Pharmacotherapeutic determinants for QTc interval prolongation in Japanese patients with mood disorder.

An increased incidence of sudden death has been observed among patients treated with antidepressants. A prolonged QTc interval is a known prognostic factor for fatal arrhythmia, and several studies have shown that the use of antidepressants can cause a prolonged QTc interval. However, few studies, especially in Japan, have compared the effects of multiple drugs on QTc interval or examined dose relationships in a clinical setting.We compared the effects of antidepressants on QT interval, corrected to QTc by Bazett's formula, in 729 Japanese patients who were diagnosed with mood disorder.Using stepwise multiple linear regression analysis, we found that the use of tricyclic antidepressants (P<0.01) and concomitant use of antipsychotics (P<0.05), as well as advanced age and being female (known factors for prolonged QTc interval; both P<0.01), significantly prolonged the QTc interval. Analysis of individual antidepressants also revealed that the use of clomipramine (P<0.01) and amitriptyline (P<0.05) significantly prolonged the QTc interval.Our results reveal that tricyclic antidepressants, especially clomipramine and amitriptyline, confer a risk of prolonged QTc interval in a dose-dependent manner. The selective serotonin reuptake inhibitors investigated (fluvoxamine, paroxetine, sertraline) were not indicated as risk factors for QTc prolongation.

Clustered lot quality assurance sampling: a pragmatic tool for timely assessment of vaccination coverage.

OBJECTIVES: To evaluate oral poliovirus vaccine (OPV) coverage of the November 2009 round in five Northern Nigeria states with ongoing wild poliovirus transmission using clustered lot quality assurance sampling (CLQAS). METHODS: We selected four local government areas in each pre-selected state and sampled six clusters of 10 children in each Local Government Area, defined as the lot area. We used three decision thresholds to classify OPV coverage: 75-90%, 55-70% and 35-50%. A full lot was completed, but we also assessed in retrospect the potential time-saving benefits of stopping sampling when a lot had been classified. RESULTS: We accepted two local government areas (LGAs) with vaccination coverage above 75%. Of the remaining 18 rejected LGAs, 11 also failed to reach 70% coverage, of which four also failed to reach 50%. The average time taken to complete a lot was 10 h. By stopping sampling when a decision was reached, we could have classified lots in 5.3, 7.7 and 7.3 h on average at the 90%, 70% and 50% coverage targets, respectively. CONCLUSIONS: Clustered lot quality assurance sampling was feasible and useful to estimate OPV coverage in Northern Nigeria. The multi-threshold approach provided useful information on the variation of IPD vaccination coverage. CLQAS is a very timely tool, allowing corrective actions to be directly taken in insufficiently covered areas.

Zinc supplementation fails to increase the immunogenicity of oral poliovirus vaccine: a randomized controlled trial.

BACKGROUND: Polio eradication remains a challenge in Pakistan and the causes for the failure to eradicate poliomyelitis are complex. Undernutrition and micronutrient deficiencies, especially zinc deficiency, are major public health problems in Pakistan and could potentially affect the response to enteric vaccines, including oral poliovirus vaccine (OPV). OBJECTIVE: To assess the impact of zinc supplementation among infants on immune response to oral poliovirus vaccine (OPV). METHODS: A double-blind, randomized placebo-controlled trial was conducted in newborns (aged 0-14 days). Subjects were assigned to either receive 10mg of zinc or placebo supplementation daily for 18 weeks. Both groups received OPV doses at birth, at 6 weeks, 10 weeks and 14 weeks. Data was collected on prior immunization status, diarrheal episodes, breastfeeding practices and anthropometric measurements at recruitment and at 6 and 18 weeks. Blood samples were similarly collected to determine the antibody response to OPV and for micronutrient analysis. Logistic regression was used to determine the relationship between seroconversion and zinc status. RESULTS: Overall, 404 subjects were recruited. At recruitment, seropositivity was already high for poliovirus (PV) serotype 1 (zinc: 91.1%; control: 90.5%) and PV2 (90.0%; 92.7%), with lower estimates for PV3 (70.0%; 64.8%). By week 18, the proportion of subjects with measured zinc levels in the normal range (i.e. ≥60 µg/dL) was significantly greater in the intervention group compared to the control group (71.9%; 27.4%; p<0.001). No significant difference in seroconversion was demonstrated between the groups for PV1, PV2, or PV3. CONCLUSIONS: There was no effect of zinc supplementation on OPV immunogenicity. These conclusions were confirmed when restricting the analysis to those with measured higher zinc levels.

