Beta2-adrenoceptor polymorphisms relate to insulin resistance and sympathetic overactivity as early markers of metabolic disease in nonobese, normotensive individuals

BACKGROUND: The genes responsible for insulin resistance are also candidate genes for insulin resistance-related diseases, such as obesity and hypertension. Functional polymorphisms in the beta2- and beta3-adrenergic receptors have been reported to be associated with diabetes, hypertension, and obesity. To clarify the relevance of the beta-adrenergic receptor polymorphisms to insulin resistance, we studied their association with polymorphisms of beta2 (Arg16Gly, Gln27Glu) and beta3 (Trp64Arg) adrenoceptor genes. METHODS: We studied 155 young, nonobese Japanese men using the homeostasis model assessment of insulin resistance (HOMA-IR) to divide individuals into insulin-sensitive and insulin-resistant groups. Insulin resistance in the participants was defined as HOMA-IR equal to or greater than the average plus 1 SD of 3.1. There were 69 men who were insulin resistant and 86 men who were insulin sensitive. Body mass index (BMI), blood pressure (BP), plasma glucose, insulin, leptin, norepinephrine (NE) levels, and the polymorphisms of Arg16Gly and Gln27Glu of the beta2- and Trp64Arg of the beta3-adrenoceptor polymorphisms were measured in all participants. RESULTS: The insulin-resistant group had higher frequency of the Gly16 allele of Arg16Gly compared with the insulin-sensitive group, whereas the frequencies of genotypes or alleles of Gln27Glu and Trp64Arg were similar. The insulin-resistant group had a higher mean HOMA-IR, fasting insulin, NE, and total fat mass compared with levels in the insulin-sensitive group, but the BMI and leptin levels were similar. The subjects carrying the Gly16 allele of the beta2-adrenoceptor gene had a higher mean HOMA-IR, fasting insulin, NE, body fat mass, and BP than those without the Gly16 allele. CONCLUSIONS: The Gly16 mutation of the beta2-adrenoceptor gene is associated with increased insulin resistance, adiposity, and BP accompanied by higher plasma NE levels early in the metabolic disease in developing obesity. These findings show an important role of beta2-adrenoceptor gene polymorphisms in the association of insulin resistance in hypertension and obesity.     

Investigating the Linear Thermal Expansion of Additively Manufactured Multi-Material Joining between Invar and Steel

This work investigated the linear thermal expansion properties of a multi-material specimen fabricated with Invar M93 and A36 steel. A sequence of tests was performed to investigate the viability of additively manufactured Invar M93 for lowering the coefficient of thermal expansion (CTE) in multi-material part tooling. Invar beads were additively manufactured on a steel base plate using a fiber laser system, and samples were taken from the steel, Invar, and the interface between the two materials. The CTE of the samples was measured between 40 °C and 150 °C using a thermomechanical analyzer, and the elemental composition was studied with energy dispersive X-ray spectroscopy. The CTE of samples taken from the steel and the interface remained comparable to that of A36 steel; however, deviations between the thermal expansion values were prevalent due to element diffusion in and around the heat-affected zone. The CTEs measured from the Invar bead were lower than those from the other sections with the largest and smallest thermal expansion values being 10.40 μm/m-K and 2.09 μm/m-K. In each of the sections, the largest CTE was measured from samples taken from the end of the weld beads. An additional test was performed to measure the aggregate expansion of multi-material tools. Invar beads were welded on an A36 steel plate. The invar was machined, and the sample was heated in an oven from 40 °C and 160 °C. Strain gauges were placed on the surface of the part and were used to analyze how the combined thermal expansions of the invar and steel would affect the thermal expansion on the surface of a tool. There were small deviations between the expansion values measured by gauges placed in different orientations, and the elongation of the sample was greatest along the dimension containing a larger percentage of steel. On average, the expansion of the machined Invar surface was 42% less than the expansion of the steel surface. The results of this work demonstrate that additively manufactured Invar can be utilized to decrease the CTE for multi-material part tooling.     

Effect of naloxone on maximal exercise performance and control of ventilation in COPD

Elevated endorphin levels in patients with COPD may act to diminish the sensation of dyspnea. Exogenous opioids decrease exertional dyspnea and increase exercise capacity in COPD patients. The purpose of this study was to determine the effects of endogenous opioids on the exercise capacity and control of breathing in patients with COPD. We hypothesized that naloxone, an opioid antagonist, would block the endogenous endorphins and decrease the exercise capacity of our patients. Six patients (mean age, 58.8 +/- 3.2 years) with COPD (mean FEV1, 1.28 +/- 0.46 L) underwent identical incremental cycle ergometer tests to exhaustion (Emax) and assessment of their hypercapnic and hypoxic ventilatory responses and mouth occlusion pressure responses following the IV administration of naloxone (0.4 mg/kg) (N) or placebo (P) in a randomized, double-blind fashion. Perceived dyspnea (modified Borg scale), breathing patterns, and expired gas levels were compared at rest and at maximal workload (WL). There was no significant difference after N compared with after P in the WL or the duration of work. At Emax there were no significant differences after N compared with after P in ventilation, the level of dyspnea, P0.1, VO2, or VCO2. The ventilatory response to CO2 production during exercise (delta VE/delta VCO2) and the ventilatory and mouth occlusion pressure responses to hypoxia and hypercapnia did not differ significantly after N compared with after P. This study does not support the hypothesis that endogenous opioids play a significant role in dampening dyspnea and facilitating exercise in patients with COPD.     

