Psilocybin restrains activity-based anorexia in female rats by enhancing cognitive flexibility: contributions from 5-HT1A and 5-HT2A receptor mechanisms.

Psilocybin has shown promise for alleviating symptoms of depression and is currently in clinical trials for the treatment of anorexia nervosa (AN), a condition that is characterised by persistent cognitive inflexibility. Considering that enhanced cognitive flexibility after psilocybin treatment is reported to occur in individuals with depression, it is plausible that psilocybin could improve symptoms of AN by breaking down cognitive inflexibility. A mechanistic understanding of the actions of psilocybin is required to tailor the clinical application of psilocybin to individuals most likely to respond with positive outcomes. This can only be achieved using incisive neurobiological approaches in animal models. Here, we use the activity-based anorexia (ABA) rat model and comprehensively assess aspects of reinforcement learning to show that psilocybin (post-acutely) improves body weight maintenance in female rats and facilitates cognitive flexibility, specifically via improved adaptation to the initial reversal of reward contingencies. Further, we reveal the involvement of signalling through the serotonin (5-HT) 1 A and 5-HT2A receptor subtypes in specific aspects of learning, demonstrating that 5-HT1A antagonism negates the cognitive enhancing effects of psilocybin. Moreover, we show that psilocybin elicits a transient increase and decrease in cortical transcription of these receptors (Htr2a and Htr1a, respectively), and a further reduction in the abundance of Htr2a transcripts in rats exposed to the ABA model. Together, these findings support the hypothesis that psilocybin could ameliorate cognitive inflexibility in the context of AN and highlight a need to better understand the therapeutic mechanisms independent of 5-HT2A receptor binding.

A transdiagnostic and translational framework for delineating the neuronal mechanisms of compulsive exercise in anorexia nervosa.

OBJECTIVE: The development of novel treatments for anorexia nervosa (AN) requires a detailed understanding of the biological underpinnings of specific, commonly occurring symptoms, including compulsive exercise. There is considerable bio-behavioral overlap between AN and obsessive-compulsive disorder (OCD), therefore it is plausible that similar mechanisms underlie compulsive behavior in both populations. While the association between these conditions is widely acknowledged, defining the shared mechanisms for compulsive behavior in AN and OCD requires a novel approach. METHODS: We present an argument that a better understanding of the neurobiological mechanisms that underpin compulsive exercise in AN can be achieved in two critical ways. First, by applying a framework of the neuronal control of OCD to exercise behavior in AN, and second, by taking better advantage of the activity-based anorexia (ABA) rodent model to directly test this framework in the context of feeding pathology. RESULTS: A cross-disciplinary approach that spans preclinical, neuroimaging, and clinical research as well as compulsive neurocircuitry and behavior can advance our understanding of when, why, and how compulsive exercise develops in the context of AN and provide targets for novel treatment strategies. DISCUSSION: In this article, we (i) link the expression of compulsive behavior in AN and OCD via a transition between goal-directed and habitual behavior, (ii) present disrupted cortico-striatal circuitry as a key substrate for the development of compulsive behavior in both conditions, and (iii) highlight the utility of the ABA rodent model to better understand the mechanisms of compulsive behavior relevant to AN. PUBLIC SIGNIFICANCE: Individuals with AN who exercise compulsively are at risk of worse health outcomes and have poorer responses to standard treatments. However, when, why, and how compulsive exercise develops in AN remains inadequately understood. Identifying whether the neural circuitry underlying compulsive behavior in OCD also controls hyperactivity in the activity-based anorexia model will aid in the development of novel eating disorder treatment strategies for this high-risk population.

Legacy and current-use toxic contaminants in Pacific sand lance (Ammodytes personatus) from Puget Sound, Washington, USA.

Forage fish are primary prey for seabirds, fish and marine mammals. Contaminant transfer and biomagnification of the toxic compounds measured in this study likely contribute to elevated levels in Puget Sound, Washington, salmon and killer whale tissues that could be sufficiently high to elicit adverse effects and hamper population recovery efforts. Polychlorinated biphenyls, polybrominated diphenyl ethers, chlorinated pesticides, polycyclic aromatic hydrocarbons, alkylphenols, and chlorinated paraffins were detected in all Pacific sand lance tissue samples generally below available health effect levels. Residual polycyclic aromatic hydrocarbon tissue concentrations near a former creosote site suggest ongoing contaminant exposure. Biomagnification calculations suggest that concentrations of polychlorinated biphenyls in some forage fish could result in predator tissue concentrations exceeding effect levels. The emerging contaminants alkylphenols and chlorinated paraffins are first reported here in Puget Sound forage fish, and their frequent detection, high production volumes and endocrine-disrupting properties highlight the need for further study.

