Age differences in diagnostic criteria of DSM-IV alcohol dependence among adults with similar drinking behaviour

Aims To test age differences in the prevalence of DSM‐IV alcohol dependence (AD) diagnostic criteria in the adult general population while controlling for drinking behaviour. Design and setting Cross‐sectional data from the 2006 German Epidemiological Survey of Substance Abuse (ESA) were used, applying a two‐stage probability sampling design. The survey used self‐administered questionnaires and telephone interviews (mixed‐mode design; 45% response rate). Participants The analytical sample consisted of n = 6984 individuals aged 18–64 years reporting alcohol consumption within the previous year. Measurements Age effects on individual AD criteria were estimated using logistic regression models, adjusting for eight mutually exclusive drinking groups (defined in terms of average daily alcohol intake and episodic heavy drinking) and socio‐economic variables. Findings When controlling for drinking behaviour, 18–24‐year‐olds were more likely to meet the criteria ‘tolerance’, ‘larger/longer’ and ‘time spent’ relative to older age groups. In contrast, the likelihood of experiencing ‘withdrawal’ symptoms increased with age. There was no significant age effect on the diagnosis of AD. Conclusions Age differences in the prevalence of specific alcohol dependence diagnostic criteria such as ‘tolerance’, ‘drinking larger amount or for longer than intended’ and ‘time spent recovering’ cannot be fully explained by differences in drinking behaviour.     

A Prospective,Randomized Comparison of Modified Pulmonary Vein Isolation Versus Conventional Pulmonary Vein Isolation in Patients with Paroxysmal Atrial Fibrillation

Modified Pulmonary Vein Isolation in AF Ablation. Introduction: Pulmonary vein isolation (PVI) is the primary ablation therapy in patients with atrial fibrillation (AF). We hypothesized that high dominant frequency (DF) sites (AF nests during sinus rhythm [SR]) adjacent to the PV ostia are associated with the atrial substrate that maintains AF, and PVI incorporating the high‐frequency AF nests may have a higher efficacy. Methods and Results: In a prospective and randomized comparison, 126 symptomatic paroxysmal AF patients that underwent PVI were enrolled. We compared the efficacy of a modified PVI (ablation line: 1.0–1.5 cm from the PV ostium with encircling the AF nests [spectral analysis with DF >70 Hz during SR, Group II]) versus the anatomy‐guided conventional PVI (Group I). In Group II, the DF value along the PV ostium was lower than 70 Hz after the PVI. The primary endpoint was the freedom from symptomatic atrial arrhythmias after a single procedure. We also followed the autonomic function by a time‐domain analysis of the heart rate variability. In both groups, AF nests were observed and electric isolation was successfully obtained in all patients. With a mean duration of 16 ± 6.1 months of follow‐up, Group II had a higher single procedure efficacy without drugs (78.7% vs 66.1%, log‐rank test: P = 0.02), and fewer repeat procedures (6.6% vs 23%; P = 0.04), as compared to Group I. Conclusion: PVI incorporating the high frequency AF nests adjacent to the PV ostia had a better single procedure efficacy. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1155–1162, November 2012)     

Adaptive screening for depression — Recalibration of an item bank for the assessment of depression in persons with mental and somatic diseases and evaluation in a simulated computer-adaptive test environment

Objective

This study conducted a simulation study for computer-adaptive testing based on the Aachen Depression Item Bank (ADIB), which was developed for the assessment of depression in persons with somatic diseases. Prior to computer-adaptive test simulation, the ADIB was newly calibrated.

Methods

Recalibration was performed in a sample of 161 patients treated for a depressive syndrome, 103 patients from cardiology, and 103 patients from otorhinolaryngology (mean age 44.1, SD = 14.0; 44.7% female) and was cross-validated in a sample of 117 patients undergoing rehabilitation for cardiac diseases (mean age 58.4, SD = 10.5; 24.8% women). Unidimensionality of the itembank was checked and a Rasch analysis was performed that evaluated local dependency (LD), differential item functioning (DIF), item fit and reliability. CAT-simulation was conducted with the total sample and additional simulated data.

