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Acute kidney injury (AKI) frequently complicates cardiac surgery and is more common among Black patients. We evaluated determinants of race-based differences in AKI rates.Serum creatinine-based criteria were used to identify adult cardiac surgical patients having postoperative AKI in the Perfusion Measures and Outcomes (PERForm) Registry (July 1, 2014, to June 30, 2019). Patient characteristics, operative details, and outcomes were compared by race (Black vs White) after excluding patients with preoperative dialysis, missing preoperative or postoperative creatinine, or other races. A mixed effects model (adjusting for demographics, comorbidities, surgical factors) used hospital as a random effect to predict postoperative stage 2 or 3 AKI. Propensity score analyses were conducted to evaluate robustness of the primary analyses.The study cohort included 34 520 patients (8% Black). More Black patients than White patients were female (43% vs 27%, P.001), and had hypertension (93% vs 87%, P.001) and diabetes mellitus (51% vs 41%, P.001). Acute kidney injury of stage 2 or greater occurred in 1697 patients (5%), more often among Black than White patients (8% vs 5%, P.001). Intraoperatively, Black patients had lower nadir hematocrits (23 vs 26, P.001), and were more likely to be given transfusions (22% vs 14%, P.001). After adjustment, Black race (compared with White) independently predicted odds for postoperative AKI (adjusted odds ratio 1.50; 95% confidence interval, 1.26 to 1.78). The multivariable findings were similar in propensity score analyses.Despite accounting for differences in risk factors and intraoperative practices, Black patients had a 50% increased odds for having moderate-severe postoperative AKI compared with White patients. Additional evaluations are warranted to identify potential targets to address racial disparities in AKI outcomes.

Few data are available to describe the changes in incidence of pediatric-onset inflammatory bowel disease (IBD). The aim of this study was to describe changes in incidence and phenotypic presentation of pediatric-onset IBD in northern France during a 24-year period.Pediatric-onset IBD (17 years) was issued from a population-based IBD study in France between 1988 and 2011. Age groups and digestive location were defined according to the Paris classification.1,350 incident cases were recorded (8.3% of all IBD) including 990 Crohn's disease (CD), 326 ulcerative colitis (UC) and 34 IBD unclassified (IBDU). Median age at diagnosis was similar in CD (14.4 years (Q1=11.8-Q3=16.0)) and UC (14.0 years (11.0-16.0)) and did not change over time. There were significantly more males with CD (females/males=0.82) than UC (females/males=1.25) (P=0.0042). Median time between onset of symptoms and IBD diagnosis was consistently 3 months (1-6). Mean incidence was 4.4/10In this population-based study, CD and UC incidences increased dramatically in adolescents across a 24-year span, suggesting that one or more strong environmental factors may predispose this population to IBD.

Background The National Health Service in England advises hospitals collect data on hospital-onset diarrhoea (HOD). Contemporaneous data on HOD are lacking. Aim To investigate prevalence, aetiology and management of HOD on medical, surgical and elderly-care wards. Methods A cross-sectional study in a volunteer sample of UK hospitals, which collected data on one winter and one summer day in 2016. Patients admitted ≥72 h were screened for HOD (definition: ≥2 episodes of Bristol Stool Type 5–7 the day before the study, with diarrhoea onset >48 h after admission). Data on HOD aetiology and management were collected prospectively. Findings Data were collected on 141 wards in 32 hospitals (16 acute, 16 teaching). Point-prevalence of HOD was 4.5% (230/5142 patients; 95% confidence interval (CI) 3.9–5.0%). Teaching hospital HOD prevalence (5.9%, 95% CI 5.1–6.9%) was twice that of acute hospitals (2.8%, 95% CI 2.1–3.5%; odds ratio 2.2, 95% CI 1.7–3.0). At least one potential cause was identified in 222/230 patients (97%): 107 (47%) had a relevant underlying condition, 125 (54%) were taking antimicrobials, and 195 (85%) other medication known to cause diarrhoea. Nine of 75 tested patients were Clostridium difficile toxin positive (4%). Eighty (35%) patients had a documented medical assessment of diarrhoea. Documentation of HOD in medical notes correlated with testing for C. difficile (78% of those tested vs 38% not tested, P Conclusion HOD is a prevalent symptom affecting thousands of patients across the UK health system each day. Most patients had multiple potential causes of HOD, mainly iatrogenic, but only a third had medical assessment. Most were not tested for C. difficile and were not isolated.

