Diastolic asynchrony is more frequent than systolic asynchrony in dilated cardiomyopathy and is less improved by cardiac resynchronization therapy.

OBJECTIVES: To compare the incidence of diastolic and systolic asynchrony, assessed by tissue Doppler imaging (TDI), in patients with congestive heart failure (CHF) and severe left ventricular (LV) dysfunction, and to assess TDI changes induced by cardiac resynchronization therapy (CRT). BACKGROUND: Thirty percent of CRT candidates are nonresponders. Besides QRS width, the presence of echographic systolic asynchrony has been used to identify future responders. Little is known about diastolic asynchrony and its change after CRT. METHODS: Tissue Doppler imaging was performed in 116 CHF patients (LV ejection fraction 26 +/- 8%). Systolic and diastolic asynchrony was calculated using TDI recordings of right ventricular and LV walls. RESULTS: The CHF group consisted of 116 patients. Diastolic asynchrony was more frequent than systolic, concerning both intraventricular (58% vs. 47%; p = 0.0004) and interventricular (72 vs. 45%; p < 0.0001) asynchrony. Systolic and diastolic asynchrony were both present in 41% patients, but one-third had isolated diastolic asynchrony. Although diastolic delays increased with QRS duration, 42% patients with narrow QRS presented with diastolic asynchrony. Conversely, 27% patients with large QRS had no diastolic asynchrony. Forty-two patients underwent CRT. Incidence of systolic intraventricular asynchrony decreased from 71% to 33% after CRT (p < 0.0001), but diastolic asynchrony decreased only from 81% to 55% (p < 0.0002). Cardiac resynchronization therapy induced new diastolic asynchrony in eight patients. CONCLUSIONS: Diastolic asynchrony is weakly correlated with QRS duration, is more frequent than systolic asynchrony, and may be observed alone. Diastolic asynchrony is less improved by CRT than systolic. Persistent diastolic asynchrony may explain some cases of lack of improvement after CRT despite good systolic resynchronization.     

Stimulation of gastrointestinal motility by loperamide in dogs

The effects of loperamide on gastrointestinal motility were investigated in conscious fasted dogs chronically fitted with strain-gauge transducers on the antrum, the jejunum, and the colon. Oral administration of loperamide (0.1 mg/kg) induced, after a delay of 20–30 min, a long-lasting (8–12 hr) stimulation of gastrointestinal motility associated with a disorganization of the cyclic activity at the three levels investigated. These effects were reproduced by a subcutaneous administration at the same dose and were antagonized by previous intravenous administration of naloxone or a quaternary opiate antagonist. Intracolonic administration (0.1 mg/kg) stimulated, after a delay of 20–30 min, colonic motility only. Intracerebroventricular loperamide (1 g/kg) induced a long-lasting (15–20 hr) inhibition of the gastric motility and a short (2-hr) disorganization of the jejunal motor profile. These data show that oral loperamide stimulates gastrointestinal motility in dogs and involves peripheral opiate receptors.     

Malaria-specific transgenic CD4(+) T cells protect immunodeficient mice from lethal infection and demonstrate requirement for a protective threshold of antibody production for parasite clearance

T cells are important in the immune response to malaria, both for their cytokines and their help for antibody production. To look at the relative importance of these roles, a T-cell receptor (TCR) transgenic mouse has been generated carrying a TCR specific for an epitope of the merozoite surface protein 1 (MSP-1) of the malaria parasite, Plasmodium chabaudi. In adoptive transfer experiments, malaria-specific CD4(+) T cells expand and produce interferon gamma (IFN-gamma) early in infection, but the population contracts quickly despite prolonged persistence of the parasite. MSP-1-specific CD4(+) cells can protect immunodeficient mice from lethal infection; however, the parasite is only completely cleared in the presence of B cells showing that T helper cells are critical. Levels of malaria-specific antibody and the speed of their production clearly correlate with the time of resolution of infection, indicating that a critical threshold of antibody production is required for parasite clearance. Furthermore, T cells specific for a shed portion of MSP-1 are able to provide help for antibody to the protective region, which remains bound to the infected erythrocyte, suggesting that MSP-1 has all of the components necessary for a good vaccine.     

