Reprogramming of Energy Metabolism in Human PKD1 Polycystic Kidney Disease: A Systems Biology Analysis.

Multiple alterations of cellular metabolism have been documented in experimental studies of autosomal dominant polycystic kidney disease (ADPKD) and are thought to contribute to its pathogenesis. To elucidate the molecular pathways and transcriptional regulators associated with the metabolic changes of renal cysts in ADPKD, we compared global gene expression data from human PKD1 renal cysts, minimally cystic tissues (MCT) from the same patients, and healthy human kidney cortical tissue samples. We found gene expression profiles of PKD1 renal cysts were consistent with the Warburg effect with gene pathway changes favoring increased cellular glucose uptake and lactate production, instead of pyruvate oxidation. Additionally, mitochondrial energy metabolism was globally depressed, associated with downregulation of gene pathways related to fatty acid oxidation (FAO), branched-chain amino acid (BCAA) degradation, the Krebs cycle, and oxidative phosphorylation (OXPHOS) in renal cysts. Activation of mTORC1 and its two target proto-oncogenes, HIF-1α and MYC, was predicted to drive the expression of multiple genes involved in the observed metabolic reprogramming (e.g., GLUT3, HK1/HK2, ALDOA, ENO2, PKM, LDHA/LDHB, MCT4, PDHA1, PDK1/3, MPC1/2, CPT2, BCAT1, NAMPT); indeed, their predicted expression patterns were confirmed by our data. Conversely, we found AMPK inhibition was predicted in renal cysts. AMPK inhibition was associated with decreased expression of PGC-1α, a transcriptional coactivator for transcription factors PPARα, ERRα, and ERRγ, all of which play a critical role in regulating oxidative metabolism and mitochondrial biogenesis. These data provide a comprehensive map of metabolic pathway reprogramming in ADPKD and highlight nodes of regulation that may serve as targets for therapeutic intervention.

Gender representation in Canadian surgical leadership and medical faculties: a cross-sectional study.

BACKGROUND: Over the past two and half decades, Canadian medical school students have become majority female, and the medical workforce is therefore increasingly comprised of female physicians. Whether this change, however, has been reflected in the gender balance within medical school faculty positions and leadership has not been well studied in Canada. METHODS: This cross-sectional study examined the genders of full-time faculty members from the most recently available AFMC data, the current heads of departments of medicine and surgery from department websites and confirmed with respective universities. RESULTS: Overall, women held 40.5% of full-time faculty positions in Canadian faculties of medicine. Female representation decreased with increasing academic rank, from 57.8% of instructors to 50.8% of assistant, 39.2% of associate, and 28.1% of full professors, respectively, with the greatest rate of increase over the past decade among full professors (0.75% per year). The heads of departments of family medicine were majority female (67%), and heads internal medicine at parity (50% female), consistent with numbers of practicing physicians. However, the heads of surgical divisions were majority male (86% overall). Accounting for the gender balance of practicing surgeons, male compared to female surgeons were 2.9 times as likely to be division head (95% CI 1.78-4.85, p < 0.0001). CONCLUSIONS: Women remain underrepresented in Canadian faculties of medicine in leadership positions. Leadership in departments of surgery has particularly low female representation, even relative to the proportion of practicing female surgeons within the respective discipline.

From Hair Loss to Vision Loss: Minoxidil-Associated CRVO in a Young Female.

Introduction: Central retinal vein occlusion (CRVO) is a common retinal vascular disorder that is most often seen in older adults and individuals with vascular risk factors. Case Presentation: We report a case of CRVO with cystoid macular edema (CME) in a young, otherwise healthy patient taking minoxidil for hair loss. The patient had no known vascular risk factors, and a comprehensive coagulability workup was negative. The CRVO with CME resolved without intervention upon cessation of minoxidil. Conclusion: Possible mechanisms for minoxidil-associated retinal vascular disorders are explored. Thorough medication histories and the consideration of possible adverse drug events in patients without traditional risk factors are recommended.

Gender trends in Canadian medicine and surgery: the past 30 years.

