The TriAGe+ Score for Vertigo or Dizziness: A Diagnostic Model for Stroke in the Emergency Department.

BACKGROUND: Vertigo or dizziness is a common occurrence, but it remains a challenging symptom when encountered in the emergency department (ED). A diagnostic score for stroke with high accuracy is therefore required. METHODS: A single-center observational study (498 patients) was conducted. The predictor variables were derived from a multivariate logistic regression analysis with Akaike information criterion. The outcome was the occurrence of stroke. We evaluated the utility of a new diagnostic score (TriAGe+) and compared it with the ABCD2 score. RESULTS: The cohorts included 498 patients (147 with stroke [29.4%]). Eight variables were included: triggers, atrial fibrillation, male gender, blood pressure ≥140/90 mm Hg, brainstem or cerebellar dysfunction, focal weakness or speech impairment, dizziness, and no history of vertigo or dizziness or labyrinth or vestibular disease. We derived the TriAGe+ score from these variables. In the cohort, the prevalence of stroke increased significantly using the diagnostic score: 5.9% for a score of 0-4; 9.1% for 5-7; 24.7% for 8-9; and 57.3% for 10-17. At a cutoff value of 10 points, the sensitivity of the score was 77.5%, the specificity was 72.1%, and the positive likelihood ratio was 3.2. When the cutoff was defined as 5 points, the score obtained a high sensitivity (96.6%) with a good negative likelihood ratio (.15). The new score outperformed the ABCD2 score for the occurrence of stroke (C statistic, .818 versus .726; P < .001). CONCLUSIONS: The TriAGe+ score can identify the occurrence of stroke in patients with vertigo or dizziness presenting to the ED.

Mutant allele frequency predicts the efficacy of EGFR-TKIs in lung adenocarcinoma harboring the L858R mutation.

BACKGROUND: Whether the mutant allele frequency (MAF) may also have predictive implications for tyrosine kinase inhibitor (TKI) therapy in patients with advanced epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma (AELAd) remains unknown. PATIENTS AND METHODS: Based on a biobanking system in conjunction with our institution, we assessed EGFR mutation status using pyrosequencing (Py) and by outsourcing laboratory tests, such as the Cycleave (Cy) and the Scorpion ARMS (A). RESULTS: Out of 705 patients enrolled in the Shizuoka Lung Cancer Mutation Study between July 2011 and March 2013, 102 AELAd patients were identified as carrying the L858R mutation (L858Rm) using Py to analyze histological specimens. Of these 102 patients, the EGFR mutation status was assessed using both Py and Cy in 48 patients: the median MAF of L858R (MAFLR) was 18.5% (range: 8%-82%), and 45 patients (94%) were identified as having an L858Rm using both Py and Cy. Three patients (6%) with discrepant L858Rm findings were only identified using Py. The plotting of a receiver operating characteristic curve to identify the discordance in L858Rm findings showed that the area under the curve for MAFLR was 0.967 (95% confidence interval: 0.91-1) and that an MAFLR of 9% resulted in high sensitivity (100%) and specificity (99%). Also, 29 patients with AELAd, excluding those with postoperative recurrences, had their L858R status assessed using Cy or A. The median age, 69 years (range: 47-84 years); male/female, 14 (48%)/15 (52%); smokers/never-smokers 13 (45%)/16 (55%); ECOG PS 0-1/2-3, 26 (90%)/3 (10%); stage IIIB/IV, 4 (14%)/25 (86%); median MAFLR, 18% (range: 8%-63%). Patients with an MAFLR of ≤9% had a significantly shorter progression-free survival (PFS) period after TKI therapy than those with an MAFLR of >9% (mPFS: 92 versus 284 days, P = 0.0027). CONCLUSION: The MAF may be a potential predictive factor of TKI treatment efficacy in patients with AELAd carrying the L858Rm.

Common variants at the GCK, GCKR, G6PC2-ABCB11 and MTNR1B loci are associated with fasting glucose in two Asian populations.

