A putative human male infertility gene DAZLA: genomic structure and methylation status

The DAZLA (DAZ Like Autosomal) gene on human chromosome 3 shares a high degree of homology with the DAZ (Deleted in AZoospermia) gene family on the Y chromosome, a gene family frequently deleted in males with azoospermia or severe oligospermia. The involvement of both DAZ and DAZLA in spermatogenesis is suggested by their testis-specific expression and their homology with a Drosophila male infertility gene, boule. Whereas male infertility resulting from deletion of the DAZ genes on the Y chromosome occurs sporadically, that due to a defective DAZLA gene is expected to be inheritable. The fraction of males with idiopathic azoospermia or oligospermia that harbour mutations in the DAZLA gene remains unknown. As a prerequisite for mutation screening, the genomic structure of the DAZLA gene was elucidated and found to consist of 11 exons spanning 19 kh. The exon/intron boundaries are conserved between DAZ and DAZLA. The 5' end of both genes are hypomethylated in spermatozoa but not in leukocytes or placenta, consistent with the expression pattern of the genes. The genomic structure of DAZLA paves the way for mutation detection in families with autosomal recessive male infertility.      

Organization, expression and polymorphism of the human persyn gene

Persyn is a recently identified member of the synuclein family with a distinct pattern of expression during pre- and postnatal development of the mouse peripheral and central nervous systems. As with other synucleins, persyn is believed to be involved in the pathogenesis of human neurodegenerative diseases. However, in contrast to other synucleins, high levels of persyn mRNA expression were also found in advanced breast carcinomas, suggesting an involvement of the encoded protein in breast tumour progression. Here we have used an antibody specific to human persyn to demonstrate that the level of this protein is increased in ageing cerebral cortex and in breast tumours. We cloned, characterized and sequenced the human persyn genomic locus and localized it to the long arm of chromosome 10 in the q23.2-q23.3 region. Sequence information was used to search for specific mutations in the protein coding regions of persyn mRNA and the persyn gene in breast tumours and tumour cell lines. No tumour-specific mutations were found, but two linked polymorphisms in the coding region were detected, both in mRNA and exons III and IV of the gene. These results suggest that development of breast tumours correlates with overexpression of the wild-type persyn protein. Detailed characterization of the human persyn locus is important for further studies of the involvement of persyn in neurodegeneration and malignancy.      

内固定基础上应用骨形态发生蛋白人工骨与自体髂骨植骨治疗骨质疏松性髋骨折的效果比较

目的:比较采用骨形态发生蛋白人工骨植骨加骨折内固定与自体髂骨植入加骨折内固定治疗骨质疏松性转子间骨折的效果。方法:选择2003-10/2005-10桂林医学院附属医院骨科收治的Ⅲ、Ⅳ、V型骨质疏松性转子间骨折患者51例,均知情同意。实验分组:随机将病例分为2组,骨形态发生蛋白人工骨植入组26例,自体髂骨植入组25例。实验干预:采用股骨上段外侧切口,DHS或加防旋钉内固定,骨形态发生蛋白人工骨由处理后的牛松质骨与成品重组人骨形态发生蛋白2按一定比例复合而成,骨折固定后在骨折缺损处、内侧及骨折周围植骨,骨形态发生蛋白人工骨组采用骨形态发生蛋白人工骨植入,自体髂骨组取自体髂骨植入。实验评估:术后定期随访,比较二组患者的基本情况、临床效果和影像学结果(骨折愈合情况和颈干角的变化)。随访时关节功能评定参照采用黄公怡等提出的标准,分为优、良、可、差4级。髋内翻分类标准为颈干角<100°。结果:术后随访1年,51例患者全部进入结果分析。①术后X射线片观察:骨形态发生蛋白人工骨组临床愈合时间短于自体髂骨组[(94.50±22.45),(116.96±15.90)d,P<0.01];骨形态发生蛋白人工骨组术后1年颈干角大于自体髂骨组[(127.19±3.23)°,(120.4±5.22)°,P<0.01]。②髋关节功能及不良事件和副反应:骨形态发生蛋白人工骨组术后以1年髋关节功能优良率优于自体髂骨组(P<0.05);骨形态发生蛋白人工骨组髋内翻、下肢短缩(>2cm)的发生率均低于自体髂骨组[髋内翻(n):4,7;下肢短缩(n):3,5,P均<0.01];钉退出二组差异均无显著性意义(P>0.05)。结论:伴有骨质疏松的转子间骨折患者,采用骨形态发生蛋白人工骨植骨优于自体髂骨植骨,可缩短骨折愈合期,减少髋内翻等并发症的发生率,提高术后髋关节功能优良率,提示骨形态发生蛋白人工骨能替代自体髂骨植骨治疗骨质疏松性转子间骨折。     

