A forward genetics screen in mice identifies recessive deafness traits and reveals that pejvakin is essential for outer hair cell function.
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Deafness is the most common form of sensory impairment in the human population and is frequently caused by recessive mutations. To obtain animal models for recessive forms of deafness and to identify genes that control the development and function of the auditory sense organs, we performed a forward genetics screen in mice. We identified 13 mouse lines with defects in auditory function and six lines with auditory and vestibular defects. We mapped several of the affected genetic loci and identified point mutations in four genes. Interestingly, all identified genes are expressed in mechanosensory hair cells and required for their function. One mutation maps to the pejvakin gene, which encodes a new member of the gasdermin protein family. Previous studies have described two missense mutations in the human pejvakin gene that cause nonsyndromic recessive deafness (DFNB59) by affecting the function of auditory neurons. In contrast, the pejvakin allele described here introduces a premature stop codon, causes outer hair cell defects, and leads to progressive hearing loss. We also identified a novel allele of the human pejvakin gene in an Iranian pedigree that is afflicted with progressive hearing loss. Our findings suggest that the mechanisms of pathogenesis associated with pejvakin mutations are more diverse than previously appreciated. More generally, our findings demonstrate that recessive screens in mice are powerful tools for identifying genes that control the development and function of mechanosensory hair cells and cause deafness in humans, as well as generating animal models for disease. (+info)
Prolonged postoperative altered mental status after methylene blue infusion during parathyroidectomy: a case report and review of the literature.
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Methylene blue (5 mg/kg) is routinely given at our institution during parathyroidectomy. The dye stains the parathyroid glands and helps in better surgical visualisation. The technique is generally considered to be safe except for causing pseudo-cyanosis. We report a case of a patient who had confusion, agitation and altered mental status during the early postoperative course probably secondary to methylene blue infusion. (+info)
Hair manganese and hyperactive behaviors: pilot study of school-age children exposed through tap water.
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BACKGROUND: Neurotoxic effects are known to occur with inhalation of manganese particulates, but very few data are available on exposure to Mn in water. We undertook a pilot study in a community in Quebec (Canada) where naturally occurring high Mn levels were present in the public water system. Our objective was to test the hypothesis that greater exposure to Mn via drinking water would be reflected in higher Mn content in hair which, in turn, would be associated with increased level of hyperactive behaviors. METHODS: Forty-six children participated in the study, 24 boys and 22 girls, 6-15 years of age (median, 11 years). Their homes received water from one of two wells (W) with different Mn concentrations: WI: mean 610 microg/L; W2: mean 160 microg/L. The Revised Conners' Rating Scale for parents (CPRS-R) and for teachers (CTRS-R) were administered, providing T-scores on the following subscales: Oppositional, Hyperactivity, Cognitive Problems/Inattention, and ADHD Index. RESULTS: Children whose houses were supplied by WI had higher hair Mn (MnH) than those supplied by W2 (mean 6.2+/-4.7 microg/g vs. 3.3+/-3.0 microg/g, p = 0.025). MnH was significantly associated with T-scores on the CTRS-R Oppositional (p = 0.020) and Hyperactivity (p = 0.002) subscales, after adjustment for age, sex, and income. All children with Oppositional and Hyperactivity T-scores > 65 had MnH > 3.0 microg/g. CONCLUSIONS: The findings of this pilot study are sufficiently compelling to warrant more extensive investigations into the risks of Mn exposure in drinking water. (+info)
The acetylcholinesterase inhibitor galantamine inhibits d-amphetamine-induced psychotic-like behavior in Cebus monkeys.
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Cholinergic receptors (AChR) are reported altered in brains from schizophrenic patients, and a growing body of evidence suggests that muscarinic receptor agonists exhibit antipsychotic potential. Centrally acting selective muscarinic receptor agonists are currently not available for clinical use, but acetylcholinesterase (AChE) inhibitors, which indirectly stimulate AChR by blocking the breakdown of acetylcholine by AChE, are widely used in the clinic against Alzheimer's disease. AChE inhibitors have been reported to exhibit antipsychotic efficacy in Alzheimer's disease patients, and these compounds have also been investigated as adjunctive treatment to antipsychotic medication in schizophrenic patients with varying results. However, monotherapy with AChE inhibitors in schizophrenic patients has not been evaluated. We wanted to investigate the antipsychotic potential of the AChE inhibitor galantamine, which also allosterically potentiates nicotinic receptor stimulation. To this end, we investigated its ability to antagonize d-amphetamine-induced psychotic-like behavior in extrapyramidal side effects (EPS)-primed Cebus monkeys. Galantamine inhibited d-amphetamine-induced unrest, arousal, and stereotypy. Side effects such as emesis, sedation, and EPS were minor or not existing. The results indicate that AChE inhibitors have antipsychotic potentials and suggest that clinical trials investigating antipsychotic effects of AChE inhibitors as monotherapy would be of interest. (+info)
Oral clonidine vs midazolam in the prevention of sevoflurane-induced agitation in children. a prospective, randomized, controlled trial.
