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Essentials An international collaboration provides a consensus for clinical definitions. This concerns thrombotic microangiopathies and thrombotic thrombocytopenic purpura (TTP). The consensus defines diagnosis, disease monitoring and response to treatment. Requirements for ADAMTS-13 are given. SummaryBackground Thrombotic thrombocytopenic purpura (TTP) and hemolytic–uremic syndrome (HUS) are two important acute conditions to diagnose. Thrombotic microangiopathy (TMA) is a broad pathophysiologic process that leads to microangiopathic hemolytic anemia and thrombocytopenia, and involves capillary and small-vessel platelet aggregates. The most common cause is disseminated intravascular coagulation, which may be differentiated by abnormal coagulation. Clinically, a number of conditions present with microangiopathic hemolytic anemia and thrombocytopenia, including cancer, infection, transplantation, drug use, autoimmune disease, and pre-eclampsia and hemolysis, elevated liver enzymes and low platelet count syndrome in pregnancy. Despite overlapping clinical presentations, TTP and HUS have distinct pathophysiologies and treatment pathways. Objectives To present a consensus document from an International Working Group on TTP and associated thrombotic microangiopathies (TMAs). Methods The International Working Group has proposed definitions and terminology based on published information and consensus-based recommendations. Conclusion The consensus aims to aid clinical decisions, but also future studies and trials, utilizing standardized definitions. It presents a classification of the causes of TMA, and criteria for clinical response, remission and relapse of congenital and immune-mediated TTP.

Octreotide (Sandostatin), a potent and long-acting octapeptide analogue of somatostatin, exhibits variable metabolic effects in type 1 diabetes. We have postulated that interindividual variability in octreotide metabolism could be responsible in part for the differences in metabolic responses reported in previous clinical studies. To this end, we determined plasma levels and MCR of octreotide during 24-hour continuous SC infusion (low dose, 200 micrograms; high dose, 400 micrograms) in nine female, C peptide-negative patients with type 1 diabetes. The metabolic effects of the analogue were assessed by measuring serum glucose, free insulin, glucagon, GH, and PP levels before and at 1- to 2-hour intervals during each dose of the analogue or control (0.9% saline solution) infusion in a single-blind randomized manner. Mean daytime (0800-0000 hours) and bedtime (0000-0800 hours) serum glucose levels decreased significantly (p less than 0.05 to 0.02) during analogue therapy compared with control. Mean serum free insulin levels were significantly (p less than 0.02) greater during octreotide infusion compared with control, despite the similar daily insulin requirements. Both doses of the analogue effectively suppressed 24-hour GH by 50%, glucagon by 50%, and PP by 80%. Steady-state octreotide levels varied considerably among patients (low, mean +/- SEM), 1000 +/- 101, range 638 to 1375 pg/ml; high, mean 1940 +/- 147, range 1032 to 2462 pg/ml). Although mean MCR values were similar with both doses, we observed greater interindividual variability (low, mean 2.45 +/- 0.30, range 1.31 to 3.78 ml/kg/min; high, mean 2.36 +/- 0.19, range 1.68 to 3.48 ml/kg/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Platelet vitamin E content and thromboxane A2 (TxA2) synthesis have been investigated in type I diabetic subjects and age- and sex-matched controls. Platelets, but not plasma, from diabetic subjects contained significantly lower vitamin E levels and synthesized significantly greater amounts of TxA2 when challenged with collagen or thrombin than platelets from control subjects. Conversion of exogenously added arachidonic acid to TxA2 was unaltered between platelets from control and diabetic groups. Platelet vitamin E content from control and diabetic groups combined exhibited a significant negative linear correlation with collagen- and thrombin-induced TxA2 production. These data suggest that low platelet vitamin E levels could be a contributing factor to the increased thromboxane synthesis demonstrated by platelets from the above type I diabetic subjects.

To date the in vivo identification and quantitation of specific hormone receptors has been difficult, time consuming, and lacking in sensitivity. We present the theory underlying a new in vivo radioreceptor assay for polypeptide hormones based on receptor theory derived from in vitro investigations and in vivo kinetic and autoradiographic studies. The assay was developed from a tissue model and a theory of hormone distribution. Measuring the labeled hormone distributed between the plasma and interstitial space in the presence or absence of excess unlabeled hormone permits the accurate determination of hormone specifically bound to receptors. This approach eliminates the problem of nonspecific binding due to free tracer, hormone degradation products, or labeled non-hormone molecules. A receptor compartment and specific binding of hormone are calculated from only four measured parameters: total tissue labeled hormone, tissue albumin, plasma labeled hormone, and plasma albumin. The method is applicable to most tissues and hormones under a variety of conditions and permits simultaneous comparison of multiple tissues in the same animal under identical conditions.

