The Phenomenon of Community Reintegration for Veterans with Burn Injury: Supportive Communities and Future-Oriented Thinking.
Combat missions in the Middle East have resulted in approximately 52,000 U.S. veterans who have been wounded in action, with 10% of whom suffered burn injuries. More than 90% of the wounded survived, but many were unable to return to military service. The purpose of this study was to investigate the factors that impacted reintegration of veterans with combat burn injuries. Using a mixed-methods approach and analysis, we asked veterans with combat burns "What was your experience reintegrating into the civilian community?" Additionally, we administered the Community Reintegration of Injured Service Members (CRIS) tool to measure the current level of reintegration. Six veterans with combat burn injury identified two major themes: supportive communities and future-oriented thinking. Supportive communities are defined as communities that are veteran-specific, provide long-term burn/injury care, are financially beneficial, and support hobbies, education, and work opportunities. Future-oriented thinking is defined as thinking in which a veteran experiences a turning point in recovery, has a desire to serve others, develops new meaning in life, and experiences posttraumatic growth. In both themes, peer support was a key component. Community reintegration was enhanced by future-oriented thinking and a supportive community, both of which can be buoyed by peer support. These findings are similar to other studies noting the importance of peer support for veterans. Studies of civilians burn survivors describe similar reintegration issues. These two factors may also be applicable to those survivors. Further qualitative inquiry into peer support in the burn community at large may reveal more actionable evidence which could enable burn survivors to meet the long-term goal of community reintegration.


Auditory affective agnosia. Disturbed comprehension of affective speech.
Hughlings Jackson noted that, although some aphasic patients were unable to use propositional speech, affective speech appeared to be spared. The purpose of this experiment was to study patients with unilateral hemispheric disease in order to ascertain if there are hemispheric asymmetries in the comprehension of affective speech. Six subjects had right temporoparietal lesions (left unilateral neglect) and six subjects had left temporoparietal lesions (fluent aphasias). These subjects were presented with 32 tape recorded sentences. In 16 trials the patients were asked to judge the emotional mood of the speaker (happy, sad, angry, indifferent) and in 16 trials the patients were asked to judge the content. Line drawings containing facial expressions of the four emotions or line drawings corresponding with the four basic contents were displayed with each sentence and the patient responded by pointing. All 12 subjects made perfect scores on the content portion of the test. On the emotional portion the right hemispheric patients scored a mean of 4-17 and the left hemispheric group scored a mean 10-17. The difference between these means is significantly (P less than 0-01) and suggests that patients with right hemispheric dysfunction and neglect have a defect in the comprehension of affective speech.


Excellent Outcome of Acute Necrotizing Encephalopathy in an Adult With Bacterial Infections, Case Report.
Acute necrotizing encephalopathy (ANE) is a rare para-infectious encephalopathy that classically occurs in children. However, ANE should be considered in the differential diagnosis of adults with symmetric brain lesions after a prodromal illness given recent reports of coronavirus disease of 2019 (COVID-19) to presumably cause ANE in adults. We report a case of a 29-year-old male presenting with fever, malaise, and rapid deterioration into coma. Brain magnetic resonance imaging revealed multifocal symmetric areas of diffusion restriction and surrounding vasogenic edema involving bilateral thalami, pons and cerebellar hemispheres with a core of susceptibility artifact, and minimal thalamic contrast enhancement, most consistent with ANE. Extensive infectious workup revealed isolated Escherichia coli and Neisseria gonorrhoeae in his urine. Despite the severe encephalopathy on initial presentation, the patient improved with intravenous antibiotics and supportive management with minimal residual deficits at 9 months follow-up. We aim to provide an overview of the radiological features, differential diagnosis, treatment and prognosis of ANE. Becoming familiarized with this rare but devastating disease will improve detection, treatment, and ultimately prognosis, especially in the era of a new pandemic.


Mucosal malignant melanomas in head and neck surgery: a retrospective study of six patients and review of the literature.
Of all malignant processes of the oral mucosa, 0.5% are malignant melanomas. Because of late diagnosis, pattern of growth, close proximity to the bone (particularly in palatinal localizations), and the correlated infiltration, malignant melanomas have a bad prognosis. In this retrospective study, six cases of patients with oral mucosal malignant melanoma are evaluated, and a critical review of the literature is presented. The female to male proportion was 1:1 with an average age of 60.2 years; all patients were treated between January 1999 and July 2007. A neck dissection was performed on two patients because of clinically positive lymph nodes; one patient received interleukin 2 therapy, and three patients received postoperative radiotherapy. Two male patients died. We recommend biopsy on every growing lesion, pigmented or nonpigmented, for the required diagnosis and, in cases of malignant melanoma, wide excision as a second step. Neck dissections should be performed in patients with clinically positive lymph nodes. Concerning interleukin 2 therapy, further studies should be performed in order to evaluate a routine application.


Childhood B cell lymphomas arising in the mediastinum.
To report the clinical features and pathology of four childhood cases of primary mediastinal non-Hodgkin's lymphoma of non-lymphoblastic pathology. Biopsy material was fixed in formol-saline and routinely processed and stained. Immunohistochemical staining was performed on paraffin wax embedded sections using the alkaline phosphatase anti-alkaline phosphatase method. The four patients presented with a large mediastinal mass and symptoms consistent with superior vena cava syndrome secondary to lymphoma. None of the patients had any clinically important disease outside the mediastinum. The four tumours had a histological appearance similar to diffuse large cell non-Hodgkin's lymphoma with sclerosis. Immunohistochemical staining showed that these tumours were of B cell origin. One patient died from infection during treatment and two patients died with progressive disease. The remaining patient remained well 43 months off all treatment. These four cases further illustrate the heterogeneity of paediatric large cell lymphomas. Clinically, they seem to be equivalent to the B cell lymphoma of the mediastinum, sclerosing type, that is seen in young (predominantly female) adults. The clinical and biological features of this type of tumour in childhood are largely unknown. Using standard treatment protocols, this tumour seems to have a poor prognosis and its optimal treatment therefore requires further clarification.


Staff retention after the privatization of township-village health centers: a case study from the Haimen City of East China.
Township-village health centers in rural areas play an important role in health service system in China. In East China's Jiangsu Province, the City of Haimen privatized all 25 township-village health centers in 2002. This study assesses the effect of privatization on staff retention among these health centers. This is a retrospective study based on 10-year administrative data from Haimen City. Three waves of administrative data were collected in 2000 (2 years before privatization), 2005 (3 years after privatization) and 2009 (7 years after privatization) for all health care providers in Haimen City, including 3 county hospitals, 6 central township health centers (CTHC) and 25 township-village health centers (TVHC). The effect of privatization on TVHCs' staff retention was evaluated in comparison with the other two types of health care providers. We conducted focus groups with people from Haimen Bureau of Health and various health care providers to help understand the context of these administrative statistics. Each township-village health centers had an average of 40 staff members before the privatization, and the majority of those staff members were their permanent staff. In 2005, three years after the privatization, a substantial amount of staff decrease (from 39.7 staff members per TVHC to 27.5 per TVHC) occurred in these township-village health centers. From 2000 to 2009, the total payroll in TVHCs decreased by almost 29%, while the number of their permanent staff members and nurses decreased by more than 40%. Among the two types of health care providers that did not go through a privatization, those central township health centers had no significant change on their payroll size during this period whereas the county hospitals' average payroll size actually increased by 20%, especially for the number of doctors. In addition, the average salary and caseload in TVHC showed similar decreasing trends from 2000 to 2009, while no such trends can be observed among the other two types of providers that did not undergo privatization. The privatization of township-village health center could have adverse effects on their staff retention, a phenomenon that occurs with a decrease in salary and caseload in these centers. To ensure that these health institutions keep providing health care for rural communities, a stronger social safety net and stronger financing of rural health insurance might be helpful in their staff retention.


Establishing final infarct volume: stroke lesion evolution past 30 days is insignificant.
Lesion volume measured on MRI has been used as an objective surrogate marker for outcome in clinical trials. However, lesion volumes vary over time because of edema and tissue loss. This study aims to determine if lesion volumes measured at 30 and 90 days after ictus significantly differ. We performed a retrospective study of 18 patients who had acute (<24 hours) DWI and follow-up fluid-attenuated inversion recovery imaging at 5, 30, and 90 days. Two expert readers segmented lesions and the mean volumes of both reads were used in all statistical analyses. Patient age was 65.8 (SD, 13.7) years and median NIHSS at baseline was 11.5. Inter-rater variability for lesion volume measurements was 3.7 (5.8) mL. Acute DWI volume was 19.3 (17.3) mL. Fluid-attenuated inversion recovery volumes for 5, 30, and 90 days were 34.3 (23.5), 18.6 (14.0), and 15.9 (13.8) mL, respectively. These volumes differed significantly (P<0.001). Linear regression revealed a strong correlation (r=0.96; P<0.001) between lesion volumes at 30 and 90 days with a slope that did not vary significantly from 1.0 (P=0.448). Lesions continue to evolve between 5 and 90 days, but by 30 days lesion volume approaches final infarct volume. While clinical response is the most meaningful outcome measure, our findings suggest that lesion volumes measured at 30 days may provide a sufficient approximation for final infarct volume for use in early phase clinical trials.


Association of anxiety with reduced baroreflex cardiac control in patients after acute myocardial infarction.
Although depression has been associated with increased mortality in patients after acute myocardial infarction (AMI), little is known about the effects of depression on autonomic nervous system control of heart rate. This study evaluated whether depression is associated with impaired baroreflex sensitivity (BRS) in patients with AMI. Two hundred four hospitalized patients with AMI were evaluated 6 +/- 3 (mean +/- SD) days after AMI. BRS was assessed using cross-spectral analysis to measure baroreceptor-mediated R-R interval oscillations. Depression was determined using the Diagnostic Interview Schedule, and severity of depressive symptoms was measured with the Beck Depression Inventory. In order to adjust for possible differences in anxiety, we also measured state anxiety using the Spielberger State Anxiety Inventory. Depression was not significantly related to BRS. However, anxiety was significantly related to low BRS in multivariate analysis, after the potentially confounding variables of age, blood pressure, and respiratory frequency were controlled for. Comparison of groups with high and low anxiety (on the basis of a median split of state anxiety scores) showed that BRS was reduced by approximately 20% in the patients with the higher anxiety scores (4.7 +/- 3.2 ms/mm Hg vs 5.7 +/- 3.3 ms/mm Hg, P <.05), after adjustment for differences in age, blood pressure, and respiratory frequency. High levels of anxiety, but not depression, are associated with reduced vagal control in patients after AMI.


