Macrophage immunomodulation through new polymers that recapitulate functional effects of itaconate as a power house of innate immunity.

Itaconate (ITA) is an emerging powerhouse of innate immunity with therapeutic potential that is limited in its ability to be administered in a soluble form. We developed a library of polyester materials that incorporate ITA into polymer backbones resulting in materials with inherent immunoregulatory behavior. Harnessing hydrolytic degradation release from polyester backbones, ITA polymers resulted in the mechanism specific immunoregulatory properties on macrophage polarization in vitro. In a functional assay, the polymer-released ITA inhibited bacterial growth on acetate. Translation to an in vivo model of biomaterial associated inflammation, intraperitoneal injection of ITA polymers demonstrated a rapid resolution of inflammation in comparison to a control polymer silicone, demonstrating the value of sustained biomimetic presentation of ITA.

Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome.

Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a "Dubowitz-like" condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome-wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy-number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next-generation sequencing. Overall, the DubS-like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.

Sleep-disordered breathing in severe mental illness: clinical evaluation of oximetry diagnosis and management limitations.

BACKGROUND: To describe the diagnosis and management pathway of sleep-disordered breathing (SDB) in a sample of patients with severe mental illness (SMI), and to assess the feasibility and patient acceptability of overnight oximetry as a first-step screening method for detecting severe SDB in this population. METHODS: The study was a retrospective audit of patients with SMI seen at a Collaborative Centre for Cardiometabolic Health in Psychosis service who were invited for overnight oximetry between November 2015 and May 2018. The adjusted oxygen desaturation index (ODI) was calculated using 4% desaturation criteria. Results were discussed with a sleep specialist and categorized into a 4-level risk probability tool for SDB. RESULTS: Of 91 adults consenting for overnight oximetry, 90 collected some oximetry data, though 11 of these 90 patients collected technically unsatisfactory oximetry. Thus 79/90 patients (88%) collected adequate oximetry data for at least one night. The oximetry traces suggested likely minimal obstructive sleep apnea (OSA) in 41 cases, moderate to severe OSA in 25 patients, severe OSA in 9 patients and possible obesity hypoventilation syndrome (OHS) in 4 cases. Full polysomnography was recommended for 39 patients but only one-third underwent testing. Nineteen patients were reviewed by a sleep specialist. Of the 10 patients who initiated CPAP, four were considered adherent to treatment. CONCLUSION: Home oximetry may be a pragmatic option for SDB screening in patients with SMI but reliable full diagnostic and management pathways need to be developed.

Pasteurella multocida line infection: a case report and review of literature.

BACKGROUND: There are as many as 300,000 visits to the emergency department in the USA with animal bites every year. The most common infection after cat or dog bite is with Pasteurella Multocida. Many people infected will also have long-term central venous access for dialysis or for other reasons. No prior reports or guidelines exist regarding the management of P. multocida bacteremia due to line infection or bacteremia in the presence of long-term central venous access. We describe the successful treatment of an individual with P. multocida bacteremia secondary to tunnelled line infection managed with line retention. CASE PRESENTATION: A 21 year-old man with a history of granulomatosis with polyangiitis on home hemodialysis presented with fever and hypotension 3 days after dialysis catheter replacement. The patient was found to be bacteremic with Pasteurella Multocida and he subsequently reported a history of cat bite to his dialysis catheter. He declined removal of the tunnelled catheter and was thereafter treated for a total of 2 weeks with intravenous ceftazidime post-dialysis and gentamicin line-locks without recurrence of infection. CONCLUSIONS: Pasteurella Multocida bacteremia in the presence of a long-term central venous catheter is potentially curable using 2 weeks of intravenous antibiotics and line retention. Further data regarding outcomes of treatment in this setting are required though in select cases clinicians faced with a similar scenario could opt for trial of intravenous therapy and retention of central venous catheter.

Lin-Gettig syndrome: Craniosynostosis expands the spectrum of the KAT6B related disorders.

