DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells.
Conventional type 1 dendritic cells (cDC1s) are central to antitumor immunity and their presence in the tumor microenvironment associates with improved outcomes in patients with cancer. DNGR-1 (CLEC9A) is a dead cell-sensing receptor highly restricted to cDC1s. DNGR-1 has been involved in both cross-presentation of dead cell-associated antigens and processes of disease tolerance, but its role in antitumor immunity has not been clarified yet. B16 and MC38 tumor cell lines were inoculated subcutaneously into wild-type (WT) and DNGR-1-deficient mice. To overexpress Flt3L systemically, we performed gene therapy through the hydrodynamic injection of an Flt3L-encoding plasmid. To characterize the immune response, we performed flow cytometry and RNA-Seq of tumor-infiltrating cDC1s. Here, we found that cross-presentation of tumor antigens in the steady state was DNGR-1-independent. However, on Flt3L systemic overexpression, tumor growth was delayed in DNGR-1-deficient mice compared with WT mice. Of note, this protection was recapitulated by anti-DNGR-1-blocking antibodies in mice following Flt3L gene therapy. This improved antitumor immunity was associated with Batf3-dependent enhanced accumulation of CD8+ T cells and cDC1s within tumors. Mechanistically, the deficiency in DNGR-1 boosted an Flt3L-induced specific inflammatory gene signature in cDC1s, including Ccl5 expression. Indeed, the increased infiltration of cDC1s within tumors and their protective effect rely on CCL5/CCR5 chemoattraction. Moreover, FLT3LG and CCL5 or CCR5 gene expression signatures correlate with an enhanced cDC1 signature and a favorable overall survival in patients with cancer. Notably, cyclophosphamide elevated serum Flt3L levels and, in combination with the absence of DNGR-1, synergized against tumor growth. DNGR-1 limits the accumulation of tumor-infiltrating cDC1s promoted by Flt3L. Thus, DNGR-1 blockade may improve antitumor immunity in tumor therapy settings associated to high Flt3L expression.


The effect of pH and transition metal ions on cysteine-assisted gold aggregation for a distinct colorimetric response.
Colorimetric detection is a promising sensing strategy that is applicable to qualitative and quantitative determination of an analyte by monitoring visually detectable color changes with the naked eye. This study explored the cysteine (Cys)-induced aggregation of gold nanoparticles (AuNPs) in order to develop a sensitive colorimetric detection method for Cys. For this purpose, we systematically investigated the colorimetric response of AuNPs to Cys with varying particle sizes and concentrations. The AuNPs with various diameters ranging from 26.5 nm to 58.2 nm were synthesized by the citrate reduction method. When dispersed in water to have the same surface area per unit volume, the smaller AuNPs (26.5 nm) exhibited a more sensitive response to Cys compared to a larger counterpart (46.3 nm). We also examined the effect of divalent first-row transition metal ions (Mn2+, Fe2+, Co2+, Ni2+, Cu2+, and Zn2+) on the Cys-induced aggregation of AuNPs. Among the tested metal ions, the addition of Cu2+ provided the highest enhancement in sensitivity to Cys regardless of pH between 3.5 and 7. The significant increase in the sensitivity caused by Cu2+ could be attributed to the capability of Cu2+ to form a highly stable chelate complex with surface-immobilized Cys, facilitating the aggregation of AuNPs. For the AuNPs-Cu2+ system at pH 7, the detection limit for Cys was determined to be 5 nM using UV-vis spectroscopy. The reported strategy showed the potential to be used for a rapid and sensitive detection of Cys and also metal ions that can facilitate Cys-mediated aggregation of AuNPs.


Evaluation of BDNF levels in patients hospitalized for physical trauma at an emergency hospital in Porto Alegre, southern Brazil.
To assess the association between brain-derived neurotrophic factor (BDNF) levels and acute stress disorder (ASD) in patients who have suffered physical trauma. Data were collected at an emergency hospital in Porto Alegre, state of Rio Grande do Sul, southern Brazil. Participants were over 18 years of age, victims of physical trauma, and had been hospitalized for a minimum of 48 hours. A total of 117 hospitalized patients who agreed to participate in the research were grouped according to the shift in which blood was collected (38 subjects from the morning shift and 79 from the afternoon shift), had their BDNF levels measured and responded to other questionnaires. Respondents were further grouped by age into three ranges: 18-30, 31-50 and 51-70 years. We found a significant difference in the distribution of BDNF between the two shifts in which blood samples were collected, with the afternoon group having higher BDNF levels (U = 1906.5, p = 0.018). A difference was observed only between the 18-30 group and the 51-70 group in the afternoon shift (Umorning = 1107, pmorning = 0.575; Uafternoon = 7175, pafternoon = 0.028). The population whose blood samples were collected in the afternoon showed significantly higher values of BDNF compared to those of the morning shift. This same population presented lower BDNF levels when associated with ASD subtypes A1, A2, and A. We hypothesize that the lower values of BDNF measured in the morning shift were due to a response to the circadian cycle of cortisol, whose action inhibits the expression of serum neurotrophins.


Reduced levels of E-cadherin correlate with progression of corticotroph pituitary tumours.
Loss of E-cadherin is an important marker of epithelial tumour progression. The aims of this study were to explore whether E-cadherin expression and localization correlate to corticotroph tumour progression, relate the expression of the E-cadherin gene (CDH1) to immunohistochemical E-cadherin staining pattern, and study whether the E-cadherin levels were correlated to methylation status of the CDH1 promoter region. Immunohistochemical analyses of E-cadherin protein were performed, as was RT-qPCR of the CDH1 and the POMC genes. Methylation pattern of the promoter region of CDH1 was measured using pyrosequencing of bisulfite-treated DNA. Forty-five patients operated at a tertiary referral centre in Oslo, Norway. Adenoma tissue sections and RNA samples from patients with verified Cushing's disease or Nelson's syndrome were collected. Expression of E-cadherin mRNA and protein in pituitary corticotroph adenomas and average percentage of methylated cytosines in a cytosine-phosphate-guanosine island of the CDH1 promoter. Correlations were observed between tumour progression and both nuclear expression of E-cadherin and reduced CDH1 mRNA. The E-cadherin expression was not determined by the methylation pattern of the CDH1 promoter. Corticotroph tumour progression was associated with reduced expression of the epithelial marker E-cadherin.


Monitoring gaseous pollutants using passive sampling in the Philadelphia region.
Air pollution can have deleterious impacts on human health and the environment. Historically, air pollution studies have focused more on cities. However, it is also important to consider the impact on large suburban populations living closer to the major cities. In this study, nitrogen oxides (nitrogen dioxide and nitric oxide), sulfur dioxide, ozone, and ammonia concentrations were measured from fifteen sites in the Greater Philadelphia area, Pennsylvania, USA using Ogawa passive samplers from September 2021 to May 2022. The fall season had the highest mean NOx concentrations (11.03 ± 4.51 ppb), and spring had the highest mean O3 concentration (18.65 ± 6.71 ppb) compared to other seasons. NOx concentrations were higher at suburban (30.43 ± 33.79 ppb) and urban sites (22.49 ± 12.54 ppb) compared to semi-rural sites (11.08 ± 9.20 ppb). SO2 was not detected in most of the measurements. The positive statistically significant correlation between NO and NH3 in urban (R2 = 0.33, p-value <0.05) and suburban sites (R2 = 0.37, p-value <0.05) during winter and spring, respectively, suggests a high attribution of traffic emissions to NH3 at urban and suburban sites. Influence of traffic emissions on air pollutant values for the study region is also supported by similar NOx concentrations between suburban and urban sites as well as decreasing NO2/NOx ratios with increased distance from expressways. This study shows that passive sampling can be effectively used for assessing spatial and seasonal variations in air pollutants within an area of diverse land use.Implications: This study presents the findings of temporal and seasonal patterns for nitrogen dioxide, nitric oxide, tropospheric ozone, and ammonia at urban, suburban, and semi-rural areas of the greater Philadelphia region. The main objective of the study is to monitor air pollution in suburban and semi-rural areas which are not monitored for air pollution. We monitored from a total of fifteen sites in three seasons to assess air pollution in suburban and semi-rural areas near the major city in the United States - Philadelphia. The findings are important to learn how air quality is affected in suburban and semi-rural areas near the major city. The study also shows the useful application of inexpensive passive sampling technique for measuring air pollution.


Respiratory mechanics in airways obstruction associated with inspiratory dyspnoea.
Inspiratory muscle strength and the flow and elastic pressure opposing inspiration were measured in seven patients with severe airways obstruction who found inspiration difficult at rest. A comparison was made of measurements obtained from seven normal subjects and five patients with airways obstruction not experiencing inspiratory dyspnoea at rest. Measurements were also obtained when inspiratory dyspnoea was induced in the normal subjects by adding an inspiratory resistance or by voluntarily increasing lung volume. Compared with the controls the inspiratory muscle strength of the patients was reduced but was not significantly less than that of the patients without inspiratory dyspnoea. The pressure required to produce inspiratory flow was significantly greater when inspiratory dyspnoea was present (P = 0-01). However, there was considerable overlap in the pressures of those with and without inspiratory dyspnoea. A better relationship was obtained when muscle strength was considered. The ratio of inspiratory muscle strength to the pressure required to produce flow was 0-24 +/- 0-07 (mean +/- SD) in patient with inspiratory dyspnoea, 0-10 +/- 0-03 in patients without inspiratory dyspnoea, and 0-033 +/- 0-019 in normal subjects. There was no overlap between the two patient groups. The ratios of the normal subjects were increased when inspiratory dyspnoea was induced and, with the exception of two cases, were all above those obtained when inspiratory dyspnoea was absent. Inspiratory dyspnoea was experienced with lower ratios in the normals than in the patients with airways obstruction.