On the comparative biology of mammalian telomeres: Telomere length co-evolves with body mass, lifespan and cancer risk.
Telomeres, the short repetitive DNA sequences that cap the ends of linear chromosomes, shorten during cell division and are implicated in senescence in most species. Telomerase can rebuild telomeres but is repressed in many mammals that exhibit replicative senescence, presumably as a tumour suppression mechanism. It is therefore important to understand the co-evolution of telomere biology and life-history traits that has shaped the diversity of senescence patterns across species. Gomes et al. previously produced a large data set on telomere length (TL), telomerase activity, body mass and lifespan among 57 mammal species. We re-analysed their data using the same phylogenetic multiple regressions and with several additional analyses to test the robustness of the findings. We found substantial inconsistencies in our results compared to Gomes et al.'s. Consistent with Gomes et al. we found an inverse association between TL and lifespan. Contrary to the analyses in Gomes et al., we found a generally robust inverse association between TL and mass, and only weak nonrobust evidence for an association between telomerase activity and mass. These results suggest that shorter TL may have been selected for in larger and longer lived species, probably as a mechanism to suppress cancer. We support this hypothesis by showing that longer telomeres predict higher cancer risk across 22 species. Furthermore, we find that domesticated species have longer telomeres. Our results call into question past interpretations of the co-evolution of telomere biology and life-history traits and stress the need for careful attention to model construction.


A Double Whammy: Severe Aortic Stenosis and Cocaine Overwhelm the Mitral Valve.
A 50-year-old man presented with acute onset dyspnea following cocaine use. He had severe aortic stenosis (AS), mild mitral regurgitation (MR) due to mitral valve prolapse, and no coronary artery disease on recent coronary angiography. He was in acute heart failure with signs of impending cardiogenic shock. Urgent bedside echocardiography revealed hyperdynamic left ventricular systolic function with acute severe MR from a ruptured chordae tendineae. The acute cocaine-induced spike of his already elevated left ventricular systolic pressure from severe AS likely precipitated chordal rupture of his vulnerable mitral valve. This patient underwent emergent mitral and aortic valve replacements. Although cocaine use has been associated with a myriad of cardiovascular complications, acute MR due to chordal rupture has not, to our knowledge, been previously reported in this setting. Prompt diagnosis with echocardiography and surgical intervention are of paramount importance in the management of acute MR.


Myogenic mechanisms in the kidney.
Myogenic mechanisms in the kidney are part of the autoregulation mechanism which maintains a constant renal blood flow at varying arterial pressure. Concomitant autoregulation of glomerular pressure and filtration indicates regulation of preglomerular resistance. Model and experimental studies were performed to evaluate two mechanisms in the kidney, myogenic response and tubuloglomerular feedback. A mathematical model showed good autoregulation through a myogenic response, aimed at maintaining a constant wall tension in each segment of the preglomerular vessels. Tubuloglomerular feedback gave rather poor autoregulation. The myogenic mechanism showed 'descending' resistance changes, starting in the larger arteries, and successively affecting downstream preglomerular vessels at increasing arterial pressures. This finding was supported by micropuncture measurements of pressure in the terminal interlobular arteries. Evidence that the mechanism was myogenic was obtained by exposing the kidney to a subatmospheric pressure of 40 mmHg; this led to an immediate increase in renal resistance, which could not be prevented by denervation or various blocking agents.


Olfactory conditioned partner preference in the female rat.
Paced copulation induces conditioned place preference in female rats. The authors examined whether associating almond-scented males with paced copulation induces conditioned partner preference. The paired group received 4 paced copulations with almond-scented males and 4 nonpaced copulations with unscented males sequentially at 4-day intervals. The unpaired group received the opposite order of association, whereas the randomly paired group received random associations. A 4th group received a single pairing. On the final test, females were placed into an open field with 2 males, 1 scented and 1 unscented. Females in the paired group solicited the scented male more frequently, and most chose the scented male for their 1st ejaculation. Thus, an odor paired with paced copulation elicits conditioned partner preference in female rats.


Medication reconciliation performed by pharmacy technicians at the time of preoperative screening.
Medication errors occur regularly in surgical patients, especially due to transfer problems at the time of hospital admission. A method for decreasing the error rate is medication reconciliation by hospital pharmacists as part of a preoperative clinic. The role of pharmacy technicians in this process has not been studied. To study the use of pharmacy technicians in medication reconciliation by measuring the effect of early reconciliation in the preoperative clinic on medication and allergy discrepancies and on inadvertent continuation of antithrombotics. A secondary objective was to study the effect of community pharmacist follow-up on recommendations to discontinue antithrombotic therapy. During the preintervention measurement period, patients received usual care by anesthesiologists, who recorded the medication and documented allergies of the patient. The intervention consisted of the addition of a pharmacy technician to the preoperative screening clinic to perform the same tasks as anesthesiologists as related to medication reconciliation. If necessary, the patient was advised on stopping the antithrombotic. On the day that the patient was supposed to stop the antithrombotic, that person's community pharmacist contacted the patient to determine whether this had been done. The main outcome measures were the proportions of patients with one or more medication discrepancy, one or more allergy discrepancy, and one or more antithrombotic error. In the preintervention period, 204 patients were evaluated; 93 were included in the postintervention analysis. The proportion of patients with one or more medication discrepancy (RR 0.29; 95% CI 0.12 to 0.71) was statistically significantly reduced in the postintervention group. The proportions of patients with one or more allergy discrepancy (RR 0.76; 95% CI 0.35 to 1.64) and one or more antithrombotic errors (RR 0.18; 95% CI 0.02 to 1.33) were reduced, but not significantly. Follow-up by the community pharmacist did not identify any patients who had not followed the preoperative clinic's advice on temporarily withholding their antithrombotics. The results of this study show that pharmacy technicians can be successfully assigned to a preoperative clinic, resulting in a statistically significant decrease in medication discrepancies.


Modulation of hunger by plasma glucose and metformin.
The plasma glucose concentration is a major short-term regulator of hunger and food intake. In patients with diabetes, therapies lowering plasma glucose are frequently associated with body weight gain, suggesting that lowered plasma glucose leads to increased feelings of hunger and food intake. However, as many physiological and symptomatic responses to low plasma glucose are attenuated after repeated episodes of hypoglycemia, this may also pertain to feelings of hunger. Here we tested whether the stimulatory effect of low plasma glucose on feelings of hunger is likewise reduced by repeated episodes of hypoglycemia. As metformin has been shown to reduce plasma glucose levels without increasing body weight and also to decrease food intake, we tested for possible interacting effects of this substance with hypoglycemia-induced hunger. Feelings of hunger were assessed by rating scales during 3 consecutive hypoglycemic clamps performed on 2 consecutive d in 15 normal weight men. Subjects were tested once while being treated with 850 mg metformin twice daily and once while receiving placebo. Treatment was started 14 d before the clamp experiments and was performed in a random order and double-blind fashion. Hypoglycemia markedly enhanced feelings of hunger (P < 0.001). However, rated feelings of hunger on the first and last hypoglycemic clamps were comparable (P = 0.304). Compared with placebo, metformin decreased feelings of hunger during hypoglycemia (P = 0.015). This reduction was not associated with a decrease in posthypoglycemic food intake as measured by the number of cookies consumed after the last clamp (P = 0.676). Data indicate that the stimulatory effect of low plasma glucose on hunger is not attenuated after repeated episodes of hypoglycemia, which implies that, in contrast to other symptoms, hunger is not subject to adaptive attenuation upon repeated hypoglycemia. Metformin attenuates hypoglycemia-induced hunger, but does not appear to influence posthypoglycemic food intake.


Heterogeneity of leukemia-initiating capacity of chronic myelogenous leukemia stem cells.
Chronic myelogenous leukemia (CML) results from transformation of a long-term hematopoietic stem cell (LTHSC) by expression of the BCR-ABL fusion gene. However, BCR-ABL-expressing LTHSCs are heterogeneous in their capacity as leukemic stem cells (LSCs). Although discrepancies in proliferative, self-renewal, and differentiation properties of normal LTHSCs are being increasingly recognized, the mechanisms underlying heterogeneity of leukemic LTHSCs are poorly understood. Using a CML mouse model, we identified gene expression differences between leukemic and nonleukemic LTHSCs. Expression of the thrombopoietin (THPO) receptor MPL was elevated in leukemic LTHSC populations. Compared with LTHSCs with low MPL expression, LTHSCs with high MPL expression showed enhanced JAK/STAT signaling and proliferation in response to THPO in vitro and increased leukemogenic capacity in vivo. Although both G0 and S phase subpopulations were increased in LTHSCs with high MPL expression, LSC capacity was restricted to quiescent cells. Inhibition of MPL expression in CML LTHSCs reduced THPO-induced JAK/STAT signaling and leukemogenic potential. These same phenotypes were also present in LTHSCs from patients with CML, and patient LTHSCs with high MPL expression had reduced sensitivity to BCR-ABL tyrosine kinase inhibitor treatment but increased sensitivity to JAK inhibitors. Together, our studies identify MPL expression levels as a key determinant of heterogeneous leukemia-initiating capacity and drug sensitivity of CML LTHSCs and suggest that high MPL-expressing CML stem cells are potential targets for therapy.


Effect of extrusion on the antioxidant capacity and color attributes of expanded extrudates prepared from purple potato and yellow pea flour mixes.
Foods with antioxidant capacity provide protection against cardio-vascular, certain forms of cancers, and Alzheimer's diseases caused by oxidative damages and contribute health benefits. The effect of extrusion cooking on the antioxidant capacity and color attributes of extruded products prepared from 3 selected formulations of purple potato and yellow pea flours using a co-rotating twin screw extruder were studied. Expansion ratios of the extruded products varied from 3.93 to 4.75. The total antioxidant capacities (TAC) of the extruded products, using DPPH assay, were 3769 to 4116 μg trolox equivalent/g dry weight sample and not significantly different (P > 0.05) from their respective raw formulations. The total phenolic contents (TP) of the extruded products varied from 2088 to 3766 μg of gallic acid equivalent/g dry weight sample and retained 73% to 83% of the TP from the raw formulations after extrusion. The total anthocyanins contents (TA) in the extrudates were 0.116 to 0.228 mg of malvidin-3-glucosides/g dry weight sample. Compared with their raw formulations, significant losses (60% to 70%) of the TA in the extruded products occurred due to extrusion cooking. Browning indices and color attributes such as brightness, chroma, and hue angle agreed with degradation of anthocyanins in the extruded products. However, extrusion cooking retained antioxidant capacities of the raw formulations in the extruded products either in their natural forms or degraded products with radical scavenging activity. This study demonstrated the potential for the production of puffed extruded food products with the improved antioxidant content from colored potatoes and pulse formulations.


