High-sensitivity C-reactive protein does not improve the differential diagnosis of HNF1A-MODY and familial young-onset type 2 diabetes: A grey zone analysis.

AIM: Low plasma levels of high-sensitivity C-reactive protein (hs-CRP) have been suggested to differentiate hepatocyte nuclear factor 1 alpha-maturity-onset diabetes of the young (HNF1A-MODY) from type 2 diabetes (T2D). Yet, differential diagnosis of HNF1A-MODY and familial young-onset type 2 diabetes (F-YT2D) remains a difficult challenge. Thus, this study assessed the added value of hs-CRP to distinguish between the two conditions. METHODS: This prospective multicentre study included 143 HNF1A-MODY patients, 310 patients with a clinical history suggestive of HNF1A-MODY, but not confirmed genetically (F-YT2D), and 215 patients with T2D. The ability of models, including clinical characteristics and hs-CRP to predict HNF1A-MODY was analyzed, using the area of the receiver operating characteristic (AUROC) curve, and a grey zone approach was used to evaluate these models in clinical practice. RESULTS: Median hs-CRP values were lower in HNF1A-MODY (0.25mg/L) than in F-YT2D (1.14mg/L) and T2D (1.70mg/L) patients. Clinical parameters were sufficient to differentiate HNF1A-MODY from classical T2D (AUROC: 0.99). AUROC analyses to distinguish HNF1A-MODY from F-YT2D were 0.82 for clinical features and 0.87 after including hs-CRP. For the grey zone analysis, the lower boundary was set to miss<1.5% of true positives in non-tested subjects, while the upper boundary was set to perform 50% of genetic tests in individuals with no HNF1A mutation. On comparing HNF1A-MODY with F-YT2D, 65% of patients were classified in between these categories - in the zone of diagnostic uncertainty - even after adding hs-CRP to clinical parameters. CONCLUSION: hs-CRP does not improve the differential diagnosis of HNF1A-MODY and F-YT2D.

Severe acute renal failure in patients treated with glucagon-like peptide-1 receptor agonists.

We report two patients with diabetes in whom acute renal failure requiring hemodialysis occurred while on treatment with glucagon-like peptide-1 receptor agonists. We discuss the mechanisms of this complication and the potential for its prevention.

Factors associated with the presence of glutamic acid decarboxylase and islet antigen-2 autoantibodies in patients with long-standing type 1 diabetes.

AIM: Glutamic acid decarboxylase (GAD) and/or islet antigen-2 (IA-2) autoantibodies (ab) are present in 90% of patients at the onset of type 1 diabetes (T1D). Few studies have shown that they may persist in the long-term. We analysed the frequency of GADab and IA-2ab and the factors associated with their persistency in patients with long-lasting T1D. METHODS: This cross-sectional study included 430 adult patients with T1D of at least 10-year duration, consecutively seen over one year. GADab and IA-2ab were determined by radio-binding assays. Autoantibodies to thyroperoxydase, gastric parietal cells and transglutaminase were assessed in 418 patients, and HLA DRB1 genotyping in 359. Parameters associated with the persistency of antibodies were studied by multivariate analysis. RESULTS: Median age at diagnosis of T1D was 12 years, and median diabetes duration was 19 years. Extrapancreatic autoimmunity was present in 38% of the patients, and associated autoimmune diseases in 21%. GADab and/or IA-2ab were found in 56% of the patients, and in 32% in those with more than 25-year diabetes duration. GADab were more frequent than IA-2ab. Female sex, an older age at diagnosis, and a shorter duration of diabetes were independently associated with the presence of ab. The same factors and the DR3 allele were associated with GADab, while only diabetes duration and the DR4 allele were associated with IA-2ab. CONCLUSION: In a large proportion of the patients with T1D, the long-term persistency of diabetes-associated antibodies allows aetiological diagnosis, even far from the onset of hyperglycaemia.

Upper extremity peripheral venous pressure measurements accurately reflect pulmonary artery pressures in patients with cavopulmonary or Fontan connections.

