Digital gastrointestinal imaging: the effect of pixel size on detection of subtle mucosal abnormalities

Five radiographs of double-contrast colon examinations demonstrating subtle mucosal changes of inflammatory bowel disease and five radiographs of healthy colonic mucosa were selected and digitized to four levels of resolution. Pixel sizes of 0.1 mm, 0.2 mm, 0.4 mm, and 0.8 mm were used. Ten radiologists interpreted the images, which were displayed on laser-printed film. Analysis of variance with repeated measures was performed and receiver operator characteristic curves were determined. The results demonstrate that the sensitivity in detecting subtle mucosal abnormalities improved as the resolution improved, with the best sensitivity at the highest resolution; more experienced readers detected details well even at the poorer levels of resolution; the resolution necessary for successfully evaluating the colonic mucosa was lower than expected; and given low noise levels, the matrix size used in conventional television fluoroscopy would be adequate for mucosal evaluation.     

Understanding and circumventing the blood-brain barrier

The blood-brain barrier presents a challenging obstacle to effective drug delivery to the central nervous system (CNS). Although biologically intended to protect the brain and spinal cord and provide a very stable fluid environment, the presence of a blood-brain barrier makes treatment of many CNS diseases difficult to achieve, as the required therapies cannot be delivered across the barrier in sufficient quantities or at all. Until relatively recently the blood-brain barrier was viewed largely as a physical barrier to diffusion, and the presence of tight junctions between endothelial cells simply prevented the passive diffusion of solutes from blood into the brain. Recent advances in cell and molecular biology have provided new insights into the function of the blood-brain barrier and it is now appreciated that, in addition to being a physical barrier, it is a complex transport and metabolic barrier and is a highly reactive and dynamic endothelium. Advances in understanding of the cell biology of the blood-brain barrier have opened new avenues and possibilities for improved drug delivery to the CNS. The challenges posed by the blood-brain barrier and the possibilities for overcoming them are reviewed.
Conclusion : Increased understanding of the molecular biology of the blood-brain barrier is now opening the way for new strategies to deliver drugs to the CNS.     

Blood pressure, lipids, lipoproteins, body fat and physical activity of Singapore children

Objective: To determine body composition, coronary risk factors and physical activity and the inter-relationships of these variables in Singaporean school children.
Methodology: This study examined 1681 children (784 boys and 897 girls) from eight primary and seven secondary schools to determine percentiles for body stature and composition, blood pressure, lipids/lipoproteins and blood glucose by gender for three age divisions. An exercise and leisure pursuit questionnaire was administered to ascertain self-reported physical activity patterns. Anthropometric data and blood pressure readings were taken. Capillary blood was drawn from each child via finger prick sampling following an overnight fast. The concentrations of total cholesterol (TCHOL), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and glucose (GLU) were determined from plasma using a dry chemistry analyser. Low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL) and the TCHOL/HDL-C ratio were determined by calculation.
Results: While 47.7% of boys and 22.0% of girls disclosed active lifestyles, differences between the active and non-active children were found in coronary risk factors TCHOL, LDL-C, TG, TCHOL/HDL-C and per cent body fat. No differences were shown between the two groups in HDL-C, GLU and blood pressure. There was a high correlation between the various measures of body composition with the highest correlation ( r =0.806, P < 0.001) found between body mass index (BMI) and waist measurements.
Conclusions: Children in this study who reported no activity or relatively little activity were found to have TCHOL, LDL-C, TG, TCHOL/HDL-C and per cent body fat that were higher than those who reported moderately high or vigorous physical activity patterns.     

