Impaired platelet procoagulant mechanisms in patients with bleeding disorders.
Activated platelets contribute to the arrest of bleeding by forming aggregates at sites of vascular injury and by providing a surface for assembling enzyme complexes involved in fibrin formation (platelet procoagulant activity; PCA). Impairment in the latter property of platelets has been observed in some disorders of hemostasis. In Scott syndrome, there is a defect in membrane vesiculation and in the surface expression of phosphatidylserine (PS), the phospholipid that is necessary for assembling the factor VIIIa/IXa (tenase) and factor Va/Xa (prothrombinase) complexes involved in thrombin formation. A family with an isolated defect in vesiculation, but normal prothrombinase activity, has also been reported. In the Quebec platelet disorder, overexpression of the fibrinolytic enzyme urokinase-type plasminogen activator results in the degradation of alpha-granule proteins, including factor V, and a specific abnormality in platelet factor V is the basis for the prothrombinase defect in platelet factor V-New York. The impaired prothrombinase activity in patients with delta-storage pool deficiency may be due to a failure to provide sufficient amounts of secreted adenine nucleotides which, when bound to P2 purinergic receptors, are necessary to maintain the intracellular Ca (2+) levels that are required for the surface expression of PS. Platelet prothrombinase activity and thrombin potential in patients with Glanzmann thrombasthenia (GPIIb-IIIa deficiency) may be decreased, normal, or increased, depending on the experimental conditions, for reasons that are not currently clear. The most consistent platelet PCA abnormality in the Bernard-Soulier syndrome (GPIb-complex deficiency) is an abnormally short serum prothrombin time, associated with a defect in the process by which an interaction between fibrin, von Willebrand factor, and GPIb promotes PCA.


Triangulating Competencies, Concepts, and Professional Development in Curriculum Revisions.
Curricular reform, as reported in the literature, has been described as a tortuous change process. This article demonstrates how a series of retreats using consensus building methodologies facilitated efficient change among a large faculty body. Nimble work groups completed discrete aspects of the project and promoted engagement. The curriculum is described, including assimilation of concepts, competencies, and professional development. Lessons learned for creating a positive and timely curricular change are presented.


Drosophila Pkd2 is haploid-insufficient for mediating optimal smooth muscle contractility.
Humans heterozygous for PKD1 or PKD2 develop autosomal dominant polycystic kidney disease, a common genetic disorder characterized by renal cyst formation and extrarenal complications such as hypertension and vascular aneurysms. Cyst formation requires the somatic inactivation of the wild type allele. However, it is unknown whether this recessive mechanism applies to life-threatening vascular aneurysms, which could involve weakening of the endothelial lining or surrounding vascular smooth muscle cells (SMCs). Drosophila Pkd2 at 33E3 (Pkd2) encodes a PKD2 family of Ca(2+)-activated Ca(2+)-permeable cation channels. We show here that loss-of-function Pkd2 mutations severely reduced the contractility of the visceral SMCs, which was restored by expressing wild type Pkd2 cDNA via a muscle-specific Gal4 driver. The effect of Pkd2 mutations alone on the skeletal muscle was minimal but was exacerbated by ryanodine-induced perturbation of intracellular Ca(2+) stores. Consistent with this, Pkd2 interacted strongly with a ryanodine receptor mutation, causing a synergistic reduction of larval body wall contraction rate that is normally regulated through Ca(2+) oscillation during excitation-contraction coupling in the skeletal muscle. These results suggest that PKD2 cooperates with the ryanodine receptor to promote optimal muscle contractility through intracellular Ca(2+) homeostasis. Further genetic analysis indicated that Pkd2 is strongly haploinsufficient for normal SMC contractility. Since Ca(2+) homeostasis is a conserved mechanism for optimal muscle performance, our results raise the possibility that inactivation of just one PKD2 copy is sufficient to compromise vascular SMC contractility and function in PKD2 heterozygous patients, thus explaining their increased susceptibility to hypertension and vascular aneurysms.


Induction of kidney heme oxygenase-1 (HSP32) mRNA and protein by ischemia/reperfusion: possible role of heme as both promotor of tissue damage and regulator of HSP32.
Presently we describe, for the first time, induction of microsomal heme oxygenase-1 (HO-1) mRNA and protein in response to ischemia/reperfusion and therefore define HO-1 as stress protein in the kidney. Specifically, Northern blot analysis of kidneys of rats subjected to bilateral ischemia for 30 min revealed an increase of 8- to 10-fold in the level of 1.8 Kb HO-1 mRNA 6 hr after reperfusion. The increase in transcript level was maintained when assessed after 24 hr. The levels of 1.3 and 1.9 Kb transcripts for the second isozyme of HO, HO-2, were decreased at both time points. The increase in HO-1 mRNA was reflected in HO-1 protein level, as judged by Western blot analysis and at the level of activity as judged by the rate of bilirubin formation. An absence of change in adrenal HO-1 mRNA level subsequent to renal ischemia/reperfusion suggested that the induction of kidney HO-1 did not reflect a generalized response of the rat organs to stress; rather, it was a target organ specific response. Moreover, in kidneys subjected to ischemia 6 and 24 hr after reperfusion, significant increases in the cellular content of heme were observed; heme is a known inducer of HO-1 synthesis. Ischemia/reperfusion also adversely affected concentration of cytochrome P-450 in both mitochondrial and the microsomal fractions of the kidney. We suggest that increase in tissue heme levels may be a significant factor in damage caused by ischemia/reperfusion to renal tissue, whereby the metalloporphyrin promotes oxygen-free radical formation.(ABSTRACT TRUNCATED AT 250 WORDS)


Residues essential for plasminogen binding by the cation-independent mannose 6-phosphate receptor.
The 300 kDa cation-independent mannose 6-phosphate receptor (CI-MPR) is a multifunctional protein that binds diverse intracellular and extracellular ligands with high affinity. The CI-MPR is a receptor for plasminogen, and this interaction can be inhibited by lysine analogues. To characterize the molecular basis for this interaction, surface plasmon resonance (SPR) analyses were performed using truncated forms of the CI-MPR and plasminogen. The results show that the N-terminal region of the CI-MPR containing domains 1 and 2, but not domain 1 alone, of the receptor's 15-domain extracytoplasmic region binds plasminogen (K(d) = 5 +/- 1 nM) with an affinity similar to that of the full-length receptor (K(d) = 20 +/- 6 nM). In addition to its C-terminal serine protease domain, plasminogen contains lysine binding sites (LBS), which are located within each of its five kringle domains, except kringle 3. We show that kringles 1-4, but not kringles 1-3, bind the CI-MPR, indicating an essential role for the LBS in kringle 4 of plasminogen. To identify the lysine residue(s) of the CI-MPR that serve(s) as an essential determinant for recognition by the LBS of plasminogen, site-directed mutagenesis studies were carried out using a construct encoding the N-terminal three domains of the CI-MPR (Dom1-3His) which contains both a mannose 6-phosphate (Man-6-P) and plasminogen binding site. The results demonstrate two lysine residues (Lys53 located in domain 1 and Lys125 located in the loop connecting domains 1 and 2) of the CI-MPR are key determinants for plasminogen binding but are not required for Man-6-P binding.


Rising hypospadias rates: disproving a myth.
Hypospadias is one of the most common congenital abnormalities occurring in males. In recent years, the prevalence of hypospadias and whether that prevalence is rising or stable has become part of a larger debate over the potential effects of so-called 'endocrine disruptors', such as phthalates and bisphenol-A, on male reproductive health. This commentary critically examines allegations suggesting a worldwide increase in hypospadias rates. Despite the lack of scientific support for this hypothesis and for related claims that the disorders of male reproductive health are related to endocrine disruptors, these constructs remain firmly entrenched in popular literature, and are being used in part to justify litigation banning suspected endocrine disruptors such as phthalates and bisphenol-A. A review of the epidemiologic data on this issue amassed to date clearly demonstrates that the bulk of evidence refutes claims for an increase in hypospadias rates. This suggests that two of the three components of alleged testicular dysfunction syndrome, i.e. decline in sperm counts and rise in urogenital anomalies, lack clinical support. It further suggests that extrapolations from data derived in laboratory animal studies about alleged occult risks to humans of various candidate compounds are unwarranted at this time.


Synthesis of nitric oxide probes with fluorescence lifetime sensitivity.
We present the rationale, synthesis and evaluation of the first activatable fluorescent probe that utilizes fluorescence lifetime change for detection of nitric oxide. The new probe DAP-LT1 features a near-infrared polymethine skeleton with a diaminobenzene functionality incorporated into the meso-position. The probe is partially quenched, and upon reaction with nitric oxide shows an increase in the fluorescence lifetime from 1.08 ns to 1.24 ns.


[Latest results of intensive care of sepsis, septic shock and multiple organ injuries].
Author is first discussing sepsis and its new categories (SIRS, MODS), its pathogenesis and symptoms. One axis of the events is the release of inflammatory and anti-inflammatory cytokines from the monocytes and macrophages, due to the precipitating injury. The other one is the activation of the polymorphonuclear leucocytes and the endothelial cells and their interaction. The basically non infectious SIRS is often maintained and worsened to MODS by the "translocation" of bacteria and endotoxins from the gut into the circulation. It is a new development the use of the serum procalcitonin level for the diagnosis, differential-diagnosis and for the evaluation of the success of the therapy. The causal therapy of the sepsis is still the surgical management of the septic focus, which should be supported by antibiotics and non-specific treatment (fluid-load, ventilation, inotropic, vasoactive and immunogenic drugs). It is new knowledge the effect of antibiotics on the immuno-system. For the treatment of SIRS, it has been tried many anti-cytokine and immunomodulating therapy; author explains the presumable causes of the failure of their majority.


Retained surfactant catheter and pneumothorax in a premature neonate.
Surfactant catheters are used to administer exogenous surfactant as a preventive and therapeutic measure for surfactant deficiency in premature neonates. We describe the case of a retained surfactant catheter in a 700 g premature neonate with associated pneumothorax.


