Modeling the impact of high thermal conductivity paper on the performance and life of power transformers.

Degradation of insulation paper is a key contributor to the failure of power transformers. Insulation degradation accelerates at elevated temperatures, which highlights the potential for better thermal management to prolong life. While several studies have analyzed the benefits of high thermal conductivity oil for reducing temperatures inside a transformer, this study is an initial assessment of the benefits of high thermal conductivity paper on transformer life. Blending particulates with cellulosic fibers offers a pathway for high thermal conductivity paper (with good dielectric properties), which can reduce internal temperatures. Presently, life extensions that can be achieved by the use of such thermally conducting papers were estimated, with the thermal conductivity of the paper being the key parameter under study. The analytical-numerical thermal model used in this study was validated against experimental measurements in a distribution transformer, adding confidence to the utility of the model. This model was then used to provide estimates of hot-spot temperature reduction resulting from the use of papers with higher thermal conductivity than baseline. Transformer life was predicted conventionally by tracking the degree of polymerization of paper over time, based on an Arrhenius model. Results indicate that increasing the thermal conductivity of paper from 0.2 W/mK (baseline) to 1 W/mK reduces the hot spot temperature by 10 °C. While degradation significantly depends on the moisture and oxygen content, the model shows that such a temperature reduction can increase life for all conditions, by as much as a factor of three.

A missense variant in CREBRF, rs373863828, is associated with fat-free mass, not fat mass in Samoan infants.

BACKGROUND/OBJECTIVES: In Samoa, where 80% of the adult population is living with obesity, understanding the determinants of adiposity and growth during infancy may inform prevention efforts. We examined the association of a missense variant, rs373863828, in the CREBRF gene with body composition in Samoan infants. Adults with one or more copies of the rs373863828 minor allele (A) have higher odds of obesity, based on body-mass index (BMI), but paradoxically decreased odds of diabetes compared to those without the allele. Our study may offer novel insight into the natural history and pathogenesis of this unexpected relationship. SUBJECTS/METHODS: In a prospective study, we measured body composition in early infancy, and at 2- and 4-months of age using anthropometry and dual-energy x-ray absorptiometry (DXA). We genotyped subjects at the CREBRF rs373863828 locus and compared infants with (AA/AG) and without (GG) the variant. In longitudinal analyses, we calculated the absolute change in each outcome from the early infant to the 4-month assessment, adjusting for baseline and other covariates. RESULTS: In cross-sectional analyses, there was no significant difference in infant BMI or fat mass by genotype. After adjusting for covariates, infants with the variant had 4.0 ± 1.8 g more bone mass (p = 0.026) and 210.9 ± 79.6 g more lean mass (p = 0.009) at 4-months and accumulated 176.9 ± 73.0 g more lean mass between the early infant and 4-month assessment (p = 0.017). CONCLUSIONS: The CREBRF rs373863828 minor allele (A) was not associated with increased BMI or adiposity in Samoan infants, but instead with increased lean and bone mass. Our findings suggest that lean (i.e., muscle) and bone mass accretion should be explored as pathways to explain the "protective" effect of the CREBRF variant against diabetes.

Effect of Ar(3p54p; 2p)+M → Ar(3p54s; 1s)+M branching ratio on optically pumped rare gas laser performance.

Optically pumped rare gas laser performance is analyzed as a function of the Ar(3p54p; 2p) + M → Ar(3p54s; 1s) + M branching ratios. Due to the uncertainty in the branching ratios, a sensitivity study is performed to determine the effect on output and absorbed pump laser intensities. The analysis is performed using a radio frequency dielectric barrier discharge as the source of metastable production for a variety of Argon in Helium mixtures over pressures ranging from 200 to 500 Torr. Peak output laser intensities show a factor of 7 increase as the branching ratio is increased from 0.25 to 1.00. The collection of Ar* in Ar(1s4) is inversely proportional to the branching ratio and decreases output laser intensity by reducing the density of species directly involved with lasing.