Sorrell AD, Lee S, Stolle C, Ellenhorn J, Grix A, Kaelin Jr WG, Weitzel JN. Clinical and functional properties of novel VHL mutation (X214L) consistent with Type 2A phenotype and low risk of renal cell carcinoma. This report describes clinical characteristics in families with a Type 2A phenotype and functional properties of a novel von Hippel Lindau variant (X214L). Pedigrees were analyzed. Analysis of von Hippel Lindau (VHL) coding exons and flanking intronic sequences in DNA from a proband with pheochromocytoma and islet cell tumor was performed. Western blot assays for VHL protein (pVHL), HIFα, and Jun B were conducted using VHL null renal clear carcinoma cell lines that were engineered to produce wild-type or X214L mutant pVHL. Pedigree analysis indicated that the variant tracked with disease and the same or similar VHL point mutations were identified in several Type 2A families. The predicted 14 amino acid extended pVHL variant, when reintroduced into VHL null cells, was stable and retained the ability to downregulate HIFα in a hydroxylation-dependent manner. In contrast, the variant was defective with respect to downregulation of JunB. pVHL X214L, like other pVHL variants associated with a low risk of clear cell renal carcinoma, largely preserves the ability to downregulate HIF. In contrast, this variant, like other pVHL variants linked to Type 2A disease, fails to suppress JunB. This underscores that JunB may play a role in the pathogenesis of Type 2A VHL disease.

Blepharophimosis syndrome (BPES) is caused by loss-of-function mutations in the single-exon forkhead transcription factor gene FOXL2 and by genomic rearrangements of the FOXL2 locus. Here, we focus on 92 new intragenic FOXL2 mutations, 34 of which are novel. Specifically, we found 10 nonsense mutations (11%), 13 missense mutations (14%), 40 deletions or insertions leading to a frameshift (43%), and 29 in-frame changes (32%), of which 28 (30%) lead to a polyalanine expansion. This study confirms the existence of two previously described mutational hotspots. Moreover, we gained novel insights in genotype-phenotype correlations, emphasizing the need to interpret genotype-phenotype correlations individually and always in the context of further clinical observations. (C) 2008 Wiley-Liss, Inc

Frontometaphyseal dysplasia is an X-linked trait primarily characterized by a skeletal dysplasia comprising hyperostosis of the skull and modeling anomalies of the tubular bones. Extraskeletal features include tracheobronchial, cardiac, and urological malformations. A proportion of individuals have missense mutations or small deletions in the X-linked gene, FLNA. We report here our experience with comprehensive screening of the FLNA gene in a group of 23 unrelated probands (11 familial instances, 12 simplex cases; total affected individuals 32) with FMD. We found missense mutations leading to substitutions in the actin-binding domain and within filamin repeats 9, 10, 14, 16, 22, and 23 of filamin A in 13/23 (57%) of individuals in this cohort. Some mutations present with a male phenotype that is characterized by a severe skeletal dysplasia, cardiac, and genitourinary malformations that leads to perinatal death. Although no phenotypic feature consistently discriminates between females with FMD who are heterozygous for FLNA mutations and those in whom no FLNA mutation can be identified, there is a difference in the degree of skewing of X-inactivation between these two groups. This observation suggests that locus heterogeneity may exist for this disorder.

This study investigated psychosocial processes associated with avoidance of health- and morality-based deterrents to performance-enhancing drug (PED) use. In-depth semi-structured interviews were conducted with 64 English male bodybuilders with experience of doping. Resultant data were content analysed deductively using definitions for the eight mechanisms of moral disengagement (MD; Bandura, A. (1991). Social cognitive theory of moral thought and action. In W. M. KurtinesJ. L. Gewirtz (Eds.), Handbook of moral behavior and development: Theory research and applications (pp. 71-129). Hillsdale, NJ: Lawrence Erlbaum Associates.), and three further themes from Boardley and Grix (2013. Doping in bodybuilders: A qualitative investigation of facilitative psychosocial processes. Qualitative Research in Sport, Exercise, and Health. Advance online publication, doi 10.1080/2159676X.2013.766809). These analyses evidenced six MD mechanisms, and all three of the themes from Boardley and Grix (2013. Doping in bodybuilders: A qualitative investigation of facilitative psychosocial processes. Qualitative Research in Sport, Exercise, and Health. Advance online publication). Subsequent frequency analyses revealed six of the eight MD mechanisms, and two of the three additional themes, were common across the sample. Overall, the findings suggest MD may help athletes circumvent health- and morality-based deterrents to doping, describe a process linking supplement and PED use and detail how some athletes may actively avoid social censure for doping by only discussing PED use with other PED users from within their training environment.

