Oral liarozole in the treatment of patients with moderate/severe lamellar ichthyosis: results of a randomized, double-blind, multinational, placebo-controlled phase II/III trial.
Oral liarozole, a retinoic acid metabolism-blocking agent, may be an alternative to systemic retinoid therapy in patients with lamellar ichthyosis. To demonstrate the efficacy and safety of once-daily oral liarozole in the treatment of moderate/severe lamellar ichthyosis. This was a double-blind, multinational, parallel phase II/III trial (NCT00282724). Patients aged ≥ 14 years with moderate/severe lamellar ichthyosis [Investigator's Global Assessment (IGA) score ≥ 3] were randomized 3 : 3 : 1 to receive oral liarozole (75 or 150 mg) or placebo once daily for 12 weeks. Assessments included: IGA; a five-point scale for erythema, scaling and pruritus severity; Short Form-36 health survey; Dermatology Life Quality Index (DLQI); and safety parameters. The primary efficacy variable was response rate at week 12 (responder: ≥ 2-point decrease in IGA from baseline). Sixty-four patients were enrolled. At week 12, 11/27 (41%; liarozole 75 mg), 14/28 (50%; liarozole 150 mg) and one out of nine (11%; placebo) patients were responders; the difference between groups (liarozole 150 mg vs. placebo) was not significant (P = 0.056). Mean IGA and scaling scores decreased from baseline in both liarozole groups at weeks 8 and 12 vs. placebo; erythema and pruritus scores were similar between treatment groups. Improvement in DLQI score was observed in both liarozole groups. Treatment with liarozole for 12 weeks was well tolerated. The primary efficacy variable did not reach statistical significance, possibly owing to the small sample size following premature termination. However, once-daily oral liarozole, 75 and 150 mg, improved scaling and DLQI and was well tolerated in patients with moderate/severe lamellar ichthyosis.


Coping styles in substance use disorder (SUD) patients with and without co-occurring attention deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD).
Patients with a substance use disorder (SUD) and co-occurring attention deficit hyperactivity disorder (ADHD) or autism spectrum disorder (ASD) often start using substances in an attempt to cope with the stress related to their ADHD or ASD. To improve treatment for these patient groups, it is important to identify and compare the various coping styles between SUD patients with and without ADHD or ASD and with subjects from a general population sample. Cross-sectional study using the Utrecht Coping List (UCL) in 50 SUD patients, 41 SUD + ADHD patients, 31 SUD + ASD patients and 1,200 railway employees. Compared with the reference group, all three SUD groups showed a significant higher mean on the Palliative reaction, Avoidance, and Passive reaction subscales of the UCL. The scores for all UCL subscales of the SUD and the SUD + ADHD groups were very similar. However, the SUD + ASD group scored higher on Passive reaction and lower on Reassuring thoughts than the SUD and the SUD + ADHD groups and lower on Expression of emotions subscale in comparison with the SUD + ADHD group. Regardless of the presence of a co-occurring disorder, SUD patients reported more palliative, avoidant and passive coping when confronted than people in the general population. In addition, SUD patients with co-occurring ASD were different from other SUD patients in their coping and professionals should take this into account when working on more adaptive coping strategies with these patients.


[Epidemiology and risk factors for prolonged hospital length of stay in children with leukemia and bacteremia. Cohort study].
Bacteremia is a frequent complication in children with cancer, which is associated with greater severity, prolonged hospitalization and mortality. Prolonged hospitalization conditions greater morbidity and risk of acquisition of intranosocomial infections. To describe risk factors for prolonged hospital length of stay in children with leukemia and bacteremia. Cohort study. Episodes of bacteremia in patients with leukemia at Garrahan Hospital from 1/1/2015 to 31/12/2016 were reviewed. We compared data from patients with a LOS of 14 days or more with those admitted for less than 14 days. Bivariate and logistic regression analysis was performed. We used Stata 13 statistical package. n = 121. Median age 59 months.81 patients (67%) had a diagnosis of acute lymphoblastic leukemia, followed by acute myeloid leukemia in 40 (33%). 96 patients (79%) had a central venous catheter (CVC), 94 patients (78%) were neutropenic. Blood cultures were positive for Enterobacteriaceae in 55 cases (45%), coagulase-negative staphylococci in 28 cases (23%), Group viridans Streptococcus in 19 (16%), Pseudomonas aeruginosa in 8 (7%). (9%). By the multivariate analysis, three factors remained significantly associated with length of stay of more than 14 days: CVC associated bacteremia (OR 21,73; CI95% 1.2-43.2; p 0.04), severe neutropenia (OR 1.75; CI95% 1.82-1.28; p 0.03) and coinfection (OR 27.4; CI95% 2.8-260.8; p 0.004). CVC associated bacteremia, severe neutropenia and viral coinfection were associated with hospital LOS of more than 14 days.


Classification Bias of the k-Nearest Neighbor Algorithm.
The k-nearest neighbor classifier has been used extensively in pattern analysis applications. This classifier can, however, have substantial bias when there is little class separation and the sample sizes are unequal. This classification bias is examined for the two-class situation and formulas presented that allows selection of values of k that yields minimum bias.


Extracerebral Tissue Damage in the Intraluminal Filament Mouse Model of Middle Cerebral Artery Occlusion.
Middle cerebral artery occlusion is the most common model of focal cerebral ischemia in the mouse. In the surgical procedure, the external carotid artery (ECA) is ligated; however, its effect on the tissue supplied by the vessel has not been described so far. C57BL/6 mice underwent 1 h of transient MCAO (tMCAO) or sham surgery. Multi-spectral optoacoustic tomography was employed at 30 min after surgery to assess oxygenation in the temporal muscles. Microstructural changes were assessed with magnetic resonance imaging and histological examination at 24 h and 48 h after surgery. Ligation of the ECA resulted in decreased oxygenation of the left temporal muscle in most sham-operated and tMCAO animals. Susceptible mice of both groups exhibited increased T2 relaxation times in the affected muscle with histological evidence of myofibre degeneration, interstitial edema, and neutrophil influx. Ligatures had induced an extensive neutrophil-dominated inflammatory response. ECA ligation leads to distinct hypoxic degenerative changes in the tissue of the ECA territory and to ligature-induced inflammatory processes. An impact on outcome needs to be considered in this stroke model.


[Factors that control stem cell differentiation. II. The sensitivity of T-differentiated lymphocytes to the action of radiation and cytostatics].
Bone marrow stem cells of the parent genotype (CBA) produce mainly erythroid colonies in the spleen of lethally irradiated recipients (CBA-C57Bl)F1. T d-lymphocytes change this differentiation pattern from the mainly erythroid to the mainly myeloid pathway. The irradiation with 100 R does not abolish this effect. The lymphocytes irradiated in vitro with 200 R or more, and incubated with Mitomycin C or Cycloheximide lost the ability to change the differentiation pattern of the transplanted cells. T d-lymphocytes are radiosensitive cells that need DNA and protein synthesis for realizing their function.


Health Care Providers' Trusted Sources for Information About COVID-19 Vaccines: Mixed Methods Study.
Information and opinions shared by health care providers can affect patient vaccination decisions, but little is known about who health care providers themselves trust for information in the context of new COVID-19 vaccines. The purpose of this study is to investigate which sources of information about COVID-19 vaccines are trusted by health care providers and how they communicate this information to patients. This mixed methods study involved a one-time, web-based survey of health care providers and qualitative interviews with a subset of survey respondents. Health care providers (physicians, advanced practice providers, pharmacists, nurses) were recruited from an integrated health system in Southern California using voluntary response sampling, with follow-up interviews with providers who either accepted or declined a COVID-19 vaccine. The outcome was the type of information sources that respondents reported trusting for information about COVID-19 vaccines. Bivariate tests were used to compare trusted information sources by provider type; thematic analysis was used to explore perspectives about vaccine information and communicating with patients about vaccines. The survey was completed by 2948 providers, of whom 91% (n=2683) responded that they had received ≥1 dose of a COVID-19 vaccine. The most frequently trusted source of COVID-19 vaccine information was government agencies (n=2513, 84.2%); the least frequently trusted source was social media (n=691, 9.5%). More physicians trusted government agencies (n=1226, 93%) than nurses (n=927, 78%) or pharmacists (n=203, 78%; P<.001), and more physicians trusted their employer (n=1115, 84%) than advanced practice providers (n=95, 67%) and nurses (n=759, 64%; P=.002). Qualitative themes (n=32 participants) about trusted sources of COVID-19 vaccine information were identified: processing new COVID-19 information in a health care work context likened to a "war zone" during the pandemic and communicating information to patients. Some providers were hesitant to recommend vaccines to pregnant people and groups they perceived to be at low risk for COVID-19. Physicians have stronger trust in government sources and their employers for information about COVID-19 vaccines compared with nurses, pharmacists, and advanced practice providers. Strategies such as role modeling, tailored messaging, or talking points with standard language may help providers to communicate accurate COVID-19 vaccine information to patients, and these strategies may also be used with providers with lower levels of trust in reputable information sources.


A novel technique for the pre-concentration and extraction of inositol hexakisphosphate from soil extracts with determination by phosphorus-31 nuclear magnetic resonance.
Inositol hexakisphosphate (IP6) is often the dominant form of soil organic phosphorus (P), but is rarely investigated because of the analytical difficulties encountered in its extraction, separation, and detection in environmental samples. In particular, recent advances in the study of soil organic P with 31P nuclear magnetic resonance (NMR) have been of limited use for the study of IP6, because the technique does not discriminate between IP6 and other forms of P. This was addressed by developing a novel analytical procedure using the retentive properties of gel-filtration gels for IP6, which allows the combined selective extraction and pre-concentration of IP6 from soil extracts with determination by 31P NMR. While the technique is still in the developmental stage, the results demonstrate that the gel does not interfere with 31P NMR analysis and retains IP6 to concentrations well above those required to give clear spectral signals. The technique has considerable potential for application to the study of IP6 in soil extracts and water samples and, with development, could help to answer fundamental questions regarding the dynamics of organic P in the environment.


