[A case of suspected vertebral artery stump syndrome assessed by CT angiography].

A 55-year-old man developed ischemic stroke in the bilateral cerebellar hemispheres and bilateral occipital lobes. He was admitted to our hospital 17 months later with recurrent ischemic stroke in the posterior circulation. The left vertebral artery (VA) was occluded on brain magnetic resonance angiography but was visualized with a delay on continuous three-phase CT angiography (CTA). Conventional angiography confirmed a to-and-fro blood flow pattern at the distal end of the left VA, therefore the patient was diagnosed with VA stump syndrome (VASS). VASS is a recurrent posterior circulation ischemic stroke caused by thrombi in an occluded unilateral VA. VASS should be suspected in patients with unilateral VA occlusion and repeated posterior-circulation ischemic stroke. The diagnostic criteria for VASS include confirmation of VA occlusion and the presence of an antegrade flow component at the distal end. In this case, the presence of collateral circulation in the VA was suspected based on CTA findings, leading to the diagnosis of VASS. It was thus suggested that devising the imaging method of CTA may help diagnose VASS.

Noniatrogenic Meningitis Caused by Streptococcus salivarius Associated with Early Esophageal Cancer and Early Gastric Cancer.

Streptococcus salivarius is part of the normal oral cavity and gastrointestinal tract microflora and an unusual cause of acute bacterial meningitis. We herein report an 81-year-old man with S. salivarius meningitis, which led to a diagnosis of early esophageal cancer and early gastric cancer. S. salivarius infection may occur through the gastrointestinal mucosa when it is disrupted in association with early gastrointestinal cancer. To our knowledge, this is the first report describing S. salivarius meningitis associated with multiple early gastrointestinal cancers in the absence of other sources of infection.

Distinctive chaperonopathy in skeletal muscle associated with the dominant variant in DNAJB4.

DnaJ homolog, subfamily B, member 4, a member of the heat shock protein 40 chaperones encoded by DNAJB4, is highly expressed in myofibers. We identified a heterozygous c.270 T > A (p.F90L) variant in DNAJB4 in a family with a dominantly inherited distal myopathy, in which affected members have specific features on muscle pathology represented by the presence of cytoplasmic inclusions and the accumulation of desmin, p62, HSP70, and DNAJB4 predominantly in type 1 fibers. Both Dnajb4F90L knockin and knockout mice developed muscle weakness and recapitulated the patient muscle pathology in the soleus muscle, where DNAJB4 has the highest expression. These data indicate that the identified variant is causative, resulting in defective chaperone function and selective muscle degeneration in specific muscle fibers. This study demonstrates the importance of DNAJB4 in skeletal muscle proteostasis by identifying the associated chaperonopathy.

Taurine depletion during fetal and postnatal development blunts firing responses of neocortical layer II/III pyramidal neurons.

Fetal and infant brains are rich in maternally derived taurine. We previously demonstrated that taurine action regulates the cation-chloride cotransporter activity and the differentiation and radial migration of pyramidal neuron progenitors in the developing neocortex of rodent fetuses. Here we examined the effects of fetal and infantile taurine depletion caused by knockout of the taurine transporter Slc6a6 on firing properties of layer II/III pyramidal neurons in the mouse somatosensory cortex at 3 weeks of postnatal age, using the whole-cell patch-clamp technique. The membrane excitability under resting conditions was similar between the neurons in knockout mice and those in wildtype littermates. However, the frequency of repetitive spike firing during moderate current injection was significantly lower, along with lower membrane voltage levels during interspike intervals in knockout neurons. When strong currents were injected, by which repetitive firing was rapidly abolished due to inactivation of voltage-gated Na+ channels in wildtype neurons, the firing in knockout neurons lasted for a much longer period than in wildtype neurons. This was due to much lower membrane voltage levels during interspike intervals in knockout neurons, promoting greater recovery of voltage-gated Na+ channels from inactivation. Thus, taurine depletion in pyramidal neurons blunted neuronal responses to external stimuli through increasing the stability of repetitive firing, presumably mediated by larger increases in membrane K+ conductance during interspike intervals.

WNK3 kinase maintains neuronal excitability by reducing inwardly rectifying K+ conductance in layer V pyramidal neurons of mouse medial prefrontal cortex.

