Phytantriol-Based Berberine-Loaded Liquid Crystalline Nanoparticles Attenuate Inflammation and Oxidative Stress in Lipopolysaccharide-Induced RAW264.7 Macrophages.
Inflammation and oxidative stress are interrelated processes that represent the underlying causes of several chronic inflammatory diseases that include asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD), allergies, diabetes, and cardiovascular diseases. Macrophages are key initiators of inflammatory processes in the body. When triggered by a stimulus such as bacterial lipopolysaccharides (LPS), these cells secrete inflammatory cytokines namely TNF-α that orchestrate the cellular inflammatory process. Simultaneously, pro-inflammatory stimuli induce the upregulation of inducible nitric oxide synthase (iNOS) which catalyzes the generation of high levels of nitric oxide (NO). This, together with high concentrations of reactive oxygen species (ROS) produced by macrophages, mediate oxidative stress which, in turn, exacerbates inflammation in a feedback loop, resulting in the pathogenesis of several chronic inflammatory diseases. Berberine is a phytochemical embedded with potent in vitro anti-inflammatory and antioxidant properties, whose therapeutic application is hindered by poor solubility and bioavailability. For this reason, large doses of berberine need to be administered to achieve the desired pharmacological effect, which may result in toxicity. Encapsulation of such a drug in liquid crystalline nanoparticles (LCNs) represents a viable strategy to overcome these limitations. We encapsulated berberine in phytantriol-based LCNs (BP-LCNs) and tested the antioxidant and anti-inflammatory activities of BP-LCNs in vitro on LPS-induced mouse RAW264.7 macrophages. BP-LCNs showed potent anti-inflammatory and antioxidant activities, with significant reduction in the gene expressions of TNF-α and iNOS, followed by concomitant reduction of ROS and NO production at a concentration of 2.5 µM, which is lower than the concentration of free berberine concentration required to achieve similar effects as reported elsewhere. Furthermore, we provide evidence for the suitability for BP-LCNs both as an antioxidant and as an anti-inflammatory agent with potential application in the therapy of chronic inflammatory diseases.


Development and validation of the Charcot-Marie-Tooth Disease Infant Scale.
Many genetic subtypes of Charcot-Marie-Tooth disease (CMT) show signs of symptomatic disease during the earliest years of life. This might be the ideal time to intervene before progression of clinical sequelae due to demyelination and axonal loss. In the absence of disease-specific clinical trial outcome measures for CMT during infancy and early childhood the aim of this study was to develop and validate a functional measure of disease severity, known as the Charcot-Marie-Tooth disease Infant Scale (CMTInfS). Development projects involved identification of a preliminary pool of 31 items representing the range of disability in affected patients aged 0-4 years from a systematic review of the literature, peer review by 12 expert clinicians and researchers in the field, design of a scoring algorithm and pilot testing in 22 participants. Subsequently, a series of validation projects were conducted based on 128 assessments of: 26 confirmed cases of inherited neuropathy (17 CMT1A, one CMT1B, one CMT1D, one CMT2C, one CMT2S, two CMT4C, one CMTX3, one Riboflavin Transporter Deficiency Type 2, and one unidentified mutation); seven 'at risk' cases and 95 unaffected healthy controls recruited through the NIH-funded Inherited Neuropathies Consortium. Validation projects included: Item, Factor and Rasch analysis, intra- and inter-rater reliability, discriminant ability and convergent validity with the CMT Pediatric Scale (CMTPedS) for children aged 3-4 years. Development and validation projects produced a psychometrically robust 15-item scale. Rasch analysis supported the viability of the CMTInfS as a unidimensional measure of disease severity and showed good overall model fit, no evidence of misfitting items or persons and was well targeted for affected children. The CMTInfS demonstrated high intra-rater reliability [intraclass correlation coefficient (ICC)3,1 0.999, 95% confidence interval 0.996-1.000) and inter-rater reliability (ICC2,1 0.997, 95% confidence interval 0.992-0.999). The CMTInfS was able to discriminate between the CMT group and controls (P = 0.006), and convergent validity demonstrated good agreement between CMTInfS and CMTPedS scores (r = 0.76, P = 0.01). The final version of the CMTInfS requires 20 min to administer and is a reliable and sensitive functional outcome measure for early onset CMT and related neuropathies.10.1093/brain/awy280_video1awy280media15970672819001.


Determination of Glucose-Independent Racial Disparity in HbA1c for Youth With Type 1 Diabetes in the Era of Continuous Glucose Monitoring.
The magnitude and importance of higher HbA1c levels not due to mean blood glucose (MBG) in non-Hispanic black (B) versus non-Hispanic white (W) individuals is controversial. We sought to clarify the relationship of HbA1c with glucose data from continuous glucose monitoring (CGM) in a young biracial population. Glycemic data of 33 B and 85 W, healthy youth with type 1 diabetes (age 14.7 ± 4.8 years, M/F = 51/67, duration of diabetes 5.4 ± 4.7 years) from a factory-calibrated CGM was compared with HbA1c. Hemoglobin glycation index (HGI) = assayed HbA1c - glucose management index (GMI). B patients had higher unadjusted levels of HbA1c, MBG, MBGSD, GMI, and HGI than W patients. Percent glucose time in range (TIR) and percent sensor use (PSU) were lower for B patients. Average HbA1c in B patients 8.3% was higher than 7.7% for W (P < .0001) after statistical adjustment for MBG, age, gender, insulin delivery method, and accounting for a race by PSU interaction effect. Higher HbA1c persisted in B patients when TIR was substituted for MBG. Predicted MBG was higher in B patients at any level of PSU. The 95th percentile for HGI was 0.47 in W patients, and 52% of B patients had HGI ≥ 0.5. Time below range was similar for both. Young B patients have clinically relevant higher average HbA1c at any given level of MBG or TIR than W patients, which may pose an additional risk for diabetes complications development. HGI ≥ 0.5 may be an easy way to identify high-risk patients.


Control by association: Transfer of implicitly primed attentional states across linked stimuli.
Although cognitive control has traditionally been viewed in opposition to associative learning, recent studies show that people can learn to link particular stimuli with specific cognitive control states (e.g., high attentional selectivity). Here, we tested whether such learned stimulus-control associations can transfer across paired-associates. In the Stimulus-Stimulus (S-S) Association phase, specific face or house images repeatedly preceded the presentation of particular scene stimuli, creating paired face/house-scene associates in memory. The Stimulus-Control (S-C) Association phase then associated these scenes with different attentional control states by probabilistically biasing specific scenes to mostly precede either congruent or incongruent trials in a Stroop task. Finally, in the Stimulus-Control Transfer (S-CT) phase, the faces and houses from the S-S phase preceded Stroop trials but were not predictive of congruency, testing whether stimulus-control associations would transfer from scenes to their associated face/house stimuli. In Experiments 1 and 3, we found that learned implicit stimulus-control associations could transfer across closely linked cues, and in Experiment 2, we showed that this transfer depended on the memory associations formed in the S-S phase. While this form of transfer learning has previously been demonstrated for stimulus-reward associations, the present study provides the first evidence for the associative transfer of stimulus-control associations across arbitrarily linked stimuli. This work demonstrates how people can learn to implicitly adapt their processing strategies in a flexible context-dependent manner and establishes a novel learning mechanism supporting the generalization of cognitive control.


Regulation of cellular polyamine levels and cellular proliferation by antizyme and antizyme inhibitor.
Polyamines are small aliphatic polycations present in all living cells. Polyamines are essential for cellular viability and are involved in regulating fundamental cellular processes, most notably cellular growth and proliferation. Being such central regulators of fundamental cellular functions, the intracellular polyamine concentration is tightly regulated at the levels of synthesis, uptake, excretion and catabolism. ODC (ornithine decarboxylase) is the first key enzyme in the polyamine biosynthesis pathway. ODC is characterized by an extremely rapid intracellular turnover rate, a trait that is central to the regulation of cellular polyamine homoeostasis. The degradation rate of ODC is regulated by its end-products, the polyamines, via a unique autoregulatory circuit. At the centre of this circuit is a small protein called Az (antizyme), whose synthesis is stimulated by polyamines. Az inactivates ODC and targets it to ubiquitin-independent degradation by the 26S proteasome. In addition, Az inhibits uptake of polyamines. Az itself is regulated by another ODC-related protein termed AzI (antizyme inhibitor). AzI is highly homologous with ODC, but it lacks ornithine-decarboxylating activity. Its ability to serve as a regulator is based on its high affinity to Az, which is greater than the affinity Az has to ODC. As a result, it interferes with the binding of Az to ODC, thus rescuing ODC from degradation and permitting uptake of polyamines.


Physical activity and clustered cardiovascular disease risk factors in young children: a cross-sectional study (the IDEFICS study).
The relevance of physical activity (PA) for combating cardiovascular disease (CVD) risk in children has been highlighted, but to date there has been no large-scale study analyzing that association in children aged ≤9 years of age. This study sought to evaluate the associations between objectively-measured PA and clustered CVD risk factors in a large sample of European children, and to provide evidence for gender-specific recommendations of PA. Cross-sectional data from a longitudinal study in 16,224 children aged 2 to 9 were collected. Of these, 3,120 (1,016 between 2 to 6 years, 2,104 between 6 to 9 years) had sufficient data for inclusion in the current analyses. Two different age-specific and gender-specific clustered CVD risk scores associated with PA were determined. First, a CVD risk factor (CRF) continuous score was computed using the following variables: systolic blood pressure (SBP), total triglycerides (TG), total cholesterol (TC)/high-density lipoprotein cholesterol (HDL-c) ratio, homeostasis model assessment of insulin resistance (HOMA-IR), and sum of two skinfolds (score CRFs). Secondly, another CVD risk score was obtained for older children containing the score CRFs + the cardiorespiratory fitness variable (termed score CRFs + fit). Data used in the current analysis were derived from the IDEFICS ('Identification and prevention of Dietary- and lifestyle-induced health EFfects In Children and infantS') study. In boys <6 years, the odds ratios (OR) for CVD risk were elevated in the least active quintile of PA (OR: 2.58) compared with the most active quintile as well as the second quintile for vigorous PA (OR: 2.91). Compared with the most active quintile, older children in the first, second and third quintiles had OR for CVD risk score CRFs + fit ranging from OR 2.69 to 5.40 in boys, and from OR 2.85 to 7.05 in girls. PA is important to protect against clustering of CVD risk factors in young children, being more consistent in those older than 6 years. Healthcare professionals should recommend around 60 and 85 min/day of moderate-to-vigorous PA, including 20 min/day of vigorous PA.


