Uptake and metabolism of fatty acids and analogues by cultured cardiac cells from chick embryo.
Cultured heart cells from chick embryo, present as a confluent monolayer in a minimal medium, take up labelled fatty acids (from C6 to C22) bound to serum albumin with a rapid incorporation into neutral and complex lipids (visible at 15 s), while beta-oxidation is delayed (visible at 15 min). Fatty acids enter the cardiac cells through two mechanisms, one involving a readily saturable process, the other resembling passive diffusion. The saturable transport system recognizes fatty acids with a high affinity, Km from 4.5 to 16 muM. The V is from 0.03 to 0.3 nmol of fatty acid incorporated min-1 (10(6) cells)-1. Competitive inhibition occurs between fatty acids while glucose, aminoacids and lactate do not compete with palmitate for the entry into the cells. The analysis of unesterified fatty acids from the usual culture medium and from the cells show a gradient of concentration up to 54-fold; moreover experiments performed in minimal medium at 20 degrees C show that fatty acids accumulate up to 28-fold in the cells. Efflux rates can be measured after loading the cells at 20 degrees C; the curves are bimodal and the pseudo first-order rate constants thus determined are in the order of 0.5 min-1, as opposed to 2.5 to 5.0 min-1 for the passive-diffusion component calculated for the influx rates. Studies on the role of serum albumin at constant and at variable fatty acid-albumin molar ratios indicate that the rate of uptake is controlled by the total fatty acid concentration and not solely by the concentration of unbound fatty acids. No labelled fatty acid was found to be bound to the cytoplasmic fraction supposed to contain the fatty acids-binding protein; our results are in favour of the presence of a specific transport system for fatty acids either at the level of subcellular organelles or more likely at the surface of cardiac cells.


Plasma corticotropin-releasing hormone and cortisol concentrations and perceived stress among pregnant women with preterm and term birth.
We sought to determine if pregnant women with poor psychosocial status or high levels of perceived stress had higher concentrations of plasma corticotropin-releasing hormone (CRH) or cortisol. This was a secondary analysis of a case-controlled study nested within a multicenter, prospective observational cohort study. Plasma CRH and cortisol concentrations and the Abbreviated Scale for the Assessment of Psychosocial Status in Pregnancy (ASAPS) were available for cases and controls. Among cases and controls, concentrations of CRH and cortisol and overall performance on the ASAPS as well as the individual components of the ASAPS were compared using Kruskal-Wallis or chi-square. There was no association between CRH or cortisol concentrations and performance on the ASAPS overall. Additionally, there was no relationship between CRH or cortisol and perceived stress. In this study, biological measures of stress assessed in the second trimester were not associated with overall psychosocial status or perceived stress. The factors contributing to the elevation in CRH that precedes some preterm birth are complex and poorly understood.


Indulging anxiety: human enhancement from a Protestant perspective.
At the heart of any ethics of human enhancement must be some normative assumptions about human nature. The purpose of this essay is to draw on themes from a Protestant theological anthropology to provide a basis for understanding and evaluating the tension between maintaining our humanity and enhancing it. Drawing primarily on the work of theologian Reinhold Niebuhr, I interpret enhancement as proceeding from the anxiety that characterizes human experience at the juncture of freedom and finiteness. Religious and moral dimensions of human sinfulness are considered in relation to cultural values that motivate human enhancement generally. I employ these dimensions in a series of benchmarks to suggest a background of theological, anthropological, and moral considerations against which enhancement is not to be condemmed but rather critically evaluated.


Intramuscular schwannoma arising from the psoas muscle presenting with femoral nerve neuropathy.
A spherical mass of the right psoas muscle was found incidentally by magnetic resonance health examination in a 43-year-old woman. The patient had complained of numbness in her right leg over the previous six months and neuralgia at the time of computed tomography-guided core biopsy, which was done to establish the diagnosis. To our knowledge, femoral nerve neuropathy caused by an intramuscular schwannoma arising from the psoas muscle has not been previously published.


Endogenous ouabain in cardiovascular function and disease.
An endogenous ouabain has been isolated and conclusively identified from several mammalian tissues, including human plasma, by a number of independent laboratories. Substantial evidence from independent laboratories in several continents is consistent with an adrenal source for most if not all of the circulating endogenous ouabain. Accumulating evidence suggests that circulating levels of endogenous ouabain in humans are modulated by dietary salt and chronic volume status. Endogenous ouabain is linked significantly with vascular function in hypertension and likely impacts the pathogenesis of heart and renal failure. Moreover, the molecular mechanism of endogenous ouabain-linked hypertension involves the sodium pump/sodium-calcium exchange duet. The outstanding analytical issues include the elucidation of distal events in the biosynthetic pathway for endogenous ouabain and identification of molecular mechanisms that regulate its secretion and clearance.


CD133 expressing pericytes and relationship to SDF-1 and CXCR4 in spinal cord injury.
Compression injury to the spinal cord (SC) results in vascular changes affecting the severity of the primary damage of the spinal cord. The recruitment of bone marrow (BM)-derived cells contribute to revascularization and tissue regeneration in a wide range of ischemic pathologies. Involvement of these cells in the vascular repair process has been investigated in an animal model of spinal cord injury (SCI). Temporal gene and protein expression of the BM-derived stem cell markers CD133 and CD34, of the mobilization factor SDF-1 and its receptor CXCR4 were determined following SC compression injury in rats. CD133 was expressed in uninjured tissue by cells surrounding arterioles identified as pericytes by co-expression of alpha-SMA. These cells mostly disappeared 2 days after injury but repopulated the tissue after 2 weeks. CD34 was expressed by endothelial cells and CD11b+ macrophages/microglia invading the injured tissue as observed 2 weeks following injury. SDF-1 was induced in reactive astrocytes and endothelial cells not until 2 weeks post-SCI. Comparison of the variation between CD34, CD133, CXCR4, and SDF-1 revealed a corresponding trend of CD133 with the SDF-1 expression. This study showed that resident microvascular CD133+ pericytes with presumptive stem cell potential are sensitive to SCI. Their decline following SCI and the delayed induction of SDF-1 may contribute to vessel destabilisation and inefficient revascularization. In addition, none of the analyzed markers could be assigned clearly to BM-derived cells. Together, our findings suggest that effective recruitment of pericytes may serve as a therapeutic option to improve microcirculation after SCI.


Report of the Skin Research Workgroups From the IDEOM Breakout at the GRAPPA 2022 Annual Meeting.
The International Dermatology Outcome Measures (IDEOM) organization presented an update on its progress related to patient-centered outcome measures for psoriasis (PsO) and psoriatic arthritis (PsA) at the 2022 annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). The Musculoskeletal (MSK) Symptoms working group presented an update on the development of the IDEOM Musculoskeletal Questionnaire (IDEOM MSK-Q). The IDEOM MSK-Q is a patient-reported outcome measure intended to capture MSK symptoms and describe their intensity and impact on health-related quality of life in patients with psoriatic disease. IDEOM also presented the progress of the integration of the Psoriasis Epidemiology Screening Tool (PEST) and Psoriatic Arthritis Impact of Disease (PsAID) questionnaires into the Epic electronic health record system. This will allow for automated PsA screening and symptom measurement in the hopes of improving disease detection and treat-to-target strategies. The Treatment Satisfaction working group discussed the development of the DermSat-7, a 7-item treatment satisfaction questionnaire specific for dermatological conditions. The DermSat-7 is currently being validated in a multicenter study of patients with PsO.


Z-matrix formalism for quantitative noise assessment of covariance nuclear magnetic resonance spectra.
Due to the limited sensitivity of many nuclear magnetic resonance (NMR) applications, careful consideration must be given to the effect of NMR data processing on spectral noise. This work presents analytical relationships as well as simulated and experimental results characterizing the propagation of noise by unsymmetric covariance NMR processing, which concatenates two NMR spectra along a common dimension, resulting in a new spectrum showing spin correlations as cross peaks that are not directly measured in either of the two input spectra. It is shown how the unsymmetric covariance spectrum possesses an inhomogeneous noise distribution across the spectrum with the least amount of noise in regions whose rows and columns do not contain any cross or diagonal peaks and with the largest amount of noise on top of signal peaks. Therefore, methods of noise estimation commonly used in Fourier transform spectroscopy underestimate the amount of uncertainty in unsymmetric covariance spectra. Different data processing procedures, including the Z-matrix formalism, thresholding, and maxima ratio scaling, are described to assess noise contributions and to reduce noise inhomogeneity. In particular, determination of a Z score, which measures the difference in standard deviations of a statistic from its mean, for each spectral point yields a Z matrix, which indicates whether a given peak intensity above a threshold arises from the covariance of signals in the input spectra or whether it is likely to be caused by noise. Application to an unsymmetric covariance spectrum, obtained by concatenating two 2D (13)C-(1)H heteronuclear, single quantum coherence (HSQC) and (13)C-(1)H heteronuclear, multiple bond correlation (HMBC) spectra of a metabolite mixture along their common proton dimension, reveals that for sufficiently sensitive input spectra the reduction in sensitivity due to covariance processing is modest.


Current outcomes after pediatric and adult intestinal transplantation.
In this article, we will review the outcomes of patients with intestinal transplant (ITx) with a focus on factors affecting long-term graft and patient survival. The most recent International Intestinal Transplant Registry reports a 1-, 5-, and 10-year graft survival of 71%, 50%, and 41% respectively, for ITx grafts transplanted since 2000. Over the past decades, significant improvements have been achieved in short-term graft and patient outcomes for ITx recipients. The improvement in short-term outcomes may be related to the focused treatment of antihuman leukocyte antigen antibodies, the use of induction immunotherapy protocols, refinements in surgical techniques, establishment of dedicated ITx units, and improved postoperative management.However, long-term graft and patient outcomes for ITx recipients remain stagnant. Issues impairing long-term outcomes of ITx include the challenges in the diagnosis and treatment of chronic rejection and antibody-mediated rejection, progressive decline in renal function, and long-term infectious and malignancy risks especially related to cytomegalovirus, Epstein-Barr virus and posttransplant lymphoproliferative disorder after ITx. Addressing and preventing early and late complications is the key to improving short-term and long-term outcomes after ITx.


