Heart rate response to orthostatic challenge in patients with dementia with Lewy bodies and Alzheimer's disease.

BACKGROUND: To elucidate the differences in autonomic dysfunction between dementia with Lewy bodies (DLB) and Alzheimer's disease using a simple and convenient method, we investigated the heart rate response to orthostatic challenge. METHODS: Ninety-seven people participated in this cross-sectional study, and data from 26 DLB patients, 29 Alzheimer's disease patients, and 25 healthy elderly individuals were analysed. Participants underwent postural changes, including 5 min in a supine position, 1 min in a sitting position, and 3 min in an orthostatic position. Their heart rates were continuously recorded. Two heart rate variables were analysed as main outcomes: (i) the difference between heart rate in the sitting position and the peak heart rate within 15 s of orthostasis, defined as the 'early heart rate increase'; and (ii) the difference between the peak heart rate and the negative peak heart rate after this, defined as 'early heart rate recovery.' An early heart rate increase has been considered to reflect parasympathetic and sympathetic functions. Early heart rate recovery is considered to reflect parasympathetic function. We also investigated the frequency domains of resting heart rate variability. RESULTS: A significant difference was observed across the three groups in early heart rate increase, and that of the DLB group was lower than that of the healthy control group. Early heart rate recovery also differed significantly across the three groups, and that of the DLB group was less than that of the healthy control group. In addition, the power of the low-frequency component, which represents both sympathetic and parasympathetic activity, was significantly decreased in the DLB group compared to the Alzheimer's disease group. CONCLUSIONS: Impaired heart rate response to standing was detected in patients with DLB. Electrocardiogram is a convenient, non-invasive method that might be useful as a subsidiary marker for DLB diagnosis and differentiation from Alzheimer's disease.

Is prolongation of corrected QT interval associated with seizures induced by electroconvulsive therapy reduced by atropine sulfate?

BACKGROUND: Electrocardiogram abnormalities have been reported during electroconvulsive therapy (ECT). A corrected QT interval (QTc) prolongation indicates delayed ventricular repolarization, which can trigger ventricular arrhythmias such as torsade de pointes (TdP). We examined the QTc changes during generalized tonic-clonic seizures induced by ECT, and the effects of atropine sulfate on these QTc changes. METHODS: We analyzed heart rate, QT interval, and QTc in 32 patients with depression who underwent ECT (25 women, 67.4 ± 8.7 years of age). The QTc from -30 to 0 seconds prestimulation was used as baseline, which was compared with QTc at 20-30 seconds and 140-150 seconds poststimulus onset. RESULTS: QTc was significantly prolonged at 20-30 seconds poststimulus, then significantly decreased at 140-150 seconds poststimulus, compared with baseline. QTc prolongation induced by ECT was significantly decreased by atropine sulfate. CONCLUSIONS: These data suggest that the risk of TdP may be enhanced by ECT. Further, the risk of cardiac ventricular arrhythmias, including TdP, may be reduced by administration of atropine sulfate.

Reduced N-acetylaspartate in the hippocampus in patients with fibromyalgia: a meta-analysis.

Fibromyalgia (FM) is a stress-associated syndrome with chronic, widespread pain. Patients with FM also present disturbances of cognition and memory. As the hippocampus is vulnerable to stress exposure and involved in cognition, memory and pain perception, we hypothesize that the abnormal function of the hippocampus is implicated in the pathophysiology of FM. N-acetylaspartate (NAA), a metabolite that can be measured using proton magnetic resonance spectroscopy (1H MRS), is recognized as a marker of neuronal structure and function. We performed a systematic review and meta-analysis of 1H MRS studies investigating NAA levels in patients with FM. A comprehensive literature search through MEDLINE, Embase and Web of Science yielded nine studies; among these nine, four studies met our criteria for inclusion. A random effect model with 51 patients with FM and 38 controls revealed a significant NAA reduction in the hippocampus. The current meta-analysis suggested a neuronal abnormality in the hippocampus in patients with FM.

Age-related change of neurochemical abnormality in attention-deficit hyperactivity disorder: a meta-analysis.

