Metabolic Studies in Kidney Stone Disease

Patients with kidney stones (n=59) and healthy controls (n=31)collected a 24-hour urine sample and later underwent a 6-hour‘fast and load’ test in which an oral calcium loadwas taken after 2 hours. In the 24-hour urine sample, mean calciumexcretion was higher in patients than controls, while mean urate,oxalate and citrate levels were similar. The patients had higherlevels of fasting plasma calcium, serum calcitriol and fastingurinary calcium, and lower levels of plasma phosphate than didthe controls. Following the calcium load, plasma and urinarycalcium increased similarly in both groups. Serum parathyroidhormone (PTH) levels were similar in both groups and decreasedsimilarly following the calcium load. Multiple linear regression, relating the presence or absenceof stone formation to all variable, found the only variablessignificantly related to stone formation to be plasma levelsof calcium (p<0.001) and phosphate (p=0.001) and fastingurinary area (p<0.001), and 24-hour urinary calcium excretion(p<0.05). Urinary oxalate and citrate were not related tostone formation. The data do not support the hypothesis thatprimary stimulation by calcitriol produces a normal fastingplasma calcium level, with an exaggerated increase after anoral calcium load. The findings instead suggest an abnormalityof parathyroid cell ‘set point’, such that PTH secretioncontinues until the plasma calcium level is a little higherand the phosphate a little lower than in controls.     

Sources of Error in the Determination of Metabolic Rate

Abstract

Background. There is significant immunoassay cross-reactivity between everolimus and sirolimus, and their routine determination using a common method may reduce the reagent costs. Methods. In 122 blood samples from kidney (n = 30) and liver (n = 92) transplant recipients, everolimus concentrations were determined using the Abbott IMx® microparticle enzyme immunoassay (MEIA) as previously described, and the Abbott sirolimus chemiluminescence magnetic microparticle immunoassay (CMIA) on the Architect-i1000® system. Results. A high correlation coefficient (r = 0.981, p < 0.001) and a linear regression MEIA = 0.73CMIA + 0.55, with an acceptable standard error of the estimate (ma68 = 0.32 ng/mL), were obtained, indicating the transferability of the results produced by both immunoassays. Conclusions. The newly-developed sirolimus CMIA assay on the Architect® platform may be a valid alternative to other immunoassays for the routine therapeutic monitoring of everolimus.     

Metabolic Studies in the African Pygmy

Major metabolic effects of human growth hormone (HGH) were assessed in the African Babinga pygmy. Plasma free fatty acid (FFA) and glucose concentrations were measured in pygmies, HGH-deficient dwarfs, Bantu tribesmen, and Caucasian controls after each received 4 mg of HGH intravenously over a 20 min period. Pygmies had an early decrease of plasma FFA and glucose concentration, but did not exhibit a later lipolytic response.In neighboring Bantu tribesmen, American controls, and HGH-deficient dwarfs, both the early and late responses to intravenous HGH were present. The failure of plasma FFA concentration to increase in the pygmy after intravenous HGH was not due to a generalized defect in lipolysis since a normal lipolytic response was obtained with epinephrine (2 mug/min for 20 min).Pygmies, like HGH-deficient dwarfs, had significantly reduced insulin responses to both oral glucose and arginine. Insulin secretion was significantly reduced when compared with either Bantu tribesmen or American controls and was not altered by 2 wk of a high carbohydrate/high protein diet. HGH treatment in pygmies (5 mg b.i.d. for 5 days) failed to augment either glucose or arginine-induced insulin secretion. Glucagon consistently caused normal insulin secretion in HGH-deficient dwarfs and was, likewise, effective in each pygmy studied. In two offspring from different pygmy mothers and Bantu fathers, insulin responses to glucose were initially normal and increased in a normal manner after HGH treatment.In previous studies, HGH failed to reduce serum urea nitrogen concentration in pygmies. Sulfation factor was found to be normal. A consideration of the data in toto is consistent with a hypothesis that the metabolic findings in the pygmy may result from partial nonresponsiveness to either HGH or to a factor generated by HGH. This defect is not transmitted as either an autosomal or sex-linked dominant trait.     

