Pregnancy impairs resistance of C57BL/6 mice to Leishmania major infection.

To determine if gestational factors affect the severity of L. major infection, this study assessed the levels of IL-4 mRNA and IFN-gamma mRNA in popliteal lymph node cells of pregnant C57BL/6 mice mated at 5 hours, 16 hours and 15 days post L. major infection using PCR. Infected pregnant C57BL/6 mice developed larger cutaneous footpad lesions compared with non-pregnant infected C57BL/6 mice. The resolution of footpad lesions commenced after 8th week in C57BL/6 mice mated at 16 hrs post L. major infection but 12 weeks in C57BL/6 mice mated at 5 hrs and 15 days post L. major infection. C57BL/6 mice that were infected 20 days post partum resolved L. major infection effectively. But, the lesions in infected pregnant C57BL/6 mice and infected non-pregnant C57BL/6 mice were not as large as in susceptible BALB/c mice. The mean litter weights were similar in pregnant infected C57BL/6 mice mated at different stages of L. major infection but were slightly lower than weights of litters from pregnant uninfected C57BL/6 mice. In 5 days infected pregnant C57BL/6 mice, the levels of IFN-gamma were raised compared with the levels of IL-4 but those mated at 15 days post L. major infection had highest level of IFN-gamma mRNA. In 10 days pregnant infected C57BL/6 mice, levels of IL-4 were raised compared with IFN-gamma but mice mated at 16 hrs post L. major infection had highest level of IL-4. In 15 days pregnant infected mice, the levels of IL-4 were higher than IFN-gamma irrespective of the stage of L. major infection when the mice were mated. Mice infected with L. major 20 days post-partum produced more IFN-gamma than IL-4 from 16 hrs post L. major infection onwards. It may be concluded that increased IL-4 in pregnant infected C57BL/6 mice impairs the resistance of C57BL/6 mice to L. major infection especially in mice that were pregnant before effective immunity (5 hours post L. major infection) is mounted against L. major infection.

Length of hospital stay and postdischarge mortality in patients with pulmonary embolism: a statewide perspective

BACKGROUND: The optimal length of stay (LOS) for patients with pulmonary embolism (PE) is unknown. Although reducing LOS is likely to save costs, the effects on patient safety are unclear. We sought to identify patient and hospital factors associated with LOS and assess whether LOS was associated with postdischarge mortality. METHODS: We evaluated patients discharged with a primary diagnosis of PE from 186 acute care hospitals in Pennsylvania (January 2000 through November 2002). We used discrete survival models to examine the association between (1) patient and hospital factors and the time to discharge and (2) LOS and postdischarge mortality within 30 days of presentation, adjusting for patient and hospital factors. RESULTS: Among 15 531 patient discharges with PE, the median LOS was 6 days, and postdischarge mortality rate was 3.3%. In multivariate analysis, patients from Philadelphia were less likely to be discharged on a given day (odds ratio [OR], 0.82; 95% confidence interval [CI], 0.73-0.93), as were black patients (OR, 0.88; 95% CI, 0.82-0.94).The odds of discharge decreased notably with greater patient severity of illness and in patients without private health insurance. Adjusted postdischarge mortality was significantly higher for patients with an LOS of 4 days or less (OR, 1.55; 95% CI, 1.21-2.00) relative to those with an LOS of 5 to 6 days. CONCLUSIONS: Several hospital and patient factors were independently associated with LOS. Patients with a very short LOS had greater postdischarge mortality relative to patients with a typical LOS, suggesting that physicians may inappropriately select patients with PE for early discharge who are at increased risk of complications

tagO is involved in the synthesis of all anionic cell-wall polymers in Bacillus subtilis 168.

Sequence homologies suggest that the Bacillus subtilis 168 tagO gene encodes UDP-N-acetylglucosamine:undecaprenyl-P N-acetylglucosaminyl 1-P transferase, the enzyme responsible for catalysing the first step in the synthesis of the teichoic acid linkage unit, i.e. the formation of undecaprenyl-PP-N-acetylglucosamine. Inhibition of tagO expression mediated by an IPTG-inducible P(spac) promoter led to the development of a coccoid cell morphology, a feature characteristic of mutants blocked in teichoic acid synthesis. Indeed, analyses of the cell-wall phosphate content, as well as the incorporation of radioactively labelled precursors, revealed that the synthesis of poly(glycerol phosphate) and poly(glucosyl N-acetylgalactosamine 1-phosphate), the two strain 168 teichoic acids known to share the same linkage unit, was affected. Surprisingly, under phosphate limitation, deficiency of TagO precludes the synthesis of teichuronic acid, which is normally induced under these conditions. The regulatory region of tagO, containing two partly overlapping sigma(A)-controlled promoters, is similar to that of sigA, the gene encoding the major sigma factor responsible for growth. Here, the authors discuss the possibility that TagO may represent a pivotal element in the multi-enzyme complexes responsible for the synthesis of anionic cell-wall polymers, and that it may play one of the key roles in balanced cell growth.