Mammalian auditory hair cells are few in number, experimentally inaccessible, and do not proliferate postnatally or in vitro. Immortal cell lines with the potential to differentiate into auditory hair cells would substantially facilitate auditory research, drug development, and the isolation of critical molecules involved in hair cell biology. We have established two conditionally immortal cell lines that express at least five characteristic hair cell markers. These markers are the transcription factor Brn3.1, the alpha 9 subunit of the acetylcholine receptor, the stereociliary protein fimbrin and the myosins VI and VIIA. These hair cell precursors permit functional studies of cochlear genes and in the longer term they will provide the means to explore therapeutic methods of stimulating auditory hair cell regeneration.

This article adds to the growing body of knowledge in sport pedagogy and focuses specifically upon the intersection of gender and disability. Its purpose is twofold, to create a typology for examining good practice in sport pedagogy that is reflective and inclusive and raises awareness of the diverse needs of all participants in physical activity 'regardless' of gender and ability for all children. We acknowledge that access to physical activity, education and sport are complex and multifaceted, however, the main purpose of this paper is to raise awareness of 'diversity' by focusing specifically upon the role of gender and ability. Through an examination of gender and disability policies in official European Union (EU) policy documents and commercial examples of policy-in-practice we propose a typology for diversity and diversity management. A close look at EU level is instructive because national policies of the member countries vary a lot with respect to diversity issues but should be in accordance in the main areas. Such a reading enables the building of a typology of recommendations for how such policy can be rendered in sport pedagogy practice. We suggest six significant, but related principles that include (1) mainstreaming; (2) teaching and coaching sensitive to difference; (3) empowerment; (4) inclusion; (5) adaptation; and (6) inner differentiation. This holistic typology seeks to 'mainstream' issues of gender and disability policy by providing a set of principles that can be applied to a range of teaching and coaching settings. © 2013 European College of Sport Science.

Background Holoprosencephaly (HPE), the most common malformation of the human forebrain, may result from mutations in over 12 genes. Sonic Hedgehog (SHH) was the first such gene discovered; mutations in SHH remain the most common cause of nonchromosomal HPE. The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences. Objective To characterise genetic and clinical findings in individuals with SHH mutations. Methods Through the National Institutes of Health and collaborating centres, DNA from approximately 2000 individuals with HPE spectrum disorders were analysed for SHH variations. Clinical details were examined and combined with published cases. Results This study describes 396 individuals, representing 157 unrelated kindreds, with SHH mutations; 141 (36%) have not been previously reported. SHH mutations more commonly resulted in non-HPE (64%) than frank HPE (36%), and non-HPE was significantly more common in patients with SHH than in those with mutations in the other common HPE related genes (p

