Deep venous thrombosis in patients with neurological diseases: A multicenter, prospective study.

OBJECTIVE: Patients with neurological diseases are liable to develop deep venous thrombosis (DVT) due to various factors. We investigated the prevalence, related factors, and prognosis of DVT in patients with neurological diseases. METHODS: Patients admitted to four hospitals due to neurological diseases were prospectively recruited. Those with cerebrovascular diseases were excluded. To screen for DVT, ultrasonography was performed in patients with possible DVT risk, such as D-dimer > 1.0 µg/dL, recent surgery, active malignant diseases, recent bone fracture, decreased activity, or treatment with immunoglobulin or steroid therapy. Clinical characteristics were compared between patients with and without DVT. RESULTS: A total of 106 patients (54 women, median 71 years old) were included. DVT was detected in 27 patients (26.0%) at the first assessment. All had DVT only in the calf; encephalopathy/meningitis (n = 4, 40.0%) had the highest prevalence of DVT among the underlying neurological diseases, followed by parkinsonian syndrome (n = 6, 37.5%). Independent predictors for DVT detection were malignant diseases (odds ratio, 11.7; 95% confidence interval, 1.0-301.4), modified Rankin Scale score ≥ 4 (5.4; 1.9-16.6), and D-dimer ≥ 2.0 µg/dL (5.7; 2.1-16.7). Ten patients were treated with anticoagulants, and no patients developed a symptomatic pulmonary embolism. No clinically evident pulmonary embolisms, systemic embolisms, or severe bleeding complications were observed in patients with DVT. CONCLUSIONS: Asymptomatic DVT is not rare in patients with neurological diseases, especially in those with malignancy, decreased activity, or elevated D-dimer. The overall prognosis is favorable, but the potential risk of development of a pulmonary embolism should be recognized.

Drastic therapy for listerial brain abscess involving combined hyperbaric oxygen therapy and antimicrobial agents.

BACKGROUND: Listeria monocytogenes (L. monocytogenes) is a rare causative pathogen of brain abscess that is often found in immunocompromised patients. Although patients with supratentorial listerial abscesses showed a longer survival with surgical drainage, the standard therapy for patients with subtentorial lesions has not been established. CASE REPORT: We report herein a patient with supra- and subtentorial brain abscesses caused by L. monocytogenes infection. These abscesses did not respond to antibiotics, and his symptoms gradually worsened. Drainage was not indicated for subtentorial lesions, and the patient was additionally treated with hyperbaric oxygen therapy, which dramatically reduced the volume of abscesses and improved the symptoms. CONCLUSIONS: This is the first report of drastic therapy for a patient with listerial brain abscesses involving combined antibiotics and hyperbaric oxygen therapy. The findings suggest that hyperbaric oxygen therapy is a good option for treating patients with deep-seated listerial abscesses and for who surgical drainage is not indicated.

Muscle biopsy findings predictive of malignancy in rare infiltrative dermatomyositis.

OBJECTIVE: The characteristic pathological muscular findings of polymyositis (PM) and dermatomyositis (DM) have been shown to reflect their different pathogeneses. Here, we characterized the muscle biopsy findings of PM and DM patients with or without malignancy. METHODS: We evaluated the muscle biopsy findings of 215 consecutive PM and DM patients admitted to our hospital between 1970 and 2009. Pathology of the lesion biopsy sections was classified into 3 types: endomysial infiltration-type, perivascular infiltration-type, and rare-infiltrative-type. RESULTS: There was no difference between the muscle pathology of PM patients with and without malignancy. However, the incidence of rare-infiltrative type muscle pathology in DM patients with malignancy was significantly higher than in those without such tumors (p=0.0345). CONCLUSION: The incidence of rare-infiltrative type muscle pathology may be a predictive marker of DM with malignancy.

Long-term outcome of polymyositis treated with high single-dose alternate-day prednisolone therapy.

BACKGROUND: We previously reported no difference in the efficacies of high-dose alternate-day (ADT) and daily-dose (DDT) prednisolone therapies in myositis patients, but that the incidence of side effects was lower in the former. The aim of the present study was to compare the long-term outcomes of both treatments in polymyositis patients. METHODS: We compared clinical courses, efficacies, adverse reactions, and outcomes of 115 consecutive, biopsy-proven polymyositis patients treated between 1970 and 2008 with ADT (32 patients) or DDT (83 patients). RESULTS: Mean onset ages, disease severity, incidences of malignancy, and response rates did not differ between the ADT and DDT groups. Adverse reactions (incidence of diabetes) were significantly higher in the DDT group. In this group, the incidences of hyperlipidemia, infection, hypertension, and psychiatric symptoms were also slightly higher, but not significantly so. The 20-year survival rate of the ADT group (68%) was significantly higher (p = 0.0112) than that of the DDT group (37%). CONCLUSION: ADT might be useful as an initial treatment option for polymyositis.

An inhibitor of transforming growth factor beta type I receptor ameliorates muscle atrophy in a mouse model of caveolin 3-deficient muscular dystrophy.

