The tooth survival of non-surgical root-filled posterior teeth and the associated prognostic tooth-related factors: A systematic review and meta-analysis.

BACKGROUND: Analysis of the survival of root-filled posterior teeth and the associated prognostic tooth-related factors will enable clinicians to predict the outcome of root canal treatment. OBJECTIVES: To investigate (i) the survival of root-filled posterior teeth and (ii) the tooth-related factors that may affect their survival. METHODS: Randomized controlled trials, comparative studies and observational studies assessing survival rates of root-filled posterior teeth with a minimum 4-year follow-up period were identified through an electronic search of the following databases up to January 2023: The Cochrane Central Register of Controlled Trials, Medline via PubMed, the Cochrane Database of Systematic Reviews, Embase, Web of Science and NIHR centre for reviews and dissemination. Two reviewers (SP and ML) independently selected the final studies based on pre-defined inclusion criteria. The Newcastle Ottawa Scale and the Cochrane Risk of Bias Tool for Randomized Trials were used to assess the risk of bias. Pooled weighted survival rates were analysed using a random effects meta-analysis model using DerSimonean and Laird methods. Descriptive analysis of studies describing any prognostic tooth-related factors was conducted. RESULTS: Of the 72 studies identified, data from 20 studies were included in the survival meta-analysis, and data from 13 of these studies were included in the descriptive analysis of tooth-related factors; 12 studies were retrospective, 7 were prospective, and one was a randomized control trial. The pooled survival rates at 4-7 years and 8-20 years of root-filled posterior teeth regardless of tooth type was 91% (95% CI, 0.85; 0.95) and 87% (95% CI, 0.77; 0.93), respectively. The prognostic tooth-related factors mentioned in the included studies were (i) remaining coronal tooth structure, (ii) ferrule, (iii) crown-to-root ratio (iv) tooth type and location (v) periodontal disease (vi) proximal contacts and (vii) cracks. CONCLUSIONS: The meta-analysis suggests that root canal treatment has a high medium to long term survival outcome. The narrative summary identified 7 factors that affect tooth survival. However, there is a paucity of evidence, and more research is needed in this area. REGISTRATION: PROSPERO Registration: CRD42021227213.

Coupling multielectrode array recordings with silver labeling of recording sites to study cervical spinal network connectivity.

Midcervical spinal interneurons form a complex and diffuse network and may be involved in modulating phrenic motor output. The intent of the current work was to enable a better understanding of midcervical "network-level" connectivity by pairing the neurophysiological multielectrode array (MEA) data with histological verification of the recording locations. We first developed a method to deliver 100-nA currents to electroplate silver onto and subsequently deposit silver from electrode tips after obtaining midcervical (C3-C5) recordings using an MEA in anesthetized and ventilated adult rats. Spinal tissue was then fixed, harvested, and histologically processed to "develop" the deposited silver. Histological studies verified that the silver deposition method discretely labeled (50-µm resolution) spinal recording locations between laminae IV and X in cervical segments C3-C5. Using correlative techniques, we next tested the hypothesis that midcervical neuronal discharge patterns are temporally linked. Cross-correlation histograms produced few positive peaks (5.3%) in the range of 0-0.4 ms, but 21.4% of neuronal pairs had correlogram peaks with a lag of ≥0.6 ms. These results are consistent with synchronous discharge involving mono- and polysynaptic connections among midcervical neurons. We conclude that there is a high degree of synaptic connectivity in the midcervical spinal cord and that the silver-labeling method can reliably mark metal electrode recording sites and "map" interneuron populations, thereby providing a low-cost and effective tool for use in MEA experiments. We suggest that this method will be useful for further exploration of midcervical network connectivity.NEW & NOTEWORTHY We describe a method that reliably identifies the locations of multielectrode array (MEA) recording sites while preserving the surrounding tissue for immunohistochemistry. To our knowledge, this is the first cost-effective method to identify the anatomic locations of neuronal ensembles recorded with a MEA during acute preparations without the requirement of specialized array electrodes. In addition, evaluation of activity recorded from silver-labeled sites revealed a previously unappreciated degree of connectivity between midcervical interneurons.