Basic concepts and practical applications of recombinant DNA techniques in detection of human papillomavirus (HPV) infection. Review article.
Recent studies on the role of infectious agents in the pathogenesis of malignancy have demonstrated a strong association between HPV and several human benign and malignant epithelial neoplasms. There are 60 distinct types of HPV, of which HPV 16, 18, 31, 33, 35 and 39 have been associated with squamous cell neoplasia of the genital tract. Rapid progress in the field of recombinant DNA technology with the availability of specific probes has enabled the detection of HPV genomic sequences in characteristic HPV lesions. In addition, HPV sequences have been found in malignant squamous cell lesions, and even in normal tissues lacking the morphologic signs of HPV infection. Currently, hybridization analysis of the nucleic acid is the most reliable method for diagnosis of HPV infections, also permitting the genotyping of these viruses. A variety of hybridization procedures have been developed with different sensitivities and specificities. Despite the divergent technical modifications, however, all hybridization tests working according to the same basic principles. The double helix of DNA composed of two complementary polynucleotide chains can be opened by heating or by increasing pH. Cooling of the two strands allows reassociation. Labeled HPV DNA or RNA probe hybridizes with the complementary sequences allowing the detection of HPV sequences in the samples. Hybridization assays can be conducted under conditions in which virtually all HPVs will be detected, but not specifically typed (low stringency) or under conditions in which the type can be identified (high stringency). Widely divergent results have been reported both in prevalence of HPV infection and distribution of different HPV types in the genital tract. These discordant results have been explained on the basis of sampling effects, differences in histopathological diagnosis, geographical variations in HPV types and interlaboratory variation in HPV detection and typing techniques. In this review the various procedures for detecting HPV sequences by hybridization and related techniques are shortly described.


The safety and efficacy of the Isola Spinal Implant System for the surgical treatment of degenerative disc disease. A prospective study.
This is a prospective study designed in consultation with and approved by the Food and Drug Administration with the purpose of determining the safety and efficacy of the Isola Spinal Implant System for the surgical treatment of patients with degenerative disc disease. To report the results of the degenerative disc disease group from the Isola Investigational Device Exemption study, which was done to determine whether the Isola Spinal Implant System is a safe and effective treatment. The safety and efficacy of transpedicular instrumentation as an adjunct in achieving lumbar spine fusion are still debated. Hospital Investigational Review Board approval of the study protocol was obtained at the 10 participating centers. One hundred twenty patients (49 men and 71 women; average age, 54 years [range, 25-83 years]) were enrolled. Clinical and radiographic follow-up evaluation was done using protocols established prospectively. Of the 120 patients, 12 (10%) had device-related problems. There were two operative and four device related complications after surgery. Six other patients had their implants removed either for local pain (two) or for looseness or breakage (four). Of 118 patients eligible for follow-up evaluation at 24 months, 107 (91%) were available for study. Fusion was achieved in 97 (91%) patients. Average combined function and pain scores improved by 2.6 points (P < 0.0001). Clinical success, as measured by combining function and pain scores, was achieved in 65% of the patients by the most stringent criteria and 73% by less stringent criteria. Clinical success was significantly higher in patients who had not had previous surgery than in those who had, 77% versus 57% (P = 0.04). The present study suggests that the Isola Spinal Implant System can be safely used, is an effective adjunct in the achievement of fusion, and yields an acceptable number of successful clinical outcomes, especially when considering the preponderance of previously operated patients included in this group.


Consumer satisfaction in schizophrenia. A 2-year randomized controlled study of two community-based treatment programs.
Quality management and quality control of health services have become increasingly important. Central to the concept of quality of care is the consumer's (the patient's) own view of the care provided. UKU (Udvalg for Kliniske Undersøgelser), a task force within the Scandinavian Society for Psychopharmacology, has designed a brief consumer satisfaction rating scale, the UKU-ConSat. The UKU-ConSat rating scale was applied in a randomised comparative two-year study of two community-based treatment programs. The study included 84 patients with schizophrenic disorders according to DSM-IV. The major finding was a significantly increased consumer satisfaction with the new community-based program "Integrated Care" in comparison with best-established practice, called "Rational Rehabilitation." Thus, the new UKU-ConSat rating scale can detect differences, not only for in-patients as has previously been shown, but also between programs in community care settings. By per item analysis it was possible to discriminate between various elements of consumer satisfaction. There were significant correlations between the UKU-ConSat total scores and other clinical outcome domains, viz. symptoms, social function, and patient as well as carer's distress. To conclude, the UKU-ConSat rating scale is suitable for quality management and monitoring of treatment programs in mental health services.


Complete Mesoscopic Parameterization of Single LNA Modifications in DNA Applied to Oncogene Probe Design.
The use of mesoscopic models to describe the thermodynamic properties of locked nucleic acid (LNA)-modified nucleotides can provide useful insights into their properties, such as hydrogen-bonding and stacking interactions. In addition, the mesoscopic parameters can be used to optimize LNA insertion in probes, to achieve accurate melting temperature predictions, and to obtain duplex opening profiles at the base-pair level. Here, we applied this type of model to parameterize a large set of melting temperatures for LNA-modified sequences, from published sources, covering all possible nearest-neighbor configurations. We have found a very large increase in Morse potentials, which indicates very strong hydrogen bonding as the main cause of improved LNA thermodynamic stability. LNA-modified adenine-thymine (AT) was found to have similar hydrogen bonding to unmodified cytosine-guanine (CG) base pairs, while for LNA CG, we found exceptionally large hydrogen bonding. In contrast, stacking interactions, which were thought to be behind the stability of LNA, were similar to unmodified DNA in most cases. We applied the new LNA parameters to the design of BRAF, KRAS, and EGFR oncogene variants by testing all possible LNA modifications. Selected sequences were then synthesized and had their hybridization temperatures measured, achieving a prediction accuracy within 1 °C. We performed a detailed base-pair opening analysis to discuss specific aspects of these probe hybridizations that may be relevant for probe design.


Chronic Hand Eczema Guidelines From an Expert Panel of the International Eczema Council.
Assessment of chronic hand eczema (CHE) is complex and warrants standardization. We sought to guide clinicians on the assessment of CHE. An electronic questionnaire regarding the diagnosis and assessment of CHE was completed by councilors (n=45) of the International Eczema Council, an international group of clinicians and researchers with expertise in CHE. The survey consisted of 52 statements for consensus. Overall, nine statements (17.3%) had strong, twenty-three (44.2%) moderate, 12 (23.1%) low, and 8 (15.4%) very low levels of agreement. Five statements had considerable disagreement, including the value of conducting a skin biopsy (62.2% disagreement), investigating for possible type 1 reactions (60.0%), conducting a fungal culture (44.4%), finding no history of relevant allergens and/or irritants (31.1%) in most or all cases, and performing patch testing irrespective of lesion location and morphology (28.9%). Agreement was generally highest among respondents from Europe (28.6-77.8% agreement), followed by Asia (7.1%-35.7% agreement), North America (0%-35.5% agreement), and other (0%-13.3% agreement). There were substantial differences of agreement, suggesting there are many knowledge and/or practice gaps with respect to CHE. Future research is needed to inform evidence-based and/or consensus guidelines for CHE.


A Scoping Review of the Essential Components of Emergency Medical Response Systems for Mass Casualty Incidents.
Emergency medical (EM) response systems require extensive coordination, particularly during mass casualty incidents (MCIs). The recognition of preparedness gaps and contextual priorities to MCI response capacity in low- and middle-income countries (LMICs) can be better understood through the components of EM reponse systems. This study aims to delineate essential components and provide a framework for effective emergency medical response to MCIs. A scoping review was conducted using 4 databases. Title and abstract screening was followed by full-text review. Thematic analysis was conducted to identify themes pertaining to the essential components and integration of EM response systems. Of 20,456 screened citations, 181 articles were included in the analysis. Seven major and 40 sub-themes emerged from the content analysis as the essential components and supportive elements of MCI medical response. The essential components of MCI response were integrated into a framework demonstrating interrelated connections between essential and supportive elements. Definitions of essential components of EM response to MCIs vary considerably. Most literature pertaining to MCI response originates from high income countries with far fewer reports from LMICs. Integration of essential components is needed in different geopolitical and economic contexts to ensure an effective MCI emergency medical response.


Flavonoids and Related Compounds in Non-Alcoholic Fatty Liver Disease Therapy.
Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, is one of the most common chronic liver diseases, which may progress to fibrosis, cirrhosis and hepatocellular carcinoma. NAFLD is characterized by the accumulation of lipids in the liver arising from multiple factors: increased fatty acid uptake, increased de novo lipogenesis, reduced fatty acid oxidation and very low density lipoproteins (VLDL) secretion. Most therapeutic approaches for this disease are often directed at reducing body mass index and improving insulin resistance through lifestyle modifications, bariatric surgery and pharmacological treatments. Nevertheless, there is increasing evidence that the use of natural compounds, as polyphenols, exert multiple benefits on the disorders associated with NAFLD. These molecules seem to be able to regulate the expression of genes mainly involved in de novo lipogenesis and fatty acid oxidation, which contributes to their lipid-lowering effect in the liver. Their antioxidant, anti-inflammatory, antifibrogenic and antilipogenic properties seem to confer on them a great potential as strategy for preventing NAFLD progression. In this review, we summarized the effects of these compounds, especially flavonoids, and their mechanisms of action, that have been reported in several studies carried out in in vitro and in vivo models of NAFLD.


