Charcot-Marie-Tooth disease type 2A with an autosomal-recessive inheritance: the first report of an adult-onset disease.

Axonal Charcot-Marie-Tooth disease (CMT) is most frequently caused by mutations in the MFN2 gene (CMT2A) that can lead to various clinical phenotypes. The age at disease onset varies, but most cases occur before adolescence. We report two Japanese sisters who presented with middle-age-onset peripheral neuropathy with distinct clinical features. In the affected sisters, a homozygous missense mutation, c.1894C>T, p.R632W, corresponding to the transmembrane domain of MFN2 was identified; this mutation was heterozygous in another non-affected sibling, demonstrating co-segregation of the genotype and phenotype. The patients developed adult-onset slowly progressive muscle weakness that was predominant in the calf muscles and sensory disturbance. Magnetic resonance imaging revealed diffuse atrophy of the spinal cord, especially in the thoracic segment, and mild atrophy of the parietal lobe and the cerebellum in both patients. Electron microscopy of the sural nerve revealed clusters of round and swollen mitochondria. This is the first case report of adult-onset CMT2A with an autosomal-recessive inheritance pattern. The phenotype caused by the MFN2 mutation in these cases is very mild, considering that the mutation causes middle-aged-onset Charcot-Marie-Tooth even in the homozygous state. The mechanism of MFN2 mutation-induced toxicity is an interesting theme that awaits further investigations.

Gemcitabine-induced CXCL8 expression counteracts its actions by inducing tumor neovascularization.

Patients with pancreatic ductal adenocarcinoma (PDAC) are frequently complicated with metastatic disease or locally advanced tumors, and consequently need chemotherapy. Gemcitabine is commonly used for PDAC treatment, but with limited efficacy. The capacity of gemcitabine to generate reactive oxygen species (ROS) in human pancreatic cancer cells, prompted us to examine its effects on the expression of pro-inflammatory cytokines and chemokines. We observed that gemcitabine enhanced selectively the expression of CXCL8 in human pancreatic cancer cells through ROS generation and NF-κB activation. In vitro blocking of CXCL8 failed to modulate gemcitabine-mediated inhibition of cell proliferation in human pancreatic cancer cells. Gemcitabine also enhanced CXCL8 expression in pancreatic cancer cells in xenografted tumor tissues. Moreover, anti-CXCL8 antibody treatment in vivo attenuated tumor formation as well as intra-tumoral vascularity in nude mice, which were transplanted with Miapaca-2 cells and treated with gemcitabine. Thus, gemcitabine-induced CXCL8 may counteract the drug through inducing neovascularization.

Design and synthesis of an in vivo-efficacious PIM3 kinase inhibitor as a candidate anti-pancreatic cancer agent.

Serine/threonine kinase PIM3 is a potential therapeutic target for pancreatic cancer. Here, we describe the evolution of our previous PIM1 inhibitor 1 into PIM3 inhibitor 11 guided by use of the crystal structure of PIM1 as a surrogate to provide a basis for rational modification. Compound 11 potently inhibits PIM3 kinase activity, as well as growth of several pancreatic cancer cell lines. In a mouse xenograft model, 11 inhibited growth of human pancreatic cancer cell line PCI66 with negligible body weight loss. Thus, 11 appears to be a promising lead compound for further optimization to develop new anti-pancreatic cancer agents.

Genome-wide analysis and expression profiling of half-size ABC protein subgroup G in rice in response to abiotic stress and phytohormone treatments.

The roles of the proteins encoded by half-size adenosine triphosphate-binding cassette transporter subgroup G (ABCG) genes in abiotic stress responses are starting to be established in the dicot model Arabidopsis thaliana. In the monocot model rice, the functions of most half-size ABCG proteins in abiotic stress responses are unknown. Rcn1/OsABCG5 is an essential transporter for growth and development under abiotic stress, but its molecular function remains largely unclear. Here, we present a comprehensive overview of all 30 half-size ABCG genes in rice, including their gene structures, phylogeny, chromosome locations, and conserved motifs. Phylogenetic analysis revealed that the half-size OsABCG proteins were divided to four classes. All seven rice intronless genes, including Rcn1/OsABCG5, were in Class III, like the 12 intronless ABCG genes of Arabidopsis. The EST and FL-cDNA databases provided expression information for 25 OsABCG genes. Semi-quantitative and quantitative RT-PCR analyses demonstrated that seven OsABCG genes were up-regulated in seedlings, shoots or roots following treatments with abiotic stresses (6, 17, 42 °C, NaCl, or mannitol) and abscisic acid. Another 15 OsABCG genes were up-regulated under at least one of the abiotic stress conditions and other phytohormones besides abscisic acid. Hierarchical clustering analysis of gene expression profiles showed that expression of the OsABCG genes could be classified into four clusters. The Rcn1/OsABCG5 cluster was up-regulated by abscisic acid and included OsABCG2, 3, 13, and 27. The present study will provide a useful reference for further functional analysis of the ABCGs in monocots.