Video camera method for simultaneous measurement of blood flow velocity and pial vessel diameter.

A new method for the simultaneous measurement of blood flow velocity and pial vessel diameter is described. The system consists basically of a high-sensitivity vidicon camera, camera control, width analyzer, video densitometer, TV monitor, desktop computer, and multi-pen recorder. The pial vessels are visualized through a cranial window at 25-200x magnification on the TV monitor. The diameter of three target vessels can be recorded simultaneously on the recorder by adjustment of controllable video signal gates using the width analyzer. At the same time, the optical densities of two targets at points upstream and downstream of the pial vessel are measured continuously with video densitometers, and their outputs are recorded on the polygraph and analyzed by the computer. The time difference in the two peaks of time--concentration curves, produced very 2-3 s at the highest frequency by the injection of a small amount of saline through the lingual artery, is measured on-line using the computer. The flow velocity in the vessel is calculated from the time difference and the distance between the two targets. The system was shown to be stable, reliable, and rapid in response. This method may provide a useful tool for research in the field of blood circulation in the brain or any other organ.

Duchenne dystrophy: reduced density of orthogonal array subunit particles in muscle plasma membrane.

Using freeze-fracture, we analyzed the density of orthogonal arrays and subunit particles in muscle plasma membrane of six patients with Duchenne muscular dystrophy and six control boys. The group median density of orthogonal arrays per 1 micron2 and the group mean density of orthogonal array subunit particles per one orthogonal array were significantly lower in Duchenne plasma membrane. The results suggested the possible impairment of orthogonal array function in the muscle plasma membrane of Duchenne muscular dystrophy.

Effects of aging on cerebral blood flow in dementia.

Regional cerebral blood flow values were measured utilizing the 133Xe inhalation method in patients with multi-infarct dementia (MID) (n = 22, age 67.4 +/- 9.8 years), in patients with senile dementia of Alzheimer type (SDAT) (n = 36, age 63.8 +/- 8.0) and in age-matched normal healthy volunteers (n = 50, age 67.5 +/- 9.3). Mean hemispheric gray matter flow values were significantly reduced in MID (P less than 0.01) and SDAT (P less than 0.01) patients compared with age-matched normal volunteers. In normal volunteers, mean flow values showed gradual declines with advancing age (r = -0.44, P less than 0.005). In MID patients there were significant decreases in flow values with advancing age (r = -0.43, P less than 0.05), but flow values were consistently lower than in age-matched normals. Reductions of flow were most evident in the distribution of both middle cerebral arteries. Unlike MID patients, patients with SDAT had diffusely reduced flow values over all age ranges without correlation with advancing age. Reductions of mean flow values in both dementia groups were significantly correlated with severity of dementia (P less than 0.05 for both groups). Cerebral blood flow reductions related to the aging process also contribute to decreased cerebral perfusion in patients with MID. This is not true in SDAT, where the disease process itself pre-empts cerebral blood flow reductions attributable to aging.

Creutzfeldt-Jakob disease: a case with extensive white matter degeneration and optic atrophy.

A 52-year-old woman is described, whose clinical features were typical of Creutzfeldt-Jakob disease except for the presence of optic atrophy. Serial CT scans showed rapid development of brain atrophy early in the course. Postmortem examination revealed extensive degeneration of the cerebral and cerebellar white matter and of the optic nerves in addition to the classic findings of Creutzfeldt-Jakob disease. It is suggested that both the grey and white matter may undergo a severe destructive process early in the course of the disease, and the possibility is discussed that the white matter involvement is not a result of neuronal loss.

