Chemical interference with DSIF complex formation lowers synthesis of mutant huntingtin gene products and curtails mutant phenotypes.

Earlier work has shown that siRNA-mediated reduction of the SUPT4H or SUPT5H proteins, which interact to form the DSIF complex and facilitate transcript elongation by RNA polymerase II (RNAPII), can decrease expression of mutant gene alleles containing nucleotide repeat expansions differentially. Using luminescence and fluorescence assays, we identified chemical compounds that interfere with the SUPT4H-SUPT5H interaction and then investigated their effects on synthesis of mRNA and protein encoded by mutant alleles containing repeat expansions in the huntingtin gene (HTT), which causes the inherited neurodegenerative disorder, Huntington's Disease (HD). Here we report that such chemical interference can differentially affect expression of HTT mutant alleles, and that a prototypical chemical, 6-azauridine (6-AZA), that targets the SUPT4H-SUPT5H interaction can modify the biological response to mutant HTT gene expression. Selective and dose-dependent effects of 6-AZA on expression of HTT alleles containing nucleotide repeat expansions were seen in multiple types of cells cultured in vitro, and in a Drosophila melanogaster animal model for HD. Lowering of mutant HD protein and mitigation of the Drosophila "rough eye" phenotype associated with degeneration of photoreceptor neurons in vivo were observed. Our findings indicate that chemical interference with DSIF complex formation can decrease biochemical and phenotypic effects of nucleotide repeat expansions.

Daily Caffeine Intake Induces Concentration-Dependent Medial Temporal Plasticity in Humans: A Multimodal Double-Blind Randomized Controlled Trial.

Caffeine is commonly used to combat high sleep pressure on a daily basis. However, interference with sleep-wake regulation could disturb neural homeostasis and insufficient sleep could lead to alterations in human gray matter. Hence, in this double-blind, randomized, cross-over study, we examined the impact of 10-day caffeine (3 × 150 mg/day) on human gray matter volumes (GMVs) and cerebral blood flow (CBF) by fMRI MP-RAGE and arterial spin-labeling sequences in 20 habitual caffeine consumers, compared with 10-day placebo (3 × 150 mg/day). Sleep pressure was quantified by electroencephalographic slow-wave activity (SWA) in the previous nighttime sleep. Nonparametric voxel-based analyses revealed a significant reduction in GMV in the medial temporal lobe (mTL) after 10 days of caffeine intake compared with 10 days of placebo, voxel-wisely adjusted for CBF considering the decreased perfusion after caffeine intake compared with placebo. Larger GMV reductions were associated with higher individual concentrations of caffeine and paraxanthine. Sleep SWA was, however, neither different between conditions nor associated with caffeine-induced GMV reductions. Therefore, the data do not suggest a link between sleep depth during daily caffeine intake and changes in brain morphology. In conclusion, daily caffeine intake might induce neural plasticity in the mTL depending on individual metabolic processes.

Correction to: Indirect choroidal neovascularization secondary to a posterior-segment intraocular foreign body - case report.

An amendment to this paper has been published and can be accessed via the original article.

Indirect choroidal neovascularization secondary to a posterior-segment intraocular foreign body - case report.

BACKGROUND: We reported a rare case of indirect choroidal neovascularization (CNV) secondary to a posterior-segment intraocular foreign body (IOFB) that was not located in the area of direct injury but in the fovea. After intravitreal injections (IVIs) of aflibercept, the choroidal neovascularization (CNV) lesion disappeared and vision improved. CASE PRESENTATION: A 26-year-old male patient suffered from a fast-shot metallic IOFB in his right eye. He underwent primary corneal repair, pars plana vitrectomy, IOFB removal and an IVI of antibiotics in the right eye. Two weeks later, cataract surgery was performed on the right eye for traumatic cataract after an episode of acute phacolytic glaucoma. The best-corrected visual acuity (BCVA) of the right eye improved to 20/20 5 months after the first surgery. However, the vision of the right eye worsened suddenly with metamorphopsia 1 year after the first surgery. Color fundus images showed a whitish lesion with faint retinal hemorrhage and surrounding sensory elevation. Fluorescein angiography (FA) revealed a lesion with early- and late-phase severe leakage. Optical coherence tomography (OCT) demonstrated a CNV lesion with surrounding subretinal fluid. The patient received an IVI of aflibercept every 8 weeks for 3 times. Finally, the BCVA of the right eye improved to 20/25. CONCLUSIONS: For rare cases of fovea-spared injury by a metallic IOFB, it is still necessary to pay close attention to the foveal microstructure to avoid possible CNV formation. Treatment with IVIs of anti-VEGF, aflibercept, as early as possible could provide good visual outcomes.

