Improved prognosis for congenital nephrotic syndrome of the Finnish type in Irish families

Congenital nephrotic syndrome of the Finnish type is a rare autosomal recessive disease with a high infant mortality without aggressive treatment. The biochemical basis of the disease is not understood fully but the disease locus has been mapped recently to chromosome 19q12-q13.1 in Finnish families. This paper describes the clinical features and outcome of 20 patients in Ireland with congenital nephrotic syndrome of the Finnish type who have presented since 1980. Before 1987, all infants died by the age of 3 years. After the introduction of daily intravenous albumin infusion, nutritional support, elective bilateral nephrectomy, and renal transplantation, mortality in the past decade has fallen to 30%, with no deaths in the past five years. Genetic linkage analysis was performed in six families in whom DNA was available and the locus responsible was mapped to the same region on chromosome 19 as in Finnish families, suggesting that Irish families share the same disease locus.

CD11b+ bone marrow-derived monocytes are the major leukocyte subset responsible for retinal capillary leukostasis in experimental diabetes in mouse and express high levels of CCR5 in the circulation

We investigated the phenotype of cells involved in leukostasis in the early stages of streptozotocin-induced diabetes in mice by direct observation and by adoptive transfer of calcein-AM-labeled bone marrow-derived leukocytes from syngeneic mice. Retinal whole mounts, confocal microscopy, and flow cytometry ex vivo and scanning laser ophthalmoscopy in vivo were used. Leukostasis in vivo and ex vivo in retinal capillaries was increased after 2 weeks of diabetes (Hb A(1c), 14.2 ± 1.2) when either donor or recipient mice were diabetic. Maximum leukostasis occurred when both donor and recipient were diabetic. CD11b(+), but not Gr1(+), cells were preferentially entrapped in retinal vessels (fivefold increase compared with nondiabetic mice). In diabetic mice, circulating CD11b(+) cells expressed high levels of CCR5 (P = 0.04), whereas spleen (P = 0.0001) and retinal (P = 0.05) cells expressed increased levels of the fractalkine chemokine receptor. Rosuvastatin treatment prevented leukostasis when both recipient and donor were treated but not when donor mice only were treated. This effect was blocked by treatment with mevalonate. We conclude that leukostasis in early diabetic retinopathy involves activated CCR5(+)CD11b(+) myeloid cells (presumed monocytes). However, leukostasis also requires diabetes-induced changes in the endothelium, because statin therapy prevented leukostasis only when recipient mice were treated. The up-regulation of the HMG-CoA reductase pathway in the endothelium is the major metabolic dysregulation promoting leukostasis.

Aneurysms increase the risk of rebleeding after stereotactic radiosurgery for hemorrhagic arteriovenous malformations

BACKGROUND AND PURPOSE:
The purpose of this study was to define the risk of rebleeding after stereotactic radiosurgery (SRS) for hemorrhagic arteriovenous malformations with or without associated intracranial aneurysms.

METHODS:
Between 1987 and 2006, we performed Gamma Knife SRS on 996 patients with brain arteriovenous malformations; 407 patients had sustained an arteriovenous malformation hemorrhage. Sixty-four patients (16%) underwent prior embolization and 84 (21%) underwent prior surgical resection. The median target volume was 2.3 mL (range, 0.1-20.7 mL). The median margin dose was 20 Gy (range, 13.5-27 Gy).

RESULTS:
The overall rate of total obliteration defined by angiography or MRI was 56%, 77%, 80%, and 82% at 3, 4, 5, and 10 years, respectively. Before obliteration, 33 patients (8%) sustained an additional hemorrhage after SRS. The overall annual hemorrhage rate until obliteration after SRS was 1.3%. The presence of a patent aneurysm was significantly associated with an increased rehemorrhage risk after SRS (annual hemorrhage rate, 6.4%) compared with patients with a clipped or embolized aneurysm (annual hemorrhage rate, 0.8%; P=0.033).

CONCLUSIONS:
When an aneurysm is identified in patients with arteriovenous malformations selected for SRS, additional endovascular or surgical strategies should be considered to reduce the risk of bleeding during the latency interval.

Structure-Phenotype Correlations of Human CYP21A2 Mutations in Congenital Adrenal Hyperplasia

Congenital Adrenal Hyperplasia (CAH) is a family of autosomal recessive disorders involving impaired synthesis of cortisol from cholesterol by adrenal cortex. The predominant causes of the disorder are mutations in the CYP21A2 gene that encodes a Cytochrome P450 21-hydroxylase enzyme, which is central to steroidogenesis. The severity of the disease depends upon the extent of impaired enzymatic activity and can be classified under severe Classical form or the mild Non-Classical form, Molecular characterisation of CYP21A2 mutations can be used to predict clinical phenotype and disease severity based upon changes it brings in 21-hydroxylase enzyme structure. A humanized model of CYP21A2 has been used to map and investigate the structural role of all known disease-causing mutations. A structural explanation of clinical manifestation allows us to put forward criteria that might allow the prediction of clinical severity of the disease.