Metabolic Studies on the Pathogenesis of Hangover

Abstract. A variety of metabolic parameters were evaluated in 23 healthy male volunteers, after ethanol administration (1.5 g/kg) and correlated to the symptoms of hangover. The degree of intoxication and hangover were estimated using a simple test program according to which 11 subjects had severe and 12 mild hangover. Sequential determinations of blood ethanol, acetaldehyde, glucose, lactate, free fatty acids (FFA), triglycerides (TG) and ketone bodies were made during the 21 hours after administration. Each subject served as his own control by taking part in an identical experimental session but receiving no ethanol. The maximal hangover occurred 12 to 14 hours after the initiation of drinking. At this time almost all of the ethanol and acetaldehyde had been eliminated from the blood. The intensity of the hangover did not correlate with the peak concentrations of ethanol or acetaldehyde in the blood. Marked hypoglycemia regularly followed the administration of ethanol, but the nadir blood glucose values had no correlation with the intensity of hangover. Ethanol induced a significant rise in blood lactate concentration, the extent of which was similar in subjects with mild or severe hangover. During the most intensive hangover plasma FFA level increased when compared to the values observed during the control period. These concentrations were significantly higher in subjects with severe hangover than in those whose hangover was mild. An increase in plasma TG concentration regularly followed ethanol administration but the extent of the rise did not correlate with the degree of intoxication or hangover. Ethanol had a marked antiketogenic effect during the first 8 hours of the experiment after which the concentration of ketone bodies rose rapidly above the control level. Again the changes showed no correlation with the intensity of hangover. The results indicate that the intensity of hangover bears little relation to the changes in the metabolite concentrations measured. This suggests that the symptoms of hangover can not be accounted for by the ethanol-induced alterations of the major blood metabolite concentrations.     

胰岛素抵抗对代谢紊乱的影响

目的：了解胰岛素抵抗（ＩＲ）与代谢紊乱的关系。方法对７７例３５－６２岁人群的ＩＲ与各种代谢紊乱的关系进行调查,以ＨＯＭＡ计算公式：空腹血浆胰岛素（ｍＵ／Ｌ）ｘ空腹血浆葡萄糖（ｍｍｏｌ／Ｌ）／２２．５计算,其值〉２．７７,定为ＩＲ。结果ＩＲ组３８例,非ＩＲ组３９例,两组间ＦＢＳ无显差异,而ＨＯＭＡＩＲ值及ＦＰＩＮＳ值,高血压,高甘油三酯,高胆固醇、超重,脂肪肝的发生率均有显差异;二种以上代谢紊乱     

Refsum''s disease: characterization of the enzyme defect in cell culture

Refsum's disease (heredopathia atactica polyneuritiformis, HAP) is an inherited neurological disorder associated with storage of the branched-chain fatty acid, phytanic acid (3,7,11,15-tetramethylhexadecanoic acid). Cultured fibroblasts derived from skin biopsies of HAP patients did not contain elevated levels of phytanate, yet showed rates of phytanate-C-(14)C oxidation less than 3% of those seen in cells from control subjects. Cells of control subjects converted phytanate to alpha-hydroxyphytanate, to pristanate (the [n-1] homologue of phytanate) and to 4,8,12-trimethyltridecanoate, compounds previously identified as intermediates on the major pathway for phytanate metabolism in animals, providing the first direct evidence that this same oxidative pathway is operative in human cells. None of these breakdown products could be found after incubation of phytanate with HAP cells. Labeled alpha-hydroxyphytanate and labeled pristanate were oxidized at normal rates by HAP cells. Oxidation of the latter proceeded at normal rates both when added to the medium at very low tracer levels and at levels 100 times greater. Phytanate was incorporated into and released from lipid esters at normal rates by HAP cells. Elevated levels of free phytanate in the medium were no more toxic to HAP cells than to control cells over the 48- to 72-hr exposures involved in these studies, as evidenced by morphologic criteria and by ability to oxidize labeled palmitate. These findings are consistent with the hypothesis that the cells from HAP patients are deficient in a single enzyme involved in the alpha-hydroxylation of phytanate, while the enzymes involved in later steps are present at normal or near-normal levels.     

Metabolomics Reveals Metabolic Biomarkers of Crohn's Disease

The causes and etiology of Crohn's disease (CD) are currently unknown although both host genetics and environmental factors play a role. Here we used non-targeted metabolic profiling to determine the contribution of metabolites produced by the gut microbiota towards disease status of the host. Ion Cyclotron Resonance Fourier Transform Mass Spectrometry (ICR-FT/MS) was used to discern the masses of thousands of metabolites in fecal samples collected from 17 identical twin pairs, including healthy individuals and those with CD. Pathways with differentiating metabolites included those involved in the metabolism and or synthesis of amino acids, fatty acids, bile acids and arachidonic acid. Several metabolites were positively or negatively correlated to the disease phenotype and to specific microbes previously characterized in the same samples. Our data reveal novel differentiating metabolites for CD that may provide diagnostic biomarkers and/or monitoring tools as well as insight into potential targets for disease therapy and prevention.     

