Replication of a rare risk haplotype on 1p36.33 for autism spectrum disorder.

Hundreds of genes have been implicated in autism spectrum disorders (ASDs). In genetically heterogeneous conditions, large families with multiple affected individuals provide strong evidence implicating a rare variant, and replication of the same variant in multiple families is unusual. We previously published linkage analyses and follow-up exome sequencing in seven large families with ASDs, implicating 14 rare exome variants. These included rs200195897, which was transmitted to four affected individuals in one family. We attempted replication of those variants in the MSSNG database. MSSNG is a unique resource for replication of ASD risk loci, containing whole genome sequence (WGS) on thousands of individuals diagnosed with ASDs and family members. For each exome variant, we obtained all carriers and their relatives in MSSNG, using a TDT test to quantify evidence for transmission and association. We replicated the transmission of rs200195897 to four affected individuals in three additional families. rs200195897 was also present in three singleton affected individuals, and no unaffected individuals other than transmitting parents. We identified two additional rare variants (rs566472488 and rs185038034) transmitted with rs200195897 on 1p36.33. Sanger sequencing confirmed the presence of these variants in the original family segregating rs200195897. To our knowledge, this is the first example of a rare haplotype being transmitted with ASD in multiple families. The candidate risk variants include a missense mutation in SAMD11, an intronic variant in NOC2L, and a regulatory region variant close to both genes. NOC2L is a transcription repressor, and several genes involved in transcription regulation have been previously associated with ASDs.

Impact of prescription drugs on second fragility fractures among US Medicare patients.

Drugs that increase the risk of fracture are commonly prescribed to survivors of a fragility fracture. This study shows that starting new high-risk medications after fracture increases the risk of a second, potentially preventable fracture. For most drug classes, however, it is safe to continue medications taken before the fracture. INTRODUCTION: Most patients who survive a fragility fracture are subsequently exposed to prescription drugs that have been linked to increased fracture risk. This study was designed to quantify the extent to which current prescribing practices result in potentially preventable second fractures. METHODS: We analyzed a cohort of 138,526 Medicare beneficiaries who returned to the community after a fragility fracture. Post-fracture drug use was defined using retail pharmacy fills. The risk of second fracture associated with individual drug classes was analyzed using Cox proportional hazard models. Data were further analyzed to determine whether there is a difference in risk between continuing previous therapy and initiating new therapy after fracture. RESULTS: Many drug classes previously identified as increasing fracture risk were not associated with increased fracture risk in this cohort. Discontinuing therapy at the time of fracture was only beneficial for patients taking selective serotonin reuptake inhibitors; however, initiating therapy in previous non-users increased second fracture risk for five classes of drugs (selective serotonin reuptake inhibitors, tricyclic antidepressants, antipsychotics, proton pump inhibitors, and non-benzodiazepine hypnotics). CONCLUSION: Discontinuing high-risk drugs after fracture was not generally protective against subsequent fractures. Preventing the addition of new medications may result in greater improvements in post-fracture care.

Oral bisphosphonates and upper gastrointestinal toxicity: a study of cancer and early signals of esophageal injury.

SUMMARY: We evaluated the association between bisphosphonate use and (1) upper gastrointestinal cancer, (2) upper endoscopy, (3) incident Barrett's esophagus, and (4) prescription antacid initiation among Medicare beneficiaries. We found no bisphosphonate-cancer association and negative bisphosphonate-Barrett's association. INTRODUCTION: Bisphosphonates can irritate the esophagus; a cancer association has been suggested. Widespread bisphosphonates use compels continued investigation of upper gastrointestinal toxicity. METHODS: Using a 40% Medicare random sample denominator, inpatient, outpatient (2003-2011), and prescription (2006-2011) claims, we studied patients age 68 and older with osteoporosis and/or oral bisphosphonate use. Inverse propensity weighting estimated marginal structural models for the effect of bisphosphonate intensity (pills per month) and cumulative bisphosphonate pills received on upper gastrointestinal cancer risk. Secondary analyses of sub-cohorts without past bisphosphonates or upper endoscopy assessed bisphosphonate initiation and risk of (1) upper endoscopy, (2) incident Barrett's esophagus, and (3) prescription antacid initiation. RESULTS: The cohort included 1.64 million beneficiaries: 87.9% women, mean age, 76.8 (standard deviation (SD) 9.3); mean follow-up, 39.6 months; 38.1% received oral bisphosphonates. Cumulative bisphosphonate receipt, among users, ranged from 4 to 252 pills (5th to 95th percentile). We identified 2,308 upper gastrointestinal cancers (0.43/1000 person years). We found no association between cumulative bisphosphonate pills and cancer, odds ratio (OR) for each additional pill 1.00 (95% confidence interval (CI) 1.00, 1.00). In sub-cohorts, compared to none, lowest cumulative bisphosphonate use (one to nine pills) was associated with higher risk of endoscopy (OR 1.11, 95% CI 1.08-1.14) and antacid initiation (OR 1.13, 95% CI 1.10-1.16); higher intensity conferred no increased risk. Higher intensity and higher cumulative bisphosphonate category were associated with lower Barrett's risk. CONCLUSIONS: We found no bisphosphonate-cancer association and negative bisphosphonate-Barrett's association. Bisphosphonate initiation appears to identify patients susceptible to early irritating effects; clinicians might offer alternatives and delay endoscopy or antacids.