Condylar remodelling and resorption after Le Fort I and bimaxillary osteotomies in patients with anterior open bite. A clinical and radiological study.
A sample of 259 patients with vertical maxillary hyperplasia, mandibular hypoplasia and anterior vertical open bite, collected from three different institutions, was analysed regarding temporomandibular joint (TMJ) sounds, condylar remodelling, and condylar resorption. All patients underwent Le Fort I osteotomies, and bilateral sagittal split advancement osteotomies were performed in 117 patients. Intraosseous wire fixation was used in 149 and rigid internal fixation in 110 patients. Cephalometric and orthopantomographic radiographs were available before surgery, immediately after surgery, one year postoperatively and at the latest follow up. The mean follow up was 69 months (range 20-210 months). The number of patients with TMJ sounds decreased from 38% to 31%. At the latest follow up 23.6% of the patients showed condylar remodelling, 7.7% unilateral condylar resorption and 7.7% bilateral condylar resorption. Condylar contours, as assessed on orthopantomographic radiographs, were classified as five different types. Condyles with preexisting radiological signs of osteoarthrosis or having a posterior inclination were at high risk for progressive resorption. Female patients with severe anterior open bite, high mandibular plane angle and a low posterior-to-anterior facial height ratio, who underwent a bimaxillary osteotomy, were prone to condylar resorption. Bone loss was predominantly found at the anterior site of the condyle. The incidence of condylar resorption was significantly higher after bimaxillary osteotomies (23%) than after only Le Fort I intrusion osteotomies (9%). Avoidance of intermaxillary fixation by using rigid internal fixation tended to reduce condylar changes, in particular in patients who underwent only a Le Fort I osteotomy. Rigid internal fixation in bimaxillary osteotomies resulted in condylar remodelling in 30% and progressive condylar resorption in 19% of the patients. Condylar changes were not significantly different after using either miniplate osteosynthesis or positional screws in bilateral sagittal split osteotomy procedures.


Analysis of longitudinal studies with death and drop-out: a case study.
The analysis of longitudinal data has recently been an active area of biostatistical research. Two main approaches to analysis have emerged, the first concentrating on modelling evolution of marginal distributions of the main response variable of interest and the other on subject-specific trajectories. In epidemiology the analysis is usually complicated by missing data and by death of study participants. Motivated by a study of cognitive decline in the elderly, this paper argues that these two types of incomplete follow-up may need to be treated differently in the analysis, and proposes an extension to the marginal modelling approach. The problem of informative drop-out is also discussed. The methods are implemented in the 'Stata' statistical package.


Patients' perceptions and satisfaction with treatment in a UK osteopathic training clinic.
This study was a descriptive and exploratory investigation of patient perceptions of treatment at an osteopathic training clinic. An open text questionnaire survey was administered by post in 2000 to all 292 patients attending the clinic in south-east England in 1998-2000. The response rate was 62%. The data were transcribed and the concepts within the data were coded using grounded theory, within an interpretive phenomenological approach. The emergent core theme "underlying personal values" describes how patients manage their search for health. Four main themes were associated with the therapeutic relationship: hope, communication, respect, and trust. Two further themes emerged: one related to the environment of a teaching clinic; and a cross-checking theme described comparisons of the clinic with NHS services and other services. The majority of patients expressed satisfaction with treatment, the explanations they received and their perceived health outcomes. The question about comfort with the manner of treatment drew out important issues around undressing, privacy and gender. This was the first study of patient attitudes in an osteopathic training clinic and has implications for their organization and service delivery. Recommendations are made for the design of future studies in this area.


Neuropsychiatric symptoms and brain morphology in patients with mild cognitive impairment and Alzheimer's disease with dementia.
We present associations between neuropsychiatric symptoms (NPS) and brain morphology in a large sample of patients with mild cognitive impairment (MCI) and Alzheimer's disease with dementia (AD dementia).Several studies assessed NPS factor structure in MCI and AD dementia, but we know of no study that tested for associations between NPS factors and brain morphology. The use of factor scores increases parsimony and power. For transparency, we performed an additional analysis with selected Neuropsychiatric Inventory - Questionnaire (NPI-Q) items. Including regional cortical thickness, cortical and subcortical volumes, we examined associations between NPS and brain morphology across the whole brain in an unbiased fashion. We reported both statistical significance and effect sizes, using linear models adjusted for multiple comparisons by false discovery rate (FDR). Moreover, we included an interaction term for diagnosis and could thereby compare associations of NPS and brain morphology between MCI and AD dementia.We found an association between the factor elation and thicker right anterior cingulate cortex across MCI and AD dementia. Associations between the factors depression to thickness of the banks of the left superior temporal sulcus and psychosis to the left post-central volume depended on diagnosis: in MCI these associations were positive, in AD dementia negative.Our findings indicate that NPS in MCI and AD dementia are not exclusively associated with atrophy and support previous findings of associations between NPS and mainly frontotemporal brain structures. Neuropsychiatric symptoms (NPS) are common in mild cognitive impairment (MCI) and Alzheimer's disease with dementia (AD dementia), but their brain structural correlates are unknown. We tested for associations between NPS and MRI-based cortical and subcortical morphometry in patients with MCI and AD dementia. Cross-sectional. Conducted in Norway. Patients with MCI (n = 102) and AD dementia (n = 133) from the Memory Clinic and the Geriatric Psychiatry Unit at Oslo University Hospital. Neuropsychiatric Inventory – Questionnaire (NPI-Q) severity indices were reduced using principal component analysis (PCA) and tested for associations with 170 MRI features using linear models and false discovery rate (FDR) adjustment. We also tested for differences between groups. For transparency, we added analyses with selected NPI-Q items. PCA revealed four factors: elation, psychosis, depression, and motor behavior.FDR adjustment revealed a significant positive association (B = 0.20, pFDR < 0.005) between elation and thickness of the right caudal anterior cingulate cortex (ACC) across groups, and significant interactions between diagnosis and psychosis (B = −0.48, pFDR < 0.0010) on the left post-central volume and between diagnosis and depression (B = −0.40, pFDR < 0.005) on the thickness of the banks of the left superior temporal sulcus. Associations of apathy, anxiety, and nighttime behavior to the left temporal lobe were replicated. The positive association between elation and ACC thickness suggests that mechanisms other than atrophy underly elation. Interactions between diagnosis and NPS on MRI features suggest different mechanisms of NPS in our MCI and AD dementia samples. The results contribute to a better understanding of NPS brain mechanisms in MCI and AD dementia.


Palm oil: Understanding barriers to sustainable consumption.
Palm oil is relatively inexpensive, versatile, and popular, generating great economic value for Southeast Asian countries. However, the growing demand for palm oil is leading to deforestation and biodiversity loss. The current study is the first to employ a capability-opportunity-motivation (COM-B) framework in green consumerism, to determine which capability, opportunity, and motivation factors strongly predict the intentional purchasing of sustainable palm oil products by Australian consumers (N = 781). Exploratory factor analysis revealed four main types of predictors of SPO purchasing-Pro-Green Consumption Attitudes, Demotivating Beliefs, Knowledge and Awareness, and Perceived Product Availability. Multiple regression revealed that these four factors explained 50% of the variability in SPO purchasing behaviour, out of which Knowledge and Awareness accounted for 18% of the unique variance. Perceived Product Availability and Pro-Green Consumption Attitudes were also significant predictors but accounted for only 2% and 1% of unique variance, respectively. These results provide a valuable foundation for designing behaviour change interventions to increase consumer demand for sustainable palm oil products.


Bioregenerative life-support systems.
Long-duration future habitation of space involving great distances from Earth and/or large crew sizes (eg, lunar outpost, Mars base) will require a controlled ecological life-support system (CELSS) to simultaneously revitalize atmosphere (liberate oxygen and fix carbon dioxide), purify water (via transpiration), and generate human food (for a vegetarian diet). Photosynthetic higher plants and algae will provide the essential functions of biomass productivity in a CELSS, and a combination of physicochemical and bioregenerative processes will be used to regenerate renewable resources from waste materials. Crop selection criteria for a CELSS include nutritional use characteristics as well as horticultural characteristics. Cereals, legumes, and oilseed crops are used to provide the major macronutrients for the CELSS diet. A National Aeronautics and Space Administration (NASA) Specialized Center of Research and Training (NSCORT) was established at Purdue University to establish proof of the concept of the sustainability of a CELSS. The Biosphere 2 project in Arizona is providing a model for predicted and unpredicted situations that arise as a result of closure in a complex natural ecosystem.


Non-Hermiticity in a kicked model: decoherence and the semiclassical limit.
We study the effects of non-Hermitian perturbations on a quantum kicked model exhibiting a localization transition. Using an exact renormalization scheme, we show that the critical line separating the extended and localized phases approaches its semiclassical limit as the imaginary part of the kicking parameter is steadily increased. Further, the metastability of the quantum states appears to be directly correlated with the deviation between the semiclassical and quantum results. This direct evidence of quantum-classical correspondence suggests that decoherence may be usefully modeled by non-Hermitian perturbations.


An integrated microfluidic chip system for single-cell secretion profiling of rare circulating tumor cells.
Genetic and transcriptional profiling, as well as surface marker identification of single circulating tumor cells (CTCs) have been demonstrated. However, quantitatively profiling of functional proteins at single CTC resolution has not yet been achieved, owing to the limited purity of the isolated CTC populations and a lack of single-cell proteomic approaches to handle and analyze rare CTCs. Here, we develop an integrated microfluidic system specifically designed for streamlining isolation, purification and single-cell secretomic profiling of CTCs from whole blood. Key to this platform is the use of photocleavable ssDNA-encoded antibody conjugates to enable a highly purified CTC population with <75 'contaminated' blood cells. An enhanced poly-L-lysine barcode pattern is created on the single-cell barcode chip for efficient capture rare CTC cells in microchambers for subsequent secreted protein profiling. This system was extensively evaluated and optimized with EpCAM-positive HCT116 cells seeded into whole blood. Patient blood samples were employed to assess the utility of the system for isolation, purification and single-cell secretion profiling of CTCs. The CTCs present in patient blood samples exhibit highly heterogeneous secretion profile of IL-8 and VEGF. The numbers of secreting CTCs are found not in accordance with CTC enumeration based on immunostaining in the parallel experiments.