Comparative analysis of the cost and effectiveness of generic and brand-name antibiotics: the case of uncomplicated urinary tract infection.

PURPOSE: Generic medications used for chronic diseases are beneficial in containing healthcare costs and improving drug accessibility. However, the effects of generic drugs in acute and severe illness remain controversial. This study aims to investigate treatment costs and outcomes of generic antibiotics prescribed for adults with a urinary tract infection in outpatient settings. METHODS: The data source was the Longitudinal Health Insurance Database of Taiwan. We included outpatients aged 20 years and above with a urinary tract infection who required one oral antibiotic for which brand-name and generic products were simultaneously available. Drug cost and overall healthcare expense of the index consultation, healthcare cost during a 42-day follow-up period, and treatment failure rates were the main dependent variables. Data were compared between brand-name and generic users from the entire cohort and a propensity score-matched samples. RESULTS: Results from the entire cohort and propensity score-matched samples were similar. Daily antibiotic cost was significantly lower among generic users than brand-name users. Significant lower total drug claims of the index consultation only existed in patients receiving the investigated antibiotics, while the drug price between brand-name and generic versions were relatively large (e.g., >50%). The overall healthcare cost of the index consultation, healthcare expenditure during a 42-day follow-up period, and treatment failure rates were similar between the two groups. CONCLUSIONS: Compared with those treated with brand-name antibiotics, outpatients who received generic antibiotics had equivalent treatment outcomes with lower drug costs. Generic antibiotics are effective and worthy of adoption among outpatients with simple infections indicating oral antibiotic treatment. Copyright © 2016 John Wiley & Sons, Ltd.

Determinants of mortality before start of and during tuberculosis treatment among elderly patients: a population-based retrospective cohort study.

BACKGROUND: people with weakened immunity because of age or co-morbidities comprised the fastest growing portion of tuberculosis (TB). Higher mortality before or during TB treatment was observed. In spite of the increasing longevity worldwide, surveys focussing specifically on elderly TB are scarce. OBJECTIVE: to identify prognostic factors of mortality before and during TB treatment among the elderly. METHODS: we provided a retrospective cohort study of patients aged 65 and above with pulmonary TB in an Asian city with ageing population. A total of 2,546 patients were enrolled, including 743 (29.2%) cases aged 85 or beyond. Study subjects were categorised by treatment outcomes: treatment success, death prior to TB treatment or death during TB treatment. Demographics and laboratory findings were compared between the three groups. RESULTS: after controlling for potential confounders, advanced age was the leading determinant of mortality. Adjusted odds ratios (AORs) of death during treatment were 1.79 (aged 75-84) and 3.43 (aged 85 and above) while comparing with patients aged 65-74. AORs of death prior to treatment were 2.95 and 5.66. Other prognostic factors included malignancy, end-stage renal disease receiving dialysis, need of intensive or long-term care, result of sputum acid-fast bacilli examination, findings of pleural effusion on chest X-ray and educational level. CONCLUSION: this research manifested significant determinants of mortality in elderly patients prior to or during TB treatment. High awareness, timely intervention and close monitoring of treatment are recommended to older TB patients, especially with the properties mentioned in this study.

Long-term effects of the global budget program and periodic price adjustment on antibacterial agents: A nationwide decomposition analysis between 2001 and 2016.