AIMS/HYPOTHESIS: To test fasting glucose association at four loci recently identified or verified by genome-wide association (GWA) studies of European populations, we performed a replication study in two Asian populations. METHODS: We genotyped five common variants previously reported in Europeans: rs1799884 (GCK), rs780094 (GCKR), rs560887 (G6PC2-ABCB11) and both rs1387153 and rs10830963 (MTNR1B) in the general Japanese (n = 4,813) and Sri Lankan (n = 2,319) populations. To identify novel variants, we further examined genetic associations near each locus by using GWA scan data on 776 non-diabetic Japanese samples. RESULTS: Fasting glucose association was replicated for the five single nucleotide polymorphisms (SNPs) at p < 0.05 (one-tailed test) in South Asians (Sri Lankan) as well as in East Asians (Japanese). In fine-mapping by GWA scan data, we identified in the G6PC2-ABCB11 region a novel SNP, rs3755157, with significant association in Japanese (p = 2.6 x 10(-8)) and Sri Lankan (p = 0.001) populations. The strength of association was more prominent at rs3755157 than that of the original SNP rs560887, with allelic heterogeneity detected between the SNPs. On analysing the cumulative effect of associated SNPs, we found the per-allele gradients (beta = 0.055 and 0.069 mmol/l in Japanese and Sri Lankans, respectively) to be almost equivalent to those reported in Europeans. CONCLUSIONS/INTERPRETATION: Fasting glucose association at four tested loci was proven to be replicable across ethnic groups. Despite this overall consistency, ethnic diversity in the pattern and strength of linkage disequilibrium certainly exists and can help to appreciably reduce potential causal variants after GWA studies.

Websites offer helpful information concerning consultation with headache specialists.

Patients with severe primary headache may benefit from consultation with headache specialists, but doctor attendance rates in Japan are very low. More headache patients might consult headache specialists if these specialists were more widely recognized by the public. To determine what information prompted patients to seek consultation with a headache specialist, we questioned 256 primary headache patients about the source of the helpful information concerning consultation with headache specialists. From 191 patients, a total of 235 responses to the questionnaire were obtained. The most common response was 'websites' (33.2%), followed by 'professionals' (23.8%), 'acquaintances' (20.9%), 'print media' (6.8%) and 'TV/radio' (3.4%). Patients who indicated websites showed the most severe pain and highest impact of headache, and accounted for 52.4% of those with cluster headaches. Development of websites concerning headache specialists would seem likely to increase doctor attendance rates for patients with primary headache.

Search for type 2 diabetes susceptibility genes on chromosomes 1q, 3q and 12q.

To systematically evaluate genetic susceptibility to type 2 diabetes (T2D) in "candidate" regions on chromosomes 1q, 3q and 12q, we examined disease association by using a total of 2,083 SNPs in two-step screening; a screening panel comprised 473 cases and 285 controls and an extended (or combined) panel involved 658 cases and 474 controls. For the total interval screened (40.9 Mb), suggestive evidence of association was provided for several annotated gene loci. For example, in the MCF2L2 gene on 3q, a significant association (a nominal P value of 0.00009) was observed when logistic regression analysis was performed for three associated SNPs (rs684846, rs35069869 and rs35368790) that belonged to different LD groups. Also, in the SLC15A4 gene on 12q, rs3765108 showed a marginally significant association with an overall estimated odds ratio of 0.79 (P=0.001). No significant association was found for known candidate gene loci on 3q, such as ADIPOQ and IGF2BP2. Using the available samples, we have observed disease associations of SNPs derived from two novel gene loci in the Japanese population through high-density searches of diabetes susceptibility in three chromosomal regions. Independent replication will clarify the etiological relevance of these genomic loci to T2D.

Association between PRKCH gene polymorphisms and subcortical silent brain infarction.

