Evidence supporting a physiological role for proANP-(1-30) in the regulation of renal excretion

The experiments, performed in pentobarbital sodium-anesthetized rats, consisted of a 1-h equilibration period followed by two 30-min control periods. Subsequently, synthetic rat pro atrial natriuretic peptide (ANP) [proANP-(1-30)] (n = 8) was given as a bolus of 10 microg in 1 ml of 0.9% saline followed by an infusion at 30 ng/min (20 microl/min) for six additional periods. Control rats (n = 6) received only 0.45% saline in the appropriate volumes. Mean arterial pressure, renal blood flow, and glomerular filtration rate did not change significantly in either group during the proANP-(1-30) infusion. Urine flow and potassium excretion increased approximately 50% in the proANP-(1-30)-infused group only (P < 0.05). Sodium excretion and fractional excretion of sodium, expressed as the change from their own baselines, were significantly increased by the proANP-(1-30) infusion (P < 0.05), whereas cGMP excretion was similar in both groups. These results suggest that the rat sequence of proANP-(1-30) produces a natriuresis in the rat independent of changes in hemodynamics and renal cGMP production. In a second study, rats (n = 8) were prepared as above and pretreated with 0.4 ml iv of rabbit serum containing an antibody directed against proANP-(1-30) (anti-proANP group). The rats were volume expanded with 3 ml of 6% albumin in Krebs and observed for 3 h to determine if the anti-proANP would attenuate the responses to volume expansion. Control rats (n = 7) received 0.4 ml of normal rabbit serum. The elevation in potassium excretion in response to volume expansion was significantly attenuated in the anti-proANP group (P < 0.05). Sodium excretion and urine flow responses also tended to be reduced but not significantly. These results suggest that in the rat, proANP-(1-30) plays a physiological role in regulating renal excretion.     

A Physiologically-Motivated Compartment-Based Model of the Effect of Inhaled Hypertonic Saline on Mucociliary Clearance and Liquid Transport in Cystic Fibrosis

Background

Cystic Fibrosis (CF) lung disease is characterized by liquid hyperabsorption, airway surface dehydration, and impaired mucociliary clearance (MCC). Herein, we present a compartment-based mathematical model of the airway that extends the resolution of functional imaging data.

Methods

Using functional imaging data to inform our model, we developed a system of mechanism-motivated ordinary differential equations to describe the mucociliary clearance and absorption of aerosolized radiolabeled particle and small molecules probes from human subjects with and without CF. We also utilized a novel imaging metric in vitro to gauge the fraction of airway epithelial cells that have functional ciliary activity.

Results

This model, and its incorporated kinetic rate parameters, captures the MCC and liquid dynamics of the hyperabsorptive state in CF airways and the mitigation of that state by hypertonic saline treatment.

Conclusions

We postulate, based on the model structure and its ability to capture clinical patient data, that patients with CF have regions of airway with diminished MCC function that can be recruited with hypertonic saline treatment. In so doing, this model structure not only makes a case for durable osmotic agents used in lung-region specific treatments, but also may provide a possible clinical endpoint, the fraction of functional ciliated airway.     

Predictors of sprint start speed: the effects of resistive ground-based vs. inclined treadmill training

There is currently no consensus with regard to the most effective method to train for improved acceleration, or with regard to which kinematic variable provides the greatest opportunity for improvement in this important performance characteristic. The purpose of this study was to determine the effects of resistive ground-based speed training and incline treadmill speed training on speed-related kinematic measures and sprint start speed. The hypothesis tested was that incline treadmill training would improve sprint start time, while the ground-based resistive training would not. Corollary hypotheses were that treadmill training would increase stride frequency and ground-based training would not affect kinematics during the sprint start. Thirty-one high school female soccer players (15.7 +/- 0.5 years) were assigned to either treadmill (n = 17) or ground-based (n = 14) training groups and trained 2 times a week for 6 weeks. The treadmill group utilized incline speed training on a treadmill, while the ground-based group utilized partner band resistance ground-based techniques. Three-dimensional motion analysis was used (4.5 m mark) before and after training to quantify kinematics during the fastest of 3 recorded sprint starts (9.1 m). Both groups decreased average sprint start time from 1.75 +/- 0.12 to 1.68 +/- 0.08 seconds (p < 0.001). Training increased stride frequency (p = 0.030) but not stride length. After training, total vertical pelvic displacement and stride length predicted 62% of the variance in sprint start time for the resistive ground-based group, while stride length and stride frequency accounted for 67% prediction of the variance in sprint start time for the treadmill group. The results of this study indicate that both incline treadmill and resistive ground-based training are effective at improving sprint start speed, although they potentially do so through differing mechanisms.     

Complications of Antiretroviral Therapy Initiation in Hospitalised Patients with HIV-Associated Tuberculosis

Background

HIV-associated tuberculosis is a common coinfection in Sub-Saharan Africa, which causes high morbidity and mortality. A sub-set of HIV-associated tuberculosis patients require prolonged hospital admission, during which antiretroviral therapy initiation may be required. The aim of this study was to document the causes of clinical deterioration of hospitalised patients with HIV-associated tuberculosis starting antiretroviral therapy in order to inform healthcare practice in low- to middle-income countries.

