Prednisone when used as treatment for rejection correlates with poor outcome.
Since January 1974, 195 of 202 (95%) renal transplants have been performed on blacks at the Howard University Hospital Transplant Center. Hypertension is the most common cause of end-stage renal disease (ESRD) at this center (57%). The immunosuppressive regimens utilized were divided into four eras. The first era (1974-1980) consisted of the prophylactic administration of prednisone, Imuran (AZA), and Minnesota antilymphocyte globulin (MAG) with high prednisone dosage used to treat rejection. One-year, two-year, and five-year patient survival rates were 59% 54%, and 41%, respectively. Graft survival rates for the same period were 53%, 47%, and 36%. In the second era (1980-1983), the same immunoprophylaxis was used but only MAG was used to reverse rejection. One-year and two-year patient survival rates were 90% and 84%. Graft survival rates for the same period were 72% and 64%. When era 1 is compared with era 2, statistically significant improvement in patient survival is evident (P less than 0.005). Graft survival rates are statistically significant for one-year graft survival (P less than 0.05). In the third era (1983-1986), cyclosporine was the principal immunosuppressive agent used along with prednisone. Rejection in this era was treated by adjusting the cyclosporine dose to keep the level between 100 ng to 150 ng per mL and in addition to high prednisone. One-year patient survival and graft survival rates were 83% and 55%, respectively. The fourth era began April 1986 and was initiated because of previous bad experiences with high doses of prednisone to treat rejection in era 1.(ABSTRACT TRUNCATED AT 250 WORDS)


A microfluidic approach to micromembrane synthesis for complex release profiles of nanocarriers.
Physically crosslinked microscale biomembranes synthesized from pure chitosan are designed and demonstrated for pH-triggered release of embedded functionalized mesoporous silica nanoparticles. Nanoparticle-loaded membranes are formed in a microfluidic channel at the junction between accurately controlled co-flowing streams to achieve highly tuneable membrane properties. After formation, the loaded membranes remain stable until contact with physiological acidic conditions, resulting in controlled nanoparticle release. Furthermore, nanoparticle-loaded membranes with complex layered architectures are synthesized using different flow schemes, thus enabling customized nanoparticle release profiles. These novel materials are well-suited for integration within small medical devices as well as off-chip applications.


Mechanism of cholesterol exchange between phospholipid vesicles.
The kinetics of cholesterol exchange between two populations of small unilamellar vesicles has been investigated. There is no change in the initial rate of this exchange process over a 100-fold change in the acceptor vesicle concentration at a constant donor concentration. These results are not consistent with a collision-dependent exchange mechanism. In support of transfer via the aqueous phase, the inclusion of a negatively charged lipid into the vesicles did not affect the exchange rate. Evidence for a water-soluble pool of cholesterol that had partitioned ut of the vesicle was obtained. Finally, cholesterol exchange was observed when donor and acceptor membranes were separated by a barrier through which neither could pass. These data together support our contention that the exchange of cholesterol between these vesicles involves a water-soluble intermediate.


Developmental origins of life history: growth, productivity, and reproduction.
There is now much evidence that early life undernutrition elevates risk of diseases like cardiovascular disease. Less clear is whether the underlying developmental plasticity in metabolism and physiology evolved to serve an adaptive function, beyond these effects on pathophysiology. This review builds from principles of life history theory to propose a functional model linking early environments with adult biology. An organism has metabolic potential in excess of survival requirements, called productivity, that supports growth before being shunted into reproduction after growth ceases. This concept from inter-specific studies leads to the prediction that plasticity in growth rate will be positively correlated with components of future adult reproductive expenditure. Consistent with this idea, evidence is reviewed that early nutrition or growth rate predict offspring size in females, and increased somatic investment related to reproductive strategy in males. Thus, population birth weight and sexual size dimorphism are predicted to increase in response to improvements in early nutrition. A striking feature of the continuity of metabolic production is its perpetuation not merely during the lifecycle but across generations: in females, growth rate predicts future nutritional investment in reproduction, which in turn determines fetal growth rate in the next generation. Growth and reproduction serve as mutually-defining templates, thus creating a phenotypic bridge allowing ecologic information to be maintained during ontogeny and transmitted to offspring. Resetting of metabolic production in response to maternal nutritional cues may serve a broader goal of integrating nutritional information within the matriline, thus providing a more reliable basis for adjusting long-term strategy.


