Similar prevalence of renovascular hypertension in selected blacks and whites.
Renovascular hypertension is a potentially curable form of high blood pressure that is thought to be extremely rare among blacks. We demonstrate, however, that in a clinically selected population, the prevalence of renovascular hypertension is similar in blacks and whites. We prospectively evaluated 167 hypertensive subjects who had one or more clinical features known to be associated with renovascular hypertension. All subjects had captopril-stimulated peripheral renin measurements and conventional renal arteriography. All significant renal artery stenoses (greater than 50% luminal narrowing) were treated with percutaneous transluminal angioplasty or surgery. Renovascular hypertension was diagnosed if there was a blood pressure response to interventional therapy, according to the criteria established by the Cooperative Study of Renovascular Hypertension. Of the total group evaluated, 24% (39 of 167) had renal artery stenosis and 14% (23 of 167) had renovascular hypertension. Renal artery stenosis or occlusion was found in 27% (26 of 97) of whites and 19% (13 of 67) of blacks (p = 0.27). Renovascular hypertension was diagnosed in 18% (17 of 97) of whites and 9% (6 of 67) of blacks evaluated (p = 0.25). Renovascular hypertension was associated with severe or refractory hypertension and with smoking, but there were no racial differences in these associations. Blacks with renovascular hypertension tended to have low captopril-stimulated peripheral renin activity. We conclude that blacks with clinical features suggestive of renovascular hypertension should be evaluated with angiography. Captopril-stimulated plasma renin may not be useful in detecting blacks with renovascular hypertension, but this and other potential screening tests require further evaluation.


Complications and outcomes of posterior fossa decompression with duraplasty versus without duraplasty for pediatric patients with Chiari malformation type I and syringomyelia: a study from the Park-Reeves Syringomyelia Research Consortium.
The aim of this study was to determine differences in complications and outcomes between posterior fossa decompression with duraplasty (PFDD) and without duraplasty (PFD) for the treatment of pediatric Chiari malformation type I (CM1) and syringomyelia (SM). The authors used retrospective and prospective components of the Park-Reeves Syringomyelia Research Consortium database to identify pediatric patients with CM1-SM who received PFD or PFDD and had at least 1 year of follow-up data. Preoperative, treatment, and postoperative characteristics were recorded and compared between groups. A total of 692 patients met the inclusion criteria for this database study. PFD was performed in 117 (16.9%) and PFDD in 575 (83.1%) patients. The mean age at surgery was 9.86 years, and the mean follow-up time was 2.73 years. There were no significant differences in presenting signs or symptoms between groups, although the preoperative syrinx size was smaller in the PFD group. The PFD group had a shorter mean operating room time (p < 0.0001), fewer patients with > 50 mL of blood loss (p = 0.04), and shorter hospital stays (p = 0.0001). There were 4 intraoperative complications, all within the PFDD group (0.7%, p > 0.99). Patients undergoing PFDD had a 6-month complication rate of 24.3%, compared with 13.7% in the PFD group (p = 0.01). There were no differences between groups for postoperative complications beyond 6 months (p = 0.33). PFD patients were more likely to require revision surgery (17.9% vs 8.3%, p = 0.002). PFDD was associated with greater improvements in headaches (89.6% vs 80.8%, p = 0.04) and back pain (86.5% vs 59.1%, p = 0.01). There were no differences between groups for improvement in neurological examination findings. PFDD was associated with greater reduction in anteroposterior syrinx size (43.7% vs 26.9%, p = 0.0001) and syrinx length (18.9% vs 5.6%, p = 0.04) compared with PFD. PFD was associated with reduced operative time and blood loss, shorter hospital stays, and fewer postoperative complications within 6 months. However, PFDD was associated with better symptom improvement and reduction in syrinx size and lower rates of revision decompression. The two surgeries have low intraoperative complication rates and comparable complication rates beyond 6 months.


Measurement of aerosol-particle trajectories using a structured laser beam.
What is believed to be a new concept for the measurement of micrometer-sized particle trajectories in an inlet air stream is introduced. The technique uses a light source and a mask to generate a spatial pattern of light within a volume in space. Particles traverse the illumination volume and elastically scatter light to a photodetector where the signal is recorded in time. The detected scattering waveform is decoded to find the particle trajectory. A design is presented for the structured laser beam, and the accuracy of the technique in determining particle position is demonstrated. It is also demonstrated that the structured laser beam can be used to measure and then correct for the spatially dependent instrument-response function of an optical-scattering-based particle-sizing system for aerosols.


Primary Care Resident Training for Obesity, Nutrition, and Physical Activity Counseling: A Mixed-Methods Study.
National guidelines have been established to support the role of primary care physicians in addressing obesity. Preparing primary care residents to recognize and treat overweight/obesity has been identified as an essential component of postgraduate medical training that is currently lacking. This study aims to identify how primary care residency programs are preparing physicians to counsel about obesity, nutrition, and physical activity (ONPA) and to examine program members' perspectives regarding the place of ONPA counseling in the curriculum, and its relevance in primary care training. Using mixed methods, we collected and analyzed data on 25 family medicine, internal medicine, and obstetrics/gynecology residency programs across Ohio. Programs averaged 2.8 hours of ONPA-related didactics per year. Ten programs (42%) taught techniques for health behavior counseling. Having any ONPA-related didactics was associated with greater counseling knowledge (p = .01) among residents but poorer attitudes (p < .001) and poorer perceived professional norms (p = .004) toward ONPA counseling. Findings from interview data highlighted similar perceived barriers to ONPA counseling across all three specialties but variation in perception of responsibility to provide ONPA counseling. While widespread expectations that primary care physicians counsel their overweight and obese patients prevail, few residency programs provide training to support such counseling.


What preoperative patient-related factors predict inpatient recovery of physical functioning and length of stay after total hip arthroplasty? A systematic review.
To identify the preoperative patient-related characteristics predicting inpatient recovery of functioning and/or length of hospital stay after elective primary total hip arthroplasty. A search was conducted of the electronic databases MEDLINE, EMBASE and CINAHL from inception through April 2014. Observational studies were selected for systematic review if they identified clinically relevant preoperative prognostic factors and reported an association between inpatient recovery of physical functioning and/or length of hospital stay. Study participants were adults undergoing an elective primary total hip arthroplasty. Fourteen studies were included, a total of 199,410 individual total hip arthroplasty procedures. Two studies investigated inpatient recovery of physical functioning, no strong level of evidence was found for a relationship between functional recovery and any of the preoperative predictors. Twelve studies investigated the length of hospital stay and reported 19 preoperative prognostic factors. A strong level of evidence suggested that higher scores on the American Society of Anaesthesiologists assessment (OR 3.34 to 6.22, +0.20 days), increased number of comorbidities (RR of 1.10, +0.59 to 1.61 days), presence of heart disease, (RR of 1.59, +0.26 days), and presence of lung disease (RR of 1.30, +0.34 days) were associated with longer lengths of hospital stay following total hip arthroplasty. For the prediction of inpatient recovery of physical functioning no factors with a strong level of evidence were found. For length of stay there was a strong level of evidence for the American Society of Anaesthesiologists score, number of comorbidities, and presence of heart or lung disease.


Evaluation of a shared approach to interprofessional learning about stroke self-management.
This article describes an evaluation of interprofessional training in a stroke self-management program (SSMP) for health and social care professionals. Sixty-six practitioners from 8 teams and 11 professions received training. The aim was to evaluate the impact of the interprofessional training on participants' beliefs and attitudes to self-management and collaboration and knowledge sharing throughout the stroke pathway. Methods included contextual mapping of the stroke pathway, before and after questionnaires, analysis of practitioners' case reflections on their use of the SSMP and semi-structured interviews. Overall, practitioners' attitudes and beliefs about self-management had changed post-training, and the majority felt the program could be used successfully throughout the stroke pathway. Practitioners felt that the interprofessional training had led to a more consistent approach to supporting self-management and had improved communication between teams about patients/goals. The project provided the opportunity for interprofessional teams to explore beliefs and attitudes to changes in practice together.


Management of patients with stroke: is it time to expand treatment options?
Approximately 700,000 people in the United States have an ischemic stroke annually. Substantial research has tested therapies for the very early treatment of ischemic stroke but, to date, only intravenous thrombolysis and intra-arterial measures to restore perfusion have shown success. Despite a 15-year effort to increase the use of these therapies, only approximately 5% of patients with stroke are currently being treated. Although most patients with stroke have some neurological recovery, more than half of stroke survivors have residual impairments that lead to disability or long-term institutionalized care. Laboratory research has demonstrated several mechanisms that help the brain to recover after a stroke. New pharmacological and cell-based approaches that are known to promote brain plasticity are emerging from laboratory studies and may soon expand the window for stroke treatment to restore function. It is time to build on this knowledge and to translate the understanding of recovery after stroke into the clinical setting. Measures that might augment recovery should become a major focus of clinical research in stroke in the 21st century.


Multisite comparison of high-sensitivity multiplex cytokine assays.
The concentrations of cytokines in human serum and plasma can provide valuable information about in vivo immune status, but low concentrations often require high-sensitivity assays to permit detection. The recent development of multiplex assays, which can measure multiple cytokines in one small sample, holds great promise, especially for studies in which limited volumes of stored serum or plasma are available. Four high-sensitivity cytokine multiplex assays on a Luminex (Bio-Rad, BioSource, Linco) or electrochemiluminescence (Meso Scale Discovery) platform were evaluated for their ability to detect circulating concentrations of 13 cytokines, as well as for laboratory and lot variability. Assays were performed in six different laboratories utilizing archived serum from HIV-uninfected and -infected subjects from the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS) and commercial plasma samples spanning initial HIV viremia. In a majority of serum samples, interleukin-6 (IL-6), IL-8, IL-10, and tumor necrosis factor alpha were detectable with at least three kits, while IL-1β was clearly detected with only one kit. No single multiplex panel detected all cytokines, and there were highly significant differences (P < 0.001) between laboratories and/or lots with all kits. Nevertheless, the kits generally detected similar patterns of cytokine perturbation during primary HIV viremia. This multisite comparison suggests that current multiplex assays vary in their ability to measure serum and/or plasma concentrations of cytokines and may not be sufficiently reproducible for repeated determinations over a long-term study or in multiple laboratories but may be useful for longitudinal studies in which relative, rather than absolute, changes in cytokines are important.