Cost Effectiveness of Insulin Glargine versus Neutral Protamin Hagedorn Insulin in the Treatment of Type 2 Diabetes Patients in Turkey.
Background: Type 2 diabetes mellitus (T2DM) poses a significant burden on population well being and healthcare expenditure in Turkey, with disease prevalence continuing to increase. Insulin treatment is necessary for patients failing to achieve glycaemic control with lifestyle modification or oral antidiabetic drugs. While neutral protamin Hagedorn (NPH) insulin has been traditionally prescribed for insulin introduction, insulin glargine has been shown to reduce glycated hemoglobin (HbA1c) with a more favourable hypoglycaemic profile. Objective: To evaluate the cost-effectiveness of insulin glargine compared to NPH insulin in patients with T2DM in Turkey, from a Social Security Institution perspective. Methods: A previously published discrete event simulation model of T2DM progression was utilised to characterise the cost-effectiveness of insulin glargine in a Turkish population given the benefits observed in clinical practice. Improvements in glycaemic control have been incorporated using data from The Health Improvement Network (THIN) database in the United Kingdom, combined with meta-regression results describing the relationship between hypoglycaemia and glycaemic control. Outcomes were evaluated over a 40-year horizon, and costs and benefits discounted at an annual rate of 3.5%. Results are reported in Turksih lira (TL), 2012. Results: Over a lifetime, the Incremental Cost-effectiveness Ratio (ICER) of insulin glargine compared to NPH was 40,101 TL per Quality-adjusted Life Year (QALY). Almost 52 hypoglycaemic events per patient were avoided with the use of insulin glargine compared to NPH, at an incremental lifetime cost of 7,140 TL per patient. The cost-effectiveness of insulin glargine is reduced when modelling only those benefits considered in the trial setting, while the cost-effectiveness profile can be expected to further improve in patients with higher HbA1c levels at baseline. Conclusion: It is difficult to interpret the results of modelling as there is no official cost-effectiveness threshold in Turkey. However, the results may be evaluated using thresholds derived according to methodology proposed by the World Health Organisation (WHO). Insulin glargine is expected to be costeffective compared to NPH insulin, with an ICER below three times the estimated gross domestic product (GDP) per capita; 56,850 TL.


PPARδ signaling mediates the cytotoxicity of DHA in H9c2 cells.
Docosahexaenoic acid (22:6n3, DHA) is an n-3 polyunsaturated fatty acid (PUFA) known to affect numerous biological functions. While DHA possesses many properties that impact cell survival such as suppressing cell growth and inducing apoptosis, the exact molecular and cellular mechanism(s) remain unknown. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate many cell pathways including cell death. As DHA acts as a ligand to PPARs the aim of this study was to examine the involvement of PPARδ in DHA-mediated cytotoxicity toward H9c2 cells. Treatment with DHA (100μM) resulted in a significant decline in cell viability, cellular metabolic activity and total antioxidant capacity coinciding with increased total proteasome activities and activity of released lactate dehydrogenase (LDH). No changes in reactive oxygen species (ROS) production or accumulation of lipid peroxidation products were observed but DHA promoted apoptotic cell death as detected by flow cytometry, increased caspase-3 activity and decreased phosphorylation of Akt. Importantly, DHA enhanced PPARδ DNA binding activity in H9c2 cells strongly signifying that the cytotoxic effect of DHA might be mediated via PPARδ signaling. Co-treatment with the selective PPARδ antagonist GSK 3787 (1μM) abolished the cytotoxic effects of DHA in H9c2 cells. Cytotoxic effects of DHA were attenuated by co-treatment with myriocin, a selective inhibitor of serine palmitoyl transferase (SPT), preventing de novo ceramide biosynthesis. LC/MS analysis revealed that treatment with DHA resulted in the accumulation of ceramide, which was blocked by GSK 3787. Interestingly, inhibition of cytochrome P450 (CYP) oxidase with MS-PPOH (50μM) abolished DHA-mediated cytotoxicity suggesting downstream metabolites as the active mediators. We further demonstrate that CYP oxidase metabolites of DHA, methyl epoxy docosapentaenoate (EDP methyl esters, 1μM) (mix 1:1:1:1:1:1; 4,5-, 7,8-, 10,11-, 13,14-, 16,17- and 19,20-EDP methyl esters) and 19,20-EDP cause cytotoxicity via activation of PPARδ signaling leading to increased levels of intracellular ceramide. These results illustrate novel pathways for DHA-induced cytotoxicity that suggest an important role for CYP-derived metabolites, EDPs.


Role of exogenous adenosine as a modulator of theophylline toxicity.
In animal models, exogenous adenosine can reverse theophylline-induced neurologic toxicity. Thus, we examined the ability of adenosine to oppose the cardiovascular toxicity of theophylline. Open-label, dose-response trial. Animal laboratory within a college of pharmacy. Ten chloral hydrate-anesthetized male Sprague-Dawley rats. Indwelling catheters were surgically inserted into the right carotid artery and right external jugular vein. Subsequently, escalating doses of adenosine (5 to 2000 micrograms) were given at theophylline doses of 0, 10, 20, 30, 40, and 50 mg/kg until a maximum slowing in heart rate occurred. Left ventricular systolic pressure and maximum positive maximal change in pressure over time (+dP/dt) were determined at baseline and at the time of maximum heart slowing, during adenosine, for each theophylline dose (0 to 50 mg/kg). Escalating doses of adenosine resulted in progressive heart rate slowing until maximum slowing occurred. The adenosine doses required to reach maximum slowing of heart rate were 118 +/- 24, 410 +/- 197, 620 +/- 256, 855 +/- 264, 944 +/- 329 and 1062 +/- 463 (SD) micrograms at theophylline doses of 0, 10, 20, 30, 40, and 50 mg/kg, respectively, which were correlated (r2 = .57, p < .001). At baseline, increasing theophylline doses produced a progressive reduction in left ventricular systolic pressure. However, adenosine at maximum slowing doses reversed this effect where left ventricular systolic pressure at 0 mg/kg of theophylline was similar to left ventricular systolic pressure at 50 mg/kg of theophylline (p < .05). At baseline, 10 to 50 mg/kg of theophylline had no significant effect on +dP/dtmax. However, adenosine (at maximum slowing) decreased +dP/dtmax before theophylline administration (p < .01). Theophylline at doses of 10 to 50 mg/kg reversed adenosine's negative inotropic effect, where +dP/dtmax values at maximum slowing were greater than values at 0 mg/kg of theophylline (p < .05). Adenosine can reverse theophylline-induced electrophysiologic and hemodynamic instability, whereas theophylline can reverse the negative inotropic actions of adenosine. However, higher adenosine doses are needed to elicit these changes as the theophylline dose increases.


Immunosuppression Adversely Affects TST but Not IGRAs in Patients with Psoriasis or Inflammatory Musculoskeletal Diseases.
The performance of the interferon gamma release assays (IGRAs) and tuberculin skin test (TST) was reviewed retrospectively in patients with psoriasis, inflammatory musculoskeletal diseases, or miscellaneous inflammatory conditions. The study was carried out over a 22-month period using 109 records of patients with psoriasis (n = 21), musculoskeletal disease (n = 74), or other inflammatory conditions (n = 14). Forty-four (48%) of 109 patients were on immunosuppressive therapy and 38/109 (35%) on systemic glucocorticoid therapy. The agreement between the IGRAs was substantial (κ = 0.71) whilst that between the IGRAs and TST was low (κ = 0.32). Logistic regression models revealed that IGRAs associated with risk factors for latent tuberculosis infection better than TST. TST was influenced by age, BCG vaccination, sex, and glucocorticoid therapy. We found that IGRAs performed equally well with low level of indeterminate results (1-2%). IGRAs were superior to TST because the latter was influenced by BCG-vaccination status and immunosuppressive therapy.


Experiences of inequitable care among Afghan mothers surviving near-miss morbidity in Tehran, Iran: a qualitative interview study.
Providing equitable maternal care to migrants is a seriously challenging task for hosting countries. Iran, the second-most accessed country for refugees from Afghanistan, has achieved maternal health improvement. However, Afghan women with near-miss morbidity faced pre-hospital delays and disparity in maternal care at hospitals. This study explores experiences of maternal care among Afghan women surviving near-miss morbidity to increase insight into healthcare improvements for migrants. A qualitative study was conducted at university hospitals in Tehran, from April 2013 to May 2014. A total of 11 Afghan women and 4 husbands were interviewed when women recovered from near-miss morbidity that occurred around the childbirth period. Mothers were identified prospectively using the WHO maternal near-miss approach. Thematic analysis was used along with a data-driven approach to organize data guided by the 'three delays model' theoretical framework. Mistreatment in the form of discrimination and insufficient medical attention were key experiences. Participants commonly perceived poor women-professional communication and delays in recognizing obstetric complications despite repeated care-seeking. Financial constraints, costly care, lack of health insurance, and low literacy were experienced barriers to accessing care to a lesser extent. Non-somatic consequences of near-miss morbidity affected mothers and families for extended periods. Near-miss survivors' experiences provided remarkable insights into maternal care of Afghans in Iran. The challenge for the health system and professionals is to provide equitable care with dignity and improve communication skills with caring attitudes toward ethnic minorities. Antenatal visits provide the best and most appropriate opportunities to tackle health illiteracy in Afghan women.


Hepatitis B virus X protein via the p38MAPK pathway induces E2F1 release and ATR kinase activation mediating p53 apoptosis.
Hepatitis B virus (HBV) X protein (pX) is implicated in hepatocellular carcinoma (HCC) pathogenesis by an unknown mechanism. Deletions or mutations of genes involved in the p53 pathway are often associated with HBV-mediated HCC, indicating rescue from p53 apoptosis is a likely mechanism in HBV-HCC pathogenesis. Herein, we determined the mechanism by which pX sensitizes hepatocytes to p53-mediated apoptosis. Although it is well established that the Rb/E2F/ARF pathway stabilizes p53, and the DNA damage-activated ATM/ATR kinases activate p53, the mechanism that coordinates these two pathways has not been determined. We demonstrate that the p38MAPK pathway activated by pX serves this role in p53 apoptosis. Specifically, the activated p38MAPK pathway stabilizes p53 via E2F1-mediated ARF expression, and also activates the transcriptional function of p53 by activating ATR. Knockdown of p53, E2F1, ATR, or p38MAPKalpha abrogates pX-mediated apoptosis, demonstrating that E2F1, ATR, and p38MAPKalpha are all essential in p53 apoptosis in response to pX. Specifically, in response to pX expression, the p38MAPK pathway activates Cdk4 and Cdk2, leading to phosphorylation of Rb, release of E2F1, and transcription of ARF. The p38MAPK pathway also activates ATR, leading to phosphorylation of p53 on Ser-18 and Ser-23, transcription of pro-apoptotic genes Bax, Fas, and Noxa, and apoptosis. In conclusion, pX sensitizes hepatocytes to p53 apoptosis via activation of the p38MAPK pathway, which couples p53 stabilization and p53 activation, by E2F1 induction and ATR activation, respectively.


What are the Particularities of Oesophageal Surgery in Cirrhotic Patients.
The aim of this paper was to review the entire literature on esophageal surgery to best define the surgical indications and the specifics of their management. The bibliographic research was carried out on Pubmed between January 1995 and June 2015, using French and English as publication languages.


