The efficacy of cimetidine in the treatment of "resistant" duodenal ulcers

In a prospective multicenter trial, 43 patients with acute duodenal ulcers unhealed after four weeks of treatment with an H2-receptor antagonist, ranitidine, were switched to treatment with another H2-receptor antagonist, cimetidine. Sixty-eight percent of the unhealed patients were successfully healed; of these patients, 81% were free of daytime pain and 89% were free of nighttime pain. Of those with residual pain, 71% and 50% showed improvement in daytime and nighttime pain severity, respectively. There were no unexpected adverse reactions reported or clinically significant changes in laboratory values measured during the study. It is concluded that cimetidine is highly effective both in healing duodenal ulcers unresponsive to ranitidine therapy and in providing continued relief of daytime and nighttime pain.     

Assessment of AlbuSure and its usefulness in identifying IDDM subjects at increased risk for developing clinical diabetic nephropathy

This study, which included 154 participants in a 10-yr follow-up study of diabetes complications, was conducted to evaluate AlbuSure (a qualitative test designed to detect urinary albumin concentrations greater than 0.03 g/L) for its ability to discriminate between albumin concentrations above and below the manufacturer's concentration threshold and to identify individuals at increased risk for developing diabetic nephropathy (i.e., those with albumin excretion rate [AER] greater than 0.0288 g/24 h). The reproducibility of AlbuSure results was also evaluated. The results of these evaluations were examined by three different types of urine collections (24 h, overnight, and timed postclinic) and overall. AlbuSure's validity was examined by comparing its results to immunonephelometrically measured concentrations and AER. When compared to albumin concentration, AlbuSure had an overall sensitivity of 81.8%, specificity of 94.8%, and positive predictive value of 90.6%. AlbuSure's sensitivity was lower (71.4%) when compared with AER; however, this was higher than the sensitivity achieved by dipsticks against AER (50.7%). On testing urine samples stored for 3 days at 4 degrees C, AlbuSure results were 100% reproducible after 1 day and had an overall reproducibility of 92% after 3 days. When urine was retested after 3 and 15 mo of storage at -70 degrees C, AlbuSure was greater than or equal to 90% reproducible, with some of the differing results attributable to corresponding changes in albumin concentration. The overnight sample appeared to be the sample of choice for testing with AlbuSure in that it showed excellent reproducibility and the highest sensitivity (compared to both albumin concentration and AER).     

Diabetes complications and glycemic control. The Pittsburgh Prospective Insulin-Dependent Diabetes Cohort Study Status Report after 5 yr of IDDM

The relationship between glycemic control and complications of insulin-dependent diabetes mellitus (IDDM) remains controversial. With the use of glycosylated hemoglobin (HbA1) to assess glycemic control from diagnosis onward, the Pittsburgh Prospective Insulin-Dependent Diabetes Mellitus Cohort Study prospectively evaluated 80 new cases of IDDM diagnosed at Children's Hospital of Pittsburgh. This study presents findings in 62 patients at 5 yr postdiagnosis. Only 7 patients, all girls, had any retinopathy (microaneurysms). These subjects had an elevated 5-yr mean HbA1 compared to those with no retinopathy (13.0 vs. 11.7%; P less than .05). Six female subjects who had an elevated albumin excretion rate (AER; greater than or equal to 20 micrograms/min) had a higher 5-yr mean HbA1 (13.3%) than the 26 subjects with AER less than 20 micrograms/min (11.8%; P less than .05). Current HbA1 was correlated with AER (r = +.36, P less than .05) and systolic blood pressure (r = +.49, P less than .01) in females. However, these associations were not observed in males. Positive correlations were found between HbA1 (5-yr mean and current) and serum triglyceride and cholesterol, but only in females was HbA1 inversely related to high-density lipoprotein cholesterol. However, HbA1 was independent of sex, HLA-DR type, and urine C-peptide status. Age adjustment did not change the above results. These analyses suggest that glycemic control is related to AER, systolic blood pressure, presence of microaneurysms, and serum triglyceride and cholesterol concentrations during the first 5 yr of IDDM. However, these associations appear to be predominant in girls.     

Psychosocial factors and complications of IDDM. The Pittsburgh Epidemiology of Diabetes Complications Study. VIII.

OBJECTIVE--To investigate whether psychosocial factors are associated with diabetic complications. RESEARCH DESIGN AND METHODS--Questionnaires on quality of life, depressive symptomatology, and personality type were completed and a clinical assessment was performed. The study population was an incident cohort of childhood-onset insulin-dependent diabetic (IDDM) subjects whose duration of IDDM was greater than or equal to 25 yr (n = 175). RESULTS--Patients with macrovascular disease (P less than 0.01) or nephropathy (P less than 0.05) reported significantly poorer quality of life compared with those who were free from all complications. Patients with macrovascular disease also reported greater depressive symptomatology (P less than 0.05). Quality of life significantly deteriorated according to the presence of multiple (greater than or equal to 4) complications (P less than 0.001). Higher depression symptom scores were also related to the presence of greater than or equal to 4 complications (P less than 0.001). Those with multiple complications reported less type A behavior than those without any complications (P less than 0.05). CONCLUSIONS--This study shows that psychosocial differences exist according to both the number and the type of diabetic complications present. Because poorer quality of life and symptoms of depression may both result form complications, prospective follow-up is needed to clarify their temporal interrelationships, and to determine whether type A personality affords any protection against complications or is diminished as a result of developing complications.     