Recurrent parotitis

(1) Recurrent parotitis is probably caused by a congenital abnormality of the salivary gland ducts with recurrent attacks of ascending infection, perhaps aided by dehydration. The parotid gland is predominantly affected probably because of its lower rate of secretion compared with the submandibular gland. (2) The condition mainly affects children between the ages of 3 and 6, with males being more commonly affected. The symptoms peak in the first year of school, and usually, but not invariably, begin to subside at puberty. By the age of 22, most patients are completely symptom-free. When the disease starts after puberty, females are predominantly affected. (3) Ultrasound is the appropriate initial investigation, and is usually supplemented by sialography. The sialography may itself cause a resolution of symptoms. (4) Treatment is conservative in the first instance, and an expectant policy is indicated. More aggressive treatment is justified only for those adults with persistent problems. This may be parotid duct ligation, parotidectomy, or tympanic neurectomy, depending upon the preference and experience of the treating physician.     

Urinary mutagenicity as a biomarker in workers exposed to benzidine: correlation with urinary metabolites and urothelial DNA adducts

Urinary mutagenicity has been used in occupational and epidemiological studies for over two decades as a cost-effective, general biomarker of exposure to genotoxic agents. However, few studies have compared urinary mutagenicity to additional biomarkers determined among low- and high-exposed groups. To address this issue, we evaluated the relationship between urinary mutagenicity and other types of biomarkers in a cross-sectional study involving 15 workers exposed to the urinary bladder carcinogen benzidine (BZ, high exposure), 15 workers exposed to BZ-dyes (low exposure), and 13 unexposed controls in Ahmedabad, India. Urinary organics were extracted by C18/methanol and evaluated for mutagenicity in the presence of S9 in the Salmonella strain YG1024, which is a frameshift strain that overproduces acetyltransferase. The results were compared to biomarker data reported recently from the same urine samples (Rothman et al., Proc. Natl Acad. Sci. USA, 93, 5084- 5089, 1996) that included a metabolite biomarker (the sum of the urinary levels of BZ + N-acetylbenzidine + N,N'-diacetylbenzidine) and a DNA adduct biomarker [a presumptive N-(3'-phosphodeoxyguanosin-8-yl)- N'-acetylbenzidine (C8dG-ABZ) DNA adduct in exfoliated urothelial cells]. The mean +/- SE urinary mutagenicity (revertants/micromol of creatinine) of the low-exposure (BZ-dye) workers was 8.2 +/- 2.4, which was significantly different from the mean of the controls (2.8 +/- 0.7, P = 0.04) as was that of the mean of the high-exposure (BZ) workers (123.2 +/- 26.1, P < 0.0001). Urinary mutagenicity showed strong, positive correlations with urinary metabolites (r = 0.88, P < 0.0001) and the level of the presumptive C8dG-ABZ urothelial DNA adduct (r = 0.59, P = 0.0006). A strong association was found between tobacco use (bidi smoking) and urinary mutagenicity among the controls (r = 0.68, P = 0.01) but not among the exposed workers (r = 0.18, P = 0.11). This study confirms the ability of a biomarker such as urinary mutagenicity to detect low-dose exposures, identify additional genotoxic exposures among the controls, and correlate strongly with urinary metabolites and DNA adducts in the target tissue (urinary bladder epithelia) in humans.      

The mouse H19 locus mediates a transition between imprinted and non- imprinted DNA replication patterns

Genes subject to genomic imprinting generally occur in clusters of hundreds of kilobases. These domains exhibit several gamete of origin- dependent manifestations, including a pattern of asynchronous replication when studied by fluorescence in situ hybridization (FISH). We find a transition from asynchronous replication at the imprinted mouse H19 gene to synchronous replication at the downstream Rpl23 gene, the human homologue of which appears to be non-imprinted. Two-colour FISH demonstrates that this transition is due solely to a difference in replication timing between the upstream and downstream chromatin on the later-replicating (maternal) chromosome. This difference is lost in mice deleted for the H19 gene body and 9.9 kb of upstream DNA when this deletion is maternally inherited, with synchronous replication patterns extending over 110 kb upstream from the deleted area. No effect is seen when the deletion is paternally inherited. The presence of a boundary element in this region has been suggested by observations of position- independent expression of H19 -containing transgenes and the blocking of accessibility of downstream enhancers to the upstream Igf2 and Ins2 genes on the maternal chromosome. The FISH studies presented here demonstrate the insulation of replication patterns within the imprinted domain from downstream, non-imprinted chromatin, mediated by an element at the H19 locus which is subject to genomic imprinting.      