Precise beam-tilt alignment and collimation are required to minimize the phase error associated with coma in high-resolution cryo-EM.
Electron microscopy at a resolution of 0.4nm or better requires more careful adjustment of the illumination than is the case at a resolution of 0.8nm. The use of current-axis alignment is not always sufficient, for example, to avoid the introduction of large phase errors, at higher resolution, due to axial coma. In addition, one must also ensure that off-axis coma does not corrupt the data quality at the higher resolution. We particularly emphasize that the standard CTF correction does not account for the phase error associated with coma. We explain the cause of both axial coma and the typically most troublesome component of off-axis coma in terms of the well-known shift of the electron diffraction pattern relative to the optical axis that occurs when the illumination is not parallel to the axis. We review the experimental conditions under which coma causes unacceptably large phase errors, and we discuss steps that can be taken when setting up the conditions of illumination, so as to ensure that neither axial nor off-axis coma is a problem.


Separation of Cells and Microparticles in Insulator-Based Electrokinetic Systems.
Presented here is the first continuous separation of microparticles and cells of similar characteristics employing linear and nonlinear electrokinetic phenomena in an insulator-based electrokinetic (iEK) system. By utilizing devices with insulating features, which distort the electric field distribution, it is possible to combine linear and nonlinear EK phenomena, resulting in highly effective separation schemes that leverage the new advancements in nonlinear electrophoresis. This work combines mathematical modeling and experimentation to separate four distinct binary mixtures of particles and cells. A computational model with COMSOL Multiphysics was used to predict the retention times (tR,p) of the particles and cells in iEK devices. Then, the experimental separations were carried out using the conditions identified with the model, where the experimental retention time (tR,e) of the particles and cells was measured. A total of four distinct separations of binary mixtures were performed by increasing the level of difficulty. For the first separation, two types of polystyrene microparticles, selected to mimic Escherichia coli and Saccharomyces cerevisiae cells, were separated. By leveraging the knowledge gathered from the first separation, a mixture of cells of distinct domains and significant size differences, E. coli and S. cerevisiae, was successfully separated. The third separation also featured cells of different domains but closer in size: Bacillus cereus versus S. cerevisiae. The last separation included cells in the same domain and genus, B. cereus versus Bacillus subtilis. Separation results were evaluated in terms of number of plates (N) and separation resolution (Rs), where Rs values for all separations were above 1.5, illustrating complete separations. Experimental results were in agreement with modeling results in terms of retention times, with deviations in the 6-27% range, while the variation between repetitions was between 2 and 18%, demonstrating good reproducibility. This report is the first prediction of the retention time of cells in iEK systems.


Characterization of Accessible Chromatin Regions in Cattle Rumen Epithelial Tissue during Weaning.
Weaning in ruminants is characterized by the transition from a milk-based diet to a solid diet, which drives a critical gastrointestinal tract transformation. Understanding the regulatory control of this transformation during weaning can help to identify strategies to improve rumen health. This study aimed to identify regions of accessible chromatin in rumen epithelial tissue in pre- and post-weaning calves and investigate differentially accessible regions (DARs) to uncover regulatory elements in cattle rumen development using the ATAC-seq approach. A total of 126,071 peaks were identified, covering 1.15% of the cattle genome. From these accessible regions, 2766 DARs were discovered. Gene ontology enrichment resulted in GO terms related to the cell adhesion, anchoring junction, growth, cell migration, motility, and morphogenesis. In addition, putative regulatory canonical pathways were identified (TGFβ, integrin-linked kinase, integrin signaling, and regulation of the epithelial-mesenchymal transition). Canonical pathways integrated with co-expression results showed that TGFβ and ILK signaling pathways play essential roles in rumen development through the regulation of cellular adhesions. In this study, DARs during weaning were identified, revealing enhancers, transcription factors, and candidate target genes that represent potential biomarkers for the bovine rumen development, which will serve as a molecular tool for rumen development studies.


Surface-bound porphyrazines: controlling reduction potentials of self-assembled monolayers through molecular proximity/orientation to a metal surface.
We report the preparation of two novel H2[pz(An;B(4-n))] porphyrazines (pzs) which were designed to position themselves quite differently when attached to a surface: one to form a standard self-assembled monolayer (SAM) roughly perpendicular to a surface, the other to lie horizontally along a surface. As the former, we synthesized a pz, 1, where one pyrrole group is functionalized with two thioethers terminated in mercaptides (SR, R = (CH2)3CONH(CH2)2S-), each protected as a disulfide, and -S-Me is attached to the other pyrrole sites; the latter is a pz, 2, with dialkoxybenzo groups fused to two trans-pyrroles of the pz ring, and SR groups are attached to the other pair of pyrroles. Nanostructures of 1 and 2 were successfully patterned on gold surfaces via dip-pen nanolithography, and the predicted molecular orientation of the resulting structures was confirmed by topographic AFM images. The two pzs exhibit similar reduction potentials in solution. Both show large shifts in potential upon surface binding, with the magnitude of the shift depending on the proximity/orientation of the pz to the surface. The first reduction potential of the "vertically" aligned 1 shifts by ca. +430 mV when incorporated in a binary pz/hexanethiol SAM, while that for 2, which lies flat, shifts by ca. +800 mV; the potential thus shifts by ca. +370 mV upon taking a given pz that stands atop a two-legged insulating "standoff" in a traditional SAM and "laying it down". We suggest these observed effects can be explained by image-charge energetics, and this is supported by a simple model.


Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas: safety and pharmacokinetics.
Endothelin receptors, particularly the ET(A) receptor, have been shown to participate in the pathophysiology of prostate and other cancers. Atrasentan, an endothelin antagonist, binds selectively to the ET(A) receptor. This study evaluated the safety, pharmacokinetics, and maximum-tolerated dose of atrasentan in cancer patients. Patients who were 18 years or older and had histologically confirmed adenocarcinoma refractory to therapy enrolled in this 28-day, open-label, phase I study. Enrollment was planned for cohorts of three patients at doses escalating from 10 to 140 mg/d. When any patient had dose-limiting toxicity, that cohort was expanded. The primary outcome variable was safety; secondary outcome variables were pharmacokinetics, tumor response, and pain relief. Thirty-one cancer patients (14 prostate) were treated at daily atrasentan doses of 10, 20, 30, 45, 60, and 75 mg (n = 3 to 8 per cohort). The most common adverse events, such as rhinitis, headache, asthenia, and peripheral edema, were reversible on drug discontinuation and responded to symptom-specific treatment. Reversible hemodilution was apparent in laboratory findings and weight gain. Clinically significant headache was the dose-limiting adverse event; the maximum-tolerated dose was 60 mg/d. Pharmacokinetics were dose-proportional across the 10- to 75-mg dose range. Atrasentan was rapidly absorbed; the time to maximum observed concentration was approximately 1.5 hours. The terminal elimination half-life was approximately 24 hours, and steady-state plasma concentrations were achieved within 7 days. Decreases in prostate-specific antigen and pain relief were noted in a patient subset. Adverse events were consistent with atrasentan's pharmacologic vasodilatory effect. Linear, dose-proportional pharmacokinetics suggest that atrasentan can be easily and consistently dosed.


Anosognosia for hemiplegia as a tripartite disconnection syndrome.
The syndrome of Anosognosia for Hemiplegia (AHP) can provide unique insights into the neurocognitive processes of motor awareness. Yet, prior studies have only explored predominately discreet lesions. Using advanced structural neuroimaging methods in 174 patients with a right-hemisphere stroke, we were able to identify three neural systems that contribute to AHP, when disconnected or directly damaged: the (i) premotor loop (ii) limbic system, and (iii) ventral attentional network. Our results suggest that human motor awareness is contingent on the joint contribution of these three systems.


Synergistic transcriptional enhancement does not depend on the number of acidic activation domains bound to the promoter.
Many eukaryotic transcriptional activator proteins contain a DNA-binding domain that interacts with specific promoter sequences and an acidic activation region that is required to stimulate transcription. Transcriptional enhancement by such activator proteins is often synergistic and promiscuous; promoters containing multiple binding sites for an individual protein or even for unrelated proteins can be 10-100 times more active than promoters with single sites. It has been suggested that such synergy reflects a nonlinear response of the basic transcription machinery to the number and/or quality of acidic activation regions. Here, we determine the transcriptional activity of Jun-Fos heterodimers containing one or two GCN4 acidic activation regions on promoters containing one or two Ap-1 target sites. Surprisingly, heterodimers with one or two acidic regions activate transcription with similar efficiency and are equally synergistic (10- to 15-fold) on promoters containing two target sites. Thus, transcriptional synergy does not depend on the number of acidic activation regions but rather on the number of proteins bound to the promoter. This suggests that synergy is mediated either by cooperative DNA binding or by alternative mechanisms in which the DNA-binding domain plays a more direct role in transcription (e.g., changes in DNA structure, nucleosome displacement, or direct interactions with the transcriptional machinery).


Use of posterior fontanelle in the ultrasound diagnosis of intraventricular/periventricular hemorrhage.
To evaluate the use of the posterior fontanelle in premature neonates (< 37 weeks) with a birth weight < 1,500 g in the ultrasound diagnosis of intraventricular/periventricular hemorrhage and to assess whether the use of the anterior fontanelle associated with the posterior fontanelle changes the interrater agreement. Eighty-five premature neonates were evaluated in this prospective study. Ultrasound was performed using the anterior fontanelle, and later, the posterior fontanelle. A consensus diagnosis between two raters was used to analyze the agreement between the anterior fontanelle alone and in association with the posterior fontanelle. If there was no consensus, a third observer was involved to decide. Agreement between the first two raters had a kappa of 0.80 (95%CI 0.76-0.84). However, when the anterior fontanelle was evaluated alone, kappa was 0.74 (95%CI 0.70-0.78). Thirty-seven hemispheres had grade II hemorrhage, of which 17 (45.9%) had their diagnosis performed using the anterior fontanelle; in 10 (27%), diagnosis was suspected by the anterior fontanelle and confirmed by the posterior fontanelle; and in 10 (27%), diagnosis was exclusively performed using the posterior fontanelle. Of the 454 hemispheres, in 20 (4.4%) the diagnosis of intraventricular hemorrhage was performed exclusively by the posterior fontanelle (p < 0.001). In this study, the anterior fontanelle associated with the posterior fontanelle was better than the use of the anterior fontanelle alone in the identification of intraventricular/periventricular hemorrhage. Ultrasound using the posterior fontanelle allowed diagnosis of unsuspected grade II hemorrhage by the anterior fontanelle. Use of the posterior fontanelle was also useful to clarify presence of hemorrhage in inconclusive examinations by the anterior fontanelle.