Serial lung scintigraphy: utility in diagnosis of pulmonary embolism

Pairs of sequential perfusion lung scans and pulmonary angiograms obtained in 45 patients were reviewed to investigate the utility of short-term, sequential scintigraphy in the diagnosis of pulmonary embolism (PE). Forty-six sequential scan pairs were reviewed; 13 were ventilation-perfusion (V-P) pairs. Angiograms were obtained within 48 hours of either the first (65%) or second (35%) perfusion scan in each pair. Sequential scintigraphic patterns were classified as showing change (i.e., improvement in defects, new defects), no change, or as being indeterminate. A changing perfusion pattern was associated with a high (20/23) likelihood of PE, but seven of 16 patients with stable perfusion patterns also had PE. The sensitivity of a changing perfusion pattern for PE was 0.74 (20/27) and its specificity was 0.75 (9/12). In two of six patients who had serial V-P studies that showed changing perfusion defects, there were matched changes in regional ventilation and angiograms were negative. The findings suggest that short-term serial perfusion lung scanning may aid the scintigraphic diagnosis of PE in certain circumstances. Serial V-P imaging is needed, however, to maximize diagnostic specificity.     

Quality of Quality Accounts: transparency of public reporting of Never Events in England. A semi-quantitative and qualitative review

ObjectivesTo describe the quality of reporting and investigation into surgical Never Events in public reports.DesignSemi-quantitative and qualitative review of published Quality Accounts for three years (2011/2–2013/14). Data on Never Events were compared with previously collated Never Events rates. Quality of reported investigations was assessed using the London Protocol.SettingEnglish National Health Service.ParticipantsAll English acute hospital trusts.ResultsQuality Accounts were available for all Trusts for all three years, of which 342 referred to years when a surgical Never Event had occurred. A total of 125 of 342 (37%) accounts failed to report any or all Never Events that had occurred; 13/342 (4%) provided full disclosure; 197 (58%) reported that some investigation had taken place. Of these 197, 61 (31%) were limited in scope; 61 (31%) were categorised as detailed reports. Task and Technology factors were the commonest factor (103/211 (49%)) Identified in investigations, followed by Individual factors (48/211 (23%)). Team and Work environment factors were identified in 29/211 (14%) and 23/211 (11%), respectively. Organisational and Management 5/211 (2%) factors were rarely identified, and the Institutional context was never discussed.ConclusionsReporting of Never Events and their investigations by English NHS Trusts in their Quality Accounts is neither consistently transparent nor adequate. As with clinical error, the true root causes are likely to be organisational rather than individual.     

The effect of baseline CD4 cell count and HIV-1 viral load on the efficacy and safety of nevirapine or efavirenz-based first-line HAART

BACKGROUND: A substantial number of patients start their first-line antiretroviral therapy at an advanced stage of an HIV-1 infection. Potential differences between specific drug regimens in antiviral efficacy and safety in these patients are of major importance. METHODS: A post-hoc analysis within the randomized controlled 2NN trial comparing efficacy between regimes containing nevirapine (NVP), efavirenz (EFV), or both, in addition to stavudine and lamivudine. Primary outcome: risk of virologic failure in different strata of baseline CD4 T-lymphocyte counts and plasma HIV-1 RNA concentrations (pVL). Virologic failure: never reaching a pVL < 400 copies/ml, or a rebound to two consecutive values > 400 copies/ml. RESULTS: The risk of virologic failure was increased at very low CD4 counts (< 25 x 10(6) cells/l) compared to CD4 counts > 200 x 10(6) cells/l [hazard ratio (HR), 1.28; 95% confidence interval (CI), 0.93-1.77]. The same was seen for a pVL > or = 100,000 copies/ml compared to a lower pVL (HR, 1.20; CI, 0.96-1.50). There were no statistically significant differences between NVP and EFV in risk of virologic failure within any of the CD4 or pVL strata, although EFV performed slightly better in the low CD4 stratum. The incidence of rash in the NVP group was significantly higher in female patients with higher CD4 cell counts, while adverse events in the EFV group were not associated with CD4 cell count. CONCLUSIONS: Initial antiretroviral therapy including NVP or EFV is effective in patients with an advanced HIV-1 infection. A high baseline CD4 cell count is associated with the occurrence of rash in female patients using NVP.     

