provide a theoretical and practical basis for improving the storage quality of frozen aquatic products

Efficacy and safety of tigecycline monotherapy vs. imipenem/cilastatin in Chinese patients with complicated intra-abdominal infections: a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Tigecycline, a first-in-class broad-spectrum glycylcycline antibiotic, has broad-spectrum in vitro activity against bacteria commonly encountered in complicated intra-abdominal infections (cIAIs), including aerobic and facultative Gram-positive and Gram-negative bacteria and anaerobic bacteria. In the current trial, tigecycline was evaluated for safety and efficacy vs. imipenem/cilastatin in hospitalized Chinese patients with cIAIs.</p> <p>Methods</p> <p>In this phase 3, multicenter, open-label study, patients were randomly assigned to receive IV tigecycline or imipenem/cilastatin for ≤2 weeks. The primary efficacy endpoints were clinical response at the test-of-cure visit (12-37 days after therapy) for the microbiologic modified intent-to-treat and microbiologically evaluable populations. Because the study was not powered to demonstrate non-inferiority between tigecycline and imipenem/cilastatin, no formal statistical analysis was performed. Two-sided 95% confidence intervals (CIs) were calculated for the response rates in each treatment group and for differences between treatment groups for descriptive purposes.</p> <p>Results</p> <p>One hundred ninety-nine patients received ≥1 dose of study drug and comprised the modified intent-to-treat population. In the microbiologically evaluable population, 86.5% (45 of 52) of tigecycline- and 97.9% (47 of 48) of imipenem/cilastatin-treated patients were cured at the test-of-cure assessment (12-37 days after therapy); in the microbiologic modified intent-to-treat population, cure rates were 81.7% (49 of 60) and 90.9% (50 of 55), respectively. The overall incidence of treatment-emergent adverse events was 80.4% for tigecycline vs. 53.9% after imipenem/cilastatin therapy (<it>P </it>< 0.001), primarily due to gastrointestinal-related events, especially nausea (21.6% vs. 3.9%; <it>P </it>< 0.001) and vomiting (12.4% vs. 2.0%; <it>P </it>= 0.005).</p> <p>Conclusions</p> <p>Clinical cure rates for tigecycline were consistent with those found in global cIAI studies. The overall safety profile was also consistent with that observed in global studies of tigecycline for treatment of cIAI, as well as that observed in analyses of Chinese patients in those studies; no novel trends were observed.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov NCT00136201</p

SalK/SalR, a Two-Component Signal Transduction System, Is Essential for Full Virulence of Highly Invasive Streptococcus suis Serotype 2

BACKGROUND: Streptococcus suis serotype 2 (S. suis 2, SS2) has evolved into a highly infectious entity, which caused the two recent large-scale outbreaks of human SS2 epidemic in China, and is characterized by a toxic shock-like syndrome. However, the molecular pathogenesis of this new emerging pathogen is still poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: 89K is a newly predicted pathogenicity island (PAI) which is specific to Chinese epidemic strains isolated from these two SS2 outbreaks. Further bioinformatics analysis revealed a unique two-component signal transduction system (TCSTS) located in the candidate 89K PAI, which is orthologous to the SalK/SalR regulatory system of Streptococcus salivarius. Knockout of salKR eliminated the lethality of SS2 in experimental infection of piglets. Functional complementation of salKR into the isogenic mutant DeltasalKR restored its soaring pathogenicity. Colonization experiments showed that the DeltasalKR mutant could not colonize any susceptible tissue of piglets when administered alone. Bactericidal assays demonstrated that resistance of the mutant to polymorphonuclear leukocyte (PMN)-mediated killing was greatly decreased. Expression microarray analysis exhibited a transcription profile alteration of 26 various genes down-regulated in the DeltasalKR mutant. CONCLUSIONS/SIGNIFICANCE: These findings suggest that SalK/SalR is requisite for the full virulence of ethnic Chinese isolates of highly pathogenic SS2, thus providing experimental evidence for the validity of this bioinformatically predicted PAI

Ligand-Dependent Conformations and Dynamics of the Serotonin 5-HT2A Receptor Determine Its Activation and Membrane-Driven Oligomerization Properties

From computational simulations of a serotonin 2A receptor (5-HT2AR) model complexed with pharmacologically and structurally diverse ligands we identify different conformational states and dynamics adopted by the receptor bound to the full agonist 5-HT, the partial agonist LSD, and the inverse agonist Ketanserin. The results from the unbiased all-atom molecular dynamics (MD) simulations show that the three ligands affect differently the known GPCR activation elements including the toggle switch at W6.48, the changes in the ionic lock between E6.30 and R3.50 of the DRY motif in TM3, and the dynamics of the NPxxY motif in TM7. The computational results uncover a sequence of steps connecting these experimentally-identified elements of GPCR activation. The differences among the properties of the receptor molecule interacting with the ligands correlate with their distinct pharmacological properties. Combining these results with quantitative analysis of membrane deformation obtained with our new method (Mondal et al, Biophysical Journal 2011), we show that distinct conformational rearrangements produced by the three ligands also elicit different responses in the surrounding membrane. The differential reorganization of the receptor environment is reflected in (i)-the involvement of cholesterol in the activation of the 5-HT2AR, and (ii)-different extents and patterns of membrane deformations. These findings are discussed in the context of their likely functional consequences and a predicted mechanism of ligand-specific GPCR oligomerization