Transfusion efficacy of ABO major-mismatched platelets (PLTs) in children is inferior to that of ABO-identical PLTs

BACKGROUND: ABO major compatibility is essential in transfusions of red blood cells but is not requisite in PLT transfusions. In adults there is some evidence that transfusion efficacy of ABO blood group-identical platelets (PLTs) is superior to major-mismatched PLTs. However, in children this question has not been investigated for more than 30 years. STUDY DESIGN AND METHODS: In a prospective study, the efficacy (based on the 1-hour percentage of PLT recovery [PPR(1hr)]) of 400 eligible ABO blood group-identical or out-of-group apheresis PLT concentrates (APCs), transfused mainly prophylactically to 50 children with hematologic malignancies, solid tumors, or aplastic anemia was investigated. The primary objective was to compare PPR(1hr) between ABO-identical and major-mismatched transfusions. RESULTS: After ABO major-mismatched transfusions, PPR(1hr) was significantly lower than after ABO blood group-identical transfusions (median 21% vs. 32%; p = 0.034). Multivariate analysis showed major-mismatched transfusions to be significantly more often unsuccessful than identical transfusions (odds ratio [OR], 3.97; 95% confidence interval [CI], 1.52-10.39; p = 0.005). Using flow cytometry and fluorescent microscopy, it could be demonstrated that PLTs of subgroup A(1), significantly expressing A antigen on their surface, were rapidly cleared from the circulation of group O or B recipients. In contrast, major-mismatched transfusions of A(2) PLTs, expressing no detectable A antigen, were as successful as identical transfusions (OR, 1.13; 95% CI, 0.16-7.88; p = 0.90). CONCLUSION: These data clearly indicate that in children ABO major-mismatched PLT transfusions result in inferior transfusion efficacy, with the only exception of group A(2) PLTs. ABO minor-mismatched PLTs showed comparable efficacy to identical transfusions.

Increased airway smooth muscle mass in children with asthma, cystic fibrosis, and non-cystic fibrosis bronchiectasis

RATIONALE: Structural alterations to airway smooth muscle (ASM) are a feature of asthma and cystic fibrosis (CF) in adults. OBJECTIVES: We investigated whether increase in ASM mass is already present in children with chronic inflammatory lung disease. METHODS: Fiberoptic bronchoscopy was performed in 78 children (median age [IQR], 11.3 [8.5-13.8] yr): 24 with asthma, 27 with CF, 16 with non-CF bronchiectasis (BX), and 11 control children without lower respiratory tract disease. Endobronchial biopsy ASM content and myocyte number and size were quantified using stereology. MEASUREMENTS AND MAIN RESULTS: The median (IQR) volume fraction of subepithelial tissue occupied by ASM was increased in the children with asthma (0.27 [0.12-0.49]; P < 0.0001), CF (0.12 [0.06-0.21]; P < 0.01), and BX (0.16 [0.04-0.21]; P < 0.01) compared with control subjects (0.04 [0.02-0.05]). ASM content was related to bronchodilator responsiveness in the asthmatic group (r = 0.66, P < 0.01). Median (IQR) myocyte number (cells per mm(2) of reticular basement membrane) was 8,204 (5,270-11,749; P < 0.05) in children with asthma, 4,504 (2,838-8,962; not significant) in children with CF, 4,971 (3,476-10,057; not significant) in children with BX, and 1,944 (1,596-6,318) in control subjects. Mean (SD) myocyte size (mum(3)) was 3,344 (801; P < 0.01) in children with asthma, 3,264 (809; P < 0.01) in children with CF, 3,177 (873; P < 0.05) in children with BX, and 1,927 (386) in control subjects. In all disease groups, the volume fraction of ASM in subepithelial tissue was related to myocyte number (asthma: r = 0.84, P < 0.001; CF: r = 0.81, P < 0.01; BX: r = 0.95, P < 0.001), but not to myocyte size. CONCLUSIONS: Increases in ASM (both number and size) occur in children with chronic inflammatory lung diseases that include CF, asthma, and BX.

