Association analysis of ANK3 gene variants in nordic bipolar disorder and schizophrenia case-control samples

Genetic variants in ankyrin 3 (ANK3) have recently been shown to be associated with bipolar disorder (BD). We genotyped three ANK3 SNPs previously found to be associated with BD (rs10994336, rs1938526, and rs9804190) in a Scandinavian BD case-control sample (N = 854/2,614). Due to evidence of genetic overlap between BD and schizophrenia (SZ), we also genotyped these three SNPs in a Scandinavian SZ case-control sample (N = 1,073/2,919). Combining our Scandinavian samples with an Icelandic sample (N = 435 BD cases, 651 SZ cases, and 11,491 healthy controls), we found rs10994336 and rs9804190 to be nominally significantly associated with BD in this combined Nordic BD sample (N = 1,289/14,105). Nominal P was 0.015/0.018 (fixed/random effect) for rs10994336 (Bonferroni corrected P = 0.044/0.053) and 0.023 for rs9804190 (Bonferroni corrected P = 0.069). None of the SNPs were significantly associated with SZ in the combined Nordic SZ case-control sample (N = 1,724/14,410). These results further support that ANK3 is a susceptibility gene specific to BD and that more than one risk locus is involved.     

Testicular descent: INSL3, testosterone, genes and the intrauterine milieu

Complete testicular descent is a sign of, and a prerequisite for, normal testicular function in adult life. The process of testis descent is dependent on gubernacular growth and reorganization, which is regulated by the Leydig cell hormones insulin-like peptide 3 (INSL3) and testosterone. Investigation of the role of INSL3 and its receptor, relaxin-family peptide receptor 2 (RXFP2), has contributed substantially to our understanding of the hormonal control of testicular descent. Cryptorchidism is a common congenital malformation, which is seen in 2-9% of newborn boys, and confers an increased risk of infertility and testicular cancer in adulthood. Although some cases of isolated cryptorchidism in humans can be ascribed to known genetic defects, such as mutations in INSL3 or RXFP2, the cause of cryptorchidism remains unknown in most patients. Several animal and human studies are currently underway to test the hypothesis that in utero factors, including environmental and maternal lifestyle factors, may be involved in the etiology of cryptorchidism. Overall, the etiology of isolated cryptorchidism seems to be complex and multifactorial, involving both genetic and nongenetic components.     

Haemophilia B: impact on patients and economic burden of disease

Worldwide, haemophilia is the most common hereditary bleeding disorder. The incidence of haemophilia B, however, is considerably less than haemophilia A and consequently appears to have received less attention in the research literature. This article aims to summarise the available evidence documenting the patient and economic burden associated with haemophilia B and current methods of disease management. Both the immediate and long-term clinical consequences of haemophilia B can have significant implications for patients in terms of functional limitations and diminished health-related quality of life (HRQOL). Evidence demonstrates that primary prophylaxis is the optimal strategy for replacing missing clotting factor IX (FIX) and managing haemophilia B. Use of recombinant FIX (rFIX) over plasma-derived FIX (pd-FIX) is also generally preferred for safety reasons. Prophylaxis using currently available rFIX products, however, requires a demanding regimen of intravenous infusions 2-3 times a week which may have significant implications for adherence and ultimately the long-term efficacy of such regimens. Only limited assessments of the cost-effectiveness of prophylactic versus on-demand FIX treatment regimens have been conducted to date. Prophylaxis, however, is generally more costly as greater quantities of FIX are consumed. Any reduction in FIX replacement dosing frequency is expected to improve patient adherence and contribute to improved clinical outcomes, further supporting the cost-effectiveness of such interventions. Although a rare disease, as economic constraints for healthcare increase, generating further information regarding the key clinical, patient and economic outcomes associated with haemophilia B will be essential for supporting improvements in care for people with haemophilia B.     

Breast cancer cells can switch between estrogen receptor α and ErbB signaling and combined treatment against both signaling pathways postpones development of resistance

The majority of breast cancers are estrogen responsive, but upon progression of disease other growth promoting pathways are activated, e.g., the ErbB receptor system. The present study focuses on resistance to the pure estrogen antagonist fulvestrant and strategies to treat resistant cells or even circumvent development of resistance. Limited effects were observed when targeting EGFR and ErbB2 with the monoclonal antibodies cetuximab, trastuzumab, and pertuzumab, whereas the pan-ErbB inhibitor CI-1033 selectively inhibited growth of fulvestrant resistant cell lines. CI-1033 inhibited Erk but not Akt signaling, which as well as Erk is important for antiestrogen resistant cell growth. Accordingly, combination therapy with CI-1033 and the Akt inhibitor SH-6 or the Protein Kinase C inhibitor RO-32-0432 was applied and found superior to single agent treatment. Further, the resistant cell lines were more sensitive to CI-1033 treatment when grown in the presence of fulvestrant, as withdrawal of fulvestrant restored signaling through the estrogen receptor α (ERα), partly overcoming the growth inhibitory effects of CI-1033. Thus, the resistant cells could switch between ERα and ErbB signaling for growth promotion. Although parental MCF-7 cell growth primarily depends on ERα signaling, a heregulin-1β induced switch to ErbB signaling rescued MCF-7 cells from the growth inhibition exerted by fulvestrant-mediated blockade of ERα signaling. This interplay between ERα and ErbB signaling could be abrogated by combined therapy targeting both receptor systems. Thus, the present study indicates that upon development of antiestrogen resistance, antiestrogen treatment should be continued in combination with signal transduction inhibitors. Further, upfront combination of endocrine therapy with pan-ErbB inhibition may postpone or even prevent development of treatment resistance.     

