Toll-Like Receptor 2-Dependent Extracellular Signal-Regulated Kinase Signaling in Mycobacterium tuberculosis-Infected Macrophages Drives Anti-Inflammatory Responses and Inhibits Th1 Polarization of Responding T Cells

Mycobacterium tuberculosis survives within macrophages and employs immune evasion mechanisms to persist in the host. Protective T helper type 1 (Th1) responses are induced, and the immune response in most individuals is sufficient to restrict M. tuberculosis to latent infection, but most infections are not completely resolved. As T cells and macrophages respond, a balance is established between protective Th1-associated and other proinflammatory cytokines, such as interleukin-12 (IL-12), interferon gamma (IFN-γ), and tumor necrosis factor alpha, and anti-inflammatory cytokines, such as IL-10. The mechanisms by which M. tuberculosis modulates host responses to promote its survival remain unclear. In these studies, we demonstrate that M. tuberculosis induction of IL-10, suppression of IL-12, and inhibition of class II major histocompatibility complex (MHC-II) molecules in infected macrophages are all driven by Toll-like receptor 2 (TLR2)-dependent activation of the extracellular signal-regulated kinases (ERK). Elimination of ERK signaling downstream of TLR2 by pharmacologic inhibition with U0126 or genetic deletion of Tpl2 blocks IL-10 secretion and enhances IL-12 p70 secretion. We demonstrate that M. tuberculosis regulation of these pathways in macrophages affects T cell responses to infected macrophages. Thus, genetic blockade of the ERK pathway in Tpl2^−/− macrophages enhances Th1 polarization and IFN-γ production by antigen-specific CD4⁺ T cells responding to M. tuberculosis infection. These data indicate that M. tuberculosis and its potent TLR2 ligands activate ERK signaling in macrophages to promote anti-inflammatory macrophage responses and blunt Th1 responses against the pathogen.     

Gastric emptying after treatment of stenosis secondary to duodenal ulceration by proximal gastric vagotomy and duodenoplasty or pyloric dilatation.

A consecutive series of 12 patients with stenosis secondary to duodenal ulceration were treated by proximal gastric vagotomy (PGV) and duodenoplasty or PGV and dilatation of the stenosis. Three months after operation the rate and pattern of gastric emptying of a solid meal was measured in each patient and compared with 18 patients with uncomplicated duodenal ulcer treated by PGV alone. Two patients developed gastric stasis in the early postoperative period which resolved with medical treatment. All patients were asymptomatic and were eating normally three months after operation. There was no significant difference in the rate of gastric emptying postoperatively between the patients who had stenosis and those who had uncomplicated duodenal ulcers. These results indicate that despite early postoperative difficulties in some patients pyloric dilatation or duodenoplasty with PGV are both effective treatments for stenosis due to duodenal ulceration.     

Maternal HIV-1 and HIV-2 infection and child survival in The Gambia

OBJECTIVE: To compare the survival of children born to HIV-1 or HIV-2 seropositive mothers with that of children born to HIV-seronegative mothers and to evaluate risk factors for mortality. DESIGN: Physician-blinded prospective study. METHODS: One hundred and one HIV-1-seropositive, 243 HIV-2-seropositive pregnant women, and 468 HIV-seronegative women (control group) matched by age, parity, and health centre, were followed up in a study of mother-to-child transmission of HIV. Mothers and children were seen at 2 and 6 months of age and subsequently followed at 3-monthly intervals up to 18 months of age. HIV infection in children was diagnosed by polymerase chain reaction at 2, 9 or 18 months and by antibody assays at 18 months. RESULTS: Fifteen per cent of children born to HIV-1-infected mothers died compared with 7% of children born to HIV-2-infected mothers [hazard ratio, 2.3; 95% confidence interval (CI), 1.1-4.7; P = 0.02], and 6% of HIV-seronegative mothers (hazard ratio, 2.6; 95% CI, 1.4-5.0; P = 0.003). Six of the 17 children known to be HIV-1 infected died compared with none among the eight HIV-2-infected children (P = 0.13). High proviral load in the babies, high antenatal maternal RNA plasma viral load, and maternal death increased child mortality significantly. CONCLUSIONS: More children born to HIV-1-infected mothers died in comparison with those born to HIV-2-infected mothers or to mothers from the control group. This effect was due to excess death in HIV-1-infected infants which was associated with a high viral load in the affected mother and child.     

Release of interleukin-12 in experimental Escherichia coli septic shock in baboons: relation to plasma levels of interleukin-10 and interferon- gamma

Interleukin (IL)-12 is thought to be a key factor for the induction of interferon gamma (IFN-gamma), a cytokine essential for the lethal effects of endotoxin. We report here on the release of the nonfunctional subunit of IL-12, p40, as well as biologically active heterodimeric IL-12, p70, after administration of a lethal (n = 5) or sublethal (n = 8) dose of live Escherichia coli to baboons. Remarkably, on lethal challenge, peak levels of p40 were observed at 3 hours that were about twofold lower than those elicited after sublethal challenge (2,813 +/- 515 pg/mL v 4,972 +/- 732 pg/mL, P < .05). This disparity was also observed, although to a lesser extent, for IL-12 p70 antigen, of which maximum levels of 91 +/- 47 pg/mL and 151 +/- 41 pg/mL were measured 6 hours after a lethal or sublethal dose of E coli, respectively. Circulating p70 antigen correlated with IL-12 biologic activity (r = 0.869; P < .001). When comparing lethal to sublethal conditions, lower peak levels of IL-12 on lethal E coli sharply contrasted with higher levels of other proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, IL-1beta, IL-6, and IL-8 observed in these animals. Lower IL-12 concentrations in the lethal group may have resulted in part from the enhanced production of IL-10, a known inhibitor of IL-12 synthesis in vitro, as peak levels of this cytokine 3 hours postchallenge inversely correlated with peak levels of IL-12, in particular p40 (r = -0.802; P < .01). Contrary to what might be expected if IFN-gamma were solely induced by IL-12, lethally challenged baboons generated threefold more IFN-gamma at 6 hours than those receiving a sublethal dose (P < .05). Moreover, higher levels of IFN- gamma were associated with lower p40/p70 ratios, suggesting that, in agreement with observations in vitro, IFN-gamma may have preferentially upregulated the release of p70 over p40. These data show that IL-12 is released in experimental septic shock in nonhuman primates and suggest that IL-10 and IFN-gamma are involved in the regulation of this release. Furthermore, this study indicates that the systemic release of IL-12 might be essential, but is not likely sufficient, to promote lethal production of IFN-gamma in sepsis.     