Results

Recalibration resulted in a strictly unidimensional item bank with 36 items, showing good Rasch model fit (item fit residuals < |2.5|) and no DIF or LD. CAT simulation revealed that 13 items on average were necessary to estimate depression in the range of − 2 and + 2 logits when terminating at SE ≤ 0.32 and 4 items if using SE ≤ 0.50. Receiver Operating Characteristics analysis showed that θ estimates based on the CAT algorithm have good criterion validity with regard to depression diagnoses (Area Under the Curve ≥ .78 for all cut-off criteria).

Conclusion

The recalibration of the ADIB succeeded and the simulation studies conducted suggest that it has good screening performance in the samples investigated and that it may reasonably add to the improvement of depression assessment.     

Facteurs associés aux perdus de vue des patients sous traitement antirétroviral dans un centre de traitement ambulatoire du VIH à Conakry,Guinée

Background

Late or inadequate therapeutic management increases the risk of mortality associated with HIV/AIDS. The aim of this study was to analyze the proportion and factors associated with loss of follow-up in HIV patients who receiving antiretroviral therapy at Conakry.

α-葡萄糖苷酶抑制剂治疗2型糖尿病的系统评价

目的评价α-葡萄糖苷酶抑制剂治疗2型糖尿病患者的效果。方法检索Cochrane图书馆、MEDLINE、EMBASE、CurrentContents、LILACS在研试验数据库,主题为α-葡萄糖苷酶抑制剂的综述的参考文献,并联系纳入试验的专家与实施者。最近检索日期为2003年月12月(CurrentContents)和2003年4月(其他数据库)。纳入α-葡萄糖苷酶抑制剂单一疗法与其它干预比较,治疗2型糖尿病疗程至少12周的随机对照试验,并且试验至少包括以下结局之一:病死率、患病率、生活质量、血糖控制、血脂、胰岛素水平、体重、不良事件。两名评价者独立阅读所有摘要,评价质量并提取数据,分歧通过协商解决或由第三位评价者裁决。由一位统计学家在对提取数据输入数据库时进行检查。我们尽量联系所有作者以核实数据。结果共纳入41个试验、8130例受试者,其中30个针对阿卡波糖,7个针对米格列醇,1个针对优格列波糖,还有3个为不同α-葡萄糖苷酶抑制剂间的比较。绝大多数研究疗程为24周,仅有2个研究超过1年。与安慰剂相比,阿卡波糖血糖控制效果更好:糖化血红蛋白–0.8%[95%CI(–0.9,–0.7)],空腹血糖–1.1mmol/L[95%CI(–1.4,–0.9)],负荷血糖–2.3mmol/L[95%CI(–2.7,–1.9)],阿卡波糖对糖化血红蛋白的作用呈非剂量依赖。我们发现其可降低负荷胰岛素,但对血脂和体重未见临床相关的作用。不良反应主要来自胃肠道且与剂量相关。相对于磺脲,阿卡波糖将空腹和负荷胰岛素水平分别降低至–24.8pmol/L[95%CI(–43.3,–6.3)]和–133.2pmol/L[95%CI(–184.5,–81.8)],但阿卡波糖引起的不良反应更多。结论关于α-葡萄糖苷酶抑制剂是否影响2型糖尿病患者的病死率和患病率仍不清楚。相反,其对血糖控制或胰岛素水平作用明显,对血脂和体重的作用差异无统计学意义。α-葡萄糖苷酶抑制剂更长疗程的效果仍不确定。阿卡波糖剂量超过50mg(TID)时不能进一步影响糖化血红蛋白水平,不良反应反而更多,与磺脲相比,α-葡萄糖苷酶抑制剂降低了空腹和负荷胰岛素水平,但在血糖控制和不良反应方面存在不利影响。     

