Nitric oxide (NO) has been implicated in the pathogenesis of renal hemodynamic changes in diabetes mellitus. However, the contribution of nitric oxide synthase (NOS) isoforms to intrarenal production of NO in diabetes remains unknown. To explore the role of NOS1 in the control of renal hemodynamics in diabetes, we assessed renal responses to inhibition of NOS1 with S-methyl-L-thiocitrulline (SMTC; administered into the abdominal aorta) in moderately hyperglycemic streptozotocin-diabetic rats (D) and their nondiabetic (C) and normoglycemic diabetic counterparts. The contribution of other NOS isoforms was also evaluated by assessing the responses to nonspecific NOS inhibition [N(G)-nitro-L-arginine methyl ester (L-NAME)] in SMTC-treated diabetic rats. The number of NOS1-positive cells in macula densa of D and C kidneys was also evaluated by immunohistochemistry. D rats demonstrated elevated glomerular filtration rate (GFR) compared with C. SMTC (0.05 mg/kg) normalized GFR in D but had no effect in C. SMTC-induced reduction of renal plasma flow (RPF) was similar in C and D. Normoglycemic diabetic rats demonstrated blunted renal hemodynamic responses to NOS1 inhibition compared with hyperglycemic animals. Mean arterial pressure was stable in all groups. L-NAME induced a further decrease in RPF, but not in GFR, in D rats treated with SMTC. Immunohistochemistry revealed increased numbers of NOS1-positive cells in D. These observations suggest that NOS1-derived NO plays a major role in the pathogenesis of renal hemodynamic changes early in the course of diabetes. NOS1 appears to be the most important isoform in the generation of hemodynamically active NO in this condition.

Objective We examined early speech and language development in children who had cerebral palsy. Questions addressed whether children could be classified into early profile groups on the basis of speech and language skills and whether there were differences on selected speech and language measures among groups. Methods Speech and language assessments were completed on 27 children with CP who were between the ages of 24-30 months (mean age 27.1 months; SD 1.8). We examined several measures of expressive and receptive language, along with speech intelligibility. Results 2-step cluster analysis was used to identify homogeneous groups of children based on their performance on the 7 dependent variables characterizing speech and language performance. Three groups of children identified were those not yet talking (44% of the sample); those whose talking abilities appeared to be emerging (41% of the sample); and those who were established talkers (15% of the sample). Group differences were evident on all variables except receptive language skills. Conclusion 85% of 2 year old children with CP in this study had clinical speech and /or language delays relative to age expectations. Findings suggest that children with CP should receive speech and language assessment and treatment to identify and treat those with delays at or before 2 years of age.

Abstract-Diabetes is associated with alterations in nitric oxide-mediated vasomotor function. The role of nitric oxide generated via the neuronal nitric oxide synthase pathway in the control of systemic and renal hemodynamics in diabetes has not been studied. To explore the hypothesis that diabetic vascular dysfunction is in part caused by altered neuronal nitric oxide synthase activity, systemic and renal hemodynamics were assessed before and after acute inhibition of this enzyme with a specific inhibitor, S-methyl-L-thiocitrulline, in control and diabetic rats. The interaction of this pathway and the renin-angiotensin system was studied in separate groups of rats pretreated with the angiotensin II receptor blocker losartan; these rats were compared with rats treated with losartan alone. Diabetic animals demonstrated higher baseline glomerular filtration rates and filtration fractions. At a low dose, the neuronal nitric oxide synthase inhibitor induced similar dose-dependent pressor responses in control and diabetic rats. Losartan abolished the pressor response in both groups. No changes in renal plasma flow or renal vascular resistance occurred in control rats. In contrast, diabetic rats responded with significant renal vasoconstriction. At a high dose, the renal vasoconstriction was similar in both groups and was not affected by losartan. In conclusion, neuronal nitric oxide synthase-derived nitric oxide plays a role in the control of systemic and renal hemodynamics in normal and diabetic rats. Diabetic rats are more sensitive to the inhibitor, suggesting increased activity of this pathway in the diabetic kidney. Furthermore, renal responses in diabetic rats were attenuated by angiotensin II receptor blockade, whereas losartan alone induced hemodynamic changes that were opposite those seen with neuronal nitric oxide synthase inhibition. This observation implicates angiotensin II as an important modulator of this nitric oxide pathway in diabetes. As recently summarized by Pieper, 1 diabetes and hyperglycemia impair endothelium-dependent vasodilation in various vascular beds, species, and experimental models. This phenomenon may contribute to increased susceptibility to the development of hypertension and vascular complications in diabetic patients. In contrast, early stages of some diabetic complications, such as nephropathy, are accompanied by local hyperperfusion, which has been shown to be, at least in part, NO dependent. [2][3][4] The nature of these local hemodynamic changes has been well studied because of their role in the initiation of the process leading ultimately to organ failure. 5 NO is synthesized as a by-product of conversion of its physiological precursor L-arginine to L-citrulline. 6 This reaction is catalyzed by a family of enzymes known as NO synthase (NOS). 7 In vascular smooth muscle cells, NO activates soluble guanylate cyclase to increase cGMP, resulting in vascular relaxation. 8 Three NOS isoforms (neuronal [nNOS, NOS1], inducible [iNOS, NOS2], and endothelial [eNOS, NOS3]) have been i...

Objective This study aimed to determine the diagnostic utility of clinician speech ratings and patient self-report for detecting early bulbar changes associated with amyotrophic lateral sclerosis (ALS), compared to instrumentation-based speech measures. Methods Thirty-six individuals with ALS and 17 healthy control participants were included. Patients’ awareness of early bulbar motor involvement was assessed using self-reported scores on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R). Clinicians’ detection of early bulbar motor involvement was assessed through perceptual speech ratings by two experienced speech-language pathologists. Participants with ALS were grouped as ‘bulbar pre-symptomatic’ or ‘bulbar symptomatic’ based on self-report and clinician ratings, and compared to healthy controls on six instrumentation-based speech measures. ROC analysis was used to compare the sensitivity and specificity of perceptual and instrumentation-based measures for detecting bulbar changes in pre-symptomatic individuals. Results Early bulbar changes that were documented using instrumentation-based measures were undetected by both patients and clinicians. ROC analyses indicated that instrumentation-based measures outperformed clinicians’ scaled severity ratings, and that percent pause time was the best measure for differentiating healthy controls from bulbar pre-symptomatic individuals with ALS. Conclusions Findings suggested that instrumentation-based measures of speech may be necessary for early detection of bulbar changes due to ALS.