Anxiety and stress responses in female oxytocin deficient mice.
Oxytocin is believed to attenuate the response of the hypothalamic-pituitary-adrenal axis to stress and to be anxiolytic. Stressors with a psychological component evoke both central and peripheral secretion of oxytocin in laboratory rodents. Oxytocin gene deletion mice provide a novel way to understand the role of oxytocin in stress and anxiety-related behaviours. We present our experience with female oxytocin deficient mice that were tested in an elevated plus maze (EPM), a behavioural test of anxiety, or exposed to psychogenic stressors (platform shaker or novel environment). Oxytocin-deficient mice not only displayed more anxiety-related behaviour, but also released more corticosterone after a psychogenic stressor and manifested greater stress-induced hyperthermia compared to wild-type mice. The diurnal variation of corticosterone and the response of corticosterone to corticotropin-releasing factor were not significantly different between genotypes. We also measured Fos-immunoreactive protein, an index of neuronal activation, in the medial amygdala of female mice after EPM testing. The medial amygdala is important for processing of psychogenic stress and anxiety and also contains oxytocin pathways and oxytocin receptors. The expression of Fos in the medial amygdala of mice not exposed to the EPM was not different between genotypes. Following EPM exposure, Fos expression was greater in oxytocin null compared to wild-type mice. Our findings support the hypothesis that central oxytocin is anxiolytic, and attenuates the stress response to psychogenic provocation in female mice.


Amplifications of proto-oncogenes in ovarian carcinoma.
Thirty-two cases of ovarian carcinoma, two of normal ovaries, four of benign epithelial ovarian tumor, and three of borderline epithelial ovarian tumor were studied using Southern blot hybridization of DNA. In 15 of the 32 cases of ovarian carcinoma, peripheral lymphocytes were also studied. The amplification rate of C-myc, C-N-ras, C-Ki-ras and C-erbB-2 in ovarian carcinoma were 50%, 44%, 31% and 25% respectively. The amplification of C-Ki-ras and C-N-ras took place chiefly in cases of early stage and those of good differentiation. The amplification of C-N-ras was also found in cases of advanced stage. The amplifications of C-myc and C-erbB-2 were chiefly found in cases above stage III and those of poor differentiation. A total of 83% of the patients who died were found to have amplifications of more than 2 proto-oncogenes, with which the amplification of C-erbB-2 was involved.


A shuttle mechanism for DNA-protein interactions. The regulation of poly(ADP-ribose) polymerase.
Previously it had been shown that poly(ADP-ribose) polymerase requires DNA for its activity and that this enzyme is auto-poly(ADP-ribosyl)ated. The studies reported here indicate that this self-modification inhibits the enzyme and decreases its affinity for DNA, as shown by sucrose gradient density centrifugation. The coupling of poly(ADP-ribose) polymerase with poly(ADP-ribose) glycohydrolase reactivates the polymerase by degrading poly(ADP-ribose) and restoring the polymerase-DNA complex. The assay of polymerase in the presence of glyco-hydrolase was made possible by use of a double-label assay involving release of 14C-labelled nicotinamide and the incorporation of 3H-labelled ADP-ribose from NAD+. These results provide the basis for a shuttle mechanism in which the polymerase can be moved on and off DNA by the action of these two enzymes. Mg2+ and histone H1 appear to activate the polymerase by increasing the affinity of the polymerase for DNA.


Direct role of dynein motor in stable kinetochore-microtubule attachment, orientation, and alignment.
Cytoplasmic dynein has been implicated in diverse mitotic functions, several involving its association with kinetochores. Much of the supporting evidence comes from inhibition of dynein regulatory factors. To obtain direct insight into kinetochore dynein function, we expressed a series of dynein tail fragments, which we find displace motor-containing dynein heavy chain (HC) from kinetochores without affecting other subunits, regulatory factors, or microtubule binding proteins. Cells with bipolar mitotic spindles progress to late prometaphase-metaphase at normal rates. However, the dynein tail, dynactin, Mad1, and BubR1 persist at the aligned kinetochores, which is consistent with a role for dynein in self-removal and spindle assembly checkpoint inactivation. Kinetochore pairs also show evidence of misorientation relative to the spindle equator and abnormal oscillatory behavior. Further, kinetochore microtubule bundles are severely destabilized at reduced temperatures. Dynein HC RNAi and injection of anti-dynein antibody in MG132-arrested metaphase cells produced similar effects. These results identify a novel function for the dynein motor in stable microtubule attachment and maintenance of kinetochore orientation during metaphase chromosome alignment.


FoldX accurate structural protein-DNA binding prediction using PADA1 (Protein Assisted DNA Assembly 1).
The speed at which new genomes are being sequenced highlights the need for genome-wide methods capable of predicting protein-DNA interactions. Here, we present PADA1, a generic algorithm that accurately models structural complexes and predicts the DNA-binding regions of resolved protein structures. PADA1 relies on a library of protein and double-stranded DNA fragment pairs obtained from a training set of 2103 DNA-protein complexes. It includes a fast statistical force field computed from atom-atom distances, to evaluate and filter the 3D docking models. Using published benchmark validation sets and 212 DNA-protein structures published after 2016 we predicted the DNA-binding regions with an RMSD of <1.8 Å per residue in >95% of the cases. We show that the quality of the docked templates is compatible with FoldX protein design tool suite to identify the crystallized DNA molecule sequence as the most energetically favorable in 80% of the cases. We highlighted the biological potential of PADA1 by reconstituting DNA and protein conformational changes upon protein mutagenesis of a meganuclease and its variants, and by predicting DNA-binding regions and nucleotide sequences in proteins crystallized without DNA. These results opens up new perspectives for the engineering of DNA-protein interfaces.


Management of radiation necrosis of the chest wall following mastectomy: a new treatment option.
A technique for covering areas of osteoradionecrosis in the medial aspect of the chest wall has been described. Utilizing a tissue expander, the skin was stretched sufficiently to obtain a suitable length whereby the medial defect could be covered and the donor site closed primarily. Such an operative approach should be considered when the patient presents with a medially located ulcer of small to moderate size and when nonirradiated skin is regionally available. Using this technique, long myocutaneous flaps that require extensive dissection, loss of functioning muscle, and resulting donor defects are avoided.


Peripheral T Cell Non-Hodgkin's Lymphoma following Treatment of Hodgkin's Lymphoma.
Previous reports have suggested that non-Hodgkin's lymphoma (NHL) is more likely to develop in patients with Hodgkin lymphoma (HL) compared to the general population. These two can occur synchronously or metachronously. We report here on a case of nodular sclerosis classical HL and T cell NHL that occurred in a patient metachronously. Peripheral T cell lymphoma (PTCL) of the patient was found about 2 years after treatment of classical HL. When the patient was diagnosed with HL, biopsy revealed typical RS cells, presenting positive for CD30 and CD15 and negative for CD79a and CD3 in immunohistochemistry. And PCR analysis showed IgH gene rearrangement; however, T cell receptor gene rearrangement and Epstein-Barr virus (EBV) were not detected on PCR analysis. After 2 years of treatment of HL, colonoscopic biopsy and lymph node biopsy showed CD3 positive atypical cells intermixed with small reactive lymphoid cells and plasma cells, indicating T cell lymphoma. PCR analysis demonstrated T cell receptor gene rearrangement and did not detect EBV. Although it is rare, synchronous or metachronous HL and NHL may occur. Therefore, we may need to ensure pathological confirmation, especially in case of lymphoma that did not respond to chemotherapy.


Evaluation of the central and peripheral components for induction of postural hypotension by guanethidine, clonidine, dopamine2 receptor agonists and 5-hydroxytryptamine1A receptor agonists.
Previously, it was observed that the severity of postural hypotension in rats after i.v. administration is: guanethidine (severe) greater than clonidine greater than dopamine2 (DA2) receptor agonists greater than 5-hydroxytryptamine1A (5-HT1A) receptor agonists (none). In this paper we investigated central and peripheral mechanisms involved in postural hypotension induced by these drugs. Intracerebroventricular or intracisternal doses of the above agents produced a fall in mean arterial pressure of 32 to 42 mm Hg and were used for evaluation of the central component. Intracerebroventricular, but not intracisternal, clonidine induced postural hypotension. DA2 or 5-HT1A receptor agonists did not induce postural hypotension after either i.c.v. or intracisternal administration. Intracerebroventricular guanethidine did not lower arterial pressure dose-dependently, or did it produce postural hypotension. A peripheral action postulated to be involved in the postural hypotension was inhibition of sympathetic neurotransmission; to evaluate this inhibition, drug effects on pressor and tachycardiac responses elicited by electrical stimulation in pithed rats were determined. Inhibition of heart rate changes by each of the drugs was: guanethidine, 60 to 100% at 0.1 to 8.0 Hz; clonidine, 20 to 40% at 0.1 to 2.0 Hz; DA2 receptor agonists, 10 to 45% at 0.1 to 2.0 Hz; and 5-HT1A receptor agonists, 20 to 40% at less than or equal to 0.5 Hz. These data indicate that the frequency selective inhibition in the peripheral sympathetic nervous system may explain the likelihood of postural hypotension for guanethidine, clonidine DA2 and 5-HT1A receptor agonists. Clonidine has some central component for induction of postural hypotension in addition to the frequency-related peripheral component.


Myeloid/natural killer (NK) cell precursor acute leukemia as a distinct leukemia type.
Myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL) has been described on the basis of its unique immunophenotype and clinical phenotype. However, there is no consensus on the characteristics for identifying this disease type because of its rarity and lack of defined distinctive molecular characteristics. In this study, multiomics analysis revealed that MNKPL is distinct from acute myeloid leukemia, T cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia (MPAL), and NOTCH1 and RUNX3 activation and BCL11B down-regulation are hallmarks of MNKPL. Although NK cells have been classically considered to be lymphoid lineage-derived, the results of our single-cell analysis using MNKPL cells suggest that NK cells and myeloid cells share common progenitor cells. Treatment outcomes for MNKPL are unsatisfactory, even when hematopoietic cell transplantation is performed. Multiomics analysis and in vitro drug sensitivity assays revealed increased sensitivity to l-asparaginase and reduced levels of asparagine synthetase (ASNS), supporting the clinically observed effectiveness of l-asparaginase.


Adenocarcinoma in a Barrett oesophagus.
A case of adenocarcinoma developing at the squamocolumnar epithelial junction of a Barrett oesophagus is reported. This rare tumour was remarkable because of the youth of the patient and because of the signet-cell cytological pattern of the neoplasm. It is postulated that both the columnar epithelial lining of the lower part of the oesophagus and the malignant change are a consequence of long-standing oesophageal reflux.


