Acid Suspends the Circadian Clock in Hypoxia through Inhibition of mTOR.

Recent reports indicate that hypoxia influences the circadian clock through the transcriptional activities of hypoxia-inducible factors (HIFs) at clock genes. Unexpectedly, we uncover a profound disruption of the circadian clock and diurnal transcriptome when hypoxic cells are permitted to acidify to recapitulate the tumor microenvironment. Buffering against acidification or inhibiting lactic acid production fully rescues circadian oscillation. Acidification of several human and murine cell lines, as well as primary murine T cells, suppresses mechanistic target of rapamycin complex 1 (mTORC1) signaling, a key regulator of translation in response to metabolic status. We find that acid drives peripheral redistribution of normally perinuclear lysosomes away from perinuclear RHEB, thereby inhibiting the activity of lysosome-bound mTOR. Restoring mTORC1 signaling and the translation it governs rescues clock oscillation. Our findings thus reveal a model in which acid produced during the cellular metabolic response to hypoxia suppresses the circadian clock through diminished translation of clock constituents.

Photoperiod-Induced Neuroplasticity in the Circadian System.

Seasonal changes in light exposure have profound effects on behavioral and physiological functions in many species, including effects on mood and cognitive function in humans. The mammalian brain's master circadian clock, the suprachiasmatic nucleus (SCN), transmits information about external light conditions to other brain regions, including some implicated in mood and cognition. Although the detailed mechanisms are not yet known, the SCN undergoes highly plastic changes at the cellular and network levels under different light conditions. We therefore propose that the SCN may be an essential mediator of the effects of seasonal changes of day length on mental health. In this review, we explore various forms of neuroplasticity that occur in the SCN and other brain regions to facilitate seasonal adaptation, particularly altered phase distribution of cellular circadian oscillators in the SCN and changes in hypothalamic neurotransmitter expression.

Differential localization of PER1 and PER2 in the brain master circadian clock.

The hypothalamic suprachiasmatic nucleus (SCN), locus of the master circadian clock, bears many neuronal types. At the cellular-molecular level, the clock is comprised of feedback loops involving 'clock' genes including Period1 and Period2, and their protein products, PERIOD1 and PERIOD2 (PER1/2). In the canonical model of circadian oscillation, the PER1/2 proteins oscillate together. While their rhythmic expression in the SCN as a whole has been described, the possibility of regional differences remains unknown. To explore these clock proteins in distinct SCN regions, we assessed their expression through the rostro-caudal extent of the SCN in sagittal sections. We developed an automated method for tracking three fluorophores in digital images of sections triply labeled for PER1, PER2, and gastrin-releasing peptide (used to locate the core). In the SCN as a whole, neurons expressing high levels of PER2 were concentrated in the rostral, rostrodorsal, and caudal portions of the nucleus, and those expressing high levels of PER1 lay in a broad central area. Within these overall patterns, adjacent cells differed in expression levels of the two proteins. The results demonstrate spatially distinct localization of high PER1 vs. PER2 expression, raising the possibility that their distribution is functionally significant in encoding and communicating temporal information. The findings provoke the question of whether there are fundamental differences in PER1/2 levels among SCN neurons and/or whether topographical differences in protein expression are a product of SCN network organization rather than intrinsic differences among neurons.

Perianal Mucinous Adenocarcinoma Found Incidentally From Perianal Mass.

Anal mucinous adenocarcinomas are very rare and usually arise from anal fistulas. We report a case of a 73-year-old man with a past medical history of hypertension admitted to our facility for evaluation of bleeding from a large, tender, left gluteal perianal mass. The patient reported the mass had been growing for over six years. On examination, an ulcerated, fungating large exophytic lesion was found extending from the anal verge laterally engulfing the left gluteus. The patient was anemic with low hemoglobin and hematocrit, as well as an elevated carcinoembryonic antigen level. A colonoscopy was performed during which an internal opening of a left-sided anal fistula was identified. The mass was biopsied and returned positive for a mucinous adenocarcinoma. Staging imaging including a computed tomography scan of the chest abdomen and pelvis did not show any metastatic disease. A magnetic resonance image of the pelvis revealed a locally invasive, heterogeneous tumor extending from the perianal soft tissue to the posterior wall of the anal canal and lower rectum. The patient was discussed at the interdisciplinary tumor board and completed five weeks of concurrent chemotherapy and radiation with 5-fluorouracil and a total of 28 fractions of radiation. He then underwent abdominoperineal resection with a vertical rectus abdominis myocutaneous flap. The patient was placed in the surgical intensive care unit and subsequently discharged in stable condition on postoperative day 14. This case highlights the presentation, diagnosis, and management of anal mucinous adenocarcinoma.

Advances in the management of atrial fibrillation with a special focus on non-pharmacological approaches to prevent thromboembolism: a review of current recommendations.

Atrial fibrillation (AFIB) is the most common heart rhythm abnormality and is associated with significant morbidity and mortality. While the treatment of AFIB involves strategies of rate with or without rhythm control, it is also essential to strategize appropriate therapies to prevent thromboembolic complications arising from AFIB. Previously, anticoagulation was the main treatment option which exposed patients to higher than usual risk of bleeding. However, with the advent of new technology, novel therapeutic options aimed at surgical or percutaneous exclusion or occlusion of the left atrial appendage in preventing thromboembolic complications from AFIB have evolved. This review evaluates recent advances and therapeutic options in treating AFIB with a special focus on both surgical and percutaneous interventions which can reduce and/or eliminate thromboembolic complications of AFIB.