Prospective changes in sleep problems in response to the daily rest period among Japanese daytime workers: A longitudinal web survey.

The daily rest period (DRP) is the daily inter-work interval and can include a sleep opportunity, leisure time, and other non-work time. A longer DRP may allow workers to increase time in bed (TIB) and adjust sleep timing, and that may reduce sleep problems such as short sleep duration, sleep debt, social jetlag, and poor sleep quality. The present study examined the longitudinal association between the DRP and these sleep problems among Japanese daytime workers. The DRP, TIB on workdays, sleep quality (Pittsburgh Sleep Quality Index [PSQI]), sleep debt and social jetlag were measured in November 2016 (n = 10,000) and February 2019 (n = 3,098). Of these, 955 permanent daytime workers were divided into five groups based on the change in the DRP duration: shortened ≥2 hr, shortened ≥1 hr, no change (<1 hr), extended ≥1 hr and extended ≥2 hr. Linear mixed-model analysis revealed significant interaction (group × time) effects on the TIB, PSQI score and sleep debt (all p < 0.001), but not on social jetlag (p = 0.476). Post hoc comparisons revealed that the TIB was decreased, and the sleep debt was increased in the shortened ≥2 hr group, whereas the TIB was increased and PSQI score was improved in the extended ≥2 hr group (all p < 0.01). These findings suggest that an extension of the DRP improves sleep quantity and quality but not sleep debt and social jetlag. Aside from extending the DRP, ensuring a sufficient sleep duration and adjusting sleep timing during the DRP may also be needed to prevent sleep problems.

Bone marrow transplantation into Abcd1-deficient mice: Distribution of donor derived-cells and biological characterization of the brain of the recipient mice.

X-linked adrenoleukodystrophy (X-ALD) is a severe inherited metabolic disease with cerebral inflammatory demyelination and abnormal accumulation of very long chain fatty acid (VLCFA) in tissues, especially the brain. At present, bone marrow transplantation (BMT) at an early stage of the disease is the only effective treatment for halting disease progression, but the underlying mechanism of the treatment has remained unclear. Here, we transplanted GFP-expressing wild-type (WT) or Abcd1-deficient (KO) bone marrow cells into recipient KO mice, which enabled tracking of the donor GFP+ cells in the recipient mice. Both the WT and KO donor cells were equally distributed throughout the brain parenchyma, and displayed an Iba1-positive, GFAP- and Olig2-negative phenotype, indicating that most of the donor cells were engrafted as microglia-like cells. They constituted approximately 40% of the Iba1-positive cells. Unexpectedly, no decrease of VLCFA in the cerebrum was observed when WT bone marrow cells were transplanted into KO mice. Taken together, murine study suggests that bone marrow-derived microglia-like cells engrafted in the cerebrum of X-ALD patients suppress disease progression without evidently reducing the amount of VLCFA in the cerebrum.

Shorter sleep duration is associated with potential risks for overwork-related death among Japanese truck drivers: use of the Karoshi prodromes from worker's compensation cases.

PURPOSE: We aimed to cross-sectionally investigate how work and sleep conditions could be associated with excessive fatigue symptoms as an early sign of Karoshi (overwork-related cerebrovascular and cardiovascular diseases; CCVDs). METHODS: We distributed a questionnaire regarding work, sleep, and excessive fatigue symptoms to 5410 truck drivers, as the riskiest occupation for overwork-related CCVDs, and collected 1992 total samples (response rate: 36.8%). The research team collected 1564 investigation reports required for compensation for Karoshi. Of them, 190 reports listed the prodromes of Karoshi, which were used to develop the new excessive fatigue symptoms inventory. RESULTS: One-way analyses of variance showed that the excessive fatigue symptoms differed significantly by monthly overtime hours (p < 0.001), daily working time (p < 0.001), work schedule (p = 0.025), waiting time on-site (p = 0.049), number of night shifts (p = 0.011), and sleep duration on workdays (p < 0.001). Multivariate mixed-model regression analyses revealed shorter sleep duration as the most effective parameter for predicting excessive fatigue symptoms. Multiple logistic regression analysis confirmed that the occurrences of CCVDs were significantly higher in the middle [adjusted ORs = 3.56 (1.28-9.94)] and high-score groups [3.55 (1.24-10.21)] than in the low-score group. CONCLUSION: The findings suggested that shorter sleep duration was associated more closely with a marked increase in fatigue, as compared with the other work and sleep factors. Hence, ensuring sleep opportunities could be targeted for reducing the potential risks of Karoshi among truck drivers.

