Preoperative oral antibiotic bowel preparation in elective resectional colorectal surgery reduces rates of surgical site infections: a single-centre experience with a cost-effectiveness analysis.

INTRODUCTION: Surgical site infections cause considerable postoperative morbidity and mortality. The aim of this study was to determine the effect on surgical site infection rates following introduction of a departmental oral antibiotic bowel preparation protocol. METHODS: A prospective single-centre study was performed for elective colorectal resections between May 2016-April 2018; with a control group with mechanical bowel preparation and treatment group with oral antibiotic bowel preparation (neomycin and metronidazole) and mechanical bowel preparation. The primary outcome of surgical site infection and secondary outcomes of anastomotic leak, length of stay and mortality rate were analysed using Fisher's exact test and independent samples t-tests. A cost-effectiveness analysis was also performed. RESULTS: A total of 311 patients were included; 156 in the mechanical bowel preparation group and 155 in the mechanical bowel preparation plus oral antibiotic bowel preparation group. The study included 180 (57.9%) men and 131 (42.1%) women with a mean age of 68 years. There was a significant reduction in surgical site infection rates (mechanical bowel preparation 16.0% vs mechanical bowel preparation plus oral antibiotic bowel preparation 4.5%; P = 0.001) and mean length of stay (mechanical bowel preparation 10.2 days vs mechanical bowel preparation plus oral antibiotic bowel preparation 8.2 days; P = 0.012). There was also a reduction in anastomotic leak and mortality rates. Subgroup analyses demonstrated significantly reduced surgical site infection rates in laparoscopic resections (P = 0.008). There was an estimated cost saving of £239.13 per patient and £37,065 for our institution over a one-year period. CONCLUSION: Oral antibiotic bowel preparation is a feasible and cost-effective intervention shown to significantly reduce the rates of surgical site infection and length of stay in elective colorectal surgery.

Do preoperative oral antibiotics increase Clostridium difficile infection rates? An analysis of 13 959 colectomy patients.

AIM: The aim of this study was to determine whether or not preoperative oral antibiotic preparation (POAP) increases the rate of Clostridium difficile colitis (CDC) in patients undergoing colectomy. METHOD: In 2015, data for colectomies had been collected prospectively and recorded in the targeted colectomy option of the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP). This was available for retrospective analysis. Data available for analysis included elective and emergency status, POAP, surgical approach, primary anastomosis and CDC status. The effect of POAP on CDC was analysed and risk adjusted for 14 separate preoperative variables. RESULTS: In all, 13 959 adult patients underwent a colectomy in 2015 (POAP group 5311 and non- POAP group 8648). The overall rate of CDC in colectomy patients was 1.6% (227/13 959). On univariate analysis, CDC was significantly less common in the POAP group than in the non-POAP group (1.2% vs 1.9%, P = 0.003). Univariate analysis of a further 41 preoperative variables revealed 14 to be associated with CDC. However, after risk adjustment with these 14 variables, POAP lost its statistical significance (adjusted OR 0.902, 95% CI 0.584-1.486, P = 0.685). Only patients with pre-existing systemic inflammatory response syndrome appeared to be at increased risk of CDC (adjusted OR 2.154, 95% CI 1.139-4.074, P = 0.018). CONCLUSION: At the very least this study suggests it is safe to use POAP in colectomy patients without increasing the rate of CDC unless they have pre-existing systemic inflammatory response syndrome.

Evaluation of the radiation dose exposure and associated cancer risks in patients having preoperative parathyroid localization.

OBJECTIVE The study aimed to evaluate the total effective and organ absorbed radiation doses associated with three- and four-phase parathyroid computed tomography (CT) and sestamibi scans used for the preoperative localisation of parathyroid adenomas in a cohort of patients with primary hyperparathyroidism at a single institution. We aimed to assess the risk of cancer incidence for the organs demonstrating the highest absorbed doses for the different imaging techniques, and more specifically determine the risk for our cohort of patients. METHODS Fifty patients with primary hyperparathyroidism had both multiphase CT and sestamibi scans. The Imaging Performance Assessment of CT Scanners (ImPACT) calculator was used to estimate the patient-effective and organ-absorbed radiations doses for all the CT examinations. For sestamibi scans, the US Nuclear Regulatory Commission NUREG/CR-6345 publication was used to estimate the dose for each patient. The attributable risks of cancer were calculated using the Health Protection Agency HPA-CRCE-028 publication. RESULTS The mean patient total effective doses were 15.9% ± 2.8 mSv, 20.2% ± 2.8  mSv and 5.6 ± 0.24 mSv for three-phase CT, four-phase CT and sestamibi examinations, respectively. In our cohort, the highest attributable lifetime risk was for lung cancer (0.03%) after multiphase CT. This compared with a tenfold lower risk for thyroid cancer (0.003%). After sestamibi, the highest risk was for colon cancer (0.06%). CONCLUSIONS Multiphase CT is associated with a higher radiation dose and thus a higher potential risk of cancer, but this risk is low in the older population that constituted the majority of our cohort.