A longitudinal study of MARS MRI scanning of soft-tissue lesions around metal-on-metal total hip arthroplasties and disease progression.

We investigated the changes seen on serial metal artefact reduction magnetic resonance imaging scans (MARS-MRI) of metal-on-metal total hip arthroplasties (MoM THAs). In total 155 THAs, in 35 male and 100 female patients (mean age 70.4 years, 42 to 91), underwent at least two MRI scans at a mean interval of 14.6 months (2.6 to 57.1), at a mean of 48.2 months (3.5 to 93.3) after primary hip surgery. Scans were graded using a modification of the Oxford classification. Progression of disease was defined as an increase in grade or a minimum 10% increase in fluid lesion volume at second scan. A total of 16 hips (30%) initially classified as 'normal' developed an abnormality on the second scan. Of those with 'isolated trochanteric fluid' 9 (47%) underwent disease progression, as did 7 (58%) of 'effusions'. A total of 54 (77%) of hips initially classified as showing adverse reactions to metal debris (ARMD) progressed, with higher rates of progression in higher grades. Disease progression was associated with high blood cobalt levels or an irregular pseudocapsule lining at the initial scan. There was no association with changes in functional scores. Adverse reactions to metal debris in MoM THAs may not be as benign as previous reports have suggested. Close radiological follow-up is recommended, particularly in high-risk groups.

Uterine balloon tamponade for the treatment of postpartum haemorrhage in resource-poor settings: a systematic review.

BACKGROUND: Effective interventions addressing postpartum haemorrhage (PPH) are critically needed to reduce maternal mortality worldwide. Uterine balloon tamponade (UBT) has been shown to be an effective technique to treat PPH in developed countries, but has not been examined in resource-poor settings. OBJECTIVES: This literature review examines the effectiveness of UBT for the treatment and management of PPH in resource-poor settings. SEARCH STRATEGY: Publications were sought through searches of five electronic databases: Medline, Cochrane Reference Libraries, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Embase and Popline. SELECTION CRITERIA: Titles and abstracts were screened for eligibility by two independent reviewers. Each reviewer evaluated the full text of potentially eligible articles by defined inclusion criteria, including the presentation of empirical data and use of UBT in resource-poor settings to treat PPH. DATA COLLECTION AND ANALYSIS: Full text of all eligible publications was collected and systematically coded. MAIN RESULTS: The search identified 13 studies that met the inclusion criteria: six case reports or case series, five prospective studies and two retrospective studies for a total of 241 women. No randomised controlled trials were identified. The studies used various types of UBT, including condom catheter (n = 193), Foley catheter (n = 5) and Sengstaken-Blakemore oesophageal tube (n = 1). In these studies, primarily conducted in tertiary-care settings rather than lower-level health facilities, UBT successfully treated PPH in 234 out of 241 women. CONCLUSIONS: UBT is an effective treatment for PPH in resource-poor settings. Further study of UBT interventions is necessary to better understand the barriers to successful implementation and use in these settings.

Vascular dysfunction in young, mid-aged and aged mice with latent cytomegalovirus infections.

Human cytomegalovirus (HCMV) is associated with vascular diseases in both immunosuppressed and immunocompetent individuals. CMV infections cycle between active and latent phases throughout life. We and others have shown vascular dysfunction during active mouse CMV (mCMV) infections. Few studies have examined changes in physiology during latent CMV infections, particularly vascular responses or whether the negative effects of aging on vascular function and fertility will be exacerbated under these conditions. We measured vascular responses in intact mesenteric and uterine arteries dissected from young, mid-aged, and aged latently mCMV-infected (mCMV genomes are present but infectious virus is undetectable) and age-matched uninfected mice using a pressure myograph. We tested responses to the α(1)-adrenergic agonist phenylephrine, the nitric oxide donor sodium nitroprusside, and the endothelium-dependent vasodilator methacholine. In young latently mCMV-infected mice, vasoconstriction was increased and vasodilation was decreased in mesenteric arteries, whereas both vasoconstriction and vasodilation were increased in uterine arteries compared with those in age-matched uninfected mice. In reproductively active mid-aged latently infected mice, mesenteric arteries showed little change, whereas uterine arteries showed greatly increased vasoconstriction. These vascular effects may have contributed to the decreased reproductive success observed in mid-aged latently mCMV-infected compared with age-matched uninfected mice (16.7 vs. 46.7%, respectively). In aged latently infected mice, vasodilation is increased in mesenteric and uterine arteries likely to compensate for increased vasoconstriction to mediators other than phenylephrine. The novel results of this study show that even when active mCMV infections become undetectable, vascular dysfunction continues and differs with age and artery origin.

