Cesarean delivery is not associated with decreased at-birth fracture rates in osteogenesis imperfecta.

PURPOSE: Osteogenesis imperfecta (OI) predisposes to recurrent fractures. Patients with the moderate to severe forms of OI present with antenatal fractures, and the mode of delivery that would be safest for the fetus is not known. METHODS: We conducted systematic analyses of the largest cohort of individuals with OI (n = 540) enrolled to date in the OI Linked Clinical Research Centers. Self-reported at-birth fracture rates were compared among individuals with OI types I, III, and IV. Multivariate analyses utilizing backward-elimination logistic regression model building were performed to assess the effect of multiple covariates, including method of delivery, on fracture-related outcomes. RESULTS: When accounting for other covariates, at-birth fracture rates did not differ based on whether delivery was by vaginal route or by cesarean delivery (CD). Increased birth weight conferred higher risk for fractures irrespective of the delivery method. In utero fracture, maternal history of OI, and breech presentation were strong predictors for choosing CD. CONCLUSION: Our study, the largest to analyze the effect of various factors on at-birth fracture rates in OI, shows that CD is not associated with decreased fracture rate. With the limitation that the fracture data were self-reported in this cohort, these results suggest that CD should be performed only for other maternal or fetal indications, not for the sole purpose of fracture prevention in OI.Genet Med 18 6, 570-576.

Occurrence of Polyphenols, Organic Acids, and Sugars among Diverse Elderberry Genotypes Grown in Three Missouri (USA) Locations.

Elderberry (Sambucus spp.) is an emerging horticultural crop used in a variety of foods, wines, and dietary supplements. A better understanding of the elderberry juice complex including its putative health-promoting compounds in relation to genetic and environmental parameters is needed. A multi-location planting of nine elderberry genotypes was established in 2008 at three geographically-diverse sites in Missouri, USA. Fruits were harvested from replicated plots 2009-2011, frozen, and later prepared for laboratory analysis. Polyphenols, organic acids, and sugars were quantified by HPLC and the results evaluated for response to genotype, site, and year. The American genotypes 'Ocoee' and 'Ozark' were consistently higher in chlorogenic acids compared to other genotypes, whereas 'Ocoee' was significantly higher in rutin than 'Ozark'. The European 'Marge' was significantly higher in isoquercitrin and other flavonoids compared to most North American genotypes. Significant differences in polyphenols were also detected among sites and production years. Malic, citric, and tartaric acids varied significantly among genotypes, sites, and years, whereas succinic, shikimic, and fumaric acids generally did not. Levels of lactic, acetic, and propionic acids were negligible in most samples. The American genotype 'Ocoee' was higher in citric and tartaric acids, while lower in malic acid. The sugars glucose and fructose also responded significantly to genotype, site, and year. 'Ocoee', 'Ozark', and 'Marge' perform very well in Missouri horticulturally and appear to have additional potential as cultivars based on their unique juice characteristics.

Fruit Composition of Elderberry (Sambucus spp.) Genotypes Grown in Oregon and Missouri, USA.

Twelve Sambucus nigra subsp. canadensis genotypes were grown at two Missouri and one Oregon (USA) locations to characterize fruit composition in 2004, 2005, and 2006. Fruit was also sampled from an additional 10 genotypes of subsp. canadensis and nigra grown in Oregon. Soluble solids content ranged from 8.9 to 12.5 °Brix, and titratable acid (as citric acid) was 0.4 to 1.7 g/100ml. Ferric ion reducing activity potential (FRAP) values were 15.6 to 30.7 µmol/g trolox equivalents. Total anthocyanin content ranged from 85 to 385 mg/100 g cyanidin-3-glucoside equivalents (C3GE) and total phenolic content was 421 to 719 mg/100 g gallic acid equivalents (GAE). Of the genotypes sampled in three locations, six genotypes were high (250-350), and four were very low in total anthocyanin (<150 mg/100 g C3GE), respectively. 'Barn' and 'Scotia' were highest, and 'Nova' lowest in total anthocyanin content among genotypes grown in Oregon. Of the total antioxidant tests used, total phenolics was the best quick test, as it is the easiest of the assays, showed the least change among years, and correlated highly with FRAP.

