Carriers of an inactivating beta-cell ATP-sensitive K(+) channel mutation have normal glucose tolerance and insulin sensitivity and appropriate insulin secretion.

OBJECTIVE: Insulin release from the pancreatic beta-cells is controlled by ATP-sensitive K(+) (K(ATP)) channels, which consist of a hetero-octameric complex of four sulfonylurea receptor 1 (SUR1) and four Kir6.2 proteins. Mutations in the SUR1 gene are the major cause of congenital hyperinsulinemia (CHI). Despite the hereditary nature of CHI, studies of glucose homeostasis in heterozygous relatives of CHI patients are lacking. Theoretically, in the heterozygous state of the SUR1 gene mutation, only 1 of 16 K(ATP) channels consists of entirely normal subunits. The aim of our study was to investigate in vivo the glucose homeostasis of heterozygous SUR1 mutation carriers. RESEARCH DESIGN AND METHODS: We studied 8 parents of CHI patients, all 8 of whom were heterozygous for the inactivating SUR1 mutation V187D, and 10 matched control subjects. We evaluated glucose tolerance and insulin secretory capacity with oral and intravenous glucose tests, rates of whole-body glucose uptake with hyperinsulinemic-euglycemic clamps, C-peptide response to hypoglycemia during hyperinsulinemic-hypoglycemic clamp, and function of the K(ATP) channels with intravenous tolbutamide test. RESULTS: Carriers of the V187D substitution had normal glucose tolerance, normal tissue sensitivity to insulin, and no signs of inappropriate insulin secretion. The normal insulin response to tolbutamide indicated that heterozygosity for the V187D mutation did not impair K(ATP) channel function. CONCLUSIONS: We conclude that the heterozygous carriers of the SUR1 mutation had normal glucose metabolism and insulin secretion, indicating that carriers of recessive K(ATP) channel mutations are unlikely to be at an increased risk of hypoglycemia or other disturbances in glucose metabolism.     

Low levels of leisure-time physical activity and cardiorespiratory fitness predict development of the metabolic syndrome

OBJECTIVE: Little is known about the association of leisure-time physical activity (LTPA) and cardiorespiratory fitness with development of the metabolic syndrome, which predisposes diseases such as diabetes and atherosclerosis. We studied the associations of LTPA and cardiorespiratory fitness with development of the metabolic syndrome (World Health Organization [WHO] and the National Cholesterol Education Program [NCEP] definitions). RESEARCH DESIGN AND METHODS: LTPA over the previous 12 months, VO(2max) (ml. kg(-1). min(-1)), and cardiovascular and metabolic risk factors were assessed in a population-based cohort of 612 middle-aged men without the metabolic syndrome. RESULTS: At the 4-year follow-up, 107 men had metabolic syndrome (WHO definition). Men engaging in >3 h/week of moderate or vigorous LTPA were half as likely as sedentary men to have the metabolic syndrome after adjustment for major confounders (age, BMI, smoking, alcohol, and socioeconomic status) or potentially mediating factors (insulin, glucose, lipids, and blood pressure), especially in high-risk men. Vigorous LTPA had an even stronger inverse association, particularly in unfit men. Men in the upper third of VO(2max) were 75% less likely than unfit men to develop the metabolic syndrome, even after adjustment for major confounders. Adjustment for possible mediating factors attenuated the association. Associations of LTPA and VO(2max) with development of the metabolic syndrome, as defined by the NCEP, were qualitatively similar. CONCLUSIONS: In particular, high-risk men engaging in currently recommended levels of physical activity were less likely to develop the metabolic syndrome than sedentary men. Cardiorespiratory fitness was also strongly protective, although possibly not independent of mediating factors.     

Duodenal secretion of phospholipase A2, amylase, and bicarbonate in chronic pancreatitis

Phospholipase A₂ has been suggested to be involved in the pathogenesis and pathophysiology of acute pancreatitis. We determined phospholipase A₂ and amylase activities in duodenal juice collected during a secretin test from 30 consecutive patients who were suspected to have chronic pancreatitis or biliary disease. The patients underwent endoscopic retrograde cholangiopancreatography (ERCP) the following day. In the 8 patients with ERCP findings of advanced chronic pancreatitis, the mean outputs of phospholipase A₂, amylase, and bicarbonate were reduced by 74%, 72%, and 60% compared to the respective values in the 13 (control) patients without a diagnosis of any pancreatic disorder or jaundice. In the 3 patients with recurrent pancreatitis but normal ERCP findings and in the 6 patients with jaundice the output values were not significantly reduced compared to those in the patients without any pancreatic disorder or jaundice. The outputs of amylase and phospholipase A₂ were not significantly interrelated, whereas the outputs of phospholipase A₂ and bicarbonate correlated well. Receiver characteristic (ROC) curves confirmed the high specificity and sensitivity of phospholipase A₂ or bicarbonate output in patients with ERCP findings of advanced chronic pancreatitis compared to those with no changes in pancreatic ducts, with similar probability values of 0.880 ± 0.111 (SEM), compared to the respective lower value of amylase, 0.676 ± 0.118. Phospholipase A₂ and bicarbonate output proved of equal value as markers of chronic pancreatitis and were superior to amylase output in the secretin test. (Received Mar. 12, 1997; accepted Aug. 22, 1997)     