Similar regulatory mechanisms of caveolins and cavins by myocardin family coactivators in arterial and bladder smooth muscle.
Caveolae are membrane invaginations present at high densities in muscle and fat. Recent work has demonstrated that myocardin family coactivators (MYOCD, MKL1), which are important for contractile differentiation and cell motility, increase caveolin (CAV1, CAV2, CAV3) and cavin (CAVIN1, CAVIN2, CAVIN3) transcription, but several aspects of this control mechanism remain to be investigated. Here, using promoter reporter assays we found that both MKL1/MRTF-A and MKL2/MRTF-B control caveolins and cavins via their proximal promoter sequences. Silencing of MKL1 and MKL2 in smooth muscle cells moreover reduced CAV1 and CAVIN1 mRNA levels by well over 50%, as did treatment with second generation inhibitors of MKL activity. GATA6, which modulates expression of smooth muscle-specific genes, reduced CAV1 and CAV2, whereas the cavins were unaffected or increased. Viral overexpression of MKL1 and myocardin induced caveolin and cavin expression in bladder smooth muscle cells from rats and humans and MYOCD correlated tightly with CAV1 and CAVIN1 in human bladder specimens. A recently described activator of MKL-driven transcription (ISX) failed to induce CAV1/CAVIN1 which may be due to an unusual transactivation mechanism. In all, these findings further support the view that myocardin family coactivators are important transcriptional drivers of caveolins and cavins in smooth muscle.


Proton Transport Across Collagen Fibrils and Scaffolds: The Role of Hydroxyproline.
Collagen is one of the most studied proteins due to its fundamental role in creating fibrillar structures and supporting tissues in our bodies. Accordingly, collagen is also one of the most used proteins for making tissue-engineered scaffolds for various types of tissues. To date, the high abundance of hydroxyproline (Hyp) within collagen is commonly ascribed to the structure and stability of collagen. Here, we hypothesize a new role for the presence of Hyp within collagen, which is to support proton transport (PT) across collagen fibrils. For this purpose, we explore here three different collagen-based hydrogels: the first is prepared by the self-assembly of natural collagen fibrils, and the second and third are based on covalently linking between collagen via either a self-coupling method or with an additional cross-linker. Following the formation of the hydrogel, we introduce here a two-step reaction, involving (1) attaching methanesulfonyl to the -OH group of Hyp, followed by (2) removing the methanesulfonyl, thus reverting Hyp to proline (Pro). We explore the PT efficiency at each step of the reaction using electrical measurements and show that adding the methanesulfonyl group vastly enhances PT, while reverting Hyp to Pro significantly reduces PT efficiency (compared with the initial point) with different efficiencies for the various collagen-based hydrogels. The role of Hyp in supporting the PT can assist in our understanding of the physiological roles of collagen. Furthermore, the capacity to modulate conductivity across collagen is very important to the use of collagen in regenerative medicine.


Watching the 'eugenic experiment' unfold: the mixed views of British eugenicists toward Nazi Germany in the early 1930s.
Historians of the eugenics movement have long been ambivalent in their examination of the links between British hereditary researchers and Nazi Germany. While there is now a clear consensus that American eugenics provided significant material and ideological support for the Germans, the evidence remains less clear in the British case where comparatively few figures openly supported the Nazi regime and the left-wing critique of eugenics remained particularly strong. After the Second World War British eugenicists had to push back against the accusation that their science was intrinsically dictatorial or totalitarian and, as a result, many of their early perceptions of the Nazis were ignored or rationalised away. Further, historians in recent years have focused more directly on the social reformist elements of eugenics, discussing the links between hereditary science and the birth control and feminist movements in addition to others. While undoubtedly making valuable contributions to the scholarly understanding of the eugenic milieu in the interwar years, these studies have neglected to recontextualize the sentiments of British eugenicists who did indeed view the Nazi government positively in the early years of the 1930s. This article argues that there was a significant, though not numerically sizable, faction in the British eugenics movement, though mostly outside the Eugenics Society itself, in the early 1930s that viewed the Nazi Germany as an admirable state for its implementation of eugenic principles. One of these figures was later interned by his own government for being too closely aligned with the German regime, though he argued that this affinity was driven by the quest for scientific truth rather than politics. Eugenics in Britain thus contained a greater diversity of views toward Germany than scholars have previously assumed, warranting more research into the individuals and organizations harbouring these views.


Clinical status of carboplatin.
Carboplatin, a cisplatin derivative, shows promise of being an effective weapon against ovarian, cervical, and small-cell lung cancer, as well as epidermoid cancer of the head and neck, with fewer toxic effects than cisplatin. It has successfully completed phase III investigation and clinical trials continue.


Serum levels of soluble IL-6 receptor in multiple myeloma as indicator of disease activity.
Serum soluble interleukin-6 receptor (sIL-6R) concentrations were measured in 50 patients with plasma cell dyscrasias using a commercially available immunoenzymatic assay kit. There were 40 patients with multiple myeloma (MM), 5 patients with monoclonal gammopathy of undetermined significance (MGUS), 3 patients with solitary plasmacytoma (SPC), 1 patient with chronic myelogenous leukaemia and multiple myeloma (CML/MM), and 1 patient with plasma cell leukaemia (PCL). We found that serum sIL-6R concentrations were higher in MM patients (62.53 +/- 38.85 ng/ml) than in 20 normal volunteers studied (36.75 +/- 13.79 ng/ml) (p < 0.01). The cut-off value of 65 ng/ml seen in 2 of our controls was arbitrarily taken as the upper limit of the control range for serum sIL-6R; according to this criterion, 14 patients with MM (35%), 1 patient with SPC, the unique patient with CML + MM, and the unique patient with PCL had elevated concentrations of the receptor. Patients with MGUS had normal sIL-6R values. In MM patients, serum sIL-6R levels correlated with the clinical phase of the disease: they were elevated in patients with early or late active disease and ranged within normal limits in patients with plateau-phase disease (p < 0.001). Thirteen of 27 patients with active MM had elevated serum sIL-6R values, i.e. 48.1%, but only 1 out of 13 patients with disease in the plateau phase, i.e. 7.7% (p < 0.05). Furthermore, in the entire group of MM patients, serum sIL-6R levels correlated with the concentrations of serum beta 2-microglobulin, (p < 0.02), CRP (p < 0.01), ferritin (p < 0.01) and LDH (p < 0.01), while they did not correlate with disease stage, haemoglobin levels, proportion of marrow myeloma cells, the values of serum IL-6, the levels of serum albumin, or the grade of bone lesions. We conclude that elevated serum sIL-6R levels should be related to the growth of myeloma cells and suggest that serum sIL-6R concentrations may be used as an indicator of disease activity.


Facile Synthesis of Iron Oxide/Graphene Nanocomposites Using Liquid Phase Plasma Method.
Liquid phase plasma (LPP) method was applied, for the first time, to the impregnation of iron oxide nanoparticles onto graphene sheet. Iron oxide nanoparticles with the size of 50 nm were precipitated with uniform dispersion on the surface of graphene sheet. The amount of iron oxide nanoparticles precipitated on graphene sheets increased with increasing LPP process times. The XPS, Raman and EDX analyses showed that the iron oxide/graphene composites synthesized by the LPP process.


Optic atrophy and sensorineural hearing loss in a family caused by an R445H OPA1 mutation.
Autosomal dominant optic atrophy (ADOA) is the most common form of inherited optic atrophy. Four genetic loci have been associated with ADOA: OPA1, OPA2, OPA3, and OPA4. Out of these four loci, only one gene has been identified, OPA1. We previously described a unique syndrome of optic atrophy, sensorineural hearing loss, ptosis, and ophthalmoplegia in two unrelated families associated with an R445H mutation in OPA1. The R445H mutation is the only OPA1 mutation that has been associated with this syndrome. In this manuscript, we clinically characterize an unrelated family with four members affected by optic atrophy and hearing loss without extraocular motility abnormalities or ptosis. This family also harbors the R445H mutation. These cases help illustrate the intra- and inter-family variability in phenotype associated with this mutation. As we continue to learn more about OPA1 and the function of its protein product, we will begin to understand the pathophysiology of optic atrophy. This understanding will ultimately lead to novel treatments directed toward preventing the visual loss and disability associated with this inherited disease.


Heterotopic mineral deposits in intact rat Achilles tendons are characterized by a unique fiber-like structure.
Heterotopic mineralization entails pathological mineral formation inside soft tissues. In human tendons mineralization is often associated with tendinopathies, tendon weakness and pain. In Achilles tendons, mineralization is considered to occur through heterotopic ossification (HO) primarily in response to tendon pathologies. However, refined details regarding HO deposition and microstructure are unknown. In this study, we characterize HO in intact rat Achilles tendons through high-resolution phase contrast enhanced synchrotron X-ray tomography. Furthermore, we test the potential of studying local tissue injury by needling intact Achilles tendons and the relation between tissue microdamage and HO. The results show that HO occurs in all intact Achilles tendons at 16 weeks of age. HO deposits are characterized by an elongated ellipsoidal shape and by a fiber-like internal structure which suggests that some collagen fibers have mineralized. The data indicates that deposition along fibers initiates in the pericellular area, and propagates into the intercellular area. Within HO deposits cells are larger and more rounded compared to tenocytes between unmineralized fibers, which are fewer and elongated. The results also indicate that multiple HO deposits may merge into bigger structures with time by accession along unmineralized fibers. Furthermore, the presence of unmineralized regions within the deposits may indicate that HOs are not only growing, but mineral resorption may also occur. Additionally, phase contrast synchrotron X-ray tomography allowed to distinguish microdamage at the fiber level in response to needling. The needle injury protocol could in the future enable to elucidate the relation between local inflammation, microdamage, and HO deposition.


Controlling the Energetic Properties of N-Methylene-C-Linked 4-Hydroxy-3,5-dinitropyrazole- and Tetrazole-Based Compounds via a Selective Mono- and Dicationic Salt Formation Strategy.
In the quest to synthesize high-performing insensitive high-energy density materials (HEDMs), the main challenge is establishing an equilibrium between energy and stability. For this purpose, we explored 4-hydroxy-3,5-dinitropyrazole- and tetrazole-based energetic scaffolds connected via a N-methylene-C bridge. The hydroxy functionality between nitro groups on the pyrazole ring promotes physical stability via inter- and intramolecular hydrogen bonding and contributes to oxygen balance, supporting better energetic performance. Due to two acidic sites (OH and NH) with different reactivities, a series of monocationic and dicationic salts were synthesized, and their overall performance was compared. All compounds synthesized in this study have high physical stability with impact sensitivity >40 J and friction sensitivity >360 N. Monocationic salts were generally found to have better thermal stability with respect to their corresponding dicationic energetic salts, which showed better energetic performance. The salt formation strategy effectively improved the thermal stability of 2 (Td = 168 °C), where most energetic salts have decomposition temperatures higher than 220 °C. All of the compounds were characterized through IR, multinuclear NMR spectroscopy, high-resolution mass spectrometry (HRMS), and elemental analysis. The structure-property relationship was studied using Hirshfeld surface analysis, noncovalent interaction (NCI) analysis, and electrostatic potential studies.