The evolution of conditional dispersal and reproductive isolation along environmental gradients.
Dispersal modulates gene flow throughout a population's spatial range. Gene flow affects adaptation at local spatial scales, and consequently impacts the evolution of reproductive isolation. A recent theoretical investigation has demonstrated that local adaptation along an environmental gradient, facilitated by the evolution of limited dispersal, can lead to parapatric speciation even in the absence of assortative mating. This and other studies assumed unconditional dispersal, so individuals start dispersing without regard to local environmental conditions. However, many species disperse conditionally; their propensity to disperse is contingent upon environmental cues, such as the degree of local crowding or the availability of suitable mates. Here, we use an individual-based model in continuous space to investigate by numerical simulation the relationship between the evolution of threshold-based conditional dispersal and parapatric speciation driven by frequency-dependent competition along environmental gradients. We find that, as with unconditional dispersal, parapatric speciation occurs under a broad range of conditions when reproduction is asexual, and under a more restricted range of conditions when reproduction is sexual. In both the asexual and sexual cases, the evolution of conditional dispersal is strongly influenced by the slope of the environmental gradient: shallow environmental gradients result in low dispersal thresholds and high dispersal distances, while steep environmental gradients result in high dispersal thresholds and low dispersal distances. The latter, however, remain higher than under unconditional dispersal, thus undermining isolation by distance, and hindering speciation in sexual populations. Consequently, the speciation of sexual populations under conditional dispersal is triggered by a steeper gradient than under unconditional dispersal. Enhancing the disruptiveness of frequency-dependent selection, more box-shaped competition kernels dramatically lower the speciation-enabling slope of the environmental gradient.


Thermolabile CPT II variants and low blood ATP levels are closely related to severity of acute encephalopathy in Japanese children.
Despite the decrease in Reye syndrome after the discontinuation of aspirin, acute encephalopathy (non-Reye syndrome type) has been continually reported in Japan. Recent studies suggested that the thermolabile phenotype of carnitine palmitoyltransferase II (CPT II) variation [F352C] was closely related to the pathomechanism of influenza-associated encephalopathy (IAE) in Japanese, causing mitochondrial ATP utilization failure during periods of high fever, resulting in brain edema. So, we analyzed CPT II polymorphism and peripheral blood ATP levels as a signal of "energy crisis" in 12 and 10 patients with acute encephalopathy, respectively. Out of the 12 patients with acute encephalopathy, six showed thermolabile CPT II variants [F352C], and of these six, two patients died in spite of intensive care. In contrast, the remaining six patients with no thermolabile CPT II variant [F352C] showed a relatively mild clinical course. Blood ATP levels of the 10 patients in the acute phase of encephalopathy were significantly lower than those during the convalescent phase and also those of patients with febrile seizure status. Our data suggest that the thermolabile F352C CPT II variant, found only in Japanese, might be one of the predisposing factors to trigger the pathomechanism of acute encephalopathy in the Japanese population, and that it is causally related to the severity of disease. The decreased blood ATP level seems to reflect systemic mitochondrial dysfunction including the blood brain barrier during the acute phase of encephalopathy.


Early exposure to Aroclor 1254 in vivo disrupts the functional synaptic development of newborn hippocampal granule cells.
Neurogenesis in the dentate gyrus is sensitive to endogenous and exogenous factors that influence hippocampal function. Ongoing neurogenesis and the integration of these new neurons throughout life thus may provide a sensitive indicator of environmental stress. We examined the effects of Aroclor 1254 (A1254), a mixture of polychlorinated biphenyls (PCBs), on the development and function of newly generated dentate granule cells. Early exposure to A1254 has been associated with learning impairment in children, suggesting potential impact on the development of hippocampus and/or cortical circuits. Oral A1254 (from the 6th day of gestation to postnatal day 21) produced the expected increase in PCB levels in brain at postnatal day 21, which persisted at lower levels into adulthood. A1254 did not affect the proliferation or survival of newborn neurons in immature animals nor did it cause overt changes in neuronal morphology. However, A1254 occluded the normal developmental increase in sEPSC frequency in the third post-mitotic week without altering the average sEPSC amplitude. Our results suggest that early exposure to PCBs can disrupt excitatory synaptic function during a period of active synaptogenesis, and thus could contribute to the cognitive effects noted in children exposed to PCBs.


Psychiatric illness predicts poor outcome after surgery for hip fracture: a prospective cohort study.
Hip fracture is common in the elderly. Previous studies suggest that psychiatric illness is common and predicts poor outcome, but have methodological weaknesses. Further studies are required to address this important issue. We prospectively recruited 731 elderly participants with hip fracture in two Leeds hospitals. Psychiatric diagnosis was made within 5 days of surgery using the Geriatric Mental State schedule and other standardized instruments, and data on confounding factors was collected. Main study outcomes were length of hospital stay, and mortality over 6 months after fracture. Fifty-five per cent of participants had cognitive impairment (dementia in 40% and delirium in 15%), 13% had a depressive disorder, 2% had alcohol misuse and 2% had other psychiatric diagnoses. Participants were likely to remain in hospital longer if they suffered from dementia, delirium or depression. The relative risks of mortality over 6 months after hip fracture were increased in dementia and delirium, but not in depression. Psychiatric illness is common after hip fracture, and has significant effects on important outcomes. This suggests a need for randomized, controlled trials of psychiatric interventions in the elderly hip fracture population.


T cell-dependent B cell activation.
B cells obtain help from T cells in the antibody response by acting as antigen-specific antigen presenting cells. A direct signal through binding of antigen to membrane Ig can enhance B cell antigen presentation and T-dependent B cell activation, but is not required for a productive interaction between a small resting B cell and a differentiated helper T cell. As a result of helper T cell recognition of antigen on the B cell surface, the T cell becomes activated and in turn activates the B cell. T cell help has two components: lymphokines which act as growth and differentiation factors for B cells, and additional signals which require cell contact and enable B cells to respond to lymphokines. Contact help activity is regulated like lymphokine synthesis and secretion. Because contact help activity is retained by fixed, activated helper T cells and plasma membranes prepared from activated T cells, contact help is likely to be owing to new proteins expressed as membrane-bound lymphokines or activation antigens on helper T cells. Once induced, contact help can be delivered to B cells independently of recognition of antigen/class II MHC. A newly identified activation antigen of helper T cells, a ligand for the B cell differentiation antigen, CD40, is a key component of contact help. The roles of other T and B cell membrane molecules in contact help are reviewed.


PcG complexes set the stage for epigenetic inheritance of gene silencing in early S phase before replication.
Polycomb group (PcG) proteins are part of a conserved cell memory system that conveys epigenetic inheritance of silenced transcriptional states through cell division. Despite the considerable amount of information about PcG mechanisms controlling gene silencing, how PcG proteins maintain repressive chromatin during epigenome duplication is still unclear. Here we identified a specific time window, the early S phase, in which PcG proteins are recruited at BX-C PRE target sites in concomitance with H3K27me3 repressive mark deposition. Notably, these events precede and are uncoupled from PRE replication timing, which occurs in late S phase when most epigenetic signatures are reduced. These findings shed light on one of the key mechanisms for PcG-mediated epigenetic inheritance during S phase, suggesting a conserved model in which the PcG-dependent H3K27me3 mark is inherited by dilution and not by de novo methylation occurring at the time of replication.


The spectral analysis of photoplethysmography to evaluate an independent cardiovascular risk factor.
In this study, we evaluate homeostatic markers correlated to autonomic nervous and endothelial functions in a population of coronary artery disease (CAD) patients versus a control group. Since CAD is the highest risk marker for sudden cardiac death, the study objective is to determine whether an independent cardiovascular risk score based on these markers can be used alongside known conventional cardiovascular risk markers to strengthen the understanding of a patient's vascular state. Sixty-five subjects (13 women) with a mean age of 62.9 years (range 40-80 years) who were diagnosed with CAD using coronary angiography (group 1) and seventy-two subjects (29 women) with a mean age of 45.1 years (range 18-85 years) who claimed they were healthy (group 2) were included in the study. These subjects underwent examination with the TM-Oxi and SudoPath systems at IPC Heart Care Centers in Mumbai, India. The TM-Oxi system takes measurements from a blood pressure device and a pulse oximeter. The SudoPath measures galvanic skin response to assess the sudomotor pathway function. Spectral analysis of the photoplethysmograph (PTG) waveform and electrochemical galvanic skin response allow the TM-Oxi and SudoPath systems to calculate several homeostatic markers, such as the PTG index (PTGi), PTG very low frequency index (PTGVLFi), and PTG ratio (PTGr). The focus of this study was to evaluate these markers (PTGi, PTGVLFi, and PTGr) in CAD patients against a control group, and to calculate an independent cardiovascular risk factor score: the PTG cardiovascular disease risk score (PTG CVD), calculated solely from these markers. We compared PTGi, PTGVLFi, PTGr, and PTG CVD scores between the CAD patient group and the healthy control group. Statistical analyses were performed using receiver operating characteristic curves to determine the specificity and sensitivity of the markers to detect CAD at optimal cutoff values for PTGi, PTGVLFi, PTGr, and PTG CVD. In addition, correlation analyses between these markers and conventional autonomic nervous system and endothelial function markers were performed to understand the possible underlying physiological sources of the differences observed in marker values between CAD patients and healthy control patients. Additionally, t-tests were performed between two subgroups of the CAD patient group to determine whether diabetic or coronary artery bypass grafting (CABG) patients have significantly different PTGi marker values. Each spectral analysis PTG marker yielded a high specificity and sensitivity to detect CAD. Most notably, the PTG CVD score had a sensitivity of 82.5% and specificity of 96.8%, at a cutoff of 2, when used to detect CAD (P=0.0001; area under the receiver operating characteristic curve =0.967). The PTG spectral analysis markers were well-correlated to other autonomic nervous system and endothelial function markers. CAD diabetic patients (n=27) had a lower PTGi value compared with the CAD non-diabetic patients (n=38): and patients that underwent CABG (n=18) had a higher PTGi value compared with the CAD without CABG surgery patients (n=47). The spectral analysis of the photoplethysmography method is noninvasive, fast, operator-independent, and cost-effective, as only an oximeter and galvanic skin response device are required in order to assess in a single testing the autonomic nervous system and endothelial function. The spectral analysis techniques used on the photoplethysmogram, as outlined in this study, could be useful when used alongside conventional known cardiovascular disease risk markers.


