Sensory over-responsivity and atypical neural responses to socially relevant stimuli in autism.

Although aversive responses to sensory stimuli are common in autism spectrum disorder (ASD), it remains unknown whether the social relevance of aversive sensory inputs affects their processing. We used functional magnetic resonance imaging (fMRI) to investigate neural responses to mildly aversive nonsocial and social sensory stimuli as well as how sensory over-responsivity (SOR) severity relates to these responses. Participants included 21 ASD and 25 typically-developing (TD) youth, aged 8.6-18.0 years. Results showed that TD youth exhibited significant neural discrimination of socially relevant versus irrelevant aversive sensory stimuli, particularly in the amygdala and orbitofrontal cortex (OFC), regions that are crucial for sensory and social processing. In contrast, ASD youth showed reduced neural discrimination of social versus nonsocial stimuli in the amygdala and OFC, as well as overall greater neural responses to nonsocial compared with social stimuli. Moreover, higher SOR in ASD was associated with heightened responses in sensory-motor regions to socially-relevant stimuli. These findings further our understanding of the relationship between sensory and social processing in ASD, suggesting limited attention to the social relevance compared with aversiveness level of sensory input in ASD versus TD youth, particularly in ASD youth with higher SOR.

A multi-method evaluation of the implementation of a cancer teamwork assessment and feedback improvement programme (MDT-FIT) across a large integrated cancer system.

BACKGROUND: Globally, Multidisciplinary Teams (MDTs) are considered the gold standard for diagnosis and treatment of cancer and other conditions, but variability in performance has led to demand for improvement tools. MDT-FIT (Multidisciplinary Team Feedback for Improving Teamwork) is an improvement programme developed iteratively with over 100 MDTs (≥1100 MDT-members). Complex interventions are often adapted to context, but this is rarely evaluated. We conducted a prospective evaluation of the implementation of MDT-FIT across an entire integrated care system (ICS). METHODS: MDT-FIT was implemented within all breast cancer MDTs across an ICS in England (n = 10 MDTs; 275 medical, nursing, and administrative members). ICS managers coordinated the implementation across the three stages of MDT-FIT: set up; assessment (self-report by team members plus independent observational assessment); team-feedback and facilitated discussion to agree actions for improvement. Data were collected using process and systems logs, and interviews with a purposively selected range of participants. Analysis was theoretically grounded in evidence-based frameworks for implementation strategies and outcomes. RESULTS: All 10 MDTs participated in MDT-FIT; 36 interviews were conducted. Data from systems and process logs covered a 9-month period. Adaptations to MDT-FIT by the ICS (e.g., coordination of team participation by ICS rather than individual hospitals; and reducing time protected for coordination) reduced Fidelity and Adoption of MDT-FIT. However, the Acceptability, Appropriateness and Feasibility of MDT-FIT remained high due to embedding implementation strategies in the development of MDT-FIT (e.g., stakeholder engagement, interactive support). CONCLUSIONS: This is a unique and comprehensive evaluation of the multi-site implementation of a complex team improvement programme. Findings support the imperative of considering implementation strategies when designing such programmes to minimize potentially negative impacts of adaptations in "real world" settings.

Sex Differences in Internalizing Symptoms and Amygdala Functional Connectivity in Neurotypical Youth.

Amygdala resting-state functional connectivity (rsFC) is altered in adolescents with internalizing disorders, though the relationship between rsFC and subclinical symptomatology in neurotypical youth remains unclear. Here we examined whether amygdala rsFC varied across a continuum of internalizing symptoms in 110 typically-developing (TD) youths 8 to 17 years old using functional magnetic resonance imaging (fMRI). We assessed overall internalizing symptoms, as well as anxious-depressed, withdrawn-depressed, and somatic complaints. Given known sex differences in the prevalence of internalizing disorders, we compared connectivity between males and females. As compared to males, females with greater internalizing, anxious-depressed, and somatic symptoms displayed greater connectivity with the cingulate gyrus, insula, and somatosensory cortices. In contrast, males with greater anxious-depressed symptoms demonstrated weaker connectivity with the subcallosal prefrontal cortex. Sex differences in rsFC in relation to symptom severity were evident for the whole amygdala and for two of its subnuclei (centromedial and superficial amygdala). Overall, results suggest that, for females, higher internalizing symptoms are associated with greater rsFC between the amygdala and regions implicated in emotional and somatosensory processing, salience detection, and action selection. Future longitudinal investigations are needed to determine whether this hyperconnectivity may confer resilience to, or pose risk for, the development of internalizing disorders.

