Follicular dendritic cells (FDC) in retroviral infection: host/pathogen perspectives

Summary: Follicular dendritic cells (FDC) are found in the follicles of virtually all secondary lymphoid tissues. In health, these cells trap and retain antigens (Ag) in the form of immune complexes and preserve them for months in their native conformation. FDC thus serve as a long-term repository of extracellular Ag important for induction and maintenance of memory responses. In retroviral infection. FDC trap and retain large numbers of retroviral particles with profound effects on FDC. FDC-trapped retrovirus induces follicular hyperplasia, and conventional Ag trapped prior to infection are lost and new Ag cannot be trapped. Concomitantly, antibody-forming cells (AFC) specific for Ag lost from FDC decrease follow I by loss of specific serum antibody (Ab). Eventually, FDC die and follicular lysis occurs. From the pathogen perspective, binding to FDC is remarkably beneficial, bringing together virus and activated target cells that are highly susceptible to infection. Furthermore, FDC permit HIV to infect surrounding cells even in the presence of a vast excess of neutralizing Ab. Preliminary data suggest that FDC maintain virus infectivity - even when the virus cannot replicate. Thus retrovirus infection monopolizes FDC networks, thereby transforming the FDC Ag repository into a highly infectious retroviral reservoir.     

Randomized parallel study of doxorubicin plus paclitaxel and doxorubicin plus cyclophosphamide as neoadjuvant treatment of patients with breast cancer.

PURPOSE: This randomized, noncomparative, parallel-group study was designed to evaluate the pathologic complete response (pCR) rate of combined doxorubicin plus paclitaxel (AP) and doxorubicin plus cyclophosphamide (AC) as neoadjuvant chemotherapy in patients with previously untreated breast cancer who were unsuitable for conservative surgery. PATIENTS AND METHODS: A total of 200 patients with T2-3, N0-1, M0 disease were randomly assigned in a 2:1 ratio to receive preoperative chemotherapy with either doxorubicin 60 mg/m(2) plus paclitaxel 200 mg/m(2) as a 3-hour infusion (AP) or doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2) (AC) every 3 weeks for 4 courses followed by surgery. RESULTS: A pCR (eradication of invasive carcinoma in tumor and in axillary lymph nodes) was found in 16% and 10% of patients in the AP and AC arms, respectively, by study center pathologists, and in 8% and 6% of patients, respectively, by independent pathologists. Patients with pCRs tended to have unifocal disease, tumors with negative hormonal receptor status, and less differentiation (Scarff, Bloom, and Richardson scale grade 3). Breast-conserving surgery was performed in 58% and 45% of patients in the AP and AC arms, respectively. An objective clinical response was achieved in 89% of patients in the AP arm and 70% in the AC arm. At a median follow-up of 31 months, disease-free survival (DFS) was higher in patients who reached pCR versus those without pCR (91% v 70%). CONCLUSION: The encouraging pathologic and clinical responses of patients with breast cancer after neoadjuvant chemotherapy with doxorubicin plus paclitaxel warrant additional investigation of paclitaxel in the neoadjuvant setting of breast cancer management.     

Phase I combining a P-glycoprotein inhibitor, MS209, in combination with docetaxel in patients with advanced malignancies.

PURPOSE: The purpose of this study was to investigate the safety and tolerability of MS209, a potent inhibitor of P-glycoprotein, when given in combination with docetaxel and to determine whether MS209 affects docetaxel pharmacokinetics. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were eligible for this phase I trial. Docetaxel as 1-hour infusion was given alone during the first cycle. MS209 was introduced as of cycle 2 and given orally 30 minutes after docetaxel infusion. The dose escalation scheme followed a modified Fibonacci model with six steps (docetaxel, 60-100 mg/m2 and MS209, 300-1,200 mg per body). RESULTS: A total of 30 patients were treated at five dose levels. Dose-limiting toxicities were febrile neutropenia, infection, stomatitis, dysphagia, and fatigue. The maximum tolerated dose was reached at level 5 (docetaxel, 80-MS: 1,200). Pharmacokinetic analysis failed to show a strong pharmacokinetic interaction between the two compounds, but at the highest dose levels, there is a trend to an increase of docetaxel AUC when this agent is given in combination with MS209. CONCLUSION: MS209 can be given in combination with docetaxel, with limited effect on docetaxel toxicity or pharmacokinetics.     