BACKGROUND: Previous studies have shown that financial strategies are beneficial for improving the appropriate use of antibiotics within a limited period of time. Long-term effects have rarely been explored. METHODS: This study evaluated the changes in expenditure and prescription patterns of antibacterial agents under the global budget (GB) program and drug price adjustment of a National Health Insurance scheme. Two structural methods, that is, the Laspeyres method and Fisher's Ideal Index decomposition method, were used to illustrate the impacts of price, volume, and drug change. RESULTS: During the first 5 years of the GB program (ie, 2001-2006), the expenses of antibacterial agents increased by 54.1%, while the volume decreased by 11% to 21.3%. Therapeutic choice was the predominant cause of expense growth. In the second and third 5-year periods (ie, 2006-2011 and 2011-2016), the driving force of therapeutic choice gradually decreased. The antibacterial expense remained stable with a slight increase in prescription volume. Periodic price adjustment contributed steadily to cost containment, by 21.9% to 39.9%. CONCLUSIONS: The GB program led to a remarkable increase in antibacterial expenses mainly attributed to therapeutic choice, especially in the early stage. In contrast, periodic price adjustment, provided steady benefits to pharmaceutical budget control without a noticeable increase in drug volume.

Changing Incidence and Characteristics of Photokeratoconjunctivitis During the COVID-19 Pandemic.

Introduction: Photokeratoconjunctivitis (PKC) is primarily caused by welding. However, inappropriate use of germicidal lamps, which have been widely used following the COVID-19 outbreak, can also cause PKC. Our goal in this study was to investigate the incidence of and changes in the causes of PKC during the coronavirus 2019 (COVID-19) pandemic. Methods: We conducted a single-center, retrospective observational study. The health records of patients who visited the emergency department in a tertiary care hospital from January 1, 2018-December 31, 2021 and were diagnosed with PKC, were reviewed. We then conducted an analysis to compare the characteristics of PKC before and after COVID-19 began and the features of PKC caused by welding and germicidal lamps. Results: There were 160 PKC cases with a clear etiology before the COVID-19 pandemic and 147 cases during the COVID-19 pandemic. No significant differences in age and gender were detected between the two groups. The incidence of PKC induced by the use of germicidal lamps during the COVID-19 pandemic was significantly higher (10.2%) than the incidence before the pandemic (3.1%). The ratio of females to males in the germicidal lamp subgroup was significantly higher than the ratio in the welding subgroup. Limitations included incomplete information due to the retrospective nature of the study, underestimation of incidence, and possible recall bias. Conclusion: In the era of COVID-19, clinicians should be aware of the hazards of germicidal lamps. Although the COVID-19 pandemic seems to show signs of easing, new infectious diseases that require protective measures could still emerge in the future. Therefore, injuries related to germicidal lamps deserve more public health attention.

Retinoblastoma Incidence in Taiwan Over a Recent 20-Year Period: A Comprehensive Nationwide Study.

Purpose: Continuous advancements in medical diagnostic technology and the growing availability of resources suggest a potential for fluctuations in the incidence rate of retinoblastoma (Rb). This study aimed to analyze incidence data of Rb patients in Taiwan from 1999 to 2018, utilizing the nationwide Taiwan Cancer Registry (TCR) database. Additionally, we investigated the treatment modalities used for these Rb patients and compared them with those observed in other countries. Patients and Methods: We conducted a retrospective cohort study utilizing data from the TCR database. The study cohort comprised individuals who were newly diagnosed with Rb between 1999 and 2018. The incidence of Rb was calculated as the number of patients with Rb per million live births, both for the entire population and for different gender groups and time periods. The trends in Rb incidence from 1999 to 2018 across various age groups and sexes were presented with the linear trend test. Results: From 1999 to 2018, a total of 248 cases of Rb were identified. The overall incidence rate over this 20-year period was 60.20 cases per million live births, corresponding to 1 case per 16,611 live births. Incidence rates for each 5-year period between 1999 and 2018 exhibited no significant differences. The study cohort was predominantly male, with 134 cases (54.03%) being males and 114 cases (45.97%) being females, resulting in an overall male-to-female sex ratio of 1.18. Females had lower relative risk than males (RR: 0.92, 95% CI: 0.72-1.19). Primary surgical intervention was the preferred treatment modality for over 75% of the cases. Conclusion: This retrospective epidemiology study, using TCR from 1999 to 2018, indicated that no discernible trend of retinoblastoma incidence in Taiwan. Nevertheless, continuous monitoring of incidence rates and exploration of treatment strategies for retinoblastoma within the Taiwanese population are important to address potential changes in developing medical practices.