Barriers and facilitators to the successful development, implementation and evaluation of care bundles in acute care in hospital: a scoping review.

BACKGROUND: Care bundles are small sets of evidence-based recommendations, designed to support the implementation of evidence-based best clinical practice. However, there is variation in the design and implementation of care bundles, which may impact on the fidelity of delivery and subsequently their clinical effectiveness. METHODS: A scoping review was carried out using the Arksey and O'Malley framework to identify the literature reporting on the design, implementation and evaluation of care bundles. The Embase, CINAHL, Cochrane and Ovid MEDLINE databases were searched for manuscripts published between 2001 and November 2017; hand-searching of references and citations was also undertaken. Data were initially assessed using a quality assessment tool, the Downs and Black checklist, prior to further analysis and narrative synthesis. Implementation strategies were classified using the Expert Recommendations for Implementing Change (ERIC) criteria. RESULTS: Twenty-eight thousand six hundred ninety-two publications were screened and 348 articles retrieved in full text. Ninety-nine peer-reviewed quantitative publications were included for data extraction. These consisted of one randomised crossover trial, one randomised cluster trial, one case-control study, 20 prospective cohort studies and 76 non-parallel cohort studies. Twenty-three percent of studies were classified as poor based on Downs and Black checklist, and reporting of implementation strategies lacked structure. Negative associations were found between the number of elements in a bundle and compliance (Spearman's rho = - 0.47, non-parallel cohort and - 0.65, prospective cohort studies), and between the complexity of elements and compliance (p < 0.001, chi-squared = 23.05). Implementation strategies associated with improved compliance included evaluative and iterative approaches, development of stakeholder relationships and education and training strategies. CONCLUSION: Care bundles with a small number of simple elements have better compliance rates. Standardised reporting of implementation strategies may help to implement care bundles into clinical practice with high fidelity. TRIAL REGISTRATION: This review was registered on the PROSPERO database: CRD 42015029963 in December 2015.

Additive effects of oxytocin receptor gene polymorphisms on reward circuitry in youth with autism.

Several common alleles in the oxytocin receptor gene (OXTR) are associated with altered brain function in reward circuitry in neurotypical adults and may increase risk for autism spectrum disorders (ASD). Yet, it is currently unknown how variation in the OXTR relates to brain functioning in individuals with ASD, and, critically, whether neural endophenotypes vary as a function of aggregate genetic risk. Here, for we believe the first time, we use a multi-locus approach to examine how genetic variation across several OXTR single-nucleotide polymorphisms (SNPs) affect functional connectivity of the brain's reward network. Using data from 41 children with ASD and 41 neurotypical children, we examined functional connectivity of the nucleus accumbens (NAcc) - a hub of the reward network - focusing on how connectivity varies with OXTR risk-allele dosage. Youth with ASD showed reduced NAcc connectivity with other areas in the reward circuit as a function of increased OXTR risk-allele dosage, as well as a positive association between risk-allele dosage and symptom severity, whereas neurotypical youth showed increased NAcc connectivity with frontal brain regions involved in mentalizing. In addition, we found that increased NAcc-frontal cortex connectivity in typically developing youth was related to better scores on a standardized measure of social functioning. Our results indicate that cumulative genetic variation on the OXTR impacts reward system connectivity in both youth with ASD and neurotypical controls. By showing differential genetic effects on neuroendophenotypes, these pathways elucidate mechanisms of vulnerability versus resilience in carriers of disease-associated risk alleles.

Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with moderately emetogenic chemotherapy: results of a randomized, double-blind phase III trial.