An in vivo radioreceptor assay for polypeptide hormones has been developed and applied to the identification of tissue insulin receptors. The theoretical basis for this assay is presented elsewhere in this issue. 125I-insulin and 131I-albumin were infused into male rats with increasing amounts of unlabeled insulin. Plasma samples were taken at 1-min intervals until the animals were killed at 5 min. Tissue samples were excised and weighed and the activity due to each isotope counted. By comparing the differential distribution of the labeled tracers and applying the results to a compartment model, the specific, displaceable binding of insulin to tissue receptors could be demonstrated. Binding was detected in the liver, muscle, fat, adrenal glands, pancreas, small intestines, and spleen.

Twelve ambulatory patients (six women and six men; mean age, 29 years) with type I diabetes were treated with a continuous subcutaneous open-loop insulin pump in an attempt to effect better glucose control. Hemoglobin A1, mean blood glucose, total cholesterol, total triglycerides, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), and the cholesterol/HDL-C ratio were assessed monthly before and after glucoregulation from five to 14 months (mean, nine months). Mean HDL-C levels increased significantly (52 +/- 4 to 60 +/- 5 mg/dL); mean cholesterol/HDL-C ratios decreased significantly (4.46 +/- 0.43 to 3.89 +/- 0.39). Mean values for triglycerides, total cholesterol, and LDL-C, all initially normal, did not change. Both mean Hb A1 levels and glucose levels fell from 11.2% +/- 0.5% to 9.8% +/- 0.5% and 177 +/- 15 mg/dL to 128 +/- 12 mg/dL, respectively. Insulin requirements decreased from 0.80 +/- 0.08 to 0.61 +/- 0.05 units/kg/24 hr. These results may favorably alter the prediction for development of accelerated atherosclerosis in type I diabetics.

VIP is a 28 amino acid peptide found in highest concentration in central and peripheral nervous tissue. This study measured VIP in pure populations of peripheral blood cells to determine the presence or absence of VIP in noninnervated tissues. Cell populations were purified by Ficoll-hypaque gradient centrifugation followed by dextran sedimentation or differential adherence to culture plates. Platelets were purified by differential centrifugation. VIP was isolated by acid-ethanol extraction and quantified by radioimmunoassay. A mean value of 1.1 +/- 0.6 ng of VIP per 10(8) cells was extracted from PMNs. This peptide appears to be a specific marker for PMNs, since it was not measurable in pure populations of lymphocytes, monocytes, erythrocytes, or platelets. Mononuclear cells obtained from five patients with AML and seven patients with CML contained measurable VIP, whereas mononuclear cells from nine of 10 patients with AMML and from five patients with ALL contained very low or unmeasurable levels of VIP. Thus, although the role of VIP in normal PMN function is unknown, measurement of VIP in leukemic cells may aid in the differential diagnosis of acute leukemias.

To determine the site of endogenous release of gastric inhibitory polypeptide (GIP), glucose perfusions (556 mmoles per liter) of duodenum, proximal jejunum, midjejunum, and ileum were performed in human volunteers using an occluding balloon perfusion technique. Preperfusion GIP concentrations were below assay sensitivity (125 pg per ml) in all subjects. After glucose perfusion, maximal serum GIP concentrations for the four groups were: duodenum, 1383 +/- 152 pg per ml; proximal jejunum, 904 +/- 87 pg per ml; midjejunum, 545 +/- 91 pg per ml, and ileum 305 +/- 38 pg per ml. Integrated GIP secretion was significantly greater with duodenal perfusion (111 +/- 21 ng-min ml-1) d proximal jejunal perfusion (69 +/- 5 ng-min ml-1), as compared to either midjejunal (47 +/- 7 ng-min ml-1) or ileal (25 +/- 6 ng-min ml-1) perfusions. Peak serum insulin concentrations and integrated insulin secretion were also significantly greater with perfusion of the duodenum or proximal jejunum. Serum glucose concentrations, integrated serum glucose, and glucose absorption were similar for the four areas perfused. The results of this study indicate that the proximal small intestine is the primary site of endogenous GIP release in man, but that smaller quantities are also released by the distal small bowel.