Baseline Soil Variation Is a Major Factor in Arsenic Accumulation in Bengal Delta Paddy Rice

Factors responsible for paddy soil arsenic accumulation in the tubewell irrigated systems of the Bengal Delta were investigated. Baseline (i.e., nonirrigated) and paddy soils were collected from 30 field systems across Bangladesh. For each field, soil sampled at dry season (Boro) harvest i.e., the crop cycle irrigated with tubewell water, was collected along a 90 m transect away from the tubewell irrigation source. Baseline soil arsenic levels ranged from 0.8 to 21. mg/kg, with lower values found on the Pliestocene Terrace around Gazipur (average, 1.6 +/- 0.2 mg/kg), and higher levels found in Holecene sediment tracts of Jessore and Faridpur (average, 6.6 +/- 1.0 mg/kg). Two independent approaches were used to assess the extent of arsenic build-up in irrigated paddy soils. First, arsenic build-up in paddy soil at the end of dry season production (irrigated - baseline soil arsenic) was regressed against number of years irrigated and tubewell arsenic concentration. Years of irrigation was not significant (P 0.711), indicating no year-on-year arsenic build-up, whereas tubewell As concentration was significant (P = 0.008). The second approach was analysis of irrigated soils for 20 fields over 2 successive years. For nine of the fields there was a significant (P <0.05) decrease in soil arsenic from year 1 to 2, one field had a significant increase, whereas there was no change for the remaining 10. Over the dry season irrigation cycle, soil arsenic built-up in soils at a rate dependent on irrigation tubewell water, 35* (tubewell water concentration in mg/kg, mg/L). Grain arsenic rises steeply at low soil/shoot arsenic levels, plateauing out at concentratations. Baseline soil arsenic at Faridpur sites corresponded to grain arsenic levels at the start of this saturation phase. Therefore, variation in baseline levels of soil arsenic leads to a large range in grain arsenic. Where sites have high baseline soil arsenic, further additional arsenic from irrigation water only leads to a gradual increase in grain arsenic concentration.

Exploring the Transcriptome of Atlantic Salmon (Salmo salar) Skin, a Major Defense Organ

The skin of fish is the first line of defense against pathogens and parasites. The skin transcriptome of the Atlantic salmon is poorly characterized, and currently only 2,089 expressed sequence tags (ESTs) out of a total of half a million sequences are generated from skin-derived cDNA libraries. The primary aim of this study was to enhance the transcriptomic knowledge of salmon skin by using next-generation sequencing (NGS) technology, namely the Roche-454 platform. An equimolar mixture of high-quality RNA from skin and epidermal samples of salmon reared in either freshwater or seawater was used for 454-sequencing. This technique yielded over 600,000 reads, which were assembled into 34,696 isotigs using Newbler. Of these isotigs, 12 % had not been sequenced in Atlantic salmon, hence representing previously unreported salmon mRNAs that can potentially be skin-specific. Many full-length genes have been acquired, representing numerous biological processes. Mucin proteins are the main structural component of mucus and we examined in greater detail the sequences we obtained for these genes. Several isotigs exhibited homology to mammalian mucins (MUC2, MUC5AC and MUC5B). Mucin mRNAs are generally > 10 kbp and contain large repetitive units, which pose a challenge towards full-length sequence discovery. To date, we have not unearthed any full-length salmon mucin genes with this dataset, but have both N- and C-terminal regions of a mucin type 5. This highlights the fact that, while NGS is indeed a formidable tool for sequence data mining of non-model species, it must be complemented with additional experimental and bioinformatic work to characterize some mRNA sequences with complex features.

Psychosocial and academic characteristics of extremely low birth weight (<or =800 g) adolescents who are free of major impairment compared with term-born control subjects

To compare academic and cognitive ability, attention, attitudes, and behavior of extremely low birth weight (ELBW) adolescents who are free of major impairments at 17 years of age with term-born control subjects.

RNAi screen identifies Jarid1b as a major regulator of mouse HSC activity

Histone methylation is a dynamic and reversible process proposed to directly impact on stem cell fate. The Jumonji (JmjC) domain-containing family of demethylases comprises 27 members which can demethylate mono-, di- and tri-methylated lysine residues of histone (or non-histone) targets. To evaluate their role in regulation of hematopoietic stem cell (HSC) behaviour we performed a RNAi-based screen and found that demethylases JARID1B (H3K4) and JHDM1F (H3K9) play opposing roles in regulation of HSC activity. Decrease in Jarid1b levels correlated with an in vitro expansion of HSC with preserved long term in vivo lympho-myeloid differentiation potential. Jarid1b knockdown was associated with an increase in expression levels of 5’ Hoxa cluster genes and CxCl5 , and reduced levels of Pu.1, Egr1 and Cav1. shRNA against Jhdmlf, in contrast, impaired hematopoietic reconstitution of bone marrow cells. Together, our studies identified Jarid1b as a negative, and Jhdmlf as a positive regulator of HSC activity.

