Locomotor activity detects subunit-selective effects of agonists and decahydroisoquinoline antagonists at AMPA/kainic acid ionotropic glutamate receptors in adult rats

Rationale In vitro studies have identified a series of decahydroisoquinoline compounds with differential selectivity for the subunits that comprise AMPA/kainic acid receptors. Compounds have been identified that have preferential activity at AMPA receptors (LY302679), whereas others (LY377770) have affinity for GluR5-kainic acid preferring subunit, which is activated by ATPA and kainic acid.Objectives These studies set out to determine if locomotor activity could differentiate these profiles in vivo.Methods Locomotor activity was assessed in photocell drums in male Lister Hooded rats.Results AMPA, kainic acid and the GluR5 selective agonist ATPA, all suppressed spontaneous locomotor activity (SLA) in rats at doses of 1.0, 5.0 and 20 mg/kg resp. All three agonists achieve micromolar concentrations measured in whole brain after dosing with 10 mg/kg SC. The decahydroisoquinoline antagonist compounds, LY302679 (GluR2), LY293558 (GluR2, 5) and LY377770 (GluR5) all decreased SLA in rats (ED_min 2.5, 5.0 and 20 mg/kg respectively). The rank order of potency at GluR2 subunits (LY302679>LY293558>LY377770) was reflected in the same rank order of activity for suppression of SLA. LY293558 reversed the suppression of SLA induced by all three agonists (0.62–2.5 mg/kg). LY377770 reversed the effects of ATPA only (ED_min 1.0 mg/kg), LY302679 (ED_min 2.5 mg/kg) attenuated the effect of kainic acid but was ineffective against AMPA and ATPA.Conclusions Both agonist and antagonist suppression of SLA is associated with greater affinity for the GluR2 subunit, while compounds with affinity for the GluR5 subunit were less potent in suppressing SLA.     

Urinary Retention,Erectile Dysfunction and Penile Anaesthesia After Circumcision: A Mixed Dissociative (conversion) Disorder

We report on the long-term followup of a mixed dissociative (conversion) disorder after circumcision in childhood.     

Combined helium-3/proton magnetic resonance imaging measurement of ventilated lung volumes in smokers compared to never-smokers

PURPOSE: To use a combination of helium-3 (3-He) magnetic resonance imaging (MRI) and proton single-shot fast spin echo (SSFSE) to compare ventilated lung volumes in groups of "healthy" smokers, smokers diagnosed with moderate chronic obstructive pulmonary disease (COPD), and never-smokers. MATERIALS AND METHODS: All study participants were assessed with spirometry prior to imaging. 3-He images were collected during an arrested breath hold, after inhaling a mixture of 200 mL of hyperpolarized 3-He/800 mL of N2. Proton SSFSE images were acquired after inhaling 1 liter of room air. The ventilated volume for each study participant was calculated from the 3-He images, and a ratio was calculated to give a percentage ventilated lung volume. RESULTS: Never-smokers exhibited a 90% mean ventilated volume. The mean ventilated lung volumes for healthy smokers and smokers diagnosed with COPD were 75.2% and 67.6%, respectively. No correlation with spirometry was demonstrated for either of the smoking groups. CONCLUSION: Combined 3-He/Proton SSFSE MRI of the lungs is a noninvasive method, using nonionizing radiation, which demonstrates ventilated airspaces and enables the calculation of ventilated lung volumes. This method appears to be sensitive to early obstructive changes in the lungs of smokers.     

