Axonal TDP-43 aggregates in sporadic amyotrophic lateral sclerosis.

AIMS: Axonal aggregates of phosphorylated (p-) transactive response DNA-binding protein 43 kDa (TDP-43) in sporadic amyotrophic lateral sclerosis (sALS) were examined in relation to propagation of the protein in the nervous system. METHODS: Brains and spinal cords of Japanese patients with sALS and control subjects were examined immunohistochemically using formalin-fixed paraffin-embedded specimens with special reference to the topographical distribution, microscopic features, presynaptic aggregates, and correlation between the aggregates in axons and the clinical course. RESULTS: (i) Aggregates of p-TDP-43 were frequently present in axons of the hypoglossal and facial nerve fibres and the spinal anterior horn cells. (ii) Aggregates of p-TDP-43 in the axons showed two characteristic microscopic features - dash-like granuloreticular aggregates (GRAs) and massive aggregates (MAs). (iii) MAs were surrounded by p-neurofilaments, but p-neurofilament immunnoreactivity decreased at the inside of axons with GRAs. (iv) Patients showing MAs and GRAs had a relatively shorter clinical course than patients without the aggregates. (v) Some neurones in the red nucleus in patients were surrounded by synapses containing p- and p-independent (i)-TDP-43, and almost all neurones had lost their nuclear TDP-43 immunoreactivity; 17% of those neurones in the red nucleus also had TDP-43-immunopositive neuronal cytoplasmic inclusions, but no postsynaptic p-TDP-43 deposition was evident. CONCLUSIONS: There are two types of axonal p-TDP-43 aggregates, MAs and GRAs, located predominantly in the facial and hypoglossal nuclei and anterior horn cells. These aggregates may influence the function of neurones, and presynaptic aggregates of the protein induce loss of p-i-TDP-43 in the nuclei of postsynaptic neurones.

Pressure-induced valence crossover and novel metamagnetic behavior near the antiferromagnetic quantum phase transition of YbNi_{3}Ga_{9}.

We report electrical resistivity, ac magnetic susceptibility, and x-ray absorption spectroscopy measurements of intermediate valence YbNi_{3}Ga_{9} under pressure and magnetic field. We have revealed a characteristic pressure-induced Yb valence crossover within the temperature-pressure phase diagram, and a first-order metamagnetic transition is found below P_{c}∼9 GPa where the system undergoes a pressure-induced antiferromagnetic transition. As a possible origin of the metamagnetic behavior, a critical valence fluctuation emerging near the critical point of the first-order valence transition is discussed on the basis of the temperature-field-pressure phase diagram.

Compact, highly efficient ytterbium doped bismuthate glass waveguide laser.

Laser slope efficiencies close to the quantum defect limit and in excess of 78% have been obtained from an ultrafast laser inscribed buried channel waveguide fabricated in a ytterbium-doped bismuthate glass. The simultaneous achievement of low propagation losses and preservation of the fluorescence properties of ytterbium ions is the basis of the outstanding laser performance.

Relationship between the localization of fibroblast growth factor 9 in prostate cancer cells and postoperative recurrence.

BACKGROUND: Fibroblast growth factor 9 (FGF9) enhances cell proliferation and invasiveness in several malignant diseases. The aim of the present study is to investigate the role of FGF9 in postoperative recurrence after radical prostatectomy. METHODS: Cell viability and invasion of LNCaP cells were assessed using MTT assay and Matrigel invasion assay, respectively, in the presence or absence of treatment with recombinant FGF9. Tissues obtained during a radical prostatectomy in 133 male patients were immunohistochemically stained using anti-FGF9 antibody. RESULTS: Cell viability and invasion of LNCaP was significantly enhanced by treatment with recombinant FGF9. Immunohistochemical staining detected FGF9-positive cells in 20 samples. The prevalence of FGF9-positive cells in cases with a Gleason score of 8 or higher was 34.2%, which was significantly higher than that in those with Gleason scores of 7 or lower (7.3%, P=0.0003), respectively. The 3-year biochemical relapse-free survival rate was 17.5% in cases with FGF9-positive cells, which was significantly lower than that in cases in which FGF9-positive cells were not detectable (75.5%, P < 0.0001). CONCLUSIONS: These results indicate that FGF9 can stimulate proliferation and invasion in prostate cancer cells, thus FGF9 could be a candidate of a predictive factor for recurrence after radical prostatectomy.