BACKGROUND: To establish the role of antiemetic therapy with neurokinin-1 (NK1) receptor antagonists (RAs) in nonanthracycline and cyclophosphamide (AC)-based moderately emetogenic chemotherapy (MEC) regimens, this study evaluated single-dose intravenous (i.v.) fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) associated with non-AC MEC. PATIENTS AND METHODS: In this international, phase III, double-blind trial, adult cancer subjects scheduled to receive ≥1 non-AC MEC on day 1 were randomized to a regimen comprising single-dose i.v. fosaprepitant 150 mg or placebo along with ondansetron and dexamethasone on day 1; control regimen recipients received ondansetron on days 2 and 3. Primary end points were the proportion of subjects achieving a complete response (CR; no vomiting and no use of rescue medication) in the delayed phase (25-120 h after MEC initiation) and safety. Secondary end points included CR in the overall and acute phases (0-120 and 0-24 h after MEC initiation, respectively) and no vomiting in the overall phase. Nausea and the Functional Living Index-Emesis were assessed as exploratory end points. RESULTS: The fosaprepitant regimen improved CR significantly in the delayed (78.9% versus 68.5%; P < 0.001) and overall (77.1% versus 66.9%; P < 0.001) phases, but not in the acute phase (93.2% versus 91.0%; P = 0.184), versus control. In the overall phase, the proportion of subjects with no vomiting (82.7% versus 72.9%; P < 0.001) and no significant nausea (83.2% versus 77.9%; P = 0.030) was also significantly improved with the fosaprepitant regimen. The fosaprepitant regimen was generally well tolerated. CONCLUSION: Single-dose fosaprepitant added to a 5-HT3 RA and dexamethasone was well tolerated and demonstrated superior control of CINV (primary end point achieved) associated with non-AC MEC. This is the first study to evaluate NK1 RA therapy as an i.v. formulation in a well-defined non-AC MEC population. CLINICALTRIALSGOV: NCT01594749 (https://clinicaltrials.gov/ct2/show/NCT01594749).

A retrospective analysis of the cost of hospitalizations for sickle cell disease with crisis in England, 2010/11.

BACKGROUND: Sickle cell disease (SCD) is an inherited blood disorder which may result in a broad range of complications including recurring and severe episodes of pain--sickle 'crises'--which require frequent hospitalizations. We assessed the cost of hospitalizations associated with SCD with crisis in England. METHODS: Hospital Episodes Statistics data for all hospital episodes in England between 2010 and 2011 recording Sickle Cell Anaemia with Crisis as primary diagnosis were used. The total cost of admissions and exceeded length of stay due to SCD were assessed using Healthcare Resource Groups tariffs. The impact of patients' characteristics on SCD admissions costs and the likelihood of incurring extra bed days were also examined. RESULTS: In 2010-11, England had 6077 admissions associated with SCD with crisis as primary diagnosis. The total cost for these admissions for commissioners was £18,798 255. The cost of admissions increases with age (children admissions costs 50% less than adults). Patients between 10 and 19 years old are more likely to stay longer in hospital compared with others. CONCLUSION: SCD represents a significant cost for commissioners and the NHS. Further work is required to assess how best to manage patients in the community, which could potentially lead to a reduction in hospital admissions and length of stay, and their associated costs.

An oral selective M3 cholinergic receptor antagonist in COPD.

Cholinergic antagonists have been used since the early 1900s as bronchodilators for chronic obstructive pulmonary disease (COPD). The present study investigated whether an oral muscarinic M3-selective anticholinergic agent (OrM3) would provide an improved therapeutic advantage compared with an inhaled anticholinergic agent in patients with COPD. A 6-week, multicentre, randomised, placebo- and active-controlled, parallel-group study was performed at 56 sites in the USA. In total, 412 male and female patients (aged 35-86 yrs) with a clinical history consistent with COPD were randomised to receive OrM3 0.5, 2, 3 or 4 mg orally once daily, ipratropium bromide 36 mug by inhalation four times daily or placebo. OrM3 demonstrated a significant dose-related improvement in serial forced expiratory volume in one second and a trend for dose-related improvement in patient-reported symptoms compared with placebo. However, at a dose that provided efficacy less than that of ipratropium, the incidence of dose-related, mechanism-based side-effects for OrM3 exceeded those observed for ipratropium. In patients with chronic obstructive pulmonary disease, the oral M3-selective agent did not offer a therapeutic advantage over inhaled ipratropium. These results do not support the hypothesis that high selectivity for muscarinic M3 receptors over airway neuronal M2 receptors will represent a more effective therapy than current inhaled anticholinergics in obstructive airway disease.

