Subserosal adenomyotic cysts and peritoneal inclusion cysts - Unusual differential diagnoses of multicystic pelvic masses: A review of two cases.

BACKGROUND: Multiloculated pelvic cysts are commonly misdiagnosed as ovarian tumors or malignancies. We report 2 patients diagnosed with subserosal adenomyotic cysts and peritoneal inclusion cysts, mimicking multiloculated pelvic tumors. We discuss their clinical presentation, investigations, operation findings, and histopathology, present a literature review. CASES: Case 1 was a 44-year-old patient with abnormal uterine bleeding. Imaging showed an enlarging multiloculated cystic structure over the right uterine wall. She underwent a diagnostic laparoscopy and right salpingo-ophorectomy. Intra-operatively, she was found to have multiple subserosal uterine cysts, diagnosed as adenomyotic cysts on histology.Case 2 was a 50-year-old patient with history of laparoscopic cystectomy done 20 years ago. She was incidentally found to have a multiloculated cystic lesion in the pelvis. The lesion was located midline, anterior and superior to the uterus and bladder. She underwent a total abdominal hysterectomy, bilateral salpingo-ophorectomy, and bladder peritonectomy. Intra-operatively, multiple cystic lesions were noted over the anterior and fundus of uterus, bladder peritoneum, and pelvic side walls. The condition was confirmed to be peritoneal inclusion cysts on histology. CONCLUSION: Subserosal adenomyotic cysts are a rare presentation of adenomyosis. They typically occur in premenopausal women. Treatment is usually by hormonal medications or surgical excision.Many patients with peritoneal inclusion cysts have a history of peritoneal insults. Surgical excision is the most commonly described management as they often mimic malignancy. Both conditions are unusual presentations of multiloculated pelvic masses. A high recurrence rate is found, hence long-term follow-up with imaging is essential.

Combinatorial morphogenetic and mechanical cues to mimic bone development for defect repair.

Endochondral ossification during long bone development and natural fracture healing initiates by mesenchymal cell condensation, directed by local morphogen signals and mechanical cues. Here, we aimed to mimic development for regeneration of large bone defects. We hypothesized that engineered human mesenchymal condensations presenting transforming growth factor-ß1 (TGF-ß1) and/or bone morphogenetic protein-2 (BMP-2) from encapsulated microparticles promotes endochondral defect regeneration contingent on in vivo mechanical cues. Mesenchymal condensations induced bone formation dependent on morphogen presentation, with BMP-2 + TGF-ß1 fully restoring mechanical function. Delayed in vivo ambulatory loading significantly enhanced the bone formation rate in the dual morphogen group. In vitro, BMP-2 or BMP-2 + TGF-ß1 initiated robust endochondral lineage commitment. In vivo, however, extensive cartilage formation was evident predominantly in the BMP-2 + TGF-ß1 group, enhanced by mechanical loading. Together, this study demonstrates a biomimetic template for recapitulating developmental morphogenic and mechanical cues in vivo for tissue engineering.

Percutaneous mechanical thrombectomy in the treatment of acute iliofemoral deep vein thrombosis: a systematic review.

BACKGROUND: Conventional treatment of deep vein thrombosis (DVT) of the lower extremities by anticoagulation alone has been proven to be insufficient to prevent recurrence and post-thrombotic syndrome (PTS). Early restoration of venous patency and preservation of valvular function by endovascular surgery has been advocated. The aim of this study was to review the efficacy and safety of percutaneous mechanical thrombectomy (PMT) against catheter-directed thrombolysis (CDT) in the treatment of acute iliofemoral DVT. METHODS: Three hundred sixty-nine articles were identified through screening of the PubMed, EMBASE, and Cochrane databases from January 2006 to December 2016. RESULTS: Fifteen retrospective studies and one prospective registry, totalling 1170 patients, were recruited for qualitative synthesis. The venous patency rate ranged from 75% to 100% with mean follow-up of 12.3 months. The rates of PTS and recurrent DVT were less than 17% and 15%, respectively. The overall mortality rate was 0.26%. Compared with CDT, PMT was shown to reduce PTS at 1 year (Villalta score: 2.1 ± 3.0 in the PMT group and 5.1 ± 4.1 in the CDT group, P=0.03) and bleeding complications (packed cells transfused: 0.2 ± 0.3 units in the pharmacomechanical thrombectomy group and 1.2 ± 0.7 units in the CDT group, P<0.05). CONCLUSION: Percutaneous mechanical thrombectomy is a safe and effective treatment for acute iliofemoral DVT in terms of restoration of venous patency, prevention of DVT recurrence, and PTS. Compared with CDT alone, PMT offers a lower risk of PTS and bleeding complications.

