229Thorium-doped calcium fluoride for nuclear laser spectroscopy.

The (229)thorium isotope presents an extremely low-energy isomer state of the nucleus which is expected around 7.8 eV, in the vacuum ultraviolet (VUV) regime. This unique system may bridge between atomic and nuclear physics, enabling coherent manipulation and precision spectroscopy of nuclear quantum states using laser light. It has been proposed to implant (229)thorium into VUV transparent crystal matrices to facilitate laser spectroscopy and possibly realize a solid-state nuclear clock. In this work, we validate the feasibility of this approach by computer modelling of thorium doping into calcium fluoride single crystals. Using atomistic modelling and full electronic structure calculations, we find a persistent large band gap and no additional electronic levels emerging in the middle of the gap due to the presence of the dopant, which should allow direct optical interrogation of the nuclear transition.Based on the electronic structure, we estimate the thorium nuclear quantum levels within the solid-state environment. Precision laser spectroscopy of these levels will allow the study of a broad range of crystal field effects, transferring Mössbauer spectroscopy into the optical regime.

Energy metabolites in pre- and postpartum dairy cattle as predictors of reproductive disorders.

This study aimed to determine values for selected energy metabolites (non-esterified fatty acid [NEFA], ß-hydroxybutyrate [BHB], urea or urea:BHB ratio), together with a body condition score, associated with an increased risk of cows developing a reproductive disorder and to investigate temporal relationships between predictors and reproductive outcome. A cohort of 98 cows on one farm was monitored weekly from four weeks before to 10 weeks after calving; 89 cows provided sufficient data to calculate commencement of luteal activity (C-LA). Cows with high NEFA × urea (Nu; product of NEFA and urea) values one and three weeks after calving were twice as likely to develop cystic ovarian disease (risk ratio 2). Cows that developed endometritis had high NEFA values one (P=0.02) or four weeks (P=0.04) before calving, or low urea:BHB ratios two weeks before calving, at calving or three weeks after calving (P=0.024, P=0.031 and P=0.001, respectively). Cows that had delayed C-LA had high NEFA values one week after calving (P=0.05) or low urea:BHB ratios three or four weeks after calving (P=0.004 and P=0.003, respectively).

Sprouty proteins: modified modulators, matchmakers or missing links?

Sprouty proteins are involved in organogenesis, particularly during the branching of endothelial tubes, and existing evidence suggests that Sprouty's point of action lies downstream of receptor signaling to inhibit the activation of the central Ras/Erk pathway. How Sprouty proteins accomplish their inhibitory action and whether they interact with other signaling pathways are significant questions. Sprouty proteins are devoid of any recognizable protein interaction domain, and clues as to how they function have been mainly derived from screening for interacting partners. Conserved across all the Sprouty proteins are three sequences: a Cbl-tyrosine kinase-binding (TKB) binding motif centered on an obligatorily phosphorylated tyrosine (Y55 in Sprouty2), a serine-rich motif (SRM) and a cysteine-rich domain (CRD). With the exception of a handful of proteins that bind to the N-terminus, most of the binding to Sprouty occurs via the CRD, predominantly by serine/threonine kinases that target sites within the SRM on Sprouty. Some of the resultant increase in phosphorylation is opposed by activated protein phosphatase 2A that binds to the N-terminal Cbl-TKB binding motif. Significantly, two ubiquitin E3 ligases also bind to the N-terminus of Sprouty: c-Cbl binds with high affinity to the TKB binding motif and SIAH2 binds constitutively to a different site; both proteins are able to direct the ubiquitination of Sprouty proteins and its destruction. The collective evidence points to Sprouty proteins as being substantially covalently-modified to control its location, stability, association, and destruction. With such stringent control of the Sproutys, the main question is what key proteins does this facilitator bring together?

Impact on renal function after endovascular aneurysm repair with uncovered supra-renal fixation assessed by serum cystatin C.

OBJECTIVE: Supra-renal fixation in endovascular aneurysm repair (SR-EVR) is used to improve the proximal seal of aortic stent grafts and appears to have minimal effect on serum creatinine. Serum cystatin C (CC) is a more sensitive marker of renal injury and, unlike creatinine, is unaffected by non-renal influence. The aim of this study was to assess the true renal effect of SR-EVR using this superior renal index. METHODS: Consecutive patients undergoing SR-EVR were prospectively recruited and compared to control groups undergoing open aneurysm repair (OR) and colorectal resection (CR). Serum CC and creatinine clearance (CrC) were determined pre-operatively and at 3, 6 and 12 months post-surgery. Renal function was compared using analyses of covariance (ANCOVA). RESULTS: Sixty-five patients (M:F; 52:13, median age 74 years) were enrolled (24 SR-EVR, 28 OR, 13 CR). Pre-operative renal function and risk factors were comparable (CC 1.04mg/l, SR-EVR; 0.96mg/l, OR; 0.97mg/l, CR). Adjusting for baseline renal function, there was no significant difference in CC or CrC between study and both control groups at 3, 6 or 12-months post-operatively. CONCLUSION: Using cystatin C as a more sensitive renal index, there was no detectable evidence of kidney dysfunction at up to one-year following EVR with uncovered bare-metal supra-renal fixation.