Painful laser stimuli induce directed functional interactions within and between the human amygdala and hippocampus.

The pathways by which painful stimuli are signaled within the human medial temporal lobe are unknown. Rodent studies have shown that nociceptive inputs are transmitted from the brainstem or thalamus through one of two pathways to the central nucleus of the amygdala. The indirect pathway projects from the basal and lateral nuclei of the amygdala to the central nucleus, while the direct pathway projects directly to the central nucleus. We now test the hypothesis that the human ventral amygdala (putative basal and lateral nuclei) exerts a causal influence upon the dorsal amygdala (putative central nucleus), during the application of a painful laser stimulus. Local field potentials (LFPs) were recorded from depth electrode contacts implanted in the medial temporal lobe for the treatment of epilepsy, and causal influences were analyzed by Granger causality (GRC). This analysis indicates that the dorsal amygdala exerts a pre-stimulus causal influence upon the hippocampus, consistent with an attention-related response to the painful laser. Within the amygdala, the analysis indicates that the ventral contacts exert a causal influence upon dorsal contacts, consistent with the human (putative) indirect pathway. Potentials evoked by the laser (LEPs) were not recorded in the ventral nuclei, but were recorded at dorsal amygdala contacts which were not preferentially those receiving causal influences from the ventral contacts. Therefore, it seems likely that the putative indirect pathway is associated with causal influences from the ventral to the dorsal amygdala, and is distinct from the human (putative) indirect pathway which mediates LEPs in the dorsal amygdala.

Attention to painful cutaneous laser stimuli evokes directed functional connectivity between activity recorded directly from human pain-related cortical structures.

Our previous studies show that attention to painful cutaneous laser stimuli is associated with functional connectivity between human primary somatosensory cortex (SI), parasylvian cortex (PS), and medial frontal cortex (MF), which may constitute a pain network. However, the direction of functional connections within this network is unknown. We now test the hypothesis that activity recorded from the SI has a driver role, and a causal influence, with respect to activity recorded from PS and MF during attention to a laser. Local field potentials (LFP) were recorded from subdural grid electrodes implanted for the treatment of epilepsy. We estimated causal influences by using the Granger causality (GRC), which was computed while subjects performed either an attention task (counting laser stimuli) or a distraction task (reading for comprehension). Before the laser stimuli, directed attention to the painful stimulus (counting) consistently increased the number of GRC pairs both within the SI cortex and from SI upon PS (SI>PS). After the laser stimulus, attention to a painful stimulus increased the number of GRC pairs from SI>PS, and SI>MF, and within the SI area. LFP at some electrode sites (critical sites) exerted GRC influences upon signals at multiple widespread electrodes, both in other cortical areas and within the area where the critical site was located. Critical sites may bind these areas together into a pain network, and disruption of that network by stimulation at critical sites might be used to treat pain. Electrical activity recorded from the somatosensory cortex drives activity recorded elsewhere in the pain network and may bind the network together; disruption of that network by stimulation at critical sites might be used to treat pain.

Association of clinical oral health status with self-rated oral health and GOHAI in Japanese adults.