Influence of T-cell depletion on chronic graft-versus-host disease: results of a multicenter randomized trial in unrelated marrow donor transplantation

Donor-derived T cells have been proposed to play a role in pathogenesis of chronic graft-versus-host disease (cGVHD). The impact of ex vivo T-cell depletion (TCD) on cGVHD was analyzed in a randomized multicenter trial involving unrelated donor marrow transplants. A total of 404 patients diagnosed with hematologic malignancies received a total body irradiation-based myeloablative conditioning regimen. GVHD prophylaxis included TCD plus cyclosporine (CSA) or unmodified grafts with CSA plus methotrexate (M/C). Median recipient age was 31.2 years (range, 0.5-55.6 years); median follow-up time since randomization was 4.2 years. The mean number of T cells infused was 1 log lower on the TCD arm. The incidence of cGVHD at 2 years was similar between the TCD and M/C arms, 29% versus 34% (P = .27), respectively. Survival at 3 years from diagnosis of cGVHD was also similar, (TCD 51% versus M/C 58%; P = .29). The proportion of patients with cGVHD who discontinued immunosuppression at 5 years was not different (TCD 72% versus M/C 63%; P = .27), and incidence of serious infections and leukemia relapse were similar on both treatment arms. In spite of a significant reduction of acute GVHD, TCD did not reduce the incidence of cGVHD or improve survival in patients who developed cGVHD.     

Inefficacy of infliximab in primary Sjögren's syndrome: results of the randomized, controlled Trial of Remicade in Primary Sjögren's Syndrome (TRIPSS)

OBJECTIVE: There is no effective treatment for patients with primary Sj?gren's syndrome (SS). Since tumor necrosis factor alpha (TNF alpha) could be a key element in the pathogenesis of primary SS, we conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the effect of infliximab in primary SS. METHODS: A total of 103 patients with primary SS were randomly assigned to receive infliximab infusions (5 mg/kg) or placebo at weeks 0, 2, and 6 and were followed up for 22 weeks. All patients fulfilled the new American-European Consensus Group criteria for SS and had active disease as assessed by values >50 mm on 2 of 3 visual analog scales (VAS) (0-100 mm) that evaluated joint pain, fatigue, and buccal, ocular, skin, vaginal, or bronchial dryness. A favorable overall response was defined as the patient having > or =30% improvement between weeks 0 and 10 in the values on 2 of the 3 VAS. Secondary end points were values on each VAS separately, the number of tender and swollen joints, the basal salivary flow rate, results of the Schirmer test for lacrimal gland function, the focus score on labial salivary gland biopsy, the level of C-reactive protein, and the erythrocyte sedimentation rate evaluated at weeks 0, 10, and 22, as well as quality of life evaluated by use of the generic Short Form 36 questionnaire administered at weeks 0, 10, and 22. RESULTS: At week 10, 26.5% of patients receiving placebo and 27.8% of patients treated with infliximab had a favorable overall response (P = 0.89), and at week 22, 20.4% of the placebo group and 16.7% of the infliximab group had a favorable response (P = 0.62). In addition, the 2 groups did not differ in any of the secondary end points over the 22 weeks of the trial. Severe adverse events reported in the infliximab group did not differ from those observed in previous studies. CONCLUSION: This randomized, double-blind, placebo-controlled study of an anti-TNF agent did not show any evidence of efficacy of infliximab in primary SS.     

Basolateral membrane targeting of a renal-epithelial inwardly rectifying potassium channel from the cortical collecting duct, CCD-IRK3, in MDCK cells

We recently cloned an inward-rectifying K channel (Kir) cDNA, CCD-IRK3 (mKir 2.3), from a cortical collecting duct (CCD) cell line. Although this recombinant channel shares many functional properties with the “small-conductance” basolateral membrane Kir channel in the CCD, its precise subcellular localization has been difficult to elucidate by conventional immunocytochemistry. To circumvent this problem, we studied the targeting of several different epitope-tagged CCD-IRK3 in a polarized renal epithelial cell line. Either the 11-amino acid span of the vesicular stomatitis virus (VSV) G glycoprotein (P5D4 epitope) or a 6-amino acid epitope of the bovine papilloma virus capsid protein (AU1) was genetically engineered on the extreme N terminus of CCD-IRK3. As determined by patch-clamp and two-microelectrode voltage-clamp analyses in Xenopus oocytes, neither tag affected channel function; no differences in cation selectivity, barium block, single channel conductance, or open probability could be distinguished between the wild-type and the tagged constructs. MDCK cells were transfected with tagged CCD-IRK3, and several stable clonal cell lines were generated by neomycin-resistance selection. Immunoprecipitation studies with anti-P5D4 or anti-AU1 antibodies readily detected the predicted-size 50-kDa protein in the transfected cells lines but not in wild-type or vector-only (PcB6) transfected MDCK cells. As visualized by indirect immunofluorescence and confocal microscopy, both the tagged CCD-IRK3 forms were exclusively detected on the basolateral membrane. To assure that the VSV G tag was not responsible for the targeting, the P5D4 epitope modified by a site-directed mutagenesis (Y2F) to remove a potential basolateral targeting signal contained in this tag. VSV(Y2F) was also detected exclusively on the basolateral membrane, confirming bona fide IRK3 basolateral expression. These observations, with our functional studies, suggest that CCD-IRK3 may encode the small-conductance CCD basolateral K channel.     