Daytime Workers with Longer Daily Rest Periods Have Smaller Sleep Debt and Social Jetlag: A Cross-Sectional Web Survey.

Objectives: The work interval duration between the end of one workday and the start of the following workday is referred to as the daily rest period (DRP). The present study examined whether DRP - a proxy for sleep opportunity between work shifts - is associated with indicators of sleep debt and social jetlag among daytime workers. Methods: We used a web-based survey to gather data on demographics, average DRP in the previous month, time in bed (TIB), bedtime, wake-up time, and sleep timing on workdays and non-workdays. The Japanese daytime workers (n = 3,914) were divided into seven DRP groups (hours) as follows: <11, 11, 12, 13, 14, 15, and ≥16. Results: The two-way analyses of covariance (DRP group x day) for TIB, mid-sleep as sleep timing, bedtime, and wake-up time showed significant interactions (all p < .001). Specifically, TIB was significantly shorter, and mid-sleep and wake-up time were significantly earlier on workdays than on non-workdays, across all DRP groups (all p < .001). Additionally, the different values for TIB (sleep debt), sleep timing (social jetlag), bedtime, and wake-up time were calculated by subtracting workdays from non-workdays. The trend analysis showed that workers with longer DRP (sleep opportunity) had smaller differences in TIB, sleep timing, and wake-up time between workdays and non-workdays (all p < .001). Conclusions: Overall, daytime workers reported significant sleep debt and misalignment between work and free sleep-wake periods. However, workers with shorter DRPs (less sleep opportunity between shifts) reported significantly greater amounts of sleep debt and social jetlag than did workers with longer DRPs.

A Novel Role of Interleukin-6 as a Regulatory Factor of Inflammation-Associated Deterioration in Osteoblast Arrangement.

Inflammatory disorders are associated with bone destruction; that is, deterioration in bone cell activities are under the control of the innate immune system. Macrophages play a central role in innate immunity by switching their polarized phenotype. A disturbed immune system causes aberrance in the ordered bone matrix microarrangement, which is a dominant determinant of bone tissue functionalization. However, the precise relationship between the immune system and bone tissue organization is unknown. In this study, the controlled in vitro co-culture assay results showed that M1-polarized macrophages disrupted the osteoblast alignment, which directly modulate the oriented bone matrix organization, by secreting pro-inflammatory cytokines. Notably, interleukin-6 was found to be a key regulator of unidirectional osteoblast alignment. Our results demonstrated that inflammatory diseases triggered bone dysfunction by regulating the molecular interaction between the immune system and bone tissue organization. These findings may contribute to the development of therapeutic targets for inflammatory disorders, including rheumatoid arthritis.

Carotid artery stenting with proximal embolic protection via the transbrachial approach: sheathless navigation of a 9-F balloon-guiding catheter.

PURPOSE: Transbrachial carotid artery stenting (TB-CAS) is performed as an alternative procedure for patients with hostile vascular anatomy of the aortic arch and aortic or peripheral artery disease. Proximal protection during TB-CAS is not generally feasible because a small size of the brachial artery may preclude using a large-diameter sheath introducer. We, herein present a novel method that enables proximal protection during TB-CAS by sheathless navigation of a 9-F balloon-guiding catheter equivalent to a 7-F sheath. METHODS: We analyzed eight consecutive patients who underwent TB-CAS with proximal protection using the sheathless method from April 2016 to June 2017. Relevant demographic, radiographic, and procedural features were retrospectively reviewed. RESULTS: We performed TB-CAS using our method for five patients with a bovine or type 3 aortic arch, for one patient with combined peripheral artery disease, and for two patients with a type 1 or 2 aortic arch. We successfully navigated the balloon-guiding catheter via the brachial artery and performed CAS under proximal flow control in all patients. However, we experienced kinking and exchange of the balloon-guiding catheter in one patient and a periprocedural thromboembolic event occurred. A pseudoaneurysm at the access site developed in one patient. CONCLUSION: TB-CAS with proximal embolic protection using the sheathless method is feasible and may provide an alternative approach in carefully selected patients who have difficult anatomy in the transfemoral approach and plaques with a high risk of distal embolization.

