Complete maternal isodisomy of chromosome 3 in a child with recessive dystrophic epidermolysis bullosa but no other phenotypic abnormalities.

The mechanobullous disease Hallopeau-Siemens recessive dystrophic epidermolysis bullosa (HS-RDEB) results from mutations in the type VII collagen gene (COL7A1) on chromosome 3p21.31. Typically, there are frameshift, splice site, or nonsense mutations on both alleles. In this report, we describe a patient with HS-RDEB, who was homozygous for a new frameshift mutation, 345insG, in exon 3 of COL7A1. However, sequencing of parental DNA showed that although the patient's mother was a heterozygous carrier of this mutation, the father's DNA contained only wild-type sequence. Microsatellite marker analysis confirmed paternity and genotyping of 28 microsatellites spanning chromosome 3 revealed that the affected child was homozygous for every marker tested with all alleles originating from a single maternal chromosome 3. Thus, the HS-RDEB phenotype in this patient is due to complete maternal isodisomy of chromosome 3 and reduction to homozygosity of the mutant COL7A1 gene locus. To our knowledge, there are no published reports of uniparental disomy (UPD) in HS-RDEB; moreover, this case represents only the third example of UPD of chromosome 3 to be reported. The severity of the HS-RDEB in this case was similar to other affected individuals and no additional phenotypic abnormalities were observed, suggesting an absence of maternally imprinted genes on chromosome 3.

Kindler syndrome: a new mutation and new diagnostic possibilities.

BACKGROUND: Kindler syndrome (KS) is a rare genetic disorder that is characterized by blistering in infancy, followed by the onset of poikiloderma and photosensitivity in childhood. The recently elucidated molecular pathogenesis involves mutations in KIND1, a gene encoding the protein kindlin-1, which is involved in the attachment of the actin cytoskeleton to the extracellular matrix in basal keratinocytes. OBSERVATIONS: We describe a child with the neonatal diagnosis of epidermolysis bullosa simplex who developed poikiloderma and skin fragility at 6 years of age. His skin showed diminished staining with anti-kindlin-1 antibody, and genetic analysis revealed that he was a compound heterozygote with a previously unreported mutation in KIND1. Ultrastructural clues to the diagnosis of KS were present in a biopsy specimen that was obtained when the patient was 10 months old, before he developed poikiloderma and photosensitivity. CONCLUSIONS: In this case, a combination of a known mutation (R271X) and a newly described mutation (1755delT) in the KIND1 gene produced loss of function in kindlin-1, leading to the clinical features of KS. Ultrastructural findings characteristic of KS were evident years before the onset of poikiloderma and sun sensitivity. In infancy, electron microscopy can enable early, accurate diagnosis of KS.

An update of immunotherapy for specific allergies.

Allergic diseases are common, disabling and potentially life threatening. The processes that lead to production of excessive allergen-specific IgE production are highly complex and heterogeneous. While current treatment strategies are limited, recent technological advances have provided a better understanding of underlying disease processes and offered new potential therapeutic targets. Optimal treatment strategies permanently modify underlying inflammatory allergic immune responses (immunotherapy) with long term alleviation of symptoms and minimal side-effects. Although these processes are still not completely understood, methods of modifying allergen recognition by the immune system have already been successful. Here, we review recent developments and future directions in allergen immunotherapy and adjunctive therapies. Specifically, we address the molecular mechanisms of allergen immunotherapy and new techniques including allergen modification, allergen gene vaccination, CpG immunostimulation, and peptide immunotherapy. Other non-allergen specific molecular targets (including receptor, cytokine and IgE targets) which may complement specific immunotherapy are also discussed. Ideally these methods will eventually be replaced by strategies targeting the prevention of allergic responses (immunoprophylaxis).

Phenotype of fetal monocytes and B lymphocytes during the third trimester of pregnancy.