A global public health convention for the 21st century.
As shown by COVID-19, infectious diseases with a pandemic potential present a grave threat to health and wellbeing. Although the International Health Regulations provide a framework of binding legal obligations for pandemic prevention, preparedness, and response, many countries do not comply with these regulations. There is a need for a renewed framework for global collective action that ensures conformity with international regulations and promotes effective prevention and response to pandemic infectious diseases. This Health Policy identifies the necessary characteristics for a new global public health security convention designed to optimise prevention, preparedness, and response to pandemic infectious diseases. We propose ten recommendations to strengthen global public health governance and promote compliance with global health security regulations. Recommendations for a new global public health security convention include greater authority for a global governing body, an improved ability to respond to pandemics, an objective evaluation system for national core public health capacities, more effective enforcement mechanisms, independent and sustainable funding, representativeness, and investment from multiple sectors, among others. The next steps to achieve these recommendations include assembling an invested alliance, specifying the operational structures of a global public health security system, and overcoming barriers such as insufficient political will, scarcity of resources, and individual national interests.


Racial disparity in liver disease: Biological, cultural, or socioeconomic factors.
Chronic liver diseases are a major public health issue in the United States, and there are substantial racial disparities in liver cirrhosis-related mortality. Hepatitis C virus (HCV) is the most significant contributing factor in the development of chronic liver disease, complications such as hepatocellular carcinoma, and the need for liver transplantation. In the United States, African Americans have twice the prevalence of HCV seropositivity and develop hepatocellular carcinoma at more than twice the rate as whites. African Americans are, however, less likely to respond to interferon therapy for HCV than are whites and have considerably lower likelihood of receiving liver transplantation, the only definitive therapy for end-stage liver disease. Even among those who undergo transplantation, African Americans have lower 2-year and 5-year graft and patient survival compared to whites. We will review these racial disparities in chronic liver diseases and discuss potential biological, socioeconomic, and cultural contributions. An understanding of their underlying mechanisms is an essential step in implementing measures to mollify racially based inequities in the burden and management of liver disease in an increasingly racially and ethnically diverse population.


Protein in optimal health: heart disease and type 2 diabetes.
Diets with increased protein and reduced carbohydrates have been shown to improve body composition, lipid and lipoprotein profiles, and glycemic regulations associated with treatment of obesity and weight loss. Derived from these outcomes, high-protein, low-carbohydrate diets are also being examined for treatment of heart disease, metabolic syndrome, and type 2 diabetes. High-protein, low-carbohydrate diets have been found to have positive effects on reducing risk factors for heart disease, including reducing serum triacylglycerol, increasing HDL cholesterol, increasing LDL particle size, and reducing blood pressure. These diets appear particularly attractive for use with individuals exhibiting the atherogenic dyslipidemia of metabolic syndrome. High-protein, low-carbohydrate diets have also been investigated for treatment of type 2 diabetes with positive effects on glycemic regulation, including reducing fasting blood glucose, postprandial glucose and insulin responses, and the percentage of glycated hemoglobin. Specific effects of increasing protein compared with reducing carbohydrates have not been extensively investigated. Additional research is needed to determine specific levels of protein, carbohydrate, and fat for optimum health of individuals who differ in age, physical activity, and metabolic phenotypes.


ARHGAP18, a GTPase-activating protein for RhoA, controls cell shape, spreading, and motility.
Rho GTPases are molecular switches that transmit biochemical signals in response to extracellular stimuli to elicit changes in the actin cytoskeleton. Rho GTPases cycle between an active, GTP-bound state and an inactive, GDP-bound state. These states are regulated by two distinct families of proteins-guanine nucleotide exchange factors and GTPase-activating proteins (GAPs). We studied the role of a previously uncharacterized GAP, ARHGAP18 (MacGAP). Overexpression of ARHGAP18 suppressed the activity of RhoA and disrupted stress fiber formation. Conversely, silencing of ARHGAP18 by small interfering RNA transfection-enhanced stress fiber formation and induced rounding of cells. We examined the role of ARHGAP18 in cell spreading and migration. Immunofluorescence analysis revealed that ARHGAP18 was localized to the leading edge during cell spreading and migration. ARHGAP18-knockdown cells showed impaired spreading, premature formation of stress fibers, and sustained activation of RhoA upon cell attachment. In addition, knockdown and overexpression of ARHGAP18 resulted in the inhibition and promotion of cell migration, respectively. Furthermore, ARHGAP18 was required for the polarization of cells for migration. Our results define ARHGAP18 as one of the crucial factors for the regulation of RhoA for the control of cell shape, spreading, and migration.


Reducing pressure ulcer incidence through Braden Scale risk assessment and support surface use.
To collect available evidence showing that some hospitals have been able to markedly reduce pressure ulcer incidence despite broad surveys in previous recent years that demonstrated little or no progress and to provide guidance to hospitals through analysis of the evidence showing incidence reduction to be expected by taking the measures indicated. At the time of the article's writing, a review of the literature was conducted using PubMed. References were sought that cited hospitals using the Braden Scale to identify at-risk patients and providing pressure-reducing surfaces to those found to be at risk. Nine hospitals were so identified. Each hospital had reduced pressure ulcer incidence through risk assessment followed by intervention that included support surface provision. Statistical measures were used to establish confidence limits for the noted improvements. Each of the hospitals reviewed had implemented a policy of risk assessment of all admitted patients using the Braden Scale followed by implementation of best practices, generally including assignment of patients judged to be at risk to a pressure-reducing support surface. Each hospital reported in the literature a rate of nosocomial prevalence, both before and after program implementation. All hospitals demonstrated improvement, although the amount of improvement varied widely. Realizing that each of the hospitals reviewed started from different baselines, used different at-risk criteria, did not utilize the same support surface, and may have implemented a variety of additional interventions, it is perhaps not surprising that the 95% confidence interval for incidence odds ratio is broad, from 0.220 to 0.508 (meta-analysis), yet clearly significant. Cost savings due to reduced need for rental of expensive low-air-loss- or fluidized-bed therapy were reported. Risk assessment of all admitted patients followed by provision of specialized support surfaces to all deemed to be at risk offers real hope of reducing the present very high rate of hospital-caused pressure ulcers. With the growing understanding that some pressure ulcers have their origin in deep tissue, it no longer makes sense to wait for the appearance of Stage I or II ulcers before taking action.


The protective role of Piper nigrum fruit extract in an ovalbumin-induced allergic rhinitis by targeting of NFκBp65 and STAT3 signalings.
Piper nigrum L. is commonly used as a traditional medicine and food in many countries. It has been reported to have anti-oxidant, anti-bacterial, anti-tumor, anti-mutagenic, anti-diabetic, and anti-inflammatory properties. However, the effect of P. nigrum on allergic rhinitis (AR) has been unclear. In the present study, an OVA-induced AR mice model were established to investigate the anti-allergic, anti-inflammation properties of P. nigrum fruit extract (PNE). Oral administrations of PNE inhibited the allergic nasal symptoms including rubbing and sneezing in the early-phage of AR. In both NALF and nasal tissue, PNE suppressed the inflammatory cells accumulation, specifically with eosinophils in NALF. Additionally, PNE prevented the activation of STAT3 and NFκBp65 signaling in the cytoplasm which led to increasing the synthesis of the anti-inflammatory Th1 cytokines and suppressing the inflammatory Th2, Th17 cytokines. These obtained results suggest that PNE has the promising strategy for immunotherapy in allergic rhinitis disease.


Disrupt of Intra-Limb APA Pattern in Parkinsonian Patients Performing Index-Finger Flexion.
Voluntary movements induce postural perturbations which are counteracted by anticipatory postural adjustments (APAs). These actions are known to build up long fixation chains toward available support points (inter-limb APAs), so as to grant whole body equilibrium. Moreover, recent studies highlighted that APAs also build-up short fixation chains, within the same limb where a distal segment is moved (intra-limb APAs), aimed at stabilizing the proximal segments. The neural structures generating intra-limb APAs still need investigations; the present study aims to compare focal movement kinematics and intra-limb APA latencies and pattern between healthy subjects and parkinsonian patients, assuming the latter as a model of basal ganglia dysfunction. Intra-limb APAs that stabilize the arm when the index-finger is briskly flexed were recorded in 13 parkinsonian patients and in 10 age-matched healthy subjects. Index-finger movement was smaller in parkinsonian patients vs. healthy subjects (p = 0.01) and more delayed with respect to the onset of the prime mover flexor digitorum superficialis (FDS, p < 0.0001). In agreement with the literature, in all healthy subjects the FDS activation was preceded by an inhibitory intra-limb APA in biceps brachii (BB) and anterior deltoid (AD), and almost simultaneous to an excitatory intra-limb APA in triceps brachii (TB). In parkinsonian patients, no significant differences were found for TB and AD intra-limb APA timings, however only four patients showed an inhibitory intra-limb APA in BB, while other four did not show any BB intra-limb APAs and five actually developed a BB excitation. The frequency of occurrence of normal sign, lacking, and inverted BB APAs was different in healthy vs. parkinsonian participants (p = 0.0016). The observed alterations in index-finger kinematics and intra-limb APA pattern in parkinsonian patients suggest that basal ganglia, in addition to shaping the focal movement, may also contribute to intra-limb APA control.


A New Approach to Body Donation for Medical Education: The Silent Mentor Programme.
Cadaveric dissection is an integral component of medical education. There had been concerns about negative impact on medical students exposed to deceased donors before their clinical years, but most studies reported overall positive outcome following this form of teaching. Due to reducing number of body donations in most parts of the world, many institutions are adopting alternative models especially for the teaching of gross anatomy. A new body donation programme that incorporate humanistic values in the procurement process was initiated by Tsu Chi University of Taiwan in 1996. Early observations following teaching with the so-called "silent mentors" noted less negative emotional impact on the students. With increasing number of body donation following the initiation of the silent mentor programme as reported in some regions, we will be able to continue the time-honoured cadaveric dissection for anatomy teaching, at the same time promoting humanistic values on junior doctors.


Detection of autoplaque-forming cells as a means for characterizing the state of reactivity of the child organism.
Counts of plaque-forming cells [PFC] in blood were determined by the method of N. N. Klemparskaya in 181 children aged 1 to 3 years living in an organized community. A raised level of autoantibody-producing cells was detected in 45% of the children. The causes responsible for this enhanced autoimmunization may have been different infectious diseases. On the basis of phenomenon of PFC count increase in the presence of penicillin in specimens in vitro, hypersensitivity to thi antibiotic in the absence of clinical manifestations of allergy was detected in 27% of children.


