Genetic variation near the hepatocyte nuclear factor-4 alpha gene predicts susceptibility to type 2 diabetes

The Finland-United States Investigation Of NIDDM Genetics (FUSION) study aims to identify genetic variants that predispose to type 2 diabetes by studying affected sibling pair families from Finland. Chromosome 20 showed our strongest initial evidence for linkage. It currently has a maximum logarithm of odds (LOD) score of 2.48 at 70 cM in a set of 495 families. In this study, we searched for diabetes susceptibility variant(s) at 20q13 by genotyping single nucleotide polymorphism (SNP) markers in case and control DNA pools. Of 291 SNPs successfully typed in a 7.5-Mb interval, the strongest association confirmed by individual genotyping was with SNP rs2144908, located 1.3 kb downstream of the primary beta-cell promoter P2 of hepatocyte nuclear factor-4 alpha (HNF4A). This SNP showed association with diabetes disease status (odds ratio [OR] 1.33, 95% CI 1.06-1.65, P = 0.011) and with several diabetes-related traits. Most of the evidence for linkage at 20q13 could be attributed to the families carrying the risk allele. We subsequently found nine additional associated SNPs spanning a 64-kb region, including the P2 and P1 promoters and exons 1-3. Our results and the independent observation of association of SNPs near the P2 promoter with diabetes in a separate study population of Ashkenazi Jewish origin suggests that variant(s) located near or within HNF4A increases susceptibility to type 2 diabetes.     

Placental transfer and tissue localization of digoxin in the pregnant rat

Serum and tissue digoxin concentrations were estimated by radioimmunoassay in maternal and fetal animals at various times following the injection of pregnant rats, on Days 19 or 20 of gestation, with digoxin (0.1 mg/kg iv). Maternal serum digoxin concentrations were 3.5 to 5 times greater than corresponding fetal concentrations during the early period of sampling (2–10 min) and ranged from 1.8- to 2.7-fold higher for the remainder of each experiment. The elimination of digoxin from maternal serum followed a biexponential pattern ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{α = 0.36}\text{hr}\text{; t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{β = 3.52}\text{hr}\text{; K}{}_{\mathrm{<mtext>el</mtext>}}\text{= 0.39}\text{hr}{}^{\mathrm{?1}}$) and was similar to that observed in placental tissue and the fetal circulation. Maternal tissue concentrations of digoxin were highest in the liver followed in descending order by the skeletal muscle, heart, and kidney. The distribution pattern in fetal tissues differed significantly as indicated: heart > kidney > liver. These data have demonstrated that digoxin is rapidly transferred across the placenta of the pregnant rat. Differences in the fetal/maternal tissue distribution patterns of the drug may reflect developmental influences upon tissue binding and/or regional perfusion.     

Sequence variation in PPARG may underlie differential response to troglitazone

Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor-gamma (PPARG) agonists used to treat type 2 diabetes. TZDs can also be used to reduce rates of type 2 diabetes in at-risk individuals. However, a large fraction of TZD-treated patients (30-40%) do not respond to TZD treatment with an improvement in insulin sensitivity (Si). We hypothesized that variation within the gene encoding PPARG may underlie this differential response to TZD therapy. We screened approximately 40 kb of PPARG in 93 nondiabetic Hispanic women (63 responders and 30 nonresponders) with previous gestational diabetes who had participated in the Troglitazone In the Prevention Of Diabetes study. TZD nonresponse was defined as the lower tertile in change in Si after 3 months of treatment. Baseline demographic and clinical measures were not different between responders and nonresponders. We identified and genotyped 131 variants including 126 single nucleotide polymorphisms and 5 insertion-deletion polymorphisms. Linkage disequilibrium analysis identified five haplotype blocks. Eight variants were associated with TZD response (P < 0.05). Three variants were also associated with changes in Si as a continuous variable. Our results suggest that PPARG variation may underlie response to TZD therapy in women at risk for type 2 diabetes.     

Macular thickness as determined by optical coherence tomography in relation to degree of myopia,axial length and vitreous chamber depth in Malay subjects

Purpose: This study aimed to determine the relationship between macular thickness and spherical equivalent refraction (SER), axial length (AL) and vitreous chamber depth (VCD) in Malay subjects. Methods: Sixty‐three subjects (aged 19–24 years) with a mean SER of ‐1.79 ± 2.24 D, mean axial length of 24.26 ± 1.35 mm and mean vitreous chamber depth of 17.02 ± 1.33 mm were included in this clinical cross‐sectional study. Stratus optical coherence tomography (Time Domain optical coherence tomography) was used to determine the thickness of the outer macular (perifovea) and inner macular (parafovea) at four different locations, that is, temporal, superior, nasal and inferior quadrants and also the fovea itself. Results: Positive correlations were found between the outer macular (perifovea) thickness and SER at the temporal (R = 0.47, p < 0.05), superior (R = 0.36, p < 0.05) and inferior (R = 0.31, p < 0.05) quadrants. Foveal thickness was also positively correlated with AL (R = 0.34, p < 0.05) and VCD (R = 0.32, p < 0.05). Negative correlations were found between outer macular thickness and axial length at the temporal (R = ‐0.46, p < 0.05), superior (R = ‐0.27, p < 0.05), nasal (R = ‐0.25, p < 0.05) and inferior (R = ‐0.36, p < 0.05) quadrants. Negative correlations were also found between outer macular thickness and VCD at the temporal (R = ‐0.51, p < 0.05), superior (R = ‐0.32, p < 0.05), nasal (R = ‐0.31, p < 0.05) and inferior (R = ‐0.40, p < 0.05) quadrants. Conclusions: This study shows that the degree of myopia and elongation of the globe are associated with thinning of most areas of the perifovea. A trend for foveal thickening in the high myopia group is also inferred, although this does not apply to the low and moderate myopia groups.     

