Effectiveness of seasonal influenza vaccine in adult Japanese workers, 2017-2020.

BACKGROUND: Previous studies have not estimated vaccine effectiveness (VE) against influenza in the working-age Japanese population. In this study, we determined VE in adult workers at a Japanese company. METHODS: We estimated VE based on self-reported data regarding influenza infections and vaccinations in employees of an auto parts manufacturing company during three influenza seasons from 2017 to 2020. VE was estimated as 100% × [1 - odds ratio (the ratio of the odds of being diagnosed with influenza among enrollees with and without influenza vaccination)]. Odds ratios were estimated using logistic regression. RESULTS: We included 11,347 worker records [3,592 (2017-18), 3,663 (2018-19), and 4,092 (2019-20)] from employees who had worked with the company throughout each influenza season. The adjusted VE was moderate and significant in the 2019-20 season (VE = 53%; 95% confidence interval [CI] = 30% to 69%) but low or negative and non-significant during the 2017-18 (VE = 28%; 95% CI = -5% to 50%) and 2018-19 (VE = -11%; 95% CI =  - 42% to 14%) seasons. CONCLUSIONS: Influenza vaccines were moderately effective during the 2019-20 season but showed low or negative effectiveness during the 2017-18 and 2018-19 seasons. Self-reports from worker records can successfully help determine VE against influenza.

Subjective and objective assessments after a change from a 4-crew, 12-h shift to a 3-crew, 12-h shift schedule: an observational study.

PURPOSE: To clarify the subjective and objective impacts of a change in a 12-h shift schedule, involving a reduction in the number of crews, on workers at an electronic parts production company. METHODS: Forty-two workers participated in this study. Subjective indicators (e.g. questionnaires) and objective indicators [e.g., psychomotor vigilance task (PVT)], as well as an activity monitor-based sleep assessment, were measured during a > 1-year period that encompassed the shift schedule change. The study outcome was a comparison of work-related injury rates measured 1 year before and after the change in shift schedule. RESULTS: After the shift schedule change, questionnaire scores regarding work-related burdens and PVT performance parameters, including mean response time and number of lapses, increased significantly. However, we also observed divergences in the trends of the subjective and objective measures 1 year after the change. Despite these variations in both types of measures, we observed no significant differences in work-related injury rates measured before and after the shift schedule change. CONCLUSION: This study revealed that a reduction in the number of crews in a 12-h shift schedule has a negative impact on the subjective and objective indicator after the change in shift schedule; only indicators of alertness did not recover at 1 year after the change. Assessments of the workers' performances and the regular implementation of health and safety programs for more than 1 year are needed to maintain workers' health after the change in shift schedule.

Increased oxytocin-monomeric red fluorescent protein 1 fluorescent intensity with urocortin-like immunoreactivity in the hypothalamo-neurohypophysial system of aged transgenic rats.

To visualize oxytocin in the hypothalamo-neurohypophysial system, we generated a transgenic rat that expresses the oxytocin-monomeric red fluorescent protein 1 (mRFP1) fusion gene. In the present study, we examined the age-related changes of oxytocin-mRFP1 fluorescent intensity in the posterior pituitary (PP), the supraoptic nucleus (SON) and the paraventricular nucleus (PVN) of transgenic rats. The mRFP1 fluorescent intensities were significantly increased in the PP, the SON and the PVN of 12-, 18- and 24-month-old transgenic rats in comparison with 3-month-old transgenic rats. Immunohistochemical staining for urocortin, which belongs to the family of corticotropin-releasing factor family, revealed that the numbers of urocortin-like immunoreactive (LI) cells in the SON and the PVN were significantly increased in 12-, 18- and 24-month-old transgenic rats in comparison with 3-month-old transgenic rats. Almost all of urocortin-LI cells co-exist mRFP1-expressing cells in the SON and the PVN of aged transgenic rats. These results suggest that oxytocin content of the hypothalamo-neurohypophysial system may be modulated by age-related regulation. The physiological role of the co-existence of oxytocin and urocortin in the SON and PVN of aged rats remains unclear.