Stereotactic radiosurgery for arteriovenous malformations, Part 1:management of Spetzler-Martin Grade I and II arteriovenous malformations

The aim of this paper was to define the outcomes and risks of stereotactic radiosurgery (SRS) for Spetzler-Martin Grade I and II arteriovenous malformations (AVMs).

Stereotactic radiosurgery for arteriovenous malformations, Part 4:management of basal ganglia and thalamus arteriovenous malformations

The authors conducted a study to define the long-term outcomes and risks of stereotactic radiosurgery (SRS) for arteriovenous malformations (AVMs) of the basal ganglia and thalamus.

Stereotactic radiosurgery for arteriovenous malformations, Part 5:management of brainstem arteriovenous malformations

In this paper, the authors' goal was to define the long-term outcomes and risks of stereotactic radiosurgery (SRS) for arteriovenous malformations (AVMs) of the medulla, pons, and midbrain.

A sibling-controlled, prospective study of outcomes at home and school in children with severe congenital heart disease

Objectives: The objectives of this study were to compare behaviour problems and competencies, at home and school, in 7-year-old children with congenital heart disease with a sibling control group, to examine the prospective determinants of outcome from infancy, and to explore whether any gains were maintained in our sub-group of children who had participated in a previous trial of psychological interventions in infancy.
Methods: A total of 40 children who had undergone surgery to correct or palliate a significant congenital heart defect in infancy were compared (Child Behavior Checklist) with a nearest-age sibling control group (18 participants). Comparisons were made between sub-groups of children and families who had and had not participated in an early intervention trial.
Results: Problems with attention, thought and social problems, and limitations in activity and school competencies, were found in comparison with siblings. Teacher reports were consistent with parents, although problems were of a lower magnitude. Disease, surgical, and neurodevelopmental functioning in infancy were related to competence outcomes but not behaviour problems. The latter were mediated by family and maternal mental health profiles from infancy. Limited, but encouraging, gains were maintained in the sub-group that had participated in the early intervention programme.
Conclusions: The present study is strengthened by its longitudinal design, use of teacher informants, and sibling control group. The patterns of problems and limitations discerned, and differential determinants thereof, have clear implications for interventions. We consider these in the light of our previously reported intervention trial with this sample and current outcomes at the 7-year follow-up.

A Randomized Controlled Trial of Interventions to Promote Adjustment in Children With Congenital Heart Disease Entering School and Their Families

Objective: To report on a randomized controlled trial of psychological interventions to promote adjustment in children with congenital heart disease and their families.
Method: Following baseline assessment, 90 children (aged 4–5 years) and their families were randomly assigned to an Intervention or Control group before entering school. 68 (76%) were retained at 10-month follow-up.
Results: Gains were observed on measures of maternal mental health and family functioning. Although no differences were found on measures of child behavior at home or school, children in the intervention group were perceived as “sick” less often by their mother and missed fewer days from school. A regression model, using baseline measures as predictors, highlighted the importance of maternal mental health, worry and child neurodevelopmental functioning for child behavioral outcomes almost a year later.
Conclusions: The intervention promoted clinically significant gains for the child and family. The program is of generalizable significance.

Examination of the physical and psychosocial determinants of health behaviour in 4-5-year-old children with congenital cardiac disease

To assess the general health and activity levels of 4- and 5-year-old children after intervention for congenital cardiac disease.

A controlled trial of early interventions to promote maternal adjustment and development in infants born with severe congenital heart disease

Background: Congenital heart disease can have a negative impact on both infant development and maternal adjustment. This study considered the impact of a new programme of early psychosocial interventions on such outcomes, following the birth of a child with severe congenital heart disease.
Methods: Seventy infants and their mothers were assigned to an intervention or control group based on order of presentation to the unit. Interventions aimed at bolstering mother–infant transactions, through psychoeducation, parent skills training and narrative therapy techniques were implemented.
Results: Clinically and statistically signi?cant gains were observed at 6-month follow-up on the mental (but not the psychomotor) scale of the Bayleys-II. Positive gains were also manifested on feeding practices, maternal anxiety, worry and appraisal of their situation.
Conclusions: A programme of generalizable psychosocial interventions is shown to have a positive impact on the infant with severe congenital heart disease and the mother.