Peroxisome proliferators do not increase DNA synthesis in purified rat hepatocytes.
There have been numerous reports that chemicals which induce peroxisomes in rodent liver increase DNA synthesis in isolated hepatic parenchymal cells, but not as well in vitro as in vivo. It is also known that tumour necrosis factor alpha (TNFalpha) is mitogenic in isolated hepatocytes. Since Kupffer cells are a major source of TNFalpha in the liver and have recently been shown to be activated by peroxisome proliferators, the possibility exists that the effect of peroxisome proliferators on DNA synthesis in parenchymal cells is via Kupffer cell contamination of isolated hepatocyte preparations. The purpose of this study was to evaluate this hypothesis by studying the effect of model peroxisome proliferators on purified hepatocyte preparations. Hepatocytes were prepared from rat liver by standard calcium-free and collagenase perfusion. Subsequently, cells were centrifuged through Percoll to remove contaminating non-parenchymal cells. Cells were at least 99.9% pure as assessed by cell counting using specific markers for hepatocytes (resorufin O-glucoside) and Kupffer cells (FITC-labelled latex beads). Hepatocytes were cultured in Williams medium + 10% fetal bovine serum for 24 h followed by culture for 48 h in Williams medium plus or minus drug or mitogen additions. Under these conditions epidermal growth factor stimulated DNA synthesis assessed by incorporation of [3H]thymidine approximately 5-fold over control levels. The peroxisome proliferators WY,14-643 and nafenopin, however, had no effect on DNA synthesis, although they did increase acyl-CoA oxidase as expected. In contrast, TNFalpha increased cell proliferation nearly 10-fold in purified hepatocytes, an effect nearly doubled by WY-14,643. Further, when conditioned medium from purified Kupffer cells incubated with WY-14,643 was added to pure hepatocytes, DNA synthesis was increased over 2-fold in a time-dependent manner. Collectively, these data support the hypothesis that peroxisome proliferators do not influence DNA synthesis in isolated hepatocytes per se. Rather, they stimulate cytokine production by Kupffer cells which in turn increases DNA synthesis in parenchymal cells. An increase in mitogenic cytokine production by Kupffer cells is necessary for stimulation of DNA synthesis in purified rat parenchymal cells.


Dynamical flexible inference of nonlinear latent factors and structures in neural population activity.
Modelling the spatiotemporal dynamics in the activity of neural populations while also enabling their flexible inference is hindered by the complexity and noisiness of neural observations. Here we show that the lower-dimensional nonlinear latent factors and latent structures can be computationally modelled in a manner that allows for flexible inference causally, non-causally and in the presence of missing neural observations. To enable flexible inference, we developed a neural network that separates the model into jointly trained manifold and dynamic latent factors such that nonlinearity is captured through the manifold factors and the dynamics can be modelled in tractable linear form on this nonlinear manifold. We show that the model, which we named 'DFINE' (for 'dynamical flexible inference for nonlinear embeddings') achieves flexible inference in simulations of nonlinear dynamics and across neural datasets representing a diversity of brain regions and behaviours. Compared with earlier neural-network models, DFINE enables flexible inference, better predicts neural activity and behaviour, and better captures the latent neural manifold structure. DFINE may advance the development of neurotechnology and investigations in neuroscience.


The therapeutic pyramid: a common factors synthesis of techniques, alliance, and way of being.
Common factors in therapy such as the therapeutic alliance and client motivation have been found to account for more change than therapy models. But common factors have been critiqued as only lists of variables that provide little practical guidance. Some researchers have demonstrated that certain common elements (e.g., the therapeutic alliance) account for more variance than others (e.g., techniques), suggesting that some factors should be emphasized over others. Such findings suggest the need for alternatives to model-based therapy, with one alternative being meta-models, or "models of models," that focus on how therapeutic factors interact with each other to produce change. The purpose of this article is to propose a meta-model describing the relationship between two specific common factors-the therapeutic alliance and interventions. We also propose a new factor-a therapist's way of being-that we believe is foundational to effective therapy. The model is proposed in pyramid format, with techniques on top, the therapeutic alliance in the middle, and therapist way of being as the foundation. The hierarchical relationships between these three concepts are discussed, along with implications for training, research, and therapy.


Connectivity percolation of polydisperse anisotropic nanofillers.
We present a generalized connectedness percolation theory reduced to a compact form for a large class of anisotropic particle mixtures with variable degrees of connectivity. Even though allowing for an infinite number of components, we derive a compact yet exact expression for the mean cluster size of connected particles. We apply our theory to rodlike particles taken as a model for carbon nanotubes and find that the percolation threshold is sensitive to polydispersity in length, diameter, and the level of connectivity, which may explain large variations in the experimental values for the electrical percolation threshold in carbon-nanotube composites. The calculated connectedness percolation threshold depends only on a few moments of the full distribution function. If the distribution function factorizes, then the percolation threshold is raised by the presence of thicker rods, whereas it is lowered by any length polydispersity relative to the one with the same average length and diameter. We show that for a given average length, a length distribution that is strongly skewed to shorter lengths produces the lowest threshold relative to the equivalent monodisperse one. However, if the lengths and diameters of the particles are linearly correlated, polydispersity raises the percolation threshold and more so for a more skewed distribution toward smaller lengths. The effect of connectivity polydispersity is studied by considering nonadditive mixtures of conductive and insulating particles, and we present tentative predictions for the percolation threshold of graphene sheets modeled as perfectly rigid, disklike particles.


Pre-conception counselling, birth weight, and congenital abnormalities in established and gestational diabetic pregnancy.
Retrospective analysis of the case notes of 91 patients attending our combined diabetic/antenatal clinic during 1983-1985 confirmed the reported advantages of pre-conception counselling in established diabetics. 70 of the subjects, however, had glucose intolerance diagnosed during pregnancy and their babies had higher corrected birth weight than established diabetics (3,474 +/- 539 v 3,199 +/- 658 g, p less than 0.025). Caesarian section rates were also increased. Six (9%) babies had congenital abnormalities and their mothers had significantly higher initial HbA1 than the rest, although HbA1 was not a good diagnostic test for glucose intolerance. The management, and even definition, of gestational diabetes is still controversial. Our data suggests that subjects with any degree of glucose intolerance in pregnancy should be managed as carefully as established diabetics and preconception counselling for high risk groups may be beneficial.


Queen and king recognition in the subterranean termite, Reticulitermes flavipes: Evidence for royal recognition pheromones.
Royal recognition is a central feature of insect societies, allowing them to maintain the reproductive division of labor and regulate colony demography. Queen recognition has been broadly demonstrated and queen recognition pheromones have been identified in social hymenopterans, and in one termite species. Here we describe behaviors that are elicited in workers and soldiers by neotenic queens and kings of the subterranean termite, Reticulitermes flavipes, and demonstrate the chemical basis for the behavior. Workers and soldiers readily perform a lateral or longitudinal shaking behavior upon antennal contact with queens and kings. When royal cuticular chemicals are transferred to live workers or inert glass dummies, they elicit antennation and shaking in a dose-dependent manner. The striking response to reproductives and their cuticular extracts suggests that royal-specific cuticular compounds act as recognition pheromones and that shaking behavior is a clear and measurable queen and king recognition response in this termite species.


The role of feeding rhythm, adrenal hormones and neuronal inputs in synchronizing daily clock gene rhythms in the liver.
The master clock in the hypothalamic suprachiasmatic nucleus (SCN) is assumed to distribute rhythmic information to the periphery via neural, humoral and/or behavioral connections. Until now, feeding, corticosterone and neural inputs are considered important signals for synchronizing daily rhythms in the liver. In this study, we investigated the necessity of neural inputs as well as of the feeding and adrenal hormone rhythms for maintaining daily hepatic clock gene rhythms. Clock genes kept their daily rhythm when only one of these three signals was disrupted, or when we disrupted hepatic neuronal inputs together with the adrenal hormone rhythm or with the daily feeding rhythm. However, all clock genes studied lost their daily expression rhythm after simultaneous disruption of the feeding and adrenal hormone rhythm. These data indicate that either a daily rhythm of feeding or adrenal hormones should be present to synchronize clock gene rhythms in the liver with the SCN.


Therapeutic cancer vaccines: advancements, challenges, and prospects.
With the development and regulatory approval of immune checkpoint inhibitors and adoptive cell therapies, cancer immunotherapy has undergone a profound transformation over the past decades. Recently, therapeutic cancer vaccines have shown promise by eliciting de novo T cell responses targeting tumor antigens, including tumor-associated antigens and tumor-specific antigens. The objective was to amplify and diversify the intrinsic repertoire of tumor-specific T cells. However, the complete realization of these capabilities remains an ongoing pursuit. Therefore, we provide an overview of the current landscape of cancer vaccines in this review. The range of antigen selection, antigen delivery systems development the strategic nuances underlying effective antigen presentation have pioneered cancer vaccine design. Furthermore, this review addresses the current status of clinical trials and discusses their strategies, focusing on tumor-specific immunogenicity and anti-tumor efficacy assessment. However, current clinical attempts toward developing cancer vaccines have not yielded breakthrough clinical outcomes due to significant challenges, including tumor immune microenvironment suppression, optimal candidate identification, immune response evaluation, and vaccine manufacturing acceleration. Therefore, the field is poised to overcome hurdles and improve patient outcomes in the future by acknowledging these clinical complexities and persistently striving to surmount inherent constraints.


[III Working Meeting SENPE-Baxter: complementary parenteral nutrition in the critically ill patient].
In the setting of a multidisciplinary debate, and after reviewing the available evidence as well as the experience from experts, the indications and management guidelines for Complementary Parenteral Nutrition (CPN) in the critically ill patient are established. The conclusion refers to the importance of its indication in all the cases where enteral nutrition (EN) is insufficient to cover at least 60% of the caloric-protein target. At least 80% of the patient's caloric requirements should be covered with EN and CPN, with the recommendation of targeting 100% of the demands.