Visual recognition memory test performance was improved in older adults by extending encoding time and repeating test trials.

OBJECTIVES: The aim of this study was to investigate whether the combination of extension of the encoding time and repetition of a test trial would improve the visual recognition memory performance in older adults. METHODS: We evaluated visual memory performance in young and older adults on a Yes-No recognition memory test under four different conditions. The conditions consisted of combinations of encoding times of two and four seconds (E2 and E4) and first and second retrieval practice test trials (T1 and T2): E2T1, E2T2, E4T1 and E4T2. Performance was evaluated by measuring hit rates, false alarm rates, discrimination ability and response bias. RESULTS: Older adults showed better improvement of hit rate and discrimination ability under the E4T2 conditions whereas young adults showed better memory performance under the E2T2 conditions. CONCLUSIONS: A longer encoding time and repetition of the test was effective in improving the visual memory performance in terms of the hit rates and discrimination ability of older adults. The results suggest that this strategy should be useful in providing a suitable work environment for older workers.

[Sleep problems in occupational health].

It is important for workers to maintain a high quality of sleep to obtain their best performance at the workplace and in daily life. Insufficient sleep and/or dyssynchrony between internal clock and external light/dark cycles cause daytime sleepiness, and could result in a reduction of the working efficiency. Sleepiness may sometimes cause enormous economic and social losses. A recent report also indicated that lack of sleep might be a risk factor for chronic health problems such as metabolic syndrome. Therefore, it is important for an occupational physician to investigate and understand the sleep problems in workers, both to prevent serious accidents or loss at the workplace and to keep workers in good health.Additionally, the proper treatment of workers with some common sleep disorders such as an obstructive sleep apnea syndrome, or a circadian rhythm sleep disorder, needs to be understood. Shift work type is important for both worker's health and work management.

Effects of paraxanthine and caffeine on sleep, locomotor activity, and body temperature in orexin/ataxin-3 transgenic narcoleptic mice.

STUDY OBJECTIVE: Caffeine, an adenosine A1 and A2a receptor antagonist, is a widely consumed stimulant and also used for the treatment of hypersomnia; however, the wake-promoting potency of caffeine is often not strong enough, and high doses may induce side effects. Caffeine is metabolized to paraxanthine, theobromine, and theophylline. Paraxanthine is a central nervous stimulant and exhibits higher potency at A1 and A2 receptors, but has lower toxicity and lesser anxiogenic effects than caffeine. DESIGN: We evaluated the wake-promoting efficacy of paraxanthine, caffeine, and a reference wake-promoting compound, modafinil, in a mice model of narcolepsy, a prototypical disease model of hypersomnia. Orexin/ataxin-3 transgenic (TG) and wild-type (WT) mice were subjected to oral administration (at ZT 2 and ZT14) of 3 doses of paraxanthine, caffeine, modafinil, or vehicle. RESULTS: Paraxanthine, caffeine, and modafinil significantly promoted wakefulness in both WT and narcoleptic TG mice and proportionally reduced NREM and REM sleep in both genotypes. The wake-promoting potency of 100 mg/kg p.o. of paraxanthine during the light period administration roughly corresponds to that of 200 mg/kg p.o. of modafinil. The wake-promoting potency of paraxanthine is greater and longer lasting than that of the equimolar concentration of caffeine, when the drugs were administered during the light period. The wake-promotion by paraxanthine, caffeine, and modafinil are associated with an increase in locomotor activity and body temperature. However, the higher doses of caffeine and modafinil, but not paraxanthine, induced hypothermia and reduced locomotor activity, thereby confirming the lower toxicity of paraxanthine. Behavioral evaluations of anxiety levels in WT mice revealed that paraxanthine induced less anxiety than caffeine did. CONCLUSIONS: Because it is also reported to provide neuroprotection, paraxanthine may be a better wake-promoting agent for hypersomnia associated with neurodegenerative diseases.

Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle.