Variation in teenage mothers' experiences of child care and other components of welfare reform: selection processes and developmental consequences.
Developmental evaluations of the current wave of welfare reform programs present challenges with regard to (1) assessing child outcomes; (2) accounting for heterogeneity among low-income families in both baseline characteristics and involvement in self-sufficiency activities and supports, and (3) development of alternatives to experimental approaches to causal inference. This study (N = 1,079) addresses these challenges by examining effects on 4- to 6-year-old children of different patterns of child care, self-sufficiency activities, and other service utilization indicators among experimental-group mothers in a 16-site welfare reform program. Outcomes in areas of cognitive ability and behavior problems were investigated. The study identified seven subgroups of participants engaging in different patterns of service utilization and activity involvement. A two-stage simultaneous equation methodology was used to account for selection, and effects on child cognitive ability of participation in specific patterns of services and activities were found. For example, children of mothers characterized by high levels of involvement in center-based child care, education, and job training showed higher levels of cognitive ability than children of mothers in groups characterized by high involvement in center-based care and education, or center-based care and job training. In addition, children of mothers in groups with high levels of involvement in any of these activities showed higher levels of cognitive ability than those with low levels of involvement. The bulk of selection effects occurred through site-level differences, rather than family-level socio-economic status or maternal depression indicators. Implications for welfare reform program and policy concerns are discussed.


Transethosome as a versatile nano vehicle for various indications and its regulatory insights.
Transethosomes, classified as 3rd generation nanocarriers, have gained global acclaim due to their profound potential in addressing diverse medical conditions. Their superior dermal penetration, attributed to essential constituents, such as edge activators and alcohol, sets them apart from other nanoformulations. The current review article embarks with an introduction followed by a comprehensive exploration of transethosome structures, differentiating them from fellow nanocarriers. A detailed analysis of characteristics and the spectrum of marketed products of various nanocarriers is also provided. Furthermore, the article offers a taxonomy of preparation methods of transethosomes and reports the frequently employed methods. It briefly surveys research studies encompassing various drug categories, spanning a wide range of medical conditions. In summary, this review article is dedicated to achieving several pivotal aims and objectives. We aim to substantiate the superior attributes of transethosomes when compared to conventional commercial products and other nanoformulations, demonstrating their clinical promise in addressing various human medical conditions. Additionally, we seek to elucidate the regulatory pathway required to secure approvals for transethosomes from relevant regulatory authorities and shine a light on their innovative potential as revealed in patent literature. Collectively, these objectives contribute to a comprehensive understanding of the significance and potential of transethosomes in the field of pharmaceutical nanotechnology.


Nursing from the casual pool: focus group study to explore the experiences of casual nurses.
The use of flexible non-contract nursing staff is increasing in Australia and in other countries where there is currently a nursing shortage. There is sparse empirical evidence relating to the experience of these nurses. This focus group study with six groups of enrolled and registered nurses in one regional health authority in New South Wales reports on the challenges and rewards of working through the casual pool. The textual data were coded and reported in themes and subthemes; the overarching theme is balance of social and professional life, while subthemes are social politics, nursing work and professional performance. The results reveal that nurses who work from the casual pool have insight into the work environment and culture of clinical teams that is untapped formally. They have little or no chance to provide clinical teams with feedback or receive feedback on their own performance. The consequence of this study has been the development of a two-way performance intervention to promote high standards of care from nurses who work from the casual pool and the promotion of safe clinical environments and cultures.


SSB peptide and DNA co-immunization induces inhibition of anti-dsDNA antibody production in rabbits.
Patients with systemic lupus erythematosus often have various autoantibodies. The relationship between these antibodies is still poorly understood. The aim of the present study was to observe the anti-SSB antibody and anti-dsDNA antibody production profiles following immunization with synthetic SSB peptide alone, DNA alone or co-immunization with these two antigens. SSB 214 - 225 aa peptide was synthesized by organic chemistry solid-phase peptide synthesis. Rabbits were immunized with the following antigens: synthetic SSB peptide linked with keyhole limpet hemocyanin (KLH), DNA, SSB plus dsDNA, KLH and PBS. Antibodies were measured by ELISA. Histopathology and direct immufluorescence assays were also applied. Anti-SSB and anti-dsDNA antibodies were produced following immunization with SSB peptide and DNA respectively. The level of SSB antibody in the co-immunization group was higher than that of the SSB peptide immunization group. The level of anti-dsDNA antibody in the co-immunization group was, however, lower than that in the DNA immunization group. Meanwhile, the level of anti-SSB antibody was higher than that of anti-DNA antibody in the co-immunization group. No morphological or immunological abnormalities were found in the heart, liver, kidney, spleen or skin tissues. Inhibition of anti-dsDNA-antibody was induced by co-immunization with synthesized SSB peptide and DNA, which might explain, at least partly, the mild disease in some LE subsets associated with SSB antibody.


Mitoguardin-1 and -2 promote maturation and the developmental potential of mouse oocytes by maintaining mitochondrial dynamics and functions.
Mitochondrial dynamics change mitochondrial morphological features and numbers as a part of adaptive cellular metabolism, which is vital for most eukaryotic cells and organisms. A disease or even death of an animal can occur if these dynamics are disrupted. Using large-scale genetic screening in fruit flies, we previously found the gene mitoguardin (Miga), which encodes a mitochondrial outer-membrane protein and promotes mitochondrial fusion. Knockout mouse strains were generated for the mammalian Miga homologs Miga1 and Miga2. Miga1/2-/- females show greatly reduced quality of oocytes and early embryos and are subfertile. Mitochondria became clustered in the cytoplasm of oocytes from the germinal-vesicle stage to meiosis II; production of reactive oxygen species increased in mitochondria and caused damage to mitochondrial ultrastructures. Additionally, reduced ATP production, a decreased mitochondrial-DNA copy number, and lower mitochondrial membrane potential were detected in Miga1/2-/- oocytes during meiotic maturation. These changes resulted in low rates of polar-body extrusion during oocyte maturation, reduced developmental potential of the resulting early embryos, and consequently female subfertility. We provide direct evidence that MIGA1/2-regulated mitochondrial dynamics is crucial for mitochondrial functions, ensure oocyte maturation, and maintain the developmental potential.


Administration of allogenic stem cells dosed to secure cardiogenesis and sustained infarct repair.
The mitotic capacity of heart muscle is too limited to fully substitute for cells lost following myocardial infarction. Emerging stem cell-based strategies have been proposed to overcome the self-renewal shortfall of native cardiomyocytes, yet there is limited evidence for their capability to achieve safe de novo cardiogenesis and repair. We present our recent experience in treating long-term, infarcted hearts with embryonic stem cells, a prototype source for allogenic cell therapy. The cardiogenic potential of the engrafted murine embryonic stem cell colony was pre-tested by in vitro differentiation, with derived cells positive for nuclear cardiac transcription factors, sarcomeric proteins and functional excitation-contraction coupling. Eight weeks after infarct, rats were randomized into sham- or embryonic stem cell-treated groups. Acellular sham controls or embryonic stem cells, engineered to express enhanced cyan fluorescent protein (ECFP) under control of the cardiac actin promoter, were injected through a 28-gauge needle at three sites into the peri-infarct zone for serial assessment of functional and structural impact. In contrast to results with sham-treated animals, stem cell therapy yielded, over the 5-month follow-up period, new ECFP-positive cardiomyocytes that integrated with the infarcted myocardium. The stem cell-treated group showed a stable contractile performance benefit with normalization of myocardial architecture post infarction. Transition of embryonic stem cells into cardiomyocytes required host signaling to support cardiac-specific differentiation and could result in tumorigenesis if the stem cell dose exceeded the heart's cardioinductive capacity. Supported by the host environment, proper dosing and administration of embryonic stem cells is thus here shown useful in the chronic management of cardiac injury promoting sustained repair.


The role of information in supporting self-care in vascular conditions: a conceptual and empirical review.
Self-care has the potential to make a significant contribution to vascular conditions, but engagement with self-care support has been limited. Lack of relevant information is highlighted by patients and policy-makers as an important barrier to effective self-care, and information provides a potentially efficient platform for changing behaviour. However, work within the social sciences has generally seen information as a necessary but insufficient driver of health behaviours. Furthermore, some groups (such as the socially disadvantaged) are expected to be less amenable to information interventions. We conducted an integrated conceptual and empirical review on information-based interventions for people with vascular disease (diabetes, heart disease and kidney disease). We reviewed conceptual and empirical work concerning the role and impact of information in self-care support to generate an explanatory framework to determine why information was effective or ineffective in encouraging self-care in patients with vascular conditions. This involved mapping relevant theories and models linking information and self-care. We also explored published systematic reviews of educational interventions in diabetes, coronary heart disease and chronic kidney disease to examine the role of information and evidence concerning its effectiveness and impact in different patient populations. The conceptual review identified variation among information interventions in terms of type, function, and their relationship to behaviour change techniques and psychological mediators of behaviour change. Key moderators of the effect of information included types of disorder, and patient capacity and resources. A wealth of educational interventions exists for diabetes and heart conditions, but the precise components of these interventions that are effective are difficult to identify. There is little evidence concerning optimal ways of tailoring interventions for socially disadvantaged groups other than ethnic minorities. A focus on printed information may not provide access to effective methods of information delivery (e.g. tailored information, use of narratives and user generated content). Developing a framework for the effective use of information needs to take account the full range of the factors identified.


[Dietotherapy of the chronic pancreatitis].
A modern pahtogenetic and etiological classification of pancreatic diseases is observed in the review and the questions of dietotherapy concerning the main forms of the disease are under consideration. There are numerous sources given from literature where the question is discussed on the fiber level, quantitative and qualitative structure of the fatty part of the ration in case of chronic pancreatitis. The majority of native and foreign authors consider it inexpedient to reduce fiber lover than 120 g per day, however there is a number of works where it is recommended to increase in the ration the quantity of carbohydrates up to 400 g, reducing some fiber at the same time. There has appeared a number of works for the recent years, where it is recommended to include mixes for enteral nutrition into the diets recommended both for acute and chronic course of the disease. Such diets are emphasized to be well bearable and high effective during the treatment of this disease.