Assessing multiple sclerosis activity: is the in vitro production of tumor necrosis factor-alpha, interleukins 2, 6, 4, and 10, and immunoglobulin G of value?

Tumor necrosis factor (TNF) alpha, interleukins (IL) 2, 4, 6, and 10, and IgG oligoclonal bands (IgG OB) in vitro production was assessed, after whole-blood stimulation with lipopolysaccharide or concanavalin A, in 61 patients presenting with relapsing-remitting, relapsing-progressive, or chronic progressive multiple sclerosis. Multiple sclerosis patients were receiving no treatment or azathioprine (AZA), cyclosporin, cyclophosphamide, subcutaneous interferon (IFN) beta 1 a, or corticosteroids (CST). Statistical correlations significantly showed that: (a) AZA lowers TNF-alpha (P = 0.002) and increases IL-4 production (P = 0.0024), and IFN-beta 1 a increases TNF-alpha and decreases IL-4 levels; (b) CST has a negative effect on TNF-alpha, IL-6, and IL-4 synthesis; and (c) AZA, IFN-beta 1 a, and CST diminish IgG OB synthesis (P = 0.001). Although our study of the dynamics of TNF-alpha, IL-2, IL-4, IL-6, and IL-10 in vitro production generally found no statistically significant correlations (partly explained by the limited number of values in the various groups), IL-6 was shown to drop during the periods surrounding relapse (P = 0.05) in the absence of treatment, while TNF-alpha (P = 0.04) and IL-6 (P < 0.05) dropped before exacerbation in the presence of AZA. In vitro production of TNF-alpha was closely and positively correlated with that of IL-6, independently of clinical features. The enhanced production of IL-10 detected before or at relapse with AZA and IFN-beta 1 a (trends) may interfere with initiation of the immune reaction and with the development of new CNS lesions. Some discrepancies with previously published results stress the difficulties in studying the state of stimulation of different populations of leukocytes by using a variety of in vitro stimuli and in establishing a correlation between mRNA studies and the amount of final or active protein produced.

Bone mineral density (BMD), micro-architecture estimation (TBS) and vertebral fracture assessment (VFA) extracted from a single DXA device in combination with clinical risk factors improve significantly the identification of women at high risk of fracture

Introduction: Osteoporosis (OP) is a systemic skeletal disease characterized by a low bone mineral density (BMD) and a micro-architectural (MA) deterioration. Clinical risk factors (CRF) are often used as a MA approximation. MA is yet evaluable in daily practice by the Trabecular Bone Score (TBS) measure. TBS is a novel grey-level texture measurement reflecting bone micro-architecture based on the use of experimental variograms of 2D projection images. TBS is very simple to obtain, by reanalyzing a lumbar DXA-scan. TBS has proven to have diagnosis and prognosis value, partially independent of CRF and BMD. The aim of the OsteoLaus cohort is to combine in daily practice the CRF and the information given by DXA (BMD, TBS and vertebral fracture assessment (VFA)) to better identify women at high fracture risk. Method: The OsteoLaus cohort (1400 women 50 to 80 years living in Lausanne, Switzerland) started in 2010. This study is derived from the cohort COLAUS who started in Lausanne in 2003. The main goals of COLAUS is to obtain information on the epidemiology and genetic determinants of cardiovascular risk in 6700 men and women. CRF for OP, bone ultrasound of the heel, lumbar spine and hip BMD, VFA by DXA and MA evaluation by TBS are recorded in OsteoLaus. Preliminary results are reported. Results: We included 631 women: mean age 67.4±6.7 y, BMI 26.1±4.6, mean lumbar spine BMD 0.943±0.168 (T-score -1.4 SD), TBS 1.271±0.103. As expected, correlation between BMD and site matched TBS is low (r2=0.16). Prevalence of VFx grade 2/3, major OP Fx and all OP Fx is 8.4%, 17.0% and 26.0% respectively. Age- and BMI-adjusted ORs (per SD decrease) are 1.8 (1.2- 2.5), 1.6 (1.2-2.1), 1.3 (1.1-1.6) for BMD for the different categories of fractures and 2.0 (1.4-3.0), 1.9 (1.4-2.5), 1.4 (1.1-1.7) for TBS respectively. Only 32 to 37% of women with OP Fx have a BMD < -2.5 SD or a TBS < 1.200. If we combine a BMD < -2.5 SD or a TBS < 1.200, 54 to 60% of women with an osteoporotic Fx are identified. Conclusion: As in the already published studies, these preliminary results confirm the partial independence between BMD and TBS. More importantly, a combination of TBS subsequent to BMD increases significantly the identification of women with prevalent OP Fx which would have been miss-classified by BMD alone. For the first time we are able to have complementary information about fracture (VFA), density (BMD), micro- and macro architecture (TBS & HAS) from a simple, low ionizing radiation and cheap device: DXA. Such complementary information is very useful for the patient in the daily practice and moreover will likely have an impact on cost effectiveness analysis.