Inversion versus retention of configuration for nucleophilic substitution at vinylic carbon.
A high-level computational study using CCSD, CCSD(T), and G2(+) levels of theory has shown that unactivated vinyl substrates such as vinyl chloride would afford gas phase, single-step halide exchange by a pure in-plane sigma-approach of the nucleophile to the backside of the C--Cl sigma bond. Geometry optimization by CCSD/6-31+G* and CCSD(T)/6-31+G* confirms the earlier findings of Glukhovtsev, Pross, and Radom that the S(N)2 reaction of Cl(-) with unactivated vinyl chloride in the gas phase occurs by a sigma attack. Complexation of vinyl chloride with Na(+) does not alter this in-plane sigma preference. However, moderately activated dihaloethylenes such as 1-chloro-1-fluoroethylene undergo gas-phase S(N)2 attack by the accepted pi-route where the nucleophile approaches perpendicular to the plane of the C==C. In the latter case a single-step pi pathway is preferred for the Cl(-) + H(2)C==CFCl reaction. This is the first definitive example at a high level of theory where a single-step pi nucleophilic vinylic substitution is preferred over a multistep mechanism in the gas phase. The activation barriers for these gas-phase single-step sigma- and pi-processes involving both naked anions and Na(+) complexes are, however, prohibitively high. Solvation and the presence of a counterion must play a dominant role in nucleophilic vinylic substitution reactions that proceed so readily in the condensed phase. In solution, nucleophilic vinylic substitution reactions involving electron-withdrawing groups on the carbon--carbon double bond (e.g., -CN, -CHO, and -NO(2)) would almost certainly proceed via a free discrete carbanionic intermediate in accord with experiment.


The barriers to internal rotation of benzaldehyde and benzoyl fluoride: "reconciliation" between theory and experiment.
This work is devoted to investigation of the known problem of the discrepancy between the experimental and theoretical values for the barrier to internal rotation of the molecules comprised of a benzene ring and a π-conjugated substituent, such as benzaldehyde and benzoyl fluoride. The possible reasons of such discrepancy are considered. As a result the conclusion was drawn that the origin of the problem is incorrectness of the assignments of the torsional levels higher than first, both for benzaldehyde and benzoyl fluoride. In addition the significant kinematic interaction between torsional vibration and out-of-plane CHO deformation was found for benzaldehyde.


Diltiazem did not induce gingival overgrowth in rats. A clinical, histological and histometric analysis.
The administration of calcium channel blockers has been associated with gingival overgrowth. However, there are few studies in humans or animals that evaluated the effect of diltiazem on gingival tissues. The present study assessed the influence of diltiazem, at different dosages and treatment duration, on gingival tissues of rats, using clinical, histological and histometric analyses. Eighty young male rats were separated into eight groups according to the dosage and duration of treatment. Rats were treated for 20 or 40 days with a daily subcutaneous injection of 5, 20 or 50 mg/kg of body weight of diltiazem. The results confirmed that diltiazem did not induce gingival overgrowth in rats. For all animals, the evaluation did not show gingival alterations regardless of the dosages and periods of treatment. The histometric analysis showed no significant change in the area of epithelium and connective tissues, although after 40 days of treatment a decrease in the area of connective tissue was observed, without statistically significant difference from control groups. Within the limits of this study, we suggest that diltiazem did not induce gingival overgrowth.


Retinopathy of prematurity in neonatal patients with birth weight greater than 1500 g in Taiwan.
To understand the characteristics, ophthalmic outcomes, and risk factors of retinopathy of prematurity (ROP) in patients with birth weight (BW) greater than 1500 g. The applicability of the ROP screening criteria to the Taiwanese population was also examined. The study included 104 eyes from 54 ROP patients who had BW greater than 1500 g from 1981 to 2008. Demographic information, disease courses, ophthalmic outcomes, and possible systemic risk factors were recorded. The infants were divided into groups of mild and severe ROP for a risk factor analysis. The mean gestational age (GA) of the infants was 31 ± 1.3 weeks, and the mean BW was 1675 ± 249 g. Mild ROP regressed in 94 eyes (90%), and 10 eyes (10%) developed severe ROP. After various treatments, the regression rates for prethreshold or threshold ROP (n = 8) and stage 4 ROP (n = 2) were 100% and 50%, respectively. Forty-eight patients (85%) had at least three associated systemic risk factors. A multiple logistic regression analysis revealed that patients with an intraventricular hemorrhage were found to have an increased chance of developing severe ROP, especially those with BW greater than 1500 g (p = 0.015). There was also a significant association between patients who had severe ROP and an increased risk of having cerebral palsy (CP) at 1.5 years of age (p = 0.013). The majority of patients with BW greater than 1500 g developed mild ROP. However, advanced ROP with poor visual outcome was also encountered in some patients.


Long-term consequences of early feeding on later obesity risk.
Some 30 years ago, Günter Dörner stated that the concentrations of hormones, metabolites and neurotransmitters during critical periods of early development will program disease risk in human adulthood, a concept that since has received enormous scientific support and broad attention. Evidence has also accumulated showing that early nutrition programs later obesity risk. Breastfeeding reduces the odds ratio for obesity at school age by about 20%, relative to formula feeding, adjusted for biological and sociodemographic confounding variables. We propose that the protective effect of breastfeeding is explained at least in part by the induction of lower rates of infant weight gain, which may be related to differences in substrate intakes with breast milk and standard infant formulae. Protein intake per kilogram body weight is some 55-80% higher in formula-fed than in breast-fed infants. We hypothesize that high early protein intakes in excess of metabolic requirements may enhance weight gain in infancy and later obesity risk (the 'early protein hypothesis'). The European Childhood Obesity Project is testing this hypothesis in a randomized double-blind intervention trial in more than 1,000 infants in 5 European countries. Infants that are not breast fed are randomized to formulae with higher or lower protein contents and are followed up to school age. If an effect of infant feeding habits on later obesity risk should be established, there is great potential for effective preventive intervention with a significant potential health benefit for the child and adult population.


Natural killer cells for cancer immunotherapy: pluripotent stem cells-derived NK cells as an immunotherapeutic perspective.
Natural killer (NK) cells play an essential role in the fight against tumor development. Over the last years, the progress made in the NK-cell biology field and in deciphering how NK-cell function is regulated, is driving efforts to utilize NK-cell-based immunotherapy as a promising approach for the treatment of malignant diseases. Therapies involving NK cells may be accomplished by activating and expanding endogenous NK cells by means of cytokine treatment or by transferring exogenous cells by adoptive cell therapy and/or by hematopoietic stem cell transplantation. NK cells that are suitable for adoptive cell therapy can be derived from different sources, including ex vivo expansion of autologous NK cells, unstimulated or expanded allogeneic NK cells from peripheral blood, derived from CD34+ hematopoietic progenitors from peripheral blood and umbilical cord blood, and NK-cell lines. Besides, genetically modified NK cells expressing chimeric antigen receptors or cytokines genes may also have a relevant future as therapeutic tools. Recently, it has been described the derivation of large numbers of functional and mature NK cells from pluripotent stem cells, both embryonic stem cells and induced pluripotent stem cells, which adds another tool to the expanding NK-cell-based cancer immunotherapy arsenal.


Respondent Understanding in Discrete Choice Experiments: A Scoping Review.
Despite the recognised importance of participant understanding for valid and reliable discrete choice experiment (DCE) results, there has been limited assessment of whether, and how, people understand DCEs, and how 'understanding' is conceptualised in DCEs applied to a health context. Our aim was to identify how participant understanding is conceptualised in the DCE literature in a health context. Our research questions addressed how participant understanding is defined, measured, and used. Searches were conducted (June 2019) in the MEDLINE, EMBASE, PsychINFO and Econlit databases, as well as hand searching. Search terms were based on previous DCE systematic reviews, with additional understanding keywords used in a proximity-based search strategy. Eligible studies were peer-reviewed journal articles in the field of health, related to DCE or best-worst scaling type 3 (BWS3) studies, and reporting some consideration or assessment of participant understanding. A descriptive analytical approach was used to chart relevant data from each study, including publication year, country, clinical area, subject group, sample size, study design, numbers of attributes, levels and choice sets, definition of understanding, how understanding was tested, results of the understanding tests, and how the information about understanding was used. Each study was categorised based on how understanding was conceptualised and used within the study. Of 306 potentially eligible articles identified, 31 were excluded based on titles and abstracts, and 200 were excluded on full-text review, resulting in 75 included studies. Three categories of study were identified: applied DCEs (n = 52), pretesting studies (n = 7) and studies of understanding (n = 16). Typically, understanding was defined in relation to either the choice context, such as attribute terminology, or the concept of choosing. Very few studies considered respondents' engagement as a component of understanding. Understanding was measured primarily through qualitative pretesting, rationality or validity tests included in the survey, and participant self-report, however reporting and use of the results of these methods was inconsistent. Those conducting or using health DCEs should carefully select, justify, and report the measurement and potential impact of participant understanding in their specific choice context. There remains scope for research into the different components of participant understanding, particularly related to engagement, the impact of participant understanding on DCE validity and reliability, the best measures of understanding, and methods to maximise participant understanding.


[Computed tomographic diagnosis of pre- and paravertebral masses in the thorax and retroperitoneum].
CT is the method of choice in the diagnostic identification and clarification of prevertebral and paravertebral space-occupying growths before initiating invasive methods of diagnosis and before surgery. CT supplies decisive information by means of the transversal tomography, which is free from overlapping, and enables determination of relative densities. A most important feature is the safe exclusion of any aortoilacal aneurysm via differential diagnosis. The possibilities and limitations of computed tomography are discussed on the basis of several examples, namely, a lateral intrathoracic meningocele, a mediastinal bronchogenic cyst, a retroperitoneal fibrosis, lymph node metastases and hypostatic abscesses.


Characterization and Comparison of Primary Care Appointment Utilization Patterns Among Military Health System Beneficiaries.
The role of primary care in the United States is vitally important to improving health outcomes, minimizing waste, and controlling cost. The Military Health System is tasked with both caring for its beneficiaries and ensuring the medical readiness of active duty service members, who often have needs unique to those in the civilian population. Balancing the number of individuals assigned to a primary care clinician with the clinician's capacity to meet their medical needs and anticipated appointment demand is a fundamental cornerstone of effective primary care clinic management in any setting. Using the Military Health System Data Repository, this cross-sectional study utilized descriptive statistics and Poisson regression to describe crude and adjusted primary care appointment utilization trends among Military Health System beneficiaries during fiscal year 2016. The primary care appointment utilization rate of the study population was 3.3 visits per person-year. The youngest and oldest age groups, women, active duty, and those enrolled to Army clinics had the highest utilization rates within each of the respective covariates. Active duty women had the highest utilization of any group in the data set, with a crude rate of 4.7 visits per person-year. Primary care utilization trends are different among different demographic subgroups within the Military Health System (MHS). Unmet demand, patient acuity, clinician continuity, robustness of team support, and other important factors that influence appointment utilization were not incorporated in this study. Superficially, these data suggest that the MHS enrollment target of 1,100-1,300 patients per full-time primary care clinician is roughly appropriate, though this should be interpreted with caution given the limitations.