BACKGROUND: While the number of women entering medicine has steadily increased since the 1970s in Canada, the gender composition along each stage of the medical training pathway has not been comprehensively reported. We therefore sought to systematically examine the gender composition of students, residents, and practicing physicians over the past 30 years in Canada. RESULTS: In this cross-sectional analysis of Canadian medical trainees including MD applicants (137,096 male, 169,099 female), MD students (126,422 male, 152, 967 female), MD graduates (29,413 male, 34,173 female), residents by the decade (24,425 male, 28,506 female) and practicing surgeons (total 7,457 male, 3,457 female), we find that increased female representation in medicine is not matched by representation in surgery, with the key being the specialty choice process. The likelihood of female applicants matriculating to medical school was less than male applicants in the 90s (OR 0.92, 95% CI 0.92-0.93), greater in the early 2000s (OR 1.03, 95% CI 1.03-1.04), and has since balanced out (OR 1.00, 95% CI 1.00-1.01), with medical school classes being nearly 60% female for the past two decades. Despite this, females have remained underrepresented in most surgical residency programs, with odds of female medical students entering surgical residency other than Ob/Gyn being about half that of male students (OR 0.56, 95% CI 0.44-0.71), resulting in a slow increase in practicing female surgeons of less than 0.5% per year in many surgical disciplines and projected parity decades or centuries in the future. CONCLUSIONS: While undergraduate medical education has been majority female in Canada for nearly three decades, females remain greatly underrepresented in the physician workforce within surgical specialties. To build a representative medical workforce equipped to care for diverse patient populations, factors influencing the specialty choices of early career physicians will need to be examined and addressed.

A latent cardiomyocyte regeneration potential in human heart disease.

Cardiomyocytes in the adult human heart show a regenerative capacity, with an annual renewal rate around 0.5%. Whether this regenerative capacity of human cardiomyocytes is employed in heart failure has been controversial. Using retrospective 14C birth dating we analyzed cardiomyocyte renewal in patients with end-stage heart failure. We show that cardiomyocyte generation is minimal in end-stage heart failure patients at rates 18-50 times lower compared to the healthy heart. However, patients receiving left ventricle support device therapy, who showed significant functional and structural cardiac improvement, had a >6-fold increase in cardiomyocyte renewal relative to the healthy heart. Our findings reveal a substantial cardiomyocyte regeneration potential in human heart disease, which could be exploited therapeutically.

Diet and Polycystic Kidney Disease: Nutrients, Foods, Dietary Patterns, and Implications for Practice.

Polycystic kidney disease (PKD) is a chronic, progressive hereditary condition characterized by abnormal development and growth of cysts in the kidneys and other organs. There is increasing interest in exploring whether dietary modifications may prevent or slow the disease course in people with PKD. Although vasopressin-receptor agonists have emerged as a novel drug treatment in advancing care for people with PKD, several recent landmark trials and clinical discoveries also have provided new insights into potential dietary-related therapeutic strategies. In this review, we summarize the current evidence pertaining to nutrients, foods, dietary patterns, cyst growth, and progression of PKD. We also describe existing evidence-based dietary care for people with PKD and outline the potential implications for advancing evidence-based dietary interventions. Semin Nephrol 43:x-xx © 2023 Elsevier Inc. All rights reserved.

Adipose Tissue and Plasma Markers Associated with HbA1c Pre- and Post-bariatric Surgery: a Cross-sectional and Cohort Study.

PURPOSE: Obesity can be associated with chronic inflammation and dysregulated expression of inflammatory adipokines that contribute to insulin resistance and type 2 diabetes. This may also affect the clinical response to bariatric surgery. Our objective was whether baseline visceral adipose tissue features and plasma adipokine are associated with HbA1c ≥0.06 at the time of Roux-en-Y gastric bypass (RYGB) surgery and with persistently elevated HbA1c at 12 months post-RYGB. METHODS: During the surgery, adipose biopsies and plasma were collected for adipokine/cytokine profile. Clinical and biochemical measurements were also collected at the time of RYGB and, in those with baseline elevated HbA1c, at 12 months post-RYGB. RESULTS: In the cross-sectional study, 109 patients (82.6% female; age 49 years; BMI 46.98 kg/m2) participated. Of those with elevated HbA1c at baseline (n = 61), 47 patients had repeated measurements at 12 months post-RYGB (23% drop-out). Using a multivariate logistic regression model, older age (adjusted odds ratio (aOR), 1.14; 95% confidence interval (CI), 1.06-1.22) and higher plasma resistin (aOR, 5.30; 95% CI, 1.25-22.44) were associated with higher odds of HbA1c ≥ 0.06, whereas higher plasma adiponectin (aOR, 0.993; 95% CI, 0.99-0.996) was associated with lower odds of HbA1c ≥0.06. In addition, baseline higher average adipose cell area (aOR, 1.0017; 95% CI, 1.0002-1.0032) and plasma resistin (aOR, 1.0004; 95% CI, 1.0000-1.0009) were associated with higher odds of having persistently elevated HbA1c at 12 months post-RYGB. CONCLUSION: Our study suggests that baseline plasma adipokine dysregulation, specifically high resistin, and adipocyte hypertrophy may affect the clinical response to RYGB.