Ambulatory arterial stiffness index is increased in hypertensive childhood disease

Arterial hypertension in adults is often associated with an increased arterial stiffness, which correlates with the ambulatory arterial stiffness index (AASI) as derived from ambulatory blood pressure (BP) measurements. The purpose of this study was to demonstrate whether children with diagnosed hypertension have an increased AASI as in hypertensive adults. AASI was calculated from 185 ambulatory BP measurements of 114 hypertensive and 71 normotensive, healthy children. Hypertensive children had higher AASI values compared with their normotensive healthy counterparts (0.370 +/- 0.120 versus 0.204 +/- 0.199, p < 0.0001). Children with longer duration of hypertension or a history of primary or secondary aortic coarctation displayed even more elevated AASI values. A receiver operator curve derived cut-off of AASI set at 0.301 distinguished (p < 0.0001) hypertensive from normotensive children with an odds ratio of 8.2, a sensitivity of 81%, and a specificity of 65%. Moreover, AASI correlated with pulse and systolic BP. In conclusion, AASI is elevated in hypertensive children and correlates with the duration and the origin of hypertension in childhood.

Pulse contour analysis: a valid assessment of central arterial stiffness in children?

In adults the contour analysis of peripheral pressure waves in the upper limb reflects central aortic stiffness. Here, we wanted to demonstrate the appropriateness of pulse contour analysis to assess large artery stiffness in children. Digital volume pulse analysis, with the computation of the stiffness index and pulse wave velocity between carotid and femoral artery, were simultaneously determined in 79 healthy children between 8 years and 15 years (mean age 11.4 years, 32 girls). The stiffness index of 42 healthy adults (mean age 45.6 years, 26 women) served as control. Pulse wave velocity between carotid and femoral artery was directly correlated with systolic pressure and mean blood pressure, as well as with pulse pressure. The results from the stiffness index of children revealed the expected values extrapolated from the linear regression of adulthood stiffness index vs. age. Childhood stiffness index positively correlated with pulse wave velocity (r(2) = 0.07, P = 0.02) but not with blood pressure parameters. The exclusion of individuals with an increased vascular tone, as indicated by a reflexion index > 90%, improved the correlation between stiffness index and pulse wave velocity (r(2) = 0.13, P = 0.001). Our data indicate that digital volume pulse-based analysis has limitations if compared with pulse wave velocity to measure arterial stiffness, mostly in patients with a high vascular tone.

Cognitive functioning, behavior, and quality of life after stroke in childhood

Rationale: To provide a better understanding of cognitive functioning, motor outcome, behavior and quality of life after childhood stroke and to study the relationship between variables expected to influence rehabilitation and outcome (age at stroke, time elapsed since stroke, lateralization, location and size of lesion). Methods: Children who suffered from stroke between birth and their eighteenth year of life underwent an assessment consisting of cognitive tests (WISC-III, WAIS-R, K-ABC, TAP, Rey-Figure, German Version of the CVLT) and questionnaires (Conner's Scales, KIDSCREEN). Results: Twenty-one patients after stroke in childhood (15 males, mean 11;11 years, SD 4;3, range 6;10-21;2) participated in the study. Mean Intelligence Quotients (IQ) were situated within the normal range (mean Full Scale IQ 96.5, range IQ 79-129). However, significantly more patients showed deficits in various cognitive domains than expected from a healthy population (Performance IQ p = .000; Digit Span p = .000, Arithmetic's p = .007, Divided Attention p = .028, Alertness p = .002). Verbal IQ was significantly better than Performance IQ in 13 of 17 patients, independent of the hemispheric side of lesion. Symptoms of ADHD occurred more often in the patients' sample than in a healthy population (learning difficulties/inattention p = .000; impulsivity/hyperactivity p = .006; psychosomatics p = .006). Certain aspects of quality of life were reduced (autonomy p = .003; parents' relation p = .003; social acceptance p = .037). Three patients had a right-sided hemiparesis, mean values of motor functions of the other patients were slightly impaired (sequential finger movements p = .000, hand alternation p = .001, foot tapping p = .043). In patients without hemiparesis, there was no relation between the lateralization of lesion and motor outcome. Lesion that occurred in the midst of childhood (5-10 years) led to better cognitive outcome than lesion in the very early (0-5 years) or late childhood (10-18 years). Other variables such as presence of seizure, elapsed time since stroke and size of lesion had a small to no impact on prognosis. Conclusion: Moderate cognitive and motor deficits, behavioral problems, and impairment in some aspects of quality of life frequently remain after stroke in childhood. Visuospatial functions are more often reduced than verbal functions, independent of the hemispheric side of lesion. This indicates a functional superiority of verbal skills compared to visuospatial skills in the process of recovery after brain injury. Compared to the cognitive outcome following stroke in adults, cognitive sequelae after childhood stroke do indicate neither the lateralization nor the location of the lesion focus. Age at stroke seems to be the only determining factor influencing cognitive outcome.