OBJECTIVE: The objective of this study was to investigate clinical oral health status relationships that affect quality of life (using the 12-item General Oral Health Assessment Index (GOHAI)) and self-rated oral health in a community of Japanese residents. METHODS: 459 residents of Yokote City, Japan aged 40-55 years had oral health examinations and completed self-administered questionnaires collecting data on age, gender, GOHAI items and self-rated oral health. Linear regression analysis was performed with GOHAI or self-rated oral health as a dependent variable and gender, age and indicators of oral health status as independent variables. RESULTS: The GOHAI indicated 42.7% of subjects were concerned about the appearance of their teeth, 30.1% were worried about teeth problems and 27.5% concerned about sensitive teeth. Analyses showed that gender, decayed teeth, oral dryness and missing teeth were significantly associated with variation in GOHAI scores, and that gender, decayed teeth, oral dryness and oral hygiene were significantly associated with variation in self-rated oral health. CONCLUSION: This study revealed that in this sample of Japanese adults aged 40-55 years, decayed teeth and oral dryness affected both GOHAI and self-rated oral health, whereas missing teeth affected GOHAI and oral hygiene affected self-rated oral health. Subjects did not recognise periodontal disease as a quality of life impacting condition or as a health problem.

Spatial attention to thermal pain stimuli in subjects with visual spatial hemi-neglect: extinction, mislocalization and misidentification of stimulus modality.

One approach to the study of disordered spatial attention is to carry out tests of extinction, in which stimuli are detected on the left when they are presented on the left alone, but not when both sides are stimulated simultaneously in a dual simultaneous stimulation (DSS) protocol. Extinction has been documented for multiple sensory modalities, but not for thermal pain stimuli, to our knowledge. We now test the hypothesis that subjects with visual spatial neglect (hemi-neglect) will have alterations in thermal pain sensation which are related to abnormal spatial attention. The results demonstrate that thermal pain extinction of hot and cold pain stimuli occurs in a proportion of subjects with hemi-neglect. In the subjects with visual spatial hemi-neglect but without thermal pain extinction, the sensation of the thermal pain stimulus on the affected (left) side was not extinguished but was often localized to the unaffected (right) side, and the submodality of the stimulus (cold or hot) was often misidentified. Ratios indicating the magnitude of extinction, mislocalization and misidentification were significantly larger on the left side of subjects with visual spatial neglect than in healthy controls or in controls with stroke but without hemineglect. The proportion of subjects with thermal pain extinction, mislocalization, or misidentification was significantly higher in subjects with hemi-neglect than those in either control group. These results demonstrate that disordered attention exerts a powerful effect upon the perception of both the location and the quality of thermal pain stimuli.

Relationship between the acid-inhibitory effects of two proton pump inhibitors and CYP2C19 genotype in Japanese subjects: a randomized two-way crossover study.

This two-way crossover study investigated possible differences between the proton pump inhibitors, omeprazole and rabeprazole, in their effect on gastric acid secretion in Japanese subjects with differing cytochrome P450, family 2, subfamily C, polypeptide 19 (CYP2C19) genotypes. A total of 23 Helicobacter pylori-negative healthy volunteers received omeprazole 20 mg/day and rabeprazole 10 mg/day. Each drug treatment was given for a continuous 7-day period allocated in random order, with an interval of at least 1 week between drug treatment periods to allow for wash-out. Intragastric pH was measured on days 1 and 7. Overall median intragastric pH levels at 7 and 8 h after the first administration were significantly higher with omeprazole. There was no significant difference in intragastric pH in homozygous extensive metabolizers, whereas intragastric pH was significantly higher with omeprazole in combined data from heterozygous extensive metabolizers and poor metabolizers at 6, 7 and 8 h after the first drug administration. There were no significant differences in intragastric pH between omeprazole and rabeprazole irrespective of genotype on day 7 of administration. In conclusion, on day 1 the time to onset of the antisecretory action of 20 mg/day omeprazole was more rapid than that of 10 mg/day rabeprazole in Japanese individuals who have a higher incidence of the CYP2C19 poor metabolizer genotype, however by day 7 no difference in antisecretory effect was found, regardless of genotype.

An 8-month-old boy with congenital fibromuscular dysplasia presenting with shock caused by sudden renal hemorrhage.