Horticultural Performance of Eight American Elderberry Genotypes at Three Missouri Locations.

American elderberry (Sambucus nigra subsp. canadensis) is being increasingly cultivated in North America for its edible and medicinal fruit and flowers, yet remains largely undeveloped as a horticultural crop. Productive genotypes with desirable horticultural attributes, including disease and insect resistance, precocity, uniform fruit ripening, and large berry size are needed in order to advance the commercial production of elderberries. A four-year study of eight elderberry genotypes was established in 2008 at three diverse Missouri (USA) locations. Phenology, plant morphology, pest susceptibility, productivity, and fruit characteristics data were collected over three growing seasons, 2009-2011. Significant differences for most phenological, horticultural, and fruit juice characteristics were observed among the three sites, three years, and eight genotypes. The genotype 'Ozark' was the earliest to break bud, produced fruit with high levels of soluble solids, and out-yielded most other genotypes at the three sites over the three-year study. None of the new genotypes produced berries as large as or larger than the standard 'York' which is known for its large fruit. Some of the genotypes tested, especially 'Ozark' show promise as potential cultivars and as breeding stock for further development of elderberry as a commercially-viable horticultural crop.

'Marge': a European Elderberry for North American Producers.

Elderberries are being increasingly produced and consumed in North America for their edible and medicinal flowers and fruits. The American elderberry (Sambucus nigra subsp. canadensis) is native to, and most often cultivated in North America. The European elderberry (S. nigra subsp. nigra) has been developed into an economically-important horticultural crop in Europe, but most European cultivars do not perform well in the midwestern USA. The genotype S. nigra subsp. nigra 'Marge' is an open-pollinated seedling of S. nigra subsp. nigra 'Haschberg', which is one of the most popular elderberry cultivars grown in Europe. In a four-year study (one establishment year followed by 3 production years; 2008-2011) at three Missouri (USA) locations, 'Marge' significantly out-performed and out-yielded eight American elderberry genotypes within the same replicated field plots. Across 3 production years at all three sites, 'Marge' achieved budbreak later, flowered earlier, suffered less Eriophyid mite damage, was taller, produced larger berries, and yielded significantly greater amounts of fruit compared with all eight American elderberry genotypes in the study. At one site, 'Marge' produced three times the yield (1.89 kg/plant) compared with the next highest-producing American elderberry genotype (0.65 kg/plant). It is an exceptionally robust and drought-resistant elderberry. The phenotypic attributes of 'Marge' are similar to that of European elderberry except that it performs exceptionally well in the midwestern USA. DNA marker results, along with phenological and morphological characteristics, indicate that 'Marge' is a European elderberry (S. nigra subsp. nigra). As with most European genotypes, 'Marge' does not fruit on first-year wood, and will therefore require a different pruning regimen compared with American elderberry for success in North American production. We do not yet know how 'Marge' will perform outside the midwestern USA, but it is so productive, unique, and mite resistant, that it merits introduction as a cultivar.

A cross-sectional multicenter study of osteogenesis imperfecta in North America - results from the linked clinical research centers.

Osteogenesis imperfecta (OI) is the most common skeletal dysplasia that predisposes to recurrent fractures and bone deformities. In spite of significant advances in understanding the genetic basis of OI, there have been no large-scale natural history studies. To better understand the natural history and improve the care of patients, a network of Linked Clinical Research Centers (LCRC) was established. Subjects with OI were enrolled in a longitudinal study, and in this report, we present cross-sectional data on the largest cohort of OI subjects (n = 544). OI type III subjects had higher prevalence of dentinogenesis imperfecta, severe scoliosis, and long bone deformities as compared to those with OI types I and IV. Whereas the mean lumbar spine area bone mineral density (LS aBMD) was low across all OI subtypes, those with more severe forms had lower bone mass. Molecular testing may help predict the subtype in type I collagen-related OI. Analysis of such well-collected and unbiased data in OI can not only help answering questions that are relevant to patient care but also foster hypothesis-driven research, especially in the context of 'phenotypic expansion' driven by next-generation sequencing.