Comparative Structural and Compositional Analyses of Cow, Buffalo, Goat and Sheep Cream.
Factors affecting milk and milk fraction composition, such as cream, are poorly understood, with most research and human health application associated with cow cream. In this study, proteomic and lipidomic analyses were performed on cow, goat, sheep and Bubalus bubalis (from now on referred to as buffalo), bulk milk cream samples. Confocal laser scanning microscopy was used to determine the composition, including protein, lipid and their glycoconjugates, and the structure of the milk fat globules. BLAST2GO was used to annotate functional indicators of cream protein. Functional annotation of protein highlighted a broad level of similarity between species. However, investigation of specific biological process terms revealed distinct differences in antigen processing and presentation, activation, and production of molecular mediators of the immune response. Lipid analyses revealed that saturated fatty acids were lowest in sheep cream and similar in the cream of the other species. Palmitic acid was highest in cow and lowest in sheep cream. Cow and sheep milk fat globules were associated with thick patches of protein on the surface, while buffalo and goat milk fat globules were associated with larger areas of aggregated protein and significant surface adsorbed protein, respectively. This study highlights the differences between cow, goat, sheep, and buffalo milk cream, which can be used to support their potential application in functional foods such as infant milk formula.


Dipolar cortico-muscular electrical stimulation: a novel method that enhances motor function in both - normal and spinal cord injured mice.
Electrical stimulation of the central and peripheral nervous systems is a common tool that is used to improve functional recovery after neuronal injury. Here we described a new configuration of electrical stimulation as it was tested in anesthetized control and spinal cord injury (SCI) mice. Constant voltage output was delivered through two electrodes. While the negative voltage output (ranging from -1.8 to -2.6 V) was delivered to the muscle via transverse wire electrodes (diameter, 500 μm) located at opposite ends of the muscle, the positive output (ranging from + 2.4 to +3.2 V) was delivered to the primary motor cortex (M1) (electrode tip, 100 μm). The configuration was named dipolar cortico-muscular stimulation (dCMS) and consisted of 100 pulses (1 ms pulse duration, 1 Hz frequency). In SCI animals, after dCMS, cortically-elicited muscle contraction improved markedly at the contralateral (456%) and ipsilateral (457%) gastrocnemius muscles. The improvement persisted for the duration of the experiment (60 min). The enhancement of cortically-elicited muscle contraction was accompanied by the reduction of M1 maximal threshold and the potentiation of spinal motoneuronal evoked responses at the contralateral (313%) and ipsilateral (292%) sides of the spinal cord. Moreover, spontaneous activity recorded from single spinal motoneurons was substantially increased contralaterally (121%) and ipsilaterally (54%). Interestingly, spinal motoneuronal responses and muscle twitches evoked by the test stimulation of non-treated M1 (received no dCMS) were significantly enhanced as well. Similar results obtained from normal animals albeit the changes were relatively smaller. These findings demonstrated that dCMS could improve functionality of corticomotoneuronal pathway and thus it may have therapeutic potential.


Spectral correction for handheld optoacoustic imaging by means of near-infrared optical tomography in reflection mode.
In vivo imaging of tissue/vasculature oxygen saturation levels is of prime interest in many clinical applications. To this end, the feasibility of combining two distinct and complementary imaging modalities is investigated: optoacoustics (OA) and near-infrared optical tomography (NIROT), both operating noninvasively in reflection mode. Experiments were conducted on two optically heterogeneous phantoms mimicking tissue before and after the occurrence of a perturbation. OA imaging was used to resolve submillimetric vessel-like optical absorbers at depths up to 25 mm, but with a spectral distortion in the OA signals. NIROT measurements were utilized to image perturbations in the background and to estimate the light fluence inside the phantoms at the wavelength pair (760 nm, 830 nm). This enabled the spectral correction of the vessel-like absorbers' OA signals: the error in the ratio of the absorption coefficient at 830 nm to that at 760 nm was reduced from 60%-150% to 10%-20%. The results suggest that oxygen saturation (SO 2 ) levels in arteries can be determined with <10% error and furthermore, that relative changes in vessels' SO 2 can be monitored with even better accuracy. The outcome relies on a proper identification of the OA signals emanating from the studied vessels.


Bryostatin 1 Promotes Synaptogenesis and Reduces Dendritic Spine Density in Cortical Cultures through a PKC-Dependent Mechanism.
The marine natural product bryostatin 1 has demonstrated procognitive and antidepressant effects in animals and has been entered into human clinical trials for treating Alzheimer's disease (AD). The ability of bryostatin 1 to enhance learning and memory has largely been attributed to its effects on the structure and function of hippocampal neurons. However, relatively little is known about how bryostatin 1 influences the morphology of cortical neurons, key cells that also support learning and memory processes and are negatively impacted in AD. Here, we use a combination of carefully designed chemical probes and pharmacological inhibitors to establish that bryostatin 1 increases cortical synaptogenesis while decreasing dendritic spine density in a protein kinase C (PKC)-dependent manner. The effects of bryostatin 1 on cortical neurons are distinct from those induced by neural plasticity-promoting psychoplastogens such as ketamine. Compounds capable of increasing synaptic density with concomitant loss of immature dendritic spines may represent a unique pharmacological strategy for enhancing memory by improving signal-to-noise ratio in the central nervous system.


Partnership working and outcomes: do health and social care partnerships deliver for users and carers?
Working in partnership, both across social care and health and with service users, has been a persistent theme of the health and social care modernisation agenda in the United Kingdom. Despite a relatively underdeveloped evidence base, the development of health and social care partnerships has continued to feature in recent policy and legislative initiatives in the United Kingdom. At the same time there has been a major shift in focus towards the outcomes that support services deliver. A central question remaining is whether the policy initiatives driving the development of health and social care partnerships are delivering improved outcomes, particularly the outcomes valued by people who use services. This article outlines research designed to explore this issue across 15 health and social care partnerships in England and Scotland, building from previous research by the Social Policy Research Unit based at the University of York. It sought to assess the extent to which health and social care partnerships deliver the outcomes that people who use services value, and to determine the features of partnership working associated with the delivery of these outcomes. A robust outcomes framework was defined, which provided the basis for interviews with those receiving support from partnerships. Working with three user-researcher organisations, interviews were completed with 230 individuals in 2006. On the basis of this, some service users were able to identify features of partnership that particularly contributed to improved outcomes. These included continuity of staff and sufficient staff and a range of resources, including the availability of long-term and preventative services. Given the definitional and methodological complexity surrounding partnership working, and the challenges of attribution, the study faced some limitations in its ability to make wider inferences about partnership and outcomes. A theory of change should be employed in future studies of this type.


Does widowhood affect memory performance of older persons?
The loss of a spouse has been found to have a negative effect on physical and mental health and leads to increased mortality. Whether conjugal bereavement also affects memory functioning has largely been unexamined. The present study investigates the effect of widowhood on memory functioning in older persons. The sample consisted of 474 married women and 690 married men aged 60-85 years in 1992, followed up in 1995 and 1998. During the study 135 (28%) of the women and 69 (10%) of the men lost their spouse. Linear regression analysis was used to examine whether widowed men and women differed from those who had not been widowed in rate of memory change over 6 years. Cross-domain latent-change models were subsequently used to evaluate the extent to which changes in memory are related to changes in other domains of functioning that may be affected by widowhood. Older adults who lost a spouse during follow-up showed a greater decline in memory over 6 years than those who remained married. A higher level of depressive symptoms at baseline was related to lower levels of memory functioning and a greater decline. Memory decline was unrelated to changes in depressive symptoms and physical health. Loss of the spouse is related to a greater decline in memory in older adults. The absence of an association with physical functioning and the weak association with mental functioning suggest that losing a spouse has an independent effect on memory functioning.


Nerve growth factor facilitates cholinergic neurotransmission between nucleus basalis and the amygdala in rat: an electrophysiological analysis.
Treatment of rats in vivo with NGF promotes the survival and enhances the neurotransmitter phenotype of basal forebrain cholinergic neurons. We showed recently (Williams et al., 1993) that NGF-induced stimulations of the cholinergic markers ChAT and high-affinity choline uptake are reflected in an enhanced synthesis and release of ACh in terminals fields of basal forebrain cholinergic neurons. The objective of the present study was to determine whether such effects translate into an enhancement in neurotransmission between nucleus basalis neurons and postsynaptic target cells, and therefore are likely to be of physiological significance. Changes in cholinergic neurotransmission after NGF were assessed by comparing the ability of cholinergic pathway activation, produced by electrical stimulation of nucleus basalis or the external capsule, to elicit intracellularly recorded muscarinic responses in basolateral amygdaloid (BLA) neurons in ventral forebrain slice preparations from NGF-treated and control Fischer 344 adult rats. Chronic infusion of NGF for 3 weeks (1.2 micrograms/d, i.c.v.) increased the likelihood of eliciting cholinergic slow depolarizations (slow EPSP) via stimulation of cholinergic pathways in the slice. In addition, the frequency-response curves for generation of the cholinergic slow EPSP by nucleus basalis or external capsule stimulation were shifted approximately twofold to the left and the EF50 values significantly reduced in neurons from NGF-treated slices, compared to those in preparations from vehicle-treated or untreated controls. Treatment with NGF also resulted in a leftward shift in the frequency-response curve for cholinergic pathway-induced blockade of the slow afterhyperpolarization, without change in the maximal inhibitory effect. The NGF-induced enhancement in cholinergic synaptic effectiveness was not accompanied by alterations in the resting membrane properties or intrinsic excitability of BLA pyramidal neurons. Nor did treatment with NGF affect their chemosensitivity or responsiveness to direct postsynaptic applications of the cholinergic carbachol. We conclude from these results that chronic administration of exogenous NGF can facilitate neurotransmission within basal forebrain cholinergic projections in normal adult brain, presumably as a consequence of its ability to stimulate presynaptic mechanisms involved in synthesis and/or release of ACh.