Repeated caffeine intake suppresses cerebral grey matter responses to chronic sleep restriction in an A1 adenosine receptor-dependent manner: a double-blind randomized controlled study with PET-MRI.

Evidence has shown that both sleep loss and daily caffeine intake can induce changes in grey matter (GM). Caffeine is frequently used to combat sleepiness and impaired performance caused by insufficient sleep. It is unclear (1) whether daily use of caffeine could prevent or exacerbate the GM alterations induced by 5-day sleep restriction (i.e. chronic sleep restriction, CSR), and (2) whether the potential impact on GM plasticity depends on individual differences in the availability of adenosine receptors, which are involved in mediating effects of caffeine on sleep and waking function. Thirty-six healthy adults participated in this double-blind, randomized, controlled study (age = 28.9 ± 5.2 y/; F:M = 15:21; habitual level of caffeine intake < 450 mg; 29 homozygous C/C allele carriers of rs5751876 of ADORA2A, an A2A adenosine receptor gene variant). Each participant underwent a 9-day laboratory visit consisting of one adaptation day, 2 baseline days (BL), 5-day sleep restriction (5 h time-in-bed), and a recovery day (REC) after an 8-h sleep opportunity. Nineteen participants received 300 mg caffeine in coffee through the 5 days of CSR (CAFF group), while 17 matched participants received decaffeinated coffee (DECAF group). We examined GM changes on the 2nd BL Day, 5th CSR Day, and REC Day using magnetic resonance imaging and voxel-based morphometry. Moreover, we used positron emission tomography with [18F]-CPFPX to quantify the baseline availability of A1 adenosine receptors (A1R) and its relation to the GM plasticity. The results from the voxel-wise multimodal whole-brain analysis on the Jacobian-modulated T1-weighted images controlled for variances of cerebral blood flow indicated a significant interaction effect between caffeine and CSR in four brain regions: (a) right temporal-occipital region, (b) right dorsomedial prefrontal cortex (DmPFC), (c) left dorsolateral prefrontal cortex (DLPFC), and (d) right thalamus. The post-hoc analyses on the signal intensity of these GM clusters indicated that, compared to BL, GM on the CSR day was increased in the DECAF group in all clusters  but decreased in the thalamus, DmPFC, and DLPFC in the CAFF group. Furthermore, lower baseline subcortical A1R availability predicted a larger GM reduction in the CAFF group after CSR of all brain regions except for the thalamus. In conclusion, our data suggest an adaptive GM upregulation after 5-day CSR, while concomitant use of caffeine instead leads to a GM reduction. The lack of consistent association with individual A1R availability may suggest that CSR and caffeine affect thalamic GM plasticity predominantly by a different mechanism. Future studies on the role of adenosine A2A receptors in CSR-induced GM plasticity are warranted.

Investigating neuroepigenetic alterations in chronic low back pain with positron emission tomography.

ABSTRACT: Epigenetics has gained considerable interest as potential mediators of molecular alterations that could underlie the prolonged sensitization of nociceptors, neurons, and glia in response to various environmental stimuli. Histone acetylation and deacetylation, key processes in modulating chromatin, influence gene expression; elevated histone acetylation enhances transcriptional activity, whereas decreased acetylation leads to DNA condensation and gene repression. Altered levels of histone deacetylase (HDAC) have been detected in various animal pain models, and HDAC inhibitors have demonstrated analgesic effects in these models, indicating HDACs' involvement in chronic pain pathways. However, animal studies have predominantly examined epigenetic modulation within the spinal cord after pain induction, which may not fully reflect the complexity of chronic pain in humans. Moreover, methodological limitations have previously impeded an in-depth study of epigenetic changes in the human brain. In this study, we employed [11C]Martinostat, an HDAC-selective radiotracer, positron emission tomography to assess HDAC availability in the brains of 23 patients with chronic low back pain (cLBP) and 11 age-matched and sex-matched controls. Our data revealed a significant reduction of [11C]Martinostat binding in several brain regions associated with pain processing in patients with cLBP relative to controls, highlighting the promising potential of targeting HDAC modulation as a therapeutic strategy for cLBP.