Comparative efficacy of two standard methods for determination of iron and zinc in fruits, pulses and cereals.

Micronutrients are essential elements needed in small amounts for adequate human nutrition and include the elements iron and zinc. Both of these minerals are essential to human well-being and an adequate supply of iron and zinc help to prevent iron deficiency anaemia and zinc deficiency, two prevalent health concerns of the developing world. The levels of zinc and, iron were measured in the Banana, Papaya, Rice, Finger millet, Soybean and Urdbean. Standard Atomic absorption spectroscopy (AAS) method was also applied to all the samples for zinc and iron analysis and compared with inductively coupled plasma mass spectroscopy (ICP-MS). It was observed that there was no matrix interference affecting the determination of both elements interested in all the samples analyzed. Average concentration relative standard deviation and standard deviation were used for the statistical evaluation of the results for both elements. Correlation coefficient was used as statistical model to compare both the techniques.

The association between sleep patterns and obesity in older adults.

BACKGROUND: Reduced sleep duration has been increasingly reported to predict obesity. However, timing and regularity of sleep may also be important. In this study, the cross-sectional association between objectively measured sleep patterns and obesity was assessed in two large cohorts of older individuals. METHODS: Wrist actigraphy was performed in 3053 men (mean age: 76.4 years) participating in the Osteoporotic Fractures in Men Study and 2985 women (mean age: 83.5 years) participating in the Study of Osteoporotic Fractures. Timing and regularity of sleep patterns were assessed across nights, as well as daytime napping. RESULTS: Greater night-to-night variability in sleep duration and daytime napping were associated with obesity independent of mean nocturnal sleep duration in both men and women. Each 1 h increase in the standard deviation of nocturnal sleep duration increased the odds of obesity 1.63-fold (95% confidence interval: 1.31-2.02) among men and 1.22-fold (95% confidence interval: 1.01-1.47) among women. Each 1 h increase in napping increased the odds of obesity 1.23-fold (95% confidence interval: 1.12-1.37) in men and 1.29-fold (95% confidence interval: 1.17-1.41) in women. In contrast, associations between later sleep timing and night-to-night variability in sleep timing with obesity were less consistent. CONCLUSIONS: In both older men and women, variability in nightly sleep duration and daytime napping were associated with obesity, independent of mean sleep duration. These findings suggest that characteristics of sleep beyond mean sleep duration may have a role in weight homeostasis, highlighting the complex relationship between sleep and metabolism.

Helicobacter pylori downregulates expression of human ß-defensin 1 in the gastric mucosa in a type IV secretion-dependent fashion.

Helicobacter pylori establishes a chronic lifelong infection in the human gastric mucosa, which may lead to peptic ulcer disease or gastric adenocarcinoma. The human beta-defensins (hßDs) are antimicrobial peptides, hßD1 being constitutively expressed in the human stomach. We hypothesized that H. pylori may persist, in part, by downregulating gastric hßD1 expression. We measured hßD1 and hßD2 expression in vivo in relation to the presence, density and severity of H. pylori infection, investigated differential effects of H. pylori virulence factors, and studied underlying signalling mechanisms in vitro. Significantly lower hßD1 and higher hßD2 mRNA and protein concentrations were present in gastric biopsies from infected patients. Those patients with higher-level bacterial colonization and inflammation had significantly lower hßD1 expression, but there were no differences in hßD2. H. pylori infection of human gastric epithelial cell lines also downregulated hßD1. Using wild-type strains and isogenic mutants, we showed that a functional cag pathogenicity island-encoded type IV secretion system induced this downregulation. Treatment with chemical inhibitors or siRNA revealed that H. pylori usurped NF-κB signalling to modulate hßD1 expression. These data indicate that H. pylori downregulates hßD1 expression via NF-κB signalling, and suggest that this may promote bacterial survival and persistence in the gastric niche.