A PCR blood test outperforms chromogranin A in carcinoid detection and is unaffected by proton pump inhibitors.
A critical requirement in neuroendocrine tumor (NET) management is a blood biomarker test that is sensitive, specific and reproducible. We evaluated a PCR-based 51-transcript signature to detect tumors, compared it with chromogranin A (CgA) and examined the confounding effect of proton pump inhibitors (PPIs), which cause falsely elevated CgA levels. The multigene signature was evaluated in two groups. Group 1: 125 prospectively collected NETs: gastroenteropancreatic NETs (n=91, including 42 pancreatic and 40 small intestinal), carcinoids of unknown primary (n=18) and other sites (n=16). Group 2: prospectively collected non-NET patients receiving PPIs (>1 month; dyspepsia, n=19; GERD, n=6; and pancreatitis, n=4) and 50 controls. All samples were analyzed by PCR (marker genes) and ELISA (DAKO-CgA). Sensitivity comparisons included χ(2), non-parametric measurements, and receiver operating characteristic (ROC) curves. Group 1: 123 NETs were PCR-positive (98.4%) compared with 50 (40%) CgA-positive (χ(2)=97.3, P<10(-26)). Significant differences (P<0.001) were noted between pancreas: PCR 95% vs CgA 29.2% (P<10(-9)) and small intestine: 100 vs 58% (P<10(-4)). The multigene test was elevated in all grades (G1-G3), in both local and disseminated disease, and was not normalized by somatostatin analog therapy. It was also elevated in 97% of CgA normal NETs. Group 2: PPI administration increased CgA in 83% and CgA was elevated in 26% of controls. PCR values were not elevated in either group. PCR performance metrics were as follows: sensitivity 98.4%, specificity 100%, positive predictive value 100%, negative predictive value 97.8%, and the ROC-derived area under the curve (AUC) was 0.997. These were significantly better than CgA (all metrics <60%; AUC, 0.54; Z-statistic, 10.44, P<0.0001). A 51-panel multigene blood transcript analysis is significantly more sensitive than plasma CgA for NET detection and is unaffected by acid suppression therapy.


Renal allograft recipient with co-existing BK virus nephropathy and pulmonary histoplasmosis: report of a case.
Renal allograft recipients are prone to opportunistic infections, rarely multiple coexisting infections, due to the immunocompromised state. To the best of our knowledge, no case of a co-existing polyoma virus nephropathy and pulmonary histoplasmosis in a renal allograft recipient has been reported so far in the available literature. A 55-year-old male renal allograft recipient underwent graft biopsy for asymptomatic graft dysfunction. The graft biopsy showed features of polyoma virus nephropathy. Soon after, he developed fever with pulmonary nodules. Fine-needle aspiration from lung nodules showed intracellular yeast forms of histoplasma. The patient responded well to amphotericin B with subsidence of fever. The co-existence of renal allograft-limited infection like polyoma virus and systemic fungal infection such as histoplasmosis should be kept in mind in a transplant recipient with graft dysfunction and non-specific systemic symptoms. Prompt recognition of these infections permits the clinician to institute appropriate therapeutic modification and improved survival.


Phellinus linteus polysaccharides mediates acetaminophen-induced hepatotoxicity via activating AMPK/Nrf2 signaling pathways.
Overdose of acetaminophen (APAP) is currently one of the main causes of hepatoxicity and acute liver injury, which is often linked to oxidative stress. Phellinus linteus polysaccharides (Phps) have shown many hepatoprotective effects, however, the mechanism of Phps on APAP-induced acute liver injury has not been further elucidated. The aim of this study is to investigate the underlying mechanism of Phps to acute liver injury. The expression of AMPK/Nrf2 and autophagy were detected using western blot. The results indicated that Phps treatment effectively alleviated APAP-induced acute liver injury by reducing alanine transaminase (ALT) and aspartate aminotransferase (AST) levels in serum. Phps significantly attenuated myeloperoxidase (MPO) activity and glutathione (GSH) depletion. Meanwhile, Phps remarkably alleviated histopathological changes. Further research found that Phps promoted AMPK pathway and up-regulated nuclear factor erythroid-2-related factor (Nrf2) transported into nucleus, and elevated heme oxygenase 1(HO-1), glutamate-cysteine ligase catalytic (GCLC), glutamate cysteine ligase modifier (GCLM) and quinone oxidoreductase (NQO1). Additionally, Phps apparently facilitated the expression of autophagy proteins (ATG3, ATG5, ATG7, and ATG12). However, the protection of pathologic changes was nearly absent in Nrf2-/- mice. Phps have potential in preventing oxidative stress in APAP-induced acute liver injury.


The influence of statins on osseointegration: a systematic review of animal model studies.
Recent research data have suggested that the beneficial action of statins in bone tissue could improve osseointegration around titanium implants by increasing the bone implant contact (BIC), the expression of bone morphogenetic protein-2 (BMP-2) and vascular endothelial growth factor (VEGF). The aim of this systematic review was to evaluate the influence of statins on osseointegration of titanium implants in animal studies. Two reviewers searched independently four databases (MEDLINE, SCOPUS, WEB OF SCIENCE and the Cochrane Library), until March 15, 2016. The Cochrane Collaboration's Tool for Assessing Risk of Bias was used to assess the quality of the included studies. Papers that reported outcome data considering bone implant contact (BIC), mechanical tests or other histological evaluation were eligible for inclusion. 312 references were eletronically retrieved, 21 full-text papers were screened and 17 studies were included. Thirteen trials presented histomorphometry data on bone implant contact measures. All of them showed a significant improved BIC when using statins. Despite data from included studies point to beneficial effects, standardized studies and with less risk of bias, are needed to clarify the role of statins on osseointegration.


Meralgia paresthetica: the diagnostic value of somatosensory evoked potentials.
Somatosensory evoked potentials elicited by stimulation of the lateral femoral cutaneous nerve were investigated in 20 able-bodied persons and 22 patients diagnosed clinically to have meralgia paresthetica. There was no statistically significant difference between the right and left sides for P0 and N1 latencies in able-bodies subjects. For all patients, abnormalities were found on the side clinically affected. The mean values were 38.11 msec for P0 and 47.49msec for N1 on the affected side and 32.62msec and 41.44msec on the unaffected side (p less than .01). The mean latency differences between the two sides P0 and N1 were 5.49msec and 6.05msec, respectively (p less than .01). Hence, this technique proved to be a useful objective diagnostic aid in meralgia paresthetica.


Information processing technology in Japan: 2.
An international symposium on New Information Processing Technologies held in Japan in March 1991 is described, based on a report by D. K. Kahaner of the U. S. Office of Naval Research Asian Office.


Early Life Stress- and Drug-Induced Histone Modifications Within the Ventral Tegmental Area.
Psychiatric illnesses are a major public health concern due to their prevalence and heterogeneity of symptom presentation resulting from a lack of efficacious treatments. Although dysregulated dopamine (DA) signaling has been observed in a myriad of psychiatric conditions, different pathophysiological mechanisms have been implicated which impede the development of adequate treatments that work across all patient populations. The ventral tegmental area (VTA), a major source of DA neurons in the brain reward pathway, has been shown to have altered activity that contributes to reward dysregulation in mental illnesses and drug addiction. It has now become better appreciated that epigenetic mechanisms contribute to VTA DA dysfunction, such as through histone modifications, which dynamically regulate transcription rates of critical genes important in synaptic plasticity underlying learning and memory. Here, we provide a focused review on differential histone modifications within the VTA observed in both humans and animal models, as well as their relevance to disease-based phenotypes, specifically focusing on epigenetic dysregulation of histones in the VTA associated with early life stress (ELS) and drugs of abuse. Locus- and cell-type-specific targeting of individual histone modifications at specific genes within the VTA presents novel therapeutic targets which can result in greater efficacy and better long-term health outcomes in susceptible individuals that are at increased risk for substance use and psychiatric disorders.


Repurposing approach identifies new treatment options for invasive fungal disease.
Drug repositioning is the process of discovery, validation and marketing of previously approved drugs for new indications. Our aim was drug repositioning, using ligand-based and structure-based computational methods, of compounds that are similar to two hit compounds previously selected by our group that show promising antifungal activity. Through the ligand-based method, 100 compounds from each of three databases (MDDR, DrugBank and TargetMol) were selected by the Tanimoto coefficient, as similar to LMM5 or LMM11. These compounds were analyzed by the scaffold trees, and up to 10 compounds from each database were selected. The structure-based method (molecular docking) using thioredoxin reductase as the target drug was performed as a complementary approach, resulting in six compounds that were tested in an in vitro assay. All compounds, particularly raltegravir, showed antifungal activity against the genus Paracoccidioides. Raltegravir, an antiviral drug, showed promising antifungal activity against the experimental murine paracoccidioidomycosis, with significant reduction of the fungal burden and decreased alterations in the lung structure of mice treated with 1 mg/kg of raltegravir. In conclusion, the combination of two in silico methods for drug repositioning was able to select an antiviral drug with promising antifungal activity for treatment of paracoccidioidomycosis.


Vagal blockade does not prevent adrenocorticotropin, cortisol, and cardiopulmonary responses to thromboxane A2.
Previously, we reported that thromboxane A2 (TxA2) mediates heart rate, adrenocorticotropin (ACTH), cortisol, and blood gas responses, although the specific site of action was not identified. In the present study, we interrupted vagal nervous transmission in chronically instrumented conscious sheep and infused the TxA2 mimetic U46619 or saline into the carotid artery or U46619 into the vena cava to determine whether TxA2 acts at vagal afferent nerves. Heart rate increased in all three groups during vagal blockade, and responses were not different between groups. Carotid artery and intravenous infusions of U46619 resulted in an increase in blood pressure, but responses were not different between groups. PaO2 decreased in response to vagal blockade in all groups, and responses were not different among groups. Arterial pH increased and PaCO2 decreased during vagal blockade in response to carotid artery U46619 infusions but not in response to vagal blockade alone or combined with carotid artery saline or intravenous U46619. ACTH, cortisol, and hematocrit increased significantly in response to carotid artery infusions of U46619 during vagal blockade but not in response to carotid artery saline or intravenous U46619 infusions. In summary, carotid artery infusions of TxA2 mimetic result in ACTH, cortisol, PaCO2, pHa, and hematocrit responses that are not prevented by vagal blockade. We conclude that these responses are mediated at a site perfused by the carotid vasculature and not at a site innervated by the vagal nerves, findings consistent with the hypothesis that TxA2 acts on the brain to mediate cardiopulmonary and pituitary-adrenal responses.