Risk factors for anastomotic leakage after colorectal resection: a retrospective analysis of 17 518 patients.

AIM: A large, prospectively collected, clinical database was analysed to determine the various pre- and intra-operative factors affecting anastomotic leakage (AL) in colorectal surgery. METHOD: Data on 17 518 patients having a colorectal resection with anastomosis, taken from the 2013 American College of Surgeons National Surgical Quality Improvement Program database, were included in the study. Multivariable logistic regression analysis was carried out to identify risk-adjusted predictive factors for AL. Statistical significance was set at P < 0.05 and confidence intervals were reported at the 95% level. RESULTS: The AL rate was 3.9% (687/17 518). Younger patients, male gender and an American Society of Anesthesiology (ASA) score of ≥ 3 (P < 0.001), smoking (P = 0.001), diabetes (P = 0.035), a preoperative serum albumin level of < 4 g/dl (P = 0.030), elective rectal cancer surgery (P = 0.024), emergency colectomy for bleeding (P = 0.013) and splenic flexure mobilization (P = 0.043) were associated with an increased risk of AL. Preoperative oral antibiotics (P < 0.001), right hemicolectomy (open or laparoscopic) and laparoscopic partial colectomy were associated with a reduced risk of AL compared with the entire group. Body mass index, preoperative chemotherapy, emergency surgery and mechanical bowel preparation were not related to AL. CONCLUSION: In contrast to most studies, younger age was found to be an independent risk factor for AL. The risk for AL was lower with laparoscopic partial colectomy and open or laparoscopic right hemicolectomy. Preoperative oral antibiotic preparation significantly reduces the risk of AL and should be incorporated as a standard protocol.

Jejunojejunal Intussusception as the Initial Presentation of Non-Hodgkin's B-Cell Lymphoma in an Adult Patient: A Case Report and Review of the Literature.

Introduction. Intussusception is a rare cause of bowel obstruction in adults and is usually associated with an underlying pathology, benign, or malignant. This is a report of a case of jejunojejunal intussusception secondary to non-Hodgkin's B-cell lymphoma in an adult patient. Case Presentation. A 74-year-old male with no previous significant medical history presented with symptoms of acute intestinal obstruction. A CT scan of the abdomen and pelvis revealed 2 areas of jejunojejunal intussusception, which were surgically managed successfully. Histopathological examination of the specimen revealed the presence of high grade diffuse large B-cell-type non-Hodgkin's lymphoma, and the patient was referred to the oncology team for further management. Discussion. B-cell lymphoma is a rare but well-documented cause of intussusception in adults, with most cases being at the ileocolic region. We present a rare case of jejunojejunal intussusception as the initial presentation of non-Hodgkin's B-cell lymphoma in an adult patient.

Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction.

Autism spectrum disorders (ASDs) have been suggested to arise from abnormalities in the canonical and non-canonical Wnt signaling pathways. However, a direct connection between a human variant in a Wnt pathway gene and ASD-relevant brain pathology has not been established. Prickle2 (Pk2) is a post-synaptic non-canonical Wnt signaling protein shown to interact with post-synaptic density 95 (PSD-95). Here, we show that mice with disruption in Prickle2 display behavioral abnormalities including altered social interaction, learning abnormalities and behavioral inflexibility. Prickle2 disruption in mouse hippocampal neurons led to reductions in dendrite branching, synapse number and PSD size. Consistent with these findings, Prickle2 null neurons show decreased frequency and size of spontaneous miniature synaptic currents. These behavioral and physiological abnormalities in Prickle2 disrupted mice are consistent with ASD-like phenotypes present in other mouse models of ASDs. In 384 individuals with autism, we identified two with distinct, heterozygous, rare, non-synonymous PRICKLE2 variants (p.E8Q and p.V153I) that were shared by their affected siblings and inherited paternally. Unlike wild-type PRICKLE2, the PRICKLE2 variants found in ASD patients exhibit deficits in morphological and electrophysiological assays. These data suggest that these PRICKLE2 variants cause a critical loss of PRICKLE2 function. The data presented here provide new insight into the biological roles of Prickle2, its behavioral importance, and suggest disruptions in non-canonical Wnt genes such as PRICKLE2 may contribute to synaptic abnormalities underlying ASDs.

