Effect of obesity on serum amiodarone concentration in Japanese patients: population pharmacokinetic investigation by multiple trough screen analysis.

OBJECTIVE: To evaluate the influence of obesity on pharmacokinetics of amiodarone (AMD) using Non-Linear Mixed Effects Modelling (NONMEM) in Japanese patients treated with oral therapy. METHOD: Serum concentrations of AMD were determined by high performance liquid chromatography. One hundred and fifty-one trough concentrations from 23 patients receiving repetitive oral AMD were collected. Body mass index (BMI) and body fat percentage were measured. RESULTS: Estimates generated using NONMEM indicated that the clearance of AMD was influenced by BMI, age and daily dosage of AMD. The final pharmacokinetic model was CL (L/h) = 0*16 * TBW * 0.53(AGE >or= 65 ) * 0*78(BMI >or= 25) * DD(0.51), V(d) (L) = 10*2 * TBW, where CL is total body clearance, TBW is total body weight (kg), DD (mg/kg/day) is daily dosage of AMD, AGE (years) >or=65 = 1 for patient was 65 years old or over and 0 otherwise, BMI (kg/m(2)) >or=25 = 1 for patient was 25 kg/m(2) or over and 0 otherwise and V(d) is apparent volume of distribution. The clearance of AMD decreased significantly by 22.3% with a BMI higher than 25 kg/m(2). The clearance of AMD also decreased significantly by 46.9% when patient age was more than 65 years. CONCLUSION: Population pharmacokinetic analysis confirms that obesity affects the pharmacokinetics of AMD.

Spleen enlargement and genetic diversity of Plasmodium falciparum infection in two ethnic groups with different malaria susceptibility in Mali, West Africa.

The high resistance to malaria in the nomadic Fulani population needs further understanding. The ability to cope with multiclonal Plasmodium falciparum infections was assessed in a cross-sectional survey in the Fulani and the Dogon, their sympatric ethnic group in Mali. The Fulani had lower parasite prevalence and densities and more prominent spleen enlargement. Spleen rates in children aged 2-9 years were 75% in the Fulani and 44% in the Dogon (P<0.001). There was no difference in number of P. falciparum genotypes, defined by merozoite surface protein 2 polymorphism, with mean values of 2.25 and 2.11 (P=0.503) in the Dogon and Fulani, respectively. Spleen rate increased with parasite prevalence, density and number of co-infecting clones in asymptomatic Dogon. Moreover, splenomegaly was increased in individuals with clinical malaria in the Dogon, odds ratio 3.67 (95% CI 1.65-8.15, P=0.003), but not found in the Fulani, 1.36 (95% CI 0.53-3.48, P=0.633). The more susceptible Dogon population thus appear to respond with pronounced spleen enlargement to asymptomatic multiclonal infections and acute disease whereas the Fulani have generally enlarged spleens already functional for protection. The results emphasize the importance of spleen function in protective immunity to the polymorphic malaria parasite.

Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation.

Ferroptosis is a form of regulated non-apoptotic cell death that has been implicated in several disease contexts. A better understanding of the ferroptotic death mechanism could lead to the development of new therapeutics for degenerative diseases, and a better understanding of how to induce ferroptosis in specific tumor contexts. We performed an unbiased genome-wide siRNA screen to find genetic suppressors of ferroptosis. We determined that loss of CARS, the cysteinyl-tRNA synthetase, suppresses ferroptosis induced by erastin, which inhibits the cystine-glutamate antiporter known as system xc(-). Knockdown of CARS inhibited erastin-induced death by preventing the induction of lipid reactive oxygen species, without altering iron homeostasis. Knockdown of CARS led to the accumulation of cystathionine, a metabolite on the transsulfuration pathway, and upregulated genes associated with serine biosynthesis and transsulfuration. In addition, inhibition of the transsulfuration pathway resensitized cells to erastin, even after CARS knockdown. These studies demonstrate a new mechanism of resistance to ferroptosis and may lead to strategies for inducing and suppressing ferroptosis in diverse contexts.

The prevalence, incidence and prognostic value of the Brugada-type electrocardiogram: a population-based study of four decades.