Improved preservation of residual beta cell function by atorvastatin in patients with recent onset type 1 diabetes and high CRP levels (DIATOR trial).
A recent randomized placebo-controlled trial of the effect of atorvastatin treatment on the progression of newly diagnosed type 1 diabetes suggested a slower decline of residual beta cell function with statin treatment. Aim of this secondary analysis was to identify patient subgroups which differ in the decline of beta cell function during treatment with atorvastatin. The randomized placebo-controlled Diabetes and Atorvastatin (DIATOR) Trial included 89 patients with newly diagnosed type 1 diabetes and detectable islet autoantibodies (mean age 30 years, 40% females), in 12 centers in Germany. Patients received placebo or 80 mg/d atorvastatin for 18 months. As primary outcome stimulated serum C-peptide levels were determined 90 min after a standardized liquid mixed meal. For this secondary analysis patients were stratified by single baseline characteristics which were considered to possibly be modified by atorvastatin treatment. Subgroups defined by age, sex or by baseline metabolic parameters like body mass index (BMI), total serum cholesterol or fasting C-peptide did not differ in C-peptide outcome after atorvastatin treatment. However, the subgroup defined by high (above median) baseline C-reactive protein (CRP) concentrations exhibited higher stimulated C-peptide secretion after statin treatment (p = 0.044). Individual baseline CRP levels correlated with C-peptide outcome in the statin group (r(2) = 0.3079, p<0.004). The subgroup with baseline CRP concentrations above median differed from the corresponding subgroup with lower CRP levels by higher median values of BMI, IL-6, IL-1RA, sICAM-1 and E-selectin. Atorvastatin treatment may be effective in slowing the decline of beta cell function in a patient subgroup defined by above median levels of CRP and other inflammation associated immune mediators. ClinicalTrials.gov NCT00974740.


Predicting amyloid-PET status in a memory clinic: The role of the novel antero-posterior index and visual rating scales.
Visual rating scales are increasingly utilized in clinical practice to assess atrophy in crucial brain regions among patients with cognitive disorders. However, their capacity to predict Alzheimer's disease (AD)-related pathology remains unexplored, particularly within a heterogeneous memory clinic population. This study aims to assess the accuracy of a novel visual rating assessment, the antero-posterior index (API) scale, in predicting amyloid-PET status. Furthermore, the study seeks to determine the optimal cohort-based cutoffs for the medial temporal atrophy (MTA) and parietal atrophy (PA) scales and to integrate the main visual rating scores into a predictive model. We conducted a retrospective analysis of brain MRI and high-resolution TC scans from 153 patients with cognitive disorders who had undergone amyloid-PET assessments due to suspected AD pathology in a real-world memory clinic setting. The API scale (cutoff ≥1) exhibited the highest accuracy (AUC = 0.721) among the visual rating scales. The combination of the cohort-based MTA and PA threshold with the API yielded favorable accuracy (AUC = 0.787). Analyzing a cohort of MCI/Mild dementia patients below 75 years of age, the API scale and the predictive model improved their accuracy (AUC = 0.741 and 0.813, respectively), achieving excellent results in the early-onset population (AUC = 0.857 and 0.949, respectively). Our study emphasizes the significance of visual rating scales in predicting amyloid-PET positivity within a real-world memory clinic. Implementing the novel API scale, alongside our cohort-based MTA and PA thresholds, has the potential to substantially enhance diagnostic accuracy.


Successful use of a soya-maize mixture in the treatment of kwashiorkor.
Forty-eight children aged 5 years or less admitted consecutively with a clinical diagnosis of kwashiorkor were randomly allocated to two groups. One group was treated with milk while the other group was fed soya-maize porridge; both groups received the same supportive treatment. The recovery rate in both groups was comparable. Protein intake and the rate of rise in serum albumin and transferrin concentrations were greater in the milk-fed group. The incidence of diarrhoea was significantly less in the children fed soya-maize. Soya-maize porridge is recommended as an effective and inexpensive treatment for kwashiorkor.


Methods to identify standard data elements in clinical and public health forms.
The fragmentation of clinical and public health systems results in divergent information collection practices, presenting challenges to standardization and EHR certification efforts. Data forms employed in public health jurisdictions nationwide reflect these differences in patient treatment, monitoring and evaluation, and follow-up, presenting challenges for data integration. To study these variations, we surveyed tuberculosis contact investigation forms from all fifty states, three municipalities and two countries. We apply statistics and cluster analysis to analyze the divergent content of contact investigation forms with the goal of characterizing normative practices and identifying a common core of data fields. We found widespread variation in data elements between states in the study, with the "Name" field being the only ubiquitous data element. Our method reveals distinct groupings of data fields employed in certain regions, allowing the simultaneous identification of core standard data fields as well as variations in practice.


Proteins of the newt oocyte nucleus: analysis of the nonhistone proteins from lampbrush chromosomes, nucleoli and nuclear sap.
An electrophoretic analysis has been carried out on the total protein of lampbrush chromosomes, nucleoli and nuclear sap, obtained from newt oocyte nuclei. In each case, distinctive and heterogeneous banding patterns are observed. The absence of detectable quantities of histones in occyte chromatin is noted. In the case of the lampbrush chromosome preparation, it is concluded that all protein species are derived from the ribonucleoprotein matrix of the lateral loops.


Resistance trends of the Bacteroides fragilis group over a 10-year period, 1997 to 2006, in Madrid, Spain.
The changes in susceptibilities of Bacteroides fragilis group strains isolated in our hospital from 1997 to 2006 were studied. A total of 1,343 clinical strains were included. The study showed differences in the resistance rates in the different species of the group. Increasing resistance to clindamycin and moxifloxacin was observed. Susceptibility to imipenem, piperacillin-tazobactam, and metronidazole remained unchanged.


Humoral Immune Response to SARS-CoV-2.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serology tests are clinically useful to document prior SARS-CoV-2 infections. Data are urgently needed to select assays with optimal sensitivity at acceptable specificity for antibody detection. A comparative evaluation was performed of 7 commercial SARS-CoV-2 serology assays on 171 sera from 135 subjects with polymerase chain reaction-confirmed SARS-CoV-2 infection (71 hospitalized patients and 64 paucisymptomatic individuals). Kinetics of IgA/IgM/IgG seroconversion to viral N and S protein epitopes were studied from 0 to 54 days after onset of symptoms. Cross-reactivity was verified on 57 prepandemic samples. Wantai SARS-COV-2 Ab ELISA and Orient Gene COVID-19 IgG/IgM Rapid Test showed superior overall sensitivity for detection of SARS-CoV-2 antibodies. Elecsys Anti-SARS-CoV-2 assay and EUROIMMUN Anti-SARS-CoV-2 combined IgG/IgA showed acceptable sensitivity (>95%) vs the consensus result of all assays from 10 days post onset of symptoms. Wantai SARS-COV-2 Ab ELISA, Elecsys Anti-SARS-CoV-2 assay, and Innovita 2019-nCoV Ab rapid test showed least cross-reactivity, resulting in an optimal analytical specificity greater than 98%. Wantai SARS-COV-2 Ab ELISA and Elecsys Anti-SARS-CoV-2 assays are suitable for sensitive and specific detection of SARS-CoV-2 antibodies from 10 days after onset of symptoms.


Genetically Engineering the Nervous System with CRISPR-Cas.
The multitude of neuronal subtypes and extensive interconnectivity of the mammalian brain presents a substantial challenge to those seeking to decipher its functions. While the molecular mechanisms of several neuronal functions remain poorly characterized, advances in next-generation sequencing (NGS) and gene-editing technology have begun to close this gap. The clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein (CRISPR-Cas) system has emerged as a powerful genetic tool capable of manipulating the genome of essentially any organism and cell type. This technology has advanced our understanding of complex neurologic diseases by enabling the rapid generation of novel, disease-relevant in vitro and transgenic animal models. In this review, we discuss recent developments in the rapidly accelerating field of CRISPR-mediated genome engineering. We begin with an overview of the canonical function of the CRISPR platform, followed by a functional review of its many adaptations, with an emphasis on its applications for genetic interrogation of the normal and diseased nervous system. Additionally, we discuss limitations of the CRISPR editing system and suggest how future modifications to existing platforms may advance our understanding of the brain.


Memory-Enhancing Effects of Mangosteen Pericarp Water Extract through Antioxidative Neuroprotection and Anti-Apoptotic Action.
Mangosteen has long been utilized as a traditional medicine in Southeast Asia. Diverse extracts of mangosteen pericarp and its bioactive xanthones exhibit various bioactivities. However, the pharmacological potential of mangosteen pericarp water extract (MPW) has not been reported yet. This study used primary cultured rat cortical cells to investigate the effect of MPW on neurotoxicity. We found that MPW inhibited neurotoxicity and production of reactive oxygen species triggered by Aβ(25-35) or excitatory amino acids. MPW inhibited caspase 3 activation and DNA fragmentation in Aβ(25-35)- or N-methyl-D-aspartate-treated cells, suggesting an anti-apoptotic action. Additionally, MPW reduced lipid peroxidation and scavenged 1,1-diphenyl-2-picrylhydrazyl radicals, assuring its antioxidant property. Furthermore, MPW suppressed β-secretase and acetylcholinesterase activities. These findings prompted us to evaluate its effect on memory dysfunction in scopolamine-treated mice using Morris water maze test. Oral administration of MPW at the dosage of 50, 100, or 300 mg/kg for four days significantly decreased the latency time to find the platform and markedly increased the swimming time in the target quadrant. Taken together, our results suggest that MPW exerts memory-enhancing effect through antioxidative neuroprotection and anti-apoptotic action. Accordingly, MPW may have a potential to prevent or treat memory impairment associated with Alzheimer's disease.


Effect of small molecular crowders on dynamics of kinesin molecular motors.
Kinesin is a motor protein that can convert chemical energy of ATP hydrolysis into mechanical energy of moving processively on microtubules. Apart from the load and ATP concentration affecting the dynamics of the motor such as velocity, run length, dissociation rate, etc., the increase of solution viscosity by supplementing crowding agents of low molecular weight into the buffer can also affect the dynamics. Here, based on our proposed model for the chemomechanical coupling of the kinesin motor, a systematically theoretical study of the motor dynamics under the variation of the viscosity and load is presented. Both the load on the motor's stalk and that on one of the two heads are considered. The theoretical results provide a consistent explanation of the available contradictory experimental results, with some showing that increasing viscosity decreases sensitively the velocity whereas others showing that increasing viscosity has little effect on the velocity. The theoretical results reproduce quantitatively the puzzling experimental data showing that under different directions of the load on the stalk, increasing viscosity has very different effects on the change of run length or dissociation rate. The theoretical results predict that in both the pure and crowded buffers the dependence of the run length on the load acting one of the two heads has very different feature from that on the load acting on the stalk.