Regional variation in human retinal vessel oxygen saturation.

The purpose of this study was to investigate regional differences in oxygen saturation of blood in first degree retinal vessels using a novel non-flash hyperspectral retinal camera (Photon etc Inc). Nine healthy individuals (mean age 24.4 ± 3.6 yrs, 5 males) were imaged at 548, 569, 586, 600, 605 and 610 nm wavelengths. Optical density values were extracted with the aid of Image-J software for blood oxygen saturation (SO2) determination. Arteriolar and venular SO2 were measured at three locations (ranging 1-3 optic nerve head radii) from the disc margin along the vessels in the superior and inferior temporal quadrants. Retinal SO2 was significantly higher in the superior temporal arteriole and venule as compared to the inferior temporal vessels (p = 0.033 and p = 0.032 for arterioles and venules, respectively). SO2 was not significantly different between the three measurement sites for any of the given vessels imaged (p > 0.05). In conclusion, greater SO2 values were found in the superior temporal first degree retinal arterioles and venules in young healthy individuals than in the equivalent inferior vessels. However, there were no detectable differences in retinal SO2 along each of the major vessels, a finding that is consistent with the concept of these vessels not contributing primarily to gas exchange. Moreover, the SO2 was consistently higher in the arterioles than in the equivalent venules (p < 0.0001).

Joint consensus statement on the vaccination of adult and paediatric haematopoietic stem cell transplant recipients: Prepared on behalf of the British society of blood and marrow transplantation and cellular therapy (BSBMTCT), the Children's cancer and Leukaemia Group (CCLG), and British Infection Association (BIA).

Haematopoietic stem cell transplant (HSCT) recipients have deficiencies in their adaptive immunity against vaccine preventable diseases. National and International guidance recommends that HSCT recipients are considered 'never vaccinated' and offered a comprehensive course of revaccination. This position statement aims to draw upon the current evidence base and existing guidelines, and align this with national vaccine availability and licensing considerations in order to recommend a pragmatic and standardised re-vaccination schedule for adult and paediatric HSCT recipients in the UK.

Transferability and fine-mapping of glucose and insulin quantitative trait loci across populations: CARe, the Candidate Gene Association Resource.

AIMS/HYPOTHESIS: Hyperglycaemia disproportionately affects African-Americans (AfAs). We tested the transferability of 18 single-nucleotide polymorphisms (SNPs) associated with glycaemic traits identified in European ancestry (EuA) populations in 5,984 non-diabetic AfAs. METHODS: We meta-analysed SNP associations with fasting glucose (FG) or insulin (FI) in AfAs from five cohorts in the Candidate Gene Association Resource. We: (1) calculated allele frequency differences, variations in linkage disequilibrium (LD), fixation indices (F(st)s) and integrated haplotype scores (iHSs); (2) tested EuA SNPs in AfAs; and (3) interrogated within ± 250 kb around each EuA SNP in AfAs. RESULTS: Allele frequency differences ranged from 0.6% to 54%. F(st) exceeded 0.15 at 6/16 loci, indicating modest population differentiation. All iHSs were <2, suggesting no recent positive selection. For 18 SNPs, all directions of effect were the same and 95% CIs of association overlapped when comparing EuA with AfA. For 17 of 18 loci, at least one SNP was nominally associated with FG in AfAs. Four loci were significantly associated with FG (GCK, p = 5.8 × 10(-8); MTNR1B, p = 8.5 × 10(-9); and FADS1, p = 2.2 × 10(-4)) or FI (GCKR, p = 5.9 × 10(-4)). At GCK and MTNR1B the EuA and AfA SNPs represented the same signal, while at FADS1, and GCKR, the EuA and best AfA SNPs were weakly correlated (r(2) <0.2), suggesting allelic heterogeneity for association with FG at these loci. CONCLUSIONS/INTERPRETATION: Few glycaemic SNPs showed strict evidence of transferability from EuA to AfAs. Four loci were significantly associated in both AfAs and those with EuA after accounting for varying LD across ancestral groups, with new signals emerging to aid fine-mapping.