Long-term administration of antisense oligonucleotides into the paraspinal muscles of mdx mice reduces kyphosis.
The mdx mouse model of muscular dystrophy has a premature stop codon preventing production of dystrophin. This results in a progressive phenotype causing centronucleation of skeletal muscle fibers, muscle weakness, and fibrosis and kyphosis. Antisense oligonucleotides alter RNA splicing to exclude the nonsense mutation, while still maintaining the open reading frame to produce a shorter, but partially functional dystrophin protein that should ameliorate the extent of pathology. The present study investigated the benefits of chronic treatment of mdx mice by once-monthly deep intramuscular injections of antisense oligonucleotides into paraspinal muscles. After 8 mo of treatment, mdx mice had reduced development of kyphosis relative to untreated mdx mice, a benefit that was retained until completion of the study at 18 mo of age (16 mo of treatment). This was accompanied by reduced centronucleation in the latissimus dorsi and intercostals muscles and reduced fibrosis in the diaphragm and latissimus dorsi. These benefits were accompanied by a significant increase in dystrophin production. In conclusion, chronic antisense oligonucleotide treatment provides clear and ongoing benefits to paralumbar skeletal muscle, with associated marked reduction in kyphosis.


Localization of Caspr2 in myelinated nerves depends on axon-glia interactions and the generation of barriers along the axon.
Cell recognition proteins of the contactin-associated protein (Caspr) family demarcate distinct domains along myelinated axons. Caspr is present at the paranodal junction formed between the axon and myelinating glial cells, whereas Caspr2 is localized and associates with K(+) channels at the adjacent juxtaparanodal region. Here we investigated the distribution of Caspr2 during development of peripheral nerves of normal and galactolipids-deficient [ceramide galactosyl transferase (CGT)-/-] mice. This mutant exhibits paranodal abnormalities, lacking all putative adhesion components of this junction, including Caspr, contactin, and neurofascin 155. In sciatic nerves of this mutant, Caspr2 was not found at the juxtaparanodal region but was concentrated instead at the paranodes with Kv1.2. Similar distribution of Caspr2 was found in the PNS of contactin knock-out mice, which also lack Caspr in their paranodes. During development of wild-type peripheral nerves, Caspr2 and Kv1.2 were initially detected at the paranodes before relocating to the adjacent juxtaparanodal region. This transition was not observed in CGT mice, where Caspr2 and Kv1.2 remained paranodal. Double labeling for Caspr and Caspr2 demonstrated that these two related proteins occupied mutually excluding domains along the axon and revealed the presence of both paranodal and internodal barrier-like structures that are delineated by Caspr. Finally, we found that the disruption of axon-glia contact in CGT-/- nerves also affects the localization of the cytoskeleton-associated protein 4.1B along the axon. Altogether, our results reveal a sequential appearance of members of the Caspr family at different domains along myelinated axons and suggest that the localization of Caspr2 may be controlled by the generation of Caspr-containing barriers along the axon.


Circulating procalcitonin and cleavage products in septicaemia compared with medullary thyroid carcinoma.
Raised plasma levels of procalcitonin (proCT) represent an early marker for septicaemia. They are related to disease severity and inversely to outcome and response to treatment. ProCT is presumably synthesised in tIssues other than the thyroid C-cells which are the source of calcitonin (CT) in normal physiology. This study compares proCT and its cleavage products in the serum of patients with septicaemia with those in medullary thyroid carcinoma (MTC). Immunoreactive proCT and its cleavage products were extracted from the serum of patients with septicaemia or MTC using octadecylsilyl silica columns and characterised by reversed phase HPLC and Western blot analysis. ProCT, CT(1-32) and the flanking peptides PAS-57 and PDN-21 were recognised with antibodies specific for the individual peptides. ProCT and a 10 kDa polypeptide were recognised with antibodies to PAS-57, CT(1-32) and PDN-21. An 8 kDa proCT fragment was detected with antibodies to CT and PDN-21. However, intact CT(1-32), PAS-57 and PDN-21, found in the serum of MTC patients, were undetectable. The results indicate partial cleavage of proCT in septicaemia different from that in MTC patients. ProCT and 10 and 8 kDa proCT fragments were recognised in the circulation of septic patients. They were different from the known proCT-processing products PAS-57, CT(1-32) and PDN-21 identified in the serum of normal subjects and of MTC patients. Distinct cleavage of proCT may contribute to the symptoms of septicaemia.


Outcome of hip resurfacing revision through the Hueter-anterior approach.
The Hueter-Anterior Approach (HAA) with its limited soft tissue and internervous dissection has been shown to be an effective approach for primary total hip and hip resurfacing arthroplasty (HRA). The purpose of this study is to evaluate the clinical outcome of patients requiring revision of HRA to total hip replacement using the HAA, assessing function and complications. We performed a retrospective review of a prospectively maintained research database. Between 2006 and 2015, 555 primary metal-on-metal (MoM) HRAs were performed via the HAA; we identified 33 hips in 30 patients that required revisions for aseptic causes to THA: aseptic loosening of acetabulum in 12 and femoral in 7, 10 for pseudotumour/ALTR, 4 for femoral neck fracture. All revision surgeries were performed through a HAA by a single surgeon who had also performed the index operation. PROMs were collected preoperatively and yearly at various timepoints postoperatively. The mean age at time of revision was 48.9 years (±5.3 SD) for 22 males (67%) and 11 females (33%). The mean time to revision surgery/failure of hip resurfacing was 3.3 years (±2.4 SD). There were 5 major reoperations with 3 infections, 1 acetabular loosening and 1 trunnionosis. There were significant improvements in multiple PROMs. The HAA is a viable surgical approach for revision of HRA with smaller initial HRA acetabular components generally requiring a relatively larger acetabular compoent at time of revision. Patients reported improvement in symptoms and function and a lower risk of subsequent reoperation than what has previously been reported for failed MoM bearings.


Comparison of prescribing criteria to evaluate the appropriateness of drug treatment in individuals aged 65 and older: a systematic review.
Because inappropriate prescribing is prevalent in individuals aged 65 and older, various criteria to assess it have been developed. This study's aim was to systematically review articles that describe criteria for assessing inappropriate prescribing in individuals aged 65 and older and to define the circumstances of their use (explicit/implicit), origins, development processes, and content. A systematic search was conducted on MEDLINE and PubMed (1990-2010) and augmented with a manual search. Original articles written in English were included if they described the development of the criteria and were aimed at people aged 65 and older. Articles that described criteria applicable only in hospital settings, specific drugs, or a particular disease or condition were excluded. Sixteen of 535 articles met the inclusion criteria. They described 14 criteria, half originating in the United States. The English-language restriction limited the search results. Most criteria were explicit, consensus validated, based totally or partly on Beers criteria, and focused on pharmacological appropriateness of prescribing and some were old. Drug- and disease-oriented explicit criteria require regular updating and are country specific. Implicit, person-specific criteria are universal and do not need updating, although their use requires up-to-date professional skills. Unlike explicit criteria, implicit criteria have been validated in people. Some of the 14 criteria were noncomprehensive, mainly because of the intended purpose. To conclude, different criteria exist for optimizing prescribing for individuals aged 65 and older. Possible deficiencies must be recognized and trade-offs made when selecting criteria for use. In the future, more-comprehensive and -timely criteria are needed.


SOX7 regulates the expression of VE-cadherin in the haemogenic endothelium at the onset of haematopoietic development.
At early stages of vertebrate ontogeny, blood and endothelial cells develop from a common mesodermal progenitor, the haemangioblast. Upon haematopoietic commitment, the haemangioblast generates blood precursors through populations of endothelial cells with haemogenic properties. Although several transcription factors have been implicated in haemangioblast differentiation, the precise mechanisms governing cell fate decisions towards the generation of haemogenic endothelium precursors remain largely unknown. Under defined conditions, embryonic stem (ES) cells can be differentiated into haemangioblast-like progenitors that faithfully recapitulate early embryonic haematopoiesis. Here, we made use of mouse ES cells as a model system to understand the role of SOX7, a member of a large family of transcription factors involved in a wide range of developmental processes. During haemangioblast differentiation, SOX7 is expressed in haemogenic endothelium cells and is downregulated in nascent blood precursors. Gain-of-function assays revealed that the enforced expression of Sox7 in haemangioblast-derived blast colonies blocks further differentiation and sustains the expression of endothelial markers. Thus, to explore the transcriptional activity of SOX7, we focused on the endothelial-specific adhesion molecule VE-cadherin. Similar to SOX7, VE-cadherin is expressed in haemogenic endothelium and is downregulated during blood cell formation. We show that SOX7 binds and activates the promoter of VE-cadherin, demonstrating that this gene is a novel downstream transcriptional target of SOX7. Altogether, our findings suggest that SOX7 is involved in the transcriptional regulation of genes expressed in the haemogenic endothelium and provide new clues to decipher the molecular pathways that drive early embryonic haematopoiesis.


Reversing Urethral Hypovascularity Through Testosterone and Estrogen Supplementation.
To determine the ability of testosterone and estrogen to reverse urethral hypovascularity secondary to hypogonadism, we analyzed the effects of testosterone and estrogen supplementation on castrated Sprague Dawley rats. Twenty four Sprague-Dawley rats were divided into 4 groups: (1) non-castrate (NC) controls; (2) castrate (C) unsupplemented rats; (3) castrate rats that received testosterone (T), or (4) castrate rats that received estradiol (E). With immunohistochemistry, we measured vessel density (endothelial cell marker CD31), expression levels of androgen receptor (AR), TIE-2, and estrogen receptors ER-alpha and GPER1. Urethral vascularity was significantly increased after both testosterone and estrogen supplementation (T: 8.92%, E: 7.66%, vs C: 3.62%; P <0.001 for both), surpassing that of NC (5.86%, P <0.001 for both). Testosterone restored AR expression to physiologic levels (T: 5.21%, NC: 4.54%, P =0.135), and upregulated expression of TIE-2 (T: 0.20%, NC: 0.43%, P <0.001), neither of which was expressed in the absence of testosterone. Expression levels of nuclear ER-alpha was nearly undetectable (0.06%-0.38%), while membrane-bound GPER1 expression was upregulated by estrogen (3.30%) compared to other groups (T: 2.01%, NC: 1.02%, C: 0.37%, P <0.01 for all). Increased vessel density was significantly associated with increased AR (r = 0.22, P = 0.019) and GPER1 expression (r = 0.25, P = 0.018) suggesting a mechanistic relationship. Testosterone and estrogen exposure both restore periurethral vascularity in castrate (hypogonadal) rats via upregulation of AR/TIE-2 and GPER1 expression. Our results provide a foundation for testosterone or estrogen replacement in hypogonadal men to reverse atrophic effects of hypogonadism on the urethra.


