Immune responses in vitro. I. Cellular requirements for the immune response by nonprimed and primed spleen cells in vitro.
A cell suspension culture system combined with a procedure which separates most macrophages from lymphoid cells was used to investigate some of the cellular requirements for direct and indirect plaque-forming cell responses by nonprimed and primed mouse spleen cells in vitro. The plaque-forming cell response to heterologous erythrocytes in cultures of nonprimed spleen cells required both macrophages and lymphoid cells for its development. A significant indirect plaque-forming cell response did not develop in cultures of nonprimed spleen cells. In contrast, cultures of separated or macrophage-poor lymphoid cells from primed mice exhibited increasing responses relative to the response of unseparated spleen cells as the interval after priming increased. The cultures of separated lymphoid cells were not entirely free of phagocytic cells. Despite some evidence which suggests that these phagocytic cells had little function in the response, one cannot ascertain whether the lymphoid cells were responding directly to a second contact with antigen or whether the few contaminating phagocytic cells were performing a function essential to the response by the lymphoid cells. Physiologically different populations of cells appear to develop after priming and are able to respond in vitro in a macrophage-poor culture. Some of the properties of these populations suggest that they are "memory cell" pools containing precursors of direct and indirect plaque-forming cells highly susceptible to a second antigenic stimulus.


Hydroxysafflor Yellow A: A Promising Therapeutic Agent for a Broad Spectrum of Diseases.
Hydroxysafflor yellow A (HSYA) is one of the major bioactive and water-soluble compounds isolated from Carthami Flos, the flower of safflower (Carthamus tinctorius L.). As a natural pigment with favorable medical use, HSYA has gained extensive attention due to broad and effective pharmacological activities since first isolation in 1993. In clinic, the safflor yellow injection which mainly contains about 80% HSYA was approved by the China State Food and Drug Administration and used to treat cardiac diseases such as angina pectoris. In basic pharmacology, HSYA has been proved to exhibit a broad spectrum of biological effects that include, but not limited to, cardiovascular effect, neuroprotection, liver and lung protection, antitumor activity, metabolism regulation, and endothelium cell protection. Although a great number of studies have been carried out to prove the pharmacological effects and corresponding mechanisms of HYSA, a systemic review of HYSA has not yet been seen. Here, we provide a comprehensive summarization of the pharmacological effects of HYSA. Together with special attention to mechanisms of actions, this review can serve as the basis for further researches and developments of this medicinal compound.


Make-A-Dice Test: Assessing the intersection of mathematical and spatial thinking.
Individuals with better spatial thinking have increased interest and greater achievement in science, technology, engineering, and mathematics (STEM) disciplines (Wai, Lubinski, & Benbow in Journal of Educational Psychology, 101, 817-835, 2009). This relationship means that STEM education may benefit from leveraging spatial thinking, but measures of spatial thinking as they relate to specific STEM disciplines are needed. The present work presents an assessment of spatial and mathematical reasoning, called Make-A-Dice. In Make-A-Dice, individuals are presented with a cube net (i.e., a flattened cube) with numbers on two sides. Their goal is to "make a dice" by filling in the blank sides using two rules: opposite sides add to 7, and the numbers 1 through 6 should be used once each. Make-A-Dice was given to adults (Study 1) and elementary students (Studies 2 and 3) along with math, spatial, and other measures, across two sessions in all studies. Make-A-Dice had both internal and test-retest reliability, with items ordered by difficulty. Furthermore, performance was related to spatial and mathematical reasoning. In Study 1, adults reported a range of strategies used to complete Make-A-Dice, and one strategy predicted performance. Studies 2 and 3 showed that Make-A-Dice is age-appropriate for elementary students. Make-A-Dice shows promise as an individual-difference measure linking spatial and mathematical thinking and has the potential to identify elementary-aged children who may benefit from spatial training.


MICROSATELLITE DEVELOPMENT IN RHODOPHYTA USING HIGH-THROUGHPUT SEQUENCE DATA(1).
Shotgun genome sequencing is rapidly emerging as the method of choice for the identification of microsatellite loci in nonmodel organisms. However, to the best of our knowledge, this approach has not been applied to marine algae so far. Herein, we report the results of using the 454 next-generation sequencing (NGS) platform to randomly sample 36.0 and 40.9 Mbp (139,786 and 139,795 reads, respectively) of the genome of two red algae from the northwest Iberian Peninsula [Grateloupia lanceola (J. Agardh) J. Agardh and a still undescribed new member of the family Cruoriaceae]. Using data mining tools, we identified 4,766 and 5,174 perfect microsatellite loci in 4,344 and 4,504 sequences/contigs from G. lanceola and the Cruoriaceae, respectively. After conservative removal of potentially problematic loci (redundant sequences, mobile elements), primer design was possible for 1,371 and 1,366 loci, respectively. A survey of the literature indicates that microsatellite density in our Rhodophyta is at the low end of the values reported for other organisms investigated with the same technology (land plants and animals). A limited number of loci were successfully tested for PCR amplification and polymorphism finding that they may be suitable for population genetic studies. This study demonstrates that random genome sequencing is a rapid, effective alternative to develop useful microsatellite loci in previously unstudied red algae.


10 GHz pulses generated across a ~100 nm tuning range using a gain-shifted mode-locked SOA ring laser.
Widely-tunable picosecond pulses have been generated from a harmonically mode-locked semiconductor optical amplifier (SOA) ring laser with a center wavelength spanning from 1491 to 1588 nm. An intra-cavity birefringence loop mirror filter is used to define a 1.6 nm comb that governs the wavelength spacing of the tunable output pulses. The filter also serves to control the spectral gain profile of the laser cavity and thus extends the tuning range. By exploiting the spectral shift of the SOA gain with different amount of optical feedback, the output can be obtained over a wid wavelength range. Applying mode-locking together with the dispersion tuning approach, 10 GHz picosecond pulses have been successfully generated over a tuning range of 97 nm.


Morphology, kinetics and secretory activity of antibody-forming cells.
Specific antibody-forming cells from spleen, bone marrow and popliteal lymph nodes were studied in mice after subcutaneous priming and intravenous boosting with horseradish peroxidase (HRP). Functional antibody-secreting capacity of these cells was correlated with their morphology at the cell population level. For this purpose, cells synthesizing anti-HRP antibody from the same cell suspensions were studied simultaneously by light and electron microscopy and by a plaque assay. It appeared that the population of cells responsible for antibody synthesis as well as antibody secretion was morphologically heterogeneous: besides plasma cells, considerable numbers of antibody-forming lymphocytes, antibody-forming plasmablasts and antibody-forming immature plasma cells were observed. Immature plasma cells constituted the majority of antibody-forming as well as antibody-secreting cells. Among the immature plasma cells in the popliteal lymph nodes proliferation occurred. Evidence is presented that the light-microscopically identified mature plasma cell is not the main antibody-forming cell. It does not show 3H-Thymidine incorporation and should be considered as a non-dividing end-cell.


Transmembrane proteoglycans control stretch-activated channels to set cytosolic calcium levels.
Transmembrane heparan sulfate proteoglycans regulate multiple aspects of cell behavior, but the molecular basis of their signaling is unresolved. The major family of transmembrane proteoglycans is the syndecans, present in virtually all nucleated cells, but with mostly unknown functions. Here, we show that syndecans regulate transient receptor potential canonical (TRPCs) channels to control cytosolic calcium equilibria and consequent cell behavior. In fibroblasts, ligand interactions with heparan sulfate of syndecan-4 recruit cytoplasmic protein kinase C to target serine714 of TRPC7 with subsequent control of the cytoskeleton and the myofibroblast phenotype. In epidermal keratinocytes a syndecan-TRPC4 complex controls adhesion, adherens junction composition, and early differentiation in vivo and in vitro. In Caenorhabditis elegans, the TRPC orthologues TRP-1 and -2 genetically complement the loss of syndecan by suppressing neuronal guidance and locomotory defects related to increases in neuronal calcium levels. The widespread and conserved syndecan-TRPC axis therefore fine tunes cytoskeletal organization and cell behavior.


Pain assessment tools for unconscious or sedated intensive care patients: a systematic review.
This paper is a report of a systematic review describing instruments developed for pain assessment in unconscious or sedated intensive care patients. Intensive care patients who are unconscious or sedated are unable to communicate and therefore recognition and assessment of the pain is difficult. To assess these patients' pain, it is important to use a valid and reliable pain assessment tool. A systematic bibliographical review was conducted, based on seven databases, covering the period from January 1987 to February 2007. A total of 1,586 abstracts was identified and reviewed, 58 papers were selected for full-text review and nine papers were included in the review. Two researchers independently reviewed the abstracts and three reviewers extracted the papers. The included papers were evaluated using a quality assessment instrument previously developed to evaluate pain assessment tools. Five different pain assessment tools were identified that had been used with unconscious or sedated intensive care patients. All five instruments included behavioural indicators and three included physiological indicators. Their psychometric properties varied and it was not possible to deduce their clinical utility. All instruments were reasonably new. In most of them psychometric testing was in an early stage or even absent. Before any of the reported instruments can be chosen in preference to others, it is essential to test their validity, reliability and feasibility further.


Influences on the access to and use of formal community care by people with dementia and their informal caregivers: a scoping review.
The literature describes the obstacles to sufficient care faced by people with dementia and their informal caregivers. Although factors influencing access and utilisation are frequently studied, the body of knowledge lacks an overview of aspects related to influence. The frequently used Behavioural Model of Health Care Use (BM) could be used to structure and explain these aspects. An adaptation of the BM emphasises psychosocial influences and appears to enrich the understanding of the use of long-term care for dementia. We conducted a scoping review with the aim of providing an overview of the aspects influencing the access to and utilisation of formal community care in dementia. Our search covered the PubMed, CINAHL, Social Science Citation Index and PsychInfo databases, as well as grey literature. Two researchers assessed the full texts for eligibility. A data extraction form was developed and tested. We analysed the main topics investigated by the studies and mapped and described the investigated psychosocial aspects according to the BM after narratively summarising the findings. We used the Mixed Method Appraisal Tool (MMAT) to critically appraise the included studies. A total of 94 studies were included: n = 55 with quantitative designs, 35 with qualitative designs and four with mixed methods. The studies investigated different services, mainly focusing on health care services. One third of the studies provided information regarding the severity of dementia. The most frequently investigated main topics were ethnicity and attitudes towards services. Psychosocial aspects were frequently investigated, although few studies considered the perspectives of people with dementia. Approximately half of the studies reported a theoretical framework. The adapted BM facilitated the structuring and description of psychosocial aspects. However, this instrument did not address topics beyond the scope of psychosocial aspects, such as sociodemographic characteristics. The access to and utilisation of formal community care for dementia can only be partly explained by individual influencing aspects. Therefore, a theoretical framework would likely help to describe this complex subject. Our findings indicate that the psychosocial categories of the adapted BM enriched the original BM, and that people with dementia should more often be included in healthcare service research to ensure a better understanding of the barriers to accessing formal community care.


