Abstract-Results from animal experimentation suggest a 2-way interaction between leptin and the sympathetic nervous system, with leptin causing sympathetic activation and conversely, with the sympathetic system exercising regulatory feedback inhibition over leptin release. We have now tested this hypothesis in humans. In the absence of results from leptin infusions, to test for sympathetic stimulation of leptin release, we sought a quantitative naturalistic linkage of sympathetic activity with leptin plasma concentration across a broad range of leptin values in men of widely differing adiposity. Renal norepinephrine spillover was correlated with plasma leptin (rϭ0.628, PϽ0.01), but other measures of sympathoadrenal function did not. To test for sympathetic and adrenomedullary inhibition of leptin release, we studied clinical models of high sympathetic tone, heart failure, and essential hypertension, in which lowered plasma leptin levels might have been expected but were not found; a model of low sympathetic activity, pure autonomic failure, in which plasma leptin level was normal (6.1Ϯ1.2 vs 12.8Ϯ3.1 ng/mL in healthy subjects); and a clinical model of reduced epinephrine secretion, healthy aging, in which plasma leptin level again was normal (5.7Ϯ1.1 ng/mL vs 4.0Ϯ0.9 ng/mL in men Ͼ60 years and Ͻ35 years, respectively). Paradoxically, leptin concentration was elevated in heart failure, caused entirely by reduced renal clearance of leptin release, 142.0Ϯ30.5 mL/min, compared with 56.9Ϯ18.9 mL/min (PϽ0.05). These results provide some support for the view that leptin stimulates the sympathetic nervous system, at least for renal sympathetic outflow, but do not confirm the concept of regulatory feedback inhibition of leptin release by the sympathetic nervous system.

Abstract-There is growing evidence that essential hypertension is commonly neurogenic and is initiated and sustained by sympathetic nervous system overactivity. Potential mechanisms include increased central sympathetic outflow, altered norepinephrine (NE) neuronal reuptake, diminished arterial baroreflex dampening of sympathetic nerve traffic, and sympathetic neuromodulation by angiotensin II. To address this issue, we used microneurography and radiotracer dilution methodology to measure regional sympathetic activity in 22 hypertensive patients and 11 normotensive control subjects. The NE transport inhibitor desipramine was infused to directly assess the potential role of impaired neuronal NE reuptake. To evaluate possible angiotensin sympathetic neuromodulation, the relation of arterial and coronary sinus plasma concentrations of angiotensin II to sympathetic activity was investigated. Hypertensive patients displayed increased muscle sympathetic nerve activity and elevated total systemic, cardiac, and renal NE spillover. Cardiac neuronal NE reuptake was decreased in hypertensive subjects. In response to desipramine, both the reduction of fractional transcardiac 3[H]NE extraction and the increase in cardiac NE spillover were less pronounced in hypertensive patients. DNA sequencing analysis of the NE transporter gene revealed no mutations that could account for reduced transporter activity. Arterial baroreflex control of sympathetic nerve traffic was not diminished in hypertensive subjects. Angiotensin II plasma concentrations were similar in both groups and were not related to indexes of sympathetic activation. Increased rates of sympathetic nerve firing and reduced neuronal NE reuptake both contribute to sympathetic activation in hypertension, whereas a role for dampened arterial baroreflex restraint on sympathetic nerve traffic and a peripheral neuromodulating influence of angiotensin II appear to be excluded. Key Words: hypertension, essential Ⅲ catecholamines Ⅲ sympathetic nervous system Ⅲ norepinephrine Ⅲ angiotensin II A lthough there is growing evidence that essential hypertension is commonly neurogenic 1,2 and is initiated and sustained by overactivity of the sympathetic nervous system, the precise causal mechanisms leading to sympathetic augmentation in hypertensive subjects are still poorly understood. Among others, possible mechanisms include increased sympathetic nerve firing rates, 1,2 altered neuronal norepinephrine (NE) reuptake, 3,4 diminished arterial baroreflex buffering of sympathetic nerve traffic, 5 and facilitation of NE release by neurohumoral factors such as angiotensin II. 6 These possibilities, however, have not yet been conclusively tested for in humans.To further address some of these issues, we combined microneurography, to measure sympathetic nerve firing rates, with relevant radiotracer methodology to comprehensively study systemic and regional kinetics of NE and its intraneuronal and extraneuronal metabolites. To directly assess whether decreased neuronal NE reuptake contributes ...