Temporal condition pattern mining in large, sparse electronic health record data: A case study in characterizing pediatric asthma.
This study introduces a temporal condition pattern mining methodology to address the sparse nature of coded condition concept utilization in electronic health record data. As a validation study, we applied this method to reveal condition patterns surrounding an initial diagnosis of pediatric asthma. The SPADE (Sequential PAttern Discovery using Equivalence classes) algorithm was used to identify common temporal condition patterns surrounding the initial diagnosis of pediatric asthma in a study population of 71 824 patients from the Children's Hospital of Philadelphia. SPADE was applied to a dataset with diagnoses coded using International Classification of Diseases (ICD) concepts and separately to a dataset with the ICD codes mapped to their corresponding expanded diagnostic clusters (EDCs). Common temporal condition patterns surrounding the initial diagnosis of pediatric asthma ascertained by SPADE from both the ICD and EDC datasets were compared. SPADE identified 36 unique diagnoses in the mapped EDC dataset, whereas only 19 were recognized in the ICD dataset. Temporal trends in condition diagnoses ascertained from the EDC data were not discoverable in the ICD dataset. Mining frequent temporal condition patterns from large electronic health record datasets may reveal previously unknown associations between diagnoses that could inform future research into causation or other relationships. Mapping sparsely coded medical concepts into homogenous groups was essential to discovering potentially useful information from our dataset. We expect that the presented methodology is applicable to the study of diagnostic trajectories for other clinical conditions and can be extended to study temporal patterns of other coded medical concepts such as medications and procedures.


Effects of adaptation to altered display gain on the control of single aimed movements.
A display gain setting defines the mapping of a movement to the real-time visual display. In two experiments we investigated how the acquired adaptation to low and high display gain affected motor control of single aimed stylus movements. Experiments differed with respect to how gain was varied. In Experiment 1, gain was realized by manipulating the surface displacements with a constant display. The results show an expected linear decrease of movement time and spatial accuracy, which is in sharp contrast with the often-reported U-shaped relation. Experiment 2 was run to study the influence of visual feedback in low- and high-gain conditions. The manipulation of gain was realized by display variation with unaltered surface displacements. The linear increase of movement time and feedback processing with gain and the unaltered spatial accuracy across conditions, suggested that participants actively adapted to the displayed visual information in altered gain conditions.


Lysozyme Fibrils Alter the Mechanism of Insulin Amyloid Aggregation.
Protein aggregation into amyloid fibrils is linked to multiple disorders. The understanding of how natively non-harmful proteins convert to these highly cytotoxic amyloid aggregates is still not sufficient, with new ideas and hypotheses being presented each year. Recently it has been shown that more than one type of protein aggregates may co-exist in the affected tissue of patients suffering from amyloid-related disorders, sparking the idea that amyloid aggregates formed by one protein may induce another protein's fibrillization. In this work, we examine the effect that lysozyme fibrils have on insulin amyloid aggregation. We show that not only do lysozyme fibrils affect insulin nucleation, but they also alter the mechanism of its aggregation.


Cardiovascular re-adjustments and baroreflex response during clinical reambulation procedure at the end of 35-day bed rest in humans.
During the reambulation procedure after 35-day head-down tilt bed rest (HDTBR) for 9 men, we recorded for the first time heart rate (HR; with electrocardiogram) and arterial pressure profiles (fingertip plethysmography) for 5 min in HDTBR and horizontal (SUP) positions, followed by 12 min in standing position, during which 4 subjects fainted (intolerant, INT) and were laid horizontal again (Recovery). We computed: mean arterial pressure (P̄; pressure profiles integral mean), stroke volume (SV; obtained with Modelflow method), and cardiac output (Q̇; SV × HR). All cardiovascular data remained stable in HDTBR and SUP for both groups (EXP). Taking the upright posture, EXP showed a decrease in SV and an increase in HR, becoming significantly different from SUP within 1 min. Further evolution of these parameters kept Q̇ stable in both groups until the second minute of standing. Afterward, in INT, P̄ precipitated without further HR increases: SV stopped being corrected and Q̇ reached 2.9 ± 0.4 L·min(-1) at the last 15 s of standing. Sudden drop in P̄ allowed identification of a low-pressure threshold in INT (70.7 ± 12.9 mm Hg), after which syncope occurred within 80 s. During Recovery, baroreflex curves showed a flat phase (P̄ increase, HR stable), followed by a steep phase (P̄ increased, HR decreased, starting when P̄ was 84.5 ± 12.5 mm Hg and Q̇ was 9.6 ± 1.5 L·min(-1)). INT, in contrast with tolerant subjects, did not sustain standing because HR was unable to correct for the P̄ drop. These results indicate a major role for impaired arterial baroreflexes in the onset of orthostatic intolerance.


Spatial and Temporal Algorithm Evaluation for Detecting Over-The-Counter Thermometer Sale Increases during 2009 H1N1 Pandemic.
Spatial outbreak detection algorithms using routinely collected healthcare data have been developed since the late 90s to identify and locate disease outbreaks. However, current well-received spatial algorithms assume only one outbreak cluster present at the same point of time which may not be valid during a pandemic when several clusters of geographic areas concurrently occur. Based on a retrospective evaluation on time-series and spatial algorithms, this paper suggests that time series analysis in detection of pandemics is still a desirable process, which may achieve more sensitive performance with better timeliness. In this paper, we first prove in theory that two existing spatial models, the likelihood ratio and the Bayesian spatial scan statistics, are not useful if multiple clusters occur at the same point of time in different geographic regions. Then we conduct a comparison between a spatial algorithm, the Bayesian Spatial Scan Statistic (BSS), and a time series algorithm, the wavelet anomaly detector (WAD), on the performance of detecting the increase of the over-the-counter (OTC) medicine sales during 2009 H1N1 pandemic. The experiments demonstrated that the Bayesian spatial algorithm responded to the increase of thermometer sales about 3 days later than the time series algorithm. Time-series algorithms demonstrated an advantage for early outbreak detection, especially when multiple clusters occur at the same time in different geographic regions. Given spatial-temporal algorithms for outbreak detection are widely used, this paper suggests that epidemiologists or public health officials would benefit by applying time series algorithms as a complement to spatial algorithms for public health surveillance.


CDC25A protein stability represents a previously unrecognized target of HER2 signaling in human breast cancer: implication for a potential clinical relevance in trastuzumab treatment.
The CDC25A-CDK2 pathway has been proposed as critical for the oncogenic action of human epidermal growth factor receptor 2 (HER2) in mammary epithelial cells. In particular, transgenic expression of CDC25A cooperates with HER2 in promoting mammary tumors, whereas CDC25A hemizygous loss attenuates the HER2-induced tumorigenesis penetrance. On the basis of this evidence of a synergism between HER2 and the cell cycle regulator CDC25A in a mouse model of mammary tumorigenesis, we investigated the role of CDC25A in human HER2-positive breast cancer and its possible implications in therapeutic response. HER2 status and CDC25A expression were assessed in 313 breast cancer patients and we found statistically significant correlation between HER2 and CDC25A (P = .007). Moreover, an HER2-positive breast cancer subgroup with high levels of CDC25A and very aggressive phenotype was identified (P = .005). Importantly, our in vitro studies on breast cancer cell lines showed that the HER2 inhibitor efficacy on cell growth and viability relied also on CDC25A expression and that such inhibition induces CDC25A down-regulation through phosphatidylinositol 3-kinase/protein kinase B pathway and DNA damage response activation. In line with this observation, we found a statistical significant association between CDC25A overexpression and trastuzumab-combined therapy response rate in two different HER2-positive cohorts of trastuzumab-treated patients in either metastatic or neoadjuvant setting (P = .018 for the metastatic cohort and P = .021 for the neoadjuvant cohort). Our findings highlight a link between HER2 and CDC25A that positively modulates HER2-targeted therapy response, suggesting that, in HER2-positive breast cancer patients, CDC25A overexpression affects trastuzumab sensitivity.


Glutamatergic and cholinergic projections to the pontine inhibitory area identified with horseradish peroxidase retrograde transport and immunohistochemistry.
Previous studies in our laboratory have shown that microinjection of acetylcholine and non-N-methyl-D-aspartate (NMDA) glutamate agonists into the pontine inhibitory area (PIA) induce muscle atonia. The present experiment was designed to identify the PIA afferents that could be responsible for these effects, by use of retrograde transport of wheat germ agglutinin conjugated horseradish peroxidase (WGA-HRP), glutamate immunohistochemistry and NADPH-diaphorase staining techniques. Experiments were performed in both decerebrate and intact cats. Dense retrograde WGA-HRP labelling was found in neurons in the periaqueductal gray (PAG) and mesencephalic reticular formation (MRF) at the red nucleus (RN) level, ventral portion of paralemniscal tegmental field (vFTP), retrorubral nucleus (RRN), contralateral side of PIA (cPIA), pontis reticularis centralis caudalis (PoC), and most rostral portion of the nucleus parvicellularis (NPV) and nucleus praepositus hypoglossi (PH) at the level of the pontomedullary junction; moderate labelling was seen in pedunculopontine nucleus, pars compacta (PPNc), laterodorsal tegmental nucleus (LDT), superior colliculus (SC), MRF and PAG at the level caudal to RN, medial and superior vestibular nuclei, and principle sensory trigeminal nucleus (5P); and light labelling was seen in dorsal raphe (DR) and locus coeruleus complex (LCC). The projection neurons were predominantly ipsilateral to the injection site, except for both vFTP and RRN, which had more projection cells on the contralateral side. Double labelled WGA-HRP/NADPH-d neurons could be found in PPNc and LDT. Double labelled WGA-HRP/glutamatergic neurons could be seen at high densities in MRF, RRN, vFTP, and cPIA, moderate densities in SC, LDT, PPNc, PoC, and NPV, and low densities in PH, 5P, DR, LCC, and PAG.(ABSTRACT TRUNCATED AT 250 WORDS)


[Current approaches to analysis of narcotic drugs in biological substances].
A method of analysis of basic narcotic drugs in urine is described. It consists in isolation by solid phase extraction, derivation and identification by gas chromatography with mass-selective detector. The approaches applied in the above method can be used for analysis of narcotic drugs undetectable by preliminary investigations as well as for urine examination for pharmacological or other biologically active substances.


