Phenomics, lipodystrophy, and the metabolic syndrome

The metabolic syndrome (MetS) is a common multiplex cluster of phenotypes strongly related to cardiovascular disease that includes central obesity with hypertension, dyslipidemia, and type 2 diabetes. The core molecular defect of the MetS is insulin resistance; indeed, the terms "MetS" and "insulin resistance syndrome" often are used interchangeably. The successful translation to clinical medicine of molecular genetic research on other rare monogenic metabolic disorders has stimulated the evaluation of such rare monogenic forms of insulin resistance as partial lipodystrophy resulting from mutations in either LMNA or PPARG genes. Careful phenotypic evaluation of carriers of monogenic insulin resistance using a range of diagnostic methods--an approach sometimes called "phenomics"--may help to find early presymptomatic biomarkers of cardiovascular disease, which, in turn, may uncover new pathways and targets for interventions for the common MetS, diabetes, and atherosclerosis.     

Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome

Fibromyalgia and widespread pain were common in Gulf War veterans with unexplained illness referred to a rheumatology clinic. Increased tenderness was demonstrated in the postmenstrual phase of the cycle compared with the intermenstrual phase in normally cycling women but not in users of oral contraceptives. Patients with fibromyalgia had high levels of symptoms that have been used to define silicone implant-associated syndrome. Tender points were found to be a common transient finding associated with acute infectious mononucleosis, but fibromyalgia was an unusual long-term outcome. The common association of fibromyalgia with other rheumatic and systemic illnesses was further explored. A preliminary study revealed a possible linkage of fibromyalgia to the HLA region. Patients with fibromyalgia were found to have an impaired ability to activate the hypothalamic pituitary portion of the hypothalamic pituitary adrenal axis as well as the sympathoadrenal system, leading to reduced corticotropin and epinephrine response to hypoglycemia. Much interest has been expressed in the literature on the possible role of autonomic dysfunction in the development or exacerbation of fatigue and other symptoms in chronic fatigue syndrome. Mycoplasma genus and mycoplasma fermentans were detected by polymerase chain reaction in patients with chronic fatigue syndrome. It was reported that myofascial temporomandibular disorder does not run in families. No major therapeutic trials in fibromyalgia, chronic fatigue syndrome, or myofascial pain syndrome were reported over the past year. The effectiveness of cognitive behavioral therapy and behavior therapy for chronic pain in adults was emphasized. A favorable outcome of fibromyalgia and chronic fatigue syndrome in children and adolescents was reported.     

Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome

The prevalence of chronic widespread pain in the general population in Israel was comparable with reports from the USA, UK, and Canada. Comorbidity with fibromyalgia (FM) resulted in somatic hyperalgesia in patients with irritable bowel syndrome. One sixth of the subjects with chronic widespread pain in the general population were also found to have a mental disorder. Mechanisms involved in referred pain, temporal summation, muscle hyperalgesia, and muscle pain at rest were attenuated by the N-methyl-D-aspartate (NMDA) antagonist, ketamine, in FM patients. Delayed corticotropin release, after interleukin-6 administration, in FM was shown to be consistent with a defect in hypothalamic corticotropin-releasing hormone neural function. The basal autonomic state of FM patients was characterized by increased sympathetic and decreased parasympathetic systems tones. The severity of functional impairment as assessed by the Medical Outcome Survey Short Form (SF-36) discriminated between patients with widespread pain alone and FM patients. Chronic fatigue syndrome (CFS) occurred in about 0.42% of a random community-based sample of 28,673 adults in Chicago, Illinois. A significant clinical overlap between CFS and FM was reported. Cytokine dysregulation was not found to be a singular or dominant factor in the pathogenesis of CFS. A favorable outcome of CFS in children was reported; two thirds recovered and resumed normal activities. No major therapeutic trials in FM and CFS were reported over the past year.     

Fatty liver, hypertension, and the metabolic syndrome

The prevalence of fatty liver in non-obese non-diabetic hypertensive patients is at least twice that of the general population and may be related to increases in insulin resistance and body weight.     

Bile acids,obesity, and the metabolic syndrome

Bile acids are increasingly recognized as key regulators of systemic metabolism. While bile acids have long been known to play important and direct roles in nutrient absorption, bile acids also serve as signalling molecules. Bile acid interactions with the nuclear hormone receptor farnesoid X receptor (FXR) and the membrane receptor G-protein-coupled bile acid receptor 5 (TGR5) can regulate incretin hormone and fibroblast growth factor 19 (FGF19) secretion, cholesterol metabolism, and systemic energy expenditure. Bile acid levels and distribution are altered in type 2 diabetes and increased following bariatric procedures, in parallel with reduced body weight and improved insulin sensitivity and glycaemic control. Thus, modulation of bile acid levels and signalling, using bile acid binding resins, TGR5 agonists, and FXR agonists, may serve as a potent therapeutic approach for the treatment of obesity, type 2 diabetes, and other components of the metabolic syndrome in humans.     

Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome

There continues to be an emerging body of literature related to fibromyalgia and the related conditions chronic fatigue syndrome and myofascial pain. During the past year, the most notable contributions included a large multicenter study providing new diagnostic criteria for the classification of fibromyalgia and clinical studies describing the overlap of fibromyalgia, chronic fatigue syndrome, and myofascial pain. Pathophysiologic studies were often preliminary and uncontrolled but the focus of these studies on abnormal nociception, neurohormones, and muscle metabolism provides an exciting hypothesis to unify pain, fatigue, and sleep disturbances, the primary symptoms of fibromyalgia. Unfortunately, new therapeutic trials were neither innovative nor especially encouraging.     

Obesity, hypertension and the metabolic syndrome

The prevalence of obesity in both developed and developing countries has increased dramatically in recent years.1Many people who are obese develop metabolic changes that increase the risk of diabetes mellitus and adverse cardiovascular outcomes. Obesity leads to the development of insulin resistance, lipid abnormalities and increased blood pressure.……     

Diet, exercise and the metabolic syndrome

The metabolic syndrome is a combination of metabolic disorders, such as dyslipidemia, hypertension, impaired glucose tolerance, compensatory hyperinsulinemia and the tendency to develop fat around the abdomen. Individuals with the metabolic syndrome are at high risk for atherosclerosis and, consequently, cardiovascular disease. However, as a result of several epidemiologic studies and some clinical trials, it has been suggested that people with the metabolic syndrome may benefit from intensive lifestyle modifications including dietary changes and adopting a physically more active lifestyle. In this review we summarize the effects of diet and physical activity on the development of the metabolic syndrome.     

Hyperuricemia, gout and the metabolic syndrome

PURPOSE OF REVIEW: The metabolic syndrome is defined by the clustering of a number of cardiovascular risk factors and entails an increased risk for cardiovascular disease and mortality from both cardiovascular disease and all causes. In the present paper, we review the most recent evidence on the association between hyperuricemia, metabolic syndrome, and cardiovascular disease. RECENT FINDINGS: Serum urate is frequently elevated in patients with the metabolic syndrome and increases with the number of components of this condition. Hyperuricemia has been related to decreased renal uric acid excretion, which may be mediated by enhanced proximal tubular sodium reabsorption and hyperinsulinemia. Recent epidemiologic studies have shed some light on the prognosis of hyperuricemia. While hyperuricemia appears to show a benign significance in low cardiovascular risk individuals, it clearly increases cardiovascular mortality in patients at high cardiovascular disease risk. SUMMARY: Clinicians should be aware of the presence of metabolic syndrome in patients with hyperuricemia or gout in order to control its components (high blood pressure, obesity, etc.) and hence reduce the risk for cardiovascular disease. Long-term, randomized interventional clinical trials are needed to test the hypothesis that urate-lowering therapy can reduce cardiovascular risk in these patients.     

Kell, Kx and the McLeod syndrome

The antigens of the Kell blood group system are carried on a 93 kDa type II glycoprotein encoded by a single gene on chromosome 7 at 7q33. XK is a 50.9 kDa protein that traverses the membrane ten times and derives from a single gene on the X chromosome at Xp21. A single disulphide bond, Kell Cys 72-XK Cys 347, links Kell to XK. The Kell component of the Kell/XK complex is important in transfusion medicine since it is a highly polymorphic protein, carrying over 23 different antigens, that can cause severe reactions if mismatched blood is transfused and in pregnant mothers antibodies to Kell may elicit serious fetal and neonatal anaemia. The different Kell phenotypes are all caused by base mutations leading to single amino acid substitutions. By contrast the XK component carries a single blood group antigen, termed Kx. The physiological functions of Kell and XK have not been fully elucidated but Kell is a zinc endopeptidase with endothelin-3-converting enzyme activity and XK has the structural characteristics of a membrane transporter. Lack of Kx, the McLeod phenotype, is associated with red cell acanthocytosis, elevated levels of serum creatine phosphokinase and late onset forms of muscular and neurological defects.     

The heart, the brain, and the Kounis syndrome.

In the elegant editorial¹ concerning the recent paper² publishedin EHJ, the authors have asked why the two seemingly unrelatedconditions, namely depression and left ventricular depression,should be related and what mediators or common pathways couldlink the two. They have concluded that as far as the brain andthe heart are