Trends in maternal age distribution and the live birth prevalence of Down's syndrome in England and Wales: 1938–2010

There have been concerns about the effects of increases in maternal age since the 1980s on the prevalence of Down''s syndrome. This study examined changes in the distribution of maternal age in England and Wales from 1938 to 2010. The live birth prevalence of Down''s syndrome in the absence of screening and subsequent termination was estimated using the numbers of babies born in England and Wales according to maternal age and the maternal age-related risk of a birth with Down''s syndrome. The proportion of women age 35 years or older at the time of giving birth reached a peak of 20% in 1945, declined to 5.5% in 1977 and rose to 20% in 2007. In the absence of screening and subsequent termination, the estimated live birth prevalence of Down''s syndrome would have mirrored these changes (2.3 per 1000 births in 1945, 1.2 per 1000 in 1976 and 2.2 per 1000 in 2007). The observed live birth prevalence (recorded by the National Down Syndrome Cytogenetic Register) was1.0 per 1000 from 1989 to 2010, due to screening and subsequent termination. In conclusion since the 1980s there has been an increase in the mean maternal age and in the expected prevalence of Down''s syndrome. When put in a longer historical context the current expected live birth prevalence is similar to that in the 1940s and the observed live birth prevalence is about 54% less than expected, due to screening and subsequent termination, and has remained reasonably constant since 1989 at 1.0 per 1000 births.     

Rapid testing versus karyotyping in Down's syndrome screening: cost-effectiveness and detection of clinically significant chromosome abnormalities

In all, 80% of antenatal karyotypes are generated by Down''s syndrome screening programmes (DSSP). After a positive screening, women are offered prenatal foetus karyotyping, the gold standard. Reliable molecular methods for rapid aneuploidy diagnosis (RAD: fluorescence in situ hybridization (FISH) and quantitative fluorescence PCR (QF-PCR)) can detect common aneuploidies, and are faster and less expensive than karyotyping.In the UK, RAD is recommended as a standalone approach in DSSP, whereas the US guidelines recommend that RAD be followed up by karyotyping. A cost-effectiveness (CE) analysis of RAD in various DSSP is lacking. There is a debate over the significance of chromosome abnormalities (CA) detected with karyotyping but not using RAD. Our objectives were to compare the CE of RAD versus karyotyping, to evaluate the clinically significant missed CA and to determine the impact of detecting the missed CA. We performed computer simulations to compare six screening options followed by FISH, PCR or karyotyping using a population of 110 948 pregnancies. Among the safer screening strategies, the most cost-effective strategy was contingent screening with QF-PCR (CE ratio of $24 084 per Down''s syndrome (DS) detected). Using karyotyping, the CE ratio increased to $27 898. QF-PCR missed only six clinically significant CA of which only one was expected to confer a high risk of an abnormal outcome. The incremental CE ratio (ICER) to find the CA missed by RAD was $66 608 per CA. These costs are much higher than those involved for detecting DS cases. As the DSSP are mainly designed for DS detection, it may be relevant to question the additional costs of karyotyping.     

Expression of cytokines,chemokines and other effector molecules in two prototypic autoinflammatory skin diseases,pyoderma gangrenosum and Sweet's syndrome