Renal transplantation in a patient with methylmalonic acidaemia

Renal insufficiency is frequently reported in mutase-deficient methylmalonic acidaemia. We present a case report of a patient with mut– methylmalonic acidaemia who developed chronic tubulointerstitial nephropathy during adolescence. At 24 years of age, she developed end-stage renal failure and underwent renal transplantation. Both plasma and urine methylmalonic acid levels decreased significantly with improved renal function following transplantation. Complications included cyclosporin toxicity and development of diabetes. Renal, metabolic, and clinical status remained improved at 3 years after the kidney transplant.     

Left ventricular filling and ventricular diastolic performance after percutaneous balloon mitral valvotomy.

The time course of left ventricular (LV) filling and LV diastolic performance were examined in 27 consecutive patients in sinus rhythm before and acutely after balloon mitral valvotomy (BMV). The mitral valve area acutely increased from 1.1 +/- 0.3 to 2.1 +/- 0.8 cm2. Simultaneous pressure-volume data were obtained using digital subtraction left ventriculography and LV micromanometer pressure before and 10 minutes after BMV. The time constant of LV isovolumic relaxation was unchanged after BMV (50 +/- 10 ms before BMV vs 47 +/- 13 ms after BMV). In addition, values before and after BMV for LV end-diastolic volume (123 +/- 29 vs 125 +/- 36 ml), end-diastolic pressure (11 +/- 4 vs 12 +/- 4 mm Hg) and diastolic filling time (337 +/- 126 vs 338 +/- 152 ms) were not altered by the procedure. After BMV the peak diastolic filling rate (403 +/- 143 vs 469 +/- 302 ml/s) was maintained despite a 36% reduction in left atrial filling pressure. There was a trend toward earlier occurrence of the peak filling rate (196 +/- 127 vs 146 +/- 148 ms, p = 0.08). The percentage of diastolic filling in the first third of diastole, however, was similar (42 +/- 9 vs 48 +/- 16%) before and after the procedure. Thus, the time course of LV filling is not significantly altered acutely after BMV, but is maintained at reduced left atrial filling pressure. Neither LV relaxation or LV chamber compliance are altered acutely after BMV.(ABSTRACT TRUNCATED AT 250 WORDS)     

Development of a validated patient satisfaction survey for sexual health clinic attendees

Patient experience of and satisfaction with health-care services is increasingly being used to evaluate and guide health-care provision. A recent systematic review failed to identify a validated method of measuring patient satisfaction in sexually transmitted infection (STI) clinics. The aim of this study was to design and validate a specific STI clinic patient satisfaction survey that could be used as a patient-derived outcome measure. Key themes of importance to patients were identified from a recent systematic review of STI clinic patient satisfaction surveys. Semi-structured interviews were performed with patients attending a sexual health clinic to further refine these themes, and then used to compile a patient questionnaire. Cognitive testing was used to provide face validity for the questionnaire design, layout and wording. The questionnaire was further reviewed and revised by the research team prior to being piloted over a five-week period. Five key patient themes were incorporated into the questionnaire and the pilot phase included responses from 936 patients. The completion rate for individual items and the whole questionnaire (95% [885/936]) was high. Internal consistency and validity also scored highly.     

Thoraxkompressionsqualität

Background

The outcome of cardiopulmonary resuscitation (CPR) depends on the quality of chest compressions. Current European Resuscitation Council (ERC) guidelines promote the development of feedback systems. However, no studies presenting satisfactory results of feedback use have been published.

Methods

A total of 60 patients with cardiac arrest (≥18 years of age) received resuscitation attempts using an automated external defibrillator (AED) with real-time feedback by the ambulance service of the City of Münster. The frequency of chest compressions, no-flow time (NFT) and depth of chest compressions were analyzed for the first three cycles of CPR and compared to the ERC guidelines 2005.

Results

Chest compression frequency did not differ significantly from the ideal as set out in the guidelines. Analysis of NFTs showed significantly longer NFT for the first cycle but NFT for the second and third cycles did not differ significantly from the ideal. The target depth of 4-5 cm was achieved in 80% of all chest compressions in the first 3 cycles.

Conclusion

With the AED real-time feedback technology used in this study standardized performance of chest compressions could be maintained in a professional ambulance service. Implementation of a feedback system requires training of ambulance staff.     

Assessing for depression in older people

Perceptions about what constitutes depression contribute to poor know edge of the condition amongst non-psychiatric medica and nurs ng staff. Stereotypes about ageing and depression go some way to explaining why depression remains under-recognised and under addressed in older people. This paper highlights some of the factors that contribute to the missed or misdiagnosis of depression. It also makes explicit some of the issues surrounding diagnosis and management of the disorder. The importance of a good health history and an appreciation of the adverse effects of drugs are identified as important in assisting to diagnose this treatable condition.