The effect of different combinations of local anaesthesia, sedative and non-steroidal anti-inflammatory drugs on daily growth rates of dairy calves after disbudding.

AIM: To assess the effect of sedation and local anaesthesia (LA) at disbudding, and the addition of meloxicam or ketoprofen treatment, on weight gain in dairy calves following disbudding. METHODS: Friesian-Jersey cross calves, from four dairy farms, were enrolled when 3-6 weeks old. All calves (n=271) were disbudded by veterinary personnel and randomly assigned to six groups: 136 were disbudded without sedation or LA, of which 31 received 20 mg meloxicam S/C and 75 received 150 mg ketoprofen I/M. A further 135 were disbudded with sedation (0.25 mg/kg xylazine I/M) and LA, of which 30 also received meloxicam and 75 received ketoprofen. Calves were weighed 3 days before, and 15 and 30 days after, disbudding (Day 0). Daily weight gain was analysed using mixed models and ANOVA. RESULTS: Complete results were obtained from 263 calves. From Day -3 to Day 15, the growth rate of calves disbudded without pain relief (0.53 (95% CI=0.47-0.60) kg/day) was less that of calves disbudded with some form of pain relief (0.65 (95% CI=0.62-0.68) kg/d; p=0.004). There was no difference between the effect of meloxicam or ketoprofen (p=1.00). An interaction between use of sedation and LA and additional non-steroidal anti-inflammatory drugs (NSAID) meant that NSAID treatment did not increase growth rates in calves disbudded with sedation and LA but did increase growth rates for calves disbudded without pain relief (p<0.05). From Day 16 to Day 30 there was no effect of NSAID treatment on growth rate, but calves receiving LA and sedation grew faster (0.74 (95% CI=0.69-0.80) kg/day) than calves disbudded without LA and sedation (0.66 (95% CI=0.61-0.71) kg/day; p=0.018). From Day -3 to Day 30, calves disbudded with sedation and LA grew faster (0.71 (95%CI=0.64-0.77) kg/day) than calves disbudded without sedation and LA (0.60 (95% CI=0.55-0.65) kg/day; p=0.011). However, addition of NSAID to sedation and LA made no further difference to growth rates (p=0.69). CONCLUSIONS: Dairy calves disbudded with no pain relief had slower growth rates than calves receiving pain relief. From Day 15 to 30 calves given no pain relief, or NSAID alone, grew more slowly than those receiving sedation and LA at disbudding. The addition of NSAID treatment to sedation and LA did not further increase growth rates. CLINICAL RELEVANCE: This study adds to the evidence that pain management when disbudding is beneficial for calf productivity as well as calf welfare.

Enhanced B Cell Alloantigen Presentation and Its Epigenetic Dysregulation in Liver Transplant Rejection.

T cell suppression prevents acute cellular rejection but causes life-threatening infections and malignancies. Previously, liver transplant (LTx) rejection in children was associated with the single-nucleotide polymorphism (SNP) rs9296068 upstream of the HLA-DOA gene. HLA-DOA inhibits B cell presentation of antigen, a potentially novel antirejection drug target. Using archived samples from 122 white pediatric LTx patients (including 77 described previously), we confirmed the association between rs9296068 and LTx rejection (p = 0.001, odds ratio [OR] 2.55). Next-generation sequencing revealed that the putative transcription factor (CCCTC binding factor [CTCF]) binding SNP locus rs2395304, in linkage disequilibrium with rs9296068 (D' 0.578, r(2) = 0.4), is also associated with LTx rejection (p = 0.008, OR 2.34). Furthermore, LTx rejection is associated with enhanced B cell presentation of donor antigen relative to HLA-nonidentical antigen in a novel cell-based assay and with a downregulated HLA-DOA gene in a subset of these children. In lymphoblastoid B (Raji) cells, rs2395304 coimmunoprecipitates with CTCF, and CTCF knockdown with morpholino antisense oligonucleotides enhances alloantigen presentation and downregulates the HLA-DOA gene, reproducing observations made with HLA-DOA knockdown and clinical rejection. Alloantigen presentation is suppressed by inhibitors of methylation and histone deacetylation, reproducing observations made during resolution of rejection. Enhanced donor antigen presentation by B cells and its epigenetic dysregulation via the HLA-DOA gene represent novel opportunities for surveillance and treatment of transplant rejection.

