Incidence of non-severe hypoglycaemia and intensity of treatment among veterans with type 2 diabetes in the U.S.A.: a prospective observational study.

AIM: To quantify the incidence of non-severe hypoglycaemic events among veterans with Type 2 diabetes and its association with primary care provider prescribing behaviour. METHODS: This was a prospective observational study involving 30 primary care providers and patients enrolled with these primary care providers, identified from computerized pharmacy records. Two sampling frames were created consisting of (1) patients not treated with insulin and receiving sulfonylurea treatment (with or without other oral hypoglycaemic agents) and (2) patients treated with insulin (with or without sulfonylureas or other oral hypoglycaemic agents). Patients recorded the frequency, proximal cause of, and response to each hypoglycaemic event over a 12-week period and made three visits to a research coordinator over 24 weeks. Data were provided to the primary care provider before their next visit and charts were reviewed for medication changes. RESULTS: A total of 265 patients were enrolled in study. During the 12 weeks of structured self-monitoring of blood glucose, patients recorded a mean (sd) of 6.9 (10.3) hypoglycaemic events. Duration of diabetes increased monotonically with increasing category of hypoglycaemic event (P < 0.001). Among insulin users, an increased frequency of hypoglycaemic events was associated with a decreased likelihood of dose intensification by primary care providers (relative risk 0.86 per event; P = 0.02) but no significant increase in tendency for dose reduction (relative risk 1.04 per event; P = 0.06). Increased frequency of hypoglycaemic events was associated with an increased likelihood of dose reduction (relative risk 1.12 per event; P = 0.03) in the sulfonylurea treatment group. CONCLUSIONS: Non-severe hypoglycaemia is common among veterans with Type 2 diabetes receiving insulin or sulfonylureas and influences the prescribing behaviour of primary care providers.

Evaluation of the effect of Myrica sapida on bronchoconstriction and bronchial hyperreactivity.

The present investigation was undertaken to evaluate the bronchodilator and bronchial hyperreactivity of the stem bark of Myrica sapida. Experimental models studied were histamine induced bronchospasm in guinea pigs, bronchoalveolar lavage fluid (BALF) in egg albumin sensitized guinea pigs, histamine release from the lung tissues of sensitized guinea pigs and histopathological studies. Ethanolic extract of M. sapida (75 mg/kg, p.o., for 7 days) showed significant protection against histamine aerosol induced bronchospasm. Significant decrease in the total and differential leukocyte counts in BALF and prevention of egg albumin induced histamine release from chopped lung tissues of sensitized guinea pigs was observed on chronic administration of ethanolic extract of M. sapida (75 mg/kg, p.o., for 15 days). Histological examination of the section of lung from sensitized guinea pigs treated with ethanolic extract of M. sapida (75 mg/kg, p.o., for 15 days) was comparable to that of the control group. These results suggest that M. sapida possesses not only bronchodilator activity but also decreases bronchial hyperresponsiveness by decreasing the infiltration of inflammatory mediators like eosinophils, neutrophils in BALF and inhibiting histamine release from lungs of sensitized guinea pigs.

Alanine in HI: a silent mutation cries out!

It is a widely held paradigm in molecular biology that a change in the third base of a codon is silent in terms of expression. In this investigation, results are presented that challenge that paradigm, at least in terms of one polymorphism in KCNJ11, which is one of five genes that have been implicated in the disorder Hyperinsulinism of Infancy. In two cohorts of Australian patients, an uneven distribution of KCNJ11 SNP's was observed. A silent polymorphism at codon 190 was over-represented in the patients who responded well to medical treatment and under-represented in those that required radical surgical intervention. In an attempt to investigate this polymorphism, it was expressed in vitro and western blot analysis showed that there were virtually no bands from the homozygous variant samples, while strong bands were seen in normal controls. The human genome is highly redundant in terms of tRNA species for each amino acids but enigmatically under-represents a number of specific codons. The polymorphism in question occurs within one such codon. We propose that the presence of a base change at the third position of codon that is not represented by a corresponding anti-codon within the human nuclear tRNA leads to a decreased rate of expression of the protein.

