The case for a ketogenic diet in the management of kidney disease.

Ketogenic diets have been widely used for weight loss and are increasingly used in the management of type 2 diabetes. Despite evidence that ketones have multiple positive effects on kidney function, common misconceptions about ketogenic diets, such as high protein content and acid load, have prevented their widespread use in individuals with impaired kidney function. Clinical trial evidence focusing on major adverse kidney events is sparse. The aim of this review is to explore the effects of a ketogenic diet, with an emphasis on the pleiotropic actions of ketones, on kidney health. Given the minimal concerns in relation to the potential renoprotective effects of a ketogenic diet, future studies should evaluate the safety and efficacy of ketogenic interventions in kidney disease.

Reduced COVID-19 severity elicited by weight loss from a medically supervised ketogenic diet in a geographically diverse ambulatory population with type 2 diabetes and obesity.

Objective: To investigate factors associated with COVID-19 severity in ambulatory individuals with type 2 diabetes mellitus (T2DM) and obesity treated with a medically supervised ketogenic diet (MSKD). Research design and methods: In this real-world, retrospective, exploratory analysis, multivariate modelling was used to assess clinical factors associated with hospitalisation for COVID-19 in a geographically diverse outpatient population with T2DM treated virtually. Results: Leading up to COVID-19 onset, non-hospitalised patients had higher average ketones (0.64 vs 0.52 mmol/L; p=0.016) and greater weight loss (6.8% vs 4.2%; p=0.009) compared with those hospitalised. Greater weight loss was significantly associated with lower likelihood of hospitalisation (adjusted OR=0.91, p=0.005), controlling for enrolment demographics and medical characteristics. Conclusions: Therapies such as MSKD, which elicit rapid, significant weight loss, may favourably impact COVID-19 hospitalisation rate and severity in individuals with T2DM and obesity.

Synthesis and in vitro evaluation of analogues of avocado-produced toxin (+)-(R)-persin in human breast cancer cells.

A structure-activity study of several new synthetic analogues of the avocado-produced toxin persin has been conducted, with compounds being evaluated for their cytostatic and pro-apoptotic effects in human breast cancer cells. A 4-pyridinyl derivative demonstrated activity comparable to that of the natural product, suggesting future directions for exploration of structure-activity relationships.

Synergistic cytotoxicity between tamoxifen and the plant toxin persin in human breast cancer cells is dependent on Bim expression and mediated by modulation of ceramide metabolism.

Phytochemicals have provided an abundant source of novel therapeutics for the treatment of human cancers. We have previously described a novel plant toxin, persin, derived from avocado leaves, which has unique in vivo actions in the mammary epithelium and Bim-dependent, cytotoxic effects in human breast cancer cells in vitro. Compounds structurally similar to persin, such as the polyunsaturated fatty acid, conjugated linoleic acid, can attenuate steroid hormone receptor signaling and modulate the response of breast cancer cells to antiestrogens. Here, we provide evidence that persin may have similar effects by showing its potent proapoptotic synergy with the antiestrogen 4-hydroxytamoxifen. However, although persin transcriptionally down-regulates estrogen receptor (ER) expression, unlike conjugated linoleic acid, it also shows efficacy in ER-negative breast cancer cells, both alone and in combination with 4-hydroxytamoxifen, whereas normal breast epithelial cells are unaffected, suggesting it may act via a distinct, ER-independent mechanism. These proapoptotic synergistic interactions are associated with increased de novo ceramide synthesis and are dependent on expression of the proapoptotic protein Bim. These data show that persin should be further investigated as a potential novel cancer therapeutic agent because it significantly enhances the sensitivity of breast cancer cells to the cytotoxic effects of tamoxifen, regardless of their ER status, while displaying apparent specificity for the malignant phenotype.

Efficacy and safety of statin monotherapy in older adults: a meta-analysis.

BACKGROUND: Statin therapy significantly reduces cardiovascular events. Older patients, however, are less likely to be prescribed statins than younger patients due to concern over lack of indication, lower predictive value of cholesterol levels, and increased risk of adverse events. To determine the effect of statins on all-cause mortality and on major cardiovascular events, including stroke, we performed a meta-analysis of statin trials that included older adult participants. METHODS: Mortality, cardiovascular events, and adverse event outcomes were extracted from published randomized, placebo-controlled clinical trials of persons aged 60 years and older. RESULTS: Data on 51,351 patients were evaluated. Statins reduced all-cause mortality by 15% (95% confidence interval, 7%-22%), coronary heart disease (CHD) death by 23% (15%-29%), fatal or nonfatal myocardial infarction (MI) by 26% (22%-30%), and fatal or nonfatal stroke by 24% (10%-35%). The relative risk of cancer comparing statins to placebo was 1.06 (0.95-1.18). Adverse event data were not consistently reported. CONCLUSIONS: Statin therapy significantly reduced all-cause and CHD mortality, as well as risk of stroke and MI. Statin therapy should be offered to older patients at high risk of atherosclerotic disease events.

