Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release: an observational study in three cohorts

Introduction

Severe sepsis is a disease of the microcirculation, with endothelial dysfunction playing a key role in its pathogenesis and subsequent associated mortality. Angiogenesis in damaged small vessels may ameliorate this dysfunction. The aim of the study was to determine whether the angiogenic factors (vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and angiopoietin-1 (Ang-1) and -2 (Ang-2)) are mortality indicators in Malawian children with severe bacterial infection.

Methods

In 293 children with severe bacterial infection, plasma VEGF, PDGF, FGF, and Ang-1 and Ang-2 were measured on admission; in 50 of the children with meningitis, VEGF, PDGF, and FGF were also measured in the CSF. Healthy controls comprised children from some of the villages of the index cases. Univariable and multivariable logistic regression analyses were performed to develop a prognostic model.

Results

The median age was 2.4 years, and the IQR, 0.7 to 6.0 years. There were 211 children with bacterial meningitis (72%) and 82 (28%) with pneumonia, and 154 (53%) children were HIV infected. Mean VEGF, PDGF, and FGF concentrations were higher in survivors than in nonsurvivors, but only PDGF remained significantly increased in multivariate analysis (P = 0.007). Mean Ang-1 was significantly increased, and Ang-2 was significantly decreased in survivors compared with nonsurvivors (6,000 versus 3,900 pg/ml, P = 0.03; and 7,700 versus 11,900 pg/ml, P = 0.02, respectively). With a logistic regression model and controlling for confounding factors, only female sex (OR, 3.95; 95% CI, 1.33 to 11.76) and low Ang-1 (OR, 0.23; 95% CI, 0.08 to 0.69) were significantly associated with mortality. In children with bacterial meningitis, mean CSF VEGF, PDGF, and FGF concentrations were higher than paired plasma concentrations, and mean CSF, VEGF, and FGF concentrations were higher in nonsurvivors than in survivors (P = 0.02 and 0.001, respectively).

Conclusions

Lower plasma VEGF, PDGF, FGF, and Ang-1 concentrations and higher Ang-2 concentrations are associated with an unfavorable outcome in children with severe bacterial infection. These angiogenic factors may be important in the endothelial dysregulation seen in severe bacterial infection, and they could be used as biomarkers for the early identification of patients at risk of a poor outcome.     

Altered regulation of metabolic pathways in human lung cancer discerned by 13C stable isotope-resolved metabolomics (SIRM)

Background  

Metabolic perturbations arising from malignant transformation have not been systematically characterized in human lung cancers in situ. Stable isotope resolved metabolomic analysis (SIRM) enables functional analysis of gene dysregulations in lung cancer. To this purpose, metabolic changes were investigated by infusing uniformly labeled ¹³C-glucose into human lung cancer patients, followed by resection and processing of paired non-cancerous lung and non small cell carcinoma tissues. NMR and GC-MS were used for ¹³C-isotopomer-based metabolomic analysis of the extracts of tissues and blood plasma.     

Colonoscopic yield of colorectal neoplasia in daily clinical practice

AIM： To assess the prevalence and location of advanced neoplasia in patients undergoing colonoscopy, and to compare the yield per indication. METHODS： In a multicenter colonoscopy survey （n = 18 hospitals） in the Amsterdam area （Northern Holland）, data of all colonoscopies performed during a three month period in 2005 were analyzed. The location and the histological features of all colonic neoplasia were recorded. The prevalence and the distribution of advanced colorectal neoplasia and differences in yield between indication clusters were evaluated. Advanced neoplasm was defined as adenoma 〉 10 mm in size, with 〉 25% villous features or with high-grade dysplasia or cancer. RESULTS： A total of 4623 eligible patients underwent a total colonoscopy. The prevalence of advanced neoplasia was 13%, with 281 （6%） adenocarcinomas and 342 （7%） advanced adenomas. Sixty-seven percent and 33% of advanced neoplasia were located in the distal and proximal colon, respectively. Of all patients with right-sided advanced neoplasia （n = 228）, 51% had a normal distal colon, whereas 27% had a synchronous distal adenoma. Ten percent of all colonoscopies were performed in asymptomatic patients, 7% of whom had advanced neoplasia. In the respective procedure indication clusters, the prevalence of rightsided advanced neoplasia ranged from 11%-57%. CONCLUSION： One out of every 7-8 colonoscopies yielded an advanced colorectal neoplasm. Colonoscopy is warranted for the evaluation of both symptomatic and asymptomatic patients.     