A randomized clinical trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants.
Since the murine monoclonal antibody OKT3 reacts with human T cells and blocks their function, we explored its effectiveness in treating T-cell-mediated rejection of renal allografts. In a prospective randomized multicenter trial, 123 patients undergoing acute rejection of cadaveric renal transplants were treated either with OKT3 daily for a mean of 14 days, with concomitant lowering of the dosage of other immunosuppressive drugs (63 patients), or with conventional high-dose steroids (60 patients). OKT3 reversed 94 per cent of the rejections--a figure that was significantly better (P = 0.009) than the 75 per cent reversal rate obtained with conventional steroid treatment. This superior reversal rate with OKT3 was reflected in an improved one-year graft survival of 62 per cent for the OKT3-treated group, as compared with 45 per cent for the steroid-treated group (P = 0.029), in patients who were all selected by virtue of having had acute rejection. We conclude that treatment with OKT3 (with concomitant lowering of the dosage of other immunosuppressive drugs) is an effective approach for acute renal-allograft rejection.


Two distinct T-cell receptor alpha-chain transcripts in a rabbit T-cell line: implications for allelic exclusion in T cells.
Information relevant to allelic exclusion in T cells has been obtained by a study of cDNA clones corresponding to alpha-chain genes of the T-cell receptor in the rabbit T-cell line RL-5. One clone contains a variable-joining-constant (VJC) sequence encoding a complete alpha chain of the T-cell receptor. A second has an identical constant region and includes a distinct variable-joining (VJ) sequence. However, a single-base deletion in the variable region places the remainder of the second transcript out-of-phase and appears to be the product of a rearrangement involving a variable region of the T-cell receptor alpha-chain pseudogene. Presence of two variable-joining-constant (VJC) transcripts in the same cell line indicates that alpha-chain gene rearrangement is not affected by transcription of a complete alpha-chain mRNA and suggests that steps after mRNA synthesis are involved in the allelic exclusion process for alpha-chain genes. Comparison of rabbit alpha-chain sequences with those of man and mouse revealed interspecies conservation in constant and variable regions. Genomic Southern blot analyses using a rabbit constant region of the T-cell receptor alpha-chain probe revealed the presence of a single constant region gene. Hybridization with variable region probes defined two distinct multigenic subfamilies. Homology between certain rabbit and murine variable regions of the T-cell receptor alpha-chain sequences suggests that the existence of subfamilies predated divergence of these species.


Influence of starch fermentation on bile acid metabolism by colonic bacteria.
Secondary bile acids (BA) may be involved in the pathogenesis of colorectal cancer. In vivo, starch malabsorption has been shown to reduce fecal excretion of secondary BA. The present in vitro study was performed to investigate the effect of starch fermentation on BA metabolism by colonic bacteria. Fecal samples of healthy volunteers were incubated in anaerobic batch cultures for 48 hours with the primary bile acids cholic (0.6 g/l) and chenodeoxycholic acid (0.4 g/l). Media were starch free or enriched with starch (10 g/l). The pH was controlled and held at 6 or 7. In the starch-free incubations, secondary BA were rapidly formed, and degradation of primary to secondary BA was complete within 24 hours. The formation of secondary BA was partially inhibited by the addition of starch to the media. This effect was stronger at pH 6 than at pH 7. Starch was rapidly and completely fermented. In conclusion, this study showed that formation of secondary BA by fecal bacteria is inhibited when starch is simultaneously fermented, an effect that is mainly, but not completely, explained by reduction of pH.


Ascent of the testis: fact or fiction.
Ascent of the testis from the normal to an undescended position has been observed in 10 patients. In 9 of them there was a complete hernial sac and it is suggested that the acquired malposition of the testis is due to partial absorption of the processus vaginalis into the parietal peritoneum. Alteration in the length of the inguinal canal with growth may be an additional contributory factor. The mean interval between the original and subsequent observations was 5.2 years, leading to a late orchiopexy at a mean age of 9.4 years.


Periapical status in subjects with regular dental care habits.
This study covered 250 subjects aged 21-60 yr subdivided into four age groups. Oral hygiene status and dental care habits were above average and the number of teeth remaining was high in all age groups (range 24.1-27.3). All subjects were radiographically examined by means of an intraoral full mouth survey. From the radiographs periapical lesions and root fillings were recorded. A total of 117 subjects (46.8%) presented with one or more periapical lesions distributed between 294 roots (2.9%) or 229 teeth (3.5%). Two-thirds of the periapical lesions were related to endodontically treated roots. Of all endodontically treated roots 28.8% were associated with a periapical lesion. Irrespective of the relative length 17.2% of the homogeneous and 37.9% of the inhomogeneous root fillings were associated with a periapical lesion. It is concluded that periapical lesions although rare in these subjects were most frequent in root filled teeth.


Cyst and endometriosis of the canal of Nuck: rare differentials for a female groin mass.
Cyst of the canal of Nuck is a rare abnormality of the female inguinal canal that can present similarly to a hernia. If incompletely obliterated, the patent canal of Nuck may predispose to an inguinal hernia or hydrocele due to direct communication with the abdominal cavity. Such defects are normally detected and repaired in early childhood but can also present later in adult life. We report the case of a 44-year-old woman who presents with a fluctuant, mobile and irreducible left-sided groin mass. Ultrasound of the groin identified a cystic structure in the canal of Nuck. The patient underwent successful open herniorrhaphy with excision of the cyst and mesh repair of the inguinal canal. Subsequent histopathological examination also revealed concurrent endometriosis of the canal of Nuck. A systematic approach to differential diagnoses for a female groin mass, further investigations and management are discussed.


Atomic Layer Coating to Inhibit Surface Crystallization of Amorphous Pharmaceutical Powders.
Preventing crystallization is a primary concern when developing amorphous drug formulations. Recently, atomic layer coatings (ALCs) of aluminum oxide demonstrated crystallization inhibition of high drug loading amorphous solid dispersions (ASDs) for over 2 years. The goal of the current study was to probe the breadth and mechanisms of this exciting finding through multiple drug/polymer model systems, as well as particle and coating attributes. The model ASD systems selected provide for a range of hygroscopicity and chemical functional groups, which may contribute to the crystallization inhibition effect of the ALC coatings. Atomic layer coating was performed to apply a 5-25 nm layer of aluminum oxide or zinc oxide onto ASD particles, which imparted enhanced micromeritic properties, namely, reduced agglomeration and improved powder flowability. ASD particles were stored at 40 °C and a selected relative humidity level between 31 and 75%. Crystallization was monitored by X-ray powder diffraction and scanning electron microscopy (SEM) up to 48 weeks. Crystallization was observable by SEM within 1-2 weeks for all uncoated samples. After ALC, crystallization was effectively delayed or completely inhibited in some systems up to 48 weeks. The delay achieved was demonstrated regardless of polymer hygroscopicity, presence or absence of hydroxyl functional groups in drugs and/or polymers, particle size, or coating properties. The crystallization inhibition effect is attributed primarily to decreased surface molecular mobility. ALC has the potential to be a scalable strategy to enhance the physical stability of ASD systems to enable high drug loading and enhanced robustness to temperature or relative humidity excursions.


Biological properties of functional flavoring produced by enzymatic esterification of citronellol and geraniol present in Cymbopogon winterianus essential oil.
The chemical composition and biological properties of citronella essential oil were modified by enzymatic esterification reaction of the major monoterpenic alcohols with cinnamic acid. The almost complete conversion of geraniol and citronellol present in the citronella (Cymbopogon winterianus) essential oil, into geranyl (99%) and citronellyl (98%) cinnamates was obtained after 48 hours of reaction using a molar ratio of 3:1 (cinnamic acid/alcohol), lipase concentration (Novozym 435) of 15% (w/w) and 70 °C. The esterified oil showed higher antimicrobial activity against Staphylococcus aureus bacteria resistant to oxacillin and penicillin and also greater larvicidal activity against Aedes aegypti larvae compared to unesterified oil. The results concerning the evaluation of toxicity against Artemia salina and cytotoxicity against monkey kidney epithelial cells also showed the superiority of the esterified oil.


Adolescents amid emerging COVID-19 pandemic in Bissau, Guinea-Bissau: a qualitative study.
Worldwide, governments have implemented restrictions on movement and gatherings to contain the COVID-19 pandemic. In the spirit of the Convention on the Rights of the Child, children have a right to express their opinion on matters of concern to them. The study aimed to describe and analyse how adolescents in the capital Bissau understood the unfolding COVID-19 pandemic and their lived experiences during the first 3 months of the pandemic. Collaborators identified participants in five urban areas in Bissau in June 2020. Semistructured, open-ended interviews were conducted with 30 adolescents aged 15-17 years, attending private and public schools or out-of-school. The interviews were conducted in Kriol, recorded, transcribed, translated and analysed. All the participants were heavily affected by the confinement measures during a state of emergency. Almost all believed in the realness of coronavirus while there were some doubts about its arrival in the country. The consequences were staying at home, enforced with increased police violence. At the same time, other violence on the streets or between neighbours had decreased. A few participants said they liked staying at home because they appreciated spending more time with their families. Most participants claimed that they and their family members tried to follow preventive measures. Almost all participants voiced concerns about the worsening financial situation at home, leading to food scarcity. Nearly all the adolescents were tired of the lockdown and worried about the pandemic's implications on their future opportunities. Study participants, here adolescents in Bissau, have a clear notion of their existence and the current situation's potential negative impact on their future. Their voices need to be heard and acted on, which may soften the lockdown's negative impact on adolescents in Guinea-Bissau, as elsewhere.