We report two patients with sagittal craniosynostosis, hypoplastic male genitalia, agenesis of the corpus callosum, thyroid abnormalities, and dysmorphic features which include short palpebral fissures and retrognathia. The clinical presentation of both patients was initially thought to be suggestive of Lin-Gettig syndrome (LGS), a multiple malformation syndrome associated with craniosynostosis that was initially reported in two brothers in 1990, with a third patient reported in 2003. Our first patient was subsequently found through exome sequencing to have a de novo mutation in KAT6B, c.4572dupT, p.(Thr1525Tyrfs*16). The second patient was ascertained as possible LGS, but KAT6B mutation testing was pursued clinically after the identification of the KAT6B mutation in Patient 1, and identified a de novo mutation, c.4205_4206delCT, p.(Ser1402Cysfs*5). The phenotypic spectrum of KAT6B mutations has been expanding since identification of KAT6B mutations in genitopatellar syndrome (GPS) and Say Barber Biesecker Young Simpson (SBBYS) syndrome patients. We show that craniosynostosis, which has not been previously reported in association with KAT6B mutations, may be part of the genitopatellar/Say Barber Biesecker Young Simpson spectrum. These two patients also further demonstrate the overlapping phenotypes of genitopatellar and SBBYS syndromes recently observed by others. Furthermore, we propose that it is possible that one or more of the previous cases of LGS may have also been due to mutation in KAT6B, and that LGS may actually be a variant within the KAT6B spectrum and not a distinct clinical entity.

Cover Image, Volume 173A, Number 10, October 2017.

The cover image, by Rani A. Bashir et al., is based on the Original Article Lin-Gettig syndrome: Craniosynostosis expands the spectrum of the KAT6B related disorders, DOI: 10.1002/ajmg.a.38355.

Cardiovascular disease (CVD) in Canadians with haemophilia: Age-Related CVD in Haemophilia Epidemiological Research (ARCHER study).

INTRODUCTION: Improvements in haemophilia care have increased life expectancy in persons with haemophilia (PWH). This ageing population presents clinicians with management challenges as they develop age-related comorbidities such as cardiovascular disease (CVD). AIMS: To assess the epidemiology of CVD risk factors and events in an ageing Canadian haemophilia population. METHODS: A retrospective, multicentre chart review was carried out at five Canadian Hemophilia Treatment Centres. PWH (A and B) ≥35 years old were included and data were extracted on CVD risk factors and events. RESULTS: Data from 294 patients' charts were analysed including 222 (75.5%) patients with haemophilia A and 72 (24.5%) patients with haemophilia B with a median age at end of follow-up of 54 years (range = 36-90). Mean follow-up duration was 5.86 years. Cardiovascular risk factors were common: hypertension 31.3% (n = 90), diabetes mellitus 10.5% (n = 29), smoking 21.8% (n = 61), obesity 27.6% (n = 69), dyslipidaemia 22.4% (n = 65), family history 8.5% (n = 24), antiretroviral therapy 12.2% (n = 36). There were 24 CVD events (8.2% of the population) with a median age at event of 63 years (range = 46-83). Events consisted of coronary artery disease (CAD), 14; cerebrovascular disease, 4; and atrial fibrillation, 7. CAD was treated with coronary artery bypass grafting in three patients and percutaneous coronary intervention in nine patients. CVD events were complicated by six bleeding events (three minor and three major). CONCLUSION: Cardiovascular disease risk factors and events are relatively common in PWH. PWH can be safely treated for CVD events with similar procedures as the non-PWH populations, though specific clotting factor prophylaxis protocols are not well defined.

Validation of a measurement tool for self-assessment of teamwork in intensive care.

BACKGROUND: Teamwork is an important contributor to patient safety and a validated teamwork measurement tool could help healthcare teams identify areas for improvement and measure progress. We explored the psychometric properties of a teamwork measurement tool when used for self-assessment. We hypothesized that the tool had a valid factor structure and that scores from participants and external assessors would correlate. METHODS: Forty intensive care teams (one doctor, three nurses) participated in four simulated emergencies, and each independently rated their team's performance at the end of each case using the teamwork measurement tool, without prior training in the use of the tool. We used exploratory factor analysis (EFA) and confirmatory factor analysis (CFA), and compared factor structure between participants and external assessors (using previously reported data). Scores from participants and external assessors were compared using Pearson's correlation coefficient. RESULTS: EFA demonstrated items loaded onto three distinct factors which were supported by the CFA. We found significant correlations between external and participant scores for overall teamwork scores and the three factors. Participants agreed with external assessors on the ranking of overall team performance but scored themselves significantly higher than external assessors. CONCLUSIONS: The teamwork measurement tool has a valid structure when used for self-assessment. Participant and external assessor scores correlated significantly, suggesting that participants could discriminate between different levels of performance, although leniency in self-assessed scores indicated the need for calibration. This tool could help structure reflection on teamwork and potentially facilitate self-directed, workplace-based improvement in teamwork.