Predictive Value of Four-Dimensional Strain Echocardiography for Adverse Cardiovascular Outcomes in ST-Elevation Myocardial Infarction Patients Treated with Primary Percutaneous Coronary Intervention.
To investigate the predictive value of four-dimensional (4D) strain echocardiography for major adverse cardiovascular events (MACE) in ST-elevation acute myocardial infarction (STEMI) patients. Consecutive STEMI patients who underwent successful primary coronary interven tion (PCI) were enrolled and followed, with 2D and 4D strain echocardiography performed within 1 week after PCI. Twenty-six first MACE were recorded in 81 patients who finished a ∼3.0 year follow-up. Compared with those without MACE, subjects with MACE were more likely to have anterior MI (73.08 vs. 38.18%, p = 0.003), significantly decreased 2D left ventricular ejection fraction (2DLVEF) and 4DLVEF (all p < 0.05), as well as an overtly compromised 4D strain parameters. The prediction models incorporating infarct location with either 2DLVEF or 4D strain parameters were then developed. Model comparisons revealed that the global area strain (GAS)-based model had the highest discriminative capacity (c statistics = 0.774) and was well calibrated for MACE. Additionally, the clinical utility of the GAS-based prediction model was verified by decision curve analysis showing a consistent positive and larger net benefit compared to the 2DLVEF-based model. Our data support a superiority of 4D strain echocardiography over conventional 2D echocardiography, especially GAS, for risk stratification in STEMI patients after successful primary PCI.


1H NMR Metabolomics Study of Metastatic Melanoma in C57BL/6J Mouse Spleen.
Melanoma is a malignant tumor of melanocytes. Although extensive investigations have been done to study metabolic changes in primary melanoma in vivo and in vitro, little effort has been devoted to metabolic profiling of metastatic tumors in organs other than lymph nodes. In this work, NMR-based metabolomics combined with multivariate data analysis is used to study metastatic B16-F10 melanoma in C57BL/6J mouse spleen. Principal Component Analysis (PCA), an unsupervised multivariate data analysis method, is used to detect possible outliers, while Orthogonal Projection to Latent Structure (OPLS), a supervised multivariate data analysis method, is employed to find important metabolites responsible for discriminating the control and the melanoma groups. Two different strategies, i.e. spectral binning and spectral deconvolution, are used to reduce the original spectral data before statistical analysis. Spectral deconvolution is found to be superior for identifying a set of discriminatory metabolites between the control and the melanoma groups, especially when the sample size is small. OPLS results show that the melanoma group can be well separated from its control group. It is found that taurine, glutamate, aspartate, O-Phosphoethanolamine, niacinamide,ATP, lipids and glycerol derivatives are decreased statistically and significantly while alanine, malate, xanthine, histamine, dCTP, GTP, thymidine, 2'-Deoxyguanosine are statistically and significantly elevated. These significantly changed metabolites are associated with multiple biological pathways and may be potential biomarkers for metastatic melanoma in spleen.


Once and Again : History of Rearing Experiences and Psychosocial Parenting Resources at Six Months in Primiparous Mothers.
Animal and human studies suggest that parenting style is transmitted from one generation to the next. The hypotheses of this study were that (1) a mother's rearing experiences (G1) would predict her own parenting resources (G2) and (2) current maternal mood, motivation to care for her offspring, and relationship with her parents would underlie this association. In a subsample of 201 first-time mothers participating in the longitudinal Maternal Adversity, Vulnerability and Neurodevelopment project, we assessed a mother's own childhood maltreatment and rearing experiences (G1) using the Childhood Trauma Questionnaire and the Parental Bonding Instrument. At 6 months postpartum, mothers completed questionnaires on parenting stress (G2), symptoms of depression, maternal motivation, and current relationship with their own parents. The sample consisted of mostly high socioeconomic status mothers recruited from Montréal (n = 135) or Hamilton (n = 66), Canada, with an age range from 18 to 43 years (M = 29.41, SD = 4.85 years). More severe maltreatment and less supportive rearing by the mother's parents (G1) predicted increased parenting stress at 6 months (G2). These associations were mediated through distinct psychosocial pathways: maltreatment (G1) on parenting stress (G2) through symptoms of depression (Z = 2.297; p = .022); maternal rearing (G1) on parenting stress (G2) through maternal motivation (Z = -2.155; p = .031) and symptoms of depression (Z = -1.842; p = .065); and paternal rearing (G1) on parenting stress (G2) through current relationship with the father (Z = -2.617; p = .009). Maternal rearing experiences predict a mother's own parenting resources though distinct psychosocial pathways, including depressed mood, maternal motivation, and social support.


Therapeutic genome editing: prospects and challenges.
Recent advances in the development of genome editing technologies based on programmable nucleases have substantially improved our ability to make precise changes in the genomes of eukaryotic cells. Genome editing is already broadening our ability to elucidate the contribution of genetics to disease by facilitating the creation of more accurate cellular and animal models of pathological processes. A particularly tantalizing application of programmable nucleases is the potential to directly correct genetic mutations in affected tissues and cells to treat diseases that are refractory to traditional therapies. Here we discuss current progress toward developing programmable nuclease-based therapies as well as future prospects and challenges.


Dietary alpha lipoic acid supplementation prevents synovial inflammation and bone destruction in collagen-induced arthritic mice.
Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by chronic inflammation and joint destruction. In this study, we investigated whether dietary supplementation with alpha lipoic acid (ALA) suppresses collagen-induced arthritis (CIA) in mice. Mice were randomly divided into three groups: (1) a control CIA group was fed a normal diet, (2) a CIA group was fed a 0.1% ALA diet (average ALA intake of 160 mg/kg/day), and (3) a CIA group was fed a 0.5% ALA diet (average ALA intake of 800 mg/kg/day). The ALA-fed mice showed a decreased incidence and severity of arthritis compared to the normal diet group. Radiographic findings revealed a dramatic decrease in bone destruction, and histological findings showed extensively suppressed pathological changes in the ALA-fed mice. The ALA-fed mice exhibited inhibited generation of tartrate resistant acid phosphatase (TRAP)-positive osteoclasts in vivo. Additionally, ALA-fed mice reduced production of various proinflammatory cytokines and the soluble receptor activator of NF-κB ligand (sRANKL) in the joint tissues and the sera. In conclusion, dietary supplementation with ALA attenuated inflammatory responses and bone destruction in CIA mice.


Calodromius bifasciatus and other Carabidae on 26 oak-trunks in a nature reserve in the Netherlands.
The discovery of Calodromius bifasciatus in the nature reserve 'De Kaaistoep', the Netherlands, initiated research on this and related carabid beetles between 2000 and 2006. During this period we investigated the trunks of 26 Pedunculate oaks, mainly during nightly observations, to learn more about arboricolous carabid species. We observed more than 3000 specimens of 24 carabid species. The majority of these species were Dromiuss.l., however Calodromius bifasciatus dominated the dataset. Our data on phenology clearly show that Calodromius bifasciatus is mainly active in winter; it even copulates just above freezing point. Other interesting observations were made as well; for instance the presence of a small sphere at the end of the abdomen and their hiding behaviour at low temperatures. Subsequently, we obtained similar information about other tree dwelling carabid species. In this article we present an overview of all species observed on the trunks, after which we shall focus on the observations made on Calodromius bifasciatus.


The Cortical Basal ganglia Functional Scale (CBFS): Development and preliminary validation.
To develop a patient/care-giver reported scale capable of easily and reliably assessing functional disability in 4 repeat tauopathies (4RTs). 4R tauopathies including progressive supranuclear palsy, corticobasal degeneration and a subset of frontotemporal dementias manifest a range of overlapping clinical phenotypes. No available rating scale is capable of evaluating the functional impact of these complex disorders. A multi-staged modified Delphi process was used to propose, evaluate and rank potential scale items providing content validity ratios. Staged cognitive pretesting involving input from examiners, patients and caregivers was followed by validation testing in patients participating in the 4R Tauopathy Neuroimaging Initiative or the PROgressive Supranuclear Palsy CorTico-Basal Syndrome MSA Longitudinal Study. Clinimetric properties were examined using classical test theory and item response methods, assessing data quality, reliability, construct validity, convergent validity and known-group validity. The resultant Cortical Basal ganglia Functional Scale (CBFS) included questions on Motor Experiences in Daily Living (14 items) and Non-Motor Experiences of Daily Living (17 items). Reliability was acceptable for internal consistency, test-retest stability, item discrimination, item-scaling thresholds and item-fit. Examination of construct validity revealed a parsimonious two-factor solution, and concurrent validity demonstrated significant correlations between the CBFS and other measures of disease severity and functional impairment. The CBFS significantly discriminated between all diagnostic groups and controls (all AUCs>90). The CBFS scores demonstrated sensitivity to change over a 12 month follow-up in patients with probable 4RTs. The CBFS is a patient/care-giver reported outcome measure with excellent clinimetric properties that captures disability correlated with motor, cognitive and psychiatric impairments.


Hypertensive Crisis From the Aquamantys Bipolar Sealing System.
Hypertension is a common occurrence during general anesthesia. Apart from pathological causes of hypertension, it is rarely extreme enough to be classified as a hypertensive crisis (systolic blood pressure >180 mm Hg or diastolic blood pressure >120 mm Hg). There is literature concerning the unintentional electrocauterization of the adrenal gland leading to hypertensive crisis, but to date, no reports have been made of adrenal stimulation from the use of an Aquamantys for hemostasis. Here, we report such a case when a hypertensive crisis (systolic blood pressure >300 mm Hg) occurred while using an Aquamantys during a liver transplant after unintentional stimulation of the adrenal glands.