Microbial water quality before and after the repair of a failing onsite wastewater treatment system adjacent to coastal waters.

AIMS: The objective was to assess the impacts of repairing a failing onsite wastewater treatment system (OWTS, i.e., septic system) as related to coastal microbial water quality. METHODS AND RESULTS: Wastewater, groundwater and surface water were monitored for environmental parameters, faecal indicator bacteria (total coliforms, Escherichia coli, enterococci) and the viral tracer MS2 before and after repairing a failing OWTS. MS2 results using plaque enumeration and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) often agreed, but inhibition limited the qRT-PCR assay sensitivity. Prerepair, MS2 persisted in groundwater and was detected in the nearby creek; postrepair, it was not detected. In groundwater, total coliform concentrations were lower and E. coli was not detected, while enterococci concentrations were similar to prerepair levels. E. coli and enterococci surface water concentrations were elevated both before and after the repair. CONCLUSIONS: Repairing the failing OWTS improved groundwater microbial water quality, although persistence of bacteria in surface water suggests that the OWTS was not the singular faecal contributor to adjacent coastal waters. A suite of tracers is needed to fully assess OWTS performance in treating microbial contaminants and related impacts on receiving waters. Molecular methods like qRT-PCR have potential but require optimization. SIGNIFICANCE AND IMPACT OF STUDY: This is the first before and after study of a failing OWTS and provides guidance on selection of microbial tracers and methods.

Tracking microbial transport through four onsite wastewater treatment systems to receiving waters in eastern North Carolina.

AIMS: To examine microbial transport through properly functioning and failing onsite wastewater treatment systems (OWTS) and its implication in surrounding water quality. METHODS AND RESULTS: Water samples were collected from monitoring wells near leach lines of OWTS and nearby ditches and receiving surface waters to analyse for Escherichia coli and enterococci. Tracer studies with Rhodamine WT (RWT) and coliphage MS2 were also carried out to understand the fate and transport of contaminants through each OWTS. Escherichia coli and enterococci concentrations were higher around failing than properly functioning OWTS by as much as 85-fold. A storm event resulting in 9·5 cm of rainfall increased E. coli and enterococci concentrations by averages of 4·1 × 10³ and 7·9 × 10³ MPN per 100 ml, respectively, in wells close to the OWTS. MS2 persisted in the wastewater distribution boxes of the OWTS for several months and was detected in some outer perimeter wells. CONCLUSIONS: Properly functioning OWTS in eastern North Carolina were effective in treating wastewater, whereas the failing OWTS affected the groundwater quality more adversely, especially after a rain storm, but had minor impact on the nearby coastal surface water. SIGNIFICANCE AND IMPACT OF THE STUDY: The study is the first description of the microbial contaminant signature stemming from properly functioning and failing systems under regular use in a high-priority coastal area.

Environmental exposures and respiratory morbidity among very low birth weight infants at 1 year of life.

INTRODUCTION: Preterm infants have a substantially increased risk of developing respiratory illnesses. The goal of this study was to consider the impact of modifiable postnatal exposures on respiratory morbidity among a cohort of very low birth weight (VLBW) infants. OBJECTIVES: (1) Assess the rates of respiratory morbidity and exposure to indoor respiratory triggers in a population of VLBW infants at 1 year; (2) determine the association between exposures and respiratory morbidity. METHODS: We enrolled 124 VLBW infants into a prospective cohort study. Parents were called at 1 year to assess respiratory outcomes and environmental exposures. We used bivariate and multivariate analyses to assess the relationship between environmental exposures and acute care for respiratory illnesses. RESULTS: At 1 year, 9% of infants had physician-diagnosed asthma, 47% required >or=1 acute visit and 11% required hospitalisation for respiratory illness. The majority of infants (82%) were exposed to at least one indoor respiratory trigger. Infants living with a smoker (61% vs 40%) and infants exposed to pests (62% vs 39%) were more likely than unexposed infants to require acute care for respiratory problems. In a multivariate regression controlling for demographics, birth weight, bronchopulmonary dysplasia, and family history of asthma or allergies, both living with a smoker (OR 2.62; CI 1.09 to 6.29) and exposure to pests (OR 4.41; CI 1.22 to 15.94) were independently associated with the need for acute care for respiratory illnesses. CONCLUSIONS: In this sample, respiratory morbidity and exposure to triggers were common. VLBW infants may benefit from interventions that decrease exposure to respiratory triggers.