Pyoderma gangrenosum (PG) and Sweet''s syndrome (SS) are two inflammatory skin diseases presenting with painful ulcers and erythematous plaques, respectively; both disorders have a debilitating clinical behaviour and PG is potentially life-threatening. Recently, PG and SS have been included among the autoinflammatory diseases, which are characterized by recurrent episodes of sterile inflammation, without circulating autoantibodies and autoreactive T cells. However, an autoinflammatory pattern clearly supporting this inclusion has never been demonstrated. We studied 16 patients with PG, six with SS and six controls, evaluating, using a sandwich-based protein antibody array method, the expression profile of inflammatory effector molecules in PG, SS and normal skin. The expressions of interleukin (IL)-1 beta and its receptor I were significantly higher in PG (P = 0·0001 for both) and SS (P = 0·004–0·040) than in controls. In PG, chemokines such as IL-8 (P = 0·0001), chemokine (C-X-C motif) ligand (CXCL) 1/2/3 (P = 0·002), CXCL 16 (P = 0·003) and regulated upon activation normal T cell expressed and secreted (RANTES) (P = 0·005) were over-expressed. In SS, IL-8 (P = 0·018), CXCL 1/2/3 (P = 0·006) and CXCL 16 (P = 0·036) but not RANTES were over-expressed, suggesting that chemokine-mediated signals are lower than in PG. Fas/Fas ligand and CD40/CD40 ligand systems were over-expressed in PG (P = 0·0001 for Fas, P = 0·009 for Fas ligand, P = 0·012 for CD40, P = 0·0001 for CD40 ligand), contributing to tissue damage and inflammation, while their role seems to be less significant in SS. Over-expression of cytokines/chemokines and molecules amplifying the inflammatory network supports the view that PG and SS are autoinflammatory diseases. The differences in expression profile of inflammatory effectors between these two disorders may explain the stronger local aggressiveness in PG than SS.     

Women's status within the household as a determinant of maternal health care use in Nigeria

BackgroundAlthough gender inequality is often cited as a barrier to improving maternal health in sub-saharan Africa, there is lack of empirical data on how women''s socio-cultural characteristics may influence use of health services in Nigeria.ObjectiveTo describe how women''s position in the household affects receipt of maternity care services.MethodsSecondary data analysis of 10,052 and 4,590 currently married women aged 15 to 49 years from the 2008 Nigerian DHS who receive skilled antenatal and delivery care at least till pregnancy was done.ResultsReceipt of skilled delivery care was by 37.9% while, natal care was by 98.4%. Education, residence and wealth index all significantly influenced receipt of maternal health care. Women who were involved in decision making on their own health (aOR=1.97; 95%CI=1.88–2.06) and were employed throughout the year (aOR=1.11; 95%CI=1.01–1.23) were more likely to receive skilled antenatal care, while those who justified physical intimate partner violence were less likely to receive both skilled antenatal care (aOR=0.92; 95%CI=0.85–0.98) and delivery services (aOR 0.54; 95% CI 0.33–0.87).ConclusionInterventions aimed at improving maternal care should promote women empowerment (decision making, self worth, educational and economic) and should involve partners.     

Wilms' tumor in patients with 9q22.3 microdeletion syndrome suggests a role for PTCH1 in nephroblastomas

Nephroblastoma (Wilms'' tumor; WT) is the most common renal tumor of childhood. To date, several genetic abnormalities predisposing to WT have been identified in rare overgrowth syndromes. Among them, abnormal methylation of the 11p15 region, GPC3 and DIS3L2 mutations, which are responsible for Beckwith–Wiedemann, Simpson–Golabi–Behmel and Perlman syndromes, respectively. However, the underlying cause of WT remains unknown in the majority of cases. We report three unrelated patients who presented with WT in addition to a constitutional 9q22.3 microdeletion and dysmorphic/overgrowth syndrome. The size of the deletions was variable (ie, from 1.7 to 8.9 Mb) but invariably encompassed the PTCH1 gene. Subsequently, we identified a somatic PTCH1 nonsense mutation in the renal tumor of one patient. In addition, by array comparative genomic hybridization method, we analyzed the DNA extracted from the blood samples of nine patients with overgrowth syndrome and WT, but did not identify any deleterious chromosomal imbalances in these patients. These findings strongly suggest that patients with constitutional 9q22.3 microdeletion have an increased risk of WT, and that PTCH1 have a role in the pathogenesis of nephroblastomas.     