Maternal use of nicotine replacement therapy during pregnancy and offspring birthweight: a study within the Danish National Birth Cohort

Lassen TH, Madsen M, Skovgaard LT, Strandberg‐Larsen K, Olsen J, Andersen A‐MN. Maternal use of nicotine replacement therapy during pregnancy and offspring birthweight: a study within the Danish National Birth Cohort. Paediatric and Perinatal Epidemiology 2010; 24: 272–281. Smoking is a well‐established risk factor for fetal growth restriction and other adverse pregnancy outcomes, and nicotine may be one of the chemical compounds that drive these associations. Nicotine replacement therapy (NRT) is a smoking cessation aid, which can facilitate smoking cessation. It is, however, unknown whether NRT used during pregnancy impairs fetal growth. The aim of this study was to estimate the association between the use of NRT during pregnancy and offspring birthweight. The study population consisted of 72 761 women enrolled in the Danish National Birth Cohort between 1996 and 2002. Information on NRT and potential confounders was obtained from two computer‐assisted telephone interviews conducted in the second and third trimesters, respectively. Multiple linear regression in a multilevel model was used to estimate the association between NRT use and birthweight adjusted for gestational age and potential confounders. The adjusted analyses showed no significant association between the duration of NRT use and birthweight (b = 0.25 g per week of NRT use [95% CI ?2.31, 2.81]) and neither was the type of NRT product (patch, gum, inhaler) associated with reduced birthweight. However, simultaneous use of more than one NRT product was associated with reduced birthweight (b = ?10.73 g per week of NRT use [95% CI ?26.51, 5.05]), although the association was not statistically significant. The results of this study suggest that maternal use of NRT in pregnancy does not seriously affect birthweight, but there could be a negative effect on birthweight associated with simultaneous use of more than one type of NRT product.     

Is the Kaiser Permanente model superior in terms of clinical integration?: a comparative study of Kaiser Permanente, Northern California and the Danish healthcare system

Background

Episodes of Emergency Department (ED) service use among older adults previously have not been constructed, or evaluated as multi-dimensional phenomena. In this study, we constructed episodes of ED service use among a cohort of older adults over a 15-year observation period, measured the episodes by severity and intensity, and compared these measures in predicting subsequent hospitalization.

Methods

We conducted a secondary analysis of the prospective cohort study entitled the Survey on Assets and Health Dynamics among the Oldest Old (AHEAD). Baseline (1993) data on 5,511 self-respondents ≥70 years old were linked to their Medicare claims for 1991-2005. Claims then were organized into episodes of ED care according to Medicare guidelines. The severity of ED episodes was measured with a modified-NYU algorithm using ICD9-CM diagnoses, and the intensity of the episodes was measured using CPT codes. Measures were evaluated against subsequent hospitalization to estimate comparative predictive validity.

Results

Over 15 years, three-fourths (4,171) of the 5,511 AHEAD participants had at least 1 ED episode, with a mean of 4.5 episodes. Cross-classification indicated the modified-NYU severity measure and the CPT-based intensity measure captured different aspects of ED episodes (kappa = 0.18). While both measures were significant independent predictors of hospital admission from ED episodes, the CPT measure had substantially higher predictive validity than the modified-NYU measure (AORs 5.70 vs. 3.31; p < .001).

Conclusions

We demonstrated an innovative approach for how claims data can be used to construct episodes of ED care among a sample of older adults. We also determined that the modified-NYU measure of severity and the CPT measure of intensity tap different aspects of ED episodes, and that both measures were predictive of subsequent hospitalization.     

What's in a Self‐report? A Comparison of Pregnant Women with Self‐reported and Hospital Diagnosed Eating Disorder

The aim of this study was to examine how similar pregnant women with self‐reported lifetime eating disorder (ED) were to pregnant women with a hospital diagnosis of ED. A total of 83 731 pregnant women enrolled in the Danish National Birth Cohort reported on ED, and by linkage to the Danish health registers, hospital diagnoses of ED were obtained. Characteristics of women with self‐reported ED, hospital diagnosed ED and without ED were compared using chi‐square tests, t‐test and logistic regression models with robust standard errors. In total, 4.8% women reported ED, and 0.5% had a hospital diagnosis of ED recorded in the health registers. Women with self‐reported ED were comparable with women with hospital diagnosed ED on most reproductive and health characteristics, while they differed from women without ED concerning all characteristics studied. Our findings highlight that women with self‐reported ED have impaired function and adverse health outcomes, consistent with diagnosable ED. Copyright © 2016 John Wiley & Sons, Ltd and Eating Disorders Association.