Fibromuscular dysplasia (FMD) is a non-atheromatous, non-inflammatory, multifocal segmental angiopathy. FMD is the most common cause of pediatric renovascular hypertension. Aneurysmal formation of the main renal artery and distal branches is a rare complication of FMD in infancy. We report an 8-month-old boy with FMD presenting with shock caused by sudden renal hemorrhage that necessitated removal of one kidney. A diagnosis of renovascular hypertension resulting from intimal type FMD with aneurysmal formation was made on the basis of the presence of hypertension, elevation of PRA and aldosterone activity, pathological findings and the results of renal angiography. Our findings suggest that it is therefore necessary to consider FMD with aneurysmal formation as a possible cause of hypertension and renal hemorrhage in infants.

Painful stimuli evoke potentials recorded from the medial temporal lobe in humans.

The role of human medial temporal structures in fear conditioning has led to the suggestion that neurons in these structures might respond to painful stimuli. We have now tested the hypothesis that recordings from these structures will demonstrate potentials related to the selective activation of cutaneous nociceptors by a painful laser stimulus (laser evoked potential, LEP) (Kenton B, Coger R, Crue B, Pinsky J, Friedman Y, Carmon A (1980) Neurosci Lett 17:301-306). Recordings were carried out through electrodes implanted bilaterally in these structures for the investigation of intractable epilepsy. Reproducible LEPs were commonly recorded both bilaterally and unilaterally, while LEPs were recorded at contacts on the left (9/14, P=0.257) as commonly as on the right (5/14), independent of the hand stimulated. Along electrodes traversing the amygdala the majority of LEPs were recorded from dorsal contacts near the central nucleus of the amygdala and the nucleus basalis. Stimulus evoked changes in theta activity were observed at contacts on the right at which isolated early negative LEPs (N2*) responses could be recorded. Contacts at which LEPs could be recorded were as commonly located in medial temporal structures with evidence of seizure activity as on those without. These results demonstrate the presence of pain-related inputs to the medial temporal lobe where they may be involved in associative learning to produce anxiety and disability related to painful stimuli.

Gastric hyposecretion in esophageal squamous-cell carcinomas.

Recently, gastric fundic atrophy is reported to be an independent risk factor for esophageal squamous-cell carcinoma (ESCC). The aim of this study is to investigate the acid secretory level in ESCC in a case-control study. From April 2004 to March 2008, 100 consecutive subjects with early ESCC and 100 age- and sex-matched asymptomatic controls were prospectively enrolled. Gastrin-stimulated acid output was assessed by endoscopic gastrin test. Conditional regression analyses were used to adjust for other potential confounders. Multivariate analyses revealed a strong association between profound hypochlorhydria and ESCC with odds ratio (95% confidence interval): 6.0 (1.9-18.4). The association remained significant after adjusting for the effect of gastric atrophy as a covariate. The association became stronger as the ESCC developed more distal site of the esophagus. This study indicates that profound hypochlorhydria is a strong independent risk factor for ESCC even after adjusting for the influence of gastric atrophy.

Relationship of smoking and smoking cessation with oral health status in Japanese men.

BACKGROUND AND OBJECTIVE: Smoking has been associated with the number of natural teeth a person has and with the likelihood of periodontitis. The purpose of this study was to determine the relationships between the number of teeth present and periodontal diseases with smoking habits in a cohort of Japanese men. MATERIAL AND METHODS: The study group comprised 1088 men, 40-75 years of age. Oral examinations were conducted in dental clinics. Information on smoking status and on oral health behavior was collected from self-administered questionnaires. The relationship between oral health status and smoking status was estimated using adjusted odds ratios. RESULTS: Compared with those whom had never smoked, the odds ratios of having more than eight missing teeth and having periodontitis, among current smokers, were 1.67 and 1.74, respectively. In those who had stopped smoking for 11 years or longer, there was no increase in the odds ratio of having more than eight missing teeth and periodontitis, compared with those whom had never smoked. CONCLUSION: Smoking has a positive association with missing teeth and periodontitis. However, smoking cessation is beneficial for oral health. The odds of having more than eight missing teeth, or of having periodontitis, in those who had never smoked was similar to that of individuals who reported that they had stopped smoking for 11 years or more.

Brillouin gain-coefficient measurement for bismuth-oxide-based photonic crystal fiber under significant beam reflection at splicing points.