Gut microbiome modified by bariatric surgery improves insulin sensitivity and correlates with increased brown fat activity and energy expenditure.

Alterations in the microbiome correlate with improved metabolism in patients following bariatric surgery. While fecal microbiota transplantation (FMT) from obese patients into germ-free (GF) mice has suggested a significant role of the gut microbiome in metabolic improvements following bariatric surgery, causality remains to be confirmed. Here, we perform paired FMT from the same obese patients (BMI > 40; four patients), pre- and 1 or 6 months post-Roux-en-Y gastric bypass (RYGB) surgery, into Western diet-fed GF mice. Mice colonized by FMT from patients' post-surgery stool exhibit significant changes in microbiota composition and metabolomic profiles and, most importantly, improved insulin sensitivity compared with pre-RYGB FMT mice. Mechanistically, mice harboring the post-RYGB microbiome show increased brown fat mass and activity and exhibit increased energy expenditure. Moreover, improvements in immune homeostasis within the white adipose tissue are also observed. Altogether, these findings point to a direct role for the gut microbiome in mediating improved metabolic health post-RYGB surgery.

Shared pathobiology identifies AMPK as a therapeutic target for obesity and autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common Mendelian kidney disease, affecting approximately one in 1,000 births and accounting for 5% of end-stage kidney disease in developed countries. The pathophysiology of ADPKD is strongly linked to metabolic dysregulation, which may be secondary to defective polycystin function. Overweight and obesity are highly prevalent in patients with ADPKD and constitute an independent risk factor for progression. Recent studies have highlighted reduced AMP-activated protein kinase (AMPK) activity, increased mammalian target of rapamycin (mTOR) signaling, and mitochondrial dysfunction as shared pathobiology between ADPKD and overweight/obesity. Notably, mTOR and AMPK are two diametrically opposed sensors of energy metabolism that regulate cell growth and proliferation. However, treatment with the current generation of mTOR inhibitors is poorly tolerated due to their toxicity, making clinical translation difficult. By contrast, multiple preclinical and clinical studies have shown that pharmacological activation of AMPK provides a promising approach to treat ADPKD. In this narrative review, we summarize the pleiotropic functions of AMPK as a regulator of cellular proliferation, macromolecule metabolism, and mitochondrial biogenesis, and discuss the potential for pharmacological activation of AMPK to treat ADPKD and obesity-related kidney disease.

Spontaneous Resolution of Optic Perineuritis in a Patient with Crohn's Disease.

Optic perineuritis (OPN) is a rare condition characterized by inflammation of the optic nerve sheath. The underlying etiologies of OPN are varied and include systemic inflammatory conditions such as Crohn's disease. It has been asserted that OPN requires prompt treatment in all cases. However, we report a case of OPN in a patient with Crohn's disease that spontaneously resolved without treatment, underscoring that observation is a reasonable approach in some cases of OPN.

Circadian rhythms in metabolic organs and the microbiota during acute fasting in mice.

The circadian clock regulates metabolism in anticipation of regular changes in the environment. It is found throughout the body, including in key metabolic organs such as the liver, adipose tissues, and intestine, where the timing of the clock is set largely by nutrient signaling. However, the circadian clocks of these tissues during the fasted state have not been completely characterized. Moreover, the sufficiency of a functioning host clock to produce diurnal rhythms in the composition of the microbiome in fasted animals has not been explored. To this end, mice were fasted 24 h prior to collection of key metabolic tissues and fecal samples for the analysis of circadian clock gene expression and microbiome composition. Rhythm characteristics were determined using CircaCompare software. We identify tissue-specific changes to circadian clock rhythms upon fasting, particularly in the brown adipose tissue, and for the first time demonstrate the rhythmicity of the microbiome in fasted animals.

