Screening for Down's syndrome: effects, safety, and cost effectiveness of first and second trimester strategies commentary: rasults may not be widely applicable authors' response

Objective: To compare the effects, safety, and cost effectiveness of antenatal screening strategies for Down's syndrome. Design: Analysis of incremental cost effectiveness. Setting: United Kingdom. Main outcome measures: Number of liveborn babies with Down's syndrome, miscarriages due to chorionic villus sampling or amniocentesis, healthcare costs of screening programme, and additional costs and additional miscarriages per additional affected live birth prevented by adopting a more effective strategy. Results: Compared with no screening, the additional cost per additional liveborn baby with Down's syndrome prevented was £22 000 for measurement of nuchal translucency. The cost of the integrated test was £51 000 compared with measurement of nuchal translucency. All other strategies were more costly and less effective, or cost more per additional affected baby prevented. Depending on the cost of the screening test, the first trimester combined test and the quadruple test would also be cost effective options. Conclusions: The choice of screening strategy should be between the integrated test, first trimester combined test, quadruple test, or nuchal translucency measurement depending on how much service providers are willing to pay, the total budget available, and values on safety. Screening based on maternal age, the second trimester double test, and the first trimester serum test was less effective, less safe, and more costly than these four options

Altered Dendritic Morphology of Purkinje cells in Dyt1 ΔGAG Knock-In and Purkinje Cell-Specific Dyt1 Conditional Knockout Mice

BACKGROUND: DYT1 early-onset generalized dystonia is a neurological movement disorder characterized by involuntary muscle contractions. It is caused by a trinucleotide deletion of a GAG (ΔGAG) in the DYT1 (TOR1A) gene encoding torsinA; the mouse homolog of this gene is Dyt1 (Tor1a). Although structural and functional alterations in the cerebellum have been reported in DYT1 dystonia, neuronal morphology has not been examined in vivo. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we examined the morphology of the cerebellum in Dyt1 ΔGAG knock-in (KI) mice. Golgi staining of the cerebellum revealed a reduction in the length of primary dendrites and a decrease in the number of spines on the distal dendrites of Purkinje cells. To determine if this phenomenon was cell autonomous and mediated by a loss of torsinA function in Purkinje cells, we created a knockout of the Dyt1 gene only in Purkinje cells of mice. We found the Purkinje-cell specific Dyt1 conditional knockout (Dyt1 pKO) mice have similar alterations in Purkinje cell morphology, with shortened primary dendrites and decreased spines on the distal dendrites. CONCLUSION/SIGNIFICANCE: These results suggest that the torsinA is important for the proper development of the cerebellum and a loss of this function in the Purkinje cells results in an alteration in dendritic structure

MFGE8 does not influence chorio-retinal homeostasis or choroidal neovascularization in vivo

Purpose: Milk fat globule-epidermal growth factor-factor VIII (MFGE8) is necessary for diurnal outer segment phagocytosis and promotes VEGF-dependent neovascularization. The prevalence of two single nucleotide polymorphisms (SNP) in MFGE8 was studied in two exsudative or “wet” Age-related Macular Degeneration (AMD) groups and two corresponding control groups. We studied the effect of MFGE8 deficiency on retinal homeostasis with age and on choroidal neovascularization (CNV) in mice. Methods: The distribution of the SNP (rs4945 and rs1878326) of MFGE8 was analyzed in two groups of patients with “wet” AMD and their age-matched controls from Germany and France. MFGE8-expressing cells were identified in Mfge8+/− mice expressing ß-galactosidase. Aged Mfge8+/− and Mfge8−/− mice were studied by funduscopy, histology, electron microscopy, scanning electron microscopy of vascular corrosion casts of the choroid, and after laser-induced CNV. Results: rs1878326 was associated with AMD in the French and German group. The Mfge8 promoter is highly active in photoreceptors but not in retinal pigment epithelium cells. Mfge8−/− mice did not differ from controls in terms of fundus appearance, photoreceptor cell layers, choroidal architecture or laser-induced CNV. In contrast, the Bruch's membrane (BM) was slightly but significantly thicker in Mfge8−/− mice as compared to controls. Conclusions: Despite a reproducible minor increase of rs1878326 in AMD patients and a very modest increase in BM in Mfge8−/− mice, our data suggests that MFGE8 dysfunction does not play a critical role in the pathogenesis of AMD

Early onset torsion dystonia (Oppenheim's dystonia)