Family Studies in Coeliac Disease

Peroral duodenojejunal biopsies were performed on 114 of 195first degree relatives of 31 index coeliac patients in 28 families.Twelve of these biopsies were characteristic of coeliac disease.Birth order did not influence the incidence of coeliac disease.The mode of inheritance is not typical of simple Mendelian inheritancebut is compatible with a polygenic inheritance with a very highheritability or a dominant inheritance with a very low rateof expression in heterozygotes. The enzyme levels and electron microscopic appearances of thehistologically normal mucosa of coeliac relatives was not differentfrom that of a control group.     

Studies on the Metabolic Clearance Rate, Apparent Distribution Space and Plasma Half-Disappearance Time of Unlabelled Human Growth Hormone in Normal Subjects and in Patients with Liver Disease, Renal Disease, Thyroid Disease and Diabetes Mellitus

Abstract. The metabolic clearance rate (MCR), half-disappearance time (T½ and apparent distribution space (DS) of unlabelled human growth hormone (HGH) have been studied using the priming dose – constant infusion technique. In 11 normal subjects MCR averaged 2.99 ml/kg/min., T½ 19.0 min. and DS 79.3 ml/kg. There were no differences between males and females and MCR was constant at HGH levels ranging from 5 to 50 ng/ml. In 10 out of 17 patients with chronic liver disease of varying severity MCR/kg was reduced below the lower limit of normal. TV₂ was prolonged in 15 of these patients. There was a very close correlation between MCR/kg and DS/kg in liver disease (r = 0.8219). Increased DS/kg accounted for the normal MCR/kg seen in some patients with severe hepatocellular failure. MCR/kg was markedly reduced in three patients'with chronic renal failure. T7₂ and DS/kg were both significantly increased in this group (48.0 min. and 117.0 ml/kg, respectively). MCR/kg and T7₂ were normal in one patient with the nephrotic syndrome but normal glomerular filtration rate. MCR/kg was not significantly different from normal in patients with thyrotoxicosis, myxoedema and uncontrolled diabetes mellitus, despite the fact that T½ shorter than normal in thyrotoxicosis and longer than normal in myxoedema. It is suggested that HGH does not normally diffuse freely from the vascular to extravascular extracellular fluid, and that normally a substantial concentration gradient exists between the vascular and extravascular compartments; under these circumstances, the liver and kidneys are the major sites of HGH metabolism. In hepatic and renal failure, this gradient is reduced and extravascular degradation sites may assume more importance in the metabolism of growth hormone. Acute fluctuations in the peripheral blood concentrations of growth hormone indicate alterations in secretion rate and not alterations in metabolism.     

Studies on the Pathogenesis of Hypertension in Cushing's Disease and Acromegaly

The pathogenesis of the hypertension associated with Cushing'ssyndrome and with acromegaly is poorly understood. We have investigatedthe possible roles of sodium retention, activation of the renin-angiotensinsystem and increased sympathetic nervous system activity inuntreated patients. In 11 patients with Cushing's disease, seven of whom were hypertensive,total exchangeable sodium was normal despite increased levelsof the mineralocorticoid hormones, 11-deoxycorticosterone andcorticosterone. The renin-angiotensin system was also normal.Cardiac sensitivity to the ß-receptor agonist isoprenalinewas increased, but this was not due to an increase in ß-adrenoceptordensity. Hypertension in Cushing's disease is neither sodium-dependentnor angiotensin II-mediated, but increased cardiac sensitivityto catecholamines, by increasing cardiac output, may contributeto the pathogenesis of hypertension. In nine patients with acromegaly (three of whom were hypertensive)total exchangeable sodium was elevated. Although no correlationbetween blood pressure and exchangeable sodium was found, hypertensionin acromegaly is probably sodium dependent. No evidence wasfound for a pathogenetic role for either the renin-angiotensin-aldosteroneor the sympathetic nervous system.     

Nonalcoholic Fatty Liver Disease in Children: Beyond Metabolic Syndrome

Nonalcoholic fatty liver disease (NAFLD) has been identified as the number one cause of liver disease in children and adolescents in the United States. This increasing rate of liver disease is directly related to obesity. Often the initial presentation of NAFLD is a child or adolescent with increased risk of cardiovascular and/or metabolic risk factors. According to the United Network of Organ Sharing, NAFLD is rapidly becoming the leading cause of chronic liver disease and liver transplants in older children. It is important for pediatric primary care providers to recognize the risk factors for NAFLD and provide a coordinated, multidisciplinary approach for interventions to prevent and limit liver disease in children and adolescents.     