Incidence of sickle cell disease in an unselected cohort of neonates born in Berlin,Germany

Sickle cell disease (SCD) does not occur in the indigenous German population. However, with the increasing numbers of immigrants its prevalence is steadily rising. Nevertheless, robust epidemiological data is not available for Germany and, consequently, the German newborn screening (NBS) program does not include SCD. Between 1 September 2011 and 30 November 2012, an unselected cohort of 34 084 Berlin newborns was tested for SCD. The results of 14 newborns were consistent with SCD and 265 babies were identified as hemoglobin S (Hb S) carriers. These data indicate a 95% probability that the incidence of SCD in Berlin is at least 2.5/10 000.     

Delorme's operation plus sphincteroplasty for complete rectal prolapse associated with traumatic fecal incontinence

Rectal prolapse associated with traumatic fecal incontinence is a rare clinical combination. This study was designed to assess Delorme''s operation with sphincteroplasty as a surgical management of this combination in terms of recurrence and improvement of fecal incontinence. In this prospective study, we enrolled patients suffering from short, full-thickness rectal prolapse associated with traumatic fecal incontinence who had been admitted to Alexandria Main University Hospital during the period of May 2010–January 2013. Preoperative data including cause of trauma, duration of symptoms, results of anal manometry, and degree of fecal incontinence using Wexner score were collected from all patients. Delorme''s procedure with overlap sphincteroplasty was done in all patients. Recurrence of prolapse and improvement of fecal incontinence were assessed after 1, 3, 6 and 12 months. The study included 13 patients aged (32±8.7) years, 9 females and 4 males. Cause of sphincteric injury included previous anal surgery in 7 patients and normal labor in 6 patients. Duration between sphincteric injury and operation was (8.08±2.47) months. Preoperative Wexner''s mean score was 16.07±3.4. Early postoperative complications included superficial wound infection (69.2%), minor wound dehiscence (61.5%), and postoperative bleeding (7.6%). Recurrence was detected in 1 patient at 6 month follow-up. Wexner''s score showed significant improvement for all patients after 6 months (4.00±2.04). In conclusion, combination of Delorme''s procedure and sphincteroplasty for treatment of patients with short complete rectal prolapse associated with traumatic fecal incontinence is a safe, effective surgical management with satisfactory results regarding anatomical and functional outcomes.     

Projected number of children with isolated spina bifida or down syndrome in England and Wales by 2020

Children with major congenital anomalies often require lifelong access to health and social care services. Estimating future numbers of affected individuals can aid health and social care planning. This study aimed to estimate the number of children aged 0–15 years living with spina bifida or Down syndrome in England and Wales by 2020. Cases of spina bifida and Down syndrome born during 1998–2013 were identified from the Northern Congenital Abnormality Survey and the National Down Syndrome Cytogenetic Register, respectively. The number of infants born with spina bifida during 1998–2019 were estimated by applying the average prevalence rate in the North of England to actual and projected births in England and Wales. Poisson regression was performed to estimate the number of infants born with Down syndrome in England and Wales during 1998–2013 and 2004–2019. The numbers of children aged 0–15 living with spina bifida or Down syndrome in 2014 and in 2020 were then estimated by multiplying year- and age-specific survival estimates by the number of affected births. An estimated 956 children with isolated spina bifida, 623 children with spina bifida and hydrocephalus and 11,592 children with Down syndrome aged 0–15 years will be living in England and Wales by 2020, increases of 7.2%, 12.0% and 12.7% since 2014, respectively. Due to improvements in survival, an increase in population size and changes in maternal age distribution at delivery, we anticipate further increases in the number of children living with spina bifida or Down syndrome by 2020.     

Clinical profile of Parkinson's disease in the Gumei community of Minhang district,Shanghai

OBJECTIVE:

We examined the demographic and clinical profiles of Parkinson''s disease in Shanghai, China, to assist in disease management and provide comparative data on Parkinson''s disease prevalence, phenotype, and progression among different regions and ethnic groups.

METHODS:

A door-to-door survey and follow-up clinical examinations identified 180 community-dwelling Han-Chinese Parkinson''s disease patients (104 males, 76 females).