The role of ATP sensitive channels in insulin secretion and the implications in persistent hyperinsulinemic hypoglycaemia of infancy (PHHI).

Persistent Hyperinsulinemic Hypoglycaemia of Infancy (PHHI) is a metabolic syndrome of unregulated insulin secretion. It is a heterogenous disease with causes linked to mutations of the ATP sensitive potassium channels of the beta cell, as well as to metabolism in the beta cell. 5 candidate genes--ABCC8, KCNJ11, GCK, GLUD1 and SCHAD have been implicated in the disease so far, however the aetiology of the disease remains unknown in up to 50% of all patients. We genotyped 43 subjects with PHHI (20 surgically treated and 23 medically treated) for disease associated mutations in the candidate genes. Mutations on ABCC8 were identified in 16 of the 20 (80%) of the surgically treated patients. One putative mutation was identified in the medically treated cohort. The polymorphism E23K on KCNJ11 that is associated with NIDDM was differentially distributed in the 2 cohorts. We discuss the mutations identified, emphasise the importance of the K-ATP channel in physiological processes and discuss the possibility that the disease is caused by mutations in other genes associated with insulin release, glucose metabolism in the beta cell or beta cell apoptosis and survival. We propose that these processes must be explored in order to further our understanding of PHHI.

Factors affecting diabetes knowledge in Type 2 diabetic veterans.

AIMS/HYPOTHESIS: To describe the clinical, psychological and social factors affecting diabetes knowledge of veterans with established Type 2 diabetes. METHODS: We conducted an observational study of 284 insulin-treated veterans with stable Type 2 diabetes. All subjects completed the University of Michigan Diabetes Research and Training Centre Knowledge Test, the Diabetes Care Profile, the Mini-Mental State Examination, the Geriatric Depression Scale, and the Diabetes Family Behaviour Checklist. Stepwise multiple linear regression was used to develop a model for the diabetes knowledge score based upon clinical and psychosocial variables. RESULTS: One hundred eighty subjects were evaluated in a derivation set. The mean age +/- SD was 65.4+/-9.6 years, 94% were men, and 36% were members of a minority group. Performance on the diabetes knowledge test was poor (64.9+/-15.3% correct). Self-perceived understanding of all management objectives explained only 6% of the variance in the knowledge scores. Multivariate analysis showed that age, years of schooling, duration of treatment, cognitive function, sex, and level of depression were independent determinants of the knowledge score. When the model was applied to 104 subjects in a validation set, there was a strong correlation between observed and predicted scores (r=0.537; p<0.001). CONCLUSIONS/INTERPRETATION: Stable, insulin-treated veterans have major deficiencies in diabetes knowledge that could impair their ability to provide self-care. A multivariate model comprised of demographic variables and psychosocial profiling can identify patients who have limited diabetes knowledge and be used to assess individual barriers to ongoing diabetes education.

Effect of benzo-ring hydroxyl groups on site-specific mutagenesis by tetrahydrobenzo[a]pyrene adducts at N(6) of deoxyadenosine.

We have previously investigated the mutations induced on replication in Escherichia coli of the M13mp7L2 genome containing each of the eight possible adducts derived from the four optically active 7,8-diol 9,10-epoxide metabolites of benzo[a]pyrene (B[a]P) by alkylation of a specific deoxyadenosine (dAdo) residue at N(6). Observed mutational frequencies depended in part on the relative spatial orientations of the three hydroxyl groups in these adducts. To determine how the presence or absence of these hydroxyl groups affects mutational response, we have synthesized 16-mer oligonucleotides with the same sequence as one of those previously studied with the diol epoxide adducts, but containing B[a]P-dAdo adducts in which two or all three of the adduct hydroxyl groups were replaced by hydrogen. Transfection of the adducted M13 constructs into SOS-induced Escherichia coli consistently gave fewer infective centers than the control construct, with viabilities ranging from 8.4 to 44.9% relative to control. In general, decreasing the number of adduct hydroxyls decreased the total frequency of substitution mutations induced. For all but one of the present adducts, the total mutational frequency was lower than that for any of the previously reported diol epoxide adducts in the same sequence. Remarkably, this (9S,10R)-adduct with cis orientation of the dAdo residue and the 9-OH group gave the highest mutational frequency of all the B[a]P adducts studied in this sequence, including the diol epoxide adducts. With the present adducts, A --> T transversions predominated, with smaller numbers of A --> G transitions and even fewer A --> C transversions.

