Sex-Dependent Effects of 7,8-Dihydroxyflavone on Metabolic Health Are Associated with Alterations in the Host Gut Microbiome

7,8-Dihydroxyflavone (DHF) is a naturally occurring flavonoid that has been reported to protect against a variety of pathologies. Chronic administration of DHF prevents high-fat diet (HFD)-induced obesity in female, but not male, mice. However, the mechanisms underlying this sexual dimorphism have not been elucidated. We have discovered that oral DHF supplementation significantly attenuates fat mass, hepatic lipid accumulation, and adipose tissue inflammation in female mice. In contrast, male mice were not protected from adiposity, and had a paradoxical worsening of hepatic lipid accumulation and adipose tissue inflammation upon DHF supplementation. Consistent with these sexually dimorphic effects on body weight and metabolic health, 7,8-DHF induced early and stable remodeling of the female intestinal microbiome. DHF supplementation significantly increased gut microbial diversity, and suppressed potentially detrimental bacteria, particularly Desulfovibrionaceae, which are pro-inflammatory and positively associated with obesity and inflammation. Changes in the female gut microbiome preceded alterations in body weights, and in silico analyses indicated that these early microbial changes were highly predictive of subsequent weight gain in female mice. While some alterations in the intestinal microbiome were also observed in male DHF-supplemented mice, these changes were distinct from those in females and, importantly, were not predictive of subsequent body weight changes in male animals. The temporality of microbial changes preceding alterations in body weight in female mice suggests a role for the gut microbiome in mediating the sexually dimorphic effects of DHF on body weight. Given the significant clinical interest in this flavonoid across a wide range of pathologies, further elucidation of these sexually dimorphic effects will aid the development of effective clinical therapies.     

Chronic Intake of Energy Drinks and Their Sugar Free Substitution Similarly Promotes Metabolic Syndrome

Energy drinks containing significant quantities of caffeine, taurine and sugar are increasingly consumed, particularly by adolescents and young adults. The putative effects of chronic ingestion of either standard energy drink, Mother^TM (ED), or its sugar-free formulation (sfED) on metabolic syndrome were determined in wild-type C57BL/6J mice, in comparison to a soft drink, Coca-Cola (SD), a Western-styled diet enriched in saturated fatty acids (SFA), and a combination of SFA + ED. Following 13 weeks of intervention, mice treated with ED were hyperglycaemic and hypertriglyceridaemic, indicating higher triglyceride glucose index, which was similar to the mice maintained on SD. Surprisingly, the mice maintained on sfED also showed signs of insulin resistance with hyperglycaemia, hypertriglyceridaemia, and greater triglyceride glucose index, comparable to the ED group mice. In addition, the ED mice had greater adiposity primarily due to the increase in white adipose tissue, although the body weight was comparable to the control mice receiving only water. The mice maintained on SFA diet exhibited significantly greater weight gain, body fat, cholesterol and insulin, whilst blood glucose and triglyceride concentrations remained comparable to the control mice. Collectively, these data suggest that the consumption of both standard and sugar-free forms of energy drinks induces metabolic syndrome, particularly insulin resistance.     

Non-alcoholic steatohepatitis

Non-alcoholic fatty liver disease (NAFLD), also referred to as metabolic associated fatty liver disease (MAFLD), is the commonest form of chronic liver disorder arising from metabolic dysregulation. It encompasses a wide spectrum of fatty liver phenotypes including isolated steatosis to non-alcoholic steatohepatitis (NASH). NASH is considered more likely to lead to grave clinical consequences such as cirrhosis and hepatocellular carcinoma, compared to simple steatosis. NASH is characterised by steatosis, inflammation, and damage to hepatocytes. Here, we present a case of a middle-aged gentleman with a background of infectious hepatitis who presented with NASH, with emphasis on terminology and histological assessment criteria of NAFLD and NASH. Reflection on and consistent effort to standardise terminology and assessment criteria will aid in addressing the scientific and clinical needs of NAFLD and NASH.     

Coronary microcirculation: autoregulation and metabolic control

The majority of studies axamining the regulation of coronary blood flow and vascular resistance have considered the coronary circulation as being composed of large conduit vessels and resistance vessels. Recently, it has become apparent that regulation of coronary microvascular resistance is not distributed uniformly, but varies across different segments or microdomains of the vasculature. Generally, small arterioles, those less than 100 m in diameter, respond differently than larger arterioles and small arteries. There are major differences in the level of autoregulatory control, myogenic control, endothelial modulation and control by metabolic factors across these various microvascular domains. There are also transmural variations which may account for some of the differences in coronary blood observed between epicardial and endocardial regions. In addition, interactions between these various regulatory mechanisms further complicate the understanding of coronary microvascular regulation. Importantly however, it may be these complex interactions and heterogeneous regulatory mechanisms which allow for adequate perfusion of the myocardium under an extreme range of metabolic conditions. This segmental distribution of regulation suggests an integrative hypothesis of regulation whereby a variety of mechanisms play a role in the overall response.Invited Contributions to the Symposium Regulation of coronary blood flow, held at the XV. World Congress of the International Society for Heart Research in Prague 1995     

Laminar organization of the extraocular muscles of the rabbit.

