Amiodarone-induced liver cirrhosis and parkinsonism: a case report.

BACKGROUND: Amiodarone-induced hepatotoxicity consists of mild liver test abnormalities and rare cases of acute hepatitis and chronic hepatic lesions, and histologically resembles the whole spectrum of alcoholic liver disease, i.e., non-alcoholic steatohepatitis. Amiodarone-induced neurotoxicity, including tremor, ataxia and peripheral neuropathy, is known, and some cases of parkinsonism following amiodarone use have also been reported. OBJECTIVE: To study the pathology of amiodarone-associated parkinsonism. DESIGN: Light and electromicroscopic examinations of a patient with liver cirrhosis and amiodarone-induced parkinsonism. RESULTS: On postmortem examination, the liver showed micronodular cirrhosis. Striking steatosis and frequent Mallory bodies were present on light microscopy. There were lysosomal inclusion bodies on electron microscopy. From these findings, amiodarone-induced liver cirrhosis was diagnosed. Brain atrophy and infarcts were not observed, and pigmentation in the substantia nigra was preserved. Histologically, there was a slightly lesser degree of neuronal loss with astrocytosis in the substantia nigra, locus ceruleus, and dorsal vagal nucleus. Lewy bodies were not found. In the cerebral white matter and basal ganglia, Alzheimer Type II astrocytes, which are abundant in hepatic encephalopathy, had deposition of electron-dense materials within the lysosomes and mitochondrial matrices. The materials were compatible with the accelerated amiodarone. CONCLUSIONS: This is the first case in which the accumulation of amiodarone in the brain was morphologically observed. Amiodarone accumulation in the brain may play a role in neurotoxicity inducing parkinsonism.

Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS.

The authors calculated the progression rate (DeltaFS) using the total revised ALS Functional Rating Scale (ALSFRS-R) and symptom duration at diagnosis in 82 Japanese patients with ALS. Survival (death or tracheostomy) differed significantly with the DeltaFS and postdiagnostic period according to log-rank testing, but Cox proportional hazards modeling revealed no strong association between total ALSFRS-R and mortality, suggesting that the DeltaFS provides an additional predictive index beyond ALSFRS-R alone.

Clinical manifestations of chronic inflammatory demyelinating polyneuropathy with anti-cardiolipin antibodies.

OBJECTIVE: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune syndrome where certain autoantibodies define clinicopathologic subgroups. In the present study, serum anti-cardiolipin antibodies (aCL) were evaluated. MATERIALS AND METHODS: We investigated aCL in sera from 21 patients diagnosed with CIDP in our hospital between 1991 and 2001. The four CIDP patients with aCL (aCL+) were compared with 17 patients without aCL (aCL-). RESULTS: All aCL+ patients displayed sensory-motor polyneuropathy, with severity and distribution of weakness resembling those in aCL- patients. Anti-nuclear antibody titer of aCL+ patients were significantly higher than those in aCL- patients. None of aCL+ patients presented clinical manifestations of primary anti-phospholipid syndrome (APS), such as thromboses or recurrent abortion. Although the aCL+ patients were older and had more complications and more severe pathologic features than aCL- patients, they responded well to steroid pulse or intravenous immunoglobulin. CONCLUSION: The aCL in CIDP apparently differ from 'autoimmune' aCL in APS, instead being among the autoantibodies pathologically involved in CIDP subgroups.

Specific binding and effects of dehydroepiandrosterone sulfate (DHEA-S) on skeletal muscle cells: possible implication for DHEA-S replacement therapy in patients with myotonic dystrophy.

Dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) are the most abundant steroidal products and major circulating steroids in humans. The serum concentrations of DHEA-S are lower in patients with myotonic dystrophy (DM) than normal controls, and possible improvement of myotonia and muscle weakness was recently reported following DHEA-S replacement therapy. However, the molecular mechanism of action of DHEA-S remains unknown. To understand the reported anti-DM action of DHEA-S, we investigated DHEA-S binding in skeletal muscle cells in vitro. We identified two populations of DHEA-S binding sites (Kd = 5-9 microM and 35-40 microM) in C2C12 myocytes. Similar binding sites were also identified in human skeletal muscles. The Kd value of the high-affinity site was within the range of serum concentrations of DHEA-S in adult humans. Our results suggest that DHEA-S might act directly on skeletal muscles under normal physiological conditions in humans.

Herpes simplex virus myelitis: clinical manifestations and diagnosis by the polymerase chain reaction method.