Compressions during defibrillator charging shortens shock pause duration and improves chest compression fraction during shockable out of hospital cardiac arrest.

BACKGROUND: Previous studies have demonstrated significant relationships between shock pause duration and survival to hospital discharge from shockable out-of hospital (OHCA) cardiac arrest. Compressions during defibrillator charging (CDC) has been proposed as a technique to shorten shock pause duration. OBJECTIVE: We sought to determine the impact of CDC on shock pause duration and CPR quality measures in shockable OHCA. METHODS: We performed a retrospective review of all treated adult OHCA occurring over a 1 year period beginning August 1, 2011 after training EMS agencies in CDC. We included OHCA patients with an initial shockable rhythm, available CPR process data and shock pause data for up to the first three shocks of the resuscitation. CDC by EMS personnel was confirmed by review of impedance channel measures. We evaluated the relationship between CDC and shock pause duration as the primary outcome measure. Secondary outcome measures investigated the association between CDC and CPR quality measures. RESULTS: Among 747 treated OHCA 149 (23.4%) presented in a shockable rhythm of which 129 (81.6%) met study inclusion criteria. Seventy (54.2%) received CDC. There was no significant difference between the CDC and no CDC group with respect to Utstein variables. Median pre-shock pause (15.0 vs. 3.5s; Δ 11.5; 95% CI: 6.81, 16.19), post-shock pause (4.0 vs. 3.0s; Δ 1.0; 95% CI: -2.57, 4.57), and peri-shock pause (21.0 vs. 9.0s; Δ 12.0; 95% CI: 5.03, 18.97) were all lower for those who received CDC. Mean chest compression fraction was significantly greater (0.77 vs. 0.70, Δ 0.07; 95% CI: 0.03, 0.11) with CDC. No significant difference was noted in compression rate or depth with CDC. Clinical outcomes did not differ between the two approaches (return of spontaneous circulation 62.7% vs. 62.9% p=0.98, survival 25.4% vs. 27.1% p=0.82), although the study was not powered to detect clinical outcome differences. CONCLUSIONS: Compressions during defibrillator charging may shorten shock pause duration and improves chest compression fraction in shockable OHCA. Given the impact on shock pause duration, further study with a larger sample size is required to determine the impact of this technique on clinical outcomes from shockable OHCA.

Successful endovascular repair of acute type B aortic dissection in undiagnosed Ehlers-Danlos syndrome type IV.

A 61-year-old man presented with an acute type B aortic dissection for which a stent-graft was introduced. He remains complication-free 4 years onwards and has since been diagnosed with Ehlers-Danlos syndrome type IV (EDS IV). His particular mutation is predicted to result in lesser levels of normal collagen and may explain his favourable outcome from endovascular intervention. Understanding the genotype-phenotype correlation may influence the choice of therapy offered to patients with EDS IV.

Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations.

BACKGROUND: Mutations in the transforming growth factor beta receptor type I and II genes (TGFBR1 and TGFBR2) cause Loeys-Dietz syndrome (LDS), characterised by thoracic aortic aneurysms and dissections (TAAD), aneurysms and dissections of other arteries, craniosynostosis, cleft palate/bifid uvula, hypertelorism, congenital heart defects, arterial tortuosity, and mental retardation. TGFBR2 mutations can also cause TAAD in the absence of features of LDS in large multigenerational families, yet only sporadic LDS cases or parent-child pairs with TGFBR1 mutations have been reported to date. METHODS: The authors identified TGFBR1 missense mutations in multigenerational families with TAAD by DNA sequencing. Clinical features of affected individuals were assessed and compared with clinical features of previously described TGFBR2 families. RESULTS: Statistical analyses of the clinical features of the TGFBR1 cohort (n = 30) were compared with clinical features of TGFBR2 cohort (n = 77). Significant differences were identified in clinical presentation and survival based on gender in TGFBR1 families but not in TGFBR2 families. In families with TGFBR1 mutations, men died younger than women based on Kaplan-Meier survival curves. In addition, men presented with TAAD and women often presented with dissections and aneurysms of arteries other than the ascending thoracic aorta. The data also suggest that individuals with TGFBR2 mutations are more likely to dissect at aortic diameters <5.0 cm than individuals with TGFBR1 mutations. CONCLUSION: This study is the first to demonstrate clinical differences between patients with TGFBR1 and TGFBR2 mutations. These differences are important for the clinical management and outcome of vascular diseases in these patients.