Measurement of glycosylated hemoglobin (HbA1) is frequently helpful to clinicians in treating patients with diabetes, since a number of studies show that this reflects a reliable index of diabetic control over time. There are several methods of measuring HbA. The chromatographic method is the most frequently used and is the standard method for large demand. We recently encountered a patient with diabetes mellitus who had substantial lactescent plasma secondary to hypertriglyceridemia that falsely raised the HbA1 level. We examined the patient in detail and determined that triglyceride concentrations greater than 1,750 mg/dL would falsely raise the HbA1 levels. In vitro studies performed by adding lipemic plasma to a control sample confirmed this. Thus, spurious elevations in HbA1 can occur in patients with lactescent plasma. This would further complicate the already existing interrelationship between glucose intolerance and hypertriglyceridemia.

A 46 year old woman is described who had a 13 half year history of watery diarrhea associated with hypokalemia and hypochlorhydria. The diarrhea was secretory as measured by triple lumen tube perfusion and was associated with an increased concentration of fasting plasma immunoreactive gastric inhibitory polypeptide (GIP) of 750 pg/ml which was stimulated to 4,000 pg/ml after a standard meal. The diarrhea decreased after partial pancreatectomy. Diffuse pancreatic islet cell hyperplasia was present and, although GIP was unmeasureable in the pancreas of normal subjects, it was at least 83 ng/g wet weight in this patient. Postoperatively, the patient's diarrhea responded dramatically to the oral administration of nicotinic acid.

Intraduodenal amino acids are known to stimulate the release of gastric inhibitory polypeptide and cholecystokinin. In order to separate and quantitate gastric inhibitory polypeptide secretion selectively, 12 normal subjects received an intraduodenal perfusion of a mixed amino acid solution (158 mM) containing either methionine, phenylalanine, tryptophan, and valine (perfusate 1), or an amino acid solution containing arginine, histidine, isoleucine, leucine, lysine, and threonine (perfusate 2). Serum concentrations of gastric inhibitory polypeptide and insulin were significantly greater in the group receiving perfusate 2 (P less than 0.001). In contrast, after administration of amino acid perfusate 1, there was only a slight increase in serum gastric inhibitory polypeptide concentration and insulin secretion increased only slightly. Mean trypsin and bilirubin outputs in the group receiving perfusate 1 were nearly 3 times greater than the outputs of the group receiving the other amino acid mixture. This study expands the importance of intraduodenal amino acid mixtures in stimulating secretion of gastric inhibitory polypeptide and insulin and quantitatively separates gastric inhibitory polypeptide release from release of hormones that stimulate pancreatic enzyme secretion, such as cholecystokinin.

Hyperthyroidism due to a TSH-secreting pituitary tumor has been noted by a number of investigators. We describe a unique case in which a 17-yr-old female presented with clinical hyperthyroidism, a goiter, and unilateral exophthalmos. Serum T4, free T4, and T3 (RIA) were consistently elevated along with elevated TSH levels (range, 10-100 microunits/ml). Skull x-rays and computed tomography scan revealed a tumor invading the right orbit. Other pituitary function studies were normal and LATs was undetectable. Surgery performed resulted in 70% removal of the pituitary tumor and confirmed the presence of tumor infiltration into the right orbit. TRH tests done pre- and postoperatively (patient still clinically hyperthyroid with elevated T4 and TSH levels) showed TSH and PRL responsiveness. Electron microscopy of the tumor demonstrated features typical of pituitary thyrotrophs. Monolayer cultures of pituitary cells released TSH over time into the media but did not respond to TRH stimulation. Pituitary adenoma tissue content of immunoreactive TSH was 65 microunits/g wet tissue and demonstrated immunosimilarity with human standard. We conclude that the patient had a TSH-secreting pituitary tumor responsive to TRH stimulation.

The effect of intraduodenal or intravenous administration of a 30-gm mixed amino acid solution of serum gastric inhibitory polypeptide (GIP), alpha-amino nitrogen (AAN), glucose, and insulin concentrations was studied in 10 normal subjects. Initially, an intraduodenal amino acid perfusion (15 ml per min X 60 min) was performed in each subject and was followed in 1 to 2 weeks by an intravenous infusion. Peak AAN concentrations occurred at 60 min after both routes of administration, but were greater with intravenous infusion, 145 +/- 5.7 mug per ml vs. 89 +/- 4.4 mug per ml (P less than 0.001). Although serum AAN levels were significantly lower after intraduodenal administration, incremental insulin concentrations were greater after intraduodenal perfusion, 77.3 +/- 8.8 muM per ml vs. 43.1 +/- 5.6 muU per ml (P less than 0.005). Total integrated insulin secretion was also greater after intraduodenal amino acids, 5000 vs. 2400 muU-min ml-1 (P less than 0.005). With intravenous amino acid infusion, serum GIP concentrations remained below the assay detection limit. After intraduodenal perfusion, a mean maximum GIP increment of 468 pg per ml occurred at 15 min. In all subjects peak GIP concentrations occurred at 15 min and preceded the maximum insulin rise by 15 to 30 min. Total integrated GIP secretion was significantly greater after intraduodenal amino acid perfusion, 13,000 pg-min ml-1 vs. no measurable response with intravenous infusion. In separate studies performed in 12 subjects, no significant changes in serum GIP concentrations occurred after intraduodenal perfusion of 0.45% saline, 0.9% saline, or 10% mannitol. The results of this study demonstrate that intraduodenal amino acid administration stimulates the secretion of GIP and suggest that endogenously released GIP may be important in the enteric mediated release of insulin.

