A new paradigm for alcohol use in older persons

BACKGROUND: Current paradigms for conceptualizing alcohol-related problems typically focus on persons who are abusing or dependent on alcohol. These paradigms may not apply to older drinkers whose alcohol use, regardless of consumption-level, can cause problems because of age-related changes in physiology and interactions with increased morbidity, medication use, and functional limitations. OBJECTIVE: We convened an expert panel# to develop clinical indications of harmful, hazardous, and nonhazardous drinking in persons 65 years of age and older. RESEARCH DESIGN AND SUBJECTS: Nine panelists with expertise in psychiatry, geriatrics, internal medicine, and alcohol research were provided with epidemiological data and a published explicit literature review of alcohol use in the elderly. The RAND/UCLA two-round panel method was used to develop the indications. After the second round, the authors wrote a draft statement that was circulated to the panelists whose comments were incorporated into a final document. RESULTS: Panelists agreed on 215 scenarios in which older peoples' use of alcohol either alone or in the presence of chronic medical conditions, medication use, symptoms, smoking, and functional limitations are hazardous or harmful. Panelists' ratings of risk did not differ significantly between persons aged 65 to 74 years and those aged 75 years and older. CONCLUSION: Alcohol use may be hazardous or harmful for older persons, particularly in conjunction with physical or emotional illnesses, medication use, functional limitations, smoking, and driving after drinking. When asking about alcohol use in older persons, clinicians need to be aware of these factors to assist in identifying and managing potential or actual alcohol-related problems.     

Sex differences in renal transplantation in Canada

To determine if a patient's sex influences access to renal transplantation in Canada, transplant recipient data for first cadaveric unrelated renal transplants were obtained from the Canadian Organ Replacement Register (CORR) for the period 1985-1992. There were 4683 first unrelated cadaveric transplant recipients during this time. Differences in the proportion of men and women registered with CORR who received a renal transplant were analyzed. In Canada between 1985 and 1992, 25% of males 40 years and older on dialysis received renal transplants compared with 18% of females (p < 0.0001, RR 1.54, 95% CI 1.40-1.67). There was no difference in the rates of transplants in males and females who were under 40 years of age. Adjusting for panel-reactive antibody data did not change the significance of the difference in transplant rates between the sexes. In Canada from 1985 to 1992, male patients with end-stage renal disease received proportionately more transplants than females.     

Mechanisms contributing to the deficits in hippocampal synaptic plasticity in mice lacking amyloid precursor protein

Abnormal processing of amyloid precursor protein (APP), in particular the generation of beta-amyloid (Abeta) peptides, has been implicated in the pathogenesis of Alzheimer's disease. This study examined the consequences of deleting the APP gene on hippocampal synaptic plasticity, and upon the biophysical properties of morphologically identified neurones in APP-null mice. The hippocampus of APP-null mice had a characteristic increase in gliosis throughout the CA1 region and a disruption of staining for the dendritic marker MAP2 and the presynaptic marker synaptophysin. The disruption of MAP2 staining was associated with a significant reduction in overall dendritic length and projection depth of biocytin labeled CA1 neurones. In two groups of APP-null mice that were examined at 8-12 months, and 20-24 months of age, there was an impairment in the formation of long-term potentiation (LTP) in the CA1 region compared to isogenic age matched controls. This LTP deficit was not associated with an alteration in the amplitude of EPSPs at low stimulus frequencies (0.033 Hz) or facilitation during a 100 Hz stimulus train, but was associated with a reduction in post-tetanic potentiation. Paired-pulse depression of GABA-mediated inhibitory post-synaptic currents was also attenuated in APP-null mice. These data demonstrate that the impaired synaptic plasticity in APP deficient mice is associated with abnormal neuronal morphology and synaptic function within the hippocampus.     

Evaluation of the efficacy, safety and physiological effects of fluvoxamine in social phobia

There is no US Food and Drug Administration (FDA) approved treatment for social phobia although data suggest efficacy for several drug classes, including beta-blockers, benzodiazepines, monoamine oxidase inhibitors, and selective serotonin reuptake inhibitors (SSRIs). The SSRIs are particularly attractive due to their favourable tolerance and safety profile. An open label trial of fluvoxamine was conducted to evaluate its efficacy and safety in the treatment of social phobia (DSM-III-R) and to assess physiological changes that may accompany treatment. Fifteen non-depressed patients, aged 22-44 years (mean 31.6 years), entered the study. A 5-min performance task (public speaking simulation) preceded and concluded the active treatment period. Cardiovascular monitoring was performed during this time and blood sampled for plasma cortisol and steady-state plasma fluvoxamine concentration (at week 7). Ten patients (5 men and 5 women) completed an active 6 week treatment period of flexible dosing (50-150 mg/day). Five patients failed to complete the study due to drowsiness (n = 2), nausea (n = 1), or were lost to follow-up (n = 2). Analysis of clinical ratings indicated a statistically significant decrease in all scales from baseline to week 7 at the conclusion of the active treatment period. Clinical benefits were still evident at follow-up 1 week after drug discontinuation. Neither physiological effects nor plasma drug concentration correlated with clinical change. Fluvoxamine appeared to be effective and well tolerated in completers. Randomized clinical trials are needed to further demonstrate the efficacy of fluvoxamine in the treatment of social phobia.     