Plasma catecholamines during exercise-induced bronchoconstriction in bronchial asthma.
Plasma levels of adrenaline and noradrenaline during and after submaximal exercise in patients with bronchial asthma were investigated. Three groups were studied comprising 10 patients with exercise-induced bronchoconstriction (EIB), 10 asthmatic patients without EIB and four normal control subjects. Plasma catecholamines were measured at rest, at the end of exercise, and five and 15 minutes after exercise. Changes in airway resistance were assessed by measuring peak expiratory flow rate. Significant differences in catecholamine levels between reacting and non-reacting patients were found. In 10 patients developing EIB adrenaline and noradrenaline levels had risen significantly by the end of exercise and remained elevated up to the fifth minute of recovery. The rise in catecholamine levels in non-reacting asthmatics was insignificant. In control subjects noradrenaline had increased significantly by the end of exercise.


Effectiveness of different central venous catheters for catheter-related infections: a network meta-analysis.
We aimed to compare the effectiveness of various catheters for prevention of catheter-related infection and to evaluate whether specific catheters are superior to others for reducing catheter-related infections. We identified randomised, controlled trials that compared different types of central venous catheter (CVC), evaluating catheter-related infections in a systematic search of articles published from January 1996 to November 2009 via Medline, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials. Network meta-analysis with a mixed treatment comparison method using Bayesian Markov Chain Monte Carlo simulation was used to combine direct within-trial, between-treatment comparisons with indirect trial evidence. Forty-eight clinical trials (12 828 CVCs) investigating 10 intervention catheters contributed to the analyses. For prevention of CVC colonisation, adjusted silver iontophoretic catheters (odds ratio: 0.58; 95% confidence interval: 0.33-0.95), chlorhexidine and silver sulfadiazine catheters (0.49; 0.36-0.64), chlorhexidine and silver sulfadiazine blue plus catheters (0.37; 0.17-0.69), minocycline-rifampicin catheters (0.28; 0.17-0.43) and miconazole-rifampicin catheters (0.11; 0.02-0.33) were associated with a significantly lower rate of catheter colonisation compared with standard catheters. For prevention of CRBSI, adjusted heparin-bonded catheters (0.20; 0.06-0.44) and minocycline-rifampicin catheters (0.18; 0.08-0.34) were associated with a significantly lower rate of CRBSI with standard catheters. Rifampicin-based impregnated catheters seem to be better for prevention of catheter-related infection compared with the other catheters.


Desmoplastic myxoid tumor, SMARCB1-mutant: clinical, histopathological and molecular characterization of a pineal region tumor encountered in adolescents and adults.
Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly occurring in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. SMARCB1-mutant tumors in adolescents and adults are rare and may show uncommon histopathological and clinical features. Here we report seven SMARCB1-deficient intracranial tumors sharing distinct clinical, histopathological and molecular features. Median age of the four females and three males was 40 years (range 15-61 years). All tumors were located in the pineal region. Histopathologically, these tumors displayed spindled and epithelioid cells embedded in a desmoplastic stroma alternating with a variable extent of a loose myxoid matrix. All cases showed loss of nuclear SMARCB1/INI1 protein expression, expression of EMA and CD34 was frequent and the Ki67/MIB1 proliferation index was low in the majority of cases (median 3%). Three cases displayed heterozygous SMARCB1 deletions and two cases a homozygous SMARCB1 deletion. On sequencing, one tumor showed a 2 bp deletion in exon 4 (c.369_370del) and one a short duplication in exon 3 (c.237_276dup) both resulting in frameshift mutations. Most DNA methylation profiles were not classifiable using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-SNE analysis and hierarchical clustering analysis, however, all tumors grouped closely together and showed similarities with ATRT-MYC. After a median observation period of 48 months, three patients were alive with stable disease, whereas one patient experienced tumor progression and three patients had succumbed to disease. In conclusion, our series represents an entity with distinct clinical, histopathological and molecular features showing epigenetic similarities with ATRT-MYC. We propose the designation desmoplastic myxoid tumor (DMT), SMARCB1-mutant, for these tumors.


A review of postnatal mental health websites: help for healthcare professionals and patients.
The internet offers an accessible and cost-effective way to help women suffering with various types of postnatal mental illness and also can provide resources for healthcare professionals. Many websites on postnatal mental illness are available, but there is little information on the range or quality of information and resources offered. The current study therefore aimed to review postnatal health websites and evaluate their quality on a variety of dimensions. A systematic review of postnatal health websites was conducted. Searches were carried out on four search engines (Google, Yahoo, Ask Jeeves and Bing) which are used by 98% of web users. The first 25 websites found for each key word and their hyperlinks were assessed for inclusion in the review. Websites had to be exclusively dedicated to postnatal mental health or have substantial information on postnatal mental illness. Eligible websites (n=114) were evaluated for accuracy of information, available resources and quality. Results showed that information was largely incomplete and difficult to read; available help was limited and website quality was variable. The top five postnatal mental illness websites were identified for (1) postnatal mental illness sufferers and (2) healthcare professionals. It is hoped these top websites can be used by healthcare professionals both for their own information and to advise patients on quality online resources.


Cross-Linguistic Variation in the Meaning of Quantifiers: Implications for Pragmatic Enrichment.
One of the most studied scales in the literature on scalar implicatures is the quantifier scale. While the truth of some is entailed by the truth of all, some is felicitous only when all is false. This opens the possibility that some would be felicitous if, e.g., almost all of the objects in the restriction of the quantifier have the property ascribed by the nuclear scope. This prediction from the standard theory of quantifier interpretation clashes with native speakers' intuitions. In Experiment 1 we report a questionnaire study on the perception of quantifier meanings in English, French, Slovenian, and German which points to a cross-linguistic variation with respect to the perception of numerical bounds of the existential quantifier. In Experiment 2, using a picture choice task, we further examine whether the numerical bound differences correlate with differences in pragmatic interpretations of the quantifier some in English and quelques in French and interpret the results as supporting our hypothesis that some and its cross-linguistic counterparts are subjected to different processes of pragmatic enrichment.


New Zealand women living with HIV/AIDS: a feminist perspective.
This paper draws on current and earlier literature, together with observational and anecdotal data to reveal the situation of HIV positive women in New Zealand. The present picture is examined in relation to data from a previously unpublished qualitative study undertaken by the author in 2001 using a feminist perspective. It would seem that dominant concerns of the women today are much the same as those surfacing in the earlier study. These include stigma and the associated problem of whether to conceal or reveal. Additionally these women are concerned that health professionals do not always take their problems seriously. Their distress is aggravated by fact of them being women suffering from what is generally seen as a male disease. The feminist perspective highlights the relative powerlessness of many women in the context of sexual relations whereby much of the prophylactic advice--such as insistence on condom use--becomes irrelevant. New women oriented education programmes are needed. It is argued that nurses are well placed to make a positive contribution in this area of care, and in fact are obligated to do so if their practice is to be consistent with the profession's declared aims with respect to cultural safety. However it is noted that there is still a degree of prejudice and ignorance to be overcome before the desired results will be achieved.


Approaches to improve epidemiological studies of diabetic neuropathy: insights from the Rochester Diabetic Neuropathy Study.
The quality of the epidemiological data on diabetic neuropathies remains poor for a variety of reasons. They include variability in 1) ascertainment of diabetes, 2) the clinical varieties of diabetic patients studied, 3) characterization of neurological dysfunction, 4) abnormal limits for neurological examinations and tests, 5) minimal criteria for neuropathy, 6) correct attribution of nondiabetic neurological disease, 7) correct attribution of type of neuropathy, 8) estimating neuropathy from use of multiple tests, and 9) estimating severity of polyneuropathy. We have tried to remedy these short-comings in the Rochester Diabetic Neuropathy Study (RDNS). It was not possible to adequately characterize and quantitate diabetic polyneuropathies using only one or two clinical or test abnormalities. To estimate severity of diabetic polyneuropathy, the results of the neurological examination and abnormalities of nerve conduction, quantitative sensory tests, and quantitative autonomic tests were combined into a composite score. One begins by scoring a standard test of neurological deficits (impairments) of the lower limbs (NIS[LL]) and adds to this transformed numbers for percentile abnormality of seven good functional tests. This NIS(LL)+7 tests score appears to provide a much more comprehensive and stable numeric score by which to diagnose and grade severity of diabetic polyneuropathy than does the use of individual clinical or test results. This test score should be useful as a measure of change in diabetic polyneuropathy for purposes of medical practice, epidemiology studies, and controlled clinical trials. The staging approach that we introduced previously continues to provide an important measure of overall severity of diabetic polyneuropathy, taking into account both symptoms and impairments.


Consensus paper: combining transcranial stimulation with neuroimaging.
In the last decade, combined transcranial magnetic stimulation (TMS)-neuroimaging studies have greatly stimulated research in the field of TMS and neuroimaging. Here, we review how TMS can be combined with various neuroimaging techniques to investigate human brain function. When applied during neuroimaging (online approach), TMS can be used to test how focal cortex stimulation acutely modifies the activity and connectivity in the stimulated neuronal circuits. TMS and neuroimaging can also be separated in time (offline approach). A conditioning session of repetitive TMS (rTMS) may be used to induce rapid reorganization in functional brain networks. The temporospatial patterns of TMS-induced reorganization can be subsequently mapped by using neuroimaging methods. Alternatively, neuroimaging may be performed first to localize brain areas that are involved in a given task. The temporospatial information obtained by neuroimaging can be used to define the optimal site and time point of stimulation in a subsequent experiment in which TMS is used to probe the functional contribution of the stimulated area to a specific task. In this review, we first address some general methodologic issues that need to be taken into account when using TMS in the context of neuroimaging. We then discuss the use of specific brain mapping techniques in conjunction with TMS. We emphasize that the various neuroimaging techniques offer complementary information and have different methodologic strengths and weaknesses.


