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Studies of the association between prenatal methylmercury exposure from maternal fish consumption during pregnancy and neurodevelopmental test scores in the Seychelles Child Development Study have found no consistent pattern of associations through age nine years. The analyses for the most recent nine-year data examined the population effects of prenatal exposure, but did not address the possibility of non-homogeneous susceptibility. This paper presents a regression tree approach: covariate effects are treated nonlinearly and non-additively and non-homogeneous effects of prenatal methylmercury exposure are permitted among the covariate clusters identified by the regression tree. The approach allows us to address whether children in the lower or higher ends of the developmental spectrum differ in susceptibility to subtle exposure effects. Of twenty-one endpoints available at age nine years, we chose the Weschler Full Scale IQ and its associated covariates to construct the regression tree. The prenatal mercury effect in each of the nine resulting clusters was assessed linearly and non-homogeneously. In addition we reanalyzed five other nine-year endpoints that in the linear analysis has a two-tailed p-value

Several reports indicate a complexity in glycosyltransferase activities which lead to several tumor associated carbohydrate structures in gastric carcinoma. The present study was aimed to identify the carbohydrate associated transferases which exhibit the most marked and consistent change of activity in gastric tumorigenesis.We examined the levels of fucosyl, beta-galactosyl-, beta-N-acetylgalactosaminyl, sialyl- and glycan:sulfotransferase activities, which generate the outer ends of oligosaccharide chains in tumorous and adjacent normal gastric tissues of the same patient in ten gastric carcinoma cases by using well defined specific synthetic acceptors utilized in our several earlier published studies as referenced in the text (e.g. Chandrasekaran et al. in J Biol Chem 279:10032-10041, 2004; Biochemistry 44:15619-15635, 2005; Carbohydr Res 341:983-994, 2006).Among glycosyltransferases only alpha1,2-fucosyltransferase (FT) was unique in showing a remarkable 40-90% decrease of activity in seven cases. Uniquely several fold elevation of Gal3Sulfo-T(2) (1.9 --156.7 fold) and Gal3Sulfo-T(4) (2.4 --149.0 fold) activities in all ten cases and moderate elevation of GlcNAc6Sulfo-T (1.3 --37.5 fold) activities in nine cases were identified. Poorly differentiated Signet ring cell carcinoma expresses mainly Gal3Sulfo-T(2) activity whereas poorly differentiated adenocarcinoma express predominantly Gal3Sulfo-T(4) activity and also GlcNAc6Sulfo-T activity. But, very low level of these sulfotransferase activities were identified in moderately differentiated gastric carcinomas as well as non-epithelial gastric stromal sarcoma.Up regulation of glycan:sulfotransferase activities and down regulation of alpha1,2-fucosyltransferase activity are apparently associated with human gastric tumorigenesis.

OBJECTIVE: Renal cytochrome P450 3A5 (CYP3A5) activity has been associated with blood pressure and salt sensitivity in humans. We determined whether CYP3A5 polymorphisms are associated with ambulatory blood pressure (ABP) and with glomerular filtration rate (GFR) in African families. METHODS: Using a cross-sectional design, 375 individuals from 72 families, each with at least two hypertensive siblings, were recruited through a hypertension register in the Seychelles (Indian Ocean). We analyzed the association between the CYP3A5 alleles (*1, *3, *6 and *7) and ABP, GFR and renal sodium handling (fractional excretion of lithium), from pedigree data, allowing for other covariates and familial correlations. RESULTS: CYP3A5*1 carriers increased their daytime systolic and diastolic ABP with age (0.55 and 0.23 mmHg/year) more than non-carriers (0.21 and 0.04 mmHg/year). CYP3A5*1 had a significant main effect on daytime systolic/diastolic ABP [regression coefficient (SE): -29.6 (10.0)/-8.2 (4.1) mmHg, P = 0.003/0.045, respectively] and this effect was modified by age (CYP3A5*1 x age interactions, P = 0.017/0.018). For night-time ABP, the effect of CYP3A5*1 was modified by urinary sodium excretion, not by age. For renal function, CYP3A5*1 carriers had a 7.6(3.8) ml/min lower GFR (P = 0.045) than non-carriers. Proximal sodium reabsorption decreased with age in non-carriers, but not in CYP3A5*1 carriers (P for interaction = 0.02). CONCLUSIONS: These data demonstrate that CYP3A5 polymorphisms are associated with ambulatory BP, CYP3A5*1 carriers showing a higher age- and sodium- related increase in ABP than non-carriers. The age effect may be due, in part, to the action of CYP3A5 on renal sodium handling.