Self-reported reasons for vaping among 8th, 10th, and 12th graders in the US: Nationally-representative results.
The study describes the most common reasons for using vaporizers (such as e-cigarettes) among US adolescents and investigates how reasons for use differ by grade, lifetime cigarette use, frequency of vaporizer use, gender, race/ethnicity, and parent education. Data were collected from 4066 students in the 8th, 10th, and 12th grades in 2015 as part of the Monitoring the Future study, a cross-sectional and nationally representative US survey. Common reasons for vaporizer use reported by respondents who had ever used a vaporizer were experimentation (53.0%), taste (37.2%), boredom (23.5%), having a good time (22.4%), and relaxation (21.6%). Reasons differed little across grades or parent education; reasons differed by lifetime use of regular cigarettes, frequency of vaping, gender, and race/ethnicity. Overall, results suggest that decisions to vape are based on curiosity, taste, and pleasure, rather than for reasons such as quitting regular cigarettes or substituting for regular cigarette smoking.


The signal transduction pathway causing the synergistic hypertrophic effects of neuropeptide Y and norepinephrine on primary cardiomyocyte.
To investigate the synergistic hypertrophic effects of neuropeptide Y (NPY) and norepinephrine (NE) and its possible signal transduction pathway on primary cardiomyocytes, neonatal cardiomyocytes were exposed to NPY, NE or angiotensin II (AnII). All three agonists induced hypertrophic effects, stimulated protein kinase C (PKC) and activated mitogen-activated protein kinase (MAPK). Moreover, NPY at sub-optimal concentration potentiated NE-, not AnII-, induced all of the above effects. Pretreatment with phorbol 12-myristate 13-acetate (PMA) completely abolished these effects for both NE and NPY. NPY potentiation was calcium-independent and pertussis toxin (PTX)-sensitive, and was different from NPY direct hypertrophic effect on cardiomyocyte, as PTX only partially abolished NPY-induced hypertrophic effects. Taken together, NPY participated in the development of cardiac hypertrophy by potentiating NE effects. The signal pathway involves PTX-sensitive G protein, PKC, MAPK, and does not require the presence of calcium.


Prevalence of Horizontal Canal Variant in 3,975 Patients With Benign Paroxysmal Positional Vertigo: A Cross-sectional Study.
Current understanding based on older studies is that pc-BPPV is far more common than hc-BPPV. Such studies are limited by small sample sizes, and often the supine roll test for hc-BPPV is not performed. To better estimate the prevalence of hc-BPPV, we studied a large cross-section of patients with VOG-diagnosed BPPV. Using a cross-sectional study of patients with BPPV, we investigated patients referred to NeuroEquilibrium specialty clinics throughout India between January 1, 2021, and December 31, 2021. All patients were evaluated with video oculography (VOG) during positional tests, and all diagnoses were confirmed by a neurotologist and neurologist. Of 3,975 patients with VOG-confirmed and specialist-diagnosed BPPV (median age, 51 years; 56.6% women), pc-BPPV accounted for 1,901 (47.8%), hc-BPPV was seen in 1,842 (46.3%), and anterior canal BPPV was found in 28 (0.7%) patients. This study found that hc-BPPV is far more common than previously reported. It is important to perform the supine roll test in addition to the Dix-Hallpike in all patients suspected with BPPV. Better training to diagnose patients with BPPV and to accurately recognize the nystagmus pattern of hc-BPPV should be a priority.


Evaluation of a Commercially Delivered Weight Management Program for Adolescents.
To evaluate a commercially available, structured short-term weight management program designed for adolescents with obesity delivered by nonhealth professionals. A multisite parallel-group randomized controlled trial was conducted to evaluate a commercial 12-week lifestyle behavioral program in commercial weight management centers in Australia. Eligible participants (13-17 years, body mass index (BMI) z score ?1.282 with no presenting morbidities) were randomized (n?=?88) to intervention or wait-list, and the program was delivered by consultants at participating weight management centers. The primary outcome was change in BMI z score. Secondary outcomes included the psychometric variables quality of life, body-esteem, and self-esteem. Data was analyzed according to intention-to-treat principles. Of 74 participants who consented to enter the study, 66 provided baseline anthropometric data and 12-week data were available for 55 individuals (74%). A significantly greater decrease in BMI z score in the intervention group (n?=?32) was observed when compared with the wait-list control group, mean difference (MD)?=??0.27?kg/m2; 95% CI, ?0.37,?0.17; P?<?.001). Participants allocated to receive the lifestyle intervention reported a greater improvement in body esteem (MD = 1.7, 95% CI, 0.3, 3.1; P?=?.02) and quality of life (MD?=?5.9, 95% CI, 0.9, 10.9; P?=?.02) compared with the wait-list control group. A structured lifestyle intervention delivered by a commercial provider in an adolescent population can result in clinically relevant weight loss and improvements in psychosocial outcomes in the short term. Further research is required to evaluate long-term outcomes. International Clinical Trials Registry: ISRCTN13602313.


SMS 201-995 prevents postprandial blood pressure reduction in normotensive and hypertensive elderly subjects.
The mechanism of postprandial blood pressure reduction in the elderly is unknown but it has been suggested that insulin and/or vasoactive gut hormones play a role in this phenomenon. The increase in insulin and other gut hormones induced by the glucose loading can be blocked by a synthetic long-acting somatostatin analogue. SMS 201-995. We carried out a double-blind randomized study on the effects of SMS 201-995 on the responses of blood pressure, heart rate, insulin and plasma noradrenaline to oral glucose loading in normotensive and hypertensive elderly subjects. After placebo was administered, mean arterial pressure fell by 15 +/- 1 mmHg (P less than 0.001) in hypertensive elderly and by 7 +/- 2 mmHg (P less than 0.01) in normotensive elderly subjects. In contrast, when SMS 201-995 was administered, blood pressure remained essentially unchanged in both groups. These data indicate that treatment with SMS 201-995 might be of value in patients with symptomatic postprandial hypotension.


Lateral hip pain: does imaging predict response to localized injection?
Lateral hip pain is a common complaint in patients with a history of lower back pain from spinal disease. These patients often are diagnosed and treated for trochanteric bursitis because of localized pain and tenderness in the lateral hip. We presumed numerous scintigraphic features could provide diagnostic criteria for diagnosing gluteus medius tendinitis and trochanteric bursitis. A study was designed to assess the scintigraphic criteria for diagnosis of trochanteric bursitis and to evaluate the relationship of trochanteric bursitis to gluteus medius tendinitis and lumbar degenerative disease in predicting relapse after injection. We evaluated 97 patients with greater trochanteric pain syndrome to find a correlation between trochanteric bursitis, gluteus medius tendinitis, and spinal degenerative disease using scintigraphy and magnetic resonance imaging. We also evaluated predictors for responding to trochanteric injection of local anesthetic/glucocorticoid injection. We found a correlation between lumbar degenerative disease, gluteus medius tendinopathy, and trochanteric bursitis. Of these, 30 of 48 patients (63%) responded to injection of local anesthetic and glucocorticoids. The major predictor of relapse of pain after injection in 18 patients was the presence of moderate to severe lumbar degenerative disease seen on scintigraphic imaging. We propose a mechanistic model of the greater trochanteric pain syndrome to explain the interrelationship and response to therapy. Scintigraphy can provide sensitive and specific diagnoses of gluteus medius tendinitis and trochanteric bursitis.


Construction of an Iodine-Labeled CS1001 Antibody for Targeting PD-L1 Detection and Comparison with Low-Molecular-Peptide Micro-PET Imaging.
Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1), the research focus in immune checkpoint regulation, play an important role in tumor immunotherapy. Inhibitors of this pathway are also the focus of tumor immunotherapy research. The PD-1/PD-L1 pathway can be blocked by selective binding to PD-L1. Clinical trials have been conducted in a variety of patients with advanced solid tumors. CS1001 is a high-affinity humanized full-length anti-PD-L1 monoclonal antibody with great clinical significance. We constructed a PD-L1-targeted radioactive molecular probe, 124/125I-labeled full-length antibody CS1001, and evaluated its binding specificity and targeting ability to PD-L1 in tumor cells and tumor models. Additionally, a comparison study with 68Ga-WL12, a PD-L1 targeting peptide, was conducted. The binding potency of 125I-CS1001 to human PD-L1 was evaluated by enzyme-linked immunosorbent assay (ELISA), and the Kd value was 52.1 ± 19.3 nM. The cellular uptake of 125I-CS1001 was examined in Chinese hamster ovary cells (CHO) and CHO expressing human PD-L1 (CHO-hPD-L1). At 2 h, the uptake values of 125I-CS1001 in CHO-hPD-L1 without blocking and in the presence of 0.1 mg non-radiolabeled CS1001 were 3.60 ± 0.08 and 0.09 ± 0.005 (%AD/2 × 105 cells, p < 0.001). Micro-PET imaging was performed between 8 to 192 h after injection of 124I-CS1001 into normal KM mice and CHO-hPD-L1 and HeLa tumor models. The standard uptake value (SUV) of relevant organs in PET images was calculated by drawing regions of interest (ROI). SUVmean of CHO-hPD-L1 tumors was significantly higher than that of HeLa tumors at 48 h (1.98 ± 0.04 vs 0.73 ± 0.14, p = 0.005). The SUVmean of 124I-CS1001 in CHO-hPD-L1 tumors at 48 h was higher than that of 68Ga-WL12 in CHO-hPD-L1 tumors at 0.5 h (1.98 ± 0.04 vs 1.09 ± 0.1 SUVmean, p = 0.007). In conclusion, this work provides a new method for monitoring and evaluating the in vivo expression of PD-L1 in tumors.