OBJECTIVES: We sought to demonstrate the prevalence, incidence and prognostic value of the Brugada-type electrocardiogram (ECG) in a general population. BACKGROUND: The Brugada syndrome is characterized by evidence of right bundle branch block and ST segment elevation in the right precordial leads, as well as sudden death caused by ventricular fibrillation. However, the natural history of the Brugada-type ECG remains unclear. METHODS: We investigated 4,788 subjects (1,956 men and 2,832 women) who were <50 years old in 1958 and had undergone biennial health examinations, including electrocardiography, through 1999. The Brugada-type ECG was defined as a terminal r' wave in lead V(1) and ST segment elevation > or =0.1 mV in leads V(1) and V(2). Unexpected death was defined as sudden death or unexplained accidental death. RESULTS: There were a total of 32 Brugada-type ECG cases; the prevalence and incidence were 146.2 in 100,000 persons and 14.2 persons per 100,000 person-years, respectively. The incidence was nine times higher among men than women, and the average age at presentation was 45 +/- 10.5 years. The Brugada-type ECG appeared intermittently in most cases and was found in 26% of subjects who died unexpectedly. Cox survival analysis revealed that mortality from unexpected death was significantly higher in subjects with a Brugada-type ECG than in control subjects (p < 0.01). Unexpected deaths were more frequent among subjects with the Brugada-type ECG who had a history of syncope (p < 0.05). CONCLUSIONS: The Brugada-type ECG is not a very rare condition in the adult Japanese population. Subjects with a Brugada-type ECG have an increased risk of unexpected death.

"Paramyxovirus-like" intranuclear inclusions occurring in the nervous system in diverse unrelated conditions.

Filamentous intranuclear inclusions similar to the "paramyxovirus-like" intranuclear inclusions described in active multiple sclerosis (MS) were observed incidentally in four patients who had diverse disorders such as rabies, mannosidosis, metachromatic leukodystrophy, cerebral aneurysm and ischemic infarcts. The observation is in support of the mounting evidence that the "virus-like" intranuclear inclusions are not specific for MS and may occur frequently in a variety of diverse conditions. Moreover, neither virological nor immunological evidence as to the viral nature of the intranuclear inclusions has been presented to date, and the intranuclear inclusions have been observed mostly in degenerating or autolyzed cells in biopsied or autopsied tissue samples. In view of all the circumstantial evidence, it is suggested that the intranuclear "paramyxovirus-like" inclusions may represent an alternation of nuclear chromatin common to antemortem degeneration and postmortem autolysis in a variety of cells, the nature of which remains to be elucidated.

Mannosidosis: pathology of the nervous system.

In a girl with mannosidosis, who died at 3 1/2 years of age, histopathological and ultrastructural changes in the nervous system are described. A widespread neuronal storage evidenced by ballooning of the neuronal perikarya is the salient histological feature and the occurrence of electron-lucent storage vacuoloes in neurons, astrocytes, endothelial cells and pericytes is the most striking ultrastructural feature of mannosidosis in the nervous system. By virtue of the deficiency of acidic alpha-mannosidases A and B, the accumulation of mannose-containing oligosaccharides in tissues and the occurrence of storage vacuoles in various cells, mannoisidosis is similar to various neuronal storage diseases associated with lysosomal enzyme deficiencies. In mannosidosis, the storage vacuoles in the neural and visceral tissues are alike with little variation in details and contain chiefly loosely dispersed, finely reticulogranular material. The storage vacuoles in neurons in mannosidosis are, therefore, distinct from those in neurons in other lysosomal storage disease such as Pompe's disease, various lipidoses and mucopolysaccharidoses. However, they resemble closely the storage vacuoles in neurons in fucosidosis and those in liver cells in various mucopolysaccharidoses.

A case of human rabies and ultrastructure of the Negri body.