Mechanisms of alloimmunization and subsequent bone marrow transplantation rejection induced by platelet transfusion in a murine model.

For many nonmalignant hematological disorders, HLA-matched bone marrow transplantation (BMT) is curative. However, due to lack of neoplasia, the toxicity of stringent conditioning regimens is difficult to justify, and reduced intensity conditioning is used. Unfortunately, current reduced intensity regimens have high rates of BMT rejection. We have recently reported in a murine model that mHAs on transfused platelet products induce subsequent BMT rejection. Most nonmalignant hematological disorders require transfusion support prior to BMT and the rate of BMT rejection in humans correlates with the number of transfusions given. Herein, we perform a mechanistic analysis of platelet transfusion-induced BMT rejection and report that unlike exposure to alloantigens during transplantation, platelet transfusion primes alloimmunity but does not stimulate full effector function. Subsequent BMT is itself an additional and distinct immunizing event, which does not induce rejection without antecedent priming from transfusion. Both CD4(+) and CD8(+) T cells are required for priming during platelet transfusion, but only CD8(+) T cells are required for BMT rejection. In neither case are antibodies required for rejection to occur.

Identification of patient safety improvement targets in successful vascular and endovascular procedures: analysis of 251 hours of complex arterial surgery.

OBJECTIVES: To investigate failures in patient safety for patients undergoing vascular and endovascular procedures to guide future quality and safety interventions. DESIGN: Single centre prospective observational study. METHODS: 66 procedures (17 thoracoabdominal and 23 abdominal aortic aneurysms, 4 carotid and 22 limb procedures) were observed prospectively over a 9-month period (251 h operating time) by two trained observers. Event logs were recorded for each procedure. Two blinded experts identified and independently categorised failures into 22 types (using a validated category tool) and severity (5-point scale). Data are expressed as median (range). Statistical analysis was performed using Mann-Whitney U, Kruskal-Wallis and Spearman's Rank tests. RESULTS: 1145 failures were identified with good inter-assessor reliability (Cronbach's alpha 0.844). The commonest failure types related to equipment (including unavailability, configuration and other failures) (269/1145 [23.5%]) and communication (240/1145 [21.0%]). A comparatively lower number of technical and psychomotor failures were identified (103 [9.0%]). The number of failures correlated with procedure duration (rho = 0.695, p < 0.001) but not anatomical site of the procedure or pathology of the disease process. Failure rate was higher in patients undergoing combined surgical/endovascular procedures compared to open surgery (median 5.7/h [IQR 4.2-8.1] vs 3.0/h [2.5-3.5]; p < 0.001). The severity of failures was similar (1.5/5 [1-2] vs 1/5 [1-2] respectively; p = 0.095). For combined procedures, failure rates were significantly higher during the endovascular phase (9.6/h [7.5-13.7]) compared to the non-endovascular phase (3.0/h [1.0-5.0]; p < 0.001). CONCLUSIONS: Failures in patient safety are common during complex arterial procedures. Few failures were severe, although minor failures during critical stages and accumulation of multiple minor failures may potentially be important. Failures occurred especially during the endovascular phase and were often related to equipment or communication aspects. Interventions to improve procedural safety and quality of care should primarily target these specific areas.

Mid-cervical interneuron networks following high cervical spinal cord injury.

Spinal interneuron (IN) networks can facilitate respiratory motor recovery after spinal cord injury (SCI). We hypothesized that excitatory synaptic connectivity between INs located immediately caudal to unilateral cervical SCI would be most prevalent in a contra- to ipsilateral direction. Adult rats were studied following chronic C2 spinal cord hemisection (C2Hx) injury. Rats were anesthetized and ventilated and a multi-electrode array was used to simultaneously record INs on both sides of the C4-5 spinal cord. The temporal firing relationship between IN pairs was evaluated using cross-correlation with directionality of synaptic connections inferred based on electrode location. During baseline recordings, the majority of detectable excitatory IN connections occurred in a contra- to- ipsilateral direction. However, acute respiratory stimulation with hypoxia abolished this directionality, while simultaneously increasing the detectable inhibitory connections within the ipsilateral cord. We conclude that propriospinal networks caudal to SCI can display a contralateral-to-ipsilateral directionality of synaptic connections and that these connections are modulated by acute exposure to hypoxia.