Analysis of the early signs of septic sacroiliitis on computed tomography.
Septic sacroiliitis is a difficult diagnosis rarely considered in an emergency in case of pelvic pain associated with fever. In these cases, a computed tomography (CT) is classically performed to exclude digestive or gynecological disorder, but the sacroiliac joint is not systematically analyzed. The aim of the present study was to detect the early signs of septic sacroiliitis on CT. In a monocentric retrospective study, the characteristics, biology, and imaging of patients with septic sacroiliitis were analyzed. Seven cases of septic sacroiliitis were included in the study. For all patients, a CT scan with contrast-enhanced acquisitions of the pelvis was performed. The 4 early signs of septic sacroiliitis frequently not evocated by a radiologist in an emergency were highlighted as follows: fat infiltration in front of the sacroiliac joint (83%), anterior bulging of the sacroiliac capsule (46%), and piriformis and iliac muscles swelling (71% for both). All patients had at least one of these signs; 86% had at least 2 signs. Magnetic resonance imaging was performed for 5 out of 7 patients and confirmed the aspect of infectious sacroiliitis. Systematic analysis of the sacroiliac joint and adjacent muscles on pelvic CT scan is necessary to avoid the unrecognition of septic sacroiliitis in case of pelvic pain with fever.


Development of a prognostic composite cytokine signature based on the correlation with nivolumab clearance: translational PK/PD analysis in patients with renal cell carcinoma.
Although several therapeutic options for patients with renal cell carcinoma (RCC) have been approved over recent years, including immune checkpoint inhibitors, considerable need remains for molecular biomarkers to assess disease prognosis. The higher pharmacokinetic (PK) clearance of checkpoint inhibitors, such as the anti-programmed death-1 (PD-1) therapies nivolumab and pembrolizumab, has been shown to be associated with poor overall survival (OS) across several tumor types. However, determination of PK clearance requires the collection and analysis of post-treatment serum samples, limiting its utility as a prognostic biomarker. This report outlines a translational PK-pharmacodynamic (PD) methodology used to derive a baseline composite cytokine signature correlated with nivolumab clearance using data from three clinical trials in which nivolumab or everolimus was administered. Peripheral serum cytokine (PD) and nivolumab clearance (PK) data from patients with RCC were analyzed using a PK-PD machine-learning model. Nivolumab studies CheckMate 009 (NCT01358721) and CheckMate 025 (NCT01668784) (n = 480) were used for PK-PD analysis model development and cytokine feature selection (training dataset). Validation of the model and assessment of the prognostic value of the cytokine signature was performed using data from CheckMate 010 (NCT01354431) and the everolimus comparator arm of CheckMate 025 (test dataset; n = 453). The PK-PD analysis found a robust association between the eight top-ranking model-selected baseline inflammatory cytokines and nivolumab clearance (area under the receiver operating characteristic curve = 0.7). The predicted clearance (high vs low) based on the cytokine signature was significantly associated with long-term OS (p < 0.01) across all three studies (training and test datasets). Furthermore, cytokines selected from the model development trials also correlated with OS of the everolimus comparator arm (p < 0.01), suggesting the prognostic nature of the composite cytokine signature for RCC. Here, we report a PK-PD translational approach to identify a molecular prognostic biomarker signature based on the correlation with nivolumab clearance in patients with RCC. This composite biomarker signature may provide improved prognostic accuracy of long-term clinical outcome compared with individual cytokine features and could be used to ensure the balance of patient randomization in RCC clinical trials.


Pomegranate extract improves a depressive state and bone properties in menopausal syndrome model ovariectomized mice.
Pomegranate is known to contain estrogens (estradiol, estrone, and estriol) and show estrogenic activities in mice. In this study, we investigated whether pomegranate extract is effective on experimental menopausal syndrome in ovariectomized mice. Prolongation of the immobility time in forced swimming test, an index of depression, was measured 14 days after ovariectomy. The bone mineral density (BMD) of the tibia was measured by X-ray absorptiometry and the structure and metabolism of bone were also analyzed by bone histomorphometry. Administration of pomegranate extract (juice and seed extract) for 2 weeks to ovariectomized mice prevented the loss of uterus weight and shortened the immobility time compared with 5% glucose-dosed mice (control). In addition, ovariectomy-induced decrease of BMD was normalized by administration of the pomegranate extract. The bone volume and the trabecular number were significantly increased and the trabecular separation was decreased in the pomegranate-dosed group compared with the control group. Some histological bone formation/resorption parameters were significantly increased by ovariectomy but were normalized by administration of the pomegranate extract. These changes suggest that the pomegranate extract inhibits ovariectomy-stimulated bone turnover. It is thus conceivable that pomegranate is clinically effective on a depressive state and bone loss in menopausal syndrome in women.


Estimation of specificity and sensitivity of three diagnostic tests for infectious salmon anaemia virus in the absence of a gold standard.
Reverse transcriptase-polymerase chain reaction (RT-PCR), virus isolation (VI) and indirect fluorescent antibody test (IFAT) are three tests currently used by the salmon industry to identify fish infected with the infectious salmon anaemia virus (ISAV). However, very limited information is available on the sensitivity and specificity of these methods. In order to evaluate these tests in fish representing a range of farmed Atlantic salmon populations, five laboratories participated in a blind study of 400 kidney samples from four groups of fish with different prevalences of ISAV. Each laboratory used its own testing protocols. Estimates of the specificity of each test were determined directly from a population assumed to be free of infection. Indirect estimates of the sensitivity and specificity of each test were obtained using maximum likelihood estimation of a latent class model (i.e. no gold standard test result available). There was a substantial difference in sensitivity and specificity of RT-PCR among the three laboratories using this test. If only the best results for the RT-PCR tests are taken into account, the maximum likelihood estimates obtained from this study suggest RT-PCR and VI are of similar high sensitivity (range 92-100%), IFAT is the least sensitive method (range 65-76%) while the three tests have similar high specificities (range 96-100%). The results of the study suggest: (1) RT-PCR tests should be standardized before they are used as a diagnostic test for prevention and control of ISAV, (2) the sensitivity of VI was higher than expected and (3) IFAT has a low sensitivity but might be a good screening test because of its low cost.


Mitochondrial DNA haplogroup D4a is a marker for extreme longevity in Japan.
We report results from the analysis of complete mitochondrial DNA (mtDNA) sequences from 112 Japanese semi-supercentenarians (aged above 105 years) combined with previously published data from 96 patients in each of three non-disease phenotypes: centenarians (99-105 years of age), healthy non-obese males, obese young males and four disease phenotypes, diabetics with and without angiopathy, and Alzheimer's and Parkinson's disease patients. We analyze the correlation between mitochondrial polymorphisms and the longevity phenotype using two different methods. We first use an exhaustive algorithm to identify all maximal patterns of polymorphisms shared by at least five individuals and define a significance score for enrichment of the patterns in each phenotype relative to healthy normals. Our study confirms the correlations observed in a previous study showing enrichment of a hierarchy of haplogroups in the D clade for longevity. For the extreme longevity phenotype we see a single statistically significant signal: a progressive enrichment of certain "beneficial" patterns in centenarians and semi-supercentenarians in the D4a haplogroup. We then use Principal Component Spectral Analysis of the SNP-SNP Covariance Matrix to compare the measured eigenvalues to a Null distribution of eigenvalues on Gaussian datasets to determine whether the correlations in the data (due to longevity) arises from some property of the mutations themselves or whether they are due to population structure. The conclusion is that the correlations are entirely due to population structure (phylogenetic tree). We find no signal for a functional mtDNA SNP correlated with longevity. The fact that the correlations are from the population structure suggests that hitch-hiking on autosomal events is a possible explanation for the observed correlations.


[Actinic enteritis as a cause of digestive bleeding of obscure origin].
Chronic actinic enteritis is a malfunction of the small bowel, occurring in the 6 months post-radiotherapy, and it can be manifestated as malabsortion, stenosis, fistula formation, local abscesses, perforation and bleeding, We report a case of an elderly patient who presents an episode of obscure gastrointestinal bleeding (OGIB) secondary to actinic enteritis. She is a 64-year- old female patient with the past medical history of cervical cancer who received radiotherapy and brachytherapy. One year after the treatment, the patient presents a chronic episode of melena and symptomatic anemia and 1 week before the admission she had hematochezia. At admission she has hemodynamic instability with a hemoglobin value of 2.7 gr/dl. We did an upper endoscopy, a colonoscopy and abdomino-pelvic tomography without any findings of the bleeding's source. Reason why an endoscopic capsule was done, showing bleeding areas in the medial and distal small bowel. The patient had another gastrointestinal bleeding requiring a surgery where they decide to do a resection of the small bowel and a right hemicholectomy. The pathology was compatible with actinic enteritis. The patient after the surgery had a torpid evolution, and finally dies. We describe this case and do a review of all the existent data around the world, because is the first case reported in Peru of an actinic enteritis as a cause of OGIB.


Dopaminergic modulation of dye coupling between neurons in the core and shell regions of the nucleus accumbens.
The presence of dye coupling and electrotonic coupling within the nucleus accumbens was examined using intracellular recording and staining in rat brain slices. In 24% of the cells examined, injection of single accumbens neurons with the dye Lucifer yellow resulted in the complete labeling of more than one cell. To examine whether this coupling is regulated by dopamine (DA), the extent of dye coupling was assessed in the presence of dopaminergic agonists and antagonists. In the core region of the accumbens, D1 receptor stimulation induced a decrease in the incidence of dye coupling; this effect could be blocked by the D1 antagonists SCH 23,390 and SCH 39,166, by the D2 antagonist sulpiride, or by depletion of DA by reserpine and alpha-methyl-p-tyrosine coadministration, but not by the atypical antipsychotic drug clozapine. In contrast, in the posterior part of the shell region, D2 receptor stimulation increased the incidence of coupling independent of the state of D1 receptor activation. Fast spikelets resembling coupling potentials were found to occur only in neurons that also showed dye coupling, and could be attenuated in core neurons by D1 receptor stimulation. These findings suggest that DA, in addition to its actions on the membrane of single neurons, may also affect neuronal integration on a network level by regulating the transfer of information between adjacent neurons within the nucleus accumbens.