A 60-year old man, eight weeks after being bitten on his finger by a stray cat, developed symptoms and signs of rabies which progressed rapidly over the next two weeks and he died of respiratory failure. Pathological examination revealed characteristic cytoplasmic inclusions in neurons of various parts of the central nervous system and the dorsal spinal and sympathetic ganglia. The diagnosis of rabies was confirmed by direct fluorescent antibody staining of the brain tissue obtained at autopsy. On histological examination, most, if not all, of the neuronal cytoplasmic inclusions were eosinophilic and homogeneous and lacked the basophilic inner granules or bodies characteristic of Negri bodies. Nevertheless, they were ultrastructurally identical with Negri bodies by virtue of being made up of finely fibrillar matrix and virus and/or related particles in varying numbers. This indicates that ultrastructurally typica Negri bodies may or may not have the histologically visible basophilic inner bodies depending upon the degree of virus replication. In light of the ultrastructural evidence, lyssa bodies described in rabies in the past may represent Negri bodies without histologically recognizable inner bodies or cytoplasmic inclusions unrelated to rabies, occurring ordinarily in normal or degenerating neurons. It is, therefore, suggested that the term, lyssa body, is obsolete and should no longer be used.

Striated muscle in the pineal gland of swine.

Striated muscle fibers (or cells) were observed in three of the six swine pineal glands. The muscle fibers occurred in clusters of several fibers about the parenchymal blood vessels. They were in general poorly developed, lacked regular cross striations and were not readily recognized histologically. The muscle fibers were, however, easily identified on electron microscopy because of the myofilaments they contain. In most of the muscle fibers, the myofilaments were arranged in ill-defined, disorderly bundles and rarely formed well-defined myofibrils and sarcomeres. The sarcotubular system was also poorly developed and triads were sparse and randomly scattered. Leptomeres were observed in several muscle fibers. The source of the muscle fibers in the pineal glands is not well understood and, whatever the source may be, the muscle fibers seem to remain poorly developed in the pineal glands.

Intracisternal A and bar-shaped particles in murine neuroblastoma C 1300.

Transplantable murine neuroblastoma C 1300 was studied ultrastructurally at varying time intervals ranging from 2 hours to 40 days before and after X-irradiation. Following X-irradiation, 2000 and 4000 rads in a single dose, the uniformly small tumor cells became progressively enlarged multinucleated and degenerated, starting at one to two days. At five to seven days, the uni- and multinucleated giant cells predominated over the small tumor cells, while the giant cells progressively disappeared therafter and the small tumor cells predominated over the giant cells at 10 to 14 days. The giant cells contained abundant subcellular organelles and the X-irradiated tumor cells apparently continued to produce the organelles until they degenerated. Two types of cytoplasmic particles, intracisternal A and bar-shaped, were observed in the tumor cells. The intracisternal A particles occurred in almost all non-irradiated tumor cells though their number varied considerably from cell to cell, while they were observed less frequently in the radiation-induced giant cells probably due to a dilution effect rather than an actual numerical decrease. The bar-shaped particles, hitherto undescribed in the neuroblastoma, were 23 nm in diameter, variable in length and occasionally tubular. They occurred only in degenerating cells regardless of X-irradiation but were encountered more frequently in irradiated tumors than in non-irradiated ones. It is suggested that they may represent an unknown degenerative product of cytoplasm and/or nucleus rather than virus particles, despite their morphological resemblance to certain virus particles.

Failure of fixation suppression of caloric nystagmus and ocular motor abnormalities.

Caloric nystagmus is substantially suppressed by visual fixation. The degree of suppression of caloric nystagmus is influenced by the condition of visual fixation. We studied the percent reduction in slow-phase velocity of caloric nystagmus by visual fixation and certain abnormalities in optokinetic nystagmus, smooth pursuit, and maintenance of ocular position of gaze in 38 patients with disorders of the CNS. The inability to suppress caloric nystagmus by visual fixation correlated with reduction in optokinetic nystagmus, deficit in smooth pursuit eye movements, and presence of gaze nystagmus. It seems probable that modulation of the vestibulo-ocular reflex is influenced by the same mechanisms that are concerned with optokinetic nystagmus, maintenance of ocular position of gaze, and smooth pursuit eye movements.

Expression of chemokine receptors on CD4+ T cells in peripheral blood from HIV-infected individuals in Uganda.