Geographic disparities in access to lung transplantation before and after implementation of the lung allocation score.

The 62 lung transplant centers in the United States are unevenly distributed. We examined whether remote dwelling (distance from one's primary residence to the nearest lung transplant center) or rural dwelling (as opposed to urban) influences patients' access to lung transplantation, and whether such relationships changed following introduction of the lung allocation score (LAS) in May 2005. Between July 2001 and February 2009, 14 015 patients were listed for lung transplantation and 7923 (56.5%) were transplanted. Americans lived a median of 90.3 miles (IQR: 45.3-159.4) from the closest transplant center. Distance from a lung transplant center was inversely associated with the hazard of being listed before LAS implementation (adjusted HR for 100 miles = 0.87 [0.83-0.90]) and afterward (0.81 [0.78-0.85]); LAS implementation did not modify this relationship (p = 0.38). Once waitlisted, distance from the closest center was not associated with time to transplantation, and among those transplanted, distance was not associated with survival. Similar results were identified for rural, as opposed to urban, residence. We conclude that geographic disparaties exist in access to lung transplantation in the United States. These are mediated by listing practices rather than by transplantation rates, and were not mitigated by LAS implementation.

Characterizing Social Functioning in School-Age Children with Sensory Processing Abnormalities.

Children with sensory abnormalities (SAs) have a variety of social problems resulting in poorer social functioning than children with typical development (TD). We describe the relationship between SAs and social functioning in school-age children with SAs, children with TD and a clinical comparison sample of children with autism spectrum disorder (ASD). Children with SAs demonstrated impaired social functioning on standardized measures. Children with SAs demonstrated worse social functioning than children with TD and equivalent social functioning to children with ASD. Increased SAs were associated with poorer social functioning across all groups. The results suggest that children with SAs experience clinically significant problems with social functioning and future research is needed to develop interventions to support social functioning in this population.

A patient-designed tissue-engineered model of the infiltrative glioblastoma microenvironment.

Glioblastoma is an aggressive brain cancer characterized by diffuse infiltration. Infiltrated glioma cells persist in the brain post-resection where they interact with glial cells and experience interstitial fluid flow. We use patient-derived glioma stem cells and human glial cells (i.e., astrocytes and microglia) to create a four-component 3D model of this environment informed by resected patient tumors. We examine metrics for invasion, proliferation, and putative stemness in the context of glial cells, fluid forces, and chemotherapies. While the responses are heterogeneous across seven patient-derived lines, interstitial flow significantly increases glioma cell proliferation and stemness while glial cells affect invasion and stemness, potentially related to CCL2 expression and differential activation. In a screen of six drugs, we find in vitro expression of putative stemness marker CD71, but not viability at drug IC50, to predict murine xenograft survival. We posit this patient-informed, infiltrative tumor model as a novel advance toward precision medicine in glioblastoma treatment.

Diagnosis of inguinal region hernias with axial CT: the lateral crescent sign and other key findings.