The Development of Indirect Carotid Cavernous Fistulas after Microvascular Ischemic 4th Nerve Palsies.

An indirect carotid cavernous fistula (CCF) is an abnormal connection between the cavernous sinus and internal or external carotid artery. Indirect CCFs often occur spontaneously, particularly in the setting of vascular risk factors such as hypertension, diabetes, and atherosclerosis. Microvascular ischemic nerve palsies (NPs) share these vascular risk factors. However, to date, no temporal relationship between microvascular ischemic NP and indirect CCF occurring sequentially has been reported. We describe the cases of 64- and 73-year-old women who developed indirect CCFs within 1-2 weeks after spontaneous resolution of a microvascular ischemic 4th NP. Both patients had complete resolution and an asymptomatic period between the 4th NP and CCF. This case highlights the shared pathophysiology and risk factors between microvascular ischemic NPs and CCFs, and emphasizes that CCFs should be kept in the differential diagnosis for red eye or recurrent diplopia in patients with previous microvascular ischemic NP.

Dietary Interventions in Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive growth of renal cysts, leading to the loss of functional nephrons. Recommendations for individuals with ADPKD to maintain a healthy diet and lifestyle are largely similar to those for the general population. However, recent evidence from preclinical models suggests that more tightly specified dietary regimens, including caloric restriction, intermittent fasting, and ketogenic diets, hold promise to slow disease progression, and the results of ongoing human clinical trials are eagerly awaited. These dietary interventions directly influence nutrient signaling and substrate availability in the cystic kidney, while also conferring systemic metabolic benefits. The present review focuses on the importance of local and systemic metabolism in ADPKD and summarizes current evidence for dietary interventions to slow disease progression and improve quality of life.

Feeding Rhythms and the Circadian Regulation of Metabolism.

The molecular circadian clock regulates metabolic processes within the cell, and the alignment of these clocks between tissues is essential for the maintenance of metabolic homeostasis. The possibility of misalignment arises from the differential responsiveness of tissues to the environmental cues that synchronize the clock (zeitgebers). Although light is the dominant environmental cue for the master clock of the suprachiasmatic nucleus, many other tissues are sensitive to feeding and fasting. When rhythms of feeding behavior are altered, for example by shift work or the constant availability of highly palatable foods, strong feedback is sent to the peripheral molecular clocks. Varying degrees of phase shift can cause the systemic misalignment of metabolic processes. Moreover, when there is a misalignment between the endogenous rhythms in physiology and environmental inputs, such as feeding during the inactive phase, the body's ability to maintain homeostasis is impaired. The loss of phase coordination between the organism and environment, as well as internal misalignment between tissues, can produce cardiometabolic disease as a consequence. The aim of this review is to synthesize the work on the mechanisms and metabolic effects of circadian misalignment. The timing of food intake is highlighted as a powerful environmental cue with the potential to destroy or restore the synchrony of circadian rhythms in metabolism.

The transfer of location-based control requires location-based conflict.

It is well supported that stimulus-driven control of attention varies depending on the degree of conflict previously encountered in a given location. Previous research has further shown that control settings established in conflict-biased locations can transfer to nearby unbiased items. However, these spatial transfer effects have only been shown using incompatible flanking arrows (i.e., stimuli that trigger spatial information) to elicit conflict in a flanker task. Here we examine the generalizability of transfer of control by examining if it can occur across a range of tasks. We employ a classic Stroop task (Experiment 1), a spatially segregated Stroop task (Experiment 2), and a spatial Stroop task (Experiment 3). Location-specific proportion compatibility effects were observed in all variations of the Stroop task tested; however, transfer to unbiased items occurred only in the spatial Stroop task in Experiment 3. This suggests that the transfer of cognitive control settings within spatial categories may occur only in tasks where the source of conflict is spatial, as arises in tasks with arrow and direction word stimuli.