Latent tuberculosis among injection drug users in a methadone maintenance treatment program, Taipei, Taiwan: TSPOT.TB versus tuberculin skin test.

BACKGROUND: Taiwan has a growing HIV/AIDS epidemic that has recently shifted to an increase among injection drug users (IDUs). IDUs co-infected with HIV and tuberculosis (TB) have a high risk of progression from latent tuberculosis infection (LTBI) to active TB. METHODS: This study aimed to determine the prevalence and correlates of LTBI among IDUs by TSPOT.TB and tuberculin skin test (TST), in a large methadone program in Taipei, Taiwan. Consenting participants were interviewed by a trained worker regarding sociodemographics, substance use history, and health factors. RESULTS: Multivariate analysis was used to determine risks associated with each test outcome. Of 287 participants, 165 (58.7%) tested TSPOT.TB-positive and 244 (85.0%) tested TST-positive. The mean age was 44 y, and 7.3% were HIV-infected. Kappa statistics indicated slight concordance between TSPOT.TB and TST. In multivariate analysis, after controlling for potential confounders, TSPOT.TB positivity was significantly associated with age ≥ 50 y (reference, 20-34 y). A history of ever having had contact with a TB-infected person was associated with TST positivity, whereas HIV infection was inversely associated with TSPOT.TB positivity and TST positivity. CONCLUSIONS: This study shows a high prevalence of LTBI in individuals at risk for HIV infection in Taipei, Taiwan. Future TB prevention programs should particularly focus on IDUs.

Impact of perioperative α1-antagonists on postoperative urinary retention in orthopaedic surgery: meta-analysis.

BACKGROUND: Postoperative urinary retention (POUR) is a common complication following orthopaedic surgery. Previous studies attempted to establish the preventative role of α1-antagonist in POUR in the general surgical population; however, there is still no consensus regarding its use in orthopaedic surgery due to limited evidence. METHODS: Electronic databases of Cochrane Library, Embase, MEDLINE, and ClinicalTrials.gov were searched by two independent investigators from inception to 1 March 2022 to identify relevant randomized clinical trials. Two reviewers independently completed a critical appraisal of included trials by using the Cochrane Risk of Bias tool version 2.0 and extracted data from included articles. Risk of POUR was summarized as risk ratio (RR) with 95 per cent confidence intervals (c.i.). Mean difference (MD) was used for meta-analysis of continuous outcomes. RESULTS: Five randomized clinical trials involving 878 patients (α1-antagonist, 434; placebo, 444) undergoing hip/knee arthroplasty and spine surgeries were included. One study was assessed as high risk of bias from the randomization process and was excluded from the final meta-analysis. There was no difference in the risk of POUR between patients taking α1-antagonist and the placebo in arthroplasty (RR, 0.64; 95 per cent c.i., 0.36 to 1.14) and in spine surgeries (RR, 1.03; 95 per cent c.i., 0.69 to 1.55). There was no difference in length of stay (MD, -0.14 days; 95 per cent c.i., -0.33 to 0.05). Use of α1-antagonist was associated with a higher risk of adverse events (RR, 1.97; 95 per cent c.i., 1.27 to 3.06), with a composite of dizziness, light-headedness, fatigue, altered mental status, and syncope being the most commonly reported symptoms. CONCLUSION: In patients undergoing spinal surgery and joint arthroplasty, routine administration of perioperative α1-antagonist does not decrease risk of POUR but does increase perioperative dizziness, light-headedness, and syncope.

Brain activity during a working memory task after daily caffeine intake and caffeine withdrawal: a randomized double-blind placebo-controlled trial.