2-Methoxyestradiol blocks estrogen-induced rat pituitary tumor growth and tumor angiogenesis: possible role of vascular endothelial growth factor.

Natural and synthetic estrogens have been associated with several types of human and animal cancers including prolactin-secreting pituitary tumors in Fischer 344 rats. These prolactin-secreting tumors are highly angiogenic and their growth is angiogenic dependent. In the present study we have utilized this model to evaluate the effect of 2-methoxyestradiol (2-ME), an endogenous estrogen metabolite that is a potent inhibitor of endothelial cell proliferation in vitro, on estrogen-induced pituitary tumor growth and angiogenesis. Adult female rats were implanted (subcutaneously) with a silastic capsule containing estradiol-17beta (E2). After seven days of constant E2 exposure animals were injected (sc) daily with 25 mg/kg of 2-ME and killed either three or 8 days later. Changes in pituitary weight and proliferating cell nuclear antigen (PCNA) labeling index indicated growth while degree of angiogenesis was determined immunohistochemically using factor VIII related antigen. The results indicate that 2-ME inhibited estrogen-induced lactotroph growth by 32% and tumor angiogenesis by 89%. Furthermore, vascular endothelial growth factor (VEGF) expression, evaluated by immunohistochemical analysis, was down-regulated concomitant with tumor angiogenic suppression. These studies suggest that 2-ME may have therapeutic potential for hormone-induced cancer and that its angiostatic activity may be modulated through down-regulation of VEGF expression.

Glycemic index and insulin response to a liquid nutritional formula compared with a standard meal.

OBJECTIVE: To determine the glycemic index and metabolic responses to a nutritional formula, and to compare these responses to those following an oral glucose meal and a standard test meal. METHODS: Six male and six female healthy non-diabetic volunteers aged 18 to 48 years met screening examination and laboratory assessment criteria. Three test meals were administered, each containing 50 g of carbohydrate: nutritional formula (NF), standard test meal (ST) and a glucose test meal (GT). Each subject underwent the three test meals on separate days in randomized sequence. Blood samples were taken at intervals over 5 hours for determination of glucose, insulin and triglycerides. RESULTS: The glycemic index was similar for the NF (60.8 +/- 13.1) and for the ST (57.8 +/- 12.9) meals. The incremental area under the curve for glucose was similar for NF and ST, but each was significantly lower than for the GT meal. The total area under the curve for insulin was significantly greater for the NF meal than for the ST meal. The serum triglyceride responses were similar for NF and ST meals. CONCLUSION: In healthy non-diabetic subjects, the blood glucose and triglyceride responses are similar for a nutritional formula compared to an isoenergetic standard test meal. However, the insulin response differs. This information is important in managing tube-fed patients.

Tin-117m(4+)DTPA: pharmacokinetics and imaging characteristics in patients with metastatic bone pain.