Leukocytoclastic vasculitis. A cutaneous expression of immune complex disease.
Thirty-nine patients with clinical, histologic, and immunofluorescence evidence of leukocytoclastic (necrotizing) vasculitis were studied for the presence of circulating immune complexes. These patients were selected prospectively during a three-year interval from patients seen in a dermatology clinic. Clinical and serologic data are summarized and representative cases are presented. This large series of patients with leukocytoclastic vasculitis emphasizes both the frequency of this disorder and the varied disease settings within which it may manifest. The immunopathologic data presented support an immune complex-mediated pathogenesis for this disease process.


Neuropeptide RFRP inhibits the pacemaker activity of terminal nerve GnRH neurons.
The terminal nerve gonadotropin-releasing hormone (TN-GnRH) neurons show spontaneous pacemaker activity whose firing frequency is suggested to regulate the release of GnRH peptides and control motivation for reproductive behaviors. Previous studies of the electrophysiological properties of TN-GnRH neurons reported excitatory modulation of pacemaker activity by auto/paracrine and synaptic modulations, but inhibition of pacemaker activity has not been reported to date. Our recent study suggests that neuropeptide FF, a type of Arg-Phe-amide (RFamide) peptide expressed in TN-GnRH neurons themselves, inhibits the pacemaker activity of TN-GnRH neurons in an auto- and paracrine manner. In the present study, we examined whether RFamide-related peptides (RFRPs), which are produced in the hypothalamus, modulate the pacemaker activity of TN-GnRH neurons as candidate inhibitory synaptic modulators. Bath application of RFRP2, among the three teleost RFRPs, decreased the frequency of firing of TN-GnRH neurons. This inhibition was diminished by RF9, a potent antagonist of GPR147/74, which are candidate RFRP receptors. RFRP2 changed the conductances for Na(+) and K(+). The reversal potential for RFRP2-induced current was altered by inhibitors of the transient receptor potential canonical (TRPC) channel (La(3+) and 2-aminoethoxydiphenyl borate) and by a less selective blocker of voltage-independent K(+) channels (Ba(2+)). By comparing the current-voltage relationship in artificial cerebrospinal fluid with that under each drug, the RFRP2-induced current was suggested to consist of TRPC channel-like current and voltage-independent K(+) current. Therefore, synaptic release of RFRP2 from hypothalamic neurons is suggested to inhibit the pacemaker activity of TN-GnRH neurons by closing TRPC channels and opening voltage-independent K(+) channels. This novel pathway may negatively regulate reproductive behaviors.


Endonasal endoscopic approach for sellar metastatic pathologies: a national observation.
Sellar metastases are rare lesions. Recent improvements in diagnosis and treatment strategies have prolonged survival but increased the probability of metastatic tumors. Evaluation with clinical symptomatology and meticulous laboratory examination is crucial. We present our multicenter national study on sellar metastases to evaluate and underline the main clinical, endocrine, and radiological considerations regarding the diagnosis and endonasal endoscopic management of such rare lesions. A medical literature-based retrospective study was planned across 13 neurosurgical centers in Turkey, where a data survey was conducted to collect information regarding sellar metastases surgically treated using the endoscopic endonasal approach, including clinical presentation, radiographic features, primary tumor origin, histopathological confirmation, time to metastasis, treatment, and patient outcomes. Between 2010 and 2020, 54 patients (22 women [40.7%] and 32 men [59.3%]) who underwent surgery with the endonasal endoscopic approach and had pathologically proven sellar metastases (overall incidence, 0.54%) were included. Of the patients, 59.3% had no known malignancy and presented with new-onset symptoms, 79.6% reported headache, 51.9% complained of some degree of visual deficits, and 50% had cranial nerve symptoms. Tissue biopsy was performed in 7.4% of the patients, whereas gross or subtotal resection was achieved in the remaining patients. To our knowledge, this is the largest series of patients surgically treated with the endonasal endoscopic approach for sellar metastases. For these patients, the treatment focus should be on management modalities for increasing quality of life instead radical treatment options with survival benefit.


Design and Analysis of a True Random Number Generator Based on GSR Signals for Body Sensor Networks.
Today, medical equipment or general-purpose devices such as smart-watches or smart-textiles can acquire a person's vital signs. Regardless of the type of device and its purpose, they are all equipped with one or more sensors and often have wireless connectivity. Due to the transmission of sensitive data through the insecure radio channel and the need to ensure exclusive access to authorised entities, security mechanisms and cryptographic primitives must be incorporated onboard these devices. Random number generators are one such necessary cryptographic primitive. Motivated by this, we propose a True Random Number Generator (TRNG) that makes use of the GSR signal measured by a sensor on the body. After an exhaustive analysis of both the entropy source and the randomness of the output, we can conclude that the output generated by the proposed TRNG behaves as that produced by a random variable. Besides, and in comparison with the previous proposals, the performance offered is much higher than that of the earlier works.


Relation of corona-specific health literacy to use of and trust in information sources during the COVID-19 pandemic.
COVID-19 has developed into a worldwide pandemic which was accompanied by an «infodemic» consisting of much false and misleading information. To cope with these new challenges, health literacy plays an essential role. The aim of this paper is to present the findings of a trend study in Switzerland on corona-specific health literacy, the use of and trust in information sources during the COVID-19 pandemic, and their relationships. Three online surveys each with approximately 1'020 individuals living in the German-speaking part of Switzerland (age ≥ 18 years) were conducted at different timepoints during the COVID-19 pandemic, namely spring, fall and winter 2020. For the assessment of corona-specific health literacy, a specifically developed instrument (HLS-COVID-Q22) was used. Descriptive, bivariate, and multivariate data analyses have been conducted. In general, a majority of the Swiss-German population reported sufficient corona-specific health literacy levels which increased during the pandemic: 54.6% participants in spring, 62.4% in fall and 63.3% in winter 2020 had sufficient corona-specific health literacy. Greatest difficulties concerned the appraisal of health information on the coronavirus. The most used information sources were television (used by 73.3% in spring, 70% in fall and 72.3% in winter) and the internet (used by 64.1, 64.8 and 66.5%). Although health professionals, health authorities and the info-hotline were rarely mentioned as sources for information on the coronavirus, respondents had greatest trust in them. On the other hand, social media were considered as the least trustworthy information sources. Respondents generally reporting more trust in the various information sources, tended to have higher corona-specific health literacy levels. Sufficient health literacy is an essential prerequisite for finding, understanding, appraising, and applying health recommendations, particularly in a situation where there is a rapid spread of a huge amount of information. The population should be supported in their capability in appraising the received information and in assessing the trustworthiness of different information sources.


Imaging of rhinosinusitis and its complications: plain film, CT, and MRI.
Conventional plain-film radiography may be used as a screening method for various pathological conditions of the sinonasal cavities. However, CT scanning remains the study of choice for the imaging evaluation of acute and chronic inflammatory diseases of sinonasal cavities. MRI is superior to CT in differentiating inflammatory conditions from neoplastic processes. The most common complications of rhinosinusitis in children occur in the orbit. The information obtained from the CT scan and MRI, together with clinical findings, may be the best guidelines for clinical management and the mode of treatment. Although intracranial complications of sinusitis are relatively rare, prompt recognition of these disease states is important to prevent permanent neurological deficit or fatality. It is prudent to obtain MRI of the sinuses, orbits, and brain whenever extensive or multiple complications of sinusitis are suspected, in addition to CT scanning. Chronic rhinosinusitis is a clinical diagnosis, confirmed and staged with the CT scan of sinonasal cavities. Chronic inflammatory disease is often associated with mucosal thickening and sclerosis of the bone, particularly within the sinuses. Chronic extramucosal fungal sinusitis develops as a saprophytic growth in retained secretions in a sinus cavity. The imaging manifestations of chronic mycotic rhinosinusitis may be nonspecific or highly suggestive of the presence of fungal infection. The presence of diffuse increased attenuation within the paranasal sinuses and nasal cavity should be considered as chronic allergic hypersensitivity aspergillosis (chronic noninvasive aspergillosis) or chronic hyperplastic sinusitis and polyposis associated with desiccated, retained mucosal secretions. The MRI characteristics of fungal sinusitis depend on the stage of the disease.


Specificity of dopachrome tautomerase and inhibition by carboxylated indoles. Considerations on the enzyme active site.
Dopachrome tautomerase (EC 22.214.171.124) catalyses the tautomerization of dopachrome to 5,6-dihydroxyindole-2-carboxylic acid (DHICA) within the melanin-formation pathway. We have analysed a series of substrate analogues and related compounds as possible substrates and inhibitors of tautomerization. The enzyme appears to be highly specific since D-dopachrome, alpha-methyldopachrome, dopaminochrome, adrenochrome methyl ether and deoxyadrenochrome are not substrates. Conversely, dopachrome tautomerase catalyses the tautomerization of dopachrome methyl ester, suggesting that a carboxy group, either free or as a methyl ester, is essential for enzyme recognition. No inhibition of dopachrome tautomerization was observed in the presence of either semiquinonic compounds, such as tropolone and L-mimosine, or pyrrole-2-carboxylic acid and unsubstituted indole. However, a number of indole derivatives, including DHICA, the product of dopachrome tautomerization, and the analogues 5-hydroxyindole-2-carboxylic and indole-2-carboxylic acid were able to inhibit the enzyme. Furthermore, indoles with a side chain at position 3 of the ring and containing a carboxylic group at the gamma-position of this chain, such as L-tryptophan or indole-3-propionic acid, are stronger inhibitors of the enzyme. Indole-3-carboxylic acid, indole-3-acetic acid and indole-3-butyric acid are very weak inhibitors, showing that the carboxylic group needs to be located at an optimal distance from the indole ring to mimic the carboxylic group at position 2 on the authentic substrate.


