Hideaki Kondo

CTLA4 gene polymorphism correlates with the mode of onset and presence of ICA512 Ab in Japanese Type 1 diabetes

Recently, the association of CTLA4 gene polymorphism with type 1 diabetes and AITD has been reported in several populations. CTLA4 was originally reported to regulate T-cell activity and T-B cognate interaction. To investigate the role of CTLA4 in autoimmune diseases, we examined the correlation between CTLA4 gene polymorphism and the clinical characteristics of Japanese patients with type 1 diabetes, including the mode of onset of diabetes and presence of islet-specific autoantibodies (GAD, ICA 512 Ab) in the serum. We studied 111 patients with type 1 diabetes and 445 normal subjects. CTLA4 exon 1 position 49 (A/G: codon 17: Thr/Ala) polymorphism was defined, employing PCR-RFLP. Sixty-three (57%) patients had AITD. The allele frequencies of G and A in both 111 patients (G: 65%; A: 35%) and 63 patients (G: 62%; A: 38%) were not significantly different from the control subjects (G: 63%; A: 37%). Serum samples of 69 patients were obtained within a year after onset and used for pancreas specific autoantibodies analysis. These samples were also used for further analysis between CTLA4 gene polymorphism and clinical characteristics. The allele frequencies of G and A in patients who presented with diabetic ketoacidosis (DK+) (G: 75%; A: 25%) were significantly different from those in DK- patients (G: 50%, A: 50%, P = 0.003). Allele and genotype analyses showed significant differences between DK+ patients and control subjects (P = 0.014, P = 0.046, respectively). Allele frequencies of G and A were not significant between patients who were positive and negative for GAD Ab, but significant for ICA 512 Ab (G: 83%, A:17% versus G: 59%, A: 41%: positive patients versus negative patients, P = 0.004). Our results showed a significant correlation between CTLA4 gene polymorphism and ICA 512 Ab. Our results also indicated that CTLA4 gene polymorphism is associated with the onset mode of Japanese type 1 diabetes and the presence of ICA512 Ab. Further analysis of this polymorphism is necessary to fully understand the pathogenesis and progression of type 1 diabetes.

Acute effects of zolpidem on daytime alertness, psychomotor and physical performance

In a double-blind cross-over study, seven athletes received zolpidem (10mg) or placebo in two sessions over two nights. Residual effects on subsequent daytime functions were evaluated objectively by measuring psychomotor and physical performance using a combined test of finger dexterity, a simple discriminatory reaction test, critical flicker fusion test (CFF), vertical jump, and 50-m sprint, as well as subjectively, by visual analog scales. Zolpidem shortened self-estimated sleep latency and increased total sleep at nighttime. There was no change in alertness and fatigue scales on the following day in the zolpidem session, but realm of daytime well-being was slightly worsened. The CFF test showed significantly better results in the zolpidem group than in the placebo group. Zolpidem did not have effects in athletic evaluation. Zolpidem has a hypnotic activity without disturbing psychomotor and physical performance on the following day when given to healthy adults, suggesting zolpidem may be used in healthy athletes to adjust their extrinsic sleep disturbances and their consecutive psychomotor and physical impairments.

Alcohol has a dose-related effect on parasympathetic nerve activity during sleep

BACKGROUND The aim of this study was to identify the acute effects of ethanol on the relationship between sleep and heart rate variability (HRV) during sleep. METHODS Ten healthy male university students were enrolled in this study. An alcoholic beverage was given to each subject at a dosage of 0 (control), 0.5 (low dose: LD), or 1.0 g (high dose: HD) of pure ethanol/kg of body weight. All experiments were performed at 3-week intervals. On the day of the experiment, a Holter electrocardiogram was attached to the subject for a 24-hour period, and the subject was instructed to drink the above-described dosage of alcoholic beverage 100 minutes before going to bed; polysomnography was then performed for 8 hours. Power spectral analysis of the HRV was performed using the maximum entropy method, and the low- (LF: 0.04 to 0.15 Hz) and high-frequency (HF: 0.15 to 0.4 Hz) components along with LF/HF ratio were calculated. RESULTS As alcohol consumption increased, the heart rate increased and the spectral power of HRV measured at each frequency range decreased. Higher doses of ethanol also increased the LF/HF ratio compared with the measured ratio of the control group. CONCLUSIONS Acute ethanol intake inhibits parasympathetic nerve activity and results in predominance of sympathetic nerve activity during sleep, in a dosage-dependent manner. The results of this study suggest that ethanol interferes with the restorative functions of sleep.