Quantitative freeze-fracture electron microscopic study of muscle plasma membrane of experimental anoxic myopathy.

The numerical change of intramembranous particles (IMP) and square arrays (SA) was investigated in the muscle plasma membrane after anoxia. The proximal portion of the hind limb of Wistar rats weighing 250-350 g was strongly tied with steel wire. The contralateral hind limb was served as control. After 3 and 6 h, the extensor digitorum longus (EDL) muscles of both control and anoxic groups were studied by freeze-fracture electron microscopy. The findings of anoxic EDL plasma membrane included the presence of band-like or patchy form particle free areas with the tendency to increase from 3 to 6 h and the preservation of SA even after 6 h of anoxia. However, the IMP and caveolae densities between control and anoxic groups were not statistically different. The group median densities of SA/micron2 of control P face were 4.9 with midrange of 2.2-9.7 and 7.1 with mid-range of 2.7-10.9 after 3 and 6 h; whereas those of anoxic P face were 6.0 with mid-range of 1.8-8.2 (P greater than 0.1) and 6.9 with mid-range of 3.3-13.5 (P greater than 0.1), respectively. These changes are quite different from those of muscle plasma membrane in Duchenne muscular dystrophy.

Long-term prognosis in ischemic cerebrovascular disease in relation to cerebral blood flow and metabolism.

The correlation between long-term prognosis and cerebral hemodynamics and oxygen consumption was investigated in 46 patients with ischemic supratentorial cerebrovascular disease. Cerebral blood flow (CBF) and cerebral oxygen consumption (CMRO2) were measured by the N2O method 1-6 months (mean 68 days) after disease onset. No significant correlation was observed among CBF, CMRO2 and activities of daily living at the time of measurement. The patients' physical condition was reevaluated by the questionnaire method 2 years or more (mean 53 months) later. The CBF values in patients who were independent after completion of the follow-up period significantly exceeded those of patients dying during the period (P less than 0.05). No correlation was observed in CMRO2. The relationship among CBF, CMRO2 and changes in physical condition during the period was evaluated. Mean CBF values in patients with better prognosis exceeded those of patients with poor prognosis. Notably, CBF values in the "improved" group significantly exceeded those in the "unchanged" or "died" group (P less than 0.05, P less than 0.01). CMRO2 was not significantly correlated with changes of physical condition. These results emphasize the importance of total CBF for long-term prognosis and indicate that flow values, rather than metabolic indices, obtained in the chronic stage can usefully predict the long-term prognosis.

Prognostic value of cerebral blood flow autoregulation in the long-term prognosis of ischemic cerebrovascular disease.

The correlation between long-term prognosis, cerebral blood flow (CBF) and CBF autoregulation was studied in 34 patients with cerebral infarction (mean age, 64 years). CBF was measured by the nitrous oxide method 1-6 months (mean 87 days) after disease onset. CBF autoregulation was evaluated quantitatively from the Dysautoregulation Index (DI) (delta CBF/delta effective MABP). Reductions in effective MABP were induced with a tilt table. No significant correlation was noted among CBF, DI and activities of daily living at the time of measurement. The patients' physical condition was reevaluated by questionnaire 2 years or more (mean 32 months) later. Better functional state at follow-up was related to higher CBF and lower DI values although the differences were not significant. The relationships among CBF, DI and changes in physical condition during the period were evaluated. The mean CBF values in patients with a better prognosis exceeded those of poor prognosis patients. The CBF values in the group who became independent significantly exceeded those in the group that deteriorated (P less than 0.05). The CBF values in the latter showed small but significant decreases during head-up tilting (P less than 0.05). The DI in this group was significantly higher than in the groups with a less severe outcome (P less than 0.01, P less than 0.05, respectively). In conclusion, determinations of CBF autoregulation, together with flow values, in the chronic state may have some value in predicting the long-term prognosis in cerebral infarction.