Providing skilled birth attendants and emergency obstetric care to the poor through partnership with private sector obstetricians in Gujarat, India.

PROBLEM: India has the world's largest number of maternal deaths estimated at 117,000 per year. Past efforts to provide skilled birth attendants and emergency obstetric care in rural areas have not succeeded because obstetricians are not willing to be posted in government hospitals at subdistrict level. APPROACH: We have documented an innovative public-private partnership scheme between the Government of Gujarat, in India, and private obstetricians practising in rural areas to provide delivery care to poor women. LOCAL SETTING: In April 2007, the majority of poor women delivered their babies at home without skilled care. RELEVANT CHANGES: More than 800 obstetricians joined the scheme and more than 176,000 poor women delivered in private facilities. We estimate that the coverage of deliveries among poor women under the scheme increased from 27% to 53% between April and October 2007. The programme is considered very successful and shows that these types of social health insurance programmes can be managed by the state health department without help from any insurance company or international donor. LESSONS LEARNED: At least in some areas of India, it is possible to develop large-scale partnerships with the private sector to provide skilled birth attendants and emergency obstetric care to poor women at a relatively small cost. Poor women will take up the benefit of skilled delivery care rapidly, if they do not have to pay for it.

Using linkage analysis to identify quantitative trait loci for sleep apnea in relationship to body mass index.

To understand the genetics of sleep apnea, we evaluated the relationship between the apnea hypopnea index (AHI) and body mass index (BMI) through linkage analysis to identify genetic loci that may influence AHI and BMI jointly and AHI independent of BMI. Haseman-Elston sibling regression was conducted on AHI, AHI adjusted for BMI and BMI in African-American and European-American pedigrees. A comparison of the magnitude of linkage peaks was used to assess the relationship between AHI and BMI. In EAs, the strongest evidence for linkage to AHI was on 6q23-25 and 10q24-q25, both decreasing after BMI adjustment, suggesting loci with pleiotropic effects. Also, a promising area of linkage to AHI but not BMI was observed on 6p11-q11 near the orexin-2 receptor, suggesting BMI independent pathways. In AAs the strongest evidence of linkage for AHI after adjusting for BMI was on chromosome 8p21.3 with linkage increasing after BMI adjustment and on 8q24.1 with linkage decreasing after BMI adjustment. Novel linkage peaks were also observed in AAs to both BMI and AHI on chromosome 13 near the serotonin-2a receptor. These analyses suggest genetic loci for sleep apnea that operate both independently of BMI and through BMI-related pathways.

Heritability of upper airway dimensions derived using acoustic pharyngometry.

Acoustic pharyngometry represents a simple, quick noninvasive method of measuring upper airway dimensions, which are predictive of sleep apnoea risk. The aim of the present study was to assess the genetic basis of upper airway size as determined using pharyngometry. Participants in the Cleveland Family Study aged >14 yrs underwent three acoustic pharyngometric measurements. Variance component models adjusted for age and sex were used to estimate the heritability of pharyngometry-derived airway measures. A total of 568 out of 655 (87%) subjects provided pharyngometric curves of sufficient quality. Although African-Americans tended to show narrower airways compared with white subjects, heritability patterns were similar in these two groups. The minimum cross-sectional area exhibited a heritability of 0.34 in white subjects and 0.39 in African-Americans, suggesting that 30-40% of the total variance in this measure is explained by shared familial factors. Estimates were unchanged after adjustment for body mass index or neck circumference. In contrast, oropharyngeal length did not show significant heritability in either ethnic group. The minimum cross-sectional area of the oropharynx is a highly heritable trait, suggesting the presence of an underlying genetic basis. These findings demonstrate the potential utility of acoustic pharyngometry in dissecting the genetic basis of sleep apnoea.