Prerenal Transplant Education and Evaluation Positively Impacts Outcomes.
Introduction: An outstanding question in kidney transplantation is how to prepare candidates and their social supports for optimal posttransplant outcomes. Project Aims: This program evaluation assessed whether a pretransplant quality improvement clinic improved clinical outcomes in the year posttransplant compared to recipients receiving standard of care. Design: The Countdown to Transplant Clinic was implemented with kidney transplant candidates expected to receive a transplant within the next few months. The clinic included an enhanced education session on posttransplant lifestyle management, confirmation of support (≥2 adults), and evaluations by transplant social work, psychology, and nephrology. Results: Seventy-five patients participated in the clinic and underwent a transplant. A retrospective chart review of posttransplant laboratory values, rehospitalizations (within 3-months posttransplant), biopsy-confirmed graft failure, and mortality (within 1-year posttransplant) were collected from both groups. Univariate and multivariate propensity score-weighted linear or logistic regression models were used to evaluate the association between clinic participation and outcomes. In models adjusting for relevant covariates, participation in The Countdown to Transplant Clinic (vs standard care) was associated with a lower coefficient of variation of serum tacrolimus (all values collected 3-12 months posttransplant), 30-day posttransplant white blood cell counts (but not 90-day), 90-day posttransplant potassium, and 30 and 31 to 90 days rehospitalizations. Clinic participation did not predict serum glucose levels at 30- or 90-days posttransplant. Due to low rates of rejection and mortality, meaningful comparisons were not possible. Conclusion: Participation in a pretransplant, multicomponent clinic may improve certain outcomes of interest posttransplantation. Pilot testing for feasibility for randomized controlled trials is a necessary next step.


Screening of Promising Chemotherapeutic Candidates from Plants against Human Adult T-Cell Leukemia/Lymphoma (VI): Cardenolides from Asclepias curassavica.
In the course of our screening program for novel chemotherapeutic candidates from plants against adult T-cell leukemia/lymphoma, the extracts of Asclepias curassavica L. showed potent activity against MT-1 and MT-2 cells. Therefore, we attempted to isolate their active components. We identified a new cardenolide, 19-dihydrocalactinic acid methyl ester (1), along with 16 known cardenolides (2-17). Their structures were determined on the basis of spectroscopic data. Almost all of the isolated cardenolides inhibited the growth of both tumor cell lines. All the doubly linked cardenolides (11-17) except for 14 showed more potent activity than the other cardenolides. A comparison of the activities of 11, 14 and 16 revealed that the presence of hydroxy or acetoxy functional groups at C-16 led to a decrease in the activity. The 50% effective concentration (EC50) value of calotropin (11) against MT-2 cells was comparable to the potency of the clinical antineoplastic drug doxorubicin. The cytotoxic effect of 11 toward normal mononuclear cells obtained from the peripheral blood (PB-MNCs) was observed at a concentration 6 to 12 times higher than that used to induce growth inhibition against MT-1 and MT-2 cells. The proportions of annexin V-positive cells after 72 h of treatment with 11 were increased, indicating that it significantly induced apoptosis in MT-1 and MT-2 cells in a concentration-dependent manner. Cell cycle experiments demonstrated that 11 arrested MT-1 and MT-2 cells at the G2/M phase. Therefore, compound 11 may be a promising candidate for the treatment of adult T-cell leukemia/lymphoma.


Molecular renormalization group coarse-graining of electrolyte solutions: application to aqueous NaCl and KCl.
Simplified, yet accurate, coarse-grained models are needed to explore the behavior of complex biological systems by means of Molecular Dynamics (MD) simulations, because many interesting processes occur at long time scales and large length scales that are not amenable to studies by atomistic simulations. The aqueous salt buffer provides an important contribution to the structure and function of biological molecules. While in many simplified models both water and salt are treated as a continuous medium, it is often desirable to describe mobile ions in an explicit manner. For example, the discrete nature of ions was shown to play a very important role in their interaction with highly charged biomolecules, such as DNA. In this work, we have derived an effective interaction potential for monovalent ions by systematically coarse-graining the all-atom NaCl and KCl aqueous solutions at several different ionic concentrations. Our approach is based on explicitly accounting for cross-correlations among various observables that constitute the compact basis set of the coarse-grained Hamiltonian. Compactness of the Hamiltonian ensures computational efficiency of the optimization procedure. In addition, it allows us to accurately reproduce many-body effects, in contrast with many existing algorithms. The resulting Hamiltonian produced ionic distributions that are virtually identical to those obtained in atomistic simulations with explicit water, capturing short-range hydration effects. Our coarse-grained model of monovalent electrolyte solutions allows the incorporation of ions into complex coarse-grained biomolecular simulations, where both electrostatic and short-range hydration effects must be taken into account.


Coping with medical error: a systematic review of papers to assess the effects of involvement in medical errors on healthcare professionals' psychological well-being.
Previous research has established health professionals as secondary victims of medical error, with the identification of a range of emotional and psychological repercussions that may occur as a result of involvement in error.2 3 Due to the vast range of emotional and psychological outcomes, research to date has been inconsistent in the variables measured and tools used. Therefore, differing conclusions have been drawn as to the nature of the impact of error on professionals and the subsequent repercussions for their team, patients and healthcare institution. A systematic review was conducted. Data sources were identified using database searches, with additional reference and hand searching. Eligibility criteria were applied to all studies identified, resulting in a total of 24 included studies. Quality assessment was conducted with the included studies using a tool that was developed as part of this research, but due to the limited number and diverse nature of studies, no exclusions were made on this basis. Review findings suggest that there is consistent evidence for the widespread impact of medical error on health professionals. Psychological repercussions may include negative states such as shame, self-doubt, anxiety and guilt. Despite much attention devoted to the assessment of negative outcomes, the potential for positive outcomes resulting from error also became apparent, with increased assertiveness, confidence and improved colleague relationships reported. It is evident that involvement in a medical error can elicit a significant psychological response from the health professional involved. However, a lack of literature around coping and support, coupled with inconsistencies and weaknesses in methodology, may need be addressed in future work.


Community genomic analysis of an extremely acidophilic sulfur-oxidizing biofilm.
Highly acidic (pH 0-1) biofilms, known as 'snottites', form on the walls and ceilings of hydrogen sulfide-rich caves. We investigated the population structure, physiology and biogeochemistry of these biofilms using metagenomics, rRNA methods and lipid geochemistry. Snottites from the Frasassi cave system (Italy) are dominated (>70% of cells) by Acidithiobacillus thiooxidans, with smaller populations including an archaeon in the uncultivated 'G-plasma' clade of Thermoplasmatales (>15%) and a bacterium in the Acidimicrobiaceae family (>5%). Based on metagenomic evidence, the Acidithiobacillus population is autotrophic (ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO), carboxysomes) and oxidizes sulfur by the sulfide-quinone reductase and sox pathways. No reads matching nitrogen fixation genes were detected in the metagenome, whereas multiple matches to nitrogen assimilation functions are present, consistent with geochemical evidence, that fixed nitrogen is available in the snottite environment to support autotrophic growth. Evidence for adaptations to extreme acidity include Acidithiobacillus sequences for cation transporters and hopanoid synthesis, and direct measurements of hopanoid membrane lipids. Based on combined metagenomic, molecular and geochemical evidence, we suggest that Acidithiobacillus is the snottite architect and main primary producer, and that snottite morphology and distributions in the cave environment are directly related to the supply of C, N and energy substrates from the cave atmosphere.


Sphere estimation network: three-dimensional nuclei detection of fluorescence microscopy images.
Purpose: Fluorescence microscopy visualizes three-dimensional subcellular structures in tissue with two-photon microscopy achieving deeper penetration into tissue. Nuclei detection, which is essential for analyzing tissue for clinical and research purposes, remains a challenging problem due to the spatial variability of nuclei. Recent advancements in deep learning techniques have enabled the analysis of fluorescence microscopy data to localize and segment nuclei. However, these localization or segmentation techniques would require additional steps to extract characteristics of nuclei. We develop a 3D convolutional neural network, called Sphere Estimation Network (SphEsNet), to extract characteristics of nuclei without any postprocessing steps. Approach: To simultaneously estimate the center locations of nuclei and their sizes, SphEsNet is composed of two branches to localize nuclei center coordinates and to estimate their radii. Synthetic microscopy volumes automatically generated using a spatially constrained cycle-consistent adversarial network are used for training the network because manually generating 3D real ground truth volumes would be extremely tedious. Results: Three SphEsNet models based on the size of nuclei were trained and tested on five real fluorescence microscopy data sets from rat kidney and mouse intestine. Our method can successfully detect nuclei in multiple locations with various sizes. In addition, our method was compared with other techniques and outperformed them based on object-level precision, recall, and F 1 score. Our model achieved 89.90% for F 1 score. Conclusions: SphEsNet can simultaneously localize nuclei and estimate their size without additional steps. SphEsNet can be potentially used to extract more information from nuclei in fluorescence microscopy images.


Factors associated with attrition, mortality, and loss to follow up after antiretroviral therapy initiation: data from an HIV cohort study in India.
Studies from sub-Saharan Africa have shown high incidence of attrition due to mortality or loss to follow-up (LTFU) after initiating antiretroviral therapy (ART). India is the third largest country in the world in terms of HIV infected people, but predictors of attrition after ART initiation are not well known. We describe factors associated with attrition, mortality, and LTFU in 3,159 HIV infected patients who initiated ART between 1 January 2007 and 4 November 2011 in an HIV cohort study in India. The study included 6,852 person-years with a mean follow-up of 2.17 years. After 5 years of follow-up, the estimated cumulative incidence of attrition was 37.7%. There was no significant difference between attrition due to mortality and attrition due to LTFU. Having CD4 counts <100 cells/µl and being homeless [adjusted hazard ratio (aHR) 3.1, 95% confidence interval (CI) 2.6-3.8] were associated with a higher risk of attrition, and female gender (aHR 0.64, 95% CI 0.6-0.8) was associated with a reduced risk of attrition. Living near a town (aHR 0.82, 95% CI 0.7-0.999) was associated with a reduced risk of mortality. Being single (aHR 1.6, 95% CI 1.2-2.3), illiteracy (aHR 1.3, 95% CI 1.1-1.6), and age <25 years (aHR 1.3, 95% CI 1-1.8) were associated with an increased risk of LTFU. Although the cumulative incidence of attrition in patients diagnosed with tuberculosis after ART initiation was 47.4%, patients who started anti-tuberculous treatment before ART had similar attrition to patients without tuberculosis (36 vs. 35.2%, P=0.19) after four years of follow-up. In this cohort study, the attrition was similar to the one found in sub-Saharan Africa. Earlier initiation of ART, improving the diagnosis of tuberculosis before initiating ART, and giving more support to those patients at higher risk of attrition could potentially reduce the mortality and LTFU after ART initiation.