A novel method for determining peroxisomal fatty acid ß-oxidation.

The purpose of this study is to establish an assay method to screen for chemical compounds that stimulate peroxisomal fatty acid ß-oxidation activity in X-linked adrenoleukodystropy (X-ALD) fibroblasts. In this investigation, we used 12-(1-pyrene)dodecanoic acid (pyrene-C12:0), a fluorescent fatty acid analog, as a substrate for fatty acid ß-oxidation. When human skin fibroblasts were incubated with pyrene-C12:0, ß-oxidation products such as pyrene-C10:0 and pyrene-C8:0 were generated time-dependently. These ß-oxidation products were scarcely detected in the fibroblasts from patients with Zellweger syndrome, a peroxisomal biogenesis disorder. In contrast, in fibroblasts with mitochondrial carnitine-acylcarnitine translocase deficiency, the ß-oxidation products were detected at a level similar to control fibroblasts. These results indicate that the ß-oxidation of pyrene-C12:0 takes place in peroxisomes, but not mitochondria, so pyrene-C12:0 is useful for measuring peroxisomal fatty acid ß-oxidation activity. In X-ALD fibroblasts, the ß-oxidation activity for pyrene-C12:0 was approximately 40 % of control fibroblasts, which is consistent with previous results using [1-(14)C]lignoceric acid as the substrate. The present study provides a convenient procedure for screening chemical compounds that stimulate the peroxisomal fatty acid ß-oxidation in X-ALD fibroblasts.

[Initial scotomas in normal tension glaucoma].

PURPOSE: To investigate risk factors for initial visual field pattern in normal tension glaucoma (NTG). PATIENTS AND METHODS: We studied 107 subjects, who underwent 24-2 or 30-2 Swedish interactive threshold algorithm standard visual fields as part of a multicenter study of newly diagnosed NTG patients. Only the eyes with initial parafoveal scotoma (IPFS) or initial nasal step (INS) Were included. IPFS was defined as a glaucomatous visual field (VF) defect in 1 hemifield (≥ 3 adjacent points with p < 5% within the central 10 degrees of fixation, ≥ 1 point with p < l% lying at the innermost paracentral points, and no VF abnormality outside the central 10 degrees). INS was defined in 1 hemifield (≥ 3 adjacent points with p < 5% in the nasal periphery outside 10 degrees of fixation, the nasal- most point with p < 1%, and no VF abnormality within the central 10 degrees). Clinical characteristics were compared between the 2 groups. RESULTS: Mean untreated intraocular pressure (IOP) (14.0 ± 1.3 vs. 16.0 ± l.4 mmHg; p = 0.0102) was significantly lower in patients with an IPFS than in patients with an INS. There were no significant differences in age (p = 0.6487) or spherical equivalent (p = 0.7561). CONCLUSION: Initial visual field pattern of NTG is influenced by untreated IOP level.

Development of an individual display optimization system based on deep convolutional neural network transition learning for somatostatin receptor scintigraphy.

Somatostatin receptor scintigraphy (SRS) is an essential examination for the diagnosis of neuroendocrine tumors (NETs). This study developed a method to individually optimize the display of whole-body SRS images using a deep convolutional neural network (DCNN) reconstructed by transfer learning of a DCNN constructed using Gallium-67 (67Ga) images. The initial DCNN was constructed using U-Net to optimize the display of 67Ga images (493 cases/986 images), and a DCNN with transposed weight coefficients was reconstructed for the optimization of whole-body SRS images (133 cases/266 images). A DCNN was constructed for each observer using reference display conditions estimated in advance. Furthermore, to eliminate information loss in the original image, a grayscale linear process is performed based on the DCNN output image to obtain the final linearly corrected DCNN (LcDCNN) image. To verify the usefulness of the proposed method, an observer study using a paired-comparison method was conducted on the original, reference, and LcDCNN images of 15 cases with 30 images. The paired comparison method showed that in most cases (29/30), the LcDCNN images were significantly superior to the original images in terms of display conditions. When comparing the LcDCNN and reference images, the number of LcDCNN and reference images that were superior to each other in the display condition was 17 and 13, respectively, and in both cases, 6 of these images showed statistically significant differences. The optimized SRS images obtained using the proposed method, while reflecting the observer's preference, were superior to the conventional manually adjusted images.