Thyroarytenoid muscle maintains normal contractile force in chronic vocal fold immobility.

BACKGROUND: Denervation of skeletal muscle typically results in irreversible denervation atrophy over time. This finding has generated controversy as to the efficacy of reinnervation procedures for chronic vocal fold immobility related to recurrent laryngeal nerve injury. OBJECTIVE: To test the hypothesis that chronic vocal fold immobility after recurrent laryngeal nerve injury does not result in diminished maximal isometric force generation in the thyroarytenoid muscle. STUDY DESIGN: Adult random-bred cats underwent either unilateral laryngeal denervation (n = 6) or sham surgery (n = 6). After 6 months, videolaryngoscopy was performed followed by in vitro measurement of maximal isometric tetanic force produced by the thyroarytenoid muscle. RESULTS: All animals in the denervation group showed right vocal fold paralysis after the initial denervation operation; none of these animals had return of appropriately phased movement with respiration. Four had intermittent disorganized twitching movements. One had these movements plus an occasional weak adduction, and one had no movement. Normal vocal fold mobility was observed in 6 of 6 animals undergoing sham surgery. The maximal isometric tetanic force measured from the thyroarytenoid muscle in the sham group was 438 mN (+/-92 mN standard deviation [SD]). The maximal isometric tetanic force measured from the thyroarytenoid muscle in the chronically immobile group was 405 mN (+/-107 mN SD). Differences were not statistically significant. CONCLUSION: Maximal isometric force in the thyroarytenoid muscle is not diminished in chronic vocal fold immobility after recurrent laryngeal nerve injury. We conclude that the possibility for restoration of contractile force to the chronically immobile thyroarytenoid muscle exists. This finding supports the pursuit of reinnervation procedures in the treatment of chronic vocal fold immobility.     

Direct demonstration that autologous bone marrow transplantation for solid tumors can return a multiplicity of tumorigenic cells

Patients with solid tumors are increasingly being treated by autologous bone marrow transplantation (BMT). Although response rates appear to be increased, disease recurrence is the commonest cause of treatment failure. Whether relapse is entirely due to residual disease in the patient or arises also from infiltrating malignant cells contained in the autologous marrow transplant has not been resolved. If the latter explanation is correct, then purging would be required as part of the transplantation procedure. We used retrovirally mediated transfer of the neomycin-resistance gene to mark BM harvested from eight patients with neuroblastoma in clinical remission. The marked marrow cells were subsequently reinfused as part of an autologous BMT. At relapse, we sought the marker gene in malignant cell populations. Three patients have relapsed, and in each the marker gene was detected by phenotypic and genetic analyses of resurgent malignant cells at medullary and extramedullary sites. Analysis of neuroblast DNA for discrete marker gene integration sites suggested that at least 200 malignant cells, each capable of tumor formation, were introduced with the autologous marrow transplant and contributed to relapse. Thus, autologous BMTs administered to patients with this solid tumor may contain a multiplicity of malignant cells that subsequently contribute to relapse. The marker-gene technique we describe should permit evaluation of the mechanisms of relapse and the efficacy of purging in patients receiving autologous marrow transplantation for other solid tumors that infiltrate the marrow.     