UV-ozone cleaning of supported poly(vinylpyrrolidone)-stabilized palladium nanocubes: effect of stabilizer removal on morphology and catalytic behavior.
Poly(vinylpyrrolidone) (PVP)-stabilized Pd nanocubes were synthesized, deposited on a carbon-based support, and subsequently treated with UV-ozone (UVO) in order to eliminate the traces of PVP still present on the surface. Cubes, being a thermodynamically unfavorable shape, are very prone to restructuring to minimize the interfacial free energy and thus allow the assessment of their morphological stability during UVO cleaning. The process of PVP removal was monitored by X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD) and in situ attenuated total reflection infrared spectroscopy (ATR-IR). High-resolution scanning electron microscopy (SEM) imaging was used to evaluate the morphology of the nanocubes. The effect of PVP removal was also studied in the hydrogenation of acetylene, showing a 4-fold increase of activity. This method can be applied to nanoparticles of other common shapes, which expose different crystal planes, in order to study the structure sensitivity of chemical reactions.


Blood lead and hemoglobin levels in Andean children with chronic lead intoxication.
This study investigated blood lead (PbB) and hemoglobin (HbB) levels in 88 children (42 females and 46 males; ages: 2-15 years; mean age: 7.2) with chronic Pb exposure, living in a highly Pb-contaminated Andean village at above 2800 meters. The mean PbB level for 88 venous blood samples was 43.2 microg/dl (SD: 25.1; range: 6.2 - 128.2 microg/dl) measured by ICP-MS, and 42.0 microg/dl (SD: 26.0; range: 5.0 - 130.0 microg/dl) by GFAAS analysis. The mean PbB level for the 42 females was 41.0 microg/dl and for 46 males, 45.0 microg/dl. Multiple regression analysis showed a significant gender by age interaction (R2 = 0.099; F = 4.173, p = 0.044), indicating a relationship between age and PbB level for males, but not for females. Simple regression analysis showed a statistically significant positive correlation between PbB levels and age for males (r = 0.416, p = 0.004), but not for females (r = -0.042, p = .793). The measured mean HbB level for the 88 children was 12.6 g/dl (12.5 g/dl for females and 12.8 g/dl for males) and lower than expected for children living in the Ecuadorian Andes. The mean altitude-corrected HbB level was 10.9 g/dl (10.8 g/dl for females and 11.1 g/dl for males). A significant inverse correlation between PbB and HbB levels was observed for the group of 88 children (r = -0.292, p = 0.006). Multiple regression analyses indicated no significant age and gender interaction (R2 = 0.014; F = 0.025, p = 0.876) for HbB levels. In conclusion, the results of this investigation indicate that the children in this Pb-contaminated, high altitude study area had chronic elevated PbB levels, which increased with age for males, and probable Pb-induced anemia.


The lipid flippase ATP10B enables cellular lipid uptake under stress conditions.
Pathogenic ATP10B variants have been described in patients with Parkinson's disease and dementia with Lewy body disease, and we previously established ATP10B as a late endo-/lysosomal lipid flippase transporting both phosphatidylcholine (PC) and glucosylceramide (GluCer) from the lysosomal exoplasmic to cytoplasmic membrane leaflet. Since several other lipid flippases regulate cellular lipid uptake, we here examined whether also ATP10B impacts cellular lipid uptake. Transient co-expression of ATP10B with its obligatory subunit CDC50A stimulated the uptake of fluorescently (NBD-) labeled PC in HeLa cells. This uptake is dependent on the transport function of ATP10B, is impaired by disease-associated variants and appears specific for NBD-PC. Uptake of non-ATP10B substrates, such as NBD-sphingomyelin or NBD-phosphatidylethanolamine is not increased. Remarkably, in stable cell lines co-expressing ATP10B/CDC50A we only observed increased NBD-PC uptake following treatment with rotenone, a mitochondrial complex I inhibitor that induces transport-dependent ATP10B phenotypes. Conversely, Im95m and WM-115 cells with endogenous ATP10B expression, present a decreased NBD-PC uptake following ATP10B knockdown, an effect that is exacerbated under rotenone stress. Our data show that the endo-/lysosomal lipid flippase ATP10B contributes to cellular PC uptake under specific cell stress conditions.


Lymphatic injury and regeneration in cardiac allografts.
Severed donor heart lymphatics are not anastomosed to recipient lymphatics in cardiac transplantation. We evaluated the effects of cellular infiltrates of T cells and macrophages on the morphology of lymphatics in heart grafts. Dark agouti hearts were transplanted to Lewis or control dark agouti rats on subtherapeutic doses of cyclosporin. Transplants were examined by immunohistology and quantitative immunofluorescence microscopy using lymphatic endothelial hyaluronan receptor-1 as a lymphatic marker and CD8 and CD68 as markers for cellular infiltration at selected intervals from 1 to 8 weeks posttransplantation. Allograft inner myocardial lymphatic density decreased by more than 30-fold at 1 week and recovered to only 15% of the native level at 8 weeks posttransplantation. In contrast, allograft lymphatics in and near the epicardium showed no significant density decline but increased in size by more than 5-fold at 2 weeks, and sustained approximately 3-fold increase at 8 weeks posttransplantation. Lymphatic changes correlated temporally with the extent of T cell and macrophage infiltration in allografts, which peaked at 2 to 3 weeks posttransplantation. When grafts were retransplanted from allogeneic to isogeneic recipients at 3 weeks posttransplantation, inner lymphatic density returned close to native level within 2 weeks after retransplantation. This is the first characterization of regional and morphologic effects of immunologic responses on heart lymphatics after transplantation. Elimination of alloimmune responses produces rapid restoration of inner lymphatic vessels, suggesting that lymphatics injured during rejection can recover when rejection is reversed during the posttransplantation course.


Kinetic investigation reveals an HIV-1 Nef-dependent increase in AP-2 recruitment and productivity at endocytic sites.
The HIV-1 accessory protein Nef hijacks clathrin adaptors to degrade or mislocalize host proteins involved in antiviral defenses. Here, using quantitative live-cell microscopy in genome-edited Jurkat cells, we investigate the impact of Nef on clathrin-mediated endocytosis (CME), a major pathway for membrane protein internalization in mammalian cells. Nef is recruited to CME sites on the plasma membrane, and this recruitment is associated with an increase in the recruitment and lifetime of the CME coat protein AP-2 and the late-arriving CME protein dynamin2. Furthermore, we find that CME sites that recruit Nef are more likely to recruit dynamin2 and transferrin, suggesting that Nef recruitment to CME sites promotes site maturation to ensure high efficiency in host protein downregulation. Implications of these observations for HIV-1 infection are discussed.


Online Moral Disengagement, Cyberbullying, and Cyber-Aggression.
The study of moral disengagement has greatly informed research on aggression and bullying. There has been some debate on whether cyberbullies and other cyber-aggressors show more or less of a tendency for moral disengagement than traditional aggressors and bullies. However, according to the triadic model of reciprocal determinism, an individual's behavior influences and is influenced by both personal factors and his/her social environment. This article reviews the literature to propose a new conceptual framework addressing how features of the online context may enable specific mechanisms that facilitate moral disengagement. Specific affordances for moral disengagement proposed here include the paucity of social-emotional cues, the ease of disseminating communication via social networks, and the media attention on cyberbullying, which may elicit moral justification, euphemistic labeling, palliative comparison, diffusion and displacement of responsibility, minimizing and disregarding the consequences for others, dehumanization, and attribution of blame. These ideas suggest that by providing affordances for these mechanisms of moral disengagement, online settings may facilitate cyber-aggression and cyberbullying.


Critical appraisal of eculizumab for atypical hemolytic uremic syndrome.
The biology of atypical hemolytic uremic syndrome has been shown to involve inability to limit activation of the alternative complement pathway, with subsequent damage to systemic endothelial beds and the vasculature, resulting in the prototypic findings of a thrombotic microangiopathy. Central to this process is the formation of the terminal membrane attack complex C5b-9. Recently, application of a monoclonal antibody that specifically binds to C5, eculizumab, became available to treat patients with atypical hemolytic uremic syndrome, replacing plasma exchange or infusion as primary therapy. This review focuses on the evidence, based on published clinical trials, case series, and case reports, on the efficacy and safety of this approach.


The development of a prototype database for the voluntary reporting of occupational exposure data on chemicals.
A prototype occupational exposure database was developed as part of a study to retrospectively collect chemical exposure data from U.K. industry. The data dictionary for the database was constructed using existing recommendations on core data elements developed by working groups from the ACGIH and the European Union. The study also made use of existing job and workplace coding schemes. The practicalities of gathering the data by voluntary donation, its storage in a database, and the transfer of suitably anonymised data to the U.K. Health and Safety Executive's National Exposure Database system were investigated and assessed. Prior to the development, several existing exposure database systems were evaluated for their suitability to store the data from the study. Though of high quality, these were found to be insufficiently flexible for the diversity of datasets encountered and so the prototype exposure database was constructed using a leading database development package. The database was successfully used to gather data and forward it in a suitable format to the U.K. Health and Safety Executive. The published recommendations on occupational exposure databases and the associated coding schemes provided a very useful foundation for designing and implementing the prototype database. However, as data collection proceeded it became clear that the existing recommendations often were poorly understood and misinterpreted, or at least interpreted differently, by different database designers, data collectors, and other users of occupational exposure data. It is suggested that several items in the ACGIH and European Union core recommendations are ambiguous and need to be clarified. Once agreed, the improved database design criteria need to be widely promoted to foster a common understanding and to encourage their use by all those involved in collecting occupational exposure data. Beyond this, recommendations for exposure databases should be augmented to facilitate easy exchange of data between organizations.