A multifunctional amphiphilic polymer as a platform for surface-functionalizing metallic and other inorganic nanostructures.
We designed a new set of polymer ligands that combine multiple metal-coordinating groups and short polyethylene glycol (PEG) moieties in the same structure. The ligand design relies on the controlled grafting of a large number of amine-terminated histamines and PEG short chains onto a poly(isobutylene-alt-maleic anhydride) backbone, via a one-step nucleophilic addition reaction. This addition reaction is highly efficient, can be carried out in organic media and does not require additional reagents. We show that when imidazole groups are used the resulting polymer ligand can strongly ligate onto metal nanostructures such as nanoparticles (NPs) and nanorods (NRs) made of gold cores. The resulting polymer-coated NPs and NRs exhibit good colloidal stability to pH changes and added electrolytes. This constitutes a departure from the use of thiol-based ligands to coordinate on Au surfaces. The present chemical approach also opens up additional opportunities for designing hydrophilic and reactive platforms where the polymer coating can be adjusted to various metal and metal oxide surfaces by simply modifying or combining the addition reaction with other metal coordinating groups. These could include iron oxide NPs and semiconductor QDs. These polymer-capped NPs and NRs can be used to develop biologically-active platforms with potential use for drug delivery and sensing.


Benefits of Distinguishing between Physical and Social-Verbal Aspects of Behavior: An Example of Generalized Anxiety.
Temperament traits and mental illness have been linked to varying degrees of imbalances in neurotransmitter systems of behavior regulation. If a temperament model has been carefully structured to reflect weak imbalances within systems of behavior regulation, then in the presence of mental illness, these profiles should exhibit distinct patterns consistent with symptoms of mental illness. In contrast to other temperament models used in studies of anxiety disorders, the Functional Ensemble of Temperament (FET) model differentiates not only between emotionality traits, but also between traits related to physical, social-verbal and mental aspects of behavior. This paper analyzed the predictions of the FET model, which maps 12 functional aspects of behavior to symptoms of generalized anxiety disorder (GAD) as described in the DSM/ICD. As an example, the paper describes a study of the coupling of sex, age and temperament traits with GAD using the FET framework. The intake records of 116 clients in treatment with confirmed diagnosis of GAD in a private psychological practice were compared using ANOVA against records of 146 healthy clients using their scores on the FET-based questionnaire, in age groups 17-24, 25-45, 46-65. Patients with GAD in all age groups reported significantly lower Social Endurance, Social Tempo, Probabilistic reasoning (but not in physical aspects of behavior) and higher Neuroticism than healthy individuals, however, no effects on the scales of Motor Endurance or Tempo were found. These findings show the benefits of differentiation between motor-physical and social-verbal aspects of behavior in psychological assessment of mental disorders.


[Superficial lymph node metastasis from ovarian cancer--an analysis of 31 cases].
From March 1958 to June 1988, 53 cases of ovarian cancer with superficial lymph node metastasis (SLM) were treated in our hospital comprising 5.6% of patients with malignant ovarian tumors in the same period. Of 53 cases, 31 were proven by histopathology, and 27 had serous adenocarcinoma. Of these 31 cases, 15 with Stage IV lesion had SLM at time when first seen in the clinic and the others developed SLM during treatment or afterwards. The median survival was 34.7, 11.8 and 12.9 months in Grades I, II and III, respectively. Prognosis is related to pathological grade. The median survival was 36.5 months in 10/31 patients treated with surgery combined with chemotherapy and radiotherapy, 9.1 months in 6/31 treated with surgery plus chemotherapy, 22.4 months in 3/31 treated with radiotherapy only and 8.5 months in 6/31 treated with chemotherapy only. It is suggested that aggressive treatment can improve survival.


Levels of plasma brain-derived tau and p-tau181 in Alzheimer's disease and rapidly progressive dementias.
Rapidly progressive dementias (RPDs) are a group of neurological disorders characterized by a rapid cognitive decline. The diagnostic value of blood-based biomarkers for Alzheimer's disease (AD) in RPD has not been fully explored. We measured plasma brain-derived tau (BD-tau) and p-tau181 in 11 controls, 15 AD patients, and 33 with RPD, of which 19 were Creutzfeldt-Jakob disease (CJD). Plasma BD-tau differentiated AD from RPD and controls (p = 0.002 and p = 0.03, respectively), while plasma and cerebrospinal fluid (CSF) p-tau181 distinguished AD from RPD (p < 0.001) but not controls from RPD (p > 0.05). The correlation of CSF t-tau with plasma BD-tau was stronger (r = 0.78, p < 0.001) than the correlation of CSF and plasma p-tau181 (r = 0.26, p = 0.04). The ratio BD-tau/p-tau181 performed equivalently to the CSF t-tau/p-tau181 ratio, differentiating AD from CJD (p < 0.0001). Plasma BD-tau and p-tau181 mimic their corresponding cerebrospinal fluid (CSF) markers. P-tau significantly increased in AD but not in RPD. Plasma BD-tau, like CSF t-tau, increases according to neurodegeneration intensity.


Age, period, and cohort effects in motor vehicle mortality in the United States, 1980-2010: the role of sex, alcohol involvement, and position in vehicle.
Although substantive declines in motor vehicle fatalities in 1980-2010 have been observed, declines by position in the vehicle and alcohol involvement have not been well elucidated. Analyses of FARS data use the Intrinsic Estimator (IE) to produce estimates of all age, period, and cohort effects simultaneously by position in the car and by alcohol involvement. Declines in MVC deaths by position in the car vary for men and women by age and cohort over time. Cohorts born before 1970 had higher risks than those born later. Analyses using proxy indicators of alcohol involvement found the highest risks for those aged 16-24. By period, these risks declined more rapidly than non- alcohol related traffic fatalities. Changes in risk patterns are consistent with evidence regarding the contributions of new technologies and public policy efforts to reduce fatalities, but gains have not been shared evenly by sex or position in the car. Greater attention is needed in reducing deaths among older drivers and pedestrians. Gender differences should be addressed in prevention efforts aimed at reducing MVCs due to alcohol involvement.


Verizon works to eliminate disparities in health care for its diverse workforce.
Eradicating disparities in health care is an ongoing process that must continue through actions from a variety of stakeholders, including employers. Verizon Communications has a diverse workforce of more than 200,000 employees and is committed to attracting and retaining a workforce that mirrors its customers, speaks their languages, and understands their needs. The company developed and implemented a comprehensive plan to help ensure that minority employees and their families receive the health care they need and deserve based on the Institute of Medicine's 2003 report Unequal Treatment.


Identification of variations in SzP proteins of Streptococcus equi subspecies zooepidemicus and the relationship between protein variants and clinical signs of infection in horses.
To determine whether previously unidentified variations of the SzP protein of Streptococcus equi subsp zooepidemicus were present in horses with various clinical signs of infection and whether any relationship could be identified between SzP protein variants and naturally occurring clinical conditions. 23 isolates of S equi subsp zooepidemicus were recovered from specimens of horses with various clinical conditions and used as a representative population of isolates for evaluation of different SzP protein variants. Genetic heterogeneity of the isolates was demonstrated by repetitive extragenic palindromic-polymerase chain reaction analysis. The SzP gene was sequenced and the presumed protein sequence determined for each isolate. Characteristics of the SzP proteins were compared among the isolates and in relation to the clinical conditions of horses from which they were recovered. The signal peptide types, number of proline-glutamic acid-proline-lysine repeats, and anchor sequences were consistent with those previously described for the SzP protein. Many of the isolates clustered with 5 previously described types on the basis of the hypervariable region of the SzP protein. One additional variant, which represented 8 of the isolates, was identified. Particular motifs in the hypervariable region accounted for many of the differences among hypervariable types. The SzP protein appears to be limited to a selected number of types. Variations in the SzP protein are frequently determined on the basis of different motifs rather than random amino acid substitutions. There does not appear to be any association of SzP protein variations and clinical manifestations of infection in horses.


Tracing long-distance electron transfer and cable bacteria in freshwater sediments by agar pillar gradient columns.
Cable bacteria (CB) perform electrogenic sulfur oxidation (e-SOx) by spatially separating redox half reactions over centimetre distances. For freshwater systems, the ecology of CB is not yet well understood, partly because they proved difficult to cultivate. This study introduces a new 'agar pillar' approach to selectively enrich and investigate CB populations. Within sediment columns, a central agar pillar is embedded, providing a sediment-free gradient system in equilibrium with the surrounding sediment. We incubated freshwater sediments from a streambed, a sulfidic lake and a hydrocarbon-polluted aquifer in such agar pillar columns. Microprofiling revealed typical patterns of e-SOx, such as the development of a suboxic zone and the establishment of electric potentials. The bacterial communities in the sediments and agar pillars were analysed over depth by PacBio near-full-length 16S rRNA gene amplicon sequencing, allowing for a precise phylogenetic placement of taxa detected. The selective niche of the agar pillar was preferentially colonized by CB related to Candidatus Electronema for surface water sediments, including several potentially novel species, but not for putative groundwater CB affiliated with Desulfurivibrio spp. The presence of CB was seemingly linked to co-enriched fermenters, hinting at a possible role of e-SOx populations as an electron sink for heterotrophic microbes. These findings add to our current understanding of the diversity and ecology of CB in freshwater systems, and to a discrimination of CB from surface and groundwater sediments. The agar pillar approach provides a new strategy that may facilitate the cultivation of redox gradient-dependent microorganisms, including previously unrecognized CB populations.


Thrombotic thrombocytopenic purpura associated with von Willebrand factor-cleaving protease (ADAMTS13) deficiency in children.
The physiopathology of thrombotic thrombocytopenic purpura (TTP) has been clarified since 1998, when it was shown that TTP in adults was most often associated with an acquired deficiency of von Willebrand factor-cleaving protease (ADAMTS13) due to autoantibodies, whereas TTP in children was most often associated with a hereditary autosomal recessive severe deficiency of ADAMTS13. The hereditary form of TPP (Upshaw-Schulman syndrome) is a very rare but life-threatening disease if adequate treatment (plasma therapy) is not administered. First manifestations occur before age 10 in two thirds of cases and as soon as birth in most cases. The subsequent course is characterized by recurrent hemolytic and thrombocytopenic crises, with intervals between relapses from every 3 to 4 weeks in two thirds of cases to several months or years in one third of cases. TTP crises are associated with cerebral vascular accidents in at least 30% of patients, with a risk of neurologic sequelae in approximately 20% of patients. Renal involvement includes frequent acute renal failure due to hemoglobinuria and/or thrombotic microangiopathy during hemolytic crisis and progressive renal deterioration in approximately 50% of cases, leading to chronic or end-stage renal failure in approximately 20% of patients. The clinical phenotype may vary from the typical congenital recurrent TTP. Some mild forms are limited to a fluctuating thrombocytopenia and may be misdiagnosed as idiopathic thrombocytopenic purpura. Phenotypic variability may be observed within a single family, which suggests a role of modifier genes. Fresh frozen plasma (FFP) replaces active ADAMTS13. Ten milliliters per kilogram FFP every 2 to 4 weeks suffices to maintain remission. FFP infusions are best used preventively, given that rescue infusions may not prevent central nervous system and renal involvement. It is hoped that plasmatic or recombinant purified ADAMTS13 will be available in the years to come.