CXCR4, a coreceptor for T cell (T)-tropic HIV-1, is preferentially expressed on naive T cells, whereas CCR5, a coreceptor for macrophage (M)-tropic HIV-1, is preferentially expressed on previously activated memory T cells and the Th1 subset of CD4+ T cells. CCR4 is preferentially expressed on the Th2 subset of CD4+ T cells. A cross-sectional flow cytometry study was conducted to evaluate the expression of CXCR4, CCR5, and CCR4 on the peripheral blood CD4+ T cells from African HIV-1-infected and uninfected Ugandan adults. The plasma viral load in HIV-1-infected individuals was also examined. Upregulation of CCR4 and CCR5 expression but no decrease in CXCR4 expression on CD4+ T cells were obtained in peripheral blood from African adults with progression of the disease. Plasma HIV-1 viremia significantly and inversely correlated with the peripheral CD4+ T cell count but did not correlate with the degree of CCR4 and CCR5 expression on the peripheral CD4+ T cells in HIV-1-infected individuals. Our present data suggest an increase in percentage of activated memory CD4+ T cells in the advanced stage of HIV-1 infection among African adults. There was no evidence of a Th1 to Th2 shift in terms of chemokine receptor expression profile with advancing disease in the peripheral blood of these subjects.

Phasic coronary artery flow velocity determined by Doppler flowmeter catheter in aortic stenosis and aortic regurgitation.

Phasic coronary artery flow velocity was recorded in 14 patients with aortic regurgitation (AR), 4 with aortic stenosis, 61 with other heart diseases and in 2 normal subjects by means of a bidirectional Doppler flowmeter catheter. The normal pattern of the phasic coronary artery flow velocity was characterized by a small forward flow during systole (S wave) and a large forward flow during diastole (D wave). The phasic coronary artery flow velocity in patients with AR showed increased S wave and decreased D wave. The area under the S-wave curve divided by the area under the D-wave curve (S/D ratio) in patients with AR increased (left coronary artery flow velocity 0.66 +/- 0.39, p less than 0.05; right coronary flow velocity 0.79 +/- 0.36, p less than 0.01) as compared with the S/D ratio in patients with other heart diseases (left coronary flow velocity 0.32 +/- 0.12; right coronary artery flow velocity 0.38 +/- 0.17). There was a tendency toward a relative positive correlation between S/D ratio values and AR cineangiographic grades. Decreased S/D ratios were observed in 4 patients with aortic stenosis. It is believed that no reports exist on phasic coronary flow velocity recorded in conscious patients who had aortic valve disease.

Possible role of supernormal atrial conduction in the genesis of atrial fibrillation in patients with idiopathic paroxysmal atrial fibrillation.

OBJECTIVE: The occurrence of supernormal excitability and conduction in the atrium has been attributed to the internodal pathways in several animal experiments. However, little is known about the role of supernormal atrial conduction (SNC) in the genesis of arrhythmias. The specific aim of this study was to evaluate prospectively the relationship between SNC, atrial conduction defects and atrial fibrillation in patients with idiopathic paroxysmal atrial fibrillation. METHODS: Programmed atrial stimulation was performed in 38 control patients (group 1), and 21 patients with idiopathic paroxysmal atrial fibrillation (group 2) to assess some determinants of atrial conduction defects, SNC, and atrial fibrillation inducibility. RESULTS: The mean P-wave duration was 99 +/- 8 ms in group 1, and 110 +/- 12 ms in group 2; p < 0.001. The maximum interatrial conduction delay was 36 +/- 40 ms in group 1, and 56 +/- 21 ms in group 2; p < 0.005. Supernormal atrial conduction was observed in 27 (71 percent) patients of group 1, and in 5 (24 percent) of group 2; p < 0.0003. The SNC zone was 70 +/- 29 ms in group 1, and 16 +/- 31 ms in group 2; p < 0.0001. The maximum decrease in conduction time during the period of SNC was 12 +/- 4 ms in group 1 and 3 +/- 6 ms in group 2; p < 0.0005. The SNC zone showed a significant inverse correlation with the P-wave duration (r = -0.53; p < 0.0005), and with the maximum conduction delay (r = -0.38; p < 0.005). CONCLUSIONS: Patients with idiopathic paroxysmal atrial fibrillation have a significantly decreased incidence of SNC than controls. There is an inverse relation between the atrial conduction defects and the SNC. The association of the absence of SNC with defects in atrial conduction may play some role in the development of atrial fibrillation in patients with idiopathic paroxysmal atrial fibrillation.