Age-associated changes in elastin and collagen content and the proportion of types I and III collagen in the lungs of mice.

We investigated the effect of aging on the extracellular matrix of the lungs by examining age-associated changes in the elastin and collagen content, and the proportion of types I and III collagen, in the whole lungs of BALB/c and SAMR1 male mice between the ages of 3 and 24 months. The elastin content was determined by the hot alkali method. The hydroxyproline content was measured and assessed to be the collagen content. The relative proportion of types I and III collagen was assessed by cyanogen bromide digestion, followed by separation of the resultant peptides by sodium dodecyl sulfate polyacrylamide gel electrophoresis. The elastin content did not change significantly with age in either strain of mice. The total collagen content of the whole lung was significantly higher at 24 months of age, although there were no significant changes with aging in the hydroxyproline content per dry lung weight nor in the proportion of type III to type I collagen. We conclude that in terms of the extracellular matrix, the lungs of aged mice are not very different in feature from the lungs of younger mice, and this is probably the simple consequence of growth of the lungs of young mice.     

Acute pancreatitis-onset carcinoma in situ of the pancreas with focal fat replacement diagnosed using serial pancreatic-juice aspiration cytologic examination (SPACE)

A 59-year-old woman was admitted for acute pancreatitis. Abdominal computed tomography and magnetic resonance imaging revealed a swollen pancreatic parenchyma with dilatation of the main pancreatic duct (MPD) of the pancreas tail, which was separated from the normal pancreas body side by a locally atrophic part of the pancreas. Magnetic resonance cholangiopancreatography showed MPD stricture in the pancreas tail with dilatation of the upstream MPD. Endoscopic ultrasonography revealed that the MPD stricture of the pancreas tail was surrounded by a blurred and hypoechoic area. Endoscopic retrograde cholangiopancreatography was performed for serial pancreatic-juice aspiration cytologic examination (SPACE). The result indicated adenocarcinoma. Distal pancreatectomy was performed, and the histopathological examination showed high-grade PanIN (carcinoma in situ of the pancreatic duct) of the pancreas tail with atrophy and fibrosis of the pancreatic parenchyma, and local fat replacement adjacent to the lesion. The final histopathological diagnosis was carcinoma in situ of the pancreatic duct of the pancreas tail. Acute pancreatitis and local fatty change of the pancreatic parenchyma with MPD stricture are important clinical manifestations of pancreatic carcinoma in situ (PCIS) and performing SPACE in cases of MPD stricture without a recognizable mass is preferable for a diagnosis of PCIS.     

Exercise-induced abnormal blood pressure responses are related to subendocardial ischemia in hypertrophic cardiomyopathy

Objectives. We examined by thallium-201 scintigraphy whether exercise-induced abnormal blood pressure response (BPR) is related to myocardial ischemia.

Background. Hemodynamic instabilities during exercise in patients with hypertrophic cardiomyopathy (HCM) are considered to be caused by abnormal reflex control of vascular resistance.

Methods. In 105 patients with HCM, exercise thallium scintigraphy was performed by means of a multistage, symptom-limited bicycle ergometer exercise test.

Results. Eighty-eight patients had normal BPR (≥25 mm Hg from baseline to peak exercise), and 17 had abnormal BPR (<25 mm Hg). Clinical characteristics including age, the prevalence of obstruction, New York Heart Association functional class and echocardiographic measurements were similar between the two groups. Left ventricular end-diastolic pressure was significantly higher in patients with abnormal BPR than in those with normal BPR (18 ± 8 vs. 14 ± 5 mm Hg, p < 0.05). Exercise-induced perfusion abnormalities including fixed and reversible perfusion defects, and left ventricular cavity dilatation (LVCD) were identified in 72 (69%) of 105 study patients. Left ventricular cavity dilatation indicates subendocardial hypoperfusion and is a marker of diffuse subendocardial ischemia. The prevalence of fixed or reversible perfusion defects was similar between the two groups. Patients with abnormal BPR had the higher prevalence of LVCD as compared to those with normal BPR (47.1 vs. 10%, p < 0.0002). Multiple logistic regression analysis revealed that LVCD was independently associated with abnormal BPR (odds ratio 3.76, 95% confidence interval 1.61 to 8.76).

Conclusions. Exercise-induced abnormal BPRs in patients with HCM are related to subendocardial ischemia during exercise.     