Ultrasound Measures of Brain Pulsatility Correlate with Subcortical Brain Volumes in Healthy Young Adults

Increasing evidence suggests that brain pulsatility is involved in the pathophysiology of various neurological and psychiatric disorders. However, it remains unclear whether high brain pulsatility is damaging to or protective of the brain in normal conditions, and this could depend on the age of the individual and the methods used to measure brain pulsatility. The goal of our study was to investigate associations between subcortical volumes and brain pulsatility as assessed with ultrasound in healthy young adults using both a conventional method (transcranial Doppler pulsatility index [TCD-PI]) and the innovative method of tissue pulsatility imaging (TPI), which allows a high level of detection of small brain movements (micrometers). Twenty-five females aged 18–55 with no history of significant medical disorder underwent magnetic resonance imaging and ultrasound assessment. The volumes of six subcortical regions known to be particularly sensitive to change in cerebral blood flow were measured and compared with brain pulsatility as assessed with TCD-PI and TPI. TCD-PI and TPI measures positively correlated with all subcortical regions, with the caudate nucleus having the strongest association. Linear regressions found that TCD-PI and TPI measures of brain pulsatility explained 16% to 67% of the variance of the subcortical volumes. Our results suggest that a greater pulsatility as assessed with ultrasound in healthy young adults may constitute a protective factor for brain structure. Ultrasound measures of brain pulsatility may be appropriate to provide costless, non-invasive, portable and highly sensitive markers of cerebral blood flow pulsatility related to brain structure.     

Worksite Health and Wellness Programs: Canadian Achievements & Prospects

Canada has experienced a substantial reduction in mortality related to cardiovascular disease (CVD). There is a general consensus that more effective and widespread health promotion interventions may lead to further reductions in CVD risk factors and actual disease states. In this paper, we briefly outline the prevalence of selected risk factors for CVD in Canada, describe characteristics of the Canadian labor market and workforce, and depict what is known about health and wellness program delivery systems in Canadian workplaces. Our review indicates that there have been numerous and diverse relevant legislative and policy initiatives to create a context conducive to improve the healthfulness of Canadian workplaces. However, there is still a dearth of evidence on the effectiveness of the delivery system and the actual impact of workplace health and wellness programs in reducing CVD risk in Canada. Thus, while a promising model, more research is needed in this area.     

Influence of obesity indices, metabolic parameters and age on cardiac autonomic function in abdominally obese men

Heart rate variability (HRV) is affected by age, hyperglycemia and accumulation of body fat. This study compares the predictive value of four measurements of adiposity/obesity on HRV and investigates the specific role of age, metabolic contributors and degree/distribution of fat in HRV alterations. The sample consisted of 97 non-diabetic and non-medicated men with features of the metabolic syndrome (50 ± 8 years of age, body mass index [BMI] 31 ± 3 kg/m², waist circumference [WC] 107 ± 9 cm, triglycerides 2.3 ± 0.7 mmol/L, fasting glucose 6.0 ± 0.5 mmol/L, insulin 156 ± 71 pmol/L; mean ± SD). WC, BMI, percent body fat (% fat, from dual energy X-ray absorptiometry) and visceral adipose tissue volume (VAT, from computed tomography) were used as measures of adiposity/obesity. HRV measures were obtained from 24-h, day- and night-time segments of Holter recordings. BMI presented no independent association with HRV. Percentage fat was the strongest obesity index to be associated with HRV: 24-h pNN50, rMSSD, HF and daytime pNN50, rMSSD, HF and LF (?0.27 ≤ std β ≤ ?0.20, P < .05). VAT was associated with 24-h SDNN, LF (std β = ?0.25 and ?0.20, P < .05, respectively) and daytime SDNN (std β = ?0.24, P < .05) while WC was associated with nighttime SDNN and SDANN (std β = 0.22 and 0.32, P < .05). In addition, age, fasting glucose, 2-h oral glucose tolerance test and triglycerides presented independent association with HRV. Adiposity/obesity measurements seem to be differently associated with HRV. An approach considering the combination of age, obesity and glucose metabolism factors could be helpful in the global cardiovascular risk management in abdominally obese men.     