COL1A2 and COL2A1 expression in temporal bone of lethal osteogenesis imperfecta

OBJECTIVE: COL1A2 and COL2A1 genes are expressed at high levels in many cochlear cells of 16- to 23-week-old human fetuses. Given these prior observations and the rare opportunity to obtain temporal bones from a deceased neonate with osteogenesis imperfecta (OI) type II, we determined the cellular distribution and level of expression of COL1A2 mRNA in OI type II inner ear compared with the expression in second-trimester human fetal cochlea. Expression of COL2A1 mRNA was assessed for its normal role in OI type II neonatal cochlea and to address potential spatial and temporal changes along with our observations in fetal cochlea. We describe our tissue in situ hybridization protocol and document its usefulness in assessing gene expression in human temporal bone obtained at autopsy. DESIGN: RNA-RNA in situ hybridization was performed in formaldehyde-fixed, decalcified, paraffin-embedded temporal bone sections from a neonate with OI type II. Semi-quantitative assessment of gene expression was performed by visual inspection of grain densities. RESULTS AND CONCLUSIONS: COL1A2 and COL2A1 were expressed at moderate-to-high levels in many membranous cochlear cells, and no dramatic alterations in pattern or level of expression of these genes was noted compared with human fetal cochlea. Consistent with in vitro studies, expression of COL1A2 in osteoblasts lining enchondral and endosteal layers is less than that in identical cells of the fetal otic capsule undergoing osteoid deposition and mineralization. Expression of COL1A2 mRNA in osteoblasts lining the outer periosteum of otic capsule is markedly higher than osteoblasts lining enchondral and endosteal layers, suggesting that differential expression may exist between osteoblasts lining endosteal, enchondral, and periosteal surfaces of bone in OI type II.     

The effect of lesions of the sensorimotor cortex and the capsular pathways on servo responses from the human long thumb flexor

Lesions of the sensorimotor cortex, or of the capsular pathways beneath it, caused (with one exception out of 14 cases) diminution "r loss of the servo responses in the thumb, which are based on the long-latency stretch reflex. When not absent the long-latency stretch reflex tended to be late in onset. When absent it was often replaced by a large early reflex response at spinal latency. In general the results are consistent with the transcortical theory of the long-latency stretch reflex for the thumb, but, in detail, they indicate that the theory will require elaboration.     

Chemistry, 13C-NMR Study and Pharmacology of Two Saponins from Colubrina asiatica

From the leaves of COLUBRINA ASIATICA B RONGEN (Rhamnaceae) two saponins have been isolated and structurally elucidated, mainly by (13)C-NMR-spectroscopic methods, as jujubogenin-3-O-[2-O-acetyl-3-O-(3-O-beta-D-xylopyranosyl-4-O-acetyl-beta-D-glucopyranosyl)-alpha-L-arabinoside] (colubrinoside) and jujubogenin-3-O- [2-O-acetyl -3-O- (2-O- beta -D- xylopyranosyl-beta-D-glucopyranosyl)-alpha-L-arabinoside] (colubrin) respectively. Both saponins inhibit the spontaneous motility of mice, even at low doses (1 mg/ kg), they show an antagonistic effect on amphetamine and exert a synergistic activity on chlordiazepoxide.     

Following in the right footsteps

An initiative which targets resources towards chiropody patients with the greatest needs has been taking place in Nottinghamshire during the past three years. Ian Morton and Peter Pratt describe its progress and outline its new goals.     

Mu and kappa opioid receptor modulation of 5-HT3 and NK-3 receptor-evoked release of acetylcholine from the guinea-pig ileum myenteric plexus

Summary The effects of three different opioid agonists on contractions and [³H]-acetylcholine (ACh) release evoked by 5-hydroxytryptamine₃ (5-HT₃) and neurokinin-3 (NK-3) receptor activation were examined in the guinea-pig ileum longitudinal muscle-myenteric plexus strip (LMMP) preparation. The selective mu ()-opioid receptor agonist (d-Ala²,NMe-Phe⁴,Gly-ol]-enkephalin) (DAMGO; 1 nM–100 nM) and the selective kappa ()-opioid receptor agonist U50488 (10 nM -1 M) inhibited contractile responses to 5-HT and to the selective NK-3 receptor agonist senktide, producing a concentration-related progressive flattening of their concentration-response curves. IC₅₀ estimates for DAMGO and U50488 were somewhat higher for inhibition of 5-HT-evoked as compared to senktide-evoked contractions, and overall lay in the range 6 nM – 51 nM. The selective delta ()-opioid receptor agonist [d-Pen^2,5]-enkephalin (DPDPE) inhibited contractile responses only at the highest concentration used (1 M). ³H-overflow from LMMP preparations preincubated with [³H]-choline was measured as an indicator of [³H]-ACh release. DAMGO (1 nM –100 nM) and U50488 (10 nM -1 M) inhibited the increases in release of [³H]-ACh evoked by 5-HT (10 M) and by senktide (10 nM) in a concentration-dependant manner. IC₅₀ estimates for DAMGO and U50488 were not significantly different for inhibition of 5-HT as compared to senktide-evoked increases in [³H]-ACh release and lay in the range 6 nM –23 nM. DPDPE again only inhibited these responses at the maximum concentration used (1 M). The inhibitory effects of DAMGO, U50488 and DPDPE on contractions and [³H]-ACh release evoked by 5-HT and senktide were completely reversed by naloxone (10 M).These results show that ACh release in the guinea-pig ileum evoked by 5-HT and senktide can be modulated to a similar extent by the opioid agonists DAMGO and U50488, but not by DPDPE. This suggests that the pathways of excitation for 5-HT₃ and NK-3 receptors converge at some level susceptible to opioid inhibition, which may be mediated by - and -, but not -, opioid receptors.