Family History Extraction From Synthetic Clinical Narratives Using Natural Language Processing: Overview and Evaluation of a Challenge Data Set and Solutions for the 2019 National NLP Clinical Challenges (n2c2)/Open Health Natural Language Processing (OHNLP) Competition.
As a risk factor for many diseases, family history (FH) captures both shared genetic variations and living environments among family members. Though there are several systems focusing on FH extraction using natural language processing (NLP) techniques, the evaluation protocol of such systems has not been standardized. The n2c2/OHNLP (National NLP Clinical Challenges/Open Health Natural Language Processing) 2019 FH extraction task aims to encourage the community efforts on a standard evaluation and system development on FH extraction from synthetic clinical narratives. We organized the first BioCreative/OHNLP FH extraction shared task in 2018. We continued the shared task in 2019 in collaboration with the n2c2 and OHNLP consortium, and organized the 2019 n2c2/OHNLP FH extraction track. The shared task comprises 2 subtasks. Subtask 1 focuses on identifying family member entities and clinical observations (diseases), and subtask 2 expects the association of the living status, side of the family, and clinical observations with family members to be extracted. Subtask 2 is an end-to-end task which is based on the result of subtask 1. We manually curated the first deidentified clinical narrative from FH sections of clinical notes at Mayo Clinic Rochester, the content of which is highly relevant to patients' FH. A total of 17 teams from all over the world participated in the n2c2/OHNLP FH extraction shared task, where 38 runs were submitted for subtask 1 and 21 runs were submitted for subtask 2. For subtask 1, the top 3 runs were generated by Harbin Institute of Technology, ezDI, Inc., and The Medical University of South Carolina with F1 scores of 0.8745, 0.8225, and 0.8130, respectively. For subtask 2, the top 3 runs were from Harbin Institute of Technology, ezDI, Inc., and University of Florida with F1 scores of 0.681, 0.6586, and 0.6544, respectively. The workshop was held in conjunction with the AMIA 2019 Fall Symposium. A wide variety of methods were used by different teams in both tasks, such as Bidirectional Encoder Representations from Transformers, convolutional neural network, bidirectional long short-term memory, conditional random field, support vector machine, and rule-based strategies. System performances show that relation extraction from FH is a more challenging task when compared to entity identification task.


Heterogeneous nitrogen fixation rates confer energetic advantage and expanded ecological niche of unicellular diazotroph populations.
Nitrogen fixing plankton provide nitrogen to fuel marine ecosystems and biogeochemical cycles but the factors that constrain their growth and habitat remain poorly understood. Here we investigate the importance of metabolic specialization in unicellular diazotroph populations, using laboratory experiments and model simulations. In clonal cultures of Crocosphaera watsonii and Cyanothece sp. spiked with 15N2, cellular 15N enrichment developed a bimodal distribution within colonies, indicating that N2 fixation was confined to a subpopulation. In a model of population metabolism, heterogeneous nitrogen (N2) fixation rates substantially reduce the respiration rate required to protect nitrogenase from O2. The energy savings from metabolic specialization is highest at slow growth rates, allowing populations to survive in deeper waters where light is low but nutrients are high. Our results suggest that heterogeneous N2 fixation in colonies of unicellular diazotrophs confers an energetic advantage that expands the ecological niche and may have facilitated the evolution of multicellular diazotrophs.


The lateral femoral wall thickness on the risk of post-operative lateral wall fracture in intertrochanteric fracture after DHS fixation: A finite element analysis.
Patients with a lateral femoral wall (LFW) fracture were reported to have high rates of re-operation and complication. Although the LFW thickness was a reliable predictor of post-operative or intra-operative LFW fracture, there was a paucity of literature evaluating the critical stress distributions on the femur and screws of intertrochanteric fractures treated with dynamic hip screw (DHS). This study aimed to investigate the biomechanical performance of intertrochanteric fractures with different LFW thickness treated with DHS device. A three-dimensional model of the proximal femur was established by computed tomography images. The intertrochanteric fracture model with three different LFW thickness (10 mm, 20.5 mm and 30 mm, respectively) was created, which was fixed by DHS. The von Mises stress on the proximal femur, lateral femoral wall, DHS and the total displacement of the device components were evaluated and compared for three different LFW thickness model. The maximum von Mises stress in the proximal fragment of the 10 and 20.5 mm model increased by 80.56% and 57.97% when compared with the 30 mm model. The peek von Mises stress around the blade entry point of the 10 mm and 20.5 mm model increased by 89.26% and 66.39% when compared with the 30 mm model. The peek von Mises in the DHS located near the junction of the barrel and side plate of each model and the 30 mm model had the smallest von Mises stress compared with the other two models. Furthermore, the maximum displacement in the 30 mm model was much smaller than that in the10mm model and 20 mm model. The intertrochanteric fracture with a thinner LFW tended to have a higher risk of LFW fracture stabilized by a DHS device. Thus, the intertrochanteric fractures with a thinner LFW should not be treated by DHS alone and the intramedullary nail or an addition of trochanteric stabilization plate(TSP) was recommended.


Lipoma arborescens (diffuse articular lipomatosis).
Lipoma arborescens (LA) (diffuse articular lipomatosis, synovial lipomatosis, Hoffa disease) is a rare intra-articular lesion of unknown etiology. This article presents three patients who had LA, which was diagnosed in the knee in two patients and in the wrist of the third patient. Details of the clinical and histomorphological examination and treatment, in addition to a review of the literature, are discussed. The article concludes that in patients with a slow increase in painless swelling of the joints, unresolving articular pain with or without limited motion, or intermittent effusions following a minor trauma, LA should be considered in the differential diagnosis. It should be remembered that LA occurs in joints other than the knee, such as the elbow, shoulder, and wrist. Although recommended surgery involves arthrotomy and synovectomy, arthroscopic synovectomy may be a useful treatment modality, particularly in the larger joints as the recurrence rate is low.


Globo-H ceramide shed from cancer cells triggers translin-associated factor X-dependent angiogenesis.
Tumor angiogenesis is a critical element of cancer progression, and strategies for its selective blockade are still sought. Here, we examine the angiogenic effects of Globo-H ceramide (GHCer), the most prevalent glycolipid in a majority of epithelial cancers and one that acts as an immune checkpoint. Here, we report that GHCer becomes incorporated into endothelial cells through the absorption of microvesicles shed from tumor cells. In endothelial cells, GHCer addition induces migration, tube formation, and intracellular Ca(2+) mobilization in vitro and angiogenesis in vivo. Breast cancer cells expressing high levels of GHCer displayed relatively greater tumorigenicity and angiogenesis compared with cells expressing low levels of Globo-H. Clincally, GHCer(+) breast cancer specimens contained higher vessel density than GHCer(-) breast cancer specimens. Mechanistic investigations linked the angiogenic effects of GHCer to its endocytosis and binding to TRAX, with consequent release of PLCβ1 from TRAX to trigger Ca(2+) mobilization. Together, our findings highlight the importance of GHC as a target for cancer therapy by providing new information on its key role in tumor angiogenesis.


Potentialities in integral care: uterine cervical cancer prevention according to the users of the family health strategy.
This study aimed to analyze the integral care in the uterine cervical cancer prevention practices in the conception of users of the Family Health Strategy through an exploratory and descriptive research with a qualitative approach. A total of 14 users who performed the Pap smear in December 2002 in four Family Health Units affiliated to Higher Education institutions were selected for the study. Data were collected between April and June 2003. We found that the users analyze and assess the praxis by issuing a value judgment about the care they receive, mainly in terms of light (relational) technologies. Concluding, humanized practices provided by professional/team favor integral care, strengthening the bond between users and health services, as well as health promotion.


Role of nontypeable Haemophilus influenzae in otitis media and chronic obstructive pulmonary disease.
In both infants and adults, infections with non-typeable Haemophilus influenzae (NTHI) results in morbidity and mortality. NTHI strains are the leading cause of bacterial otitis media infections (both acute and recurrent) in young children and are also responsible for chronic obstructive pulmonary disease (COPD) exacerbations in current and former smokers. The realization that NTHI causes serious infections in humans has generated interest in the study of the pathogenesis associated with this bacterium and also stimulated considerable efforts towards the evaluation of candidate vaccines that will elicit protective immunity. As NTHI is exclusively a human pathogen and has not been associated with any diseases in other mammals, special efforts have been necessary to establish animal models of NTHI infection to generate useful data on the pathogenesis of infection and efficacy of potential vaccines. This article provides a brief summary of the role of NTHI in disease and the work that has been accomplished by us and several other investigators.


Correlates of adaptive behavior profiles in a large cohort of children with autism: The autism speaks Autism Treatment Network registry data.
Children with autism spectrum disorder have deficits in adaptive functioning. This study examines the adaptive behavior, its association with cognitive ability, gender, age, and symptom severity in children with autism spectrum disorder. Using data from Autism Treatment Network registry, the adaptive behavior profiles were examined in 2538 school-aged children (between 5 and 17 years, mean: 8.8 years, standard deviation: 3.0) who had an overall intelligence quotient and Vineland Adaptive Behavior Scale scores available. The children were grouped according to their intelligence quotient (low intelligence quotient < 70; borderline intelligence quotient = 70-85; average intelligence quotient > 85), age (5-10 and 11-17 years), and gender for the analyses. Significantly lower Vineland Adaptive Behavior Scale scores were found in borderline and average intelligence quotient groups when compared to mean intelligence quotient, while an opposite pattern was seen in the low intelligence quotient group, with better adaptive behavior scores than mean intelligence quotient. Vineland Adaptive Behavior Scale standard scores were positively correlated with intelligence quotient and poorly associated with autism spectrum disorder severity. Younger children had significantly higher Vineland Adaptive Behavior Scale scores. Adjusted comparisons by gender were not significant. Adaptive behavior profiles in the intelligence quotient categories are discussed. This study confirms a positive relationship between adaptive behavior and intellectual function in autism and indicates that children with higher intelligence quotient and older age are specifically impaired, with lower adaptive behavior, highlighting the need for assessment and targeted intervention in these groups. Future directions for research are discussed.