Crossed-gratings volume hologram: backward reflection with high angular and spectral selectivity.
A new type of reflective hologram with both high angular and spectral selectivity is suggested. With novel design of crossed gratings inside the volume hologram, unusual angular selectivity is achieved via coupling of four waves. Analytic solution with spectral and angular detuning from Bragg regime is derived. The compensation between these two detuning forms an interesting figure of saddle shape.


Integrating zebrafish toxicology and nanoscience for safer product development.
The design, manufacture and application of safer products and manufacturing processes have been important goals over the last decade and will advance in the future under the umbrella of "Green Chemistry". In this review, we focus on the burgeoning diversity of new engineered nanomaterials (ENMs) and the prescient need for a nanotoxicology paradigm that quickly identifies potentially hazardous nanochemistries. Advances in predictive toxicological modeling in the developing zebrafish offer the most immediate translation to human hazard that is practically achievable with high throughput approaches. Translation in a vertebrate model that is also a low cost alternative to rodents for hazard prediction has been a desirable but elusive testing paradigm. The utility of zebrafish, if applied early in the ENM discovery pipeline, could greatly enhance efforts toward greener and more efficient nanoscience. Early pipeline detection of human and environmental health impacts will quickly inform decisions in the design and production of safer commercial ENMs.


Elastic tape reduces dyspnea and improves health status in the short term in nonobese COPD males: A randomized controlled trial.
The elastic tape(ET) is a novel intervention that acutely improves exercise capacity in laboratory tests; however, its effect on a patient's daily life remains unknown. This randomized controlled trial evaluated the effects of ET on daily life physical activity(DLPA), dyspnea symptoms, health status, and health-related quality of life(HRQoL) in individuals with COPD. Fifty males with moderate to very severe COPD were randomly assigned to an intervention group (ETG., n = 25), receiving ET on the chest wall and abdomen, or a control group(CG, n = 25). The intervention was for 14 days. DLPA (accelerometry; steps per day, and sedentary time), dyspnea symptoms (transition dyspnea index, TDI; and modified Medical Research Council, mMRC), health status (COPD assessment test, CAT), and health-related quality of life (HRQoL, CRQ) were evaluated at baseline and on Day 21 after the intervention. No change in the DLPA was observed in between-group comparison. GC presented a reduction in step counts after 21days(-707,p < 0.05) while ETG. maintained(-114,p > 0.94). However, ET reduced dyspnea symptoms in all TDI domains(functional, task, and effort) and on the mMRC scale after 14 days compared with CG(p < 0.01). Also, the ETG. improved CAT score compared to the CG, reaching minimal clinical important difference(MCID)(-4.4 score, p < 0.01). The ETG. also improved in most CRQ domains reaching MCID after 21 days. ET does not modify DLPA but reduces dyspnea and improves health status and HRQoL in nonobese males with moderate to very severe COPD in the short term. This novel and low-cost intervention improves COPD symptoms.


Change in adult health following medical priority rehousing: a longitudinal study.
Over 90 per cent of local housing authorities in England allocate medical priority for rehousing (MPR) to applicants with medical or care needs but very few studies have been undertaken to investigate the health effects of this practice. This longitudinal study compares the change in health status of adult applicants for MPR who were rehoused with applicants who were not rehoused. A total of 566 households applying for MPR were interviewed before any rehousing, and of these 253 households were re-interviewed between 9 and 12 months later. Data from initial and follow-up interviews were analysed for 227 adults, of whom 104 were rehoused. The rehoused and not rehoused groups were not significantly different in terms of health status, gender, education, income or housing conditions, but participants who were not rehoused were more likely to report mobility problems and to be aged over 50. Health data were collected by interview using the Short Form 36 (SF-36) questionnaire. Questions were also asked about housing conditions and the local neighbourhood, instrumental activities of daily living (IADL) and health-related behaviour. The health status of adult applicants for MPR was very poor. Those who were not rehoused experienced a slight improvement in five dimensions of the SF-36 whereas those who were rehoused experienced much larger improvements in six dimensions. For those who were rehoused, significant net improvements occurred in reports of tiredness, feeling depressed, sleeplessness, use of prescribed medication, use of medical services and problems with IADL. No changes occurred in reports of respiratory problems, longstanding illness or disability, use of antidepressants, sleeping pills or tranquillizers, smoking or social support. MPR was associated with improvements in mental health status and mobility, and among respondents aged 50 years or under with a reduced use of prescribed medication and medical services. Whereas most applicants applied for MPR because of mobility problems, they were less likely than other applicants to be rehoused. The health improvements that appeared to occur should be qualified by the extent of unmet need for appropriately adapted housing and the high level of ill-health that persisted even among adults who were rehoused.


Iodine determination in animal feed by inductively coupled plasma mass spectrometry - results of a collaborative study.
A collaborative study was conducted in order to fully validate the performance characteristics and to evaluate the suitability of a method for determination of iodine in animal feed. The method consists of an alkaline extraction in tetramethylammonium hydroxide (TMAH) solution followed by the determination of iodine by inductively coupled plasma-mass spectrometry (ICP-MS). The method was validated for different types of feed and feed materials with a broad concentration range of 0.65-622 mg I/kg. Good agreement was found between the overall mean mass fraction values from the collaborative trial (13.8 ± 1.3 mg I/kg and 0.657 ± 0.228 mg I/kg) and the values previously determined in proficiency tests for two of the test materials (12.65 ± 2.47 mg I/kg and 0.72 ± 0.22 mg I/kg) indicating satisfactory accuracy of the method. Reproducibility standard deviations were between 7.85% and 34.65% and the HorRat values were under the acceptable limit of 2 so the between-laboratory precision was considered acceptable. Based on the statistical evaluation of the results it was concluded that the method is suitable for its intended purpose; it has been accepted as European Standard EN17050:2017 by the European Committee for Standardisation (CEN).


Iron chelation by cranberry juice and its impact on Escherichia coli growth.
The various health benefits of Vaccinium macrocarpon (cranberry) are well documented and have been attributed mainly to its antioxidant capacity and anti-adhesive activity. Several different mechanisms have been proposed to explain the possible role of cranberries, cranberry juice, and cranberry extracts in inhibiting bacterial growth. These mechanisms of action (i.e., inhibition of the microbial growth) have not been thoroughly studied. Here, we took advantage of current advances in microarray technology and used GeneChip® Escherichia coli genome 2.0 arrays to gain insight into the molecular mechanisms involved in the impact of cranberry juice on the properties of E. coli growth. The inclusion of cranberry juice in bacterial growth media was found to significantly impact the doubling time of E. coli. The gene expression results revealed altered expression of genes associated with iron transport and essential metabolic enzymes as well as with adenosine triphosphate (ATP) synthesis and fumarate hydratase in these cultures. The altered expression of genes associated with iron transport was consistent with the strong iron chelating capability of proanthocyanidins, a major constituent of cranberry juice. The iron depletion effect was confirmed by adding exogenous iron to the growth media. This addition partially reversed the inhibitory effect on bacterial growth observed in the presence of cranberry juice/extracts.


Complexation of procainamide with hydroxide-containing compounds.
The complexation of procainamide with hydroxide-containing compounds, ethanol, fructose, glucose, glycerin, lactose, maltose, propylene glycol, sorbitol, and sucrose, have been studied. Procainamide formed a complex with glucose, lactose, and maltose, all of which contain a hemiacetal group, whereas fructose and sucrose do not. The percent of complex formed was dependent on the pH of the solution, with an optimum range of approximately 4-5.2. As with glucose, the percent of complex formed was directly related to the concentration of lactose in the solution. In dry mixtures, procainamide did not form a complex with glucose or lactose. The complex formed with lactose or maltose could be completely reversed by adding hydrochloric acid. A similar observation with glucose was reported earlier. In the optimum pH range, equilibrium was established in approximately 24 hr, and the process of complexation followed the equation for reversible reactions.


Tumor suppressor Hippo/MST1 kinase mediates chemotaxis by regulating spreading and adhesion.
Chemotaxis depends on a network of parallel pathways that coordinate cytoskeletal events to bias cell movement along a chemoattractant gradient. Using a forward genetic screen in Dictyostelium discoideum, we identified the Ste20 kinase KrsB, a homolog of tumor suppressors Hippo and MST1/2, as a negative regulator of cell spreading and substrate attachment. The excessive adhesion of krsB(-) cells reduced directional movement and prolonged the streaming phase of multicellular aggregation. These phenotypes depended on an intact kinase domain and phosphorylation of a conserved threonine (T176) within the activation loop. Chemoattractants triggered a rapid, transient autophosphorylation of T176 in a heterotrimeric G protein-dependent and PI3K- and TorC2-independent manner. The active phosphorylated form of KrsB acts to decrease adhesion to the substrate. Taken together these studies suggest that cycling between active and inactive forms of KrsB may provide the dynamic regulation of cell adhesion needed for proper cell migration and chemotaxis. KrsB interacts genetically with another D. discoideum Hippo/MST homolog, KrsA, but the two genes are not functionally redundant. These studies show that Hippo/MST proteins, like the tumor suppressor PTEN and oncogenes Ras and PI3K, play a key role in cell morphological events in addition to their role in regulating cell growth.


MR of cerebellar cortical dysplasia.
MR imaging findings are described in four patients with cerebellar cortical dysplasia. Typically, cerebellar disorganized folia were seen as an irregular bumpy gray-white matter interface. In addition, cystlike cortical abnormalities were observed in two patients and associated supratentorial developmental abnormalities were seen in three patients. To our knowledge, cerebellar cortical dysplasia without supratentorial abnormalities, as seen in one patient, has not been reported before. We suggest that cerebellar cortical dysplasia represents a spectrum of abnormalities ranging from mild to extensive in severity.


