Long-term circadian disruption shortens life span and dampens blood pressure diurnal rhythms in stroke-prone spontaneously hypertensive rats.

Environmental cues such as light and timing of food intake influence molecular clocks that produce circadian rhythmicity of many biological functions. The master circadian clock is entrained by light input and synchronizes with peripheral clocks in every organ of the body. Careers that require rotating shift work schedules predispose workers to a constant desynchronization of these biological clocks and are associated with increased risk of cardiovascular disease. We used a stroke-prone spontaneously hypertensive rat model exposed to a known biological desynchronizer, chronic environmental circadian disruption (ECD), to test the hypothesis that it would accelerate the time to stroke onset. We then investigated whether time-restricted feeding could delay stroke onset and evaluated its usefulness as a countermeasure when combined with the constant disruption of the light cycle. We found that phase advancing of the light schedule accelerated stroke onset. Restricting food access time to 5 h/day regardless of lighting profoundly delayed stroke onset in both standard 12-h:12-h light/dark or ECD-lighting conditions compared with ad libitum feeding; however, acceleration by ECD versus control lighting conditions was still observed. Since hypertension is a precursor to stroke in this model, we assessed blood pressure in a small cohort longitudinally using telemetry. Mean daily systolic and diastolic blood pressure increased in a similar manner across rats in control and ECD conditions, thus hypertension was not grossly accelerated to cause earlier strokes. However, we observed intermittent dampening of rhythms after each shift of the light cycle reminiscent of a relapsing-remitting nondipping state. Our results suggest that constant disruption of environmental rhythms may be associated with an increased risk of cardiovascular complications in the presence of cardiovascular risk factors.NEW & NOTEWORTHY This stroke-prone spontaneously hypertensive rat model significantly delayed stroke onset with the timed food restriction intervention. Blood pressure recordings in this same model were continuous through the 3 mo and showed dampened systolic rhythms after each shift in the lighting schedule.

Environmental circadian disruption suppresses rhythms in kidney function and accelerates excretion of renal injury markers in urine of male hypertensive rats.

Nontraditional work schedules, such as shift work, have been associated with numerous health issues, including cardiovascular and metabolic disease. These work schedules can chronically misalign environmental timing cues with internal circadian clock systems in the brain and in peripheral organs, leading to dysfunction of those systems and their associated biological processes. Environmental circadian disruption in the kidney may be an important factor in the increased incidence of hypertension and adverse health outcomes in human shift workers. The relationship between renal rhythmicity and injury resilience is not well understood, especially in the context of environmental, rather than genetic, manipulations of the circadian system. We conducted a longitudinal study to determine whether chronic shifting of the light cycle that mimics shift work schedules would disrupt output rhythms of the kidney and accelerate kidney injury in salt-loaded male spontaneously hypertensive, stroke-prone rats. We observed that chronic shifting of the light-dark (LD) cycle misaligned and decreased the amplitude of urinary volume rhythms as the kidney phase-shifted to match each new lighting cycle. This schedule also accelerated glomerular and tubular injury marker excretion, as quantified by nephrin and KIM-1 compared with rats kept in a static LD cycle. These data suggest that disrupted rhythms in the kidney may decrease resilience and contribute to disease development in systems dependent on renal and cardiovascular functions.

Shift work influences the outcomes of Chlamydia infection and pathogenesis.

Shift work, performed by approximately 21 million Americans, is irregular or unusual work schedule hours occurring after 6:00 pm. Shift work has been shown to disrupt circadian rhythms and is associated with several adverse health outcomes and chronic diseases such as cancer, gastrointestinal and psychiatric diseases and disorders. It is unclear if shift work influences the complications associated with certain infectious agents, such as pelvic inflammatory disease, ectopic pregnancy and tubal factor infertility resulting from genital chlamydial infection. We used an Environmental circadian disruption (ECD) model mimicking circadian disruption occurring during shift work, where mice had a 6-h advance in the normal light/dark cycle (LD) every week for a month. Control group mice were housed under normal 12/12 LD cycle. Our hypothesis was that compared to controls, mice that had their circadian rhythms disrupted in this ECD model will have a higher Chlamydia load, more pathology and decreased fertility rate following Chlamydia infection. Results showed that, compared to controls, mice that had their circadian rhythms disrupted (ECD) had higher Chlamydia loads, more tissue alterations or lesions, and lower fertility rate associated with chlamydial infection. Also, infected ECD mice elicited higher proinflammatory cytokines compared to mice under normal 12/12 LD cycle. These results imply that there might be an association between shift work and the increased likelihood of developing more severe disease from Chlamydia infection.