Amyloid-beta (Abeta) accumulation in the brain extracellular space is a hallmark of Alzheimer's disease. The factors regulating this process are only partly understood. Abeta aggregation is a concentration-dependent process that is likely responsive to changes in brain interstitial fluid (ISF) levels of Abeta. Using in vivo microdialysis in mice, we found that the amount of ISF Abeta correlated with wakefulness. The amount of ISF Abeta also significantly increased during acute sleep deprivation and during orexin infusion, but decreased with infusion of a dual orexin receptor antagonist. Chronic sleep restriction significantly increased, and a dual orexin receptor antagonist decreased, Abeta plaque formation in amyloid precursor protein transgenic mice. Thus, the sleep-wake cycle and orexin may play a role in the pathogenesis of Alzheimer's disease.

The transcriptional repressor DEC2 regulates sleep length in mammals.

Sleep deprivation can impair human health and performance. Habitual total sleep time and homeostatic sleep response to sleep deprivation are quantitative traits in humans. Genetic loci for these traits have been identified in model organisms, but none of these potential animal models have a corresponding human genotype and phenotype. We have identified a mutation in a transcriptional repressor (hDEC2-P385R) that is associated with a human short sleep phenotype. Activity profiles and sleep recordings of transgenic mice carrying this mutation showed increased vigilance time and less sleep time than control mice in a zeitgeber time- and sleep deprivation-dependent manner. These mice represent a model of human sleep homeostasis that provides an opportunity to probe the effect of sleep on human physical and mental health.

Central AMPK contributes to sleep homeostasis in mice.

AMP-activated protein kinase (AMPK) is an energy-sensing molecular signal involved in glucose and lipid metabolism. The known interaction of sleep with energy metabolism led us to investigate the role of central AMPK in sleep homeostasis. Sleep deprivation (SD) for 6 h increased p-AMPK protein in the hypothalamus and also increased the mRNA level of Ca(2+)/calmodulin (CaM)-dependent protein kinase kinase beta (CaMKK2), an activator of AMPK, and carnitine palmitoyltransferase 1 (CPT1), a downstream signaling factor of AMPK. Central injection of compound C (CC), an inhibitor of AMPK, suppressed EEG delta power during NREM sleep, while 5-aminoimidazole-4-carboxamide riboside (AICAR), an activator of AMPK, enhanced EEG delta power. The treatment of both CC and AICAR attenuated rebound responses of delta power in NREM sleep after SD. These results indicate that central AMPK is involved in the regulation of sleep depth and sleep homeostasis.

Specificity of direct transition from wake to REM sleep in orexin/ataxin-3 transgenic narcoleptic mice.

To create operational criteria for polygraphic assessments of direct transitions from wake to REM sleep (DREM), as a murine analog of human cataplexy, we have analyzed DREM episodes in congenic lines of orexin/ataxin-3 transgenic [TG] mice and wild-type littermates. The sleep stage of each 10-second epoch was visually scored using our standard criteria. Specificity of DREM for narcoleptic TG mice and sensitivity to detect DREM was evaluated using different DREM criteria. We found that DREM transitions by 10-second epoch scoring are not specific for narcoleptic TG mice and also occur in WT mice during light period. These wake-to-REM transitions in WT mice (also seen in TG mice during light period) were characteristically different from DREM transitions in TG mice during dark period; they tended to occur as brief bouts of wakefulness interrupting extended episodes of REM sleep, suggesting that these transitions do not represent abnormal manifestations of REM sleep. We therefore defined the DREM transitions by requiring a minimum number of preceding wake epochs. Requiring no fewer than four consecutive epochs of wakefulness produced the best combination of specificity (95.9%) and sensitivity (66.0%). By definition, DREM in dark-period is 100% specific to narcolepsy and was 95.9% specific overall. In addition, we found that desipramine, a trycyclic anticataplectic, potently reduces DREM, while two wake-promoting compounds have moderate (D-amphetamine) and no (modafinil) effect on DREM; the effects mirror the anticataplectic effects of these compounds reported in canine and human narcolepsy. Our definition of DREM in murine narcolepsy may provide good electrophysiological measures for cataplexy-equivalent episodes.