Acute caffeine intake has been found to increase working memory (WM)-related brain activity in healthy adults without improving behavioral performances. The impact of daily caffeine intake-a ritual shared by 80% of the population worldwide-and of its discontinuation on working memory and its neural correlates remained unknown. In this double-blind, randomized, crossover study, we examined working memory functions in 20 young healthy non-smokers (age: 26.4 ± 4.0 years; body mass index: 22.7 ± 1.4 kg/m2; and habitual caffeine intake: 474.1 ± 107.5 mg/day) in a 10-day caffeine (150 mg × 3 times/day), a 10-day placebo (3 times/day), and a withdrawal condition (9-day caffeine followed by 1-day placebo). Throughout the 10th day of each condition, participants performed four times a working memory task (N-Back, comprising 3- and 0-back), and task-related blood-oxygen-level-dependent (BOLD) activity was measured in the last session with functional magnetic resonance imaging. Compared to placebo, participants showed a higher error rate and a longer reaction time in 3- against 0-back trials in the caffeine condition; also, in the withdrawal condition we observed a higher error rate compared to placebo. However, task-related BOLD activity, i.e., an increased attention network and decreased default mode network activity in 3- versus 0-back, did not show significant differences among three conditions. Interestingly, irrespective of 3- or 0-back, BOLD activity was reduced in the right hippocampus in the caffeine condition compared to placebo. Adding to the earlier evidence showing increasing cerebral metabolic demands for WM function after acute caffeine intake, our data suggest that such demands might be impeded over daily intake and therefore result in a worse performance. Finally, the reduced hippocampal activity may reflect caffeine-associated hippocampal grey matter plasticity reported in the previous analysis. The findings of this study reveal an adapted neurocognitive response to daily caffeine exposure and highlight the importance of classifying impacts of caffeine on clinical and healthy populations.

Do proton pump inhibitors affect the effectiveness of chemotherapy in colorectal cancer patients? A systematic review with meta-analysis.

Proton pump inhibitors (PPI), one of the most commonly prescribed medications, carry a myriad of adverse events. For colorectal cancer (CRC) patients, it still remains unclear whether the concurrent use of proton pump inhibitors (PPI) would negatively affect chemotherapy. PubMed, Medline, Embase, and Cochrane Library were searched from inception to 10 June 2022, to identify relevant studies involving CRC patients receiving chemotherapy and reporting comparative survival outcomes between PPI users and non-users. Meta-analyses were performed using random-effects models. We identified 16 studies involving 8,188 patients (PPI = 1,789; non-PPI = 6,329) receiving either capecitabine-based or fluorouracil-based regimens. The overall survival (HR, 1.02; 95% CI, 0.91 to 1.15; I2 = 0%) and progression-free survival (HR, 1.15; 95% CI, 0.98 to 1.35; I2 = 29%) were similar between PPI users and non-users in patients taking capecitabine-based regimens, with low statis-tical heterogeneity. Although the subgroup analysis indicated that early-stage cancer patients taking capecitabine monotherapy with concurrent PPI had a significantly higher disease progression rate (HR, 1.96; 95% CI, 1.21 to 3.16; I2 = 0%) than those who did not use PPIs, both groups had comparable all-cause mortality (HR, 1.31; 95% CI, 0.75 to 2.29; I2 = 0%). On the other hand, there was little difference in both OS and PFS in both early- and end-stage patients taking capecitabine combination therapy between PPI users and non-users. Conversely, the use of concomitant PPI in patients taking fluorouracil-based regimens contributed to a marginally significant higher all-cause mortality (HR, 1.18; 95% CI, 1.00 to 1.40; I2 = 74%), but with high statistical heterogeneity. In conclusion, PPI has little survival influence on CRC patients treated with capecitabine-based regimens, especially in patients taking capecitabine combination therapy. Thus, it should be safe for clinicians to prescribe PPI in these patients. Although patients treated with fluorouracil-based regimens with concomitant PPI trended toward higher all-cause mortality, results were subject to considerable heterogeneity. Systematic Review Registration: identifier https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022338161.

Time to Recover From Daily Caffeine Intake.