Environmental Circadian Disruption Increases Stroke Severity and Dysregulates Immune Response.

Understanding the health consequences of chronic disruption of circadian rhythms can contribute to improving prevention strategies for shift workers. Chronic circadian disruption in shift work has been linked to a higher risk of stroke. Dysregulated immune responses are also linked to circadian disruption and may be a factor in stroke outcomes in shift workers. In this study, we test the hypotheses that specific schedules of circadian disruption exacerbate inflammatory responses in the brain, causing an increase in infarct size after experimentally induced ischemic stroke. Mice were exposed to 1 of 5 different lighting schedules followed by a 30-min middle cerebral artery occlusion, then reperfusion and 3-day recovery. A history of weekly phase advances resulted in an increased infarct volume versus the control lighting schedule. These effects were shift-direction specific, nonpermanent, and required multiple shifts to occur. In a separate cohort, stereotaxic injections of lipopolysaccharide were given bilaterally after exposure to 1 of 3 different lighting schedules. Ratios of pro- to anti-inflammatory cytokine expression show dysregulated responses after a history of phase advances. We conclude that chronic circadian disruption leads to worsened stroke outcome in a direction- and schedule-specific manner likely because of priming of the inflammatory response in the brain. These pieces of evidence suggest that the health impacts of shift work may be improved by targeting shift work scheduling, inflammatory mediators, or both.

Case report: a case of diffuse unilateral subacute neuroretinitis (DUSN) in a child.

BACKGROUND: Diffuse unilateral subacute neuroretinitis (DUSN) is a rare cause of posterior uveitis in the United Kingdom. It typically presents unilaterally in children and young adults but rarely bilateral cases have been reported. It is also rare to have multiple worms in the same eye causing the clinical picture. In this article, we present a challenging case of DUSN in a young girl unresponsive to conventional treatments suggesting the possibility of multiple worms being present in the same eye. CASE PRESENTATION: An 8-year-old girl presented with a 2-month history of headaches. On occasions the headaches were associated with redness and watering of her left eye. She denied any visual loss or visual symptoms. Her visual acuity was reduced to 6/30 in her left eye. Fundal examination revealed a unilateral chorioretinitis. Investigation did not reveal a specific cause for the chorioretinitis. Over 15 months her visual acuity improved to 6/9 but the fundal appearance changed and a diagnosis of DUSN was made. She was treated with focal laser, systemic anti-helminthic and immunosuppressive treatments but continued to develop new, active areas of chorioretinitis, raising the possibility of multiple worms in the sub-retinal space. There is also a concern as to other central nervous system (CNS) involvement given her significant and ongoing headaches. CONCLUSION: We present a challenging case of DUSN in a young girl; a condition that remains rare in the UK. She was unresponsive to both focal laser and systemic anti-helminthic and immunosuppressive treatments suggesting the possibility of multiple worms being present in the sub-retinal space. This case highlights the difficulties often encountered in the treatment of DUSN, even when a worm can be identified. Her visual prognosis is poor as there was ongoing recurrence of active chorioretinitis.

Torpedo maculopathy: disease spectrum and associated choroidal neovascularisation in a paediatric population.

PURPOSE: Torpedo maculopathy is a rare lesion of the retinal pigment epithelium. This study set out to look at these lesions in the paediatric population and determine the spectrum and features of the disease. METHODS: The paediatric ophthalmology database was used to identify eight children with torpedo maculopathy between 2012 and 2017. Fundal images and optical coherence tomography (OCT) was used to analyse the cases. RESULTS: Eight patients with torpedo maculopathy were identified, making the prevalence approximately 2 per 100,000 population under 16 years old. The OCT images were classified using the previously described subtypes: Type 1 in patients 5 and 6 and Type 2 in patients 1, 2, 3, 4 and 8. The average age of presentation of Type 1 and Type 2 lesions was 8 and 7 years old respectively. We also report patient 8, who is the youngest reported case of choroidal neovascular membrane associated with torpedo maculopathy. Good anatomical response to a single injection of anti-Vegf was shown. CONCLUSIONS: This study is the first case series of torpedo maculopathy in the paediatric population. Contrary to previous reports of two distinct types of lesion on OCT representing different stages of the same disease, our case series indicates that Type 1 and Type 2 lesions are in fact different phenotypic entities both of which can occur at a young age. We also present the associated risk of choroidal neovascular membrane formation which is an important consideration for long term follow-up.