No deterioration in insulin sensitivity, but impairment of both pancreatic β-cell function and glucose sensitivity, in Japanese women with former gestational diabetes mellitus

To identify the primary pathogenic factors involved in the development of Type 2 diabetes mellitus (DM), we studied Japanese women with former gestational diabetes mellitus (GDM) who are at risk for the later development of Type 2 DM. We used the minimal model analysis derived from frequently sampled intravenous glucose tolerance test (FSIGT). The subjects consisted of eight non‐obese women with a history of GDM and eight non‐obese normal women as control subjects. The 75 g oral glucose tolerance test (75 g OGTT) performed within 6 months of delivery confirmed that all the subjects with former GDM had a normal glucose tolerance. Insulin sensitivity (SI) derived from the minimal model analysis was not different between the two groups. Glucose effectiveness at zero insulin (GEZI), reflecting tissue glucose sensitivity, was significantly lower in former GDM patients than in control subjects (1.18 ± 0.34 vs 2.26 ± 0.29 × 10−2 min−1, p < 0.05). The early phase insulin secretion found in FSIGT was markedly reduced to 56 % of that observed in control subjects (1250 ± 187.4 vs 2223 ± 304.3 pmol l−1 min, p < 0.01). Our results indicate that in former GDM patients, who are Japanese and non‐obese, impairment of the acute insulin response to glucose and a decrease in tissue glucose sensitivity rather than insulin sensitivity are the primary pathogenic factors involved. Copyright

Association between heart rate variability, blood pressure and autonomic activity in cyclic alternating pattern during sleep.

STUDY OBJECTIVES Cyclic alternating pattern (CAP) is frequently followed by changes in heart rate (HR) and blood pressure (BP), but the sequential associations between CAP and autonomic nerve activity have not been studied. The study aimed to reveal the precise changes in heart rate variability (HRV) during phase A of the CAP cycle. DESIGN Polysomnography was recorded according to the CAP Atlas (Terzano, 2002), and BP and electrocardiogram were simultaneously recorded. The complex demodulation method was used for analysis of HRV and evaluation of autonomic nerve activity. SETTING Academic sleep laboratory. PARTICIPANTS Ten healthy males. MEASUREMENTS AND RESULTS The increase in HR (median [first quartile - third quartile]) for each subtype was as follows: A1, 0.64 (-0.30 to 1.69), A2, 1.44 (0.02 to 3.79), and A3, 6.24 (2.53 to 10.76) bpm (A1 vs. A2 P < 0.001, A1 vs. A3 P < 0.001, A2 vs. A3 P < 0.001). The increase in BP for each subtype was as follows: A1, 1.23 (-2.04 to 5.75), A2, 1.76 (-1.46 to 9.32), and A3, 12.51 (4.75 to 19.94) mm Hg (A1 vs. A2 P = 0.249, A1 vs. A3 P < 0.001, A2 vs. A3 P < 0.001). In all of phase A, the peak values for HR and BP appeared at 4.2 (3.5 to 5.4) and 8.4 (7.0 to 10.3) seconds, respectively, after the onset of phase A. The area under the curve for low-frequency and high-frequency amplitude significantly increased after the onset of CAP phase A (P < 0.001) and was higher in the order of subtype A3, A2, and A1 (P < 0.001). CONCLUSIONS All phase A subtypes were accompanied with increased heart rate variability, and the largest heart rate variability was seen in subtype A3, while a tendency for less heart rate variability was seen in subtype A1.

An association analysis of HLA-DQB1 with narcolepsy without cataplexy and idiopathic hypersomnia with/without long sleep time in a Japanese population

Narcolepsy without cataplexy (NA w/o CA) (narcolepsy type 2) is a lifelong disorder characterized by excessive daytime sleepiness and rapid eye movement (REM) sleep abnormalities, but no cataplexy. In the present study, we examined the human leukocyte antigen HLA-DQB1 in 160 Japanese patients with NA w/o CA and 1,418 control subjects. Frequencies of DQB1*06:02 were significantly higher in patients with NA w/o CA compared with controls (allele frequency: 16.6 vs. 7.8%, P=1.1×10−7, odds ratio (OR)=2.36; carrier frequency: 31.3 vs. 14.7%, P=7.6×10−8, OR=2.64). Distributions of HLA-DQB1 alleles other than DQB1*06:02 were compared between NA w/o CA and narcolepsy with cataplexy (NA-CA) to assess whether the genetic backgrounds of the two diseases have similarities. The distribution of the HLA-DQB1 alleles in DQB1*06:02-negative NA w/o CA was significantly different from that in NA-CA (P=5.8×10−7). On the other hand, the patterns of the HLA-DQB1 alleles were similar between DQB1*06:02-positive NA w/o CA and NA-CA. HLA-DQB1 analysis was also performed in 186 Japanese patients with idiopathic hypersomnia (IHS) with/without long sleep time, but no significant associations were observed.