Measurements of OH reactivity and photochemical ozone production in the urban atmosphere.
Measurements of OH reactivity (i.e., OH loss rates) in the troposphere are essential for discussing tropospheric OH photochemistry. In July and August 2003, we observed the total OH reactivity in a suburban area of Tokyo. More than 90% of the data of the measured OH loss rates were higher than the calculated values with simultaneously measured concentrations of various trace species even though the rate coefficient of the OH + NO2 reaction was measured by us. We concluded that this discrepancy is due to the existence of unmeasured volatile organic compounds (VOCs). We estimated the potential of the photochemical ozone production in the case of including the unknown species as VOCs and excluding the missing sink, respectively. When the unknown species were included as VOCs, the potential increases from 32% to 88%. This result indicates the photochemical production rates of ozone in the urban air are substantially greater than expected.


Circulating microRNA-590-5p functions as a liquid biopsy marker in non-small cell lung cancer.
Despite the availability of various diagnostic procedures, a tissue biopsy is still indispensable for the routine diagnosis of lung cancer. However, inaccurate diagnoses can occur, leading to inefficient cancer management. In this context, use of circulating microRNAs (miRNAs) may serve as diagnostic tools as liquid biopsies, and as biomarkers to better understand the molecular mechanisms involved in the progression of cancer. We identified miR-590-5p as a potential prognostic marker in the progression of non-small cell lung cancer (NSCLC). We were able to detect this miRNA in blood plasma samples of NSCLC patients through quantitative real-time PCR. Our data showed an ~7.5-fold downregulation of miR-590-5p in NSCLC patients compared to healthy controls, which correlated with several clinicopathological features. Further, overexpression of miR-590-5p led to decreased cell viability, proliferation, colony formation, migration, and invasion potential of lung cancer cells, whereas its knockdown showed the opposite effect. In addition, the levels of several proteins involved in the epithelial-to-mesenchymal transition negatively correlated with miR-590-5p levels in lung adenocarcinoma cells and tumors of NSCLC patients. Further, dual-luciferase reporter assays identified STAT3 as a direct target of miR-590-5p, which negatively regulated STAT3 activation and its downstream signaling molecules (eg, Cyclin D1, c-Myc, Vimentin, and β-catenin) involved in tumorigenesis. Taken together, our study suggests that miR-590-5p functions as a tumor suppressor in NSCLC through regulating the STAT3 pathway, and may serve as a useful biomarker for the diagnosis/prognosis of NSCLC, and as a potential therapeutic target for the treatment of NSCLC.


Oxygen reduction catalyzed by a water-soluble binuclear copper(ii) complex from a neutral aqueous solution.
A water-soluble binuclear CuII complex, synthesized using a polypyridine-polyamide ligand, was able to catalyze oxygen reduction to water from neutral aqueous solutions. Electrocatalytic results suggested that one CuII center was first reduced by one electron to form a CuIICuI species, which reacted with O2 to give a superoxide radical intermediate.


Intestinal Barrier Interactions with Specialized CD8 T Cells.
The trillions of microorganisms that reside in the gastrointestinal tract, essential for nutrient absorption, are kept under control by a single cell barrier and large amounts of immune cells. Intestinal epithelial cells (IECs) are critical in establishing an environment supporting microbial colonization and immunological tolerance. A large population of CD8+ T cells is in direct and constant contact with the IECs and the intraepithelial lymphocytes (IELs). Due to their location, at the interphase of the intestinal lumen and external environment and the host tissues, they seem ideally positioned to balance immune tolerance and protection to preserve the fragile intestinal barrier from invasion as well as immunopathology. IELs are a heterogeneous population, with a large innate-like contribution of unknown specificity, intercalated with antigen-specific tissue-resident memory T cells. In this review, we provide a comprehensive overview of IEL physiology and how they interact with the IECs and contribute to immune surveillance to preserve intestinal homeostasis and host-microbial relationships.


Primary structure of a barley-grain aspartic proteinase. A plant aspartic proteinase resembling mammalian cathepsin D.
Two enzymatically active heterodimeric forms of an aspartic proteinase, a putative 32 kDa + 16 kDa precursor form and a putative 29 kDa + 11 kDa mature form, are present in resting barley grains (Sarkkinen, P., Kalkkinen, N., Tilgmann, C., Siuro, J., Kervinen, J. & Mikola, L., 1990, in the press). The cDNA corresponding to this enzyme has been cloned and sequenced. The full-length 1863-bp cDNA sequence codes for an open reading frame of 508 amino acids. The open reading frame consists of a 66-amino acid preprosequence and a 442-amino acid mature protein. Comparison of the N-terminal amino acid sequences of the enzyme subunits with the sequence of the cDNA clone indicates that the heterodimeric enzyme is translated as a proenzyme which is processed into two subunits. The localisation of the experimentally determined N-terminal amino acid sequences of all four subunits (32 kDa + 16 kDa and 29 kDa + 11 kDa) in the same transcript, as well as the detection of only one 2.0-kb mRNA on Northern blots from resting seeds, clearly indicates that the larger (32 kDa + 16 kDa) enzyme is an intermediate precursor form of the smaller (29 kDa + 11 kDa) enzyme. The processing pattern of the barley enzyme, which is the first sequenced plant aspartic proteinase, differs from that of all other known aspartic proteinases. The barley enzyme is highly similar to mammalian and yeast aspartic proteinases, especially to human and porcine cathepsin D. This similarity is clearly dispersed over two regions, separated by a dissimilar, barley-specific region of 104 amino acids.


Susceptibility of 100 filamentous fungi: comparison of two diffusion methods, Neo-Sensitabs and E-test, for amphotericin B, caspofungin, itraconazole, voriconazole and posaconazole.
We compared the E-test method to that of the Neo-Sensitabs tablet diffusion assay for evaluating the in vitro susceptibility of 100 clinical isolates of filamentous fungi (Aspergillus spp., Fusarium spp., Scedosporium spp., zygomycetes and other molds) to amphotericin B, itraconazole, voriconazole, caspofungin, and posaconazole. We determined the categorical agreement level between E-test minimum inhibitory concentrations (MIC) and tablet end-points, as opposed to the following disagreement parameters: very major error - resistant parameter (R) in E-test and susceptible (S) in tablet; major error - S by E-test and R by tablet; minor error - shifts between S and susceptible dose-dependent (S-DD) or S-DD and R. We also performed linear regression analyses and computed Pearson's correlation coefficients (R values) between the log transforms of MICs and the inhibition zone diameters of the five studied antifungal agents. For itraconazole we obtained 97% categorical agreement and R = -0.727. Categorical agreement for caspofungin and voriconazole was 96% and R =-0.821 and R = -0.789, respectively. For posaconazole the categorical agreement was 94% and R =-0.743. Amphotericin B exhibited a lower degree of agreement (76%, R = -0.672), especially in studies of Aspergillus spp. Our results suggest a potential value of the Neo-Sensitabs assay for in vitro susceptibility testing of molds to itraconazole, voriconazole, caspofungin and posaconazole, while amphotericin B exhibited an overall lower degree of agreement.


Ligamentous injury-induced ankle instability causing posttraumatic osteoarthritis in a mouse model.
This study aims to explore the relationship between surgically-induced ankle instability and posttraumatic osteoarthritis (PTOA) in a mouse model, and to provide reference for clinical practice. Ligamentectomy was performed on 24 eight-week-old male C57BL/6 J mice, which were divided into three groups. Both the anterior talofibular ligament (ATFL) and the calcaneofibular ligament (CFL) were severed in the CFL + ATFL group, while only the CFL was removed in the CFL group. The SHAM group was set as the blank control group. A wheel-running device was used to accelerate the development of ankle osteoarthritis (OA). Balance measurement, footprint analysis, and histological analysis were used to assess the degree of ankle instability and OA. According to the balance test results, the CFL + ATFL group demonstrated the highest number of slips and the longest crossing beam time at 8 weeks postoperatively. The results of gait analysis exhibited that the CFL + ATFL group had the most significant asymmetry in stride length, stance length, and foot base width compared to the CFL and SHAM groups. The OARSI score of the CFL + ATFL group (16.7 ± 2.18) was also much higher than those of the CFL group (5.1 ± 0.96) and the SHAM group (1.6 ± 1.14). Based on the mouse model, the findings indicate that severe ankle instability has nearly three times the chance to develop into ankle OA compared to moderate ankle instability.


Use of kefir peptide (Kef-1) as an emerging approach for the treatment of oxidative stress and inflammation in 2K1C mice.
The benefits of kefir consumption are partially due to the rich composition of bioactive molecules released from its fermentation. Angiotensin-converting enzyme (ACE) inhibitors are bioactive molecules with potential use in the treatment or prevention of hypertension, heart failure, and myocardial infarction. Here, the in vivo actions of the Kef-1 peptide, an ACE inhibitor derived from kefir, were evaluated in an angiotensin II-dependent hypertension model. The Kef-1 peptide showed a potential anti-hypertensive effect. Additionally, Kef-1 exhibited systemic antioxidant and anti-inflammatory activities. In smooth muscle cells (SMCs), the Kef-1 peptide decreased ROS production through the reduced participation of NADPH oxidase and mitochondria. The aorta of 2K1C mice treated with Kef-1 showed lesser wall-thickening and partial restoration of the endothelial structure. In conclusion, these novel findings highlight the in vivo biological potential of this peptide demonstrating that Kef-1 may be a relevant nutraceutical treatment for cardiovascular diseases.


Intracorneal Stromal Ring Can Affect the Biomechanics of Ectatic Cornea.
The biomechanical properties of ecstatic cornea undergo changes. This study evaluates the biomechanical changes of ecstatic cornea after implantation of two types of intracorneal stromal ring (ICR). For doing this prospective cross-sectional study, 32 patients with keratoconus (KCN) were randomly divided into two 16-member groups (group I: MyoRing, group II: KeraRing). The main inclusion criteria were transparent cornea with no scar in the central part, corneal thickness >450 µ in the incision region, keratometry within 48-52 diopters, and progressive course of corneal thinning. Biomechanics of the cornea was evaluated by "ORA" and "Corvis" devices. All of the data were recorded and analyzed before implantation of the rings and 6 months thereafter. The mean ages of patients of groups I and II were 26 ± 6.55 and 33.86 ± 8.5, respectively. The postoperative change of sphere refraction was significant in both groups. However, reduction in the astigmatism was significant only in group I. In addition, the change of flat meridian keratometry (Kf) was significant before and after ring implantation in group I, unlike group II. The changes in CH and CRF parameters (ORA) were not significant in either group before and after the operation. Besides, only HRC parameter (Corvis) decreased significantly in both groups before and after the operation. Both MyoRing and KeraRings have positive effects on the biomechanics of cornea at least during the first year after implantation. Comparison of these two types of ICR did not show significant differences in Corvis and ORA parameters.