Increase in urinary leukotriene LTE4 levels in acute asthma: correlation with airflow limitation.

BACKGROUND: Leukotrienes play a key role in the pathophysiology of chronic asthma. Activation of leukotriene pathways is accompanied by rises in detectable urinary levels of leukotriene E4 (LTE4). The relationship between urinary LTE4 levels and factors associated with acute asthma has not been determined. METHODS: Adults aged 15-54 years presenting with moderate to severe acute asthma were evaluated at emergency departments in 16 US sites. Forced expiratory volume in 1 second (FEV1) was measured during the first 60 minutes after arrival and at specified times until discharge or admission. Urine samples for measurement of LTE4 levels were obtained either on arrival at the study site and/or before discharge. Patients were seen 2 weeks later for follow up, at which time repeat FEV1 measurements and urine samples for LTE4 were obtained. RESULTS: One hundred and eighty four patients were evaluated; LTE4 results from both the acute and follow up periods were available for analysis in 146. Urinary LTE4 levels were increased during asthma exacerbations compared with levels obtained 2 weeks later (geometric means 111.7 and 75.6 pg/mg creatinine, respectively, mean percentage change -32.3; 95% confidence interval (CI) for the mean percentage change -39.6 to -24.3, p<0.001). The correlation between improvement in FEV1 and decline in LTE4 over the 2 week interval was significant (p<0.001, r=0.43). CONCLUSIONS: Activation of leukotriene pathways in acute asthma is correlated with the degree of airflow obstruction, and resolution of the asthma exacerbation is associated with a reduction in leukotriene levels.

Endosomal sorting of amyloid precursor protein-P-selectin chimeras influences secretase processing.

Amyloid beta protein, the major component of the senile plaques in Alzheimer's disease, is generated by secretory and endocytic processing of amyloid precursor protein. Internalized amyloid precursor protein either recycles to the plasma membrane, where alpha-secretase resides, or moves to acidic compartment(s) for beta-secretase exposure. While the trans-Golgi network contains beta-secretase activity, recent examination of the subcellular distribution of this proteinase, called BACE, has led to the suggestion that beta-secretase activity might also reside at the plasma membrane and in endosomes. To examine the role of endocytic compartments in beta-secretase processing of amyloid precursor protein, the wild-type and endosomal sorting mutant P-selectin cytoplasmic domains were used to control movement of amyloid precursor protein through endosomes. Amyloid precursor protein/P-selectin, which is sorted from early to late endosomes, undergoes significantly less alpha-secretase cleavage, and more beta-secretase cleavage, than amyloid precursor protein/P-selectin768A, a mutant that recycles more efficiently to the cell surface. Our results demonstrate that endosomal sorting influences relative exposure of the amyloid precursor protein/P-selectin chimeras to alpha- and beta-secretase activities, and suggest that, because delivery to late endocytic compartments favors beta-secretase processing of amyloid precursor protein, there is likely limited beta-secretase activity in early endosomes or at the cell surface. We propose that the trans-Golgi network may be involved in both secretory and endocytic generation of amyloid beta protein.

Working in a flawed mental health care system: an ethical challenge.