Genome-wide association study of primary dentition pit-and-fissure and smooth surface caries.

Dental caries continues to be the most common chronic disease in children today. Despite the substantial involvement of genetics in the process of caries development, the specific genes contributing to dental caries remain largely unknown. We performed separate genome-wide association studies of smooth and pit-and-fissure tooth surface caries experience in the primary dentitions of self-reported white children in two samples from Iowa and rural Appalachia. In total, 1,006 children (ages 3-12 years) were included for smooth surface analysis, and 979 children (ages 4-14 years) for pit-and-fissure surface analysis. Associations were tested for more than 1.2 million single nucleotide polymorphisms, either genotyped or imputed. We detected genome-wide significant signals in KPNA4 (p value = 2.0E-9), and suggestive signals in ITGAL (p value = 2.1E-7) and PLUNC family genes (p value = 2.0E-6), thus nominating these novel loci as putative caries susceptibility genes. We also replicated associations observed in previous studies for MPPED2 (p value = 6.9E-6), AJAP1 (p value = 1.6E-6) and RPS6KA2 (p value = 7.3E-6). Replication of these associations in additional samples, as well as experimental studies to determine the biological functions of associated genetic variants, are warranted. Ultimately, efforts such as this may lead to a better understanding of caries etiology, and could eventually facilitate the development of new interventions and preventive measures.

Genome-wide association studies of pit-and-fissure- and smooth-surface caries in permanent dentition.

While genetics clearly influences dental caries risk, few caries genes have been discovered and validated. Recent studies have suggested differential genetic factors for primary dentition caries and permanent dentition caries, as well as for pit-and-fissure- (PF) and smooth- (SM) surface caries. We performed separate GWAS for caries in permanent-dentition PF surfaces (1,017 participants, adjusted for age, sex, and the presence of Streptococcus mutans) and SM surfaces (1,004 participants, adjusted for age, education group, and the presence of Streptococcus mutans) in self-reported whites (ages 14 to 56 yrs). Caries scores were derived based on visual assessment of each surface of each tooth; more than 1.2 million SNPs were either successfully genotyped or imputed and were tested for association. Two homologous genes were suggestively associated: BCOR (Xp11.4) in PF-surface caries (p value = 1.8E-7), and BCORL1 (Xq26.1) in SM-surface caries (p value = 1.0E-5). BCOR mutations cause oculofaciocardiodental syndrome, a Mendelian disease involving multiple dental anomalies. Associations of other plausible cariogenesis genes were also observed for PF-surface caries (e.g., INHBA, p value = 6.5E-6) and for SM-surface caries (e.g., CXCR1 and CXCR2, p value = 1.9E-6). This study supports the notion that genes differentially affect cariogenesis across the surfaces of the permanent dentition, and nominates several novel genes for investigation.

INSIG2 variants, dietary patterns and metabolic risk in Samoa.