Symmetry Breaking and Error Correction in Open Quantum Systems.
Symmetry-breaking transitions are a well-understood phenomenon of closed quantum systems in quantum optics, condensed matter, and high energy physics. However, symmetry breaking in open systems is less thoroughly understood, in part due to the richer steady-state and symmetry structure that such systems possess. For the prototypical open system-a Lindbladian-a unitary symmetry can be imposed in a "weak" or a "strong" way. We characterize the possible Z_{n} symmetry-breaking transitions for both cases. In the case of Z_{2}, a weak-symmetry-broken phase guarantees at most a classical bit steady-state structure, while a strong-symmetry-broken phase admits a partially protected steady-state qubit. Viewing photonic cat qubits through the lens of strong-symmetry breaking, we show how to dynamically recover the logical information after any gap-preserving strong-symmetric error; such recovery becomes perfect exponentially quickly in the number of photons. Our study forges a connection between driven-dissipative phase transitions and error correction.


A plasma lipid signature predicts incident coronary artery disease.
Dyslipidemia is a hallmark of cardiovascular disease but is characterized by crude measurements of triglycerides, HDL- and LDL cholesterol. Lipidomics enables more detailed measurements of plasma lipids, which may help improve risk stratification and understand the pathophysiology of cardiovascular disease. Lipidomics was used to measure 184 lipids in plasma samples from the Malmö Diet and Cancer - Cardiovascular Cohort (N = 3865), taken at baseline examination. During an average follow-up time of 20.3 years, 536 participants developed coronary artery disease (CAD). Least absolute shrinkage and selection operator (LASSO) were applied to Cox proportional hazards models in order to identify plasma lipids that predict CAD. Eight plasma lipids improved prediction of future CAD on top of traditional cardiovascular risk factors. Principal component analysis of CAD-associated lipids revealed one principal component (PC2) that was associated with risk of future CAD (HR per SD increment =1.46, C·I = 1.35-1.48, P < 0.001). The risk increase for being in the highest quartile of PC2 (HR = 2.33, P < 0.001) was higher than being in the top quartile of systolic blood pressure. Addition of PC2 to traditional risk factors achieved an improvement (2%) in the area under the ROC-curve for CAD events occurring within 10 (P = 0.03), 15 (P = 0.003) and 20 (P = 0.001) years of follow-up respectively. A lipid pattern improve CAD prediction above traditional risk factors, highlighting that conventional lipid-measures insufficiently describe dyslipidemia that is present years before CAD. Identifying this hidden dyslipidemia may help motivate lifestyle and pharmacological interventions early enough to reach a substantial reduction in absolute risk.


Gestational Diabetes Mellitus: Predictive Value of Fetal Growth Measurements by Ultrasonography at 22-24 Weeks: A Retrospective Cohort Study of Medical Records.
Early intervention of gestational diabetes mellitus (GDM) is effective in reducing pregnancy disorders. Fetal growth, measured by routine ultrasound scan a few weeks earlier before GDM diagnosis, might be useful to identify women at high risk of GDM. In the study, generalized estimating equations were applied to examine the associations between ultrasonic indicators of abnormal fetal growth at 22-24 weeks and the risk of subsequent GDM diagnosis. Of 44,179 deliveries, 8324 (18.8%) were diagnosed with GDM between 24 and 28 weeks. At 22-24 weeks, fetal head circumference (HC) < 10th, fetal femur length (FL) < 10th, and estimated fetal weight (EFW) < 10th percentile were associated with 13% to 17% increased risks of maternal GDM diagnosis. Small fetal size appeared to be especially predictive of GDM among women who were parous. Fetal growth in the highest decile of abdominal circumference (AC), HC, FL and EFW was not associated with risk of subsequent GDM. The observed mean difference in fetal size across gestation by GDM was small; there was less than 1 mm difference for AC, HC, and FL, and less than 5 g for EFW before 24 weeks. Despite similar mean fetal growth among women who were and were not later diagnosed with GDM, mothers with fetuses in the lowest decile of HC, FL and EFW at 22-24 weeks tended to have higher risk of GDM.


Ultrasound Alleviates Lipopolysaccharide-Induced Colonic Damage.
Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the intestinal tract. There is currently no effective cure for IBD. The aim of this study was to evaluate the protective effect of low-intensity pulsed ultrasound (LIPUS) on lipopolysaccharide (LPS)-induced intestinal damage in a C57BL/6 mouse model. Colonic inflammation was induced by LPS injection (0.75 mg/kg, i.p.) for 7 days. A 1.0 MHz ultrasound transducer was used with a duty cycle of 5% and a repetition frequency of 1 Hz. LIPUS was applied to the abdominal region for 15 min/day from days 1 to 6 at both intensity of 0.5 W/cm2 or 1.0 W/cm2. Colonic samples were collected for macroscopic and westerm blotting analysis. First, the optimal dose of LPS for experiments was investigated. Our results demonstrated that LIPUS alleviates colonic damage by reducing colon shortening and increasing the levels of tight junction proteins such as Occludin and ZO-1. These findings show that abdominal LIPUS stimulation may be a novel therapeutic strategy for IBD through enhancement of tight junction protein levels and attenuation of colonic length.


[The regional medical demographic characteristics in the Russian Federation].
The analysis of the aspects of demographic situation in several regions of the Russian Federation is made to determine the divergence of levels of life expectancy from 1998 to 2005. The key role of the male premature mortality in this respect is demonstrated. The contradiction of the revealed trends with the logic of development of resources supply and volumes of provided medical care is explained.


Treatment of Hypercalcemia of Malignancy in Adults: An Endocrine Society Clinical Practice Guideline.
Hypercalcemia of malignancy (HCM) is the most common metabolic complication of malignancies, but its incidence may be declining due to potent chemotherapeutic agents. The high mortality associated with HCM has declined markedly due to the introduction of increasingly effective chemotherapeutic drugs. Despite the widespread availability of efficacious medications to treat HCM, evidence-based recommendations to manage this debilitating condition are lacking. To develop guidelines for the treatment of adults with HCM. A multidisciplinary panel of clinical experts, together with experts in systematic literature review, identified and prioritized 8 clinical questions related to the treatment of HCM in adult patients. The systematic reviews (SRs) queried electronic databases for studies relevant to the selected questions. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make recommendations. An independent SR was conducted in parallel to assess patients' and physicians' values and preferences, costs, resources needed, acceptability, feasibility, equity, and other domains relevant to the Evidence-to-Decision framework as well as to enable judgements and recommendations. The panel recommends (strong recommendation) in adults with HCM treatment with denosumab (Dmab) or an intravenous (IV) bisphosphonate (BP). The following recommendations were based on low certainty of the evidence. The panel suggests (conditional recommendation) (1) in adults with HCM, the use of Dmab rather than an IV BP; (2) in adults with severe HCM, a combination of calcitonin and an IV BP or Dmab therapy as initial treatment; and (3) in adults with refractory/recurrent HCM despite treatment with BP, the use of Dmab. The panel suggests (conditional recommendation) the addition of an IV BP or Dmab in adult patients with hypercalcemia due to tumors associated with high calcitriol levels who are already receiving glucocorticoid therapy but continue to have severe or symptomatic HCM. The panel suggests (conditional recommendation) in adult patients with hypercalcemia due to parathyroid carcinoma, treatment with either a calcimimetic or an antiresorptive (IV BP or Dmab). The panel judges the treatments as probably accessible and feasible for most recommendations but noted variability in costs, resources required, and their impact on equity. The panel's recommendations are based on currently available evidence considering the most important outcomes in HCM to patients and key stakeholders. Treatment of the primary malignancy is instrumental for controlling hypercalcemia and preventing its recurrence. The recommendations provide a framework for the medical management of adults with HCM and incorporate important decisional and contextual factors. The guidelines underscore current knowledge gaps that can be used to establish future research agendas.


A Pilot Study to Evaluate the Effects of Perfusion-decellularized Porcine Hepatic-derived Wound Matrix on Difficult-to-heal Diabetic Foot Ulcers.
The purpose of this prospective pilot study is to evaluate the effects of a novel perfusion-decellularized porcine hepatic-derived wound matrix (PDPHD-WM) on very difficult-to-heal diabetic foot ulcers (DFUs). For the intent of this study, a very difficult-to-heal DFU is one with a duration > 3 months despite using at least 1 advanced healing modality. Seven patients were enrolled in the study for a length of 14 weeks, including a 2-week run-in phase of standard-of-care therapy with saline gel and offloading in a CAM walker. Average wound duration was 25.5 months (range, 5-48 months). The PDPHD-WM was applied after the run-in phase and assessed weekly by the investigator. An average of 2.1 applications of the graft were performed (range, 1-4) over the study period. Three patients (42.9%) reached complete wound closure, 2 had partial wound closure (28.6%), 1 (14.3%) had worsening of his wound, and 1 (14.3%) was removed from the study due to osteomyelitis. Average percent wound closure over the 12-week treatment period was 56% for all patients and 77% when only those wounds that improved were included in the data. In addition, a bimodal population distribution was noted in this small series. Patients who demonstrated an early response continued on to closure or near-closure (4 patients), while those who showed little or no early response remained unclosed at the end of the study. These results suggest that PDPHD-WM may be an appropriate modality to treat difficult-to-heal DFUs, and a larger randomized placebo-controlled trial should be performed to investigate these findings. To the best of the authors' knowledge, this is the first collected data on using PDPHD-WM to treat DFUs.


Ganciclovir-mediated in vivo elimination of myeloid leukemic cells expressing the HSVtk gene induces HSVtk loss variants.
The in vivo elimination of suicide gene-expressing tumor cells with prodrug treatment can induce protective immunity against wild-type tumors. In this study, we determined the efficacy and safety of the in vivo elimination of HSVtk expressing cells with ganciclovir treatment of a bystander cell killing-insensitive leukemic cell line. The retroviral construct pLTk+NeoDeltaMo, containing the HSVtk gene and the NeoR gene in a bicistronic unit, was introduced into rat leukemic LT12 cells. LT12/Tk+N cells showed a 1000- to 10 000-fold increased sensitivity to ganciclovir in vitro. In vitro mixing experiments demonstrated that LT12 cells were not susceptible to bystander cell lysis by LT12/Tk+N-2 cells exposed to ganciclovir. Rats injected s.c. with cloned LT12/Tk+N-2 cells developed tumors reaching a diameter of 3-4 cm after 40 days. Rats treated with gan- ciclovir twice daily for 5 consecutive days starting at day 7 did not develop s.c. tumors. Large established s.c. LT12/Tk+N-2 tumors completely regressed after ganciclovir treatment. However, recurrences of s.c. tumors were observed that were no longer sensitive to ganciclovir treatment. In vitro analysis of aspirates from the recurrent tumors demonstrated loss of HSVtk expression. In vitro culture of LT12/Tk+N-2 cells in soft agar in the presence of ganciclovir indicated that the frequency with which HSVtk-loss variants occurred is approximately one per 104 cells. The in vivo occurrence of HSVtk-loss variants escaping ganciclovir-induced elimination may have important implications for vaccination protocols using HSVtk gene expressing tumor cells that are not susceptible to bystander cell killing.