The building of Collective Health and health policies - Contributions from Journal Ciência & Saúde Coletiva.
This paper aimed to analyze the contribution of Journal Ciência & Saúde Coletiva (C&SC) to the construction of the CH field, particularly in its relationships with the Health Policy, understood both as an academic discipline and as a scope of practice. We reviewed papers published between 1996 and 2019 in the C&SC. Titles and abstracts of the 397 documents on health policies were read to measure the magnitude and identify the main themes and theoretical-methodological approaches. Thirty-five documents were selected and read in full among the 142 revised ones to investigate the Journal's contribution to CH's construction. The analysis was based on Bourdieu's sociology. It revealed that C&SC was established as a space for the construction of CH in multiple dimensions, particularly concerning the reflexivity on the field. Specifically, concerning the Health Policy, despite the small percentage of documents on the issue (6.8%), it encompassed the different meanings of this subject for the field. The authors discuss the possible relationships between the characteristics identified and the historical process of incorporating this subject in the various areas of CH.


Ampicillin may aggravate clinical and experimental myasthenia gravis.
Ampicillin trihydrate aggravated the symptoms of two myasthenic patients. One patient had severe temporary weakness after an ampicillin sodium challenge. Ampicillin increased the preexisting electrical decrement in three rabbits with experimental autoimmune myasthenia gravis while the drug had no deleterious effects in less affected or normal animals. Myasthenic patients receiving ampicillin should be closely monitored for possible acute exacerbations.


Emulsomes meet S-layer proteins: an emerging targeted drug delivery system.
Here, the use of emulsomes as a drug delivery system is reviewed and compared with other similar lipidic nanoformulations. In particular, we look at surface modification of emulsomes using S-layer proteins, which are self-assembling proteins that cover the surface of many prokaryotic organisms. It has been shown that covering emulsomes with a crystalline S-layer lattice can protect cells from oxidative stress and membrane damage. In the future, the capability to recrystallize S-layer fusion proteins on lipidic nanoformulations may allow the presentation of binding functions or homing protein domains to achieve highly specific targeted delivery of drug-loaded emulsomes. Besides the discussion on several designs and advantages of composite emulsomes, the success of emulsomes for the delivery of drugs to fight against viral and fungal infections, dermal therapy, cancer, and autoimmunity is summarized. Further research might lead to smart, biocompatible emulsomes, which are able to protect and reduce the side effects caused by the drug, but at the same time are equipped with specific targeting molecules to find the desired site of action.


The clinical, molecular, and therapeutic features of patients with IL10/IL10R deficiency: a systematic review.
Interleukin10 (IL10) and IL10 receptor (IL10R) deficiencies are monogenic inborn errors of immunity (IEI) causing early-onset inflammatory bowel diseases (IBD). In this report, we systematically reviewed articles that included related keywords using PubMed, Web of Science, and Scopus databases. The articles were screened for eligibility criteria before data extraction. We assessed 286 patients (44.5% female) with IL10 and/or IL10R deficiencies who were predominantly from China (40.7%), Italy (13.9%), and South Korea (8.5%). The median age of onset was 1.0 (0.3-4.0) months with a median age of genetic diagnosis at 16.0 (7.4-81.0) months. Consanguinity was reported in all evaluable patients with IL10 deficiency and in 38.2% of patients with IL10R deficiency (22.9% of patients with IL10RA, and 79.4% of patients with IL10RB deficiency). The most prevalent mutations in IL10RA were c.301C>T (p.R101W) and c.537G>A (p.T179T), those in IL10RB were c.139A>G (p.K47E) and c.611G>A (p.W204X). Auto-inflammation and enteropathy were present in all cases. The first presentation of both groups was protracted diarrhea (45.7%), bloody diarrhea (17.8%), and colitis (15.5%). Patients with IL10R deficiency had a high frequency of dermatologic manifestations (50.5%) and failure to thrive (60.5%), while IL10-deficient patients lacked those complications. In the majority of patients, the basic immunologic parameters were in normal ranges. Of the entire publications, 30.7% underwent hemopoietic stem cell transplantation, 57.5% surgery, and 86.6% immunosuppressive treatment. The 10-year survival rate was higher in patients with IL10 deficiency than in patients with IL10R deficiency. In conclusion, IL10/IL10R deficiency predominantly presents with treatment-resistant, early-onset IBD within the first months of life. We detected no clear correlation between the phenotype of patients carrying the same variant. The high prevalence of distinct clinical manifestations reported in IL10RA- and IL10RB-deficient patients might be attributable to the interactions between the target tissue and cytokines other than IL10 capable of binding to IL10RB. These results gain translational significance by contributing to earlier diagnosis, adequate therapy, and avoiding delay in the diagnosis and unfavorable outcomes.


Optic nerve head structure in glaucoma: astrocytes as mediators of axonal damage.
Increased intraocular pressure (IOP) is recognised as the principal risk factor for the development of glaucomatous cupping of the optic disc. The hypothesis that it disrupts the function of retinal ganglion cell axons by increasing mechanical forces on the lamina cribrosa of the optic nerve head has received considerable experimental support. However, many patients with glaucoma will have progressive cupping even though the IOPs remain within the normal range, suggesting that mechanical compression is unlikely to be the sole cause of optic nerve damage. Clinical studies have emphasised the role of other factors, such as optic nerve head ischaemia, in generating optic disc cupping. One of the outstanding problems in understanding optic nerve head dysfunction in glaucoma has been the elucidation of the pathways that could integrate the effects of IOP and ischaemia to generate the characteristic changes seen. This review considers the role that optic nerve head astrocytes might play in the initiation of axon damage, based on the hypothesis that these cells are sensitive to mechanical or ischaemic factors and are important for the maintenance of retinal ganglion physiology. It discusses their role in the remodelling of the structure of the lamina cribrosa and the effect that this might have on axon function. Recent evidence has shown that the modulation of astrocyte activity, for example by the reduction of the production of nitric oxide, may prevent retinal ganglion cell death in ocular hypertension. The possibility that astrocyte-axon interactions are important in the development of glaucomatous optic neuropathy suggests new avenues of therapeutic intervention, not related to the control of IOP, that would prevent retinal ganglion cell death in glaucoma.


Peripheral endothelial dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystem disease. Evidence for disturbed vascular regulation comes from various studies showing cerebral hypoperfusion and orthostatic intolerance. The peripheral endothelial dysfunction (ED) has not been sufficiently investigated in patients with ME/CFS. The aim of the present study was to examine peripheral endothelial function in patients with ME/CFS. Thirty-five patients [median age 40 (range 18-70) years, mean body mass index 23.8 ± 4.2 kg/m2 , 31% male] with ME/CFS were studied for peripheral endothelial function assessed by peripheral arterial tonometry (EndoPAT2000). Clinical diagnosis of ME/CFS was based on Canadian Criteria. Nine of these patients with elevated antibodies against β2-adrenergic receptor underwent immunoadsorption, and endothelial function was measured at baseline and 3, 6, and 12 months follow-up. ED was defined by reactive hyperaemia index ≤1.81. Twenty healthy subjects of similar age and body mass index were used as a control group. Peripheral ED was found in 18 of 35 patients (51%) with ME/CFS and in 4 healthy subjects (20%, P < 0.05). Patients with ED, in contrast to patients with normal endothelial function, reported more severe disease according to Bell score (31 ± 12 vs. 40 ± 16, P = 0.04), as well as more severe fatigue-related symptoms (8.62 ± 0.87 vs. 7.75 ± 1.40, P = 0.04) including a higher demand for breaks [9.0 (interquartile range 7.0-10.0) vs. 7.5 (interquartile range 6.0-9.25), P = 0.04]. Peripheral ED showed correlations with more severe immune-associated symptoms (r = -0.41, P = 0.026), such as sore throat (r = -0.38, P = 0.038) and painful lymph nodes (r = -0.37, P = 0.042), as well as more severe disease according to Bell score (r = 0.41, P = 0.008) and symptom score (r = -0.59, P = 0.005). There were no differences between the patient group with ED and the patient group with normal endothelial function regarding demographic, metabolic, and laboratory parameters. Further, there was no difference in soluble vascular cell adhesion molecule and soluble intercellular adhesion molecule levels. At baseline, peripheral ED was observed in six patients who underwent immunoadsorption. After 12 months, endothelial function had improved in five of these six patients (reactive hyperaemia index 1.58 ± 0.15 vs. 2.02 ± 0.46, P = 0.06). Peripheral ED is frequent in patients with ME/CFS and associated with disease severity and severity of immune symptoms. As ED is a risk factor for cardiovascular disease, it is important to elucidate if peripheral ED is associated with increased cardiovascular morbidity and mortality in ME/CFS.


Regulation of gelatinase in human skin organ cultures by glucocorticoids.
Hydrocortisone and dexamethasone prevent the appearance of gelatinase in serum-free explant cultures of normal human skin. Hydrocortisone inhibits maximally at 10(-6) M and dexamethasone at 10(-8) M in culture medium. Glucocorticoids at these concentrations do not cause a generalized decrease in protein synthesis; thus the effect on gelatinase shows specificity. The reduction in gelatinase activity caused by dexamethasone can be overcome in the presence of dexamethasone 21-mesylate, a glucocorticoid antagonist that binds irreversibly to the cytoplasmic steroid receptor. These data suggest that the enzymes of collagen degradation, collagenase and gelatinase, may be coregulated.


Family Mealtime Q-Sort: A measure of mealtime practices.
Studies outlining the protective functions of shared family meals suggest that helping families experience successful meals is an important goal. Measuring the effectiveness of family mealtime interventions necessitates the ability to quantify both the frequency and context of shared mealtimes. This article introduces a new instrument, the Family Mealtime Q-Sort, describes its development, and presents preliminary data about its psychometric properties. Data from initial evaluation of the Family Mealtime Q-Sort using family mealtime videos (N = 51) demonstrate acceptable interrater reliability, promising validity, and the ability to compare family mealtimes to an independently derived, culturally appropriate standard. The results suggest that the Q-sort adequately measures important dimensions of a successful mealtime including a positive atmosphere, making use of the shared time to engage in meaningful conversation, and proceeding with a clear plan and minimal distractions. Further research on the tool is warranted.