BACKGROUND/OBJECTIVES: Association of insulin-induced gene 2 (INSIG2) variants with obesity has been confirmed in several but not all follow-up studies. Differences in environmental factors across populations may mask some genetic associations and therefore gene-environment interactions should be explored. We hypothesized that the association between dietary patterns and components of the metabolic syndrome could be modified by INSIG2 variants. SUBJECTS/METHODS: We conducted a longitudinal study of adiposity and cardiovascular disease risk among 427 and 290 adults from Samoa and American Samoa (1990-1995). Principal component analysis on food items from a validated food frequency questionnaire was used to identify neotraditional and modern dietary patterns. We explored gene-dietary pattern interactions with the INSIG2 variants rs9308762 and rs7566605. RESULTS: Results for American Samoans were mostly nonsignificant. In Samoa, the neotraditional dietary pattern was associated with lower triglycerides, body mass index (BMI), waist circumference, systolic and diastolic blood pressure and fasting glucose (all P-for-trend<0.05). The modern pattern was significantly associated with higher triglycerides, BMI, waist circumference and lower high-density lipoprotein-cholesterol (all P-for-trend<0.05). A significant interaction for triglycerides was found between the modern pattern and the rs9308762 polymorphism (P=0.04). Those from Samoa consuming the modern pattern have higher triglycerides if they are homozygous for the rs9308762 C allele. CONCLUSIONS: The common INSIG2 variant rs9308762 was associated with poorer metabolic control and a greater sensitivity of trigylcerides to a modern dietary pattern. Environmental factors need to be taken into account when assessing genetic associations across and within populations.

Clustering tooth surfaces into biologically informative caries outcomes.

UNLABELLED: Dental caries affects most adults worldwide; however, the risk factors for dental caries do not necessarily exert their effects uniformly across all tooth surfaces. Instead, the actions of some risk factors may be limited to a subset of teeth/surfaces. Therefore, we used hierarchical clustering on tooth surface-level caries data for 1,068 Appalachian adults (ages 18-75 yrs) to group surfaces based on co-occurrence of caries. Our cluster analysis yielded evidence of 5 distinct groups of tooth surfaces that differ with respect to caries: (C1) pit and fissure molar surfaces, (C2) mandibular anterior surfaces, (C3) posterior non-pit and fissure surfaces, (C4) maxillary anterior surfaces, and (C5) mid-dentition surfaces. These clusters were replicated in a national dataset (NHANES 1999-2000, N = 3,123). We created new caries outcomes defined as the number of carious tooth surfaces within each cluster. We show that some cluster-based caries outcomes are heritable (i.e., under genetic regulation; p < 0.05), whereas others are not. Likewise, we demonstrate the association between some cluster-based caries outcomes and potential risk factors such as age, sex, educational attainment, and toothbrushing habits. Together, these results suggest that the permanent dentition can be subdivided into groups of tooth surfaces that are useful for understanding the factors influencing cariogenesis. ABBREVIATIONS: COHRA, Center for Oral Health in Appalachia, the principal study sample; C1-5, clusters 1-5, groups of similarly behaving tooth surfaces identified through hierarchical clustering; DMFS index, decayed, missing, or filled surfaces, a traditional caries measure representing the number of affected surfaces across the entire dentition; DMFS1-5, partial DMFS indices representing the number of affected surfaces within a hierarchical cluster; and NHANES, National Health and Nutrition Examination Survey, the secondary study sample.

GWAS of dental caries patterns in the permanent dentition.

The importance of susceptibility genes in the risk for dental caries has been clearly established. While many candidate caries genes have been proposed, to date, few of them have been rigorously validated through observational and experimental studies. Moreover, most genetic epidemiological studies have analyzed global caries phenotypes that ignore the possibility that genes may exert differential effects across tooth surfaces of the dentition. Therefore, we performed genome-wide association studies (GWAS) of 5 novel dental caries phenotypes (developed by clustering the permanent dentition into categories of tooth surfaces based on co-occurrence of caries) to nominate new candidate caries genes. GWAS was performed in 920 self-reported white participants, aged 18 to 75 years, with genotype data on 518,997 genetic variants. We identified a significant genetic association between dental caries of the anterior mandibular teeth and LYZL2 (p value = 9e-9), which codes a bacteriolytic agent thought to be involved in host defense. We also identified a significant genetic association between caries of the mid- dentition tooth surfaces and AJAP1 (p value = 2e-8), a gene possibly involved in tooth development. Suggestive genetic associations were also observed for ABCG2, PKD2, the dentin/bone SCPP sub-family, EDNRA, TJFBR1, NKX2-3, IFT88, TWSG1, IL17D, and SMAD7 (p values < 7e-6). We nominate these novel genes for future study.