Herpes simplex virus (HSV) myelitis has previously been reported to be a form of acute ascending necrotizing myelitis caused by HSV type 2 (HSV-2). We studied neurological symptoms, clinical course, magnetic resonance imaging (MRI) findings, and diagnosis by polymerase chain reaction (PCR) methods in 9 patients with HSV myelitis. In 6 cases, disease onset was marked by sensorimotor disturbances of lower extremities and urinary disturbances, with the transverse myelopathy gradually ascending to the cervicothoracic spinal cord level. The other 3 cases showed transverse myelopathy without an ascending pattern. Six cases showed acute progression, while 3 cases showed a subacute course. There were 2 cases with recurrent episodes. Three patients recovered, however, in the remaining 6 patients severe sequelae such as paraplegia persisted despite antiviral therapy. MRI showed a hyperintense lesion on T2-weighted images. Gadolinium enhancement was observed in 2 cases, and 1 case showed a hyperintense lesion both on T1- and on T2-weighted images, suggesting hemorrhagic necrosis. HSV-2 was detected by PCR techniques in all 6 cases with an ascending pattern. HSV-1 DNA was detected in 2 and HSV-2 DNA in 1 of the 3 cases with a nonascending pattern. Our findings demonstrate diverse clinical manifestations of HSV myelitis.

Inhibition of migration and proliferation of vascular smooth muscle cells by dehydroepiandrosterone sulfate.

Dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) are the most abundant steroids in humans, and their serum concentrations progressively decrease with age. Although relationships between DHEA(-S) and many age-related illnesses have been postulated, the mechanisms for their effects remain unknown, and specific receptors for these molecules have not been identified. In this paper, to investigate the role of DHEA(-S) in atherogenesis, we studied the proliferation and migration of a rabbit vascular smooth muscle cell line, SM-3, in the presence of DHEA(-S). Cellular proliferation was inhibited by DHEA-S, and to a lesser extent by DHEA. Modified Boyden's chamber assays revealed that DHEA-S inhibited the migration of SM-3 cells toward PDGF-BB. In cell attachment assays, DHEA-S inhibited the attachment of SM3 cells to fibronectin. It was suggested that the inhibitory effect of DHEA-S for SM-3 proliferation and migration was due to the decreased interaction with fibronectin. Scatchard analysis revealed the presence of two populations of DHEA-S binding sites in the nuclear fraction, and a smaller number in the cytosolic fraction. Since the dissociation constant of the higher affinity site was similar to the serum DHEA-S concentration in humans (Kd = 5.8 microM), this binding site could be functional under physiologic conditions. These findings suggest that there may be receptor-mediated anti-atherogenic actions of DHEA-S.

Inhibition of smooth muscle cell migration by the p21 cyclin-dependent kinase inhibitor (Cip1).

In vascular smooth muscle cells (SMCs), proliferation and migration contribute to lesion formation after arterial injury. In the cell cycle, several cyclin-dependent kinases (cdks) inhibitors are implicated in the regulating of cyclin-cdk activity such as p21Cip1, p16Ink4 and p27Kip1. Although Cip1 inhibits SMC proliferation, its effects on SMC migration are unknown. To test the hypothesis that Cip1 inhibits SMCs migration and proliferation, we transfected the Cip1 gene into a strain of rabbit aortic SMCs (SM3 cells). Both the spreading and the attachment of Cip1-transfected SM3 cells to extracellular matrices (ECMs) were inhibited compared to that of vector-transfected cells. In the modified Boyden's chamber assay the effect of fibronectin on the migratory activity of Cip1-transfected SM3 cells was significantly less than that of vector transfected cells in response to PDGF-BB. These data suggested that Cip1 inhibited both the migration and proliferation of SMC.

Effects of androgen receptor polyglutamine tract expansion on proliferation of NG108-15 cells.

Expansion of the polyglutamine tracts in the androgen receptor (AR) has been recognized as a cause of X-linked spinal and bulbar muscular atrophy (SBMA). In the present study, NG108-15 cells were stably transfected with expression vectors coding for either the wild type (WT) AR gene (CAG repeat number = 22) or a mutated (MT) AR gene (CAG repeat number = 52). Cells proliferation and cell cycle parameters were evaluated for NG108-15-WT and NG108-15-MT cells in the presence or absence of androgen. NG108-15-WT cells demonstrated an androgen-dependent increase in cell number, while NG108-15-MT cells did not. Our results demonstrate that expansion of polyglutamine tracts in the AR may affect the proliferation and differentiation of nerve cells.

Transcriptional activation by the androgen receptor in X-linked spinal and bulbar muscular atrophy.