Slow diffusion of lactose out of galectin-3 crystals monitored by X-ray crystallography: possible implications for ligand-exchange protocols.
Galectin-3 is a multifunctional carbohydrate-binding protein that has roles in cancer progression. In addition to carbohydrate-dependent extracellular functions, galectin-3 participates in carbohydrate-independent intracellular signalling pathways, including apoptosis, via protein-protein interactions, some of which engage the carbohydrate-binding groove. When ligands bind within this site, conformational rearrangements are induced and information on unliganded galectin-3 is therefore valuable for structure-based drug design. Removal of cocrystallized lactose from the human galectin-3 carbohydrate-recognition domain was achieved via crystal soaking, but took weeks despite low affinity. Pre-soaking to remove lactose enabled the subsequent binding of cryoprotectant glycerol, whereas when the lactose was not removed a priori the glycerol could not displace it in the short cryosoaking time frame. This slow diffusion of lactose out of the crystals contrasts with the entrance of glycerol, which takes place within minutes. The importance of the removal of incumbent ligands prior to attempts to introduce alternative ligands is indicated, even for proteins exhibiting low affinity for ligands, and has significance for ligand exchange in structure-based drug design.


The Use of Computer Tomography in Ophthalmology.
Fifty-three orbital lesions of various types were studied by computer tomography to assess the capabilities and limitations of this technique. Although CT scanning in ophthalmology is in its infancy, results showed that it is useful in the investigation of a number of pathological conditions, including congenital anomalies, arteriovenous malformations, bone lesions, trauma, inflammation, granulomas, pseudotumors, epidermoid cysts, and tumors arising in or near the optic nerve, behind the optic bulb, or in the lacrimal region, as well as changes following eye surgery.


Crystal structure of α-1,4-glucan lyase, a unique glycoside hydrolase family member with a novel catalytic mechanism.
α-1,4-Glucan lyase (EC 184.108.40.206) from the red seaweed Gracilariopsis lemaneiformis cleaves α-1,4-glucosidic linkages in glycogen, starch, and malto-oligosaccharides, yielding the keto-monosaccharide 1,5-anhydro-D-fructose. The enzyme belongs to glycoside hydrolase family 31 (GH31) but degrades starch via an elimination reaction instead of hydrolysis. The crystal structure shows that the enzyme, like GH31 hydrolases, contains a (β/α)8-barrel catalytic domain with B and B' subdomains, an N-terminal domain N, and the C-terminal domains C and D. The N-terminal domain N of the lyase was found to bind a trisaccharide. Complexes of the enzyme with acarbose and 1-dexoynojirimycin and two different covalent glycosyl-enzyme intermediates obtained with fluorinated sugar analogues show that, like GH31 hydrolases, the aspartic acid residues Asp(553) and Asp(665) are the catalytic nucleophile and acid, respectively. However, as a unique feature, the catalytic nucleophile is in a position to act also as a base that abstracts a proton from the C2 carbon atom of the covalently bound subsite -1 glucosyl residue, thus explaining the unique lyase activity of the enzyme. One Glu to Val mutation in the active site of the homologous α-glucosidase from Sulfolobus solfataricus resulted in a shift from hydrolytic to lyase activity, demonstrating that a subtle amino acid difference can promote lyase activity in a GH31 hydrolase.


Prognostic impact of venous thromboembolism on the course of sarcoidosis: A multicenter retrospective case-control study.
Sarcoidosis is an independent risk factor for venous thromboembolism (VTE). However, the characteristics and clinical evolution of sarcoidosis patients presenting a VTE (sarcoidosis/VTE group) in the course of their disease are not known. Consequently, if VTE occurrence is associated with a more severe disease is still pending. We conducted a retrospective case-control study of sarcoidosis/VTE patients compared to matched sarcoidosis controls without VTE in two French tertiary centers, analysed and compared the clinical, biological, functional, imaging and evolutive profiles of the two groups. Sixty-one patients were included with at least one episode of VTE during course of sarcoidosis. At sarcoidosis onset (before/at the time of VTE occurrence) the number of affected organs, radiological stages and pulmonary functional tests were not significantly different between the two groups. In contrast, we found that sarcoidosis/VTE patients required more frequently a systemic immunosuppressive therapy (corticosteroids and/or immunosuppressors, 79% versus 58%; p = 0.008). The functional course was also poorer in sarcoidosis/VTE patients with a more frequent decrease in functional vital capacity (33% versus 18% in sarcoidosis/VTE patients and controls, respectively, p = 0.008). Finally, sarcoidosis/VTE patients presented more frequently with pulmonary hypertension (10% versus 1% in patients and controls, respectively, p = 0.006), and their survival was significantly worse (log-rank p <0.001). The occurrence of VTE during sarcoidosis is associated with a more severe disease and a poorer prognosis. The occurrence of VTE during sarcoidosis might signal a more inflammatory and/or evolutive disease in sarcoidosis/VTE patients and should be taken in consideration when designing therapeutic strategies for them.


Expression of connective tissue growth factor/hypertrophic chondrocyte-specific gene product 24 (CTGF/Hcs24/CCN2) during distraction osteogenesis.
To investigate the localization and expression of connective tissue growth factor/hypertrophic chondrocyte-specific gene product 24/CCN family member 2 (CTGF/Hcs24/CCN2) during distraction osteogenesis in the rat femur, we studied a total of 54 male rats (11 weeks old). We performed osteotomy in the midshaft of the right femur. After 7 days (lag phase), distraction was started, at the rate of 0.25 mm/12 h for 21 days (distraction phase) by using a small external fixator, and this was followed by a 7-day consolidation phase. Localization and expression of CTGF/Hcs24 during distraction osteogenesis in the femur were examined by immunostaining, in situ hybridization, and reverse transcriptase polymerase chain reaction (RT-PCR). Immunostaining showed the localization of CTGF/Hcs24 in various cells located in the bone-forming area around the osteotomy site. During the distraction phase, in situ hybridization showed that CTGF/Hcs24 mRNA was expressed not only in hypertrophic chondrocytes and osteoblasts but also in fibroblast-like cells and mesenchymal cells at sites of end-ochondral ossification, and not only in osteoblasts but also in pre-osteoblasts and fibroblast-like cells at sites of intramembranous ossification. RT-PCR showed higher level expression of CTGF/Hcs24 mRNA in the distracted group than in the nondistracted group. These results revealed an elevated pattern of CTGF/Hcs24 mRNA expression during distraction osteogenesis, and suggest that CTGF/Hcs24 may play some roles in the endochondral and intramembranous ossification processes that occur during distraction osteogenesis.


Reducing end modification on cellulose nanocrystals: strategy, characterization, applications and challenges.
Different from traditional chemical surface modification, localized modification of the reducing end groups of cellulose nanocrystals (CNCs), i.e. the active aldehyde groups, provides new opportunities for diverse functional applications of this renewable nanomaterial without altering its surface chemistry and properties. Numerous reviews have deeply discussed the surface modification of the hydroxyl groups of CNCs, but no critical comment has been reported on the reducing end modification approach. This review is a comprehensive summary on the modification of the CNC reducing end, presenting the reaction mechanisms and conditions, discussing the different chemical modification strategies and characterization techniques, potential applications and future challenges in this field. In addition, the comparison between surface and end modification strategies of CNCs will highlight the potential of reducing end-functionalized CNCs to be used in various applications as an alternative to traditional surface-modified CNCs, or as additional functional nanoparticles for the design of advanced functional materials.


An innovative method to assess clinical reasoning skills: Clinical reasoning tests in the second national medical science Olympiad in Iran.
Clinical reasoning plays a major role in the ability of doctors to make a diagnosis and reach treatment decisions. This paper describes the use of four clinical reasoning tests in the second National Medical Science Olympiad in Iran: key features (KF), script concordance (SCT), clinical reasoning problems (CRP) and comprehensive integrative puzzles (CIP). The purpose of the study was to design a multi instrument for multiple roles approach in clinical reasoning field based on the theoretical framework, KF was used to measure data gathering, CRP was used to measure hypothesis formation, SCT and CIP were used to measure hypothesis evaluation and investigating the combined use of these tests in the Olympiad. A bank of clinical reasoning test items was developed for emergency medicine by a scientific expert committee representing all the medical schools in the country. These items were pretested by a reference group and the results were analyzed to select items that could be omitted. Then 135 top-ranked medical students from 45 medical universities in Iran participated in the clinical domain of the Olympiad. The reliability of each test was calculated by Cronbach's alpha. Item difficulty and the correlation between each item and the total score were measured. The correlation between the students' final grade and each of the clinical reasoning tests was calculated, as was the correlation between final grades and another measure of knowledge, i.e., the students' grade point average. The combined reliability for all four clinical reasoning tests was 0.91. Of the four clinical reasoning tests we compared, reliability was highest for CIP (0.91). The reliability was 0.83 for KF, 0.78 for SCT and 0.71 for CRP. Most of the tests had an acceptable item difficulty level between 0.2 and 0.8. The correlation between the score for each item and the total test score for each of the four tests was positive. The correlations between scores for each test and total score were highest for KF and CIP. The correlation between scores for each test and grade point average was low to intermediate for all four of the tests. The combination of these four clinical reasoning tests is a reliable evaluation tool that can be implemented to assess clinical reasoning skills in talented undergraduate medical students, however these data may not generalizable to whole medical students population. The CIP and KF tests showed the greatest potential to measure clinical reasoning skills. Grade point averages did not necessarily predict performance in the clinical domain of the national competitive examination for medical school students.