雷公藤红素对IL-1和IL-2活性及PGE2释放的抑制作用

雷公藤红素0.1～1.0μg/ml在试管内能降低LPS诱导的小鼠腹腔巨噬细胞外和细胞内白细胞介素-1(IL-1)的活性,也能抑制ConA诱导的小鼠脾细胞产生白细胞介素-2(IL-2).动态观察表明,雷公藤红素经预处理8h和3h后已能分别抑制IL-1和IL-2的产生。此外,雷公藤红素能降低A23187刺激家兔滑膜细胞释放前列腺素E₂(PGE₂)。     

Severe road traffic injuries in Kenya, quality of care and access

Background

Road traffic injuries (RTI) are on increase in developing countries. Health care facilities are poorly equipped to provide the needed services.

Objective

Determine access and quality of care for RTI casualties in Kenya.

Design

Cross-sectional survey

Setting

53 large and medium size private, faith-based and public hospitals.

Participants

In-patient road traffic crash casualties and health personnel in the selected hospitals were interviewed on availability of emergency care and resources. Onsite verification of status was undertaken.

Results

Out of 310 RTI casualties interviewed, 72.3%, 15.6% and 12.2% were in public, faith-based and private hospitals, respectively. Peak age of the injured was 15–49 years. First aid was availed to 16.0% of casualties. Unknown persons transported 76.5% of the injured. Police and ambulance vehicles transported 6.1% and 1.4%, respectively. 51.9% reached health facilities within 30 minutes of crash and medical care provided to 66.2% within one hour. 40.8% of recipient facilities were adequately prepared for RTI emergencies.

Conclusions

Most RTI casualties were young and from poor backgrounds. Training of motorists and general public in first aid should be considered in RTI control initiatives. Availability of basic trauma care medical supplies in public health facilities was highly deficient.     

Diagnostic significance of Wada procedure in very young children and children with developmental delay

Localization of vital components of neurological functioning has to be performed before epilepsy surgery can be considered in children with intractable epilepsy. This study reports the experience with the Wada procedure in very young children and/or developmentally delayed children with an a priori considerable chance of failing the procedure. The aim of this study was to indicate the applicability of this procedure in this patient group. The Wada procedure is described in 16 children under 10 years of age and/or have intelligence quotient scores below 50 and/or are critically ill and/or are behaviourally disturbed. Information on motor, language and memory functioning is obtained in respectively 13/15, 9/13, and 5/11 children. Nine children underwent epilepsy surgery without postoperative impairment of neurological functioning. In five children epilepsy surgery was not performed because of the results of the Wada procedure or the lack of information during the Wada procedure. One child became seizure-free before surgery. Even in very young, developmentally delayed or behaviourally disturbed children, the Wada test can provide important information with respect to the decision pro or contra epilepsy surgery.     

Hoechst staining and exposure to UV laser during flow cytometric sorting does not affect the frequency of detected endogenous DNA nicks in abnormal and normal human spermatozoa

Controlling the sex of offspring by the separation of X and Y chromosome-bearing spermatozoa using flow cytometry has been reported as a clinical technique aiding prevention of X-linked diseases. Although this technique has resulted in several hundred normal births in animals and at least one human birth, there is still concern over its genetic safety due to the involvement of two potentially mutagenic agents: UV light and the fluorochrome dye, Hoechst 33342 (H33342). Human spermatozoa, particularly those considered abnormal, may be more likely to suffer DNA damage following exposure to mutagenic agents, compared with other mammalian species. The stability of normal fresh and decondensed human spermatozoa were examined after exposure to a range of levels of UV and H33342 staining, using an assay that detects endogenous nicks in the DNA of spermatozoa. The stability of abnormal and normal, fresh and frozen-thawed human spermatozoa was examined following UV laser, H33342 staining and flow cytometry treatments utilizing the same assay. There was an increase in the presence of endogenous nicks when spermatozoa were decondensed compared with fresh spermatozoa. There was no increase in the incidence of nicks in any group of spermatozoa after UV and fluorochrome exposure compared with controls without exposure.