Wearable sensor device-based detection of decreased heart rate variability in Parkinson's disease.

The evidence that heart rate variability (HRV) decreases during early Parkinson's disease (PD) largely depends on electrocardiogram data. In this study, we examined HRV in PD using wearable sensors and assessed various evaluation methods for detecting disease-related alterations. We evaluated 27 patients with PD and 23 disease controls. The wearable sensors POLAR V800 HR and POLAR H10 were used for the HRV measurements. The participants wore the two sensors for approximately 24 h, and long-term HRV data were acquired. We analyzed the standard deviation of normal R-R intervals (SDNN) and coefficient of variation of R-R intervals (CVRR) for every 100 consecutive beats. Focusing on the fluctuation of SDNN and CVRR, we extracted the minimum, first decile, first quartile, and median values of SDNN and CVRR. The area under the receiver operating characteristic curve (AUC) for each HRV parameter was calculated to differentiate PD from the disease controls. The minimum values of SDNN and CVRR had the highest AUC (SDNN: AUC 0.90, 95% confidence interval [CI] 0.78-0.96; CVRR: AUC 0.90, CI 0.76-0.96) among the evaluation methods tested. The minimum values of SDNN and CVRR were significantly decreased in PD (SDNN: 9.5 ± 4.0 ms vs. 4.4 ± 2.0 ms, p < 0.0001; CVRR: 1.15 ± 0.33% vs. 0.65 ± 0.24%, p < 0.0001). We detected decreased HRV in PD using wearable sensors. Analyzing the minimum values of the HRV parameter in long-term recordings appears to be appropriate for detecting the decrease in HRV in PD.

Impaired pain processing and its association with attention disturbance in patients with amyotrophic lateral sclerosis.

BACKGROUND: Cognitive dysfunction characterized by executive dysfunction and persistent attention function has been reported in patients with amyotrophic lateral sclerosis (ALS); however, it is unclear if this contributes to the pain processing deficits associated with the disease. OBJECTIVE: We clarified the relationship between pain processing and both cognitive function and sensory symptoms in patients with ALS. METHODS: We enrolled 23 patients with ALS and 14 healthy control subjects. We examined pain-related somatosensory evoked potentials (SEPs) using an intra-epidermal needle electrode. We evaluated cognitive function and the clinical characteristics of sensation and analyzed their relationships with pain-related SEPs. RESULTS: Pain-related SEP amplitudes were significantly lower, while the rate of amplitude attenuation due to habituation or change in attention was significantly greater in patients with ALS than in control subjects. There were no significant differences in pain-related SEP parameters between patients with or without sensory symptoms. Instead, pain-related SEP amplitude and its rate of attenuation were correlated with cognitive dysfunction, particularly with attention domains. CONCLUSIONS: Our results suggest that attention deficit, but not sensory nerve involvement, is a major cause of the alterations in pain-related SEP in patients with ALS.

Difference in cardiovascular response during orthostatic stress in Parkinson's disease and multiple system atrophy.

Although orthostatic hypotension is more prominent in multiple system atrophy (MSA) than in Parkinson's disease (PD), there is no study comparing the degree of decrease in total peripheral resistance and cardiac response during orthostatic stress between both diseases. In this study, we examined whether there is a difference in cardiovascular response between MSA and PD. We examined the results of the head-up tilt test in 68 patients with MSA, 28 patients with cardiac non-denervated PD, and 70 patients with cardiac denervated PD whose total peripheral resistance after 60° tilting was lower than the value at 0°. Differences in cardiac output and blood pressure changes were compared against the decrease in total peripheral resistance. There was no difference in the degree of decrease in total peripheral resistance among the three groups. However, the slope of the regression line revealed that the increase in cardiac output against the change in total peripheral resistance was significantly lower in the MSA group than in the cardiac non-denervated and denervated PD groups, and that the decrease in systolic blood pressure against the change in total peripheral resistance was significantly greater in the MSA group than in the cardiac non-denervated and denervated PD groups. In MSA, the cardiac response during orthostatic stress is lower than that in PD, possibly underlying the fact that orthostatic hypotension is more prominent in MSA than in PD.