Progesterone receptor activation mediates LH-induced type-I pituitary adenylate cyclase activating polypeptide receptor (PAC(1)) gene expression in rat granulosa cells.
We have previously reported that the pituitary adenylate cyclase activating polypeptide (PACAP) gene is regulated in ovarian granulosa cells by the autocrine and/or paracrine interaction between progesterone and its nuclear receptor progesterone receptor (PR). To initiate studies on the functional significance of the progesterone-induced PACAP production in luteinizing granulosa cells, we sought to determine the expression and hormonal regulation of PACAP receptors in the rat ovary. The relative mRNA levels of three known PACAP receptor subtypes (PAC(1), VPAC(1), and VPAC(2)) were determined in ovaries of immature rats treated with gonadotropins, by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) assays. Results show that all PAC(1), VPAC(1), and VPAC(2) transcripts are expressed at a detectable level in immature rat ovaries. Importantly, the ovarian level of PAC(1), but not VPAC(1) or VPAC(2), mRNA notably changes during gonadotropin challenges. Ovarian PAC(1) mRNA expression decreases during the pregnant mare's serum gonadotropin (PMSG)-induced follicular phase but substantially increases during the human chorionic gonadotropin (hCG)-induced periovulatory period. Because the hCG-induced increase in ovarian PAC(1) mRNA expression is attributable to the hormone-induced PAC(1) mRNA expression in granulosa cells of the preovulatory follicles, we next examined whether hCG regulates PAC(1) mRNA expression by directly acting on granulosa cells. When granulosa cells isolated from PMSG (40 h)-primed immature rats were challenged with hCG (or forskolin), PAC(1), but not VPAC(1) or VPAC(2), mRNA expression significantly increased within 6 h. Because the LH-induced PAC(1) mRNA expression (6 h) proceeds PR activation (3 h) in granulosa cells as the LH-induced PACAP mRNA expression (6 h) does, we further determined the cause-effect relationship among LH, PR activation and PAC(1) receptor gene expression, by examining the effect of PR antagonist, ZK98299, on the ability of LH to increase PAC(1) mRNA levels in luteinizing granulosa cells. Results show that ZK98299 inhibited the stimulatory effect of hCG (or forskolin) on PAC(1) mRNA expression, at the level of all known splice variants of PAC(1) mRNA in granulosa cells. In summary, our results demonstrating that PR activation is critical for the LH-induced PAC(1) gene expression in luteinizing granulosa cells suggest that PR activation regulates the finely tuned expression of the PACAP/PACAP receptor genes in luteinizing granulosa cells and thus dictates the timing of the autocrine and/or paracrine function of PACAP in preovulatory follicles.


Risk-responsive orbitofrontal neurons track acquired salience.
Decision making is impacted by uncertainty and risk (i.e., variance). Activity in the orbitofrontal cortex, an area implicated in decision making, covaries with these quantities. However, this activity could reflect the heightened salience of situations in which multiple outcomes-reward and reward omission-are expected. To resolve these accounts, rats were trained to respond to cues predicting 100%, 67%, 33%, or 0% reward. Consistent with prior reports, some orbitofrontal neurons fired differently in anticipation of uncertain (33% and 67%) versus certain (100% and 0%) reward. However, over 90% of these neurons also fired differently prior to 100% versus 0% reward (or baseline) or prior to 33% versus 67% reward. These responses are inconsistent with risk but fit well with the representation of acquired salience linked to the sum of cue-outcome and cue-no-outcome associative strengths. These results expand our understanding of how the orbitofrontal cortex might regulate learning and behavior.


Patterns of Hemodialysis Catheter Dysfunction Defined According to National Kidney Foundation Guidelines As Blood Flow <300 mL/min.
Blood flow rate (BFR) <300 mL/min commonly is used to define hemodialysis catheter dysfunction and the need for interventions to prevent complications. The objective of this study was to describe patterns of unplanned BFR <300 mL/min during catheter hemodialysis using data from DaVita dialysis facilities and the United States Renal Data System. Patients were included if they received at least eight weeks of hemodialysis exclusively through a catheter between 08/04 and 12/06, and catheter hemodialysis was the first treatment modality following diagnosis of end-stage renal disease (first access), or it immediately followed at least one 30-day period of dialysis exclusively through a fistula or graft (replacement access). Actual BFR <300 mL/min despite a planned BFR ≥300 mL/min defined catheter dysfunction during each dialysis session. There were 3,364 patients, 268,363 catheter dialysis sessions, and 19,118 (7.1%) sessions with catheter dysfunction. Almost two-thirds of patients had ≥1 catheter dysfunction session, and 30% had ≥1 catheter dysfunction session per month. Patients with catheter as a replacement access had a higher rate of catheter dysfunction than those with a catheter as first access (hazard ratio: 1.13; P = 0.04). Catheter dysfunction affects almost one-third of catheter dialysis patients each month and two-thirds overall.


Fourier transforms for fast and quantitative Laser Speckle Imaging.
Laser speckle imaging is a powerful imaging technique that visualizes microscopic motion within turbid materials. At current two methods are widely used to analyze speckle data: one is fast but qualitative, the other quantitative but computationally expensive. We have developed a new processing algorithm based on the fast Fourier transform, which converts raw speckle patterns into maps of microscopic motion and is both fast and quantitative, providing a dynamnic spectrum of the material over a frequency range spanning several decades. In this article we show how to apply this algorithm and how to measure a diffusion coefficient with it. We show that this method is quantitative and several orders of magnitude faster than the existing quantitative method. Finally we harness the potential of this new approach by constructing a portable laser speckle imaging setup that performs quantitative data processing in real-time on a tablet.


The status of the genus Pelczaria (Poston 1994) and the species Pelczaria aurantia (Poston 1994). Request for an Opinion.
Based upon the results of another publication [P. Schumann et al. (2000). Int J Syst Evol Microbiol 50, 1421-1424) it is concluded that the culture Pelczaria aurantia ATCC 49321T (= DSM 12801T) currently being distributed does not conform to the description of the type strain of Pelczaria aurantia (Poston 1994) and the type species of the genus Pelczaria (Poston 1994). It is proposed that the Judicial Commission consider (1) that the organism currently deposited as ATCC 49321T and DSM 12801T be recognized as a member of the species Kocuria rosea; (2) that the organism deposited as ATCC 49321T and DSM 12801T as the type strain of the species does not represent a strain of the species Pelczaria aurantia; (3) to place the name Pelczaria aurantia (Poston 1994) on the list of rejected names if a suitable replacement strain, or a neotype, cannot be found within 2 years of publication of this Request (Rule 18c); (4) to place the genus name Pelczaria (Poston 1994) on the list of rejected names [c.f. Recommendation 20d (3)] if a suitable replacement type strain or a neotype for the type species of the genus Pelczaria (Poston 1994) cannot be found as outlined in (3).


Vasoactive intestinal polypeptide and the ocular innervation.
The indirect immunofluorescence technique with antisera to vasoactive intestinal polypeptide (VIP) stains peripheral nerve fibers in both the anterior segment and the posterior segment of rat, guinea pig, cat, and rhesus monkey eyes. While immunoreactive corneal nerves are lacking, all four species have a prominent innervation of the superficial limbal blood vessels. The aqueous humor outflow apparatus of the rat, guinea pig, and cat, but not the monkey, contain VIP-like immunoreactive nerves. All four animals have immunoreactive iris nerve fibers, tending either to surround large blood vessels or to lie as free stromal nerves. Only in the cat are immunoreactive nerve fibers seen within the iris muscles. A modest number of VIP-like immunoreactive nerves are present in the ciliary body of all four animals; immunoreactive nerve fibers within the ciliary processes occur only in the rat and guinea pig. VIP-like immunoreactive nerves are found in the choroid of all four animals. An association of immunoreactive nerve fibers to uveal melanocytes also is apparent. The present findings expand several prior immunohistochemical studies of mammalian eyes in which the VIP-like immunoreactive nerves to the choroid was emphasized.


γ-H2AX detection in somatic and germ cells of mice.
The phosphorylation of histone H2AX at serine 139 (γ-H2AX) is one of the first steps of DNA damage response and its detection is widely used as a sensitive marker for DNA double-strand breaks induced by ionizing radiation or other genotoxic agents. Immuno-stained phosphorylated histone can be measured in single cells by flow cytometry or single γ-H2AX foci can be visualized and counted microscopically in histological or cytological preparations. Animal studies are well recognized as important tools to study mechanisms of in vivo response to genotoxic stress. Tissues are composed by many cell types differing for function, differentiation, and proliferative capacity. In particular, due to the complexity of spermatogenesis and the heterogeneity of testicular cell subpopulations, an accurate characterization of damage in this tissue is difficult and requires an approach which allows the identification of damage in the different cellular compartments. This chapter presents techniques for γ-H2AX detection in mouse bone marrow and testicular cells. Furthermore, advantages and weaknesses of flow cytometric and microscopic methods are described.