Quantitative determination of trigonelline in mouse serum by means of hydrophilic interaction liquid chromatography-MS/MS analysis: Application to a pharmacokinetic study.
Trigonelline is a pyridine alkaloid found in fenugreek seeds and coffee beans. Most of the previous studies are concerned with the quantification of trigonelline along with other constituents in coffee herbs or beverages. Only a few have focused on its determination in animal or human tissues by applying different modes of HPLC with UV or MS detection. The aim of the study was to develop and validate a fast and simple method for trigonelline determination in serum by the use of hydrophilic interaction liquid chromatography (HILIC) with ESI-MS/MS detection. Separation of trigonelline was achieved on a Kinetex HILIC column operated at 35°C with acetonitrile-ammonium formate (10 mm, pH = 3) buffer mixture (55:45, v/v) as the mobile phase. The developed method was successfully applied to determine trigonelline concentration in mouse serum after intravenous administration of 10 mg/kg. The developed assay is sensitive (limit of detection = 1.5 ng/mL, limit of quantification = 5.0 ng/mL) and linear in a concentration range from 5.0 to 250.0 ng/mL. Sample preparation is limited to deproteinization, centrifugation and filtration. The application of the HILIC mode of chromatography with MS detection and selection of deuterated trigonelline as internal standard allowed a rapid and precise method of trigonelline quantification to be to developed.


Case report: an unusual case of gallbladder cancer in an automotive worker.
Mucinous adenocarcinoma of the gallbladder was found at autopsy in a 65-year-old male. The tumor was composed predominantly of signet ring cells, an uncommon histologic form. In addition, there was an atypical pattern of metastasis, with cancer involving not only the walls of the cystic duct, large and small bowels, peritoneum, abdominal nodes, and omentum, but also the kidneys, ureters, lungs, and heart. Although the patient lacked the common predisposing factors for gallbladder cancer, he did work in an industry with a significant relative risk for the development of this cancer.


NMR exchange broadening arising from specific low affinity protein self-association: analysis of nitrogen-15 nuclear relaxation for rat CD2 domain 1.
Nuclear spin relaxation monitored by heteronuclear NMR provides a useful method to probe the overall and internal molecular motion for biological macromolecules over a variety of time scales. Nitrogen-15 NMR relaxation parameters have been recorded for the N-terminal domain of the rat T-cell antigen CD2 (CD2d1) in a dilution series from 1.20 mM to 40 microM (pH 6.0, 25 degrees C). The data have been analysed within the framework of the model-free formalism of Lipari and Szabo to understand the molecular origin of severely enhanced transverse relaxation rates found for certain residues. These data revealed a strong dependence of the derived molecular correlation time tau c upon the CD2d1 protein concentration. Moreover, a number of amide NH resonances exhibited exchange broadening and chemical shifts both strongly dependent on protein concentration. These amide groups cluster on the major beta-sheet surface of CD2d1 that coincides with a major lattice contact in the X-ray structure of the intact ectodomain of rat CD2. The complete set of relaxation data fit well to an equilibrium monomer-dimer exchange model, yielding estimates of exchange rate constants (kON = 5000 M-1 s-1; kOFF = 7 s-1) and a dissociation constant (KD approximately 3-6 mM) that is consistent with the difficulty in detecting the weak interactions for this molecule by alternative biophysical methods. The self-association of CD2d1 is essentially invariant to changes in buffer composition and ionic strength and the associated relaxation phenomena cannot be explained as a result of neglecting anisotropic rotational diffusion in the analysis. These observations highlight the necessity to consider low affinity protein self-association interactions as a source of residue specific exchange phenomena in NMR spectra of macromolecular biomolecules, before the assignment of more elaborate intramolecular conformational mechanisms.


Ethics of Artificial Intelligence in Radiology: Summary of the Joint European and North American Multisociety Statement.
This is a condensed summary of an international multisociety statement on ethics of artificial intelligence (AI) in radiology produced by the ACR, European Society of Radiology, RSNA, Society for Imaging Informatics in Medicine, European Society of Medical Imaging Informatics, Canadian Association of Radiologists, and American Association of Physicists in Medicine. AI has great potential to increase efficiency and accuracy throughout radiology, but it also carries inherent pitfalls and biases. Widespread use of AI-based intelligent and autonomous systems in radiology can increase the risk of systemic errors with high consequence and highlights complex ethical and societal issues. Currently, there is little experience using AI for patient care in diverse clinical settings. Extensive research is needed to understand how to best deploy AI in clinical practice. This statement highlights our consensus that ethical use of AI in radiology should promote well-being, minimize harm, and ensure that the benefits and harms are distributed among stakeholders in a just manner. We believe AI should respect human rights and freedoms, including dignity and privacy. It should be designed for maximum transparency and dependability. Ultimate responsibility and accountability for AI remains with its human designers and operators for the foreseeable future. The radiology community should start now to develop codes of ethics and practice for AI that promote any use that helps patients and the common good and should block use of radiology data and algorithms for financial gain without those two attributes. This article is a simultaneous joint publication in Radiology, Journal of the American College of Radiology, Canadian Association of Radiologists Journal, and Insights into Imaging. Published under a CC BY-NC-ND 4.0 license. Online supplemental material is available for this article.


Flexibility in reaction time analysis: many roads to a false positive?
In the present article, we explore the influence of undisclosed flexibility in the analysis of reaction times (RTs). RTs entail some degrees of freedom of their own, due to their skewed distribution, the potential presence of outliers and the availability of different methods to deal with these issues. Moreover, these degrees of freedom are usually not considered part of the analysis itself, but preprocessing steps that are contingent on data. We analysed the impact of these degrees of freedom on the false-positive rate using simulations over real and simulated data. When several preprocessing methods are used in combination, the false-positive rate can easily rise to 17%. This figure becomes more concerning if we consider that more degrees of freedom are awaiting down the analysis pipeline, potentially making the final false-positive rate much higher.


Fetal Lymphatic Malformations: More Variable Than We Think?
Lymphatic malformations are benign lesions that result from abnormal development of the lymphatic and venous systems. These lesions may be detected during routine prenatal ultrasound screening, and typically demonstrate imaging findings of a multiseptate cystic lesion lacking solid components, vascularity, and calcifications. We report 73 cases of prenatally detected lymphatic malformations and describe greater variability in their prenatal sonographic appearance than previously reported, including purely cystic lesions and mixed cystic and solid lesions with calcifications. Appreciation of this increased variability is important in providing accurate prenatal diagnosis, counseling, and management.


Factors Associated With Discussions of Human Immunodeficiency Virus Pre-Exposure Prophylaxis in Men Who Have Sex With Men.
Background: Pre-exposure prophylaxis (PrEP) with emtricitabine/tenofovir disoproxil fumarate (Truvada) is highly effective at preventing human immunodeficiency virus (HIV) transmission in high-risk populations, including in men who have sex with men (MSM). In 2019, the US Preventive Services Task Force released an A recommendation to offer PrEP to persons at high risk of HIV acquisition. Despite the demonstrated efficacy of PrEP, areas with high HIV incidence, such as Louisiana, have historically had low PrEP prescription rates. The objective of this study was to determine the factors associated with whether providers in the Ochsner Health System (OHS) discussed PrEP with HIV-negative MSM patients. Methods: Investigators extracted electronic medical record data on all HIV-negative MSM patients who had at least one outpatient visit at OHS between July 1, 2012 and July 1, 2016 and manually reviewed a random sample of 115 charts. Results: Subjects were predominantly Caucasian (75.7%) with a mean age of 37.6 years. A PrEP discussion was documented for 34 (29.6%) patients. Multivariate modeling showed that having a PrEP discussion was associated with 3 factors: being assigned to a primary care provider known to specialize in MSM care (odds ratio [OR] 5.05, 95% confidence interval [CI] 1.81-14.10; P=0.002), having a documented history (positive or negative) of sexually transmitted infection vs no documentation (OR 5.41, 95% CI 1.80-16.23; P=0.003), and having documentation of condom use (consistent or inconsistent) vs no documentation (OR 3.32, 95% CI 1.27-8.74; P=0.015). Conclusion: Despite evidence that PrEP significantly reduces sexual transmission of HIV in MSM, PrEP discussions with MSM across OHS were undesirably low. Additional resources need to be aimed at increasing PrEP uptake and should focus on providing skills-based training and education in PrEP and MSM care to healthcare providers. With increased knowledge of and familiarity with PrEP prescribing guidelines, more providers will be better equipped to identify at-risk patients and to discuss prevention options such as PrEP.


Action Generation Adapted to Low-Level and High-Level Robot-Object Interaction States.
Our daily environments are complex, composed of objects with different features. These features can be categorized into low-level features, e.g., an object position or temperature, and high-level features resulting from a pre-processing of low-level features for decision purposes, e.g., a binary value saying if it is too hot to be grasped. Besides, our environments are dynamic, i.e., object states can change at any moment. Therefore, robots performing tasks in these environments must have the capacity to (i) identify the next action to execute based on the available low-level and high-level object states, and (ii) dynamically adapt their actions to state changes. We introduce a method named Interaction State-based Skill Learning (IS2L), which builds skills to solve tasks in realistic environments. A skill is a Bayesian Network that infers actions composed of a sequence of movements of the robot's end-effector, which locally adapt to spatio-temporal perturbations using a dynamical system. In the current paper, an external agent performs one or more kinesthetic demonstrations of an action generating a dataset of high-level and low-level states of the robot and the environment objects. First, the method transforms each interaction to represent (i) the relationship between the robot and the object and (ii) the next robot end-effector movement to perform at consecutive instants of time. Then, the skill is built, i.e., the Bayesian network is learned. While generating an action this skill relies on the robot and object states to infer the next movement to execute. This movement selection gets inspired by a type of predictive models for action selection usually called affordances. The main contribution of this paper is combining the main features of dynamical systems and affordances in a unique method to build skills that solve tasks in realistic scenarios. More precisely, combining the low-level movement generation of the dynamical systems, to adapt to local perturbations, with the next movement selection simultaneously based on high-level and low-level states. This contribution was assessed in three experiments in realistic environments using both high-level and low-level states. The built skills solved the respective tasks relying on both types of states, and adapting to external perturbations.