A range of prostanoid agonists were tested for activity on isolated ring preparations of piglet saphenous vein. The selective TxA2-mimetic (TP-receptor agonist), U-46619, contracted the preparation in a concentration-related fashion. These contractions were inhibited by the TP-receptor blocking drug, GR32191B, producing a pA2 of 7.8 (slope = 1.6). Prostanoid-induced relaxant responses were studied on preparations which had been pre-contracted using an EC60 concentration of phenylephrine (mean EC60 = 0.97 microM), in the presence of GR32191B (1 microM), to block contractile TP-receptors. Under these conditions, PGD2, PGE2, PGF2 alpha, PGI2, and U-46619, all caused concentration-related relaxation. PGE2 was the most potent agonist (EC50 = 0.23nM), whereas, all of the other agonists were at least 1,000-fold weaker, providing strong evidence for the presence of inhibitory EP-receptors. The selective synthetic EP-agonists, sulprostone (EP1/EP3) and AH13205X (EP2), were next tested for relaxant activity. While both compounds caused concentration-related relaxant activity, they were respectively 6,000 and 11,000-fold less potent than PGE2. The potent TP-receptor blocking drugs, AH22921X and AH23848B, were both weak antagonists of PGE2 but not isoproterenol-induced relaxant responses of piglet saphenous vein in a concentration-related fashion. These two compounds had pA2 values against PGE2 of 5.3 and 5.4 respectively, with regression slopes not significantly different from unity. In contrast, neither compound at a concentration of 30 microM had any antagonist activity against prostanoid-induced effects on guinea-pig fundus (EP1), rabbit ear artery (EP2) or guinea-pig vas deferens (EP3). In conclusion, the piglet saphenous vein contains TP-receptors mediating smooth muscle contraction, and a PGE2-specific (EP) receptor mediating relaxation. The inhibitory EP-receptor does not appear to be of the EP1, EP2 or EP3-subtypes, and appears therefore to be a novel subtype which we tentatively term EP4, and the potent TP-receptor blocking drugs, AH22921X and AH23848B, appear to be weak, but specific EP4-receptor blocking drugs.

We identified the presumably rare event of de novo mutation in an autosomal recessive disorder, glycogen storage disease type II (GSDII). GSDII results from inherited deficiency of acid alpha-glucosidase (acid maltase) and both the expressed and structural gene (designated GAA) have been isolated. The mutation was a deletion of 13 nt of coding sequence (delta nt 1456-1468) on the paternally derived allele of the proband. The delta nt 1456-1468 results in a reading frameshift and a premature termination signal upstream of the enzyme catalytic site. Paternity was confirmed by presence of two downstream, uncommon amino acid substitutions (E689K, W746C) in both proband and father and by comparison of nine short tandem repeats. The maternal allele carried a newly identified deleterious C647W missense mutation in a highly conserved area of the protein. The C647W mutation was also found in a second unrelated proband, heteroallelic with a deletion extending from IVS17 to IVS18.

Genetic mutations responsible for oblique facial clefts (ObFC), a unique class of facial malformations, are largely unknown. We show that loss-of-function mutations in SPECC1L are pathogenic for this human developmental disorder and that SPECC1L is a critical organizer of vertebrate facial morphogenesis. During murine embryogenesis, Specc1l is expressed in cell populations of the developing facial primordial, which proliferate and fuse to form the face. In zebrafish, knockdown of a SPECC1L homolog produces a faceless phenotype with loss of jaw and facial structures, and knockdown in Drosophila phenocopies mutants in the integrin signaling pathway that exhibit cell-migration and -adhesion defects. Furthermore, in mammalian cells, SPECC1L colocalizes with both tubulin and actin, and its deficiency results in defective actin-cytoskeleton reorganization, as well as abnormal cell adhesion and migration. Collectively, these data demonstrate that SPECC1L functions in actin-cytoskeleton reorganization and is required for proper facial morphogenesis.

We report on 7 patients (6 M, 1 F) with Coffin-Lowry syndrome who have a sensorineural hearing deficit in addition to developmental delay and characteristic facial changes. One of the patients also had a history of premature exfoliation of primary teeth. These are previously unappreciated clinical signs that may aid in the early diagnosis of Coffin-Lowry syndrome. Early diagnosis and recognition of a hearing deficit in the patient can lead to the use of hearing aids to help the patient achieve his or her full potential. These "new" clinical manifestations expand the phenotype of Coffin-Lowry syndrome and constitute an additional indication of pleiotropy.

Two 2-year-old males underwent muscle biopsy that established the histopathologic diagnosis of Becker dystrophy in one, and Duchenne dystrophy in the other. Concomitant contracture testing with caffeine or halothane was normal for malignant hyperthermia (MH). The results suggest that acute hypermetabolism or acute rhabdomyolysis during anesthesia, in patients with these disorders, is related to the X-linked myopathy and its associated muscle deterioration, rather than to the autosomal dominant MH.