Histoplasma capsulatum in planktonic and biofilm forms: in vitro susceptibility to amphotericin B, itraconazole and farnesol.
It is believed that most microbial infections are caused by pathogens organized in biofilms. Recently, it was shown that the dimorphic fungus Histoplasma capsulatum, estimated to be the most common cause of fungal respiratory diseases, is also able to form biofilm. Although the antifungal therapy commonly used is effective, refractory cases and recurrences have been reported. In the search for new compounds with antimicrobial activity, the sesquiterpene farnesol has gained prominence for its antifungal action. This study aimed to evaluate the in vitro susceptibility of H. capsulatum var. capsulatum to the antifungal agents itraconazole and amphotericin B, and farnesol alone and combined, as well as to determine the in vitro antifungal activity of these compounds against biofilms of this pathogen. The results show that farnesol has antifungal activity against H. capsulatum in the yeast and filamentous phases, with MIC values ranging from 0.0078 to 0.00312 µM. A synergistic effect (fractional inhibitory concentration index ≤0.5) between itraconazole and farnesol was found against 100 and 83.3 % of the isolates in yeast and mycelial forms, respectively, while synergism between amphotericin B and farnesol was only observed against 37.5 and 44.4 % of the isolates in yeast and filamentous forms, respectively. Afterwards, the antifungal drugs, itraconazole and amphotericin B, and farnesol alone, and the combination of itraconazole and farnesol, were tested against mature biofilms of H. capsulatum, through XTT (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide) metabolic assay, and the itraconazole and amphotericin B showed lower antibiofilm activity when compared to farnesol alone and farnesol combined with itraconazole. In conclusion, farnesol showed promising results as an antifungal agent against H. capsulatum and also showed adjuvant action, especially when combined with itraconazole, increasing the fungal susceptibility to this drug.


rs10737680 polymorphism in complement factor H and neovascular age-related macular degeneration in Yogyakarta, Indonesia.
Neovascular age-related macular degeneration (nAMD) is one of the main causes of blindness in developed countries. Complement factor H (CFH) is one of the genes involved in the pathogenesis of nAMD. This study investigated the rs10737680 polymorphism in CFH and its conferred susceptibility to nAMD in Yogyakarta, Indonesia. This case-control hospital-based study recruited participants consisting of 96 patients with nAMD and 101 controls without nAMD from the Eye Polyclinic of Sardjito Hospital, YAP Eye Hospital, and Hardjolukito Hospital Yogyakarta. nAMD was diagnosed when fundus examination, fundus photographs, and optical coherence tomography revealed hard or soft drusen in the macular area measuring > 63 µm that appeared below the retinal pigment epithelium, with or without macular hypo- or hyperpigmentation, and was accompanied by choroidal neovascularization. Genomic DNA was extracted using a commercial DNA isolation kit. The restriction fragment length polymorphism technique was used to identify the rs10737680 polymorphism in CFH. The mean (standard deviation [SD]) age of the nAMD group was not homogeneous with that of the control group (P < 0.05); 65.41 (9.74) years versus 68.24 (7.82) years. The number of patients with hypertension in the nAMD group was significantly higher than in the control group (P < 0.05). In the nAMD group, the genotype distribution indicated homozygous risk allele in 34.38%, heterozygous risk allele in 57.29%, and homozygous non-risk allele in 8.33%. In the control group, the genotype distribution indicated homozygous risk allele in 21.78%, heterozygous risk allele in 36.63%, and homozygous non-risk allele in 41.58%. Statistical analysis between the two study groups according to homozygous risk allele genotype (odds ratio [OR], 7.87; 95% confidence interval [CI], 2.88-22.79) and heterozygous genotype (OR, 7.80; 95% CI, 3.11-21.19) showed a significant difference (both P < 0.01). Homozygous risk allele was less frequent than heterogeneous risk allele in patients with nAMD; however, both increased the risk for nAMD. Although the homozygous or heterozygous risk-alleles were detected in most patients, yet other important genetic or environmental factors could be involved in the pathogenesis of nAMD. Overall, we found a significant association between rs10737680 polymorphism in CFH and the susceptibility to nAMD in Yogyakarta, Indonesia; however, future studies are needed to fully delineate the mechanism.


Unveiling novel RNA viruses in trematodes parasitizing common periwinkle: Implications for host-parasite interactions.
This study characterized novel RNA viruses, parasites of parasites, or hyperparasites identified during transcriptomic analyses of two trematode species, Cryptocotyle lingua and Himasthla elongata, infecting a sea snail, Littorina littorea. According to the viral genome structures and phylogenetic analysis, Cryptolin alternavirus (ClRNAV1), Cryptolin calicivirus (ClRNAV2) and Himastelon rhabdovirus 1 (HeRNAV1) were respectively classified within the families Alternaviridae, Caliciviridae and Rhabdoviridae. They replicate species-specifically in two studied phases of trematode live cycle: intramolluscan parthenogenetic rediae and free-swimming cercariae. ClRNAV1 showed significantly higher expression in C. lingua cercariae relative to rediae. HeRNAV1's similarity to rabies viruses raises questions about its potential effects on the nervous system of H. elongata. This 'trematode rabies' could enable the use of genetically modified viruses for developing new methods to control the spread and intensity of diseases caused by trematodes.


Feasibility and acceptability of a mental health stigma intervention for low-income South African caregivers: A qualitative investigation.
Common mental health illnesses such as depression and anxiety disorders are increasing globally. There remain significant gaps in health services provision and support for mental illness linked to stigma in developing countries. Our study aimed to assess the feasibility and acceptability of a mental health intervention for caregivers of mental health service users. Low-income South African communities. Our study qualitatively assessed the feasibility of an anti-stigma mental health intervention for family caregivers in low-income settings. The intervention was structured into five sessions delivered over three days. Caregivers attended all the sessions at a centralised community venue. Semi-structured qualitative interviews were held separately with caregivers (n = 10) and their service users (n = 9) eight weeks post-intervention. Interviews were translated verbatim from local languages to English prior to framework analysis. Post-intervention, service users reported improved family relations and understanding of mental illness among family members. The intervention was reported as acceptable and helpful by caregivers as it increased knowledge, fostering better relationships with service users. Group discussions were noted as a critical driver of intervention success. Widespread mental health stigma within communities remained a key concern for caregivers and service users. With the government's drive for deinstitutionalisation, the need to integrate anti-stigma interventions within community mental health services is vital, as is the need for population-wide anti-stigma interventions to support the integration of mental health service users within communities.


Provision of acute oncology services in the UK: data from the Society for Acute Medicine Benchmarking Audit 2022 (SAMBA22).
Acute oncology services (AOS) manage acute cancer-related presentations alongside acute medical teams. This study assessed AOS provision against national peer review measures and the burden of acute cancer-related admissions. The 2022 Society for Acute Medicine Benchmarking Audit surveyed UK hospitals, collecting hospital-level and patient-level data for all medical admissions over a 24-h period. Logistic regression models were constructed to identify differences in patient outcomes for cancer-related admissions. Most hospitals (n=120 or 91.6%) reported having an AOS. There was heterogeneity in AOS provision, with many failing to meet peer-review measures. Of the 7,116 patients, 542 (7.6%) were cancer-related admissions. Cancer-related admissions had greater clinical acuity (p<0.05), length of stay (p<0.001) and 14-day mortality (adjusted odds ratio (OR)=3.54, 95% confidence interval (CI): 2.41-5.22, p<0.001) compared with other medical admissions. Increasing availability of AOS with integration of ambulatory pathways are vital next steps to improving care for acute cancer-related admissions.


Effects of COVID-19 on home visiting services for vulnerable families: A cross-state analysis of enrollment, engagement, and attrition patterns.
COVID-19 has resulted in massive health and economic consequences, with effects felt most acutely by populations that were disadvantaged prior to the pandemic. For families with young children, the effects have been compounded by service interruptions, though there is a lack of empirical evidence that demonstrates how COVID-19 has affected home visiting programs. This cross-state study is the first to examine the effects of the pandemic on home visiting enrollment, engagement, and retention patterns. Program implementation records gathered from 2017-2020 in Arkansas and Wisconsin were analyzed. Both states operate a large network of home visiting programs that serve predominantly low-income families and that are supported by the federal Maternal, Infant, and Early Childhood Home Visiting program. Trends prior to COVID were compared to post-COVID trends (March 12 to December 31, 2020) in program enrollments, service capacity, visitation frequency, service modalities, attrition rates, and service duration. Compared to average pre-pandemic enrollments from 2017-2019, post-COVID enrollments decreased by 33-36%. Total visits fell by 15-24%; the percentage of completed visits relative to expected visits declined more modestly. However, the average duration of services increased post-COVID while rates of early program dropout decreased. The findings suggest that enrollment and engagement in home visiting decreased during the COVID-19 pandemic, which is unfortunate given the large number of vulnerable families served nationwide. Further research is needed to examine how COVID affected both consumer and program behaviors. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Quantitative analysis of gait pattern and energy consumption in children with cerebral palsy.
The measurement of oxygen consumption during walking allows the quantification of gait expenditure, mainly in patients with musculoskeletal disabilities, as in cerebral palsy (CP). In this study, first, an experimental set up for the acquisition of energy consumption during gait analysis (GA) was proposed; secondly, some parameters of energy expenditure were analyzed to characterize pathological gait from an energetic point of view. Twenty CP children and 20 healthy children were evaluated during two consecutive sessions (session 1: only GA was performed; session 2: K4b2 was used during GA acquisition). The results revealed that the experimental set up was comfortable for all subjects. The absence of any differences in GA values between the two sessions showed that the use of a device for energy acquisition does not modify gait pattern. Energy expenditure index and oxygen cost presented abnormal values in comparison with normality and they were significant to quantify energy expenditure in CP children.


Biogenic amine profile in unripe Arabica coffee beans processed according to dry and wet methods.
Immature coffee fruit processing contributes to a high amount of defective beans, which determines a significant amount of low-quality coffee sold in the Brazilian internal market. Unripe bean processing was tested, taking the levels of bioactive amines as criteria for evaluating the extent of fermentation and establishing the differences between processing methods. The beans were processed by the dry method after being mechanically depulped immediately after harvest or after a 12 h resting period in a dry pile or immersed in water. Seven bioactive amines were quantified: putrescine, spermine, spermidine, serotonin, cadaverine, histamine, and tyramine, with global amounts ranging from 71.8 to 80.3 mg/kg. The levels of spermine and spermidine were lower in the unripe depulped coffee than in the natural coffee. The specific conditions of dry and wet processing also influenced cadaverine levels, and histamine was reduced in unripe depulped coffee. A resting period of 12 h does not induce significant alteration on the beans and can be improved if performed in water. These results confirm that peeling immature coffee can decrease fermentation processes while providing more uniform drying, thus reducing the number of defects and potentially increasing beverage quality.


Lower-dose psycholytic therapy - A neglected approach.
Lysergic acid diethylamide (LSD) and similar psychoactive drugs have been used in psychotherapy since 1949, when the first clinical study with lower-dose LSD showed therapeutically relevant effects. This caused an intense interest among psychotherapists and researchers, alike, on an international scale. In 1960, the use of serial lower-dose LSD/psilocybin sessions in a psychoanalytical framework, which was dominant at the time, was named "psycholytic therapy". Psycholytic therapy was usually conducted in clinical environments, on both an inpatient and outpatient basis. Psycholytic therapy was developed and established over a 15-year period on the European continent, where it was used at 30 clinical treatment centers and by more than 100 outpatient psychotherapists. Psycholytic approaches were employed minimally in North America, where the psychedelic approach (use of one or two high-dose sessions for "personality-transforming mystical experiences") became the dominant method in use. The leading figure in psycholytic therapy was Professor Hanscarl Leuner in Germany, who laid the ground with his uniquely fine grained analysis of the LSD reaction in a 1962 monograph. He was central in establishing and distributing psycholytic therapy in Europe and abroad. The article provides comprehensive background information and outlines the essential features of psycholytic therapy. Evidence for the efficacy of psycholytic therapy is reviewed and a case for the inclusion of the psycholytic approach in the field of substance-assisted psychotherapy is made.