Polyglutamine tracts encoded by trinucleotide CAG repeats have been found in some transcription factors. Expansion of the polyglutamine tracts in the androgen receptor (AR) has been recognized as a cause of X-linked spinal and bulbar muscular atrophy (SBMA). To study the role of AR as a transcription factor in SBMA, we constructed AR genes encoding expanded polyglutamine tracts (repeat numbers = 52, 92, 132, and 212), and analyzed AR-induced transcriptional activation in NG108-15 cells. We found that AR-induced transcriptional activation gradually decreased with increasing glutamine repeat numbers, and polyglutamine expansion caused a specific reduction in transcription activity in motor neurons. However, the degree of reduction was slight in comparison with the normal AR gene and that of SBMA. Thus, subtle disorders of transcriptional control may occur in SBMA.

Functional expression of the type 1 inositol 1,4,5-trisphosphate receptor promoter-lacZ fusion genes in transgenic mice.

Inositol 1,4,5-trisphosphate receptor (IP3R) is an inositol 1,4,5-trisphosphate (InsP3)-gated Ca2+ release channel. Type 1 IP3R (IP3R1) is the neuronal member of the IP3R family in the CNS and is predominantly expressed in cerebellar Purkinje cells. To elucidate the molecular mechanisms responsible for coupling gene expression to neuronal InsP3/Ca2+ signaling, we have studied the structure and function of the 5'-flanking region of the mouse IP3R1 gene. The cloned 5'-flanking region has several sequences sharing identity with motifs for known transcriptional regulation. We have fused 5'-flanking regions 1N from -528 to +169 and 4N from -4,187 to +169 to a beta-galactosidase gene (lacZ) as a reporter marker and have characterized their in vivo gene expression. Both 1N and 4N fusion genes functioned as a strong promoter in a neuroblastoma-glioma hybrid cell line NG108-15. Moreover, both 1N and 4N transgenic mouse lines carrying these 1N and 4N fusion genes showed characteristic patterns of beta-galactosidase activity in the CNS that are almost consistent with that of the endogenous IP3R1 protein, thereby suggesting that the 1N region from -528 to +169 contains sequence elements responsible for regulating gene expression in neurons and for specifying predominant expression in cerebellar Purkinje cells.

Herpes simplex virus type 2 infections presenting as brainstem encephalitis and recurrent myelitis.

We describe here 3 patients with central nervous system infection caused by herpes simplex virus type 2 (HSV-2); one patient with brainstem encephalitis and two with recurrent transverse thoracic myelitis. All three patients showed increased IgG antibodies to HSV in the cerebrospinal fluid (CSF). HSV-2 DNA was demonstrated in the CSF by polymerase chain reaction (PCR) amplification. Upon treatment with acyclovir, one patient with myelitis partially recovered and the others completely recovered. It is important to recognize the wide spectrum of clinical manifestations of HSV-2 infection in the central nervous system (CNS).

Lymphocytapheresis in combination with immunosuppressive drugs for refractory myasthenia gravis: two-color flow cytometric analysis of changes in peripheral blood lymphocyte subsets.

We carried out lymphocytapheresis (LCP) in combination with the administration of immunosuppressive drugs in patients with myasthenia gravis (MG), who were resistant to conventional immunosuppressive therapy, and examined its efficacy and effects on peripheral blood lymphocyte subsets. LCP was carried out once a week for 1 month (one course, 4 times) using a continuous-flow blood cell separator. Immunosuppressive medication (prednisolone or prednisolone and azathioprine) was continued during the course of treatment. After LCP, clinical improvement was noted in 5 of 6 patients. Anti-AChR antibody titers and the number of lymphocytes were significantly reduced in all patients. A significant decrease in CD4+CD45RA- (memory) T cell level and significant increase in CD4+CD45RA+ (naive) T cell level were also observed. In the patients having good response to LCP, follow-up evaluation showed long-term clinical improvements, as well as the memory T cell level staying at the decreased level. Our study suggests that LCP in combination with the administration of immunosuppressive drugs can suppress the disease activity of MG.

Multiple types of ryanodine receptor/Ca2+ release channels are differentially expressed in rabbit brain.