The with-no-lysine (WNK) family of serine-threonine kinases and its downstream kinases of STE20/SPS1-related proline/alanine-rich kinase (SPAK) and oxidative stress-responsive kinase-1 (OSR1) may regulate intracellular Cl- homeostasis through phosphorylation of cation-Cl- co-transporters. WNK3 is expressed in fetal and postnatal brains, and its expression level increases during development. Its roles in neurons, however, remain uncertain. Using WNK3 knockout (KO) mice, we investigated the role of WNK3 in the regulation of the intracellular Cl- concentration ([Cl-]i) and the excitability of layer V pyramidal neurons in the medial prefrontal cortex (mPFC). Gramicidin-perforated patch-clamp recordings in neurons from acute slice preparation at the postnatal day 21 indicated a significantly depolarized reversal potential for GABAA receptor-mediated currents by 6 mV, corresponding to the higher [Cl-]i level by ~4 mM in KO mice than in wild-type littermates. However, phosphorylation levels of SPAK and OSR1 and those of neuronal Na+-K+-2Cl- co-transporter NKCC1 and K+-Cl- co-transporter KCC2 did not significantly differ between KO and wild-type mice. Meanwhile, the resting membrane potential of neurons was more hyperpolarized by 7 mV, and the minimum stimulus current necessary for firing induction was increased in KO mice. These were due to an increased inwardly rectifying K+ (IRK) conductance, mediated by classical inwardly rectifying (Kir) channels, in KO neurons. The introduction of an active form of WNK3 into the recording neurons reversed these changes. The potential role of KCC2 function in the observed changes of KO neurons was investigated by applying a selective KCC2 activator, CLP290. This reversed the enhanced IRK conductance in KO neurons, indicating that both WNK3 and KCC2 are intimately linked in the regulation of resting K+ conductance. Evaluation of synaptic properties revealed that the frequency of miniature excitatory postsynaptic currents (mEPSCs) was reduced, whereas that of inhibitory currents (mIPSCs) was slightly increased in KO neurons. Together, the impact of these developmental changes on the membrane and synaptic properties was manifested as behavioral deficits in pre-pulse inhibition, a measure of sensorimotor gating involving multiple brain regions including the mPFC, in KO mice. Thus, the basal function of WNK3 would be the maintenance and/or development of both intrinsic and synaptic excitabilities.

[A case of colchicine myopathy in which the long-term use of colchicine hampered the recovery].

A 69-year-old woman was admitted to our hospital because of limb weakness. She was diagnosed to have chronic renal failure due to diabetes mellitus and had suffered from pericardial effusion at 67 years of age. She started taking colchicine 18 months before admission and thereafter gradually developed muscle weakness in her limbs and had become bedridden at the time of admission. The withdrawal of colchicine improved her limb weakness, and therefore we diagnosed her to have colchicine myopathy. Her muscle strength did not completely recover even after six months from cessation of colchicine. It was suggested that renal failure and muscle disuse had prevented the full recovery of her muscles in addition to the long-term use of colchicine. Typical colchicine myopathy improves rapidly, but the long-term use of colchicine is considered to cause muscle weakness. Although the CK level was elevated, the elevated CK and myopathy had been overlooked because the CK baseline was low due to the patient's small amount of muscle mass. Moreover, the estimated GFR was recorded to be higher than her actual renal function due to her small amount of muscle mass, therefore the risk of colchicine myopathy in this case remained unrecognized.

[A case of human adjuvant disease with clinical features of Guillain-Barré syndrome].

A 69-year-old female developed subacute diplopia, right peripheral facial nerve palsy, bilateral upper and lower extremities dysesthesia and weakness 50 years after silicone injection for breast augmentation. Motor conduction study revealed prolonged distal latency and reduced amplitude in the median, ulnar, and peroneal nerves. Sensory conduction velocities were reduced in the median and ulnar nerves, and sensory potential in the sural nerve could not be recorded. While intravenous immunoglobulin therapy was ineffective, explantation of silicone breast implants improved her neurological symptoms. Histopathological study of axillary lymph node revealed foreign body granulomas and macrophages phagocyting silicone. The patient was diagnosed with human adjuvant disease presenting clinical features of Guillain-Barré syndrome. Human adjuvant disease should be considered in the patients with implants like silicone and neurological symptoms.

Rostrocaudal Areal Patterning of Human PSC-Derived Cortical Neurons by FGF8 Signaling.

