Genetic Abnormalities in FOXP1 Are Associated with Congenital Heart Defects

The etiology for the majority of congenital heart defects (CHD) is unknown. We identified a patient with unbalanced atrioventricular septal defect (AVSD) and hypoplastic left ventricle who harbored an ～0.3 Mb monoallelic deletion on chromosome 3p14.1. The deletion encompassed the first four exons of FOXP1, a gene critical for normal heart development that represses cardiomyocyte proliferation and expression of Nkx2.5. To determine whether FOXP1 mutations are found in patients with CHD, we sequenced FOXP1 in 82 patients with AVSD or hypoplastic left heart syndrome. We discovered two patients who harbored a heterozygous c.1702C>T variant in FOXP1 that predicted a potentially deleterious substitution of a highly conserved proline (p.Pro568Ser). This variant was not found in 287 controls but is present in dbSNP at a 0.2% frequency. The orthologous murine Foxp1 p.Pro596Ser mutant protein displayed deficits in luciferase reporter assays and resulted in increased proliferation and Nkx2.5 expression in cardiomyoblasts. Our data suggest that haploinsufficiency of FOXP1 is associated with human CHD.     

The effect of wrist surgery on the kinematic consistency of joint axis reconstruction in a static posture

Three‐dimensional analysis of wrist motion is a growing focus in orthopedic research, however, our understanding of its validity (accuracy and reliability) remains limited. Nine human cadavers were tested to estimate wrist joint axes alignment in a postural static pose. The objective was to investigate a rater's ability to reliably align three skin‐ tracked wrist joint coordinate system (WJCS) definitions across baseline and reconstructive wrist states (intact, mid‐carpal arthrodesis, and proximal‐row carpectomy). Two WJCSs (legacy, anatomic) were based on palpated bony landmarks and the third (functional) was based on both landmarks and passive flexion‐extension motion. A coordinate frame based on the anatomic definition was tracked with bone pins and served as a reference. Each WJCS was tested in each wrist state and in three forearm position (45° pronation, neutral, 45° supination). The angular offset about each axis of the WJCS frames were calculated with respect to the reference in flexion‐extension, radial‐ulnar deviation, and pronation‐supination for every iteration. Reliability and root mean square deviation values were analyzed across wrist states. Our data suggest that no WJCS is uniformly more reliable than another. The functional WJCS definition was most consistent across intact and post‐operative states for pronation‐supination offset, but this was dependent on rater interpretation. It still however offers the practical benefit of requiring fewer landmarks. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1341–1347, 2015.     

The metabolic syndrome: what to treat, how to treat, what are the goals?

Metabolic syndrome is a cluster of risk factors for cardiovascular disease that include obesity, atherogenic dyslipidemia, raised blood pressure, and insulin resistance. The growing trend of obesity is associated with increased prevalence of metabolic syndrome. Optimizing diet and exercise are still the leading therapy for controlling the metabolic syndrome. Based on the current evidence, further emphasis should be placed on aggressive management of other metabolic risk factors such as high blood pressure and dyslipidemia.     

Indinavir uncovers different contributions of GLUT4 and GLUT1 towards glucose uptake in muscle and fat cells and tissues

AIMS/HYPOTHESIS: Insulin-dependent glucose influx in skeletal muscle and adipocytes is believed to rely largely on GLUT4, but this has not been confirmed directly. We assessed the relative functional contribution of GLUT4 in experimental models of skeletal muscle and adipocytes using the HIV-1 protease inhibitor indinavir. METHODS: Indinavir (up to 100 micro mol/l) was added to the glucose transport solution after insulin stimulation of wild-type L6 muscle cells, L6 cells over-expressing either GLUT4myc or GLUT1myc, 3T3-L1 adipocytes, isolated mouse brown or white adipocytes, and isolated mouse muscle preparations. RESULTS: 100 micro mol/l indinavir inhibited 80% of both basal and insulin-stimulated 2-deoxyglucose uptake in L6GLUT4myc myotubes and myoblasts, but only 25% in L6GLUT1myc cells. Cell-surface density of glucose transporters was not affected. In isolated soleus and extensor digitorum longus muscles, primary white and brown adipocytes, insulin-stimulated glucose uptake was inhibited 70 to 80% by indinavir. The effect of indinavir on glucose uptake was variable in 3T3-L1 adipocytes, averaging 45% and 67% inhibition of basal and maximally insulin-stimulated glucose uptake, respectively. In this cell, fractional inhibition of glucose uptake by indinavir correlated positively with the fold-stimulation of glucose uptake by insulin, and was higher with sub-maximal insulin concentrations. The latter finding coincided with an increase only in GLUT4, but not GLUT1, in plasma membrane lawns. CONCLUSION/INTERPRETATION: Indinavir is a useful tool to assess different functional contributions of GLUT4 to glucose uptake in common models of skeletal muscle and adipocytes.     

