Treating Legg-Perthes Disease

Treatment for Legg-Perthes disease should provide dynamic maintenance of the femoral head in the acetabulum, with the hip in moderate abduction and some internal rotation, and minimize stress of body weight on the avascular femoral head. The trilateral socket hip abduction orthosis accomplishes both goals while allowing the patient to be ambulatory and to participate in normal daily activities.     

Effects of benfluorex on fatty acid and glucose metabolism in isolated rat hepatocytes: from metabolic fluxes to gene expression

The effects of benfluorex and two of its metabolites (S 422-1 and S 1475-1) on fatty acid and glucose metabolic fluxes and specific gene expression were studied in hepatocytes isolated from 24-h fasted rats. Both benfluorex and S 422-1 (0.1 or 1 mmol/l) reduced beta-oxidation rates and ketogenesis, whereas S 1475-1 had no effect. At the same concentration, benfluorex and S 422-1 were more efficient in reducing gluconeogenesis from lactate/pyruvate than S 1475-1. Benfluorex inhibited gluconeogenesis at the level of pyruvate carboxylase (45% fall in acetyl-CoA concentration) and of glyceraldehyde-3-phosphate dehydrogenase (decrease in ATP/ADP and NAD(+)/NADH ratios). Accordingly, neither benfluorex nor S 422-1 inhibited gluconeogenesis from dihydroxyacetone, but both stimulated gluconeogenesis from glycerol. In hepatocytes cultured in the presence of benfluorex or S 422-1 (10 or 100 micromol/l), the expression of genes encoding enzymes of fatty acid oxidation (carnitine palmitoyltransferase [CPT] I), ketogenesis (hydroxymethylglutaryl-CoA synthase), and gluconeogenesis (glucose-6-phosphatase, PEPCK) was decreased, whereas mRNAs encoding glucokinase and pyruvate kinase were increased. By contrast, Glut-2, acyl-CoA synthetase, and CPT II gene expression was not affected by benfluorex or S 422-1. In conclusion, this work suggests that benfluorex mainly via S 422-1 reduces gluconeogenesis by affecting gene expression and metabolic status of hepatocytes.     

Activity and functional significance of the renal kallikrein-kinin-system in polycystic kidney disease of the rat

Activity and functional significance of the renal kallikrein-kinin-system in polycystic kidney disease of the rat.BACKGROUND: The kallikrein-kinin-system is a complex multienzymatic system that has been implicated in the control of systemic blood pressure, glomerular filtration rate, and proteinuria. The present study investigated its functional role in rat polycystic kidney disease (PKD), which is characterized by progressive renal failure and proteinuria in the absence of systemic hypertension and stimulated renin-angiotensin-system.METHODS: Kallikrein and bradykinin levels were measured in plasma and urine of rats with polycystic kidneys and compared to non-affected controls (SD) and rats with reduced renal mass. The functional relevance of the kallikrein-kinin system (KKS) was assessed by the effects of a short-term treatment with either a selective bradykinin (BK) B1-receptor antagonist (des-Arg9-[Leu8]-BK), a B2-receptor antagonist (HOE 140), an angiotensin converting enzyme inhibitor (ramipril), or an angiotensin II-receptor blocker (HR 720) on systemic and renal parameters.RESULTS: Urine levels of kallikrein were increased threefold in 9-month-old PKD, and BK excretion was increased tenfold in 3-month and 30-fold in 9-month-old PKD compared to age-matched SD rats. Blood pressure in 9-month-old PKD rats was decreased to the same degree by ramipril and HR 720. In contrast, only ramipril and HOE 140 significantly reduced proteinuria and albuminuria, independent from creatinine clearance. This effect was accompanied by an increased excretion of bradykinin. The B1 receptor antagonist had no influence on functional renal parameters.CONCLUSIONS: The present study demonstrates an age-dependent activation of the renal KKS in rats with polycystic kidney disease. The bradykinin B2-receptor is involved in the pathogenesis of proteinuria, independent from systemic blood pressure or creatinine clearance. The antiproteinuric effect of ramipril in this model is angiotensin II-independent and related to its influence on the renal KKS.     

Aortic arch reconstruction with pulmonary autograft patch aortoplasty

OBJECTIVE: The optimal technique for aortic arch reconstruction through median sternotomy is still under debate. We have introduced the technique of pulmonary autograft patch aortoplasty as a reliable alternative. METHODS: The outcomes of 51 infants who underwent neonatal repair of interrupted aortic arch (n = 28) or coarctation associated with ventricular septal defect (n = 23) since 1992 were analyzed. The patients were reviewed in three groups according to the aortic arch reconstruction technique: group I underwent direct anastomosis (n = 23), group II underwent homograft or pericardial patch aortoplasty (n = 8), and group III underwent pulmonary autograft patch aortoplasty (n = 20). The pulmonary autograft patch consisted in the anterior wall of the main pulmonary artery, between the supracommissural level and the divided ductus arteriosus. The created defect was replaced with fresh autologous pericardium. RESULTS: All patients except 1 were discharged without significant residual gradient at the level of the aortic arch. At a median delay of 7 months (range 2-51 months), 11 patients (22%) had recurrence of arch obstruction and underwent balloon angioplasty (n = 8) or surgical correction (n = 3). One patient who had undergone direct anastomosis required reoperation for bronchial compression. At a median follow-up of 29 months, the actuarial freedoms from recurrent arch obstruction were 81% for direct anastomosis, 28% for homograft or pericardial patch aortoplasty, and 100% for pulmonary autograft aortoplasty (P =.03 for group III vs group I and P <.0001 for group III vs group II). CONCLUSIONS: The aortic arch repair associated with pulmonary autograft patch augmentation resulted in superior midterm outcomes and therefore constitutes a reliable alternative to the direct anastomosis technique. It allowed complete relief of anatomic afterload and diminished the anastomotic tension, thus reducing the risk of restenosis and tracheobronchial compression. We observed a significantly higher rate of recurrence after patch aortoplasty with other materials.     