Prevalence and symptoms of attention-deficit hyperactivity disorder (ADHD) change with advancing age. However, neurochemical background of such age-related change is yet to be elucidated. We therefore conducted a meta-analysis of 16 proton magnetic resonance spectroscopy studies comprising 270 individuals with ADHD and 235 controls. Standardized mean differences were calculated and used as an effect size. Sensitivity analyses and meta-regression to explore the effect of age on neurochemical abnormality were performed. A random effects model identified a significantly higher-than-normal N-acetylaspartate (NAA) in the medial prefrontal cortex (mPFC), but no significant differences of other metabolites in that area. No significant difference in metabolite levels was demonstrated in any other region. Sensitivity analysis of children with ADHD revealed significantly higher-than-normal NAA, whereas no significant difference was found in adults with ADHD. Meta-regression revealed significant correlation between advanced age and normal levels of NAA in the mPFC, suggesting that age-dependent abnormality of NAA level in the mPFC is a potential neural basis of age-related change of symptoms of ADHD.

The validity and usefulness of the Japanese version of the Calgary sleep apnea quality of life index in patients with obstructive sleep apnea hypopnea syndrome.

OBJECTIVE: The main purpose of this study was to translate the Calgary sleep apnea quality of life index (SAQLI) and to evaluate the reliability, validity and responsiveness of the Japanese version of the SAQLI (SAQLI-J). METHODS: Translation of the SAQLI questionnaire into the SAQLI-J questionnaire was performed following the guidelines of cross-cultural adaptation of health-related quality of life (QOL) measures. All patients completed the following questionnaires both at baseline and three months later: the SAQLI-J, the medical outcome survey short form (SF-36) and the Epworth sleepiness scale (ESS). The SAQLI-J was conducted by an interviewer. PATIENTS: One hundred and fifteen obstructive sleep apnea hypopnea syndrome (OSAHS) patients were recruited into the present study. RESULTS: The internal consistency and test-retest reliability of the total SAQLI-J scores (SAQLI-J total) were both excellent. Regarding construct validity, the SAQLI-J was tested by measuring the inter-domain correlation between the SAQLI-J domains and the SF-36 domains. All of the SAQLI-J domains and the SAQLI-J total were found to be moderately to highly correlated with the domains of the SF-36. Moreover, the responsiveness of the SAQLI-J total measured according to the standardized response mean was found to be moderate, and the SAQLI-J was found to be more responsive than the SF-36 for detecting changes in the QOL after continuous positive airway pressure treatment. CONCLUSION: The results suggest that the SAQLI-J is a valid, reliable and responsive health-related QOL questionnaire for use in Japanese OSAHS patients.

Differences in the Treatment Response to Antithyroid Drugs versus Electroconvulsive Therapy in a Case of Recurrent Catatonia due to Graves' Disease.

We reported a case which presented recurrent episodes of catatonia as a result of Graves' disease with hyperthyroidism. The patient showed different treatment response in each episodes; in the first episode, psychiatric and physical symptoms were resolved by a combination of antithyroid and anxiolytic therapies, while in the second episode, the combination therapy did not ameliorate her symptoms and ECT was indicated. We postulated that decreased CSF level of TTR and the resulting susceptibility to the derangement of peripheral thyroid function might be involved in this different treatment response.

Reduction of N-acetylaspartate in the medial prefrontal cortex correlated with symptom severity in obsessive-compulsive disorder: meta-analyses of (1)H-MRS studies.

Structural and functional neuroimaging findings suggest that disturbance of the cortico-striato-thalamo-cortical (CSTC) circuits may underlie obsessive-compulsive disorder (OCD). However, some studies with (1)H-magnetic resonance spectroscopy ((1)H-MRS) reported altered level of N-acetylaspartate (NAA), they yielded inconsistency in direction and location of abnormality within CSTC circuits. We conducted a comprehensive literature search and a meta-analysis of (1)H-MRS studies in OCD. Seventeen met the inclusion criteria for a meta-analysis. Data were separated by frontal cortex region: medial prefrontal cortex (mPFC), dorsolateral prefrontal cortex, orbitofrontal cortex, basal ganglia and thalamus. The mean and s.d. of the NAA measure were calculated for each region. A random effects model integrating 16 separate datasets with 225 OCD patients and 233 healthy comparison subjects demonstrated that OCD patients exhibit decreased NAA levels in the frontal cortex (P=0.025), but no significant changes in the basal ganglia (P=0.770) or thalamus (P=0.466). Sensitivity analysis in an anatomically specified subgroup consisting of datasets examining the mPFC demonstrated marginally significant reduction of NAA (P=0.061). Meta-regression revealed that NAA reduction in the mPFC was positively correlated with symptom severity measured by Yale-Brown Obsessive Compulsive Scale (P=0.011). The specific reduction of NAA in the mPFC and significant relationship between neurochemical alteration in the mPFC and symptom severity indicate that the mPFC is one of the brain regions that directly related to abnormal behavior in the pathophysiology of OCD. The current meta-analysis indicates that cortices and sub-cortices contribute in different ways to the etiology of OCD.