OBJECTIVE: Psychiatrists are under immense ethical pressure when practicing in circumstances that reasonable, informed colleagues would regard as not "good enough" in that they do not adequately meet the needs of patients and patients' families. This article is an examination of the ethical quandaries that ensue and options for response. METHOD: The authors explore the ways in which mental health systems may become flawed and compare philosophical arguments that deal with the predicament of working in such systems. RESULTS: The principle of fidelity to the patient is compromised in flawed systems, thus threatening professional integrity. Arguments for efficiency or the greater good in the provision of mental health care fail as remedies since they both lead to harms for particular clinical groups, as well as downgrading of a psychiatrist's integrity. CONCLUSIONS: Psychiatrists should submit to the principle of fidelity in working with patients. Since flawed systems undermine fidelity, threatening the patient's interests, psychiatrists are morally responsible for working to improve such systems.

Comparison of gas-phase free-radical populations in tobacco smoke and model systems by HPLC.

We used an improved method for trapping carbon-centered radicals (.R) from the gas-phase to compare radical suites trapped from various tobacco smoke and model smoke systems. Using a nitroxide trap, 3-amino-2,2,5,5-tetramethyl-1-pyrrolidinyloxy (3AP), on solid support, we trapped radicals directly from the gas phase, washed them off the support, and analyzed them with HPLC. Separation of the trapped radicals showed that each tobacco type produced a unique radical suite of 4-10 distinct peaks. Gas mixtures used to model tobacco smoke consisted of nitric oxide, air, isoprene, and methanol. The model systems produced radical suites of four major and several minor peaks, two of which matched peaks in tobacco smoke chromatograms. Quantities of radicals trapped from tobacco smoke were: 54 +/- 2 nmol .R per Marlboro cigarette, 66 +/- 9 nmol .R per Djarum clove cigarette, and 185 +/- 9 nmol .R per Swisher Sweet cigar. In these experiments oxygen competes with the nitroxide trap for gas-phase radicals. A kinetic analysis of the O2 competition shows that actual radical concentrations in the smoke were approximately 100-fold higher than measured.

The Ile164 beta(2)-adrenoceptor polymorphism alters salmeterol exosite binding and conventional agonist coupling to G(s).

beta(2)-adrenoceptors (beta(2)AR) are polymorphic at amino acid 164 (Thr or Ile) of the fourth transmembrane domain. In transfected fibroblasts, six agonists commonly used in the treatment of bronchospasm were studied. Isoproterenol, albuterol, metaproterenol, terbutaline, formoterol, and salmeterol displayed decreased binding affinities (K(i)s were 1.2-3.0-fold higher) and a significant degree of impaired maximal stimulation of adenylyl cyclase ( approximately 40%), was observed with all agonists for the Ile164 receptor. The ratios of signal transduction efficiencies (Tau function, Ile164/Thr164) varied from a low of 0.17 for terbutaline to 0.49 for salmeterol. In addition, Ile164 bound salmeterol at the exosite, as delineated in perfusion washout studies, at a decreased level (31+/-4.8% vs. 49+/-4.4% retained salmeterol, respectively, P=0.02). In cAMP production studies under perfusion conditions, this decreased exosite binding caused a approximately 50% decrease in the duration of action of salmeterol at Ile164 (t(1/2)=21.0+/-3.6 vs. 46.8+/-4.1 min for Thr164, P=0.001). The durations of action for isoproterenol and formoterol under similar perfusion conditions were not different between the two receptors. These in vitro results indicate the Ile164 polymorphic receptor represents a pharmacogenetic locus for the most commonly utilized agonists in the treatment of asthma with a unique phenotype for salmeterol.

AP-3 adaptor functions in targeting P-selectin to secretory granules in endothelial cells.

