Towards a combined prognostic index for survival in HIV infection: the role of ‘non‐HIV’ biomarkers

Background

As those with HIV infection live longer, ‘non‐AIDS’ condition associated with immunodeficiency and chronic inflammation are more common. We ask whether ‘non‐HIV’ biomarkers improve differentiation of mortality risk among individuals initiating combination antiretroviral therapy (cART).

Methods

Using Poisson models, we analysed data from the Veterans Aging Cohort Study (VACS) on HIV‐infected veterans initiating cART between 1 January 1997 and 1 August 2002. Measurements included: HIV biomarkers (CD4 cell count, HIV RNA and AIDS‐defining conditions); ‘non‐HIV’ biomarkers (haemoglobin, transaminases, platelets, creatinine, and hepatitis B and C serology); substance abuse or dependence (alcohol or drug); and age. Outcome was all cause mortality. We tested the discrimination (C statistics) of each biomarker group alone and in combination in development and validation data sets, over a range of survival intervals, and adjusting for missing data.

Results

Of veterans initiating cART, 9784 (72%) had complete data. Of these, 2566 died. Subjects were middle‐aged (median age 45 years), mainly male (98%) and predominantly black (51%). HIV and ‘non‐HIV’ markers were associated with each other (P<0.0001) and discriminated mortality (C statistics 0.68–0.73); when combined, discrimination improved (P<0.0001). Discrimination for the VACS Index was greater for shorter survival intervals [30‐day C statistic 0.86, 95% confidence interval (CI) 0.80–0.91], but good for intervals of up to 8 years (C statistic 0.73, 95% CI 0.72–0.74). Results were robust to adjustment for missing data.

Conclusions

When added to HIV biomarkers, ‘non‐HIV’ biomarkers improve differentiation of mortality. When evaluated over similar intervals, the VACS Index discriminates as well as other established indices. After further validation, the VACS Index may provide a useful, integrated risk assessment for management and research.     

Delivery room management of very low birth weight infants in Germany,Austria and Switzerland - a comparison of protocols

Background

Surveys from the USA, Australia and Spain have shown significant inter-institutional variation in delivery room (DR) management of very low birth weight infants (VLBWI, < 1500 g) at birth, despite regularly updated international guidelines.

Objective

To investigate protocols for DR management of VLBWI in Germany, Austria and Switzerland and to compare these with the 2005 ILCOR guidelines.

Methods

DR management protocols were surveyed in a prospective, questionnaire-based survey in 2008. Results were compared between countries and between academic and non-academic units. Protocols were compared to the 2005 ILCOR guidelines.

Results

In total, 190/249 units (76%) replied. Protocols for DR management existed in 94% of units. Statistically significant differences between countries were found regarding provision of 24 hr in house neonatal service; presence of a designated resuscitation area; devices for respiratory support; use of pressure-controlled manual ventilation devices; volume control by respirator; and dosage of Surfactant. There were no statistically significant differences regarding application and monitoring of supplementary oxygen, or targeted saturation levels, or for the use of sustained inflations. Comparison of academic and non-academic hospitals showed no significant differences, apart from the targeted saturation levels (SpO₂) at 10 min. of life. Comparison with ILCOR guidelines showed good adherence to the 2005 recommendations.

Summary

Delivery room management in German, Austrian and Swiss neonatal units was commonly based on written protocols. Only minor differences were found regarding the DR setup, devices used and the targeted ranges for SpO₂ and FiO₂. DR management was in good accordance with 2005 ILCOR guidelines, some units already incorporated evidence beyond the ILCOR statement into their routine practice.     

Mitral valve surgery for mitral regurgitation caused by Libman-Sacks endocarditis: a report of four cases and a systematic review of the literature

Libman-Sacks endocarditis of the mitral valve was first described by Libman and Sacks in 1924. Currently, the sterile verrucous vegetative lesions seen in Libman-Sacks endocarditis are regarded as a cardiac manifestation of both systemic lupus erythematosus (SLE) and the antiphospholipid syndrome (APS). Although typically mild and asymptomatic, complications of Libman-Sacks endocarditis may include superimposed bacterial endocarditis, thromboembolic events, and severe valvular regurgitation and/or stenosis requiring surgery. In this study we report two cases of mitral valve repair and two cases of mitral valve replacement for mitral regurgitation (MR) caused by Libman-Sacks endocarditis. In addition, we provide a systematic review of the English literature on mitral valve surgery for MR caused by Libman-Sacks endocarditis. This report shows that mitral valve repair is feasible and effective in young patients with relatively stable SLE and/or APS and only localized mitral valve abnormalities caused by Libman-Sacks endocarditis. Both clinical and echocardiographic follow-up after repair show excellent mid- and long-term results.     