Impact of orthostatic hypotension on wheelchair use in patients with Parkinson's disease.

Wheelchair use is an important indicator of disease progression in Parkinson's disease (PD). Here, we investigated whether orthostatic hypotension (OH) affects the time to wheelchair use. We examined 33 PD patients with OH and 95 without OH. Median time to start using a wheelchair calculated from the time of disease onset was significantly shorter in patients with OH than in those without OH (12.0 vs 19.0 years; p < 0.001). Thus, appropriate management of OH and motor function is necessary.

Relationship between cardiac parasympathetic dysfunction and the anteroposterior diameter of the medulla oblongata in multiple system atrophy.

PURPOSE: Neurodegeneration of the nucleus ambiguus and the dorsal vagal motor nucleus has been implicated in cardiac parasympathetic dysfunction in multiple system atrophy (MSA). The nucleus ambiguus and the dorsal vagal motor nucleus, which are located in the medulla oblongata (MO), control the autonomic-specifically, the parasympathetic-functions of the body. The aim of our study was to investigate the relationship between cardiac parasympathetic dysfunction and the anteroposterior diameter of the MO in MSA by quantitatively analyzing magnetic resonance imaging (MRI) outcome measures. METHODS: We retrospectively assessed 40 consecutive patients with probable MSA and 25 age- and sex-matched controls. The anteroposterior diameter of the MO at two locations (MO diameter-A and -B) and the diameters of the midbrain and pons were measured by conventional MRI. A cardiac parasympathetic function score (CP-score) and cardiac sympathetic function score (CS-score) were generated by calculating the z-scores of multiple autonomic function tests. The relationship between the scores and the measured diameters of the brainstem was also investigated. RESULTS: The CP-score and CS-score were significantly lower in the patients with MSA than in the controls (CP-score: 0.61 ± 0.75 vs. - 0.38 ± 0.52, p < 0.001; CS-score: 0.91 ± 1.06 vs. - 0.57 ± 1.07, p < 0.001). Also, in the patients with MSA, the CP-score was significantly correlated with MO diameter-A (r = 0.40, p = 0.010), and the CS-score was significantly correlated with the diameter of the midbrain (r = 0.33, p = 0.038). CONCLUSION: The anteroposterior diameter of the MO is a potential imaging marker of parasympathetic dysfunction in MSA.

Anti-ganglioside complex antibody profiles in a recurrent complicated case of GQ1b-seronegative miller fisher syndrome and Bickerstaff brainstem encephalitis: a case report.

BACKGROUND: Guillain-Barré syndrome (GBS), Miller Fisher syndrome (MFS) and Bickerstaff brainstem encephalitis (BBE) are a group of autoimmune neurological disorders (GBS spectrum disorder) that rarely recur. Recently, anti-ganglioside complex antibodies (GSC-Abs) were identified in patients with GBS spectrum disorder. However, there has been no case report describing GSC-Abs profiles in a recurrent case showing different phenotypes. CASE PRESENTATION: We report the case of a 33-year-old male patient with GQ1b-seronegative BBE-GBS after two prior episodes of MFS-GBS. Our patient showed ophthalmoplegia, ataxia, areflexia and a weakness of the extremities (MFS and GBS symptoms) in all episodes. In the episode reported here, our patient showed disturbed consciousness and an extensor response to cutaneous plantar stimulation was observed (BBE symptoms), with severe disability and requirement for artificial respiration management. GSC-Abs detected in previous episodes were also detected in the subsequent episodes, while new GSC-Abs emerged in each episode. Interestingly, whereas antibodies to GA1/GQ1b and GA1/GT1a, which are commonly identified in patients with GBS, MFS or BBE, appeared in all episodes, antibodies to GD1a/GD1b and GD1b/GT1b, which are predominantly associated with severe disability and the requirement for artificial respiration management in GBS, emerged for the first time in this episode. CONCLUSION: This study reports novel phenomena about the GSC-Abs profiles and its relationship with clinical features in a case with recurrent GBS spectrum disorder, showing different phenotypes in different episodes. Further studies are required to reveal the significance of the GSC-Abs profiles in recurrent GBS spectrum disorder.