Adherence with statins in a real-life setting is better when associated cardiovascular risk factors increase: a cohort study.
While the factors for poor adherence for treatment with statins have been highlighted, the impact of their combination on adherence is not clear. To estimate adherence for statins and whether it differs according to the number of cardiovascular risk factors. A cohort study was conducted using data from the main French national health insurance system reimbursement database. Newly treated patients with statins between September 1 and December 31, 2004 were included. Patients were followed up 15 months. The cohort was split into three groups according to their number of additional cardiovascular risk factors that included age and gender, diabetes mellitus and cardiovascular disease (using co-medications as a proxy). Adherence was assessed for each group by using four parameters: (i) proportion of days covered by statins, (ii) regularity of the treatment over time, (iii) persistence, and (iv) the refill delay. 16,397 newly treated patients were identified. Of these statin users, 21.7% did not have additional cardiovascular risk factors. Thirty-one percent had two cardiovascular risk factors and 47% had at least three risk factors. All the parameters showed a sub-optimal adherence whatever the group: days covered ranged from 56% to 72%, regularity ranged from 23% to 33% and persistence ranged from 44% to 59%, but adherence was better for those with a higher number of cardiovascular risk factors. The results confirm that long-term drug treatments are a difficult challenge, particularly in patients at lower risk and invite to the development of therapeutic education.


Simultaneous Infection With Porcine Reproductive and Respiratory Syndrome and Influenza Viruses Abrogates Clinical Protection Induced by Live Attenuated Porcine Reproductive and Respiratory Syndrome Vaccination.
The porcine respiratory disease complex (PRDC) is responsible for significant economic losses in the pig industry worldwide. Porcine reproductive and respiratory syndrome virus (PRRSV) and swine influenza virus are major viral contributors to PRDC. Vaccines are cost-effective measures for controlling PRRS, however, their efficacy in the context of co-infections has been poorly investigated. In this study, we aimed to determine the effect of PRRSV-2 and swine influenza H3N2 virus co-infection on the efficacy of PRRSV modified live virus (MLV) vaccination, which is widely used in the field. Following simultaneous challenge with contemporary PRRSV-2 and H3N2 field isolates, we found that the protective effect of PRRS MLV vaccination on clinical disease and pathology was abrogated, although viral load was unaffected and antibody responses were enhanced. In contrast, co-infection in non-immunized animals reduced PRRSV-2 viremia and H3N2 virus load in the upper respiratory tract and potentiated T cell responses against both PRRSV-2 and H3N2 in the lung. Further analysis suggested that an upregulation of inhibitory cytokines gene expression in the lungs of vaccinated pigs may have influenced responses to H3N2 and PRRSV-2. These findings provide important insights into the effect of viral co-infections on PRRS vaccine efficacy that may help identify more effective vaccination strategies against PRDC in the field.


Ponatinib modulates the metabolic profile of obese mice by inhibiting adipose tissue macrophage inflammation.
Obesity-induced metabolic syndrome is a rapidly growing conundrum, reaching epidemic proportions globally. Chronic inflammation in obese adipose tissue plays a key role in metabolic syndrome with a series of local and systemic effects such as inflammatory cell infiltration and inflammatory cytokine secretion. Adipose tissue macrophages (ATM), as one of the main regulators in this process, are particularly crucial for pharmacological studies on obesity-related metabolic syndrome. Ponatinib, a multi-targeted tyrosine kinase inhibitor originally used to treat leukemia, has recently been found to improve dyslipidemia and atherosclerosis, suggesting that it may have profound effect on metabolic syndrome, although the mechanisms underlying have not yet been revealed. Here we discovered that ponatinib significantly improved insulin sensitivity in leptin deficient obese mice. In addition to that, ponatinib treatment remarkably ameliorated high fat diet-induced hyperlipidemia and inhibited ectopic lipid deposition in the liver. Interestingly, although ponatinib did not reduce but increase the weight of white adipose tissue (WAT), it remarkably suppressed the inflammatory response in WAT and preserved its function. Mechanistically, we showed that ponatinib had no direct effect on hepatocyte or adipocyte but attenuated free fatty acid (FFA) induced macrophage transformation from pro-inflammatory to anti-inflammatory phenotype. Moreover, adipocytes co-cultured with FFA-treated macrophages exhibited insulin resistance, while pre-treat these macrophages with ponatinib can ameliorate this process. These results suggested that the beneficial effects of ponatinib on metabolic disorders are achieved by inhibiting the inflammatory phenotypic transformation of ATMs, thereby maintaining the physiological function of adipose tissue under excessive obesity. The data here not only revealed the novel therapeutic function of ponatinib, but also provided a theoretical basis for the application of multi-target tyrosine kinase inhibitors in metabolic diseases.


Nuclear translocation of IFN-gamma is an intrinsic requirement for its biologic activity and can be driven by a heterologous nuclear localization sequence.
We have previously identified a nuclear localization sequence (NLS) in interferon-gamma (IFN-gamma). This NLS functions intracellularly by forming a complex with its transcription factor Stat1alpha and the nuclear importer of Stat1alpha, the importin-alpha analog NPI-1. The stability of this complex and the subsequent nuclear translocation of the complexed Stat1alpha are dependent on the integrity of this NLS, showing that Stat1alpha nuclear import is mediated by the IFN-gamma NLS. In this study, to directly evaluate the intrinsic requirement of nuclear IFN-gamma toward its biologic activities, we engineered a chimeric in which the IFN-gamma NLS has been substituted by a heterologous NLS, namely, the prototypical NLS of the SV40 large T antigen, which would drive nuclear translocation of IFN-gamma in a sequence-nonspecific manner. The chimeric, IFN-gamma-SV, was equally active in antiviral and antiproliferative assays as the wild-type IFN-gamma. Interestingly, IFN-gamma-SV was also translocated to the nucleus and was also recovered intracellularly as a complex with the Stat1alpha importer NPI-1, like wild-type IFN-gamma. Comparison with an NLS deletion mutant showed that deletion or changes within the NLS motif of IFN-gamma were inconsequential to the high-affinity extracellular binding to the IFN-gamma receptor complex, yet the presence of an NLS was critical to the expression of the biologic activities of IFN-gamma and its NPI-1 complexation ability. Our data conclusively demonstrate that nuclear translocation of IFN-gamma is an intrinsic requirement for the full expression of the biologic activities of IFN-gamma and strengthen the conclusion that nuclear chaperoning of Stat1alpha is the primary role of IFN-gamma nuclear translocation. This type of ligand imprinting by sequestering of activated Stat may contribute to the specificity of Stat nuclear transcription.


Midterm follow-up after computed tomography angiography planned left atrial appendage closure.
While studies have shown the advantages of computed tomography angiography (CTA) over transesophageal echocardiography (TEE) in left atrial appendage closure (LAAC) preprocedural planning for WATCHMAN™ legacy and FLX devices, there has been no reported long-term data for this approach. We sought to evaluate long-term outcomes using CTA-based preprocedural planning for LAAC using the WATCHMAN™ device. A prospective analysis of 231 consecutive patients who underwent LAAC in a single, large academic hospital in the United States was conducted over a 5-year period. CTA-guided preprocedural planning was performed in all. Procedural success, adverse events, length of procedure, number of devices used, and length of stay were evaluated. Rates of death, cerebral embolism, systemic embolism, and major and minor bleeding were recorded. Adjusted predicted stroke and major bleeding rates were derived from CHA2DS2-Vasc and HAS-BLED scores, respectively. From January 26, 2017, to November 23, 2021, 231 patients underwent LAAC with CTA preprocedural planning by two operating physicians. The mean age of patients was 76.5 ± 8.4. 59.7% of patients were male. Mean CHA2DS2VASc and HAS-BLED scores were 4.5 ± 1.4 and 3.9 ± 0.9, respectively. All procedures were performed with intracardiac echo (100%). The procedural success rate was 99.1%. The CTA sizing strategy accurately predicted the implant size in 93.5% of patients. Mean number of devices used was 1.10 ± 0.3. Peri-procedural complication rate was 2.2%. 6 patients were lost to follow-up. Mean follow-up was 608.94 days with a total of 377.04 patient years. Median follow-up period of 368 days (interquartile range: 209-1067 days). There were 51 deaths from all causes (13.52 per 100 patient-years), 10 cases of cerebral embolism (2.65 per 100 patient-years), 2 cases of systemic embolism (0.53 per 100 patient-years), 17 cases of major bleeding (4.50 per 100 patient-years), and 31 cases of minor bleeding (8.2 per 100 patient-years). All-cause mortality at 1, 2, and 3 years was 12.7%, 20.9%, and 29.2%, respectively. CV event rates at 1, 2, and 3 years were 2.1%, 6.6%, and 10.5%, respectively. CTA-based preprocedural planning is accurate in predicting device size for LAAC and associated with excellent clinical outcomes at 5 years.


"Real-time" risk models of postoperative morbidity and mortality for liver transplants.
A comprehensive description of morbidity and mortality risk factors for post liver transplant has not been available to date. In this study, we established real-time risk models of postoperative morbidities and mortality in liver transplant recipients using two Japanese nationwide databases. Data from two Japanese nationwide databases were combined and used for this study. We developed real-time prognostic models for morbidity and mortality from a derivation cohort (n = 1472) and validated the findings with an independent cohort (n = 395). Preoperative variables (C1), preoperative and intraoperative variables (C2), and all variables including postoperative morbidities within 30 days (C3) were analyzed to evaluate the independent risk factors for postoperative morbidity and mortality. We established real-time risk models for morbidity and mortality. Areas under the curve (AUC) of C1 and C2 risk models for mortality were 0.74 (0.63-0.82) and 0.79 (0.69-0.86), respectively. Multivariate logistic analysis using C3 showed that hemoglobin <10 g/dL, operative time (hours), and five postoperative morbidities (prolonged ventilation >48 hours, coma >24 hours, renal dysfunction, postoperative systemic sepsis, and serum total bilirubin ≥10 mg/dL) represented independent risk factors for mortality (AUC = 0.87, 95% confidence interval [CI]: 0.78-0.93). Real-time risk models of postoperative morbidities and mortality at various perioperative time points in liver transplant recipients were established. These novel approaches may improve postoperative outcomes of liver transplant recipients. Furthermore, these real-time risk models may be applicable to other surgical procedures.