Maternal hyperglycemia in singleton pregnancies conceived by IVF may be modified by first-trimester BMI.

STUDY QUESTION: Does IVF independently increase the risk of gestational diabetes mellitus (GDM) and is this increase in risk modified by maternal body mass index? SUMMARY ANSWER: IVF appears to be an independent risk factor for GDM and elevated blood glucose levels in overweight women (BMI > 25 kg/m2). WHAT IS KNOWN ALREADY: IVF has been associated with increased risk of GDM, but most previous studies did not adequately assess confounding or effect modification by other risk factors. STUDY DESIGN, SIZE, DURATION: Cross-sectional study using data from 1089 women with singleton pregnancies who participated in a Singaporean birth cohort study (GUSTO) and received a 75 g oral glucose tolerance test (OGTT) at 26-28 weeks gestation. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 1089 women (n = 1013 conceived spontaneously, n = 76 conceived through IVF) with singleton pregnancies received a 75 g OGTT at 26-28 weeks gestation. Fasting and 2 h postprandial blood glucose levels were assayed. World Health Organization criteria (1999) standard criteria were used to classify GDM: ≥7.0 mmol/L for fasting and/or ≥7.8 mmol/L for 2-h postprandial plasma glucose levels, which was the clinical guideline in use during the study. MAIN RESULTS AND THE ROLE OF CHANCE: IVF pregnancies had nearly double the odds of GDM (OR = 1.83, 95% CI: 1.03-3.26) and elevated fasting (mean difference = 0.12 mmol/L, 95% CI: 0.00-0.24) and OGTT 2-h blood glucose levels (mean difference = 0.64 mmol/L, 95% CI: 0.27-1.01), after adjusting for commonly recognized risk factors for GDM. After stratification by first-trimester BMI, these increased risks of GDM (OR = 3.54, 95% CI: 1.44-8.72) and elevated fasting (mean difference = 0.39 mmol/L, 95% CI: 0.13-0.65) and 2-h blood (mean difference = 1.24 mmol/L, 95% CI: 0.56-1.91) glucose levels were significant only in the IVF group who is also overweight or obese (BMI > 25 kg/m2). LIMITATIONS REASONS FOR CAUTION: One limitation of our study is the absence of a 1 h post-OGTT plasma glucose sample, as we were using the 1999 WHO diagnostic criteria (the clinical guideline in Singapore) at the time of our study, instead of the revised 2013 WHO diagnostic criteria. Our cohort may not be representative of the general Singapore obstetric population, although participants were recruited from the two largest maternity hospitals in the country and include both private and subsidized patients. WIDER IMPLICATIONS OF THE FINDINGS: IVF appears to be an independent risk factor for GDM and elevated blood glucose levels in overweight women. Our findings reinforce the need to advise overweight or obese women contemplating IVF to lose weight before the procedure to reduce their risk of GDM and hyperglycemia-related adverse outcomes arising therefrom. In settings where universal GDM screening is not routine, overweight or obese women who conceive by IVF should be screened. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Singapore National Research Foundation under its Translational and Clinical Research (TCR) Flagship Program and administered by the Singapore Ministry of Health's National Medical Research Council (NMRC), Singapore (NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014). Additional funding was provided by the Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR). K.M.G. and Y.S.C. have received lecture fees from Nestle Nutrition Institute and Danone, respectively. K.M.G., Y.S.C. and S.Y.C. are part of an academic consortium that has received research funding from Abbott Nutrition, Nestec and Danone. The other authors have nothing to disclose. The other authors have nothing to disclose. TRIAL REGISTRATION NUMBER: N/A.

Biocompatibility study on Ni-free Ti-based and Zr-based bulk metallic glasses.

