Protochordate concordant xenotransplantation settings reveal outbreaks of donor cells and divergent life span traits

If fulminate rejection in allogeneic and xenogeneic engraftments is not an evolutionary relict feature, then any treatment that ablates the host surveillance's effector arms capabilities and eliminates graft vs. host reactivity should induce donor chimerism in transplant settings. We demonstrate here marked proliferative response of Botryllus (Urochordata) blood cells months following their infusions (2×10⁴–10⁵ blood cells per host) into the concordant xenogeneic environment of irradiated Botrylloides soma. The state of infused cells was followed by Botryllus specific microsatellite alleles on DNA samples from host zooids and vascular system. Increased growth rates and life spans of engrafted hosts in some cases, and sudden chimerical death following the outbreak of donor cells in others, indicate a ‘double-edged sword’ expression of concurrent evolutionary selected mechanisms. This DES phenomenon in immunity underlies divergent stem cell competition phenomena in multicellular organisms, leading in mammals, to cases of autoimmune diseases vis-à-vis long-lasting microchimerism events following an iatrogenic transplantation.     

Long-term therapy with intravenous immunoglobulin is beneficial in patients with autoimmune diseases

The objective of our study is to evaluate the clinical response, steroid-sparing and adverse affects of long-term intravenous immunoglobulin (IVIG) treatment for autoimmune diseases. Patients were recruited from the Rheumatology clinic. All patients fulfilled the ACR criteria for the appropriate autoimmune disease. Beneficial effects of IVIG therapy in systemic lupus erythematosus (SLE) patients were evaluated utilizing the SLEDAI score. Clinical remission in patients with other autoimmune diseases was evaluated by a rheumatologist. Data were retrieved retrospectively from an IVIG database (Excel program). Seventeen patients—SLE (n = 11) and other autoimmune diseases (n = 6)—received a high dose IVIG protocol monthly for 6 months, followed by therapy every 2–3 months. The patients received a mean of 7.9 courses/patient. The mean follow-up for long-term therapy was 30 months. The response to IVIG treatment was remission in 12 patients. Change in the SLEDAI score following IVIG therapy was significant (p < 0.05). In responders, IVIG harbored a significant steroid-sparing effect (p < 0.05). Mild and transient adverse effects persisted with long-term therapy in 50% of patients. Severe adverse effects (pulmonary embolism and seizures) occurred early in two patients with SLE and secondary anti-phospholipid syndrome. Long-term IVIG therapy is beneficial and carries a good safety profile for SLE and other autoimmune diseases.     

Neural activation during the processing of ambiguous fearful facial expressions: an ERP study in anxious and nonanxious individuals

Event-related brain potentials (ERPs) were recorded from anxious and nonanxious participants during performance on a fear detection task. Sequential presentation of gradually increasing fear cues from neutral to fearful allowed an examination of anxiety-related differences in the neural activation patterns corresponding to participants' overt detection of fear in ambiguous stimuli as well as the activation patterns corresponding to stages of fear processing preceding overt fear detection. While centro-parietal Late Positive Potential (LPP) amplitude of nonanxious participants was significantly modulated by increases in stimulus fear intensity preceding overt fear detection, no such LPP sensitivity was detected in anxious participants. Additionally, anxiety group differences as well as emotion related modulation were found for earlier ERP components (P1, P2 and EPN). These findings reveal an anxiety-related dissociation between the early and late processing stages of threat processing. Implications are discussed in light of existing theories of cognitive biases in anxiety.     

Practicing attachment in the real world: improving maternal insightfulness and dyadic emotional availability at an outpatient community mental health clinic

The purpose of the study was to examine the efficacy of an attachment-based intervention program practiced at an outpatient clinic. Changes in parental insightfulness and dyadic emotional availability were assessed in 32 mother–child dyads from pre- to post-intervention. At both data collection points, mothers were interviewed with the Insightfulness Assessment and the mother–child dyad was observed in play sessions coded with the Emotional Availability Scales. Findings revealed a strong association between maternal insightfulness and dyadic emotional availability, both before and after treatment. In terms of intervention efficacy, positive gains were observed in both insightfulness and dyadic emotional availability from pre- to post-intervention. Mothers who changed their classifications from non-insightful to insightful following the intervention showed the greatest gains in emotional availability. These findings have important implications for the type of interventions and service delivery model that could work in real world clinical settings.     