Xenon-enhanced CT CBF measurements in cerebral AVM's before and after excision. Contribution to pathogenesis and treatment.

Unlike neurological deficits resulting from intracranial hemorrhage in patients with cerebral arteriovenous malformation (AVM), which have well defined etiology, the pathogenesis and treatment of progressive and/or fluctuating non-hemorrhagic neurological and psychological deficits require clarification. Values for local cerebral blood flow (LCBF) and local partition coefficients (L lambda) were measured by the method using stable xenon (Xe)-computerized tomography (CT-CBF) scanning, and were compared to 133Xe inhalation values using external probes in 16 patients with cerebral AVM's. Values were measured by both methods before and after total excision of AVM's in five cases. Neurological and mental status assessments were compared with LCBF results. Clinical improvement was most evident after total excision of AVM's. Other procedures, such as clipping of vessels, partial excision, and ventriculoperitoneal shunting for hydrocephalus, were associated with frequent complications. Embolization carried risks of cerebral infarction and was not efficacious unless combined with excision. Medical treatment resulted in poor or unsuccessful seizure control, with neurological deterioration despite anticonvulsant therapy. Compared with age-matched normal individuals, LCBF values in patients with AVM's were significantly reduced, particularly adjacent to the AVM's. Mean L lambda values for gray and white matter were normal. After excision, LCBF values in gray and white matter increased significantly up to normal. Due to overestimation of CBF by shunt flow with the 133Xe method of measurement, no correlation was found with results of the CT-CBF method before AVM excision, but significant correlation of the two methods resulted after excision. If accurate LCBF values are obtained by high resolution, direct measurement of tracer clearance from brain tissue, progressive and/or fluctuating neuropsychological deficits correlate with the degree of cerebral steal.

Cytotoxic activity of vitamins K1, K2 and K3 against human oral tumor cell lines.

Vitamin K1, K2 and K3 were compared for their cytotoxic activity, radical generation and O2- scavenging activity. Among these compounds, vitamin K3 showed the highest cytotoxic activity against human oral tumor cell lines (HSC-2, HSG), human promyelocytic leukemic cell line (HL-60) and human gingival fibroblast (HGF). Vitamin K3 induced internucleosomal DNA fragmentation in HL-60 cells, but not in HSC-2 or HSG cells. The cytotoxic activity of vitamins K2 and K1 was one and two orders lower, respectively, than K3. Vitamin K2, but not vitamin K3, showed tumor-specific cytotoxic action. ESR spectroscopy showed that only vitamin K3 produced radical(s) under alkaline condition and most potently enhanced the radical intensity of sodium ascorbate and scavenged O2- (generated by hypoxanthine-xanthine oxidase reaction system); vitamin K2 was much less active whereas vitamin K1 was inactive. These data suggest that the cytotoxic activity of vitamin K3 is generated by radical-mediated oxidation mechanism and that this vitamin has two opposing actions (that is, antioxidant and prooxidant), depending on the experimental conditions.

[A case of respiratory dyskinesia due to clebopride malate].

Clebopride malate is therapeutically used for the treatment of peptic ulcer. This drug has potent antidopaminergic activity that causes acute dystonic reaction, parkinsonism and tardive dyskinesia as adverse effects. Here, we have reported an 86-year-old man who developed abnormal involuntary movement of respiratory muscles and lower limb muscles after this drug had been given for four months. This involuntary movement appeared spontaneously at resting state and disappeared during sleep. Surface EMG demonstrated a synchronous grouping discharge in m. orbicularis oris, m. sternocleidomastoideus and m. interstales which synchronized with diaphragmatic movement on cinefluorography. Involuntary movement of the lower limbs was synchronous bilaterally and had little relationship with diaphragmatic movement. This involuntary movement was irregular not only in rhythm but also in duration. According to this irregular nature, we diagnosed this involuntary movement as respiratory dyskinesia with limb dyskinesia that belongs to tardive dyskinesia. After cessation of clebopride malate limb dyskinesia disappeared rapidly and respiratory dyskinesia markedly decreased. We emphasize that respiratory dyskinesia should be differentiated from psychogenic hyperventilation as easily misdiagnosed on initial examination.