After the bidirectional cavopulmonary or Fontan operation, the physiologic consequence is passive flow of the systemic venous return to the pulmonary arteries. Knowledge of pulmonary artery pressure (PA) is valuable in the management of these patients, and obtaining this information without the need for a central line or cardiac catheterization would be advantageous. The aim of this study was to evaluate the correlation between upper extremity peripheral venous (PV) pressures and PA or superior vena cava (SVC) pressures in patients who have undergone cavopulmonary or Fontan connections. During cardiac catheterization, 19 patients with complex cyanotic heart disease who had undergone a cavopulmonary shunt or Fontan procedure were studied. Simultaneous pressure measurements were obtained from the peripheral intravenous line placed prior to the procedure and the SVC or PA. The mean pressures were compared. The mean PV pressure was 17.5 +/- 5.6 mmHg. The mean SVC or PA pressure was 16.1 +/- 5.4 mmHg. The mean difference was 1.5 +/- 1.5 mmHg ( p < 0.001). The correlation coefficient PV to SVC or PA pressure was 0.97 ( p < 0.001). PV pressure measurements taken from an upper extremity accurately reflect PA pressures in patients who have undergone a cavopulmonary shunt or Fontan procedure.

Reptilian echocardiography: insights into ontogeny and phylogeny?

We describe the echocardiographic findings in a large reptile-the carpet python. If ontogeny recapitulates phylogeny, the study of reptilian hearts may provide insights into human cardiac development. In addition, the reptilian heart has unique structural and physiological adaptations that may broaden our perspective on evolutionary cardiac adaptation.

Microbubbles and mitral valve prostheses - transesophageal echocardiographic evaluation.

OBJECTIVE: To assess whether microbubbles are associated with a specific type of mitral valve prosthesis and to investigate the relationship of microbubbles to ventricular function and mitral regurgitation. One of the types of spontaneous echocardiographic contrast observed in patients with prosthetic heart valves has been described as microbubbles. METHODS: Clinical data and videotapes of patients with a prosthetic mitral valve who had undergone transesophageal echocardiography at the UCLA Medical Center between May 1989 and February 1995 were retrospectively reviewed. There were 109 studies (74 patients) available for review by two independent observers. RESULTS: Microbubbles occurred in 49 of the 66 studies of St. Jude valves ( 74%), eight of the 12 studies of Bjork Shiley valves (67%), four of four studies of Medtronic valves (100%) and zero of 23 studies of tissue valves (0%). Patients with an estimated ejection fraction greater than 45% were found to have a much higher likelihood of having microbubbles observed. There was no statistically significant association between the degree of mitral regurgitation and the observation of microbubbles. CONCLUSIONS: Microbubbles are a common phenomenon occurring in patients with mechanical mitral prostheses compared with tissue mitral valve prostheses. Their formation depends on the systolic ventricular function, suggesting a cavitation-like phenomenon participating in their formation perhaps due to the rate or velocity of the valve closure.

Carotid artery volume flow: in vivo measurement with time-domain-processing US.

PURPOSE: To evaluate carotid artery volume-flow measurements with time-domain-processing ultrasonography (US). MATERIALS AND METHODS: Volume-flow measurements were obtained in the carotid arteries of nine swine with time-domain-processing US. Four swine were prepared with a model of an arteriovenous shunt. Flow through the carotid artery was varied by means of a number of physiologic and pharmacologic interventions. The reference standard for volume flow consisted of measurements with transit-time US flowmetry. At a limited number of measurement points, this reference standard was validated against true volume flow measured with timed collection. RESULTS: For flow rates less than 500 mL/min, a linear correlation existed between measurements with time-domain processing and the US flow meter (r2 = .96, P < .001, slope = 1.117). Values above 500 mL/min were less well correlated with the reference standard. True flow was underestimated with both methods, less so with time-domain processing than with US flowmetry (underestimation, 10% versus 21%). Measurements were significantly less reproducible with time-domain processing than with US flowmetry (P < .001). Interobserver variability was negligible. CONCLUSION: Because of operator errors, measurements with time-domain processing should be repeated at least three times to ensure accuracy and may be inaccurate in flow rates over 500 mL/min.