Factors influencing physical activity in patients with early rheumatoid arthritis: A mixed-methods study.
The goal of this study was to provide a greater understanding of physical activity in patients with early rheumatoid arthritis. The aim was twofold: first to explore if physical activity was associated with factors in the clinical picture of rheumatoid arthritis in this patient group, and second, to explore factors influencing physical activity in patients with early rheumatoid arthritis. A total of 66 patients with early rheumatoid arthritis were included in the study. A sequential explanatory mixed-methods design was used, where quantitative data from a questionnaire were analysed with Mann-Whitney, post hoc Kruskal-Wallis and χ2 test in order to detect differences between groups, and find possible associations between physical activity and independent variables, such as disease activity, health-related quality of life and physical function. Qualitative data were collected in a follow-up questionnaire with open-ended questions that focused on factors influencing physical activity. Associations between physical activity, disease activity and health-related quality of life were seen in patients with early rheumatoid arthritis together with strong negative correlations between physical activity and physical function. Patients on sick leave showed the strongest associations between disease-related variables and lower levels of physical activity. The findings from the qualitative analysis showed that physical limitations, awareness as a motivational factor and external environment factors influenced physical activity in patients with early rheumatoid arthritis. The results showed a complex underlying motive where physical, psychological and environmental factors influenced the physical activity in patients with early rheumatoid arthritis. In order to provide more effective health interventions, it is important to consider the complex nature of practicing physical activity, where a person-centred approach should be considered. Factors such as physical limitations, economic aspects and time for practicing physical activity should be included in the person-centred approach.


Incomplete suppression of distractor-related activity in the frontal eye field results in curved saccades.
Saccades in the presence of distractors show significant trajectory curvature. Based on previous work in the superior colliculus (SC), we speculated that curvature arises when a movement is initiated before competition between the target and distractor goals has been fully resolved. To test this hypothesis, we recorded frontal eye field (FEF) activity for curved and straight saccades in search. In contrast to the SC, activity in FEF is normally poorly correlated with saccade dynamics. However, the FEF, like the SC, is involved in target selection. Thus if curvature is caused by incomplete target selection, we expect to see its neural correlates in the FEF. We found that saccades that curve toward a distractor are accompanied by an increase in perisaccadic activity of FEF neurons coding the distractor location, and saccades that curve away are accompanied by a decrease in activity. In contrast, for FEF neurons coding the target location, there is no significant difference in activity between curved and straight saccades. To establish that the distractor-related activity is causally related to saccade curvature, we applied microstimulation to sites in the FEF before saccades to targets presented without distractors. The stimulation was subthreshold for evoking saccades and the temporal structure of the stimulation train resembled the activity recorded for curved saccades. The resulting movements curved toward the location coded by the stimulation site. These results support the idea that saccade curvature results from incomplete suppression of distractor-related activity during target selection.


Association between physical activity and all-cause mortality: A 15-year follow-up using a compositional data analysis.
The association between the composition of movement behaviors and mortality risk, acknowledging the composition nature of daily time data, is limited explored. The aim was to investigate how the composition of time spent in sedentary behaviors (SB), light intensity physical activity (LIPA), and moderate-to-vigorous physical activity (MVPA) is associated with all-cause mortality, in a cohort with 15 years follow-up time, using compositional data analysis. Eight hundred fifty-one participants (56% women, mean age 53 years) provided objectively assessed physical activity data using an ActiGraph accelerometer and were followed for 15 years. Association of daily time composition of movement behaviors with risk of mortality was explored using compositional data analysis and hazard ratios (HR) of mortality were estimated based on a cox regression model. A significant (P < .001) positive association between time spent in SB relative to time in other behaviors and a significant (P = .018) negative association between time spent in LIPA relative to time in other behaviors, with all-cause mortality, were found. Substituting time spent in LIPA or MVPA with time in SB increased the hazard for all-cause mortality, with greater effect found for MVPA (20 minutes replacement; HR 1.26, 95% CI 1.04-1.52) than for LIPA (20 minutes replacement; HR 1.06, 95% CI 0.65-1.73). In a public health perspective, it is recommended to substitute SB with either LIPA or MVPA, but for individuals with little time spent in MVPA, the most important message may be to try to maintain that behavior.


Factors influencing the integration of evidence-based task-strengthening strategies for hypertension control within HIV clinics in Nigeria.
Evidence-based task-strengthening strategies for hypertension (HTN) control (TASSH) are not readily available for patients living with HIV in sub-Saharan Africa where the dual burden of HTN and HIV remains high. We are conducting a cluster randomized controlled trial comparing the effectiveness of practice facilitation versus a self-directed control (i.e., receipt of TASSH with no practice facilitation) in reducing blood pressure and increasing the adoption of task-strengthening strategies for HTN control within HIV clinics in Nigeria. Prior to implementing the trial, we conducted formative research to identify factors that may influence the integration of TASSH within HIV clinics in Nigeria. This mixed-methods study was conducted with purposively selected healthcare providers at 29 HIV clinics, followed by a 1-day stakeholder meeting with 19 representatives of HIV clinics. We collected quantitative practice assessment data using two instruments: (a) an adapted Service Availability and Readiness Assessment (SARA) tool to assess the capacity of the clinic to manage NCDs and (b) Implementation Climate Scale to assess the degree to which there is a strategic organizational climate supportive of the evidence-based practice implementation. The quantitative data were analyzed using descriptive statistics and measures of scale reliability. We also used the Consolidated Framework for Implementation Research (CFIR), to thematically analyze qualitative data generated and relevant to the aims of this study. Across the 29 clinics surveyed, the focus on TASSH (mean=1.77 (SD=0.59)) and educational support (mean=1.32 (SD=0.68)) subscales demonstrated the highest mean score, with good-excellent internal consistency reliability (Cronbach's alphas ranging from 0.84 to 0.96). Within the five CFIR domains explored, the major facilitators of the intervention included relative advantage of TASSH compared to current practice, compatibility with clinic organizational structures, support of patients' needs, and intervention alignment with national guidelines. Barriers included the perceived complexity of TASSH, weak referral network and patient tracking mechanism within the clinics, and limited resources and diagnostic equipment for HTN. Optimizing healthcare workers' implementation of evidence-based TASSH within HIV clinics requires attention to both the implementation climate and contextual factors likely to influence adoption and long-term sustainability. These findings have implications for the development of effective practice facilitation strategies to further improve the delivery and integration of TASSH within HIV clinics in Nigeria. ClinicalTrials.gov , NCT04704336.


The essential neutral sphingomyelinase is involved in the trafficking of the variant surface glycoprotein in the bloodstream form of Trypanosoma brucei.
Sphingomyelin is the main sphingolipid in Trypanosoma brucei, the causative agent of African sleeping sickness. In vitro and in vivo characterization of the T. brucei neutral sphingomyelinase demonstrates that it is directly involved in sphingomyelin catabolism. Gene knockout studies in the bloodstream form of the parasite indicate that the neutral sphingomyelinase is essential for growth and survival, thus highlighting that the de novo biosynthesis of ceramide is unable to compensate for the loss of sphingomyelin catabolism. The phenotype of the conditional knockout has given new insights into the highly active endocytic and exocytic pathways in the bloodstream form of T. brucei. Hence, the formation of ceramide in the endoplasmic reticulum affects post-Golgi sorting and rate of deposition of newly synthesized GPI-anchored variant surface glycoprotein on the cell surface. This directly influences the corresponding rate of endocytosis, via the recycling endosomes, of pre-existing cell surface variant surface glycoprotein. The trypanosomes use this coupled endocytic and exocytic mechanism to maintain the cell density of its crucial variant surface glycoprotein protective coat. TbnSMase is therefore genetically validated as a drug target against African trypanosomes, and suggests that interfering with the endocytic transport of variant surface glycoprotein is a highly desirable strategy for drug development against African trypanosomasis.


Processing speed and working memory performance in those with both ADHD and a reading disorder compared with those with ADHD alone.
In previous studies, children with both Attention-Deficit Hyperactivity Disorder (ADHD) and a Reading Disorder were found to have more difficulties with processing speed, working memory, and timed as opposed to non-timed executive functioning (EF) measures when compared with those with either disorder alone. The current study found that older adolescents and adults with both disorders also had more difficulties on processing speed and working memory measures than individuals who only had ADHD. There were no differences among non-timed EF scores. These results add support to the premise that common underlying features may be contributing to the high co-morbidity between these disorders and associated cognitive weaknesses.


Identification of protein IT of the intestinal cytoskeleton as a novel type I cytokeratin with unusual properties and expression patterns.
A major cytoskeletal polypeptide (Mr approximately 46,000; protein IT) of human intestinal epithelium was characterized by biochemical and immunological methods. The polypeptide, which was identified as a specific and genuine mRNA product by translation in vitro, reacted, in immunoblotting after SDS-PAGE, only with one of numerous cytokeratin (CK) antisera tested but with none of many monoclonal CK antibodies. In vitro, it formed heterotypic complexes with the type II CK 8, as shown by blot binding assays and gel electrophoresis in 4 M urea, and these complexes assembled into intermediate filaments (IFs) under appropriate conditions. A chymotrypsin-resistant Mr approximately 38,000 core fragment of protein IT could be obtained from cytoskeletal IFs, indicating its inclusion in a coiled coil. Antibodies raised against protein IT decorated typical CK fibril arrays in normal and transformed intestinal cells. Four proteolytic peptide fragments obtained from purified polypeptide IT exhibited significant amino acid sequence homology with corresponding regions of coils I and II of the rod domain of several other type I CKs. Immunocytochemically, the protein was specifically detected as a prominent component of intestinal and gastric foveolar epithelium, urothelial umbrella cells, and Merkel cells of epidermis. Sparse positive epithelial cells were noted in the thymus, bronchus, gall bladder, and prostate gland. The expression of protein IT was generally maintained in primary and metastatic colorectal carcinomas as well as in cell cultures derived therefrom. A corresponding protein was also found in several other mammalian species. We conclude that polypeptide IT is an integral IF component which is related, though somewhat distantly, to type I CKs, and, therefore, we propose to add it to the human CK catalogue as CK 20.