The bicuspid aortic valve: an integrated phenotypic classification of leaflet morphology and aortic root shape.

OBJECTIVE: To establish a classification of bicuspid aortic valve (BAV) that includes both leaflet morphology and aortic shape. SETTING: Two academic medical centres of the University of Washington, Seattle. PATIENTS: 191 adult patients with BAV. INTERVENTIONS: Review of clinical data and transthoracic echocardiograms. MAIN OUTCOME MEASURES: Assessment of leaflet morphology; valve function; aortic shape and dimensions. RESULTS: We identified three morphologies: type 1, fusion of right and left coronary cusp (n = 152); type 2, right and non-coronary fusion (n = 39); and type 3, left and non-coronary fusion (n = 1). Comparing type 1 and 2 BAV, there were no significant differences in age, height, weight, blood pressure or aortic valve function. Type 1 was more common in men (69 vs 45%). The aortic sinuses were larger in type 1, while type 2 had larger arch dimensions. Myxomatous mitral valves were more common in type 2 BAV (13% vs 2.6%, p<0.05). Three aortic shapes were defined: normal (N), sinus effacement (E), and ascending dilatation (A). Comparing type 1 to type 2 BAV, shape N was more common in type 1 (60% vs 32%), and type A was more common in type 2 (35% vs 54%,); type E was rare (p<0.01 across all groups). CONCLUSION: A comprehensive BAV phenotype includes aortic shape. Type 1 BAV is associated with male gender and normal aortic shape but a larger sinus diameter. Type 2 leaflet morphology is associated with ascending aorta dilatation , larger arch dimensions and higher prevalence of myxomatous mitral valve disease.

Endoscopic retrograde cholangiopancreatography and gastroduodenoscopy after Roux-en-Y gastric bypass.

BACKGROUND: The use of Roux-en-Y gastric bypass (RYGB) for morbid obesity has raised concern that subsequent endoscopic evaluation of the gastric remnant and duodenum is difficult. By gaining percutaneous access to the gastric remnant, however, both gastroduodenoscopy and endoscopic retrograde cholangiopancreatography (ERCP) can be performed easily. This report describes the results of a novel technique for performing "transgastrostomy" gastroduodenoscopy and ERCP. METHODS: Six patients with a RYGB for morbid obesity underwent transgastric remnant endoscopic evaluations. If a gastric remnant tube had not been placed during prior surgery, one was placed percutaneously by an interventional radiologist. The tube tract then was dilated to either 20- or 24-Fr. At the time of endoscopy, the gastrostomy tube was removed and the skin anesthetized. Then either a pediatric duodenoscope (outer diameter, 7.5 mm) or a slim gastroscope (outer diameter, 5.9 mm) was inserted through the gastrostomy tube tract. RESULTS: Percutaneous gastroduodenoscopy was successfully performed for all six patients. The findings included two patients with prepyloric ulcers identified and assessed with a biopsy, one patient with intestinal metaplasia and a benign gastric polyp, and three patients with a normal gastric remnant and duodenum. A nonstrictured enteroenterostomy was noted in one of the three patients with a normal endoscopic evaluation. Percutaneous transgastrostomy ERCP was performed for three of the six patients who underwent gastroduodenoscopy. The findings included one patient who had papillary fibrosis treated with a sphincterotomy, a second patient with a normal biliary tree, and a third patient with a normal pancreatic duct. Selective cannulation of the common bile duct was not successful in the third patient. CONCLUSION: The transgastrostomy endoscopic route ensures access to the excluded stomach and proximal small bowel after RYGB. This route is safe and effective, allowing the use of a duodenoscope to improve the cannulation success rate for ERCPs in this patient population.

Cell columns in articular cartilage physes questioned: a review.