MAPK14 and CNR1 gene variant interactions: effects on brain volume deficits in schizophrenia patients with marijuana misuse.

BACKGROUND: Adolescent marijuana use is associated with increased risk for schizophrenia. We previously reported that marijuana misuse in conjunction with specific cannabinoid receptor 1 (CNR1) genetic variants (rs12720071-G-allele carriers) contributed to white-matter (WM) brain volume deficits in schizophrenia patients. In this study, we assessed the influence of another cannabinoid-related gene, mitogen-activated protein kinase 14 (MAPK14), and potential MAPK14-CNR1 gene-gene interactions in conferring brain volume abnormalities among schizophrenia patients with marijuana abuse/dependence. MAPK14 encodes a member of the MAPK family involved in diverse cellular processes, including CNR1-induced apoptosis. METHOD: We genotyped 235 schizophrenia patients on nine MAPK14 tag single nucleotide polymorphisms (tSNPs). Approximately one quarter of the sample had marijuana abuse or dependence. Differential effects of MAPK14 tSNPs on brain volumes across patients with versus without marijuana abuse/dependence were examined using ANCOVA. RESULTS: Of the MAPK14 tSNPs, only rs12199654 had significant genotype effects and genotype × marijuana misuse interaction effects on WM volumes. rs12199654-A homozygotes with marijuana abuse/dependence had significantly smaller total cerebral and lobar WM volumes. The effects of MAPK14 rs12199654 on WM volume deficits remained significant even after controlling for the CNR1 rs12720071 genotype. There were significant main effects of the MAPK14 CNR1 diplotype and diplotype × marijuana interaction on WM brain volumes, with both genetic variants having additive contributions to WM volume deficits only in patients with marijuana misuse. CONCLUSIONS: Given that CNR1-induced apoptosis is preceded by increased MAPK phosphorylation, our study suggests that potential MAPK14-CNR1 gene-gene interactions may mediate brain morphometric features in schizophrenia patients with heavy marijuana use.

Statistical epistasis and progressive brain change in schizophrenia: an approach for examining the relationships between multiple genes.

Although schizophrenia is generally considered to occur as a consequence of multiple genes that interact with one another, very few methods have been developed to model epistasis. Phenotype definition has also been a major challenge for research on the genetics of schizophrenia. In this report, we use novel statistical techniques to address the high dimensionality of genomic data, and we apply a refinement in phenotype definition by basing it on the occurrence of brain changes during the early course of the illness, as measured by repeated magnetic resonance scans (i.e., an 'intermediate phenotype.') The method combines a machine-learning algorithm, the ensemble method using stochastic gradient boosting, with traditional general linear model statistics. We began with 14 genes that are relevant to schizophrenia, based on association studies or their role in neurodevelopment, and then used statistical techniques to reduce them to five genes and 17 single nucleotide polymorphisms (SNPs) that had a significant statistical interaction: five for PDE4B, four for RELN, four for ERBB4, three for DISC1 and one for NRG1. Five of the SNPs involved in these interactions replicate previous research in that, these five SNPs have previously been identified as schizophrenia vulnerability markers or implicate cognitive processes relevant to schizophrenia. This ability to replicate previous work suggests that our method has potential for detecting a meaningful epistatic relationship among the genes that influence brain abnormalities in schizophrenia.

Novel copy number variants in children with autism and additional developmental anomalies.