Temporary and definitive external fixation of war injuries: use of a French dedicated fixator

Purpose

External fixation is the recommended stabilization method for both open and closed fractures of long bones in forward surgical hospitals. Specific combat surgical tactics are best performed using dedicated external fixators. The Percy Fx© (Biomet) fixator was developed for this reason by the French Army Medical Service, and has been used in various theatres of operations for more than ten years.

Methods

The tactics of Percy Fx© (Biomet) fixator use were analysed in two different situations: for the treatment of French soldiers wounded on several battlefields and then evacuated to France and for the management of local nationals in forward medical treatment facilities in Afghanistan and Chad.

Results

Overall 48 externals fixators were implanted on 37 French casualties; 28 frames were temporary and converted to definitive rigid frames or internal fixation after medical evacuation. The 77 Afghan patients totalled 85 external fixators, including 13 temporary frames applied in Forward Surgical Teams (FSTs) prior to their arrival at the Kabul combat support hospital. All of the 47 Chadian patients were treated in a FST with primary definitive frames because of delayed surgical management and absence of higher level of care in Chad.

Conclusion

Temporary frames were mostly used for French soldiers to facilitate strategic air medical evacuation following trauma damage control orthopaedic principles. Definitive rigid frames permitted achieving treatment of all types of war extremity injuries, even in poor conditions.     

Characterization of antigens recognized by monoclonal and polyclonal antibodies directed against uvomorulin.

Uvomorulin is a cell surface glycoprotein involved in compaction of early mouse embryo. Antibodies, either monoclonal or polyclonal, raised against a purified tryptic fragment of uvomorulin recognize, in a detergent lysate of embryonal carcinoma cells metabolically labeled with 35S, three molecules (120, 100, and 88 kDa) that are not related, as judged by peptide mapping. Only the 120-kDa form is related to the tryptic fragment of uvomorulin and, thus, is considered as the native form of uvomorulin. Although all three products are apparently detectable at the cell surface, only the 120-kDa form is glycosylated. Coimmunoprecipitation of the three different polypeptides is probably due to shared epitopes rather than to their presence in a multimeric complex.     

Adiponectinemia in visceral obesity: impact on glucose tolerance and plasma lipoprotein and lipid levels in men

The present study examined the associations between a major adipokine, adiponectin, and adiposity indices as well as metabolic risk variables in a sample of 190 untreated asymptomatic men. Anthropometric measurements and a complete fasting plasma lipoprotein and lipid profile were obtained, and subjects underwent an oral glucose tolerance test. Fasting plasma adiponectin concentrations were determined by an ELISA. Although all adiposity and adipose tissue (AT) distribution indices were negatively correlated with plasma adiponectin levels (-0.14 /=30 kg/m(2)) but who markedly differed in their level of visceral AT (< vs. >/=130 cm(2); n = 15) revealed significant differences in adiponectin levels (7.0 +/- 3.0 vs. 11.1 +/- 4.9 microg/ml; P < 0.02 for men with high vs. low visceral AT, respectively). Finally, when men were stratified into tertiles of visceral AT and further classified on the basis of the 50th percentile of adiponectin levels (8.8 microg/ml), a 3 x 2 ANOVA revealed an independent contribution of adiponectin on the variation of high-density lipoprotein cholesterol levels (P < 0.002) and of the glucose area (P < 0.02). These results support the notion that adiponectin concentration is influenced to a greater extent by visceral than sc obesity. Furthermore, adiponectin predicts glucose tolerance and plasma high-density lipoprotein cholesterol levels in a manner that is partly independent from the contribution of visceral adiposity.