加强2型糖尿病患者的代谢控制效果的随访研究

目的了解强化门诊随访对2型糖尿病患者各项代谢指标控制状况的影响。方法收集门诊600例2型糖尿病患者,进行为期1年的随访观察,其中坚持随访患者380例(随访组)、失访0.5~1年的患者220例(对照组),收集两组各项代谢指标,比较遵医行为。结果随访组患者干预后按医嘱服药、合理饮食、适当运动三项遵医行为及FBG、HbAlc、BP、TG、LDL-C、BMI及mAlb较干预前均有显著改善。结论强化对糖尿病患者的门诊随访可明显改善患者的遵医行为有利于患者代谢指标的改善。     

Mediastino-abdominal Lipomatosis: Deep Accumulation of Fat Mimicking a Respiratory Disease and Ascites. Clinical Aspects and Metabolic Studies in vitro

We report on clinical and metabolic studies of a newly delineatedlipomatosis, cha.racterised by an abnormal mediastinal and abdominalaccumulation of fat, without obesity. The clinical fea tures,which occurred in all the patients studied, are: 1. Exertional dyspnoea due to a space-occupying mediastinalaccumulation of fat, without evidence of cardiac or pulmonarydisease. 2. A pseudo-ascitic abdominal enlargement, due to intra-and retroperitoneal accumulation of fatty tissue. 3. Insulin-independentdiabetes mellitus. Type IV hyperlipidaemia and elevated levels of plasma uric acidwere observed in four patients. Intra-abdominal lipomatous tissue,obtained during laparoscopy from four patients, demon strateda reduced lipolytic response to ß-adrenergic stimulation.Thus, fat deposition in the ab dominal and mediastinal areascould be causally related to defective lipid mobilization inlipo matocytes. Lipoprotein lipase activity in abdominal adiposetissue were normal in two patients (10.0 and 10.6 nmol/g/min)and markedly elevated in another two patients (373 and 49.9nmol/g/min), as compared with controls (12.7±2.1 nmol/g/min).When expressed on per cell basis, LPL activity in lipomatoustissue was significantly higher than in control tissue (3.21±1.1nmol/10⁵cell/min vs 0.92±0.16 nmol/10⁵ cell/min). Lipoprotein fractionation did not demonstrate consistent modificationof the serum lipo protein pattern. HDL and HDL₂ cholesterolvalues were reduced, even in patients with elevated LPL activityin adipose tissue.     

Independent Metabolic Syndrome Variants Predict New-Onset Coronary Artery Disease

OBJECTIVE

Any combination of metabolic abnormalities may constitute the metabolic syndrome (MetS), conferring coronary artery disease (CAD) risk, but the independent effect of different combinations on CAD onset remains unknown.

RESEARCH DESIGN AND METHODS

Healthy adult siblings (n = 987) of premature CAD (<60 years) case subjects were followed for 9.8 ± 3.8 years. Baseline MetS variables (insulin sensitivity index, waist circumference, systolic blood pressure, HDL cholesterol, and triglycerides) were recombined into five principal components (PC1–5), and risk factor–adjusted proportional hazards for CAD onset of median-dichotomized PCs were estimated.

RESULTS

The significant hazard ratios were as follows: for PC1 (all abnormalities except blood pressure) 1.66 (P = 0.036), PC2 (high blood pressure levels, high HDL cholesterol) 1.71 (P = 0.016), and PC4 (low HDL cholesterol, high insulin sensitivity, low triglycerides) 2.0 (P = 0.001). Traditionally defined MetS had a hazard ratio of 1.32 (P = 0.18).

CONCLUSIONS

Independent MetS variants identified by PC analysis may explain metabolic mechanisms that increase CAD risk better than the presence of traditional MetS.Acommon approach to examining the metabolic syndrome (MetS) uses a simple count without taking into account the correlation structure of dichotomous metabolic abnormalities including increased blood pressure, high triglyceride levels, low HDL cholesterol levels, abdominal obesity, and impaired glucose control (1). The goal of this study was to define the structure of independent patterns of metabolic syndrome variables and determine their ability to predict new-onset coronary artery disease (CAD).     

非糜烂性反流病研究概况

非糜烂性反流病(NERD)是指有典型胃食管反流症状而无内镜下食管黏膜损害表现的疾病,约占胃食管反流病(GERD)的60%~70%,其发病机制复杂,既与GERD有相似之处,又有其特殊性,主要包括酸反流与非酸反流、内脏高敏感、应激和精神因素等多种原因。其发病机制的多样性和复杂性是导致患者对抑酸治疗总体效果不佳的主要原因,强力抑酸治疗改善症状的疗效明显低于伴食管炎患者。现就NERD研究概况进行综述。