Inhibiting glycogen synthase kinase-3 reduces endotoxaemic acute renal failure by down-regulating inflammation and renal cell apoptosis

Background and purpose:

Excessive inflammation and apoptosis are pathological features of endotoxaemic acute renal failure. Activation of glycogen synthase kinase-3 (GSK-3) is involved in inflammation and apoptosis. We investigated the effects of inhibiting GSK-3 on lipopolysaccharide (LPS)-induced acute renal failure, nuclear factor-κB (NF-κB), inflammation and apoptosis.

Experimental approach:

The effects of inhibiting GSK-3 with inhibitors, including lithium chloride (LiCl) and 6-bromo-indirubin-3′-oxime (BIO), on LPS-treated (15 mg·kg⁻¹) C3H/HeN mice (LiCl, 40 mg·kg⁻¹ and BIO, 2 mg·kg⁻¹) and LPS-treated (1 µg·mL⁻¹) renal epithelial cells (LiCl, 20 mM and BIO, 5 µM) were studied. Mouse survival was monitored and renal function was analysed by histological and serological examination. Cytokine and chemokine production, and cell apoptosis were measured by enzyme-linked immunosorbent assay and terminal deoxynucleotidyl transferase-mediated dUTP–biotin nick-end labelling staining, respectively. Activation of NF-κB and GSK-3 was determined by immunostaining and Western blotting, respectively.

Key results:

Mice treated with GSK-3 inhibitors showed decreased mortality, renal tubular dilatation, vacuolization and sloughing, blood urea nitrogen, creatinine and renal cell apoptosis in response to endotoxaemia. Inhibiting GSK-3 reduced LPS-induced tumour necrosis factor-α (TNF-α) and CCL5/RANTES (released upon activation of normal T-cells) in vivo in mice and in vitro in murine kidney cortical collecting duct epithelial M1 cells. Inhibiting GSK-3 did not block TNF-α-induced cytotoxicity in rat kidney proximal tubular epithelial NRK52E or in M1 cells.

Conclusions and implications:

These results suggest that GSK-3 inhibition protects against endotoxaemic acute renal failure mainly by down-regulating pro-inflammatory TNF-α and RANTES.     

Combined treatment with Denbinobin and Fas ligand has a synergistic cytotoxic effect in human pancreatic adenocarcinoma BxPC-3 cells

Background and purpose:

Human pancreatic carcinoma is a highly malignant cancer. Previous studies have shown that the decoy receptor 3 (DcR3) for Fas ligand (FasL) plays significant roles in tumour progression and immune suppression. In the present study, we evaluated the anti-cancer activity of a natural compound, denbinobin (5-hydroxy-3,7-dimethoxy-1,4-phenanthraquinone), through decreasing DcR3 levels in human pancreatic adenocarcinoma cell lines.

Experimental approach:

We used immunoprecipitation and ELISA assays to examine DcR3 levels, and used FACS to determine the percentage of cells with a sub-G1 DNA content.

Key results:

AsPC-1 and BxPC-3 human pancreatic cancer cells express high levels of DcR3. Denbinobin concentration-dependently decreased DcR3 levels in BxPC-3 cells. MTT and flow cytometry assays indicated that BxPC-3 was FasL-resistant because high concentrations (100 ng·mL⁻¹) of soluble FasL did not inhibit cell growth. However, combinations of denbinobin (3 µmol·L⁻¹) with lower concentrations of soluble FasL (10, 30 and 50 ng·mL⁻¹) or membrane-bound FasL, were synergistic on cell growth inhibition and apoptosis. Exogenous excess DcR3 reversed this synergistic effect. We observed no significant increase in the levels of surface Fas, cleaved forms of caspase-8, -3, -9, Bax, Bid, Bcl-xL, cytochrome c or mitochondrial membrane potentials following denbinobin treatment. However, denbinobin treatment increased the levels of apoptosis-inducing factor.

Conclusions and implications:

Denbinobin and FasL trigger a synergistic cytotoxic effect in human pancreatic adenocarcinoma cells. Denbinobin mediated a decrease in levels of DcR3, which played a major role in this synergistic effect, and also increased caspase-independent apoptosis, via apoptosis-inducing factor.     

