Systemic activation of the transient receptor potential vanilloid subtype 4 channel causes endothelial failure and circulatory collapse: Part 2

The transient receptor potential (TRP) vanilloid subtype 4 (V4) is a nonselective cation channel that exhibits polymodal activation and is expressed in the endothelium, where it contributes to intracellular Ca2+ homeostasis and regulation of cell volume. The purpose of the present study was to evaluate the systemic cardiovascular effects of GSK1016790A, a novel TRPV4 activator, and to examine its mechanism of action. In three species (mouse, rat, and dog), the i.v. administration of GSK1016790A induced a dose-dependent reduction in blood pressure, followed by profound circulatory collapse. In contrast, GSK1016790A had no acute cardiovascular effects in the TRPV4-/- null mouse. Hemodynamic analyses in the dog and rat demonstrate a profound reduction in cardiac output. However, GSK1016790A had no effect on rate or contractility in the isolated, buffer-perfused rat heart, and it produced potent endothelial-dependent relaxation of rodent-isolated vascular ring segments that were abolished by nitric-oxide synthase (NOS) inhibition (N-nitro-L-arginine methyl ester; L-NAME), ruthenium red, and endothelial NOS (eNOS) gene deletion. However, the in vivo circulatory collapse was not altered by NOS inhibition (L-NAME) or eNOS gene deletion but was associated with (concentration and time appropriate) profound vascular leakage and tissue hemorrhage in the lung, intestine, and kidney. TRPV4 immunoreactivity was localized in the endothelium and epithelium in the affected organs. GSK1016790A potently induced rapid electrophysiological and morphological changes (retraction/condensation) in cultured endothelial cells. In summary, inappropriate activation of TRPV4 produces acute circulatory collapse associated with endothelial activation/injury and failure of the pulmonary microvascular permeability barrier. It will be important to determine the role of TRPV4 in disorders associated with edema and microvascular congestion.     

Temporal trends in maternal mortality in Canada II: estimates based on hospitalization data

ObjectivesWorld Health Organization reports based on Canadian Vital Statistics data suggest a recent increase in maternal mortality mrates in Canada. Since Vital Statistics data typically provide inaccurate estimates of maternal mortality, we examined temporal trends in Canada using hospitalization data.MethodsWe identified in-hospital deaths among women aged 15 to 54 years from the Canadian Institute for Health Information’s hospitalization database from 1996–1997 to 2007–2008. Maternal deaths during delivery were identified, and other in-hospital deaths were linked with prior pregnancy/delivery hospitalization records. Maternal mortality rates, 95% confidence intervals, and risk ratios (RRs) were estimated.ResultsThe maternal mortality rate in Canada was 9.2 per 100 000 deliveries (95% CI 7.6 to 11.2) in 1996 to 1999 and 9.0 per 100 000 deliveries (95% CI 7.4 to 10.9) in 2005 to 2007 (P for trend = 0.22). Older maternal age (RR 9.9 and 3.1 for ≥ 45 years and 40 to 44 years vs. 20 to 24 years), delivery by Caesarean section (RR 4.5 vs. vaginal delivery), and early gestation delivery (RR 20.1 and 5.9 for 20 to 27 weeks and 28 to 36 weeks vs. ≥ 37 weeks) were associated with higher maternal mortality. Cardiovascular diseases (rate 4.7 per 100 000 deliveries, 95% CI 3.9 to 5.5) were the most common diagnoses associated with maternal death. The rate of late maternal death (from 43 to 365 days after delivery) was 5.4 per 100 000 deliveries.ConclusionThere was no increase in maternal mortality in Canada from 1996 to 2007. Increases observed in Canadian Vital Statistics data likely reflect improvements in the ascertainment of maternal death. Hospitalization data can serve as a timely and comprehensive source for monitoring trends in maternal mortality in Canada.     

Argatroban anticoagulation in intensive care patients: effects of heart failure and multiple organ system failure

We retrospectively evaluated argatroban dosing patterns, clinical outcomes, and the effects of heart failure and multiple organ system failure on dosing requirements in 65 adult, intensive care patients administered argatroban anticoagulation for clinically suspected heparin-induced thrombocytopenia (n=56) or history of heparin-induced thrombocytopenia (n=9). Argatroban was initiated then titrated to achieve target activated partial thromboplastin times 1.5 to 3 times normal control (ie, 42-84 seconds). Overall, argatroban was initiated at 1.14+/-0.62 microg/kg/min (mean+/-SD) and administered for 11.4+/-9.5 days, with comparable dosing patterns between patients with suspected, versus previous, heparin-induced thrombocytopenia. Sixty-four (98.5%) patients achieved target activated partial thromboplastin times, typically following no or one dose adjustment. Therapeutic doses were lower in patients with, versus without, heart failure (0.58+/-0.28 vs 0.97+/-0.6 microg/kg/min, P= .042) and decreased as the number of failed organ systems increased from 1 to 2 to =3 (1.10+/-0.67 vs 0.87+/-0.47 vs 0.58+/-0.47 microg/kg/min, P= .008). From argatroban initiation until patient discharge or death, 11 (16.9%) patients (3 off argatroban) developed thromboembolic complications; 14 (21.5%) died (11 off argatroban, 7 from multiple organ system failure); and 1 (1.5%) required amputation. Nine patients (13.8%) experienced bleeding, none fatal. This experience suggests that argatroban administered at approximately 1 micro/kg/min provides adequate levels of anticoagulation in many intensive care unit patients with suspected or previous heparin-induced thrombocytopenia. Reduced doses are needed when heart failure or multiple organ system failure is present.     