A 15-year longitudinal follow-up study of heart rate and heart rate variability in healthy elderly persons.

BACKGROUND: Few researchers have conducted heart rate (HR) studies in healthy very elderly subjects aged 70 years or older, and there are no longitudinal follow-up studies in this population. The objective of this study was to evaluate long-term changes in HR and heart rate variability (HRV) with aging in healthy elderly persons by means of comparison between two Holter monitor recordings obtained at an interval of 15 years. METHODS: The study population consisted of 15 healthy elderly persons (10 women and 5 men) aged 64 to 80 years (mean 70 +/- 4.1) at the first recording, and 79 to 95 years old (mean 85 +/- 4.1 years) at the second recording 15 years later. Nighttime (midnight to 5 AM) and daytime (noon to 5 PM) HR and HRV were obtained, and paired t tests were performed to assess the differences in each parameter of nighttime and daytime HR and HRV between the two (15-year interval) Holter monitor recordings. RESULTS: The results of the t-test comparisons were as follows: there was a significant increase in minimal, maximal, and average HRs (nighttime, p < .01; daytime, p < .05, respectively). On the other hand, with regard to HRV, there was a significant nighttime decrease in the SDNN index (mean of standard deviations of normal RR intervals between adjacent QRS complexes resulting from sinus node depolarizations for all 5-minute segments) (p = .0086), and a significant daytime increase in the NN50 (number of adjacent normal RR intervals >50 milliseconds) per hour (p = .0425). Moreover, there was a significant decrease in the low-frequency (LF) component (nighttime, p = .0151; daytime, p = .0032), and a significant decrease in the LF/HF ratio (nighttime, p = .0270; daytime, p = .0371), but there was no significant change in the nighttime or daytime high-frequency (HF) component. CONCLUSIONS: HR increased with age over the 15-year period in the healthy elderly persons. As for concurrent changes in HRV, however, the parameters of sympathetic modulation decreased, and the parameters of parasympathetic modulation were unchanged or slightly increased.

Electrophysiologic demonstration of anterograde fast and slow pathways within the His bundle in patients with normal intraventricular conduction.

Electrophysiological evidence of functional longitudinal dissociation has been shown in different structures of the normal conduction system of the heart and in anomalous atrioventricular (AV) pathways. The typical sudden fast-to-slow jump phenomenon, which is commonly observed in patients with dual AV nodal pathways, has not been demonstrated so far within the normal His bundle. Herein we report unusual electrophysiological properties of the His bundle in two patients with normal intraventricular conduction. Of 86 patients with discontinuous anterograde AV function curves, programmed atrial stimulation revealed dual anterograde His bundle pathways in only 2 (2.3%) patients. Extrastimuli introduced at critically timed coupling intervals produced a sudden marked increase in H2-V2 interval suggesting failure of fast pathway with conduction proceeding through a slower pathway with shorter refractory period. With further decreasing coupling intervals, the second H2-V2 curve showed decremental conduction which allowed a type II gap phenomenon in the right bundle branch to occur in one of the patients. No echo beats were observed. These results provide the first electrophysiological demonstration, in patients with normal intraventricular conduction, of anterograde failure of a fast His bundle pathway with subsequent conduction through a slow His bundle pathway. His bundle duality was manifested by dual conduction times and refractory periods. These observations further expand our knowledge on the electrophysiologic properties of the His bundle.

Significance of elevated urinary human intestinal alkaline phosphatase in Japanese people exposed to environmental cadmium.

Urinary human intestinal alkaline phosphatase (IAP), beta 2-microglobulin (beta 2-MG) and N-acetyl-beta-D-glucosaminidase (NAG) were analyzed in 40 Japanese environmental-cadmium (Cd)-exposed and 40 non-exposed subjects to evaluate early biological markers for Cd-induced renal damage. All urinary indicators were significantly higher in the Cd-exposed subjects than non-exposed subjects. A fourth-order function was fitted for the relationship between beta 2-MG and IAP or NAG. The beta 2-MG concentration corresponding to the inflexion point for IAP was smaller than that for NAG. This result may support the contention that the cells containing IAP are damaged earlier than those containing NAG, and that IAP is a useful marker for detecting renal tubular dysfunction in people moderately exposed to Cd. However, in the stage of severe renal damage, the combination of IAP and beta 2-MG is considered to be more useful.