Studies of bilateral hemispheric somatosensory evoked potentials (SEP) were carried out on 17 comatose patients following closed-head injury. Control evoked potentials were obtained from 74 normal volunteers. A prognosis of potential recovery or nonrecovery from coma was made in all 17 patients based on the SEP analyses. All subjects underwent bilateral median and peroneal nerve stimulation and responses were averaged from scalp electrodes placed over the somatotopic sensory cortex for the wrist and leg. The prognostic outcome of all 17 patients was accurately predicted following SEP analysis. Results show that 4 of 17 patients with prognoses of “positive recovery” had eight defined SEP peaks present within a time base analysis of 300 ms. Twelve patients with prognoses of “negative recovery” had five or less SEP peaks present within a time base of 500 ms. The majority of the “negative recovery” patients showed only SEP primary waveform components consisting of two peaks. The data suggest a potentially useful method using SEP analysis to prognosticate the possible recovery from clinical coma.     

Plasma levels and half lives of thioridazine and some of its metabolites

Summary Plasma-levels of thioridazine, mesoridazine, sulphoridazine and two other metabolites were determined in ten older chronic psychotic patients on thioridazine therapy. The plasma-level before the morning dose of thioridazine was the most reliable parameter for clinical studies. An intra-individual relationship between lower doses of thioridazine and plasma-levels was found. The percentage contribution of psychoactive compounds to the total sum of thioridazine plus metabolites ranged from 43–74%. The mean early disappearance half-life of thioridazine was 5 hours, and its mean late disapperance half-life was 26 hours.     

Metabolic risk factors in patients with ureteropelvic junction obstruction and renal calculi

PURPOSE: We performed a prospective study to determine the incidence and spectrum of metabolic abnormalities predisposing to stone formation in patients with ureteropelvic junction obstruction and renal calculi. MATERIALS AND METHODS: A total of 47 consecutive patients with congenital ureteropelvic junction obstruction underwent metabolic evaluation of stone risk factors. Of these patients 21 had associated stones (study group), while 26 did not (control group). Logistical regression, Wilcoxon rank sum and Fisher's exact tests were performed to determine whether there was a significant difference between these groups in regard to the presence of metabolic risk factors. RESULTS: Demographically and symptomatically the 2 groups were equivalent except that the study patients were older. The 24-hour urinary excretion of calcium was significantly higher in study than in the control patients (p = 0.007). While the incidence of hypercalciuria and hyperuricosuria was also higher in the study population, these differences were not significant (p = 0.08 and 0.07, respectively). CONCLUSIONS: Metabolic abnormalities predisposing to stone formation are present more frequently in patients with ureteropelvic junction obstruction who have associated stones compared to those who do not. As such, urinary stasis alone does not explain stone formation in these cases. Rather, the local physiological environment of urine likely has a predisposing role. In addition to restoring unobstructed urinary flow, consideration should be given to metabolic evaluation and prophylactic treatment for affected patients.     

干休所代谢综合征流行病学调查及生活方式强化干预

目的:调查北京136个军队老年集聚社区居民代谢综合征(m etabolic syndrom e,MS)的患病率及危险因素;探讨生活方式强化干预对MS患者早期治疗及降低危险因素的效果。方法:于2004年5~6月对北京136个以离退休干部为主体的军队社区、2 335名医疗体系属于我院的常住居民通过健康体检后进行MS的筛查和评价;对明确诊断MS患者实施健康教育、饮食和运动等生活方式强化干预。结果:在被调查的2 335人中MS患病率为28.7%,具有4个危险因素者占6.9%。饮食、运动干预后饮食结构趋于合理,中、老年组平均体重指数下降2~4 kg。结论:对MS高危人群进行常规筛查和评价,可促进MS的早期临床诊断;生活方式强化干预可增强老年人维护健康的意识,积极的防治有利于MS的转归及防止并发症的发生及发展。     

Mitochondrial DNA Copy Number Is Associated With Treatment Response and Cognitive Function in Euthymic Bipolar Patients Receiving Valproate

BackgroundBipolar disorder (BD) is associated with cognitive impairment and mitochondrial dysfunction. However, the associations among mitochondrial DNA copy number (MCN), treatment response, and cognitive function remain elusive in BD patients.MethodsSixty euthymic BD patients receiving valproate (VPA) and 66 healthy controls from the community were recruited. The indices of metabolic syndrome (MetS) were measured. Quantitative polymerase chain reaction analysis of blood leukocytes was used to measure the MCN. Cognitive function was measured by calculating perseverative errors and completed categories on the Wisconsin Card Sorting Test (WCST). The VPA treatment response was measured using the Alda scale.ResultsBD patients had significantly higher MCN, triglyceride, and C-reactive protein (CRP) levels, waist circumference, and worse performance on the WCST than the controls. Regression models showed that BD itself and the VPA concentration exerted significant effects on increased MCN levels. Moreover, the receiver operating characteristic curve analysis showed that an MCN of 2.05 distinguished VPA responders from nonresponders, with an area under the curve of 0.705 and a sensitivity and specificity of 0.529 and 0.816, respectively. An MCN level ≥2.05 was associated with 5.39 higher odds of being a VPA responder (P = .006). BD patients who were stratified into the high-MCN group had a higher VPA response rate, better WCST performance, lower CRP level, and less MetS.ConclusionsThe study suggests a link between the peripheral MCN and cognitive function in BD patients. As an inflammatory status, MetS might modulate this association.