Rocky Mountain spotted fever.
Rocky Mountain spotted fever, the most prevalent rickettsial disease in the United States, is one of the most severe of all infectious diseases. It remains an important infectious disease because of its prevalence, the difficulty of clinical diagnosis, potentially fatal outcome, and lack of a widely available sensitive and specific diagnostic test during the acute stage of the illness.


Rehabilitation--an emerging allied health profession.
Rehabilitation is perceived as the third phase of health care following preventive health care and curative medicine. The rehabilitation specialist assists the health care team in facilitating the patient to live and work with what he has left. The unique role of the rehabilitation specialist in the health care system is described, as well as his/her relation to traditional helth care personnel. The University of Texas Health Science Center at Dallas in the School of Allied Health Sciences has offered professional education at both the undergraduate and graduate levels in the Department of Rehabilitation Science for the past five years. The curriculum description, student characteristics, and employment placements are distinguishing features of each program and describe how this rehabilitation specialist is educated.


Effects of a Myrciaria jaboticaba peel extract on starch and triglyceride absorption and the role of cyanidin-3-O-glucoside.
The purpose of this study was to perform a parallel and comparative investigation of the effects of a Myrciaria jaboticaba (common name jabuticaba) peel extract and of its constituent cyanidin-3-O-glucoside on the overall process of starch and triglyceride intestinal absorption. The peel extract inhibited both the porcine pancreactic α-amylase and the pancreatic lipase but was 13.6 times more potent on the latter (IC50 values of 1963 and 143.9 μg mL-1, respectively). Cyanidin-3-O-glucoside did not contribute significantly to these inhibitions. The jabuticaba peel extract inhibited starch absorption in mice at doses that were compatible with its inhibitory action on the α-amylase. No inhibition of starch absorption was found with cyanidin-3-O-glucoside doses compatible with its content in the extract. The extract also inhibited triglyceride absorption, but at doses that were considerably smaller than those predicted by its strength in inhibiting the pancreatic lipase (ID50 = 3.65 mg kg-1). In this case, cyanidin-3-O-glucoside was also strongly inhibitory, with 72% inhibition at the dose of 2 mg kg-1. When oleate + glycerol were given to mice, both the peel extract and cyanidin-3-O-glucoside strongly inhibited the appearance of triglycerides in the plasma. The main mechanism seems, thus, not to be the lipase inhibition but rather the inhibition of one or more steps (e.g., transport) in the events that lead to the transformation of free fatty acids in the intestinal tract into triglycerides. Due to the low active doses, the jabuticaba peel extract presents many favourable perspectives as an inhibitor of fat absorption and cyanidin-3-O-glucoside seems to play a decisive role.


Apoptosis induction by retinoids in eosinophilic leukemia cells: implication of retinoic acid receptor-alpha signaling in all-trans-retinoic acid hypersensitivity.
Hypereosinophilic syndrome (HES) has recently been recognized as a clonal leukemic lesion, which is due to a specific oncogenic event that generates hyperactive platelet-derived growth factor receptor-alpha-derived tyrosine kinase fusion proteins. In the present work, the effect of retinoids on the leukemic hypereosinophilia-derived EoL-1 cell line and on primary HES-derived cells has been investigated. We show that all-trans-retinoic acid (ATRA) inhibits eosinophil colony formation of HES-derived bone marrow cells and is a powerful inducer of apoptosis of the EoL-1 cell line. Apoptosis was shown in the nanomolar concentration range by phosphatidylserine externalization, proapoptotic shift of the Bcl-2/Bak ratio, drop in mitochondrial membrane potential, activation of caspases, and cellular morphology. Unlike in other ATRA-sensitive myeloid leukemia models, apoptosis was rapid and was not preceded by terminal cell differentiation. Use of isoform-selective synthetic retinoids indicated that retinoic acid receptor-alpha-dependent signaling is sufficient to induce apoptosis of EoL-1 cells. Our work shows that the scope of ATRA-induced apoptosis of malignancies may be wider within the myeloid lineage than thought previously, that the EoL-1 cell line constitutes a new and unique model for the study of ATRA-induced cell death, and that ATRA may have potential for the management of clonal HES.


ATP Citrate Lyase and LncRNA NONMMUT010685 Play Crucial Role in Nonalcoholic Fatty Liver Disease Based on Analysis of Microarray Data.
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease with unclear molecular mechanisms. Our study intended to identify potential long non-coding RNAs (lncRNAs) and genes, and to determine the potential molecular mechanisms of NAFLD pathogenesis. The microarrays of GSE24031 and GSE57425 were downloaded from the Gene Expression Omnibus database. GSE24031 included 4 control and 4 model mice and GSE57425 included 3 control and 3 model mice on the basis of GPL1261 platform. Differentially expressed lncRNAs and mRNAs between control and NAFLD liver tissue were calculated. Gene ontology (GO), pathway enrichment analyses, co-expression network and PPI were performed to analyze the biological roles and pathways for the differentially expressed lncRNAs and mRNAs. Non-alcoholic steatohepatitis (NASH) rats were further chosen to investigate the key protein identified based on co-expression network and protein-protein interaction (PPI) network data. A total of 6 significantly up-regulated and 39 down-regulated lncRNAs, 340 up-regulated and 281 down-regulated mRNAs were identified. LncRNA-mRNA co-expression network were analyzed to show a total of 16 key lncRNAs (node degree > 10) in NAFLD samples compared to control tissues. Three key protein identified on co-expression network and protein-protein interaction (PPI) network data were verified in NASH in vivo. The protein level of ATP-citrate lyase (Acly) was significantly increased while lncNONMMUT010685 and NONMMUT050689 in NAFLD samples, whose regulator gene was x-box binding protein 1 (XBP1) and receptor-interacting protein 1 kinase (RIPK1) respectively, were gradually reduced in NASH. In summary, we found a set of lncRNAs and mRNAs differentially expressed in the development of NAFLD. LncRNA Ttc39aos1 and Acly, may be crucial biomarkers for NAFLD. LncRNA NONMMUT010685 and NONMMUT050689, the regulator of XBP1 gene and RIPK1 gene respectively, played important roles in the development of NAFLD.


[Focused ultrasound in research on somatic reception].
Focused ultrasound has been used to induce the following skin sensations: tactile and temperature ones; specific and unspecific pain, underskin or deep sensations: tactile sensations and some varieties of pain (muscle, periosteum and so on). It has been established that: somatic reception is attributed to mechanoreception; the same receptive structures are cold and warm ones; ultrasound has the sensibilized action. Sensation differences of corporal and auricular acupuncture points and some accidental skin underskin spots have been investigated.


Otorhinolaryngologic computer-assisted biopsies of the Iceman.
The Iceman is a prehistoric, completely preserved, 5300-year-old male human mummy. To obtain the first biopsy specimens from inside the Iceman while meeting an extended standard of hygiene and following precise intraoperative guidance to the site of biopsy and keeping tissue damage to a minimum. Biopsy specimens from the nose, the maxillary sinus, and the larynx of the Iceman were obtained. Special caution had to be taken while performing the biopsies to not contaminate the Iceman with heavy metals or remnants of microorganisms. The Iceman, a cadaver kept frozen in a glacier for 5300 years. The Iceman is in an excellent state of preservation and will allow fundamental histological, morphological, and molecular genetic insights into early man. The biopsies were planned and executed with the aid of Interventional Video Tomography, a system that guides the surgeon to the target area by combining live video with existing imaging modalities. The system does not need mechanical fixation of the subject (the Iceman) and is barely in physical contact with the subject; thus, it was the ideal tool for guiding the surgeon to the site of the biopsy samplings through a tiny canal into the nose, the maxillary sinus, and the larynx of the Iceman. We have obtained a number of tissue samples by precisely guided 3-dimensional navigation. Unnecessary tissue damage was avoided. Visual inspection of the extracted mucosa showed typical human cadaver tissue, despite its age, without clinical abnormalities. Currently, the samples are being investigated by various international scientific groups.


Photodynamic therapy with motexafin lutetium for rectal cancer: a preclinical model in the dog.
Local recurrence of rectal cancer remains a significant clinical problem despite multi-modality therapy. Photodynamic Therapy (PDT) is a cancer treatment which generates tumor kill through the production of singlet oxygen in cells containing a photosensitizing drug when exposed to laser light of a specific wavelength. PDT is a promising modality for prevention of local recurrence of rectal cancer for several reasons: tumor cells may selectively retain photosensitizer at higher levels than normal tissues, the pelvis after mesorectal excision is a fixed space amenable to intra-operative illumination, and PDT can generate toxicity in tissues up to 1 cm thick. This study evaluated the safety, tissue penetration of 730 nm light, normal tissue toxicity and surgical outcome in a dog model of rectal resection after motexafin lutetium-mediated photodynamic therapy. Ten mixed breed dogs were used. Eight dogs underwent proctectomy and low rectal end to end stapled anastomosis. Six dogs received the photosensitizing agent motexafin lutetium (MLu, Pharmacyclics, Inc., Sunnyvale, CA) of 2 mg/kg preoperatively and underwent subsequent pelvic illumination of the transected distal rectum of 730 nm light with light doses ranging from 0.5 J/cm(2) to 10 J/cm(2) three hours after drug delivery. Two dogs received light, but no drug, and underwent proctectomy and low-rectal stapled anastomosis. Two dogs underwent midline laparotomy and pelvic illumination. Light penetration in tissues was determined for small bowel, rectum, pelvic sidewall, and skin. Clinical outcomes were recorded. Animals were sacrificed at 14 days and histological evaluation was performed. All dogs recovered uneventfully. No dog suffered an anastomotic leak. Severe tissue toxicity was not seen. Histological findings at necropsy revealed mild enteritis in all dogs. The excitation light penetration depths were 0.46 +/- 0.18, 0.46 +/- 0.15, and 0.69 +/- 0.39 cm, respectively, for rectum, small bowel, and peritoneum in dogs that had received MLu. For control dogs without photosensitizer MLu, the optical penetration depths were longer: 0.92 +/- 0.63, 0.67 +/- 0.10, and 1.1 +/- 0.80 cm for rectum, small bowel, and peritoneum, respectively. Low rectal stapled anastomosis is safe when performed with MLu-mediated pelvic PDT in a dog model. Significant tissue penetration of 730 nm light into the rectum and pelvic sidewall was revealed without generation of significant toxicity or histological sequelae. Penetration depths of 730 nm light in pelvic tissue suggest that microscopic residual disease of less than 5 mm are likely to be treated adequately with MLu-mediated PDT. This approach merits further investigation as an adjuvant to total mesorectal excision and chemoradiation for rectal cancer.