The neonate typically exhibits an immature immune response compared with the adult, yet the fetus is able to generate antigen-specific responses from around 20-22 weeks of gestation. Although antigen-presenting cells (APCs) must have attained the necessary level of maturity to support this, very little is known about the phenotype and function of these populations during human fetal development. Whole blood flow cytometry was, therefore, utilised to phenotype fetal/neonatal circulating monocytes and B cells throughout the third trimester of pregnancy. The percentage of B cells (CD19+) expressing MHC Class II was comparable to the adult at all gestations, whereas the percentage of MHC Class II-positive monocytes (CD14+) increased significantly over gestation (P=0.0008) but remained lower than the adult at term. In contrast, the percentage of CD40+ or CD86+ fetal/neonatal monocytes at all gestations was comparable to the adult, but there was a maturational increase in the percentage of CD40+ or CD86+ B cells (P=0.007) to adult levels by term. The expression of CD14 itself (mean fluorescence intensity, MFI) showed a trend to increase over gestation (P=0.062) and, although all CD14+ cells expressed other receptors associated with innate immune responses (CD11b and CD35), there was fluctuation in the intensity of expression over gestation. Functional immaturity of neonatal antigen-specific immune responses could be associated with reduced co-stimulation provided by both monocytes (via reduced MHC Class II) and B cells (via reduced CD40 and CD86); altered innate responsiveness of monocytes could also contribute.

Immunoregulatory molecules during pregnancy and at birth.

Regulation of the maternal immune response to the fetal allograft is essential for the success of pregnancy and delivery of a well-developed neonate. Numerous mechanisms have been postulated to mediate this. We hypothesised that the potent immunosuppressive molecules TGF-beta1 and IL-10 could contribute to this regulation in the mother and neonate during gestation. In comparison to non-pregnant women, TGF-beta1 and cortisol levels were increased significantly in mid (16-18 weeks) and late pregnancy (>37 weeks, no labour), with levels of both highest in late gestation. In contrast, IL-10 levels were significantly lower in maternal plasma in mid-gestation compared with that from late pregnancy and from non-pregnant women. TGF-beta1, IL-10 and cortisol were all detectable in umbilical cord blood plasma with TGF-beta1 levels significantly decreased in association with labour in contrast to cortisol levels that increased with labour. IL-10 levels in cord plasma were comparable to those of adults and did not change with mode of delivery. Elevated levels of TGF-beta1, but not IL-10, in the maternal and neonatal circulation could have a role in immunoregulation of the maternal response to the fetal allograft as well as growth and development of the fetus.

Capitalizing on the teachable moment: osteoarthritis physical activity and exercise net for improving physical activity in early knee osteoarthritis.

BACKGROUND: Practice guidelines emphasize the use of exercise and weight reduction as the first line of management for knee osteoarthritis (OA). However, less than half of the people with mild OA participate in moderate intensity physical activity. Given that physical activities have been shown to reduce pain, improve quality of life, and have the potential to reduce the progression of joint damage, many people with OA are missing the benefits of this inexpensive intervention. OBJECTIVE: The objectives of this study are (1) to develop a behavioral theory-informed Internet intervention called Osteoarthritis Physical Activity & Exercise Net (OPEN) for people with previously undiagnosed knee OA, and (2) to assess the efficacy of the OPEN website for improving physical activity participation through a proof-of-concept study. METHODS: OPEN was developed based on the theory of planned behavior. Efficacy of this online intervention is being assessed by an ongoing proof-of-concept, single-blind randomized controlled trial in British Columbia, Canada. We are currently recruiting participants and plan to recruit a total of 252 sedentary people with previously undiagnosed knee OA using a set of validated criteria. Half of the participants will be randomized to use OPEN and receive an OA education pamphlet. The other half only will receive the pamphlet. Participants will complete an online questionnaire at baseline, 3 months, and 6 months about their participation in physical activities, health-related quality of life, and motivational outcomes. In addition, we will perform an aerobic fitness test in a sub-sample of participants (n=20 per study arm). In the primary analysis, we will use logistic regression to compare the proportion of participants reporting being physically active at or above the recommended level in the 2 groups, adjusting for baseline measurement, age, and sex. RESULTS: This study evaluates a theory-informed behavioral intervention at a time when people affected with OA tend to be more motivated to adopt an active lifestyle (ie, at the early stage of OA). Our approach, which consisted of the identification of early knee OA followed immediately by an online intervention that directly targets physical inactivity, can be easily implemented across communities. CONCLUSIONS: Our online intervention directly targets physical inactivity at a time when the joint damage tends to be mild. If OPEN is found to be effective in changing long-term physical activity behaviors, it opens further opportunities to promote early diagnosis and to implement lifestyle interventions. TRIAL REGISTRATION: Clinicaltrial.gov: NCT01608282; http://clinicaltrials.gov/ct2/show/NCT01608282 (Archived by WebCite at http://www.webcitation.org/6G7sBBayI).

Administration of oxaliplatin to a pregnant woman with rectal cancer.