Validation of volume flow measurements in blood vessels with quantitative color velocity imaging using a physiologic model of the circulation.

RATIONALE AND OBJECTIVES: Color velocity imaging-quantitative (CVI-Q) is a new sonographic technique designed to measure volume flow (VF) in blood vessels. We attempted to validate VF measurements with CVI-Q in an in vitro model of the circulation. METHODS: We validated CVI-Q in a flow phantom mimicking physiologic conditions by connecting isolated porcine arteries 4-14 mm in diameter to a calibrated perfusion roller pump generating pulsatile flow with porcine blood. Pump flow was varied stepwise from 0 to 1,000 ml/min. CVI-Q VF measurements were performed using a 7.5-MHz linear array transducer. VF results then were compared with pump flow calibration values through linear regression. RESULTS: A good correlation (r2 = .98-.99, slope = 0.88-1.02) was obtained from 0 to 400-600 ml/min. The degree of correlation depended on vessel diameter, with linearity being maintained over a somewhat larger range in medium-sized vessels. At higher flows, variability increased significantly. CONCLUSION: VF measurements with CVI-Q are accurate in a physiologic flow range. At supraphysiologic flow rates, as are encountered within arteriovenous fistulae, CVI-Q may give inaccurate results. Awareness of possible pitfalls and limitations of the technique is important for obtaining accurate and reproducible results.

Transplantation of a temperature-sensitive, nerve growth factor-secreting, neuroblastoma cell line into adult rats with fimbria-fornix lesions rescues cholinergic septal neurons.

The HT4 cell line was derived from infection of a mouse neuroblastoma cell line with a retrovirus that encoded the temperature-sensitive (ts) mutant of SV40 large T antigen. At nonpermissive temperature, HT4 cells differentiated with neuronal morphology, expressed neuronal antigens, synthesized nerve growth factor (NGF) mRNA, and secreted biologically active NGF in vitro. We sought to establish whether transplanted HT4 cells expressed class I major histocompatibility complex (MHC) antigens, a partial requirement for recognition by cytotoxic T lymphocytes (CTL), and thus be susceptible to xenograft rejection. Differentiated HT4 cells expressed marginally detectable levels of class I MHC antigens, but demonstrated higher levels of class I MHC expression after treatment with interferon-gamma. However, HT4 cells were resistant to direct lysis by perforin, the pore-forming protein of CTLs, and thus may have potential use in xenograft experiments. To address whether HT4 cells secrete NGF in vivo, HT4 cells were transplanted into adults rats with unilateral fimbria-fornix transections. A ts cell line derived from P4 cerebellum, BT1, that does not differentiate with neuronal phenotype or synthesize NGF in vitro, was transplanted as a control. Six weeks posttransplant. HT4 cells had integrated into host CNS without forming tumors. In BT1 transplants, the number of medial septal acetylcholinesterase (AChE)-positive cells was reduced to 26-39% of the contralateral control side, depending on the rostrocaudal level. In HT4 transplants, the number of cholinergic septal neurons was 58-78% of the contralateral side. This percentage was significantly (P less than 0.005) greater than that seen with BT1 transplants, indicating that transplanted HT4 cells secrete NGF in vivo and rescue cholinergic septal neurons following fimbria-fornix transection.

SB subregion of the human major histocompatibility complex: gene organization, allelic polymorphism and expression in transformed cells.

The SB region of the human major histocompatibility complex (MHC) has been cloned from cosmid and lambda phage libraries made from the human B-lymphoblastoid cell line Priess (DR4/4, DC4/4, SB3/4). Two alpha genes and two beta genes are encoded in the 100 kb long SB region in the order SB alpha-SB beta-SX alpha-SX beta. The SB alpha and SB beta genes encode the alpha and beta subunits of the SB subset of class II MHC molecules. Both the SX alpha and the SX beta genes are pseudogenes in the haplotype examined. From the isolated clones, the two haplotypes of the Priess cell line, SB3 and SB4, are distinguished by nucleotide sequencing and blot hybridization analyses. Restriction site polymorphisms between the SB3 and SB4 clones were observed only in relatively small regions of the SB beta and SX beta genes. A mouse macrophage cell line was transfected with one of the cosmid clones containing both SB alpha and SB beta genes. Expression of the alpha and beta genes was detected by fluorescene-activated cell sorting (FACS) and two-dimensional gel electrophoresis using SB-specific monoclonal antibodies.