Primary drug resistance and transmission analysis of HIV-1 in acute and recent drug-naïve seroconverters in Singapore

Objectives

The aim of the study was to elucidate primary drug resistance and transmission of HIV‐1 in acute and recent drug‐naïve seroconverters in Singapore.

Methods

Acute and recent HIV‐1 seroconverters were enrolled in the study. The HIV‐1 polymerase (pol) gene was sequenced and used for genotypic drug resistance analysis and phylogenetic analysis. HIV‐1 transmission clusters were inferred from phylogenetic clustering analysis.

Results

Of the 60 subjects analysed, 95% were men, and 73.3% were men who have sex with men (MSM). Six HIV‐1 subtypes were identified, including CRF01_AE (46.7%), subtypes B (30%), B′ (15%) and G (1.7%), CRF33_01B (1.7%) and CRF34_01B (5%). Primary genotypic resistance was detected in only one (1.7%) subtype B variant. Thirty‐one patients (51.7%) were phylogenetically clustered, of whom 90% reported having local risk exposure, compared with 59% of the patients who were not phylogenetically clustered [odds ratio (OR) 6.35, 95% confidence interval (CI) 1.65–23.95]. MSM (OR 5.63, 95% CI 1.17–27.15), high viral load (OR 4.28, 95% CI 1.37–13.36) and young age (OR 0.92, 95% CI 0.85–0.99) were independently associated with clustered individuals.

Conclusions

In Singapore, HIV‐1 primary resistance is insignificant; individuals with seroconversion account for about half of onward transmission among recently infected seroconverters. MSM, high viral load and young age are factors that facilitate transmission. Early detection of these individuals is of paramount importance for the prevention of HIV‐1 transmission.

     

Cerebral hyperperfusion syndrome post‐carotid artery stenting

Cerebral hyperperfusion syndrome is increasingly recognized as a complication in carotid artery stenting for severe internal carotid artery stenosis. This study reviews the cases of hyperperfusion syndrome occurring after this procedure. We reviewed our database of 170 cases of internal carotid artery stenting carried out at our hospital between January 1999 and June 2006. A radiology search was also carried out to identify those who had CT or MRI within 1 month of post‐carotid artery stenting. We had four patients who developed cerebral hyperperfusion syndrome. One patient developed cerebral oedema, one patient had petechial intracerebral haemorrhage and two patients had large intracerebral haemorrhages, one of whom died. This gives a risk of 2.3% (95% confidence interval 2.27–2.323). All patients with cerebral haemorrhage presented within 6 h. Both patients with large intracerebral haemorrhage had carotid stenting within 3 weeks after presentation of symptoms and all had critically severe stenosis of 95% or more. In our series, large intracerebral haemorrhage has occurred only in patients who have been treated early. Cerebral hyperperfusion is an uncommon but serious complication post‐carotid stenting. Further studies comparing early treatment of endarterectomy and carotid stenting are awaited.     

新型植骨与内固定方法治疗上肢骨不连93例

1临床资料1990-01/2003-12采用新型植骨方法结合天鹅型记忆接骨器[1]治疗上肢骨干骨不连93(男60,女33)例,107(肱骨50,尺桡骨28,尺骨14,桡骨11,锁骨4)根,年龄10～80(平均37.6)岁.所有病例入我院前已行1～5(平均1.7)次手术.植骨以自体髂骨为主,必要时辅以同种异体骨植骨.内固定采用我院张春才发明,以镍钛记忆合金制成,由鹅体、鹅颈、鹅翼组成的天鹅型记忆接骨器[1](Swan-like Memorablycompressive Connector , SMC).     

腹膜外途径腹腔镜前列腺癌根治术(附2例报告)

目的 报告腹膜外途径腹腔镜前列腺癌根治术的初步体会。方法 分别于2005年4月、12月，经腹膜外途径进行腹腔镜前列腺癌根治术2例。结果 2例均获成功，首例手术时间为7小时20分钟，第2例为3小时20分钟。术中分别输红细胞悬液3单位、2单位。首例术后出现尿漏12d，术后23d带导尿管出院，半月后膀胱造影提示无尿漏后拔导尿管，站立后有尿失禁，术后4个月后尿失禁完全消失；第2例患者术后未出现尿漏，于术后10d拔除导尿管，拔管后即无尿失禁，术后15d出院。结论 腹膜外途径腹腔镜前列腺癌根治术是安全、可行的，较传统的经耻骨后径路的开放性手术及经腹腔途径的腹腔镜前列腺癌根治术均有一定的优势。