Pre-pregnancy and pregnancy-related factors and the risk of excessive or inadequate gestational weight gain.

OBJECTIVE: Gestational weight gain consistent with the Institute of Medicine's recommendations is associated with better maternal and infant outcomes. The objective was to quantify the effect of pre-pregnancy factors, pregnancy-related health conditions, and modifiable pregnancy factors on the risks of inadequate and excessive gestational weight gain. METHOD: A longitudinal cohort of pregnant women (N=1100) who completed questions about diet and weight gain during pregnancy and delivered a singleton, full-term infant. RESULTS: Gestational weight gain was inadequate for 14% and excessive for 53%. Pre-pregnancy factors contributed 74% to excessive gain, substantially more than pregnancy-related health conditions (15%) and modifiable pregnancy factors (11%). Pre-pregnancy factors, pregnancy-related health conditions, and modifiable pregnancy factors contributed fairly equally to the risk of inadequate gain. CONCLUSION: Interventions to prevent excessive gestational gain may need to start before pregnancy. Women at risk for inadequate gain would also benefit from interventions directed toward modifiable factors during pregnancy.

Poly(beta-hydroxybutyrate-co-beta-hydroxyvalerate) supports in vitro osteogenesis.

Studies have demonstrated that polymeric biomaterials have the potential to support osteoblast growth and development for bone tissue repair. Poly(beta-hydroxybutyrate-co-beta-hydroxyvalerate) (PHBV), a bioabsorbable, biocompatible polyhydroxy acid polymer, is an excellent candidate that, as yet, has not been extensively investigated for this purpose. As such, we examined the attachment characteristics, self-renewal capacity, and osteogenic potential of osteoblast-like cells (MC3T3-E1 S14) when cultured on PHBV films compared with tissue culture polystyrene (TCP). Cells were assayed over 2 weeks and examined for changes in morphology, attachment, number and proliferation status, alkaline phosphatase (ALP) activity, calcium accumulation, nodule formation, and the expression of osteogenic genes. We found that these spindle-shaped MC3T3-E1 S14 cells made cell-cell and cell-substrate contact. Time-dependent cell attachment was shown to be accelerated on PHBV compared with collagen and laminin, but delayed compared with TCP and fibronectin. Cell number and the expression of ALP, osteopontin, and pro-collagen alpha1(I) mRNA were comparable for cells grown on PHBV and TCP, with all these markers increasing over time. This demonstrates the ability of PHBV to support osteoblast cell function. However, a lag was observed for cells on PHBV in comparison with those on TCP for proliferation, ALP activity, and cbfa-1 mRNA expression. In addition, we observed a reduction in total calcium accumulation, nodule formation, and osteocalcin mRNA expression. It is possible that this cellular response is a consequence of the contrasting surface properties of PHBV and TCP. The PHBV substrate used was rougher and more hydrophobic than TCP. Although further substrate analysis is required, we conclude that this polymer is a suitable candidate for the continued development as a biomaterial for bone tissue engineering.

Mathematical derivation of the minimally acceptable all-porcelain margin angle.

There is limited research defining the minimally acceptable porcelain margin angle required to withstand the stresses incurred during seating a restoration. A mathematical model was derived to calculate this critical porcelain margin angle. The factors involved in margin fracture were determined to be the tensile strength of the porcelain, the axial reduction, the diameter of the tooth, the porcelain margin angle, and the seating force. As the seating force increases, the porcelain margin angle required to prevent failure also increases. Increasing either the axial reduction or the diameter of the tooth allowed the minimum porcelain margin angle to decrease.

Urinary incontinence in elderly women: findings from the Health, Aging, and Body Composition Study.