The neuronal Ca2+ signal is induced by a rise in the intracellular free Ca2+ concentration ([Ca2+]i), and is thought to be important for higher brain function. Dynamic changes in [Ca2+]i are affected by the spatial distributions of various Ca(2+)-increasing molecules (channels and receptors). The ryanodine receptor (RyR) is an intracellular channel through which Ca2+ is released from intracellular stores. To define the contribution of neuronal Ca2+ signaling via the RyR channel, we examined RyR type-specific gene expression in rabbit brain by in situ hybridization histochemistry. The neuronal RyR was composed of three distinct types, two types dominant in skeletal (sRyR) and cardiac (cRyR) muscle, respectively, and a novel brain type (bRyR). sRyR was distinguished by its high level of expression in cerebellar Purkinje cells. cRyR was predominantly expressed throughout nearly the entire brain, and was characterized by its markedly high level of expression in the olfactory nerve layer, layer VI of the cerebral cortex, the dentate gyrus, cerebellar granule cells, the motor trigeminal nucleus, and the facial nucleus. bRyR expression was the least widely distributed throughout the brain, and was high in the hippocampal CA1 pyramidal layer, caudate, putamen, and dorsal thalamus. This investigation demonstrates that the heterogeneous distribution of neuronal RyRs may be implicated in distinct Ca(2+)-associated brain functions. Moreover, it should be noted that cRyR, a typical CICR channel, is distributed widely throughout the brain, suggesting that in a variety of cell types, the amplification of neuronal Ca2+ signals is functionally accompanied by a rise in [Ca2+]i, such as Ca2+ influx stimulated by neuronal activity. This widespread distribution of the neuronal RyR family indicates that Ca2+ signals via the intracellular stores should be considered in studies of neuronal Ca2+ dynamics.

Distinctive functional properties of the neuronal BII (class E) calcium channel.

Functional diversity of voltage-dependent calcium channels (VDCC) is primarily due to the existence of six distinct genes of the channel-forming subunit alpha 1, which can be further classified into the L-type and neuronal non-L-type subfamilies. We have examined functional properties of the calcium channel BII expressed from the cloned cDNA, in Xenopus oocytes, and compared the results with the other members of the non-L-type subfamily, the BI and BIII channels. The BII channel is a high voltage-activated calcium channel pharmacologically features by its unique sensitivity to the inorganic blocker Ni2. The decaying component of the BII current shows high sensitivity to Ni2+ similar to that of the low voltage-activated channels and the R-type channel in cerebellar granule cells, whereas the sustained component is relatively resistant to Ni2+ as are the other high voltage-activated calcium channels. Dihydropyridines, omega-CgTx-GVIA, and omega-Aga-IVA, which have been used to discriminate L-, N-, and P-types, do not affect the BII current. The mode of modulation of the BII channel by auxiliary subunits is strikingly different from that observed in the L-type channels. Both activation and inactivation rates of the BII current are decelerated by coexpression of the beta subunit, and this effect is cancelled by further coexpression of the alpha 2 subunit. In situ tissue distribution studies indicate a higher level of BII mRNA expression in the hippocamus compared to other brain regions, revealing important difference in the relative abundance of BI, BII, and BIII channels in brain tissues. Overall, the results suggest that the BII channel forms a novel functional category of VDCC that is different from T-, L-, N-, and P-type.

[Three cases of herpes simplex virus type 2 myelitis--detection of HSV2 DNA in cerebrospinal fluid].

Polymerase chain reaction (PCR) technique has been successfully used to detect herpes simplex virus (HSV) from patients with HSV encephalitis. By PCR assay capable of differentiating HSV1 and 2, we detected HSV 2 DNA in cerebrospinal fluid (CSF) from patients with HSV myelitis and discussed the clinical findings. Three cases of HSV myelitis (a 49-year-old female, two 38- and 44-year-old males) were studied. All cases were characterized by transverse myelopathy of the thoracic cord, and two patients had recurrence. In all cases HSV1 antibodies were significantly elevated in serum and CSF. We used 500 microliters of CSF for PCR, and prepared one common upstream primer and two type specific downstream primers for HSV1 and HSV2. Using three primers simultaneously different sizes of PCR products were amplified from HSV1 and HSV2 DNA. PCR products subjected to electrophoresis on 1.2% agarose and stained with ethidium bromide. Still more southern blot hybridization was performed to detect DNA by 35S-end-labelled oligonucleotide prove. HSV2 DNA was amplified from CSF in all cases by PCR, and HSV2 DNA was detected at both first and second episode in two relapsing myelitis. No case of relapsing myelitis by HSV2 has been reported. The PCR technique is useful for diagnosis of HSV1 and 2 myelitis, and its would suggest that some patients of idiopathic myelopathy could be due to HSV2 myelitis and HSV2 myelitis may not be rare.

Report of a case of Crohn's disease associated with hyper-creatine phosphokinase-emia.

A young male patient with myositis associated with Crohn's disease is reported. His serum creatine phosphokinase (CPK) level was markedly elevated, but he had no muscle symptoms. The serum CPK level was not correlated with the activity of Crohn's disease. Muscle biopsy showed myositis with only degeneration of the muscle fibers and infiltration of inflammatory cells. The etiology of myositis in this case was not clear. Diagnosis of myositis based on a muscle biopsy in patients with Crohn's disease showing an elevated serum CPK level without any discernible cause has not been reported previously. Careful attention to the serum CPK and muscle symptoms in patients with Crohn's disease is suggested.