Comparison of transthoracic echocardiography using second harmonic imaging, transcranial Doppler and transesophageal echocardiography for the detection of patent foramen ovale in stroke patients.

AIMS: The comparison of three imaging methods to determine which is the most accurate and reliable for the detection of right-to-left shunt. METHODS AND RESULTS: One hundred and seven patients who were hospitalized for stroke underwent: a transthoracic echocardiography (TTE) using second harmonic, a transcranial Doppler (TCD) and a transesophageal echocardiography (TEE) from August 2003 to April 2004. All studies were recorded on a videotape and were studied by a physician blinded to the study. With TTE and TEE, we found 44 (41%) patent foramen ovales. All contrast tests were positive with TCD for these 44 patients. For two patients, the contrast test was positive only with TTE and TCD. We found four false negative contrast tests with TTE. Among the 63 patients who had a negative contrast test with TEE and TTE, the results were the same with TCD for 59 of them; we were not able to determine a cause for the four positive tests. CONCLUSION: This study confirms that transesophageal echocardiography has limitations in the diagnosis of patent foramen ovale. In this study, the negative predictive value of transcranial Doppler was excellent. Therefore, this examination is able to exclude a patent foramen ovale with a high level of confidence.     

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.     

Immunological markers after long-term treatment interruption in chronically HIV-1 infected patients with CD4 cell count above 400 x 10(6) cells/l

OBJECTIVE: To analyse immunological markers associated with CD4+ lymphocyte T-cell count (CD4+) evolution during 12-month follow-up after treatment discontinuation. METHOD: Prospective observational study of chronically HIV-1 infected patients with CD4+ above 400 x 10(6) cells/l. RESULTS: CD4+ changes took place in two phases: an initial rapid decrease in the first month (-142 x 10(6) cells/l on average), followed by a slow decline (-17 x 10(6) cells/l on average) The second slope of CD4+ decline was not correlated with the first and only baseline plasma HIV RNA was associated with it. The decline in CD4+ during the first month was steeper in patients with higher CD4+ and weaker plasma HIV RNA baseline levels. Moreover, the decline was less pronounced (P < 10(-4)) in patients with CD4+ nadir above 350 x 10(6) cells/l (-65 x 10(6) cells/l per month) in comparison with those below 350 x 10(6) cells/l (-200 x 10(6) cells/l per month). A high number of dendritic cells (DCs) whatever the type was associated with high CD4+ at the time of treatment interruption and its steeper decline over the first month. Moreover, the myeloid DC level was stable whereas the lymphoid DC count, which tended to decrease in association with decrease in CD4+, was negatively correlated with the HIV RNA load slope. CONCLUSIONS: The results support the use of the CD4+ nadir to predict the CD4+ dynamic after treatment interruption and consideration of the CD4+ count after 1-month of interruption merely reflects the 12-month level of CD4+. Although DCs seem to be associated with the CD4+ dynamic, the benefit of monitoring them has still to be defined.     

Influence of systemic inflammatory response syndrome and sepsis on outcome of critically ill infected patients

The clinical significance of the systemic inflammatory response in infected patients remains unclear. We examined risk factors for hospital mortality in 3,608 intensive care unit patients included in the European Sepsis Study. Patients were categorized as having infection without or with (i.e., sepsis) systemic inflammatory response, severe sepsis, and septic shock, on the first day of infection. Hospital mortality varied from 25 to 60% according to sepsis stage, but did not differ between the first two categories (hazard ratio, 0.94; p = 0.55), whereas there was a grading of severity from sepsis to severe sepsis (1.53, p < 10-4) and septic shock (2.64, p < 10-4). Within each stage, mortality was unaffected by the number of inflammatory response criteria. Prognostic factors identified by Cox regression included comorbid conditions, severity of acute illness and acute organ dysfunction, shock, nosocomial infection, and infection caused by aerobic gram-negative bacilli, enterobacteria, Staphylococcus aureus, and infection from a digestive or unknown source. We conclude that whereas the categorization of infection by the presence of organ dysfunction or shock has strong prognostic significance, infection and sepsis have similar outcomes, unaffected by the presence or number of inflammatory response criteria. Refinement of risk stratification of patients presenting with infection and no organ dysfunction is needed.