Diffusion tensor imaging studies of mild traumatic brain injury: a meta-analysis.

OBJECTIVES: To assess the possibility that diffusion tensor imaging (DTI) can detect white matter damage in mild traumatic brain injury (mTBI) patients via systematic review and meta-analysis. METHODS: DTI studies that compared mTBI patients and controls were searched using MEDLINE, Web of Science, and EMBASE, (1980 through April 2012). RESULTS: A comprehensive literature search identified 28 DTI studies, of which 13 independent DTI studies of mTBI patients were eligible for the meta-analysis. Random effect model demonstrated significant fractional anisotropy (FA) reduction in the corpus callosum (CC) (p=0.023, 95% CIs -0.466 to -0.035, 280 mTBIs and 244 controls) with no publication bias and minimum heterogeneity, and a significant increase in mean diffusivity (MD) (p=0.015, 95% CIs 0.062 to 0.581, 154 mTBIs and 100 controls). Meta-analyses of the subregions of the CC demonstrated in the splenium FA was significantly reduced (p=0.025, 95% CIs -0.689 to -0.046) and MD was significantly increased (p=0.013, 95% CIs 0.113 to 0.950). FA was marginally reduced in the midbody (p=0.099, 95% CIs -0.404 to 0.034), and no significant change in FA (p=0.421, 95% CIs -0.537 to 0.224) and MD (p=0.264, 95% CIs -0.120 to 0.438) in the genu of the CC. CONCLUSIONS: Our meta-analysis revealed the posterior part of the CC was more vulnerable to mTBI compared with the anterior part, and suggested the potential utility of DTI to detect white matter damage in the CC of mTBI patients.

[Neoadjuvant and adjuvant chemotherapy with methotrexate, cisplatin and bleomycin for advanced penile cancer: a case report].

A 58-year-old male consulted our hospital because of penile swelling and pain with bilateral inguinal lymphadenopathy. Pathological examination of the penile tumor and right superficial inguinal lymph node biopsy demonstrated moderately differentiated squamous cell carcinoma with lymph node metastasis. We diagnosed the tumor inoperable radically and adjuvant chemotherapy with methotrexate, cisplatin and bleomycin was administered, followed by partial penectomy and left superficial lymphadenectomy. The surgical specimens showed few viable tumor cells. This combination chemotherapy is suggested to be effective for the treatment of advanced penile cancer.

[Electroconvulsive therapy for neurological disorders].

Electroconvulsive therapy (ECT) recovers the brain function through generalized convulsion induced by electrical stimulation of the brain. While the primary targets of ECT are psychiatric disorders such as depression, schizophrenia, and schizoaffective disorder, it has been well documented that ECT has therapeutic effects on muscular rigidity of Parkinson's disease and neuroleptics-induced malignant syndrome. Recently we demonstrated that ECT reduces intractable pain and allodynia associated with deafferentation pain disorders by recovering the function of the thalamic nucleus. ECT, if applied on appropriate clinical assessments, may contribute to the therapeutics of neuropsychiatric disorders.

Central connection of the optic, oculomotor, trochlear and abducens nerves in medaka, Oryzias latipes.

Medaka (Oryzias latipes) is one of the few vertebrate experimental animals in which inbred lines have been established. It is also a species that has advanced in genetic studies in a manner comparable to zebrafish. This fish is therefore a good model for studying functional organization of the nervous system, but anatomical analysis of its nervous system has been limited to embryonic stages. In the present study, we investigated anatomy of cranial nerves in adult fish focusing on the visual function, using an inbred strain of medaka. Cranial nerves of medaka were labeled using biocytin, revealing a central distribution of retinofugal terminals, retinopetal neurons, and oculomotor, trochlear and abducens motor neurons. The optic nerve of the adult medaka was of a complete decussation type. Retinofugal terminals were located in 8 brain nuclei, the suprachiasmatic nucleus, nucleus pretectalis superficialis, nucleus dorsolateralis thalami, area pretectalis pars dorsalis (APd), area pretectalis pars ventralis (APv), nucleus of the posterior commissure (NPC), accessory optic nucleus, and the tectum opticum. Retinopetal neurons were identified in 6 brain nuclei, the ganglion of the terminal nerve, preoptic retinopetal nucleus, nucleus dorsolateralis thalami, APd, APv, and NPC. The oculomotor neurons were mostly labeled ipsilaterally and were located dorsomedially, abutting the fasciculus longitudinalis medialis in the mesencephalon. The trochlear nucleus was located contralaterally and dorsolaterally adjacent to the fasciculus longitudinalis medialis in the mesencephalon. The abducens nucleus was located ipsilaterally in a ventrolateral part of the rhombencephalic reticular formation. These results, generally similar to those in other teleosts, provide the basis for future behavioral and genetic studies in medaka.