Hypocretin receptor expression in canine and murine narcolepsy models and in hypocretin-ligand deficient human narcolepsy.

STUDY OBJECTIVE: To determine whether hypocretin receptor gene (hcrtR1 and hcrtR2) expression is affected after long-term hypocretin ligand loss in humans and animal models of narcolepsy. DESIGN: Animal and human study. We measured hcrtR1 and hcrtR2 expression in the frontal cortex and pons using the RT-PCR method in murine models (8-week-old and 27-week-old orexin/ataxin-3 transgenic (TG) hypocretin cell ablated mice and wild-type mice from the same litter, 10 mice for each group), in canine models (8 genetically narcoleptic Dobermans with null mutations in the hcrtR2, 9 control Dobermans, 3 sporadic ligand-deficient narcoleptics, and 4 small breed controls), and in humans (5 narcolepsy-cataplexy patients with hypocretin deficiency (average age 77.0 years) and 5 control subjects (72.6 years). MEASUREMENT AND RESULTS: 27-week-old (but not 8-week-old) TG mice showed significant decreases in hcrtR1 expression, suggesting the influence of the long-term ligand loss on the receptor expression. Both sporadic narcoleptic dogs and human narcolepsy-cataplexy subjects showed a significant decrease in hcrtR1 expression, while declines in hcrtR2 expression were not significant in these cases. HcrtR2-mutated narcoleptic Dobermans (with normal ligand production) showed no alteration in hcrtR1 expression. CONCLUSIONS: Moderate declines in hcrtR expressions, possibly due to long-term postnatal loss of ligand production, were observed in hypocretin-ligand deficient narcoleptic subjects. These declines are not likely to be progressive and complete. The relative preservation of hcrtR2 expression also suggests that hypocretin based therapies are likely to be a viable therapeutic options in human narcolepsy-cataplexy.

Sleep and EEG features in genetic models of Down syndrome.

Down syndrome is characterized by a host of behavioral abnormalities including sleep disturbances. Sleep and EEG was studied at the age of 3 months in two mouse models of the condition, Ts65Dn and Ts1Cje, carrying one extra copy of partially overlapping segments of the mmu chromosome 16 (equivalent to the human chromosome 21). We found that the Ts65Dn mice showed increased waking amounts at the expense of non-REM sleep, increased theta power during sleep and a delayed sleep rebound after sleep deprivation. In contrast, Ts1Cje had limited sleep and EEG abnormalities, showing only a delayed sleep rebound after sleep deprivation and no difference in theta power. We previously found that mice over-expressing the human APPwt transgene, a gene triplicated in Ts65Dn but not Ts1Cje, also show increased wake and theta power during sleep. These results demonstrate abnormalities in sleep and EEG in Ts65Dn mice and underscore a possible correlation between App overexpression and hippocampal theta oscillations.

CSF histamine levels in rats reflect the central histamine neurotransmission.

Reduced cerebrospinal fluid (CSF) histamine levels were found in human hypersomnia. To evaluate the functional significance of changes in CSF histamine levels, we measured the levels in rats across 24h, after the administration of wake-promoting compounds modafinil, amphetamine, and thioperamide, and after sleep deprivation and food deprivation. Thioperamide significantly increased CSF histamine levels with little effects on locomotor activation. Both modafinil and amphetamine markedly increased the locomotor activity, but had no effects on histamine. The levels are high during active period and are markedly elevated by sleep deprivation, but not by food deprivation. Our study suggests that CSF histamine levels in rats reflect the central histamine neurotransmission and vigilance state changes, providing deeper insight into the human data.

CSF orexin-A/hypocretin-1 concentrations in patients with intracerebral hemorrhage (ICH).