An Unusual Presentation of Acute Fibrinous and Organizing Pneumonia.
BACKGROUND Acute fibrinous and organizing pneumonia (AFOP) is a newly evolving rare non-infectious lung pathology, characterized by intra-alveolar fibrin balls on histology. It is often difficult to diagnose and is usually mistaken for other lung pathologies. We present an interesting case of AFOP with unusual radiologic findings and disease course. CASE REPORT A 56-year-old woman presented with a 1-day history of high-grade fever, chills, and profuse sweating. She was febrile to 101.2 degree Fahrenheit on presentation. On physical examination, she had decreased air entry in the left upper lobe of the lung. Laboratory testing showed a white cell count of 27,000 cells per microliter of blood with left shift. A chest radiograph showed a left upper lobe consolidation. Computed tomography (CT) of the chest without intravenous contrast showed advanced centrilobular emphysema and left upper lobe consolidation measuring 6.2×5.9 cm. The patient was started on antibiotics. She clinically improved and was discharged on oral antibiotics. After discharge, a trans-bronchial lung biopsy showed acute inflammatory cell infiltrate with intra-alveolar fibrin balls but no hyaline membrane formation or significant eosinophils. These findings were consistent with acute fibrinous and organizing pneumonia. However, she was subsequently lost to follow-up. CONCLUSIONS Our case adds to the literature a new and unusual finding of upper lobe infiltrates, in contrast to most cases presenting as bilateral lower lobe infiltrates. In our case, symptomatic improvement after antibiotic treatment suggests a possible role of antibiotics in management of this entity.


Quantum State Reduction by Matter-Phase-Related Measurements in Optical Lattices.
A many-body atomic system coupled to quantized light is subject to weak measurement. Instead of coupling light to the on-site density, we consider the quantum backaction due to the measurement of matter-phase-related variables such as global phase coherence. We show how this unconventional approach opens up new opportunities to affect system evolution. We demonstrate how this can lead to a new class of final states different from those possible with dissipative state preparation or conventional projective measurements. These states are characterised by a combination of Hamiltonian and measurement properties thus extending the measurement postulate for the case of strong competition with the system's own evolution.


Rewarding teaching faculty with a reimbursement plan.
To develop a system for measuring the teaching effort of medical school faculty and to implement a payment system that is based on it. An interventional study with outcomes measured before and after the intervention. A department of internal medicine with a university hospital and an affiliated Veterans Administration hospital. We assigned a value in teaching units to each teaching activity in proportion to the time expended by the faculty and the intensity of their effort. We then calculated total teaching units for each faculty member in the Division of General Internal Medicine and for combined faculty effort in each subspecialty division in the Department of Medicine. After determining the dollar value for a teaching unit, we distributed discretionary teaching dollars to each faculty member in the Division of General Internal Medicine and to each subspecialty division according to total teaching units. The distribution of discretionary teaching dollars was determined. In the year after the intervention, there was a substantial redistribution of discretionary teaching dollars among divisions. Compared with an increase in total discretionary dollars of 11.4%, the change in allocation for individual divisions ranged from an increase of 78.2% to a decrease of -28.5%. Further changes in the second year after the intervention were modest. The distribution of teaching units among divisions was similar to the distribution of questions across subspecialties on the American College of Physicians In-Training Examination (r =.67) and the American Board of Internal Medicine Certifying Examination (r =.88). It is possible to measure the value of teaching effort by medical school faculty and to distribute discretionary teaching funds among divisions according to the value of teaching effort. When this intervention was used at our institution, there were substantial changes in the amounts received by some divisions. We believe that the new distribution more closely approximates the desired distribution because it reflects the desired emphasis on knowledge as measured by two of the most experienced professional groups in internal medicine. We also believe that our method is flexible and adaptable to the needs of most clinical teaching


Fetal spleen stroma drives macrophage commitment.
The role of the fetal spleen in hematopoeisis remains largely unknown. In this particular environment, we show that hematopoietic stem cells do not proliferate, but that they lose multipotency and differentiate exclusively into mature macrophages. B lymphocytes in the spleen derive from committed B cell precursors that are likely to have immigrated from the fetal liver. We developed fetal spleen stromal cell lines that are unique in their capacity to expand myeloid precursors, resulting in large numbers of mature macrophages. These lines secrete high levels of anti-inflammatory molecules. By phenotype, fetal splenic macrophages are reminiscent of their adult counterparts found in the red pulp. We postulate that F4/80(+) splenic macrophages participate in fetal erythropoiesis, as well as in the formation of the splenic architecture.


Scoliosis intensive out-patient rehabilitation based on Schroth method.
Conservative management of idiopathic scoliosis (IS) and other spinal deformities is a real alternative to surgical treatment. Most of adolescent with IS can be managed conservatively with high safety. Many infantile and juvenile cases show also a good immediate response to conservative care, which can be considered a sign of good prognosis. Only patients showing a continue deterioration even treated conservatively with efficient techniques should be considered candidates to surgical correction and stabilization. Rehabilitation (including specific exercises) and bracing are usually involved in conservative care of IS. In this paper we describe our personal approach in conservative scoliosis care regarding rehabilitation. Bracing has been described in a different paper also published in the present book. Specific exercises can change the signs and symptoms in scoliosis patients. Specialists in physiotherapy for spinal deformities teach the patient how to perform a routine of 'curve pattern' specific exercises with the purpose to facilitate the correction of the asymmetric posture and to teach the patient to maintain the corrected posture in daily activities. Principles of correction are based on those developed by the German physiotherapist K. Schroth.


The effect of nano-hydroxyapatite/chitosan scaffolds on rat calvarial defects for bone regeneration.
This study aims at determining the biological effect of 75/25 w/w nano-hydroxyapatite/chitosan (nHAp/CS) scaffolds on bone regeneration, in terms of fraction of bone regeneration (FBR), total number of osteocytes (Ost), and osteocyte cell density (CD), as well as its biodegradability. Two critical-size defects (CSDs) were bilaterally trephined in the parietal bone of 36 adult Sprague-Dawley rats (18 males and 18 females); the left remained empty (group A), while the right CSD was filled with nHAp/CS scaffold (group B). Two female rats died postoperatively. Twelve, 11, and 11 rats were euthanized at 2, 4, and 8 weeks post-surgery, respectively. Subsequently, 34 specimens were resected containing both CSDs. Histological and histomorphometric analyses were performed to determine the FBR, calculated as [the sum of areas of newly formed bone in lateral and central regions of interest (ROIs)]/area of the original defect, as well as the Ost and the CD (Ost/mm2) in each ROI of both groups (A and B). Moreover, biodegradability of the nHAp/CS scaffolds was estimated via the surface area of the biomaterial (BmA) in the 2nd, 4th, and 8th week post-surgery. The FBR of group B increased significantly from 2nd to 8th week compared to group A (P = 0.009). Both the mean CD and the mean Ost values of group B increased compared to group A (P = 0.004 and P < 0.05 respectively). Moreover, the mean value of BmA decreased from 2nd to 8th week (P = 0.001). Based on histological and histomorphometric results, we support that 75/25 w/w nHAp/CS scaffolds provide an effective space for new bone formation.


Effects of noise on lidar data inversion with the backward algorithm.
The lidar data-inversion algorithm widely known as the Klett method (and its more elaborate variants) has long been used to invert elastic-lidar data obtained from atmospheric sounding systems. The Klett backward algorithm has also been shown to be robust in the face of uncertainties concerning the boundary condition. Nevertheless electrical noise at the photoreceiver output unavoidably has an impact on the data-inversion process, and describing in an explicit way how it affects retrieval of the atmospheric optical coefficients can contribute to improvement in inversion quality. We examine formally the way noise disturbs backscatter-coefficient retrievals done with the Klett backward algorithm, derive a mathematical expression for the retrieved backscatter coefficient in the presence of noise affecting the signal, and assess the noise impact and suggest ways to limit it.


Use of preventive services by men enrolled in Medicare+Choice plans.
We examined the effect of demographic and socioeconomic factors on use of preventive services (prostate-specific antigen testing, colorectal cancer screening, and influenza vaccination) among elderly men enrolled in 2 Medicare+Choice health plans. Data were derived from administrative files and a survey of 1915 male enrollees. We used multivariate logistic regression to assess the effects of enrollee characteristics on preventive service use. Age, marital status, educational attainment, and household wealth were associated with receipt of one or more preventive services. However, the effects of these variables were substantially attenuated relative to earlier studies of Medicare. Some Medicare HMOs have been successful in attenuating racial and socioeconomic disparities in the use of preventive services by older men.


Near-Infrared Photoactivatable Nitric Oxide Donors with Integrated Photoacoustic Monitoring.
Photoacoustic (PA) tomography is a noninvasive technology that utilizes near-infrared (NIR) excitation and ultrasonic detection to image biological tissue at centimeter depths. While several activatable small-molecule PA sensors have been developed for various analytes, the use of PA molecules for deep-tissue analyte delivery and monitoring remains an underexplored area of research. Herein, we describe the synthesis, characterization, and in vivo validation of photoNOD-1 and photoNOD-2, the first organic, NIR-photocontrolled nitric oxide (NO) donors that incorporate a PA readout of analyte release. These molecules consist of an aza-BODIPY dye appended with an aryl N-nitrosamine NO-donating moiety. The photoNODs exhibit chemostability to various biological stimuli, including redox-active metals and CYP450 enzymes, and demonstrate negligible cytotoxicity in the absence of irradiation. Upon single-photon NIR irradiation, photoNOD-1 and photoNOD-2 release NO as well as rNOD-1 or rNOD-2, PA-active products that enable ratiometric monitoring of NO release. Our in vitro studies show that, upon irradiation, photoNOD-1 and photoNOD-2 exhibit 46.6-fold and 21.5-fold ratiometric turn-ons, respectively. Moreover, unlike existing NIR NO donors, the photoNODs do not require encapsulation or multiphoton activation for use in live animals. In this study, we use PA tomography to monitor the local, irradiation-dependent release of NO from photoNOD-1 and photoNOD-2 in mice after subcutaneous treatment. In addition, we use a murine model for breast cancer to show that photoNOD-1 can selectively affect tumor growth rates in the presence of NIR light stimulation following systemic administration.