Cholecystokinin and EGF activate a MAPK cascade by different mechanisms in rat pancreatic acinar cells.
The effects of activating the Gq protein-coupled cholecystokinin (CCK) receptor on different proteins/signaling molecules in the mitogen-activated protein kinase (MAPK) cascade in pancreatic acinar cells were analyzed and compared with the effects of activating the tyrosine kinase-coupled epidermal growth factor (EGF) receptor. Both EGF and CCK octapeptide rapidly increased the activity of the MAPKs [extracellular signal-regulated kinase (ERK) 1 and ERK2], reaching a maximum within 2.5 min when 3.9- and 8.5-fold increases, respectively, were observed. The EGF-induced increase of MAPK activity was transient, with only a slight elevation after 30 min, whereas CCK-stimulated MAPK remained at a high level of activation to 60 min. The protein kinase C inhibitor GF-109203X abolished the activation by phorbol ester and inhibited the effect of CCK by 78% but had no effect on EGF-activated MAPK activity. EGF and CCK activated both forms of MAPK kinase (MEK), with CCK having a much larger effect, activating MEK1 by 6-fold and MEK2 by 10-fold, whereas EGF activated both MEKs by only 2-fold. Immunoblotting revealed three different forms of Raf in pancreatic acinar cells. Of the total basal Raf kinase activity, 3.7% was Raf-A, 89.0% was Raf-B, and 7.3% was c-Raf-1. All three forms of Raf were stimulated to a greater extent by CCK than by EGF, which was especially evident for Raf-A and c-Raf-1. The effect of CCK in activating Rafs was at least partially mimicked by stimulation with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate. EGF significantly increased GTP-bound Ras by 183 and 164% at 2.5 and 10 min, respectively; CCK and TPA had no measurable effect. Our study suggests that CCK and EGF activate the MAPK cascade by distinct mechanisms in pancreatic acinar cells.


Physiochemical property space distribution among human metabolites, drugs and toxins.
The current approach to screen for drug-like molecules is to sieve for molecules with biochemical properties suitable for desirable pharmacokinetics and reduced toxicity, using predominantly biophysical properties of chemical compounds, based on empirical rules such as Lipinski's "rule of five" (Ro5). For over a decade, Ro5 has been applied to combinatorial compounds, drugs and ligands, in the search for suitable lead compounds. Unfortunately, till date, a clear distinction between drugs and non-drugs has not been achieved. The current trend is to seek out drugs which show metabolite-likeness. In identifying similar physicochemical characteristics, compounds have usually been clustered based on some characteristic, to reduce the search space presented by large molecular datasets. This paper examines the similarity of current drug molecules with human metabolites and toxins, using a range of computed molecular descriptors as well as the effect of comparison to clustered data compared to searches against complete datasets. We have carried out statistical and substructure functional group analyses of three datasets, namely human metabolites, drugs and toxin molecules. The distributions of various molecular descriptors were investigated. Our analyses show that, although the three groups are distinct, present-day drugs are closer to toxin molecules than to metabolites. Furthermore, these distributions are quite similar for both clustered data as well as complete or unclustered datasets. The property space occupied by metabolites is dissimilar to that of drugs or toxin molecules, with current drugs showing greater similarity to toxins than to metabolites. Additionally, empirical rules like Ro5 can be refined to identify drugs or drug-like molecules that are clearly distinct from toxic compounds and more metabolite-like. The inclusion of human metabolites in this study provides a deeper insight into metabolite/drug/toxin-like properties and will also prove to be valuable in the prediction or optimization of small molecules as ligands for therapeutic applications.


Minimal dose requirements for nasal mupirocin and its role in the control of epidemic MRSA.
Staphylococci are still a leading cause of hospital infection. The success of nasal mupirocin for the control of epidemic methicillin-resistant Staphylococcus aureus (EMRSA), the prevention of colonization of central venous cannulae, and the prevention of septicaemia in haemodialysis patients should encourage the use of minimal dose regimens to minimize the emergence of mupirocin resistance. Mupirocin applied to the anterior nares 4-times daily usually eliminates S. aureus, including EMRSA, within 48 h. Elimination is sustained for several weeks in patients and staff. We recently found that a single dose, or a regimen of 4-times daily for 2 days, eliminated nasal carriage of S. aureus within 24 h; 7 days after a single dose, 92% of the subjects were still cleared; 7 days after the 2-day course, 96% remained free of nasal S. aureus. Ward personnel who are nasal carriers of EMRSA can, provided that other carriage sites are negative, return to work after 2 days of a 4-times daily intranasal regimen. The UK guidelines, recently published in this Journal, recommend an aggressive approach to identifying and eliminating EMRSA, including the elimination of nasal carriage. This approach is increasingly associated with the control of EMRSA in the UK and elsewhere.


A conformational switch in HP1 releases auto-inhibition to drive heterochromatin assembly.
A hallmark of histone H3 lysine 9 (H3K9)-methylated heterochromatin, conserved from the fission yeast Schizosaccharomyces pombe to humans, is its ability to spread to adjacent genomic regions. Central to heterochromatin spread is heterochromatin protein 1 (HP1), which recognizes H3K9-methylated chromatin, oligomerizes and forms a versatile platform that participates in diverse nuclear functions, ranging from gene silencing to chromosome segregation. How HP1 proteins assemble on methylated nucleosomal templates and how the HP1-nucleosome complex achieves functional versatility remain poorly understood. Here we show that binding of the key S. pombe HP1 protein, Swi6, to methylated nucleosomes drives a switch from an auto-inhibited state to a spreading-competent state. In the auto-inhibited state, a histone-mimic sequence in one Swi6 monomer blocks methyl-mark recognition by the chromodomain of another monomer. Auto-inhibition is relieved by recognition of two template features, the H3K9 methyl mark and nucleosomal DNA. Cryo-electron-microscopy-based reconstruction of the Swi6-nucleosome complex provides the overall architecture of the spreading-competent state in which two unbound chromodomain sticky ends appear exposed. Disruption of the switch between the auto-inhibited and spreading-competent states disrupts heterochromatin assembly and gene silencing in vivo. These findings are reminiscent of other conditionally activated polymerization processes, such as actin nucleation, and open up a new class of regulatory mechanisms that operate on chromatin in vivo.


Physiological pharmacokinetic and pharmacodynamic model of physostigmine in the rat.
A physiological model for physostigmine disposition was developed in the rat which incorporated anatomical, physiological, and biochemical parameters, i.e. tissue volume, plasma flow rates, drug metabolism, and tissue-to-plasma partition coefficients. Predicted concentrations of physostigmine in different tissue compartments were consistent with the experimental observations in the rat following an iv dose. Part of this study also compared the time course changes in measured effect, as percentage change in cholinesterase activity in brain, and related these changes to the plasma or brain drug level in either a combined pharmacokinetic-pharmacodynamic (plasma physostigmine-effect relationship) or a dynamic model (brain physostigmine-effect relationship). Fitting the time course of the effect in a pharmacokinetic-pharmacodynamic model required an effect compartment with the equilibration rate constant between it and the plasma compartment. Both models help to understand whether the cholinesterase activity is homogeneous or heterogenous in the brain.


[Endothelin and ATP-sensitive potassium channel mediate electrophysiological changes induced by hypoxia in rabbit sinoatrial node].
The role of ET and KATP channel in hypoxia-induced negative chronotropic effect of pacemaker cells in rabbit sinoatrial node was studied with intracellular microelectrode technique. The results obtained were as follows: (1) Hypoxia produced a progressive decrease in the velocity of diastolic depolarization (VDD) of pacemaker cells resulting in a reduced rate of pacemaker firing (RPF), and induced a decrease in APD, especially APD50. (2) KATP channel opener cromakalim markedly induced a negative chronotropic effect in a concentration-dependent manner and significantly shortened APD50. KATP channel blocker glibenclamide alleviated the effects of hypoxia on pacemaker cells, thereby suggesting the involvement of KATP channel in the hypoxia-induced effects. (3) By superfusion of ET-1, the hypoxia-induced decrease in RPF was remarkably potentiated and the occurrence of pacemaker arrest was shifted to an earlier time. The hypoxia-induced effects could be effectively attenuated after pretreatment with BQ-123, implying the role of endogenous ET-1 release in hypoxia-induced effects. It is concluded that the negative chronotropic effect and the decrease in APD induced by hypoxia may be attributed to the activation of KATP channel and the release of endogenous ET.


Alzheimer's disease and long-term care: the assessment of the patient.
We briefly touched on the excitement, then quickly moved into the trenches. There are models for providing accurate assessments, both for patients with dedicated families and for those who are isolated. The models are imperfect, and await improvement from our colleagues and students. We have also documented the fact that families know what they are talking about (hardly a revelation to experienced clinicians). A refinement in the diagnosis of Alzheimer's disease is that depression and medical illness are more likely to aggravate Alzheimer's than to imitate it. An understanding of this element will help in keeping our evaluation and treatment plans accurate and useful. There is plenty of work for all of us--scientists, clinicians, and caretakers--who are involved with the assessment and long-term care of those with Alzheimer's. We may use different means toward the common goal of reducing suffering, but we all need each other.


SNI case of the week: Initial concomitant use of gabapentin, clonidine, and prednisone may enhance suicidal ideation: A case report.
Suicide cases are the end product of a combination of biological, clinical, psychological, social, and cultural risk/protective factors, and attempts to remain unpredictable. A 43-year-old male presented to the hospital with jaundiced skin/eyes of 7 days' duration. He had a history of a major depressive disorder and chronic alcohol consumption (e.g., 3-5 alcoholic drinks/day for the past 15 years). Studies documented acute hepatic disease (e.g., biopsy-documented hepatocellular alcoholic hepatitis), accompanied by a cholestatic disease. The patient was discharged on clonidine, iron multivitamin, folic acid, gabapentin, and prednisone. Eight days postdischarge from the hospital, he committed suicide (e.g., self- inflicted gunshot wound to the head). Concomitant administration of gabapentin, prednisone, and clonidine, especially if used for the first time, may play a synergistic effect in increasing a patient's suicide risk.


Environmental Canalization of Life Span and Gene Expression in Caenorhabditis elegans.
Animals, particularly poikilotherms, exhibit distinct physiologies at different environmental temperatures. Here, we hypothesized that temperature-based differences in physiology could affect the amount of variation in complex quantitative traits. Specifically, we examined, in Caenorhabditis elegans, how different temperatures (15°C, 20°C, and 25°C) affected the amount of interindividual variation in life span and also expression of three reporter genes-transcriptional reporters for vit-2, gpd-2, and hsp-16.2 (a life-span biomarker). We found the expected inverse relationship between temperature and average life span. Surprisingly, we found that at the highest temperature, there were fewer differences between individuals in life span and less interindividual variation in expression of all three reporters. We suggest that growth at 25°C might canalize (reduce interindividual differences in) life span and expression of some genes by eliciting a small constitutive heat shock response. Growth at 25°C requires wild-type hsf-1, which encodes the main heat shock response transcriptional activator. We speculate that increased chaperone activity at 25°C may reduce interindividual variation in gene expression by increasing protein folding efficiency. We hypothesize that reduced variation in gene expression may ultimately cause reduced variation in life span.


