Subliminal and supraliminal processing of reward-related stimuli in anorexia nervosa.

BACKGROUND: Previous studies have highlighted the role of the brain reward and cognitive control systems in the etiology of anorexia nervosa (AN). In an attempt to disentangle the relative contribution of these systems to the disorder, we used functional magnetic resonance imaging (fMRI) to investigate hemodynamic responses to reward-related stimuli presented both subliminally and supraliminally in acutely underweight AN patients and age-matched healthy controls (HC). METHODS: fMRI data were collected from a total of 35 AN patients and 35 HC, while they passively viewed subliminally and supraliminally presented streams of food, positive social, and neutral stimuli. Activation patterns of the group × stimulation condition × stimulus type interaction were interrogated to investigate potential group differences in processing different stimulus types under the two stimulation conditions. Moreover, changes in functional connectivity were investigated using generalized psychophysiological interaction analysis. RESULTS: AN patients showed a generally increased response to supraliminally presented stimuli in the inferior frontal junction (IFJ), but no alterations within the reward system. Increased activation during supraliminal stimulation with food stimuli was observed in the AN group in visual regions including superior occipital gyrus and the fusiform gyrus/parahippocampal gyrus. No group difference was found with respect to the subliminal stimulation condition and functional connectivity. CONCLUSION: Increased IFJ activation in AN during supraliminal stimulation may indicate hyperactive cognitive control, which resonates with clinical presentation of excessive self-control in AN patients. Increased activation to food stimuli in visual regions may be interpreted in light of an attentional food bias in AN.

Decreased adiponectin links elevated adipose tissue autophagy with adipocyte endocrine dysfunction in obesity.

BACKGROUND/OBJECTIVES: Adipose tissue (AT) autophagy gene expression is elevated in human obesity, correlating with increased metabolic risk, but mechanistic links between the two remain unclear. Thus, the objective of this study was to assess whether elevated autophagy may cause AT endocrine dysfunction, emphasizing the putative role of adiponectin in fat-liver endocrine communication. SUBJECTS/METHODS: We utilized a large (N=186) human AT biobank to assess clinical associations between human visceral AT autophagy genes, adiponectin and leptin, by multivariate models. A broader view of adipocytokines association with elevated autophagy was assessed using adipocytokine array. Finally, to establish causality, ex vivo studies utilizing a murine AT-hepatocyte cell line co-culture system was used. RESULTS: Circulating high-molecular-weight adiponectin and leptin levels were associated with human omental-AT expression of ATG5 mRNA, associations that remained significant (ß=-0.197, P=0.011; ß=0.267, P<0.001, respectively) in a multivariate model adjusted for age, sex, body mass index and interleukin-6 (IL-6). A similar association was observed with omental-AT LC3A mRNA levels. Bafilomycin-A1 (Baf A) pretreatment of AT explants from high-fat-fed (HFF) mice had no effect on the secretion of some AT-derived endocrine factors, but partially or fully reversed obesity-related changes in secretion of a subset of adipocytokines by >30%, including the obesity-associated upregulation of IL-6, vascular endothelial growth factor, tumor necrosis factor alpha (TNFα) and certain insulin-like growth factor-binding proteins, and the HFF-induced downregulated secretion of IL-10 and adiponectin. Similarly, decreased adiponectin and increased leptin secretion from cultured adipocytes stimulated with TNFα+IL-1ß was partially reversed by small interfering RNA-mediated knockdown of ATG7. AT explants from HFF mice co-cultured with Hepa1c hepatoma cells impaired insulin-induced Akt and GSK3 phosphorylation. This effect was significantly reversed by pretreating explants with Baf A, but not if adiponectin was immunodepleted from the conditioned media. CONCLUSIONS: Reduced secretion of adiponectin may link obesity-associated elevated AT autophagy/lysosomal activity with adipose endocrine dysfunction.

Temporal delay discounting in acutely ill and weight-recovered patients with anorexia nervosa.