A peptide probe for detection of various beta-amyloid oligomers.
Aggregation of β-amyloid (Aβ) is implicated in the pathology of Alzheimer's disease (AD). A considerable amount of data has identified soluble Aβ oligomers as potentially significant toxic agents. Rapid, specific and quantitative detection is preferred for accurate profiling of structurally unstable Aβ oligomers as well as for implementation of high-throughput assays for pharmaceutical applications. PG46 is an engineered Aβ variant, constructed by integrating Aβ self-recognition sequences with the conformation-sensitive biarsenical fluorescent dye, FlAsH. PG46 was found to be an effective peptide probe, which detected Aβ oligomers specifically and quantitatively within one hour. However, PG46 was highly aggregation-prone and displayed a limited repertoire of detectable Aβ oligomers. Here, we report the creation of a novel molecular probe, PG44, by C-terminal truncation of PG46. PG44 exhibited a reduced self-aggregation propensity and a different conformation when compared to PG46, and generated specific FlAsH fluorescence signals as a result of binding to various Aβ oligomers, including those not readily detectable by PG46. We also show that sensitivity of PG44 for detection of certain Aβ oligomers may be increased by lowering PG44 concentration and thus decreasing the extent of self-aggregation of PG44. Our results suggest that PG44 can serve as an important molecular probe with a broadened repertoire of detectable Aβ oligomeric aggregates. We believe that detection of Aβ oligomers using our peptide probe would potentially contribute toward a better understanding of the molecular basis of Aβ oligomerization and the development of Aβ oligomer-based early diagnostics as well as therapeutic drugs targeting Aβ oligomers.


Effects of Continuous Care Model on Depression, Anxiety, and Stress in Iranian Elderly in Shiraz.
Psychological disorders such as depression, anxiety, and stress are among the most common health problems in old age. Continuous care and support can be effective and help elderly people to adapt to successive losses, especially if provided within the framework of a model. The present study aimed to determine the effects of the continuous care model (CCM) on depression, anxiety, and stress (DAS) in the Iranian elderly in Shiraz. The present quasi-experimental study was performed on older adults who attended the Soroush elderly day care center in Shiraz (Iran) from September 2014 to June 2015. A total of 50 eligible elderly participated in the study and were randomly assigned to an intervention group (N=25) and a control group (N=25). The CCM was implemented in the intervention group, whereas the control group received the routine care as offered by the day care center. CCM involves four stages, namely orientation, sensitization, control, and evaluation. The data were collected using the depression, anxiety, stress Scale (DASS-21) questionnaire and a demographic data sheet. The data were analyzed using the SPSS software (version 22.0) with the independent sample t test, paired sample t test, Chi-square test, fisher exact test, multivariate analysis of covariance and the Pearson correlation coefficient. P<0.05 was considered statistically significant. The majority of the participants were women, 44 (88%), with the mean age of 63.4±2.96 years. Following the implementation of the CCM, there was a statistically significant difference in the mean DAS scores between the intervention and control group (P<0.001). The implementation of CCM not only reduced psychological problems (DAS) in the elderly, but also improved and strengthened their psychological condition.


Construction of Infectious Clones for Human Enteroviruses.
The infectious clone has been constructed for years via various mechanisms using reverse genetics of viral RNA into cDNA. The mechanism of construction has evolved to DNA-launch plasmids which simplify infectious clone manipulation and expression in mammalian cells. Infectious clones have enormously allowed manipulation of the enterovirus genome to discover antivirals, viral replication mechanisms, and functions of essential viral proteins. Here we will be discussing methods for the production of DNA-launch human enterovirus infectious clones and viral genome engineered with a fluorescent reporter gene.


Esophageal reconstruction for hypopharyngoesophageal strictures after corrosive injury.
To evaluate the surgical outcome of patients with caustic stricture of the hypopharyngoesophagus. During a 25-year period, we performed esophageal reconstruction in 152 patients with diffuse or multiple caustic esophageal stricture. Of them, esophageal substitute was pulled up and anastomosed to the hypopharynx in 50 (33%) patients, and anastomosed to the cervical esophagus in the other 102 (67%) patients. Patients whose esophageal substitute anastomosed to the hypopharynx were enrolled to the present study. Among these 50 study patients, 13 underwent ablation of damaged organs and feeding jejunostomy in acute stage of corrosive injury, and the remaining 37 patients were initially organ preserved with or without feeding gastrostomy or jejunostomy. Six patients had respiratory distress caused by laryngotracheal stricture. The ileocolon (28/50) was commonly used as an esophageal substitute in reconstruction and most substitutes (43/50) went through the substernal route. There was one operative death. Eight (16%) patients had major early postoperative complications. Six patients underwent revision for late stenosis of hypopharyngeal anastomosis, and one redoing reconstruction using the jejunum because of failure of the transplanted ileocolon. Postoperatively, swallow function and maintaining body weight were considered good in 42 patients (84%) after an average of 8 months follow-up. Five of six patients who underwent concomitant tracheostomy or laryngosurgery for laryngotracheal stricture got unsatisfactory result. The surgical outcome of the study patients was worse than that in patients with esophageal substitute anastomosed to a healthy cervical esophagus. In the later group of patients, 95/102 (93%) had good swallow function and only 7/102 (6.8%) had major early complications. Caustic stricture of the hypopharyngoesophagus is a challenging reconstructive problem. A successful reconstruction requires a correct hypopharyngeal opening and anastomosis, a good esophageal substitute, and a patent esophageal route and airway.


An Instrumental Electrode Configuration for 3D Ultrasound Modulated Electrical Impedance Tomography.
Ultrasound modulated electrical impedance tomography (UMEIT) is a novel hybrid imaging technique, which utilizes coupling between electric and acoustic modalities. Based on the forward solver along different current directions, an instrumental electrode configuration is proposed for 3D UMEIT. The proposed electrode configuration can produce a similar longitudinal current, making the power density distribution on the x-y plane approximately consistent with the corresponding conductivity distribution. Then, this satisfying power density is adopted to reconstruct a higher-resolution conductivity distribution. Therefore, the proposed electrode configuration contributes to improving the image reconstruction quality of UMEIT. Also, to clearly demonstrate its meaning in theory, the forward solver results are analyzed from an electrical point of view. In addition, the nonlinear partial differential equation (PDE) relating the power density to the measured data is derived again with a more reasonable expression. Finally, simulation with realistic geometry model of human breast is done and feasibility verifying experiment is made. Both simulation and experimental results validate the feasibility of the proposed electrode configuration.


Rapid instructed task learning (but not automatic effects of instructions) is influenced by working memory load.
The ability to efficiently perform actions immediately following instructions and without prior practice has previously been termed Rapid Instructed Task Learning (RITL). In addition, it was found that instructions are so powerful that they can produce automatic effects, reflected in activation of the instructions in an inappropriate task context. RITL is hypothesized to rely on limited working memory (WM) resources for holding not-yet implemented task rules. Similarly, automatic effects of instructions presumably reflect the operation of task rules kept in WM. Therefore, both were predicted to be influenced by WM load. However, while the involvement of WM in RITL is implicated from prior studies, evidence regarding WM involvement in instructions-based automaticity is mixed. In the current study, we manipulated WM load by increasing the number of novel task rules to be held in WM towards performance in the NEXT paradigm. In this task, participants performed a series of novel tasks presented in mini-blocks, each comprising a) instructions of novel task rules; b) a NEXT phase measuring the automatic activation of these instructed rules, in which participants advance the screen using a key-press; and c) a GO phase in which the new rules are first implemented and RITL is measured. In three experiments, we show a dissociation: While RITL (rule implementation) was impaired by increased WM load, the automatic effects of instructions were not robustly influenced by WM load. Theoretical implications are discussed.


Inducible Deletion of Protein Kinase Map4k4 in Obese Mice Improves Insulin Sensitivity in Liver and Adipose Tissues.
Studies in vitro suggest that mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) attenuates insulin signaling, but confirmation in vivo is lacking since Map4k4 knockout is lethal during embryogenesis. We thus generated mice with floxed Map4k4 alleles and a tamoxifen-inducible Cre/ERT2 recombinase under the control of the ubiquitin C promoter to induce whole-body Map4k4 deletion after these animals reached maturity. Tamoxifen administration to these mice induced Map4k4 deletion in all tissues examined, causing decreased fasting blood glucose concentrations and enhanced insulin signaling to AKT in adipose tissue and liver but not in skeletal muscle. Surprisingly, however, mice generated with a conditional Map4k4 deletion in adiponectin-positive adipocytes or in albumin-positive hepatocytes displayed no detectable metabolic phenotypes. Instead, mice with Map4k4 deleted in Myf5-positive tissues, including all skeletal muscles tested, were protected from obesity-induced glucose intolerance and insulin resistance. Remarkably, these mice also showed increased insulin sensitivity in adipose tissue but not skeletal muscle, similar to the metabolic phenotypes observed in inducible whole-body knockout mice. Taken together, these results indicate that (i) Map4k4 controls a pathway in Myf5-positive cells that suppresses whole-body insulin sensitivity and (ii) Map4k4 is a potential therapeutic target for improving glucose tolerance and insulin sensitivity in type 2 diabetes.


Community paediatrics in Ontario: 1996 paediatric physician resource study.
Physician resource planning is a basic underpinning of the management of the health care system. Accurate data on physician numbers and distribution are essential to the process of planning. This paper presents the results of a study commissioned by the Paediatric Executive of the Ontario Medical Association to provide an updated profile of the number and distribution of paediatricians in Ontario in 1995/96.


Contributed review: Review of integrated correlative light and electron microscopy.
New developments in the field of microscopy enable to acquire increasing amounts of information from large sample areas and at an increased resolution. Depending on the nature of the technique, the information may reveal morphological, structural, chemical, and still other sample characteristics. In research fields, such as cell biology and materials science, there is an increasing demand to correlate these individual levels of information and in this way to obtain a better understanding of sample preparation and specific sample properties. To address this need, integrated systems were developed that combine nanometer resolution electron microscopes with optical microscopes, which produce chemically or label specific information through spectroscopy. The complementary information from electron microscopy and light microscopy presents an opportunity to investigate a broad range of sample properties in a correlated fashion. An important part of correlating the differences in information lies in bridging the different resolution and image contrast features. The trend to analyse samples using multiple correlated microscopes has resulted in a new research field. Current research is focused, for instance, on (a) the investigation of samples with nanometer scale distribution of inorganic and organic materials, (b) live cell analysis combined with electron microscopy, and (c) in situ spectroscopic and electron microscopy analysis of catalytic materials, but more areas will benefit from integrated correlative microscopy.


Evaluating the Arrhenius equation for developmental processes.
The famous Arrhenius equation is well suited to describing the temperature dependence of chemical reactions but has also been used for complicated biological processes. Here, we evaluate how well the simple Arrhenius equation predicts complex multi-step biological processes, using frog and fruit fly embryogenesis as two canonical models. We find that the Arrhenius equation provides a good approximation for the temperature dependence of embryogenesis, even though individual developmental intervals scale differently with temperature. At low and high temperatures, however, we observed significant departures from idealized Arrhenius Law behavior. When we model multi-step reactions of idealized chemical networks, we are unable to generate comparable deviations from linearity. In contrast, we find the two enzymes GAPDH and β-galactosidase show non-linearity in the Arrhenius plot similar to our observations of embryonic development. Thus, we find that complex embryonic development can be well approximated by the simple Arrhenius equation regardless of non-uniform developmental scaling and propose that the observed departure from this law likely results more from non-idealized individual steps rather than from the complexity of the system.