Taiwanofungus camphoratus (Syn Antrodia camphorata) extract and amphotericin B exert adjuvant effects via mitochondrial apoptotic pathway.
The use of multiple drugs in cancer therapy increases the efficacy of the potential therapeutic effects. In this study, the authors investigated the adjuvant effects of an ethanol extract of solid-state cultivated Taiwanofungus camphoratus (TCEE) and amphotericin B (AmB) in the human cancer cell lines RPMI7951 and MG63. Taiwanofungus camphoratus is a well-known Chinese medicine in Taiwan, and AmB is a widely used antifungal agent. The authors demonstrated that TCEE pretreatment followed by AmB treatment effectively inhibited cell growth. The combination of sublethal doses of TCEE and AmB revealed a significant growth inhibitory effect in both cell lines. The combination of TCEE and AmB but not AmB alone induced phosphatidylserine externalization and loss of mitochondrial membrane potential. Cell cycle analyses revealed that combination of TCEE and AmB triggered G2/M arrest and significant apoptosis after 48 hours. These effects were greater than those achieved using TCEE or AmB alone. Furthermore, the authors demonstrated that the drugs increased the levels of p21(Cip1/Waf1) and pro-apoptotic protein Bax and reduced the level of anti-apoptotic protein Bcl-2. Taken together, the results showed that the combination treatment of TCEE and AmB displays strong adjuvant effects, which are indicated by the inhibition of cell proliferation in 2 human cancer cell lines, RPMI7951 and MG63. These findings suggest possible therapeutic applications and alternative medicines using this drug combination.


ABO genotyping of suspects from sperm DNA isolated from postcoital samples in sex crimes.
In sexual assaults against women, one key to identifying the suspect is ABO phenotyping or the typing of other polymorphic markers of the seminal fluid in the victim's vagina. However, ABO phenotyping is frequently unsuccessful, since mixtures of fluids cannot be separated to be subjected to conventional methods for the detection of antibody or antigen material. We therefore studied ABO blood group genotyping of sperm DNA isolated from contaminating vaginal fluid by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Seminal samples of genotypes OO, AO, BO and AB were experimentally mixed with vaginal fluid (OO, AO, BO and AB), and were successfully separated and genotyped by this method. In practice, we also separated and genotyped the seminal DNA of suspects from contaminated postcoital vaginal fluid obtained in 4 sexual assaults. These forensic samples were easily separated and completely genotyped. This reliable ABO genotyping method by PCR-RFLP, using separated sperm DNA, should be of value in forensic identification in sexual assaults.


The use of comet assay to assess DNA integrity of boar spermatozoa following liquid preservation at 5 degrees C and 16 degrees C.
The comet assay, under neutral conditions, allows the assessment of DNA integrity influenced by sperm ageing, which is manifested in DNA double-strand breaks. Here, we attempted to use a modified neutral comet assay test (single-cell gel electrophoresis), to our knowledge for the first time, to assess DNA integrity of boar spermatozoa during liquid storage for 96 h at 5 degrees C and 16 degrees C. In this comet assay protocol we used 2% beta-mercaptoethanol prior to the lysis procedure, to aid in removing nuclear proteins. Ejaculates from 3 boars (designated A, C and G) were diluted with a standard semen extender, Kortowo-3 (K-3), which was supplemented with lipoprotein fractions extracted from hen egg yolk (LPFh) or ostrich egg yolk (LPFo). Irrespective of the extender type, the percentage of comet-detected spermatozoa with damaged DNA increased gradually during prolonged storage at 5 degrees C and 16 degrees C. Spermatozoa stored in K-3 extender exhibited elevated levels of DNA damage at both storage temperatures. Significant differences in DNA damage among the boars were more pronounced during storage in LPF-based extenders at 5 degrees C: spermatozoa of boars A and G were less susceptible to DNA damage. The percent of tail DNA in comets was lower in LPF-based extenders, and there were individual variations among the boars. We observed that changes in DNA integrity were dependent on the extender type and storage temperature. A higher level of DNA instability was observed in K-3 extended semen compared with K-3/LPFh or K-3/LPFo extended semen during storage at 5 degrees C. No significant difference in the level of DNA damage between K-3/LPFh and K-3/LPFo was observed. It seems that a long-term storage can affect genomic integrity of boar spermatozoa. The modified neutral comet assay can be used to detect low levels of DNA damage in boar spermatozoa during liquid preservation. Therefore, screening for sperm DNA damage may be used as an additional test of sperm function that can have diagnostic value in practice.


A revision of the Pediacus Shuckard 1839 (Coleoptera: Cucujidae) of Asia and Australasia.
The Pediacus Shuckard fauna of Asia and Australasia is revised. Eighteen species are recorded, described and illustrated from the regions and a key to species is provided. Nine new species are described: Pediacus australis sp. nov. (Australia, Papua New Guinea, Philippines, Thailand), P. carinatus sp. nov. (Indonesia, Malaysia, Thailand), P. fujianensis sp. nov. (China), P. japonicoides sp. nov. (Taiwan); P. leei sp. nov. (Taiwan), P. pendleburyi sp. nov. (Malaysia), P. sinensis sp. nov. (China), P. taiwanensis sp. nov. (Taiwan) and P. thomasi sp. nov. (Taiwan). A checklist of the Pediacus fauna of the world is given, listing a total of 31 species.


High Folate, Perturbed One-Carbon Metabolism and Gestational Diabetes Mellitus.
Folate is a dietary micronutrient essential to one-carbon metabolism. The World Health Organisation recommends folic acid (FA) supplementation pre-conception and in early pregnancy to reduce the risk of fetal neural tube defects (NTDs). Subsequently, many countries (~92) have mandatory FA fortification policies, as well as recommendations for periconceptional FA supplementation. Mandatory fortification initiatives have been largely successful in reducing the incidence of NTDs. However, humans have limited capacity to incorporate FA into the one-carbon metabolic pathway, resulting in the increasingly ubiquitous presence of circulating unmetabolised folic acid (uFA). Excess FA intake has emerged as a risk factor in gestational diabetes mellitus (GDM). Several other one-carbon metabolism components (vitamin B12, homocysteine and choline-derived betaine) are also closely entwined with GDM risk, suggesting a role for one-carbon metabolism in GDM pathogenesis. There is growing evidence from in vitro and animal studies suggesting a role for excess FA in dysregulation of one-carbon metabolism. Specifically, high levels of FA reduce methylenetetrahydrofolate reductase (MTHFR) activity, dysregulate the balance of thymidylate synthase (TS) and methionine synthase (MTR) activity, and elevate homocysteine. High homocysteine is associated with increased oxidative stress and trophoblast apoptosis and reduced human chorionic gonadotrophin (hCG) secretion and pancreatic β-cell function. While the relationship between high FA, perturbed one-carbon metabolism and GDM pathogenesis is not yet fully understood, here we summarise the current state of knowledge. Given rising rates of GDM, now estimated to be 14% globally, and widespread FA food fortification, further research is urgently needed to elucidate the mechanisms which underpin GDM pathogenesis.


[Orthopedic surgery and traumatology].
Terrorist explosions cause destruction of material goods and human injury on such a scale that the provision of healthcare in available centers can be compromised. In the last few years we have witnessed terrible terrorist attacks that affect us increasingly closely. The authors describe the intervention of the Department of Traumatology of a university hospital in response to a terrorist attack that left nearly 2,000 persons wounded and 191 dead. As usually occurs in these attacks, the victims' lesions were characterized by the severity and extension of the tissue damage, including penetrating wounds, blast injuries and burns. Critical analysis of previous disasters described by our colleagues in the medical literature is useful to avoid future errors.


Mechanisms of neurodegeration in type 2 diabetes and the neuroprotective potential of dipeptidyl peptidase 4 inhibitors.
Prospective epidemiological studies suggest that type 2 diabetes is a risk factor for neurodegenerative pathologies such as Alzheimer disease, vascular dementia, and Parkinson disease. Drugs that act as incretin receptor agonists or inhibit the proteolytic degradation of incretins (dipeptidyl peptidase 4 inhibitors) have been approved since 2005 for use in diabetes treatment. Dipeptidyl peptidase 4 (DPP4) cleaves N-terminal dipeptides from polypeptides when the second residue is proline, hydroxyproline, dehydroproline or alanine. The inhibition of DPP4 hydrolytic activities extends the halflife of these peptides by preventing their degradation. Several peptides have been identified as DPP4 substrates, including neuropeptides, chemokines, and the incretin hormones; hence the pleomorphic effects of DPP4 inhibition. Recently, the neuroprotective properties of these drugs have been evaluated in cell cultures and animal models, not yet in human trials. Although mechanisms distinct from glycaemic control alone have been claimed to account for protection against neuronal degeneration, the precise cellular mechanism by which DPP4 inhibitors exert their neuroprotective effects remain unknown. The present review is focused on the candidate pathways that could be involved in mediating DPP4 inhibitors-mediated protection against neuronal degeneration.


Altitude affects the reproductive performance in monoicous and dioicous bryophytes: examples from a Brazilian Atlantic rainforest.
Short life cycles and trade-offs linked to breeding systems make bryophytes good models for the study of plant reproductive strategies. Our aim was to test if differences in sexual reproductive performance of bryophytes in tropical rainforests are driven by the breeding system of the species (monoicous or dioicous) or are mainly affected by the habitat. The reproductive performance (sexual branches, gametangia (sex organs), fertilization and sporophyte production) of 11 species was repeatedly monitored and analysed from populations at sea-level and montane sites of a Brazilian Atlantic rainforest over 15 months. Monoicous species had the highest reproductive performance, particularly for sexual branches, fertilized gametangia and sporophyte production. Species at the sea-level site produced more sexual branches and had more female-biased sex ratios of gametangia than species in the montane site. Fertilizations were more frequent at the montane site, but sporophyte frequency was similar between the two sites. Fertilization tended to occur mostly in the periods of heavy rain (October to December). Breeding system is not the only major influence on the reproductive performance of bryophytes. We show that habitat is also an important factor determining life-history differentiation. Female-biased sex ratios and low rates of fertilization are seen to be compensated for by high production of reproductive structures at the initial phases of the reproductive cycle.