Autosomal recessive cutis laxa (ARCL) describes a group of syndromal disorders that are often associated with a progeroid appearance, lax and wrinkled skin, osteopenia and mental retardation(1-3). Homozygosity mapping in several kindreds with ARCL identified a candidate region on chromosome 17q25. By high- throughput sequencing of the entire candidate region, we detected disease-causing mutations in the gene PYCR1. We found that the gene product, an enzyme involved in proline metabolism, localizes to mitochondria. Altered mitochondrial morphology, membrane potential and increased apoptosis rate upon oxidative stress were evident in fibroblasts from affected individuals. Knockdown of the orthologous genes in Xenopus and zebrafish led to epidermal hypoplasia and blistering that was accompanied by a massive increase of apoptosis. Our findings link mutations in PYCR1 to altered mitochondrial function and progeroid changes in connective tissues

The purpose for presenting these cases is to report on clinical observations that may have relevance for improvement in individuals responding minimally to their environment as a result of a severe traumatic brain injury. Specifically, the authors observe that there is a sub-group of minimally responsive patients who, when given sensory stimulation, show an increase in responding that is being under-reported with current assessment instruments. Further, subtle changes in responding can occur over a wide temporal gradient and under-reporting of said changes may result in the premature cessation of a beneficial therapeutic intervention. Advantages and disadvantages of the instruments that have been developed to specifically assess responses to sensory stimulation are discussed. The authors' observations suggest that clinical findings do not correlate with assessment scores. These provisory observations indicate that there is a need to develop methodologically sound tools that will accurately monitor individuals throughout the rehabilitative process.

We report the first frame-shift truncation mutation in a mitochondrial DNA (mtDNA)-encoded subunit II of cytochrome c oxidase (COXII). The mutation was identified by temporal temperature gradient gel electrophoresis (TTGE) followed by direct DNA sequencing in an infant who died at 12 days of age following a course of apnea, bradycardia, and severe lactic acidosis. The patient had a twin brother who died at two days of age of similar course. The mutation, 8042delAT, produced a truncated protein that was 72 amino acids shorter than the wild type protein. The mutant protein, missing one third of the amino acid residues at the C-terminal essential for hydrophilic interaction with cytochrome c, ligand binding to CuA and Mg, and the formation of proton and water channels, apparently has devastating effects on mitochondrial respiratory function.

We screened 120 children with sporadic multiple congenital anomalies and either growth or mental retardation for uniparental disomy (UPD) or subtelomeric deletions. The screening used short tandem repeat polymorphisms (STRP) from the subtelomeric regions of 41 chromosome arms. Uninformative marker results were reanalyzed by using the next available marker on that chromosome arm. In total, approximately 25,000 genotypes were generated and analyzed for this study. Subtelomeric deletions of 1 Mb in size were excluded for 27 of 40 chromosome arms. Among the 120 subjects none was found to have UPD, but five subjects (4%, 95% confidence interval 1-9%) were found to have a deletion or duplication of one or more chromosome arms. We conclude that UPD is not a frequent cause of undiagnosed multiple congenital anomaly syndrome. In addition, we determined that 9p and 7q harbor chromosome length variations in the normal population. We conclude that subtelomeric marker analysis is effective for the detection of subtelomeric duplications and deletions, although it is labor intensive. Given a detection rate that is similar to prior studies and the large workload imposed by STRPs, we conclude that STRPs are an effective, but impractical, approach to the determination of segmental aneusomy given current technology.

X-linked ocular albinism (OA1), Nettleship-Falls type, is characterized by decreased ocular pigmentation, foveal hypoplasia, nystagmus, photodysphoria, and reduced visual acuity. Affected males usually demonstrate melanin macroglobules on skin biopsy. We now report results of deletion and mutation screening of the full-length OA1 gene in 29 unrelated North American and Australian X-linked ocular albinism (OA) probands, including five with additional, nonocular phenotypic abnormalities (Schnur et al. 1994). We detected 13 intragenic gene deletions, including 3 of exon 1, 2 of exon 2, 2 of exon 4, and 6 others, which span exons 2-8. Eight new missense mutations were identified, which cluster within exons 1, 2, 3, and 6 in conserved and/or putative transmembrane domains of the protein. There was also a splice acceptor-site mutation, a nonsense mutation, a single base deletion, and a previously reported 17-bp exon 1 deletion. All patients with nonocular phenotypic abnormalities had detectable mutations. In summary, 26 (approximately 90%) of 29 probands had detectable alterations of OA1, thus confirming that OA1 is the major locus for X-linked OA.