Phosphorylation of Chromatin-associated Proteins in Lemna and Hordeum.
Sterile embryos of barley (Hordeum vulgare) and cultures of Lemna perpusilla have been labeled with (32)Pi and the chromatin proteins prepared and separated by acid-urea and sodium dodecyl sulfate gel electrophoresis. Under these conditions chromatin proteins became labeled and the gel radioactivity profiles which were complex indicated a probable minimum of 15 to 20 proteins phosphorylated with molecular weights ranging from 10(4) to 10(5). The majority of the radioactivity, 80 to 90% of the total, is found in the acidic protein fraction and this can be recovered as serine phosphate after partial acid hydrolysis.Nuclei have been isolated from Lemna and barley and found to possess endogenous kinase activity. In vitro labeling of these nuclei with (32)P-adenosine triphosphate indicated that similar proteins appear to become labeled as in vivo labeling with (32)Pi but the proportions of label in each protein were different.


Circulating immune complexes correlate with collagen carboxypropeptide in patients with essential hypertension.
Recent evidence indicates that skewed immune responses occur in patients with essential hypertension (EH), which may be involved in the development of EH. This study aimed to evaluate the plasma levels of immune complexes (IC), procollagen type I collagen carboxypropeptide (TICP), and von Willebrand factor (vWF) in EH patients. A total of 121 patients with EH were enrolled in this study (EH group). Thirty healthy volunteers were recruited to serve as the control group. The plasma levels of circulating IC (CIC), vWF and procollagen TICP were measured. Multiple linear regression assays were performed with the data to determine the correlation between EH and these parameters. The results showed that compared with the healthy control group, the plasma levels of CIC, vWF and TICP in the EH group were significantly higher than that in healthy control group, which was positively correlated with EH. The levels of CIC were also positively correlated with vWF and TICP in plasma. The results suggest that skewed immune responses exist in patients with EH.


Robustness Improvement of Visual Templates Matching Based on Frequency-Tuned Model in RatSLAM.
This paper describes an improved brain-inspired simultaneous localization and mapping (RatSLAM) that extracts visual features from saliency maps using a frequency-tuned (FT) model. In the traditional RatSLAM algorithm, the visual template feature is organized as a one-dimensional vector whose values only depend on pixel intensity; therefore, this feature is susceptible to changes in illumination intensity. In contrast to this approach, which directly generates visual templates from raw RGB images, we propose an FT model that converts RGB images into saliency maps to obtain visual templates. The visual templates extracted from the saliency maps contain more of the feature information contained within the original images. Our experimental results demonstrate that the accuracy of loop closure detection was improved, as measured by the number of loop closures detected by our method compared with the traditional RatSLAM system. We additionally verified that the proposed FT model-based visual templates improve the robustness of familiar visual scene identification by RatSLAM.


Pivotal Role of Regulator of G-protein Signaling 12 in Pathological Cardiac Hypertrophy.
Cardiac hypertrophy is a major predictor of heart failure and is regulated by diverse signaling pathways. As a typical multi-domain member of the regulator of G-protein signaling (RGS) family, RGS12 plays a regulatory role in various signaling pathways. However, the precise effect of RGS12 on cardiac hypertrophy remains largely unknown. In this study, we observed increased expression of RGS12 in the development of pathological cardiac hypertrophy and heart failure. We then generated genetically engineered mice and neonatal rat cardiomyocytes to investigate the effects of RGS12 during this pathological process. Four weeks after aortic banding, RGS12-deficient hearts showed decreased cardiomyocyte cross area (374.7±43.2 μm(2) versus 487.1±47.9 μm(2) in controls; P<0.05) with preserved fractional shortening (43.0±3.4% versus 28.4±2.2% in controls; P<0.05), whereas RGS12-overexpressing hearts exhibited increased cardiomyocyte cross area (582.4±46.7 μm(2) versus 474.8±40.0 μm(2) in controls; P<0.05) and reduced fractional shortening (20.8±4.1% versus 28.6±3.2% in controls; P<0.05). RGS12 also contributed to angiotensin II-induced hypertrophy in isolated cardiomyocytes. Mechanistically, our data indicated that the activation of MEK1/2-ERK1/2 signaling may be responsible for the prohypertrophic action of RGS12. In addition, the requirement of the MEK1/2-ERK1/2 signaling for RGS12-mediated cardiac hypertrophy was confirmed in rescue experiments using the MEK1/2-specific inhibitor U0126. In conclusion, our findings provide a novel diagnostic and therapeutic target for pathological cardiac hypertrophy and heart failure.


Prevalence and outcomes of re-positive nucleic acid tests in discharged COVID-19 patients.
The prevalence and outcomes of patients who had re-activation of coronavirus disease 2019 (COVID-19) after discharge remain poorly understood. We included 126 consecutively confirmed cases of COVID-19 with 2-month follow-up data after discharge in this retrospective study. The upper respiratory specimen using a reverse-transcription polymerase chain reaction test of three patients (71 years [60-76]) were positive within 11-20 days after their discharge, with an event rate of 19.8 (95%CI 2.60-42.1) per 1,000,000 patient-days. Moreover, all re-positive patients were asymptomatic. Our findings suggest that few recovered patients may still be virus carriers even after reaching the discharge criteria.


[Extracorporeal lithotripsy: comparative study with magnetic resonance, ultrasonography, and nuclear medicine of short-term renal changes produced by piezoelectric and electrohydraulic equipment].
Ultrasound, Nuclear Magnetic Resonance (NMR) and Nuclear Medicine (NM) were used to evaluate short-term changes and renal complications (within the first 10 days) induced by extracorporeal lithotrity (ESWL) from two separate lithotripters. To this end, a consecutive prospective study with 18 randomly selected patients, all candidates to ESWL, was conducted. ESWL was performed using a piezoelectric lithotripter in 10 patients and an electrohydraulic equipment in 8 patients. Qualitative evaluation of images was done with ultrasound and NMR (changes in renal morphology: shape, cortico-medullary definition, size, changes in perirenal space), and with isotopic renogram (global renal function); while quantitative evaluation was done with NMR (measurement of signal intensity on cortex, marrow and muscle), and with isotopic renogram (semiquantitative assessment of unilateral renal function and renal excretory function). ESWL with piezoelectric and electrohydraulic lithotripter shows a low short-term complication rate: changes of cortico-medullary differentiation (ultrasound in 27.8% cases, NMR in 5.6%) and perirenal striations (NMR in 11%). No renal function changes were found. These observations have not been quantitatively corroborated; we have not found statistically significant differences between changes produced after ESWL either with piezoelectric or electrohydraulic lithotripters.


Prevalence and determinants of RH alloimmunization in Rh-negative women in teaching hospitals of Addis Ababa, Ethiopia: a hospital-based cross-sectional study.
Despite the implementation of immunization with an anti-D antigen for pregnant women, adverse pregnancy outcomes continue to occur in Ethiopia and most Sub-Saharan African countries. Consequently, the woman's obstetric care is compromised, and there is an increase in perinatal morbidity and mortality. In Ethiopia, the burden of the disease is not well understood, and no research has been conducted in the study area. Therefore, this study aims to determine the prevalence and determinants of Rh alloimmunization in Rh-negative women receiving care at Addis Ababa teaching hospitals. An institutional-based cross-sectional study was conducted from 5 October 2020 to 5 May 2021, among 328 Rh-negative pregnant women who received antenatal care and delivery services at Teaching Hospitals under Addis Ababa University. Face-to-face interviews were used to gather data using a pre-tested structured questionnaire, and a chart review was performed using a checklist. The data were entered into Epidata version 3.1 and analyzed using SPSS version 22. Multivariable analysis and logistic regression were used to evaluate the predictors, and the results were presented as an adjusted odds ratio (AOR) with a 95% confidence interval. Statistical significance was declared at a p-value < 0.05. Among Rh-D negative individuals, 56(17.1%) were alloimunized with 95% CI (15.1%, 19.23%). The prevalence of Rh-D negative was 2.1% with 95% CI (1.56%, 2.76%). Factors such as unemployment [AOR = 2.28, 95% CI: 1.21, 4.28], failure to use anti-D prophylaxis in previous pregnancy [AOR = 2.08, 95% CI: 1.10, 3.92), and the presence of sensitizing events [AOR = 0.52, 95% CI: 0.27, 0.84] were statistically significant with the outcome variables. This study pointed out that the prevalence of Rh was relatively large and that almost one in every five pregnant women was alloimunized. Factors such as unemployment and failure to use anti-D prophylaxis in a previous pregnancy were found to be associated with outcome variables. Therefore, all stakeholders and concerned entities should prioritize enhancing access and affordability to anti-D prophylaxis to prevent the occurrence of Rh alloimmunization and its associated adverse outcomes.


Effects of sumatriptan on growth hormone releasing hormone-stimulated growth hormone secretion in acromegaly.
Sumatriptan (SU), a specific 5-HT1D receptor agonist, was recently shown to be able to increase growth hormone (GH) levels in normals, but not in acromegalics, while no effect was seen on prolactine (PRL). SU is also able to produce an increase in GH response to growth hormone releasing hormone (GHRH) in prepubertal children. In this study we investigated whether SU administration influences GHRH-induced GH secretion in 8 acromegalics, and 6 age-matched normal volunteers, as a control group. We evaluated the effects of SU (6 mg s.c.) or placebo (PL) administration on GHRH (1 microgram/kg bw i.v.)-induced GH and PRL secretion. After SU priming the GH response to GHRH did not changed in acromegalics, but significantly decreased in controls, in comparison with that observed after PL plus GHRH. In acromegalics, no difference in GH peak was seen after SU plus GHRH and PL plus GHRH, nor was any difference seen in AUC between tests. In controls, no difference was seen in GH peaks, while SU priming significantly (P < 0.03) decreased the AUC 90-120 min of GH after GHRH administration. In acromegalics, SU did not change the slight GHRH-induced increase in PRL levels. Our study documents that 5-HT1 D receptors do not interfere with GHRH-stimulated GH secretion in acromegalic subjects. In normals, SU is able to decrease GH response to GHRH, thus confirming that 5-HT1D receptors are able to modulate GH secretion in normals.