Patient- and physician-level determinants of blood pressure response to treatment in normal weight and overweight patients (the PREVIEW study).

BACKGROUND AND AIMS: Obesity combined with hypertension places patients at greater risk for target-organ damage and cardiovascular disease. The purpose of this secondary analysis was to identify physician- and patient-levels determinants of blood pressure (BP) values and predictors of uncontrolled BP through subgroup analysis by body mass index (BMI). METHODS AND RESULTS: We conducted a subgroup analysis of 3006 patients with High-BMI (BMI >25 kg/m(2); n=2124) and Normal-BMI (BMI<25 kg/m(2); n=882) treated by 504 physicians and enrolled in PREVIEW, a Belgian prospective, multi-center, pharmaco-epidemiological study of 90-day second-line treatment with valsartan. Physician- and patient-level determinants of BP values and BP control were identified by means of hierarchical linear and logistic regression. Blood pressure values and control after 90 days of treatment were consistently lower for the High-BMI group. The 25.5% of variance in 90-day systolic and 28.3% of the variance in 90-day diastolic BP were attributable to physician-level determinants for the High-BMI group; versus 27.3% and 29.8% for the Normal-BMI group (ICC=0.273 and 0.298, respectively). Determinants of 90-day BP values and predictors of uncontrolled BP varied considerably by BMI status. CONCLUSION: Several common and unique patient- and physician-level determinants of BP values and control were identified for the High-BMI and Normal-BMI groups. These findings highlight the need for differentiating healthcare interventions to account for patient and physician variables, particularly with respect to effective BP management in vulnerable populations.

Non-Psychosis Symptoms of Clozapine Withdrawal: a Systematic Review.

OBJECTIVE: Clozapine is a potent antipsychotic medication with a complex receptor profile. It is reserved for treatment-resistant schizophrenia. We systematically reviewed studies of non-psychosis symptoms of clozapine withdrawal. METHODS: CINAHL, Medline, PsycINFO, PubMed, and the Cochrane Database of Systematic Reviews were searched using the keywords 'clozapine,' and 'withdrawal,' or 'supersensitivity,' 'cessation,' 'rebound,' or 'discontinuation'. Studies related to non-psychosis symptoms after clozapine withdrawal were included. RESULTS: Five original studies and 63 case reports / series were included in analysis. In 195 patients included in the five original studies, approximately 20% experienced non-psychosis symptoms following discontinuation of clozapine. In 89 patients in four of the studies, 27 experienced cholinergic rebound, 13 exhibited extrapyramidal symptoms (including tardive dyskinesia), and three had catatonia. In 63 case reports / series included, 72 patients with non-psychosis symptoms were reported, which were catatonia (n=30), dystonia or dyskinesia (n=17), cholinergic rebound (n=11), serotonin syndrome (n=4), mania (n=3), insomnia (n=3), neuroleptic malignant syndrome (NMS) [n=3, one of them had both catatonia and NMS], and de novo obsessive compulsive symptoms (n=2). Restarting clozapine appeared to be the most effective treatment. CONCLUSIONS: Non-psychosis symptoms following clozapine withdrawal have important clinical implications. Clinicians should be aware of the possible presentations of symptoms to ensure early recognition and management. Further research is warranted to better characterise the prevalence, risk factors, prognosis, and optimal drug dosing for each withdrawal symptom.

Characterization of adaptive statistical iterative reconstruction algorithm for dose reduction in CT: A pediatric oncology perspective.