Safety and reliability are crucial issues for medical instruments and implants. In the past few decays, bulk metallic glasses (BMGs) have drawn attentions due to their superior mechanical properties, good corrosion resistance, antibacterial and good biocompatibility. However, most Zr-based and Ti-based BMGs contain Ni as an important element which is prone to human allergy problem. In this study, the Ni-free Ti-based and Zr-based BMGs, Ti40Zr10Cu36Pd14, and Zr48Cu36Al8Ag8, were selected for systematical evaluation of their biocompatibility. Several biocompatibility tests, co-cultural with L929 murine fibroblast cell line, were carried out on these two BMGs, as well as the comparison samples of Ti6Al4V and pure Cu. The results in terms of cellular adhesion, cytotoxicity, and metallic ion release affection reveal that the Ti40Zr10Cu36Pd14 BMG and Ti6Al4V exhibit the optimum biocompatibility; cells still being attached on the petri dish with good adhesion and exhibiting the spindle shape after direct contact test. Furthermore, the Ti40Zr10Cu36Pd14 BMG showed very low Cu ion release level, in agreement with the MTT results. Based on the current findings, it is believed that Ni-free Ti-based BMG can act as an ideal candidate for medical implant.

Single-tube tetradecaplex panel of highly polymorphic microsatellite markers < 1 Mb from F8 for simplified preimplantation genetic diagnosis of hemophilia A.

Essentials Preimplantation genetic diagnosis (PGD) of severe hemophilia A relies on linkage analysis. Simultaneous multi-marker screening can simplify selection of informative markers in a couple. We developed a single-tube tetradecaplex panel of polymorphic markers for hemophilia A PGD use. Informative markers can be used for linkage analysis alone or combined with mutation detection. SUMMARY: Background It is currently not possible to perform single-cell preimplantation genetic diagnosis (PGD) to directly detect the common inversion mutations of the factor VIII (F8) gene responsible for severe hemophilia A (HEMA). As such, PGD for such inversion carriers relies on indirect analysis of linked polymorphic markers. Objectives To simplify linkage-based PGD of HEMA, we aimed to develop a panel of highly polymorphic microsatellite markers located near the F8 gene that could be simultaneously genotyped in a multiplex-PCR reaction. Methods We assessed the polymorphism of various microsatellite markers located ≤ 1 Mb from F8 in 177 female subjects. Highly polymorphic markers were selected for co-amplification with the AMELX/Y indel dimorphism in a single-tube reaction. Results Thirteen microsatellite markers located within 0.6 Mb of F8 were successfully co-amplified with AMELX/Y in a single-tube reaction. Observed heterozygosities of component markers ranged from 0.43 to 0.84, and ∼70-80% of individuals were heterozygous for ≥ 5 markers. The tetradecaplex panel successfully identified fully informative markers in a couple interested in PGD for HEMA because of an intragenic F8 point mutation, with haplotype phasing established through a carrier daughter. In-vitro fertilization (IVF)-PGD involved single-tube co-amplification of fully informative markers with AMELX/Y and the mutation-containing F8 amplicon, followed by microsatellite analysis and amplicon mutation-site minisequencing analysis. Conclusions The single-tube multiplex-PCR format of this highly polymorphic microsatellite marker panel simplifies identification and selection of informative markers for linkage-based PGD of HEMA. Informative markers can also be easily co-amplified with mutation-containing F8 amplicons for combined mutation detection and linkage analysis.

First genome sequences of buffalo coronavirus from water buffaloes in Bangladesh.

We report the complete genome sequences of a buffalo coronavirus (BufCoV HKU26) detected from the faecal samples of two domestic water buffaloes (Bubalus bubalis) in Bangladesh. They possessed 98-99% nucleotide identities to bovine coronavirus (BCoV) genomes, supporting BufCoV HKU26 as a member of Betacoronavirus 1. Nevertheless, BufCoV HKU26 possessed distinct accessory proteins between spike and envelope compared to BCoV. Sugar-binding residues in the N-terminal domain of S protein in BCoV are conserved in BufCoV HKU26.

Hydrogen sulfide protects testicular germ cells against heat-induced injury.

OBJECTIVE: The present study was designed to investigate whether H2S can protect testicular germ cells against heat exposure induced injury and the underlying mechanisms. RESULTS: It was found that all three H2S generating enzymes, cystathionine ß-synthase (CBS), cystathionine γ-lysase (CSE), and 3-mercaptopyruvate sulfurtransferase (3 MST), were expressed in mouse testicular tissue. Three episodes of heat exposure (42 °C, 30 min/day, 3 days) significantly decreased endogenous H2S production and down-regulated the expression of CBS and CSE in testes. In primary cultured testicular germ cells, exogenous application of NaHS (an H2S donor) attenuated heat stress (42 °C, 30 min) induced cell death and apoptosis. This was mediated by the inhibitory effects of H2S on cytochrome C release and the ratio of the Bax/Bcl-2. NaHS also improved mitochondrial function by decreasing oxygen consumption and increasing ATP production. NaHS treatment also stimulated SOD activity and reduced ROS production. CONCLUSIONS: Our results revealed both physiological and pharmacological roles of H2S in testicular germ cells. Exogenous application of H2S may protect germ cells by preservation of mitochondrial function and stimulation of anti-oxidant activity.