A systematic genome-wide screen for mutations affecting organogenesis in Medaka, Oryzias latipes.

A large-scale mutagenesis screen was performed in Medaka to identify genes acting in diverse developmental processes. Mutations were identified in homozygous F3 progeny derived from ENU-treated founder males. In addition to the morphological inspection of live embryos, other approaches were used to detect abnormalities in organogenesis and in specific cellular processes, including germ cell migration, nerve tract formation, sensory organ differentiation and DNA repair. Among 2031 embryonic lethal mutations identified, 312 causing defects in organogenesis were selected for further analyses. From these, 126 mutations were characterized genetically and assigned to 105 genes. The similarity of the development of Medaka and zebrafish facilitated the comparison of mutant phenotypes, which indicated that many mutations in Medaka cause unique phenotypes so far unrecorded in zebrafish. Even when mutations of the two fish species cause a similar phenotype such as one-eyed-pinhead or parachute, more genes were found in Medaka than in zebrafish that produced the same phenotype when mutated. These observations suggest that many Medaka mutants represent new genes and, therefore, are important complements to the collection of zebrafish mutants that have proven so valuable for exploring genomic function in development.

Mutations affecting somite formation in the Medaka (Oryzias latipes).

The metameric structure of the vertebrate trunk is generated by repeated formation of somites from the unsegmented presomitic mesoderm (PSM). We report the initial characterization of nine different mutants affecting segmentation that were isolated in a large-scale mutagenesis screen in Medaka (Oryzias latipes). Four mutants were identified that show a complete or partial absence of somites or somite boundaries. In addition, five mutations were found that cause fused somites or somites with irregular sizes and shapes. In situ hybridization analysis using specific markers involved in the segmentation clock and antero-posterior (A-P) polarity of somites revealed that the nine mutants can be compiled into two groups. In group 1, mutants exhibit defects in tailbud formation and PSM prepatterning, whereas A-P identity in the somites is defective in group 2 mutants. Three mutants (planlos, pll; schnelles ende, sne; samidare, sam) have characteristic phenotypes that are similar to those in zebrafish mutants affected in the Delta/Notch signaling pathway. The majority of mutants, however, exhibit somitic phenotypes distinct from those found in zebrafish, such as individually fused somites and irregular somite sizes. Thus, these Medaka mutants can be expected to provide clues to uncovering novel components essential for somitogenesis.

Genetic dissection of the formation of the forebrain in Medaka, Oryzias latipes.

The forebrain, consisting of the telencephalon and diencephalon, is essential for processing sensory information. To genetically dissect formation of the forebrain in vertebrates, we carried out a systematic screen for mutations affecting morphogenesis of the forebrain in Medaka. Thirty-three mutations defining 25 genes affecting the morphological development of the forebrain were grouped into two classes. Class 1 mutants commonly showing a decrease in forebrain size, were further divided into subclasses 1A to 1D. Class 1A mutation (1 gene) caused an early defect evidenced by the lack of bf1 expression, Class 1B mutations (6 genes) patterning defects revealed by the aberrant expression of regional marker genes, Class 1C mutation (1 gene) a defect in a later stage, and Class 1D (3 genes) a midline defect analogous to the zebrafish one-eyed pinhead mutation. Class 2 mutations caused morphological abnormalities in the forebrain without considerably affecting its size, Class 2A mutations (6 genes) caused abnormalities in the development of the ventricle, Class 2B mutations (2 genes) severely affected the anterior commissure, and Class 2C (6 genes) mutations resulted in a unique forebrain morphology. Many of these mutants showed the compromised sonic hedgehog expression in the zona-limitans-intrathalamica (zli), arguing for the importance of this structure as a secondary signaling center. These mutants should provide important clues to the elucidation of the molecular mechanisms underlying forebrain development, and shed new light on phylogenically conserved and divergent functions in the developmental process.

Mutations affecting retina development in Medaka.