Genome-wide association scan for childhood caries implicates novel genes.

Dental caries is the most common chronic disease in children and a major public health concern due to its increasing incidence, serious health and social co-morbidities, and socio-demographic disparities in disease burden. We performed the first genome-wide association scan for dental caries to identify associated genetic loci and nominate candidate genes affecting tooth decay in 1305 US children ages 3-12 yrs. Affection status was defined as 1 or more primary teeth with evidence of decay based on intra-oral examination. No associations met strict criteria for genome-wide significance (p < 10E-7); however, several loci (ACTN2, MTR, and EDARADD, MPPED2, and LPO) with plausible biological roles in dental caries exhibited suggestive evidence for association. Analyses stratified by home fluoride level yielded additional suggestive loci, including TFIP11 in the low-fluoride group, and EPHA7 and ZMPSTE24 in the sufficient-fluoride group. Suggestive loci were tested but not significantly replicated in an independent sample (N = 1695, ages 2-7 yrs) after adjustment for multiple comparisons. This study reinforces the complexity of dental caries, suggesting that numerous loci, mostly having small effects, are involved in cariogenesis. Verification/replication of suggestive loci may highlight biological mechanisms and/or pathways leading to a fuller understanding of the genetic risks for dental caries.

Robot-assisted simple prostatectomy for severe benign prostatic hyperplasia.

PURPOSE: To validate the feasibility of robot-assisted simple retropubic prostatectomy (RSP) for men with severe benign prostatic hyperplasia (>80 g). PATIENTS AND METHODS: Institutional Review Board approval was not sought for this series. Men were offered RSP by two surgeons with a combined experience of >350 robot-assisted radical prostatectomies. The RSP replicated previously published robotic and laparoscopic techniques. Postoperative management consisted of continuous bladder irrigation and closed suction pelvic drainage without suprapubic catheterization. RESULTS: A total of nine men were treated. Indications for RSP included urinary retention in three patients, failed medical management in eight patients, and refusal of medical management in one. Average age was 68 years, mean prostate-specific antigen level was 17.4 ng/mL, and the average preoperative gland size (height-width-length volume) was 136.5 g (range 86-265 g). No operative or immediate postoperative complications occurred, and no transfusions were needed. Average blood loss, operative time, and console time were 206 mL, 183 minutes, and 147 minutes, respectively. Average pathologic adenoma volume was 112 g (range 53-220 g). Average hospitalization time and catheterization time were 32 hours and 13 days, respectively. The mean preoperative International Prostate Symptom Score was 17.8 compared with 7.77 at 6 months postoperatively (P=0.0096, 95% CI 2.83 - 17.40), with a mean follow-up time of 9.25 months. The mean Sexual Health Inventory for Men score was 12.7 preoperatively compared with 12.5 postoperatively (P=0.74, 95% confidence interval - 6.66-9.16). Persistent, severe urinary incontinence (4-6 pads per day) occurred in one patient. CONCLUSIONS: RSP is safe and reproducible when performed by experienced robotic surgeons and provides similar benefits to those associated with robot-assisted radical prostatectomy. In our limited experience, hemostasis was markedly decreased when compared with the open technique. Further investigation is necessary before widespread application of RSP.

Anti-EMMPRIN monoclonal antibody as a novel agent for therapy of head and neck cancer.