[Campylobacter jejuni meningitis in an immunocompetent adult male].

A 51-year-old man with no underlying disease was referred to our hospital, complaining of mild headache. In May 2004 he developed headache of sudden onset in the occipital region and neck pain. He visited our hospital the following morning. At the first visit, there was no fever and only an analgesic was prescribed. The headache alleviated, with only occasional mild episodes thereafter. However, 2 days later, the headache aggravated again, associated this time with elevated body temperature (38 degrees C). The patient visited our hospital and a lumbar puncture was performed; examination of the cerebrospinal fluid revealed marked elevation of the cell count (mononuclear cell-dominant). The patient was admitted to the hospital and started on treatment with cefotaxime and acyclovir. However, the symptoms persisted and 10 days later, the cerebrospinal fluid culture yielded a growth of Campylobacter jejuni (C. jejuni). The antibiotic was therefore changed to panipenem, which resulted in prompt resolution of the symptoms. To the best of our knowledge, meningitis caused by C. jejuni in an immunocompetent adult is extremely rare. This case highlights the importance of bearing in mind the possibility of C. jejuni meningitis in a patient of meningitis associated with mononuclear cell-dominant pleocytosis of the cerebrospinal fluid.

Rice Stomatal Closure Requires Guard Cell Plasma Membrane ATP-Binding Cassette Transporter RCN1/OsABCG5.

Water stress is one of the major environmental stresses that affect agricultural production worldwide. Water loss from plants occurs primarily through stomatal pores. Here, we report that an Oryza sativa half-size ATP-binding cassette (ABC) subfamily G protein, RCN1/OsABCG5, is involved in stomatal closure mediated by phytohormone abscisic acid (ABA) accumulation in guard cells. We found that the GFP-RCN1/OsABCG5-fusion protein was localized at the plasma membrane in guard cells. The percentage of guard cell pairs containing both ABA and GFP-RCN1/OsABCG5 increased after exogenous ABA treatment, whereas they were co-localized in guard cell pairs regardless of whether exogenous ABA was applied. ABA application resulted in a smaller increase in the percentage of guard cell pairs containing ABA in rcn1 mutant (A684P) and RCN1-RNAi than in wild-type plants. Furthermore, polyethylene glycol (drought stress)-inducible ABA accumulation in guard cells did not occur in rcn1 mutants. Stomata closure mediated by exogenous ABA application was strongly reduced in rcn1 mutants. Finally, rcn1 mutant plants had more rapid water loss from detached leaves than the wild-type plants. These results indicate that in response to drought stress, RCN1/OsABCG5 is involved in accumulation of ABA in guard cells, which is indispensable for stomatal closure.

Global aphasia without hemiparesis: the underlying mechanism examined by transcranial magnetic stimulation.

INTRODUCTION: Global aphasia without hemiparesis (GAWH) is a rare stroke syndrome. Using transcranial magnetic stimulation (TMS), we evaluated 2 possible pathogenic mechanisms for GAWH: sparing of the decussated pyramidal tract, or alternatively, compensation by the ipsilateral pyramidal tract. METHODS: Six patients were diagnosed to have GAWH by the Standard Language Test of Aphasia for Japanese. All patients underwent brain magnetic resonance (MR) imaging and angiography. According to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria, stroke subtype was determined as 3 patients with cardioembolic stroke, 2 with large-artery atherosclerosis, and 1 with another type. All patients underwent TMS, using a figure-of-8 coil, from 3 to 12 months after the onset, and motor evoked potentials were recorded on the abductor digiti minimi muscles. RESULTS: All patients had left-sided frontal or temporal lesions that were confirmed by MR diagnostic imaging. No motor evoked potential could be recorded by ipsilateral TMS. In 3 patients, brain stimulation on either side evoked the same amplitude on the contralateral abductor digiti minimi, whereas in the other 3 patients, the amplitude was suppressed on the right side. The infarction in the former patients was caused by cardioembolism and in the latter was not. In serial slices of brain MR imaging, the pyramidal tract was spared in the former and was involved to various degrees in the latter 3 patients. CONCLUSIONS: We recommend that GAWH was caused by the sparing of the decussated pyramidal tract. The pyramidal tract was intact in cases of GAWH caused by cardioembolism and subclinically impaired by other causes.