Shared genetic basis for obstructive sleep apnea and adiposity measures.

INTRODUCTION: Obesity and obstructive sleep apnea each have a substantial genetic basis and commonly coexist in individuals. The degree to which the genetic underpinnings for these disorders overlap has not been previously quantified. METHODS: A total of 1802 individuals from 310 families in the Cleveland Family Study underwent home sleep studies as well as standardized assessment of body mass index (BMI) and circumferences at the waist, hip and neck. In 713 participants with laboratory sleep studies, fasting blood samples were assayed for leptin, adiponectin and resistin. Variance component models were used to estimate heritability and genetic correlations. RESULTS: The heritability of the apnea hypopnea index (AHI) was 0.37+/-0.04 and 0.33+/-0.07 for home and laboratory sleep studies, respectively. The genetic correlations between AHI and anthropomorphic adiposity measures ranged from 0.57 to 0.61, suggesting that obesity can explain nearly 40% of the genetic variance in sleep apnea. The magnitude of the genetic correlations between apnea severity and adipokine levels was substantially less than those with anthropomorphic measures, ranging from 0.11 to 0.46. After adjusting for BMI, no significant genetic correlation with apnea severity was observed for any of the other adiposity measures. CONCLUSIONS: Substantial but not complete overlap in genetic bases exists between sleep apnea and anthropomorphic indices of adiposity, and this overlap accounts for more than one-third of the genetic variance in apnea severity. These findings suggest that genetic polymorphisms exist that importantly influence sleep apnea susceptibility through both obesity-dependent and -independent pathways.

The association between sleep duration and obesity in older adults.

BACKGROUND: Reduced sleep has been reported to predict obesity in children and young adults. However, studies based on self-report have been unable to identify an association in older populations. In this study, the cross-sectional associations between sleep duration measured objectively and measures of weight and body composition were assessed in two cohorts of older adults. METHODS: Wrist actigraphy was performed for a mean (s.d.) of 5.2 (0.9) nights in 3055 men (age: 67-96 years) participating in the Osteoporotic Fractures in Men Study (MrOS) and 4.1 (0.8) nights in 3052 women (age: 70-99 years) participating in the Study of Osteoporotic Fractures (SOF). A subgroup of 2862 men and 455 women also underwent polysomnography to measure sleep apnea severity. RESULTS: Compared to those sleeping an average of 7-8 h per night, and after adjusting for multiple risk factors and medical conditions, a sleep duration of less than 5 h was associated with a body mass index (BMI) that was on average 2.5 kg/m(2) (95% confidence interval (CI): 2.0-2.9) greater in men and 1.8 kg/m(2) (95% CI: 1.1-2.4) greater in women. The odds of obesity (BMI >or= 30 kg/m(2)) was 3.7-fold greater (95% CI: 2.7-5.0) in men and 2.3-fold greater in women (95% CI: 1.6-3.1) who slept less than 5 h. Short sleep was also associated with central body fat distribution and increased percent body fat. These associations persisted after adjusting for sleep apnea, insomnia and daytime sleepiness. CONCLUSIONS: In older men and women, actigraphy-ascertained reduced sleep durations are strongly associated with greater adiposity.

Cytochrome P450 2C9 mediated metabolism in people with and without cancer.

