Neuropharmacological characterization of 1-aminocyclopropane-1-carboxylate and 1-aminocyclobutane-1-carboxylate, ligands of the N-methyl-D-aspartate-associated glycine receptor

Following intravenous administration, 1-aminocyclobutane-1-carboxylate (ACBC, 100 mg/kg), a N-methyl-D-aspartate (NMDA)-associated glycine receptor antagonist, was eliminated with a T1/2 of 5 min in mouse brain and 4 min in rat cerebrospinal fluid (CSF). 1-Aminocyclopropane-1-carboxylate (ACC), a NMDA-associated glycine receptor agonist, was found to have a T1/2 of less than 5 min in mouse brain. ACC and ACBC did not alter basal cerebellar cGMP. Glycine and D-serine increased cGMP, and 1-hydroxy-3-aminopyrrolidone-2 (HA-966), a glycine antagonist, reversed the D-serine-induced increases in cGMP. In contrast, ACBC did not reverse the D-serine-induced increases in cGMP. These data suggest that despite their brain bioavailability and marked potency at the glycine receptor in vitro, ACC and ACBC are rapidly inactivated and thus have limited in vivo utility.     

Coeliac haemodynamic effects of endothelin-1, endothelin-3, proendothelin-1 [1-38] and proendothelin-3 [1-41] in conscious rats.

1. Conscious, chronically-instrumented, Long Evans rats were given bolus doses of endothelin-1, endothelin-3 (both at 0.01 and 0.1 nmol kg-1), proendothelin-1 [1-38] and proendothelin-3 [1-41] (both 0.1 and 1 nmol kg-1) in order to compare their effects on coeliac haemodynamics, because it has been reported that, in conscious dogs, endothelin-1 has paradoxical, prolonged hyperaemic vasodilator effects in this vascular bed. Measurements were made also of mesenteric and hindquarters haemodynamics for comparison. In a separate experiment, endothelin-1 (0.1 nmol kg-1) was given before and 20 min after the onset of an infusion of mecamylamine (50 mumol kg h-1) to ensure that the responses measured were not confounded by rapid reflex changes in autonomic activity. 2. None of the peptides caused any increases in coeliac flow or any sustained rises in coeliac vascular conductance, although such changes were clear-cut in the hindquarters vascular bed following the higher dose of endothelin-1 and endothelin-3. In animals treated with mecamylamine the regional haemodynamic effects of the higher dose endothelin-1 were not different from those in animals with intact baroreflexes. 3. Although the lower dose of both endothelin-1 and endothelin-3 caused less marked coeliac, than mesenteric vasoconstriction, this difference was not apparent with the higher dose of the peptides, or with proendothelin-1 [1-38]. However, proendothelin-3 [1-41] had less marked coeliac and hindquarters vasoconstrictor effects than proendothelin-1 [1-38], in spite of both peptides causing similar changes in mesenteric haemodynamics.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diagnosis: Chronic kidney disease, now what!

The occupational health nurse can play an important role in supporting employees with CKD and ESRD by recognizing risk factors such as diabetes and hypertension associated with CKD. The occupational health nurse should encourage compliance with treatment regimens that retard or delay progression of kidney disease into the next stage, especially blood pressure and glucose control. When employees are in need of diagnostic testing, the occupational health nurse can describe the testing procedures such as laboratory values, ultrasounds, and biopsies, and explain the five stages of CKD. The occupational health nurse can assist employees in Stage 4 or 5 CKD in deciding on a treatment option modality that best suits their individual lifestyles, after they have seen a nephrologist and kidney patient educator. In addition, the occupational health nurse can guide employees with difficult lifestyle changes and provide support during the adjustment process. The occupational health nurse also can play a key role in facilitating and coordinating those changes with the renal social worker. Together they can explore available resources, such as the NKF, the American Association of Kidney Patients, and kidneydirections.com. See the Sidebar on pages 295 to 296 for other available resources. Kidney disease can be a devastating diagnosis. Support and education are key to a successful lifestyle transition. Employees who have CKD and work with an occupational health nurse who is informed about their disease and its stages of progression can benefit from educational processes that create informed choices to delay or retard the progression of their renal disease.     

A double blind placebo controlled trial of the calcium entry blocking drug, nicardipine, in the treatment of vasospasm following severe head injury

A double blind, placebo controlled trial of nicardipine in the treatment of high Doppler Flow Velocity (DFV) following severe head injury (Glasgow Coma Score (GSC) less than or equal to 8) was performed. Thirty patients with high DFV (greater than or equal to 100 cm/s for 6 h duration) on transcranial Doppler ultrasound, were treated with nicardipine or placebo for 24 h (2.5 mg/h, increasing in steps of 2.5 mg/h at 2 h intervals (maximum rate 7.5 mg/h) depending on response of DFV). DFV was measured hourly for 24 h and then every 12 h for 2 days. Nicardipine significantly reduced DFV below the threshold of 100 cm/s (16/19 cf placebo 3/11, chi-square p less than 0.001). In the nicardipine treated group maximum DFV was significantly reduced (p less than 0.001) and time with DFV below 100 was significantly longer. Rises in DFV were significantly reduced by the drug if the DFV was normal at the time of entry. High DFV returned on cessation of the infusion. No unexpected or adverse side effects were seen. No clinical benefit was demonstrable.     