Peri-diaphragmatic lung volume assessed by computed tomography correlates with quality of life in patients with chronic obstructive pulmonary disease

Background and objective: Health-related quality of life (HRQoL) is important in the management of chronic obstructive pulmonary disease (COPD). In patients with emphysema, lung hyperinflation identified radiologically as shortening and flattening of the diaphragm is associated with impaired HRQoL. It remains unclear whether shortening of the diaphragm and/or alteration in chest wall shape are associated with reduced pulmonary function and HRQoL. Methods: Pulmonary function testing and chest computed tomography (CT) were performed, and the St. George's Respiratory Questionnaire (SGRQ) was administered to 123 patients with COPD. Using CT images, the ratio of volume of lung region adjacent to the diaphragm dome to total lung volume (DLV%) was evaluated as a novel CT index, and conventional indices, including percent low attenuation volume (LAV%), wall area percent (WA%), total lung volume and diaphragm length (Ldi) were calculated. Results: DLV% was significantly correlated with Ldi. DLV% and Ldi were inversely correlated with lung hyperinflation, assessed as the ratio of residual volume to total lung capacity, independent of LAV% and WA%. Unlike Ldi, DLV% was inversely associated with all components and total scores for the SGRQ, independent of the severity of emphysema and airflow limitation. Conclusions: Reduced lung volume around the diaphragm correlated with lung hyperinflation and HRQoL, independent of emphysema severity. This needs to be verified in additional studies.     

The effects of dietary weight loss with or without exercise training on liver enzymes in obese metabolic syndrome subjects

Aim: Insulin resistance and visceral adiposity are predisposing factors for fatty liver disease. The main objectives of this study were (i) to compare the effects of caloric restriction (CR) alone or together with moderate‐intensity aerobic exercise training (CR+EX) on liver enzymes, a surrogate marker of liver injury, in obese metabolic syndrome (MetS) subjects and (ii) to identify anthropometric, metabolic, cardiovascular and dietary predictors of changes in liver enzymes. Methods: Sedentary men and women (n = 63), aged 55 ± 6 (s.d.) years with body mass index 32.7 ± 4.1 kg/m² and confirmed MetS, were randomized to 12‐week CR, CR+EX or no treatment (Control). Results: Weight loss averaged 7.6% in the CR and 9.1% in the CR+EX group (time effect, p < 0.001; group effect, p = 0.11); insulin sensitivity improved by 49 and 45%, respectively (both p < 0.001). Fitness (maximal oxygen consumption) increased by 19% in the CR+EX group only (p < 0.001). Alanine aminotransferase (ALT) levels decreased by 20% in the CR and 24% in the CR+EX group (time effect, both p < 0.001; group effect, p = 0.68); corresponding values for γ‐glutamyltransferase (GGT) were ?28 and ?33%, respectively (time effect, both p < 0.001; group effect, p = 0.28). Reduction in abdominal fat mass (measured by DXA from L1 to L4) independently predicted ΔALT (r = 0.42, p = 0.005) and ΔGGT (r = 0.55, p < 0.001), whereas change in dietary saturated fat intake was independently associated with ΔALT (r = 0.35, p = 0.03). Conclusions: Reductions in central adiposity and saturated fat intake are key drivers of improvement in liver enzymes during lifestyle interventions. Exercise training did not confer significant incremental benefits in this study.     

Chronic ischemic colonic lesion caused by phlebosclerosis with calcification

We report here two patients in both of whom ileus finally developed and chronic ischemic colonic lesion caused by phlebosclerosis with calcification was diagnosed. We believe that phlebosclerosis is an old-fashioned diagnostic term, but appropriate here because of the remarkable calcification of the sclerotic walls of the colic veins that seems to be one of the most important hallmarks of this previously unrecognized, "new" condition. Phlebosclerosis could be a novel type of ischemic colitis because of its unique clinical presentations, although the pathogenesis of this unusual venopathy remains unknown.     

Lamivudine treatment enabling right hepatectomy for hepatocellular carcinoma in decompensated cirrhosis

A 69-year-old man was admitted to our hospital in October 2003, for further examination of two liver tumors. He was diagnosed with hepatocellular carcinoma (HCC) arising from decompensated hepatitis B virus (HBV)-related cirrhosis. Long-term lamivudine administration improved liver function dramatically despite repeated treatment for HCC. His Child-Pugh score was 9 points at start of lamivudine treatment, improving to 5 points after 1 year. His indocyanine green at 15 min after injection test score was 48% before lamivudine treatment, improving to 22% after 2 years and to 5% after 4 years. Radiofrequency ablation controlled the HCC foci and maintained his liver function. In April 2009, abdominal computed tomography revealed a tumor thrombus in the right portal vein. Since his indocyanine green test results had improved to less than 10%, we performed a right hepatectomy, which was successful. To our knowledge, there have been no documented reports of patients undergoing successful right hepatectomy for HCC arising from decompensated cirrhosis. The findings observed in our patient indicate the importance of nucleoside analogs for treating HBV-related HCC.