OBJECTIVE: To estimate the prevalence of and risk factors for stress and urge incontinence in a biracial sample of well-functioning older women. METHODS: We performed a cross-sectional analysis of 1,584 white and black women, aged 70-79 years, enrolled in a longitudinal cohort study. Participants were asked about incontinence, medical problems, and demographic and reproductive characteristics and underwent physical measurements. Using multivariable logistic regression, we compared women reporting at least weekly incontinence with those without incontinence. RESULTS: Overall, 21% reported incontinence at least weekly. Of these, 42% reported predominantly urge incontinence, and 40% reported stress. Nearly twice as many white women as black women reported weekly incontinence (27% versus 14%, P <.001). Factors associated with urge incontinence included white race (odds ratio [OR] 3.1, 95% confidence interval [CI] 2.0-4.8), diabetes treated with insulin (OR 3.5, 95% CI 1.6-7.9), depressive symptoms (OR 2.7, 95% CI 1.4-5.3), current oral estrogen use (OR 1.7, 95% CI 1.1-2.6), arthritis (OR 1.7, 95% CI 1.1-2.6), and decreased physical performance (OR 1.6 per point on 0-4 scale, 95% CI 1.1-2.3). Factors associated with stress incontinence were chronic obstructive pulmonary disease (OR 5.6, 95% CI 1.3-23.2), white race (OR 4.1, 95% CI 2.5-6.7), current oral estrogen use (OR 2.0, 95% CI 1.3-3.1), arthritis (OR 1.6, 95% CI 1.0-2.4), and high body mass index (OR 1.3 per 5 kg/m2, 95% CI 1.1-1.6). CONCLUSION: Urinary incontinence is highly prevalent, even in well-functioning older women, whites in particular. Many risk factors differ for stress and urge incontinence, suggesting differing etiologies and prevention strategies.

Association between the GCG polymorphism of the selenium dependent GPX1 gene and the risk of young onset prostate cancer.

Epidemiological studies have suggested an association between low selenium levels and the development of prostate cancer. Human cellular glutathione peroxidase I (hGPX1) is a selenium-dependent enzyme that protects against oxidative damage and its peroxidase activity is a plausible mechanism for cancer prevention by selenium. The GPX1 gene has a GCG repeat polymorphism in exon 1, coding for a polyalanine tract of five to seven alanine residues. To test if the GPX1 GCG repeat polymorphism associates with the risk of young-onset prostate cancer we conducted a case-control study. The GPX1Ala genotypes were determined for 267 prostate cancer cases and 260 control individuals using polymerase chain reaction (PCR) amplification with fluorescently labelled primers and an ABI 377 automated genotyper. Associations between specific genotypes and the risk of prostate cancer were examined by logistic regression. We found no significant association between the GPX1 genotypes and prostate cancer. There was however an increased frequency of the GPX1Ala6/Ala6 genotype in the prostate cancer cases compared to controls (OR: 1.67; 95% CI: 0.97-2.87). The result of this study suggests that the GPX1 genotype is unlikely to be associated with the risk of developing prostate cancer.

HPC2/ELAC2 polymorphisms and prostate cancer risk: analysis by age of onset of disease.

The candidate prostate cancer susceptibility gene HPC2/ELAC2 has two common coding polymorphisms: (Ser-->Leu 217) and (Ala-->Thr 541). The Thr541 variant in the HPC2/ELAC2 gene has previously been reported to be at an increased frequency in prostate cancer cases. To evaluate this hypothesis we genotyped 432 prostate cancer patients (including 262 patients diagnosed 55 years (OR=1.27, 95% CI 0.59-2.74). We conclude that any association between the Thr541 variant and prostate cancer is likely to be weak.

High-fructose diet preserves beta-cell mass and prevents diabetes in nonobese diabetic mice: A potential role for increased insulin receptor substrate-2 expression.

We demonstrate that a high-fructose diet reduces the incidence of diabetes in nonobese diabetic (NOD) mice (31.2% v 57.1% on regular chow (RC); P =.009). In a second cohort of mice, we evaluated potential mechanisms for the protective effect of the high-fructose (HF) diet and whether the metabolic changes are strain-specific. Sixty NOD and 60 Balb/c mice were randomized at weaning into HF- and RC-fed groups (30 mice each) and followed for 28 weeks. Glucose tolerance testing demonstrated improved glucose tolerance in HF diet groups (P =.001 in Balb/c; P =.04 in NOD mice at 6 months). beta-cell mass was preserved in NOD mice on the HF diet, but remained unchanged in Balb/c mice. In NOD mice, hepatic insulin receptor substrate (IRS)-2 protein expression increased by 2-fold (P =.01 for 2 v 6 months) in HF-fed mice and was 53% +/- 15% higher (P =.01) in the HF diet versus RC groups at 6 months of age. IRS-2 expression was also increased in skeletal muscle of NOD mice and in both liver and muscle of Balb/c mice. Our data suggest that a HF diet improves glucose tolerance in both NOD and Balb/c mice. The improved glucose tolerance may be related to increased IRS-2 expression and, in NOD mice, preservation of beta-cell mass.

Relationship between glutathione S-transferase M1, P1 and T1 polymorphisms and early onset prostate cancer.