Differentiation of direct inguinal hernias, indirect inguinal hernias, and femoral hernias is often difficult at clinical examination and presents challenges even at diagnostic imaging. With the advent of higher-resolution multidetector computed tomography (CT), the minute anatomic detail of the inguinal region can be better delineated. The authors examine the appearance of these hernias at axial CT, as the axial plane remains the diagnostic mainstay of evaluation of acute abdomen. They review and label key anatomic structures, present cases of direct and indirect inguinal hernias and femoral hernias, and demonstrate their anatomic differences on axial images. Direct inguinal hernias protrude anteromedial and inferior to the course of the inferior epigastric vessels, whereas indirect inguinal hernias protrude posterolateral and superior to the course of those vessels. The proposed lateral crescent sign may be useful in diagnosis of early direct inguinal hernias, as it represents lateral compression and stretching of the inguinal canal fat and contents by the hernia sac. Femoral hernias protrude inferior to the course of the inferior epigastric vessels and medial to the common femoral vein, often have a narrow funnel-shaped neck, and may compress the femoral vein, causing engorgement of distal collateral veins. Familiarity with these anatomic differences at axial CT, along with the lateral crescent sign of direct inguinal hernias, may help the radiologist better assist the clinician in accurate diagnosis of the major types of hernias of the inguinal region. Supplemental material available at http://radiographics.rsna.org/lookup/suppl/doi:10.1148/rg.312105129/-/DC1.

Mutations in the TSGA14 gene in families with autism spectrum disorders.

Linkage to 7q has been the most robust genetic finding in familial autism. A previous scan of multiplex families with autism spectrum disorders found a linkage signal of genome-wide significance at D7S530 on 7q32. We searched a candidate imprinted region at this location for genetic variants in families with positive linkage scores. Using exon resequencing, we identified three rare potentially pathogenic variants in the TSGA14 gene, which encodes a centrosomal protein. Two variants were missense mutations (c.664C>G; p.P206A and c.766T>G; p.C240G) that changed conserved residues in the same protein domain; the third variant (c.192+5G>A) altered splicing, which resulted in a protein with an internal deletion of 16 residues and a G33D substitution. These rare TSGA14 variants are enriched in the affected subjects (6/348 patients versus 2/670 controls, Fisher's exact two tailed P = 0.022). This is the first report of a possible link of a gene with a centrosomal function with familial autism.

Chronic focal epileptiform discharges induced by injection of iron into rat and cat cortex.

A single injection of 5 or 10 microliters of ferrous or ferric chloride into rat or cat sensorimotor cortex resulted in chronic recurrent focal paroxysmal electroencephalographic discharges as well as behavioral convulsions and electrical seizures. Recurrent focal epileptiform discharge caused by cortical injection of iron salts suggests that the development of human posttraumatic epilepsy may depend, in part, on the neurochemical alterations induced by the principal metallic ions found in whole blood.

Potent analgesic effects of GDNF in neuropathic pain states.

Neuropathic pain arises as a debilitating consequence of nerve injury. The etiology of such pain is poorly understood, and existing treatment is largely ineffective. We demonstrate here that glial cell line-derived neurotrophic factor (GDNF) both prevented and reversed sensory abnormalities that developed in neuropathic pain models, without affecting pain-related behavior in normal animals. GDNF reduces ectopic discharges within sensory neurons after nerve injury. This may arise as a consequence of the reversal by GDNF of the injury-induced plasticity of several sodium channel subunits. Together these findings provide a rational basis for the use of GDNF as a therapeutic treatment for neuropathic pain states.

Enhancing Low-Intensity Coaching in Parent Implemented Early Start Denver Model Intervention for Early Autism: A Randomized Comparison Treatment Trial.

Short-term low intensity parent implemented intervention studies for toddlers with autism spectrum disorder (ASD) have found it difficult to demonstrate significantly improved developmental scores or autism severity compared to community treatment. We conducted a randomized comparative intent-to-treat study of a parent implemented intervention to (1) test the effects of an enhanced version on parent and child learning, and (2) evaluate the sensitivity to change of proximal versus distal measures of child behavior. We randomized 45 children with ASD, 12-30 months of age, into one of two versions of parent-implemented Early Start Denver Model (P-ESDM), the basic model, in which we delivered 1.5 h of clinic-based parent coaching weekly, and an enhanced version that contained three additions: motivational interviewing, multimodal learning tools, and a weekly 1.5-h home visit. We delivered the intervention for 12 weeks and measured child and parent change frequently in multiple settings. We found a time-by-group interaction: parents in the enhanced group demonstrated significantly greater gains in interaction skills than did parents in the non-enhanced group. Both interventions were associated with significant developmental acceleration; however, child outcomes did not differ by group. We found a significant relationship between degree of change in parental interaction skill and rate of children's improvement on our proximal measure. Parents in both groups reported satisfaction with the intervention. These findings suggest that parent skills improved more in the enhanced group than the comparison group. Children in the two groups showed similar improvements. Rate of individual parent learning was associated with greater individual child progress on a measure quite proximal to the treatment, though not on standardized assessments.