Fabrication and laser patterning of polystyrene optical oxygen sensor films for lab-on-a-chip applications.

We present a novel and simple method for patterning oxygen-sensitive polystyrene thin films and demonstrate its potential for integration with microfluidic lab-on-a-chip devices. Optical oxygen sensing films composed of polystyrene with an embedded luminescent oxygen-sensitive dye present a convenient option for the measurement of oxygen levels in microfluidic and lab-on-a-chip devices; however, patterning and integrating the films with poly(dimethylsiloxane) (PDMS) microfluidic devices has proven difficult due to a residue after dry etch patterning that inhibits subsequent PDMS bonding. Our new method uses mask-less laser ablation by a commercial laser ablation system to define the outline of the structures and subsequent bulk film removal by aqueous lift-off. Because the bulk film is peeled or lifted off of the substrate rather than etched, the process is compatible with standard PDMS plasma bonding. We used ToF-SIMS analysis to investigate how laser ablation facilitates this fabrication process as well as why dry etching polystyrene inhibits PDMS plasma bonding. The results of this analysis showed evidence of chemical species formed during the laser ablation and dry etching processes that can produce these effects. Our new method's mask-less nature, simplicity, speed, and compatibility with PDMS bonding make it ideally suited for single-use lab-on-a-chip applications. To demonstrate the method's compatibility with PDMS microfluidics, we also present a demonstration of the sensors' integration into a microfluidic oxygen gradient generator device.

Academy of Medicine-Ministry of Health Clinical Practice Guidelines: assessment and management of infertility at primary healthcare level.

The Academy of Medicine (AMS) and Ministry of Health (MOH) have developed the clinical practice guidelines on Assessment and Management of Infertility at Primary Healthcare Level to provide doctors and patients in Singapore with evidence-based treatment for infertility. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the AMS-MOH clinical practice guidelines on Assessment and Management of Infertility at Primary Healthcare Level, for the information of SMJ readers. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Ministry of Health website: http://www.moh.gov.sg/content/moh_web/healthprofessionalsportal/doctors/guidelines/cpg_medical/2013/cpgmed_infertility.html. The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines.

Anti-Müllerian hormone versus antral follicle count for defining the starting dose of FSH.

This pilot study compared the efficacy and safety of two simple dosing algorithms, one based on anti-Müllerian Hormone (AMH) and the other on the antral follicle count (AFC), to determine the starting dose of recombinant FSH (rFSH) for ovarian stimulation in 348 women. Patients were randomized to a predefined AMH- or AFC-based algorithm. The proportion of cycles with the desired response was similar when rFSH dose was determined using AMH or AFC (35.2% versus 28.4%). There was a significant difference between the groups in the proportion of cycles with a hyperresponse (8.6% and 17.4%, but the incidence of ovarian hyperstimulation syndrome was similar (1.1% and 4.6%). There were no significant differences between two groups in outcomes, including implantation (19.3% versus 19.0%), clinical pregnancy (38.0% versus 46.9%), multiple pregnancy (16.5% versus 15.2%) and miscarriage (7.0% versus 8.3%). However, statistically significant differences in ovarian response were evident among the AMH and AFC subgroups: for AMH, Desired and Hypo; for AFC, Hypo and Hyper. This pilot study provides information for developing protocols to further validate the use of either AMH or AFC to guide the starting dose of rFSH in ovarian stimulation. The ideal outcome for couples undergoing IVF treatment is the birth of a healthy baby. One factor that might influence this is retrieving an adequate number of eggs, which are obtained using various treatment protocols. A group of drugs called gonadotrophins have been used for more than 20years to stimulate the ovaries to produce eggs. However, the dose to start treatment has not been clearly defined. A few studies have looked at ways to use the best gonadotrophin dose for each woman, but to be useful in the clinic any approach needs to be simple and easy to use. This study compared the effectiveness and safety of two simple approaches to determining the starting dose of recombinant FSH (rFSH) for ovarian stimulation in women undergoing IVF. One was based on the concentration of a hormone secreted by developing eggs (anti-Müllerian hormone; AMH) and the other on the number of developing follicles (antral follicle count; AFC). The number of cycles achieving the desired response in terms of number of eggs was similar when rFSH dose was guided using AMH or AFC, and the incidence of ovarian hyperstimulation syndrome was also similar. In addition, rates of clinical pregnancy, multiple pregnancy and miscarriage did not differ between the two groups. However, patients with low AMH concentrations or low AFC had a poor response to ovarian stimulation. This pilot study provides useful information from which new studies can further assess these approaches to personalizing treatment during IVF.

