Donepezil for the treatment of behavioral symptoms in patients with Alzheimer's disease

Behavioral and psychologic symptoms of dementia (BPSD) are common manifestations in mid- and late-stage Alzheimer's disease (AD). Traditional treatments for BPSD are neuroleptics and sedatives, which are not devoid of serious adverse effects. A number of studies show beneficial effects in the treatment of BPSD with acetylcholinesterase inhibitors (AChEI). The present study aimed to evaluate the effect of donepezil (using the generic drug Memorit) as monotherapy for AD patients suffering from BPSD. Twenty-eight consecutive patients followed at the Memory Outpatient Clinic and Psychogeriatric Department of the Abarbanel Mental Health Center were treated with donepezil for 6 months. Starting dose was 5 mg daily during the first 4 weeks and continuation with 10 mg daily thereafter. Treatment effects were evaluated using the Mini Mental State Examination (MMSE), the Neuro-Psychiatric Inventory (NPI), and the Clinical Global Impression of Change Scale (CGIC) caregiver version. Twenty-four of 28 patients completed the study. Of these, five patients needed additional rescue neuroleptic treatment due to incomplete response. The mean dose of donepezil was 9.10 mg/day (median 10 mg/day). The overall NPI improved significantly from 33.4 to 21.2 (p = 0.008). The mean CGIC at study's end was 3.0 (mild improvement). The cognitive scores did not change significantly. When compared to the patients who completed the study, patients who discontinued had higher mean scores on the irritability and agitation subscales of the NPI, they were older, and they had longer disease duration and lower MMSE mean scores. Three adverse events were recorded: one syncope causing a toe phalanx fracture and gastrointestinal complaints that resolved over time in two additional patients. Acetylcholinesterase inhibitors should be considered for the treatment of BPSD before neuroleptic treatment is instituted in AD patients with low levels of irritability and agitation.     

Clinical characteristics and muscle pathology in myopathic mitochondrial DNA depletion

Four nonrelated children with myopathic mitochondrial DNA depletion are described. Two of them initially had normal motor development and two had mild motor delay. Motor arrest and regression started at age 6 to 21 months. All four had mitochondrial DNA:nuclear DNA ratios reduced to 16 to 22% of the control mean and mutations in their mitochondrial thymidine kinase 2. Muscle pathology was genotype related: homozygosity for a missense mutation at position 181 was associated with severe myopathic changes, including marked variation in muscle fiber size, myofiber necrosis, regeneration, and interstitial fibrosis, whereas homozygosity for a missense mutation at position 90 was associated with essentially normal muscle histology. No ragged red fibers were detected in any study child. Mitochondrial DNA depletion should be considered in children with myopathy, worsening hypotonia, motor regression, and death during infancy or early childhood. The severity of pathologic findings on muscle biopsy is variable and may correlate with specific mutations and thymidine kinase 2 protein residual activity.     

Ionic current basis of electrocardiographic waveforms: a model study

Body surface electrocardiograms and electrograms recorded from the surfaces of the heart are the basis for diagnosis and treatment of cardiac electrophysiological disorders and arrhythmias. Given recent advances in understanding the molecular mechanisms of arrhythmia, it is important to relate these electrocardiographic waveforms to cellular electrophysiological processes. This modeling study establishes the following principles: (1) voltage gradients created by heterogeneities of the slow-delayed rectifier (I(Ks)) and transient outward (I(to)) potassium current inscribe the T wave and J wave, respectively; T-wave polarity and width are strongly influenced by the degree of intercellular coupling through gap-junctions. (2) Changes in [K+]o modulate the T wave through their effect on the rapid-delayed rectifier, I(Kr). (3) Alterations of I(Ks), I(Kr), and I(Na) (fast sodium current) in long-QT syndrome (LQT1, LQT2, and LQT3, respectively) are reflected in characteristic QT-interval and T-wave changes; LQT1 prolongs QT without widening the T wave. (4) Accelerated inactivation of I(Na) on the background of large epicardial I(to) results in ST elevation (Brugada phenotype) that reflects the degree of severity. (5) Activation of the ATP-sensitive potassium current, I(K(ATP)), is sufficient to cause ST elevation during acute ischemia. These principles provide a mechanistic cellular basis for interpretation of electrocardiographic waveforms.     

Renal cell carcinoma in pregnancy

Renal cell carcinoma is a rarely reported neoplasm in pregnancy. The pregnancy demands special consideration in terms of the diagnostic evaluation and management. Two patients with renal cell carcinoma who presented during the second trimester of pregnancy and underwent radical nephrectomy are reported with a review of published studies. It seems that because the mother's welfare is the primary concern, surgical management need not be delayed.     