Redox-sensitive calcium/calmodulin-dependent protein kinase IIα in angiotensin II intra-neuronal signaling and hypertension.
Dysregulation of brain angiotensin II (AngII) signaling results in modulation of neuronal ion channel activity, an increase in neuronal firing, enhanced sympathoexcitation, and subsequently elevated blood pressure. Studies over the past two decades have shown that these AngII responses are mediated, in part, by reactive oxygen species (ROS). However, the redox-sensitive target(s) that are directly acted upon by these ROS to execute the AngII pathophysiological responses in neurons remain unclear. Calcium/calmodulin-dependent protein kinase II (CaMKII) is an AngII-activated intra-neuronal signaling protein, which has been suggested to be redox sensitive as overexpressing the antioxidant enzyme superoxide dismutase attenuates AngII-induced activation of CaMKII. Herein, we hypothesized that the neuronal isoform of CaMKII, CaMKII-alpha (CaMKIIα), is a redox-sensitive target of AngII, and that mutation of potentially redox-sensitive amino acids in CaMKIIα influences AngII-mediated intra-neuronal signaling and hypertension. Adenoviral vectors expressing wild-type mouse CaMKIIα (Ad.wtCaMKIIα) or mutant CaMKIIα (Ad.mutCaMKIIα) with C280A and M281V mutations were generated to overexpress either CaMKIIα isoform in mouse catecholaminergic cultured neurons (CATH.a) or in the brain subfornical organ (SFO) of hypertensive mice. Overexpressing wtCaMKIIα exacerbated AngII pathophysiological responses as observed by a potentiation of AngII-induced inhibition of voltage-gated K+ current, enhanced in vivo pressor response following intracerebroventricular injection of AngII, and sensitization to chronic peripheral infusion of AngII resulting in a more rapid increase in blood pressure. In contrast, expressing the mutant CaMKIIα in CATH.a neurons or the SFO failed to intensify these AngII responses. Taken together, these data identify neuronal CaMKIIα as a redox-sensitive signaling protein that contributes to AngII-induced neuronal activation and hypertension.


[Nitrogen sparing effect of fatty emulsions during parenteral feeding of white rats with thyrotoxicosis].
A study was made of the nitrogen-protective action of fat emulsions (intralipid and lipidine) in parenteral administration of caseine hydrolysate to 65 rats with thyrotoxicosis. When caseine hydrolysate was used in combination with fat emulsions and physiological metabolic regulators the level of free amino acids in the blood and tissues (the skeletal muscle, the heart and the liver) proved to decrease; the weight of the animals rose.


Real-time atomic scale imaging of nanostructural evolution in aluminum alloys.
We present a new approach to study the three-dimensional compositional and structural evolution of metal alloys during heat treatments such as commonly used for improving overall material properties. It relies on in situ heating in a high-resolution scanning transmission electron microscope (STEM). The approach is demonstrated using a commercial Al alloy AA2024 at 100-240 °C, showing in unparalleled detail where and how precipitates nucleate, grow, or dissolve. The observed size evolution of individual precipitates enables a separation between nucleation and growth phenomena, necessary for the development of refined growth models. We conclude that the in situ heating STEM approach opens a route to a much faster determination of the interplay between local compositions, heat treatments, microstructure, and mechanical properties of new alloys.


Implementation science in resource-poor countries and communities.
Implementation science in resource-poor countries and communities is arguably more important than implementation science in resource-rich settings, because resource poverty requires novel solutions to ensure that research results are translated into routine practice and benefit the largest possible number of people. We reviewed the role of resources in the extant implementation science frameworks and literature. We analyzed opportunities for implementation science in resource-poor countries and communities, as well as threats to the realization of these opportunities. Many of the frameworks that provide theoretical guidance for implementation science view resources as contextual factors that are important to (i) predict the feasibility of implementation of research results in routine practice, (ii) explain implementation success and failure, (iii) adapt novel evidence-based practices to local constraints, and (iv) design the implementation process to account for local constraints. Implementation science for resource-poor settings shifts this view from "resources as context" to "resources as primary research object." We find a growing body of implementation research aiming to discover and test novel approaches to generate resources for the delivery of evidence-based practice in routine care, including approaches to create higher-skilled health workers-through tele-education and telemedicine, freeing up higher-skilled health workers-through task-shifting and new technologies and models of care, and increasing laboratory capacity through new technologies and the availability of medicines through supply chain innovations. In contrast, only few studies have investigated approaches to change the behavior and utilization of healthcare resources in resource-poor settings. We identify three specific opportunities for implementation science in resource-poor settings. First, intervention and methods innovations thrive under constraints. Second, reverse innovation transferring novel approaches from resource-poor to research-rich settings will gain in importance. Third, policy makers in resource-poor countries tend to be open for close collaboration with scientists in implementation research projects aimed at informing national and local policy. Implementation science in resource-poor countries and communities offers important opportunities for future discoveries and reverse innovation. To harness this potential, funders need to strongly support research projects in resource-poor settings, as well as the training of the next generation of implementation scientists working on new ways to create healthcare resources where they lack most and to ensure that those resources are utilized to deliver care that is based on the latest research results.


Contribution of auditory cortex to sound localization in the monkey (Macaca mulatta).
Monkeys with lesions of auditory cortex were tested for their ability to localize the source of brief sounds. Although those deprived of primary auditory cortex bilaterally were able to indicate the direction of a sound with near-normal acuity, they were unable to locate its source. This dissociation of abilities suggest that the role of auditory cortex in sound localization is not so much sensory or perceptual as it is auditomotor or associative. Thus, sound localization joins loudness, pitch, and most other traditional attributes of sound as dimensions whose discrimination does not depend on auditory cortex. The question would now seem to turn to whether or not auditory cortex is necessary for any sensory discrimination whatever.


Sun exposure and melanoma prognostic factors.
Previous studies have reported an association between sun exposure and the increased survival of patients with cutaneous melanoma (CM). The present study analyzed the association between ultraviolet (UV) light exposure and various prognostic factors in the Italian Clinical National Melanoma Registry. Clinical and sociodemographic features were collected, as well as information concerning sunbed exposure and holidays with sun exposure. Analyses were performed to investigate the association between exposure to UV and melanoma prognostic factors. Between December 2010 and December 2013, information was obtained on 2,738 melanoma patients from 38 geographically representative Italian sites. A total of 49% of the patients were >55 years old, 51% were men, 50% lived in the north of Italy and 57% possessed a high level of education (at least high school). A total of 8 patients had a family history of melanoma and 56% had a fair phenotype (Fitzpatrick skin type I or II). Of the total patients, 29% had been diagnosed with melanoma by a dermatologist; 29% of patients presented with a very thick melanoma (Breslow thickness, >2 mm) and 25% with an ulcerated melanoma. In total, 1% of patients had distant metastases and 13% exhibited lymph node involvement. Holidays with sun exposure 5 years prior to CM diagnosis were significantly associated with positive prognostic factors, including lower Breslow thickness (P<0.001) and absence of ulceration (P=0.009), following multiple adjustments for factors such as sociodemographic status, speciality of doctor performing the diagnosis and season of diagnosis. Sunbed exposure and sun exposure during peak hours of sunlight were not significantly associated with Breslow thickness and ulceration. Holidays with sun exposure were associated with favorable CM prognostic factors, whereas no association was identified between sunbed use and sun exposure during peak hours of sunlight with favorable CM prognostic factors. However, the results of the present study do not prove a direct causal effect of sun exposure on melanoma prognosis, as additional confounding factors, including vitamin D serum levels, may have a role.


Incidence and determinants of high-sensitivity troponin and natriuretic peptides elevation at admission in hospitalized COVID-19 pneumonia patients.
Myocardial involvement in the course of coronavirus disease 2019 (COVID-19) pneumonia has been reported, though not fully characterized yet. The aim of the present study is to undertake a joint evaluation of hs-Troponin and natriuretic peptides (NP) in patients hospitalized for COVID-19 pneumonia. In this multicenter observational study, we analyzed data from n = 111 patients. Cardiac biomarkers subgroups were identified according to values beyond reference range. Increased hs-Troponin and NP were found in 38 and 56% of the cases, respectively. As compared to those with normal cardiac biomarkers, these patients were older, had higher prevalence of cardiovascular diseases (CVD) and had more severe COVID-19 pneumonia by higher CRP and D-dimer and lower PaO2/FIO2. Two-dimensional echocardiography performed in a subset of patients (n = 24) showed significantly reduced left ventricular ejection fraction in patients with elevated NP (p = 0.02), whereas right ventricular systolic function (tricuspid annular plane systolic excursion) was significantly reduced both in patients with high hs-Troponin and NP (p = 0.022 and p = 0.03, respectively). Both hs-Troponin and NP were higher in patients with in-hospital mortality (p = 0.001 and p = 0.002, respectively). On multivariable analysis, independent associations were found of hs-Troponin with age, PaO2/FIO2 and D-dimer (B = 0.419, p = 0.001; B = - 0.212, p = 0.013; and B = 0.179, p = 0.037, respectively) and of NP with age and previous CVD (B = 0.480, p < 0.001; and B = 0.253, p = 0.001, respectively). Myocardial involvement at admission is common in COVID-19 pneumonia. Independent associations of hs-Troponin with markers of disease severity and of NP with underlying CVD might point toward existing different mechanisms leading to their elevation in this setting.


[Functional radiographic anatomy of the terminal sphincter duct of the biliary pancreatic system].
The improvement of techniques of surgical operations on the bile ducts, especially on their terminal portion, as well as on the pancreas generates a need in deeper knowledge of the function of terminal sphincters of ducts--the general bile and main pancreatic ducts, and Oddi's sphincter that regulate the ingress of bile and pancreatic juice in the digestive tract lumen. This knowledge will make it possible to determine the most adequate variant of treatment, which is closest to the physiological one, in each particular case.