We investigate a six-air-hole bismuth-oxide-based photonic crystal fiber (Bi-PCF) in terms of Brillouin characteristics. One huge challenge in measuring the Brillouin properties of the Bi-PCF is the nonnegligible beam reflection at the splicing points, which can be attributed to the mirroring effect caused by different refractive indices of silica and bismuth fibers. To solve the problem we propose a method that is based on the combination of a pump-probe beat lock-in scheme and a normalized gain curve-fitting technique. Using this method, successful characterization of Brillouin properties for a 1.16-m-long Bi-PCF is experimentally demonstrated. With the measured Brillouin gain coefficient and the known chi((3)) nonlinearity parameters, the Kerr nonlinearity figure-of-merit (F(nl-SBS)), including the stimulated Brillouin scattering-caused pump-power limit, is also estimated for the Bi-PCF.

Mental arithmetic leads to multiple discrete changes from baseline in the firing patterns of human thalamic neurons.

Primate thalamic action potential bursts associated with low-threshold spikes (LTS) occur during waking sensory and motor activity. We now test the hypothesis that different firing and LTS burst characteristics occur during quiet wakefulness (spontaneous condition) versus mental arithmetic (counting condition). This hypothesis was tested by thalamic recordings during the surgical treatment of tremor. Across all neurons and epochs, preburst interspike intervals (ISIs) were bimodal at median values, consistent with the duration of type A and type B gamma-aminobutyric acid inhibitory postsynaptic potentials. Neuronal spike trains (117 neurons) were categorized by joint ISI distributions into those firing as LTS bursts (G, grouped), firing as single spikes (NG, nongrouped), or firing as single spikes with sporadic LTS bursting (I, intermediate). During the spontaneous condition (46 neurons) only I spike trains changed category. Overall, burst rates (BRs) were lower and firing rates (FRs) were higher during the counting versus the spontaneous condition. Spike trains in the G category sometimes changed to I and NG categories at the transition from the spontaneous to the counting condition, whereas those in the I category often changed to NG. Among spike trains that did not change category by condition, G spike trains had lower BRs during counting, whereas NG spike trains had higher FRs. BRs were significantly greater than zero for G and I categories during wakefulness (both conditions). The changes between the spontaneous and counting conditions are most pronounced for the I category, which may be a transitional firing pattern between the bursting (G) and relay modes of thalamic firing (NG).

Rebamipide, a cytoprotective drug, increases gastric mucus secretion in human: evaluations with endoscopic gastrin test.

We have previously developed a rapid, simple endoscopic method for evaluating gastrin-stimulated maximal acid output (the endoscopic gastrin test, EGT). In EGT, gastric fluid newly secreted over 10 min after gastrin stimulation is collected under direct endoscopic visualization. In this study, employing the EGT, we evaluated the effect of rebamipide, a cytoprotective anti-ulcer drug, on gastric mucus secretion. In ten Helicobacter pylori-negative healthy volunteers, gastric juice was collected by EGT prior to and after 4-week administration of rebamipide. The collected gastric juice was subjected to analysis for gastric mucus output. Total gastric mucin output was significantly increased by 53% by rebamipide administration from 3.2 +/- 1.2 mg hexose/10 min to 4.9 +/- 2.2 mg hexose/10 min (P < 0.01). Further analysis by ion-exchange chromatography revealed that rebamipide administration induced a specific increase in acidic mucin rich in sialic acid. Applying EGT, this study demonstrated that rebamipide administration increased gastric mucus secretion in human.

The human thalamic somatic sensory nucleus [ventral caudal (Vc)] shows neuronal mechanoreceptor-like responses to optimal stimuli for peripheral mechanoreceptors.