Would a switch from typical antipsychotics to risperidone be beneficial for elderly schizophrenic patients? A naturalistic, long-term, retrospective, comparative study

Elderly chronic schizophrenia patients are particularly difficult to treat because of aging-related changes, cognitive impairment, and comorbid physical illness. This article describes a naturalistic, retrospective study of typical antipsychotic treatment versus risperidone for elderly psychotic inpatients. Fifty-one patients, mean age 72.7 + 5.9 years, mean disease duration 33.1 + 12.0 years, who met the DSM-IV criteria for schizophrenia or schizoaffective disorder were treated by risperidone (n = 26) or typical antipsychotic treatment (n = 25) during acute exacerbation and followed up for 18 months. Patients were rated using the clinical global impression (CGI) scale and positive and negative symptom scale (PANSS), and their body weight was recorded at baseline, 6 months, and 18 months. Both treatment groups improved on all rating scales at 18 months. Levels of decrease in PANSS positive and total scores were more prominent in patients treated with risperidone (p < 0.01 and p < 0.05, respectively). The change in CGI scores reached significance only after 18 months and was more pronounced in the risperidone group (p < 0.01). Anti-Parkinsonian medications were used more frequently in the typical antipsychotic group, whereas benzodiazepines were used more frequently in the risperidone group. Body mass index increased minimally after 18 months in the risperidone group (+ 0.3 kg/m2), whereas a larger (+ 1.1 kg/m2), albeit not statistically significant, increase was recorded in the typical antipsychotic group. Emergence of side effects was less frequent in patients treated with risperidone (4/26 vs. 16/25 patients, p < 0.01). The results of this study demonstrate that in elderly chronic schizophrenic patients, switching from typical antipsychotics to risperidone is effective and well tolerated.     

Very late-onset schizophrenia-like psychosis: clinical and imaging characteristics in comparison with elderly patients with schizophrenia

Studies of late-onset schizophrenia began in the early 1940s with work by M. Bleuler. Despite this fact, the emphasis on age of onset in young adulthood distracted researchers of schizophrenia from accumulating data on the subgroup of patients whose disease onset is in late life. Recently, the diagnostic entity of very late-onset schizophrenia-like psychosis (VLOSLP) was proposed for patients with disease onset after age 60 years, and it may have validity and clinical utility. The present study aims to prospectively identify patients suffering from VLOSLP over a 2-year period and to compare them with elderly schizophrenia patients on measures of brain structure, demographics, and treatment response, so that distinct features, if any, can be identified. Twenty-one VLOSLP patients (15 women, 6 men; mean age, 78.1 years) were enrolled and compared with 21 age- and gender-matched elderly schizophrenia patients. All had undergone brain CT scan, and all were treated with risperidone. The VLOSLP group was characterized by more education, higher percentage being married, more pronounced cerebellar atrophy, and better response to treatment. The authors suggest that VLOSLP is a valid diagnostic entity and that its features imply that involvement of neurodegenerative process may be etiologically relevant to psychosis with onset in late life.     

Posttraumatic sagittal osseous bar in the spinal canal of an adult: a case report

Diastematomyelia is a congenital anomaly wherein the distal spinal canal is bisected by a longitudinally oriented septum made up of fibrous tissue, cartilage, or bone. The main lesion is expressed by characteristic gait disturbances and dysfunction of the anal and vesical sphincters resulting from damage to the cord or cauda equina. Symptoms almost invariably begin during childhood. By the time symptoms appear, the damage is largely irreversible. In rare instances, the neuropathic expression of diastematomyelia is delayed until adult life. Only a dozen such cases have been reported. Described herein is the case of a patient in whom the typical symptoms appeared at 28 years of age. Decompression laminectomy and resection of the septum relieved the symptoms completely and permanently. The pathogenesis of nerve damage in diastematomyelia is thought to be different in patients with adult-onset disease than in children. This could explain why surgical treatment has a better prognosis in adults.     

The activity of antiepileptic drugs as histone deacetylase inhibitors

PURPOSE: Valproic acid (VPA), one of the widely used antiepileptic drugs (AEDs), was recently found to inhibit histone deacetylases (HDACs). HDAC inhibitors of a wide range of structures, such as hydroxamic acids, carboxylic acids, and cyclic tetrapeptides, have various effects on transformed and nontransformed cells, including neuromodulation and neuroprotection. The aim of this study was to assess comparatively the activity of traditional and newer AEDs as HDAC inhibitors. METHODS: After incubation of HeLa cells with the tested AEDs, histone hyperacetylation was assessed by immunoblotting with an antibody specific to acetylated histone H4. Direct HDAC inhibition by AEDs was estimated by using HeLa nuclear extract as an HDACs source and an acetylated lysine substrate. RESULTS: We found that in addition to VPA, topiramate (TPM) inhibited HDACs with apparent Ki values of 2.22 +/- 0.67 mM. Although levetiracetam (LEV) had no direct effect on HDACs, its major carboxylic acid metabolite in humans, 2-pyrrolidinone-n-butyric acid (PBA), inhibited HDACs with Ki values of 2.25 +/- 0.78 mM. The AEDs LEV, phenobarbital, phenytoin, carbamazepine, ethosuximide, gabapentin, and vigabatrin did not inhibit HDACs. The compounds that directly inhibited HDACs also induced the accumulation of acetylated histone H4 in HeLa cells. The effects of TPM and PBA on histone acetylation were significant at 0.25 mM and 1 mM, respectively. CONCLUSIONS: We found that in addition to VPA, the newer AED TPM and the major metabolite of LEV, PBA, are able to induce histone hyperacetylation in human cells, although with lower potencies than VPA.