Rationale and clinical results of inhibiting interleukin-5 for the treatment of severe asthma.
Severe asthma is responsible for considerable morbidity and a high proportion of the healthcare costs attributable to asthma. Management is not straightforward as the clinical, pathological and physiological features are heterogeneous and the relationships between these features are poorly understood. In recent years significant progress has been made in understanding this heterogeneity and eosinophilic asthma has emerged as a potentially clinically important phenotype because treatment with monoclonal antibodies against IL-5 is effective. This has required a change in our understanding of the role of eosinophilic airway inflammation in airways disease and the developments of reliable biomarkers of eosinophilic airway inflammation. We will review these developments and describe the clinical experience so far with treatment with monoclonal antibiotics against IL-5.


Is perfectionism categorical or dimensional? A taxometric analysis.
Considerable debate exists within the perfectionism literature regarding whether perfectionism is most accurately conceptualized as a dimensional or categorical construct. Specifically, some researchers have viewed perfectionism as a continuous construct, with extreme scores being associated with negative psychological outcomes (e.g., obsessive-compulsive disorder, eating disorders, etc.). In contrast, others have argued that two distinct forms of perfectionism exist (i.e., adaptive vs. maladaptive perfectionism) that are associated with both positive and negative outcomes. The purpose of this study was to examine the latent structure of perfectionism using taxometric procedures to determine whether perfectionism is most accurately conceptualized as taxonic (categorical) or dimensional (continuous). We applied four taxometric procedures (maximum eigenvalue [Waller & Meehl, 1998], maximum covariance [Meehl & Yonce, 1996], mean above minus below a cut [Meehl & Yonce, 1994], and latent-mode factor analysis [Waller & Meehl, 1998]) to perfectionism data collected from 2 large nonclinical samples. Results provided convergent evidence for a dimensional conceptualization of perfectionism across samples, perfectionism measures, and statistical procedures. We discuss the implications of these findings for the theory, assessment, and investigation of perfectionism are discussed.


Distribution of the scaffolding proteins PSD-95, PSD-93, and SAP97 in isolated PSDs.
We compared the distribution of three scaffolding proteins, all belonging to a family of membrane-associated guanylate kinases, thought to have key roles in the organization of the postsynaptic density (PSD). Isolated PSDs readily adhered to treated glass coverslips where they were labeled with immunogold and rotary shadowed for analysis by EM. The distribution of proteins within individual PSDs were measured by counting and mapping individual immunogold particles. PSD-95, as previously described, is distributed evenly throughout the PSD. We find here that PSD-93 has a nearly identical distribution suggesting that PSD-95 and PSD-93 could perform similar roles. SAP97, in contrast, is concentrated near edges of cleft sides of the PSDs, and in small clumps on their cytoplasmic sides. The homogenous distribution of PSD-95 and PSD-93 throughout the PSD is consistent with their being part of a backbone that stabilizes their various binding partners within the PSD. The distribution of SAP97 confirms that this protein is actually an integral component of the PSD, and suggests that it may have a role in inserting or stabilizing its main binding partner, Glu-R1, at the edge of the PSD.


Rationale for an early detection program for bladder cancer.
A total of 356,557 new cases were diagnosed annually worldwide in 2009, it was estimated that 52,810 new patients were to be diagnosed with bladder cancer and there were 10,180 projected deaths from the disease in the USA. Despite being the fourth commonest cancer in men, we do not have an early detection/screening program for bladder cancer. The review was aimed at looking at the evidence for the rationale for an early detection program for bladder cancer. A detailed search on bladder cancer epidemiology, diagnosis, pathology, tumor markers, treatment outcomes, screening, morbidity and mortality of bladder cancer was carried out on Pubmed central/Medline. Original articles, review articles, monograms, book chapters on bladder cancer, text books on urological oncology, oncology and urology were reviewed. The latest information for new articles before publication was last accessed in June 2010. Bladder cancer is the fourth commonest cancer in men, the annual death rate from this disease is significant and every year there is an increase in its incidence globally. The prognosis of bladder cancer is stage and grade dependent; the lower the stage (T2 or less) the better is the survival. Delay in the diagnosis and treatment does alter the overall outcome. Therefore, there is a clear need for early detection of bladder cancer and screening program. Although we do not have an ideal marker for bladder cancer, it is time we maximize the potential of markers such as UroVysion, NMP22 along with cytology to start such a program. May be as a first step the early detection and screening program could be started in high-risk population. It is not worth waiting till we find the best marker as it would be unfair to our patients. The fear of unnecessary tests and treatment in bladder cancer after its detection in screening program is without any substance. The cost-effectiveness of such a program is certainly comparable to that is used for colon or breast and for prostate as well.


Psychometric validity of the Shirom-Melamed Burnout Measure and the Burnout Assessment Tool: a systematic review.
In the absence of internationally recognised standardised criteria, several patient-reported outcome measures (PROMs) have been developed to measure occupational burnout. The aim of this study was to extend our 2021 review of the psychometric validity of five PROMs to the Shirom-Melamed Burnout Measure (SMBM) and the Burnout Assessment Tool (BAT). To do that we ran a systematic literature search in the MEDLINE, PsycINFO, and Embase databases following our previous methodological framework and the COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN). We assessed the level of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) guideline. We identified 694 publications on SMBM and 421 on BAT, but the final review includes eight papers on SMBM and three on BAT. Of the seven psychometric properties assessed for SMBM, content, structural, and criterion validity were rated as insufficient, whereas the quality of evidence for construct and internal consistency was high and moderate, respectively. Of the nine psychometric properties assessed for BAT, content, structural, criterion, and construct validity was moderate and internal consistency was high. One limitation of this study is that we did not assess cross-cultural validity, because the number of studies reviewed is too small and content validity can only be assessed based on the original PROM version rather than translation. To conclude, BAT is superior to SMBM in terms of psychometric validity, but the quality of evidence for some properties is low or very low, suggesting a need for additional validation studies.


The influence of exercise on cognitive abilities.
Scientific evidence based on neuroimaging approaches over the last decade has demonstrated the efficacy of physical activity improving cognitive health across the human lifespan. Aerobic fitness spares age-related loss of brain tissue during aging, and enhances functional aspects of higher order regions involved in the control of cognition. More active or higher fit individuals are capable of allocating greater attentional resources toward the environment and are able to process information more quickly. These data are suggestive that aerobic fitness enhances cognitive strategies enabling to respond effectively to an imposed challenge with a better yield in task performance. In turn, animal studies have shown that exercise has a benevolent action on health and plasticity of the nervous system. New evidence indicates that exercise exerts its effects on cognition by affecting molecular events related to the management of energy metabolism and synaptic plasticity. An important instigator in the molecular machinery stimulated by exercise is brain-derived neurotrophic factor, which acts at the interface of metabolism and plasticity. Recent studies show that exercise collaborates with other aspects of lifestyle to influence the molecular substrates of cognition. In particular, select dietary factors share similar mechanisms with exercise, and in some cases they can complement the action of exercise. Therefore, exercise and dietary management appear as a noninvasive and effective strategy to counteract neurological and cognitive disorders.


A non-homogeneous dynamic Bayesian network with sequentially coupled interaction parameters for applications in systems and synthetic biology.
An important and challenging problem in systems biology is the inference of gene regulatory networks from short non-stationary time series of transcriptional profiles. A popular approach that has been widely applied to this end is based on dynamic Bayesian networks (DBNs), although traditional homogeneous DBNs fail to model the non-stationarity and time-varying nature of the gene regulatory processes. Various authors have therefore recently proposed combining DBNs with multiple changepoint processes to obtain time varying dynamic Bayesian networks (TV-DBNs). However, TV-DBNs are not without problems. Gene expression time series are typically short, which leaves the model over-flexible, leading to over-fitting or inflated inference uncertainty. In the present paper, we introduce a Bayesian regularization scheme that addresses this difficulty. Our approach is based on the rationale that changes in gene regulatory processes appear gradually during an organism's life cycle or in response to a changing environment, and we have integrated this notion in the prior distribution of the TV-DBN parameters. We have extensively tested our regularized TV-DBN model on synthetic data, in which we have simulated short non-homogeneous time series produced from a system subject to gradual change. We have then applied our method to real-world gene expression time series, measured during the life cycle of Drosophila melanogaster, under artificially generated constant light condition in Arabidopsis thaliana, and from a synthetically designed strain of Saccharomyces cerevisiae exposed to a changing environment.


Elevated nerve growth factor levels in young spontaneously hypertensive rats.
It is generally agreed that sympathetic innervation of vascular tissues in spontaneously hypertensive rats (SHR) is greater than that existing in vascular tissues from normotensive Wistar-Kyoto (WKY) rats. One factor responsible for regulation of the growth of peripheral sympathetic nerves is the peptide nerve growth factor, which is released from effector cells. In the present study, an enzyme immunoassay was used to measure nerve growth factor levels in mesenteric arteries (densely innervated) and aortas (sparsely innervated) from both young (20-day-old) and mature (6-month-old) SHR and WKY rats. The nerve growth factor content of mesenteric arteries and aortas from 20-day-old SHR was significantly greater than that present in corresponding tissues from WKY rats. In contrast, the nerve growth factor content found in mesenteric arteries and aortas of adult SHR did not differ significantly from that found in the corresponding adult WKY rat tissues. Moreover, when the tissues were obtained from adult animals, nerve growth factor levels were substantially higher in mesenteric arteries compared with aortas, regardless of the rat strain. These results support the hypothesis that the greater nerve growth factor content of vascular tissues from young SHR is involved in the early increased sympathetic innervation of blood vessels in this animal model of hypertension.