The detection and discrimination of categorical yellow

Threshold detection of most spectral tights presented on a white background is subserved by colour opponent mechanisms which produce distinct percepts of colours. Five ranges of wavelengths can be discriminated: red, yellow, green, blue and violet (Mullen and Kulikowski (1990) Wavelength discrimination at detection threshold. J. Opt. Soc. Am. A7 , 733–742). However, under most viewing conditions yellow can also be detected and discriminated by activating the achromatic mechanism. Using 2-alternative forced-choice we studied detection and discrimination between spots (1 deg) which were either spectral colours or while (matching the background in colour temperature), with and without masking the achromatic mechanisms. For low colour temperatures of white (2700 K), yellow could be discriminated from white at slight suprathreshold levels of detection. However, at a colour temperature of 6800K and with masking, the yellow-white discrimination threshold for 565–574 nm was also close to detection threshold (as for other wavelengths). We conclude that it is possible to demonstrate the rote of the blue-yellow opponent mechanism in categorical perception of yellow (at threshold) by sensitizing its yellow branch and by suppressing the achromatic mechanism.     

M-mode echocardiographic findings in children with idiopathic restrictive cardiomyopathy

Summary The M-mode echocardiographic findings in five pediatric patients, ages 4–15 years, with primary idiopathic restrictive cardiomyopathy, diagnosed by cardiac catheterization, and of 12 normal children (control group) are presented. The M-mode echocardiographic findings in patients with restrictive cardiomyopathy were (1) normal left and right ventricular end-diastolic dimension, (2) normal left ventricular posterior wall and interventricular septal thickness (three patients) or mild concentric hypertrophy (two patients), (3) normal opening and closing velocity of the mitral valve, (4) consistently enlarged left atrium (more than 40 mm) in all, and (5) right ventricular systolic time intervals compatible with pulmonary artery hypertension. The left ventricular ejection phase parameters (systolic time intervals, shortening fraction, and mean velocity of circumferential fiber shortening) were normal. Left ventricular relaxation phase parameters (diastolic function) were abnormal. The isovolumic relaxation time index was prolonged, 68±40 ms (±SD), in the study group as compared with 11±6 ms (±SD) in the control group (P<0.001). Percent relaxation of left ventricular posterior wall endocardium at 50% of diastole was decreased, 58±4% (±SD), in the study group as compared with 85±6% (±SD) in the control group (P<0.005). We conclude that M-mode echocardiography provides arelatively useful and specific noninvasive method for the diagnosis of primary restrictive cardiomyopathy in pediatric patients. This work was supported in part by NHLBI grant HL07436.     

Spectral sensitivity in patients with dysthyroid eye disease

The majority of patients with dysthyroid eye disease have an acquired colour vision defect. However, no psychophysical investigation of selective damage to colour or flicker pathways has been carried out. In order to clarify the nature of the visual pathology, we have used a psychophysical technique (spectral sensitivity) to selectively stimulate the chromatic and achromatic mechanisms. Spectral spots of size 1° presented at a rate of 1 Hz on a bright 1000 td white background are detected by the chromatic mechanism but a rate of 25 Hz reveals the achromatic mechanism. Fifteen patients (28 eyes) between the ages of 50–70 years were tested. The study showed that all patients had reduced spectral sensitivity, either 1 Hz, 25 Hz or both. The patients with reduced 1 Hz or 25 Hz spectral sensitivity only had a shorter systemic and ocular duration of the condition, had no proptosis, normal intraocular pressures in primary gaze, slightly higher intraocular pressures on upgaze, normal visual field plots and FM 100-Hue error scores higher than the normal age-matched values. The patients with reduced both 1 Hz and 25 Hz spectral sensitivities had a longer systemic and ocular duration of the condition, had proptosis, normal intraocular pressures in primary position, higher intraocular pressures on upgaze and higher FM 100-Hue error scores than the age-matched normals and those in Groups 1 and 2. A total of 50% of patients in Group 3 had defective visual field plots. These data suggest that there is damage of the large achromatic fibres and small chromatic fibres in dysthyroid eye disease. The mechanism of the damage could be one of ischaemic or mechanical or both.