Impaired self-monitoring ability on reaction times of psychomotor vigilance task of nurses after a night shift.

The cognitive ability to self-monitor one's current performance is important for hospital nurses to maintain safety and health. However, studies on the effects of rotating shift work on self-monitoring ability are insufficient. We examined the differences in self-monitoring accuracy across shifts in a rotating three-shift system among 30 female ward nurses (mean age 28.2 years). Their self-monitoring ability was calculated by subtracting the predicted reaction times of the psychomotor vigilance task performed just before exiting the workplace from the actual reaction times. A mixed-effect model was employed to assess the effects of shift, awake hours, and prior sleep duration on self-monitoring ability. We observed impaired self-monitoring ability in nurses, particularly after the night shift. Although actual performance remained high across all shifts, their self-predictions on reaction times became pessimistic in the night shift, resulting in a difference of approximately-100 msec. The effect of the shift on self-monitoring was obvious even after adjusting for sleep duration and hours awake. Our findings indicate that the misalignment between their working hours and circadian rhythms may affect even professional nurses. Occupational management that emphasizes maintaining circadian rhythms will improve the safety and health of nurses.

Angiopoietin-related growth factor antagonizes obesity and insulin resistance.

Angiopoietin-related growth factor (AGF), a member of the angiopoietin-like protein (Angptl) family, is secreted predominantly from the liver into the systemic circulation. Here, we show that most (>80%) of the AGF-deficient mice die at about embryonic day 13, whereas the surviving AGF-deficient mice develop marked obesity, lipid accumulation in skeletal muscle and liver, and insulin resistance accompanied by reduced energy expenditure relative to controls. In parallel, mice with targeted activation of AGF show leanness and increased insulin sensitivity resulting from increased energy expenditure. They are also protected from high-fat diet-induced obesity, insulin resistance and nonadipose tissue steatosis. Hepatic overexpression of AGF by adenoviral transduction, which leads to an approximately 2.5-fold increase in serum AGF concentrations, results in a significant (P < 0.01) body weight loss and increases insulin sensitivity in mice fed a high-fat diet. This study establishes AGF as a new hepatocyte-derived circulating factor that counteracts obesity and related insulin resistance.

The effect of sleep restriction and psychological load on the diurnal metabolic changes in tryptamine-related compounds in human urine.

OBJECTIVE: The effect of a severely stressful situation (sleep restriction and psychological load) on the diurnal changes in novel tryptamine-related compounds (hydroxydiacetyltryptamine, sulphatoxymelatonin, and dihydromelatonin) was evaluated in human subjects for 16 days. METHODS: The subjects were allowed to sleep for 5 h on days three through 12 and for 8 h on the other days. On days three through 12, the subjects were asked to perform a psychological task. The first two and the last 4 days were viewed as control days. A performance test was administered to evaluate the extent of the subjects' fatigue. Total urine was sampled by collecting it into bottles three times a day [(1) during the sleeping period, (2) in the morning, and (3) in the afternoon]. Seven tryptamine-related compounds in urine were assayed using HPLC-fluorometry. RESULTS: The urine melatonin level was high at night and low during the day. In contrast, urinary levels of hydroxydiacetyltryptamine and sulphatoxydiacetyltryptamine were low at night and high during the day. Dihydromelatonin was undetectable in urine during the sleeping period. Sleep restriction and psychological load did not affect diurnal changes in urinary melatonin, hydroxydiacetyltryptamine, sulphatoxydiacetyltryptamine, or N-acetylserotonin levels. The concentrations of hydroxymelatonin and sulphatoxymelatonin in urine did not show diurnal changes and decreased gradually during the experimental days. A principal component analysis confirmed the diurnal changes and suggested two novel metabolic pathways: (1) N-acetylserotonin to sulphtoxydiacetyltryptamine via hydroxydiacetyltryptamine, and (2) melatonin to dihydromelatonin. CONCLUSION: Severely stressful situations did not affect diurnal changes in melatonin, hydroxydiacetyltryptamine, sulphatoxydiacetyltryptamine, or N-acetylserotonin levels in urine.