Autism is a neurodevelopmental disorder characterized by three core symptom domains: ritualistic-repetitive behaviors, impaired social interaction, and impaired communication and language development. Recent studies have highlighted etiologically relevant recurrent copy number changes in autism, such as 16p11.2 deletions and duplications, as well as a significant role for unique, novel variants. We used Affymetrix 250K GeneChip Microarray technology (either NspI or StyI) to detect microdeletions and duplications in a subset of children from the Autism Genetic Resource Exchange (AGRE). In order to enrich our sample for potentially pathogenic CNVs we selected children with autism who had additional features suggestive of chromosomal loss associated with developmental disturbance (positive criteria filter) but who had normal cytogenetic testing (negative criteria filter). We identified families with the following features: at least one child with autism who also had facial dysmorphology, limb or digit abnormalities, or ocular abnormalities. To detect changes in copy number we used a publicly available program, Copy Number Analyser for GeneChip® (CNAG) Ver. 2.0. We identified novel deletions and duplications on chromosomes 1q24.2, 3p26.2, 4q34.2, and 6q24.3. Several of these deletions and duplications include new and interesting candidate genes for autism such as syntaxin binding protein 5 (STXBP5 also known as tomosyn) and leucine rich repeat neuronal 1 (LRRN1 also known as NLRR1). Lastly, our data suggest that rare and potentially pathogenic microdeletions and duplications may have a substantially higher prevalence in children with autism and additional developmental anomalies than in children with autism alone.

Pax6 3' deletion results in aniridia, autism and mental retardation.

The PAX6 gene is a transcription factor expressed early in development, predominantly in the eye, brain and gut. It is well known that mutations in PAX6 may result in aniridia, Peter's anomaly and kertatisis. Here, we present mutation analysis of a patient with aniridia, autism and mental retardation. We identified and characterized a 1.3 Mb deletion that disrupts PAX6 transcriptional activity and deletes additional genes expressed in the brain. Our findings provide continued evidence for the role of PAX6 in neural phenotypes associated with aniridia.

A randomized, controlled trial of routine early abdominal computed tomography in patients presenting with non-specific acute abdominal pain.

AIM: To compare the effect of an initial early computed tomography (CT) examination versus standard practice (SP) on the length of hospital stay, diagnostic accuracy, and mortality of adults presenting with acute abdominal pain. MATERIALS AND METHODS: Two hundred and five adults presenting with acute abdominal pain were randomized to undergo an early CT examination or current SP, which comprised supine abdominal and erect chest radiography. One hundred and ninety-eight patients (99 in each arm) were included in the analysis. The primary endpoint was the duration of inpatient stay; secondary endpoints were diagnostic certainty and mortality. RESULTS: There was no significant difference in the length of hospital stay between the two arms (p=0.20). At randomization 36% (35 of 96) of CT patients and 49% (48 of 98) of SP patients were correctly diagnosed; 24h after randomization the correct diagnosis had been established in 84% of CT patients and 73% of SP patients. This refinement in diagnostic certainty was significantly better in the CT group (p<0.001). There was no difference in mortality between the two trial arms (p=0.31). CONCLUSION: Early abdominal CT in patients with acute abdominal pain improves diagnostic certainty, but does not reduce the length of hospital stay and 6 month mortality.

Catechol-O-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow.

The catechol-O-methyl transferase (COMT) gene is considered a leading schizophrenia candidate gene. Although its role in increasing schizophrenia susceptibility has been conflicting, recent studies suggest the valine allele may contribute to poor cognitive function in schizophrenia. V(158)M COMT genotype was obtained on 159 schizophrenia patients and 84 healthy controls. The effects of COMT genotype on four measures of working memory/executive functions (Wisconsin Card Sorting, digit span backward, Trail Making and N-back tests) and on MRI frontal brain volumes were examined. Genotype distributions were not significantly different between patients and controls. There were no significant genotype or genotype-by-group effects on any working memory/executive function measures. No genotype or genotype-by-diagnosis interaction effects were found with MRI frontal lobe volumes. Randomization analyses using [(15)O]H(2)O positron emission tomography (PET) cerebral blood flow data found Val/Val patients had higher frontal lobe activation than Met/Met patients while performing the one-back task. Overall, these findings do not support a major role for COMT in increasing susceptibility for schizophrenia or in mediating frontal lobe function. Age-related changes and phenotypic heterogeneity of schizophrenia may influence the complex relationships between COMT genotype and cognition.

Examination of AVPR1a as an autism susceptibility gene.