Caffeine elicits widespread effects in the central nervous system and is the most frequently consumed psychostimulant worldwide. First evidence indicates that, during daily intake, the elimination of caffeine may slow down, and the primary metabolite, paraxanthine, may accumulate. The neural impact of such adaptions is virtually unexplored. In this report, we leveraged the data of a laboratory study with N = 20 participants and three within-subject conditions: caffeine (150 mg caffeine × 3/day × 10 days), placebo (150 mg mannitol × 3/day × 10 days), and acute caffeine deprivation (caffeine × 9 days, afterward placebo × 1 day). On day 10, we determined the course of salivary caffeine and paraxanthine using liquid chromatography-mass spectrometry coupled with tandem mass spectrometry. We assessed gray matter (GM) intensity and cerebral blood flow (CBF) after acute caffeine deprivation as compared to changes in the caffeine condition from our previous report. The results indicated that levels of paraxanthine and caffeine remained high and were carried overnight during daily intake, and that the levels of paraxanthine remained elevated after 24 h of caffeine deprivation compared to placebo. After 36 h of caffeine deprivation, the previously reported caffeine-induced GM reduction was partially mitigated, while CBF was elevated compared to placebo. Our findings unveil that conventional daily caffeine intake does not provide sufficient time to clear up psychoactive compounds and restore cerebral responses, even after 36 h of abstinence. They also suggest investigating the consequences of a paraxanthine accumulation during daily caffeine intake.

Regular Caffeine Intake Delays REM Sleep Promotion and Attenuates Sleep Quality in Healthy Men.

Acute caffeine intake can attenuate homeostatic sleep pressure and worsen sleep quality. Caffeine intake-particularly in high doses and close to bedtime-may also affect circadian-regulated rapid eye movement (REM) sleep promotion, an important determinant of subjective sleep quality. However, it is not known whether such changes persist under chronic caffeine consumption during daytime. Twenty male caffeine consumers (26.4 ± 4 years old, habitual caffeine intake 478.1 ± 102.8 mg/day) participated in a double-blind crossover study. Each volunteer completed a caffeine (3 × 150 mg caffeine daily for 10 days), a withdrawal (3 × 150 mg caffeine for 8 days then placebo), and a placebo condition. After 10 days of controlled intake and a fixed sleep-wake cycle, we recorded electroencephalography for 8 h starting 5 h after habitual bedtime (i.e., start on average at 04:22 h which is around the peak of circadian REM sleep promotion). A 60-min evening nap preceded each sleep episode and reduced high sleep pressure levels. While total sleep time and sleep architecture did not significantly differ between the three conditions, REM sleep latency was longer after daily caffeine intake compared with both placebo and withdrawal. Moreover, the accumulation of REM sleep proportion was delayed, and volunteers reported more difficulties with awakening after sleep and feeling more tired upon wake-up in the caffeine condition compared with placebo. Our data indicate that besides acute intake, also regular daytime caffeine intake affects REM sleep regulation in men, such that it delays circadian REM sleep promotion when compared with placebo. Moreover, the observed caffeine-induced deterioration in the quality of awakening may suggest a potential motive to reinstate caffeine intake after sleep.

The impact of daily caffeine intake on nighttime sleep in young adult men.

Acute caffeine intake can delay sleep initiation and reduce sleep intensity, particularly when consumed in the evening. However, it is not clear whether these sleep disturbances disappear when caffeine is continuously consumed during daytime, which is common for most coffee drinkers. To address this question, we investigated the sleep of twenty male young habitual caffeine consumers during a double-blind, randomized, crossover study including three 10-day conditions: caffeine (3 × 150 mg caffeine daily), withdrawal (3 × 150 mg caffeine for 8 days, then switch to placebo), and placebo (3 × placebo daily). After 9 days of continuous treatment, electroencephalographically (EEG)-derived sleep structure and intensity were recorded during a scheduled 8-h nighttime sleep episode starting 8 (caffeine condition) and 15 h (withdrawal condition) after the last caffeine intake. Upon scheduled wake-up time, subjective sleep quality and caffeine withdrawal symptoms were assessed. Unexpectedly, neither polysomnography-derived total sleep time, sleep latency, sleep architecture nor subjective sleep quality differed among placebo, caffeine, and withdrawal conditions. Nevertheless, EEG power density in the sigma frequencies (12-16 Hz) during non-rapid eye movement sleep was reduced in both caffeine and withdrawal conditions when compared to placebo. These results indicate that daily caffeine intake in the morning and afternoon hours does not strongly impair nighttime sleep structure nor subjective sleep quality in healthy good sleepers who regularly consume caffeine. The reduced EEG power density in the sigma range might represent early signs of overnight withdrawal from the continuous presence of the stimulant during the day.