[Characteristics of compensated mental disorders caused by overwork among drivers and non-drivers in the Japanese trucking industry].

OBJECTIVES: This study examined the characteristics of occupational mental disorders among those involved in the transport and postal activities in the trucking industry. METHOD: We examined 237 out of 3,517 cases of occupational mental disorders, compensated between the fiscal years 2010 and 2017. An assessment was made for sex, "life-or-death" status at compensation, age at the onset and suicide, the diagnosis according to the International Classification of Diseases, Tenth Revision, and other factors regarding occupational compensation. The participants were divided into two groups: truck drivers and non-truck drivers. RESULTS: Men accounted for approximately 90% of the cases. Depressive episode (F32) was the most common diagnosis in drivers and non-drivers, thus constituting 65 out of 149 and 48 out of 88 cases, respectively. The next most common type of mental disorder was adjustment disorders (F43.2), with 34 out of 149 drivers and 24 out of 88 non-drivers reporting them. Furthermore, the majority of drivers that had posttraumatic stress disorder (24 out of 27 cases) reported that they "suffered a serious illness or injury" and "experienced or witnessed a terrible accident or disaster." Occupational disasters due to long working hours were 52.4% for drivers and 73.9% for non-drivers. A total of 30.8% of the drivers reported working long hours since they joined the company. CONCLUSION: Drivers' long working hours entail waiting at the origin and cargo destination site, handling cargo, and incidental tasks other than driving. Thus, the reduction in work hours regarding these tasks needs to be a fundamental goal, and measures that include mental health care for accidents and miserable experiences must be implemented. However, long working hours for non-drivers are likely linked to job expansion/increase and reassignment/relocation. These findings highlight that to prevent overwork-related mental disorders, appropriate actions should be taken considering different sources of exposure for drivers or non-drivers.

Shift-Work Schedule Intervention for Extending Restart Breaks after Consecutive Night Shifts: A Non-randomized Controlled Cross-Over Study.

More knowledge is required to determine the optimal shiftwork schedule to reduce the harmful effects of short restart breaks between shifts. This 5-month intervention study aimed to examine the effectiveness of extended restart breaks from 31 h to 55 h after consecutive night shifts by considering the characteristics of the circadian rhythm to mitigate fatigue and sleep among 30 shift-working nurses. Subjective and objective variables, such as vital exhaustion, distress, hair cortisol, salivary C-reactive protein, and sleep mattress sensor sensation, were repeatedly measured to examine the differences between the intervention and control conditions. Two-way (condition × time) multilevel analyses showed significantly lower levels of vital exhaustion and distress in the intervention condition (p = 0.005 and p = 0.004, respectively). However, the expected benefit of the intervention was not observed in objectively measured variables. These findings suggested that an extended restart break after consecutive night shifts can moderately decrease occupational fatigue and stress.

[Examining the association between work-life factors and health disorders/excessive fatigue among Japanese truck drivers].