[A case of chronic toluene intoxication with abnormal MRI findings: abnormal intensity areas in cerebral white matter, basal ganglia, internal capsule, brain stem and middle cerebellar peduncle].

We reported a case of 21 years old man of chronic toluene intoxication with abnormal intensity areas on MRI in cerebral white matter, basal ganglia, internal capsule (especially posterior limb), brain stem and middle cerebellar peduncle. The patient developed various neurological abnormalities such as blurred vision, ataxic speech, gaze evoked horizontal nystagmus, bilateral pyramidal tract sign and limb ataxia after 8 years sniffing of thinner (mainly toluene). MRI examination revealed diffuse high intensity areas in cerebral white matter on T1 weighted image. On T2 weighted image, high intensity areas of deep cerebral white matter, internal capsule (especially posterior limb), cerebral peduncle, ventral pons and middle cerebellar peduncle were noted. Basal ganglia (caudate nucleus, lenticular nucleus and thalamus) were displayed as low intensity area on T2 weighted image. These high intensity areas of internal capsule, brain stem and middle cerebellar peduncle on T2 weighted image would be significant for understanding pyramidal tract sign and cerebellar sign of this case. On the basis of neuropathological descriptions of chronic toluene intoxication, these high intensity areas of T2 weighted image were presumed to be demyelinating lesions of the central nervous system.

[A case of cough hemiplegia].

We reported a patient with internal carotid artery occlusion (ICAO) who developed cough-induced transient hemiplegia. A 63-year-old man with chronic obstructive pulmonary disease experienced several episodes of cough-induced left hemiplegia during drinking and smoking. Selective cerebral angiography demonstrated right ICAO at the vessel origin, with 50% stenosis of the left internal carotid artery. Collateral circulation from the right external to internal carotid artery branches and through the anterior communicating artery was poorly observed on the angiograms. Right middle cerebral artery branches were well visualized on vertebral angiograms at the late phase through the posterior and anterior pericallosal arteries. Due to this collateral blood supply, the right middle cerebral artery territory formed the most distal part of the cerebral circulation and was vulnerable to a reduction of cerebral blood flow. We considered that systemic hemodynamic disturbances by identical mechanisms to those observed in cough syncope may have brought about transient ischemia in the right middle cerebral artery territory which was manifested in the patient's unusual clinical presentation of ICAO "cough hemiplegia".

[Symptomatological rubral tremor caused by vertebral-basilar artery embolism].

Rubral tremor is a distinct clinical entity as described by Gorden Holmes. We have reported here a 44 years old woman with rubral tremor appearing about 2 months after an embolic attack of vertebral-basilar artery. On neurological examination there were left homonymous hemianopsia, dysarthria very mild weakness of left upper and lower limbs with clumsiness of her left lower limb and the tremor of the left upper limb. Muscle tone was increased in her left upper limb with dystonic posturing. The tremor of her left upper limb was present at rest with regular rhythm of 2.8 Hz. This tremor included the reciprocal movements such as radial and ulnar flexion of the left wrist and independent movements of different fingers. It was accentuated by postural adjustment and by guided voluntary movements and disappeared during sleep. Surface EMG demonstrated that the grouping discharge was seen not only alternatingly but also synchronously between agonists and antagonists. A brain MRI image revealed multiple lesions including right thalamus and left cerebellum. No lesions were detected in brain stem. On the basis of MRI, it was questionable whether the lesion involved the dentate nucleus in the left cerebellum although the lesion was located at the medulla near the dentate nucleus extending from the cortex. So-called rubral tremor could be generated in lesions of cerebello-rubro-thalamic system without rubral lesion itself.

[Anticardiolipin antibody in cerebral infarction].