We report on two families with autosomal dominant brachydactyly of hands and feet and hypertension. All affected members of the first family had proportionate short stature. However, the propositus and the affected relatives in the second family were only short compared to unaffected relatives. The hypertension was medically responsive in all cases. The propositus in the second family had poor compliance and a striking generalized vasculopathy. All patients were of normal intelligence and had a normal facial appearance. The brachydactyly-short stature-hypertension syndrome was first reported by Bilginturan et al. [1973] in a Turkish family and the families reported by us are Caucasian and Hispanic. The gene causing this condition in the original Turkish family was recently mapped to 12p. Our report expands our existing knowledge and the ethnic diversity of this syndrome.

One hundred nineteen individuals from 11 families with X-linked ocular albinism (OA1) were studied with respect to both their clinical phenotypes and their linkage genotypes. In a four-generation Australian family, two affected males and an obligatory carrier lacked cutaneous melanin macroglobules (MMGs); ocular features were identical to those of Nettleship-Falls OA1. Four other families had more unusual phenotypic features in addition to OA1. All OA1 families were genotyped at DXS16, DXS85, DXS143, STS, and DXS452 and for a CA-repeat polymorphism at the Kallmann syndrome locus (KAL). Separate two-point linkage analyses were performed for the following: group A, six families with biopsy-proved MMGs in at least one affected male; group B, four families whose biopsy status was not known; and group C, OA-9 only (16 samples), the family without MMGs. At the set of loci closest to OA1, there is no clear evidence in our data set for locus heterogeneity between groups A and C or among the four other families with complex phenotypes. Combined multipoint analysis (LINKMAP) in the 11 families and analysis of individual recombination events confirms that the major locus for OA1 resides within the DXS85-DXS143 interval. We suggest that more detailed clinical evaluations of OA1 individuals and families should be performed for future correlation with specific mutations in candidate OA1 genes.

A male patient with a de novo proximal interstitial deletion of the short arm of chromosome 1 (46XY), del(1)(p13p22.3) is described with multiple anomalies and developmental delay. This patient's clinical manifestations are compared to previously reported patients with deletions of chromosome 1p.© 1992 Wiley-Liss, Inc.

An 11-year-old boy had dyskeratosis congenita, elevated fetal hemoglobin level, X-linked ocular albinism, and juvenile-onset diabetes mellitus. A review of the international literature revealed that elevated fetal hemoglobin has been noted in 15 reported cases of dyskeratosis congenita. It is a previously unrecognized, commonly associated finding in dyskeratosis congenita that may provide insight into the location and function of the gene for dyskeratosis congenita.

Four subjects with thermolabile methylenetetrahydrofolate reductase (MTHFR) were discovered among 16 "obligate" heterozygotes for severe MTHFR deficiency and their family members. All four subjects had less than 25% of normal mean MTHFR specific activity in lymphocyte extracts. Three of them with normal serum folate and cyanocobalamin had intermediate hyperhomocysteinemia, and one with high serum folate and cyanocobalamin had no excessive accumulation of serum homocysteine. The biochemical features in these four subjects are distinguishable from subjects homozygous for the thermolabile MTHFR, whose specific activity is approximately 50% of the normal mean, and from heterozygotes for severe MTHFR deficiency, in whom the enzyme is thermostable and has a specific activity of about 50% of the normal mean. We propose that these four subjects are genetic compounds of the allele for the severe mutation and the allele for thermolabile mutation of the MTHFR gene. It is postulated that subjects with this genetic compound are more susceptible to the development of intermediate hyperhomocysteinemia despite normal folate and B12 levels. Nonetheless, hyperhomocysteinemia due to this compound heterozygosity is correctable by oral folic acid therapy.