To investigate the role of gastric inhibitory polypeptide (GIP), a potent inhibitor of gastric acid secretion, in the hypersecretion associated with duodenal ulcer, we compared the serum GIP concentrations in 11 healthy subjects and 16 duodenal ulcer patients after the stimulation of GIP release by a mixed meal. Fasting and postprandial serum gastrin and GIP concentrations were measured by radioimmunoassay at frequent intervals after the ingestion of a test meal. The duodenal ulcer patients showed an augmented and significantly greater release of GIP as well as of gastrin compared to normal subjects. These results indicate that a defective GIP release cannot account for the gastric hypersecretion seen in patients with duodenal ulcer. The mechanism of the increased GIP response in patients with duodenal ulcer is not clear from these studies.

Twelve type I diabetic patients with established diabetic nephropathy were treated for 12 months with the insulin pump to determine whether glucoregulation would influence the clinical course of proteinuria. All of the subjects were known to have arterial hypertension and were receiving antihypertension medication. Despite good glucose control, as assessed by total glycosylated hemoglobin level, two clinical courses were observed: six patients demonstrated a progression in proteinuria and six appeared to experience a reduction in proteinuria. The group demonstrating a progression had significantly higher mean arterial pressure at six and 12 months of study compared with the group with a reduction in proteinuria. These results suggest that arterial hypertension is an important risk factor in the progression of diabetes nephropathy. Further studies should be designed to recognize early proteinuria and hypertension to determine whether mean normal glucose values and BP over a prolonged period will prevent renal failure.

Platelets from patients with type 1 diabetes have exhibited more sensitivity to aggregation when compared with platelets from controls without diabetes after challenge with platelet-activating factor (PAF). The production of thromboxane B2 (TxB2) and 12-hydroxyeicosatetraenoic acid (12-HETE) and the release of 5-hydroxytryptamine (5HT) were increased when the platelets were challenged by PAF (5.0 X 10(-6) mol/L and 1.0 X 10(-6) mol/L). The production of TxB2 and 12-HETE and the release of 5HT were related to the irreversible biphasic aggregation profiles observed in the patients with diabetes. Inhibition of thromboxane A2 (TxA2) production by acetylsalicylic acid abolished the secondary wave of aggregation of platelets from patients with diabetes, changing an irreversible aggregation to a reversible one. Inhibition of both TxA2 and 12-HETE production by eicosatetraynoic acid did not contribute further to the inhibition caused by acetylsalicylic acid alone, indicating that 12-HETE was not involved in the secondary wave of aggregation. These data show that the increased aggregation observed in the platelets from the group with diabetes in response to PAF results in part from their higher production of TxA2 and release of 5HT.

A change in the brand of shellac thinner used to make an alcoholic beverage resulted in six deaths from methanol poisoning. In screening all potentially poisoned persons available with serum methanol, ethanol, pH, and electrolyte determinations, many asymptomatic methanol poisonings were discovered. A correlation was established between severity of illness and level of ethanol, further suggesting a protective effect. Among different types of treatment used with the 12 hospitalized cases peritoneal dialysis was shown to be effective, with a clearance rate five to ten times that obtained with forced fluid diuresis.

Six female diabetics, 14 to 31 years of age, had erratic control for years and developed resistance to subc. insulin (2.5-30.0 units/kg/day) but had normal response to I.V. insulin (0.35-0.9 units/kg/day). Three patients required continuous I.V. insulin infusion for 6 mos to 1 year. Euglycemia was achieved, when aprotinin (a protease inhibitor) and regular insulin (0.7-1.4 units/kg/day) was given subc. Plasma levels of free insulin rose and ketonuria subsided. Four patients had episodes of spontaneous severe hypoglycemia, before and during aprotinin therapy, requiring I.V. glucose for 2 to 60 days. Days and weeks after the last sub . injection of ins. hypoglycemia and hyperinsulinemia (50 to 2000 μU free insulin/ml) persisted, C-peptide was