Recently, a large-scale genetic epidemiological study has shown significant association of single nucleotide polymorphisms (SNPs) in the protein kinase C eta (PRKCH) gene with cerebral infarction, particularly, with lacunar infarction. To extend the findings, we tested association of two SNPs previously reported--rs3783799 and rs2230500--in PRKCH with silent lacunar infarction (SLI), which has drawn substantial attention in the aging societies. Disease association was tested in the case-control study design. Subjects with and without SLI were recruited from people who underwent a health-screening examination including brain MRI. Two SNPs were genotyped and proven to be in complete linkage disequilibrium (D'=1.00, r(2)=1.00) and thus showed comparable results of disease association, which were reproduced in two panels collected independently. In the entire population involving 295 cases and 497 controls, two SNPs remained to be significantly associated with SLI under a dominant model even after adjustment for confounding factors such as hypertension (e.g., genetic effects of rs2230500, P=0.0026 for AA+AG vs. GG, adjusted odds ratio=1.27; 95% CI, 1.09-1.48). As the two SNPs appear to be common only in Asian people, further replication study is warranted in the other Asian populations as well as the Japanese.

Clinical features of probable medication-overuse headache: a retrospective study in Japan.

This study examined the clinical picture of probable medication-overuse headache (MOH) and the presence of any features peculiar to Japan. In a retrospective study of 47 patients, type of primary headache, type of medicine overused, method and result of withdrawal were investigated. Among the 47 patients, 80.9% had migraine only, and 85.1% overused combination medications. While 36 patients (76.6%) succeeded in withdrawal, five patients (10.6%) failed. One patient (2.1%) had not improved by 2 months after withdrawal and was diagnosed with chronic migraine and chronic tension-type headache without MOH. The remaining five patients (10.6%) dropped out. All dropout patients were recommended abrupt inpatient withdrawal, but chose abrupt outpatient withdrawal. As features peculiar to Japan, many patients with probable MOH overused combination analgesics, particularly females.

[Effect of weekly docetaxel in patients with recurrent breast cancer].

A pilot trial was conducted to assess the tolerability and efficacy of a regimen with weekly docetaxel (TXT) in patients with metastatic breast cancer. The chemotherapy regimen consisted of a 30-minute weekly intravenous infusion of docetaxel (22-33 mg/m2/wk). Each 8-week cycle included 6 weekly treatments, followed by two weeks of rest. Thirteen patients were treated. All patients were evaluable for response: 0 CR (0%), 7 PR (53.8%), 3 NC (23.1%), 3 PD (23.1%). These results are almost the same as those with the administration of TXT (60 mg/m2) q3 wks. Toxicities observed were mild (< or = grade 2) and reversible, and included fatigue, nausea, neutropenia, and alopecia. This preliminary experience suggests a high level of clinical activity and excellent tolerability of the chemotherapy regimen at the given dose and schedule in patients with metastatic breast cancer.

Regulation of the glv operon in Bacillus subtilis: YfiA (GlvR) is a positive regulator of the operon that is repressed through CcpA and cre.

Maltose metabolism and the regulation of the glv operon of Bacillus subtilis, comprising three genes, glvA (6-phospho-alpha-glucosidase), yfiA (now designated glvR), and glvC (EIICB transport protein), were investigated. Maltose dissimilation was dependent primarily upon the glv operon, and insertional inactivation of either glvA, glvR, or glvC markedly inhibited growth on the disaccharide. A second system (MalL) contributed to a minor extent to maltose metabolism. Northern blotting revealed two transcripts corresponding to a monocistronic mRNA of glvA and a polycistronic mRNA of glvA-glvR-glvC. Primer extension analysis showed that both transcripts started at the same base (G) located 26 bp upstream of the 5' end of glvA. When glvR was placed under control of the spac promoter, expression of the glv operon was dependent upon the presence of isopropyl-beta-D-thiogalactopyranoside (IPTG). In regulatory studies, the promoter sequence of the glv operon was fused to lacZ and inserted into the amyE locus, and the resultant strain (AMGLV) was then transformed with a citrate-controlled glvR plasmid, pHYCM2VR. When cultured in Difco sporulation medium containing citrate, this transformant [AMGLV(pHYCM2VR)] expressed LacZ activity, but synthesis of LacZ was repressed by glucose. In an isogenic strain, [AMGLVCR(pHYCM2VR)], except for a mutation in the sequence of a catabolite-responsive element (cre), LacZ activity was expressed in the presence of citrate and glucose. Insertion of a citrate-controlled glvR plasmid at the amyE locus of ccpA(+) and ccpA mutant organisms yielded strains AMCMVR and AMCMVRCC, respectively. In the presence of both glucose and citrate, AMCMVR failed to express the glv operon, whereas under the same conditions high-level expression of both mRNA transcripts was found in strain AMCMVRCC. Collectively, our findings suggest that GlvR (the product of the glvR gene) is a positive regulator of the glv operon and that glucose exerts its effect via catabolite repression requiring both CcpA and cre.