A novel plant toxin, persin, with in vivo activity in the mammary gland, induces Bim-dependent apoptosis in human breast cancer cells.

Phytochemicals have provided an abundant and effective source of therapeutics for the treatment of cancer. Here we describe the characterization of a novel plant toxin, persin, with in vivo activity in the mammary gland and a p53-, estrogen receptor-, and Bcl-2-independent mode of action. Persin was previously identified from avocado leaves as the toxic principle responsible for mammary gland-specific necrosis and apoptosis in lactating livestock. Here we used a lactating mouse model to confirm that persin has a similar cytotoxicity for the lactating mammary epithelium. Further in vitro studies in a panel of human breast cancer cell lines show that persin selectively induces a G2-M cell cycle arrest and caspase-dependent apoptosis in sensitive cells. The latter is dependent on expression of the BH3-only protein Bim. Bim is a sensor of cytoskeletal integrity, and there is evidence that persin acts as a microtubule-stabilizing agent. Due to the unique structure of the compound, persin could represent a novel class of microtubule-targeting agent with potential specificity for breast cancers.

Hypothyroidism.

Hypothyroidism is common, potentially serious, often clinically overlooked, readily diagnosed by laboratory testing, and eminently treatable. The condition is particularly prevalent in older women, in whom autoimmune thyroiditis is common. Other important causes include congenital thyroid disorders, previous thyroid surgery and irradiation, drugs such as lithium carbonate and amiodarone, and pituitary and hypothalamic disorders. Worldwide, dietary iodine deficiency remains an important cause. Hypothyroidism can present with nonspecific constitutional and neuropsychiatric complaints, or with hypercholesterolaemia, hyponatraemia, hyperprolactinaemia, or hyperhomocysteinaemia. Severe untreated hypothyroidism can lead to heart failure, psychosis, and coma. Although these manifestations are neither specific nor sensitive, the diagnosis is confirmed or excluded by measurements of serum thyrotropin and free thyroxine. Thyroxine replacement therapy is highly effective and safe, but suboptimal dosing is common in clinical practice. Patient noncompliance, drug interactions, and pregnancy can lead to inadequate treatment. Iatrogenic thyrotoxicosis can cause symptoms, and, even when mild, provoke atrial fibrillation and osteoporosis. We summarise present understanding of the history, epidemiology, pathophysiology, and clinical diagnosis and management of hypothyroidism.

Variants in scavenger receptor class B type I gene are associated with HDL cholesterol levels in younger women.

OBJECTIVE: Variants within the scavenger receptor class B type I (SCARB1) receptor gene have been previously associated with lipid levels, especially in women, with some studies reporting the association to be stronger in the presence of diabetes or post-menopausal estrogen use. Based on the reported gender-specific association and modification effect of estrogen on lipid levels according to SCARB1 variants, we explored the relationship between SCARBI single nucleotide polymorphisms (SNPs) and lipid levels in an Amish population to assess sex and age differences. METHODS: Eight SCARB1 SNPs, identified from public databases, were genotyped in 919 subjects. RESULTS: Rs5888 and rs3782287 were in high linkage disequilibrium (LD), with r(2) > 0.8. None of the SNPs were significantly associated with lipid levels in men; however in women, rs5888 (p = 0.04) and rs5891 (p < 0.001) were significantly associated with higher HDL-C levels. Rs5891 had an allele frequency of 3% and predicts a missense mutation (Ile135Val), which may be functional. Moreover, rs3782287 (p = 0.023) and rs5888 (p = 0.003) were significantly associated with higher HDL-C levels in women younger than 50 years but not in women aged 50 years or older (p for interaction between age and rs5888 = 0.045). None of the SNP effects on HDL-C were modified in the presence of diabetes, in either men or women. CONCLUSIONS: SCARB1 SNPs influence HDL-C levels in women, particularly in those less than 50 years old. CONDENSED ABSTRACT: We assessed associations between SCARB1 SNPs and lipid traits in 919 Amish men and women. Two SNPs, rs3782287 and rs5888, were significantly associated with higher HDL-C levels in women younger than 50 years but not in women aged 50 years or older, supporting an interaction between common sequence variants in SCARB1 and estrogen on HDL-C.