Enhanced antitumorigenic effects in glioblastoma on double targeting of pleiotrophin and its receptor ALK

In adults, glioblastomas are the most lethal and most frequent malignant brain tumors, and the poor prognosis despite aggressive treatment indicates the need to establish novel targets for molecular intervention. The secreted growth factor pleiotrophin (PTN, HB-GAM, HBNF, OSF-1) shows mitogenic, chemotactic, and transforming activity. Whereas PTN expression is tightly regulated during embryogenesis and is very limited in normal adult tissues, a marked PTN up-regulation is seen in tumors including glioblastomas. Likewise, the PTN receptor anaplastic lymphoma kinase (ALK) has been shown previously to be upregulated and functionally relevant in glioblastoma. In this study, we explore the antitumorigenic effects of the simultaneous ribozyme-mediated knockdown of both receptor and ligand. Various glioblastoma cell lines are analyzed for PTN and ALK expression. Beyond the individual efficacies of several specific ribozymes against PTN or ALK, respectively, antiproliferative and proapoptotic effects of a single gene targeting approach are strongly enhanced on double knockdown of both genes in vitro. More importantly, this results in the abolishment of tumor growth in an in vivo subcutaneous tumor xenograft model. Finally, the analysis of various downstream signaling pathways by antibody arrays reveals a distinct pattern of changes in the activation of signal transduction molecules on PTN/ALK double knockdown. Beyond the already known ones, it identifies additional pathways relevant for PTN/ALK signaling. We conclude that double targeting of PTN and ALK leads to enhanced antitumorigenic effects over single knockdown approaches, which offers novel therapeutic options owing to increased efficacy also after prolonged knockdown.

Primary pelvic pyomyositis in a neonate

Primary pyomyositis is a bacterial infection occurring in skeletal muscle with no obvious local or adjacent cause. It is classically an infection of the tropics, although it is reported in temperate climates with increasing frequency. Tropical pyomyositis occurs predominantly in children aged between 2 and 5 and in adults aged between 20 and 45 years, whereas most temperate pyomyositis cases occur in adults. Using a magnetic resonance imaging scan, we made the diagnosis of staphylococcal pelvic pyomyositis in a Swiss term-born infant with an initial working diagnosis of septic hip osteoarthritis.

Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome in childhood: a report of ten cases and review of the literature

Chronic recurrent multifocal osteomyelitis is a rare chronic inflammatory musculoskeletal process observed in children and young adults. Recently, the acronym SAPHO syndrome (for synovitis, acne, pustulosis, hyperostosis, osteitis) was coined to emphasise the association between osteo-articular inflammations and different skin abnormalities which are aseptic and filled with neutrophils. In adults, chronic recurrent multifocal osteomyelitis is now a classical manifestation of SAPHO syndrome. Chronic skin disorders were seen in eight of ten children on follow-up at the University Children's Hospitals in Bern and Zurich and in 61 of 260 paediatric cases reported in the literature. The different skin lesions were palmoplantar pustulosis (n = 40), non-palmoplantar pustulosis (n = 6), psoriasis vulgaris (n = 16) or severe acne (n = 4). More rarely Sweet syndrome (n = 2) or pyoderma gangrenosum (n = 1) were reported. Conclusion: The synovitis, acne, pustulosis, hyperostosis, osteitis syndrome is pertinent even in paediatrics since skin involvement is frequent.

Pulmonary renal syndrome in childhood: a report of twenty-one cases and a review of the literature

In adults, the term specific pulmonary renal syndrome describes disorders with pulmonary and glomerular manifestations and includes Wegener's granulomatosis, Goodpasture disease, and systemic lupus erythematosus. Nonspecific pulmonary renal syndrome refers to either pulmonary disease complicating glomerular disease, or glomerular diseases following pulmonary disease. Since little is known regarding pulmonary renal syndrome in childhood, we reviewed the charts of 21 pediatric patients with pulmonary renal syndromes treated by the Department of Pediatrics, University of Bern between 1991 and 1998; we also reviewed the pediatric literature that deals with specific pulmonary renal syndromes. Specific pulmonary renal syndrome was noted in 3 children with systemic vasculitis (Wegener granulomatosis, N = 2; microscopic polyangiitis, N = 1) and 2 with systemic lupus erythematosus. Nonspecific pulmonary renal syndrome was observed in 12 patients with pulmonary edema (N = 9), pulmonary thromboembolism (N = 2), and pulmonary infection (N = 1) complicating the course of a glomerular disease, and in 4 children with a pulmonary disease followed by a glomerular disease. Review of the literature disclosed 52 cases of specific pulmonary renal syndrome other than systemic lupus erythematosus: Wegener granulomatosis (N = 28), Goodpasture disease (N = 13), and Henoch-Schönlein purpura (N = 11). In addition, hemolytic uremic syndrome complicated pneumococcal pneumonia in 32 cases. We conclude that pulmonary renal syndromes need to be looked for in childhood. Apart from Wegener granulomatosis, Goodpasture disease, and systemic lupus erythematosus, Henoch-Schönlein purpura and hemolytic-uremic syndrome occasionally have both pulmonary and renal features.