Neonatal periventricular leukomalacia preceded by fetal periventricular echodensity.

OBJECTIVE: The purpose of this prospective study is to verify whether fetal periventricular echodensity (PVE) precedes neonatal periventricular leukomalacia (PVL). METHODS: Fetal brains were studied with transvaginal scan in 63 high-risk fetuses from 17 to 32 weeks of pregnancy, PVE echogenicity was quantified with ultrasonic histogram, and neonatal brains and clinical courses were studied after birth. RESULTS: No fetal cystic PVL was found, instead, fetal PVE was detected in 42 fetuses. The quantified echogenicity value was higher in PVE than in normal brain. Four cases developed neonatal PVL among 28 preterm and 1 among 14 term births. Neonatal PVL developed in the 23 cases of persistent fetal PVE, whereas no neonatal PVL was found when fetal PVE was negative or disappeared. Cord compression signs were common in PVL cases. CONCLUSION: Neonatal PVL was preceded by antepartum persistent fetal PVE in the present study.

Clinicopathological study of an autopsy case with sensory-dominant polyradiculoneuropathy with antiganglioside antibodies.

A previously reported patient presenting sensory-dominant neuropathy with antiganglioside antibodies, bound preferentially to polysialogangliosides including GD1b, was autopsied. While axonal degeneration was predominant in the sural nerve, many demyelinated fibers were present in the spinal roots. Dorsal roots had undergone significant damage. These pathological findings were well correlated with the electrophysiological results showing decreased F-wave conduction velocities and conduction blocks in motor nerves and decreased or absent sensory action potentials in sensory nerves, with distribution of GD1b in nerve tissues such as dorsal root ganglia and paranodal myelin in the ventral and dorsal roots.

Echogenicity of fetal lung and liver quantified by the grey-level histogram width.

Grey-level histogram width (GLHW) values of fetal lung and liver were studied in 52 healthy fetuses in 24 to 38 weeks of pregnancy, comparing them to the mean grey level (MGL), grey-level standard deviation (GLSD) and the coefficient of variation (GLCV). Fetal lung GLHW was larger in 30-38 weeks than at 24-29 weeks, but there was no change in liver GLHW. GLHW was smaller in fetal lung than in the liver in 24-29 weeks, with no difference in 30-38 weeks. The lung/liver GLHW ratios were less than 1 in 24-29 weeks, but they were 1 or more in 30-35 weeks. Both MGL of fetal lung and liver showed linear increases during pregnancy, but no difference was found between the two. Fetal lung GLSD tended to decrease during pregnancy. The GLCV values of fetal lung and liver decreased during pregnancy, and differed between 24-29 weeks and 30-38 weeks, whereas there was no difference between fetal lung and liver. The correlation coefficients of GLHW and MGL of fetal lung and liver to the weeks of pregnancy were moderate, and the coefficients of GLSD and GLCV to the weeks of pregnancy were small. In conclusion, quantitatively measured echogenicity of fetal lung increased in 30 or more weeks of pregnancy, and suggested antepartum changes of fetal lung tissue. The GLHW is reliable, because it was reproducible in various gain settings of various ultrasonic imaging devices. The MGL, GLSD and GLCV are less reliable, because the grey level varied by the gain changes among various machines.