Skeletal muscle expressing Pro104Leu mutant caveolin 3 (CAV3(P104L)) in mouse becomes atrophied and serves as a model of autosomal dominant limb-girdle muscular dystrophy 1C. We previously found that caveolin 3-deficient muscles showed activated intramuscular transforming growth factor beta (TGF-ß) signals. However, the cellular mechanism by which loss of caveolin 3 leads to muscle atrophy is unknown. Recently, several small-molecule inhibitors of TGF-ß type I receptor (TßRI) kinase have been developed as molecular-targeting drugs for cancer therapy by suppressing intracellular TGF-ß1, -ß2, and -ß3 signaling. Here, we show that a TßRI kinase inhibitor, Ki26894, restores impaired myoblast differentiation in vitro caused by activin, myostatin, and TGF-ß1, as well as CAV3(P104L). Oral administration of Ki26894 increased muscle mass and strength in vivo in wild-type mice, and improved muscle atrophy and weakness in the CAV3(P104L) mice. The inhibitor restored the number of satellite cells, the resident stem cells of adult skeletal muscle, with suppression of the increased phosphorylation of Smad2, an effector, and the upregulation of p21 (also known as Cdkn1a), a target gene of the TGF-ß family members in muscle. These data indicate that both TGF-ß-dependent reduction in satellite cells and impairment of myoblast differentiation contribute to the cellular mechanism underlying caveolin 3-deficient muscle atrophy. TßRI kinase inhibitors could antagonize the activation of intramuscular anti-myogenic TGF-ß signals, thereby providing a novel therapeutic rationale for the alternative use of this type of anticancer drug in reversing muscle atrophy in various clinical settings.

Sporadic juvenile amyotrophic lateral sclerosis caused by mutant FUS/TLS: possible association of mental retardation with this mutation.

We present two cases of patients with juvenile amyotrophic lateral sclerosis (ALS), who had no history of familial ALS. The symptoms of both patients started as weakness of the unilateral upper limb and neck, and extended to bulbar and respiratory weakness in a relatively short period. Of note, the first patient was mentally retarded before the onset of weakness. Fused in sarcoma/translocated in liposarcoma (FUS/TLS) gene analyses revealed mutations of p. G492EfsX527 (c. 1475delG), which is a novel deletion/frameshift mutation, in the first patient and p. R514S mutation (c. 1542G > T) in the second patient. Molecular analysis revealed that the mutant FUS/TLS, especially the deletion/frameshift mutation, showed significant cytoplasmic localization in transfected motor neuron-like cells. Our findings suggest the association of mental retardation with the FUS/TLS mutation. Further investigation, including the effect of FUS/TLS on cognitive function, would aid better understanding of FUS/TLS proteinopathies.

Rescue from respiratory dysfunction by transduction of full-length dystrophin to diaphragm via the peritoneal cavity in utrophin/dystrophin double knockout mice.

Duchenne muscular dystrophy (DMD) is an inherited severe muscle wasting disorder with, thus far, no effective therapy. DMD causes respiratory and cardiac failure as well as muscle wastage. Among the various symptoms, respiratory insufficiency is a major cause of death in DMD patients at about 20 years of age. So, naturally, the improvement of respiratory function will extend the patient's life. We report here, for the first time, a sensitive procedure using whole-body plethysmography to monitor respiratory parameters detected in the utrophin/dystrophin double knockout mouse (dko mouse), showing quite similar systemic symptoms to human DMD including restrictive ventilatory impairment. Furthermore, we show that a highly efficient dystrophin-transduction to the dko's diaphragm--achieved by simple intraperitoneal injection of a helper-dependent adenovirus vector (HDAdv) containing the full-length dystrophin expression cassette--provided beneficial results. In spite of dystrophin expression only in the diaphragm, this focal gene transfer could result in the rescue from ventilatory impairment (increased tidal volume (TV) and improvement of compensatory hyperpnea). Our result suggests that a DMD patient's mortal ventilatory impairment may be improved via technically easy means through the intraperitoneal injection of HDAdv.

Muscle fiber type-predominant promoter activity in lentiviral-mediated transgenic mouse.

Variations in gene promoter/enhancer activity in different muscle fiber types after gene transduction was noticed previously, but poorly analyzed. The murine stem cell virus (MSCV) promoter drives strong, stable gene expression in hematopoietic stem cells and several other cells, including cerebellar Purkinje cells, but it has not been studied in muscle. We injected a lentiviral vector carrying an MSCV-EGFP cassette (LvMSCV-EGFP) into tibialis anterior muscles and observed strong EGFP expression in muscle fibers, primary cultured myoblasts, and myotubes isolated from injected muscles. We also generated lentiviral-mediated transgenic mice carrying the MSCV-EGFP cassette and detected transgene expression in striated muscles. LvMSCV-EGFP transgenic mice showed fiber type-dependent variations in expression: highest in types I and IIA, intermediate in type IID/X, and lowest in type IIB fibers. The soleus and diaphragm muscles, consisting mainly of types I and IIA, are most severely affected in the mdx mouse model of muscular dystrophy. Further analysis of this promoter may have the potential to achieve certain gene expression in severely affected muscles of mdx mice. The Lv-mediated transgenic mouse may prove a useful tool for assessing the enhancer/promoter activities of a variety of different regulatory cassettes.