High-frequency ultrasound imaging of the duodenum and colon in patients with symptomatic giardiasis in comparison to amebiasis and healthy subjects

Aim:  The application of ultrasound may be suitable for evaluating the effects of intestinal cytoskeletal rearrangement of the duodenum and colon as a result of exposure to live Giardia lamblia trophozoites. We studied the sonographic appearance of the duodenum and colon in giardiasis compared with amebiasis and healthy subjects.
Methods:  Sonographic images obtained from 100 consecutive patients with symptomatic giardiasis were compared to those taken from 40 patients with amebiasis and 40 healthy subjects. B-mode ultrasound examination of the duodenum and colon was performed using a 7.5 MHz annular array transducer. Gray scale images with water contrast were acquired.
Results:  Normal duodenum and colon echoanatomy were demonstrated. Giardial lesions of the duodenum and colon were associated with increased wall thickness when compared with healthy subjects ( P  < 0.05). Furthermore, giardial lesions were characterized by increased wall echogenicity, flattening or loss of duodenal folds and/or colonic haustration, hyperechoic floating foci (HFF) demonstrating chaotic motility, increased peri-lesional tissue echogenicity, and altered colonic peristalsis. In amebiasis, focal hyperechoic wall thickening was seen at lesion sites identified as amebomas with increased wall echogenicity, but otherwise normal duodenal folds and colonic haustration. There were no HFF with chaotic motility, rather intestinal contents showed bulk motility in patients with amebiasis. There was no focal colonic wall motion abnormality observed.
Conclusion:  B-mode imaging with water contrast demonstrated details of duodenal and colonic echoanatomy. There were sonographic features of giardial lesions of the duodenum and colon that were distinct from those in amebiasis and healthy subjects.     

A comparison between erythrocyte sedimentation rate (ESR) and selected acute-phase proteins in the elderly.

The erythrocyte sedimentation rate (ESR) and selected acute-phase proteins (APPs) were studied in 101 elderly people (mean age, 72 years) to determine their utility as diagnostic aids in subjects with underlying infections or inflammation. ESR and values for serum immunoglobulin A (IgA), the fourth component of complement (C4), haptoglobin, and alpha-1-antitrypsin (AAT) all correlated with infection or inflammation. C4 was the only test predictive of mortality at six months. Neither ESR nor any of the APPs demonstrated concomitantly high sensitivity, specificity, and positive predictive values. Receiver-operating characteristic curve analysis revealed low true positive to false positive ratios for all of the tests studied. In the elderly, measurement of APPs as a guide to underlying infection or inflammation has limited utility and offers no advantage over the traditional low-cost ESR.     

Novel Henneguya spp. (Cnidaria: Myxozoa) from cichlid fish in the Amazon basin cluster by geographic origin

Parasitology Research - We describe three new Henneguya spp. (Myxobolidae) found parasitizing two species of cichlid fish from the Amazon basin, Brazil: H. tucunarei n. sp. from gill filaments of...     

Low reproducibility of many lactate markers during incremental cycle exercise

Reports on reproducibility of lactate markers usually considered only two trials. The authors assessed reproducibility of power output at seven markers in 11 fit subjects over at least six trials under tightly controlled conditions. Subjects undertook incremental exercises (50 W start, +50 W every 3 min to exhaustion) on a cycle ergometer. At each trial blood lactate concentration was determined at rest and within the final 30 s of each stage. The Rest+1, 2.0 and 4.0 mmol/l markers were determined by interpolation, the D-max and nadir using a quadratic model and the lactate slope index using an exponential plus constant model, and a visual turnpoint was determined empirically. Intraclass correlations and coefficients of variation assessed reproducibility. Power output at all markers differed significantly between subjects, but not between trials. Intraclass correlation coefficients were respectively 0.799, 0.794, 0.807, 0.903, 0.677, 0.769 and 0.648, and corresponding standard errors of measurement 11.9, 9.2, 9.1, 2.5, 9.2, 10.8 and 24.7 W. Statistical powers of detecting a 30 W increment at these markers were 0.30, 0.43, 0.42, 0.98, 0.58, 0.38 and 0.18 respectively. These results indicate that only the D-max marker has good reproducibility and that it alone can identify small but meaningful changes in training status with sufficient statistical power.