UNLABELLED: Biokinetics and imaging characteristics of 117mSn(4+)DTPA have been studied in patients with metastatic bone pain. METHODS: Seventeen patients with bone pain due to metastasis were given three dose levels: 180 microCi/kg (6.66 MBq/kg), 229 microCi/kg (8.47 MBq/kg) and 285 microCi/kg (10.55 MBq/kg) body weight. Periodic blood and daily urine samples were collected for 14 days to measure percent injected activity retained in blood and that excreted in urine. Simultaneous anterior and posterior view whole-body images were obtained under identical scan settings at 1, 3.5 and 24 hr and on Days 3 and 7 and between 4-6 and 8-10 wk postinjection. The total body retention was calculated using the geometric mean counts. RESULTS: After intravenous injection, the total body clearance of 117mSn(4+)DTPA shows two components: a soft-tissue component and a bone component. The soft-tissue component accounts for 22.4% of the dose and consists of four subcomponents with an average biologic clearance half-time of 1.45 days (range 0.1-3.2 days). The bone component accounting for the remaining 77.6% of the dose shows no biologic clearance. A mean 22.4% of the dose is excreted in urine in 14 days; 11.4% within 24 hr. The uptake pattern appears similar to that of 99mTc-MDP. Peak uptake is observed in normal bone by 24 hr and metastatic lesions by 3-7 days. Pain palliation was observed with all three doses levels. CONCLUSION: Among the four potential bone pain palliation radionuclides, 117mSn(4+)DTPA demonstrates the highest bone uptake and retention. Some biokinetic and radionuclidic features of 117mSn(4+)DTPA are similar to other agents, but many features are different and unique and may make it an ideal bone pain palliation agent. Double-blind comparative studies are needed to determine its exact role in bone pain palliation.

(+/-)-3-[4'-(N,N-dimethylamino)cinnamyl]benzazepine analogs: novel dopamine D1 receptor antagonists.

Neurochemical studies and structure-activity relationships of dopamine D1 receptor ligands suggest that their intrinsic activity may depend on the conformational state or binding site at which they interact on the receptor protein. Important differences in the modes of binding of these ligands may confer their agonist, partial agonist, or antagonist properties. In an effort to develop novel dopamine D1 antagonists and investigate the D1 antagonist pharmacophore, a series of (+/-)-(N-alkylamino)benzazepines were prepared in which (+/-)-7-chloro-8-hydroxy-3-[6-(N,N-dimethylamino)hexyl]-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzazepine (1) demonstrated the highest binding affinity (Ki = 49.3 nM) and selectivity to dopamine D1 receptors. This compound inhibited dopamine-stimulated adenylyl cyclase, in rat caudate, confirming a D1 receptor antagonist profile. From this initial series of N-alkylamino-substituted benzazepines, structure-activity relationships suggested that the terminal amino function was necessary for optimal binding affinity and selectivity at D1 vs D2 sites. Further, addition of this side chain to the D1 agonist pharmacophore (e.g., 7,8-dihydroxy-3-[4-(N,N-dimethylamino)butyl]-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine) greatly decreased binding affinity at D1 receptors. These data suggested that a binding domain that may be unique to the D1 antagonists may have been identified. In an attempt to exploit an apparent amine-accepting binding domain on the D1 receptor, a series of (+/-)-3-[4'-(N,N-dimethylamino)cinnamyl]benzazepine analogs was designed and prepared, as D1 antagonists. In this series, (+/-)-7-chloro-8-hydroxy-3-[4'-(N,N-dimethylamino)cinnamyl]-1-phenyl-2,3,4,5 -tetrahydro-1H-3-benzazepine (6a) showed the highest binding affinity (Ki = 60.3 nM) for dopamine D1 receptors. Compound 6a was a potent dopamine D1 antagonist as evidenced by its ability to block dopamine-stimulated adenylyl cyclase activity in rat caudate (predicted Ki value = 18.4 nM). Molecular modeling studies demonstrated that the most potent and selective dopamine D1 antagonists, in both series, contained terminal amino groups 8-9 A away from the 3-position benzazepine nitrogen. Compounds that lacked a terminal amine function or where this moiety was less than 7 A away from the benzazepine nitrogen demonstrated significantly lower binding affinities. Therefore, this series of (+/-)-3-[4'-(N,N-dimethylamino)cinnamyl]benzazepines also appears to be identifying an amine-accepting binding domain on the dopamine D1 receptor protein that may be further explored for the development of novel dopamine D1 antagonists.