The C2H2-type zinc finger protein ZFP182 is involved in abscisic acid-induced antioxidant defense in rice.
C(2) H(2) -type zinc finger proteins (ZFPs) are thought to play important roles in modulating the responses of plants to drought, salinity and oxidative stress. However, direct evidence is lacking for the involvement of these ZFPs in abscisic acid (ABA)-induced antioxidant defense in plants. In this study, the role of the rice (Oryza sativa L. sub. japonica cv. Nipponbare) C(2) H(2) -type ZFP ZFP182 in ABA-induced antioxidant defense and the relationship between ZFP182 and two rice MAPKs, OsMPK1 and OsMPK5 in ABA signaling were investigated. ABA treatment induced the increases in the expression of ZFP182, OsMPK1 and OsMPK5, and the activities of superoxide dismutase (SOD) and ascorbate peroxidase (APX) in rice leaves. The transient gene expression analysis and the transient RNA interference (RNAi) analysis in protoplasts showed that ZFP182, OsMPK1 and OsMPK5 are involved in ABA-induced up-regulation in the activities of SOD and APX. Besides, OsMPK1 and OsMPK5 were shown to be required for the up-regulation in the expression of ZFP182 in ABA signaling, but ZFP182 did not mediate the ABA-induced up-regulation in the expression of OsMPK1 and OsMPK5. These results indicate that ZFP182 is required for ABA-induced antioxidant defense and the expression of ZFP182 is regulated by rice MAPKs in ABA signaling.


Activation of protein kinase C by coexisting diacylglycerol-enriched and diacylglycerol-poor lipid domains.
To test the hypothesis that activation of protein kinase C (PKC) is related to the interface between coexisting diacylglycerol- (DAG-) enriched and DAG-poor phases, the thermotropic phase behavior of the ternary mixtures dimyristoylphosphatidylcholine (DMPC)/dimyristoylphosphatidylserine (DMPS)/dioleoylglycerol (DO), DMPC/DMPS/1-palmitoyl-2-oleoylglycerol (PO), and DMPC/DMPS/dimyristoylglycerol (DM) was analyzed and compared with the ability of the lipid mixtures to support PKC activity. Differential scanning calorimetry (DSC) was used to monitor the gel-to-liquid crystalline phase transition as a function of the mole fraction of DO (chiDO), PO (chiPO), or DM (chiDM) in DMPC/DMPS (1:1) multilamellar vesicles (MLVs) and of chiDO in large unilamellar vesicles (LUVs). The addition of DAG at low mole fractions gave rise to the appearance of two or more overlapping transitions. The phase boundaries of the ternary mixtures deduced from the partial phase diagrams were chiDO = approximately 0.10 and approximately 0.3 for DMPC/DMPS/DO, chiPO = approximately 0.05 and approximately 0.4 for DMPC/DMPS/PO, and chiDM = approximately 0.025 and approximately 0.5-0.6 for DMPC/ DMPS/DM. Above these mole fractions of DAG, the transitions again became very sharp. The ability of the lipid mixtures to support activity of PKC alpha and PKC eta was examined below and above the gel-to-liquid crystalline phase transition. In the gel phase, PKC activity went through a maximum as a function of increasing mole fraction of each DAG and was restricted to lipid compositions in which coexisting phases were observed. Maximal activity decreased with increasing saturation of the DAG. In the fluid state, maximal PKC activity was shifted to higher DO mole fractions and the peak was much broader. Collectively, these data support a role for both the presence and nature of interface between compositionally distinct domains in activation of PKC.


Gambogic acid-induced G2/M phase cell-cycle arrest via disturbing CDK7-mediated phosphorylation of CDC2/p34 in human gastric carcinoma BGC-823 cells.
Molecular mechanisms of cell-cycle arrest caused by gambogic acid (GA), a natural product isolated from the gamboge resin of Garcinia hanburryi tree, have been investigated using BGC-823 human gastric carcinoma cells as a model. Based on our 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazoliumbromide (MTT) assay and flow cytometric analysis, treatment of BGC-823 cells with growth suppressive concentrations of GA caused an irreversible arrest in the G(2)/M phase of the cell cycle. Western blot analysis demonstrated that GA-induced cell-cycle arrest in BGC-823 cells was associated with a significant decrease in CDC2/p34 synthesis, which led to the accumulation of phosphorylated-Tyr(15) (inactive) form of CDC2/p34. Real-time PCR, western blot and kinase activity assays revealed that GA-induced reduction of CDC2/p34 expression was mediated through the inhibition of cyclin-dependent kinase (CDK)-activating kinase (CDK7/cyclin H) activity. In addition, GA-treated cells were shown to have a low level of CDK7 kinase-phosphorylated-Thr(161) CDC2/p34 (active). Taken together, our results suggested that the inhibited proliferation of GA-treated BGC-823 cells was associated with the decreased production of CDK7 mRNA and protein, which in turn, resulted in the reduction of CDK7 kinase activity. The reduced CDK7 kinase activity is responsible for the inactivation of CDC2/p34 kinase and the irreversible G(2)/M phase cell-cycle arrest of human gastric carcinoma BGC-823 cells.


Enhanced level and metabolic regulation of methionyl-transfer ribonucleic acid synthetase in different strains of Escherichia coli K-12.
The methionyl-transfer ribonucleic acid (tRNA) synthetase of Escherichia coli K-12 eductants carrying P2-mediated deletions in the region of the structural gene of this enzyme was investigated. No structural alteration of this enzyme was observed in three eductants examined. These were isolated from strain AB311, which had a threefold higher level of methionyl-tRNA synthetase than most haploid strains examined. In two of the three eductants studied, the level of this enzyme was twofold higher than in their parental strain regardless of growth conditions used. In contrast, isoleucyl-, leucyl-, and valyl-tRNA synthetases had similar levels in all strains examined. Like valyl-tRNA synthetase, but to a lesser extent, methionyl-tRNA synthetase was subject to metabolic regulation. Coupling between the level of methionyl-tRNA synthetase and growth rate was observed even in strains that had an enhanced level of methionyl-tRNA synthetase. These results suggest that the formation of methionyl-tRNA synthetase remains subject to metabolic regulation even when the repression-like mechanism that controls the synthesis of this enzyme is altered. In addition, we report that in the merodiploid strain EM20031, which was haploid for the valyl-tRNA synthetase structural gene and diploid for the structural genes of methionyl-tRNA synthetase and D-serine deaminase, the levels of these latter two enzymes varied to a minor yet significant extent with the phosphate concentration of the culture medium; under the same conditions, the level of valyl-tRNA synthetase remained unchanged. Moreover, no variation of the levels of these three enzymes in response to phosphate was observed in the haploid strain HfrH. These results indicate that in the merodiploid strain EM20031, which carries the episome F32, the number of episomes per chromosome varies to some extent according to the phosphate concentration of the culture medium.


Evaluation of wideband frequency responses and nonlinear frequency compression for children with cookie-bite audiometric configurations.
Previous research has suggested that use of nonlinear frequency compression (NLFC) can improve audibility for high-frequency sounds and speech recognition of children with moderate to profound high-frequency hearing loss. Furthermore, previous studies have generally found no detriment associated with the use of NLFC. However, there have been no published studies examining the effect of NLFC on the performance of children with cookie-bite audiometric configurations. For this configuration of hearing loss, frequency-lowering processing will likely move high-frequency sounds to a lower frequency range at which a greater degree of hearing loss exists. The purpose of this study was to evaluate and compare the effects of wideband amplification and NLFC on high-frequency audibility and speech recognition of children with cookie-bite audiometric configurations. This study consisted of a within-participant design with repeated measures across test conditions. Seven children, ages 6-13 yr, with cookie-bite audiometric configurations and normal hearing or mild hearing loss at 6000 and 8000 Hz, were recruited. Participants were fitted with Phonak Nios S H2O III behind-the-ear hearing aids and Oticon Safari 300 behind-the-ear hearing aids. The participants were evaluated after three 4-to 6-wk intervals: (1) Phonak Nios S H2O III without NLFC, (2) Phonak Nios S H2O III with NLFC, and (3) Oticon Safari 300 with wideband frequency response extending to 8000 Hz. The order in which each technology was used was counterbalanced across participants. High-frequency audibility was evaluated by assessing aided thresholds (dB SPL) for warble tones and the high-frequency phonemes /sh/ and /s/. Speech recognition in quiet was measured with the University of Western Ontario (UWO) Plurals Test, the UWO Distinctive Features Difference (DFD) Test, and the Phoneme Perception Test vowel-consonant-vowel nonsense syllable test. Sentence recognition in noise was evaluated with the Bamford-Kowal-Bench Speech-In-Noise (BKB-SIN) Test. Repeated-measures analyses of variance were used to analyze the data collected in this study. The results across the three different conditions were compared. No difference in performance across conditions was observed for detection of high-frequency warble tones and the speech sounds /sh/ and /s/. No significant difference was seen across conditions for speech recognition in quiet when measured with the UWO Plurals Test, the UWO-DFD Test, and the Phoneme Perception Test vowel-consonant-vowel nonsense syllable test. Finally, there were also no differences across conditions on the BKB-SIN Test. These results suggest that NLFC does not degrade or improve audibility for and recognition of high-frequency speech sounds as well as sentence recognition in noise when compared with wideband amplification for children with cookie-bite audiometric configurations.


The distribution of the cost of multiple sclerosis in the UK: how do costs vary by illness severity?
To derive robust estimates for the cost of multiple sclerosis (MS) based on a variety of cost factors across a number of different cost perspectives. This is essential to perform credible pharmacoeconomic evaluations of alternative MS therapies. Here we present a detailed analysis of previously published MS cost data for the UK to which we fit a seemingly unrelated regression. This allows us to assess the size and significance of different cost factors, and account for the covariance between cost perspectives. We show that disability severity, disease type, relapse status, treatment type and time of treatment, sex, age, educational status, and time since diagnosis, are significant cost factors, with the significance of each dependent on the cost perspective chosen. This analysis provides a statistical model that may be used to better estimate individual patient costs across a range of demographic and cost perspectives, for use by health planners and in pharmacoeconomic evaluations.


Left ear advantages in detecting emotional tones using dichotic listening task in an Arabic sample.
Advantages associated with the left ear (right brain hemisphere) have been reported in some studies. Of these, some have specifically suggested that the left ear has a more heightened ability to detect emotional tones. Meanwhile others have pointed to factors such as age and gender as potentially leading to manifestations of human laterality. This study investigates which brain hemisphere is more involved in emotional processing of auditory information in Arab participants. We aimed to replicate the previous studies because no single study has been done in the Arabic region previously. Additionally, people in this region prefer to use the right side of their body, e.g., hand, ear, foot, etc., for most daily tasks. To acquire data a dichotic listening task (DLT) was administered to 28 male and 23 female (Edinburgh, UK) university students aged 19 to 38; 13 were left-handed and 38 were right-handed. The results showed a significant left ear advantage in the auditory processing of emotional information. There was a significant negative correlation between ear preference and handedness. Left ear advantage related only to handedness. Thus right-handed participants were more likely than left-handers to have a left ear advantage. The relationship between ear preference and gender was non-significant. The conclusion that might be drawn from this study is that the left ear (right hemisphere) is more involved in emotional processing than the right ear (left hemisphere), especially for right-handed people.