PURPOSE: Extracellular matrix metalloprotease inducer (EMMPRIN) is a tumor surface protein that promotes growth and is overexpressed in head and neck cancer. These features make it a potential therapeutic target for monoclonal antibody (mAb)-based therapy. Because molecular therapy is considered more effective when delivered with conventional cytotoxic agents, anti-EMMPRIN therapy was assessed alone and in combination with external beam radiation. EXPERIMENTAL DESIGN: Using a murine flank model, loss of EMMPRIN function was achieved by transfection with a small interfering RNA against EMMPRIN or treatment with a chimeric anti-EMMPRIN blocking mAb. Cytokine expression was assessed for xenografts, tumor cells, fibroblasts, and endothelial cells. RESULTS: Animals treated with anti-EMMPRIN mAb had delayed tumor growth compared with untreated controls, whereas treatment with combination radiation and anti-EMMPRIN mAb showed the greatest reduction in tumor growth (P = 0.001). Radiation-treated EMMPRIN knockdown xenografts showed a reduction in tumor growth compared with untreated knockdown controls (P = 0.01), whereas radiation-treated EMMPRIN-expressing xenografts did not show a delay in tumor growth. Immunohistochemical evaluation for Ki67 and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) resulted in a reduction in proliferation (P = 0.007) and increased apoptosis in anti-EMMPRIN mAb-treated xenografts compared with untreated controls (P = 0.087). In addition, we provide evidence that EMMPRIN suppression results in decreased interleukin 1beta (IL-1beta), IL-6, and IL-8 cytokine production, in vitro and in vivo. CONCLUSIONS: These data suggest that anti-EMMPRIN antibody inhibits tumor cell proliferation in vivo and may represent a novel targeted treatment option in head and neck squamous cell carcinoma.

A whole genome linkage scan identifies multiple chromosomal regions influencing adiposity-related traits among Samoans.

We conducted a genome-wide scan in 46 pedigrees, with 671 phenotyped adults, from the independent nation of Samoa to map quantitative trait loci (QTLs) for adiposity-related phenotypes, including body mass index (BMI), abdominal circumference (ABDCIR), percent body fat (%BFAT), and fasting serum leptin and adiponectin. A set of 378 autosomal and 14 X chromosomal microsatellite markers were genotyped in 572 of the adults. Significant genetic correlations (0.82-0.96) were detected between pairs of BMI, ABDCIR, %BFAT and leptin. Suggestive linkages were found on 13q31 (LOD = 2.30 for leptin, LOD = 2.48 for %BFAT, LOD = 2.04 for ABDCIR, and LOD = 2.09 for BMI) and on 9p22 (LOD = 3.08 for ABDCIR and LOD = 2.53 for %BFAT). Furthermore, bivariate linkage analyses indicated that the genetic regions on 9p22 (bivariate LOD 2.35-3.10, LOD(eq) (1df) 1.88-2.59) and 13q31 (bivariate LOD 1.96-2.64, LOD(eq) 1.52-2.21) might harbor common major genes with pleiotropic effects. Other regions showing suggestive linkage included 4q22 (LOD = 2.95) and 7p14 (LOD = 2.64) for %BFAT, 2q13 for adiponectin (LOD = 2.05) and 19q12 for BMI-adjusted leptin (LOD = 2.03). Further fine mapping of these regions may help identify the genetic variants contributing to the development of obesity in Samoan adults.

Controlling nanoparticle delivery in magnetic nanoparticle hyperthermia for cancer treatment: experimental study in agarose gel.

In magnetic nanoparticle hyperthermia for cancer treatment, controlling the heat distribution and temperature elevations is an immense challenge in clinical applications. In this study we evaluate magnetic nanofluid transport and heat distribution induced by commercially available magnetic nanoparticles injected into the extracellular space of biological tissue using agarose gel with porous structures similar to human tissue. The nanofluid distribution in the gel is examined via digital images of the nanofluid spreading in the gel. A radio-frequency electromagnetic field is applied to the gel following the nanofluid injection and the initial rates of temperature rise at various locations are measured to obtain the specific absorption rate (SAR) distribution. By adjusting the gel concentration and injection flow rate, the results have demonstrated that a relatively low injection rate leads to a spherically shaped nanofluid distribution in the gels which is desirable for controlling temperature elevations. The SAR distribution shows that the nanoparticle distribution in the gel is not uniform with a high concentration of the nanoparticles close to the injection site. We believe that the experimental study is the first step towards providing guidance for designing better treatment protocol for future clinical applications.