OBJECTIVES: To compare cytochrome P450 activity in people with and without cancer and examine the relationship between CYP2C9 activity and serum cytokine levels. PATIENTS AND METHODS: 10 subjects with cancer who were currently receiving treatment and 10 additional subjects without cancer who were matched to the subjects with cancer based on gender and race were enrolled into the study. Serial blood samples were drawn to measure tolbutamide in the plasma before and after oral tolbutamide 500 mg. Total urine excreted was collected from 0 to 12 h following the dose. Tolbutamide and its metabolites were measured in plasma and urine by HPLC. CYP2C9 genotype was determined by PCR and pyrosequencing and cytokine values were determined by ELISA. RESULTS: The mean apparent oral clearance (cancer, 19.5 +/- 10.5 vs. non-cancer, 15.8 +/- 5.0 ml/min) and the mean urinary metabolic ratio from 0 to 12 h were similar (838 +/- 693 vs. 775 +/- 390). Neither age nor genotype statistically affected the outcomes. Mean interleukin-6 (7.2 +/- 9.4 vs. 1.5 +/- 1.3 pg/ml) and tissue necrosis factor-a (26.2 +/- 71.2 vs. 1.5 +/- 1.3 pg/ml) were 5- to 7-fold higher, respectively, in subjects with cancer. No statistically significant correlation between cytokine values and oral clearance or urinary metabolic ratio was found. CONCLUSIONS: CYP2C9 activity as measured by apparent oral clearance and urinary metabolic ratio following oral tolbutamide appear similar in people with and without cancer. Serum cytokine values appear higher in patients with cancer, although the differences did not reach statistical significance.

Inhibition of calcitriol receptor binding to vitamin D response elements by uremic toxins.

The genomic action of calcitriol (1,25-dihydroxy-vitamin D3) is mediated through the interaction of the calcitriol receptor (VDR) with vitamin D response elements (VDREs). Although renal failure is associated with resistance to the action of calcitriol, the mechanism of this resistance is not well understood. Therefore, we used the electrophoretic mobility shift assay to compare the ability of VDRs from normal and renal failure rats to bind to the osteocalcin gene VDRE. The results indicate that VDRs from renal failure rats have only half the DNA binding capacity as VDRs from control rats, despite identical calcitriol binding. Furthermore, incubation of normal VDRs with a uremic plasma ultrafiltrate resulted in a loss of > 50% of the binding sites for the osteocalcin VDRE. When VDRs bound to DNA as heterodimers with retinoid X receptors, the inhibitory effect of the uremic ultrafiltrate was due to a specific interaction with the VDR, not retinoid X receptors. In addition, uremic ultrafiltrate blocked calcitriol-induced reporter gene activity in transfected JEG-3 cells. Taken together, the results indicate that an inhibitory effect of a uremic toxin(s) on VDR-VDRE binding could underlie the calcitriol resistance of renal failure.

Antipsychotic pharmacogenomics in first episode psychosis: a role for glutamate genes.

Genetic factors may underlie beneficial and adverse responses to antipsychotic treatment. These relationships may be easier to identify among patients early in the course of disease who have limited exposure to antipsychotic drugs. We examined 86 first episode patients (schizophrenia, psychotic bipolar disorder and major depressive disorder with psychotic features) who had minimal to no prior antipsychotic exposure in a 6-week pharmacogenomic study of antipsychotic treatment response. Response was measured by change in Brief Psychiatric Rating Scale total score. Risperidone monotherapy was the primary antipsychotic treatment. Pharmacogenomic association studies were completed to (1) examine candidate single-nucleotide polymorphisms (SNPs) in genes known to be involved with glutamate signaling, and (2) conduct an exploratory genome-wide association study of symptom response to identify potential novel associations for future investigation. Two SNPs in GRM7 (rs2069062 and rs2014195) were significantly associated with antipsychotic response in candidate gene analysis, as were two SNPs in the human glutamate receptor delta 2 (GRID2) gene (rs9307122 and rs1875705) in genome-wide association analysis. Further examination of these findings with those from a separate risperidone-treated study sample demonstrated that top SNPs in both studies were overrepresented in glutamate genes and that there were similarities in neurodevelopmental gene categories associated with drug response from both study samples. These associations indicate a role for gene variants related to glutamate signaling and antipsychotic response with more broad association patterns indicating the potential importance of genes involved in neuronal development.