PURPOSE: This study demonstrates a means of implementing an adaptive statistical iterative reconstruction (ASiR™) technique for dose reduction in computed tomography (CT) while maintaining similar noise levels in the reconstructed image. The effects of image quality and noise texture were assessed at all implementation levels of ASiR™. Empirically derived dose reduction limits were established for ASiR™ for imaging of the trunk for a pediatric oncology population ranging from 1 yr old through adolescence∕adulthood. METHODS: Image quality was assessed using metrics established by the American College of Radiology (ACR) CT accreditation program. Each image quality metric was tested using the ACR CT phantom with 0%-100% ASiR™ blended with filtered back projection (FBP) reconstructed images. Additionally, the noise power spectrum (NPS) was calculated for three common reconstruction filters of the trunk. The empirically derived limitations on ASiR™ implementation for dose reduction were assessed using (1, 5, 10) yr old and adolescent∕adult anthropomorphic phantoms. To assess dose reduction limits, the phantoms were scanned in increments of increased noise index (decrementing mA using automatic tube current modulation) balanced with ASiR™ reconstruction to maintain noise equivalence of the 0% ASiR™ image. RESULTS: The ASiR™ algorithm did not produce any unfavorable effects on image quality as assessed by ACR criteria. Conversely, low-contrast resolution was found to improve due to the reduction of noise in the reconstructed images. NPS calculations demonstrated that images with lower frequency noise had lower noise variance and coarser graininess at progressively higher percentages of ASiR™ reconstruction; and in spite of the similar magnitudes of noise, the image reconstructed with 50% or more ASiR™ presented a more smoothed appearance than the pre-ASiR™ 100% FBP image. Finally, relative to non-ASiR™ images with 100% of standard dose across the pediatric phantom age spectrum, similar noise levels were obtained in the images at a dose reduction of 48% with 40% ASIR™ and a dose reduction of 82% with 100% ASIR™. CONCLUSIONS: The authors' work was conducted to identify the dose reduction limits of ASiR™ for a pediatric oncology population using automatic tube current modulation. Improvements in noise levels from ASiR™ reconstruction were adapted to provide lower radiation exposure (i.e., lower mA) instead of improved image quality. We have demonstrated for the image quality standards required at our institution, a maximum dose reduction of 82% can be achieved using 100% ASiR™; however, to negate changes in the appearance of reconstructed images using ASiR™ with a medium to low frequency noise preserving reconstruction filter (i.e., standard), 40% ASiR™ was implemented in our clinic for 42%-48% dose reduction at all pediatric ages without a visually perceptible change in image quality or image noise.

Role of phIGFBP-1 and ultrasound cervical length in predicting pre-term labour.

This prospective observational study was to evaluate the efficacy of combining phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) and transvaginal ultrasound cervical length (CL) compared with either indicator alone in predicting pre-term labour (PTL). Women with singleton pregnancy between 24 and 36 weeks' gestation with evidence of PTL were subjected to phIGFBP-1 and CL tests. Of the 51 women, five were tested positive (phIGFBP-1 positive and CL <2.5 cm) for combination of phIGFBP-1 and CL (four delivered within 1 week), whereas 46 tested negative, of which, only one delivered. A much higher negative predictivity (NP), positive predictivity (PP) and specificity (SP) in the combination test was seen compared with phIGFBP-1 or CL alone (NP: 97.8% vs 97.7% vs 97.1%; PP: 80.0% vs 51.1% and CL 23.5%; SP: 97.8% vs 93.5% vs 71.1%, respectively). The cervical os dilatation of 2 cm with combined positive test (p = 0.001) indicated a higher likelihood of PTL.

Agrin-induced acetylcholine receptor clustering is mediated by the small guanosine triphosphatases Rac and Cdc42.

During neuromuscular junction formation, agrin secreted from motor neurons causes muscle cell surface acetylcholine receptors (AChRs) to cluster at synaptic sites by mechanisms that are insufficiently understood. The Rho family of small guanosine triphosphatases (GTPases), including Rac and Cdc42, can mediate focal reorganization of the cell periphery in response to extracellular signals. Here, we investigated the role of Rac and Cdc42 in coupling agrin signaling to AChR clustering. We found that agrin causes marked muscle-specific activation of Rac and Cdc42 in differentiated myotubes, as detected by biochemical measurements. Moreover, this activation is crucial for AChR clustering, since the expression of dominant interfering mutants of either Rac or Cdc42 in myotubes blocks agrin-induced AChR clustering. In contrast, constitutively active Rac and Cdc42 mutants cause AChR to aggregate in the absence of agrin. By indicating that agrin-dependent activation of Rac and Cdc42 constitutes a critical step in the signaling pathway leading to AChR clustering, these findings suggest a novel role for these Rho-GTPases: the coupling of neuronal signaling to a key step in neuromuscular synaptogenesis.

Staining for intracytoplasmic lumina and CAM5.2 increases the detection rate for bile duct cancers.