Gene therapy applications for fracture-healing.
Biologic therapies to promote fracture-healing such as use of bone morphogenetic proteins (BMPs) are being increasingly employed in multiple clinical scenarios. However, it has been challenging to design therapies that deliver sufficient quantities of protein over a sustained time period. A potential solution is the application of gene therapy that transfers genetic information to host cells at the fracture site, resulting in the continuous and localized production of the desired proteins. This approach has demonstrated tremendous potential in preclinical animal models of fracture-healing. This article will review the current state of gene therapy approaches to fracture-healing with an emphasis on potential clinical applications.


Variation and Trends in Antidepressant Prescribing for Men Undergoing Treatment for Nonmetastatic Prostate Cancer: A Population-based Cohort Study.
Psychological distress is prevalent among men with prostate cancer (PCa). However, the variation in antidepressant use among individuals throughout the survivorship period is unknown. We sought to examine the variation and trends in receipt of antidepressants after PCa treatment, among patients with nonmetastatic PCa. Using population-based linked administrative data, we identified men ≥66 yr old who underwent surgery (n=4952), radiotherapy (n=4994), or surveillance (n=2136), and these men were matched to general population controls (n=57127). One year prior to PCa treatment, 7.7% of men received an antidepressant prescription, which increased to 10.5% in the year after treatment. In difference-in-differences analysis, adjusted for demographic and health characteristics, men had increased odds of antidepressant receipt up to 5 yr after surgery (odds ratio [OR] 1.49; 95% confidence interval [CI] 1.35-1.64; p≤0.0001) or radiotherapy (OR 1.33; 95% CI 1.21-1.47; p≤0.0001). Men did not have an increased risk of antidepressant receipt up to 5 yr after surveillance (OR 1.15; 95% CI 0.94-1.41; p=0.16). Limitations include the potential for selection bias and misclassification due to the retrospective design of the study and the use of administrative databases. Thus, men with nonmetastatic PCa who initially receive surgery or radiotherapy, but not those who initially undergo surveillance, have an increased risk of antidepressant receipt after treatment. PATIENT SUMMARY: In this report, we examined antidepressant prescription for men after treatment of nonmetastatic prostate cancer across the entire population of men ≥66 yr in Ontario, Canada, from 2002 to 2009. For men diagnosed with nonmetastatic prostate cancer, the risk of antidepressant receipt at 5 yr after treatment was significantly increased after surgery or radiotherapy, but not after surveillance. Providers and patients should consider the psychological effects of prostate cancer treatment during the survivorship period.


Clients' Experiences of Returning to the Trauma Site during PTSD Treatment: An Exploratory Study.
Visits to the location of the trauma are often included in trauma-focused cognitive behavioural therapy (TF-CBT) for post-traumatic stress disorder (PTSD), but no research to date has explored how service users experience these visits, or whether and how they form an effective part of treatment. The study aimed to ascertain whether participants found site visits helpful, to test whether the functions of the site visit predicted by cognitive theories of PTSD were endorsed, and to create a grounded theory model of how site visits are experienced. Feedback was collected from 25 participants who had revisited the scene of the trauma as part of TF-CBT for PTSD. The questionnaire included both free text items, for qualitative analysis, and forced-choice questions regarding hypothesized functions of the site visit. Overall, participants found the site visits helpful, and endorsed the functions predicted by the cognitive model. A model derived from the feedback illustrated four main processes occurring during the site visit: "facing and overcoming fear"; "filling in the gaps"; "learning from experiences" and "different look and feel to the site", which, when conducted with "help and support", usually from the therapist, led to a sense of "closure and moving on". Therapist-accompanied site visits may have various useful therapeutic functions and participants experience them positively.


HPV in HIV-Infected Women: Implications for Primary Prevention.
There is growing evidence that human immunodeficiency virus (HIV)-infected women might have a different human papillomavirus (HPV) type distribution in cervical dysplasia specimens as compared to the general population. This has implications for primary prevention. We aimed to obtain preliminary data on the HPV genotypes prevalent in histological samples of HIV-infected women with cervical intraepithelial neoplasia (CIN) 3/CIS of the cervix in Miami, FL, USA. Retrospective data were collected on HIV-infected women referred to the University of Miami-Jackson Memorial Hospital colposcopy clinic between years 2000 and 2008. The histology slides of CIN 3/CIS biopsies underwent pathological review and sections were cut from these archived specimens for HPV DNA extraction. HPV genotyping was then performed using the GeneSquare™ HPV genotyping assay. We report on our first set of 23 samples. Eight high-risk HPV types were detected. Types in decreasing order of frequency were 16, 35, 45, 52, 59, 31, 58, and 56. Most cases had multiple infections. HPV type 16 was the most common (45%) followed by HPV-35 and -45 with equal frequency (40%). No samples contained HPV-18. Our preliminary results suggest that cervical dysplasia specimens of HIV-infected women more likely (55%) contain non-16 and -18 high-risk HPV types. We show that this held true for histologically confirmed severe dysplasia and carcinoma-in situ. Epidemiological studies guide vaccine development, therefore HPV type prevalence in CIS and invasive cervical cancer among HIV-infected women should be more rigorously explored to ensure that this highly vulnerable population receives appropriate primary prevention.


Effect of Lithium on Neurocognitive Functioning.
Lithium is the first choice drug for the long-term prophylaxis of depressive and manic episodes in bipolar disorder (BD). Both experimental and clinical studies show either neuroprotective or neurotoxic effects of lithium on brain function, reflecting the propensity of lithium to affect different brain structures. In most experimental studies, lithium, in therapeutic doses, exerts a favourable influence on various cognitive functions. Patients with BD present cognitive problems of mild intensity across mood states, worsening during manic or depressive episodes and, sometimes, also persisting during euthymia. Meta-analyses, comparing bipolar patients treated with lithium with those without the drug show a moderate negative effect of this drug on cognition and, among clinicians, negative impact on cognitive functioning is considered one of the side effect of the drug. In some studies, the effect of lithium on cognitive function in BD was shown to be associated with a prophylactic efficacy of the drug against an occurrence of affective episodes. Excellent lithium responders, having no affective recurrences during lithium therapy, perform on cognitive functions tests similar to those of age-matched, healthy control subjects. Some studies also found a reduction by lithium the risk of dementia in BD subjects. Possible mechanisms alleviating negative impact of lithium on cognition in BD can be connected with the prevention of affective recurrences, improvement of neural plasticity, antiviral action against herpes infection and using the drug in appropriate doses.


Expression of SLCO1B3 is associated with intratumoral cholestasis and CTNNB1 mutations in hepatocellular carcinoma.
Recent studies have shown that intratumoral cholestasis is a hallmark of CTNNB1 mutations in hepatocellular carcinomas (HCC). Here, we analyzed the expressions of genes involved in bile acid and bilirubin metabolism and their correlation with the mutational status of CTNNB1 in a series of HCC. The expressions of CYP7A1 and CYP27A1, which encode rate-limiting enzymes in bile acid synthesis, were unaltered or only marginally increased in CTNNB1-mutated HCC compared with those in HCC with wild-type CTNNB1. Among the genes involved in bile acid and bilirubin transport, the expression of SLCO1B3 was significantly elevated in HCC with CTNNB1 mutations, whereas the expression of ABCC4 was elevated in HCC with wild-type CTNNB1. Immunohistochemistry confirmed the frequent expression of SLCO1B3 in CTNNB1-mutated HCC at the protein level, but not in most HCC with wild-type CTNNB1. Immunohistochemistry for MRP4 (encoded by ABCC4) partly agreed with ABCC4 expression, but most cases did not express detectable levels of MRP4. Notably, all HCC with bile accumulation, including those without CTNNB1 mutations, expressed SLCO1B3, suggesting that SLCO1B3 expression, rather than CTNNB1 mutation, is the critical determinant of intratumoral cholestasis. As SLCO1B3 is involved in the uptake of a number of chemotherapeutic and diagnostic agents, SLCO1B3 expression and the status of CTNNB1 mutation might need to be considered in the drug delivery to HCC.


Single-gene deletion mutants of Escherichia coli with altered sensitivity to bicyclomycin, an inhibitor of transcription termination factor Rho.
We have screened the entire KEIO collection of 3,985 single-gene knockouts in Escherichia coli for increased susceptibility or resistance to the antibiotic bicyclomycin (BCM), a potent inhibitor of the transcription termination factor Rho. We also compared the results to those of a recent study we conducted with a large set of antibiotics (A. Liu et al., Antimicrob. Agents Chemother. 54:1393-1403, 2010). We find that deletions of many different types of genes increase sensitivity to BCM. Some of these are involved in multidrug sensitivity/resistance, whereas others are specific for BCM. Mutations in a number of DNA recombination and repair genes increase BCM sensitivity, indicating that DNA damage leading to single- and double-strand breaks is a downstream effect of Rho inhibition. MDS42, which is deleted for all cryptic prophages and insertion elements (G. Posfai et al., Science 312:1044-1046, 2006), or W3102 deleted for the rac prophage-encoded kil gene, are partially resistant to BCM (C. J. Cardinale et al., Science 230:935-938, 2008). Deletion of cryptic prophages also overcomes the increased BCM sensitivity in some but not all mutants examined here. Deletion of the hns gene renders the cell more sensitive to BCM even in the Δkil or MDS42 background. This suggests that BCM activates additional modes of cell death independent of Kil and that these could provide a target to potentiate BCM killing.


[Immunohistochemical observation on the proliferative activity of rat liver in early hepatocarcinogenesis].
Anti-BrdU immunoperoxidase staining was used for cytogenetic investigation of altered foci and nodules in rat liver induced by a procedure including intraperitoneal injection of diethylnitrosamine (DEM), feeding of 2-acetoaminoflurene (2-AAF) and 2/3 hepatectomy. Variation in number and size of the altered foci as well as the number of BrdU-positive hepatocytes inside and outside the foci were clearly observed in the early stage of hepatocarcinogenesis. A predominant distribution of BrdU-positive cells was obtained in the peripheral zone of the altered nodules favorable in explaining the phenomenon of monoclonal origin of the altered hepatocytes inside the nodules. This study also indicated that BrdU-immunoperoxidase staining is a reliable and convenient method in studying the dynamic change of DNA-replication in the process of active hepatocellular proliferation.