双切口套法预防开放性胃肠手术后切口感染的临床效果观察

目的：探讨双切口套法预防开放性胃肠手术后切口感染的临床效果。方法选取2013年3月~2014年8月在本院实施开放性胃肠手术的75例患者作为研究对象,随机分为观察组(38例)和对照组(37例)。观察组在开放性胃肠手术中采用双切口套法,对照组术中不使用任何切口保护套。比较两组的手术时间、术后首次排气时间、首次排便时间、住院时间及切口感染率。结果两组的手术时间比较,差异无统计学意义(P>0.05)。观察组的术后首次排气时间、首次排便时间及住院时间显著短于对照组,差异有统计学意义(P<0.05)。观察组的切口感染率为2.63%,显著低于对照组的16.22%,差异有统计学意义(P<0.05)。结论双切口套法可以明显降低开放性胃肠手术后的切口感染率,提高临床疗效。     

Monoclonal antibodies recognizing epitopes on the extracellular face and intracellular N-terminus of the human erythrocyte anion transporter (band 3) and their application to the analysis of South East Asian ovalocytes

This report describes the production and characterization of 13 rodent monoclonal antibodies to the human erythrocyte anion transport protein AE1 (syn. band 3). Eleven antibodies (4 murine and 7 rat) recognize epitopes dependent on the integrity of the third extracellular loop of the protein. Two antibodies (1 murine and 1 rat) recognize epitopes on the N-terminal cytoplasmic domain. Quantitative binding studies using radioiodinated IgG and Fab fragments of antibodies to extracellular epitopes on AE1 ranged from 77,000 to 313,000 (IgG) and from 241,000 to 772,000 (Fab) molecules bound at saturation. The results indicate that the epitopes recognized by different antibodies vary in their accessibility and suggest that there is heterogeneity in the organization of individual AE1 molecules in the red blood cell membrane. Quantitative binding studies on South East Asian ovalocytes using several antibodies to AE1 and an anti-Wrb show a marked reduction in the number of antibody molecules bound at saturation. These results are consistent with the existence of highly cooperative interactions between transmembrane domains of AE1 in normal erythrocytes and the disruption of these interactions in the variant AE1 found in South East Asian ovalocytes.     

Impact of an acceptance facilitating intervention on diabetes patients’ acceptance of Internet-based interventions for depression: A randomized controlled trial

Aims

To (1) determine diabetes patients’ acceptance of Internet-based interventions (IBIs) for depression, to (2) examine the effectiveness of an acceptance facilitating intervention (AFI) and to (3) explore subgroup specific effects.

Methods

141 diabetes patients from two inpatient rehabilitation units and one outpatient clinic in Germany were randomly allocated to an intervention (IG) and a no-intervention control group (CG). The IG received an AFI consisting of a personal information session before filling-out a questionnaire on patients’ acceptance of IBIs, predictors of acceptance (performance expectancy, effort expectancy, social influence, facilitating conditions, and Internet anxiety) as well as sociodemographic, depression-related and diabetes-related variables. The CG filled out the questionnaire immediately. Patients’ acceptance of IBIs was measured with a four-item scale (sum-score ranging from 4 to 20).

Results

The CG showed a low (50.7%) to medium (40.8%) acceptance with only 8.5% of all diabetes patients reporting a high acceptance of IBIs for depression. The AFI had no significant effect on acceptance (IG: M = 10.55, SD = 4.69, n = 70; KG: M = 9.65, SD = 4.27, n = 71; d = 0.20 [95%-CI: −0.13;0.53]) and the predictors of acceptance. Yet, subgroup analyses yielded a trend for depressed, diabetes-related distressed, female and younger (<59) participants and for those who do not frequently use the Internet to profit from the AFI.

Conclusion

Diabetes patients show a rather low acceptance toward IBIs for depression. Findings indicate that the AFI is likely to be effective in the subgroup of depressed, diabetes-related distressed, female or younger diabetes patients, but not in the whole target population. Hence, AFIs might need to be tailored to the specific needs of subpopulations.     