Unusual C25 steroids produced by a sponge-derived Penicillium citrinum.
[structure: see text] Structurally unique steroids, isocyclocitrinol A (1) and 22-acetylisocyclocitrinol A (2), were isolated from the extract of a saltwater culture of sponge-derived Penicilliun citrinum. The structures were established by analysis of 1D and 2D NMR data. The absolute structures were determined on the basis of X-ray structure analysis and application of modified Mosher's method. Furthermore, the structure of cyclocitrinol (3a) previously isolated from a terrestrial P. citrinum was revised as 3b. Compounds 1 and 2 showed weak antibacterial activity against Staphylococcus epidermidis and Enterococcus durans.


[Some effects of pH, diuretics and organic acids on the uptake of oxalate in a renal tubular cell line (LLC-PK1)].
The effects of changes in extracellular pH and treatments with diuretics or some organic acids on the uptake of oxalate were studied in an epithelial cell line of renal origin (LLC-PK1 cells). The oxalate uptake into the cells exhibited a marked sensitivity to extracellular, pH, in the present results with acidic pH stimulating and alkaline pH inhibiting the DIDS sensitive uptakes. The uptake of oxalate was clearly inhibited by DIDS, proportionally to the concentrations from 10 microM to 1 mM. Furosemide, chlorothiazide, probenecid and acetazolamide inhibited the oxalate uptake significantly. Probenecid has the most potency on the inhibition of the uptake in high concentrations, and acetazolamide needed a high concentration for the small effect. However, allopurinol has no effect on the uptake as well as dicarboxylates (malate, succinate and phenyl succinate) and organic acids (urate and para-amino hippurate). We discussed the mechanisms of the inhibition against the oxalate uptake concerning with each drug. It was suggested that probenecid may inhibit the oxalate carriers directly, while furosemide, chlorothiazide and acetazolamide may inhibit then by the direct actions and some secondary effects which are provided by those drugs.


Understanding nanoscale temperature gradients in magnetic nanocontacts.
We have determined the temperature profile in magnetic nanocontacts under applied current densities typical of spin-torque oscillators (∼10(8) A/cm2). The study combines experimental measurements of the electrical and magnetic properties of the nanocontacts and full three-dimensional simulations of the heat and current flow in these systems. It is found that the quadratic current-induced increase of the resistance due to Joule heating is independent of the applied temperature from 6 to 300 K. In terms of magnetization dynamics, the measured current-induced vortex nucleation, a thermally activated process, is found to be consistent with local temperatures increases of between 147 and 225 K. Simulations reproduce the experimental findings and show that significant thermal gradients exist out to 450 nm from the nanocontact.


Psoriatic Spondylitis: A Disease Manifestation in Debate: Evidences to Know for the Clinical Rheumatologist.
With the advent of classification criteria for psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), patients with axial manifestations associated with psoriasis, initially described in the l950s as a specific entity termed psoriatic spondylitis (PS), are now categorized within PsA, ankylosing spondylitis (AS), and axSpA. Thus, different terms are used to describe axial disease in patients with PsA including PS, axial psoriatic arthritis (axPsA), and psoriatic spondyloarthritis. Patients with PS may present with inflammatory and/or mechanical back pain, but also may display axial disease on imaging despite not complaining of back pain. Cervical spondylitis has been reported in 35% to 75% of patients with PsA. Axial disease is silent in 20% and 25% of patients with axial PsA and PsA, respectively. The majority of axPsA patients have peripheral arthritis alongside the axial involvement, whereas only 2% to 5% of PsA patients have solely axial arthritis with no peripheral arthritis.A debate is currently underway as to whether inflammatory axial disease and psoriasis represent axSpA with psoriasis or a subset of PsA named axPsA. Studies have recognized that axial disease in PsA patients seems to be different demographically, genetically, clinically, and radiographically when compared with AS with or without psoriasis. This narrative review summarizes current knowledge regarding axial involvement of PsA in terms of history, terminology, classification, epidemiology, clinical presentation, imaging, diagnosis, and treatment, with the aim of providing advice for management of PS in clinical evidence-based practice. Data-driven studies are needed to develop clear, nonoverlapping classification criteria for spinal involvement in PsA.


Heterogeneous catalysts.
Proven catalysts exist in many different forms and with many different kinds of composition. An understanding of how catalysts function is beginning to emerge in a few areas, and some superior catalysts have been developed as a result of this knowledge. Applications of new techniques and disciplines should lead to impressive advances in the years ahead.


COF-Net on CNT-Net as a Molecularly Designed, Hierarchical Porous Chemical Trap for Polysulfides in Lithium-Sulfur Batteries.
The hierarchical porous structure has garnered considerable attention as a multiscale engineering strategy to bring unforeseen synergistic effects in a vast variety of functional materials. Here, we demonstrate a "microporous covalent organic framework (COF) net on mesoporous carbon nanotube (CNT) net" hybrid architecture as a new class of molecularly designed, hierarchical porous chemical trap for lithium polysulfides (Li2Sx) in Li-S batteries. As a proof of concept for the hybrid architecture, self-standing COF-net on CNT-net interlayers (called "NN interlayers") are fabricated through CNT-templated in situ COF synthesis and then inserted between sulfur cathodes and separators. Two COFs with different micropore sizes (COF-1 (0.7 nm) and COF-5 (2.7 nm)) are chosen as model systems. The effects of the pore size and (boron-mediated) chemical affinity of microporous COF nets on Li2Sx adsorption phenomena are theoretically investigated through density functional theory calculations. Benefiting from the chemical/structural uniqueness, the NN interlayers effectively capture Li2Sx without impairing their ion/electron conduction. Notably, the COF-1 NN interlayer, driven by the well-designed microporous structure, allows for the selective deposition/dissolution (i.e., facile solid-liquid conversion) of electrically inert Li2S. As a consequence, the COF-1 NN interlayer provides a significant improvement in the electrochemical performance of Li-S cells (capacity retention after 300 cycles (at charge/discharge rate = 2.0 C/2.0 C) = 84% versus 15% for a control cell with no interlayer) that lies far beyond those accessible with conventional Li-S technologies.


Severe aortic stenosis with low aortic valve calcification: characteristics and outcome following transcatheter aortic valve implantation.
High aortic valve calcification (AVC) assessed with CT may be used to differentiate between severe and non-severe aortic stenosis (AS). Nonetheless, in some cases patients with low calcification are diagnosed with haemodynamically severe AS. The prevalence, mechanism of valve stenosis and implications for transcatheter aortic valve implantation (TAVI) of low AVC severe AS remain unclear. We assessed the clinical and haemodynamic characteristics and the outcome of patients with severe AS and low AVC that undergo TAVI. Ninety-three patients that had low CT aortic valve calcification score (AVCS) were compared to 470 patients with high AVCS. High gradient severe AS was found among 53.8% (50/93) of the patients with low AVCS vs. 86% (404/470) of the patients with high AVCS (P < 0.001). Device success rate was similar between both groups. There were significantly lower rates of postprocedural paravalvular regurgitation (PVR) in the low AVCS group (≥ mild PVR: 12.9% vs. 23.6%; P = 0.03). Overall, there were only two cases (0.4%) of valve embolization in patients with high AVCS and 1 (1.1%) in patients with low AVCS (P = 0.42). Thirty-day mortality and major complications were similar between groups. Balloon-expandable TAVI in patients with a mildly calcified aortic valve was not associated with increased risk of valve embolization or mortality. We demonstrated high device success and lower rates of PVR for these patients. These findings suggest that in patients with evidence of haemodynamically severe AS at echocardiography, the presence of low ACVS at CT should not preclude the consideration of TAVI.


Leptin acts via lateral hypothalamic area neurotensin neurons to inhibit orexin neurons by multiple GABA-independent mechanisms.
The adipocyte-derived hormone leptin modulates neural systems appropriately for the status of body energy stores. Leptin inhibits lateral hypothalamic area (LHA) orexin (OX; also known as hypocretin)-producing neurons, which control feeding, activity, and energy expenditure, among other parameters. Our previous results suggest that GABAergic LHA leptin receptor (LepRb)-containing and neurotensin (Nts)-containing (LepRb(Nts)) neurons lie in close apposition with OX neurons and control Ox mRNA expression. Here, we show that, similar to leptin, activation of LHA Nts neurons by the excitatory hM3Dq DREADD (designer receptor exclusively activated by designer drugs) hyperpolarizes membrane potential and suppresses action potential firing in OX neurons in mouse hypothalamic slices. Furthermore, ablation of LepRb from Nts neurons abrogated the leptin-mediated inhibition, demonstrating that LepRb(Nts) neurons mediate the inhibition of OX neurons by leptin. Leptin did not significantly enhance GABAA-mediated inhibitory synaptic transmission, and GABA receptor antagonists did not block leptin-mediated inhibition of OX neuron activity. Rather, leptin diminished the frequency of spontaneous EPSCs onto OX neurons. Furthermore, leptin indirectly activated an ATP-sensitive potassium (K(ATP)) channel in OX neurons, which was required for the hyperpolarization of OX neurons by leptin. Although Nts did not alter OX activity, galanin, which is coexpressed in LepRb(Nts) neurons, inhibited OX neurons, whereas the galanin receptor antagonist M40 (galanin-(1-12)-Pro3-(Ala-Leu)2-Ala amide) prevented the leptin-induced hyperpolarization of OX cells. These findings demonstrate that leptin indirectly inhibits OX neurons by acting on LHA LepRb(Nts) neurons to mediate two distinct GABA-independent mechanisms of inhibition: the presynaptic inhibition of excitatory neurotransmission and the opening of K(ATP) channels.


Feedback control system simulator for the control of biological cells in microfluidic cross slots and integrated microfluidic systems.
Control systems for lab on chip devices require careful characterisation and design for optimal performance. Traditionally, this involves either extremely computationally expensive simulations or lengthy iteration of laboratory experiments, prototype design, and manufacture. In this paper, an efficient control simulation technique, valid for typical microchannels, Computed Interpolated Flow Hydrodynamics (CIFH), is described that is over 500 times faster than conventional time integration techniques. CIFH is a hybrid approach, utilising a combination of pre-computed flows and hydrodynamic equations and allows the efficient simulation of dynamic control systems for the transport of cells through micro-fluidic devices. The speed-ups achieved by using pre-computed CFD solutions mapped to an n-dimensional control parameter space, significantly accelerate the evaluation and improvement of control strategies and chip design. Here, control strategies for a naturally unstable device geometry, the microfluidic cross-slot, have been simulated and optimal parameters have been found for proposed devices capable of trapping and sorting cells.