Roles of autophagy in lymphocytes: reflections and directions.
Recent studies have revealed that autophagy, a fundamental intracellular process, plays many different roles in lymphocyte development and function. Autophagy regulates naive T-lymphocyte homeostasis, specifically by regulating mitochondrial quality and turnover, and is necessary for the proliferation of mature T cells. Autophagy also acts as a cellular death pathway in lymphocytes, both upon prolonged cytokine withdrawal and during acute antigen-receptor stimulation if improperly regulated. Furthermore, during HIV infection, hyperinduction of autophagy leads to massive T-cell death in uninfected CD4(+) T cells, and is rescued by inhibiting autophagic initiation. Constitutively high levels of autophagy in thymic epithelial cells are necessary for optimal processing and presentation of endogenous antigens, and required for proper positive and negative selection of developing thymocytes. Autophagy also promotes the survival of B lymphocytes, as well as the development of early B-cell progenitors. In B cells, autophagy is an alternative death pathway, as antigen-receptor stimulation in the absence of costimulation induces a potent autophagic death. Thus, autophagy plays a complex role in lymphocytes and is regulated during their lifespan to ensure a healthy immune system.


Dental implants.
The use of dental implants in the oral rehabilitation of partially or fully edentulous patients has become a frequently used treatment modality in everyday practice. The main reason for this development is that critical principles for implant predictability have been established in the last twenty years. Today, researchers and clinicians of all dental subspecialties including cosmetic dentistry are working at refining techniques and extending the limits of the field. This paper is intended to point the reader to interesting publications from 1991 through 1992.


Fluorescence in situ hybridization on early porcine embryos.
Insight into the normal and abnormal function of an interphase nucleus can be revealed by using fluorescence in situ hybridization (FISH) to determine chromosome copy number and/or the nuclear position of loci or chromosome territories. FISH has been used extensively in studies of mouse and human early embryos, however, translation of such methods to domestic species have been hindered by the presence of high levels of intracytoplasmic lipid in these embryos which can impede the efficiency of FISH. This chapter describes in detail a FISH protocol for overcoming this problem. Following extensive technical development, the protocol was derived and optimized for IVF porcine embryos to enable investigation of whole chromosome and subchromosomal regions by FISH during these early stages of development. Porcine embryos can be generated in-vitro using semen samples from commercial companies and oocytes retrieved from discarded abattoir material. According to our method, porcine embryos are lyzed and immobilized on slides using Hydrochloric acid and "Tween 20" detergent, prior to pretreatment with RNase A and pepsin before FISH. The method described has been optimized for subsequent analysis of FISH in two dimensions since organic solvents, which are necessary to remove the lipid, have the effect of flattening the nuclear structure. The work in this chapter has focussed on the pig; however, such methods could be applied to bovine, ovine, and canine embryos, all of which are rich in lipid.


New approaches to management of multiple myeloma.
A new era of multiple myeloma (MM) management includes new approaches such as genetic marking and gene therapy, immunotherapy, stimulation of graft versus myeloma effect, etc. Intensive clinical research is also focused on the detection of minimal residual disease and bone marrow purging. Autoregulatory loop of myeloma cells and detection of genes responsible for pathological transformation of B-line cells is of great research interest. Clinical trials have begun and the first results are promising, though preliminary. The safety of the patients and the public must be major concern of all investigators. The combinations of new types of therapeutical approaches with the most efficient regimens used until now could form a new type of MM management strategy that better involves minimal residual disease.


Point of care testing for INR monitoring: where are we now?
Point of care (POC, or near patient) testing for measurement of the international normalized ratio (INR) has facilitated the devolution of service delivery from the traditional hospital outpatient setting. However it must be undertaken within the confines of safe practice involving quality control procedures. The evaluation of INR POC tests should be closely related to the clinical issues of management and, specifically, improving the quality of care. One benefit of POC testing is in the increased motivation that some practitioners feel, being able to perform diagnostic tests without sending samples to a laboratory. POC for INR testing within primary care eliminates the delay in waiting for the result to be processed by the hospital laboratory, and the subsequent delay in informing the patient of their dosing advice. This review describes the utilization of POC testing outside the laboratory setting to develop models of care for oral anticoagulation management.


Determination of drug-induced changes in functional MRI signal using a pharmacokinetic model.
As the applications of functional magnetic resonance imaging (fMRI) expand, there is a need for the development of new strategies for data extraction and analysis that do not require the presentation of stimuli in a repeated on/off pattern. A description and evaluation of a method and computer algorithm for the detection and analysis of brain activation patterns following acute drug administration using fMRI are presented. A waveform analysis protocol (WAP) input function has been developed that is based upon the single-dose pharmacokinetics of a drug of interest. As a result of this analysis, regional brain activation can be characterized by its localization and intensity of activation, onset of action, time to peak effect, and duration of action. A global statistical test for significant drug effects based upon the probability of a voxel being activated by a saline vehicle injection is applied to grouped data on a voxel by voxel basis. Representative data are presented using nicotine as a prototypical agent. Using this method, statistically significant drug-induced brain activation has been identified in several key cortical and subcortical brain regions.


Prevalence of disabilities and associated health conditions among adults--United States, 1999.
In the United States, the number of persons reporting disabling conditions increased from 49 million during 1991-1992 to 54 million during 1994-1995. During 1996, direct medical costs for persons with disability were $260 billion. Surveillance of disability prevalence and associated health conditions is useful in setting policy, anticipating the service needs of health systems, assisting state programs, directing health promotion and disease prevention efforts, and monitoring national health objectives. The U.S. Bureau of the Census and CDC analyzed data from the Survey of Income and Program Participation (SIPP) to determine national prevalence estimates of adults with disabilities and associated health conditions. This report summarizes findings of that analysis, which indicate that disability continues to be an important public health problem, even among working adults, and arthritis or rheumatism, back or spine problems, and heart trouble/hardening of the arteries remain the leading causes. Better health promotion and disease prevention may reduce the prevalence of disability-associated health conditions.


High-resolution achromatic X-ray optical systems for broad-band imaging and for focusing attosecond pulses.
Achromatic focusing systems for hard X-rays are examined which consist of a refractive lens paired with a diffractive lens. Compared with previous analyses, we take into account the behaviour of thick refractive lenses, such as compound refractive lenses and waveguide gradient index refractive lenses, in which both the focal length and the position of the principal planes vary with wavelength. Achromatic systems formed by the combination of such a thick refractive lens with a multilayer Laue lens are found that can operate at a focusing resolution of about 3 nm, over a relative bandwidth of about 1%. With the appropriate distance between the refractive and diffractive lenses, apochromatic systems can also be found, which operate over relative bandwidth greater than 10%. These systems can be used to focus short pulses without distorting them in time by more than several attoseconds. Such systems are suitable for high-flux scanning microscopy and for creating high intensities from attosecond X-ray pulses.


Enhancing fraction in glioma and its relationship to the tumoral vascular microenvironment: A dynamic contrast-enhanced MR imaging study.
EnF is a newly described measure of proportional tumor enhancement derived from DCE-MR imaging. The aim of this study was to assess the relationship between EnF and the more established DCE-MR imaging parameters: K(trans), v(e), and v(p). Forty-two patients with 43 gliomas (16 grade II, 3 grade III, and 24 grade IV) were studied. Imaging included pre- and postcontrast T1-weighted sequences through the lesion and T1-weighted DCE-MR imaging. Parametric maps of EnF, K(trans), v(e), and v(p) were generated. Voxels were classified as enhancing if the IAUC was positive (EnF(IAUC)(60>0)). A threshold of IAUC > 2.5 mmol.s was used to generate EnF(IAUC)(60>2.5). Both measures of EnF were compared with the DCE-MR imaging parameters (K(trans), v(e), and v(p)). In grade II gliomas, EnF(IAUC60>0) and EnF(IAUC60>2.5) correlated with v(p) (R(2) = 0.6245, P < .0005; and R(2) = 0.4727, P = .003) but not with K(trans) or v(e). In grade IV tumors, both EnF(IAUC60>0) and EnF(IAUC60>2.5) correlated with K(trans) (R(2) = 0.3501, P = .001; and R(2) = 0.4699, P < .0005) and v(p) (R(2) = 0.1564, P = .01; and R(2) = 0.2429, P = .007), but not with v(e). Multiple regression analysis showed K(trans) as the only independent correlate of both EnF(IAUC60>0) and EnF(IAUC60>2.5) for grade IV tumors. This study suggests that in grade II tumors, EnF reflects v(p) and varies due to changes in vascular density. In grade IV gliomas, EnF is affected by K(trans) with secondary associated changes in v(p).


Chinese Versus United States Workplace Ageism as GATE-ism: Generation, Age, Tenure, Experience.
Ageism is a pan-cultural problem, and correspondingly, increased research attention worldwide has focused on how a person's age drives prejudice against them. Nevertheless, recent work argues that chronological age alone is a limited predictor of prejudice-particularly in the workplace, where age conflates intertwined elements (e.g., life stage and work experience), and across cultures, in which the nature of ageism can substantially differ. A recent organizational behavior (GATE) framework advocates for extending beyond numerical age alone, focusing instead on prejudice arising from workers' perceived Generation (birth cohort), Age (life stage), Tenure (time with organization), and Experience (accumulated skillset over time). In addition to clarifying the multifaceted nature of workplace ageism, GATE helps uncover potential cultural ageism differences. Using the United States and China as focal Western and Eastern prototypes, the current paper compares Eastern and Western cultures through a GATE Lens. Eastern and Western cultures adopt different perceptions of generations (e.g., United States "Boomers," versus Chinese "Cultural Revolution" generation), elder life stages (United States warm-but-incompetent older adults, versus Eastern pragmatic elder resource concerns), organizational tenure expectations (Western job-hopping, versus Eastern filial-piety-based loyalty), and desired experience levels (shaped different by higher Eastern frequency of mandatory retirement practices and family business ventures). Moreover, existing research offers clues for how workplace GATE-ism likely differs between cultures, but more research is needed. Future research should adopt a nuanced GATE conception of "age"-ism, toward enhanced ageism understanding and the ability to utilize a globally aging workforce.