Chordoid meningioma. A case report.

We report on a 62-year-old woman without Castleman's syndrome diagnosed with chordoid meningioma. A white, encapsulated brain tumor was located in the parietal lobe of the left hemisphere of the cerebrum, adhered to the dura, and was separated from the cerebrum. The tumor revealed a multilobular arrangement of two types of neoplastic cells, and the surrounding myxoid stroma was separated by incomplete fibrous septa. Neoplastic cells consisted of myxomatous and meningothelial cells. The former made up about four-fifths of the tumor, had a vacuolar cytoplasm, and were arranged in a chordoma-like cord pattern. They were floating in myxoid stroma. The latter had an eosinophilic spindle or epithelioid cytoplasm and were disposed in lobules. Coarse eosinophilic materials positive for periodic acid-Schiff stain were deposited among them. Transitional cells between two types of cells were also observed. Both neoplastic cells were positive for vimentin and Leu-7 (CD57) in their cytoplasm, and were consistently negative for epithelial membrane antigen, S-100 protein, and cytokeratin.

Evidence of three clinical subgroups in patients with dual atrioventricular nodal pathways.

We attempted to test the hypothesis that dual atrioventricular (A-V) nodal pathways with second-degree atrioventricular block (2nd A-V block) present as a different clinical entity from those with A-V nodal reentranttachycardia (AVNRT). By evaluation with Holter monitoring (2.9 +/- 2.5 recordings/patient) and 12-lead electrocardiogram (11.9 +/- 11.6), 177 patients with dual A-V nodal pathways could be divided into three subgroups. Thirty-two patients had 2nd A-V block only (2nd A-V block group), 57 had AVNRT only (AVNRT group), 88 had neither 2nd A-V block nor AVNRT (silent group), and none had 2nd A-V block and AVNRT both. Electrophysiologic studies showed that the atrio-His interval was significantly greater (P < 0.0001) and the maximal 1:1 atrioventricular conduction rate was lower (P < 0.0001) in the 2nd A-V block group than in the other two groups. These differences were nullified after the administration of atropine. These results suggest that patients with dual A-V nodal pathways can be classified into three clinical subgroups based on the presence of either 2nd A-V block or AVNRT. We suggest also that patients of the 2nd A-V block group may have a more augmented vagal tone on the A-V node than the other two groups.

Temporal lobe lesion demonstrating features of dysembryoplastic neuroepithelial tumor and ganglioglioma: a transitional form?

We report an unusual multimodular glioneuronal lesion found in a temporal lobe from a 17-year-old boy with complex partial seizure. Histologically, this lesion was located within the cortex of the middle temporal gyrus and consisted of multinodular foci and the surrounding cortical dysplasia, resembling dysembryoplastic neuroepithelial tumor (DNT). However, it was quite different in the following respects from usual DNT: 1 nodule found in the subpial area consisted entirely of mature atypical neuronal cells separated by a reticulin fiber network connecting to the pia mater and the area around and between the above nodule, whereas another neighboring nodule, which contained many oligodondroglia-like round cells as well as occasional neuronal cells and fibrillary astrocytic cells, showed scattered neuronal cells in the well-differentiated fibrillary astrocytic stroma, the histological features being those of ganglioglioma (GG). We consider that the present case is a good example of the transitional form between DNT and GG. At 25 months following total lesion extirpation, the patient is healthy and free from seizures.

Cerebellar hemangioendothelioma.

We report a 26-year-old woman with cellular hemangioendothelioma that may be the third case diagnosed as cerebellar hemangioendothelioma. The tumor was composed of numerous vascular channels lined by endothelial cells and aggregates of large round endothelial cells. Transitional cells were also present. The large round cells were positive for CD34 and vimentin in their abundant cytoplasm that contained 1 or some red blood cells, revealing intracytoplasmic lumina. The patient remains free of disease over 5 years after tumor resection.