BACKGROUND AND STUDY AIMS: Endoscopic biopsies have a low sensitivity for diagnosing malignant bile duct strictures. Tumor markers detected by mucin staining and immunohistochemistry may help to determine the malignancy of a biopsy specimen where histologic evaluation alone is nondiagnostic. PATIENTS AND METHODS: 61 patients who underwent forceps biopsies were retrospectively identified, yielding 49 and 40 biopsy specimens for strictures finally diagnosed as benign and malignant, respectively. Biopsy specimens were histologically evaluated and stained for p53, Ki-67, carcinoembryonic antigen (CEA), CA19-9, CAM5.2, and presence of intracytoplasmic lumina (ICL). Sensitivity, specificity, positive and negative predictive values (PPV and NPV), and positive and negative likelihood ratios (PLR and NLR) were calculated to evaluate the performance of each test. RESULTS: Histology alone provided sensitivity and specificity of 53 % and 100 %. Addition of ICL or CAM5.2 increased sensitivity to 73 % or 60 %, respectively, and provided excellent specificity, PPV, and PLR (ICL, 98 %, 97 %, and 36; CAM5.2, 100 %, 100 %, and infinite). Both stains in combination increased the sensitivity to 75 %. Staining for Ki-67, p53, CEA, and CA19-9 increased the sensitivity to detect malignancy (range 60 % to 83 %), but significantly reduced the specificity, PPV and PLR (ranges 73 % to 90 %, 72 % to 86 %, and 3 to 7, respectively). Markers in all combinations performed poorly as a negative test (NPV 69 % to 87 %, and NLR 0.19 to 0.55). CONCLUSIONS: Staining for tumor markers ICL and CAM5.2 can improve the diagnostic value of endoscopic biopsies, and may change the course of management for patients with indeterminate histological findings.

Randomised trial of CPAP vs bilevel support in the treatment of obesity hypoventilation syndrome without severe nocturnal desaturation.

BACKGROUND: Untreated, obesity hypoventilation is associated with significant use of health care resources and high mortality. It remains unclear whether continuous positive airway pressure (CPAP) or bilevel ventilatory support (BVS) should be used as initial management. The aim of this study was to determine if one form of positive pressure is superior to the other in improving daytime respiratory failure. METHODS: A prospective randomised study was performed in patients with obesity hypoventilation referred with respiratory failure. After exclusion of patients with persisting severe nocturnal hypoxaemia (Spo(2) < 80% for > 10 min) or carbon dioxide retention (> 10 mm Hg) despite optimal CPAP, the remaining patients were randomly assigned to receive either CPAP or BVS over a 3-month period. The primary outcome was change in daytime carbon dioxide level. Secondary outcome measures included daytime sleepiness, quality of life, compliance with treatment and psychomotor vigilance testing. RESULTS: Thirty-six patients were randomised to either home CPAP (n = 18) or BVS (n = 18). The two groups did not differ significantly at baseline with regard to physiological or clinical characteristics. Following 3 months of treatment, daytime carbon dioxide levels decreased in both groups (CPAP 6 (8) mm Hg; BVS 7 (7) mm Hg) with no between-group differences. There was no difference in compliance between the two treatment groups (5.8 (2.4) h/night CPAP vs 6.1 (2.1) h/night BVS). Although both groups reported an improvement in daytime sleepiness, subjective sleep quality and psychomotor vigilance performance were better with BVS. CONCLUSIONS: Both CPAP and BVS appear to be equally effective in improving daytime hypercapnia in a subgroup of patients with obesity hypoventilation syndrome without severe nocturnal hypoxaemia. TRIAL REGISTRATION NUMBER: Australian Clinical Trials Registry ACTRN01205000096651.

Hippocampal alpha 5 subunit-containing GABA A receptors are involved in the development of the latent inhibition effect.

Hippocampal GABA(A) receptors containing the alpha 5 subunit have been implicated in the modulation of hippocampal-dependent learning, presumably via their tonic inhibitory influence on hippocampal glutamatergic activity. Here, we examined the expression of latent inhibition (LI)--a form of selective learning that is sensitive to a number of manipulations targeted at the hippocampal formation, in alpha 5(H105R) mutant mice with reduced levels of hippocampal alpha 5-containing GABA(A) receptors. A single pre-exposure to the taste conditioned stimulus (CS) prior to the pairing of the same CS with LiCl-induced nausea was effective in reducing the conditioned aversion against the taste CS in wild-type mice--thus constituting the LI effect. LI was however distinctly absent in male alpha 5(H105R) mutant mice. Hence, a partial loss of hippocampal alpha 5 GABA(A) receptors is sufficient to alter one major form of selective learning, albeit this was not seen in the female. This observed phenotype suggests that specific activation of these extrasynaptic GABA(A) receptors may confer therapeutic potential against the failure to show selectivity in learning by human psychotic patients.