Characteristics of pectens in diurnal and nocturnal birds and a new functional proposal relating to non-visual opsins.

The pecten is a fold-structured projection at the ocular fundus in bird eyes, showing morphological diversity between the diurnal and nocturnal species. However, its biological functions remain unclear. This study investigated the morphological and histological characteristics of pectens in wild birds. Additionally, the expression of non-visual opsin genes was studied in chicken pectens. These genes, identified in the chicken retina and brain, perceive light periodicity regardless of visual communication. Similar pleat numbers have been detected among bird taxa; however, pecten size ratios in the ocular fundus showed noticeable differences between diurnal and nocturnal birds. The pectens in nocturnal brown hawk owl show extremely poor vessel distribution and diameters compared with that of diurnal species. RT-PCR analysis confirmed the expression of Opn5L3, Opn4x, Rrh and Rgr genes. In situ hybridization analysis revealed the distribution of Rgr-positive reactions in non-melanotic cells around the pecten vessels. This study suggests a novel hypothesis that pectens develop dominantly in diurnal birds as light acceptors and contribute to continuous visual function or the onset of periodic behaviour.

Analysis of Pattern Formation by Colored Petri Nets With Quantitative Regulation of Gene Expression Level.

Modeling and simulation are becoming indispensable tools for studying multicellular events such as pattern formation during embryonic development. In this paper, we propose a new approach for analyzing multicellular biological phenomena by combining colored hybrid Petri nets (ColHPNs) with newly devised biological experiments that can control level of a gene quantitatively. With this approach, we analyzed patterning of the boundary cells in the Drosophila large intestine, where one-cell-wide domain of boundary cells differentiate through Delta-Notch signaling. Biological experiments regulating the level of Delta resulted in six distinct patterns of boundary cells correlating with the level of Delta. All these patterns were successfully reproduced by simulation based on ColHPN modeling only by changing the parameter related to the level of Delta. By monitoring the concentration of the active form of Notch in each cell during simulation, it was revealed that these distinct modes of patterning correlate with the fluctuation range of active Notch. Combination of simulation and quantitative manipulation of a gene activity described here is a reliable and powerful approach for analyzing and understanding the patterning process regulated by Notch signaling. This approach can be easily adapted to address other similar pattern formation issues in the systems biology area.

The wide-ranging clinical and genetic features in Japanese families with valosin-containing protein proteinopathy.

Mutations in the valosin-containing protein (VCP) gene are known to cause various neurodegenerative disorders. Here, we report 8 Japanese patients [6 men, 2 women; median age at onset: 49.5 (range, 35-58) years] from 5 unrelated families with VCP missense mutations. Although 7 of 8 patients were diagnosed with either inclusion body myopathy or amyotrophic lateral sclerosis, 1 patient showed demyelinating polyneuropathy, which was confirmed by longitudinal nerve conduction studies. Sural nerve biopsy of the patient revealed intranuclear ubiquitin staining in Schwann cells. Three known pathogenic VCP mutations (p.Arg191Gln, p.Arg155Cys, and p.Ile126Phe) were detected. A novel mutation, c.293 A>T (p.Asp98Val), was also identified in a patient with amyotrophic lateral sclerosis and frontotemporal dementia. This mutation was predicted to be "deleterious" or "disease causing" using in silico mutation analyses. In conclusion, demyelinating polyneuropathy may be a novel phenotype caused by VCP mutations. The p.Asp98Val mutation was found to be a novel pathogenic mutation of VCP proteinopathy. We believe our cases represent a wide clinical spectrum of VCP mutations.

Antioxidant treatment during preservation of bovine ovaries increased the development potential of embryos.