Caveolin-1 expression level in cancer associated fibroblasts predicts outcome in gastric cancer.
Altered expression of epithelial or stromal caveolin-1 (Cav-1) is observed in various types of human cancers. However, the clinical significance of Cav-1 expression in gastric cancer (GC) remains largely unknown. The present study aims to explore the clinicopathological significance and prognostic value of both tumor cells and cancer associated fibroblasts (CAFs) Cav-1 in GC. Quantum dots immunofluorescence histochemistry was performed to examine the expression of Cav-1 in 20 cases of gastritis without intestinal metaplasia (IM), 20 cases of gastritis with IM and 286 cases of GC. Positive rates of epithelial Cav-1 in gastritis without IM, gastritis with IM and GC showed a decreasing trend (P = 0.012). Low expression of Cav-1 in CAFs but not in tumor cells was an independent predictor of poor prognosis in GC patients (P = 0.034 and 0.005 respectively in disease free survival and overall survival). Cav-1 level in tumor cells and CAFs showed no significant correlation with classic clinicopathological features. Loss of epithelial Cav-1 may promote malignant progression and low CAFs Cav-1 level herald worse outcome of GC patient, suggesting CAFs Cav-1 may be a candidate therapeutic target and a useful prognostic marker of GC.


Spatiotemporal mating pattern variation in a wind-pollinated Mediterranean shrub.
Spatiotemporal variation in mating patterns is poorly known in wind-pollinated plant species. Here, we analysed mating patterns of the wind-pollinated dioecious shrub Pistacia lentiscus by genotyping 904 seeds from 30 mother plants with eight microsatellite markers in a high-density population in two consecutive flowering seasons. We found significant differences in some mating system estimates between years, particularly in the levels of correlated paternity. Overall, within-mothers correlated paternity was higher in 2007 than in 2006 (r(pWM) = 0.085 and 0.030), which translated into an effective number of fathers (N(ep)) of 11.8 and 33.6 respectively. Using a smoothing interpolation technique, we show that the effective pollen cloud was spatially structured in patches of high- and low-genetic diversity, which do not remain constant from year to year. In 2006, the among-mothers correlated paternity (r(pAM)) showed no trend with distance, suggesting no restriction of pollen dispersal. However, in 2007, r(pAM) was greater than zero at short distances, revealing the existence of small-scale patterns of pollen dispersal. The fact that the studied seasons were climatically homogeneous during the flowering time suggested that the observed differences might be ascribed to between-year phenological variation of individuals in the studied population or other (unknown) factors. Numerical simulations, based on the real data set, indicated that the clumping of males and decreasing plant density, which is related to different types of pollen limitation, greatly increase correlated mating in this wind-pollinated species, which is of relevance under the frame of the continuous anthropogenic habitat disturbance suffered by Mediterranean ecosystems.


A new comprehensive method for detection of livestock-related pathogenic viruses using a target enrichment system.
We tested usefulness of a target enrichment system SureSelect, a comprehensive viral nucleic acid detection method, for rapid identification of viral pathogens in feces samples of cattle, pigs and goats. This system enriches nucleic acids of target viruses in clinical/field samples by using a library of biotinylated RNAs with sequences complementary to the target viruses. The enriched nucleic acids are amplified by PCR and subjected to next generation sequencing to identify the target viruses. In many samples, SureSelect target enrichment method increased efficiencies for detection of the viruses listed in the biotinylated RNA library. Furthermore, this method enabled us to determine nearly full-length genome sequence of porcine parainfluenza virus 1 and greatly increased Breadth, a value indicating the ratio of the mapping consensus length in the reference genome, in pig samples. Our data showed usefulness of SureSelect target enrichment system for comprehensive analysis of genomic information of various viruses in field samples.


The Effect of Drug-Related Problems on Blood Glucose Level in the Treatment of Patients with Type 2 Diabetes Mellitus.
The study aimed to investigate the effect of drug-related problems (DRPs) on changes in blood glucose level (BGL) in the treatment of type 2 diabetes mellitus (T2DM) patients. This three-month prospective cross-sectional study was conducted to patients of T2DM with complications hospitalised in Haji Adam Malik (HAM) Hospital, Medan, Indonesia period from July to October 2018. DRPs were identified and classified by using Cipolle DRP classification and trustable literature. The data obtained were analysed by Chi-Square test (p < 0.05 implied that there was a significant relationship). This study involved 81 T2DM patients, 52 (64.2%) of the patients were male, and 29 (35.8%) of them were female. Most (30.9%) of patients were at the age of 51-60 years. Combination of rapid-acting and long-acting insulin was the most frequently provided antidiabetic drugs (69.1%). There were 68 DRPs experienced by 32 (39.5%) of the patients. Percentage of DRP experienced by the 32 patients by number: 1 DRP, 53.1; 2 DRPs, 28.1; 3 DRPs, 3.1; 4 DRPs, 3.1; 5 DRPs, 3.1; 7 DRPs, 9.3. This study showed that 27.2% and 12.3 % of the patients had hyperglycemia and hypoglycemia, respectively. There was no significant relationship between BGL and indication without drug therapy (p = 0.064), ineffective provided drug (p = 0.079), and there was a significant relationship between BGL and irrational dose (p = 0.000). Furthermore, there was a significant relationship between hypoglycemia and adverse drug reaction (p = 0.000). DRPs are common among T2DM patients and still required the attention and appropriate actions of healthcare providers.


Cervicovaginal microbiota, women's health, and reproductive outcomes.
The human microbiome project has shown a remarkable diversity of microbial ecology within the human body. The vaginal microbiota is unique in that in many women it is most often dominated by Lactobacillus species. However, in some women it lacks Lactobacillus spp. and is comprised of a wide array of strict and facultative anaerobes, a state that broadly correlates with increased risk for infection, disease, and poor reproductive and obstetric outcomes. Interestingly, the level of protection against infection can also vary by species and strains of Lactobacillus, and some species although dominant are not always optimal. This factors into the risk of contracting sexually transmitted infections and possibly influences the occurrence of resultant adverse reproductive outcomes such as tubal factor infertility. The composition and function of the vaginal microbiota appear to play an important role in pregnancy and fertility treatment outcomes and future research in this field will shed further translational mechanistic understanding onto the interplay of the vaginal microbiota with women's health and reproduction.


Plasmonic Bloch oscillations in monolayer graphene sheet arrays.
We investigate the spatial plasmonic Bloch oscillations (BOs) in the monolayer graphene sheet arrays (MGSAs) as the surface plasmon polaritons (SPPs) between graphene in the arrays experience weak coupling. In order to realize BOs, linear gradient of the potential is introduced by changing the chemical potentials of individual graphene sheets or the interlayer space between graphene. Numerical simulations show that the complete plasmonic BOs can be observed in the former MGSAs. However, only harmonic oscillations occur in the latter of varying interlayer space. Theoretical analysis based on the coupled-mode theory agrees well with the numerical simulations.


Role of dipole elongation in orientationally ordered liquids.
A recent study shows that the dipole elongation in the extended dipole model plays a significant role in the phase transitions of liquid crystal phases. In this paper, molecular dynamics (MD) simulations were performed for the dipole model with different distances between the two charges keeping the total dipole moment the same. The potential energy consists of the Lennard-Jones potential and the site-site electrostatic contribution of partial charges. Detailed analyses were made with respect to the average order parameters (P(1)) and (P(2)) as functions of density along with other thermodynamic properties. When the reduced dipole elongations are 0.16 and 0.32, respectively, it is shown that the chainlike structures in the low density regime, liquid phases with columnar and smectic orders, and solid phases are formed; the phase with nematic order is not present anymore. At 0.64, the phases with antiferroelectric order were favored. The transition is found at the reduced elongation 0.55. It shows that the phase transitions are quite sensitive to the molecular charge distribution; this simple system could exhibit rather rich phase behaviors, which represents a significant advance in identifying molecular and state parameters of the future ferroelectric liquids.


COVID-19 Patients With Pulmonary Hypertension Hospitalized in the United States During the Early Pandemic: Analysis of In-Hospital Mortality, Clinical Outcomes, and Racial Disparities.
Coronavirus Disease 2019 (COVID-19) has been linked to severe consequences among hospitalized patients diagnosed with pulmonary hypertension (PH), as evidenced by a limited number of studies. Our retrospective study employed the National Inpatient Sample (NIS) database to evaluate in-hospital mortality and various clinical outcomes in COVID-19 patients with and without PH. This study included all patients ages 18 years and above who were hospitalized in the United States from January 1,2020 to December 31, 2020 with a COVID-19 diagnosis. The patients were then divided into 2 cohorts based on their PH status. After multivariate adjustment, we discovered that COVID-19 patients with PH experienced considerably higher in-hospital mortality, longer hospital stays, and higher costs of hospitalization when compared to COVID-19 patients without PH. Moreover, we observed an increased dependence on invasive and noninvasive positive pressure ventilation among COVID-19 patients with PH, indicating more severe respiratory failure. Our findings suggest that COVID-19 patients with PH had a heightened risk of acute pulmonary embolism and myocardial infarction while hospitalized. Lastly, among COVID-19 patients with PH, Hispanic and Native American patients demonstrated a persistently higher risk of in-hospital mortality compared to other racial groups. To our knowledge, this is the most comprehensive study of outcomes for COVID-19 patients with PH. The observed inpatient mortality appears to be driven by in-hospital complications, particularly pulmonary embolism. Given the substantial mortality and complications associated with COVID-19 and PH, we advocate for SARS-CoV-2 vaccination and the implementation of aggressive nonpharmacological preventive measures.