Wide awake at bedtime? Effects of caffeine on sleep and circadian timing in male adolescents - A randomized crossover trial.

Adolescents often suffer from short and mistimed sleep. To counteract the resulting daytime sleepiness they frequently consume caffeine. However, caffeine intake may exaggerate sleep problems by disturbing sleep and circadian timing. In a 28-hour double-blind randomized crossover study, we investigated to what extent caffeine disturbs slow-wave sleep (SWS) and delays circadian timing in teenagers. Following a 6-day ambulatory phase of caffeine abstinence and fixed sleep-wake cycles, 18 male teenagers (14-17 years old) ingested 80 mg caffeine vs. placebo in the laboratory four hours prior to an electro-encephalographically (EEG) recorded nighttime sleep episode. Data were analyzed using both frequentist and Bayesian statistics. The analyses suggest that subjective sleepiness is reduced after caffeine compared to placebo. However, we did not observe a strong caffeine-induced reduction in subjective sleep quality or SWS, but rather a high inter-individual variability in caffeine-induced SWS changes. Exploratory analyses suggest that particularly those individuals with a higher level of SWS during placebo reduced SWS in response to caffeine. Regarding salivary melatonin onsets, caffeine-induced delays were not evident at group level, and only observed in participants exposed to a higher caffeine dose relative to individual bodyweight (i.e., a dose > 1.3 mg/kg). Together, the results suggest that 80 mg caffeine are sufficient to induce alertness at a subjective level. However, particularly teenagers with a strong need for deep sleep might pay for these subjective benefits by a loss of SWS during the night. Thus, caffeine-induced sleep-disruptions might change along with the maturation of sleep need.

Caffeine-dependent changes of sleep-wake regulation: Evidence for adaptation after repeated intake.

BACKGROUND: Circadian and sleep-homeostatic mechanisms regulate timing and quality of wakefulness. To enhance wakefulness, daily consumption of caffeine in the morning and afternoon is highly common. However, the effects of such a regular intake pattern on circadian sleep-wake regulation are unknown. Thus, we investigated if daily daytime caffeine intake and caffeine withdrawal affect circadian rhythms and wake-promotion in habitual consumers. METHODS: Twenty male young volunteers participated in a randomised, double-blind, within-subject study with three conditions: i) caffeine (150 mg 3 x daily for 10 days), ii) placebo (3 x daily for 10 days) and iii) withdrawal (150 mg caffeine 3 x daily for eight days, followed by a switch to placebo for two days). Starting on day nine of treatment, salivary melatonin and cortisol, evening nap sleep as well as sleepiness and vigilance performance throughout day and night were quantified during 43 h in an in-laboratory, light and posture-controlled protocol. RESULTS: Neither the time course of melatonin (i.e. onset, amplitude or area under the curve) nor the time course of cortisol was significantly affected by caffeine or withdrawal. During withdrawal, however, volunteers reported increased sleepiness, showed more attentional lapses as well as polysomnography-derived markers of elevated sleep propensity in the late evening compared to both the placebo and caffeine condition. CONCLUSIONS: The typical pattern of caffeine intake with consumption in both the morning and afternoon hours may not necessarily result in a circadian phase shift in the evening nor lead to clear-cut benefits in alertness. The time-of-day independent effects of caffeine withdrawal on evening nap sleep, sleepiness and performance suggest an adaptation to the substance, presumably in the homeostatic aspect of sleep-wake regulation.