A novel mutation (Cys6Gly) in the Cu/Zn superoxide dismutase gene associated with rapidly progressive familial amyotrophic lateral sclerosis.

Autosomal-dominant familial amyotrophic lateral sclerosis (FALS) is associated with mutation in the gene that encodes Cu/Zn superoxide dismutase (SOD1). We identified a novel missense mutation of SOD-1 (Cys6Gly) in exon 1 in a Japanese woman and her family. The illness showed rapid progression similarly to the FALS with a mutation of Cys6Phe that was reported by Morita et al. (1996) (Morita, M., Aoki, M., Abe, K., Hasegawa, T., Sakuma, R., Onodera, Y., Ichikawa, N., Nishizawa, M. and Itoyama, Y., A novel two-base mutation in the Cu/Zn superoxide dismutase gene associated with familial amyotrophic lateral sclerosis in Japan. Neurosci. Lett., 205 (1996) 79-82). Mutation of the cystein at amino acid 6 might be associated with the rapid progression of ALS.

Neural Network Computer Analysis of Fetal Heart Rate.

> Objective: A nonsubjective evaluation of intrapartum fetal heart rate (FHR) with a neural network (NNW) computer system and its clinical application. Methods: Eight simple FHR data were input into the NNW computer after 16-step normalizations. The computer was composed of 40 units in the input layer, 30 in intermediate layer, and 3 in the output layer, and the probabilities to be normal, suspicious, and pathological were obtained at the output. Before use, the computer was trained 10,000 times by 50-min teacher FHR data of 20 cases with known outcomes. The trained NNW computer was tested by FHRs of another 29 cases. The outcome probabilities in 15 min were calculated every 5 min in another 10 cases, and the bar graphs of the probabilities were displayed in sequence in the trendgrams. Results: The trained NNW computer was 100% accurate in the internal check; in the external check 86% of the results were evaluated correctly with the cardiotocogram, Apgar score, and umbilical arterial pH of the 29 test cases. The FHR scores of our conventional computer FHR analysis were higher in the suspicious and pathological groups than the normal group, and the fetal distress index was high in the pathological group. The trendgrams were simply accurate in typically normal or abnormal cases, transitory abnormal probabilities were shown in intermediate cases, and mixed suspicious and pathological probabilities suggested pathological outcome. Conclusions: The outcome probabilities and their trendgrams in the NNW FHR analysis are promising in objective decision making in the intrapartum stage.

Increased plasma lipid peroxidation in patients with aceruloplasminemia.

Aceruloplasminemia is a newly recognized autosomal recessive disorder of iron metabolism due to mutations in the ceruloplasmin gene. Although the presence of these mutations reveals an essential role for ceruloplasmin in human biology, the mechanisms of tissue injury in this disease are unknown. We report here on the identification of increased plasma lipid peroxidation in multiple affected family members with aceruloplasminemia. Consistent with the absence of serum ceruloplasmin, plasma ferroxidase activity was markedly reduced and serum ferritin was significantly increased. Plasma lipid peroxidation was determined as thiobarbituric acid-reactive products (TBA products) in plasma samples from control, heterozygote, and affected patients. Basal levels of lipid peroxides were three times control values in patients with aceruloplasminemia and were significantly increased in these patients in the presence of copper ions and hydrogen peroxide. In each case these increases were suppressed by the addition of exogenous ceruloplasmin. These data suggest that increased susceptibility to lipid peroxidation may contribute to the unique neuropathology observed in patients with aceruloplasminemia and imply a role for free radical-mediated tissue injury in degenerative disorders of the basal ganglia.

The problem of de novo colorectal carcinoma.