超声引导下心包穿刺置管引流术治疗心包积液的疗效分析

 目的 探讨超声引导下心包穿刺置管引流急慢性心包积液的疗效。方法 回顾分析2009-01至2019-08医院161例行超声引导下心包穿刺置管引流术患者的临床资料,并对其病因、症状、缓解情况进行分析。结果 161例心包积液患者前三位的病因分别为肿瘤、心力衰竭、创伤或手术,经超声引导下心包穿刺置管术治疗后症状缓解率均在70%以上。结论 超声引导下心包穿刺置管引流术治疗心包积液疗效确切,可作为临床治疗心包积液特别是急性心包压塞的首选治疗方式。     

Crystal structure of the proteasomal deubiquitylation module Rpn8-Rpn11

The ATP-dependent degradation of polyubiquitylated proteins by the 26S proteasome is essential for the maintenance of proteome stability and the regulation of a plethora of cellular processes. Degradation of substrates is preceded by the removal of polyubiquitin moieties through the isopeptidase activity of the subunit Rpn11. Here we describe three crystal structures of the heterodimer of the Mpr1–Pad1–N-terminal domains of Rpn8 and Rpn11, crystallized as a fusion protein in complex with a nanobody. This fusion protein exhibits modest deubiquitylation activity toward a model substrate. Full activation requires incorporation of Rpn11 into the 26S proteasome and is dependent on ATP hydrolysis, suggesting that substrate processing and polyubiquitin removal are coupled. Based on our structures, we propose that premature activation is prevented by the combined effects of low intrinsic ubiquitin affinity, an insertion segment acting as a physical barrier across the substrate access channel, and a conformationally unstable catalytic loop in Rpn11. The docking of the structure into the proteasome EM density revealed contacts of Rpn11 with ATPase subunits, which likely stabilize the active conformation and boost the affinity for the proximal ubiquitin moiety. The narrow space around the Rpn11 active site at the entrance to the ATPase ring pore is likely to prevent erroneous deubiquitylation of folded proteins.In eukaryotes, the ubiquitin (Ub) proteasome system (UPS) is responsible for the regulated degradation of proteins (1–5). The UPS plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer needed. Consequently, the UPS is critically involved in numerous cellular processes, including cell cycle progression, apoptosis, and DNA damage repair, and malfunctions of the system often result in disease.The 26S proteasome executes the degradation of substrates that are marked for destruction by the covalent attachment of polyubiquitin chains. It is a molecular machine of 2.5 MDa comprising two subcomplexes, the 20S core particle (CP) and one or two 19S regulatory particles (RPs), which associate with the ends of the cylinder-shaped CP (6–8). The recognition and recruitment of polyubiquitylated substrates, their deubiquitylation, ATP-dependent unfolding, and translocation into the core particle take place in the RP. The structurally and mechanistically well-characterized CP houses the proteolytic activities and sequesters them from the environment, thereby avoiding collateral damage (9).The RPs attach to the outer α-rings of the CP, which control access to the proteolytic chamber formed by the inner β-subunit rings (10). Recently, the molecular architecture of the 26S holocomplex was established using cryo-EM–based approaches (11, 12), and a pseudoatomic model of the holocomplex was put forward (13). The RP is formed by two subcomplexes, known as the base and the lid, which assemble independently (12, 14). The base contains the hetero-hexameric AAA-ATPase ring (Rpt1–Rpt6), which drives the conformational changes required for substrate processing, including unfolding and translocation into the CP (15, 16). The base also contains the largest RP non-ATPase subunits, Rpn1 and Rpn2, and the Ub receptor Rpn13. The second resident Ub receptor, Rpn10, is not part of either the base or the lid; it binds only to the assembled 26S proteasome and is positioned close to the ATPase module.The lid scaffold is composed of the Rpn3, Rpn5, Rpn6, Rpn7, Rpn8, Rpn9, Rpn11, and Rpn12 subunits (14). These subunits can be grouped according to their domain structures. Rpn3, Rpn5, Rpn6, Rpn7, Rpn9, and Rpn12 each comprise an N-terminal helix repeat segment, a proteasome-COP9/signalosome-eIF3 (PCI) module, and a long helix at the C terminus (8). The Rpn8 and Rpn11 subunits each consist of an Mpr1–Pad1–N-terminal (MPN) domain, followed by long C-terminal helices (Fig. 1A). The PCI subunits form a horseshoe-shaped structure and the MPN domains form a heterodimer, which are connected by a large helical bundle, to which all subunits contribute (13, 17, 18). Each of these eight subunits has paralogs in the COP9/signalosome (CSN) and the elongation initiation factor 3 (eIF3), which likely adopt a similar architecture (18–21).Open in a separate windowFig. 