A simple guide to determine the magnification of radiographs and to improve the accuracy of preoperative templating.

Templates are used in the preoperative planning of many orthopaedic procedures. The magnification of the bones on preoperative radiographs can vary despite using standardised radiological techniques. Templates will give misleading measurements unless this magnification is quantified. A coin may be used to calculate the magnification, with significant improvement in the accuracy of templating (p = 0.05). A group of patients undergoing uncemented arthroplasty of the hip was at high risk for intraoperative fracture of the femur because the magnification of the radiograph was larger than that of the template.

Decreased expression of the NADH:ubiquinone oxidoreductase (complex I) subunit 4 in 1-methyl-4-phenylpyridinium -treated human neuroblastoma SH-SY5Y cells.

Oxidative stress and mitochondrial dysfunction have been implicated in Parkinson's disease (PD) pathology. NADH:ubiquinone oxidoreductase (complex I) (EC 1.6.99.3) enzyme activity is aberrant in both PD and 1-methyl-4-phenylpyridinium (MPP(+)) models of PD. Reverse transcription polymerase chain reaction of RNA isolated from MPP(+)-treated human neuroblastoma SH-SY5Y cells identified changes in steady-state mRNA levels of the mitochondrial transcript for subunit 4 of complex I (ND4). Expression of ND4 decreased to nearly 50% after 72 h of MPP(+) (1 mM) exposure. The expression of other mitochondrial transcripts did not change significantly under the same conditions. Pre-incubation of cells with the free-radical spin-trap, N-tert-butyl-alpha-(2-sulfophenyl)-nitrone prior to MPP(+) exposure, prevented decreases in cell viability and ND4 expression. This suggests that functional defects in complex I enzyme activity in PD and MPP(+) toxicity may result from changes in steady-state mRNA levels and that free radicals may be important in this process.

Fatal injury: characteristics and prevention of deaths at the scene.

BACKGROUND: Almost half of all trauma deaths occur at the scene. It is important to determine if these deaths can be prevented. METHODS: Penetrating or blunt force trauma deaths were identified through the Office of the Medical Examiner during a 2-year period. Data were also obtained through review of these records. RESULTS: There were 312 deaths at the scene that received no medical care. Almost 60% were firearm-related. About 80% of the victims were men, and 55% of these deaths occurred in people between 20 and 49 years old. Suicide accounted for nearly half of these deaths. Eighty percent of these injured people had Abbreviated Injury Scale scores of 5 or 6. CONCLUSION: Almost 60% of deaths at the scene occurred at the same time as injury and reflect severe injury to vital regions of the body. These findings suggest that primary prevention of the initial event causing injury may be more important than definitive prehospital emergency medical care to prevent these deaths.

[Labrum lesions from the viewpoint of arthroscopic hip surgery]. / Die Labrumläsion aus der Sicht eines arthroskopischen Hüftchirurgen.

The torn acetabular labrum is a classical indication for hip arthroscopy. Clinical and imaging diagnosis are not so reliable compared to hip arthroscopy, which also allows therapeutic intervention. Advances in the technique of arthroscopic examination of the hip joint enable an accurate diagnosis of a torn acetabular labrum as well as arthroscopic resection of such pathology. During 267 consecutive hip arthroscopies, 37 labral lesions (13.9%) could be identified and were resected successfully. The morphological classification of labral tears, and their frequency was allocated to radial flap tears (57%), fibrillated radial tears (22%), longitudinal peripheral tears (16%) and unstable labra (5%). One year after surgery, 78% of the patients were improved, whereas 5 were not improved and 3 had worsened. Larger series with longer follow-up should be reported enabling scientific assessment of the procedure. At this early stage, however, we would recommend that all patients with a suspected labral tear should undergo hip arthroscopy.

Identification of a novel serine protease-like molecule in human brain.

