Clinical interventions to break the obesity and cancer link: a narrative review.

Excess body weight is a significant risk factor for the development and recurrence of many types of cancer. Patients with a history or current diagnosis of cancer who are overweight or have obesity have an increased risk of cancer treatment-related morbidity, recurrence, and decreased quality of life. Weight loss and maintenance of a healthy body weight may reduce cancer morbidity and recurrence in cancer survivors. While guidelines for cancer survivorship elaborate sufficiently on lifestyle interventions, little guidance is provided when considering additional therapies like anti-obesity pharmacotherapy or bariatric surgery for weight loss. This review will highlight and address current recommendations and feasible interventions that clinicians may consider to further reduce the incidence and recurrence of cancer in patients with obesity.

Hydralazine-induced liver injury: a review and discussion.

Hydralazine is a commonly prescribed antihypertensive agent. Some of its labelled adverse reactions include lupus-like syndrome, tachycardia, headache and fever. Despite its well-known side effects, little is known about hydralazine's hepatotoxic effects. We report the case of a 54-year-old female patient who was started on hydralazine for hypertension management but later presented with hydralazine-induced liver injury. Her initial presentation consisted of non-specific symptoms and a hepatocellular injury pattern. Liver biopsy revealed hepatic steatosis. Three weeks after discontinuation of hydralazine, the patient's liver enzymes normalised, and her symptoms resolved. Few studies have examined the incidence and mechanism by which hydralazine induces a liver injury pattern. With this case, we review the literature, the pathogenesis involved and the eventual management of hydralazine-induced liver injury. We propose close monitoring of liver enzymes for patients on hydralazine throughout their treatment course.

Weight loss interventions in living donor liver transplantation as a tool in expanding the donor pool: A systematic review and meta-analysis.

BACKGROUND: With increasing rates of liver transplantation and a stagnant donor pool, the annual wait list removals have remained high. Living donor liver transplantation (LDLT) is an established modality in expanding the donor pool and is the primary method of liver donation in large parts of the world. Marginal living donors, including those with hepatic steatosis, have been used to expand the donor pool. However, due to negative effects of steatosis on graft and recipient outcomes, current practice excludes overweight or obese donors with more than 10% macro vesicular steatosis. This has limited a potentially important source to help expand the donor pool. Weight loss is known to improve or resolve steatosis and rapid weight loss with short-term interventions have been used to convert marginal donors to low-risk donors in a small series of studies. There is, however, a lack of a consensus driven standardized approach to such interventions. AIM: To assess the available data on using weight loss interventions in potential living liver donors with steatotic livers and investigated the feasibility, efficacy, and safety of using such donors on the donor, graft and recipient outcomes. The principal objective was to assess if using such treated donor livers, could help expand the donor pool. METHODS: We performed a comprehensive literature review and meta-analysis on studies examining the role of short-term weight loss interventions in potential living liver donors with hepatic steatosis with the aim of increasing liver donation rates and improving donor, graft, and recipient outcomes. RESULTS: A total of 6 studies with 102 potential donors were included. Most subjects were males (71). All studies showed a significant reduction in body mass index post-intervention with a mean difference of -2.08 (-3.06, 1.10, I 2 = 78%). A significant reduction or resolution of hepatic steatosis was seen in 93 of the 102 (91.2%). Comparison of pre- and post-intervention liver biopsies showed a significant reduction in steatosis with a mean difference of -21.22 (-27.02, -15.43, I 2 = 56%). The liver donation rates post-intervention was 88.5 (74.5, 95.3, I 2 = 42%). All donors who did not undergo LDLT had either recipient reasons or had fibrosis/steatohepatitis on post intervention biopsies. Post-operative biliary complications in the intervention group were not significantly different compared to controls with an odds ratio of 0.96 [(0.14, 6.69), I 2 = 0]. The overall post-operative donor, graft, and recipient outcomes in treated donors were not significantly different compared to donors with no steatosis. CONCLUSION: Use of appropriate short term weight loss interventions in living liver donors is an effective tool in turning marginal donors to low-risk donors and therefore in expanding the donor pool. It is feasible and safe, with comparable donor, graft, and recipient outcomes, to non-obese donors. Larger future prospective studies are needed.

Analysis of the impact of COVID-19 pandemic on house-staff in the USA: addressing the ripple effects.

Background: The novel corona virus has changed the way individuals interact with each other and society. In the medical sector, this has affected the residents and fellows who spend the majority of their time on the front lines. Methods: We conducted a cross-sectional survey to assess the impact of the COVID-19 pandemic on the lives and training of house-staff across the USA. Respondents in our survey reported feeling significantly overwhelmed by the ongoing pandemic. Results: The majority of house-staff were significantly concerned about the lack of protective equipment, inability to safeguard themselves from infection and inability to look after their families. Concerns regarding contracting the infection and transmitting it to their loved ones were reported as a cause of mental distress among resident physicians. Increasing patient load, lack of protective equipment, and disruption of educational and academic activities during the COVID-19 pandemic have all reportedly affected the training and overall well-being of resident physicians. Conslusion: Our study adds further support for measures to safeguard house-staff with proper protective equipment and ensure adequate support for both mental and physical well-being during these challenging times.

Primary Care in Cuba: Considerations for the U.S.

In 2017, we traveled to Cuba to learn about the nation's approach to health care. Despite being a developing nation, Cuba boasts health care indicators that are comparable to those of the United States and other developed nations. Emphasizing prevention and proactive care, the Cuban health care system provides lessons to inform future U.S. health care reform efforts in order to contain medical costs while providing quality care. Visiting with Cuban health care professionals over the course of eight days, and interviewing American physicians who were trained in Cuba but practice in the U.S., this paper provides an overview of key differences in primary health care in Cuba and primary care practice in the U.S. Our work has three main themes: how Cuban medicine approaches primary health care, the importance of medical curriculum in establishing these priorities, and the prioritization of the clinical encounter over technologically-advanced interventions.