Total transvaginal mesh (TVM) technique for treatment of pelvic organ prolapse: a 3-year prospective follow-up study

Introduction and hypothesis

To evaluate clinical outcomes at 3 years following total transvaginal mesh (TVM) technique to treat vaginal prolapse.

Methods

Prospective, observational study in patients with prolapse ≥stage II. Success was defined as POP-Q-stage 0-I and absence of surgical re-intervention for prolapse. Secondary outcome measures were: quality of life (QOL), prolapse-specific inventory (PSI), impact on sexual activity and complications.

Results

Ninety women underwent TVM repair, 72 a hysterectomy. Anatomical failure rate was 20.0% at 3 years. Three patients required re-intervention for prolapse. Improvements in QOL- and PSI-scores were observed at 1 and 3 years. Vaginal mesh extrusion occurred in 14.4% patients. After 3 years, 4.7% asymptomatic extrusions remained present. Of 61 sexually active women at baseline, a significant number of patients (41%) ceased sexual activity by 3 years; de novo dyspareunia was reported by 8.8%. One vesico-vaginal fistula resolved after surgery.

Conclusion

Medium-term results demonstrate that the TVM technique provides a durable prolapse repair.     

Ventromedial Hypothalamic Nitric Oxide Production Is Necessary for Hypoglycemia Detection and Counterregulation

OBJECTIVE

The response of ventromedial hypothalamic (VMH) glucose-inhibited neurons to decreased glucose is impaired under conditions where the counterregulatory response (CRR) to hypoglycemia is impaired (e.g., recurrent hypoglycemia). This suggests a role for glucose-inhibited neurons in the CRR. We recently showed that decreased glucose increases nitric oxide (NO) production in cultured VMH glucose-inhibited neurons. These in vitro data led us to hypothesize that NO release from VMH glucose-inhibited neurons is critical for the CRR.

RESEARCH DESIGN AND METHODS

The CRR was evaluated in rats and mice in response to acute insulin-induced hypoglycemia and hypoglycemic clamps after modulation of brain NO signaling. The glucose sensitivity of ventromedial nucleus glucose-inhibited neurons was also assessed.

RESULTS

Hypoglycemia increased hypothalamic constitutive NO synthase (NOS) activity and neuronal NOS (nNOS) but not endothelial NOS (eNOS) phosphorylation in rats. Intracerebroventricular and VMH injection of the nonselective NOS inhibitor N^G-monomethyl-l-arginine (l-NMMA) slowed the recovery to euglycemia after hypoglycemia. VMH l-NMMA injection also increased the glucose infusion rate (GIR) and decreased epinephrine secretion during hyperinsulinemic/hypoglycemic clamp in rats. The GIR required to maintain the hypoglycemic plateau was higher in nNOS knockout than wild-type or eNOS knockout mice. Finally, VMH glucose-inhibited neurons were virtually absent in nNOS knockout mice.

CONCLUSIONS

We conclude that VMH NO production is necessary for glucose sensing in glucose-inhibited neurons and full generation of the CRR to hypoglycemia. These data suggest that potentiating NO signaling may improve the defective CRR resulting from recurrent hypoglycemia in patients using intensive insulin therapy.Intensive insulin therapy significantly reduces the onset and progression of hyperglycemia-related complications in patients with type 1 and advanced type 2 diabetes. However, intensive insulin therapy also causes a clinically adverse effect: hypoglycemia (1). Powerful neuroendocrine and autonomic counterregulatory mechanisms protect the brain from hypoglycemia (2,3). These protective mechanisms, known as the counterregulatory response (CRR) to hypoglycemia, involve the release of hormones (e.g., glucagon, epinephrine) that restore euglycemia by stimulating hepatic glucose production and inhibiting peripheral glucose uptake (3). Although the physiology of the CRR is well understood, the underlying cellular mechanisms by which the brain senses hypoglycemia and initiates the CRR remain elusive.During hypoglycemia, central and peripheral glucose sensors detect declining glucose levels (4). In the brain, the ventromedial hypothalamus, which includes the arcuate nucleus and the ventromedial nucleus (VMN), is important in the initiation of the CRR (5–7). This region contains specialized glucose-sensing neurons (GSNs). Ventromedial hypothalamic (VMH) GSN electrical activity is regulated by physiologically relevant changes in extracellular glucose levels (8–11). Glucose-excited neurons decrease, whereas glucose-inhibited neurons increase, their input resistance, membrane potential, and action potential frequency when extracellular glucose is reduced (10). Many studies suggest that VMH glucose-inhibited neurons play a critical role in the control of the CRR (4). For example, the response of VMH glucose-inhibited neurons to decreased glucose is impaired under conditions where the CRR is impaired (e.g., recurrent hypoglycemia) (12,13).Nitric oxide (NO) is a gaseous messenger produced by NO synthase (NOS). Two classes of NOS have been identified in the brain: the inducible NOS (iNOS) and the constitutive NOS, which includes the neuronal NOS (nNOS) and endothelial NOS (eNOS) isoforms (14). Hypothalamic NO is involved in the regulation of food intake and glucose homeostasis (15–18). In support of this, we have recently shown that VMH glucose-inhibited neurons produce NO via nNOS in response to decreased extracellular glucose levels (19,20). Therefore, in this study, we test the hypothesis that NO production by VMH glucose-inhibited neurons is necessary for the CRR to hypoglycemia. We tested this hypothesis using a combination of in vivo and in vitro techniques in wild-type rats and mice as well as in transgenic nNOS and eNOS knockout mice.