Proteolysis of the amyloid beta protein precursor (APP) is a key event in the development of Alzheimer's disease. In our search for proteases that can cleave APP and liberate the amino terminus of the amyloidogenic beta protein, we characterized a calcium-dependent serine protease (CASP) which is present in reactive astrocytes and cross-reacts with anti-cathepsin G antibodies. We wanted to take advantage of this cross-reactivity to clone the cDNA of CASP and eventually evaluate its tissue distribution. Screening of two human fetal brain cDNA libraries with anti-cathepsin G antibodies led to the identification of a cDNA coding for a novel protein whose only homology to known proteins is to the active site of trypsin-type serine proteases. We called this protein the novel serine protease (NSP). NSP exists in at least three differentially spliced forms, one of which is expressed predominantly in brain and testis. Immunohistochemistry and immunoprecipitation with antibodies generated against NSP show that it is expressed and secreted by a variety of cells and that, in brain, it is found primarily in cerebrovascular smooth muscle cells and reactive astrocytes.

Rupture of the spleen in a patient with metastatic angiosarcoma of the breast.

Angiosarcoma of the breast is a rare tumour. We report a young woman who required an urgent mastectomy for bleeding. Metastatic disease resulted in her spleen rupturing after minor abdominal trauma. This has not been previously described.

The torn acetabular labrum - a hip arthroscopist's view.

The torn acetabular labrum is a classical indication for hip arthroscopy. Clinical and imaging diagnosis are not so reliable compared to hip arthroscopy, which also allows therapeutic intervention. Advances in the technique of arthroscopic examination of the hip joint enable an accurate diagnosis of a torn acetabular labrum as well as arthroscopic resection of such pathology. During 267 consecutive hip arthroscopies, 37 labral lesions (13,9 %) could be identified and were resected successfully. The morphological classification of labral tears, and their frequency was allocated to radial flap tears (57 %), fibrillated radial tears (22 %), longitudinal peripheral tears (16 %) and unstable labra (5 %). One year after surgery, 78 % of the patients were improved, whereas 5 were not improved and 3 had worsened. Larger series with longer follow-up should be reported enabling scientific assessment of the procedure. At this early stage, however, we would recommend that all patients with a suspected labral tear should undergo hip arthroscopy.

A simple laser guide to reduce the screening time during the insertion of dynamic hip screws.

A simple laser pointer can be used to guide the radiographer to position the image intensifier during the insertion of a dynamic hip screw in the treatment of fractures of the trochanteric area of the proximal femur. This significantly reduces the screening time and, by implication, the amount of radiation for the theatre staff and patient.

Staphylococcus aureus meningitis--a rare complication of iliacus muscle abscess.

Staphylococcus aureus meningitis is a rare but well recognized condition which had a high mortality and incidence of neurological sequelae. It is usually associated with chronic underlying conditions. A case is reported of S. aureus meningitis in a previously healthy young man. The epidemiology, microbiological findings and treatment of this condition are discussed.

Extrusion of Teflon aortic pledgets from a sternal wound six years after cardiac surgery.

We present a case of a cardiac surgery patient with a persistent low-grade discharge from his sternal wound for over six years. It finally healed when some suture material and Teflon felt pledgets were extruded. These had been used intraoperatively to close the aortic cannulation site. The extrusion of prosthetic material from this site after this length of time has never been described.

Insulin-like growth factor-I regulates transcription of the elastin gene through a putative retinoblastoma control element. A role for Sp3 acting as a repressor of elastin gene transcription.

Previous studies have demonstrated that insulin-like growth factor-I (IGF-I) increases elastin gene transcription in aortic smooth muscle cells and that this up-regulation is accompanied by a loss of protein binding to the proximal promoter. Sp1 has been identified as one of the factors whose binding is lost, and in the present study we show that Sp3 binding is also abrogated by IGF-I, but in a selected manner. In functional analyses using Drosophila SL-2 cells, Sp1 expression can drive transcription from the elastin proximal promoter, while co-expression of Sp3 results in a repression of Sp1 activity. Footprint and gel shift analyses position the IGF-I responsive sequences to a putative retinoblastoma control element (RCE). Mutation of the putative RCE sequence as assessed by transient transfection of smooth muscle cells results in an increase in reporter activity equal in magnitude to that conferred by IGF-I on the wild type promoter. Together these results support the hypothesis that IGF-I-mediated increase in elastin transcription occurs via a mechanism of derepression involving the abrogation of a repressor that appears to be Sp3 binding to the RCE.