OBJECTIVE: To report the outcome of a search of the literature for evidence in support of the published [Brown RA, Blunn GW, Salisbury JR, Byers PD. Two patterns of calcification in primary (physeal) and secondary (epiphyseal) growth cartilage. Clin Orthop1993;294:318-24] observation that there are differences in the cellular organisation and ossification between the articular growth cartilage and the metaphyseal physis, i.e., dual patterns of ossification. METHOD: The search of the journal literature was by Medline. Many references came from found articles, and from textbooks. The source texts were at the libraries of the Royal Society of Medicine, The Wellcome Trust and the British Library. RESULTS: (1) The search produced nine authors whose observations make up the bulk of the paper, which support the dual pattern of physes. (2) But there were also articles in favour of the single pattern of cellular organisation and ossification, in which, nevertheless, there were illustrations which were inconsistent with this, and favoured the duality. (3) The third section of the results mainly concerns the role of osteoclasts in the ossification process in articular physes. They are generally regarded as insufficient in number to play a solo part. Quantitative data about osteoclasts are limited; mathematical modelling is proposed as a more objective test. CONCLUSION: Objective, assessable criteria are presented in favour of a modification in our understanding of articular cartilage, and could, and should be augmented by further testing of the hypothesis. Some lines of enquiry are suggested.

Neurological presentation of Ehlers-Danlos syndrome type IV in a family with parental mosaicism.

Ehlers-Danlos syndrome type IV (EDS-IV) is an autosomal-dominant disorder caused by a defect of type III collagen which leads to ruptures of arteries and hollow organs. Neurological presentation with muscle involvement and flexion contractures of the finger joints is uncommon. We clinically characterized seven members of a family with EDS-IV. The index patient, a young woman with an acrogeric face, suffered chronic muscle pain and cramps, Achilles tendon retraction, finger flexion contractures and seizures. The mother had similar features and had experienced an ischemic stroke. Biochemical study in cultured fibroblasts and molecular analysis of the COL3A1 gene led to the diagnosis of EDS-IV. A glycine substitution, p.G883V, within the triple helix of the alpha 1(III) chain, was found in the index patient and in the mother. The maternal grandfather and an aunt each had an abdominal aortic aneurysm, the rupture of which was the cause of death in the latter, at 40 years of age. Surprisingly, we found the mutation, as a mosaic, in the asymptomatic maternal grandmother. This expands the clinical spectrum of EDS type IV and confirms that in some families mosaicism can be identified as the source of the mutation.

Testing for osteogenesis imperfecta in cases of suspected non-accidental injury.

To evaluate if laboratory testing for osteogenesis imperfecta (OI) identifies children unrecognised by clinical examination in instances where non-accidental injury (NAI) is suspected as the likely cause of fracture, we carried out a retrospective review of available medical records and biochemical test results from 262 patients. Cultured fibroblasts were received for biochemical testing for OI from children in whom the diagnosis of NAI was suspected. Eleven of the samples had alterations in the amount or structure of type I collagen synthesised, consistent with the diagnosis of OI, and in 11 others we could not exclude OI. Referring physicians correctly identified children with OI in six of the 11 instances established by biochemical studies, did not identify OI by clinical examination in three, and there was inadequate clinical information to know in two others. Biochemical testing was inconclusive in 11 infants in whom the diagnosis of OI could not be excluded, none of whom were thought to be affected by the referring clinicians. Four children believed to have OI by clinical examination had normal biochemical studies, a false positive clinical diagnosis attributed, in large part, to the use of scleral hue (a feature that is age dependent) as a major diagnostic criterion. Given the inability to identify all children with OI by clinical examination in situations of suspected NAI, laboratory testing for OI (and other genetic predispositions for fractures) is a valuable adjunct in discerning the basis for fractures and may identify a small group of children with previously undiagnosed OI.

A single amino acid substitution (D1441Y) in the carboxyl-terminal propeptide of the proalpha1(I) chain of type I collagen results in a lethal variant of osteogenesis imperfecta with features of dense bone diseases.