Orexins/hypocretins are neuropeptides that have various physiological effects, including the regulation of both the feeding behavior neuroendocrine functions and sleep-wakefulness cycle. Recent studies have suggested that the orexin system may also be involved in neuronal damage in the clinical setting and animal experiments. The aim of this study was to examine the role of the hypothalamic orexin-A/hypocretin-1 system in patients with intracerebral hemorrhage (ICH). The CSF orexin-A/hypocretin-1 levels were measured in 11 ICH patients. CSF orexin-A/hypocretin-1 levels were low in ICH patients during the 13 days following the ICH event. The mean CSF orexin-A/hypocretin-1 levels were 61.1+/-22.3 (S.D.) pg/ml (range 27.5-106.9 pg/ml). The decreasing in the CSF orexin-A/hypocretin-1 levels was not related to the severity of ICH. The CSF orexin-A/hypocretin-1 levels were lower in the thalamic hemorrhage patients than those in other patients (48.5+/-23.3 pg/ml vs. 65.2+/-21.2 pg/ml; p=0.03.) These data indicate that orexin-A/hypocretin-1 may therefore play an important role in the various physiological responses including sleep, feeding, and the overall metabolism in ICH patients.

Neuropeptides as possible targets in sleep disorders: special emphasis on hypocretin-deficient narcolepsy.

Sleep disorders are disturbances of usual sleep patterns or behaviors caused by deregulation of neuronal synchronicity and of the balance of the neurotransmitter system involved in sleep regulation. Insomnia and hypersomnia are frequent sleep disorders, and these are most often treated pharmacologically with hypnotics and wake-promoting compounds. These compounds act on classical neurotransmitter systems, such as benzodiazepines on gamma amino butyric acid (GABA)(A) receptors, and amphetamine-like stimulants on monoaminergic terminals to modulate neurotransmission. In addition, acetylcholine, amino acids, lipids and proteins (cytokines) and peptides, are known to significantly modulate sleep, and thus, are possibly involved in the pathophysiology of some sleep disorders. Due to recent developments in molecular biological techniques, many neuropeptides have been newly identified, and some are found to significantly modulate sleep. Recent discoveries also include the finding that the impairment of hypocretin/orexin neurotransmission (a recently isolated hypothalamic neuropeptide and receptor system), is the major pathophysiology of narcolepsy with cataplexy. A hypocretin replacement therapy is anticipated to reverse the disease symptoms in humans. In this article, we will review the history of neuropeptide research, sleep modulatory effects of various neuropeptides, and the general strategies for the pharmacological therapeutics targeting the peptidergic systems by referring to hypocretin-deficient narcolepsy as an immediate example.

Neuropeptides as possible targets in sleep disorders.

Insomnia and hypersomnia are frequent sleep disorders, and they are most often treated pharmacologically with hypnotics and wake-promoting compounds. These compounds act on classical neurotransmitter systems, such as benzodiazepines on GABA-A receptors, and amfetamine-like stimulants on monoaminergic terminals to modulate neurotransmission. In addition, acetylcholine, amino acids, lipids and proteins (cytokines) and peptides, are known to significantly modulate sleep and are, therefore, possibly involved in the pathophysiology of some sleep disorders. Due to the recent developments of molecular biological techniques, many neuropeptides have been newly identified, and some are found to significantly modulate sleep. It was also discovered that the impairment of the hypocretin/orexin neurotransmission (a recently isolated hypothalamic neuropeptide system) is the major pathophysiology of narcolepsy, and hypocretin replacement therapy is anticipated to treat the disease in humans. In this article, the authors briefly review the history of neuropeptide research, followed by the sleep modulatory effects of various neuropeptides. Finally, general strategies for the pharmacological therapeutics targeting the peptidergic systems for sleep disorders are discussed.

Sex difference in body weight gain and leptin signaling in hypocretin/orexin deficient mouse models.