Thrombin binding and response in platelets from patients with dyslipoproteinemias: increased stimulus-response coupling in type II hyperlipoproteinemia

Platelets were obtained from patients with various hyperlipidemias [type II, type V, lecithin-cholesterol acyltransferase (LCAT) deficiency] and hypolipidemias (abetalipoproteinemia, Tangier disease) to ascertain relationships among plasma lipids, platelet lipids, thrombin binding and thrombin-induced platelet aggregation, and to compare these data with those previously obtained on stimulus-response coupling in platelets following in vitro modification of membrane microviscosity. Washed platelets were studied for their ability to bind 125I-thrombin in the range of 10(-10) to 10(-6) mol/L (10 mU/mL to 100 U/mL) and to aggregate with thrombin at concentrations less than 10(-9) mol/L (100 mU/mL). The values for binding and aggregation in eight patients from six kindred with familial hypercholesterolemia, taken as a group, fell in the low normal range. If divided into two groups, patients with overt cardiovascular disease bound normal amounts of thrombin but were more responsive to it, whereas patients without overt cardiovascular disease bound lower amounts of thrombin but gave an aggregation response in the normal range. These results suggest that platelet hyperresponsiveness in familial hypercholesterolemia arises from an alteration in the coupling mechanism between thrombin binding and response such that platelets from patients with familial hypercholesterolemia are able to respond with lower receptor occupancy than is the case with normal platelets. Thrombin binding and aggregation were within normal ranges for platelets from abetalipoproteinemia patients (N = 4) and type V hyperlipoproteinemia (N = 2), although in the latter case the response appeared to be less at very low thrombin concentrations (less than 30 mU/mL). Thrombin binding was elevated in Tangier disease (N = 3) but with lower responsiveness at lower thrombin concentrations. Thrombin binding was also elevated in LCAT deficiency (N = 2), and one patient showed increased and another showed decreased aggregation responses. In general, increased plasma cholesterol levels resulted in increased stimulus-response coupling (type II), whereas increased triglyceride levels resulted in decreased coupling (type V, Tangier), and there was no apparent alteration in the coupling mechanism with overall reduction in plasma lipid levels as in abetalipoproteinemia.     

Pharmacokinetics of Nevirapine: Once-Daily Versus Twice-Daily Dosing in the 2NN Study

Abstract

Objective: As part of the large international, randomized 2NN trial, the pharmacokinetics of nevirapine in once-daily 400 mg and twice-daily 200 mg dosing regimens were investigated. Method: Treatment-naive HIV-1-infected patients were randomized to receive nevirapine 400 mg once daily or 200 mg twice daily, in combination with lamivudine and stavudine. Blood samples were collected at several time-points (day 3, weeks 1, 2, 4, 24, and 48). Differences in pharmacokinetics between once- versus twice-daily dosing were investigated with nonlinear mixed effects modelling (NONMEM). Results: In total, 2,899 nevirapine plasma concentrations were available from 578 patients. Dosage and dosing frequency did not influence clearance or volume of distribution of nevirapine, indicating linear pharmacokinetic behavior of nevirapine whether given as a single daily dose or as divided doses over 24 hours. During steady state, the C_min was lower (3.26 mg/L vs. 4.44 mg/L; p < .001) and the C_max was higher (7.88 mg/L vs. 6.55 mg/L; p < .001) in the once-daily arm. However, compared to total variability in nevirapine levels for both treatments, these differences were minor. During steady state, total exposure, measured as AUC_24h, was comparable for both regimens (133 mg/L*h vs. 133 mg/L*h; p = .084). Conclusion: The daily exposure to nevirapine (AUC_24h) was similar for the 400 mg once-daily and the 200 mg twice-daily dosing regimens. The C_min of nevirapine is lower and the C_max of nevirapine is higher for the once-daily regimen as compared to the twice-daily regimen. As a result, 200 mg nevirapine dosed twice daily may be preferred over 400 mg nevirapine dosed once daily.     

Should prophylactic antibiotics be used routinely in epistaxis patients with nasal packs?

Introduction

The current mainstream practice in otolaryngology departments relating to the use of prophylactic antibiotics in epistaxis patients requiring nasal packing is highly variable. This is due primarily to the lack of any validated guidelines. As such, we introduced a new treatment algorithm resulting in significant reduction of use in the systemic antibiotics, with emphasis instead on the use of topical antibiotics. The results were validated through a complete audit cycle.

Methods

A total of 57 patients undergoing nasal packing for spontaneous epistaxis were studied. Reaudit occurred after the implementation of new guidelines. Telephone surveys were conducted six weeks after hospital discharge, assessing infective nasal symptoms as well as rebleeding and readmission rates.

Results

Systemic antibiotic prescribing in anterior nasal packing fell by 58.2% between audit cycles with no statistically significant associated increase in infective nasal symptoms, rebleeding or readmission rates six weeks following hospital discharge.

Conclusions

Systemic prophylactic antibiotics are unnecessary in the majority of epistaxis patients with nasal packs. The use of topical antibiotics such as Naseptin^® may be more appropriate, cheaper and as effective. Implementation of this treatment algorithm will help standardise systemic antibiotic usage in epistaxis patients with nasal packing and should reduce costs associated with unnecessary use of such medication.