Role of vascular endothelial cell growth factor in Ovarian Hyperstimulation Syndrome.

Controlled ovarian hyperstimulation with gonadotropins is followed by Ovarian Hyperstimulation Syndrome (OHSS) in some women. An unidentified capillary permeability factor from the ovary has been implicated, and vascular endothelial cell growth/permeability factor (VEGF) is a candidate protein. Follicular fluids (FF) from 80 women who received hormonal induction for infertility were studied. FFs were grouped according to oocyte production, from group I (0-7 oocytes) through group IV (23-31 oocytes). Group IV was comprised of four women with the most severe symptoms of OHSS. Endothelial cell (EC) permeability induced by the individual FF was highly correlated to oocytes produced (r2 = 0.73, P < 0.001). Group IV FF stimulated a 63+/-4% greater permeability than FF from group I patients (P < 0. 01), reversed 98% by anti-VEGF antibody. Group IV fluids contained the VEGF165 isoform and significantly greater concentrations of VEGF as compared with group I (1,105+/-87 pg/ml vs. 353+/-28 pg/ml, P < 0. 05). Significant cytoskeletal rearrangement of F-actin into stress fibers and a destruction of ZO-1 tight junction protein alignment was caused by group IV FF, mediated in part by nitric oxide. These mechanisms, which lead to increased EC permeability, were reversed by the VEGF antibody. Our results indicate that VEGF is the FF factor responsible for increased vascular permeability, thereby contributing to the pathogenesis of OHSS.

Three small nucleolar RNAs identified from the spliced leader-associated RNA locus in kinetoplastid protozoans.

First characterized in Trypanosoma brucei, the spliced leader-associated (SLA) RNA gene locus has now been isolated from the kinetoplastids Leishmania tarentolae and Trypanosoma cruzi. In addition to the T. brucei SLA RNA, both L. tarentolae and T. cruzi SLA RNA repeat units also yield RNAs of 75 or 76 nucleotides (nt), 92 or 94 nt, and approximately 450 or approximately 350 nt, respectively, each with significant sequence identity to transcripts previously described from the T. brucei SLA RNA locus. Cell fractionation studies localize the three additional RNAs to the nucleolus; the presence of box C/D-like elements in two of the transcripts suggests that they are members of a class of small nucleolar RNAs (snoRNAs) that guide modification and cleavage of rRNAs. Candidate rRNA-snoRNA interactions can be found for one domain in each of the C/D element-containing RNAs. The putative target site for the 75/76-nt RNA is a highly conserved portion of the small subunit rRNA that contains 2'-O-ribose methylation at a conserved position (Gm1830) in L. tarentolae and in vertebrates. The 92/94-nt RNA has the potential to form base pairs near a conserved methylation site in the large subunit rRNA, which corresponds to position Gm4141 of small rRNA 2 in T. brucei. These data suggest that trypanosomatids do not obey the general 5-bp rule for snoRNA-mediated methylation.

Maternal immune activation during pregnancy increases limbic GABAA receptor immunoreactivity in the adult offspring: implications for schizophrenia.

Prenatal exposures to a variety of infections have been associated with an increased incidence of schizophrenia. We have reported that a single injection of the synthetic cytokine releaser PolyI:C to pregnant mice produced offspring that exhibited multiple schizophrenia-related behavioral deficits in adulthood. Here, we characterized the effect of maternal inflammation during fetal brain development on adult limbic morphology and expression of GABAA-receptors. The PolyI:C treatment did not induce morphological abnormalities but resulted in a significant increase in GABAA receptor subunit alpha2 immunoreactivity (IR) in the ventral dentate gyrus and basolateral amygdala in adult treated compared to control subjects. Correlative analyses between the a2 subunit IR in the ventral dentate gyrus and the performance in the prepulse inhibition paradigm revealed a significant correlation in controls that was however absent in the pathological condition. These results suggest that prenatal immune activation-induced disturbances of early brain development result in profound alterations in the limbic expression of GABAA receptors that may underlie the schizophrenia-related behavioral deficits in the adult mice.