L'angioplastie coronaire chez le patient âgé [Coronary angioplasty in elderly patients]

Percutaneous transluminal coronary angioplasty (PTCA) is a widely accepted treatment of symptomatic coronary heart disease providing prompt and prolonged clinical, improvement in most patients. We have examined the value of this therapy in a group of 91 patients in their eighth decade treated by 133 consecutive angioplasties. Most patients had refractory or instable angor in spite of optimal pharmacotherapy. Multivessel disease was present in 67% and maintained left-ventricular function in 92% of the patients. The angiographic success rate of PTCA was 84%; technical failures occurred in 12% and adverse events in 14%. Two patients died. The rate of symptomatic restenosis was 24%. Survival and patients free of myocardial events were at 89% and 60%, respectively, estimated by Kaplan-Meier analysis. PTCA is an efficient and acceptable treatment for the elderly patient with severe and drug-resistant angina. Two years after PTCA the majority of patients was asymptomatic.

The mycobacterial cord factor adjuvant analogue trehalose-6,6'-dibehenate (TDB) activates the Nlrp3 inflammasome.

The success of a vaccine consists in the induction of an innate immune response and subsequent activation of the adaptive immune system. Because antigens are usually not immunogenic, the addition of adjuvants that activate innate immunity is required. The mycobacterial cord factor trehalose-6,6'-dimycolate (TDM) and its synthetic adjuvant analogue trehalose-6,6'-dibehenate (TDB) rely on the C-type lectin Mincle and the signaling molecules Syk and Card9 to trigger innate immunity. In this study, we show that stimulation of bone marrow-derived dendritic cells (BMDCs) with TDB induces Nlrp3 inflammasome-dependent IL-1β secretion. While Card9 is required for NF-κB activation by TDB, it is dispensable for TDB-induced activation of the Nlrp3 inflammasome. Additionally, efflux of intracellular potassium, lysosomal rupture, and oxygen radical (ROS) production are crucial for caspase-1 processing and IL-1β secretion by TDB. In an in vivo inflammation model, we demonstrate that the recruitment of neutrophils by TDB is significantly reduced in the Nlrp3-deficient mice compared to the wild-type mice, while the production of chemokines in vitro is not influenced by the absence of Nlrp3. These results identify the Nlrp3 inflammasome as an essential mediator for the induction of an innate immune response triggered by TDB.

Laparoscopic Roux-en-Y gastric bypass: initial 2-year experience.

BACKGROUND: Roux-en-Y gastric bypass (RYGBP)-essentially a restrictive bariatric procedure-is currently considered the gold standard for the surgical treatment of morbid obesity. Open surgery in obese patients is associated with a high risk of cardiopulmonary complications, wound infection, and late incisional hernia. Laparoscopic surgery has been shown to reduce perioperative morbidity and to improve postoperative recovery for various procedures. Herein we present our results with laparoscopic RYGBP after an initial 2-year experience. METHODS: A prospective database was created in our department beginning without the first laparoscopic bariatric procedure. To provide a complete follow-up of 6 months, the results of all patients operated on between June 1999 and August 2001 were reviewed. Early surgical results, weight loss, correction of comorbidities, and improvement of quality of life were evaluated. RESULTS: A total of 107 patients were included. There were 82 women and 25 men, with a mean age of 39.7 years (range, 19-58). RYGBP was a primary procedure in 80 cases (49 morbidly obese and 31 superobese patients) and a reoperation after failure or complication of another bariatric operation in 27 cases. Mean duration of surgery was 168 min for morbidly obese patients, 196 min for surperobese patients, and 205 min for reoperated patients (p <0.01). Conversion to open surgery was necessary in two cases. A total of 22 patients (20.5%) developed complication. Nine of them (8.4%) required reoperation for leak (five cases, or 4.6%), bowel occlusion (three cases, or 2.8%), or subphrenic abscess (one case, or 0.9%). mortality was 0.9%. Major morbidity decreased over time (first two-thirds, 12.5%, last third, 2.7%). major morbidity decreased over time (first two-thirds, 12.5%; last third, 2.7%). Excess weight loss of -50% was achieved in >80% of the patients, corresponding to a loss of 15 body mass index (BMI) units in morbidly obese patients and 20 BMI units in superobese patients. In the vast majority of patients, comorbidities improved or disappeared over time and quality of life improved. CONCLUSIONS: Laparoscopic Roux-en-Y gastric bypass is feasible, but it is a very complex operation. Indeed, it is associated with a long and steep learning curve, as reflected in the high number of major complications among our first 70 patients. The learning curve probably includes between 100 and 150 patients. With increasing experience, the morbidity rate becomes more acceptable and comparable to that of open RYGBP. The results in terms of weight loss and correction of comorbidities are similar to those obtained after open surgery, at least in the short term. However, only surgeons with extensive experience in advanced laparoscopic as well as bariatric surgery should attempt this procedure.