TAS1R- and TAS2R-type taste receptors are expressed in the gustatory system, where they detect sweet- and bitter-tasting stimuli, respectively. These receptors are also expressed in subsets of cells within the mammalian gastrointestinal tract, where they mediate nutrient assimilation and endocrine responses. For example, sweeteners stimulate taste receptors on the surface of gut enteroendocrine L cells to elicit an increase in intracellular Ca2+ and secretion of the incretin hormone glucagon-like peptide-1 (GLP-1), an important modulator of insulin biosynthesis and secretion. Because of the importance of taste receptors in the regulation of food intake and the alimentary responses to chemostimuli, we hypothesized that differences in taste receptor efficacy may impact glucose homeostasis. To address this issue, we initiated a candidate gene study within the Amish Family Diabetes Study and assessed the association of taste receptor variants with indicators of glucose dysregulation, including a diagnosis of type 2 diabetes mellitus and high levels of blood glucose and insulin during an oral glucose tolerance test. We report that a TAS2R haplotype is associated with altered glucose and insulin homeostasis. We also found that one SNP within this haplotype disrupts normal responses of a single receptor, TAS2R9, to its cognate ligands ofloxacin, procainamide and pirenzapine. Together, these findings suggest that a functionally compromised TAS2R receptor negatively impacts glucose homeostasis, providing an important link between alimentary chemosensation and metabolic disease.

Insensitivity to the bitter-tasting compound 6-n-propylthiouracil (PROP) has been proposed as a marker for individual differences in taste perception that influence food preference and intake. The principal genetic determinants of phenotypic variation in PROP taste sensitivity are alleles of the TAS2R38 gene, which encodes a chemosensory receptor sensitive to thiourea compounds including PROP and phenylthiocarbamide. Members of the TAS2R family are expressed in the gustatory system, where they function as bitter taste receptors, and throughout the gut, where their physiological roles in prandial, gut-derived hormone release are beginning to be elucidated. To better understand the relationship between TAS2R function and ingestive behaviors, we asked if TAS2R38 variants are associated with one or more of three eating behaviors: restraint, disinhibition, and hunger. We genotyped a single nucleotide polymorphism (SNP) located within the TAS2R38 gene, rs1726866 (T785C, Val262Ala) in 729 nondiabetic individuals (381 females, 348 males) within the Amish Family Diabetes Study. Eating behaviors were assessed using the Three-Factor Eating Questionnaire. An association analysis between rs1726866 and these three traits revealed a significant association of the PROP-insensitive “T” allele with increased disinhibition (p = 0.03). Because eating behaviors differ substantially between males and females, we subsequently performed sex-stratified analyses, which revealed a strong association in females (p = 0.0002) but not in males. Analyses with other SNPs in close proximity to rs1726866 suggest that this locus is principally responsible for the association. Therefore, our results indicate that a polymorphism in TAS2R38 is associated with differences in ingestive behavior.

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This project changed practice by substituting last-image capture for digital-spot images without affecting vesicoureteral reflux grading while reducing radiation exposure. Monitoring DAP is a better assessment of radiation exposure than is fluoroscopy time.

Although the prevalence of malignancy in average risk women under age 40 presenting with a palpable breast abnormality is low, the management of benign‐appearing palpable abnormalities remains controversial. This study assesses the imaging evaluation, subsequent management, and outcomes of women under age 40 presenting with a palpable area of concern. This study also evaluates the costs, utility, and outcomes of BI‐RADS 3 assessment in this patient population. A single institution retrospective case review from July 2010 through June 2013 identified women under age 40 presenting with a new palpable breast abnormality. Diagnostic imaging evaluation was performed. BI‐RADS assessments and recommendations were recorded prospectively. Outcome was determined by tissue diagnosis, 2 years of surveillance, or search of the hospital tumor registry. Performance measures were calculated. Among 1440 cases, 1052 were initially assessed as BI‐RADS 1 or 2 (73.1%), 184 as BI‐RADS 3 (12.8%), 182 as BI‐RADS 4 (12.6%), and 22 as BI‐RADS 5 (1.5%). In all, 30 breast malignancies were diagnosed (cancer yield 2.1%). All 30 cancers were initially categorized as BI‐RADS 4 or 5. No BI‐RADS 1, 2, or 3 findings proved malignant. The imaging evaluation sensitivity was 100%, specificity was 87.7%, and accuracy was 87.9%. The negative predictive value was 100% and the positive predictive value was 14.7%. Average risk women under age 40 presenting with a palpable abnormality have a low prevalence of breast cancer. Imaging evaluation has a high sensitivity and negative predictive value, thereby allowing for confident characterization and appropriate management recommendations. For palpable solid masses with benign imaging features in women under age 40, short‐term interval follow‐up with subsequent periodic imaging or clinical examination for a total of 2 years is a cost‐effective and safe alternative to biopsy.

A randomized four-way crossover study was carried out in 12 healthy volunteers to investigate the pharmacokinetics of a new oral combination of frusemide (40 mg) and amiloride (5 mg), formulated as a single tablet. The experimental design of this bioequivalence study used commercially-available 40 mg frusemide tablets and 5 mg amiloride tablets as reference drugs, administered either separately or concomitantly. From a statistical analysis of plasma levels of frusemide and amiloride, no significant differences between the reference drugs alone and the combination tablet were seen in peak plasma levels, mean times to peak or mean areas under the plasma concentration-time curves (AUCs). The ratio of AUCs of the combination tablet to the reference drugs approached a limiting value many hours prior to complete elimination of the drug and hence reliable bioavailability comparisons were possible with blood sampling up to 24 hours post-dose.

No abstract

Urinary volume and electrolyte excretion were monitored for 24 hours in 12 elderly, catheterized patients with mild congestive cardiac failure. Five timed collections (0 to 3, 3 to 6, 6 to 9, 9 to 12 and 12 to 24 hours) were made after single doses of 40 mg frusemide, 5 mg amiloride and a combination tablet containing both 40 mg frusemide and 5 mg amiloride. Patients received each therapy according to a Latin Square design, with a 6-day washout phase separating the three study periods. The study periods consisted of a 24-hour control urinary collection, immediately followed by diuretic and a further 24-hour urine collection. Diuretics were not administered immediately prior to the study or during the washout phases. Amiloride, as expected, showed mild diuretic and natriuretic properties, but in the 12 to 24-hour period it induced a greater diuresis (p less than 0.05) than did frusemide or the combination. Frusemide and the combination tablet both produced a rapid and powerful diuresis in the 0 to 3-hour post-dose period and did not differ significantly in urine output at any time point. However, a difference in natriuretic activity was seen between frusemide and the combination, with the latter producing a significantly greater sodium excretion in the 12 to 24-hour period (p less than 0.05). Potassium-retaining activity throughout the 24 hours was marked after amiloride, with potassium excretion being significantly less (p less than 0.05) than either control, frusemide or the combination.(ABSTRACT TRUNCATED AT 250 WORDS)