RESULTS:

The average age at onset was 65.16±9.60 years. The most common initial symptom was tremor (112 patients, 62.22%), followed by rigidity (38, 21.11%), bradykinesia (28, 15.56%) and tremor plus rigidity (2, 1.11%). Tremor as the initial symptom usually began in a single limb (83.04% of patients). The average duration from onset to mild Parkinson''s disease (Hoehn-Yahr phase 1–2) was 52.74±45.64 months. Progression from mild to moderate/severe Parkinson''s disease (phase≥3) was significantly slower (87.07±58.72 months; p<0.001), except for patients presenting initially with bradykinesia (53.83±24.49 months). Most patients (149/180, 82.78%) took levodopa with or without other drugs. The Hamilton Anxiety Scale revealed symptoms of clinical anxiety in 35 patients, and the Hamilton Depression Scale revealed depressive symptoms in 88 patients. The depressed or anxious subgroup (123 patients) demonstrated a significantly younger age at onset (55.54±7.68 years) compared with the overall mean (p<0.05).

CONCLUSION:

Unilateral limb tremor was the most common initial symptom, and motor function deteriorated slowly over ≈4−9 years. Earlier-onset patients experience greater psychiatric dysfunction.     

Sjögren's syndrome: An underdiagnosed condition in mixed connective tissue disease

OBJECTIVE:

To determine the prevalence of sicca symptoms, dry eye, and secondary Sjögren''s syndrome and to evaluate the severity of dry eye in patients with mixed connective tissue disease.

METHODS:

In total, 44 consecutive patients with mixed connective tissue disease (Kasukawa''s criteria) and 41 healthy controls underwent Schirmer''s test, a tear film breakup time test, and ocular surface staining to investigate dry eye. In addition, the dry eye severity was graded. Ocular and oral symptoms were assessed using a structured questionnaire. Salivary gland scintigraphy was performed in all patients. Classification of secondary Sjögren''s syndrome was assessed according to the American-European Consensus Group criteria.

RESULTS:

The patients and controls had comparable ages (44.7±12.4 vs. 47.2±12.2 years) and frequencies of female gender (93 vs. 95%) and Caucasian ethnicity (71.4 vs. 85%). Ocular symptoms (47.7 vs. 24.4%) and oral symptoms (52.3 vs. 9.7%) were significantly more frequent in patients than in controls. Fourteen (31.8%) patients fulfilled Sjögren''s syndrome criteria, seven of whom (50%) did not have this diagnosis prior to study inclusion. A further comparison of patients with mixed connective tissue disease with or without Sjögren''s syndrome revealed that the former presented significantly lower frequencies of polyarthritis and cutaneous involvement than did the patients without Sjögren''s syndrome. Moderate to severe dry eye was found in 13 of 14 patients with mixed connective tissue disease and Sjögren''s syndrome (92.8%).

CONCLUSIONS:

Sjögren''s syndrome, particularly with moderate to severe dry eye, is frequent in patients with mixed connective tissue disease. These findings alert the physician regarding the importance of the appropriate diagnosis of this syndrome in such patients.     

Newborn bloodspot screening for Duchenne Muscular Dystrophy: 21 years experience in Wales (UK)

Duchenne muscular dystrophy (DMD), a progressive X-linked neuromuscular disorder, has an estimated worldwide incidence of 1:3500 male births. Currently, there are no curative treatments and the mean age of diagnosis is 5 years. In addition, subsequent pregnancies frequently occur before a diagnosis is made in an index case. An ‘opt in'' screening programme was introduced in Wales in 1990 with the aim to: reduce the diagnostic delay, permit reproductive choice and allow planning of the care of the affected boy. Newborn bloodspots were collected routinely as part of the Wales newborn screening programme. Specific consent was obtained for this test separately from the other tests. During the 21-year period, 369 780 bloodspot cards were received from male infants, of these 343 170 (92.8%) were screened using a bloodspot creatine kinase (CK) assay following parental consent. A total of 145 cases had a raised CK activity (≥250 U/l) and at follow-up, at 6–8 weeks of age, 79 cases had a normal serum CK (false-positive rate 0.023%) and 66 cases had an elevated serum CK. DMD was confirmed in 56 cases by genotyping/muscle biopsy studies, Becker muscular dystrophy in 5 cases and other rarer forms of muscular dystrophy in 5 cases. This long-term study has so far identified 13 false-negative cases. The incidence of DMD in Wales of 1:5136 during this period is lower than that of 1:4046 before commencement of screening in Wales. Screening has reduced the diagnostic delay enabling reproductive choice for parents of affected boys and earlier administration of current therapies.     