Human nerve growth factor receptor and cytosine deaminase fusion genes

Cytosine deaminase (CD) converts 5-fluorocytosine (5-FC) to the toxic metabolite 5-fluorouracil (5-FU), and has been investigated extensively as a potential tool for selective cellular eradication. In this paper, genetic constructs were designed to express the CD enzyme fused to the transmembrane and extracellular domains of the human nerve growth factor receptor (NGFR), thus allowing for positive identification of transduced cells by flow cytometry and positive selection by magnetic bead technology. Constructs were designed to encode a [Gly(4)Ser](2) flexible linker between the nucleic acid coding sequences for the NGFR and CD genes. Retroviral vectors constructed with wild-type CD and NG/CD fusion genes were used to transduce 3T3 fibroblasts and the human T cell line CEM. The function of CD fusion genes was comparable to that of wild-type genes as determined in cytotoxicity assays. By flow cytometry, the NGFR antigen was detectable after expression of the fusion gene derived from either Escherichia coli (NG/CDe) or Saccharomyces cerevisiae (NG/CDs), but the greatest antigen density was observed in cells transduced with the NG/CDs vector. Similarly, superior 5-FC sensitivity was observed with NG/CDs fusion gene in both murine fibroblasts and human T cells. In addition, CEM cells expressing NG/CDs were more efficiently eliminated in vivo. Engineering of cells utilizing the chimeric NG/CD genes provides a new modality in gene therapy allowing positive and negative selection using a single protein-coding sequence.     

Spatiotemporal characteristics of SR Ca(2+) uptake and release in detubulated rat ventricular myocytes

In cardiac ventricular myocytes, sarcoplasmic reticulum (SR) Ca(2+) load is a key determinant of SR Ca(2+) release. This release normally occurs predominantly from SR junctions at sarcolemmal invaginations (t-tubules), ensuring synchronous SR Ca(2+) release throughout the cell. However under conditions of Ca(2+) overload, spontaneous SR Ca(2+) release and propagating Ca(2+) waves can occur, which are pro-arrhythmic. We used detubulated rat ventricular myocytes to determine the dependence of Ca(2+) wave propagation on SR Ca(2+) load, and the role of t-tubules in SR Ca(2+) uptake and spontaneous release. After SR Ca(2+) depletion, recovery of Ca(2+) transient amplitude (and SR Ca(2+) load) was slower in detubulated than control myocytes (half-maximal recovery: 9.9+/-1.4 vs. 5.5+/-0.7 beats). In detubulated myocytes the extent and velocity of Ca(2+) propagation from the cell periphery increased with each beat and depended steeply on SR Ca(2+) load. Isoproterenol (ISO) accelerated recovery, increased maximal propagation velocity and reduced the threshold SR Ca(2+) load for propagation. Ca(2+) spark frequency was uniform across control cell width and was similar at the periphery of detubulated cells. However, internal Ca(2+) spark frequency in detubulated cells was 75% lower (despite comparable local SR Ca(2+) load); this transverse spark frequency profile was similar to that in atrial myocytes. We conclude that: (1) t-tubule Ca(2+) fluxes normally control SR Ca(2+) refilling; (2) Ca(2+) wave propagation depends steeply on SR Ca(2+) content (3) SR-t-tubule junctions are important in initiating SR Ca(2+) release and (4) ISO enhances propagation of SR Ca release, but not the initiation of SR Ca release events (for given SR Ca(2+) loads).     

When Are Type 1 Diabetic Patients at Risk for Cardiovascular Disease?

This discussion of increased cardiovascular risk in patients with type 1 diabetes reviews recent data concerning glycemia and the role of glycemic control in type 1 diabetes, as well as observations of an association with haptoglobin genotype and coronary artery disease events. This genetic predisposition also leads to oxidative damage and appears to be associated with profound high-density lipoprotein dysfunction. This article also briefly discusses recent data on general cardiovascular risk factors and provides updated comments concerning the association of coronary artery disease with other diabetes complications, especially renal disease.     

Adiponectin: good, bad, or just plain ugly?

It has been suggested that adiponectin has antiatherogenic, anti-inflammatory, and insulin-sensitizing properties. However, studies in humans have reported inverse as well as positive associations between adiponectin concentrations and disease states. This Commentary discusses the apparent conflict in the literature.