BACKGROUND: Patients with anorexia nervosa (AN) are characterized by a very low body weight but readily give up immediate rewards (food) for long-term goals (slim figure), which might indicate an unusual level of self-control. This everyday clinical observation may be quantifiable in the framework of the anticipation-discounting dilemma. METHOD: Using a cross-sectional design, this study compared the capacity to delay reward in 34 patients suffering from acute AN (acAN), 33 weight-recovered AN patients (recAN) and 54 healthy controls. We also used a longitudinal study to reassess 21 acAN patients after short-term weight restoration. A validated intertemporal choice task and a hyperbolic model were used to estimate temporal discounting rates. RESULTS: Confirming the validity of the task used, decreased delay discounting was associated with age and low self-reported impulsivity. However, no group differences in key measures of temporal discounting of monetary rewards were found. CONCLUSIONS: Increased cognitive control, which has been suggested as a key characteristic of AN, does not seem to extend the capacity to wait for delayed monetary rewards. Differences between our study and the only previous study reporting decreased delay discounting in adult AN patients may be explained by the different age range and chronicity of acute patients, but the fact that weight recovery was not associated with changes in discount rates suggests that discounting behavior is not a trait marker in AN. Future studies using paradigms with disorder-specific stimuli may help to clarify the role of delay discounting in AN.

Hidradenitis suppurativa and metabolic syndrome: a comparative cross-sectional study of 3207 patients.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic relapsing inflammatory skin disease. OBJECTIVES: To evaluate the association between HS and metabolic syndrome and its component morbidities in a large, community-based cohort of patients with HS, using the database of Clalit Health Services, the largest public healthcare provider in Israel. METHODS: A cross-sectional study was performed. Metabolic syndrome was defined as the presence of at least three of the following conditions: diabetes, hyperlipidaemia, hypertension and obesity. The association between HS and metabolic syndrome was assessed by a multivariate logistic regression model, adjusting for age, sex, diabetes, hypertension, hyperlipidaemia, obesity and smoking status. RESULTS: The study included 3207 patients with HS (general frequency of 0·07%) diagnosed by a dermatologist in primary-care centres, and 6412 age- and sex-matched control patients without HS. HS was significantly associated with metabolic syndrome [odds ratio (OR) 1·61, 95% confidence interval (CI) 1·36-1·89], diabetes (OR 1·41, 95% CI 1·19-1·66), obesity (OR 1·71, 95% CI 1·53-1·91), hyperlipidaemia (OR 1·14, 95% CI 1·02-1·28) and hypertension (OR 1·19, 95% CI 1·03-1·38). CONCLUSIONS: We found an association between HS and diabetes, hyperlipidaemia, obesity, hypertension and metabolic syndrome among a large community-based cohort of patients with HS. Clinicians should take into account that patients with HS may have one or more undiagnosed components of metabolic syndrome despite their young age. Thus, appropriate targeted screening is advised.

The incidence of hypoglycaemia in Muslim patients with type 2 diabetes treated with sitagliptin or a sulphonylurea during Ramadan: a randomised trial.

AIMS: To compare the incidence of symptomatic hypoglycaemia in fasting Muslim patients with type 2 diabetes treated with sitagliptin or a sulphonylurea during Ramadan. METHODS: Patients with type 2 diabetes (age ≥ 18 years) who were treated with a stable dose of a sulphonylurea with or without metformin for at least 3 months prior to screening, who had an HbA(1c) < 10% and who expressed their intention to daytime fast during Ramadan were eligible for this open-label study. Patients were randomised in a 1 : 1 ratio to either switch to sitagliptin 100 mg qd or to remain on their prestudy sulphonylurea. Patients completed daily diary cards to document information on hypoglycaemic symptoms and complications. The primary end-point was the overall incidence of symptomatic hypoglycaemia recorded during Ramadan. RESULTS: Of the 1066 patients randomised, 1021 (n = 507 for sitagliptin and n = 514 for sulphonylurea) returned at least one completed diary card and were included in the analysis. The proportion of patients who recorded one or more symptomatic hypoglycaemic events during Ramadan was lower in the sitagliptin group (6.7%) compared with the sulphonylurea group (13.2%). The risk of symptomatic hypoglycaemia was significantly decreased with sitagliptin relative to sulphonylurea treatment (Mantel-Haenszel relative risk ratio [95% CI] = 0.51 [0.34, 0.75]; p < 0.001). There were no reported events that required medical assistance (i.e. visits to physician or emergency room or hospitalisations) or were considered severe (i.e. events that caused loss of consciousness, seizure, coma or physical injury) during Ramadan. CONCLUSIONS: In Muslim patients with type 2 diabetes who observed the fast during Ramadan, switching to a sitagliptin-based regimen decreased the risk of hypoglycaemia compared with remaining on a sulphonylurea-based regimen. The incidence of hypoglycaemia was lower with gliclazide relative to the other sulphonylurea agents and similar to that observed with sitagliptin.