Rapid Increase to Double Breathing Rate Appears During REM Sleep in Synchrony with REM –A Higher CNS Control of Breathing? –

Breathing rate (BR) during rapid eye movement (REM) sleep is known to fluctuate largely, while increases in BR during REM sleep reported were small. In our mice experiments, we found that mice exhibit a rapid increase in instantaneous BR (RIBR) of >2 fold during natural sleep with accompanying atonia, laying their sides down. The RIBR was further found in a sleeping mouse attached with EEG electrodes when the EEG amplitude and delta wave power were lower. Therefore, it is likely that mice show RIBRs during REM sleep. Interestingly, similar RIBRs accompanied by atonia and REM burst during REM sleep were also found in humans by standard polysomnographic studies in 11 healthy volunteers (age: 22.3 +/- 2.8) with BR measurement by nasal/oral airflow sensors and chest/abdomen belt sensors. All subjects underwent RIBR of doubled BR at least once a night. As SpO(2) before RIBRs was a level not effective to be a respiratory stimulant (96.7 +/- 1.6 %, n = 63), the RIBR seems to be controlled by higher central nervous system rather than autonomic nervous system control on response to central and peripheral chemical sensors. In fact, tachypnea with suppressed amplitude during RIBR resulted in a slight fall in SpO(2) (96.4 +/- 1.7 %, p = 0.0007). In the present study, RIBRs accompanied by atonia and REM were not necessarily consistent in change in rate and/or amplitude, therefore, these various pattern of RIBRs may be potential indices of dreams with various emotional contents. Analysis of instantaneous BR, thus, may be a helpful tool for understanding the neural control of breathing during REM sleep.

Multiple endocrine neoplasia type 2 with malignant pheochromocytoma — Long term follow-up of a case by131I-meta-iodobenzylguanidine scintigraphy—

The case of a 33-year-old Japanese man, who has Multiple Endocrine Neoplasia Type 2 (MEN IIa) (Sipple’s syndrome) with malignant pheochromocytoma, is reported. He had survived for twelve years since the initial diagnosis of malignant pheochromocytoma. Within this period, he had undergone131I-meta-iodobenzylguanidine scintigraphy twice, in 1983 and 1990. This is the first case in Japan of a longterm surviving patient with malignant pheochromocytoma followed up by131I-MIBG scintigraphy. Although he had no exacerbation of clinical symptoms or urinary catecholamine levels, second scintigraphy clearly showed an increase in the tumor size, new metastasis of the malignant pheochromocytoma and exacerbation of the medullary thyroid carcinoma. Compared with any other roentgenological device and hormonal data,131I-MIBG scintigraphy was seen to be a good tool for evaluating the localization and the progression of tumors.131I-MIBG scintigraphy is a useful procedure not only for initial diagnosis but also for judging progression in a case of advanced malignant pheochromocytoma.

Human T-cell Leukemia Virus-1 Infection is Associated with Atherosclerosis as Measured by Carotid Intima-Media Thickness in Japanese Community-Dwelling Older People

The association between human T-cell leukemia virus-1 (HTLV-1) and atherosclerosis remains to be determined. This case-control study aimed to investigate this association as measured by carotid intima-media thickness (CIMT). HTLV-1 infection was positively associated with CIMT, independent of atherosclerotic risks.

Hypocretin Status in Neurological Disorders in Relation to Excessive Sleepiness and Cataplexy

A tight association (90–95%) between human narcolepsy-cataplexy and hypocretin orexin deficiency has recently been revealed (1, 2, 3, 4, 5, 6, 7, 8). Hypocretins are hypothalamic neuropeptides involved in various fundamental hypothalamic functions including sleep-wake control, energy homeostasis, and autonomic and neuroendocrine functions (9, 10, 11). Hypocretin-containing neurons are located exclusively in the lateral hypothalamic area (LHA). Narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations (HH), and sleep paralysis (SP) (i.e., the narcolepsy tetrad) (5,12). Since hypocretin deficiency in narcolepsy is also tightly associated with human leukocyte antigen (HLA) DR2/DQ6 (DQB1*0602) positivity, an acquired cell loss of hypocretin-containing neurons along with the autoimmune process is suggested in so-called idiopathic cases of narcolepsy (4,5). The term idiopathic narcolepsy has been used for cases of narcolepsy unassociated with apparent radiographical or clinical evidence of brain pathology apart from sleep-related abnormalities. Hypocretin deficiency in the brain can be determined clinically via cerebrospinal fluid (CSF) hypocretin-1 measures; CSF hypocretin-1 levels in healthy subjects are above 200 pg/mL regardless of gender, age (from neonatal to the 70s), and time of CSF collection (2,4,12). Owing to the specificity and sensitivity of low CSF hypocretin-1 levels (<110pg/mL or one-third of the mean normal value), narcolepsy-cataplexy is high among various sleep disorders (5,13,14), CSF hypocretin measures will be included in the diagnostic criteria for narcolepsy-cataplexy in the second revision of the International Classification of Sleep Disorders (ICSD).