The cerebral cortex is subdivided into distinct areas that have particular functions. The rostrocaudal (R-C) gradient of fibroblast growth factor 8 (FGF8) signaling defines this areal identity during neural development. In this study, we recapitulated cortical R-C patterning in human pluripotent stem cell (PSC) cultures. Modulation of FGF8 signaling appropriately regulated the R-C markers, and the patterns of global gene expression resembled those of the corresponding areas of human fetal brains. Furthermore, we demonstrated the utility of this culture system in modeling the area-specific forebrain phenotypes [presumptive upper motor neuron (UMN) phenotypes] of amyotrophic lateral sclerosis (ALS). We anticipate that our culture system will contribute to studies of human neurodevelopment and neurological disease modeling.

The Possible Link between GABAergic Dysfunction and Cognitive Decline in a Patient with Idiopathic Hypoparathyroidism.

Idiopathic hypoparathyroidism (IHP) is accompanied by cognitive impairment. We report the case of a 70-year-old IHP patient with cognitive disturbance. Brain computed tomography showed bilateral calcification in basal ganglia, thalamus, and cerebellum. Neuropsychological assessment revealed low scores for intelligence, memory, and perseverative errors. Brain positron emission tomography showed a significant reduction in [(18)F]-Fludeoxyglucose (FDG) uptake in bilateral frontal, left temporal and parietal cortices, along with a marked reduction in [(11)C]-flumazenil binding in left frontal, temporal, parietal, and bilateral cerebellum. These findings suggest cognitive impairment in IHP may be ascribed to GABAergic dysfunction, thus leading to, or coexisting with, cerebral hypometabolism.

GABA-A receptor impairment in cerebellar ataxia with anti-glutamic acid decarboxylase antibodies.

Antibodies against glutamic acid decarboxylase (GAD-Abs) are associated with cerebellar ataxia, which is refractory to treatment with GABAergic drugs. To investigate the GABAergic neuronal system in vivo, we performed a combined positron emission tomography (PET) study with [(11)C]-flumazenil and [(18)F]-fluorodeoxyglucose (FDG) in three patients with cerebellar ataxia with GAD-Abs. The GABA-A receptor function was investigated using flumazenil, which is a selective GABA-A receptor ligand, while FDG-PET using a three-dimensional stereotactic surface projection analysis was performed to estimate the metabolic rates of glucose (MRGlc) in the patients. GABAergic drugs showed no efficacy for the cerebellar ataxia in all three patients, and all three displayed a significant decrease in flumazenil binding in the cerebellum. No MRGlc decrease in the cerebellum was found in the two patients who presented with amelioration of cerebellar ataxia following intravenous immunoglobulin (IVIG) therapy, whereas a significant MRGlc decrease in the cerebellar hemisphere was observed in another patient who showed severe cerebellar atrophy on magnetic resonance images and no response to the IVIG therapy. The decreased flumazenil binding in the present patients indicated cerebellar GABA-A receptor impairment, which may be due to either neuronal cell loss, as demonstrated by the decreased MRGlc, or a dysfunction in GABAergic neuronal inhibition. Although GAD-Abs have been postulated to prevent the synthesis of GABA, resulting in decreased GABAergic transmission, the GABA-A receptor impairment may play another pathogenic role in cerebellar ataxia associated with GAD-Abs resulting in a condition refractory to GABAergic drug therapy.

[A case of cerebral amyloid angiopathy with reversible white matter lesions and multiple cerebral microbleeds].

A 59-year-old woman presented with a 7-year history of headache. She showed no neurological abnormality. T(2) weighted magnetic resonance (MR) images showed a hyperintense signal in the white matter in the bilateral parieto-occipital lobe without abnormal enhancement. A small amount of prednisolone was administered for rheumatoid arthritis. After prednisolone was discontinued, the T(2) weighted images showed an expansion of the hyperintense signal lesions seen in the white matter, and T(2) weighted image showed multiple foci of petechial bleeding in the cortex and subcortex of the bilateral occipital lobe. A brain biopsy specimen from the right occipital lobe revealed deposition of amyloid in the subarachnoidal and cortical vessel walls and transmural infiltration of a few lymphocytes, eosinophils, and giant histiocytes. Subsequently the patient was diagnosed with central nervous system vasculitis associated with cerebral amyloid angiopathy (CAA). After 5 months, the T(2) weighted images showed a remarkable regression of the hyperintense signal lesions in the white matter of the bilateral parieto-occipital lobe without the administration of any maintenance immunosuppressive agents. However, T(2) weighted image showed an increase of multiple cortico-subcortical foci of petechial bleeding. Her headache did not improve during the illness. Thus, we should consider the diagnosis of CAA when patients present with reversible white matter lesions and multiple cerebral microbleeds simultaneously.