We discuss the diagnostic value of nuclear scintigraphy in the management of infections after cochlear implantation. A 56-year-old female (Case 1) and a 46-year-old female (Case 2) developed complaints of diffuse headache, 4 and 5 months after cochlear implantation, without other signs of infection during examination, laboratorial testing and initial computed tomography. In Case 1 we performed a technetium 99 m-difosfate scintigraphy, which showed an increased uptake in the right petrosal bone, suggestive of chronic osteomyelitis. This case failed conservative treatment and underwent complete explantation, after which 67gallium-citrate single-photon emission computed tomography normalized during follow-up. In Case 2 inflammation at the site of the cochlear implant was confirmed by performing a positron emission tomography scan, which showed an increased uptake. Case 2 was treated successfully with antibiotics. Both have no signs of recurrent infection. Nuclear scintigraphy can be the single valuable tool in case of a late low-grade infection after cochlear implantation. Delayed low-grade chronic osteomyelitis of the petrosal bone is a rare but dramatic complication after cochlear implantation. It can develop with minimal signs of infection.

G. S. Dell, K. D. Reed, D. R. Adams, and A. S. Meyer (2000) proposed a "breadth-of-constraint" continuum on phoneme errors, using artificial experiment-wide constraints to investigate a putative middle ground between local and language-wide constraints. The authors report 5 experiments that test the idea of the continuum and the location of the experiment-wide constraints within it. Experiments 1 and 2 replicated the findings of Dell et al. on the experiment-wide constraints but showed only chance adherence to the local positional constraints. Experiment 3 showed that the latter constraints are uniquely affected by the form of practice used. Experiments 4 and 5 investigated the time course and robustness of the experimental constraints by reversing them during testing. This caused no difficulty when occurring between blocks (Experiment 4) but caused short-lived disruption when occurring within block (Experiment 5). The authors propose that the results do not support the idea of a continuum, but that the experiment-wide constraints reflect a local biasing of language-wide constraints, probably related to the need for rapid learning.

BackgroundWe assessed the prevalence of risk factors for cardiovascular disease (CVD) in a middle-income country in rapid epidemiological transition and estimated direct costs for treating all individuals at increased cardiovascular risk, i.e. following the so-called "high risk strategy".MethodsSurvey of risk factors using an age- and sex-stratified random sample of the population of Seychelles aged 25–64 in 2004. Assessment of CVD risk and treatment modalities were in line with international guidelines. Costs are expressed as US$ per capita per year.Results1255 persons took part in the survey (participation rate of 80.2%). Prevalence of main risk factors was: 39.6% for high blood pressure (≥140/90 mmHg or treatment) of which 59% were under treatment; 24.2% for high cholesterol (≥6.2 mmol/l); 20.8% for low HDL-cholesterol (2) and 22.1% for the metabolic syndrome. Overall, 43% had HBP, high cholesterol or diabetes and substantially increased CVD risk. The cost for medications needed to treat all high-risk individuals amounted to US $45.6, i.e. $11.2 for high blood pressure, $3.8 for diabetes, and $30.6 for dyslipidemia (using generic drugs except for hypercholesterolemia). Cost for minimal follow-up medical care and laboratory tests amounted to $22.6.ConclusionHigh prevalence of major risk factors was found in a rapidly developing country and costs for treatment needed to reduce risk factors in all high-risk individuals exceeded resources generally available in low or middle income countries. Our findings emphasize the need for affordable cost-effective treatment strategies and the critical importance of population strategies aimed at reducing risk factors in the entire population.