Magnetoencephalographic analysis of cortical activity in adults with and without Down syndrome.

BACKGROUND: This preliminary study served as a pilot for an ongoing analysis of spectral power in adults with Down syndrome (DS) using a 151 channel whole head magnetoencephalography (MEG). The present study is the first step for examining and comparing cortical responses during spontaneous and task related activity in DS. METHOD: Cortical responses were recorded with a 151 channel whole head MEG system in three adults with DS and three age-matched adults without DS. MEG data were obtained at rest with eyes open and during observation of point-light displays of human motion and object motion. Data from both groups were evaluated by spectral analysis. RESULTS: The preliminary results showed greater alpha (8-14 Hz) power particularly in the occipital and parietal areas during the eyes open condition in the adults with DS in relation to a normal comparison group. The visual task had little effect on alpha power in the comparison group. Engaging in the visual task reduced power in alpha across all regions in the DS group to the level observed in comparisons. In the gamma band (30-50 Hz), power values were similar across both groups for the eyes open condition. In the comparison group, large reductions in gamma were observed in the occipital and bilateral temporal areas during the visual task. This change was not observed in the DS group. CONCLUSIONS: The results from this pilot study suggest that MEG may be useful in characterizing task-specific changes in cortical activity in individuals with DS. Future studies with a larger group of individuals will further contribute to our understanding of the neurophysiology of Down syndrome.

Genome-wide scan for adiposity-related phenotypes in adults from American Samoa.

OBJECTIVE: To detect quantitative trait loci influencing adiposity-related phenotypes assessed by body mass index (BMI), abdominal circumference (ABDCIR), percent body fat (%BFAT) and fasting serum leptin and adiponectin using a whole genome linkage scan of families from American Samoa. DESIGN: Family-based linkage analysis, the probands and family members were unselected for obesity. SUBJECTS: A total of 583 phenotyped American Samoan adults, of which 578 were genotyped in 34 pedigrees. MEASUREMENTS: A total of 377 autosomal and 18 X chromosome microsatellite markers were typed at an approximate average spacing of 10 cM spanning the genome. Multipoint LOD (logarithm of the odds) scores were calculated using variance-components approaches and SOLAR/LOKI software. The covariates simultaneously evaluated were age, sex, education, farm work and cigarette smoking, with a significance level of 0.1. Due to the stochastic nature of LOKI, we report the average of maximum LOD scores from 10 runs. RESULTS: Significant linkage to leptin was found at 6q32.2 with LOD of 3.83. Suggestive linkage to leptin was found at 16q21:LOD=2.98, 1q42.2:LOD=1.97, 5q11.2:LOD=2.08, 12q24.23:LOD=2.00, 19p13.3:LOD=2.05; adiponectin was linked to 13q33.1-q22.1:LOD=2.41; %BFAT was linked to 16q12.2-q21, LOD=2.24; ABDCIR was linked to 16q23.1:LOD=1.95; %BFAT-adjusted leptin to 14q12, LOD=2.01; %BFAT-adjusted ABDCIR to 1q31.1, LOD=2.36, to 3q27.3-q28, LOD=2.10 and to 12p12.3, LOD=2.04. CONCLUSION: We found strong evidence for a major locus on 6q23.2 influencing serum leptin levels in American Samoans. The 16q21 region appears to harbor a susceptibility locus that has significant pleiotrophic effects on phenotypes BMI, %BFAT, leptin and ABDCIR as shown by bivariate linkage analyses. Several other loci of varying significance were detected across the genome.

The effect of the addition of a polyglutamate motif to RGD on peptide tethering to hydroxyapatite and the promotion of mesenchymal stem cell adhesion.