We investigated the anticardiolipin antibody (ACA) in a series of patients with cerebral infarction without systemic lupus erythematosus (SLA). Clinical and laboratory data were assessed from a series of 250 non-SLE patients with cerebral infarction who visited our clinic from 1988 to 1990. The concentration of anticardiolipin IgG antibody was measured by an enzyme-linked immunosorbent assay technique. An elevated ACA level was defined as one which was greater than 3 standard deviations above the mean level for normal controls. We examined the CT findings and risk factors for stroke such as hypertension, diabetes mellitus, hyperlipidemia and cardiac disease. Laboratory data such as the platelet count, the presence of lupus anticoagulant and a biologic false-positive test for syphilis were also investigated. Among the 250 patients with infarction, IgG ACA was detected in 22 (8.8%). There was no significant difference in incidence of ACA between the patients with cerebral thrombosis and those with cerebral embolism. On CT scan, multiple cerebral infarcts were noted in 18 of the 22 patients. As regards the location of the infarct, the cerebral cortex together with the basal ganglia was more common than isolated lesions of the cortex or basal ganglia. Concerning the risk factors for stroke, hypertension was noted in 12, diabetes mellitus in 2, hyperlipidemia in 2 and cardiac disease in 2. Lupus anticoagulant and thrombocytopenia were not detected in any of the cases. A biologic false-positive test for syphilis was observed in one case. Dementia was present in 12 of the 22 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

[A case of plasma cell granuloma associated with cerebral infarction].

A 36-year-old male complained of double-vision and pain of left orbita. On admission, T1-weighted Gd-enhanced MR image of his head showed high intensity lesion in the left carvenous sinus, and his chest X-P showed multiple coin lesions. Microscopic findings of lung open biopsy specimen showed prolifelation of mature plasma cell in the granuloma and the patient was diagnosed as having plasma cell granuloma. Although the lung lesions had a tendency to spontaneous remission, we started the steroid pulse therapy and betamethasone (8 mg/day) therapy for intracranial lesion. Then the lung lesions vanished and we decreased the dose of betamethasone from 8 mg/day to 6 mg/day. As the results, the intracranial lesion of this patient expanded and left middle cerebral artery occluded, resulting in right hemiparesis and total aphasia. This is the first case report of plasma cell granuloma with a lesion in the central nervous system associated with cerebral infarction.

A study evaluating poliovirus antibodies and risk factors associated with polio seropositivity in low socioeconomic areas of Pakistan.

BACKGROUND: Seroprevalence studies provide important data on performance of immunization programs, susceptible groups and populations at-risk of future outbreaks. Identifying risk factors that affect seroconversion of the oral polio vaccine (OPV) will enable the polio eradication initiatives to increase seroprevalence. This paper describes the first population-based seroprevalence survey in Pakistan. METHODS: This study evaluated the seroprevalence of poliovirus (PV) types 1, 2, and 3 antibodies to OPV in an illustrative sample of 554 subjects 6-11 months of age in three geographic locations of Pakistan (Lahore, Karachi, and Peshawar) representing a low socioeconomic at-risk populations. Antibody titers were measured and sero protection rates and geometric median titers were compared among different geographic regions and populations, as were demographics and OPV vaccination history collected by questionnaire. Univariate and multivariate analyses were conducted on subject characteristics to assess for potential risk factors for failure to sero-convert. RESULTS: The average seroprevalence of PV1, PV2, and PV3 was 96.0%, 87.9% and 86.7%, respectively. The lowest sero protection rate for all three serotypes was for Karachi with 90.2%, 73.8%, and 78.8% for PV1, PV2, and PV3, respectively. Significant regional variation in PV3 seroprevalence was found (range: 74.2-100%). In the univariate analysis, age, total and campaign OPV doses were associated with higher seroprevalence, whereas stunting, respondent education and diarrhea in the past six months were significant risk factors for failure to sero-convert. CONCLUSIONS: These findings demonstrate consistently high levels of antibody response to PV1 and more geographically varied response to PV2 and PV3. Additionally, important risk factors affecting seropositivity were identified.