Nontuberculous Mycobacterial Infections After Cosmetic Procedures: A Systematic Review and Management Algorithm.
Nontuberculous mycobacterium (NTM) infection following cosmetic procedures usually results from inadequate sterile techniques and contamination from nonsterile water. These infections are difficult to diagnose and treat. This study aimed to describe the characteristics of NTM infections acquired after an aesthetic procedure, identify high-risk patients and high-risk cosmetic procedures, and provide a diagnostic and management algorithm for NTM infections occurring after cosmetic procedures. On December 20, 2017 an online search of the Medline database was done. All articles describing NTM infection in cosmetic procedures were included in this review. In total, 92 patients with a mean age of 38.35 years were included in this review. Cosmetic procedures performed in the Dominican Republic were the most common source of infection and were noted in 33 patients. The procedure that resulted in the highest proportion of the infections was mesotherapy (34%). In most of the cases, the diagnosis was missed at the initial presentation and a short course of inadequate antibiotics was unsuccessful. Nontuberculous mycobacterium infections are hard to diagnose and difficult to treat, sometimes leading to severe irreversible sequalae. Aesthetic practitioners should know when to suspect and how to prevent, diagnose, and treat NTM infections.


Cytokine therapy of malignant melanoma.
Melanoma is a malignant neoplasia of melanocyte origin appearing mainly in the skin. About one third of all melanomas detected disseminate, with the metastatic spread occurring either via lymphatic or blood vessels. In the treatment of advanced melanoma the conventional chemotherapy or radiotherapy has not been very successful. Melanoma is known to have immunologically provocative features. In recent years immunological therapies, mainly cytokines, have been applied in the treatment of melanoma. The most widely used cytokines are Interferons and interleukin-2. These agents are used either alone or in combination with each other or with chemotherapeutics. Interferon and interleukin-2 therapies have yielded response rates of 15-20% on average, whereas combinations of immunotherapy and chemotherapy offer response rates as high as 50-60%. Unfortunately, average survival of patients with disseminated melanoma has been short, from 6 to 12 months. The immunotherapy approach has yielded some long-term responses and probably even a cure for a small proportion of patients. Understanding of basic mechanisms of tumour destruction by cytokines and new agents coming into clinical use will undoubtedly further improve treatment results.


Efficacy of the extradural administration of lofentanil, buprenorphine or saline in the management of postoperative pain. A double-blind study.
Sixty postoperative orthopaedic patients were randomly assigned to three equal groups to study, in a double-blind fashion, the analgesic effects, durations of action and side effects of the extradural administration of lofentanil 5 micrograms, buprenorphine 0.3 mg or physiological saline. No systemic analgesics were given before, during or after surgery, and all the patients had operations on the lower extremities under extradural analgesia (lignocaine and bupivacaine). Eleven millilitre of the test drug was injected at T12-L1 as soon as pain occurred in the postoperative period. We observed a long duration of action and a marked analgesic effect with lofentanil, a shorter duration of action and less pain suppression with buprenorphine and a rather marked placebo effect after saline. The only side effect noticed in this study was drowsiness in three patients in the lofentanil group and in two patients in the buprenorphine group.


Cues intrinsic to the retina induce nAChR gene expression during development.
Recent studies of optic nerve regeneration in goldfish have indicated that the optic tectum plays an important role in modulating the induction of nicotinic acetylcholine receptor (nAChR) gene expression in regenerating retinal ganglion cells (Heiber, Agranoff, and Goldman, 1992, J. Neurochem. 58:1009-1015). These observations suggest that induction of these genes is regulated by brain target regions. The appearance of nAChR mRNA in the developing rat retina coincides with a time when ganglion cells are sending axons to their brain targets (Hoover and Goldman, 1992, Exp. Eye Res. 54:561-571). Might a mechanism similar to that seen during goldfish optic nerve regeneration also mediate induction of nAChR gene expression during development of the mammalian retina? This possibility was tested by either transplanting embryonic rat retina to different brain regions, or explanting it to organ culture and assaying for nAChR gene expression. These studies showed that induction of the nAChR genes in developing rat retina is independent of the environment in which the retina develops. These results indicate that either the retinal microenvironment or a signal intrinsic to the retinal ganglion cell is responsible for this induction.


A Comprehensive COVID-19 Daily News and Medical Literature Briefing to Inform Health Care and Policy in New Mexico: Implementation Study.
On March 11, 2020, the New Mexico Governor declared a public health emergency in response to the COVID-19 pandemic. The New Mexico medical advisory team contacted University of New Mexico (UNM) faculty to form a team to consolidate growing information on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its disease to facilitate New Mexico's pandemic management. Thus, faculty, physicians, staff, graduate students, and medical students created the "UNM Global Health COVID-19 Intelligence Briefing." In this paper, we sought to (1) share how to create an informative briefing to guide public policy and medical practice and manage information overload with rapidly evolving scientific evidence; (2) determine the qualitative usefulness of the briefing to its readers; and (3) determine the qualitative effect this project has had on virtual medical education. Microsoft Teams was used for manual and automated capture of COVID-19 articles and composition of briefings. Multilevel triaging saved impactful articles to be reviewed, and priority was placed on randomized controlled studies, meta-analyses, systematic reviews, practice guidelines, and information on health care and policy response to COVID-19. The finalized briefing was disseminated by email, a listserv, and posted on the UNM digital repository. A survey was sent to readers to determine briefing usefulness and whether it led to policy or medical practice changes. Medical students, unable to partake in direct patient care, proposed to the School of Medicine that involvement in the briefing should count as course credit, which was approved. The maintenance of medical student involvement in the briefings as well as this publication was led by medical students. An average of 456 articles were assessed daily. The briefings reached approximately 1000 people by email and listserv directly, with an unknown amount of forwarding. Digital repository tracking showed 5047 downloads across 116 countries as of July 5, 2020. The survey found 108 (95%) of 114 participants gained relevant knowledge, 90 (79%) believed it decreased misinformation, 27 (24%) used the briefing as their primary source of information, and 90 (79%) forwarded it to colleagues. Specific and impactful public policy decisions were informed based on the briefing. Medical students reported that the project allowed them to improve on their scientific literature assessment, stay current on the pandemic, and serve their community. The COVID-19 briefings succeeded in informing and guiding New Mexico policy and clinical practice. The project received positive feedback from the community and was shown to decrease information burden and misinformation. The virtual platforms allowed for the continuation of medical education. Variability in subject matter expertise was addressed with training, standardized article selection criteria, and collaborative editing led by faculty.


[The long-term behavior of the valve bladder as a function of the initial treatment and its effect on early kidney failure].
In approximately 25-40% of infants presenting with posterior urethral valves (PUV) renal insufficiency will develop before adolescence. In some these patients, renal dysplasia, bladder dysfunction and mismanagement may precipitate renal failure at even earlier age. The goals of this study were to determine whether long-term bladder dysfunction was more frequent in children who underwent early temporary pyelostomy than in those who underwent valve ablation, and to know if bladder dysfunction and mismanagement, in some patients, could be responsible of early renal failure. Urodynamic studies were performed in 59 boys with severe PUV divided into two groups based on initial treatment. A) Valve ablation (30 p.); B) Cutaneous pyeloureterostomy (29 p.). At the end of the study 22 boys had chronic renal failure. Of the 59 boys, 42% (25 p.) had bladders with overdistended or normal behaviour, 58% (34 p.) had bladder dysfunction (instability 37%, low compliance 15%, myogenic failure 5%). The 89% of low compliance bladders, 66% of myogenic failure and 23% of those with instability were in CRF. No difference at all was found in bladder function between boys treated as neonates by high diversion or valve ablation. Of the group in chronic renal failure (22 p.), only 7 patients (32%) had bladders with normal behaviour and in five of these patients a mismanagement was directly related with a quicker renal deterioration. The 58% of our boys with severe PUV have some type of bladder dysfunction. Neonatal pyelo-ureterostomy does not increase long-term bladder dysfunction. Surgical mismanagement should be added to bladder dysfunction as contributors to earlier renal failure.


Helical fluid and (Hall)-MHD turbulence: a brief review.
Helicity, a measure of the breakage of reflectional symmetry representing the topology of turbulent flows, contributes in a crucial way to their dynamics and to their fundamental statistical properties. We review several of their main features, both new and old, such as the discovery of bi-directional cascades or the role of helical vortices in the enhancement of large-scale magnetic fields in the dynamo problem. The dynamical contribution in magnetohydrodynamic of the cross-correlation between velocity and induction is discussed as well. We consider next how turbulent transport is affected by helical constraints, in particular in the context of magnetic reconnection and fusion plasmas under one- and two-fluid approximations. Central issues on how to construct turbulence models for non-reflectionally symmetric helical flows are reviewed, including in the presence of shear, and we finally briefly mention the possible role of helicity in the development of strongly localized quasi-singular structures at small scale. This article is part of the theme issue 'Scaling the turbulence edifice (part 2)'.


Identification of the Plant Ribokinase and Discovery of a Role for Arabidopsis Ribokinase in Nucleoside Metabolism.
Ribose can be used for energy or as a component of several important biomolecules, but for it to be used in either capacity it must first be phosphorylated by ribokinase (RBSK). RBSK proteins are part of the phosphofructokinase-B (pfkB) family of carbohydrate kinases. Sequence comparisons of pfkB proteins from the model plant Arabidopsis thaliana with the human and Escherichia coli RBSK identified a single candidate RBSK, At1g17160 (AtRBSK). AtRBSK is more similar to predicted RBSKs from other plant species and known mammalian and prokaryotic RBSK than to all other PfkB proteins in Arabidopsis AtRBSK contains a predicted chloroplast transit peptide, and we confirmed plastid localization using AtRBSK fused to YFP. Structure prediction software verified that the AtRBSK sequence mapped onto a known RBSK structure. Kinetic parameters of purified recombinant AtRBSK were determined to be Kmribose = 150 μm ± 17 μm, KmATP = 45 μm ± 5.6 μm, and kcat = 2.0 s-1 Substrate inhibition was observed for AtRBSK (KiATP = 2.44 mm ± 0.36 mm), as has been demonstrated for other RBSK proteins. Ribose accumulated in Arabidopsis plants lacking AtRBSK. Such plants grew normally unless media was supplemented with ribose, which led to chlorosis and growth inhibition. Both chlorosis and ribose accumulation were abolished upon the introduction of a transgene expressing AtRBSK-MYC, demonstrating that the loss of protein is responsible for ribose hypersensitivity. Ribose accumulation in plants lacking AtRBSK was reduced in plants also deficient in the nucleoside ribohydrolase NSH1, linking AtRBSK activity to nucleoside metabolism.