Derlin-1 overexpression ameliorates mutant SOD1-induced endoplasmic reticulum stress by reducing mutant SOD1 accumulation.

Unfolded protein responses, including induction of stress sensor kinases, chaperones, and apoptotic mediators, are involved in the familial amyotrophic lateral sclerosis (ALS) model related to mutant Cu/Zn superoxide dismutase (SOD1) and sporadic ALS. We hypothesized that the endoplasmic reticulum-resident factor Derlin-1 plays a pivotal role in the regulation of misfolded proteins evoked by mutant SOD1. We show that Derlin-1 overexpression reduced mutant SOD1-induced cell toxicity and increased cell viability by suppressing the activation of the ER stress pathway factors: immunoglobulin-binding protein, activating transcription factor 6 p50, and C/EBP homologous protein. Interestingly, exogenous Derlin-1 resulted in a decrease in the amount of mutant SOD1, and a lesser decrease in that of wild-type SOD1, in transfected cells. Reduced SOD1 protein expression was observed in the microsomal fraction of wild-type and mutant SOD1 cells. Our results indicate that Derlin-1 regulates the turn over of SOD1 by promoting the proteasomal and autophagosomal degradation of SOD1 protein, but not by decreasing mutant SOD1 mRNA levels. Insights into the effects of Derlin-1 on mutant SOD1 may facilitate advancements in the treatment of motor neuron degeneration associated with ALS.

Mdx respiratory impairment following fibrosis of the diaphragm.

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease that causes respiratory or cardiac failure and results in death at about 20 years of age. An animal model of DMD, the mdx mouse, is commonly used to estimate dystrophic pathology. The pathological features of limb muscles are relatively mild, however the diaphragm is severely affected and exhibits a degenerative pattern similar to that observed in human DMD. Although, the muscle strength assay of the dystrophic diaphragm has been used to estimate mdx respiratory impairment, systemic functional assessments compared with histopathological analysis have not been demonstrated. Here, we report a sensitive procedure using whole-body plethysmography to monitor respiratory parameters detected during early respiratory insufficiency in the mdx mouse. The dystrophic changes in the diaphragm lead to respiratory dysfunctions. These methods may be useful to assess the therapeutic approaches for the mdx mouse.

[Cardioembolic stroke manifested by isolated tonic seizure of the left upper limb].

We reported a 61-year old man with cardioembolic stroke manifested by isolated tonic seizure of the left upper limb. He had a history of chronic atrial fibrillation and transient ischemic attack. He was brought to our hospital by ambulance, when he suddenly had isolated tonic seizure of left upper limb. On admission, he had no neurological symptoms and signs. Brain diffusion weighted MR image disclosed high intensity area in the right parietal lobe, although T2-weighted image did not show any abnormalities. On 8th day, a high intensity area was observed both on the diffusion-weighted and T2-weighted MR images. In case of isolated tonic seizure of left upper limb, careful examination of stroke is required especially if the patient had a high risk of stroke.

[Decerebrate rigidity after bilateral carotid arteries occlusion].

We reported a 77-year-old woman with atrial fibrillation. She was admitted to our hospital because of bradycardia and disturbance of consciousness. She regained consciousness soon after the admission, however on the 3rd day of admission, she abruptly fell into a coma. Neurological examination revealed decerebrate rigidity, conjugate eye deviation to the right, and bilateral Babinski signs, but remaining oculocephalic reflex in both vertical and horizontal directions. Diffusion-weighed MR image of the brain on the same day demonstrated extensive hyperintense lesions in the bilateral hemispheres, sparing the brainstem. On the duplex carotid ultrasonography just after the MR study, oscillating intraluminal thrombi occluded the right common carotid and the left internal carotid artery. We diagnosed the patient as having bilateral carotid occlusions by cardioembolic mechanism.

[Posterior encephalopathy syndrome in two patients after cancer surgery with transfusion].

We here report two patients (58-year-old, 77-year-old women) who presented themselves with generalized convulsion, impaired consciousness and hypertension several days after cancer surgery and transfusion. MRI T2 weighted images show an extensive area of increased signal intensity along the occipital cortex, but the underlying white matter revealed slight high signal intensity on diffusion weighted images. Despite similarities of those two cases to posterior leukoencephalopathy syndrome, they differ since the neuroimaging abnormalities are mostly in the occipital cortex. It is likely that the posterior cerebral cortex and white matter are vulnerable to circulatory, vascular and metabolic/toxic impairments. Depending on the abnormalities of many physiological variables, either the subcortical white matter, cortical gray or both might become a major target of this syndrome.