Transcriptional induction of proto-oncogene fos by HSV-2.
HSV-2 induces the transcription of c-fos gene in both human (diploid) cell strains and mouse (heteroploid) cell lines. HSV-1 is incapable of such induction. The induction of transcription is rapid and transient in both cell types. The product of transcriptional induction of c-fos in mouse cells is mainly a 4.5 kb fos mRNA along with lesser amount of a 2.2 kb fos mRNA, while in human cells the 4.5 kb mRNA is the only detectable product. Both the 4.5 kb and 2.2 kb fos mRNAs are mature gene products as judged by their presence exclusively in the cytoplasm of infected mouse L929 cells, while a 3.5 kb putative precursor of the 2.2 kb fos mRNA appears exclusively in the nucleus. In infected human WI38 cells, the 4.5 kb mRNA also appears exclusively in the cytoplasm. Virus specific protein synthesis is an absolute requirement for the transcriptional activation. The 4.5 kb fos mRNA is under different control mechanisms since it is not induced by serum stimulation of serum starved cells as is the 2.2 kb fos transcript. Moreover, in serum starved cells simultaneously stimulated by serum and infected, only the 2.2 kb fos transcript can be superinduced by the protein synthesis inhibitor cycloheximide, while the appearance of the 4.5 kb fos mRNA is completely blocked by this treatment.


Purification, crystallization and preliminary X-ray analysis of two nudix hydrolases from Deinococcus radiodurans.
Two nudix hydrolases from Deinococcus radiodurans have been purified and crystallized. Diffraction data have been collected to 1.4 and 1.9 A resolution for DR1025 and DR0079, respectively. DR1025 belongs to space group P4(1)2(1)2/P4(3)2(1)2, with unit-cell parameters a = b = 53.2, c = 122.6 A (unit-cell Volume 346 883 A(3), V(M) = 2.5 A(3) Da(-1), solvent content 50.2%). DR0079 belongs to space group C222(1), with unit-cell parameters a = 34.1, b = 157.2, c = 126.5 A (unit-cell Volume 677 308 A(3), V(M) = 2.2 A(3) Da(-1), solvent content 44.0%). The calculated cell content of DR1025 indicates the presence of one molecule in the asymmetric unit. Dynamic light scattering and gel filtration suggest it to be a dimer in solution. The space group and unit-cell parameters of DR0079 indicate the presence of two molecules per asymmetric unit. Gel filtration and NMR spectroscopy suggest it to be a monomer in solution.


Evaluating the benefit of event adjudication of cardiovascular outcomes in large simple RCTs.
Event adjudication in randomized controlled trials is thought to be a necessary step to remove noise and potential bias from the results [1,2]. However, this hypothesis has not been widely evaluated. We conducted a meta-analysis of a series of cardiovascular outcomes trials and estimated the effect of adjudication on treatment estimates and on the number of outcomes included the trials. Data were retrieved from all cardiovascular outcomes trials conducted at the Population Health Research Institute (PHRI) between 1993 and 2006. These data included 10 trials with over 9000 events from 95,038 individuals. Differences in the log odds ratios between adjudicated and reported outcomes were analyzed and summarized using a ratio of odds ratios. Both masked and unmasked trials were included in this analysis. There were no effects of event adjudication on the estimates of treatment effect for the primary outcomes, myocardial infarction (MI), stroke, or cardiovascular/vascular death. For the trial primary outcomes, the effect of adjudication vs. reported events was OR ratio = 1.00 [95% confidence interval (CI): 0.97-1.02]. There were also no significant differences in the number of outcomes included in the trials. Results were the same for masked and unmasked trials. The number of unmasked trials were small, and this analysis was restricted to cardiovascular endpoints reported from trials managed by a single coordinating center, with similar sets of procedures. Individual patient data were not used for the analysis. This systematic meta-analysis failed to detect any effect of event adjudication on study conclusions and the numbers of events included in the final analyses were minimally changed. Given the considerable effort required to perform adjudication, there is a need to demonstrate that this process does indeed increase the sensitivity of trials. There is a need to conduct more systematic analyses of the effect of event adjudication in other trials to determine if this process is truly worthwhile.


(-)-Epigallocatechin-3-gallate enhances poly I:C-induced interferon-λ1 production and inhibits hepatitis C virus replication in hepatocytes.
To investigate the effect of (-)-epigallocatechin-3-gallate (EGCG) on polyinosinic-polycytidylic acid (poly I:C)-triggered intracellular innate immunity against hepatitis C virus (HCV) in hepatocytes. A cell culture model of HCV infection was generated by infecting a hepatoma cell line, Huh7, with HCV JFH-1 strain (JFH-1-Huh7). Poly I:C with a high molecular weight and EGCG were used to stimulate the JFH-1-Huh7 cells. Real-time reverse transcription-polymerase chain reaction was used to detect the expression levels of intracellular mRNAs and of intracellular and extracellular HCV RNA. Enzyme-linked immunosorbent assay was used to evaluate the interferon (IFN)-λ1 protein level in the cell culture supernatant. Immunostaining was used to examine HCV core protein expression in Huh7 cells. Our recent study showed that HCV replication could impair poly I:C-triggered intracellular innate immune responses in hepatocytes. In the current study, we showed that EGCG treatment significantly increased the poly I:C-induced expression of Toll-like receptor 3 (TLR3), retinoic acid-inducible gene I, and IFN-λ1 in JFH-1-Huh7 cells. In addition, supplementation with EGCG increased the poly I:C-mediated antiviral activity in JFH-1-Huh7 cells at the intracellular and extracellular HCV RNA and protein levels. Further investigation of the mechanisms showed that EGCG treatment significantly enhanced the poly I:C-induced expression of IFN-regulatory factor 9 and several antiviral IFN-stimulated genes, including ISG15, ISG56, myxovirus resistance A, and 2'-5'-oligoadenylate synthetase 1, which encode the key antiviral elements in the IFN signaling pathway. Our observations provide experimental evidence that EGCG has the ability to enhance poly I:C-induced intracellular antiviral innate immunity against HCV replication in hepatocytes.


Liposome functionalization with copper-free "click chemistry".
The modification of liposomal surfaces is of interest for many different applications and a variety of chemistries are available that makes this possible. A major disadvantage of commonly used coupling chemistries (e.g. maleimide-thiol coupling) is the limited control over the site of conjugation in cases where multiple reactive functionalities are present, leading to heterogeneous products and in some cases dysfunctional conjugates. Bioorthogonal coupling approaches such as the well-established copper-catalyzed azide-alkyne cycloaddition (CuAAC) "click" reaction are attractive alternatives as the reaction kinetics are favorable and azide-containing reagents are widely available. In the work described here, we prepared lipids containing a reactive cyclooctyne group and, after incorporation into liposomes, demonstrated successful conjugation of both a small molecule dye (5'-TAMRA-azide) as well as a larger azide-containing model protein based upon a designed ankyrin repeat protein (azido-DARPin). By applying the strain-promoted azido-alkyne cycloaddition (SPAAC) the use of Cu(I) as a catalyst is avoided, an important advantage considering the known deleterious effects associated with copper in cell and protein studies. We demonstrate complete control over the number of ligands coupled per liposome when using a small molecule azide with conjugation occurring at a reasonable reaction rate. By comparison, the conjugation of a larger azide-modified protein occurs more slowly, however the number of protein ligands coupled was found to be sufficient for liposome targeting to cells. Importantly, these results provide a strong proof of concept for the site-specific conjugation of protein ligands to liposomal surfaces via SPAAC. Unlike conventional approaches, this strategy provides for the homogeneous coupling of proteins bearing a single site-specific azide modification and eliminates the chance of forming dysfunctional ligands on the liposome. Furthermore, the absence of copper in the reaction process should also make this approach much more compatible with cell-based and in vivo applications.


Applying a Gene Reversal Rate Computational Methodology to Identify Drugs for a Rare Cancer: Inflammatory Breast Cancer.
The aim of this study was to utilize a computational methodology based on Gene Reversal Rate (GRR) scoring to repurpose existing drugs for a rare and understudied cancer: inflammatory breast cancer (IBC). This method uses IBC-related gene expression signatures (GES) and drug-induced gene expression profiles from the LINCS database to calculate a GRR score for each candidate drug, and is based on the idea that a compound that can counteract gene expression changes of a disease may have potential therapeutic applications for that disease. Genes related to IBC with associated differential expression data (265 up-regulated and 122 down-regulated) were collated from PubMed-indexed publications. Drug-induced gene expression profiles were downloaded from the LINCS database and candidate drugs to treat IBC were predicted using their GRR scores. Thirty-two (32) drug perturbations that could potentially reverse the pre-compiled list of 297 IBC genes were obtained using the LINCS Canvas Browser (LCB) analysis. Binary combinations of the 32 perturbations were assessed computationally to identify combined perturbations with the highest GRR scores, and resulted in 131 combinations with GRR greater than 80%, that reverse up to 264 of the 297 genes in the IBC-GES. The top 35 combinations involve 20 unique individual drug perturbations, and 19 potential drug candidates. A comprehensive literature search confirmed 17 of the 19 known drugs as having either anti-cancer or anti-inflammatory activities. AZD-7545, BMS-754807, and nimesulide target known IBC relevant genes: PDK, Met, and COX, respectively. AG-14361, butalbital, and clobenpropit are known to be functionally relevant in DNA damage, cell cycle, and apoptosis, respectively. These findings support the use of the GRR approach to identify drug candidates and potential combination therapies that could be used to treat rare diseases such as IBC.