Sonic hedgehog is required during an early phase of oligodendrocyte development in mammalian brain.
Oligodendrocyte precursor development in the embryonic spinal cord is thought to be regulated by the secreted signal, Sonic hedgehog (Shh). Such precursors can be identified by the expression of Olig genes, encoding basic helix-loop-helix factors, in the spinal cord and brain. However, the signaling pathways that govern oligodendrocyte precursor (OLP) development in the rostral central nervous system are poorly understood. Here, we show that Shh is required for oligodendrocyte development in the mouse forebrain and spinal cord, and that Shh proteins are both necessary and sufficient for OLP production in cortical neuroepithelial cultures. Moreover, adenovirus-mediated Olig1 ectopic expression can promote OLP formation independent of Shh activity. Our results demonstrate essential functions for Shh during early phases of oligodendrocyte development in the mammalian central nervous system. They further suggest that a key role of Shh signaling is activation of Olig genes.


Relationship between Decreased Serum Superoxide Dismutase Activity and Metabolic Syndrome: Synergistic Mediating Role of Insulin Resistance and β-Cell Dysfunction.
The interplays of cellular aging and oxidative stress (OS) markers form a complex network, which has been reported to be interrelated with numerous age-related and metabolic diseases, including metabolic syndrome (MS). However, given the multifactorial mechanisms of MS, several important confounders such as dietary factors and the reciprocal effect among these markers have not been considered and adjusted in previous investigations regarding the associations of cellular aging and OS markers with MS and its related metabolic abnormalities. To explicate this, we conducted a cross-sectional study among 533 Chinese adults. All the participants underwent a 75 g oral glucose tolerance test. Dietary data were collected via a 24-hour dietary recall and subsequently analyzed by a registered dietitian using nutrition calculation software. Clinical diagnosis of MS was made according to the revised National Cholesterol Education Program Adult Treatment Panel III criteria (2004) with waist circumference cutoff modified for an Asian population. The leukocyte telomere length, mitochondrial DNA copy number, 8-hydroxy-2-deoxyguanosine, superoxide dismutase (SOD) activity, and glutathione reductase were examined. SOD activity was significantly decreased in MS subjects (62.06 ± 16.89 U/mL vs. 56.25 ± 22.61 U/mL, P = 0.001) and exhibited a descending trend across sequential increase of MS component number (P for trend = 0.031). SOD activity is modestly correlated with glucose indicators and insulin sensitivity and β-cell function indices and was independently and negatively correlated with the level of triglyceride. An independent association between SOD activity and MS was observed after adjusting for metabolic indicators, dietary factors, cellular aging, and OS markers, as well as insulin sensitivity and β-cell function indices. However, the statistical significance of the association between SOD activity and MS was attenuated after adjusting for the Matsuda insulin sensitivity index (ISIM) and insulin secretion-sensitivity index-2 (ISSI-2), suggesting a possible mediating effect. Therefore, we conducted a mediation model analysis, which showed that decreased ISIM and ISSI-2 partially and synergistically mediated the contribution of decreased SOD activity to MS. In conclusion, decreased SOD activity is an independent predictor for increased risk of MS, and insulin resistance and β-cell dysfunction partially mediate the relationship between decreased SOD activity and MS.


Abrasiveness of conventional and specific denture-cleansing dentifrices.
This study analyzed the weight loss and surface roughness caused in Plexiglass specimens by conventional dentifrices (Sorriso, Colgate and Close Up) and specific dentifrices used for cleaning of dentures (Corega and Dentu Creme). Plexiglass specimens were divided into 6 groups (n=6) including: a control (distilled water - DW) and experimental groups. Brushing was performed in a toothbrushing machine with a soft brush and a dentifrice suspension and DW according to different brushing times (50, 100, 200 and 250 min -18,000, 36,000, 72,000 and 90,000 cycles, respectively, calculated to correspond to 1, 2, 4 and 5 years of regular brushing). The results of weight loss and surface roughness were analyzed by ANOVA and Tukey's test at 5% significance level. In all tested times, the effect of DW was insignificant. Dentifrices differed significantly from DW in the initial period. Corega dentifrice caused greater mass loss in all studied times, followed by Close Up. Dentifrices resulted in a surface roughness similar to the DW at 50 min. In the other times, Sorriso, Colgate and Corega caused more surface roughness than DW. In conclusion, specific dentifrices caused larger mass loss and lower surface roughness as conventional dentifrice.


The anti-microbial peptide SR-0379 stimulates human endothelial progenitor cell-mediated repair of peripheral artery diseases.
Ischemia is a serious disease, characterized by an inadequate blood supply to an organ or part of the body. In the present study, we evaluated the effects of the anti-microbial peptide SR-0379 on the stem cell-mediated therapy of ischemic diseases. The migratory and tube-forming abilities of human endothelial progenitor cells (EPCs) were enhanced by treatment with SR-0379 in vitro. Intramuscular administration of SR-0379 into a murine ischemic hindlimb significantly enhanced blood perfusion, decreased tissue necrosis, and increased the number of blood vessels in the ischemic muscle. Moreover, co-administration of SR-0379 with EPCs stimulated blood perfusion in an ischemic hindlimb more than intramuscular injection with either SR-0379 or EPCs alone. This enhanced blood perfusion was accompanied by a significant increase in the number of CD31- and α-SMApositive blood vessels in ischemic hindlimb. These results suggest that SR-0379 is a potential drug candidate for potentiating EPC-mediated therapy of ischemic diseases. [BMB Reports 2017; 50(10): 504-509].


[Measures for Overcoming Barriers to Palliative Care of Patients with Chronic Heart Failure: A Delphi Method].
Patients with chronic heart failure receive less palliative care than those suffering from malignant diseases, even though they experience a similar disease burden. Studies found that this might be caused by the cyclic course of disease, which makes determination of the appropriate time difficult, lack of knowledge regarding content and structure of palliative care, and insufficient interprofessional communication. However, research suggests that patients with chronic heart failure benefit from palliative care. In this study, academic experts and experienced clinical practitioners developed measures in order to overcome the previously identified barriers. Furthermore, measures were evaluated regarding their relevance and practicability. In a next step, measures rated as both relevant and practical were ranked regarding their importance. Those perceived as important and practical mainly focused on better education for and better cooperation between professionals.


Elastin-like polypeptide based nanoparticles: design rationale toward nanomedicine.
Elastin-like polypeptides (ELPs) are characterized by a high sequence control, temperature responsiveness and biocompatibility, which make them highly interesting as smart materials for application in nanomedicine. In particular the construction of ELP-based nanoparticles has recently become a focal point of attention in materials research. This review will give an overview of the ELP-based nanoparticles that have been developed until now and their underlying design principles. First a short introduction on ELPs and their stimulus-responsive behavior will be given. This characteristic has been applied for the development of ELP-based block copolymers that can self-assemble into nanoparticles. Both the fully ELP-based as well as several ELP hybrid materials that have been reported to form nanoparticles will be discussed, which is followed by a concise description of the promising biomedical applications reported for this class of materials.


Unraveling Hydrophobic Interactions at the Molecular Scale Using Force Spectroscopy and Molecular Dynamics Simulations.
Interactions between hydrophobic moieties steer ubiquitous processes in aqueous media, including the self-organization of biologic matter. Recent decades have seen tremendous progress in understanding these for macroscopic hydrophobic interfaces. Yet, it is still a challenge to experimentally measure hydrophobic interactions (HIs) at the single-molecule scale and thus to compare with theory. Here, we present a combined experimental-simulation approach to directly measure and quantify the sequence dependence and additivity of HIs in peptide systems at the single-molecule scale. We combine dynamic single-molecule force spectroscopy on model peptides with fully atomistic, both equilibrium and nonequilibrium, molecular dynamics (MD) simulations of the same systems. Specifically, we mutate a flexible (GS)5 peptide scaffold with increasing numbers of hydrophobic leucine monomers and measure the peptides' desorption from hydrophobic self-assembled monolayer surfaces. Based on the analysis of nonequilibrium work-trajectories, we measure an interaction free energy that scales linearly with 3.0-3.4 kBT per leucine. In good agreement, simulations indicate a similar trend with 2.1 kBT per leucine, while also providing a detailed molecular view into HIs. This approach potentially provides a roadmap for directly extracting qualitative and quantitative single-molecule interactions at solid/liquid interfaces in a wide range of fields, including interactions at biointerfaces and adhesive interactions in industrial applications.


China's classification-based forest management: procedures, problems, and prospects.
China's new Classification-Based Forest Management (CFM) is a two-class system, including Commodity Forest (CoF) and Ecological Welfare Forest (EWF) lands, so named according to differences in their distinct functions and services. The purposes of CFM are to improve forestry economic systems, strengthen resource management in a market economy, ease the conflicts between wood demands and public welfare, and meet the diversified needs for forest services in China. The formative process of China's CFM has involved a series of trials and revisions. China's central government accelerated the reform of CFM in the year 2000 and completed the final version in 2003. CFM was implemented at the provincial level with the aid of subsidies from the central government. About a quarter of the forestland in China was approved as National EWF lands by the State Forestry Administration in 2006 and 2007. Logging is prohibited on National EWF lands, and their landowners or managers receive subsidies of about 70 RMB (US$10) per hectare from the central government. CFM represents a new forestry strategy in China and its implementation inevitably faces challenges in promoting the understanding of forest ecological services, generalizing nationwide criteria for identifying EWF and CoF lands, setting up forest-specific compensation mechanisms for ecological benefits, enhancing the knowledge of administrators and the general public about CFM, and sustaining EWF lands under China's current forestland tenure system. CFM does, however, offer a viable pathway toward sustainable forest management in China.


Aquaporin functionality in roots of Zea mays in relation to the interactive effects of boron and salinity.
Zea mays L. cv. amylacea, a plant tolerant of B and salinity, was used to determine the involvement of aquaporin functionality in the interactive effects of B and salinity. Also, growth, chlorophyll concentration, and water relations were studied. While growth and chlorophyll concentration did not show noticeable changes under saline conditions, the decrease in leaf water potential and osmotic potential, together with the marked decrease of stomatal conductance and root hydraulic conductance, showed that the plants were adjusted osmotically. However, no effect of B was observed. The very weak response of the Lpc of salt-stressed roots to Hg suggested that water channels were greatly reduced in number or, if present, were non-functional. The evidence that substantial B movement can occur through diffusion and channel-mediated transport is compelling, and could account for B uptake under conditions of adequate or greater B supply. Therefore, the reduction in the functionality of aquaporins for NaCl-treated plants could be related to the reduction of B concentrations in roots and leaves in B + NaCl-treated plants, in comparison with plants treated only with B.