An overview of computer algorithms for deconvolution-based assessment of in vivo neuroendocrine secretory events.
The availability of increasingly efficient computational systems has made feasible the otherwise burdensome analysis of complex neurobiological data, such as in vivo neuroendocrine glandular secretory activity. Neuroendocrine data sets are typically sparse, noisy and generated by combined processes (such as secretion and metabolic clearance) operating simultaneously over both short and long time spans. The concept of a convolution integral to describe the impact of two or more processes acting jointly has offered an informative mathematical construct with which to dissect (deconvolve) specific quantitative features of in vivo neuroendocrine phenomena. Appropriate computer-based deconvolution algorithms are capable of solving families of 100-300 simultaneous integral equations for a large number of secretion and/or clearance parameters of interest. For example, one application of computer technology allows investigators to deconvolve the number, amplitude and duration of statistically significant underlying secretory episodes of algebraically specifiable waveform and simultaneously estimate subject- and condition-specific neurohormone metabolic clearance rates using all observed data and their experimental variances considered simultaneously. Here, we will provide a definition of selected deconvolution techniques, review their conceptual basis, illustrate their applicability to biological data and discuss new perspectives in the arena of computer-based deconvolution methodologies for evaluating complex biological events.


A multifunctional supercapacitor based on 2D nanosheets on a flexible carbon nanotube film.
The manufacture of multifunctional and high-performance wearable supercapacitors (SCs) requires a new class of flexible electrodes with high conductivity, high mechanical stability, good water-proof ability and self-healable capability. Herein, we report a stretchable and self-healable SC based on a MoS2/PEDOT/CNT electrode. The specific capacitance of the SC could be retained up to 81.98% even after the 21st breaking/healing cycle. Furthermore, a sheet-type asymmetric supercapacitor (ASC) based on a MoS2/PEDOT/CNT positive electrode and SnS2/CNT negative electrode is constructed, and it exhibits high performance with an extended potential window of 1.7 V, areal capacitance of 103.76 mF cm-2 at 1.5 mA cm-2, and outstanding stability with no capacitance degradation under a wide range of bending conditions. The ASC is sealed by polyimide films, and it shows high electrochemical stability in hot water and under high speed centrifugation conditions, indicating good water-proof ability and wearability. The as-prepared ASC is also encapsulated in elastic films to provide 225% stretchability. The ASC devices packaged in all these ways exhibit high capacitance retention (>90%) under various bending and dynamic conditions.


[Alcoholic liver disease: the roles of genetic-epigenetic factors and the effect of abstinence].
The pathogenesis of alcoholic liver disease depends not only on the toxic effects of alcohol, but also on the complex interaction of host's and environmental factors. Thus, the genetic pre-disposition, co-morbidities and behavioral factors all play a role in the individual variations in the disease outcomes. On the other hand, the essential part of the therapeutic strategy is the complete withdrawal of the harmful etiological agent. The present paper is devoted to overview the genetics, the environmental factors and the effects of abstinence in alcoholic liver disease. Genetic variants in two enzymes involved in the metabolism of ethanol, alcohol-dehydrogenase ADH1B *2 and aldehyde-dehydrogenase ALDH2 *2 through increasing the blood level of acetaldehyde, may play a "protective" role against alcoholism. The P450 CYP2E1 *5 c2, an inducible microsomal oxidase, upregulated by ethanol and by formation of acetaldehyde and reactive oxygen species, increases liver toxicity. Three novel gene polymorphisms - such as the patatin-like phospholipase domain-containing 3 (PNPLA3 I148M C>G), the transmembrane 6 superfamily member 2 (TM6SF2 E167K), and the membrane-bound O-acyltransferase domain-containing 7 (MB0AT7 rs641738 C>T) - have been proven as risk factors of steatosis, fibrosis and even hepatocellular carcinoma in both alcoholic and non-alcoholic fatty liver disease patients. Alcohol-induced epigenetic effects, reversible but inheritable gene expression alterations - as histon modulations, DNA methylation and micro-RNA-s - are of importance in the pathogenesis as well, and in the future, they may serve as diagnostic markers and therapeutic targets. Women are at greater risk of developing alcoholic cirrhosis, furthermore, malnutrition, obesity, diabetes, smoking, and hepatitis virus infections are also risk factors. Alcoholic liver disease should be regarded as a preventable disease. Several clinical studies revealed that abstinence may result in the regression of steatohepatitis and fibrosis, compensation of cirrhosis, improving disease outcome and increasing survival even in patients with advanced stages. Early diagnosis and multidisciplinary interventions are highly required to achieve long-term abstinence and to prevent alcoholic cirrhosis. Orv Hetil. 2019; 160(14): 524-532.


Blood flow distribution in sorbent beds: analysis of a new sorbent device for hemoperfusion.
A new polymer-based sorbent cartridge has been recently developed for enhancing middle molecule removal during hemodialysis. The cartridge (Betasorb, Renaltech, New York, USA) has been designed to be placed in series with the dialyzer in the blood circuit. It is therefore important to evaluate the distribution of flow into the blood compartment of the device in order to assess if the surface of the sorbent is utilized to the best. For this purpose, a special imaging technique was utilized. Cartridges were analyzed during a simulated in vitro circulation at 250 and 350 ml/min of blood flow and 25% and 40% hematocrit. Cartridges were placed in vertical position and a cross longitudinal section 1 cm thick was analyzed in sequence by a helical scanner. Dye was injected into the arterial inlet and the progressive distribution was evaluated by sequential densitometrical measures carried out automatically by the machine. The sequential images analyzed by the scanner demonstrated excellent distribution of the flow in the blood compartment with minimal difference between the central and the peripheral regions of the compartment. In particular the following flow velocity pattern could be observed under the different experimental conditions tested. We may conclude that the cartridge design is adequate and no channelling effects could be detected in the blood compartment. The flow distribution is slightly affected by changes in flow rate and hematocrit showing an optimal utilization of the available surface for molecule adsorption.


Social distancing measures: barriers to their implementation and how they can be overcome - a systematic review.
Despite their central role in the global response to the COVID-19 pandemic and previous infectious disease outbreaks, factors influencing the acceptability and implementation of social distancing measures are poorly understood. This systematic review aims to identify such factors drawing on qualitative literature. A systematic search was carried out in eleven databases. Papers were included in the review if they reported on qualitative studies of factors influencing the implementation of social distancing measures in potentially epidemic infectious diseases. An adapted meta-ethnographical approach was used for synthesis. Review findings were assessed for strength and reliability using GRADE-CERQual. Twenty-nine papers were included from the systematic search that yielded 5620 results, and supplementary methods. The review identifies two broad categories of barriers to social distancing measures: individual- or community-level psychosocial phenomena, and shortcomings in governmental action or communication. Based on this, 25 themes are identified that can be addressed to improve the implementation of social distancing. Among other findings, the review identifies the need for good communication as well as the need for authorities to provide comprehensive support as two key opportunities to increase acceptability and adherence. Further important enablers of adherence are adequate preparedness and appropriate legislation, the presence of community involvement, solidarity within communities and trust in governments and authorities.


Thioflavin T as a fluorescence probe for monitoring RNA metabolism at molecular and cellular levels.
The intrinsically stochastic dynamics of mRNA metabolism have important consequences on gene regulation and non-genetic cell-to-cell variability; however, no generally applicable methods exist for studying such stochastic processes quantitatively. Here, we describe the use of the amyloid-binding probe Thioflavin T (ThT) for monitoring RNA metabolism in vitro and in vivo. ThT fluoresced strongly in complex with bacterial total RNA than with genomic DNA. ThT bound purine oligoribonucleotides preferentially over pyrimidine oligoribonucleotides and oligodeoxyribonucleotides. This property enabled quantitative real-time monitoring of poly(A) synthesis and phosphorolysis by polyribonucleotide phosphorylase in vitro. Cellular analyses, in combination with genetic approaches and the transcription-inhibitor rifampicin treatment, demonstrated that ThT mainly stained mRNA in actively dividing Escherichia coli cells. ThT also facilitated mRNA metabolism profiling at the single-cell level in diverse bacteria. Furthermore, ThT can also be used to visualise transitions between non-persister and persister cell states, a phenomenon of isogenic subpopulations of antibiotic-sensitive bacteria that acquire tolerance to multiple antibiotics due to stochastically induced dormant states. Collectively, these results suggest that probing mRNA dynamics with ThT is a broadly applicable approach ranging from the molecular level to the single-cell level.


Study on Main Drugs and Drug Combinations of Patient-Controlled Analgesia Based on Text Mining.
In recent years, with the continuous understanding of pain knowledge and the continuous improvement of quality of life requirements, patient-controlled analgesia (PCA) has been widely used in a variety of pain patients. In this study, text mining technology was used to analyze relevant literature, try to find out the main drugs of PCA, classify the drugs, and dig out the important drug combination rules. PCA studies were retrieved from PubMed database in recent 10 years, and the bibliographic information of the literatures was taken as mining sample. First, the names of the drugs in the sample were identified by MetaMap package; then, Bicomb software was used to extract high-frequency drugs for the word frequency analysis and to construct a drug-sentence matrix. Finally, "hclust" package and "arules" package of R were used for the cluster analysis and association analysis of drugs. 39 main PCA drugs were screened out. Morphine, dexmedetomidine, and fentanyl were the top three drugs. Through cluster analysis, these drugs were divided into two clusters, one containing 26 common drugs and the other containing 13 core drugs. The association analysis of these drugs was carried out, and 22 frequent itemsets and 6 association rules were obtained. The maximum frequent 1-itemset was {Morphine} and the maximum frequent 2-itemset was {Morphine, Ropivacaine}. The research results have certain guidance and reference value for clinicians and researchers. In addition, it provides a way to study the relationship between drugs from the perspective of text mining.


Human MAIT cells exit peripheral tissues and recirculate via lymph in steady state conditions.
Mucosal-associated invariant T cells (MAIT cells) recognize bacterial metabolites as antigen and are found in blood and tissues, where they are poised to contribute to barrier immunity. Recent data demonstrate that MAIT cells located in mucosal barrier tissues are functionally distinct from their blood counterparts, but the relationship and circulation of MAIT cells between blood and different tissue compartments remains poorly understood. Previous studies raised the possibility that MAIT cells do not leave tissue and may either be retained or undergo apoptosis. To directly address if human MAIT cells exit tissues, we collected human donor-matched thoracic duct lymph and blood and analyzed MAIT cell phenotype, transcriptome, and T cell receptor (TCR) diversity by flow cytometry and RNA sequencing. We found that MAIT cells were present in the lymph, despite being largely CCR7- in the blood, thus indicating that MAIT cells in the lymph migrated from tissues and were capable of exiting tissues to recirculate. Importantly, MAIT cells in the lymph and blood had highly overlapping clonotype usage but distinct transcriptome signatures, indicative of differential activation states.


