Myocardial infarction (MI) leading to heart failure (HF) is a major cause of death worldwide. Previous studies revealed that the circadian system markedly impacts cardiac repair post-MI, and that light is an important environmental factor modulating the circadian influence over healing. Recent studies suggest that gut physiology also affects the circadian system, but how it contributes to cardiac repair post-MI and in HF is not well understood. To address this question, we first used a murine coronary artery ligation MI model to reveal that an intact gut microbiome is important for cardiac repair. Specifically, gut microbiome disruption impairs normal inflammatory responses in infarcted myocardium, elevates adverse cardiac gene biomarkers, and leads to worse HF outcomes. Conversely, reconstituting the microbiome post-MI in mice with prior gut microbiome disruption improves healing, consistent with the notion that normal gut physiology contributes to cardiac repair. To investigate a role for the circadian system, we initially utilized circadian mutant Clock ∆19/∆19 mice, revealing that a functional circadian mechanism is necessary for gut microbiome benefits on post-MI cardiac repair and HF. Finally, we demonstrate that circadian-mediated gut responses that benefit cardiac repair can be conferred by time-restricted feeding, as wake time feeding of MI mice improves HF outcomes, but these benefits are not observed in MI mice fed during their sleep time. In summary, gut physiology is important for cardiac repair, and the circadian system influences the beneficial gut responses to improve post-MI and HF outcomes.

Circadian rhythms are fundamentally important for cardiovascular health, including heart rate, blood pressure, and molecular gene and protein responses. Rhythms also play a direct role in the pathophysiology of heart disease, such as in the timing of onset and severity of myocardial infarction, sudden cardiac death, ventricular arrhythmias, and stroke. Importantly, a flurry of new studies reveals translational applications for circadian biology to clinical medicine, and especially cardiology. Circadian medicine is a promising new approach that targets the heart's daily physiologic and molecular rhythms to benefit the treatment of patients with cardiovascular disease.

Tuberculosis is a stern, difficult to treat chronic infection caused by acid-fast bacilli that tend to take a long time to be eradicated from the host’s environment. It requires the action of both innate and adaptive immune systems by the host. There are various pattern recognition receptors present on immune cells, which recognize foreign pathogens or its product and trigger the immune response. The epigenetic modification plays a crucial role in triggering the susceptibility of the host towards the pathogen and activating the host’s immune system against the invading pathogen. It alters the gene expression modifying the genetic material of the host’s cell. Epigenetic modification such as histone acetylation, alteration in non-coding RNA, DNA methylation and alteration in miRNA has been studied for their influence on the pathophysiology of tuberculosis to control the spread of infection. Despite several studies being conducted, many gaps still exist. Herein, we discuss the immunopathophysiological mechanism of tuberculosis, the essentials of epigenetics and the recent encroachment of epigenetics in the field of tuberculosis and its influence on the outcome and pathophysiology of the infection.

Purpose Ocular surface mucins and glycocalyx are critical for providing ocular hydration as well lubrication and repelling pathogens or allergens. Elevated levels of tear proinflammatory cytokines in dry eye may have detrimental effect on mucins and glycocalyx. The present study tested the effect of proinflammatory cytokines IL-6, TNF-α, and IFN-γ on membrane-tethered mucins expression, glycocalyx, and viability of ocular surface epithelial cells. Methods Stratified cultures of human corneal and conjunctival epithelial cells were exposed to different concentrations of IL-6, TNF-α, and IFN-γ for 24 hours. The mucins gene and protein expressions were quantified by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). The glycocalyx was imaged using confocal microscopy after staining with Alexa 488-conjugated wheat germ agglutinin lectin. Apoptotic and necrotic cell death was quantified using flow cytometry. Results IL-6, TNF-α, and IFN-γ treatment resulted in a significant increase in mucins (MUC)1 and MUC4 gene and protein expression in human corneal epithelial cells but caused no significant changes in the levels of these mucins in conjunctival epithelial cells. Further, these cytokines decreased MUC16 expression in both corneal and conjunctival epithelial cells. Moreover, no notable change in glycocalyx or apoptotic cell death in corneal and conjunctival epithelial cells was noted with any of the tested cytokines, but IL-6 and TNF-α exposure increased necrotic cell death in corneal and conjunctival epithelial cells, respectively. Conclusions Our results demonstrate that proinflammatory cytokines have differential effects on human corneal and conjunctival epithelial cell mucins expression, but do not cause any damage to ocular surface epithelial cell glycocalyx.

ObjectivesTo explore the use of intraperitoneal chemotherapy in conjunction with cytoreductive surgery for the treatment of peritoneal surface malignancy and highlight the challenges this provides for the hospital pharmacist.MethodsA literature search for relevant articles was performed using MEDLINE, PubMed and Cochrane databases. The following keywords and phrases were used: ‘hyperthermic intraperitoneal chemotherapy’, ‘early postoperative intraperitoneal chemotherapy’, ‘carrier solutions’ and ‘cytoreductive surgery’. Local experience was also shared, referencing national guidelines and published literature.ResultsThe rationale behind intraperitoneal chemotherapy is to directly administer drugs into the peritoneal cavity and achieve exposure of higher concentrations of cytotoxic agents to tumour nodules within the abdomen and on peritoneal surfaces for a prolonged period of time, without significant systemic toxicity. This has been widely demonstrated in intraoperative and early postoperative settings. Hydrophilic chemotherapy drugs with high molecular weights and permeable to the peritoneum, but slow plasma clearance create high concentrations of the drug in the peritoneal cavity, with lower systemic circulation. Commonly used drugs include mitomycin C, oxaliplatin, cisplatin, doxorubicin and 5-fluorouracil. Newer drugs such as the taxanes and bevacizumab have also shown promise. Heat increases drug penetration into body tissues and destroys tumour cells directly by causing damage to cells that have inherently faulty heat regulation pathways and also increases the cytotoxic effect of selected chemotherapeutic agents. Optimal temperature for hyperthermic intraperitoneal drug administration is between 41 and 43°C in a carrier solution that is compatible with the drug chosen. For early postoperative intraperitoneal chemotherapy high molecular weight starch carrier solutions prolong intraperitoneal dwell time and exposure of drug to tumour cells. Drugs are administered intraoperatively with the abdomen open or closed for between 30 and 120 min depending on the drug chosen and local protocols. Drug doses are traditionally calculated using body surface area. Toxicity such as neutropenia is encountered far less than with systemic chemotherapy.ConclusionsThis paper discusses the rationale for intraperitoneal drug administration following cytoreductive surgery and describes appropriate drug selection, methods of drug delivery and potential challenges in the use of the intraperitoneal route. It provides evidence and practical guidance for hospital pharmacists who may be involved in the surgical management of peritoneal malignancy particularly in dose calculation, preparation and administration of intraperitoneal chemotherapy.