Low bone mineral density, renal dysfunction, and fracture risk in HIV infection: a cross-sectional study

BACKGROUND: Reduced bone mineral density (BMD) is common in adults infected with human immunodeficiency virus (HIV). The role of proximal renal tubular dysfunction (PRTD) and alterations in bone metabolism in HIV-related low BMD are incompletely understood. METHODS: We quantified BMD (dual-energy x-ray absorptiometry), blood and urinary markers of bone metabolism and renal function, and risk factors for low BMD (hip or spine T score, -1 or less) in an ambulatory care setting. We determined factors associated with low BMD and calculated 10-year fracture risks using the World Health Organization FRAX equation. RESULTS: We studied 153 adults (98% men; median age, 48 years; median body mass index, 24.5; 67 [44%] were receiving tenofovir, 81 [53%] were receiving a boosted protease inhibitor [PI]). Sixty-five participants (42%) had low BMD, and 11 (7%) had PRTD. PI therapy was associated with low BMD in multivariable analysis (odds ratio, 2.69; 95% confidence interval, 1.09-6.63). Tenofovir use was associated with increased osteoblast and osteoclast activity (P< or = .002). The mean estimated 10-year risks were 1.2% for hip fracture and 5.4% for any major osteoporotic fracture. CONCLUSIONS: In this mostly male population, low BMD was significantly associated with PI therapy. Tenofovir recipients showed evidence of increased bone turnover. Measurement of BMD and estimation of fracture risk may be warranted in treated HIV-infected adults.

Different effects of cyclosporin A on bone remodeling in young and adult rats

Reported effects of cyclosporin A (Sandimmun, CsA) on bone have been both contradictory and controversial. Thus, stimulation of new bone formation as well as increased mineral and matrix resorption have been observed. To investigate the response of basal mineral and matrix turnover to CsA treatment at different stages of skeletal development, comparative experiments were conducted in young growing female rats and in adults. Fifty-six young animals (study A) and 40 adults (study B) received orally either the carrier substance or 5, 15, and 30 mg/kg CsA for 30 days. The following parameters were measured: (a) total skeletal mineral content by dual energy X-ray absorptiometry (DEXA) on days 1 and 30; (b) tibial trabecular volume at day 30; (c) serum osteocalcin at 5-day intervals; (d) urinary deoxypyridinoline (Dpd) excretion (days 1, 15, and 30); and (e) plasma levels of CsA. Results can be summarized as follows: in young rats (study A), total skeletal mineral was not modified by the 5- and 15-mg/kg doses of CsA, whereas 30 mg/kg induced a significant decrease (-15%, p < 0.01). This parameter was not significantly modified in adult animals (study B) subjected to the same doses. The administration of 5 mg/kg CsA did not alter tibial trabecular volume in young rats, but 15 and 30 mg/kg significantly lowered this parameter (-16.3%, p < 0.02, and -42%, p < 0.001, respectively). In adult rats, tibial trabecular volume remained unchanged with the exception of the group receiving 30 mg/kg which exhibited significantly lower values (-28%, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of the prevalence of Trichinella spp. in red foxes and Eurasian lynxes from Switzerland

Trichinella spp. larvae have not been detected in Swiss pigs, horses, or wild boar for many decades, whereas the parasite was repeatedly isolated from red foxes and Eurasian lynxes. Whenever the isolated larvae could be subjected to genotyping, T. britovi was found as infective agent. The present study was initiated to re-assess the epidemiological situation of Trichinella infection in Swiss carnivorous wildlife, namely in red foxes and lynxes. Tissue samples from 1,298 foxes were collected between 2006 and 2007, and those of 55 lynxes between 1999 and 2007. All samples were tested by a standard artificial digestion method and a multiplex-PCR to determine the species and/or genotypes of recovered larvae. Trichinella larvae were found in 21 foxes (1.6%) and 15 lynxes (27.3%), and T. britovi was identified as infecting species in all cases. The geographic distribution of positive foxes showed two main clusters: one in Central Switzerland and one in the West of the country, where also many lynxes were found to be positive. While the prevalence for Trichinella infection in foxes was not statistically correlated with sex or age class, the prevalence in lynx was significantly higher in males compared to females, and in adults compared to juveniles.