The overnight preservation of bovine ovaries would be highly useful in the subsequent harvest of viable oocytes for reproductive study. The present study aimed to optimize conditions for overnight preservation of bovine ovaries by examining the effects of temperature, solution and supplementation. In Experiment 1, the rate of development to the blastocyst stage of oocytes derived from ovaries preserved at 15°C was higher than that at either 5 or 25°C (p < 0.05). In Experiment 2, the rate of development to the blastocyst stage of oocytes derived from ovaries preserved in University of Wisconsin solution was higher than when PBS or saline was used (p < 0.05). In Experiment 3, oocytes preserved in saline supplemented with 0.3 mM glutathione (GSH) exhibited an increase in the rate of blastocyst formation compared with oocytes supplemented with 0 or 3 mM GSH (p < 0.05). In Experiment 4, supplementation with 10 µM epigallocatechin gallate during ovary preservation increased the rate of blastocyst formation (p < 0.05). The blastocysts derived from ovaries stored in saline supplemented with GSH at 15°C for 24 h were shown to develop into normal offsprings following transfer to recipient heifers. Our studies indicate that bovine IVM/IVF embryos derived from ovaries preserved in saline supplemented with an antioxidant at 15°C for 24 h can successfully develop to the blastocyst stage and result in offspring.

A nerve conduction study predicts the prognosis of sporadic amyotrophic lateral sclerosis.

OBJECTIVE: To clarify the relationship between nerve conduction study (NCS) and prognosis in patients with amyotrophic lateral sclerosis (ALS). METHODS: We included 190 patients with sporadic ALS. We used onset age, sex, onset site (bulbar vs. spinal), revised El Escorial criteria category (definite vs. others), and the King's clinical systems, and the Milano-Torino (MiToS) functional staging systems, and decline rates of revised ALS functional rating scale (ALSFRS-R) as known prognostic factors. An NCS was performed on the median, ulnar, tibial, and sural nerves. The endpoint was death or the introduction of tracheostomy positive-pressure ventilation. Multivariate analysis for each NCS variable, known prognostic factors was performed using Cox stepwise proportional hazards analysis. Univariate analysis was performed for NCS variables that showed a significant association with prognosis in multivariate analysis. Survival was analyzed with a Kaplan-Meier curve and log-rank test. RESULTS: The Cox model identified the compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes of the median nerve as prognostic factors. In the log-rank test, patients with higher median nerve CMAP amplitude had a significantly better prognosis than those with lower amplitude, regardless of age. And prognosis was better in the group with lower median nerve SNAP amplitude only in patients younger than the 25th percentile (~ 57 years). CONCLUSIONS: CMAP and SNAP amplitudes of the median nerve are considered to be independent prognostic factors of sporadic ALS.

Association of orthostatic blood pressure with the symptoms of orthostatic hypotension and cognitive impairment in patients with multiple system atrophy.

The degree and frequency of orthostatic hypotension (OH) are high in patients with multiple system atrophy (MSA); however, the association of orthostatic blood pressure (BP) with the symptoms of OH and cognitive impairment in these patients remains unclear. The aim of this study was to clarify whether absolute BP and/or changes in BP during standing are related to OH symptoms and cognitive impairment in patients with MSA. Thirty-two patients with MSA were examined using the head-up tilt and cognitive function tests. OH symptoms were evaluated using a patient-reported scale. The results were compared with those for 15 age- and sex-matched healthy controls. Seventeen of the 32 (53.1%) patients had OH, with eight of them exhibiting OH symptoms, which were related to the absolute BP value at 60° tilt. However, OH symptoms were not related to the degree of decrease in BP during the tilt test, and they were frequently observed in patients with a mean BP of <80 mmHg at 60° tilt (sensitivity, 67%; specificity, 91%). Cognitive dysfunction assessed by the Mini-Mental State Examination (MMSE; ≤ 26) was also associated with a low mean BP at 60° tilt (odds ratio, 1.32; 95% confidence interval, 1.04-1.67; p = 0.02). The upright BP value is associated with OH symptoms and the MMSE score in patients with MSA. Thus, careful observation of OH symptoms can enable early management of BP and the detection of cognitive impairment in these patients.

The abdominal skin of female Sprague-Dawley rats is more sensitive than the back skin to drug-induced phototoxicity.