Recent studies in human and animal models of narcolepsy have suggested that obesity in narcolepsy may be due to deficiency of hypocretin signaling, and is also under the influence of environmental factors and the genetic background. In the current study, using two hypocretin/orexin deficient narcoleptic mouse models (i.e. preproorexin knockout (KO) and orexin/ataxin-3 transgenic (TG) mice) with cross-sectional assessments, we have further analyzed factors affecting obesity. We found that both KO and TG narcoleptic mice with mixed genetic backgrounds (N4-5, 93.75-96.88% genetic composition of C57BL/6) tended to be heavier than wild type (WT) mice of 100-200 days old. The body weight of heterozygous mice was intermediate between those of KO and WT mice. Obesity was more prominent in females in both KO and TG narcoleptic mice and was associated with higher serum leptin levels, suggesting a partial leptin resistance. Obesity is less prominent in the congenic TG narcoleptic mice, but is still evident in females. Our results confirmed that hypocretin/orexin ligand deficiency is one of the critical factors for the obese tendency in narcolepsy. However, multiple factors are also likely to affect this phenotype, and a sex difference specific alteration of leptin-hypocretin signaling may be involved.

Change in intrathoracic pressure in rats with spontaneous and controlled ventilation during microgravity by parabolic flight.

We previously reported that the intrathoracic pressure (ITP) decreases and the transmural pressure of the aortic wall (TMP) increases during 4.5 s of microgravity (muG) induced by free drop. To examine the ITP response to a longer period of muG in the absence of the respiratory rate (RR) decrease, i.e., bradypnea, which occurs at the onset of muG, we measured the aortic blood pressure at the diaphragma level (AP) and ITP. We then calculated the TMP at the aortic arch level during 20 s of muG induced by parabolic flight in anesthetized rats (n = 7) with either spontaneous ventilation (SPN-V) or controlled ventilation (CONT-V). In the SPN-V group, the bradypnea was observed in all rats after the onset of the muG (RR change -13.9 +/- 2.9/min). The ITP during muG (-9.3 +/- 0.9 mmHg) was significantly lower than that during 1 G (-7.7 +/- 0.9 mmHg), and the TMP was significantly increased during muG (112 +/- 6 mmHg) compared to 1 G (103 +/- 5 mmHg). Similar changes in ITP and TMP were observed in the CONT-V group: During muG and 1G, respectively, the ITP was -8.4 +/- 0.6 mmHg and -5.9 +/- 0.7 mmHg, and the TMP was 112 +/- 6 mmHg and 101 +/- 6 mmHg, whereas no change in RR was observed because of the controlled ventilation. These results show that the ITP decreases and the TMP increases during muG, and they are not affected by a disturbance of respiratory rhythm.

Sequence of forebrain activation induced by intraventricular injection of hypertonic NaCl detected by Mn2+ contrasted T1-weighted MRI.

In order to define the sequence of forebrain activation involved in osmoregulation, central activation in response to intracerebroventricular injection of NaCl solution (10 microl of 0.15, 0.5, or 1.5 M) was detected using manganese-contrasted magnetic resonance imaging (MRI) in anesthetized rats. Changes in renal sympathetic nerve activity (RNA) were also measured, and the time courses of forebrain activation and RNA changes compared. NaCl injection resulted in rapid activation of the subfornical organ (SFO), organum vasculosum lamina terminalis (OVLT), and periventricular regions and the lateral hypothalamic area (LHA), then of the paraventricular hypothalamic nucleus (PVN) and supraoptic nucleus (SON). The delay in activation in the PVN and SON showed a wide variation from 0 to 5.78 min, and the average delay in the PVN (2.88+/-0.34 min) and SON (2.90+/-0.39 min) was significantly greater than that in the SFO (0.40+/-0.10 min) and OVLT (0.74+/-0.13 min). NaCl (1.5 M) injection elicited a rapid, large increase in RNA, which consisted of two components, an early rapid increase at 99 s after injection (160+/-27%) and a slower increase at 9 min after injection (209+/-34%). These results suggest that the PVN and SON are activated not only by the afferent input from the SFO and OVLT but also by diffusion of the hypertonic stimulus to these regions and probably by their intrinsic osmosensitivity. The PVN might be responsible for the second slower component of the RNA response, but cannot be responsible for the first component.