Complications of gallstones: the Mirizzi syndrome, gallstone ileus, gallstone pancreatitis, complications of "lost" gallstones.

Gallstones cause various problems besides simple biliary colic and choplecystitis. With chronicity of inflammation caused by gallstone obstruction of the cystic duct, the gallbladder may fuse to the extrahepatic biliary tree, causing Mirizzi syndrome, or fistulize into the intestinal tract, causing so-called gallstone ileus. Stones may pass out of the gallbladder and travel downstream through the common bile duct to obstruct the ampulla of Vater resulting in gallstone pancreatitis, or pass out of the gallbladder inadvertently during surgery, resulting in the syndromes associated with lost gallstones. This article examines these varied and complex complications, with recommendations for management based on the literature, the data, and perhaps some common sense.

Effects of delta9-tetrahydrocannabinol in Lewis lung adenocarcinoma cells in tissue culture.

We found a dose-related decrease in DNA synthesis in transformed cell cultures treated with delta9-tetrahydrocannabinol (delta9-THC). The decrease, observed over a 4-hour period, was not accompanied by a change in the radioactive precursor pool as compared to that of control culture. The distribution of labeled products clearly differed from that observed after treatment with cytosine arabinoside. delta9-THC inhibited DNA synthesis at some point beyond the uptake of 3H-thymidine.

Leukemia inhibitory factor determines the growth status of injured adult sensory neurons.

Conditioning injury to adult mammalian sensory neurons enhances their regeneration potential. Here we show that leukemia inhibitory factor (LIF) is a fundamental component of the conditioning response. Conditioning injury in vivo significantly increases the intrinsic growth capacity of sensory neurons in vitro from LIF+/+ mice. This conditioning effect is significantly blunted in sensory neurons from LIF-/- mice. Enhanced growth is rescued in vitro in LIF-/- mice by the addition of exogenous LIF, and the effect blocked by human LIF-05, an LIF receptor antagonist. Furthermore, we demonstrate that LIF promotes elongating but not arborizing neurite outgrowth in vitro and is required for normal regeneration of injured adult sensory neurons in vivo. LIF is also functionally protective to peptidergic sensory neurons after nerve damage in vivo. Our results indicate that the alteration in intrinsic growth status of injured sensory neurons depends, at least in part, on LIF.

Neuroprotective effect of mild hypothermia in patients undergoing coronary artery surgery with cardiopulmonary bypass: a randomized trial.

BACKGROUND: Neuropsychological deficits occur in 30% to 80% of patients undergoing heart surgery and are due in part to ischemic cerebral injury during cardiopulmonary bypass. We tested whether mild hypothermia, the most efficacious neuroprotective strategy found in laboratory studies, improved cognitive outcome in patients undergoing coronary artery surgery. METHODS AND RESULTS: Patients 60 years or older scheduled for coronary artery surgery were enrolled. During cardiopulmonary bypass, patients were initially cooled to 32 degrees C then randomly assigned to rewarming to 37 degrees C (control) or 34 degrees C (hypothermic), with no further intraoperative warming. Testing was scheduled preoperatively and 1 week and 3 months postoperatively. Eleven tests were combined into 3 cognitive domains: memory, attention, and psychomotor speed and dexterity. A patient was classified as having a cognitive deficit if a decrease of >/=0.50 SD was realized in 1 or more domains. The incidence of cognitive deficits 1 week after surgery, which was the primary outcome, was 62% () in the control group and 48% () in the hypothermic group (relative risk 0.77, P=0.048). In the hypothermic group, the magnitude of deterioration in attention and in speed and dexterity was reduced by 55.6% (P=0.038) and 41.3% (P=0.042), respectively. At 3 months, the hypothermic group still performed better on one test of speed and dexterity (grooved pegboard). There was no difference in morbidity or mortality. CONCLUSIONS: Our findings support a neuroprotective effect of mild hypothermia in patients undergoing coronary artery surgery and should encourage physicians and perfusionists to pay careful attention to brain temperature during cardiopulmonary bypass.

Impaired left atrial mechanical function after cardioversion: relation to the duration of atrial fibrillation.