In vivo phototoxicity studies are important to predict drug-induced phototoxicity in humans; however, a standard methodology has not established. To determine differences in sensitivity to drug-induced phototoxicity among various skin sites, we evaluated phototoxic reactions in the back and abdominal skin of female Sprague-Dawley rats orally dosed with phototoxic drugs (pirfenidone, 8-methoxysoraren, doxycycline, and lomefloxacin) or a non-phototoxic drug (gatifloxacin) followed by solar-simulated light irradiation comprising 18J/cm2 ultraviolet A. Tissue reactions were evaluated by macroscopic and microscopic examination and immunohistochemistry for γ-H2AX, and tissue concentrations of pirfenidone, doxycycline, and lomefloxacin were measured by tandem mass spectrometry. In addition, the thicknesses of the skin layers at both sites were measured in drug-naïve rats. The abdominal skin showed more severe reactions to all phototoxic drugs than the back skin, whereas the minimal erythema dose in drug-naïve rats and skin concentrations of each drug were comparable between the sites. Furthermore, histopathological lesions and γ-H2AX-positive cells in the abdominal skin were detected in deeper layers than in the back skin. The stratum corneum and dermis in the abdominal skin were significantly thinner than in the back skin, indicating a difference in the depth of light penetration and potentially contributing to the site differences observed in sensitivity to phototoxicity. Gatifloxacin did not induce any phototoxic reactions at either site. In conclusion, the abdominal skin is more sensitive to drug-induced phototoxicity than the back skin and may represent a preferable site for irradiation in this rat phototoxicity model.

Pyrene did not induce gene mutation in red blood cell Pig-a assay and PIGRET assay in rats.

A new in vivo gene mutation assay has been developed based on the phosphatidylinositol glycan anchor biosynthesis, Class A gene (Pig-a in rodents) as an endogenous reporter. Although a large number of chemicals have been evaluated in the rat Pig-a assay in 28-day repeat dose regimens, there was limited reporting of rat Pig-a assay after a single dose. A collaborative study by the Mammalian Mutagenicity Study group, which is a subgroup of the Japanese Environmental Mutagen Society, was conducted to verify the usefulness of the rat Pig-a assay after a single dose as a short-term genotoxicity test. As a part of this collaborative study, the in vivo mutagenicity of a single dose of pyrene (Pyr) was investigated in the red blood cell (RBC Pig-a assay) and in reticulocytes (PIGRET) of rats. Eight-week old male rats were orally dosed with Pyr at 500, 1000, and 2000 mg/kg or ethylnitrosourea (ENU) at 10 and 40 mg/kg as a positive control. The animals in each group were examined for Pig-a mutant frequencies (MF) except for animals in the 2000mg/kg group because of mortality or severe toxicity. The Pig-a MF in RBCs and reticulocytes, as CD59 negative cells, were evaluated once a week for 4 weeks after the dosing. With a single exposure to ENU, the Pig-a MF in both RBCs and reticulocytes increased in a time- and dose-dependent manner. In contrast, no statistically significant effect was observed in rats dosed with Pyr at 500 and 1000 mg/kg. Therefore, Pyr was concluded to be negative in the RBC Pig-a assay and the PIGRET assay after a single oral administration in rats. The result was consistent with previously reported Pig-a assays with repeat dose regimens.

Red blood cell Pig-a assay and PIGRET assay in rats with azathioprine.

A new in vivo gene mutation assay has been developed based on the phosphatidylinositol glycan anchor biosynthesis, Class A gene (Pig-a in rodents) as an endogenous reporter. Using this Pig-a assay, the in vivo mutagenicity of a single dose of azathioprine (Aza) was investigated in red blood cells (RBC Pig-a assay) and reticulocytes (PIGRET) of rats. Eight-week old male rats were orally dosed once with Aza at 50, 100 and 200mg/kg or ethylnitrosourea (ENU) at 10 and 40mg/kg as a positive control. Because 4 out of 6 animals at 200mg/kg of Aza died 3days after the dosing, this dose group was excluded for analyses. The frequencies of Pig-a mutants in RBCs and reticulocytes (RET) were evaluated once a week for 4 weeks after the treatment. With a single exposure to ENU, the frequencies of Pig-a mutants in both RBCs and RETs increased in a time- and dose-dependent manner. In contrast, with Aza small effects that were not statistically significant were observed in rats at 21 and 14days in the RBC Pig-a and PIGRET assays respectively. Based on the present results, the mutagenic potential of Aza is negligible after single oral administration in rats.