P-selectin, a cell adhesion protein participating in the early stages of inflammation, contains multiple sorting signals that regulate its cell surface expression. Targeting to secretory granules regulates delivery of P-selectin to the cell surface. Internalization followed by sorting from early to late endosomes mediates rapid removal of P-selectin from the surface. We show here that the P-selectin cytoplasmic domain bound AP-2 and AP-3 adaptor complexes in vitro. The amino acid substitution L768A, which abolishes endosomal sorting and impairs granule targeting of P-selectin, reduced binding of AP-3 adaptors but not AP-2 adaptors. Turnover of P-selectin was 2.4-fold faster than turnover of transferrin receptor in AP-3-deficient mocha fibroblasts, similar to turnover of these two proteins in AP-3-competent cells, demonstrating that AP-3 function is not required for endosomal sorting. However, sorting P-selectin to secretory granules was defective in endothelial cells from AP-3-deficient pearl mice, demonstrating a role for AP-3 adaptors in granule assembly in endothelial cells. P-selectin sorting to platelet alpha-granules was normal in pearl mice, consistent with earlier evidence that granule targeting of P-selectin is mechanistically distinct in endothelial cells and platelets. These observations establish that AP-3 adaptor functions in assembly of conventional secretory granules, in addition to lysosomes and the 'lysosome-like' secretory granules of platelets and melanocytes.

The evolution of medical technology: lessons from the Burgess Shale.

Many forthcoming medical advances-growth factors, tissue engineering, gene therapy, attachable prosthetic limbs, and implantable computers--are so new that as yet there is no clinical experience with them. Each therapeutic technique will evolve in an environment containing few guideposts to help judge its efficacy and safety. Recent developments in evolution theory (based on an analysis of Cambrian fossils in Canada's Burgess Shale quarry) suggest that evolution passes, at times, through innovative cycles of progress--when diversification of design leads to perfection of form--with the concomitant production of many unsuccessful models. The evolution of the total knee replacement is a perfect example of the process, because many of the early devices have proven to be dismal failures. However, modern knee replacements would not have been developed without them. Because the risk of unforeseen complications associated with new medical products cannot be discerned in advance, each patient-consumer should have the opportunity to intelligently weigh an innovative product's risk potential against its possible benefit. The proposal made here, for a temporary New Product status for new drugs and devices after a product is cleared by the Food and Drug Administration for general marketing, provides a mechanism for making such decisions.

A third specificity-determining site in mu 2 adaptin for sequences upstream of Yxx phi sorting motifs.

Internalization signals of the Yxx phi type (phi = bulky hydrophobic side chain) interact with the mu 2 chain of AP-2 adaptors. Internalization activity is intolerant of non-conservative substitution of either the tyrosine or the phi side chains, which bind to hydrophobic pockets in mu 2 adaptin in a conformation described as 'a two pinned plug into a socket'. P-selectin, a type I transmembrane protein, contains the Yxx phi-like sequence YGVF in its cytoplasmic domain, but substitution of either the tyrosine or phenylalanine with alanine in the full-length protein causes only small changes in the rate of endocytosis. It is shown here that the sequence YGVF contained within a peptide corresponding to the 17 COOH-terminal amino acids of P-selectin binds to mu 2 adaptin in the same fashion previously seen for other Yxx phi motifs. In addition, the P-selectin peptide binds to a third hydrophobic pocket in mu 2 adaptin through a leucine at position Y-3 in the peptide. This structure suggests that some sequences can function as a 'three pinned plug', in which internalization activity is not critically dependent on any one of the three interacting side chains.

The effects of ulnar axial malalignment on supination and pronation.

BACKGROUND: Forearm fractures are common injuries in both adults and children. Despite efforts to obtain anatomical alignment, axial rotational malunions occur, resulting in a decreased range of motion and a poor appearance. The objective of this study was to quantify loss of forearm rotation after simulation of ulnar malunions in supination and pronation. METHODS: Six fresh-frozen cadaveric upper extremities (mean age at the time of death, 79.4+/-2.8 years) were used to quantify loss of forearm rotation after simulation of axial rotational malunions of the ulna. First, maximum forearm rotation in supination and pronation was measured at torques of 6.8, 13.6, and 20.4 kilograms-centimeter applied with use of a custom jig. Following a midshaft ulnar osteotomy, a custom adjustable internal fixation plate was used to simulate axial rotational malunions of the ulna of 0, 15, 30, and 45 degrees in both directions. Measurements in supination and pronation were then repeated at the prespecified torques. Analysis of variance, with a p value of 0.05, was used for statistical analysis. RESULTS: In all instances, a decrease in forearm rotation after simulation of the ulnar rotational malunion was accompanied by an increase in rotation in the opposite direction. Supination and pronation were significantly influenced, whereas the total arc of rotation was not affected by ulnar rotational malunion. At a torque of 20.4 kilograms-centimeter, pronation malunions of 15, 30, and 45 degrees resulted in a mean loss of supination (and standard error of the mean) of 5+/-1, 11+/-1, and 20+/-1 degrees, respectively, and supination malunions of 15, 30, and 45 degrees resulted in a mean loss of pronation of 4+/-1, 10+/-2, and 18+/-4 degrees, respectively. The ratio of the simulated rotational malunion to the loss of motion was larger than one. CONCLUSIONS: Ulnar rotational malunions do not lead to a significant change in the total arc of forearm rotation. Instead, loss of motion in one direction is accompanied by increased motion in the opposite direction. Even with a 45-degree ulnar rotational malunion, forearm rotation decreases no more than 20 degrees.