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BACKGROUND: This randomized, double-blind study tested the hypothesis that, in comparison with midazolam, premedication with oral clonidine reduces the incidence of emergence agitation in preschool children anaesthetized with sevoflurane. METHODS: Sixty-eight ASA I-II children undergoing circumcision were randomized into three groups to receive different oral premedication given 30 min before anaesthesia: midazolam 0.5 mg kg-1, clonidine 2 microg kg-1, and clonidine 4 microg kg-1. Sevoflurane anaesthesia was administered via a facemask (O2/N2O: 40/60). Analgesia was with penile block (bupivacaine 0.5% 0.3 ml kg-1) and rectal paracetamol (30 mg kg-1). During the first postoperative hour, children were evaluated using a modified 'objective pain scale'. RESULTS: Only the 4 microg kg-1 dose of clonidine was associated with a significant reduction in emergence agitation. Fewer children in the clonidine 4 microg kg-1 group displayed agitation (25%) than in the midazolam group (60%) (P=0.025). Incidence of hypotension and bradycardia, time to first micturition and first drink did not differ among groups. CONCLUSIONS: In comparison with midazolam, clonidine 4 microg kg-1 reduced sevoflurane-induced emergence agitation without increasing postoperative side-effects. (+info)
Clinical review: agitation and delirium in the critically ill--significance and management.
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Agitation is a psychomotor disturbance characterized by a marked increase in motor and psychological activity in a patient. It occurs very frequently in the intensive care setting. It may be isolated, or accompanied by other mental disorders, such as severe anxiety and delirium. Frequently, agitation is a sign of brain dysfunction and, as such, may have adverse consequences, for at least two reasons. First, agitation can interfere with the patient's care and second, there is evidence demonstrating that the prognosis of agitated (and delirious) patients is worse than that of non-agitated (non-delirious) patients. These conditions are often under-diagnosed in the intensive care unit (ICU). Consequently, a systematic evaluation of this problem in ICU patients should be conducted. Excellent tools are presently available for this purpose. Treatment, including prevention, must be undertaken without delay, and the ICU physician should follow logical, strict and systematic rules when applying therapy. (+info)
Light treatment for neuropsychiatric behaviors in Alzheimer's disease.
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Neuropsychiatric behaviors are common in people with Alzheimer's disease (AD) and make both professional and lay caregiving difficult. Light therapy has been somewhat successful in ameliorating disruptive behaviors. This randomized trial tested the effects of morning or afternoon bright light exposure compared with usual indoor light on the presence, frequency, severity, and occupational disruptiveness of neuropsychiatric behaviors in nursing home residents with AD. Light was administered for 1 hr daily (Monday-Friday) for 10 weeks. The Neuropsychiatric Inventory-Nursing Home was used to assess behavior at baseline and end of the intervention. Analyses revealed statistically significant differences between groups on agitation/aggression, depression/dysphoria, aberrant motor behavior, and appetite/eating disorders. The magnitude of change was small and may not represent clinically significant findings. Agitation/aggression and nighttime behaviors commonly occurred and were highly correlated with occupational disruptiveness. Interventions that decrease the presence and/or severity of neuropsychiatric behaviors have the potential to significantly decrease caregiver burden. (+info)
Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: the Cache County Study.
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BACKGROUND: Neuropsychiatric symptoms are nearly universal in dementia, yet little is known about their longitudinal course in the community. OBJECTIVE: To estimate point and 5-year period prevalence of neuropsychiatric symptoms in an incident sample of 408 dementia participants from the Cache County Study. METHODS: The Neuropsychiatric Inventory assessed symptoms at baseline and at 1.5 years, 3.0 years, 4.1 years, and 5.3 years. Point prevalence, period prevalence and mean symptom severity at each time point were estimated. RESULTS: Point prevalence for delusions was 18% at baseline and 34-38% during the last three visits; hallucinations, 10% at baseline and 19-24% subsequently; agitation/aggression fluctuated between 13% and 24%; depression 29% at baseline and 41-47% subsequently; apathy increased from 20% at baseline to 51% at 5.3 years; elation never rose above 1%; anxiety 14% at baseline and 24-32% subsequently; disinhibition fluctuated between 2% and 15%; irritability between 17% and 27%; aberrant motor behavior gradually increased from 7% at baseline to 29% at 5.3 years. Point prevalence for any symptom was 56% at baseline and 76-87% subsequently. Five-year period prevalence was greatest for depression (77%), apathy (71%), and anxiety (62%); lowest for elation (6%), and disinhibition (31%). Ninety-seven percent experienced at least one symptom. Symptom severity was consistently highest for apathy. CONCLUSIONS: Participants were most likely to develop depression, apathy, or anxiety, and least likely to develop elation or disinhibition. Give converging evidence that syndromal definitions may more accurately capture neuropsychiatric co-morbidity in dementia, future efforts to validate such syndromes are warranted. (+info)