Cerebrovascular Complications Associated With Iatrogenic Fungal Meningitis Following Surgical Procedures in Mexico.
The current fungal meningitis outbreak caused by contaminated epidural anesthesia with Fusarium solani among patients who underwent surgical procedures in Matamoros, Mexico remains a cause of concern. Its association with an increased susceptibility for cerebrovascular complications (CVC) has not been reported. This single-center study describes 3 patients with a unique pattern of CVC attributed to fungal meningitis. A retrospective case series of patients diagnosed with fungal meningitis following surgical procedures under contaminated epidural anesthesia who developed a unique pattern of CVC during their hospitalization. Three female patients (mean age, 35 years) with CVC due to iatrogenic fungal meningitis were included. Positive Fungitell β-D-glucan assay in cerebrospinal fluid was documented in all cases, and F. solani was confirmed by polymerase chain reaction in case 3. All cases were complicated by severe vertebrobasilar circulation vasculopathy and arterial dissections with resultant subarachnoid hemorrhage and intraventricular hemorrhage, ultimately leading to patients' death. The death toll from the ongoing fungal meningitis outbreak keeps rising, underscoring the need for early recognition and aggressive treatment. We highlight the risk for vertebrobasilar circulation CVC among these patients. The angioinvasive nature of F. solani is yet to be clarified; however, a clear pattern has been observed. Public health awareness should be raised and a strong response should be pursued.


Epidemiology and Direct Medical Cost of Osteoporotic Hip Fracture in Chile.
The osteoporotic hip fracture is associated with a high impact on morbidity, mortality, and health expenditure. The Chilean health system is made up of a mixed care system, with the public system called FONASA and the private system called ISAPRE. The people with lower incomes are listed on FONASA and correspond to 80.8% of the population. The aims of this study were to describe the incidence of hip fracture in the Chilean population from the age of 45 years and to estimate the direct medical cost of this disease. The records of the Department of the Health Statistics and Information of the Ministry of Health were used, from which the number of national hospital discharges due to hip fractures was obtained (codes S720, S721, and S722 of the ICD-10), in adults aged 45 years or older, by sex, from 2006 to 2017. The cost of osteoporotic hip fracture treatment in the public health system was obtained from the data of the surgical treatment according to the payment method associated with diagnosis (PAD bonus). A surgical intervention budget was used in a private clinic to calculate the direct cost of osteoporotic hip fracture in the private system. Between 2006 and 2017, the number of hospital discharges due to osteoporotic hip fracture in adults aged 45 years and older has increased progressively, registering 9.583 hospital discharges for this cause in 2017, which corresponds to 50% more than those recorded in 2006, with a 3 : 1 F/M ratio. The mean annual rate of hip fractures is 148.7 per 100,000 inhabitants aged above 45 years. The individual cost of managing an osteoporotic hip fracture in the public system was USD$ 3,919, and USD$ 9,092 in the private health system. The incidence of hip fracture was comparable with data from Southern European countries and from neighboring countries, such as Argentina and Uruguay. Hospitalization cost of hip fracture in Chile was 34 million USD per year. Hip fracture constitutes a serious healthcare problem in Chile, and efforts for the prevention and management of osteoporosis are needed.


Viability of high intensity interval training in persons with spinal cord injury-a perspective review.
Spinal cord injury (SCI) leads to loss of sensory and motor function below the level of injury leading to paralysis and limitations to locomotion. Therefore, persons with SCI face various challenges in engaging in regular physical activity, which leads to a reduction in physical fitness, increases in body fat mass, and reduced physical and mental health status. Moderate intensity continuous training (MICT) is recommended to enhance physical fitness and overall health status in this population, but it is not always effective in promoting these benefits. High intensity interval training (HIIT) has been promoted as an alternative to MICT in individuals with SCI due to its documented efficacy in healthy able-bodied individuals as well as those with chronic disease. However, the body of knowledge concerning its application in this population is limited and mostly composed of studies with small and homogeneous samples. The aim of this review was to summarize the existing literature regarding the efficacy of HIIT on changes in health- and fitness-related outcomes in this population, denote potential adverse responses to HIIT, describe how participants perceive this modality of exercise training, and identify the overall feasibility of interval training in persons with SCI.


Correlation Between Steroid Therapy and Lipid Profile in Systemic Lupus Erythematosus Patients.
Systemic lupus erythematosus (SLE) is an autoimmune disease with high mortality and morbidity rates, one of the causes of which is cardiovascular events. Dyslipidaemia is known to be one of the main risk factors for cardiovascular disorders and can be induced by steroid therapy, which is commonly administered to SLE patients. This study aimed to determine whether there is a correlation between steroid dose and lipid profile in SLE patients. The study was a correlative analytic study with a cross-sectional design. Data were obtained from the Hasan Sadikin Lupus Registry (HSLR) and the medical records of patients registered in the Rheumatology Division, Dr Hasan Sadikin Hospital, Bandung, from 2008 to 2019. Inclusion criteria were SLE patients who had undergone lipid profile examination and received steroid therapy. We excluded patients taking cyclosporine A or statins, and patients treated with steroids for less than a year. A simple random sampling method was performed and Pearson's correlation test was used for the analysis. We recruited 41 female patients with an average age of 30.88 ± 9.29 years old. The average dose of steroid in this study was 5.63 mg/day, while the average lipid profile was 177.51 mg/dL, 105.22 mg/dL, 61 mg/dL and 92.98 mg/dL for total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides, respectively. Correlations between steroid dose and total cholesterol (r = 0.375; p = 0.016), and between steroid dose and triglyceride level (r = 0.416; p = 0.007) were statistically significant in SLE patients. However, this study showed no correlation between steroid and HDL level (r = 0.206; p = 0.196) or LDL level (r = 0.308; p = 0.05). This study showed that the applied steroid dose in SLE patients correlated with total cholesterol and triglyceride levels, but not with HDL or LDL.


Balloon dilation technology: let the truth be told.
Balloon dilation technology (BDT), also known as balloon sinuplasty, has been in clinical use since September, 2005. Prior to BDT, surgeons performed a procedure called FESS, or functional endoscopic sinus surgery, for patients with chronic sinusitis. As is true with any new technology or procedure in medicine, a debate often ensues between early adopters and mainstream practitioners. Over the past 7 years, much has been discussed, debated, and learned about BDT. What follows is a review of the origins of the BDT: the theory, technology, indications and applications; and a review of the pertinent outcomes literature. Independent of how one feels about BDT, the evidence strongly supports its safety, efficacy, and growing popularity among patients and physicians alike.


Ascorbic-acid transporter Slc23a1 is essential for vitamin C transport into the brain and for perinatal survival.
The only proven requirement for ascorbic acid (vitamin C) is in preventing scurvy, presumably because it is a cofactor for hydroxylases required for post-translational modifications that stabilize collagen. We have created mice deficient in the mouse ortholog (solute carrier family 23 member 1 or Slc23a1) of a rat ascorbic-acid transporter, Svct2 (ref. 4). Cultured embryonic fibroblasts from homozygous Slc23a1(-/-) mice had less than 5% of normal ascorbic-acid uptake. Ascorbic-acid levels were undetectable or markedly reduced in the blood and tissues of Slc23a1(-/-) mice. Prenatal supplementation of pregnant females did not elevate blood ascorbic acid in Slc23a1(-/-) fetuses, suggesting Slc23a1 is important in placental ascorbic-acid transport. Slc23a1(-/-) mice died within a few minutes of birth with respiratory failure and intraparenchymal brain hemorrhage. Lungs showed no postnatal expansion but had normal surfactant protein B levels. Brain hemorrhage was unlikely to be simply a form of scurvy since Slc23a1(-/-) mice showed no hemorrhage in any other tissues and their skin had normal skin 4-hydroxyproline levels despite low ascorbic-acid content. We conclude that Slc23a1 is required for transport of ascorbic acid into many tissues and across the placenta. Deficiency of the transporter is lethal in newborn mice, thereby revealing a previously unrecognized requirement for ascorbic acid in the perinatal period.


Role of buoyant flame dynamics in wildfire spread.
Large wildfires of increasing frequency and severity threaten local populations and natural resources and contribute carbon emissions into the earth-climate system. Although wildfires have been researched and modeled for decades, no verifiable physical theory of spread is available to form the basis for the precise predictions needed to manage fires more effectively and reduce their environmental, economic, ecological, and climate impacts. Here, we report new experiments conducted at multiple scales that appear to reveal how wildfire spread derives from the tight coupling between flame dynamics induced by buoyancy and fine-particle response to convection. Convective cooling of the fine-sized fuel particles in wildland vegetation is observed to efficiently offset heating by thermal radiation until convective heating by contact with flames and hot gasses occurs. The structure and intermittency of flames that ignite fuel particles were found to correlate with instabilities induced by the strong buoyancy of the flame zone itself. Discovery that ignition in wildfires is critically dependent on nonsteady flame convection governed by buoyant and inertial interaction advances both theory and the physical basis for practical modeling.


Synthesis of the tetrasaccharide motif and its structural analog corresponding to the lipopolysaccharide of Escherichia coli O75.
Extraintestinal pathogenic E. coli are mostly responsible for a diverse spectrum of invasive human and animal infections leading to the urinary tract infections. Bacterial lipopolysaccharides are responsible for their pathogenicity and their interactions with host immune responses. In spite of several breakthroughs in the development of therapeutics to combat urinary tract infections and related diseases, the emergence of multidrug-resistant bacterial strains is a serious concern. Lipopolysaccharides are attractive targets for the development of long-term therapeutic agents to eradicate the infections. Since the natural sources cannot provide the required amount of oligosaccharides, development of chemical synthetic strategies for their synthesis is relevant to gain access to a reservoir of oligosaccharides and their close analogs. Two tetrasaccharide derivatives were synthesized from a single disaccharide intermediate. β-D-mannoside moiety was prepared from β-D-glucoside moiety following oxidation-reduction methodology. A [2+2] stereoselective block glycosylation strategy has been adopted for the preparation of tetrasaccharide derivative. α-D-glucosamine moiety was prepared from α-D-mannosidic moiety following triflate formation at C-2 and S(N)(2) substitution. A one-pot iterative glycosylation exploiting the orthogonal property of thioglycoside was carried out during the synthesis of tetrasaccharide analog. Synthesis of the tetrasaccharide motif (1) and its structural analog (2) corresponding to the lipopolysaccharide of Escherichia coli O75 was successfully achieved in excellent yield. Most of the reactions are clean and high yielding. Both compounds 1 and 2 were synthesized as their 4-methoxyphenyl glycoside, which can act as a temporary anomeric protecting group for further use of these tetrasaccharides in the preparation of glycoconjugates.