Methods

Prospective, observational cohort study of adult inpatients with HIV-associated tuberculosis starting antiretroviral therapy in a dedicated tuberculosis hospital in Cape Town, South Africa. Causes of clinical deterioration and outcome were recorded in the first 12 weeks of antiretroviral therapy. Patients with rifampicin-resistant tuberculosis were excluded.

Results

Between May 2009 and November 2010, 112 patients (60% female), with a median age of 32 years were enrolled. At baseline the median CD4 count was 55 cells/mm³ (IQR 31–106) and HIV viral load 5.6 log copies/mL. All patients had significant comorbidity: 82% were bed-bound, 65% had disseminated tuberculosis and 27% had central nervous system tuberculosis. Seventy six patients (68%) developed 144 clinical events after starting antiretroviral therapy. TB-IRIS, hospital-acquired infections and significant drug toxicities occurred in 42%, 20.5% and 15% of patients respectively. A new opportunistic disease occurred in 15% of patients and a thromboembolic event in 8%. Mortality during the 12 week period was 10.6%.

Conclusions

High rates of TB-IRIS, hospital-acquired infections and drug toxicities complicate the course of patients with HIV-associated tuberculosis starting antiretroviral therapy in hospital. Despite the high morbidity, mortality was relatively low. Careful clinical management and adequate resources are needed in hospitalised HIV-TB patients in the 1^st three months following ART initiation.     

B-type natriuretic peptide decreases gastric emptying and absorption

Natriuretic peptides have been shown to decrease contractility of isolated gastric smooth muscle cells. However there is a paucity of research showing whether this effect has functional significance in the whole animal. The objective of this study was to test whether intravenously administered B-type Natriuretic Peptide (BNP) has an effect on gastric emptying and/or absorption in a whole animal mouse model. C57BL/6-Wild-type (WT) and Natriuretic Peptide Receptor type A (NPR-A) knockout (KO) mice were used in these studies. Gastric contractility was examined in anesthetized mice before and after BNP vs. vehicle injection. Gastric emptying of gavage fed 70 Kilo Dalton (kDa) FITC-dextran and absorption of 4 kDa FITC-dextran were compared in BNP vs. vehicle treated conscious WT and KO mice. BNP decreased gastric contractility (measured in change in intragastric pressure) from 2.26 +/- 0.29 to 1.44 +/- 0.11 mmHg (P < 0.05), pressure returned to 2.08 +/- 0.17 after 5 BNP half-lives (P < 0.05). There was no significant change in the vehicle or KO. BNP also decreased gastric emptying in WT mice compared to vehicle, 87.8 +/- 0.8% vs. 97.3 +/- 1.04% (P < 0.05) and this effect showed a dose-response relationship. In KO mice emptying was 95.8 +/- 0.5% (BNP) vs. 91.7 +/- 0.7% (Vehicle) (P > 0.05). The absorption in WT mice was 28.2 +/- 7.8 (relative fluorescence units) for BNP vs. 91 +/- 25.9 for vehicle (P < 0.05). For KO mice absorption was 64.3 +/- 14.9 for BNP vs. 60.6 +/- 17.4 for vehicle (P > 0.05). The results show that BNP decreases intragastric pressure, emptying and absorption by acting via the NPR-A receptor. We postulate that this effect is aimed at decreasing preload through decreased water and electrolyte absorption from the GI tract and may also be responsible for the symptoms of impaired gastrointestinal function observed in heart failure patients.     

Methionine-oxidized horse heart cytochrome c. III. Ascorbate reduction and the methionine-80-sulfur-iron linkage

The ascorbate reduction of the CT-cytochromes—two chemically generated forms of horse heart cytochrome c, F^III and F^II, with both methionines, 80 and 65, as methionine sulfoxides, no iron-sulfur linkage, and potentiometric and physiological oxidoreduction properties distinct from those of the native protein and one another (J. Pande et al., 1987)—has been investigated using a stopped-flow technique. The reaction was monitored at 550 nm, and studies were conducted in 10 mM phosphate +0.17 M NaCl buffer,pH 7.4. Both CT-cytochromes are reduced by triphasic profiles, a faster and an intermediate ascorbate-dependent reaction and a slow, ascorbate-independent process. Both CT-cytochromes contain three molecular forms in slow equilibrium, two reducing directly by reaction with ascorbate and a third through conversion to one of the reducible forms. Like the reaction of the native protein, the ascorbate dependence of both the rapid and the intermediate process is nonlinear, approaching saturation values at high concentrations. The ascorbate profiles of the pseudo-first-order reduction constants are typical of the model for the reduction reaction of the unmodified protein, binding followed by a first-order reduction reaction (Myer et al., 1980; Myer and Kumar, 1984), but with distinct kinetic parameters, the first-order reduction constants and the protein-ascorbate stability constants. It has been concluded that the functional-conformational differences between the two CT-cytochromes are not operational to any significant extent in the reduction reaction with ascorbate. The methionine-80-sulfur-iron linkage of the protein is not a crucial requirement for the ascorbate reduction of the protein. The mechanism of the reaction in the main is also insensitive to the replacement of Met-80-S from heme coordination and/or the associated conformational-oxidoreduction properties of the protein. Of the two aspects of the reaction, the efficiency of the electron-transfer reaction and the stability of the ascorbate dianion-protein complex, the former is dependent on the integrity of the structural-conformational state of the molecule.