Affective Primacy vs. Cognitive Primacy: Dissolving the Debate.
When people see a snake, they are likely to activate both affective information (e.g., dangerous) and non-affective information about its ontological category (e.g., animal). According to the Affective Primacy Hypothesis, the affective information has priority, and its activation can precede identification of the ontological category of a stimulus. Alternatively, according to the Cognitive Primacy Hypothesis, perceivers must know what they are looking at before they can make an affective judgment about it. We propose that neither hypothesis holds at all times. Here we show that the relative speed with which affective and non-affective information gets activated by pictures and words depends upon the contexts in which stimuli are processed. Results illustrate that the question of whether affective information has processing priority over ontological information (or vice versa) is ill-posed. Rather than seeking to resolve the debate over Cognitive vs. Affective Primacy in favor of one hypothesis or the other, a more productive goal may be to determine the factors that cause affective information to have processing priority in some circumstances and ontological information in others. Our findings support a view of the mind according to which words and pictures activate different neurocognitive representations every time they are processed, the specifics of which are co-determined by the stimuli themselves and the contexts in which they occur.


Inference of seasonal and pandemic influenza transmission dynamics.
The inference of key infectious disease epidemiological parameters is critical for characterizing disease spread and devising prevention and containment measures. The recent emergence of surveillance records mined from big data such as health-related online queries and social media, as well as model inference methods, permits the development of new methodologies for more comprehensive estimation of these parameters. We use such data in conjunction with Bayesian inference methods to study the transmission dynamics of influenza. We simultaneously estimate key epidemiological parameters, including population susceptibility, the basic reproductive number, attack rate, and infectious period, for 115 cities during the 2003-2004 through 2012-2013 seasons, including the 2009 pandemic. These estimates discriminate key differences in the epidemiological characteristics of these outbreaks across 10 y, as well as spatial variations of influenza transmission dynamics among subpopulations in the United States. In addition, the inference methods appear to compensate for observational biases and underreporting inherent in the surveillance data.


Association between Sleep Disordered Breathing and Nighttime Driving Performance in Mild Cognitive Impairment.
The effect of sleep disordered breathing (SDB) on driving performance in older adults has not been extensively investigated, especially in those with mild cognitive impairment (MCI). The aim of this study was to examine the relationship between severity measures of SDB and a simulated driving task in older adults with and without MCI. Nineteen older adults (age ≥50) meeting criteria for MCI and 23 age-matched cognitively intact controls underwent neuropsychological assessment and a driving simulator task in the evening before a diagnostic sleep study. There were no differences in driving simulator performance or SDB severity between the two groups. In patients with MCI, a higher oxygen desaturation index (ODI) was associated with an increased number of crashes on the simulator task, as well as other driving parameters such as steering and speed deviation. Poorer driving performance was also associated with poorer executive functioning (set-shifting) but the relationship between ODI and crashes was independent of executive ability. While driving ability did not differ between older adults with and without MCI, oxygen saturation dips in MCI were related to worse driving performance. These results suggest that decreased brain integrity may render those with SDB particularly vulnerable to driving accidents. In older adults, both cognition and SDB need to be considered concurrently in relation to driving ability. (JINS, 2017, 23, 502-510).


A semantic framework to protect the privacy of electronic health records with non-numerical attributes.
Structured patient data like Electronic Health Records (EHRs) are a valuable source for clinical research. However, the sensitive nature of such information requires some anonymisation procedure to be applied before releasing the data to third parties. Several studies have shown that the removal of identifying attributes, like the Social Security Number, is not enough to obtain an anonymous data file, since unique combinations of other attributes as for example, rare diagnoses and personalised treatments, may lead to patient's identity disclosure. To tackle this problem, Statistical Disclosure Control (SDC) methods have been proposed to mask sensitive attributes while preserving, up to a certain degree, the utility of anonymised data. Most of these methods focus on continuous-scale numerical data. Considering that part of the clinical data found in EHRs is expressed with non-numerical attributes as for example, diagnoses, symptoms, procedures, etc., their application to EHRs produces far from optimal results. In this paper, we propose a general framework to enable the accurate application of SDC methods to non-numerical clinical data, with a focus on the preservation of semantics. To do so, we exploit structured medical knowledge bases like SNOMED CT to propose semantically-grounded operators to compare, aggregate and sort non-numerical terms. Our framework has been applied to several well-known SDC methods and evaluated using a real clinical dataset with non-numerical attributes. Results show that the exploitation of medical semantics produces anonymised datasets that better preserve the utility of EHRs.


Absence of an effect of terfenadine on guinea pig brain histamine H1-receptors in vivo determined by receptor binding techniques.
Alpha-[4-(1,1-Dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1- piperidinebutanol (terfenadine, RMI 9918, Triludan, Teldane, resp.) inhibition of the in vitro binding of [3H]mepyramine to histamine H1-receptors prepared from guinea pig brain and ileum was characterized under several experimental conditions. After an intraperitoneal injection of 5 mg/kg of either terfenadine or chlorpheniramine, brain and ileum were obtained to determine in vitro the binding of [3H]mepyramine to histamine H1-receptors. While the binding of ligand to receptors from the ileum of both terfenadine and chlorpheniramine treated animals was almost completely inhibited, the ligand binding to receptors from brains of chlorpheniramine treated but not terfenadine treated animals was affected. When terfenadine was added to receptor homogenates from guinea pig brain and ileum, it antagonized the binding of [3H]mepyramine to receptors from both tissues. The potency of terfenadine antagonism of ligand binding was similar to both ileal (IC50, 200 nmol/l) and brain (IC50, 300 nmol/l) receptors. The kinetics of in vitro antagonism by terfenadine of [3H]mepyramine binding to receptors is unique in that antagonism of ligand binding by terfenadine was enhanced by a longer incubation of the receptors with this drug and H1-receptor blockade by terfenadine could not be reversed by extensive washing of these receptors at 25 degrees C. These results show that terfenadine treatment does not result in sufficient levels in the brain to inhibit central histamine receptors at a dose which overwhelmingly inhibits histamine receptors in peripheral tissue. It is proposed that terfenadine slowly associates with the H1-receptor and forms a stable complex from which it dissociates quite slowly.


Interleukin-17 contributes to the pathogenesis of autoimmune hepatitis through inducing hepatic interleukin-6 expression.
T helper cells that produce IL-17 (Th17 cells) have recently been identified as the third distinct subset of effector T cells. Emerging data suggests that Th17 cells play an important role in the pathogenesis of many liver diseases by regulating innate immunity, adaptive immunity, and autoimmunity. In this study, we examine the role and mechanism of Th17 cells in the pathogenesis of autoimmune hepatitis (AIH). The serum levels of IL-17 and IL-23, as well as the frequency of IL-17+ cells in the liver, were significantly elevated in patients with AIH, compared to other chronic hepatitis and healthy controls. The hepatic expressions of IL-17, IL-23, ROR-γt, IL-6 and IL-1β in patients with AIH were also significantly increased and were associated with increased inflammation and fibrosis. IL-17 induces IL-6 expression via the MAPK signaling pathway in hepatocytes, which, in turn, may further stimulate Th17 cells and forms a positive feedback loop. In conclusion, Th17 cells are key effector T cells that regulate the pathogenesis of AIH, via induction of MAPK dependent hepatic IL-6 expression. Blocking the signaling pathway and interrupting the positive feedback loop are potential therapeutic targets for autoimmune hepatitis.


Surveillance for invasive Streptococcus pneumoniae disease among hospitalized children in Bangladesh: antimicrobial susceptibility and serotype distribution.
Vaccines offer the prospect of primary disease prevention of pneumococcal disease in childhood. For introduction of such vaccines in developing countries, information about disease epidemiology is necessary. We evaluated antimicrobial susceptibility and serotype distribution of invasive Streptococcus pneumoniae disease in children aged <5 years in a network of 7 hospitals in Bangladesh from May 2004 through May 2007. Of 17,969 blood cultures and 3765 cerebrospinal fluid cultures, 139 yielded S. pneumoniae isolates; 94 were from meningitis cases, 13 were from pneumonia cases, and 32 were from sepsis cases. Among the children with positive culture results, 73% were aged <12 months and 90% were aged <24 months. Complete resistance against penicillin, chloramphenicol, and cotrimoxazole was found in 0%, 6%, and 32% of isolates, respectively. Of the 37 serotypes observed, the predominant serotypes were 2 (17%), 1 (12%), 14 (7%), 5 (6%), 7F (6%), 45 (7%), and 12A (4%). Serotypes differed between meningitis cases and nonmeningitis cases, especially for serotype 2 (25% of meningitis cases vs. 0% of pneumonia cases; P < .001). The 7-, 10-, and 13-valent vaccines would cover 20% (95% confidence interval [CI], 13%-27%), 43% (95% CI, 35%-51%), and 50% (95% CI, 42%-58%) of these cases of invasive pneumococcal disease overall, with higher coverage of nonmeningitis cases, compared with meningitis cases (7-valent coverage, 23% vs. 18%; 10-valent coverage, 55% vs. 38%; 13-valent coverage, 66% vs. 42%). High levels of nonsusceptibility to cotrimoxazole and susceptibility to penicillin suggest that penicillin may be a drug of choice for treatment of invasive pneumococcal disease. Although serotype distribution is diverse, with changes over time and differences between syndromes observed, implementation of use of the currently available 10- or 13-valent vaccines would have a substantial impact on pneumococcal disease in Bangladesh.


Alterations in pp60c-src accompany differentiation of neurons from rat embryo striatum.
Cultured neurons from rat embryo striatum were found to contain two structurally distinct forms of pp60c-src. The 60-kilodalton (kDa) form appeared similar to pp60c-src from cultured rat fibroblasts or astrocytes. The 61-kDa form was specific to neurons and differed in the NH2-terminal 18 kDa of the molecule. In undifferentiated neurons the predominant phosphorylated species of pp60c-src was the fibroblast form. Upon differentiation, a second phosphorylated form of pp60c-src was detected. This form had two or more additional sites of serine phosphorylation within the NH2-terminal 18-kDa region of the molecule, one of which was Ser-12. The specific protein-tyrosine kinase activity of the total pp60c-src population increased 14-fold, as measured by autophosphorylation, or 7-fold, as measured by phosphorylation of an exogenous substrate, as striatal neurons differentiated. This elevation in protein kinase activity occurred without a detectable decrease in Tyr-527 phosphorylation or increase in Tyr-416 phosphorylation. Our results support the idea that the expression of the neuron-specific form of pp60c-src and the increase in specific protein kinase activity may be important for neuronal differentiation.