(+/-)-(N-alkylamino)benzazepine analogs: novel dopamine D1 receptor antagonists.

(+/-)-(N-Alkylamino)benzazepine analogs were prepared as novel dopamine D1 receptor antagonists to further elucidate the role of these receptor subtypes in the pharmacology and toxicology of cocaine. In the first series of compounds, (+/-)-7-chloro-8-hydroxy-3- [6-(N,N-dimethylamino)-hexyl]-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepi ne (15) showed the highest affinity (Ki = 49.3 nM) and subtype-selectivity for dopamine D1 over dopamine D2, 5-HT2a, and 5-HT2c receptors. Compounds 7a [(+/-)-7-Chloro-8-hydroxy-3-[4-(N,N-dimethylamino)butyl]-1-phenyl- 2,3,4,5-tetrahydro-1H-3-benzazepine], 11 [(+/-)-7-chloro-8-hydroxy-3-[6-[(N,N-dimethylamino)hexyl]-1- phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-cyanoborane], and 15 were moderately potent dopamine D1 receptor antagonists as evidenced by their ability to block dopamine-stimulated adenylyl cyclase activity in rat caudate (predicted Ki values = 60, 34, and 21 nM, respectively). Compound 7a appears to be unique in that, despite its relatively potent inhibition of dopamine stimulated adenylyl cyclase, it demonstrated relatively weak binding affinity at the dopamine D1 receptors (Ki = 811 nM). Unlike previously reported N-alkylbenzazepines, where a significant loss in dopamine D1 receptor binding affinity was observed when successive increases in the alkyl side chain size at the benzazepine nitrogen were made, several of these novel N-alkylamino analogs demonstrated high-affinity binding with an optimal chain length of six carbons. This initial series of compounds appears to be identifying another binding domain on the dopamine D1 receptor protein that has not previously been characterized and that accepts an amino function. Further, these compounds may serve as templates for the design of peripherally active dopamine D1 receptor antagonists.

Effects of oxazepam on anxiety: implications for Fowles' psychophysiological interpretation of Gray's model.

The present dose-response study investigated the effects of the benzodiazepine oxazepam (Serax) on anxiety as measured by autonomic and self-report indices in a nonclinical sample. Given Fowles' (1980, 1988) theory that electrodermal activity primarily reflects the activity of the behavioral inhibition system (BIS) while heart rate primarily reflects the activity of the behavioral activation system (BAS), we predicted that electrodermal indices of anxiety would be more affected by oxazepam than heart rate. Psychophysiological and self-report measures were recorded prior to and following a speech stressor in subjects given placebo (n = 17), 15 mg oxazepam (n = 19), and 30 mg oxazepam (n = 17). Anxiolytic effects were found during stressed state as measured by skin conductance level but not heart rate or self-reported anxiety. Furthermore, the anxiolytic effects of oxazepam were noted only during the stressful phases of the experiment. The results are viewed as supportive of Fowles' motivational interpretation of the distinction between heart rate and electrodermal responding.

Calcinosis and metastatic calcification due to vitamin D intoxication. A case report and review.

Vitamin D, a fat-soluble vitamin, can be associated with significant morbidity when prescribed in large doses. We describe a hypoparathyroid patient with vitamin D intoxication who developed painful periarticular calcinosis, nephrocalcinosis with hypertension and chronic renal failure in addition to band keratopathy and hearing loss. He was treated with combination therapy including prednisone, phosphate-binding antacid, phenytoin and disodium etidronate. After 20 months of follow-up there was a significant reduction of periarticular calcinosis, but no improvement in renal function, band keratopathy or hearing loss and possible calcification of the ossicles. The clinicopathologic features of metastatic calcification and the various treatment modalities are reviewed.