A Novel Mutation in a Critical Region for the Methyl Donor Binding in DNMT3B Causes Immunodeficiency,Centromeric Instability,and Facial Anomalies Syndrome (ICF)

Purpose

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is an extremely rare autosomal recessive disease. The immune phenotype is characterized by hypogammaglobulinemia in the presence of B cells. T cell lymphopenia also develops in some patients. We sought to further investigate the immune defect in an ICF patient with a novel missense mutation in DNMT3B and a severe phenotype.

Methods

Patient lymphocytes were examined for subset counts, immunoglobulin levels, T and B cell de novo production (via excision circles) and receptor repertoire diversity. Mutated DNMT3B protein structure was modeled to assess the effect of a mutation located outside of the catalytic region on protein function.

Results

A novel homozygous missense mutation, Ala585Thr, was found in DNMT3B. The patient had decreased B cell counts with hypogammaglobulinemia, and normal T cell counts. CD4⁺ T cells decreased over time, leading to an inversion of the CD4⁺ to CD8⁺ ratio. Excision circle copy numbers were normal, signifying normal de novo lymphocyte production, but the ratio between naïve and total B cells was low, indicating decreased in vivo B cell replication. T and B cell receptor repertoires displayed normal diversity. Computerized modeling of the mutated Ala585 residue suggested reduced thermostability, possibly affecting the enzyme kinetics.

Conclusions

Our results highlight the existence of a T cell defect that develops over time in ICF patient, in addition to the known B cell dysfunction. With intravenous immunoglobulin (IVIG) treatment ameliorating the B cell defect, the extent of CD4⁺ lymphopenia may determine the severity of ICF immunodeficiency.

     

Infants thinner at birth exhibit smaller kidneys for their size in late gestation in a sample of fetuses with appropriate growth

Fetal ultrasound measurements were employed to investigate the relationship between weight and ponderal index at birth and kidney size during the second (23 weeks) and third (32 weeks) trimesters of pregnancy in a sample of 25 normally growing fetuses. Kidney volume and kidney volume / fetal weight ratio at 32 weeks are significantly and positively related to both weight and ponderal index at birth, controlling for sex, gestational age at birth, and day of ultrasound measurement. A second‐degree polynomial relationship approximates the predictability of kidney volume fetal weight ratio at 23 weeks to that at 32 weeks, demonstrating shifting growth rates in fetal organ and body growth relationships during midgestation. Sex and parental size are suggested as contributing to these patterns. Females have a surge in renal growth between 23 and 32 weeks to catch up to earlier growing males, and maternal weight significantly predicts incremental growth in kidney volume and the kidney volume / fetal weight ratio at 32 weeks of gestation. The observation that fetuses relatively thin at birth have relatively smaller kidneys for their size in late gestation suggests that the influence of maternal weight on birth outcome may act through organ growth. Am. J. Hum. Biol. 14:398–406, 2002. © 2002 Wiley‐Liss, Inc.     

3-Methylglutaconic aciduria type III in a non-Iraqi-Jewish kindred: clinical and molecular findings

Type III 3-methylglutaconic aciduria (MGA) (MIM 258501) consists of early bilateral optic atrophy, later development of spasticity, extrapyramidal dysfunction and occasionally cognitive deficits, and urinary excretion of 3-methylglutaconic acid and 3-methylglutaric acid. The presence of the disorder in an Iraqi-Jewish genetic isolate led to mapping of the OPA3 gene to chromosome 19q13.2-q13.3, followed by isolation of the gene itself. OPA3 consists of two exons and codes for a peptide of 179 amino acids. Iraqi-Jewish patients with type III MGA are homozygous for a splice site founder mutation in OPA3 (IVS1-1G>C) which abolishes mRNA expression in fibroblasts. Here we report a novel mutation in OPA3 (320-337del) in a Kurdish-Turkish patient with optic atrophy and 3-methylglutaconic and 3-methylglutaric aciduria, previously carrying the diagnosis of type IV MGA. We conclude that type III MGA occurs in patients of non-Iraqi-Jewish ancestry, and should be considered in patients with type IV MGA that have optic atrophy and ataxia.     