Proliferation and plasticity of human beta cells on physiologically occurring laminin isoforms

We have previously characterized the molecular composition of human islet basement membranes and shown that human beta cells bind to laminin 511 (LM511) through integrin α3β1 and Lutheran glycoprotein. We have now investigated the impact of physical contact between cultured human beta cells and the laminin isoforms occurring in their natural niche. Human islet preparations derived from 15 donors were used, beta cells and duct cells were purified by magnetic sorting. Overall beta-cell proliferation was low or undetectable. However, in many experiments the only proliferating beta cells were detected in contact with the laminin isoforms that are found in the human islets in vivo (511 and 411). Purified ductal and beta cells underwent epithelial–mesenchymal transition (EMT). LM511 partially blocked this dedifferentiation of purified beta cells, and did not affect purified duct cells. Interactions with the surrounding basement membrane are important for the growth and function of human beta cells. However, only a very limited level of beta-cell proliferation can be induced by exogenous factors. LM511 may be a useful substrate for human beta-cell maintenance in vitro.     

Development and Characterization of Amorphous Thermoplastic Matrix Graphene Nanocomposites

The aim of the present work is the development of amorphous thermoplastic matrix nanocomposites based on graphite nanoparticles. Different types of graphite were used, including unmodified graphite, graphene nanoplatelets and graphite intercalation compounds. Graphite intercalation compounds were subjected to thermal treatment to attain exfoliation of the nanofiller. The exfoliation process was studied by means of thermal analysis. The nanofillers and nanocomposites were characterized by means of X-ray Diffraction (XRD) and Scanning Electron Microscope (SEM) analysis. The nanocomposites were further characterized by means of mechanical and dielectric analysis. The flammability of the nanocomposites was also analyzed. Results obtained indicate that addition of the nanofiller allows improving the proprieties of the amorphous thermoplastic matrix. The effect of the degree of dispersion of the nanofiller is particularly relevant for the dielectric properties of the nanocomposites, whereas no direct correlation between degree of dispersion and mechanical properties can be observed.     

CDT by Anion-Exchange Chromatography Followed by RIA as a Marker of Heavy Drinking Among Men

Carbohydrate-deficient transferrin, CDT, had previously been reported to be an excellent marker for alcoholism. The present population-based study examined the diagnostic value of CDT among consecutive middle-aged males including 122 social drinkers (mean alcohol consumption 88 ± 79 g per week) and 77 non-alcoholic heavy drinkers (301 ± 195 g/wk). Ninety-six men with a well-documented history of chronic alcoholism (≥1000 g/wk) were used as a reference group. The CDT (containing mainly isotransferrin with pl = 5.8 and 5.9) was separated by anion exchange chromatography and assayed by RIA. The CDT values of social drinkers (mean ± SD = 14 ± 5 U/I) were significantly lower than those of heavy drinkers (19 ± 13 U/I, p < 0.01) and alcoholics (34 ± 18 U/I, p < 0.001). In the whole material CDT correlated positively with alcohol consumption ( r = 0.53, p < 0.001). At a specificity of 91.8%, CDT found 28.6% of the heavy drinkers and 79.2% of the alcoholics; the best traditional marker, GGT, with a specificity of 86.9%, found 35.1% and 64.6%, respectively. In conclusion, CDT is a specific marker, which is superior to traditional markers for identifying alcoholics. Unfortunately, it does not seem to provide additional power for identifying the important group, non-alcoholic heavy drinkers.     