PURPOSE: The platinum agent oxaliplatin could be useful in treatment of cancer in pregnant women, but it is fetotoxic in rats and its effect on the human fetus is unknown. METHODS: Oxaliplatin was administered to a 25-year-old pregnant woman with metastatic rectal cancer from 20 to 30 weeks gestational age as part of the mFOLFOX-6 regimen. RESULTS: The patient gave birth to a healthy girl at 33 weeks gestational age. At follow-up, the 3-year-old child had achieved all appropriate growth and developmental milestones. DISCUSSION: Oxaliplatin is a component of several modern chemotherapy regimens. This report demonstrates the administration of oxaliplatin in the second and third trimesters of pregnancy without apparent fetal harm.

Randomized trial of a nurse-administered, telephone-based disease management program for patients with heart failure.

BACKGROUND: Heart failure is a common and important cause of morbidity and mortality. Disease management offers promise in reducing the need for hospitalization and improving quality of life for heart failure patients, but experimental data on the efficacy of such programs are limited. METHODS AND RESULTS: A total of 151 patients hospitalized with heart failure were randomized to usual care or scheduled telephone calls by specially trained nurses promoting self-management and guideline-based therapy as prescribed by primary physicians. Nurses also screened patients for heart failure exacerbations, which they managed with supplemental diuretics or by contacting the primary physician for instructions. Outcomes included time to hospital encounter, mortality, number and cost of hospitalizations, functional status, and satisfaction with care. Intervention patients had a longer time to encounter (hazard ratio [HR] = 0.67; 95% confidence interval [CI] 0.47-0.96; P = .029), hospital readmission (HR = 0.67; CI 0.46-0.99; P = .045), and heart failure-specific readmission (HR = 0.62; CI 0.38-1.03; P = .063). The number of admissions, hospital days, and hospital costs were significantly lower during the first 6 months after intervention but not at 1 year. The intervention had little effect on functional status, mortality, and satisfaction with care. CONCLUSION: A nurse-administered, telephone-based disease management program delayed subsequent health care encounters, but had minimal impact on other outcomes.

Fetal immune responsiveness and routes of allergic sensitization.

There is much interest in the role of early-life events in the subsequent development of atopy and/or atopic disease. Despite the ongoing debate about the intrauterine exposure of the fetus to environmental allergens and the establishment of T-cell memory, it is clear that the immunological response of the neonate at risk of atopy is more immature than that of the neonate likely to be non-atopic. The reasons for this remain unknown, but might reflect maternally transmitted signals that adapt the neonatal immune response. An inadvertent consequence of this might be an inappropriate host response to environmental signals such as those from microbial products during early post-natal life that result in an inability to dampen neonatal T helper 2-skewed responses. The developing gastrointestinal tract and theexogenous factors that impact on this, such as microbial flora and breast milk, should therefore be a focus of investigation.

Reduced soluble CD14 levels in amniotic fluid and breast milk are associated with the subsequent development of atopy, eczema, or both.

BACKGROUND: Exposure to various microbial products in early life reduces the risk of atopy. Such exposure induces downregulation of T(H)2 allergy-biased responses by means of pattern recognition molecules, such as CD14, an LPS receptor. OBJECTIVE: We sought to determine whether infant and maternal levels of soluble CD14 (sCD14) are associated with the atopic outcomes of infants. METHODS: Levels of sCD14 in plasma, amniotic fluid, and breast milk were measured with a specific ELISA in different cohorts. Expression of toll-like receptors in the fetal gut was examined by using RT-PCR. RESULTS: Soluble CD14 levels increased during fetal development and postnatally, attaining adult levels by around 4 months of age, with an overshoot of adult levels from 6 months of age. There was no difference in plasma sCD14 levels at birth of children with a high compared with those with a low risk of development of atopy. Amniotic fluid sCD14 levels at midgestation (16-17 weeks) were significantly lower when the child was subsequently atopic (P <.05). Soluble CD14 levels in breast milk collected 3 months postpartum were significantly lower in children with eczema at 6 months of age, irrespective of whether they were atopic (P =.003). Transcripts for toll-like receptor 4, which would enable transmembrane signaling for LPS/sCD14 complexes, were expressed within fetal gut and skin. CONCLUSION: Exposure to reduced levels of sCD14 in the fetal and neonatal gastrointestinal tract is associated with the development of atopy, eczema, or both. Thus the exogenous supply of sCD14 might influence immunologic reactivity both locally and systemically in early life and thereby influence disease outcome.