Confirming Maximal Oxygen Uptake: Is Heart Rate the Answer?
This study investigates heart rate (HR), in 11 young adults (22.4±3.21yr), at V̇O2max, to ascertain whether measured maximal heart rate (HRmax), as determined by a plateau in HR (HRplat), can reliably confirm V̇O2max. V̇O2max and HRplat were determined, using the parameters of a V̇O2≤50 ml•min-1 and a ∆HR≤2b•min-1, respectively, over the final 60 s of sampling. V̇O2 was also independently determined using a verification phase protocol. A HRplat was achieved by 91% of participants (∆HR=1.3±1b•min-1) and critically the time at which HRmax was reached coincided with that at which V̇O2max was achieved. Moreover RER and ΔRER criteria were reached significantly earlier (p<0.05) than V̇O2max, whilst age-related heart rate maximums (HRage), were not achieved by many participants. The results suggest that a HRplat ≤2 b•min-1 is a more accurate method, within the group tested, to determine whether a 'true' V̇O2max has been achieved, than other secondary criteria and potentially avoids the requirement for an additional verification phase.


Consumer understanding and preferences for different nutrition information panel formats.
The study was conducted to assess the level of understanding and the ability to extract information from a nutrition information panel (NIP) among women (n = 232, 20-59 years) in the Klang Valley, an urban area in Malaysia. The study involved the currently used format in Malaysia and three other formats, namely (i) based on Guideline Daily Amount (GDA), (ii) Multiple Traffic Light (MTL) and (iii) combination of GDA/MTL. Four hypermarkets were chosen for the face-to-face interview using a questionnaire. Subjects were selected using a convenient sampling method. The mean score for level of understanding was the highest for the current format (3.46 ± 1.12) compared to the other three tested formats (GDA = 3.09 ± 1.03, MTL = 2.72 ± 0.97, GDA/MTL combination 3.09 ± 1.36). However, most of the respondents (68.1%) would prefer the current NIP format to be changed due to difficulty in understanding (43.1%) and perceived the nutrition information to be insufficient (23.3%) and over simplified (21.6%). When other NIP formats were introduced, GDA format was the most preferred (mean score 3.52 ± 0.84) compared to the other formats (MTL = 3.41 ± 0.98; GDA/ MTL combination = 3.29 ± 0.91), including the current format used in Malaysia (3.16 ± 0.85). These findings suggest that the preferred NIP format does not necessarily lead to correct interpretation of the nutrition information. The current format should be further promoted and explained to the public to improve its usage and consumer understanding.


Cardiac Electropharmacological Effects of Antidiarrheal Drug Loperamide and Its Antidote Naloxone in Anesthetized Guinea Pigs.
Cardiac electropharmacological effects of an antidiarrheal drug loperamide and its antidote naloxone were assessed in isoflurane-anesthetized guinea pigs. Intravenous administration of loperamide at 0.01-0.1 mg/kg did not affect parameters of electrocardiogram (ECG) or monophasic action potential (MAP) of the right ventricle. Additional administration of loperamide at 1 mg/kg prolonged the QT interval and MAP duration of the ventricle accompanied with increments of the PQ interval and QRS width. The potency of loperamide for QT-interval prolongation was about 100-times lower than that of dofetilide, in spite that similar inhibitory effects on the human Ether-a-go-go Related Gene (hERG) K+ channels have been reported between loperamide and dofetilide, implying lower accessibility of loperamide to the K+ channels. Intravenous administration of naloxone at 0.003-0.3 mg/kg, which effectively inhibits µ-opioid receptors, did not affect ECG parameters including QT interval or MAP duration. Furthermore, the loperamide-induced cardiac electrophysiological changes were not modified in the presence of naloxone at 0.3 mg/kg. These results suggest that loperamide has a potential to delay cardiac conduction and repolarization in the in vivo condition. Since naloxone did not modify ECG parameters and loperamide-induced ECG changes, naloxone is confirmed to possess acceptable cardiac safety when used as an antidote.


Common and distinct neural networks involved in fMRI studies investigating morality: an ALE meta-analysis.
Morality is an important social construct necessary for understanding what is right and wrong. Neuroimaging studies investigating morality have used a wide variety of paradigms and implicated many different brain areas. Yet, it remains unclear whether differences amongst morality tasks are the cause for such heterogeneous findings. Therefore, in the present study, a series of activation likelihood estimation (ALE) meta-analyses were conducted on 123 datasets (inclusive of 1963 participants) to address this question. The ALE meta-analyses revealed a series of common brain areas associated with all moral tasks, including medial prefrontal cortex, lateral orbitofrontal cortex, amygdala, temporoparietal junction, and precuneus. However, individual and contrast analyses also revealed unique networks associated with each moral modality, suggesting that different moral tasks recruit specialised brain regions.


A rapid increase in the normal white cell counts without blasts as the initial presentation of T-cell acute lymphoblastic leukaemia.
A 5-year-old girl with multiple enlarged cervical lymph nodes consistent with Epstein-Barr virus infection showed a rapid increase in the white blood cell counts (myeloid cells and lymphocytes) without blasts over a week period. Bone marrow evaluation performed after a week's observation unexpectedly showed replacement of the marrow with T lymphoblasts. A presentation of T-cell acute lymphoblastic leukaemia (T-ALL) in this fashion is very unusual. We postulate that the T-lymphoblasts may have been secreting granulocyte colony stimulating factor like substance. We are unable to find a similar case report in the literature, and thus we wish to report this case. The patient has been treated with Children's Oncology Group T-ALL protocol, and has been in continuous remission.


Lifestyle among long-term survivors of cancers in young adulthood.
To investigate lifestyle in a population-based sample of long-term (≥ 5 years since diagnosis) young adult cancer survivors (YACSs), and explore factors associated with not meeting the lifestyle guidelines for physical activity (PA), body mass index (BMI), and smoking. YACSs (n = 3558) diagnosed with breast cancer (BC), colorectal cancer (CRC), non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), or localized malignant melanoma (MM) between the ages of 19 and 39 years and treated between 1985 and 2009 were invited to complete a mailed questionnaire. Survivors of localized MM treated with limited skin surgery served as a reference group for treatment burden. In total, 1488 YACSs responded (42%), and 1056 YACSs were evaluable and included in the present study (74% females, average age at survey 49 years, average 15 years since diagnosis). Forty-four percent did not meet PA guidelines, 50% reported BMI ≥ 25 and 20% smoked, with no statistically significant differences across diagnostic groups. Male gender, education ≤ 13 years, comorbidity, lymphedema, pain, chronic fatigue, and depressive symptoms were associated with not meeting single and/or an increasing number of lifestyle guidelines. A large proportion of long-term YACSs do not meet the lifestyle guidelines for PA, BMI, and/or smoking. Non-adherence to guidelines is associated with several late effects and/or comorbidities that should be considered when designing lifestyle interventions for YACSs.


Resection of metachronous pancreatic cancer 4 years after pancreaticoduodenectomy for stage III pancreatic adenocarcinoma.
Pancreatic adenocarcinoma frequently recurs in patients even after resection with curative intent. The majority of these are early recurrences and are associated with metastatic disease, thus not amenable to repeat resection. Here we report a patient who underwent completion pancreatectomy for a metachronous pancreatic adenocarcinoma. This patient initially presented with painless jaundice and computed tomography (CT) revealed a mass in the head of the pancreas. Brushings obtained at endoscopic retrograde cholangiopancreatography (ERCP) were positive for adenocarcinoma. This patient then underwent a Whipple procedure and final pathology demonstrated stage III pancreatic ductal adenocarcinoma. Adjuvant therapy included gemcitabine and erlotinib. This patient was followed with physical examinations and serial laboratory and imaging studies. There was no evidence of disease for four years at which time and sharp elevation in CA-19-9 was found. Subsequent imaging revealed a mass in the remnant pancreas. Curative intent completion pancreatectomy was then performed which confirmed the presence of pancreatic adenocarcinoma. This was followed by adjuvant Gemcitabine based chemotherapy and chemoradiation. One year later the patient is alive with no evidence of disease. Thus, in highly selected patients with recurrent or metachronous pancreatic cancer, repeat pancreatectomy can be considered, but the course of treatment should be considered in a multidisciplinary setting.


Cellular and biochemical actions of adrenal glucocorticoid hormones on rat thymic lymphocytes.
The molecular, biochemical, and cellular effects of adrenal glucocorticoid hormones on thymic lymphocytes are reviewed, with emphasis on their relationship to the growth suppressive and lethal actions that occur in lymphoid tissues when glucocorticoids are administered to the whole animal. The data support the hypothesis that the hormonal inhibition of growth and development is a consequence of its ability to suppress cellular energy production, causing the cells to behave as though they were in a more stringent environment. Slight changes in ratios of adenine and guanine nucleotides appear to account for the reordering of metabolic priorities that occurs, with processes related to growth and development curtailed in favor of those more essential to immediate cell survival. The lethal glucocorticoid actions appear to be the result of the operation of separate mechanisms (unrelated to energy metabolism) that lead to lethal attack at the level of the nuclear membrane. Resistance to the lethal effects appears to occur via the selection (in the case of cancer cells where the animal or patient is undergoing chemotherapy with glucocorticoids) or the normal development (in the case of immunologically noncommitted thymocytes progressing to immunologically committed ones) of cells with hardier membranes. This progression is associated with a change in a few cellular proteins. One such protein appears identical in both kinds of cells, offering itself as a candidate for an intracellular mechanism conferring resistance. Evidence is also presented for the appearance of hormone-induced proteins that could be metabolic regulators that mediate the individual cellular and biochemical actions of glucocorticoids. It is proposed that toxins could alter cellular metabolism through mechanisms similar to those utilized by steroid hormones, or possibly alter the sensitivity of cells to steroids, or vice versa.


Autoantibody testing: procedures and significance in systemic rheumatic diseases.
The detection of ANA and the determination of their precise biochemical specificity is an important adjunct to the investigation of patients that have systemic rheumatic disease. Some of these antibodies have clearcut diagnostic and prognostic significance giving the informed clinician important information in the management of diseases with protean manifestations. The performance of the ANA test should be undertaken with a clear understanding of the importance of the substrate being used and the interpretation of certain patterns of staining. For most nuclear antigens (DNA, nRNP, Sm, etc.) cropreserved organ sections are adequate. However, antibodies directed to other antigens (PCNA, centromere, etc.) are best detected on tissue culture cell substrates. The availability of reference sera [99] has become an important advancement in the standarization of these tests. In spite of a large body of literature relating to the biochemistry and clinical significance of these antibodies much more needs to be done to complete our understanding of the role of these antibodies in the pathogenesis of disease.