Beckwith Wiedemann syndrome: A population-based study on prevalence,prenatal diagnosis,associated anomalies and survival in Europe

Beckwith Wiedemann syndrome is a complex developmental disorder characterized by somatic overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycemia, and predisposition to embryonal tumors. We present epidemiological and clinical aspects of patients with Beckwith Wiedemann syndrome diagnosed prenatally or in the early years of life, using data from EUROCAT (European Surveillance of Congenital Anomalies) registries. The study population consisted of 371 cases identified between January 1990 and December 2015 in 34 registries from 16 European countries. There were 15 (4.0%) terminations of pregnancy after prenatal detection of severe anomaly/anomalies, 10 fetal deaths (2.7%), and 346 (93.3%) live-births. Twelve (3.6%) of the 330 live-births with available information on survival died in the first week of life, of those eleven (91.6%) were preterm. First-year survival rate was 90.9%. Prematurity was present in 40.6% of males and 33.9% of females. Macrosomia was found in 49.2% and 43.3% of preterm males and females, respectively. Of term newborns, 41.1% of males and 24% of females were macrosomic. Out of 353 cases with known time of diagnosis, 39.9% were suspected prenatally, 36.3% at birth, 7.6% were diagnosed in the first week of life, and 16.2% in the first year of life. The mean gestational age at prenatal diagnosis by obstetric ultrasound was 19.8?±?6.2 (11–39) gestational weeks. The mean prenatal diagnosis of cases where parents opted for termination of pregnancy was 15.3?±?2.4 (11–22) gestational weeks, and the mean gestational age at termination was 19.3?±?4.1 (13–26) gestational weeks. The prenatal detection rate was 64.1% (141/220) with no significant change over time. There were 12.7% of familial cases. The study confirmed the association of assisted reproductive technologies with Beckwith Wiedemann syndrome, as 7.2% (13/181) of patients were conceived by one of the methods of assisted reproductive technologies, which was three times higher compared to the general population of the countries included in the study. Twin pregnancies of undetermined zygosity were recorded in 5.7% (21/365) cases, and were on average three to four times more common than in European countries that participated in the study. The estimated mean prevalence of classical Beckwith Wiedemann syndrome in Europe was 3.8 per 100,000 births or 1:26,000 births.     

Patients' understanding of advance directives and cardiopulmonary resuscitation

OBJECTIVE: To describe understanding of end-of-life issues and compare characteristics of patients with and without advance directives. SETTING: A 325-bed community teaching hospital. MEASUREMENTS: Questionnaires were administered to all patients admitted to the medical-surgical wards. RESULTS: Of 755 patients admitted during the study period, 264 patients participated in the study, and 82 (31%) had living wills. Patients with living wills were more likely to be white, Protestant, and highly educated. Most (76%) created them with a lawyer or family member, whereas only 7% involved physicians. Although these patients were able to identify some components of cardiopulmonary resuscitation (CPR), few (19%) understood the prognosis after CPR. After explaining CPR, 37% of those with living wills did not want it, which was not stated in their directive or hospital record. If life-sustaining therapies were already started, 39% of these patients stated that they would not want CPR or mechanical ventilation if the likelihood of recovery was < or =10%. Patients without living wills either had not heard (18%) or did not know enough (51%) about them. After education, 5% did not want CPR, and 32% would terminate life-sustaining therapies if the likelihood of recovery was < or =10%. Seventy percent of these patients expressed interest in creating a living will. CONCLUSIONS: Patients with living wills understand poorly "life-sustaining therapies" and the implications of their advance directives. Most fail to involve physicians in creating directives. A significant number of those without living wills have end-of-life wishes that could be addressed by and appear open to the idea of creating advance directives.     

Genetic fitness and selection intensity in a population affected with high-incidence spinocerebellar ataxia type 1

Spinocerebellar ataxia type 1 (SCA1) is the major and likely the only type of autosomal dominant cerebellar ataxia in the Sakha (Yakut) people of Eastern Siberia. The prevalence rate of SCA1 has doubled over the past 21 years peaking at 46 cases per 100,000 rural population. The age at death correlates closely with the number of CAG triplet repeats in the mutant ATXN1 gene (r = ?0.81); most patients with low-medium (39–55) repeat numbers survived until the end of reproductive age. The number of CAG repeats expands in meiosis, particularly in paternal transmissions; the average total increase in intergenerational transmissions in our cohort was estimated at 1.6 CAG repeats. The fertility rates of heterozygous carriers of 39–55 CAG repeats in women were no different from those of the general Sakha population. Overall, the survival of mutation carriers through reproductive age, unaltered fertility rates, low childhood mortality in SCA1-affected families, and intergenerational transmission of increasing numbers of CAG repeats in the ATXN1 gene indicate that SCA1 in the Sakha population will be maintained at high prevalence levels. The low (0.19) Crow’s index of total selection intensity in our SCA1 cohort implies that this mutation is unlikely to be eliminated through natural selection alone.     