[The use of linear-array real-time echography in veterinary obstetrics and gynecology].
For the past few years, two-dimensional diagnostic ultrasound methods have become available to veterinary medicine. In particular, linear-array real-time ultrasound would appear to be a very suitable diagnostic tool in the examination of the female genital organs of domestic mammals. The principles of this technique and the equipment available are described, and particular attention is paid to the method by which a diagnosis of pregnancy may be established in various animal species. In dogs and goats shaving will have to be done before the sound-transmitting/receiving transducer can be placed on the abdominal skin. This is not required in pigs and sheep, in which the skin of the inguinal area usually is bare. In mares and cows, the transducer can be introduced into the rectum, thereby minimizing the distance to the genital organs. Personal preliminary observations and the published experience reported by other investigators suggest that linear-array real-time ultrasound can be used: in (early) pregnancy diagnosis, early confirmation of non-pregnancy, prediction of the number of foetuses (mare, cow, sheep and goat), determination and quantification of embryonic/foetal mortality, to assess the viability of a foetus before/during parturition, to diagnose the possible presence of other foetuses on the completion of delivery (bitch, cat, sow), in the diagnosis of an enlarged, though non-pregnant, uterus and in the diagnosis of the ovaries. It can be expected that more quantitative information will come available for each of these uses within the next few years.


Exploratory analysis of cortical thickness in low- and high-fit young adults.
Studies have shown changes in the human brain associated with physical activity and cardiorespiratory fitness (CRF). The effects of CRF on cortical thickness have been well-described in older adults, where a positive association between CRF and cortical thickness has been reported, but the impact of sustained aerobic activity in young adults remains poorly described. Here, exploratory analysis was performed on cortical thickness data that was collected in groups of fit and sedentary young adults. Twenty healthy sedentary individuals (<2 h/week physical activity) were compared to 20 active individuals (>6 h/week physical activity) and cortical thickness was measured in 34 cortical areas. Cortical thickness values were compared between groups, and correlations between cortical thickness and VO2 max were tested. Cardiorespiratory fitness was significantly higher in active individuals compared to sedentary individuals. Cortical thickness was lower in regions of the left (lateral and medial orbitofrontal cortex, pars orbitalis, pars triangularis, rostral anterior cingulate cortex, superior temporal cortex and frontal pole) and right (lateral and medial orbitofrontal cortex and pars opercularis) hemispheres. Only the left frontal pole and right lateral orbitofrontal cortical thickness remained significant after false discovery rate correction. Negative correlations were observed between VO2 max and cortical thickness in the left (frontal pole) and right (caudal anterior cingulate and medial orbitofrontal cortex) hemispheres. The present exploratory analysis supports previous findings suggesting that neuroplastic effects of cardiorespiratory fitness may be attenuated in young compared with older individuals, underscoring a moderating effect of age on the relationship between fitness and cortical thickness.


Global Survey on Telemedicine Utilization for Movement Disorders During the COVID-19 Pandemic.
The COVID-19 pandemic restricted usual healthcare management for movement-disorders patients, with a consequent upsurge in telemedicine to bridge the gap. To assess global telemedicine usage in the context of the pandemic. The Movement Disorder Society (MDS) Telemedicine Study Group surveyed telemedicine experts from 40 countries across all continents in March-April 2020. Four domains of telemedicine were assessed: legal regulations, reimbursement, clinical use, and barriers; comparing emerging responses to the pandemic versus the baseline scenario. All forms of telemedicine for movement disorders increased globally, irrespective of country income categorization, as an immediate response to the pandemic. This was aided by widespread availability of technology and updated government regulations. However, privacy concerns, lack of reimbursement, limited access, and lack of telemedicine training were barriers highlighted worldwide. Questions remain about the longevity and extent of changes in regulations and reimbursement regarding telemedicine in the aftermath of the pandemic. © 2020 International Parkinson and Movement Disorder Society.


Developmental signaling: does it bridge the gap between cilia dysfunction and renal cystogenesis?
For more than a decade, evidence has accumulated linking dysfunction of primary cilia to renal cystogenesis, yet molecular mechanisms remain undefined. The pathogenesis of renal cysts is complex, involving multiple cellular aberrations and signaling pathways. Adding to this complexity, primary cilia exhibit multiple roles in a context-dependent manner. On renal epithelial cells, primary cilia act as mechanosensors and trigger extracellular Ca(2+) influx in response to laminar fluid flow. During mammalian development, primary cilia mediate the Hedgehog (Hh), Wnt, and Notch pathways, which control cell proliferation and differentiation, and tissue morphogenesis. Further, experimental evidence suggests the developmental state of the kidney strongly influences renal cystic disease. Thus, we review evidence for regulation of Ca(2+) and cAMP, key molecules in renal cystogenesis, at the primary cilium, the role of Hh, Wnt, and Notch signaling in renal cystic disease, and the interplay between these developmental pathways and Ca(2+) signaling. Indeed if these developmental pathways influence renal cystogenesis, these may represent novel therapeutic targets that can be integrated into a combination therapy for renal cystic disease.


Access to Primary, Mental Health, and Specialty Care: a Comparison of Medicaid and Commercially Insured Populations in Oregon.
To describe how access to primary and specialty care differs for Medicaid patients relative to commercially insured patients, and how these differences vary across rural and urban counties, using comprehensive claims data from Oregon. Cross-sectional study of risk-adjusted access rates for two types of primary care providers (physicians; nurse practitioners (NPs) and physician assistants (PAs)); four types of mental health providers (psychiatrists, psychologists, advanced practice NPs or PAs specializing in mental health care, behavioral specialists); and four physician specialties (obstetrics and gynecology, general surgery, gastroenterology, dermatology). 420,947 Medicaid and 638,980 commercially insured adults in Oregon, October 2014-September 2015. Presence of any visit with each provider type, risk-adjusted for sex, age, and health conditions. Relative to commercially insured individuals, Medicaid enrollees had lower rates of access to primary care physicians (- 11.82%; CI - 12.01 to - 11.63%) and to some specialists (e.g., obstetrics and gynecology, dermatology), but had equivalent or higher rates of access to NPs and PAs providing primary care (4.33%; CI 4.15 to 4.52%) and a variety of mental health providers (including psychiatrists, NPs and PAs, and other behavioral specialists). Across all providers, the largest gaps in Medicaid-commercial access rates were observed in rural counties. The Medicaid-commercial patient mix was evenly distributed across primary care physicians, suggesting that access for Medicaid patients was not limited to a small subset of primary care providers. This cross-sectional study found lower rates of access to primary care physicians for Medicaid enrollees, but Medicaid-commercial differences in access rates were not present across all provider types and displayed substantial variability across counties. Policies that address rural-urban differences as well as Medicaid-commercial differences-such as expansions of telemedicine or changes in the workforce mix-may have the largest impact on improving access to care across a wide range of populations.


Visual Experience Shapes the Neural Networks Remapping Touch into External Space.
Localizing touch relies on the activation of skin-based and externally defined spatial frames of reference. Psychophysical studies have demonstrated that early visual deprivation prevents the automatic remapping of touch into external space. We used fMRI to characterize how visual experience impacts the brain circuits dedicated to the spatial processing of touch. Sighted and congenitally blind humans performed a tactile temporal order judgment (TOJ) task, either with the hands uncrossed or crossed over the body midline. Behavioral data confirmed that crossing the hands has a detrimental effect on TOJ judgments in sighted but not in early blind people. Crucially, the crossed hand posture elicited enhanced activity, when compared with the uncrossed posture, in a frontoparietal network in the sighted group only. Psychophysiological interaction analysis revealed, however, that the congenitally blind showed enhanced functional connectivity between parietal and frontal regions in the crossed versus uncrossed hand postures. Our results demonstrate that visual experience scaffolds the neural implementation of the location of touch in space.SIGNIFICANCE STATEMENT In daily life, we seamlessly localize touch in external space for action planning toward a stimulus making contact with the body. For efficient sensorimotor integration, the brain has therefore to compute the current position of our limbs in the external world. In the present study, we demonstrate that early visual deprivation alters the brain activity in a dorsal parietofrontal network typically supporting touch localization in the sighted. Our results therefore conclusively demonstrate the intrinsic role that developmental vision plays in scaffolding the neural implementation of touch perception.


Reconciling fault-tolerant distributed algorithms and real-time computing.
We present generic transformations, which allow to translate classic fault-tolerant distributed algorithms and their correctness proofs into a real-time distributed computing model (and vice versa). Owing to the non-zero-time, non-preemptible state transitions employed in our real-time model, scheduling and queuing effects (which are inherently abstracted away in classic zero step-time models, sometimes leading to overly optimistic time complexity results) can be accurately modeled. Our results thus make fault-tolerant distributed algorithms amenable to a sound real-time analysis, without sacrificing the wealth of algorithms and correctness proofs established in classic distributed computing research. By means of an example, we demonstrate that real-time algorithms generated by transforming classic algorithms can be competitive even w.r.t. optimal real-time algorithms, despite their comparatively simple real-time analysis.


One-year clinical evaluation of a two-step self-etch adhesive with and without additional enamel etching technique in cervical lesions.
The aim of this study was to determine the clinical performance of a two-step self-etch adhesive with and without additional enamel etching technique to advanced non-carious cervical sclerotic lesions. Twenty-two patients (mean age = 51.5) having at least two pairs of non-carious cervical erosion/attrition/abfraction lesions with incisal or occlusal margins in enamel and gingival margins in dentine/cementum were included in the study. The two-step self-etch adhesive (AdheSE; Ivoclar-Vivadent) was either applied following the self-etch approach on both enamel and dentine (AdheSE non-etch), or a similar application including additional acid-etching of the enamel cavity margins with 37% phosphoric acid (AdheSE etch). Resin composite Point 4 was used for all 104 restorations. Restorations were evaluated at baseline and at one year according to the modified United States Public Health Service (USPHS) criteria. Data were analysed by using McNemar's test (p <0.05). There were no significant differences in the marginal adaptation both at the cervical and enamel margins between AdheSE non-etch and AdheSE etch groups (p >0.05). At one year, marginal discolouration was evident in the AdheSE non-etch group but it was not statistically significant from the AdheSE etch group (p = 0.12). Postoperative sensitivity was 5% at baseline and reduced to 2% at one year. At one year, the two-step self-etch adhesive with and without additional enamel etching technique showed excellent clinical results to advanced non-carious cervical sclerotic lesions.