A simple liquid chromatographic method based on intramolecular excimer-forming derivatization and fluorescence detection for the determination of tyrosine and tyramine in urine.

A liquid chromatographic (LC) method for sensitive and selective fluorometric determination of p-hydroxyphenylethylamino group containing compounds is described. This method is based on an intramolecular excimer-forming fluorescence derivatization with a pyrene reagent, 4-(1-pyrene)butanoyl chloride, followed by reversed-phase LC. The analytes, containing an amino moiety and a phenolic hydroxyl moiety in a molecule, were converted to the corresponding dipyrene-labeled derivatives by one-step derivatization. The dipyrene-labeled derivatives afforded intramolecular excimer fluorescence (440-540 nm), which can clearly be discriminated from the normal fluorescence (360-420 nm) emitted from reagent blanks. The derivatives of tyrosine and tyramine could be separated by reversed-phase LC on ODS column under conditions of isocratic elution. The detection limits (signal-to-noise ratio = 3) for tyrosine and tyramine were 4.5 and 2.6 fmol per 20 microL injection, which corresponded to analyte concentrations of 0.9 and 0.5 nM, respectively.

Environmental factors affecting black/white coloration of the silken girdle in the swallowtail butterfly, Atrophaneura alcinous (Lepidoptera: Papilionidae).

The silken girdles of pupae of the swallowtail butterfly Atrophaneura alcinous show black and white color diphenism. Field observations revealed that all pupae observed on non-food plants and the leaves and stems of the larval food plant Aristolochia debilis were classified as a silken girdle of a black type, while a large portion of pupae pupating on the twigs and trunks of cherry trees in close proximity to A. debilis were classified as a silken girdle of a black type. Additionally, all pupae observed on the surfaces of artificial objects in areas where there are no surrounding plants or trees were classified as a silken girdle of a white type. We demonstrated the effect of day length and the texture, light, plant odor and humidity of pupation sites on the coloration of the silken girdle in A. alcinous. Regardless of long-day or short-day day length conditions, light conditions of constant light or dark, or the presence of a plant odor of A. debilis as environmental cues, all larvae placed at over 80% relative humidity (R.H.) developed into pupae with a silken girdle of a black type. However, all larvae developed into pupae with a silken girdle of a white type when R.H. was below 75%. Furthermore, when pupae with a silken girdle of a white type were transferred to conditions of 90% R.H. within 24 hr of pupation, the white color of the silken girdle changed into a black type within 24 hr of the transfer. The present data suggest that the induction of a black coloration of the silken girdle in A. alcinous requires a R.H. of approximately 80% or more as an environmental factor.

Fargesin improves lipid and glucose metabolism in 3T3-L1 adipocytes and high-fat diet-induced obese mice.

This study examined the effects of fargesin, a neolignan isolated from Magnolia plants, on obesity and insulin resistance and the possible mechanisms involved in these effects in 3T3-L1 adipocytes and high-fat diet (HFD)-induced obese mice. Fargesin promoted the glucose uptake in 3T3-L1 adipocytes. In HFD-induced obese mice, fargesin decreased the body weight gain, white adipose tissue (WAT), and plasma triglyceride, non-esterified fatty acid and glucose levels, and improved the glucose tolerance. Fargesin increased glucose transporter 4 (GLUT4) protein expression and phosphorylation of Akt, AMP-activated protein kinase (AMPK), and acetyl-CoA carboxylase (ACC) in both 3T3-L1 adipocytes and WAT of HFD-induced obese mice. Fargesin also decreased the mRNA expression levels of fatty acid oxidation-related genes, such as peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyltransferase-1 (CPT-1), uncoupling protein-2 (UCP-2) and leptin in WAT. Taken together, the present findings suggest that fargesin improves dyslipidemia and hyperglycemia by activating Akt and AMPK in WAT.