Recurrent microdeletions and microduplications of approximately 555 kb at 16p11.2 confer susceptibility to autism spectrum disorder (ASD) in up to 1% of ASD patients. No physical or behavioural ...features have been identified that distinguish these individuals as having a distinct ASD subtype, but clinical data are limited.
We report five autistic probands identified by microarray analysis with copy number variation (CNV) of 16p11.2 (three deletions, two duplications). Each patient was assessed for ASD and dysmorphic features. We also describe a deletion positive 26-month-old female who has developmental delay (DD) and autistic features.
Proband 1 (female with ASD, de novo deletion) is not dysmorphic. Proband 2 (male with autism, de novo deletion) and proband 3 and his brother (males with autism, inherited deletions) are dysmorphic, but the two probands do not resemble one another. The mother of proband 3 has mild mental retardation (MR), minor dysmorphism and meets the criteria for ASD. Proband 4 (dysmorphic autistic male, de novo duplication) had a congenital diaphragmatic hernia. Proband 5 (non-dysmorphic ASD female with a duplication) has two apparently healthy duplication positive relatives. Probands 1 and 2 have deletion negative siblings with ASD and Asperger syndrome, respectively. Proband 6 (a female with DD and an inherited duplication) is dysmorphic, but has oligohydramnios sequence.
The phenotypic spectrum associated with CNV at 16p11.2 includes ASD, MR/DD and/or possibly other primary psychiatric disorders. Compared with the microduplications, the reciprocal microdeletions are more likely to be penetrant and to be associated with non-specific major or minor dysmorphism. There are deletion positive ASD probands with a less severe phenotype than deletion negative ASD siblings underscoring the significant phenotypic heterogeneity.
Copy number variation has emerged as an important cause of phenotypic variation, particularly in relation to some complex disorders. Autism spectrum disorder (ASD) is one such disorder, in which ...evidence is emerging for an etiological role for some rare penetrant de novo and rare inherited copy number variants (CNVs). De novo variation, however, does not always explain the familial nature of ASD, leaving a gap in our knowledge concerning the heritable genetic causes of this disorder. Extended pedigrees, in which several members have ASD, provide an opportunity to investigate inherited genetic risk factors. In this current study, we recruited 19 extended ASD pedigrees, and, using the Illumina HumanOmni2.5 BeadChip, conducted genome-wide CNV interrogation. We found no definitive evidence of an etiological role for segregating CNVs in these pedigrees, and no evidence that linkage signals in these pedigrees are explained by segregating CNVs. However, a small number of putative de novo variants were transmitted from BAP parents to their ASD offspring, and evidence emerged for a rare duplication CNV at 11p13.3 harboring two putative ‘developmental/neuropsychiatric’ susceptibility gene(s),
GSTP1
and
NDUFV1
.
Clinical experience with testosterone suggests a wide range of indications for selective androgen receptors modulators (SARMs), including hypogonadism, osteoporosis, CNS indications and muscle ...wasting conditions. ACADIA has identified several novel chemical classes of SARMs ranging from full and partial agonists to full antagonists. We report here the in vitro and in vivo profile of one of these SARMs, named ACP‐105. In cell based assays ACP‐105 was found to be a potent and selective androgen receptor agonist. Studies using castrated rats demonstrated that ACP‐105 potently suppressed the luteinizing hormone surge and had robust anabolic effects on the levator ani muscle. Tissues specificity was demonstrated in that ACP‐105 had minimal trophic effects on prostate in castrated animals and no detectable trophic effect on prostate of intact rats. ACP‐105 behaves as a partial androgen receptor agonist, partially reversing the androgenic effect of exogenous testosterone. Taken together these results suggest that ACP‐105 may provide a superior therapeutic alternative to testosterone as it has anabolic effects similar to testosterone on muscle mass, while having considerably less effects on the prostate.
To compare early routine pharmacologic treatment of moderate-to-large patent ductus arteriosus (PDA) at the end of week 1 with a conservative approach that requires prespecified respiratory and ...hemodynamic criteria before treatment can be given.
A total of 202 neonates of <28 weeks of gestation age (mean, 25.8 ± 1.1 weeks) with moderate-to-large PDA shunts were enrolled between age 6 and 14 days (mean, 8.1 ± 2.2 days) into an exploratory randomized controlled trial.
At enrollment, 49% of the patients were intubated and 48% required nasal ventilation or continuous positive airway pressure. There were no differences between the groups in either our primary outcome of ligation or presence of a PDA at discharge (early routine treatment ERT, 32%; conservative treatment CT, 39%) or any of our prespecified secondary outcomes of necrotizing enterocolitis (ERT, 16%; CT, 19%), bronchopulmonary dysplasia (BPD) (ERT, 49%; CT, 53%), BPD/death (ERT, 58%; CT, 57%), death (ERT,19%; CT, 10%), and weekly need for respiratory support. Fewer infants in the ERT group met the rescue criteria (ERT, 31%; CT, 62%). In secondary exploratory analyses, infants receiving ERT had significantly less need for inotropic support (ERT, 13%; CT, 25%). However, among infants who were ≥26 weeks gestational age, those receiving ERT took significantly longer to achieve enteral feeding of 120 mL/kg/day (median: ERT, 14 days range, 4.5-19 days; CT, 6 days range, 3-14 days), and had significantly higher incidences of late-onset non-coagulase-negative Staphylococcus bacteremia (ERT, 24%; CT,6%) and death (ERT, 16%; CT, 2%).
In preterm infants age <28 weeks with moderate-to-large PDAs who were receiving respiratory support after the first week, ERT did not reduce PDA ligations or the presence of a PDA at discharge and did not improve any of the prespecified secondary outcomes, but delayed full feeding and was associated with higher rates of late-onset sepsis and death in infants born at ≥26 weeks of gestation.
ClinicalTrials.gov: NCT01958320.
In the PDA-TOLERATE trial, persistent (even for several weeks) moderate to large patent ductus arteriosus (PDA) was not associated with an increased risk of BPD when the infant required <10 days of ...intubation. However, in infants requiring intubation for ≥10 days, prolonged PDA exposure (≥11 days) was associated with an increased risk of moderate/severe BPD.
As part of a safety summit sponsored by Fluor Hanford Occupational Health and Safety, it was noted that Health Physics Technicians (HPTs) have one of the highest injury rates at Hanford. A ...multi-disciplined team made up of HPTs, health physics professionals, health physics management, indostrial hygienists, and medical personnel was established to determine causes and corrective actions. Committee activities included reviewing and characterizing occupational injuries and illnesses, assessing areas affecting the health of HPTs, soliciting field input, performing field evaluations of tasks, and making recommendations for improvements to senior management. Five areas showed a need for immediate improvement: manmachine interface (human factors and ergonomics), work environment, procedures, people, and communications. A key area of risk identified is the lack of ergonomic design considerations of the survey instruments currently used. There are several cases of cumulative trauma disorder requiring surgery. These cases are directly related to use of health physics instrumentation and/or survey techniques. The committee has made ergonomics and instrument redesign/modification its key initiative for 2001. The committee is encouraging vendor support and is seeking feedback from other health physics organizations regarding their experience and any recommendations they would like to make. Some success has already been achieved through an ergonomics-training program aimed at all HPTs and their supervisors. In addition, there have been several changes made to the way surveys are conducted, survey frequencies have been reduced, and the way modifications have been made to existing instrumentation. This is a long-term initiative with broad support within the Hanford HPT community. This document reports the progress made thus far on the initiative.
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