Primary hyperaldosteronism in childhood due to unilateral macronodular hyperplasia. Case report.

We present the first report of primary hyperaldosteronism in childhood due to unilateral macronodular hyperplasia. A 10-year-old white boy with severe hypertension (150/100 mm Hg), hypokalemia (1.4 mEq/liter), and suppressed plasma renin activity (PRA) (less than 0.1 ng/ml/hr) demonstrated fixed PRA and aldosterone (aldo) levels that did not change with alteration of dietary sodium. The paradoxical decrease in serum aldo on assumption of upright posture suggested a tumor. Prolonged ACTH administration produced a continuous rise in blood pressure, but a transient rise in aldo. A minimal decrease in urinary aldo during dexamethasone administration was noted, excluding dexamethasone-suppressible hyperaldosteronism. Blood pressure normalized with spironolactone. Computerized transaxial tomography, iodocholesterol scanning, and adrenal venography were not diagnostic of a discrete adrenal lesion. Although hyperplasia is more common than an adenoma as a cause of hyperaldosteronism in childhood, a tumor was predicted, since adrenal vein hormone sampling with ACTH stimulation lateralized aldosterone secretion unequivocally to the left adrenal gland. However, left adrenalectomy revealed macronodular hyperplasia. Postoperatively, there was reversal of hypertension, hypokalemia, and hyperaldosteronism. Thus, in childhood, unilateral hypersecretion of aldosterone may result from nodular hyperplasia, rather than a discrete adenoma.

Genotyping steroid 21-hydroxylase deficiency: hormonal reference data.

Hormonal reference data, in the form of nomograms relating baseline and stimulated levels of adrenal hormones, provide a means of genotyping steroid 21-hydroxylase (21-OH) deficiency in congenital adrenal hyperplasia. Data from both 360- and 60-min ACTH stimulation tests are given. The serum hormone concentrations that have proven most useful in classifying 21-OH deficiency are 17-hydroxyprogesterone and delta 4-androstenedione. These nomograms clearly distinguish the patient with classical 21-OH deficiency from those with the milder symptomatic and asymptomatic nonclassical forms of 21-OH deficiency (previously referred to as late onset and cryptic forms) as well as heterozygotes for all of the forms and those subjects predicted by HLA genotyping to be unaffected. The nomograms also can identify individuals heterozygous for 21-OH deficiency in the general population who have a characteristic heterozygote response. These nomograms provide a powerful tool by which to assign the 21-OH deficiency genotype. Patients whose hormonal values fall on the regression line within a defined group are assigned to that group. In view of the strong correlation between the 60- and 360-min ACTH stimulation tests, the less cumbersome and shorter 60-min test can be used with the same confidence as the longer test.

Gastrointestinal bleeding and amyloidosis.

Although gastrointestinal bleeding is well known in patients with amyloidosis, when it occurs as the initial or sole overt manifestation of the disease it is much rarer and frequently causes diagnostic difficulty. This subject is reviewed in the context of a patient who underwent multiple invasive and noninvasive examinations to achieve this diagnosis. Both upper and lower gastrointestinal bleeding of all degrees has been shown to occur with amyloidosis. It appears that diffuse involvement of the gastrointestinal tract is much more common than a specific lesion. Our patient was ultimately found to have multiple waxy amyloid plaques and extremely friable jejunal mucosa at endoscopy. Radiographically, amyloidosis may cause diffuse thickening of the mucosal folds, a finding that carries a broad differential diagnosis. Arteriography, although not used frequently as a diagnostic modality in amyloidosis, may reveal luminal irregularities, truncation, and diffuse attenuation of the vasculature. The treatment of amyloidosis thus far has been unrewarding and difficult. Several new therapeutic measures which appear promising are discussed.