Only hydrosalpinges visible on ultrasound are associated with reduced implantation and pregnancy rates after in-vitro fertilization

A retrospective analysis of clinical and laboratory data was made of all in-vitro fertilization (IVF) patients with tubal pathology who had their first ever embryo transfer cycle between January 1st, 1992 and September 1st, 1996. The aim of the study was to determine the effect of the presence of a hydrosalpinx, whether or not visible by ultrasound, on pregnancy, multiple pregnancy and implantation rates in our patient population. The IVF success rate was also analysed by calculating cumulative ongoing pregnancy rates of the same patient group using the lifetime table approach. In the presence of an ultrasound-visible hydrosalpinx, rates of pregnancy and multiple pregnancy appeared reduced, but the differences were not significant. The rates of implantation, clinical implantation and ongoing implantation were significantly lower in the presence of an ultrasound- visible hydrosalpinx (odds ratios 0.33-0.46, C.I. 0.21-0.96). The cumulative chance of achieving an ongoing pregnancy after one or more IVF cycles was significantly reduced in the presence of an ultrasound- visible hydrosalpinx (relative hazard 0.36, C.I. 0.22-0.59). In the presence of a hydrosalpinx not visible by ultrasound the IVF outcome was not reduced. This retrospective study confirms that patients with hydrosalpinges have an impaired IVF outcome. Unique to this study and previously unobserved is the finding that there is a subgroup of patients with hydrosalpinges, those with ultrasound-visible hydrosalpinges, which is exclusively responsible for this impaired outcome.      

Molecular characterization of breakpoints in patients with holoprosencephaly and definition of the HPE2 critical region 2p21

Holoprosencephaly (HPE) is a common developmental defect involving the brain and face in humans. Cytogenetic deletions in patients with HPE have localized one of the HPE genes (HPE2) to the chromosomal region 2p21. Here we report the molecular genetic characterization of nine HPE patients with cytogenetic deletions or translocations involving 2p21. We have determined the parental origin of the deleted chromosomes and defined the HPE2 critical region between D2S119 and D2S88/D2S391. As a first step towards cloning the HPE2 gene which is crucial for normal brain development we have constructed a YAC contig which spans the smallest region of deletion overlap. Several of these YACs could be identified which span three different 2p21 breakpoints in HPE patients. These YACs narrow the HPE2 critical region to less than 1 Mb and are now being further analyzed to identify the gene causing holoprosencephaly on chromosome 2.      

Increased insulin concentrations in nondiabetic offspring of diabetic parents

Insulin resistance is thought by many to be the primary defect that results in non-insulin-dependent diabetes mellitus (NIDDM). An implication of this theory is that prediabetic persons have higher serum insulin levels than normal subjects. We assessed serum insulin concentrations in a cohort of 1497 nondiabetic Mexican Americans, a population at high risk for NIDDM, according to whether their parents or siblings had diabetes. It was assumed that prediabetic persons would be more likely to have strong family histories of diabetes. We found a stepwise increase in fasting insulin levels in nondiabetics with neither, one, or both parents with diabetes (69.8, 77.8, and 94.6 pmol per liter, respectively; P = 0.002). Similar results were observed for insulin sum (the total of insulin concentrations in the fasting state and at 30, 60, and 120 minutes after a 75-g oral glucose load). The differences in insulin sums according to family history remained statistically significant in analyses of covariance, which controlled for variations in body-mass index, body-fat distribution, and level of blood glucose. Subjects without diabetes who had a diabetic sibling had higher fasting concentrations of insulin than subjects without a diabetic sibling (83.2 vs. 69.6 pmol per liter), but the difference was not statistically significant. We conclude that prediabetic persons, who would be expected to be more numerous in kindreds with progressively stronger family histories of diabetes, have hyperinsulinemia. This supports the insulin-resistance hypothesis.