Multiple variants aggregate in the neuregulin signaling pathway in a subset of schizophrenia patients.

Despite the strongly held view that schizophrenia (SZ) shows substantial genetic heterogeneity, pathway heterogeneity, as seen in cancer where different pathways are affected in similar tumors, has not been explored. We explore this possibility in a case-only study of the neuregulin signaling pathway (NSP), which has been prominently implicated in SZ and for which there is detailed knowledge on the ligand- and receptor-processing steps through ß- and γ-secretase cleavage. We hypothesize that more than one damaging variants in the NSP genes might be necessary to cause disease, leading to an apparent clustering of such variants in only the few patients with affected NSP. We analyze linkage and next-generation sequencing results for the genes encoding components of the pathway, including NRG1, NRG3, ERBB4, ß-secretase and the γ-secretase complex. We find multiple independent examples of supporting evidence for this hypothesis: (i) increased linkage scores over NSP genes, (ii) multiple positive interlocus correlations of linkage scores across families suggesting each family is linked to either many or none of the genes, (iii) aggregation of predicted damaging variants in a subset of individuals and (iv) significant phenotypic differences of the subset of patients carrying such variants. Collectively, our data strongly support the hypothesis that the NSP is affected by multiple damaging variants in a subset of phenotypically distinct patients. On the basis of this, we propose a general model of pathway heterogeneity in SZ, which, in part, may explain its phenotypic variability and genetic complexity.

Neutralization of the γ-secretase activity by monoclonal antibody against extracellular domain of nicastrin.

Several lines of evidence suggest that aberrant Notch signaling contributes to the development of several types of cancer. Activation of Notch receptor is executed through intramembrane proteolysis by γ-secretase, which is a multimeric membrane-embedded protease comprised of presenilin, nicastrin (NCT), anterior pharynx defective 1 and PEN-2. In this study, we report the neutralization of the γ-secretase activity by a novel monoclonal antibody A5226A against the extracellular domain of NCT, generated by using a recombinant budded baculovirus as an immunogen. This antibody recognized fully glycosylated mature NCT in the active γ-secretase complex on the cell surface, and inhibited the γ-secretase activity by competing with the substrate binding in vitro. Moreover, A5226A abolished the γ-secretase activity-dependent growth of cancer cells in a xenograft model. Our data provide compelling evidence that NCT is a molecular target for the mechanism-based inhibition of γ-secretase, and that targeting NCT might be a novel therapeutic strategy against cancer caused by aberrant γ-secretase activity and Notch signaling.

Multimedia analysis + visual analytics = multimedia analytics.

To deal with the extent and variety of digital media, researchers are combining multimedia analysis and visual analytics to form the new field of multimedia analytics. This article gives some historical background, discusses surveys of related research, describes initial multimedia analytics research, and reports on benchmark datasets.

Favorable therapeutic index of the direct factor Xa inhibitors, apixaban and rivaroxaban, compared with the thrombin inhibitor dabigatran in rabbits.

BACKGROUND: Apixaban is an oral, direct factor Xa (FXa) inhibitor in late-stage clinical development. This study assessed effects of the direct FXa inhibitors, apixaban and rivaroxaban, vs. the direct thrombin inhibitor, dabigatran, on venous thrombosis (VT), bleeding time (BT) and clotting times in rabbits. METHODS: We induced the formation of non-occlusive thrombus in VT models by placing threads in the vena cava, and induced bleeding by the incision of cuticles in anesthetized rabbits. Apixaban, rivaroxaban and dabigatran were infused IV to achieve a stable plasma level. Clotting times, including the activated partial thromboplastin time (aPTT), prothrombin time (PT), modified PT (mPT) and thrombin time (TT), were measured. RESULTS: Apixaban, rivaroxaban and dabigatran exhibited dose-related efficacy in preventing VT with EC(50) of 65, 33 and 194 nm, respectively. At doses for 80% reduction of control thrombus, apixaban, rivaroxaban and dabigatran prolonged BT by 1.13 +/- 0.02-, 1.9 +/- 0.1-* and 4.4 +/- 0.4-fold*, respectively (*P < 0.05, vs. apixaban). In the treatment model, these inhibitors equally prevented growth of a preformed thrombus. Antithrombotic doses of apixaban and rivaroxaban prolonged aPTT and PT by <3-fold with no effect on TT. Dabigatran was > or = 50-fold more potent in prolonging TT than aPTT and PT. Of the clotting assays studied, apixaban, rivaroxaban and dabigatran responded the best to mPT. CONCLUSION: Comparable antithrombotic efficacy was observed between apixaban, rivaroxaban and dabigatran in the prevention and treatment of VT in rabbits. Apixaban and rivaroxaban exhibited lower BT compared with dabigatran at equivalent antithrombotic doses. The clinical significance of these findings remains to be determined.