Walker-Warburg syndrome (WWS) is an autosomal recessive disorder manifest by characteristic brain and eye malformations. We reviewed data on 21 of our patients and an additional 42 patients from the literature. From this review, we expand the phenotype to include congenital muscular dystrophy (CMD) and cleft lip and/or palate (CLP), and revise the diagnostic criteria. Four abnormalities were present in all patients checked for these anomalies: type II lissencephaly (21/21), cerebellar malformation (20/20), retinal malformation (18/18), and CMD (14/14). We propose that these comprise necessary and sufficient diagnostic criteria for WWS. Two other frequently observed abnormalities, ventricular dilatation with or without hydrocephalus (20/21) and anterior chamber malformation (16/21), are helpful but not necessary diagnostic criteria because they were not constant. All other abnormalities occurred less frequently. Congenital macrocephaly with hydrocephalus (11/19) was more common than congenital microcephaly (3/19). Dandy-Walker malformation (10/19) was sometimes associated with posterior cephalocele (5/21). Additional abnormalities included slit-like ventricles (1/21), microphthalmia (8/21), ocular colobomas (3/15), congenital cataracts (7/20), genital anomalies in males (5/8), and CLP (4/21). Median survival in our series was 9 months. A related autosomal recessive disorder, Fukuyama congenital muscular dystrophy, consists of similar but less severe brain changes and CMD. It differs from WWS because of consistently less frequent and severe cerebellar and retinal abnormalities. We think that WWS is identical to "cerebro-oculo-muscular syndrome" and "muscle, eye, and brain disease."

Retinoic acid, an analogue of vitamin A, is known to be teratogenic in laboratory animals and has recently been implicated in a few clinical case reports. To study the human teratogenicity of this agent, we investigated 154 human pregnancies with fetal exposure to isotretinoin, a retinoid prescribed for severe recalcitrant cystic acne. The outcomes were 95 elective abortions, 26 infants without major malformations, 12 spontaneous abortions, and 21 malformed infants. A subset of 36 of the 154 pregnancies was observed prospectively. The outcomes in this cohort were 8 spontaneous abortions, 23 normal infants, and 5 malformed infants. Exposure to isotretinoin was associated with an unusually high relative risk for a group of selected major malformations (relative risk = 25.6; 95 per cent confidence interval, 11.4 to 57.5). Among the 21 malformed infants we found a characteristic pattern of malformation involving craniofacial, cardiac, thymic, and central nervous system structures. The malformations included microtia/anotia (15 infants), micrognathia (6), cleft palate (3), conotruncal heart defects and aortic-arch abnormalities (8), thymic defects (7), retinal or optic-nerve abnormalities (4), and central nervous system malformations (18). The pattern of malformation closely resembled that produced in animal studies of retinoid teratogenesis. It is possible that a major mechanism of isotretinoin teratogenesis is a deleterious effect on cephalic neural-crest cell activity that results in the observed craniofacial, cardiac, and thymic malformations.

Summary Thirty-two unrelated patients with features of Saethre-Chotzen syndrome, a common autosomal dominant condition of craniosynostosis and limb anomalies, were screened for mutations in TWIST,FGFR2, and FGFR3. Nine novel and three recurrent TWIST mutations were found in 12 families. Seven families were found to have the FGFR3 P250R mutation, and one individual was found to have an FGFR2 VV269–270 deletion. To date, our detection rate for TWIST or FGFR mutations is 68% in our Saethre-Chotzen syndrome patients, including our five patients elsewhere reported with TWIST mutations. More than 35 different TWIST mutations are now known in the literature. The most common phenotypic features, present in more than a third of our patients with TWIST mutations, are coronal synostosis, brachycephaly, low frontal hairline, facial asymmetry, ptosis, hypertelorism, broad great toes, and clinodactyly. Significant intra- and interfamilial phenotypic variability is present for either TWIST mutations or FGFR mutations. The overlap in clinical features and the presence, in the same genes, of mutations for more than one craniosynostotic condition—such as Saethre-Chotzen, Crouzon, and Pfeiffer syndromes—support the hypothesis that TWIST and FGFR s are components of the same molecular pathway involved in the modulation of craniofacial and limb development in humans.

Polymicrogyria (PMG) is one of a large group of human cortical malformations that collectively account for a significant percentage of patients with epilepsy, congenital neurological deficits, and intellectual disability. PMG is characterized by an excess of small gyri and abnormal cortical lamination. The most common distribution is bilateral, symmetrical, and maximal, in the region surrounding the sylvian fissures, and is known as "bilateral perisylvian polymicrogyria" (BPP). Most cases are sporadic, although several families have been observed with multiple affected members, usually following an X-linked inheritance pattern. Here we report the first genetic locus for BPP mapped by linkage analysis in five families. Linkage places the critical region for BPP at Xq28 (LOD score 3.08 in Xq28, distal to DXS8103 by multipoint analysis). We suggest that this region contains a gene that is necessary for correct neuronal organization and that the identification of this gene will both enhance our understanding of normal cortical development and accelerate the identification of other genes responsible for PMG.