1.Biochemical activity of the Rpn8-Rpn11 fusion protein. (A) Domain structures of Rpn8, Rpn11 and the fusion protein. (B) Ub₄ cleavage activity of 26S proteasome, WT Rpn8-Rpn11 and Rpn8-Rpn11 (E48Q). Cleavage of labeled peptide from Ub₄ was detected by the change in fluorescence polarization after 1hr incubation at 37 °C at the indicated concentrations. Values are normalized to maximum cleavage activity of 26S proteasome. The used 26S proteasome preparation contained only trace amounts of the DUB Ubp6.The lid strengthens the interaction between the CP and RP (17) and deubiquitylates substrates before their processing by the AAA-ATPase module and the CP. Cleavage of polyubiquitin chains from the substrate enables recycling of Ub into the cellular pool, and the removal of the unfolding-resistant Ub moieties promotes translocation of substrates. The MPN domain of Rpn11 contains the catalytic site for deubiquitylation (22, 23). Rpn11 belongs to the JAB1/MPN/Mov34 metalloenzyme (JAMM) family of metalloproteases, which provide the isopeptidase activities in the proteasome, CSN, and exo-deubiquitylating enzymes (DUBs), such as associated molecule with the SH3 domain of STAM-like protein (AMSH-LP). The signature motif for this family is a conserved glutamate upstream of a zinc-coordinating catalytic loop, H(S/T)HX₇SXXD, first revealed in the structure of an archaeal homolog, AfJAMM (24). The substrate-binding mode of JAMM DUBs was clarified by the crystal structure of AMSH-LP in complex with Lys63-linked diubiquitin (25). The other proteasomal MPN subunit, Rpn8, is catalytically inactive; it does not contain the JAMM motif and appears to have mainly a supporting role for Rpn11. Isolated Rpn11 is catalytically inactive, as is the isolated lid (22). Rpn11 is activated upon integration into the 26S holocomplex and is dependent on ATP hydrolysis (23). The 26S proteasome was recently shown to undergo large-scale conformational changes from a substrate-accepting conformation to a substrate-engaged conformation that may be critical for Rpn11 function (15, 26), but the mechanistic basis for the regulation of Rpn11 remains unclear. Loss-of-function mutants of the JAMM motif cause stalling of substrates above the mouth of the ATPase module and lead to clogging of the 26S proteasome (23, 26).Inhibitors of human Rpn11 (hRpn11, also known as POH1) have been proposed as potential antitumor agents working upstream of the β5 proteolytic subunits in the UPS. The β5 subunits have been clinically validated by the approval of bortezomib and carilfzomib for the treatment of hematologic malignancies. siRNA and mutagenesis studies show that expression of the zinc catalytic domain of hRpn11 is essential for cell survival (27). Inhibition of hRpn11 in combination with EGFR inhibition has been suggested to be beneficial in the treatment of nonsmall cell lung cancer (28). Overexpression of hRpn11 in cancer cells has been linked to their tumor escape from cytotoxic agents (29). Thus, hRpn11 is an attractive target for pharmacologic intervention of the UPS.Here we present three crystal structures of the catalytically active Rpn8/Rpn11 MPN heterodimer from Saccharomyces cerevisiae, revealing the details of the Rpn11 active site and the mode of interaction with other subunits. Not all structures show proper active site geometry, hinting at possible mechanisms preventing activation outside of the proteasome complex. The access path for the C-terminal peptide of the substrate-bound Ub is blocked by a highly conserved insertion specific to Rpn11. Fitting of the Rpn8-Rpn11 crystal structure into the cryo-EM density of both the substrate-accepting and substrate-engaged proteasome revealed how the subcomplex is situated between base and PCI domain subunits, which involves long insertions unique to Rpn11 and Rpn8. Contacts to the coiled coils and the oligosaccharide-binding fold (OB) domain ring of the AAA subunits appear to control active site geometry and proper access of the isopeptide bond segment. In the substrate-engaged proteasome, the catalytic center becomes situated just above the maw of the ATPase ring.