Neurophysiological tools to investigate consumer's gender differences during the observation of TV commercials.
Neuromarketing is a multidisciplinary field of research whose aim is to investigate the consumers' reaction to advertisements from a neuroscientific perspective. In particular, the neuroscience field is thought to be able to reveal information about consumer preferences which are unobtainable through conventional methods, including submitting questionnaires to large samples of consumers or performing psychological personal or group interviews. In this scenario, we performed an experiment in order to investigate cognitive and emotional changes of cerebral activity evaluated by neurophysiologic indices during the observation of TV commercials. In particular, we recorded the electroencephalographic (EEG), galvanic skin response (GSR), and heart rate (HR) in a group of 28 healthy subjects during the observation of a series of TV advertisements that have been grouped by commercial categories. Comparisons of cerebral indices have been performed to highlight gender differences between commercial categories and scenes of interest of two specific commercials. Findings show how EEG methodologies, along with the measurements of autonomic variables, could be used to obtain hidden information to marketers not obtainable otherwise. Most importantly, it was suggested how these tools could help to analyse the perception of TV advertisements and differentiate their production according to the consumer's gender.


Altered contractile response of penis under hypoxia with metabolic acidosis.
Previous studies concerning ischemic priapism revealed that hypoxia alters the erectile and contractile responses of penis. But the effects of accompanying acidosis on those responses have not been fully evaluated or understood yet. We performed this study to elucidate the role of acidosis on the trabecular smooth muscle contractility like in ischemic priapism. Under the general anesthesia, 55 mature male cats were conditioned to systemic metabolic acidosis by hypoventilation by animal ventilator. The changes of intracavernous pressure (ICP) to erectogenic agents (acetylcholine, L-arginine, prostaglandin E1: PGE1), erectolytic agents (epinephrine, thromboxane A2; TXA2), K channel-related drugs (pinacidil, 4-aminopyridine, tetraethylammonium; TEA, glibenclamide) and calcium ionophore were monitored at Set 1 (PO2 > 60 mmHg, pH > 7.25), Set 2 (PO2 < 30 mmHg, 7.25 > pH > 7.0), Set 3 (PO2 < 30 mmHg, pH < 7.0), and Set 4 (PO2 > 60 mmHg, pH < 7.0) in vivo. At Set 1 and Set 2, epinephrine, TXA2, and ionomycin decreased the ICP by acetylcholine or PGE1 (n = 9, P < 0.01). The decrease of ICP was in order of epinephrine, TXA2 and ionomycin. Acidosis reduced the increase of ICP to acetylcholine or PGE1 (n = 8, P < 0.01), TXA2 or ionomycin did not affect ICP under severe acidosis but epinephrine decreased ICP even under severe acidosis (n = 7, P < 0.05). Pretreatment of potassium channel blockers did not suppress the increase of ICP by erectogenic agents under acidosis (n = 6, P < 0.05). Pinacidil did not affect ICP under acidosis (n = 6, P < 0.01). These results suggest that acidosis impairs the contractile response of cavernous smooth muscle to erectolytic agents. It may be the results of the interference by [H+] with the intra and extracellular mechanisms that regulate the homeostasis of [Ca2]. Conclusively, besides hypoxia, acidosis is another limiting factor of trabecular smooth muscle contractility like in ischemic priapism.


Radical radiotherapy for prostate cancer: patterns of care in Sweden 1998-2016.
Introduction: Radiotherapy is an established treatment option for prostate cancer (PCa), both as primary treatment and secondary treatment after radical prostatectomy (RP). Since 1998, detailed data on radiotherapy delivered to Swedish men with PCa (e.g. treatment modalities, absorbed doses, fractionation) have been collated within PCa data Base Sweden (PCBaSe). This study reports patterns of radical radiotherapy for PCa in Sweden over the past two decades.Materials and methods: All men with non-metastatic PCa (1998-2016) who received external beam radiotherapy (EBRT) or high or low dose-rate brachytherapy (HDR-BT/LDR-BT) were identified in PCBaSe. Analyses included: trends in radiation techniques, fractionation patterns and total doses over time; PCa-specific survival comparing treatment in 2007-2017 with 1998-2006; and regional variation in type of primary radiotherapy.Results: About 20,876 men underwent primary radiotherapy. The main treatment modalities include conventionally fractionated (2.0 Gy/fraction) EBRT (51%), EBRT with HDR-BT boost (27%) and hypofractionated (>2.4 Gy/fraction) EBRT (11%). EBRT with photon or proton boost and HDR-BT and LDR-BT monotherapies were each used minimally. Use of dose-escalated EBRT (>74 Gy) and moderate hypofractionation increased over time, while use of HDR-BT declined. Considerable regional variation in treatment modalities was apparent. Risk of PCa death following primary radiotherapy had declined for intermediate-risk (HR: 0.60; 95%CI 0.47-0.87) and high-risk PCa (HR: 0.72; 95%CI 0.61-0.86).Discussion: Increased use of dose escalation and hypofractionated EBRT has occurred in Sweden over the past two decades, reflecting current evidence and practice guidelines. Disease-specific outcomes have also improved. Data collected in PCBaSe provide an excellent resource for further research into RT use in PCa management.


Therapeutic options in the management of metastatic breast cancer.
Breast cancer is the second leading cause of cancer-related death in women in the United States, and for nearly all with metastatic disease at presentation or relapse it will be incurable. The goals of therapy are to optimize quality of life and, if possible, prolong time to progression of disease and death. For a select group of patients an aggressive surgical approach may be considered. Initial palliation with endocrine therapy should be the primary consideration for patients with metastatic hormone receptor-positive tumors. Cytotoxic chemotherapy is appropriate for those with hormone-refractory disease, rapidly progressive visceral disease, or early relapse after adjuvant therapy. If a tumor overexpresses HER2, targeted treatment with trastuzumab (Herceptin) or lapatinib (Tykerb) is possible. Consequently, accurate determination of the status of these predictive markers in tissue (possibly from a recurrence site) is key. Other novel agents are adding to the wide choices of standard chemotherapies already available. This review offers an approach to the selection of individualized and rational therapies for patients with metastatic breast cancer.


Identification of peptidases in Nicotiana tabacum leaf intercellular fluid.
Peptidases in the extracellular space might affect the integrity of recombinant proteins expressed in, and secreted from, plant cells. To identify extracellular peptidases, we recovered the leaf intercellular fluid from Nicotiana tabacum plants by an infiltration-centrifugation method. The activity of various peptidases was detected by an in vitro assay in the presence of specific inhibitors, using BSA and human serum gamma-globulin as substrates. Peptidases were detected by 1- and 2-D zymography in a polyacrylamide gel containing gelatin as substrate. Proteolytic activity was observed over a wide range of molecular masses equal to, or higher than, 45 kDa. To identify the peptidases, the extracellular proteins were digested with trypsin and analyzed by LC and MS. Seventeen peptides showing identity or similarity to predicted plant aspartic, cysteine, and serine peptidases have been identified. The extracellular localization of a cysteine peptidase aleurain homolog was also shown.


Dietary inference from upper and lower molar morphology in platyrrhine primates.
The correlation between diet and dental topography is of importance to paleontologists seeking to diagnose ecological adaptations in extinct taxa. Although the subject is well represented in the literature, few studies directly compare methods or evaluate dietary signals conveyed by both upper and lower molars. Here, we address this gap in our knowledge by comparing the efficacy of three measures of functional morphology for classifying an ecologically diverse sample of thirteen medium- to large-bodied platyrrhines by diet category (e.g., folivore, frugivore, hard object feeder). We used Shearing Quotient (SQ), an index derived from linear measurements of molar cutting edges and two indices of crown surface topography, Occlusal Relief (OR) and Relief Index (RFI). Using SQ, OR, and RFI, individuals were then classified by dietary category using Discriminate Function Analysis. Both upper and lower molar variables produce high classification rates in assigning individuals to diet categories, but lower molars are consistently more successful. SQs yield the highest classification rates. RFI and OR generally perform above chance. Upper molar RFI has a success rate below the level of chance. Adding molar length enhances the discriminatory power for all variables. We conclude that upper molar SQs are useful for dietary reconstruction, especially when combined with body size information. Additionally, we find that among our sample of platyrrhines, SQ remains the strongest predictor of diet, while RFI is less useful at signaling dietary differences in absence of body size information. The study demonstrates new ways for inferring the diets of extinct platyrrhine primates when both upper and lower molars are available, or, for taxa known only from upper molars. The techniques are useful in reconstructing diet in stem representatives of anthropoid clade, who share key aspects of molar morphology with extant platyrrhines.


Accuracy in clinical chemistry - who will kiss Sleeping Beauty awake?
Triggered by recent criticism from parties outside the clinical chemistry community on poor analytical accuracy of measurement procedures used for evaluating the calcium-parathyroid hormone-vitamin D axis, I argue, in this opinion paper, strongly in favor of prioritizing the establishment of accuracy. I make a proposal on how the clinical chemistry profession could tackle the challenges focused at the conceptual, technical, and organizational level. The profession should "rehearse" the basic concepts of measurement, because they need to be understood before one can look for pragmatic solutions when a purist's approach cannot be realized in a foreseeable time. This is illustrated for the measurement of thyroid stimulating hormone (TSH). To solve problems encountered at the technical level of establishing reference measurement systems, in particular when this is not possible according to the point of view of purism, the profession should have the courage to agree on pragmatic solutions, without neglecting, however, the technical progress. This is exemplified by way of a solution for measurement of FT4 in serum water and TSH. Because the technical question is also inseparably connected to the specification of the analytical quality required for measurements, I propose that the profession sets realistic specifications for calibration tolerance, limits for batch acceptance, linearity, etc. Last but not least, I call upon organizing and implementing the accuracy process with utmost care, i.e., in a concerted action with all parties involved in patient care. The driving force towards accuracy should come from the test developers, while the lead should be taken by the clinical chemistry community, itself being guided by the clinical professions.