Early onset torsion dystonia (EOTD) is a rare movement disorder characterized by involuntary, repetitive, sustained muscle contractions or postures involving one or more sites of the body. A US study estimated the prevalence at approximately 1 in 30,000. The estimated prevalence in the general population of Europe seems to be lower, ranging from 1 in 330,000 to 1 in 200,000, although precise numbers are currently not available. The estimated prevalence in the Ashkenazi Jewish population is approximately five to ten times higher, due to a founder mutation. Symptoms of EOTD typically develop first in an arm or leg in middle to late childhood and progress in approximately 30% of patients to other body regions (generalized dystonia) within about five years. Distribution and severity of symptoms vary widely between affected individuals. The majority of cases from various ethnic groups are caused by an autosomal dominantly inherited deletion of 3 bp (GAG) in the DYT1 gene on chromosome 9q34. This gene encodes a protein named torsinA, which is presumed to act as a chaperone protein associated with the endoplasmic reticulum and the nuclear envelope. It may interact with the dopamine transporter and participate in intracellular trafficking, although its precise function within the cell remains to be determined. Molecular genetic diagnostic and genetic counseling is recommended for individuals with age of onset below 26 years, and may also be considered in those with onset after 26 years having a relative with typical early onset dystonia. Treatment options include botulinum toxin injections for focal symptoms, pharmacological therapy such as anticholinergics (most commonly trihexiphenydil) for generalized dystonia and surgical approaches such as deep brain stimulation of the internal globus pallidus or intrathecal baclofen application in severe cases. All patients have normal cognitive function, and despite a high rate of generalization of dystonia, 75% of those patients are able to maintain ambulation and independence, and therefore a comparatively good quality of life, with modern treatment modalities

Transcriptional Activation of REST by Sp1 in Huntington's Disease Models

In Huntington's disease (HD), mutant huntingtin (mHtt) disrupts the normal transcriptional program of disease neurons by altering the function of several gene expression regulators such as Sp1. REST (Repressor Element-1 Silencing Transcription Factor), a key regulator of neuronal differentiation, is also aberrantly activated in HD by a mechanism that remains unclear. Here, we show that the level of REST mRNA is increased in HD mice and in NG108 cells differentiated into neuronal-like cells and expressing a toxic mHtt fragment. Using luciferase reporter gene assay, we delimited the REST promoter regions essential for mHtt-mediated REST upregulation and found that they contain Sp factor binding sites. We provide evidence that Sp1 and Sp3 bind REST promoter and interplay to fine-tune REST transcription. In undifferentiated NG108 cells, Sp1 and Sp3 have antagonistic effect, Sp1 acting as an activator and Sp3 as a repressor. Upon neuronal differentiation, we show that the amount and ratio of Sp1/Sp3 proteins decline, as does REST expression, and that the transcriptional role of Sp3 shifts toward a weak activator. Therefore, our results provide new molecular information to the transcriptional regulation of REST during neuronal differentiation. Importantly, specific knockdown of Sp1 abolishes REST upregulation in NG108 neuronal-like cells expressing mHtt. Our data together with earlier reports suggest that mHtt triggers a pathogenic cascade involving Sp1 activation, which leads to REST upregulation and repression of neuronal genes

Does involvement in a cohort study improve health and affect health inequalities? A natural experiment

Abstract Background Evidence suggests that the process of taking part in health research can improve participants\u2019 health, independent of any intended intervention. However, no research has yet explored whether these effects differ across socioeconomic groups. If the effect of mere participation in health research also has a social gradient this could increase health inequalities and bias research results. This study used the Born in Bradford family cohort (BIB) to explore whether simply taking part in BIB had improved participants\u2019 health and, if so, whether this effect was mediated by socioeconomic status. Methods Survey data on self-reported health behaviours were collected between 2007 and 2010 as part of BIB. These were augmented by clinical data on birth weight. Pregnant women on their second pregnancy, joining BIB for the first time formed the control group. Their health was compared to women on their second pregnancy who had both pregnancies within the study, who formed the exposed group. In order to limit the inherent bias in a non-randomised study, propensity score analysis was used, matching on age, ethnicity, education and date of questionnaire. The results were then compared according to mothers' education. Results Of six outcomes tested, only alcohol consumption showed a statistically significant reduction with exposure to BIB (OR: 0.35, 95% CIs 0.13, 0.92). Although effect estimates were larger for women with higher education compared to lower education, these effects were not statistically significant. Conclusions Despite one significant finding, these results overall are insufficient to conclude that simply taking part in BIB affected participants\u2019 health. We recommend that socioeconomic status is considered in future studies testing effects of research participation, and that randomised studies with larger sample sizes are conducted

Impact of seasonal variation, age and smoking status on human semen parameters: The Massachusetts General Hospital experience