Acquired loss of renal nuclease activity is restricted to DNaseI and is an organ-selective feature in murine lupus nephritis

An acquired loss of renal DNaseI promotes transformation of mild mesangial lupus nephritis into membranoproliferative end-stage organ disease. In this study, we analyzed expression profiles of DNaseI in other organs of lupus-prone (NZB×NZW)F1 mice during disease progression to determine whether silencing of the renal DNaseI gene is an organ-specific feature or whether loss of DNaseI reflects a systemic error in mice with sever lupus nephritis. The present results demonstrate normal or elevated levels of DNaseI mRNA and enzyme activity in liver, spleen, and serum samples from (NZB×NZW)F1 mice throughout all the stages of lupus nephritis. DNaseI activity was dramatically reduced only in kidneys of mice with sever nephritis and was the only nuclease that was down-regulated, whereas six other nucleases (DNaseII1 to 3, caspase-activated DNase, Dnase2a, and endonuclease G) were approximately normally expressed in kidneys, liver, and spleen. Loss of renal DNaseI was not accompanied by changes in serum DNaseI activity, suggesting independent mechanisms of DNaseI regulation in circulation and in kidneys and an absence of compensatory up-regulation of serum DNaseI activity in the case of renal DNaseI deficiency. Thus, silencing of renal DNaseI is a unique renal feature in membranoproliferative lupus nephritis. Determining the mechanism(s) responsible for DNaseI down-regulation might lead to the generation of new therapeutic targets to treat and prevent progressive lupus nephritis.     

Evaluation of data obtained from military disability medical administrative databases for service members with schizophrenia or bipolar disorder

OBJECTIVE: We are studying associations between selected biomarkers and schizophrenia or bipolar disorder among military personnel. To assess potential diagnostic misclassification and to estimate the date of illness onset, we reviewed medical records for a subset of cases. METHODS: Two psychiatrists independently reviewed 182 service medical records retrieved from the Department of Veterans Affairs. Data were evaluated for diagnostic concordance between database diagnoses and reviewers. Interreviewer variability was measured by using proportion of agreement and the kappa statistic. Data were abstracted to estimate date of onset. RESULTS: High levels of agreement existed between database diagnoses and reviewers (proportion, 94.7%; kappa = 0.88) and between reviewers (proportion, 92.3%; kappa = 0.87). The median time between illness onset and initiation of medical discharge was 1.6 and 1.1 years for schizophrenia and bipolar disorder, respectively. CONCLUSIONS: High levels of agreement between investigators and database diagnoses indicate that diagnostic misclassification is unlikely. Discharge procedure initiation date provides a suitable surrogate for disease onset.     

Erythrocyte C3d and C4d for monitoring disease activity in systemic lupus erythematosus

Objective

Disease activity in systemic lupus erythematosus (SLE) is typically monitored by measuring serum C3 and C4. However, these proteins have limited utility as lupus biomarkers, because they are substrates rather than products of complement activation. The aim of this study was to evaluate the utility of measuring the erythrocyte‐bound complement activation products, erythrocyte‐bound C3d (E‐C3d) and E‐C4d, compared with that of serum C3 and C4 for monitoring disease activity in patients with SLE.

Methods

The levels of E‐C3d and E‐C4d were measured by flow cytometry in 157 patients with SLE, 290 patients with other diseases, and 256 healthy individuals. The patients with SLE were followed up longitudinally. Disease activity was measured at each visit, using the validated Systemic Lupus Activity Measure (SLAM) and the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).

Results

At baseline, patients with SLE had higher median levels of E‐C3d and E‐C4d (P < 0.0001) in addition to higher within‐patient and between‐patient variability in both E‐C3d and E‐C4d when compared with the 2 non‐SLE groups. In a longitudinal analysis of patients with SLE, E‐C3d, E‐C4d, serum C3, and anti–double‐stranded DNA (anti‐dsDNA) antibodies were each significantly associated with the SLAM and SELENA–SLEDAI. In a multivariable analysis, E‐C4d remained significantly associated with these SLE activity measures after adjusting for serum C3, C4, and anti‐dsDNA antibodies; however, E‐C3d was associated with the SLAM but not with the SELENA–SLEDAI.

Conclusion

Determining the levels of the erythrocyte‐bound complement activation products, especially E‐C4d, is an informative measure of SLE disease activity as compared with assessing serum C4 levels and should be considered for monitoring disease activity in patients with SLE.