Pupil dilations induced by barely conscious reward goal-priming.
The topic of unconscious influences on behavior has long been explored as a way of understanding human performance and the neurobiological correlates of intention, motivation and action. Previous research using transcranial magnetic stimulation has demonstrated that barely visible priming of an action concept, when combined with reward in the form of a consciously perceived positive stimulus, can alter the state of the motor system and enhance the maximal voluntary force level. One possible explanation is that positive stimulus-induced reward signals are processed by the dopaminergic system in the basal ganglia, motivating individuals to increase the effort they invest in particular behaviors, or to recruit the resources necessary for maintaining those behaviors. If so, given that the dopaminergic system has functionally and anatomically close connections with the noradrenergic system, we hypothesize that the state of the noradrenergic system may be enhanced by the same process. In accord with this hypothesis, we observed that barely visible goal priming with reward caused pupil dilation, suggesting that activity in the noradrenergic system increased. Importantly, this enhancement was accompanied by an unconscious increase in handgrip force. This is the first objective evidence that the pupil-linked neuromodulatory system is related to implicit learning of the link between physical exertion and reward, probably in the noradrenergic system, resulting in more forceful voluntary motor action in the absence of conscious awareness.


Interpreting dual ELISA and qPCR data for bacterial kidney disease of salmonids.
Although there are a variety of methods available for the detection of Renibacterium salmoninarum, the causative agent of bacterial kidney disease in salmon and trout, the enzyme-linked immunosorbent assay (ELISA) is probably the most widely used method. However, ELISA measures bacterial antigen, which does not necessarily reflect the number of cells present. We hypothesized that dual analysis of kidney tissue by ELISA and a quantitative real-time polymerase chain reaction assay (qPCR) would provide complementary information about antigen level and the number of bacterial genomes. We found that DNA extracted from the insoluble fraction of the ELISA tissue preparation produced the same qPCR result as DNA extracted directly from frozen tissue, permitting true dual analysis of the same tissue sample. We examined kidney tissue in this manner from individual free-ranging juvenile Chinook salmon and antibiotic-treated captive subadult Chinook salmon and observed 3 different patterns of results. Among the majority of fish, there was a strong correlation between the ELISA value and the qPCR value. However, subsets of fish exhibited either low ELISA values with elevated qPCR values or higher ELISA values with very low qPCR values. These observations suggest a conceptual model that allows inferences about the state of infection of individual fish based on dual ELISA/qPCR results. Although this model requires further assessment through experimental infections and treatments, it may have utility in broodstock selection programs that currently apply egg-culling practices based on ELISA alone.


Ketoconazole in the treatment of dermatomycosis in cats and dogs.
Ketoconazole (Nizoral, Janssen Pharmaceutica) a new systemic antimycotic was tested in dermatomycosis in cats and dogs. The daily dose (10 mg/kg body weight) was administered for 10 or 20 days without any other measures being taken. After the 20-day treatments new hair growth was observed in 96.7 per cent of the cats and 89.9 per cent of the dogs. Clinical cure was complete in 96.8 per cent of the cats and 90.5 per cent of the dogs. Particularly the good tolerance in the cat was appreciated. There were practically no side-effects in dogs (except vomiting in two pups) or in cats.


New Onset Hypertension Linked to Generic Cyclosporine Substitution in Post-Renal Transplant Patient.
This is case report and review of the literature focused on generic substitutions of cyclosporine and its consequences. The pharmacokinetics and pharmacodynamics of the generic substitutions are clear different than the parent compound Sandimmune and can lead to different outcomes, as was the case in this report. A detailed accounting of the patients history led to the discovery of the problem and sorting back to a the branded drug supported the hypothesis.


Presence of triatominae (Hemiptera, Reduviidae) and risk of transmission of Chagas disease in Colima, México.
With the purpose of evaluating the risk of transmission of the Chagas disease in the State of Colima, México, an entomological survey was performed to obtain triatominae and the rate of infection by Trypanosoma cruzi determined by examination of its dejections. Two hundred eighteen houses located in 16 villages were sampled. In each house the intradomestic and peridomestic habitats were examined by the man-hour-house method, sensor boxes and mouse-baited traps. Also, 12 silvatic places were explored around the same areas using the same techniques as the ones sampled. In total, 456 specimens were captured, of which 139 correspond to Triatoma phyllosoma pallidipennis; 80 to T.p. longipennis; one specimen of T. dimidiata and 236 nymphs of Triatoma sp. Two hundred ninety seven insects were captured in the intradomestic habitat, 132 in the peridomestic and 26 in the silvatic. The index of positive houses was 27%, located in the central area of the state. The rate of natural infection with T. cruzi showed 25.6%. This results confirmed the presence of two important vectors of the Chagas disease in Colima. Its preference for the domestic habitat and its high levels of natural infection with T. cruzi suggested the existence of a significant risk for its transmission in this area of the country.


Studies on protein processing for membrane-bound spinach leaf mitochondrial processing peptidase integrated into the cytochrome bc1 complex and the soluble rat liver matrix mitochondrial processing peptidase.
The plant mitochondrial processing peptidase (MPP) that catalyses the cleavage of the presequences from precursor proteins during or after protein import is a membrane-bound enzyme that constitutes an integral part of the bc1 complex of the respiratory chain. In contrast, MPP from mammals is soluble in the matrix space and does not form part of the respiratory chain. In the present study, we have compared the substrate specificity of the isolated spinach leaf bc1/MPP with rat liver MPP using synthetic signal peptides and different mitochondrial precursor proteins. Inhibition studies of processing with synthetic peptides showed a similar inhibition pattern for plant and rat MPP activity. A peptide derived from the presequence of rat liver mitochondrial aldehyde dehydrogenase (ALDH) was a potent inhibitor of the spinach and rat MPP. Two nonprocessed signal peptides, rhodanese and linker-deleted ALDH (a form of ALDH that lacks the RGP linker connecting two helices in the presequence) had lower inhibitory effects towards each protease. The signal peptide from thiolase, another nonprocessed protein, had little inhibitory effect on MPP. Peptides derived from presequence of the plant Nicotiana plumbaginifolia F1 beta also showed a similar inhibitory pattern with rat MPP as with spinach MPP processing. In-vitro synthesised precursors of plant N. plumbaginifolia F1 beta and rat liver ALDH were cleaved to mature form by both spinach and rat MPP. However, the efficiency of processing was higher with the homologous precursor. Linker-deleted ALDH, rhodanese, and thiolase were not processed by the mammalian or plant MPP. However, both forms of MPP cleaved a mutated form of rhodanese that possesses a typical MPP cleavage motif, RXY S. Addition of the same cleavage motif to thiolase did not result in processing by either MPP. These results show that similar higher-order structural elements upstream from the cleavage site are important for processing by both the membrane-bound plant and the soluble mammalian MPP.


Endocrine emergencies in pregnancy.
A number of endocrine conditions and emergencies have unique characteristics when present in the pregnant woman. Often the abnormal endocrine state affects both mother and fetus and the various diagnostic and therapeutic approaches have to be altered to avoid harming the fetus. Furthermore, the pregnant state itself may alter the natural course of the underlying endocrine condition. Prolactinomas may enlarge due to the hormonal milieu of pregnancy, causing mass effects and even apoplexy. Anticipation of this possibility and prompt recognition may prevent disastrous consequences. This stimulatory state may extend to the normal pituitary, resulting in Sheehan's syndrome. An acute form of Sheehan's may go unrecognized, leading to unnecessary maternal deaths. Autoimmune endocrine disorders may sometimes be exacerbated and at other times be ameliorated during pregnancy. Witness the development of lymphocytic hypophysitis during pregnancy, a condition best left alone if it can be diagnosed without surgery. Graves's disease usually improves during pregnancy but it may occasionally flare, resulting in potentially lethal thyroid storm. The various therapeutic alternatives for hyperthyroidism are very much affected by effects on the fetus. Cushing's syndrome has very bad consequences for the fetus and must be diagnosed and treated urgently, if not emergently. Phaeochromocytomas are always endocrine emergencies requiring urgent and sometimes emergent treatment. Hyperparathyroidism is usually mild, but severe hypercalcaemia can be a true endocrine emergency. Recognition of the interactions of these endocrine conditions and their specific treatments with the complicated maternal-fetal unit makes their diagnosis and treatment simultaneously both difficult and extremely rewarding.


Deconjugation kinetics of glucuronidated phase II flavonoid metabolites by beta-glucuronidase from neutrophils.
Flavonoids are inactivated by phase II metabolism and occur in the body as glucuronides. Mammalian beta-glucuronidase released from neutrophils at inflammatory sites may be able to deconjugate and thus activate flavonoid glucuronides. We have studied deconjugation kinetics and pH optimum for four sources of beta-glucuronidase (human neutrophil, human recombinant, myeloid PLB-985 cells, Helix pomatia) with five flavonoid glucuronides (quercetin-3-glucuronide, quercetin-3'-glucuronide, quercetin-4'-glucuronide, quercetin-7-glucuronide, 3'-methylquercetin-3-glucuronide), 4-methylumbelliferyl-beta-D-glucuronide, and para-nitrophenol-glucuronide. All substrate-enzyme combinations tested exhibited first order kinetics. The optimum pH for hydrolysis was between 3.5-5, with appreciable hydrolysis activities up to pH 5.5. At pH 4, the K(m) ranged 44-fold from 22 microM for quercetin-4'-glucuronide with Helix pomatia beta-glucuronidase, to 981 microM for para-nitrophenol-glucuronide with recombinant beta-glucuronidase. V(max) (range: 0.735-24.012 micromol x min(-1) x unit(-1) [1 unit is defined as the release of 1 microM 4-methylumbelliferyl-beta-D-glucuronide per min]) and the reaction rate constants at low substrate concentrations (k) (range: 0.002-0.062 min(-1) x (unit/L)(-1) were similar for all substrates-enzyme combinations tested. In conclusion, we show that beta-glucuronidase from four different sources, including human neutrophils, is able to deconjugate flavonoid glucuronides and non-flavonoid substrates at fairly similar kinetic rates. At inflammatory sites in vivo the pH, neutrophil and flavonoid glucuronide concentrations seem favorable for deconjugation. However, it remains to be confirmed whether this is actually the case.