Impaired reciprocal social interaction is one of the core features of autism. While its determinants are complex, one biomolecular pathway that clearly influences social behavior is the arginine-vasopressin (AVP) system. The behavioral effects of AVP are mediated through the AVP receptor 1a (AVPR1a), making the AVPR1a gene a reasonable candidate for autism susceptibility. We tested the gene's contribution to autism by screening its exons in 125 independent autistic probands and genotyping two promoter polymorphisms in 65 autism affected sibling pair (ASP) families. While we found no nonconservative coding sequence changes, we did identify evidence of linkage and of linkage disequilibrium. These results were most pronounced in a subset of the ASP families with relatively less severe impairment of language. Thus, though we did not demonstrate a disease-causing variant in the coding sequence, numerous nontraditional disease-causing genetic abnormalities are known to exist that would escape detection by traditional gene screening methods. Given the emerging biological, animal model, and now genetic data, AVPR1a and genes in the AVP system remain strong candidates for involvement in autism susceptibility and deserve continued scrutiny.

Cellular characterization of the tropism of recombinant adenovirus for the adrenal glands.

BACKGROUND: Recombinant adenoviruses are widely used in gene therapy clinical trials. A particular tropism for the adrenal glands has been reported but the precise cellular base for this tropism has not been determined. MATERIALS AND METHODS: Recombinant adenoviruses were injected intravenously into Balb/c nu/nu or C57BL/6 mice. Seventy-two hours later, the animals were sacrificed and the adrenal glands and livers collected. The glands were sectioned and analyzed using immunohistochemical methods to detect adenoviral epitopes and transgene expression. Total RNA were extracted from the liver and adrenal glands of some animals and subjected to real-time RT-PCR. RESULTS: The only cell type infected in the adrenal glands of Balb/c nu/nu or C57BL/6 mice is the adrenocortical cells in the zona fasciculata. Quantitatively, the relative level of gene expression in the adrenal gland is comparable but lower than that measured in the liver. CONCLUSIONS: Systemic injection of recombinant adenovirus could be used as a procedure to restore adrenal steroidogenesis in clinical gene therapy protocols. In addition, our study suggest that adrenal dysfunction should be considered when criteria are established to assess the safety of gene therapy formulations administered systemically.

Linkage disequilibrium at the Angelman syndrome gene UBE3A in autism families.

Autistic disorder is a neurodevelopmental disorder with a complex genetic etiology. Observations of maternal duplications affecting chromosome 15q11-q13 in patients with autism and evidence for linkage and linkage disequilibrium to markers in this region in chromosomally normal autism families indicate the existence of a susceptibility locus. We have screened the families of the Collaborative Linkage Study of Autism for several markers spanning a candidate region covering approximately 2 Mb and including the Angelman syndrome gene (UBE3A) and a cluster of gamma-aminobutyric acid (GABA(A)) receptor subunit genes (GABRB3, GABRA5, and GABRG3). We found significant evidence for linkage disequilibrium at marker D15S122, located at the 5' end of UBE3A. This is the first report, to our knowledge, of linkage disequilibrium at UBE3A in autism families. Characterization of null alleles detected at D15S822 in the course of genetic studies of this region showed a small (approximately 5-kb) genomic deletion, which was present at somewhat higher frequencies in autism families than in controls.

Chromosomal abnormalities in a clinic sample of individuals with autistic disorder.

We examined data from the largest reported sample of autistic individuals who have been karyotyped with the aim of providing additional information in the search for autism disease genes. Individuals seen in the University of Iowa's Child and Adolescent Psychiatry Clinic since 1980 who had been diagnosed with autism were cross-referenced with the University of Iowa's Cytogenetics Laboratory database. We determined the number of individuals referred for cytogenetic testing and, of these, the number found to have gross cytological abnormalities. Medical records were reviewed for all cases with such abnormalities. Between 1980 and 1998, 898 subjects seen in the clinic were diagnosed with autism. Of these, 278 (30.1%) were referred for cytological studies; 25 (9.0%) of these were found to have chromosomal abnormalities. The most common chromosomal abnormalities were Fragile X, other sex chromosome anomalies, and chromosome 15 abnormalities. These data support the contribution of chromosomal abnormalities to a small but significant number of cases of autism, and highlight the involvement of chromosome 15 and the sex chromosomes.

Evidence supporting WNT2 as an autism susceptibility gene.