Epstein–Barr virus antibodies mark systemic lupus erythematosus and scleroderma patients negative for anti‐DNA

Systemic lupus erythematosus (SLE) is an autoimmune disease that can attack many different body organs; the triggering event is unknown. SLE has been associated with more than 100 different autoantibody reactivities – anti‐dsDNA is prominent. Nevertheless, autoantibodies to dsDNA occur in only two‐thirds of SLE patients. We previously reported the use of an antigen microarray to characterize SLE serology. We now report the results of an expanded study of serology in SLE patients and scleroderma (SSc) patients compared with healthy controls. The analysis validated and extended previous findings: two‐thirds of SLE patients reacted to a large spectrum of self‐molecules that overlapped with their reactivity to dsDNA; moreover, some SLE patients manifested a deficiency of natural IgM autoantibodies. Most significant was the finding that many SLE patients who were negative for autoantibodies to dsDNA manifested abnormal antibody responses to Epstein–Barr virus (EBV): these subjects made IgG antibodies to EBV antigens to which healthy subjects did not respond or they failed to make antibodies to EBV antigens to which healthy subjects did respond. This observation suggests that SLE may be associated with a defective immune response to EBV. The SSc patients shared many of these serological abnormalities with SLE patients, but differed from them in increased IgG autoantibodies to topoisomerase and centromere B; 84% of SLE patients and 58% of SSc patients could be detected by their abnormal antibodies to EBV. Hence an aberrant immune response to a ubiquitous viral infection such as EBV might set the stage for an autoimmune disease.     

Downward percentile crossing as an indicator of an adverse prenatal environment

Background: Postnatal health sequelae of low birth weight have been attributed to ‘poor fetal growth’ from inferred adverse prenatal environments; risks augmented by infant growth rates. Identifying prenatal growth-restricting events is essential to clarify pathways and mechanisms of fetal growth.

Aim: The specific aim of this investigation was to examine whether an episode of preterm labor may compromise fetal growth.

Subjects and methods: Fetal size at the end of the second trimester and birth were compared among women with uncomplicated pregnancies (n = 3167) and those who experienced an episode of preterm labor (<37 weeks) and subsequently delivered at term (≥37 weeks, n = 147). Fetal weight estimated from ultrasound measures, and changes in weight standard scores across the third trimester investigated significant centile crossing (>0.67 standard deviation score change).

Results: Fetuses delivered at term after an episode of preterm labor were smaller at birth relative to their peers than at the end of the second trimester, and were 47% more likely to experience clinically significant downward centile crossing (p < 0.05) than their peers (OR 1.47, 95% CI 1.04–2.07).

Conclusion: An episode of preterm labor may signal an adverse prenatal environment for term-delivered neonates. Epidemiologically silent events in the natural history of pregnancy are an understudied source of fetal growth compromise as inferred by small birth size among peers.     

A founder truncating variant in GDF1 causes autosomal‐recessive right isomerism and associated congenital heart defects in multiplex Arab kindreds

The genetic basis of congenital heart malformations associated with disruption of left–right (L–R) asymmetry is broad and heterogenous, with variants in over 25 genes implicated thus far. Of these, deleterious variants in the Growth/Differentiation Factor 1 (GDF1) gene have been shown to cause heterotaxy with varied complex heart malformations of left–right patterning, in 23 individuals reported to date, either in monoallelic or biallelic state. We report three unrelated individuals exhibiting right isomerism with congenital heart defects, each originating from a consanguineous kindred of Arab‐Muslim descent. Using whole exome sequencing, a shared novel homozygous truncating c.608G > A (p.W203*) variant in the GDF1 gene was revealed as the molecular basis of their disease. Subsequently, targeted sequencing of this variant showed full segregation with the disease in these families, with a total of over 15 reportedly affected individuals, enabling genetic counseling, prenatal diagnosis, and planning of future pregnancies. Our findings further confirm the association of biallelic GDF1 variants, heterotaxy and congenital heart defects of left–right patterning, and expand the previously described phenotypic spectrum and mutational profile. Moreover, we suggest targeted screening for the p.W203* variant in relevant clinical circumstances.