Rapid transport of internalized P-selectin to late endosomes and the TGN: roles in regulating cell surface expression and recycling to secretory granules.

Prior studies on receptor recycling through late endosomes and the TGN have suggested that such traffic may be largely limited to specialized proteins that reside in these organelles. We present evidence that efficient recycling along this pathway is functionally important for nonresident proteins. P-selectin, a transmembrane cell adhesion protein involved in inflammation, is sorted from recycling cell surface receptors (e.g., low density lipoprotein [LDL] receptor) in endosomes, and is transported from the cell surface to the TGN with a half-time of 20-25 min, six to seven times faster than LDL receptor. Native P-selectin colocalizes with LDL, which is efficiently transported to lysosomes, for 20 min after internalization, but a deletion mutant deficient in endosomal sorting activity rapidly separates from the LDL pathway. Thus, P-selectin is sorted from LDL receptor in early endosomes, driving P-selectin rapidly into late endosomes. P-selectin then recycles to the TGN as efficiently as other receptors. Thus, the primary effect of early endosomal sorting of P-selectin is its rapid delivery to the TGN, with rapid turnover in lysosomes a secondary effect of frequent passage through late endosomes. This endosomal sorting event provides a mechanism for efficiently recycling secretory granule membrane proteins and, more generally, for downregulating cell surface receptors.

An ethical argument for a right to mental health care.

The author reviews moral arguments supporting a right to medical care, as well as empirical data concerning the effects of mental illness on society, and explores their relevance to a rights-based claim to mental health care. He concludes that there is ample ethical justification for a right to mental health care, given the obvious benefit it would convey to individuals and to society at large. He believes that this compelling moral claim should be translated into health policy.

Blocking P-selectin protects from ischemia/reperfusion-induced acute renal failure.

Acute renal failure (ARF) in response to ischemia-reperfusion is thought to be associated with neutrophil infiltration. Neutrophil recruitment depends on adhesion molecules, including P-selectin. Our study sought to characterize the role of P-selectin in ischemia-reperfusion (I/R) -induced acute renal failure (ARF). In wild-type (wt) and P-selectin-deficient (P-/-) mice (both C57BL/6), ARF was induced by 32 min bilateral renal ischemia, followed by reperfusion (I/R). Wt showed a 12- and 20-fold increase in creatinine at 24 and 48 h after I/R, respectively. Similar changes were seen in blood urea nitrogen (BUN). By contrast, in P-/- creatinine and BUN increased only moderately (fourfold over sham). In wt, renal myeloperoxidase activity, indicating neutrophil infiltration, peaked after 24 h (19-fold over sham). This was significantly attenuated in P-/- (fivefold over sham). Western blot analysis revealed maximum P-selectin expression 12 h after I/R in wt. Immunostaining detected P-selectin in glomerular endothelium and in platelets adherent in glomerular and peritubular vessels. Postischemic injection of P-selectin antibody at 10 min after reperfusion, but not isotype control antibody, protected wt from ARF similar to the protection seen in P-/-. We conclude that blocking P-selectin even after onset of reperfusion protects mice from I/R-induced ARF, suggesting potential therapeutic strategies aimed at blocking P-selectin.