OBJECTIVES: Karoshi problems (overwork-related deaths and disorders caused by cerebrovascular and cardiovascular diseases) still occur in Japan. Truck drivers, who are in one of the riskiest occupations, are reported to show an increased prevalence of hypertension, obesity, hyperlipidemia, and diabetes, which are characteristic of Karoshi. Their health problems also include excessive fatigue. This cross-sectional study aimed to examine the association between work-life factors and health disorders/excessive fatigue among Japanese truck drivers. METHODS: We distributed a questionnaire regarding work hours, health status, lifestyle, burden of driving, and excessive fatigue to 5,410 truck drivers and collected a total of 1,947 responses, all from males. The association between work-life factors and health outcomes was evaluated by multivariable logistic regression analysis adjusted for age, drinking, and smoking status. RESULTS: The prevalence rates of obesity, hypertension, hyperlipidemia, diabetes, cardiovascular disease, cerebrovascular disease, and excessive fatigue were 22.2%, 19.3%, 8.5%, 5.6%, 2.5%, 0.7%, and 6.0%, respectively. Significant associations were observed for long-haul trips (two days or more) with obesity (adjusted odds ratio 1.5 [95% Confidence Interval 1.1-2.1]), local and night trips with hypertension (1.5 [1.0-2.2]), early morning awakening on workdays with obesity (1.5 [1.1-2.1]), being indoor-oriented on weekends with hypertension (1.5 [1.1-2.0]); and heavy burden of driving at night with hyperlipidemia (2.0 [1.3-3.0]). The adjusted odds ratios were significant for waking after sleep onset (2.6 [1.2-5.3]) and lack of sleep satisfaction (2.7 [1.4-5.1]) on workdays, less than six hours of sleep (2.8 [1.0-7.8]) and lack of sleep satisfaction (2.8 [1.5-5.2]) on weekends, 0-3 days off per month (3.6 [1.3-10.2]), and heavy burden of driving at night (2.2 [1.0-4.8]) with excessive fatigue. CONCLUSIONS: The present findings highlight that night and early morning work, heavy burden of night driving, and the resultant decreases in the quality and quantity of sleep may represent shared risk factors for health disorders and excessive fatigue among truck drivers. Adequate measures should be taken to limit the amount of night and early morning work, reduce the burden of night driving, and ensure days off for sleep opportunities and leisure activities, with the goal of preventing Karoshi.

Identification and relative quantitation of an orphan G-protein coupled receptor SREB2 (GPR85) protein in tissue using a linear ion trap mass spectrometer.

SREB2 (GPR85) is an orphan G-protein coupled receptor (GPCR) whose function is unknown. We previously prepared a SREB2-overexpressing transgenic mouse for functional analysis but were unable to confirm SREB2 protein expression level by immunochemical or biochemical methods. In this article, we report mass spectrometric identification and relative quantitative analysis of SREB2 in the forebrains of transgenic and wild type mice using nanoliquid chromatography coupled with a linear ion-trap mass spectrometer. By analyzing Chinese hamster ovary (CHO) cells overexpressing the SREB2 gene, we identified a proteotypic SREB2 peptide, GPTPPTLLGIR. Using a stable isotope-labeled analog as an authentic peptide for protein identification and as an internal control for relative quantitation, SREB2 was directly identified from the membrane fraction of forebrains from wild type and SREB2 transgenic mice. SREB2 protein expression level in the transgenic mouse was estimated to be 3-fold higher than that in the wild type littermate.

The evolutionarily conserved G protein-coupled receptor SREB2/GPR85 influences brain size, behavior, and vulnerability to schizophrenia.

The G protein-coupled receptor (GPCR) family is highly diversified and involved in many forms of information processing. SREB2 (GPR85) is the most conserved GPCR throughout vertebrate evolution and is expressed abundantly in brain structures exhibiting high levels of plasticity, e.g., the hippocampal dentate gyrus. Here, we show that SREB2 is involved in determining brain size, modulating diverse behaviors, and potentially in vulnerability to schizophrenia. Mild overexpression of SREB2 caused significant brain weight reduction and ventricular enlargement in transgenic (Tg) mice as well as behavioral abnormalities mirroring psychiatric disorders, e.g., decreased social interaction, abnormal sensorimotor gating, and impaired memory. SREB2 KO mice showed a reciprocal phenotype, a significant increase in brain weight accompanying a trend toward enhanced memory without apparent other behavioral abnormalities. In both Tg and KO mice, no gross malformation of brain structures was observed. Because of phenotypic overlap between SREB2 Tg mice and schizophrenia, we sought a possible link between the two. Minor alleles of two SREB2 SNPs, located in intron 2 and in the 3' UTR, were overtransmitted to schizophrenia patients in a family-based sample and showed an allele load association with reduced hippocampal gray matter volume in patients. Our data implicate SREB2 as a potential risk factor for psychiatric disorders and its pathway as a target for psychiatric therapy.

Hypertensive cerebral hemorrhage with undetectable plasma vascular endothelial growth factor levels in a patient receiving intravitreal injection of aflibercept for bilateral diabetic macular edema: a case report.