Although the response of human cutaneous mechanoreceptors to controlled stimuli is well studied, it is not clear how these peripheral signals may be reflected in neuronal activity of the human CNS. We now test the hypothesis that individual neurons in the human thalamic principal somatic sensory nucleus [ventral caudal (Vc)] respond selectively to the optimal stimulus for one of the four mechanoreceptors. The optimal stimuli for particular mechanoreceptors were defined as follows: Pacinian corpuscles (PC), vibration at 128 Hz; rapidly adapting (RA), vibration at 32 or 64 Hz; slowly adapting type 1 (SA1), edge; slowly adapting type 2 (SA2), skin stretch. Nineteen neurons had a significant response to at least one optimal stimulus, and 17 had a significantly greater response to one stimulus than to the other three, including 7 PC-related, 7 RA-like, 3 SA1-like, and 2 SA2-like neurons. One of each of the SA1- and SA2-like thalamic neurons responded to vibration with firing rates that were lower than those to edge or stretch but not significantly. Except in the case of PC-related neurons, the receptive field (RF) sizes were larger for these thalamic neurons than for the corresponding mechanoreceptor. Von Frey thresholds were higher than those for the corresponding human RA and SA1 mechanoreceptors. These results suggest that there is a convergence of pathways transmitting input from multiple mechanoreceptors of one type on single thalamic neurons via the dorsal columns. They are also consistent with the presence of primate thalamic elements of modality and somatotopic isorepresentation.

Relationship of smoking and smoking cessation with number of teeth present: JPHC Oral Health Study*.

BACKGROUND: Smoking is associated with the number of teeth. The purpose of this study was to determine the relationship of number of teeth with smoking and smoking cessation. METHODS: Subjects included 547 males aged between 55 and 75 years. Oral examinations were conducted in 2005. Smoking status information was collected from questionnaire surveys conducted in 1990, 1995, 2000, and 2005. The relationship between having more than eight missing teeth and smoking status was estimated with adjusted odds ratio. RESULTS: Comparing with never smokers, odds ratios of having more than eight missing teeth among current and former smokers were 1.96 and 1.86, respectively. The odds ratios in those who had stopped smoking for

Cold stimuli evoke potentials that can be recorded directly from parasylvian cortex in humans.

Anatomic, imaging, and lesion studies suggest that insular or parietal opercular cortical structures mediate the sensation of nonpainful cold. We have now tested the hypothesis that cold stimuli evoke electrical responses from these cortical structures in humans. We recorded the response to cold stimuli from electrodes implanted directly over parasylvian cortex for the investigation of intractable seizures. The results demonstrate that slow potentials can be evoked consistently over structures adjacent to the sylvian fissure in response to nonpainful cold. The polarity of these cold evoked potentials (EPs) for electrodes above the sylvian fissure is opposite to those below. These results suggest that the generator of cold EPs is close to the sylvian fissure in the parietal operculum or insula.

Masticatory ability and functional tooth units in Japanese adults.

The purposes of this study were (i) to examine the relationship between the number of natural teeth and the number of functional tooth units in Japanese adults, (ii) to evaluate how functional tooth units relate to subjective masticatory ability and (iii) to determine the minimum number of natural teeth and functional tooth units needed to maintain adequate self-assessed chewing function. A self-administered questionnaire was given and dental examination was conducted for 2164 residents aged 40 to 75 years. Counts were made on the number of functional tooth units of natural teeth (n-functional tooth units), the sum of natural teeth and artificial teeth on implant-supported and fixed prostheses (nif-functional tooth units) and the sum of natural teeth and artificial teeth on implant-supported, fixed and removable prostheses (total-functional tooth units). The average number of natural teeth, n-functional tooth units and nif-functional tooth units decreased with age, but these were often replaced by functional tooth units from artificial teeth on removable prostheses. Total-functional tooth units in 50-59 year old people were slightly lower compared with those in other age groups. Subjects who reported that they could chew every food item on an average had 23.4 total natural teeth, 12.6 posterior natural teeth, 7.6 n-functional tooth units, 8.6 nif-functional tooth units and 10.4 total-functional tooth units, and subjects without chewing difficulties had fewer functional tooth units from removable prostheses. Maintaining 20 and more natural teeth and at least eight nif-functional tooth units is important in reducing the likelihood of self-assessed chewing difficulties.