Kinetics of the human leucocyte Na(+)-H+ antiport in essential hypertension

Many membrane abnormalities have been described in human essential hypertension that may lead to an increased intracellular Na+ content, an example being reduced Na+ efflux by the sodium pump. We have previously found increased Na(+)-H+ antiport activity in leucocytes of hypertensive subjects. In the present study we examined the kinetics of this pump in 16 hypertensive and 20 carefully matched normotensive subjects by loading cells to different intracellular pH levels (as measured by fluorimetry) using a double-ionophore technique. The maximal rate of ethyl isopropyl amiloride-sensitive H+ efflux was significantly raised in leucocytes from the hypertensive subjects [75.3 +/- 6.2 versus 48.8 +/- 2.1 mmol/l per min in normotensives (mean +/- s.e.m.); P less than 0.001]. There was no difference in the affinity of the Na(+)-H+ antiport for intracellular H+. Intracellular buffering power at different internal pH levels in the range 6.0-7.1 did not differ in the two groups. We conclude that one reason for the reported intracellular alkalinity and increased sodium content of leucocytes from hypertensive subjects in bicarbonate-free media could be an increased number of active Na(+)-H+ exchangers or an increased turnover rate for each exchanger. A similar defect in vascular smooth muscle could account for the increased tone and thickening of the media. The abnormal maximal transport capacity of the leucocyte may be a useful membrane marker for future studies in human hypertension.     

Increased sympathetic nervous activity and the effects of its inhibition with clonidine in alcoholic cirrhosis.

OBJECTIVE: To study disturbances in sympathetic nervous system function in patients with alcoholic cirrhosis and the effect of clonidine on such disturbances. DESIGN: Cross-sectional physiologic and neurochemical evaluation of patients with cirrhosis and of healthy controls; an uncontrolled trial of intravenous clonidine in the cirrhotic patients. PATIENTS: Forty-four hospitalized patients with biopsy-proven alcoholic cirrhosis and 31 healthy controls. INTERVENTIONS: Intravenous clonidine. MAIN OUTCOME MEASURES: Radiotracer-derived measures of norepinephrine release to plasma, central hemodynamics, wedge hepatic vein pressure, and measures of renal function. MAIN RESULTS: In patients with cirrhosis, clonidine reduced previously elevated norepinephrine overflow rates for the whole body, kidneys, and hepatomesenteric circulation. This sympathetic inhibition was accompanied by the following potentially clinically beneficial effects: the lowering of renal vascular resistance (median reduction, 24%; 95% CI, 14% to 31%), the elevation of glomerular filtration rate (median increase, 27%; CI, 14% to 39%), and the reduction of portal venous pressure (median reduction, 25%; CI, 18% to 32%). The norepinephrine and hemodynamic responses to graded clonidine dosing (1, 2, and 3 micrograms/kg body weight intravenously) indicated that the sympathetic outflow to the hepatomesenteric circulation was more sensitive to pharmacologic suppression with clonidine than was the sympathetic outflow to the systemic circulation. CONCLUSIONS: The sympathetic nerves to the kidneys, heart, and hepatomesenteric circulation are stimulated in patients with cirrhosis. Clonidine inhibits these activated sympathetic outflows differentially, which could possibly provide a basis for the selective pharmacologic treatment of portal hypertension in patients with cirrhosis.     

New developments in the medical management of overactive bladder

Overactive bladder (OAB) is a clinical syndrome describing the symptom complex of urgency, with or without urgency incontinence and is usually associated with frequency and nocturia. Whilst the majority of women will benefit from initial management with conservative and behavioural intervention a significant number will require medical therapy. Antimuscarinics are currently the most widely prescribed drugs for OAB although very often persistence with medication is limited due to lack of efficacy or intolerable adverse effects.     

Inflamed tumor-associated adipose tissue is a depot for macrophages that stimulate tumor growth and angiogenesis

Tumor-associated stroma is typified by a persistent, non-resolving inflammatory response that enhances tumor angiogenesis, growth and metastasis. Inflammation in tumors is instigated by heterotypic interactions between malignant tumor cells, vascular endothelium, fibroblasts, immune and inflammatory cells. We found that tumor-associated adipocytes also contribute to inflammation. We have analyzed peritumoral adipose tissue in a syngeneic mouse melanoma model. Compared to control adipose tissue, adipose tissue juxtaposed to implanted tumors exhibited reduced adipocyte size, extensive fibrosis, increased angiogenesis and a dense macrophage infiltrate. A mouse cytokine protein array revealed up-regulation of inflammatory mediators including IL-6, CXCL1, MCP-1, MIP-2 and TIMP-1 in peritumoral versus counterpart adipose tissues. CD11b(+) macrophages contributed strongly to the inflammatory activity. These macrophages were isolated from peritumoral adipose tissue and found to over-express ARG1, NOS2, CD301, CD163, MCP-1 and VEGF, which are indicative of both M1 and M2 polarization. Tumors implanted at a site distant from subcutaneous, anterior adipose tissue were strongly growth-delayed, had fewer blood vessels and were less populated by CD11b(+) macrophages. In contrast to normal adipose tissue, micro-dissected peritumoral adipose tissue explants launched numerous vascular sprouts when cultured in an ex vivo model. Thus, inflamed tumor-associated adipose tissue fuels the growth of malignant cells by acting as a proximate source for vascular endothelium and activated pro-inflammatory cells, in particular macrophages.     

Low-Frequency Fatigue in Individuals With Spinal Cord Injury

Abstract

Background/Objective: This study examined magnitude and recovery of low-frequency fatigue (LFF) in the quadriceps after electrically stimulated contractions in spinal cord-injured (SCI) and able-bodied subjects.

Subjects: Nine SCI (ASIA A-C, levels C5-T9, injured 13.6 ± 12.2 years) and 9 sedentary able-bodied subjects completed this study.

Methods: Fatigue was evoked in 1 thigh, and the nonfatigued leg served as a control. The fatigue test for able-bodied subjects lasted 15 minutes. For SCI, stimulation was adjusted so that the relative drop in force was matched to the able-bodied group. Force was assessed at 20 (P20) and 100 Hz (PI 00), and the ratio of P20/P100 was used to evaluate LFF in thighs immediately after, at 10, 20, and 60 minutes, and at 2, 4, 6, and 24 hours after a fatigue test.

Results: The magnitude of LFF (up to 1 hour after fatigue) was not different between able-bodied and patients with SCI. However, recovery of LFF over 24 hours was greater in able-bodied compared with patients with SCI in both the experimental (P < 0.001) and control legs (P < 0.001). The able-bodied group showed a gradual recovery of LFF over time in the experimental leg, whereas the SCI group did not.

Conclusions: These results show that individuals with SCI are more susceptible to LFF than able-bodied subjects. In SCI, simply assessing LFF produced considerable LFF and accounted for a substantial portion of the response. We propose that muscle injury is causing the dramatic LFF in SCI, and future studies are needed to test whether “fatigue” in SCI is actually confounded by the effects of muscle injury.