Osteogenesis imperfecta (OI) is characterised by brittle bones and caused by mutations in the type I collagen genes, COL1A1 and COL1A2. We identified a mutation in the carboxyl-terminal propeptide coding region of one COL1A1 allele in an infant who died with an OI phenotype that differed from the usual lethal form and had regions of increased bone density. The newborn female had dysmorphic facial features, including loss of mandibular angle. Bilateral upper and lower limb contractures were present with multiple fractures in the long bones and ribs. The long bones were not compressed and their ends were radiographically dense. She died after a few hours and histopathological studies identified extramedullary haematopoiesis in the liver, little lamellar bone formation, decreased osteoclasts, abnormally thickened bony trabeculae with retained cartilage in long bones, and diminished marrow spaces similar to those seen in dense bone diseases such as osteopetrosis and pycnodysostosis. The child was heterozygous for a COL1A1 4321G-->T transversion in exon 52 that changed a conserved aspartic acid to tyrosine (D1441Y). Abnormal proalpha1(I) chains were slow to assemble into dimers and trimers, and abnormal molecules were retained intracellularly for an extended period. The secreted type I procollagen molecules synthesised by cultured dermal fibroblasts were overmodified along the full length but had normal thermal stability. These findings suggest that the unusual phenotype reflected both a diminished amount of secreted type I procollagen and the presence of a population of stable and overmodified molecules that might support increased mineralisation or interfere with degradation of bone.

Deletions and duplications of Gly-Xaa-Yaa triplet repeats in the triple helical domains of type I collagen chains disrupt helix formation and result in several types of osteogenesis imperfecta.

Triple helix formation is a prerequisite for the passage of type I procollagen from the endoplasmic reticulum and secretion from the cell to form extracellular fibrils that will support mineral deposition in bone. Analysis of cDNA from 11 unrelated individuals with osteogenesis imperfecta (OI) revealed the presence of 11 novel, short in-frame deletions or duplications of three, nine, or 18 nucleotides in the helical coding regions of the COL1A1 and COL1A2 collagen genes. Triple helix formation was impaired, type I collagen alpha chains were post-translationally overmodified, and extracellular secretion was markedly reduced. With one exception, the obligate Gly-Xaa-Yaa repeat pattern of amino acids in the helical domains was not altered, but the Xaa- and Yaa position residues were out of register relative to the amino acid sequences of adjacent chains in the triple helix. Thus, the identity of these amino acids, in addition to third position glycines, is important for normal helix formation. These findings expand the known repertoire of uncommon in-frame deletions and duplications in OI, and provide insight into normal collagen biosynthesis and collagen triple helix formation.

Evaluating blunt abdominal trauma with sonography: a cost analysis.

Ultrasonography (US) is becoming increasingly utilized in the United States for the evaluation of blunt abdominal trauma (BAT). The objective of this study was to assess the cost impact of utilizing US in the evaluation of patients with BAT in a major trauma center. All patients sustaining BAT during a 6-month period before US was used at our institution (Jan-Jun 1993) were compared to BAT patients from a recent period in which US has been utilized (Jan-Jun 1995). The numbers of US, computed tomography (CT), and diagnostic peritoneal lavage (DPL) were tabulated for each group. Financial cost for each of these procedures as determined by our finance department were as follows: US $96, CT $494, DPL $137. These numbers are representative of actual hospital expenditures exclusive of physician fees as calculated in 1994 U.S. dollars. Cost analysis was performed with t test and chi squared test, and significance was defined as P < 0.05. There were 890 BAT admissions in the 1993 study period and 1033 admissions in the 1995 study period. During the 1993 period, 642 procedures were performed on the 890 patients to evaluate the abdomen: 0 US, 466 CT, and 176 DPL (see table) [table: see text]. This compares to 801 procedures on the 1,033 patients in 1995: 552 US, 228 CT, and 21 DPL. Total cost was $254,316 for the 1993 group and $168,501 for the 1995 group. Extrapolated to a 1-year period, a significant (P < 0.05) cost savings of $171,630 would be realized. Cost per patient evaluated was significantly reduced from $285.75 in 1993 to $163.12 in 1995 (P < 0.05). This represents a 43 per cent reduction in per patient expenditure for evaluating the abdomen. By effectively utilizing ultrasonography in the evaluation of patients with blunt abdominal trauma, a significant cost savings can be realized. This effect results chiefly from an eight-fold reduction in the use of DPL, and a two-fold reduction in the use of CT.