In a large scale mutagenesis screen of Medaka we identified 60 recessive zygotic mutations that affect retina development. Based on the onset and type of phenotypic abnormalities, the mutants were grouped into five categories: the first includes 11 mutants that are affected in neural plate and optic vesicle formation. The second group comprises 15 mutants that are impaired in optic vesicle growth. The third group includes 18 mutants that are affected in optic cup development. The fourth group contains 13 mutants with defects in retinal differentiation. 12 of these have smaller eyes, whereas one mutation results in enlarged eyes. The fifth group consists of three mutants with defects in retinal pigmentation. The collection of mutants will be used to address the molecular genetic mechanisms underlying vertebrate eye formation.

Mutations affecting retinotectal axonal pathfinding in Medaka, Oryzias latipes.

We screened for mutations affecting retinotectal axonal projection in Medaka, Oryzias latipes. In wild-type Medaka embryos, all the axons of retinal ganglion cells (RGCs) project to the contralateral tectum, such that the topological relationship of the retinal field is maintained. We labeled RGC axons using DiI/DiO at the nasodorsal and temporoventral positions of the retina, and screened for mutations affecting the pattern of stereotypic projections to the tectum. By screening 184 mutagenized haploid genomes, seven mutations in five genes causing defects in axonal pathfinding were identified, whereas mutations affecting the topographic projection of RGC axons were not found. The mutants were grouped into two classes according to their phenotypes. In mutants of Class I, a subpopulation of the RGC axons branched out either immediately after leaving the eye or after reaching the midline, and this axonal subpopulation projected to the ipsilateral tectum. In mutants of Class II, subpopulations of RGC axons branched out after crossing the midline and projected aberrantly. These mutants will provide clues to understanding the functions of genes essential for axonal pathfinding, which may be conserved or partly divergent among vertebrates.

Mutations affecting the formation of posterior lateral line system in Medaka, Oryzias latipes.

We performed a systematic screen for mutations affecting the trajectory of axons visualized by immunohistochemical staining of Medaka embryos with anti-acetylated tubulin antibody. Among the mutations identified, yanagi (yan) and kazura (kaz) mutations caused specific defects in projection of the posterior lateral line (PLL) nerve. In yan and kaz mutant embryos, the PLL nerve main bundle was misrouted ventrally and dorsally or anteriorly. Medaka semaphorin3A, sdf1, and cxcr4 cDNA fragments were cloned to allow analysis of these mutants. There were no changes in semaphorin3A or sdf1 expression in mutant embryos, suggesting that the tissues expressing semaphorin3A or sdf1 that are involved in PLL nerve guidance are present in these mutant embryos. Double staining revealed that the mislocated PLL primordium and growth cone of the ectopically projected PLL nerve were always colocalized in both yan and kaz mutant embryos, suggesting that migration of PLL primordia and PLL nerve growth cones are not uncoupled in these mutants. Although homozygous yan larvae showed incomplete migration of the PLL primordium along the anteroposterior axis, ventral proneuromast migration was complete, suggesting that ventral migration of the proneuromast does not require the signaling affected in yan mutants. In addition to the PLL system, the distribution of primordial germ cells (PGCs) was also affected in both yan and kaz mutant embryos, indicating that yan and kaz genes are required for the migration of both PLL primordia and PGCs. Genetic linkage analysis indicated that kaz is linked to cxcr4, but yan is not linked to sdf1 or cxcr4. These mutations will provide genetic clues to investigate the molecular mechanism underlying formation of the PLL system.

Mutations affecting thymus organogenesis in Medaka, Oryzias latipes.

The thymus is an organ for T lymphocyte maturation and is indispensable for the establishment of a highly developed immune system in vertebrates. In order to genetically dissect thymus organogenesis, we carried out a large-scale mutagenesis screening for Medaka mutations affecting recombination activating gene 1 (rag1) expression in the developing thymus. We identified 24 mutations, defining at least 13 genes, which led to a marked reduction of rag1 expression in the thymus. As thymus development depends on pharyngeal arches, we classified those mutations into three classes according to the defects in the pharyngeal arches. Class 1 mutants had no or slight morphological abnormalities in the pharyngeal arches, implying that the mutations may include defects in such thymus-specific events as lymphocyte development and thymic epithelial cell maturation. Class 2 mutants had abnormally shaped pharyngeal arches. Class 3 mutants showed severely attenuated pharyngeal arch development. In Class 2 and Class 3 mutants, the defects in thymus development may be due to abnormal pharyngeal arch development. Those mutations are expected to be useful for identifying the molecular mechanisms underlying thymus organogenesis.