Fibromatosis in a young Bernese Mountain Dog: clinical, imaging, and histopathological findings

A young, intact, male Bernese Mountain Dog was presented to the animal hospital for lameness and diffuse thickening of the soft tissue in the right hind limb. Magnetic resonance imaging revealed multiple, multilobular, space-occupying lesions within and between the muscles of the right femur. Biopsies taken from the lesions revealed an infiltrative mass composed mainly of collagen fibers and a low density of benign-appearing fibroblasts. These findings were compatible with a diagnosis of a fibromatosis. Taking the age of onset into account, infantile fibromatosis was most likely. A deep fibromatosis, similar to that seen in adults, could not be excluded based on histology.

Methodological considerations and practical recommendations for the application of peripheral arterial tonometry in children and adolescents

Endothelial dysfunction is recognized as the primum movens in the development of atherosclerosis. Its crucial role in both cardiovascular morbidity and mortality has been confirmed. In the past, research was hampered by the invasive character of endothelial function assessment. The development of non-invasive and feasible techniques to measure endothelial function has facilitated and promoted research in various adult and paediatric subpopulations. To avoid user dependence of flow-mediated dilation (FMD), which evaluates nitric oxide dependent vasodilation in large vessels, a semi-automated, method to assess peripheral microvascular function, called peripheral arterial tonometry (Endo-PAT®), was recently introduced. The number of studies using this technique in children and adolescents is rapidly increasing, yet there is no consensus with regard to either measuring protocol or data analysis of peripheral arterial tonometry in children and adolescents. Most paediatric studies simply applied measuring and analysing methodology established in adults, a simplification that may not be appropriate. This paper provides a detailed description of endothelial function assessment using the Endo-PAT for researchers and clinicians. We discuss clinical and methodological considerations and point out the differences between children, adolescents and adults. Finally, the main aim of this paper is to provide recommendations for a standardised application of Endo-PAT in children and adolescents, as well as for population-specific data analysis methodology.

Gender-specific modulation of immune system complement gene expression in marine medaka Oryzias melastigma following dietary exposure of BDE-47

BDE-47 is one of the most widely found congeners of PBDEs in marine environments. The potential immunomodulatory effects of BDE-47 on fish complement system were studied using the marine medaka Oryzias melastigma as a model fish. Three-month-old O. melastigma were subjected to short-term (5 days) and long-term (21 days) exposure to two concentrations of BDE-47 (low dose at 290 +/- 172 ng/day; high dose at 580 +/- 344 ng/day) via dietary uptake of BDE-47 encapsulated in Artemia nauplii. Body burdens of BDE-47 and other metabolic products were analyzed in the exposed and control fish. Only a small amount of debrominated product, BDE-28, was detected, while other metabolic products were all under detection limit. Transcriptional expression of six major complement system genes involved in complement activation: C1r/s (classical pathway), MBL-2 (lectin pathway), CFP (alternative pathway), F2 (coagulation pathway), C3 (the central component of complement system), and C9 (cell lysis) were quantified in the liver of marine medaka. Endogenous expression of all six complement system genes was found to be higher in males than in females (p < 0.05). Upon dietary exposure of marine medaka to BDE-47, expression of all six complement genes were downregulated in males at day 5 (or longer), whereas in females, MBl-2, CFP, and F2 mRNAs expression were upregulated, but C3 and C9 remained stable with exposure time and dose. A significant negative relationship was found between BDE-47 body burden and mRNA expression of C1r/s, CFP, and C3 in male fish (r = -0.8576 to -0.9447). The above findings on changes in complement gene expression patterns indicate the complement system may be compromised in male O. melastigma upon dietary exposure to BDE-47. Distinct gender difference in expression of six major complement system genes was evident in marine medaka under resting condition and dietary BDE-47 challenge. The immunomodulatory effects of BDE-47 on transcriptional expression of these complement components in marine medaka were likely induced by the parent compound instead of biotransformed products. Our results clearly demonstrate that future direction for fish immunotoxicology and risk assessment of immunosuppressive chemicals must include parallel evaluation for both genders.