The macrophage scavenger receptor CD163 functions as an innate immune sensor for bacteria

The plasma membrane glycoprotein receptor CD163 is a member of the scavenger receptor cystein-rich (SRCR) superfamily class B that is highly expressed on resident tissue macrophages in vivo. Previously, the molecule has been shown to act as a receptor for hemoglobin-haptoglobin complexes and to mediate cell-cell interactions between macrophages and developing erythroblasts in erythroblastic islands. Here, we provide evidence for a potential role for CD163 in host defense. In particular, we demonstrate that CD163 can function as a macrophage receptor for bacteria. CD163 was shown to bind both Gram-positive and -negative bacteria, and a previously identified cell-binding motif in the second scavenger domain of CD163 was sufficient to mediate this binding. Expression of CD163 in monocytic cells promoted bacteria-induced proinflammatory cytokine production. Finally, newly generated antagonistic antibodies against CD163 were able to potently inhibit cytokine production elicited by bacteria in freshly isolated human monocytes. These findings identify CD163 as a macrophage receptor for bacteria and suggest that, during bacterial infection, CD163 on resident tissue macrophages acts as an innate immune sensor and inducer of local inflammation.     

Pharyngocutaneous fistula following total laryngectomy: a single institution’s 10-year experience

The etiology of postoperative pharyngocutaneous fistula (PCF) formation following major head and neck surgery is multifactorial and the incidence varies greatly. We reviewed retrospectively the records of 108 consecutive patients who underwent a total laryngectomy during the period from December 1992 to December 2002 at the Helsinki University Central Hospital, Helsinki, Finland. PCF occurred postoperatively in 19 (18%) patients. Two additional patients (2%) developed a PCF later than 30 days after laryngectomy. Nineteen percent of these patients with fistula formation had received previous radiation therapy and laryngectomy was performed for local recurrence. Eighteen (86%) of the all fistulae closed spontaneously and surgical closure of the fistula was performed in three (14%) cases. We conclude that the PCFs in our patient population occurred both in radiated and nonirradiated patients. Although most fistulae close spontaneously without surgical intervention this complication leads to prolonged hospitalization and increased patient morbidity.This paper has been presented at the American Laryngological Association Annual Meeting, Phoenix, Arizona, April 30–May 1, 2004.     

Blood Pressure Profiles 5 to 10 Years After Transplant in Pediatric Solid Organ Recipients

Arterial hypertension is a major risk factor for cardiovascular disease after solid organ transplantation, emphasizing the need for blood pressure (BP) monitoring. The authors studied 24‐hour ambulatory BP monitoring (ABPM) parameters (index, load, dipping) and their predictive value with regard to hypertension as well as correlations with graft function and metabolic parameters such as obesity and dyslipidemias. The ABPM profiles of 111 renal, 29 heart, and 13 liver transplant recipients were retrospectively analyzed 5 to 10 years after transplant (median 5.1 years). The BP profiles among the different transplant groups were similar. The BP index and load were abnormal especially at nighttime and the nocturnal BP dipping was often blunted (in 49% to 83% of the patients). The BP variables were found to be equally valued when assessing hypertension. BP load of 50% instead of 25% seems to be a more adequate cutoff value. The BP variables correlated poorly with the metabolic parameters and kidney function. Antihypertensive medication did not notably change the ABPM profile in renal transplant recipients. Hypertension, including nocturnal hypertension, is present in children receiving solid organ transplant, underlining the importance of use of ABPM in the follow‐up of these patients.     

First case report of exacerbated ulcerative colitis after anti-interleukin-6R salvage therapy

We present the case of a 53-year-old woman with long-standing ulcerative colitis and severe, steroid-dependent disease course unresponsive to treatment with azathioprine, methotrexate, anti-TNF antibodies (infliximab, adalimumab) and tacrolimus, who refused colectomy as a therapeutic option. As the pro-inflammatory cytokine interleukin-6 (IL-6) had been identified as a crucial regulator in the immunopathogenesis of inflammatory bowel diseases, we treated the patient with biweekly intravenous infusions of an anti-IL-6R antibody (tocilizumab) for 12 wk. However, no clinical improvement of disease activity was noted. In fact, endoscopic, histological and endomicroscopic assessment demonstrated exacerbation of mucosal inflammation and ulcer formation upon anti-IL-6R therapy. Mechanistic studies revealed that tocilizumab treatment failed to suppress intestinal IL-6 production, impaired epithelial barrier function and induced production of pro-inflammatory cytokines such as TNF, IL-21 and IFN-γ. Inhibition of IL-6 by tocilizumab had no clinical benefit in this patient with intractable ulcerative colitis and even led to exacerbation of mucosal inflammation. Our findings suggest that anti-IL-6R antibody therapy may lead to aggravation of anti-TNF resistant ulcerative colitis. When targeting IL-6, the differential responsiveness of target cells has to be taken into account, as IL-6 on the one side promotes acute and chronic mucosal inflammation via soluble IL-6R signaling but on the other side also strongly contributes to epithelial cell survival via membrane bound IL-6R signaling.