There is evidence suggesting that polymorphic variations in the glutathione S-transferases (GSTs) are associated with cancer susceptibility. Inter-individual differences in cancer susceptibility may be mediated in part through polymorphic variability in the bioactivation and detoxification of carcinogens. The GSTs have been consistently implicated as cancer susceptibility genes in this context. The GST supergene family includes several loci with well characterized polymorphisms. Approximately 50% of the Caucasian population are homozygous for deletions in GSTM1 and approximately 20% are homozygous for deletions in GSTT1, resulting in conjugation deficiency of mutagenic electrophiles to glutathione. The GSTP1 gene has a polymorphism at codon 105 resulting in an Ile to Val substitution which consequently alters the enzymatic activity of the protein and this has been suggested as a putative high-risk genotype in various cancers. We investigated the relationship between GST polymorphisms and young onset prostate cancer in a case-control study. GSTM1, GSTT1 and GSTP1 genotypes were determined for 275 prostate cancer patients and for 280 geographically matched control subjects. We found no significant difference in the frequency of GSTM1 or GSTT1 null genotypes between cases and controls. GSTP1 genotype was, however, significantly associated with prostate cancer risk: the Ile/Ile homozygotes had the lowest risk and there was a trend in increasing the risk with the number of 105 Val alleles: Ile/Val odds ratio (OR)= 1.30 (95% FCI 0.99-1.69), Val/Val OR = 1.80 (95% FCI 1.11-2.91); Ptrend = 0.026. These results suggest that the GSTP1 polymorphism may be a risk factor for developing young onset prostate cancer. We also found that carrying more than one putative high-risk allele in the carcinogen metabolizing GST family was associated with an elevated risk for early onset prostate cancer (OR 2.48, 95% FCI 1.22-5.04, Ptrend = 0.017).

Digoxin to facilitate late second-trimester abortion: a randomized, masked, placebo-controlled trial.

OBJECTIVE: To examine the efficacy of digoxin for decreasing operative time, difficulty, and pain of late second-trimester surgical abortions. METHODS: We performed a randomized, double-masked, placebo-controlled trial of intra-amniotic digoxin for second-trimester dilation and evacuation (D&E) involving 126 consecutive women at an inner-city public hospital. Eligible women had gestational ages of 20-23.1 weeks, spoke English or Spanish, and were at least 16 years old. Digoxin (1 mg) or saline was injected intra-amniotically 24 hours before the procedure, at cervical laminaria insertion. The primary outcome was procedure duration. Sample size was based on 80% power to detect a difference of 3.5 minutes between groups. RESULTS: The two groups were similar in demographic factors, obstetric histories, and gestational duration. The average gestational length was 22.5 weeks. There was no difference in procedure duration (mean +/- standard deviation) between groups (placebo 14.7 +/- 7.0, digoxin 15.4 +/- 8.0). There were no differences in blood loss estimated by surgeons, pain scores, procedure difficulty scores, or complications between groups. Vomiting was significantly more common in those who received digoxin (placebo 3.1%, digoxin 16.1%). Most subjects (91%) reported that they preferred their fetuses were dead before the abortions. CONCLUSION: Although digoxin did not increase efficacy of late second-trimester abortion, patient preference might justify its use.

Heterophile antibodies indicate progression of autoimmunity in human type 1 diabetes mellitus before clinical onset.

We previously reported serum cytokines in a group of long term non-progressors to Type 1 diabetes; this reactivity detected in ELISA is now identified as heterophile antibody in some sera. Here, we characterize heterophile antibody activity. A 14 kDa-polypeptide from heterophile antibody containing serum bound to an anti-IL-4 column, but IL-4 was not detected by Western blot or by MS/MS sequencing. However, in 2/13 heterophile antibody positive sera, T-cell growth was potentiated and was blocked by an anti-human immunoglobulin. To examine the relationship between low affinity heterophile antibody presence and disease progression, 1100 archived serum samples were analyzed with two pairs of antibodies from 443 diabetes-free first degree relatives of Type 1 diabetes mellitus patients for heterophile antibody; 95 individuals developed diabetes on follow-up. Twenty-two individuals, whose serum was heterophile antibody positive with the second pair of antibodies (but negative with the first pair of antibodies), had a significantly higher incidence of developing diabetes after five years. Thirty-seven individuals with heterophile antibody reactivity with the first pair of antibodies, regardless of reactivity with the second pair of antibodies, had a significantly lower incidence of developing diabetes. While we cannot exclude the presence of genuine cytokine in all sera, these data indicate the presence of distinct groups of heterophile antibodies in patients at high risk to develop diabetes. Thus, anti-Ig heterophilic antibodies with different immunochemical reactivities are linked to the progression of or protection from Type 1 diabetes autoimmunity.