We estimated the heritability of ambulatory systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) in east African families with at least 2 hypertensive siblings and living in the Seychelles islands (Indian Ocean). The sample consisted of 314 individuals (147 men and 167 women), both normotensive and hypertensive, from 76 pedigrees (mean±SD of 4.1±2.8 persons per pedigree). After a 2-week off-treatment period, daytime and nighttime ambulatory blood pressure (BP) was monitored. Office BP was measured with a standard mercury sphygmomanometer. We estimated by maximum likelihood the age- and sex-adjusted heritabilities from the additive polygenic component of the variance of the traits allowing for the presence of other familial correlations. We also adjusted for ascertainment (ie, for the fact that 2 siblings had to be hypertensive) and examined the effect of adjusting for body mass index, 24-hour urinary excretion of sodium and potassium, plasma renin activity, and plasma aldosterone concentration. Heritability estimates (±SE) for ambulatory SBP, DBP, and PP were, respectively, 0.37±0.12/0.24±0.12/0.54±0.12 for daytime and 0.34±0.13/ 0.37±0.15/0.47±0.12 for nighttime measurements ( P

Publisher Summary Mercury is ubiquitous in the environment, and the amount an individual comes in contact with it is increasing. The organic form of methyl mercury (MeHg) is very toxic to the central nervous system (CNS). All fish contain small amounts of MeHg, and everyone who consumes fish or seafood is exposed to it. Once inside the body, MeHg readily crosses the placenta and the blood–brain barrier and enters the CNS. MeHg poisoning episodes have clearly demonstrated that the developing fetal brain is especially sensitive, and it can be seriously impaired, even when the mother has no symptoms. The events in Japan confirm that consuming fish that is heavily contaminated with MeHg can damage the developing CNS. However, interpreting the Japanese experience is complicated by the very high exposures and the presence of other toxins in the factory waste. Studies of poisoning in Iraq suggest that a level of prenatal exposure of around 10 ppm measured in maternal hair might adversely affect the developing fetus. Individuals who consume fish with only background levels of MeHg can achieve a hair level of 10 ppm or greater. However, there are no reported cases of mild disability after prenatal MeHg exposure and no reports of poisoning from fish consumption outside of Japan.

This paper describes the structure and operation of a new differential phase angular rate sensor and analyses it's response to input rotation. It employs a vibrating beam mass structure that is forced into an elliptical path when subject to rotation due to the Coriolis effect. Two sensing elements are strategically located to sense a combination of drive and Coriolis force on each to create a phase differential representative of the input rotation rate. A general model is developed describing the device operation. The main advantages of the phase detection scheme are shown, including removing the need to maintain constant drive amplitude, independence of sensing element gain factor and novel response shapes. A ratio of device parameters is defined and shown to determine the device response shape. This ratio can be varied to give a high sensitivity around zero input rate or a response shape not seen before, that can give maximum sensitivity around an offset from the zero-rate input. This may be exploited in an array configuration for a highly accurate device over a wide input range. A worked example shows how the developed equations can be used as design tools to achieve a desired response.