Mandibulofacial dysostosis with microcephaly (MFDM) is a rare sporadic syndrome comprising craniofacial malformations, microcephaly, developmental delay, and a recognizable dysmorphic appearance. Major sequelae, including choanal atresia, sensorineural hearing loss, and cleft palate, each occur in a significant proportion of affected individuals. We present detailed clinical findings in 12 unrelated individuals with MFDM; these 12 individuals compose the largest reported cohort to date. To define the etiology of MFDM, we employed whole-exome sequencing of four unrelated affected individuals and identified heterozygous mutations or deletions of EFTUD2 in all four. Validation studies of eight additional individuals with MFDM demonstrated causative EFTUD2 mutations in all affected individuals tested. A range of EFTUD2-mutation types, including null alleles and frameshifts, is seen in MFDM, consistent with haploinsufficiency; segregation is de novo in all cases assessed to date. U5-116kD, the protein encoded by EFTUD2, is a highly conserved spliceosomal GTPase with a central regulatory role in catalytic splicing and post-splicing-complex disassembly. MFDM is the first multiple-malformation syndrome attributed to a defect of the major spliceosome. Our findings significantly extend the range of reported spliceosomal phenotypes in humans and pave the way for further investigation in related conditions such as Treacher Collins syndrome. © 2012 The American Society of Human Genetics.

The dyssegmental dysplasias are lethal forms of neonatal short-limbed dwarfism in which vertebral segmentation defects and short, thick, bowed long bones are the prominent radiographic features. Clinically, unusual facies, short neck, narrow thorax, cleft palate, and reduced joint mobility are commonly seen. To date, 18 cases of dyssegmental dysplasia have been reported. Reports of three pairs of affected sibs suggest autosomal recessive inheritance. We have studied eight additional cases of dyssegmental dysplasia, including one pair of affected sibs. Clinical, radiographic, and histologic examination of these new cases and review of the literature demonstrates the presence of at least two distinct forms of dyssegmental dysplasia. The milder form, "dyssegmental dysplasia, type Rolland-Desbuquois," is characterized clinically by frequent survival beyond the newborn period and by distinct radiographic changes resembling Kniest dysplasia. The severe form, "dyssegmental dysplasia, type Silverman-Handmarker," is characterized by stillbirth or death within the first few days of life and by distinct and more severe radiographic changes. In addition, we have demonstrated chondro-osseous morphologic differences between the two disorders by light and electron microscopy. We conclude that there are at least two forms of dyssegmental dysplasia, each autosomal recessive, which can be delineated on clinical, radiographic and morphologic grounds.

This report describes inclusion body hepatitis in a 12-week-old leghorn-type cockerel. The cockerel had come from a specific-pathogen-free flock and was reared in a positive-pressure isolator until 6 weeks old. Grossly, the cockerel was jaundiced, and the liver was swollen and had small white foci throughout. Histologically, there were foci of hepatic necrosis and basophilic inclusion bodies in the nuclei of numerous hepatocytes. A fowl adenovirus, isolated from the liver, was found to belong to serotype 2/12. The bursa of Fabricius had some degenerative changes, but these were not consistent with infectious bursal disease, nor was there evidence of seroconversion to infectious bursal disease virus in the remaining chickens.

During gastrointestinal bleeding associated with cirrhosis, the presence of blood within the lumen of the gut may cause or favorise the onset of hepatic coma. Digestive lavage by rapid intragastric infusion of an isotonic solution based upon mannitol may reduce the mortality due to hepatic coma. The value of this method was studied retrospectively by comparison of two series of haemorrhagic complications: Group I-1971-1976: 224 haemorrhagic complications treated in the usual manner; Group II-1976-1977: 127 haemorrhagic complications treated in accordance with a protocol which included digestive lavage. The results indicate the prognostic significance of certain clinical signs (ascites, jaundice, shock), and also made it possible to determine the cause of death and to demonstrate a reduction in mortality in the group treated by digestive lavage (p0.02), concerning only deaths as a result of hepatic coma (p0.01) above all in forms with a poor initial prognosis with shock or decompensation with jaundice and ascites.