From April 1985 to March 1995, colonoscopy was carried out at our institution in 24,059 patients, 31,800 times in symptomatic and/or asymptomatic average risk persons. 184 submucosal invasive carcinomas were detected. Unlike protruding-type lesion, the depressed-type invades the submucosal layer, even though the size is within 10 mm. The depressed type of invasive carcinoma accounted for 20 lesions, and represented 10.9% (20 of 184) of all the invasive carcinomas. The pit pattern of depressed-type lesions shows a small round pit (type IIIs pit pattern) and that of carcinoma lesions shows the irregular pit and non-structure (type V pit pattern).

Aceruloplasminemia: molecular characterization of this disorder of iron metabolism.

Ceruloplasmin is an abundant alpha 2-serum glycoprotein that contains 95% of the copper found in the plasma of vertebrate species. We report here on the identification of a genetic defect in the ceruloplasmin gene in a patient previously noted to have a total absence of circulating serum ceruloplasmin in association with late-onset retinal and basal ganglia degeneration. In this patient T2 (transverse relaxation time)-weighted magnetic resonance imaging of the brain revealed basal ganglia densities consistent with iron deposition, and liver biopsy confirmed the presence of excess iron. Although Southern blot analysis of the patient's DNA was normal, PCR amplification of 18 of the 19 exons composing the human ceruloplasmin gene revealed a distinct size difference in exon 7. DNA sequence analysis of this exon revealed a 5-bp insertion at amino acid 410, resulting in a frame-shift mutation and a truncated open reading frame. The validity of this mutation was confirmed by analysis of DNA from the patient's daughter, which revealed heterozygosity for this same 5-bp insertion. The presence of this mutation in conjunction with the clinical and pathologic findings demonstrates an essential role for ceruloplasmin in human biology and identifies aceruloplasminemia as an autosomal recessive disorder of iron metabolism. These findings support previous studies that identified ceruloplasmin as a ferroxidase and are remarkably consistent with recent studies on the essential role of a homologous copper oxidase in iron metabolism in yeast. The clinical and laboratory findings suggest that additional patients with movement disorders and nonclassical Wilson disease should be examined for ceruloplasmin gene mutations.

Corticostriatal and corticotectal projections from visual cortical areas 17, 18 and 18a in the pigmented rat.

Regions of the visual cortex and the deep layers of the superior colliculus (SC) have been suggested to be functionally linked via an 'indirect' pathway through the basal ganglia. The present report demonstrates projections from the striate (area 17) and extrastriate (areas 18 and 18a) visual cortex in Long-Evans hooded rats to the striatum (ST) and SC with anterograde (biocytin) and retrograde (WGA-HRP and fluorescent dyes) tracers. Biocytin injections into each cortical area produced markedly different patterns of labeling in ST and SC. Injections into area 17 resulted in a dense labeling in the superficial layers of SC, with little labeling present in the deep layers of SC or ST. In contrast, injections into area 18a, which produced marked labeling in the deep layers of SC with moderate in the superficial layers, resulted in dense labeling in the caudal two-thirds of the dorsal region of ST; injections into area 18 produced numerous terminals mainly in the deep layers of SC and in the rostral two-thirds of the dorsal aspect of ST. WGA-HRP injections into ST resulted in numerous retrogradely labeled pyramidal neurons in areas 18 and 18a, but only a few labeled neurons were observed in area 17. Corticostriatal neurons in extrastriate visual cortex were distributed predominantly in layer V, with smaller numbers in layers II and III, whereas corticotectal neurons were located only in layer V of both the striate and extrastriate visual cortex. Although corticostriatal and corticotectal neurons were intermingled in layer V, no double-labeled neurons were observed following injections of different fluorescent dyes into ST and SC. It appears, therefore, that: 1) the major source of visual input to both ST and the deep layers of SC in the rat arises not from the primary visual cortex but from extrastriate visual areas; and that 2) the projections from the extrastriate visual area to ST and SC originate from different populations of corticofugal neurons.