We examined WNT2 as a candidate disease gene for autism for the following reasons. First, the WNT family of genes influences the development of numerous organs and systems, including the central nervous system. Second, WNT2 is located in the region of chromosome 7q31-33 linked to autism and is adjacent to a chromosomal breakpoint in an individual with autism. Third, a mouse knockout of Dvl1, a member of a gene family essential for the function of the WNT pathway, exhibits a behavioral phenotype characterized primarily by diminished social interaction. We screened the WNT2 coding sequence for mutations in a large number of autistic probands and found two families containing nonconservative coding sequence variants that segregated with autism in those families. We also identified linkage disequilibrium (LD) between a WNT2 3'UTR SNP and our sample of autism-affected sibling pair (ASP) families and trios. The LD arose almost exclusively from a subgroup of our ASP families defined by the presence of severe language abnormalities and was also found to be associated with the evidence for linkage to 7q from our previously published genomewide linkage screen. Furthermore, expression analysis demonstrated WNT2 expression in the human thalamus. Based on these findings, we hypothesize that rare mutations occur in the WNT2 gene that significantly increase susceptibility to autism even when present in single copies, while a more common WNT2 allele (or alleles) not yet identified may exist that contributes to the disorder to a lesser degree.

Population-based association analyses of the HOPA12bp polymorphism for schizophrenia and hypothyroidism.

HOPA is an Xq13 chromosome gene that codes for a RXR nuclear receptor co-activator. In a prior study of the genetic basis of schizophrenia, we showed that exonic polymorphisms in HOPA were associated with increased risk of schizophrenia and hypothyroidism in a large cohort of probands from New York. In an attempt to replicate these findings, we examined this relationship in a cohort of 173 schizophrenic probands (128 males and 45 females providing 218 alleles) from Iowa. Consistent with the prior findings, we found an increased rate of the HOPA12bP exonic polymorphism in schizophrenic probands compared with random newborn controls (9 of 218 alleles vs. 33 of 2,049 alleles, P < 0.02). Furthermore, retrospective review of the medical records showed that two of the nine probands possessing the HOPA12bp allele in whom thyroid function was assessed were hypothyroid compared with 6 of 164 probands possessing the normal HOPAwild allele(s) (P < 0.06). We conclude that the HOPA12bp polymorphism shows a nominally significant association with schizophrenia and a nominal trend for association with hypothyroidism in our study and that further studies are required to define the features of this syndrome and the molecular mechanisms of disease pathogenesis.

Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder.

Autistic disorder (MIM 209850) is currently viewed as a neurodevelopmental disease. Reelin plays a pivotal role in the development of laminar structures including the cerebral cortex, hippocampus, cerebellum and of several brainstem nuclei. Neuroanatomical evidence is consistent with Reelin involvement in autistic disorder. In this study, we describe several polymorphisms identified using RNA-SSCP and DNA sequencing. Association and linkage were assessed comparing 95 Italian patients to 186 ethnically-matched controls, and using the transmission/disequilibrium test and haplotype-based haplotype relative risk in 172 complete trios from 165 families collected in Italy and in the USA. Both case-control and family-based analyses yield a significant association between autistic disorder and a polymorphic GGC repeat located immediately 5' of the reelin gene (RELN) ATG initiator codon, as well as with specific haplotypes formed by this polymorphism with two single-base substitutions located in a splice junction in exon 6 and within exon 50. Triplet repeats located in 5' untranslated regions (5'UTRs) are indicative of strong transcriptional regulation. Our findings suggest that longer triplet repeats in the 5'UTR of the RELN gene confer vulnerability to autistic disorder.

Tumor necrosis factor receptor-II: heritability and effect on brain morphology in schizophrenia.

A growing body of research suggests the involvement of immune system factors in central nervous system development and in pathophysiology related to schizophrenia.(1,2) We therefore investigated the Tumor Necrosis Factor Receptor-II (TNF-RII), a TNFalpha receptor expressed in fetal brain, as a candidate disease gene for schizophrenia. We also investigated the relationship between TNF-RII and adult brain morphology. The study sample consisted of 140 probands diagnosed with schizophrenia or schizophreniform disorder, 197 parents of the probands (a subset of which formed 62 proband-parent trios), and 46 psychiatrically normal control subjects. A bi-allelic TNF-RII polymorphism was examined for evidence of association, with none being found between this polymorphism and schizophrenia. Subjects with schizophrenia homozygous for allele 1, however, had larger ventricles and smaller frontal lobes than subjects with at least one copy of allele 2. On follow-up testing, they also had an earlier, less variable age of onset for their illness. We found no support, therefore, for TNF-RII as a disease susceptibility gene for schizophrenia. The gene may, however, modify phenotypic aspects of the disease such as brain morphology and age of onset of illness.