Background The prevalence of hyperuricemia has rarely been investigated in developing countries. The purpose of the present study was to investigate the prevalence of hyperuricemia and the association between uric acid levels and the various cardiovascular risk factors in a developing country with high average blood pressures (the Seychelles, Indian Ocean, population mainly of African origin). Methods This cross-sectional health examination survey was based on a population random sample from the Seychelles. It included 1011 subjects aged 25 to 64 years. Blood pressure (BP), body mass index (BMI), waist circumference, waist-to-hip ratio, total and HDL cholesterol, serum triglycerides and serum uric acid were measured. Data were analyzed using scatterplot smoothing techniques and gender-specific linear regression models. Results The prevalence of a serum uric acid level >420 μmol/L in men was 35.2% and the prevalence of a serum uric acid level >360 μmol/L was 8.7% in women. Serum uric acid was strongly related to serum triglycerides in men as well as in women (r = 0.73 in men and r = 0.59 in women, p < 0.001). Uric acid levels were also significantly associated but to a lesser degree with age, BMI, blood pressure, alcohol and the use of antihypertensive therapy. In a regression model, triglycerides, age, BMI, antihypertensive therapy and alcohol consumption accounted for about 50% (R2) of the serum uric acid variations in men as well as in women. Conclusions This study shows that the prevalence of hyperuricemia can be high in a developing country such as the Seychelles. Besides alcohol consumption and the use of antihypertensive therapy, mainly diuretics, serum uric acid is markedly associated with parameters of the metabolic syndrome, in particular serum triglycerides. Considering the growing incidence of obesity and metabolic syndrome worldwide and the potential link between hyperuricemia and cardiovascular complications, more emphasis should be put on the evolving prevalence of hyperuricemia in developing countries.

Although the Naval Postgraduate School (NPS) was established in 1909 on the campus of the United States Naval Academy, the Department of Aeronautics was not established until 1947. The initial mission of the Department of Aeronautics was to better prepare naval aviation officers for the transition from piston engine powered aircraft to gas turbine powered jet aircraft. In 1987 the Department was expanded to include the field of astronautics. In this paper the educational objectives, programs, and developments in the major areas of concentration are briefly described for the purpose of providing a historical perspective on the Department’s development, major accomplishments and current status.

Sulfated glycoconjugates regulate biological processes such as cell adhesion and cancer metastasis. We examined the acceptor specificities and kinetic properties of three cloned Gal:3-O-sulfotransferases (Gal3STs) ST-2, ST-3, and ST-4 along with a purified Gal3ST from colon carcinoma LS180 cells. Gal3ST-2 was the dominant Gal3ST in LS180. While the mucin core-2 structure Galbeta1,4GlcNAcbeta1,6(3-O-MeGalbeta1,3)GalNAcalpha-O-Bn (where Bn is benzyl) and the disaccharide Galbeta1,4GlcNAc served as high affinity acceptors for Gal3ST-2 and Gal3ST-3, 3-O-MeGalbeta1,4GlcNAcbeta1,-6(Galbeta1,3)GalNAcalpha-O-Bn and Galbeta1,3GalNAcalpha-O-Al (where Al is allyl) were efficient acceptors for Gal3ST-4. The activities of Gal3ST-2 and Gal3ST-3 could be distinguished with the Globo H precursor (Galbeta1,3GalNAcbeta1,3Galalpha-O-Me) and fetuin triantennary asialoglycopeptide. Gal3ST-2 acted efficiently on the former, while Gal3ST-3 showed preference for the latter. Gal3ST-4 also acted on the Globo H precursor but not the glycopeptide. In support of the specificity, Gal3ST-2 activity toward the Galbeta1,4GlcNAcbeta unit on mucin core-2 as well as the Globo H precursor could be inhibited competitively by Galbeta1,4GlcNAcbeta1,6(3-O-sulfoGalbeta1,3)GalNAcalpha-O-Bn but not 3-O-sulfoGalbeta1,-4GlcNAcbeta1,6(Galbeta1,3)GalNAcalpha-O-Bn. Remarkably these sulfotransferases were uniquely specific for sulfated substrates: Gal3ST-3 utilized Galbeta1,4(6-O-sulfo)-GlcNAcbeta-O-Al as acceptor, Gal3ST-2 acted efficiently on Galbeta1,3(6-O-sulfo)GlcNAcbeta-O-Al, and Gal3ST-4 acted efficiently on Galbeta1,3(6-O-sulfo)GalNAcalpha-O-Al. Mg(2+), Mn(2+), and Ca(2+) stimulated the activities of Gal3ST-2, whereas only Mg(2+) augmented Gal3ST-3 activity. Divalent cations did not stimulate Gal3ST-4, although inhibition was noted at high Mn(2+) concentrations. The fine substrate specificities of Gal3STs indicate a distinct physiological role for each enzyme.