Arterial antithrombotic and bleeding time effects of apixaban, a direct factor Xa inhibitor, in combination with antiplatelet therapy in rabbits.

BACKGROUND: Optimal treatment of arterial thrombosis may include a combination of antiplatelet and anticoagulant drugs. We evaluated apixaban, a direct and highly selective factor Xa inhibitor, in combination with clinically relevant doses of aspirin and/or clopidogrel for prevention of arterial thrombosis in rabbits. METHODS: Studies were conducted in rabbit models of electrically induced carotid artery thrombosis and cuticle bleeding time (BT). Apixaban 0.04 and 0.3 mg kg(-1) h(-1) or aspirin 1 mg kg(-1) h(-1) was infused intravenous (i.v.) continuously from 1 h before artery injury or cuticle bleed until the end of the experiment. Clopidogrel at 3 mg kg(-1) was dosed orally once daily for three days, with the last dose given 2 h before injury. RESULTS: Control thrombus weight and BT averaged 8.6 +/- 0.9 mg and 181 +/- 12 s, respectively (n = 6 per group). Effective doses of apixaban that reduced thrombus weight by 20 and 50% (ED(20) and ED(50)) were 0.04 and 0.3 mg kg(-1) h(-1) i.v., respectively. Addition of aspirin to apixaban ED(20) and ED(50) significantly reduced the thrombus weight from 7.4 +/- 0.5 to 5.3 +/- 0.3 and 3.6 +/- 0.3 mg, respectively, with no significant increases in BT (190 +/- 7 s vs.181 +/- 9 and 225 +/- 11 s, respectively). Addition of aspirin and apixaban (ED(20) dose) to clopidogrel produced a further significant reduction in thrombus weight from 5.3 +/- 0.3 to 0.7 +/- 0.1 mg. This combination of clopidogrel and aspirin with apixaban (ED(20) dose) produced a significant but moderate BT increase of 2.1 times control. CONCLUSIONS: The combination of apixaban and aspirin or apixaban, aspirin and clopidogrel can reduce formation of occlusive arterial thrombosis without excessive increases in BT in rabbits.

Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice.

beta-Site APP-cleaving enzyme 1 (BACE1) is required for the penultimate cleavage of the amyloid-beta precursor protein (APP) leading to the generation of amyloid-beta peptides that is central to the pathogenesis of Alzheimer's disease. In addition to its role in endoproteolysis of APP, BACE1 participates in the proteolytic processing of neuregulin 1 (NRG1) and influences the myelination of central and peripheral axons. Although NRG1 has been genetically linked to schizophrenia and NRG1(+/-) mice exhibit a number of schizophrenia-like behavioral traits, it is not known whether altered BACE1-dependent NRG1 signaling can cause similar behavioral abnormalities. To test this hypothesis, we analyze the behaviors considered to be rodent analogs of clinical features of schizophrenia in BACE1(-/-) mice with impaired processing of NRG1. We demonstrate that BACE1(-/-) mice exhibit deficits in prepulse inhibition, novelty-induced hyperactivity, hypersensitivity to a glutamatergic psychostimulant (MK-801), cognitive impairments, and deficits in social recognition. Importantly, some of these manifestations were responsive to treatment with clozapine, an atypical antipsychotic drug. Moreover, although the total amount of ErbB4, a receptor for NRG1 was not changed, binding of ErbB4 with postsynaptic density protein 95 (PSD95) was significantly reduced in the brains of BACE1(-/-) mice. Consistent with the role of ErbB4 in spine morphology and synaptic function, BACE1(-/-) mice displayed reduced spine density in hippocampal pyramidal neurons. Collectively, our findings suggest that alterations in BACE1-dependent NRG1/ErbB4 signaling may participate in the pathogenesis of schizophrenia and related psychiatric disorders.