Depressive symptoms and risk for malnutrition among hospitalized elderly people.

OBJECTIVES: To explore the association between depressive symptoms and risk for malnutrition in hospitalized elderly people. METHODS: 195 hospitalized medical patients older than 65 years of age were studied in a cross-sectional design. Depression was assessed by 30-item Geriatric Depression Scale (GDS), nutritional status was evaluated by the Mini-Nutritional Assessment (MNA). Eating and digestive problems were assessed using selected items of Nutrition Risk Index (NRI), cognitive and functional status by Folstein and Barthel indices respectively; demographic data, diagnoses and medications were obtained from medical records. RESULTS: The prevalence of depression in the studied population was 28%. MNA scores were significantly lower among depressed patients as compared with non-depressed (22.86 vs. 24.96, p < 0.001), indicating a higher risk for undernutrition among depressed persons. After controlling for age, cognitive status, functional ability, and number of illnesses, undernutrition was significantly associated with depression (OR = 2.23; 95% CI: 1.04-4.8). CONCLUSIONS: Nutritional risk is associated with depression in aged inpatients. Close case management of the elderly hospitalized patients that include assessment and treatment for both disorders may be beneficial.

Increased red cell aggregation is correlated with HbA1C and lipid levels in type 1 but not type 2 diabetes.

The present study was designed to study RBC aggregability in type 1 and type 2 DM by a new method based on the dielectric properties of disperse systems. This dielectric method has a significantly higher sensitivity to detect enhanced RBC aggregation in DM than other methods. Aggregability is increased in type 1 DM and even more markedly in type 2 diabetic patients. The enhanced RBC aggregation in type 1 diabetes was significantly correlated with the levels of HbA(1C), cholesterol and triglycerides. However, no correlation between metabolic control and RBC aggregability was found in type 2 DM. The in vitro addition of non-toxic, low molecular weight dextran improves the high RBC aggregation in diabetes type 2. In the future, low molecular weight dextran may be used in DM patients clinically to lower the risk for vascular complications, after the problem of filtration is solved.

[Trends and characteristics of diabetes-related lower limb amputations in the Negev, 1996-1999].

BACKGROUND: The loss of a lower limb because of diabetic foot problems such as infections is an important complication of diabetes mellitus. The goals of this study were: (1) to examine trends in incidence of diabetic-related lower limb amputations in the Negev, (2) to describe the clinical characteristics of patients who underwent amputations in the Soroka University Medical Center and (3) to estimate in-hospital mortality and its predictors. METHODS: This study included all diabetic patients who underwent non-traumatic lower limb amputation in the Soroka Hospital during the period 1996-1999. The computerized hospitalization files and surgery logs during the study period were reviewed for ICD-9 diagnoses of diabetes and amputations. For each patient, hospitalization records were abstracted and data on socio-demographic and clinical characteristics were collected. RESULTS: During the study period 411 amputations were performed on 250 diabetic patients (1.6 amputation/person). The estimated mean annual incidence rate of lower limb amputations in the Negev was 5 per 1000 diabetic patients, 27.3 per 100,000 total population, and 45 per 100,000 adults above 18 years of age. The mean age was 68 (SD +/- 11.4) years. The most frequent types of surgery were standard below-knee amputation. Fourteen percent of patients died during hospitalization. Systolic blood pressure, white blood count and serum creatinine at admission were independent predictors of in-hospital mortality. CONCLUSIONS: The incidence of lower limb amputation in the Negev is similar to that reported in other countries. Interventions directed to early detection of diabetic foot problems may have an impact on the reduction of lower limb amputations and related mortality.

The HIV protease inhibitor nelfinavir induces insulin resistance and increases basal lipolysis in 3T3-L1 adipocytes.