Congenital adrenal hyperplasia and lower urinary tract symptoms

OBJECTIVES: To assess urinary symptoms in adult women with congenital adrenal hyperplasia (CAH), as feminizing surgery in infancy is current standard practice for CAH and one of the indications for surgery is to reduce urinary symptoms. PATIENTS, SUBJECTS AND METHODS: In a case-control study, 19 women with CAH, of whom 16 had had childhood feminizing genital surgery, and age-matched women with no CAH, were evaluated. Subjects and controls completed the Bristol Female Lower Urinary Tract Symptoms (BFLUTS) questionnaire. RESULTS: Urge incontinence was reported in 13 (68%) patients and three (16%) controls (P = 0.003); stress incontinence was present in 47% and 26%, respectively (P = 0.31). Results from the controls were comparable with those documented in larger studies on normal populations. Nine of the patients felt that their urinary symptoms had an adverse effect on their lives, compared with only one of the controls (P = 0.008). CONCLUSION: Patients with a diagnosis of CAH are more likely to have significant urinary symptoms than normal controls. At present it is not clear whether this is a result of surgery or an effect of CAH. In at least two-thirds of patients surgery did not achieve the objective of reducing urinary symptoms.     

Zinc absorption and kinetics during pregnancy and lactation in Brazilian women

BACKGROUND: Adjustments in zinc absorption and endogenous excretion maintain zinc homeostasis in nonpregnant adults fed low-zinc diets. The effects on zinc homeostasis of a low zinc intake during pregnancy and lactation have not been described in a longitudinal study. OBJECTIVE: We examined longitudinal changes in fractional zinc absorption (FZA) and zinc kinetics in 10 healthy Brazilian women who habitually consumed a marginal zinc diet ( approximately 9 mg Zn/d). DESIGN: Zinc status was measured at 10-12 (early pregnancy; EP) and 34-36 (late pregnancy; LP) wk of pregnancy and at 7-8 wk after delivery (early lactation; EL). Zinc kinetics and FZA were studied by using stable isotopic tracers. RESULTS: Zinc intake averaged 9 +/- 3 mg/d throughout the study. FZA increased from 29 +/- 6% at EP to 43 +/- 10% at LP and to 39 +/- 13% at EL (P < 0.05). FZA was inversely related to plasma zinc at EL (r = -0.73, P = 0.02) and LP (r = -0.72, P = 0.07). Plasma zinc mass was 23% greater at LP than at EP or EL (P < 0.05). The amount of zinc (mg/d) that fluxed between plasma and the most-rapidly-turning-over extravascular pool was 53% greater at LP than at EP or EL (P < 0.05). The zinc flux between plasma and the less-rapidly-turning-over zinc pool at EL was 27% greater than that at EP or LP, but this difference was not significant. CONCLUSIONS: FZA increased significantly in women with marginal zinc intakes during pregnancy and lactation; the increase was higher in women with low plasma zinc. Plasma zinc was distributed into a different exchangeable pool at LP than at EL.     

Does β-amyloid plaque formation cause structural injury to neuronal processes?

The precise role of beta-amyloid plaque formation in the cascade of brain cell changes that lead to neurodegeneration and dementia in Alzheimer's disease has been unclear. Studies have indicated that neuronal processes surrounding and within plaques undergo a series of biochemical and morphological alterations. Morphological alterations include reactive, degenerative and sprouting-related 'dystrophic' neuritic structures, derived principally from axons, which involve specific changes in cytoskeletal proteins such as tau and NF triplet proteins. More compact and fibrous plaques are associated with more extensive neuritic pathology than non-fibrillar, diffuse beta-amyloid deposits. Cortical apical dendritic processes are either 'clipped' by plaque formation or are bent around more compact plaques. Examination of cases of 'pathological' brain ageing, which may represent a preclinical form of Alzheimer's disease, demonstrated that the earliest neuritic pathology associated with plaques was similar to the reactive changes that follow structural injury to axons. In vivo and in vitro experimental models of structural injury to axons produce identical reactive changes that subsequently lead to an attempt at regenerative sprouting by damaged axons. Thus, beta-amyloid plaque formation may cause structural injury to axons that is subsequently followed by an aberrant sprouting response that presages neurodegeneration and dementia. Identification of the key neuronal alterations underlying the pathology of Alzheimer's disease may provide new avenues for therapeutic intervention.