[Biology of the citrus blackfloy, Aleurocanthus woglumi Ashby (Hemiptera: Aleyrodidae), in three host plants].
The citrus blackfloy, Aleurocanthus woglumi Ashby, was detected in Brazil in 2001. The aim of this research was to evaluate the biology, biometry and host preference of A. woglumi in sweet orange, acid lime Tahiti and mango. Experiments were set in laboratory conditions with insects collected in rangpur lime plants in Manaus, State of Amazonas, from January to June of 2006. The following parameters were evaluated: number of spirals (ovopositions) and eggs per plant, number of eggs by spiral per plant, survival of the immatures (eggs, 1st, 2nd, 3rd and 4th instars), and length and survival of the immature stage. The mean embrionary period was 15 days for the three hosts. The 4th nymph (puparium) was the longest during nymph development. Second and third instars had the highest survival. The mean length of the egg-adult cycle was 70 days for the three hosts evaluated. The eggs were laid in a spiral shape on the adaxial leaf surface. The 1st instars moved to short distances from the spiral, while the 2nd, 3rd and 4th are sessile and have bristles on the whole body. Based on the highest oviposition and the highest survival of the immature stage of the citrus blackfloy in acid lime Tahiti, this plant can be considered the most suitable host to A. woglumi.


Hematologic abnormalities of the immunodeficient mouse mutant, viable motheaten (mev).
We have studied the hematopoietic system of the immunodeficient mouse mutant, viable motheaten (mev/mev). These mice usually die by 9 weeks of age from severe pneumonitis. The lungs at that time are infiltrated with granulocytes, macrophages, and lymphocytes. Granulocyte and macrophage precursor cells (CFU-GM) are dramatically increased in the spleens of mev/mev mice, whereas the bone marrow population of these precursors is decreased when compared with littermate control animals. The CFU-GM population retained its normal dependence on granulocyte-macrophage colony-stimulating factor (GM-CSF) for proliferation and differentiation. In contrast, the frequency of an erythroid precursor (CFU-E) was dramatically increased in spleen and showed increased sensitivity to erythropoietin (Epo). Moreover, a splenic CFU-E subpopulation formed normally appearing erythroid colonies in the absence of exogenous Epo. The bone marrow CFU-E population was significantly diminished in size when compared with either wildtype C57BL/6J mice or mice heterozygous for the mev allele. Unlike the CFU-E population, erythroid burst-forming unit (BFU-E) frequency in mev/mev mice was diminished both in bone marrow and in spleen, although the total number of splenic BFU-E was increased because of splenomegaly in these animals. BFU-E retained their dependence on the presence of both Epo and a source of interleukin 3 (IL-3) for proliferation and differentiation into erythroid bursts. Spleen cells from mev/mev mice, when stimulated in vitro with pokeweed mitogen, failed to produce significant quantities of IL-3. Comparison with medium or +/mev heterozygotes revealed that mev/mev spleen cell-conditioned medium showed a 40-fold reduction in burst-promoting activity. Thus, in viable motheaten mice, there is a major shift in hematopoiesis from bone marrow to spleen, which is accompanied by a diminished capacity of spleen cells to produce burst-promoting activity. These data and those from other studies suggest that the hematopoietic microenvironment of marrow may be impaired in this mutant.


Development of gelatin/carboxymethylcellulose active films containing Hass avocado peel extract and their application as a packaging for the preservation of berries.
This study aimed to evaluate the effect of incorporating different concentrations (0, 200, 300, and 400 mg L-1) of avocado peel extracts (EE-AP) on the physicochemical properties and antifungal activity of gelatin-carboxymethylcellulose (Gel-CMC) films and their applicability in berry preservation. The results showed that incorporating EE-AP was compatible with the Gel-CMC film and enhanced the mechanical properties without affecting the integrity and thermal properties. The 200 mg L-1 of EE-AP concentration on films offered the best barrier properties against water vapor (2.90 × 10-11 g m-1 s-1 Pa-1). FTIR identified the intramolecular and intermolecular interactions between the functional groups of biopolymers and the EE-AP. The results obtained revealed that EE-AP incorporation into gelatin-carboxymethylcellulose films significantly decreased the moisture content (from 12.48 to 11.02%) and solubility (from 40.13 to 35.39%) of the films. All films incorporated with EE-AP showed higher colorimetric parameters and opacity than the control film (p < 0.05). The DPPH radical scavenging ability of the Gel-CMC films was increased from 24.16 to 41.12, 57.21, and 63.47%, as the extract concentration increased. Active films presented excellent ultraviolet-visible light barrier properties. The antioxidant pigments (flavonoids and chlorophylls) were estimated spectrophotometrically through absorbance. In vitro tests indicated high effectiveness to inhibit the growth of Rhizopus stolonifer and Aspergillus niger. A preservation study indicated the absence of fungal development in berries over six days of storage. In conclusion, gelatin-carboxymethylcellulose films with EE-AP represent a potential option for active packaging and can preserve fresh fruit.


Burnout in the intensive care units in Western Greece.
Prevention of burnout is a national imperative, and blame-free investigations of clinical events are advocated. Reflective inquiry techniques are helpful in processing adverse events while minimizing blame. The purpose of the present study was to investigate the factors inducing occupational exhaustion, staff perceptions through their interdisciplinary collaboration and communication, as well as the possibility of any conflicts in the Intensive Care Units of Western Greece. Moreover, we also aimed at developing an inter-professional peer-review program to process emotions and improve teamwork, which will also lead to the improvement of the care provided to patients. Healthcare workers of four Intensive Care Units from three (3) Hospitals in Western Greece participated in the present study. Our manuscript included all items according to STROBE statement. We found a moderate to high choice in the collaboration scale and showed that one of the major reasons for conflict was the lack of mutual understanding between coworkers. It was also shown that all participants were characterized by moderate to high levels of occupational exhaustion. Effective relationships to establish constructive communication, require the development of skills aiming at building mutual understanding. Possible proposals for future directions in this area of research are discussed. Aiming at improving clinical practice it would be helpful the design of staff support services for better management of exhaustion.


Microscopic and Macroscopic Studies of the Development of Puccinia hemerocallidis in Resistant and Susceptible Daylily Cultivars.
Infection and colonization of eight daylily cultivars, which varied in resistance to daylily rust, by Puccinia hemerocallidis was studied macroscopically and microscopically. After germination of urediniospores, appressoria formed at the tip of germ tubes and the fungus penetrated the host through stomatal openings 2 days after inoculation (DAI). Under the infection sites, intercellular hyphae aggregated and formed uredia, which released urediniospores 8 DAI. Resistant cultivars, characterized by the development of rapid death of host cells, were separated into three qualitative categories based on absence and presence of necrotic lesions without or with sporulation. In highly resistant cvs. Prairie Blue Eyes and Bertie Ferris, no macroscopic disease symptoms were observed on leaf surfaces although a few collapsed cells were detected microscopically. Both resistant and moderately resistant reactions were characterized by necrotic lesions with many collapsed cells under infection sites. The difference between these two reactions was that uredia and urediniospores were observed in the moderately resistant cv. Chicago Apache, but not in resistant cvs. Buttered Popcorn and Stella De Oro. Susceptible cultivars, characterized by the absence of a hypersensitive response, were separated into two qualitative categories based on restriction of intercellular hyphal growth that delayed development of uredia and formation of urediniospores. Compared to the susceptible cv. Pardon Me, moderately susceptible cvs. Mary Todd and Chorus Line had a delayed latent period and reduced amount of sporulation. The results indicate that hypersensitive cell death is one of the resistance responses to daylily rust. Necrotic lesions on leaf surfaces are associated with the number of collapsed host cells. Delayed latent period and reduced sporulation that resulted from restriction of intercellular hyphal growth could represent another type of resistance response in the daylily-rust pathosystem.


Analytical Method Development for 19 Alkyl Halides as Potential Genotoxic Impurities by Analytical Quality by Design.
Major issues in the pharmaceutical industry involve efficient risk management and control strategies of potential genotoxic impurities (PGIs). As a result, the development of an appropriate method to control these impurities is required. An optimally sensitive and simultaneous analytical method using gas chromatography with a mass spectrometry detector (GC-MS) was developed for 19 alkyl halides determined to be PGIs. These 19 alkyl halides were selected from 144 alkyl halides through an in silico study utilizing quantitative structure-activity relationship (Q-SAR) approaches via expert knowledge rule-based software and statistical-based software. The analytical quality by design (QbD) approach was adopted for the development of a sensitive and robust analytical method for PGIs. A limited number of literature studies have reviewed the analytical QbD approach in the PGI method development using GC-MS as the analytical instrument. A GC equipped with a single quadrupole mass spectrometry detector (MSD) and VF-624 ms capillary column was used. The developed method was validated in terms of specificity, the limit of detection, quantitation, linearity, accuracy, and precision, according to the ICH Q2 guideline.


Reduced-dose craniospinal irradiation is feasible for standard-risk adult medulloblastoma patients.
Medulloblastoma is the most common malignant brain tumor in children, but accounts for only 1% of brain cancers in adults. For standard-risk pediatric medulloblastoma, current therapy includes craniospinal irradiation (CSI) at reduced doses (23.4 Gy) associated with chemotherapy. Whereas most same-stage adult patients are still given CSI at 36 Gy, with or without chemotherapy, we report here on our use of reduced-dose CSI associated with chemotherapy for older patients. We gathered non-metastatic patients over 18 years old (median age 28 years, range 18-48) with minimal or no residual disease after surgery, no negative histological subtypes, treated between 1996-2018 at the Centre Léon Bérard (Lyon) and the INT (Milano). A series of 54 children with similar tumors treated in Milano was used for comparison. Forty-four adults were considered (median follow-up 101 months): 36 had 23.4 Gy of CSI, and 8 had 30.6 Gy, plus a boost to the posterior fossa/tumor bed; 43 had chemotherapy as all 54 children, who had a median 83-month follow-up. The PFS and OS were 82.2 ± 6.1% and 89 ± 5.2% at 5 years, and 78.5 ± 6.9% and 75.2 ± 7.8% at ten, not significantly different from those of the children. CSI doses higher than 23.4 Gy did not influence PFS. Female adult patients tended to have a better outcome than males. The results obtained in our combined series are comparable with, or even better than those obtained after high CSI doses, underscoring the need to reconsider this treatment in adults.