HIV protease inhibitors (HPIs) are potent antiretroviral agents clinically used in the management of HIV infection. Recently, HPI therapy has been linked to the development of a metabolic syndrome in which adipocyte insulin resistance appears to play a major role. In this study, we assessed the effect of nelfinavir on glucose uptake and lipolysis in differentiated 3T3-L1 adipocytes. An 18-h exposure to nelfinavir resulted in an impaired insulin-stimulated glucose uptake and activation of basal lipolysis. Impaired insulin stimulation of glucose up take occurred at nelfinavir concentrations >10 micromol/l (EC(50) = 20 micromol/l) and could be attributed to impaired GLUT4 translocation. Basal glycerol and free fatty acid (FFA) release were significantly enhanced with as low as 5 micromol/l nelfinavir, displaying fivefold stimulation of FFA release at 10 micromol/l. Yet, the antilipolytic action of insulin was preserved at this concentration. Potential underlying mechanisms for these metabolic effects included both impaired insulin stimulation of protein kinase B Ser 473 phosphorylation with preserved insulin receptor substrate tyrosine phosphorylation and decreased expression of the lipolysis regulator perilipin. Troglitazone pre- and cotreatment with nelfinavir partly protected the cells from the increase in basal lipolysis, but it had no effect on the impairment in insulin-stimulated glucose uptake induced by this HPI. This study demonstrates that nelfinavir induces insulin resistance and activates basal lipolysis in differentiated 3T3-L1 adipocytes, providing potential cellular mechanisms that may contribute to altered adipocyte metabolism in treated HIV patients.

Evidence for a clinically important adverse effect of fiber-enriched diet on the bioavailability of levothyroxine in adult hypothyroid patients.

To evaluate the effect of dietary fiber supplements on levothyroxine (T4) bioavailability in hypothyroid patients, dietary fiber-containing supplementation was withheld from patients requiring disproportionately high doses of T4, in whom a dietary history revealed ingestion of a dietary fiber supplement. The dose of T4 was maintained at a constant level. Serum thyrotropin (TSH) was assessed before and after removal of the dietary fiber supplements. T4 requirements, reflected by either decreased serum TSH or by decreased T4 dose, was observed in conjunction with decreased dietary fiber intake compared with T4 requirement during increased dietary fiber intake. In vitro experiments carried out to determine the mechanism of interaction between dietary fiber and T4 revealed dose dependent, nonspecific adsorption of levothyroxine by wheat bran. These results indicate a decrease in T4 bioavailability by dietary fiber through a mechanism involving nonspecific adsorption of T4 to dietary fibers. Increased intake of dietary fiber may account for the need for larger than expected doses of T4 in some hypothyroid patients.

The patient with unstable angina: no evidence of MI.

A 53-year-old type 2 diabetic woman with macrovascular complications as well as the components of the metabolic syndrome presents with an unstable angina and ST depression on electromiogram. The negative impact of female gender, microvascular complications, and metabolic parameters on cardiovascular risk and prognosis, are emphasized. The lack of evidence for hormone replacement, antioxidant or universal folic acid therapy is underscored. Treatment options including PTCA and stenting augmented with low molecular weight heparin, clopidrogel and IIb/IIIa antagonists as well as optimal metabolic control are discussed.

[Prevalence of fibromyalgia in type 2 diabetes mellitus].

This study aimed to assess the prevalence of fibromyalgia and other pain characteristics among patients with type 2 diabetes mellitus. We assessed 137 patients with type 2 diabetes mellitus and a control group of 139 patients matched for age and sex that do not suffer from diabetes mellitus. We examined 9 of 18 typical tender points and 4 control points with a dolorimeter. There was no difference in the prevalence of fibromyalgia among men in both groups. However, diabetic men had more tender points than men in the control group and their threshold for pain at the corresponding tender points was significantly lower compared to that of the men in the control group. The diabetic men also reported more pain than patients in the control group. Diabetic women, on the other hand, had a significantly higher prevalence of fibromyalgia than women in the control group: 23.3% versus 10.6% respectively (p = 0.043). There was no significant difference in the number of tender points and the pain threshold in the two groups of women. Diabetic women reported more pain than the women in the control group. In both diabetic men and women the number of tender points and dolorimeter count directly correlated with the duration of diabetes.