A novel angiotensin I-converting enzyme mutation (S333W) impairs N-domain enzymatic cleavage of the anti-fibrotic peptide, AcSDKP.

BACKGROUND: Angiotensin I-converting enzyme (ACE) has two functional N- and C-domain active centers that display differences in the metabolism of biologically-active peptides including the hemoregulatory tetrapeptide, Ac-SDKP, hydrolysed preferentially by the N domain active center. Elevated Ac-SDKP concentrations are associated with reduced tissue fibrosis. RESULTS: We identified a patient of African descent exhibiting unusual blood ACE kinetics with reduced relative hydrolysis of two synthetic ACE substrates (ZPHL/HHL ratio) suggestive of the ACE N domain center inactivation. Inhibition of blood ACE activity by anti-catalytic mAbs and ACE inhibitors and conformational fingerprint of blood ACE suggested overall conformational changes in the ACE molecule and sequencing identified Ser333Trp substitution in the N domain of ACE. In silico analysis demonstrated S333W localized in the S1 pocket of the active site of the N domain with the bulky Trp adversely affecting binding of ACE substrates due to steric hindrance. Expression of mutant ACE (S333W) in CHO cells confirmed altered kinetic properties of mutant ACE and conformational changes in the N domain. Further, the S333W mutant displayed decreased ability (5-fold) to cleave the physiological substrate AcSDKP compared to wild-type ACE. CONCLUSIONS AND SIGNIFICANCE: A novel Ser333Trp ACE mutation results in dramatic changes in ACE kinetic properties and lowered clearance of Ac-SDKP. Individuals with this mutation (likely with significantly increased levels of the hemoregulatory tetrapeptide in blood and tissues), may confer protection against fibrosis.

Excessive daytime sleepiness and obstructive sleep apnea in patients with sarcoidosis.

BACKGROUND: Systemic symptoms are common in sarcoidosis and are associated with a decreased quality of life. Excessive daytime sleepiness (EDS) often is associated with obstructive sleep apnea (OSA) but may be a systemic symptom independently associated with sarcoidosis. The aim of this study was to assess the relationship between sarcoidosis and EDS. METHODS: In a retrospective analysis, we used Epworth Sleepiness Scale scores to compare sleepiness in 62 patients with sarcoidosis with 1,005 adults without sarcoidosis referred for polysomnography for suspicion of OSA. Linear regression models controlled for covariates. In a subgroup analysis of patients with sarcoidosis, sleepiness scores and polysomnograms were compared between those with normal and those with abnormal pulmonary function based on total lung capacity. RESULTS: EDS was more common in patients with sarcoidosis than in those without, and sarcoidosis remained an independent predictor of increased sleepiness after controlling for covariates. Compared with control patients referred for polysomnography, fewer patients with sarcoidosis had clinically significant OSA. However, among patients with sarcoidosis, OSA was more severe in those with abnormal lung function. CONCLUSIONS: Sarcoidosis is independently associated with EDS. Sleepiness may contribute to the morbidity of sarcoidosis and should be followed even after treating for potentially coexisting OSA or depression. Abnormal lung function in sarcoidosis may contribute to OSA, although the mechanisms for this are not known.

The orphan receptor Gpr83 regulates systemic energy metabolism via ghrelin-dependent and ghrelin-independent mechanisms.

The G protein-coupled receptor 83 (Gpr83) is widely expressed in brain regions regulating energy metabolism. Here we report that hypothalamic expression of Gpr83 is regulated in response to nutrient availability and is decreased in obese mice compared with lean mice. In the arcuate nucleus, Gpr83 colocalizes with the ghrelin receptor (Ghsr1a) and the agouti-related protein. In vitro analyses show heterodimerization of Gpr83 with Ghsr1a diminishes activation of Ghsr1a by acyl-ghrelin. The orexigenic and adipogenic effect of ghrelin is accordingly potentiated in Gpr83-deficient mice. Interestingly, Gpr83 knock-out mice have normal body weight and glucose tolerance when fed a regular chow diet, but are protected from obesity and glucose intolerance when challenged with a high-fat diet, despite hyperphagia and increased hypothalamic expression of agouti-related protein, Npy, Hcrt and Ghsr1a. Together, our data suggest that Gpr83 modulates ghrelin action but also indicate that Gpr83 regulates systemic metabolism through other ghrelin-independent pathways.

p62 links ß-adrenergic input to mitochondrial function and thermogenesis.

The scaffold protein p62 (sequestosome 1; SQSTM1) is an emerging key molecular link among the metabolic, immune, and proliferative processes of the cell. Here, we report that adipocyte-specific, but not CNS-, liver-, muscle-, or myeloid-specific p62-deficient mice are obese and exhibit a decreased metabolic rate caused by impaired nonshivering thermogenesis. Our results show that p62 regulates energy metabolism via control of mitochondrial function in brown adipose tissue (BAT). Accordingly, adipocyte-specific p62 deficiency led to impaired mitochondrial function, causing BAT to become unresponsive to ß-adrenergic stimuli. Ablation of p62 leads to decreased activation of p38 targets, affecting signaling molecules that control mitochondrial function, such as ATF2, CREB, PGC1α, DIO2, NRF1, CYTC, COX2, ATP5ß, and UCP1. p62 ablation in HIB1B and BAT primary cells demonstrated that p62 controls thermogenesis in a cell-autonomous manner, independently of brown adipocyte development or differentiation. Together, our data identify p62 as a novel regulator of mitochondrial function and brown fat thermogenesis.