Transcranial Magnetic Stimulation (TMS) during pregnancy: a fetal risk factor.
To examine reports of Transcranial Magnetic Stimulation (TMS) during pregnancy for evidence of fetal risk. PubMed was used to locate relevant literature for the years 1998-2020 and reference lists were examined for materials not located electronically. Ten reports were located dealing with 67 births over 20 years. Stimulation was applied is all trimesters, at low and high frequency, and as intermittent theta-burst stimulation. No mother or baby experienced a serious event. Certainty awaits large, standardized studies. However, the available reports provide no evidence that TMS to mother during pregnancy has detrimental effects on the fetus.


The acetone extract of Sclerocarya birrea (Anacardiaceae) possesses antiproliferative and apoptotic potential against human breast cancer cell lines (MCF-7).
Interesting antimicrobial data from the stem bark of Sclerocarya birrea, which support its use in traditional medicine for the treatment of many diseases, have been delineated. The current study was aimed to further study some pharmacological and toxicological properties of the plant to scientifically justify its use. Anticancer activity of water and acetone extracts of S. birrea was evaluated on three different cell lines, HT-29, HeLa, and MCF-7 using the cell titre blue viability assay in 96-well plates. Apoptosis was evaluated using the acridine orange and propidium iodide staining method, while morphological structure of treated cells was examined using SEM. The acetone extract exhibited remarkable antiproliferative activities on MCF-7 cell lines at dose- and time-dependent manners (24 h and 48 h of incubation). The extract also exerted apoptotic programmed cell death in MCF-7 cells with significant effect on the DNA. Morphological examination also displayed apoptotic characteristics in the treated cells, including clumping, condensation, and culminating to budding of the cells to produce membrane-bound fragmentation, as well as formation of apoptotic bodies. The acetone extract of S. birrea possesses antiproliferative and apoptotic potential against MCF-7-treated cells and could be further exploited as a potential lead in anticancer therapy.


Detection of familial hypercholesterolaemia: external validation of the FAMCAT clinical case-finding algorithm to identify patients in primary care.
The vast majority of individuals with familial hypercholesterolaemia in the general population remain unidentified worldwide. Recognising patients most likely to have the condition, to enable targeted specialist assessment and treatment, could prevent major coronary morbidity and mortality. We aimed to evaluate a clinical case-finding algorithm, the familial hypercholesterolaemia case ascertainment tool (FAMCAT), and compare it with currently recommended methods for detection of familial hypercholesterolaemia in primary care. In this external validation study, FAMCAT regression equations were applied to a retrospective cohort of patients aged 16 years or older with cholesterol assessed, who were randomly selected from 1500 primary care practices across the UK contributing to the QResearch database. In the main analysis, we assessed the ability of FAMCAT to detect familial hypercholesterolaemia (ie, its discrimination) and compared it with that of other established clinical case-finding approaches recommended internationally (Simon Broome, Dutch Lipid Clinic Network, Make Early Diagnosis to Prevent Early Deaths [MEDPED] and cholesterol concentrations higher than the 99th percentile of the general population in the UK). We assessed discrimination by area under the receiver operating curve (AUROC; ranging from 0·5, indicating pure chance, to 1, indicating perfect discrimination). Using a probability threshold of more than 1 in 500 (prevalence of familial hypercholesterolaemia), we also assessed sensitivity, specificity, positive predictive values, and negative predictive values in the main analysis. A sample of 750 000 patients who registered in 1500 UK primary care practices that contribute anonymised data to the QResearch database between Jan 1, 1999, and Sept 1, 2017, was randomly selected, of which 747 000 patients were assessed. FAMCAT showed a high degree of discrimination (AUROC 0·832, 95% CI 0·820-0·845), which was higher than that of Simon Broome criteria (0·694, 0·681-0·703), Dutch Lipid Clinic Network criteria (0·724, 0·710-0·738), MEDPED criteria (0·624, 0·609-0·638), and screening cholesterol concentrations higher than the 99th percentile (0·581, 0·570-0·591). Using a 1 in 500 probability threshold, FAMCAT achieved a sensitivity of 84% (1028 predicted vs 1219 observed cases) and specificity of 60% (443 949 predicted vs 745 781 observed non-cases), with a corresponding positive predictive value of 0·84% and a negative predictive value of 99·2%. FAMCAT identifies familial hypercholesterolaemia with greater accuracy than currently recommended approaches and could be considered for clinical case finding of patients with the highest likelihood of having hypercholesterolaemia in primary care. UK National Institute for Health Research School for Primary Care Research.


Aurintricarboxylic acid induces a distinct activation of the IGF-I receptor signaling within MDA-231 cells.
Aurintricarboxylic acid (ATA), a polymeric carboxylated triphenylmethane derivate, prevents apoptotic death in a variety of cell systems. Recently, we have shown that the survival promoting effect of ATA is transduced via activation of the IGF-I receptor (IGF-IR) signaling pathway. In breast cancer MDA-231 cells exposed either to the protein synthesis inhibitors cycloheximide or ricin or to the anticancer drug adriamycin, we have found that ATA, but not IGF-1, is a powerful antiapoptotic agent. The purpose of this study was to compare the ability of ATA and IGF-I to activate the IGF-IR signaling cascade and to correlate this ability to their survival potency. MDA-231 cells were exposed to ATA or IGF-I, up to 7 h, and the dynamics of activation of the IGF-IR signaling cascade was evaluated. Our results show that: 1) The amount of tyrosine phosphorylated IGF-IR proteins was greater after exposure to ATA, compared with IGF-I. 2) Two phosphorylated IGF-IR beta-subunits (a 95-kDa and a 75-kDa) were induced after exposure to ATA, whereas IGF-1 induced only the 95-kDa form. Immunoprecipitation of both receptor forms by antibodies against the alpha-subunit and against the carboxy terminus of the beta-subunit of the IGF-IR suggests that the 75-kDa form could be the beta-chain truncated at the amino terminus above the alpha-beta disulphide bridges. 3) The ATA-activated IGF-IR forms underwent slow dephosphorylation, compared with a rapid dephosphorylation of the IGF-I activated receptor. 4) The insulin receptor substrate-1/2-associated PI3K, Shc proteins, and the kinases Akt and Erk1/2, downstream mediators of the antiapoptotic signaling by IGF-IR, were activated to a higher extent and for a longer time period by ATA, compared with IGF-I. Taken together, the sustained activation of the IGF-IR signaling pathway by ATA may explain its stronger antiapoptotic effect. We suggest that this enhanced activity, and the different susceptibility of the IGF-IR to certain proteases and phosphatases, may indicate a distinct conformation of the ATA-activated IGF-IR.


Huntington disease: genetics and epidemiology.
Huntington disease (HD) is an autosomal dominant disorder in which the major gene expression occurs in the central nervous system. It is characterized by the appearance of progressive chorea and dementia, usually in adult life. One tragic aspect of the disorder, due to its late age of onset and, until recently, lack of a presymptomatic marker, is that transmission of the disease to offspring invariably occurs before symptoms develop in the parent. Although the onset of symptoms and the rate of progression may vary, the prognosis is one of relentless deterioration. The major pathological features of HD are a primary loss of cells in the caudate nucleus and putamen (striatum) but other regions of the basal ganglia, hypothalamus, and brain stem are also involved. Not only is there neuronal loss but there is also a decrease in the level of a number of neurotransmitters and associated enzymes, together with abnormalities in some receptor sites. Martin [1] described the disease as "genetically programmed cell death in the human central nervous system."


Aqueous extract of pomegranate enriched in ellagitannins prevents anxiety-like behavior and metabolic changes induced by cafeteria diet in an animal model of menopause.
Women around menopause are vulnerable to present psychiatric and metabolic disorders; thus, therapies that contribute to treat both pathologies are required. Previous reports showed that an aqueous extract of pomegranate (Punica granatum), enriched in ellagitannins, exerts an antidepressant-like effect in ovariectomized rats. We analyze whether this aqueous extract of P. granatum (AE-PG) prevents the anxiety-like behavior induced by a cafeteria diet (CAF) in middle-aged ovariectomized rats at the same time that it prevents an increase in body weight, glucose, lipids, and the changes on mRNA expression of the peroxisome proliferator-activated receptor-gamma (PPAR-γ) in the liver. Also, the effects of AE-PG on the protein levels of PPAR-γphospho-PPAR-γ, extracellular signal-regulated protein kinase (ERK1/2) and phospho-ERK1/2 were measured in the hippocampus and amygdala. CAF induced anxiety-like behavior, augmented lipids and glucose blood levels, body weight, visceral fat, insulin resistance, and decreased mRNA expression of PPAR-γ in the liver. In rats fed with the CAF, AE-PG prevented the anxiety-like behavior, reduced body weight, lowered lipid levels, reduced insulin resistance, and increased PPAR-γ mRNA expression in the liver. In the hippocampus, ERK1/2 but not PPAR-γ protein levels were decreased by CAF, while AE-PG prevented these effects. In the amygdala, CAF increased the phosphorylation of PPARγ, and AE-PG prevented it. In contrast, AE-PG rescued the decreased ERK1/2 protein level in the hippocampus caused by CAF. In conclusion, AE-PG treatment prevented anxiogenic and metabolic effects induced by CAF, and its effects appear to be mediated by ERK1/2 and PPARγ depending on the brain area studied.


Quadriplegia due to pachymeningitis, vasculitis and sepsis in a patient with rheumatoid arthritis: a case report.
We report the case of a 84-year-old man, with history of rheumatoid arthritis, admitted the Hospital for a fall and complaining of dysaesthesia and pain located to the cervical spine and arms. Within a few hours after admission, fever and acute, progressive, ascendant quadriplegia became evident. Magnetic resonance imaging (MRI) of cervical spine showed spinal canal stenosis between C4-C6 with spinal cord compression. Hemocultures resulted positive for Staphylococcus aureus. The clinical picture rapidly evolved to sepsis with a fatal multi-organ failure. An autopsy found a osteosclerosis narrowing the neurocanal at the level of C3-C6, and recent cervical medulla infarction. A histological exam revealed the presence of a suppurative pachymeningitis with local phenomenas of periradiculitis, vasculitis and thrombosis of the anterior medullar artery, associated with coagulative necrosis of the neural tissue.