Renal injury due to perinatal asphyxia has not been systematically evaluated. The available studies have used variable definitions, incomplete investigations and none had a control group. The aim of this study was to evaluate systematically the renal functions in severely asphyxiated newborns and to find if abnormal renal function tests can predict adverse outcome (death or neurologic abnormality at discharge). In a prospective case-control design, 25 inborn babies>or=34 weeks gestation having asphyxia (5 min Apgaror=5 min) were enrolled as 'cases'. Simultaneously 25 gestation and weight matched babies with no asphyxia were enrolled as 'controls'. Renal function tests, calculated renal indices using timed urine collections and excretion of beta2-microglobulin and N-acetyl-beta-D-glucosaminidase (NAG) were monitored in both the groups for first 4 days of life. Fourteen (56 per cent) asphyxiated babies had acute renal failure (ARF) as compared to 1 (4 per cent) control (p=0.002). Blood urea and serum creatinine values were significantly higher in asphyxiated babies on day 4 but not on day 2. Renal failure index and FeNa were higher in asphyxiated babies on both day 2 and day 4, but creatinine clearance was not different. Urinary excretion of both beta2-microglobulin and NAG was higher in the asphyxiated babies on day 2 as well as day 4. Five minute Apgar1.5 mg/dl alone had the best specificity and positive predictive value. The renal parameters were however poorer predictors of adverse outcome in comparison to clinical markers like 5 min Apgar

Conclusion:The orally active direct factor Xa inhibitor rivaroxaban appears effective in treatment of proximal deep-vein thrombosis (DVT).Summary: There is a major need for an orally active anticoagulant that does not require long-term monitoring or dose adjustment. A potential anticoagulant meeting those requirements is rivaroxaban . This is an oral direct factor Xa inhibitor currently under clinical development. This study was a parallel-group, randomized, doseranging, phase II trial in patients with proximal DVT. The study was designed to evaluate the safety and efficacy of BAY 59-7939, using doses of 10, 20, or 30 mg twice daily (BID) or 40 mg once daily compared with enoxaparin, 1 mg/kg BID, followed by a vitamin K antagonist. Treatments were administered for 12 weeks. The primary end point was "improvement in thrombotic burden" at 3 weeks. This was assessed by quantitative compression duplex ultrasonography and defined as Ն4point improvement in a thrombus score without recurrent symptomatic DVT or a DVT-related death.The primary efficacy end point was achieved in 53% (53 in 100) patients treated with 10 mg of rivaroxaban. Primary efficacy end points were also achieved in 59.2% (58 of 98), 56.9% (69 of 109), and 43.8% (49 of 112) patients receiving 20 or 30 mg BID or 40 mg once daily of rivaroxaban. In the 109 patients treated with enoxaparin and a vitamin K antagonist, the primary end point was achieved in 45.9% (50 of 109) patients. There was no significant trend in the dose-response relationship between the primary efficacy end point and rivaroxaban BID (P ϭ .67). In the patients receiving 10 or 20 mg of rivaroxaban BID or 40 mg once daily, major bleeding was observed in 1.7%. In the patients receiving 30 mg BID of rivaroxaban, major bleeding occurred in 3.3%. There were no major bleeding events with an enoxaparin and vitamin K antagonist.Comment: This was essentially a phase II proof-of-concept trial of a new oral anticoagulant. Clearly, a safe orally administered anticoagulant that requires no monitoring would be a major step forward. The data justified performance of a larger phase III evaluation. Although the mechanism of action of rivaroxaban is different than ximelagatran, the hepatic toxicity associated with ximelagatran (Drug Safety 2005;28:351-70) mandates intense surveillance for liver toxicity in a phase III study of rivaroxaban.

The short-term application of CPAP results in an inhibition of cardiac sympathetic nervous activity. Further investigation into the potential value of long-term CPAP in CHF patients is warranted.

SummaryWe describe the clinical presentation, diagnostic and management issues in five cases of non-islet cell tumor hypoglycemia (NICTH), diagnosed at a tertiary care institute over a period of 15 years. The clinical, laboratory, and histopathological findings of these patients along with diagnostic utility of IGF2:IGF1 ratio are discussed. The mean age of presentation was 52 years, with a male predominance (3:2). Three patients presented with recurrent episodes of fasting hypoglycemia and it was detected in other two patients during hospitalization. Two patients had acromegaloid features that regressed following treatment. One patient had hypokalemia. Low levels of insulin, C-peptide, GH, and IGF1 were invariably found in all. The IGF2 level was elevated in only one patient; however, IGF2:IGF1 ratio was more than 10 in four of the five patients. The mean tumor size was 16.4 cm and mean weight was 3.6 kg. Four patients had mesenchymal tumors and one had epithelial tumor. NICTH is a rare cause of hypoglycemia. Hypoinsulinemic hypoglycemia with low IGF1 and IGF2:IGF1 ratio more than 10 is suggestive of this entity.Learning points NICTH should be considered in patients presenting with tumor of mesenchymal origin and hypoglycemia.Hypoinsulinemic hypoglycemia with low IGF1 is a strong biochemical evidence of NICTH.IGF2:IGF1 ratio of more than 10 is a complementary investigation in the absence of an assay facility for IGF2.

Peripheral sympathoneural alpha-2 adrenoceptors are functionally important in inhibiting NE release in the healthy human. In heart failure, this function is lost. This finding offers further insights into the mechanisms responsible for high circulating levels of NE in patients with heart failure. In addition, it suggests that selective targeting of peripheral presynaptic alpha-2 adrenoceptors will not achieve sympathoinhibition in heart failure.

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