Mucosal Sparing Radiation Therapy in Resected Oropharyngeal Cancer.
To report the outcomes of patients with favorable risk oropharyngeal cancer that underwent adjuvant radiation therapy with omission of the primary site from the clinical target volume (CTV). A retrospective study of 40 patients treated with transoral surgery (TOS) followed by neck only radiation using intensity modulated radiation therapy (IMRT) with exclusion of the primary site. For all patients, a CTV of the primary surgical bed was contoured to obtain the estimated incidental dose to the primary site. Median follow-up was 51 months (range, 13-155 months). The median radiation therapy (RT) dose to the neck was 6000 cGy (range, 5400-6400 cGy). The mean incidental dose to the primary tonsillar site was 4320 cGy (SD ± 480 cGy) and to the primary base of tongue site was 4060 cGy (SD ± 420 cGy). There were no local failures and only 1 regional failure, resulting in 97.5% locoregional control rate at 4 years. Two patients developed distant metastases, without evidence of locoregional recurrence, for a 4-year overall survival rate of 97%. Our analysis suggests that mucosal sparing RT after TOS in favorable risk oropharyngeal cancer patients may provide comparable oncologic and improved functional outcomes compared to conventional treatment in selected patients.


Substrate affinity of photosensitizers derived from chlorophyll-a: the ABCG2 transporter affects the phototoxic response of side population stem cell-like cancer cells to photodynamic therapy.
Photosensitizers (PS) synthesized with the aim of optimizing photodynamic therapy (PDT) of tumors do not always fulfill their potential when tested in vitro and in vivo in different tumor models. The ATP-dependent transporter ABCG2, a multidrug resistant pump expressed at variable levels in cancerous cells, can bind and efflux a wide range of structurally different classes of compounds including several PS used preclinically and clinically such as porphyrins and chlorins. ABCG2 may lower intracellular levels of substrate PS below the threshold for cell death in tumors treated by PDT, leaving resistant cells to repopulate the tumor. To determine some of the structural factors that affect substrate affinity of PS for ABCG2, we used an ABCG2-expressing cell line (HEK 293 482R) and its nonexpressing counterpart, and tyrosine kinase ABCG2 inhibitors in a simple flow cytometric assay to identify PS effluxed by the ABCG2 pump. We tested a series of conjugates of substrate PS with different groups attached at different positions on the tetrapyrrole macrocycle to examine whether a change in affinity for the pump occurred and whether such changes depended on the position or the structure/type of the attached group. PS without substitutions including pyropheophorbides and purpurinimides were generally substrates for ABCG2, but carbohydrate groups conjugated at positions 8, 12, 13, and 17 but not at position 3 abrogated ABCG2 affinity regardless of structure or linking moiety. At position 3, affinity was retained with the addition of iodobenzene, alkyl chains and monosaccharides, but not with disaccharides. This suggests that structural characteristics at position 3 may offer important contributions to requirements for binding to ABCG2. We examined several tumor cell lines for ABCG2 activity, and found that although some cell lines had negligible ABCG2 activity in bulk, they contained a small ABCG2-expressing side population (SP) thought to contain cells which are responsible for initiating tumor regrowth. We examined the relevance of the SP to PDT resistance with ABCG2 substrates in vitro and in vivo in the murine mammary tumor 4T1. We show for the first time in vivo that the substrate PS HPPH (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a) but not the nonsubstrate PS HPPH-Gal (a galactose conjugate of HPPH) selectively preserved the SP which was primarily responsible for regrowth in vitro. The SP could be targeted by addition of imatinib mesylate, a tyrosine kinase inhibitor which inhibits the ATPase activity of ABCG2, and prevents efflux of substrates. A PDT resistant SP may be responsible for recurrences observed both preclinically and clinically. To prevent ABCG2 mediated resistance, choosing nonsubstrate PS or administering an ABCG2 inhibitor alongside a substrate PS might be advantageous when treating ABCG2-expressing tumors with PDT.


Quantification of Motion Palpation.
The palpation of motions is at the heart of the practice of foreign-trained osteopaths. When practicing osteopathic manual therapy (care provided by foreign-trained osteopaths) in the cranial field or osteopathic cranial manipulative medicine, the palpation of small motions (several tens of micrometers) is a key process. However, to the authors' knowledge, the smallest detectable motion has not been identified. To quantify motion detection capacity by passive palpation. Participants were instructed to hold a mechanical device containing a micrometric actuator between their hands and report when they felt motion while 6 series of 27 random motions were generated by the actuator. After each series, if a participant succeeded or failed to detect motion with a confidence level of greater than 98%, the motions in the next series were set to a smaller or larger magnitude, respectively. After 6 series, the individual motion detection capacity was recorded. Statistical significance was set at P=.02. A total of 21 participants were selected, comprising 14 osteopaths and 7 nonosteopaths. The average performance of the sample was 148 μm. Thirteen participants (62%) perceived motions of 200 μm or less, and 7 participants (33%) detected motions of 50 μm or less with bare hands. Osteopathic training did not notably affect the performance. Osteopaths were twice as likely to claim detection of nonexisting motions than to miss existing ones, whereas nonosteopaths were equally subject to both types of errors. The data show human passive palpatory sensitivity to be in the range of several tens of micrometers. This range is comparable to that reported for calvarial motion (10-50 μm).


Transcriptional control of adipogenesis.
Adipocyte differentiation is coordinatedly regulated by several transcription factors. C/EBP beta, C/EBP delta and ADD-1/SREBP-1 are active early during the differentiation process and induce the expression and/or activity of the peroxisome proliferator activated receptor-gamma (PPAR gamma), the pivotal coordinator of the adipocyte differentiation process. Activated PPAR gamma induces exit from the cell cycle and triggers the expression of adipocyte-specific genes, resulting in increased delivery of energy to the cells. C/EBP alpha, whose expression coincides with the later stages of differentiation, cooperates with PPAR gamma in inducing additional target genes and sustains a high level of PPAR gamma in the mature adipocyte as part of a feedforward loop. Altered activity and/or expression of these transcription factors might underlie the pathogenesis of disorders characterized by increased or decreased adipose tissue depots.


Framing natural assets for advancing sustainability research: translating different perspectives into actions.
Sustainability is a key challenge for humanity in the context of complex and unprecedented global changes. Future Earth, an international research initiative aiming to advance global sustainability science, has recently launched knowledge-action networks (KANs) as mechanisms for delivering its research strategy. The research initiative is currently developing a KAN on "natural assets" to facilitate and enable action-oriented research and synthesis towards natural assets sustainability. 'Natural assets' has been adopted by Future Earth as an umbrella term aiming to translate and bridge across different knowledge systems and different perspectives on peoples' relationships with nature. In this paper, we clarify the framing of Future Earth around natural assets emphasizing the recognition on pluralism and identifying the challenges of translating different visions about the role of natural assets, including via policy formulation, for local to global sustainability challenges. This understanding will be useful to develop inter-and transdisciplinary solutions for human-environmental problems by (i) embracing richer collaborative decision processes and building bridges across different perspectives; (ii) giving emphasis on the interactions between biophysical and socioeconomic drivers affecting the future trends of investments and disinvestments in natural assets; and (iii) focusing on social equity, power relationships for effective application of the natural assets approach. This understanding also intends to inform the scope of the natural asset KAN's research agenda to mobilize the translation of research into co-designed action for sustainability.


Efficacy of mycophenolate mofetil in patients failing 6-mercaptopurine or azathioprine therapy for Crohn's disease.
Mycophenolate mofetil (MMF) is a novel immunomodulator that may be effective in the treatment of chronic active and perianal Crohn's disease (CD). The aim of this study is to assess the efficacy of MMF in CD patients who failed or were intolerant of 6-mercaptopurine (6-MP) or azathioprine (AZA). Eleven CD patients were treated with MMF after a failed course of 6-MP/AZA, and their records reviewed retrospectively. Reasons for 6-MP/AZA intolerance or failure were recorded. Response to MMF was determined by calculation of the Harvey-Bradshaw index and ability to taper steroids. Adverse reactions to MMF were recorded. Eleven patients were identified who failed a previous trial of 6-MP/AZA and other immunomodulators and required immunomodulator therapy. Of 11 patients who started MMF, four had early adverse reactions within 8 weeks and stopped the medication. Of the remaining seven patients who took MMF for at least 8 weeks, one had a complete response, two had a partial response, and four had no response to the medication. In patients who failed 6-MP/AZA, MMF was of benefit in 3 of 11 patients with only one complete responder. This lower-than-expected response rate may indicate that patients who are resistant to 6-MP or AZA may also be resistant to MMF.


In vitro activity and in vivo correlates of alloantigen-specific murine suppressor T cells induced by allogeneic pregnancy.
The fetus that results from allogeneic mating in an outbred population bears a variety of antigens against which the maternal immune system reacts, but the type of immunity that is elicited by pregnancy does not mediate graft rejection. Previous studies have demonstrated the presence of nonspecific non-thymus derived suppressor cells in the lymph nodes draining the uterus (DLN) and in the uterine decidua during first allogeneic pregnancy. These suppressor cells appear to be small lymphoid cells that inhibit the generation of cytotoxic T cells (CTL) against paternal alloantigens. We now report that after a single allogeneic pregnancy, C3H and A strain mice develop paternal alloantigen-specific suppressor T cells (Thy-1.2+, Lyt-1-2+) that are distributed systemically in peripheral lymph nodes and spleen. These suppressor cells appear to act directly on CTL generation because the frequency of CTL precursors and the ability to produce T helper cells in response to paternal alloantigens remains unchanged after allogeneic pregnancy. Suppressor T cell activity could be detected both in vitro and in vivo, and the presence of suppression in vivo was associated with increased uterine weight 5 days after inoculation of allogeneic paternal tumor cells into the uterus of pseudopregnant mice. Nevertheless, both subcutaneous and intrauterine tumor inocula regressed in these mice with suppressor T cells. The possible role of suppressor T cells in contrast to non-T suppressor cells in successful reproduction and allopregnancy-induced tolerance is discussed.