     

Phenothiazines inhibit S100A4 function by inducing protein oligomerization

S100A4, a member of the S100 family of Ca²⁺-binding proteins, regulates carcinoma cell motility via interactions with myosin-IIA. Numerous studies indicate that S100A4 is not simply a marker for metastatic disease, but rather has a direct role in metastatic progression. These observations suggest that S100A4 is an excellent target for therapeutic intervention. Using a unique biosensor-based assay, trifluoperazine (TFP) was identified as an inhibitor that disrupts the S100A4/myosin-IIA interaction. To examine the interaction of S100A4 with TFP, we determined the 2.3 Å crystal structure of human Ca²⁺-S100A4 bound to TFP. Two TFP molecules bind within the hydrophobic target binding pocket of Ca²⁺-S100A4 with no significant conformational changes observed in the protein upon complex formation. NMR chemical shift perturbations are consistent with the crystal structure and demonstrate that TFP binds to the target binding cleft of S100A4 in solution. Remarkably, TFP binding results in the assembly of five Ca²⁺-S100A4/TFP dimers into a tightly packed pentameric ring. Within each pentamer most of the contacts between S100A4 dimers occurs through the TFP moieties. The Ca²⁺-S100A4/prochlorperazine (PCP) complex exhibits a similar pentameric assembly. Equilibrium sedimentation and cross-linking studies demonstrate the cooperative formation of a similarly sized S100A4/TFP oligomer in solution. Assays examining the ability of TFP to block S100A4-mediated disassembly of myosin-IIA filaments demonstrate that significant inhibition of S100A4 function occurs only at TFP concentrations that promote S100A4 oligomerization. Together these studies support a unique mode of inhibition in which phenothiazines disrupt the S100A4/myosin-IIA interaction by sequestering S100A4 via small molecule-induced oligomerization.     

Use of the Global Test Statistic as a Performance Measurement in a Reananlysis of Environmental Health Data

Performance measurement is increasingly viewed as an essential component of environmental and public health protection programs. In characterizing program performance over time, investigators often observe multiple changes resulting from a single intervention across a range of categories. Although a variety of statistical tools allow evaluation of data one variable at a time, the global test statistic is uniquely suited for analyses of categories or groups of interrelated variables. Here we demonstrate how the global test statistic can be applied to environmental and occupational health data for the purpose of making overall statements on the success of targeted intervention strategies.In a previous study, Enander et al.¹ evaluated the compliance of the Rhode Island automotive refinishing industry sector with state and federal environmental, health, and safety regulations. Baseline and postintervention data were collected on 24 performance indicator variables at 82 randomly sampled facilities. The Fisher exact test was used in making statistical comparisons of proportions between baseline and postintervention data on each performance indicator. In addition to assessing each P value against the nominal .05 level of significance to determine the indicators that showed improvement, the authors used a modified Bonferroni adjustment to control the overall type 1 error rate.We describe global test statistics that we used to reach an overall conclusion about auto body compliance in performance categories identified by Enander et al. This statistical approach represents an additional method that public and environmental health professionals can use to analyze categorical data and make overall statements on the success of targeted intervention strategies. The global test statistic was originally proposed by O''Brien,² with further work by Pocock et al.³ In clinical trials or in the context of an inspection program, the objective is to show improvements in postsetting indicator variables. The traditional procedure is to test all variables simultaneously via the Hotelling T² approach when the variables have a multivariate normal distribution. However, the T² test is 2 sided, and therefore conclusions on overall improvement cannot be made.In Bonferroni procedures, conclusions are made one variable at a time. In reviewing global test procedures, Geller⁴ and others have noted that the intercorrelations among variables can range from moderate to high. In the Bonferroni methods, information about the relationship between variables is not used, and thus there is a loss of power. In the case of highly correlated variables, global procedures are much less conservative than the Bonferroni procedures. A variable-specific method is more appropriate in answering questions relating to effectiveness as measured by individual variables, whereas a global method might be more appropriate in answering questions relating to effectiveness as measured by uniform improvement across all variables. Thus, the 2 methods complement each other.To assist in computing global statistics, the University of Rhode Island''s Computer Science and Statistics Department has posted the program online at http://www.cs.uri.edu/∼dymo-van. Because the program uses MATLAB, users need to have access to this package.     

Protective effects of 7-nitroindazole on ketamine-induced neurotoxicity in rat forebrain culture

Ketamine, a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, is used as a pediatric anesthetic for surgical procedures. Recent data suggest that anesthetic drugs may cause neurodegeneration during development. The purpose of this study was to determine the dose and temporal response of ketamine using newborn rat forebrain cultures and also to determine if co-administration of 7-nitroindazole, a nitric oxide synthase (NOS) inhibitor, could protect or reverse ketamine-induced cell death. Neural cells collected from the rat forebrain were incubated for 24h with 1, 10 or 20 microM ketamine alone or with ketamine plus 1, 5, 10 or 20 microM 7-nitroindazole. Ketamine (10 microM) caused an increase in DNA fragmentation and elevated immunoreactivity to nitrotyrosine, a marked reduction in the expression of the neuronal marker polysialic acid neural cell adhesion molecule (PSA-NCAM) and in mitochondrial metabolism, as well as an increased Bax/BCL-XL ratio. No significant effect was observed in the release of lactate dehydrogenase (LDH). Ketamine-induced neurotoxic effects were effectively blocked by 7-nitroindazole (10 microM). These data indicate a role for nitric oxide in the enhanced degeneration induced by ketamine in vitro and also suggest that blocking neuronal nitric oxide synthase (nNOS) may help reduce the risk of ketamine in pediatrics.