Use of continuous subcutaneous insulin infusion pump in patients with type 2 diabetes mellitus

PURPOSE: In patients with type 2 diabetes, the control of hyperglycemia is often difficult despite full doses of oral hypoglycemic agents and extremely large doses of insulin. These patients pose a major management problem. The authors therefore investigated whether insulin given as a subcutaneous continuous infusion of insulin (CSII) would result in an improvement in glucose homeostasis. METHODS: Four patients with badly controlled type 2 diabetes, on treatment with extremely high doses of insulin and oral hypoglycemic agents, were started on CSII. RESULTS: All four patients had a marked improvement in plasma glucose concentrations with a corresponding fall in HbA1c levels. This improvement was associated with a marked fall in the insulin doses necessary to maintain adequate glucose homeostasis. CONCLUSIONS: Since HbA1c levels fell from levels that would be associated with diabetic complications to those at which complications are markedly reduced, we recommend that patients with type 2 diabetes uncontrolled on extremely high doses of insulin be given a trial of treatment with CSII.     

Can Sonography Distinguish a Supraorbital Notch From a Foramen?

Diagnostic tools for evaluating the supraorbital rim in preparation for nerve decompression surgery in patients with chronic headaches are currently limited. We evaluated the use of sonography to diagnose the presence of a supraorbital notch or foramen in 11 cadaver orbits. Sonographic findings were assessed by dissecting cadaver orbits to determine whether a notch or foramen was present. Sonography correctly diagnosed the presence of a supraorbital notch in 7 of 7 cases and correctly diagnosed a supraorbital foramen in 4 of 4 cases. We found that sonography had 100% sensitivity in diagnosing a supraorbital notch and foramen. This tool may therefore be helpful in characterizing the supraorbital rim preoperatively and may influence the decision to use a transpalpebral or endoscopic approach for supraorbital nerve decompression as well as the decision to use local or general anesthesia.     

Cosmetic arm lengthening with monorail fixator

Upper limb length discrepancy is a rare occurrence. Humerus shortening may need specialized treatment to restore the functional and cosmetic status of upper limb. We report a case of humerus lengthening of 9 cm with a monorail external fixator and the result was observed during a 2-year follow-up. Humerus lengthening needs specialized focus as it is not only a cosmetic issue but also a functional demand. The monorail unilateral fixator is more functional and cosmetically acceptable, and thus becomes an effective treatment option.     

Plasma IL-6 and IL-10 Concentrations Predict AKI and Long-Term Mortality in Adults after Cardiac Surgery

Inflammation has an integral role in the pathophysiology of AKI. We investigated the associations of two biomarkers of inflammation, plasma IL-6 and IL-10, with AKI and mortality in adults undergoing cardiac surgery. Patients were enrolled at six academic centers (n=960). AKI was defined as a ≥50% or ≥0.3-mg/dl increase in serum creatinine from baseline. Pre- and postoperative IL-6 and IL-10 concentrations were categorized into tertiles and evaluated for associations with outcomes of in-hospital AKI or postdischarge all-cause mortality at a median of 3 years after surgery. Preoperative concentrations of IL-6 and IL-10 were not significantly associated with AKI or mortality. Elevated first postoperative IL-6 concentration was significantly associated with higher risk of AKI, and the risk increased in a dose-dependent manner (second tertile adjusted odds ratio [OR], 1.61 [95% confidence interval (95% CI), 1.10 to 2.36]; third tertile adjusted OR, 2.13 [95% CI, 1.45 to 3.13]). First postoperative IL-6 concentration was not associated with risk of mortality; however, the second tertile of peak IL-6 concentration was significantly associated with lower risk of mortality (adjusted hazard ratio, 0.75 [95% CI, 0.57 to 0.99]). Elevated first postoperative IL-10 concentration was significantly associated with higher risk of AKI (adjusted OR, 1.57 [95% CI, 1.04 to 2.38]) and lower risk of mortality (adjusted HR, 0.72 [95% CI, 0.56 to 0.93]). There was a significant interaction between the concentration of neutrophil gelatinase-associated lipocalin, an established AKI biomarker, and the association of IL-10 concentration with mortality (P=0.01). These findings suggest plasma IL-6 and IL-10 may serve as biomarkers for perioperative outcomes.     

Diabetes and cancer: two diseases with obesity as a common risk factor

There is a growing body of evidence to support a connection between diabetes (predominantly type 2), obesity and cancer. Multiple meta‐analyses of epidemiological data show that people with diabetes are at increased risk of developing many different types of cancers, along with an increased risk of cancer mortality. Several pathophysiological mechanisms for this relationship have been postulated, including insulin resistance and hyperinsulinaemia, enhanced inflammatory processes, dysregulation of sex hormone production and hyperglycaemia. In addition to these potential mechanisms, a number of common risk factors, including obesity, may be behind the association between diabetes and cancer. Indeed, obesity is associated with an increased risk of cancer and diabetes. Abdominal adiposity has been shown to play a role in creating a systemic pro‐inflammatory environment, which could result in the development of both diabetes and cancer. Here, we examine the relationship between diabetes, obesity and cancer, and investigate the potential underlying causes of increased cancer risk in individuals with diabetes. Current treatment recommendations for reducing the overall disease burden are also explored and possible areas for future research are considered.