Macrophage activation and Fcgamma receptor-mediated signaling do not require expression of the SLP-76 and SLP-65 adaptors

The Src-homology 2 domain-containing, leukocyte-specific phosphoprotein of 76 kDa (SLP-76) is a hematopoietic adaptor that plays a central role during immunoreceptor-mediated activation of T lymphocytes and mast cells and collagen receptor-induced activation of platelets. Despite similar levels of expression in macrophages, SLP-76 is not required for Fc receptor for immunoglobulin G (IgG; FcgammaR)-mediated activation. We hypothesized that the related adaptor SLP-65, which is also expressed in macrophages, may compensate for the loss of SLP-76 during FcgammaR-mediated signaling and functional events. To address this hypothesis, we examined bone marrow-derived macrophages (BMM) from wild-type (WT) mice or mice lacking both of these adaptors. Contrary to our expectations, SLP-76(-/-) SLP-65(-/-) BMM demonstrated normal FcgammaR-mediated activation, including internalization of Ig-coated sheep red blood cells and production of reactive oxygen intermediates. FcgammaR-induced biochemical events were normal in SLP-76(-/-) SLP-65(-/-) BMM, including phosphorylation of phospholipase C and the extracellular signaling-regulated kinases 1 and 2. To determine whether macrophages functioned normally in vivo, we infected WT and SLP-76(-/-) SLP-65(-/-) mice with sublethal doses of Listeria monocytogenes (LM), a bacterium against which the initial host defense is provided by activated macrophages. WT and SLP-76(-/-) SLP-65(-/-) mice survived acute, low-dose infection and showed no difference in the number of liver or spleen LM colony-forming units, a measure of the total body burden of this organism. Taken together, these data suggest that neither SLP-76 nor SLP-65 is required during FcgammaR-dependent signaling and functional events in macrophages.     

LSECtin interacts with filovirus glycoproteins and the spike protein of SARS coronavirus

Cellular attachment factors like the C-type lectins DC-SIGN and DC-SIGNR (collectively referred to as DC-SIGN/R) can augment viral infection and might promote viral dissemination in and between hosts. The lectin LSECtin is encoded in the same chromosomal locus as DC-SIGN/R and is coexpressed with DC-SIGNR on sinusoidal endothelial cells in liver and lymphnodes. Here, we show that LSECtin enhances infection driven by filovirus glycoproteins (GP) and the S protein of SARS coronavirus, but does not interact with human immunodeficiency virus type-1 and hepatitis C virus envelope proteins. Ligand binding to LSECtin was inhibited by EGTA but not by mannan, suggesting that LSECtin unlike DC-SIGN/R does not recognize high-mannose glycans on viral GPs. Finally, we demonstrate that LSECtin is N-linked glycosylated and that glycosylation is required for cell surface expression. In summary, we identified LSECtin as an attachment factor that in conjunction with DC-SIGNR might concentrate viral pathogens in liver and lymph nodes.     

Brief report: cognitive functioning in children with Tourette's syndrome with and without comorbid ADHD

OBJECTIVE: To examine whether patients with Tourette's syndrome (TS) with and without comorbid attention deficit and hyperactivity disorder (ADHD) differ in cognitive functioning and whether a higher level of cognitive functioning is associated with severity of TS symptoms and psychosocial functioning. METHODS: Cognitive functioning, symptom severity, and psychosocial functioning were examined in 40 patients (33 boys, 7 girls; age range 6-18 years) with TS, of whom 17 had the comorbid diagnosis of ADHD. RESULTS: Patients with a comorbid ADHD diagnosis evidenced poorer performance than those with TS alone with respect to severity of TS symptoms, psychosocial functioning, verbal and performance intelligence, and word fluency, but not on tests of cognitive flexibility. Psychosocial functioning was predicted by symptom severity, but not by intelligence or fluency. CONCLUSIONS: Results confirm prior findings that comorbid ADHD is associated with more TS symptoms and worse psychosocial and cognitive functioning, and motivate whether cognitive flexibility plays a role in moderating the deleterious psychosocial effects of Tourette's syndrome and ADHD.     

I Get by with a Little Help from my Family and Friends: Adolescents' Support for Diabetes Care

Evaluated and compared the support provided by family membersand friends for adolescents' diabetes care. Family and friendsupport also were examined in relation to other measures ofsocial support, to demographic variables (age, gender, durationof diabetes) and to adherence. Using a structured interview,74 adolescents with diabetes described the ways that familymembers and friends provided support for diabetes management(insulin shots, blood glucose monitoring, eating proper meals,exercise), and for helping them to "feel good about their diabetes."Families provided more support than friends for three managementtasks (insulin injections, blood glucose monitoring, meals);this support was largely instrumental. In contrast, friendsprovided more emotional support for diabetes than families.Greater family support was related to younger age, shorter diseaseduration, and better treatment adherence. Implications of thefindings include encouraging parents to remain involved in adolescents'treatment management, and involving peers as supportive companionsfor meals and exercise.