Fournier's ganrene in the HIV era

Background

Fournier''s gangrene is a devastating condition that affects mostly patients whose immunity has been reduced. There is increasing evidence for increasing incidence of the disease in those with HIV disease.

Objective

To evaluate the presentation, bacteriology and outcome of Fournier''s gangrene in our area in recent times in view of the high prevalence in Nairobi and its environs.

Results

One hundred and forty six patients were treated for Fournier''s gangrene during the study period; all were male. They had a mean age of 38.6 years (range 2 months – 86 years). HIV infection was the most common associated underlying illness (16.4 %), followed by diabetes mellitus and alcoholism (11%).

Conclusions

HIV infection is emerging as leading predisposing factor and has overtaken diabetes in predisposing for Fournier''s gangrene in Kenyatta National Hospital.     

Depletion of potential A2M risk haplotype for Alzheimer's disease in long-lived individuals

Risk alleles for age-related diseases are expected to decrease in frequency in the population strata of increasing age. Consistent with this hypothesis, earlier studies showed a depletion of the Alzheimer''s disease risk factor APOE^*ɛ4 in long-lived individuals (LLIs). To evaluate whether this observation also holds for a previously suggested Alzheimer''s disease risk haplotype in the A2M gene, we analyzed this particular haplotype in 1042 German LLIs (aged 95–100 years) and 1040 younger individuals (aged 60–75 years). Our results show a significant depletion of this haplotype in LLIs, thus confirming it as a mortality factor in the elderly. Consequently, our data support an involvement of the suggested A2M risk haplotype in the pathogenesis of Alzheimer''s disease and adds new evidence to the risk-allele depletion hypothesis.     

Measurement of thyroid stimulating immunoglobulins using a novel thyroid stimulating hormone receptor–guanine nucleotide-binding protein, (GNAS) fusion bioassay

Hyperthyroidism, defined by overproduction of thyroid hormones, has a 2–3% prevalence in the population. The most common form of hyperthyroidism is Graves'' disease. A diagnostic biomarker for Graves'' disease is the presence of immunoglobulins which bind to, and stimulate, the thyroid stimulating hormone receptor (TSHR), a G-protein coupled receptor (GPCR). We hypothesized that the ectopically expressed TSHR gene in a thyroid stimulating immunoglobulin (TSI) assay could be engineered to increase the accumulation of the GPCR pathway second messenger, cyclic AMP (cAMP), the molecule measured in the assay as a marker for pathway activation. An ectopically expressing TSHR-mutant guanine nucleotide-binding protein, (GNAS) Chinese hamster ovary (CHO) cell clone was constructed using standard molecular biology techniques. After incubation of the new clone with sera containing various levels of TSI, GPCR pathway activation was then quantified by measuring cAMP accumulation in the clone. The clone, together with a NaCl-free cell assay buffer containing 5% polyethylene glycol (PEG)6000, was tested against 56 Graves'' patients, 27 toxic thyroid nodule patients and 119 normal patients. Using receiver operating characteristic analysis, when comparing normal with Graves'' sera, the assay yielded a sensitivity of 93%, a specificity of 99% and an efficiency of 98%. Total complex precision (within-run, across runs and across days), presented as a percentage coefficient of variation, was found to be 7·8, 8·7 and 7·6% for low, medium and high TSI responding serum, respectively. We conclude that the performance of the new TSI assay provides sensitive detection of TSI, allowing for accurate, early detection of Graves'' disease.     

Correlates of diarrhoea among children below the age of 5 years in Sudan

Background

The Millennium Development Goals recognise child health and survival as an important socio-development issue.