Assessment of physician perceptions on the fatality of cancer.

A questionnaire was developed to evaluate internists' perceptions about patients' survival of cancer as compared with other diseases. The questionnaire consisted of four pairs of survival-matched cancer and non-cancer diseases. The questionnaire was administered to 42 faculty members and 37 resident physicians in the Department of Medicine at the University of Missouri-Columbia. Physicians rated patients' survival of cancer to be significantly lower than patients' survival of comparable non-cancer diseases (p less than 0.001). Resident physicians estimated patients' survival of breast cancer to be significantly lower (p less than 0.007) and estimated the survival of lung cancer to be significantly higher than the faculty members' estimate (p less than 0.003). These physicians' perceptions could adversely affect the quality of care and the degree of consideration given to both cancer and non-cancer patients. The differences observed in faculty members' and resident physicians' responses were attributed to the greater knowledge and clinical experience of faculty rather than differences in attitudes toward cancer.

Spontaneous decline in exercise-induced proteinuria during a 100-mile triathlon.

To study the effect of prolonged exercise on glomerular permeability and proteinuria, we collected serial urine samples from six athletes during a 100-mile triathlon. Urine collected just before, at the midpoint of, and immediately after the race was analyzed for creatinine by an automated chemistry analyzer, pack method, and for microalbumin by radioimmunoassay. By midrace, the urinary albumin-creatinine ratio increased from the prerace mean +/- SEM of 3.5 +/- 0.5 to 38.3 +/- 11.7 mg/g. The ratio then declined to 12.5 +/- 2.7 mg/g by the end of the race (P less than .04). Similarly, the urinary albumin level increased significantly from 5.9 +/- 0.7 to 80.5 +/- 26.8 micrograms/mL by midrace, followed by a decline to 39.2 +/- 12.9 micrograms/mL. The initial increase in albuminuria was expected and reflects the increase in exercise-induced cardiac output and glomerular permeability. The subsequent decline in albuminuria and albumin-creatinine ratio, despite continued exercise, was unexpected and indicates a decrease in glomerular permeability. Further study is warranted to determine the mechanism of this apparently protective renal response to prolonged exercise.

Aspartame and its constituent amino acids: effects on prolactin, cortisol, growth hormone, insulin, and glucose in normal humans.

Because large doses of phenylalanine stimulate prolactin secretion in man, we studied the acute effects of oral doses of aspartame (0.534 g, equivalent to the amount of aspartame in approximately 1 L beverage), aspartic acid (0.242 g), and phenylalanine (0.3 and 1.0 g) on serum prolactin and other hormones in normal humans. Prolactin was not stimulated by any of the aspartame meals, aspartic acid, or 0.3 g phenylalanine; a small rise in serum prolactin, similar to that produced by a high-protein mixed meal, followed ingestion of 1.0 g phenylalanine. Serum growth hormone showed no statistically significant changes in response to any of the experimental meals whereas cortisol and insulin fell slightly and glucose rose slightly during each of the meals. We conclude that these doses of aspartame do not alter secretion of prolactin, cortisol, growth hormone, or insulin in normal individuals.

Alcohol decreases insulin sensitivity in healthy subjects.

To study the effect of alcohol on glucose and insulin metabolism, a simultaneous infusion of glucose and insulin was given for 150 min to healthy volunteers, once during alcohol and once during calorie-free gingerale (control) ingestion. During alcohol intake, the average steady-state (between 100 and 150 min) glucose of 5.44 +/- 0.39 mmol/l. and the average steady-state insulin of 6.3 +/- 1.1 ng/ml were significantly higher than those (4.0 +/- 0.39 mmol/l. of glucose and 4.4 +/- 0.6 ng/ml of insulin) observed during the control state. Despite the higher steady-state insulin concentrations, the glucose metabolism was significantly less during alcohol ingestion. These findings suggest alcohol-induced impairment in glucose metabolism is caused by a decreased tissue sensitivity to insulin.