OBJECTIVES: We hypothesized that the time course of the recovery of atrial systolic function may be related to the duration of atrial fibrillation before cardioversion and sought to study noninvasively the recovery of left atrial mechanical function utilizing serial transthoracic Doppler studies. BACKGROUND: Recovery of atrial mechanical function may be delayed for several weeks after successful cardioversion of atrial fibrillation to sinus rhythm. METHODS: After successful cardioversion, 60 patients with atrial fibrillation of brief (< or = 2 weeks, 17 patients), moderate (> 2 to 6 weeks, 22 patients) or prolonged (> 6 weeks, 21 patients) duration were followed up with serial transmitral pulsed Doppler echocardiography immediately (60 patients) and at 24 h (45 patients), 1 week (41 patients), 1 month (31 patients) and > 3 months (30 patients) after cardioversion. RESULTS: Atrial mechanical function is greater immediately and at 24 h and 1 week after cardioversion in patients with "brief" compared with "prolonged" atrial fibrillation. In all groups, atrial mechanical function increases over time, ultimately achieving similar levels. Full recovery of atrial mechanical function, however, is achieved within 24 h in patients with brief atrial fibrillation, within 1 week in patients with moderate-duration atrial fibrillation and within 1 month in patients with prolonged atrial fibrillation. CONCLUSIONS: Recovery of left atrial mechanical function is related to the duration of atrial fibrillation before cardioversion. These findings have important implications for assessing the early hemodynamic benefit of successful cardioversion.

Radical gastrectomy for cancer of the stomach.

Carcinoma of the stomach remains one of the most common causes of cancer deaths in the world. The only treatment to offer hope for cure or long-term palliation is surgery. Optimal surgical resection requires an adequate margin of normal tissue around the tumor,dissection of perigastric lymph nodes, and en-bloc removal of organs involved by direct extension. Extended lymphadenectomy has not been shown to offer survival advantage in the West.

Brain structural abnormalities in young children with autism spectrum disorder.

OBJECTIVE: To explore the specific gross neuroanatomic substrates of this brain developmental disorder, the authors examine brain morphometric features in a large sample of carefully diagnosed 3- to 4-year-old children with autism spectrum disorder (ASD) compared with age-matched control groups of typically developing (TD) children and developmentally delayed (DD) children. METHODS: Volumes of the cerebrum, cerebellum, amygdala, and hippocampus were measured from three-dimensional coronal MR images acquired from 45 children with ASD, 26 TD children, and 14 DD children. The volumes were analyzed with respect to age, sex, volume of the cerebrum, and clinical status. RESULTS: Children with ASD were found to have significantly increased cerebral volumes compared with TD and DD children. Cerebellar volume for the ASD group was increased in comparison with the TD group, but this increase was proportional to overall increases in cerebral volume. The DD group had smaller cerebellar volumes compared with both of the other groups. Measurements of amygdalae and hippocampi in this group of young children with ASD revealed enlargement bilaterally that was proportional to overall increases in total cerebral volume. There were similar findings of cerebral enlargement for both girls and boys with ASD. For subregion analyses, structural abnormalities were observed primarily in boys, although this may reflect low statistical power issues because of the small sample (seven girls with ASD) studied. Among the ASD group, structural findings were independent of nonverbal IQ. In a subgroup of children with ASD with strictly defined autism, amygdalar enlargement was in excess of increased cerebral volume. CONCLUSIONS: These structural findings suggest abnormal brain developmental processes early in the clinical course of autism. Research currently is underway to better elucidate mechanisms underlying these structural abnormalities and their longitudinal progression.

Missing T-cell receptor V beta families following blood transfusion. The role of HLA in development of immunization and tolerance.

Previously, we showed that donor-specific CTL nonresponsiveness occurs in transfused recipients sharing one HLA haplotype (or at least one HLA-B and one HLA-DR antigen) with the blood donor. The aim of the present study was to disclose the distinct effects of BT on the T-cell receptor repertoire and to analyze which factors determine the tolerizing versus immunizing properties of BT. We show here that recipients of HLA-sharing BT develop not only donor-specific CTL nonresponsiveness posttransfusion, but also a significant decrease in the usage of one to three V beta families as shown by PCR. In contrast, recipients of non-HLA-sharing BT remained donor-specific CTL responders and did not decrease the usage of V beta families. In addition, these patients generated high-affinity CTL for donor antigens which could not be blocked by anti-CD8 mAb. Our results show that major alterations occur in the CTL and TCR V beta repertoire following BT. We hypothesize that the fate of transfused allogeneic lymphocytes in the host is based on the degree of sharing of HLA antigens with the host. This relationship determines the ultimate outcome of BT: immunization versus tolerization.