Objectives

To determine the correlates of diarrhoea among children aged below 5 years in north Sudan.

Methods

We conducted secondary data analysis of the Sudan Multiple Cluster Indicators Survey II.

Results

Altogether, 23,295 children were included in the survey. Half (50.0%) of the children were males, and 22.5% of them were of age less than one year. Boys were 3% (p=0.044) more likely to have diarrhoea compared to girls. Compared with the oldest age group (48–59 months), children less than 6 months of age and those aged 36–47 months had 25% and 18% lower prevalence of diarrhoea, respectively, while children aged 6–24 months and those aged 24–35 months had 1.5 fold and 1.17 fold higher prevalence of diarrhoea. Children in urban areas were 6% more likely to have diarrhoea. Children from households with 1 or 2 people per room were 8% less likely to have diarrhoea compared to children from households with more than 3 people per room.

Conclusions

Diarrhoea was associated with child''s age, gender, and social status. Our findings provide a useful baseline for interventions and comparisons with future studies.     

Down syndrome birth weight in England and Wales: Implications for clinical practice

The aim of this study was to determine if syndrome‐specific birth weight charts were beneficial for babies with Down syndrome in England and Wales. Birth weights of 8,825 babies with Down syndrome born in England and Wales in 1989–2010 were obtained from the National Down Syndrome Cytogenetic Register. Birth weight centiles for 30–42 weeks gestation by sex were fitted using the LMS method and were compared to those for unaffected babies from the UK‐WHO growth charts. For babies born with Down syndrome the median birth weight from 37 to 42 weeks was 2,970 g (10th–90th centile: 2,115–3,680) for boys and 2930 g (2,100–3,629) for girls, and the modal age of gestation was 38 weeks, 2 weeks earlier than for unaffected babies. At 38 weeks gestation they were only slightly lighter than unaffected babies (159 g for boys and 86 g for girls). However at 40 weeks gestation the shortfall was much greater (304 g and 239 g, respectively). In neonates with Down syndrome there is little evidence of growth restriction before 38 weeks gestation, so up to this age it is appropriate to use the UK‐WHO birth weight charts. Thereafter birth weight is below that of unaffected babies and it should be plotted on the UK Down syndrome growth charts. © 2015 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.     

Twenty-year trends in the prevalence of Down syndrome and other trisomies in Europe: impact of maternal age and prenatal screening

This study examines trends and geographical differences in total and live birth prevalence of trisomies 21, 18 and 13 with regard to increasing maternal age and prenatal diagnosis in Europe. Twenty-one population-based EUROCAT registries covering 6.1 million births between 1990 and 2009 participated. Trisomy cases included live births, fetal deaths from 20 weeks gestational age and terminations of pregnancy for fetal anomaly. We present correction to 20 weeks gestational age (ie, correcting early terminations for the probability of fetal survival to 20 weeks) to allow for artefactual screening-related differences in total prevalence. Poisson regression was used. The proportion of births in the population to mothers aged 35+ years in the participating registries increased from 13% in 1990 to 19% in 2009. Total prevalence per 10 000 births was 22.0 (95% CI 21.7–22.4) for trisomy 21, 5.0 (95% CI 4.8–5.1) for trisomy 18 and 2.0 (95% CI 1.9–2.2) for trisomy 13; live birth prevalence was 11.2 (95% CI 10.9–11.5) for trisomy 21, 1.04 (95% CI 0.96–1.12) for trisomy 18 and 0.48 (95% CI 0.43–0.54) for trisomy 13. There was an increase in total and total corrected prevalence of all three trisomies over time, mainly explained by increasing maternal age. Live birth prevalence remained stable over time. For trisomy 21, there was a three-fold variation in live birth prevalence between countries. The rise in maternal age has led to an increase in the number of trisomy-affected pregnancies in Europe. Live birth prevalence has remained stable overall. Differences in prenatal screening and termination between countries lead to wide variation in live birth prevalence.