BACKGROUND: To investigate the relationship of human semen parameters with season, age and smoking status. METHODS: The present study used data from subjects recruited into an ongoing cross-sectional study on the relationship between environmental agents and semen characteristics. Our population consisted of 306 patients who presented to the Vincent Memorial Andrology Laboratory of Massachusetts General Hospital for semen evaluation. Sperm concentration and motility were measured with computer aided sperm analysis (CASA). Sperm morphology was scored using Tygerberg Kruger strict criteria. Regression analyses were used to investigate the relationships between semen parameters and season, age and smoking status, adjusting for abstinence interval. RESULTS: Sperm concentration in the spring was significantly higher than in winter, fall and summer (p < 0.05). There was suggestive evidence of higher sperm motility and percent of sperm with normal morphology in the spring than in the other seasons. There were no statistically significant relationships between semen parameters and smoking status, though current smokers tended to have lower sperm concentration. We also did not find a statistically significant relationship between age and semen parameters. CONCLUSIONS: We found seasonal variations in sperm concentration and suggestive evidence of seasonal variation in sperm motility and percent sperm with normal morphology. Although smoking status was not a significant predictor of semen parameters, this may have been due to the small number of current smokers in the study

Factors associated with serum 25-hydroxyvitamin D concentrations in older people in Europe: the EUREYE study.

BACKGROUND/OBJECTIVES: We aimed to describe serum 25-hydroxyvitamin D (25OHD) concentrations in older Europeans and to investigate associations between 25OHD and lifestyle factors, including dietary intake and supplement use. SUBJECTS/METHODS: Men and women aged ≥ 65 years were recruited from seven centres across north to south Europe. Serum 25OHD2 and 25OHD3 concentrations were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) in 4495 samples and total 25OHD (25OHD2 + 25OHD3) was adjusted for season of blood collection. RESULTS: The mean (25th, 75th quartile) of seasonally adjusted 25OHD was 46 (34, 65) nmol/L, with the highest concentration of 25OHD in Bergen [61 (49, 79) nmol/L], and the lowest in Paris [36 (24, 57) nmol/L)]. Vitamin D deficiency (25-50 nmol/L) and vitamin D insufficiency (50-75 nmol/L) were found in 41 and 33% of the population, respectively. In multivariable analysis controlled for confounders, seasonally adjusted 25OHD concentrations were significantly (p < 0.05) lower in smokers and participants with self-reported diabetes and higher with increasing dietary vitamin D, and supplement use with fish liver oil, omega-3, and vitamin D. Additionally, in further analysis excluding Bergen, 25OHD was associated with higher intakes of oily fish and increasing UVB exposure. We observed low concentrations of 25OHD in older people in Europe. CONCLUSIONS: Our findings of the higher 25OHD concentrations in supplement users (omega-3 fish oil, fish liver oil, vitamin D) add to current recommendations to reduce vitamin D deficiency. We were unable to fully assess the role of dietary vitamin D as we lacked information on vitamin D-fortified foods

Smoking and dietary inadequacy among Inuvialuit women of child bearing age in the Northwest Territories, Canada

Objective The prevalence of smoking in Aboriginal Canadians is higher than non-Aboriginal Canadians, a behavior that also tends to alter dietary patterns. Compared with the general Canadian population, maternal smoking rates are almost twice as high. The aim of this study was to compare dietary adequacy of Inuvialuit women of childbearing age comparing smokers versus non-smokers. Research methods & procedures A cross-sectional study, where participants completed a culturally specific quantitative food frequency questionnaire. Non-parametric analysis was used to compare mean nutrient intake, dietary inadequacy and differences in nutrient density among smokers and non-smokers. Multiple logistic regression analyses were performed for key nutrients inadequacy and smoking status. Data was collected from three communities in the Beaufort Delta region of the Northwest Territories, Canada from randomly selected Inuvialuit women of childbearing age (19-44 years). Results Of 92 participants, 75% reported being smokers. There were no significant differences in age, BMI, marital status, education, number of people in household working and/or number of self employed, and physical activity between smokers and non-smokers. Non-parametric analysis showed no differences in nutrient intake between smokers and non-smokers. Logistic regression however revealed there was a positive association between smoking and inadequacies of vitamin C (OR = 2.91, 95% CI, 1.17-5.25), iron (OR = 3.16, 95% CI, 1.27-5.90), and zinc (OR = 2.78, 95% CI, 1.12-4.94). A high percentage of women (>60%), regardless of smoking status, did not meet the dietary recommendations for fiber, vitamin D, E and potassium. Conclusions This study provides evidence of inadequate dietary intake among Inuvialuit of childbearing age regardless of smoking behavior