Pharmacogenetic effect of the UGT polymorphisms on mycophenolate is modified by calcineurin inhibitors.
Mycophenolic acid (MPA) is glucuronidated primarily by uridine diphosphate glucuronosyltransferase enzymes (UGT) 1A9 and 1A8. These enzymes are highly polymorphic resulting in low activity and high expression phenotypes. We hypothesized that polymorphisms of UGT1A9 and 1A8 may alter MPA pharmacokinetics in kidney transplantation. One hundred seventeen kidney (n = 93), pancreas (n = 11), or simultaneous kidney and pancreas (SPK) (n = 13) transplant recipients were studied for the effect of UGT1A9 and UGT1A8 polymorphisms on MPA dose-corrected trough concentrations. Individuals were genotyped for UGT1A8 and UGT1A9 polymorphisms (1A8*2, 1A8*3, 1A9*3, 1A9-275 and 1A9-2152). Linear regression was used to estimate the effect of UGT polymorphisms on the individual's mean MPA dose-corrected trough concentration with and without stratification by calcineurin inhibitor. A multiple linear regression analysis was performed to assess the dependence between the average MPA dose-corrected trough concentration and age, gender, UGT genotype (1A8*2, 1A8*3, 1A9*3, 1A9-275, 1A9-2152), serum albumin, hemoglobin (Hgb), hematocrit (HCT), liver transaminases (AST, ALT), serum creatinine, and bilirubin. Mycophenolic acid dose-corrected trough concentrations were 60% higher in subjects heterozygous or homozygous for UGT1A8*2 than in those with the wild type (p = 0.02); however, this effect was dependent on concomitant calcineurin inhibitor. When subjects were stratified by calcineurin inhibitor status, the UGT1A8*2 effect was only apparent in the tacrolimus group (p < 0.01). Mycophenolic acid dose-corrected trough concentrations were 70% lower in carriers of the UGT1A9 -275T>A/-2152 C>T polymorphism who received cyclosporine (p < 0.01). There was no effect of the UGT1A9 -275T>A/-2152C>T polymorphism in the tacrolimus group. The effect of UGT1A8 and UGT1A9 variants on MPA metabolism appears to be modified by concomitant calcineurin inhibitor therapy. Confirmatory in vivo and in vitro studies are needed.


Kalirin-7 prevents dendritic spine dysgenesis induced by amyloid beta-derived oligomers.
Synapse degeneration and dendritic spine dysgenesis are believed to be crucial early steps in Alzheimer's disease (AD), and correlate with cognitive deficits in AD patients. Soluble amyloid beta (Aβ)-derived oligomers, also termed Aβ-derived diffusible ligands (ADDLs), accumulate in the brain of AD patients and play a crucial role in AD pathogenesis. ADDLs bind to mature hippocampal neurons, induce structural changes in dendritic spines and contribute to neuronal death. However, mechanisms underlying structural and toxic effects are not fully understood. Here, we report that ADDLs bind to cultured mature cortical pyramidal neurons and induce spine dysgenesis. ADDL treatment induced the rapid depletion of kalirin-7, a brain-specific guanine-nucleotide exchange factor for the small GTPase Rac1, from spines. Kalirin-7 is a key regulator of dendritic spine morphogenesis and maintenance in forebrain pyramidal neurons and here we show that overexpression of kalirin-7 prevents ADDL-induced spine degeneration. Taken together, our results suggest that kalirin-7 may play a role in the early events leading to synapse degeneration, and its pharmacological activation may prevent or delay synapse pathology in AD.


Dietary immunosuppressants do not enhance UV-induced skin carcinogenesis, and reveal discordance between p53-mutant early clones and carcinomas.
Immunosuppressive drugs are thought to cause the dramatically increased risk of carcinomas in sun-exposed skin of organ transplant recipients. These drugs differ in local effects on skin. We investigated whether this local impact is predictive of skin cancer risk and may thus provide guidance on minimizing the risk. Immunosuppressants (azathioprine, cyclosporine, tacrolimus, mycophenolate mofetil, and rapamycin) were assessed on altering the UV induction of apoptosis in human skin models and of p53 mutant cell clones (putative tumor precursors) and ensuing skin carcinomas (with mutant p53) in the skin of hairless mice. Rapamycin was found to increase apoptosis (three-fold), whereas cyclosporine decreased apoptosis (three-fold). Correspondingly, a 1.5- to five-fold reduction (P = 0.07) or a two- to three-fold increase (P < 0.001) was found in cell clusters overexpressing mutant p53 in chronically UV-exposed skin of mice that had been fed rapamycin or cyclosporine, respectively. Deep sequencing showed, however, that the allelic frequency (∼5%) of the hotspot mutations in p53 (codons 270 and 275) remained unaffected. The majority of cells with mutated p53 seemed not to overexpress the mutated protein. Unexpectedly, none of the immunosuppressants admixed in high dosages to the diet accelerated tumor development, and cyclosporine even delayed tumor onset by approximately 15% (P < 0.01). Thus, in contrast to earlier findings, the frequency of p53-mutant cells was not predictive of the incidence of skin carcinoma. Moreover, the lack of any accelerative effect on tumor development suggests that immunosuppressive medication is not the sole cause of the dramatic increase in skin cancer risk in organ transplant recipients.


Commentary on "Effectiveness of motor imagery and action observation training on musculoskeletal pain intensity: A systematic review and meta-analysis" by Suso-Marti et al.
This journal recently published a paper by Suso-Marti et al., entitled "Effectiveness of motor imagery and action observation training on musculoskeletal pain intensity: A systematic review and meta-analysis" (2020). Motor imagery training and action observation training are rehabilitation approaches that involve imagining oneself executing a particular action, and watching actions that are performed by others, respectively. Both are thought to activate similar neural substrates that are responsible for the actual execution of an action (Eaves et al., 2016). Motor imagery and action observation have been used to enhance motor skill performance in several groups - including athletes and musicians who require highly accurate and precise movement for professional performances, and a similar approach has been employed during rehabilitation with variable outcomes in people after stroke, spinal cord injury and persistent pain.


A set of aspartyl protease-deficient strains for improved expression of heterologous proteins in Kluyveromyces lactis.
Secretion of recombinant proteins is a common strategy for heterologous protein expression using the yeast Kluyveromyces lactis. However, a common problem is degradation of a target recombinant protein by secretory pathway aspartyl proteases. In this study, we identified five putative pfam00026 aspartyl proteases encoded by the K. lactis genome. A set of selectable marker-free protease deletion mutants was constructed in the prototrophic K. lactis GG799 industrial expression strain background using a PCR-based dominant marker recycling method based on the Aspergillus nidulans acetamidase gene (amdS). Each mutant was assessed for its secretion of protease activity, its health and growth characteristics, and its ability to efficiently produce heterologous proteins. In particular, despite having a longer lag phase and slower growth compared with the other mutants, a Δyps1 mutant demonstrated marked improvement in both the yield and the quality of Gaussia princeps luciferase and the human chimeric interferon Hy3, two proteins that experienced significant proteolysis when secreted from the wild-type parent strain.


Opinions of Argentinean neonatologists on the initiation of life-sustaining treatment in preterm infants.
In June 2014, the Argentinean Ministry of Health published guidelines for the management of neonates born at the limit of viability (≤25 weeks of gestation). We explored the opinion of neonatologists in Buenos Aires, Argentina, regarding the initiation of life-sustaining treatment (LST) in critically ill neonates, focusing on the effect of sociocultural factors on their opinion. An anonymous survey was designed to explore the opinions of Argentinean neonatologists on whether or not to initiate LST in newborns born prematurely. Five hundred eighty neonatologists from 36 neonatal units were invited to participate, and 315 specialists from 34 neonatal units completed the survey (response rate 54%). The survey was conducted between June 2014 and February 2015. 9.5% (30/315) of the neonatologists answered they would begin LST on neonates born at 22 weeks, 42.5% (134/315) at 23 weeks, 37% (117/315) at 24 weeks, 7% (22/315) at 25 weeks, and 4% (12/315) at ≥26 weeks. Cumulatively then, 96% of participants stated they would start LST at 25 weeks of gestation or less. On multivariate analysis, a "transcendent" value of life and lack of consideration of the local legal framework for making medical decisions in the delivery room were statistically associated with an opinion in favor of initiation of LST in neonates born at the limit of viability. More than 50% of the Argentinean neonatologists surveyed answered they would initiate treatment at a gestational age of less than 23 weeks, despite the fact that the recommendations of the Argentinean Ministry of Health are to only give comfort care for these neonates. The opinion of most Argentinean neonatologists surveyed thus differs from that recommended by the guidelines of Argentina. The most frequent opinion of Argentinean neonatologists was to initiate LST in neonates at the limit of viability. Certain factors, in particular the sense of a transcendent meaning to life and lack of consideration of the local legal framework for making medical decisions in the delivery room, seem to influence the decision to start LST.


Cataract Surgery Practices in the Republic of Korea: A Survey of the Korean Society of Cataract and Refractive Surgery 2018.
To describe current cataract surgery practice patterns and changing trends among Korean ophthalmologists. A survey of members of the Korean Society of Cataract and Refractive Surgery was performed in July 2018. One hundred and two (12.7%) of 801 questionnaires were returned for analysis. The data were analyzed using descriptive statistics and compared with previous surveys. Most of the respondents (75%) had been in practice for 6 or more years and performed an average of 31 cataract surgeries per month. The preferred method for cataract surgery was phacoemulsification (95%); 5% used a femtosecond laser. The use of topical anesthesia markedly increased from 69% (2012) to 80% (2018). The use of optical biometry exceeded that of ultrasound A-scan biometry. A multifocal intraocular lens was used by 76% of the respondents compared with 44% of the respondents in 2012. Topical nonsteroidal anti-inflammatory drugs were used by 70% of the respondents postoperatively. Most (59%) of these anti-inflammatory drugs were prescribed for 4 weeks. This survey provided a comprehensive update of the present cataract surgery practices in the Republic of Korea. The results emphasized the increasing use of premium intraocular lenses, optical biometry, and topical anesthesia.