Mimicking endogenous bone-binding proteins, RGD peptides have been synthesized with polyacidic amino acid domains in order to ionically tether the peptides to bone-like synthetic biomaterials, including hydroxyapatite (HA). However, a direct comparison of unmodified RGD with polyacidic-conjugated RGD has not been performed, and thus a benefit for the acidic domain has not been established. We evaluated the peptide/HA bond of RGD peptides with and without an attached polyglutamate sequence (E(7)), as well as examined mesenchymal stem cell (MSC) adhesion and morphology as they were affected by the conjugated peptide. We found that significantly more E(7)RGD was bound to HA than RGD at all coating concentrations tested, and moreover, more E(7)RGD was retained on the HA surface even after extended washing in serum-free media. Consistent with in vitro results, higher levels of E(7)RGD than RGD remained on HA that had been implanted in vivo for 24 h, indicating that the polyacidic domain improved peptide-binding efficiency. At several peptide concentrations, E(7)RGD increased cell adhesion compared to RGD surfaces, establishing a biological benefit for the E(7) modification. In addition, HA pre-coated sequentially with low-density E(7)RGD (1-10 microg/ml) and serum (FBS) stimulated cell adhesion and spreading, compared to either coating alone, suggesting that an ionic linkage allows for the potential adsorption of serum proteins to unoccupied sites, which may be important for bone formation in vivo. Collectively, these results suggest that tethering peptides to HA via a polyglutamate domain is an effective method for improving the peptide/HA bond, as well as for enhancing MSC adhesion.

Analysis of IMGSAC autism susceptibility loci: evidence for sex limited and parent of origin specific effects.

BACKGROUND AND METHODS: Autism is a severe neurodevelopmental disorder, which has a complex genetic predisposition. The ratio of males to females affected by autism is approximately 4:1, suggesting that sex specific factors are involved in its development. We reported previously the results of a genomewide screen for autism susceptibility loci in 83 affected sibling pairs (ASP), and follow up analysis in 152 ASP. Here, we report analysis of an expanded sample of 219 ASP, using sex and parent of origin linkage modelling at loci on chromosomes 2, 7, 9, 15, and 16. RESULTS: The results suggest that linkage to chromosomes 7q and 16p is contributed largely by the male-male ASP (MLS = 2.55 v 0.12, and MLS = 2.48 v 0.00, for the 145 male-male and 74 male-female/female-female ASP on chromosomes 7 and 16 respectively). Conversely linkage to chromosome 15q appears to be attributable to the male-female/female-female ASP (MLS = 2.62 v 0.00, for non-male and male-male ASP respectively). On chromosomes 2 and 9, all ASP contribute to linkage. These data, supported by permutation, suggest a possible sex limited effect of susceptibility loci on chromosomes 7, 15, and 16. Parent of origin linkage modelling indicates two distinct regions of paternal and maternal identity by descent sharing on chromosome 7 (paternal MLS = 1.46 at approximately 112 cM, and maternal MLS = 1.83 at approximately 135 cM; corresponding maternal and paternal MLS = 0.53 and 0.28 respectively), and maternal specific sharing on chromosome 9 (maternal MLS = 1.99 at approximately 30 cM; paternal MLS = 0.02). CONCLUSION: These data support the possibility of two discrete loci underlying linkage of autism to chromosome 7, and implicate possible parent of origin specific effects in the aetiology of autism.

Bilateral testicular adrenal rests after bilateral adrenalectomies in a cushingoid patient with von Hippel-Lindau disease.

We report a case of bilateral testicular masses in a 25-year-old man with von Hippel-Lindau disease presenting with cushingoid symptoms. His medical history was significant for bilateral adrenalectomies secondary to pheochromocytomas, and he began steroid therapy at that time. After exhaustive endocrinologic, radiographic, and physical examinations, the testicular masses were postulated to be active adrenal rest tissue. Bilateral testicular venous sampling found elevated glucocorticoids that were responsive to dexamethasone suppression, which confirmed the testicular masses as testicular adrenal rests without the need for surgical intervention. Successful conservative management consisted of appropriate steroid manipulation and radiographic evaluation and resulted in the resolution of presenting symptoms, a decrease in size of the bilateral testicular masses, and testicular conservation in this young man.