The synthesis of an octasaccharide containing the dimeric Lex oligosaccharide structure found in PSGL-1 carbohydrate chains is reported. Several approaches were investigated employing regioselective and stereoselective glycosylation procedures, and a novel Lewisx trisaccharide donor, 7, was prepared and utilized as a key intermediate building block in the scheme developed for the construction of octasaccharide 3. Toward the preparation of 7, investigations into the influence of different protecting groups upon the relative reactivities of disaccharide acceptor moieties, 25 or 26, and the fucosyl donors, 10 and 11, were conducted using similar glycosylating conditions. Dramatic differences were noted between the effects of electron-donating and electron-withdrawing groups upon the reactivity of the acceptor hydroxyl. A similar effect upon the glycosylating capability of the donor molecule was, likewise, observed. The repeat use of donor 7 was instrumental in the synthesis of the desired dimeric octasacchar...

Synthesis of core-2 branched tetrasaccharides 1-3, in which a fluorine atom was substituted at the 3 or 4-position of galactose residues is described. Glycosyl imidates 13, and 19 were prepared and used to provide novel glycosyl disaccharide donors 15 and 21, respectively. Coupling of acceptor 7 with glycosyl bromide 6 provides a disaccharide that was further converted into disaccharide acceptor 8. The coupling of acceptor 14 with donor 13, and acceptor 20 with donor 19 provided disaccharides that were converted to disaccharide donors 15 and 21. respectively. Regioselective glycosylation of acceptors 8, and 16 with donors 9, 15, and 21 provided tetrasaccharides 10,17, and 22 respectively, which were systematically deprotected to targets 1-3.

Human colon carcinoma cell fucosyltransferase (FT) in contrast to the FTs of several human cancer cell lines, utilized GlcNAcbeta1,4GlcNAcbeta-O-Bn as an acceptor, the product being resistant to alpha1,6-L-Fucosidase and its formation being completely inhibited by LacNAc Type 2 acceptors. Further, this enzyme was twofold active towards the asialo agalacto glycopeptide as compared to the parent asialoglycopeptide. Only 60% of the GlcNAc moieties were released from [14C]fucosylated asialo agalacto triantennary glycopeptide by jack bean beta-N-acetylhexosaminidase. These alpha1,3-L-fucosylating activities on multiterminal GlcNAc residues and chitobiose were further examined by characterizing the products arising from fetuin triantennary and bovine IgG diantennary glycopeptides and their exoglycosidase-modified derivatives using lectin affinity chromatography. Utilization of [14C]fucosylated glycopeptides with cloned FTs indicated that Lens culinaris lectin and Aleuria aurantia lectin (AAL) required, respectively, the diantennary backbone and the chitobiose core alpha1,6-fucosyl residue for binding. The outer core alpha1,3- but not the alpha-1,2-fucosyl residues decreased the binding affinity of AAL. The AAL-binding fraction from [14C]fucosylated asialo fetuin, using colon carcinoma cell extract, contained 60% Endo F/PNGaseF resistant chains. Similarly AAL-binding species from [14C]fucosylated TFA-treated bovine IgG using colon carcinoma cell extract showed significant resistance to endo F/PNGaseF. However, no such resistance was found with the corresponding AAL non- and weak-binding species. Thus colon carcinoma cells have the capacity to fucosylate the chitobiose core in glycoproteins, and this alpha1,3-L-fucosylation is apparently responsible for the AAL binding of glycoproteins. A cloned FT VI was found to be very similar to this enzyme in acceptor substrate specificities. The colon cancer cell FT thus exhibits four catalytic roles, i.e., alpha1,3-L-fucosylation of: (a) Galbeta1,4GlcNAcbeta-; (b) multiterminal GlcNAc units in complex type chain; (c) the inner core chitobiose of glycopeptides and glycoproteins; and (d) the nonreducing terminal chiotobiose unit.