BACKGROUND: Intravitreal injections of anti-vascular endothelial growth factor are commonly used to treat macular diseases, including diabetic macular edema. Anti-vascular endothelial growth factor drugs can enter the systemic circulation after intravitreal injections and appear to suppress circulating vascular endothelial growth factor levels. However, whether this can cause any systemic adverse events remains unknown. CASE PRESENTATION: A 70-year-old Japanese man diagnosed with diabetic macular edema in both eyes was treated with anti-vascular endothelial growth factor intravitreal injections. One month after receiving two intravitreal injections of aflibercept 1 week apart for diabetic macular edema in both eyes, he complained of a severe acute headache. The patient was diagnosed with hypertensive cerebral hemorrhage of the occipital lobe based on an elevated blood pressure of 195/108 mmHg and the results of computed tomography and magnetic resonance imaging of his brain. The patient was treated with an intravenous injection of nicardipine hydrochloride to lower his systemic blood pressure. Two days after the stroke, the patient began oral treatment with 80 mg/day telmisartan, which was continued for 3 days, and the telmisartan dose was reduced to 40 mg/day thereafter. His blood pressure promptly dropped to 130/80 mmHg, and his severe headache disappeared. One year after the cerebrovascular stroke, the telmisartan was discontinued because his blood pressure stabilized at a normal level. His plasma vascular endothelial growth factor levels were measured via specific enzyme-linked immunosorbent assay before and after the intravitreal injections of aflibercept. Immediately before the injections, the vascular endothelial growth factor level was 28 pg/ml, but it rapidly fell below the detection limit within 1 week, where it remained for over 2 months. Two days before the cerebral hemorrhage, his plasma vascular endothelial growth factor level was below the detection limit, and 2 months later after the stroke, his plasma vascular endothelial growth factor level recovered to 41 pg/ml. CONCLUSION: This case suggests that hypertension and resultant cerebral hemorrhage can occur in patients with diabetic macular edema when plasma vascular endothelial growth factor levels are systemically decreased below the detection limit for a prolonged time after local injections of anti-vascular endothelial growth factor agents into the vitreous cavity. Therefore, severely reduced plasma vascular endothelial growth factor levels could be a higher risk factor to develop generally infrequent stroke. Ophthalmologists should be aware of possible severe reduction of plasma vascular endothelial growth factor levels and resultant increase in blood pressure after intravitreal injections of an anti-vascular endothelial growth factor drug. If the plasma vascular endothelial growth factor levels could be monitored more easily and quickly during the treatment, it would help to prevent adverse events.

Stratification-Based Investigation of Adjunctive Brimonidine or Timolol to a Prostaglandin Analogue in Japanese Patients with Normal-Tension Glaucoma.

PURPOSE: We previously investigated the efficacy and safety of adding 0.1% brimonidine (Brim) or 0.5% timolol (Tim) to prostaglandin analogue (PGA) monotherapy to treat patients with normal-tension glaucoma (NTG) with intraocular pressure (IOP) of ≤16 mmHg. Herein, we describe an additional post-hoc stratifying analysis of the possible differences in the effect of IOP-lowering and pulse rate (PR) after adjunctive Brim or Tim to PGA. PATIENTS AND METHODS: This study included 128 subjects. Patients with NTG treated with PGA were stratified based on their baseline IOP. The changes in IOP from baseline and the effect of patient factors on IOP changes were investigated. Patients were stratified by age for investigation of their PR and blood pressure (BP). The change and the effect of patient factors on PR and BP were investigated. RESULTS: After stratification analysis, in 52 eyes treated with Brim and 61 eyes with Tim with baseline IOP 12 ≤ IOP ≤ 16 mmHg, both eye drops lowered IOP significantly (P < 0.0001), and the IOP-lowering efficacy of Brim was non-inferior to that of Tim. However, in 9 Brim- and 6 Tim-treated eyes with baseline IOP of <12 mmHg, no statistically significant decrease in IOP was evident with either eye drop. In the Tim group, PR decreased significantly (P < 0.05) after stratification by age. CONCLUSION: The IOP-lowering efficacy of Brim was non-inferior to that of Tim after stratification by baseline IOP (12 ≤ IOP ≤ 16 mmHg). The discrepancy in the IOP-lowering effects of Brim and Tim observed in the previous study was thought to be related to enrolled subjects with low baseline IOP. PR decreased significantly in the Tim group even after age stratification. PR should be considered when selecting ß-blockers for glaucoma treatment.