The synthesis of an octasaccharide containing the dimeric Le(x) oligosaccharide structure found in PSGL-1 carbohydrate chains is reported. Several approaches were investigated employing regioselective and stereoselective glycosylation procedures, and a novel Lewis(x) trisaccharide donor, 7, was prepared and utilized as a key intermediate building block in the scheme developed for the construction of octasaccharide 3. Toward the preparation of 7, investigations into the influence of different protecting groups upon the relative reactivities of disaccharide acceptor moieties, 25 or 26, and the fucosyl donors, 10 and 11, were conducted using similar glycosylating conditions. Dramatic differences were noted between the effects of electron-donating and electron-withdrawing groups upon the reactivity of the acceptor hydroxyl. A similar effect upon the glycosylating capability of the donor molecule was, likewise, observed. The repeat use of donor 7 was instrumental in the synthesis of the desired dimeric octasaccharide structure 3. The structure and purity of 3 and important intermediates were fully characterized by DQF-COSY, TOCSY, ROESY, and ESI mass spectroscopy.

Prostate carcinoma LNCaP cells were unique among several human cancer cell lines which include two other prostate cancer cell lines, PC-3 and DU-145, in expressing alpha1,2-L-fucosyltransferase (FT) as an exclusive FT activity. Affinity gel-GDP and Sephacryl S100 HR columns were used for a partial purification of this enzyme from 3.9 x 10(9) LNCaP cells (approximately 200-fold; 40% yield). The K(m) value (2.7 mM) for the LacNAc type 2 acceptor was quite similar to the one reported for the cloned blood group H gene-specified alpha1,2-FT [Chandrasekaran et al. (1996) Biochemistry 35, 8914-8924]. N-Ethylmaleimide was a potent inhibitor (K(i ) 12.5 microM). The enzyme showed four-fold acceptor preference for the LacNAc type 2 unit in comparison to the T-hapten in mucin core 2 structure. Its main features were similar to those of the cloned enzyme: (1) C-6 sulfation of terminal Gal in the LacNAc unit increased the acceptor efficiency, whereas C-6 sialylation abolished acceptor ability; (2) C-6 sulfation of GlcNAc in LacNAc type 2 decreased by 80% the acceptor ability, whereas LacNAc type 1 was unaffected; (3) Lewis x did not serve as an acceptor; (4) the C-4 hydroxyl rather than the C-6 hydroxyl group of the GlcNAc moiety in LacNAc type1 was essential for activity; and (5) the acrylamide copolymer of Galbeta1,3GlcNAcbeta-O-Al was the best acceptor among the acrylamide copolymers. Additionally, highly significant biological features of alpha1,2FT were identified in the present study. The synthesis of Globo H and Lewis b determinants became evident from the fact that Galbeta1,3GalNAcbeta1,3Galalpha-O-Me and Galbeta1,3(Fucalpha1,4)Glc-NAcbeta1,3Galbeta-O-Me served as high-affinity acceptors for this enzyme. Further, D-Fucbeta1,3Gal-NAcbeta1,3Galalpha-O-Me was a very efficient acceptor, indicating that the C-6 hydroxyl group of the terminal Gal moiety in Globo H is not essential for the enzyme activity. Thus, the present study was able to demonstrate three different catalytic roles of LNCaP alpha1,2-FT, namely, the expressions of blood group H, Lewis b from Lewis a, and Globo H.