Vitamins C and E for asthma and exercise-induced bronchoconstriction.
The association between dietary antioxidants and asthma or exercise-induced bronchoconstriction (EIB) is not fully understood. Vitamin C and vitamin E are natural antioxidants that are predominantly present in fruits and vegetables; inadequate vitamin E intake is associated with airway inflammation. It has been postulated that the combination may be more beneficial than either single antioxidant for people with asthma and exercise-induced bronchoconstriction. To assess the effects of supplementation of vitamins C and E versus placebo (or no vitamin C and E supplementation) on exacerbations and health-related quality of life (HRQL) in adults and children with chronic asthma. To also examine the potential effects of vitamins C and E on exercise-induced bronchoconstriction in people with asthma and in people without a diagnosis of asthma who experience symptoms only on exercise. Trials were identified from the Cochrane Airways Review Group Specialised Register and from trial registry websites. Searches were conducted in September 2013. We included randomised controlled trials of adults and children with a diagnosis of asthma. We separately considered trials in which participants had received a diagnosis of exercise-induced bronchoconstriction (or exercise-induced asthma). Trials comparing vitamin C and E supplementation versus placebo were included. We included trials in which asthma management for treatment and control groups included similar background therapy. Short-term use of vitamins C and E at the time of exacerbation or for cold symptoms in people with asthma is outside the scope of this review. Two review authors independently screened the titles and abstracts of potential studies and subsequently screened full-text study reports for inclusion. We used standard methods as expected by The Cochrane Collaboration. It was not possible to aggregate the five included studies (214 participants). Four studies (206 participants) addressed the question of whether differences in outcomes were seen when vitamin C and E supplementation versus placebo was provided for participants with asthma, and only one of those studies (160 children) included a paediatric population; the remaining three studies included a combined total of just 46 adults. An additional study considered the question of whether differences in outcomes were noted when vitamin C and E supplementation was compared with placebo for exercise-induced asthma; this trial included only eight participants. The randomisation process of the trials were unclear leading us to downgrade the quality of the evidence. Four of the studies were double blind while the other study was single blind.None of these studies provided data on our two prespecified primary outcome measures: exacerbations and HRQL. Lung function data obtained from the studies were inconclusive. The only studies that provided any suggestion of an effect, and only with some outcomes, were the paediatric study, especially for children with moderate to severe asthma, and the small study on exercise-induced asthma. Even so, this evidence was judged to be at moderate/low quality. Only one study contributed data on asthma symptoms and adverse events, reporting no evidence of an effect of the intervention for symptoms and that one participant in the treatment group dropped out due to cystitis. It is not possible to draw firm conclusions from this review with respect to the comparison of vitamin C and E supplementation versus placebo in the management of asthma or exercise-induced bronchoconstriction. We found only one study relevant to exercise-induced bronchoconstriction; most included participants came from studies designed to assess the effect of vitamin supplementation on the impact of atmospheric pollutants (such as ozone). Evidence is lacking on the comparison of vitamin C and E supplementation versus placebo for asthma with respect to outcomes such as HRQL and exacerbations, which were not addressed by any of the included studies.When compared with lung function tests alone, HRQL scores and exacerbation frequency are better indicators of the severity of asthma, its impact on daily activities and its response to treatment in a patient population. These end points are well recognised in good quality studies of asthma management. However, clinical studies of vitamins C and E in the management of asthma using these important end points of exacerbations and effects on quality of life are not available, and evidence is insufficient to support robust conclusions on the role of vitamin C and E supplementation in asthma and exercise-induced breathlessness.


Medication-invariant resting aperiodic and periodic neural activity in Parkinson's disease.
Parkinson's disease (PD) has been associated with greater total power in canonical frequency bands (i.e., alpha, beta) of the resting electroencephalogram (EEG). However, PD has also been associated with a reduction in the proportion of total power across all frequency bands. This discrepancy may be explained by aperiodic activity (exponent and offset) present across all frequency bands. Here, we examined differences in the eyes-open (EO) and eyes-closed (EC) resting EEG of PD participants (N = 26) on and off medication, and age-matched healthy controls (CTL; N = 26). We extracted power from canonical frequency bands using traditional methods (total alpha and beta power) and extracted separate parameters for periodic (parameterized alpha and beta power) and aperiodic activity (exponent and offset). Cluster-based permutation tests over spatial and frequency dimensions indicated that total alpha and beta power, and aperiodic exponent and offset were greater in PD participants, independent of medication status. After removing the exponent and offset, greater alpha power in PD (vs. CTL) was only present in EO recordings and no reliable differences in beta power were observed. Differences between PD and CTL in the resting EEG are likely driven by aperiodic activity, suggestive of greater relative inhibitory neural activity and greater neuronal spiking. Our findings suggest that resting EEG activity in PD is characterized by medication-invariant differences in aperiodic activity which is independent of the increase in alpha power with EO. This highlights the importance of considering aperiodic activity contributions to the neural correlates of brain disorders.


Seasonal reproduction and delayed sexual maturity in mound-building mice Mus spicilegus.
In the mound-building mouse, Mus spicilegus, which is found from Central to Eastern Europe, reproduction is seasonal and limited to spring and summer. In autumn, the mice build voluminous mounds composed of vegetable matter covered with earth, where juvenile animals (autumnal individuals) over-winter in groups without reproducing. Autumnal animals delay reproduction until the next spring when they are 6 months old. The influence and interactions of environmental (short light period and cold temperature (C conditions) compared with long light period and temperate temperature (T conditions)) and social factors (lack of odours from breeding adults (NB conditions) compared with presence of odours from breeding adults (B conditions)) on reproduction and sexual maturation were studied. Forty groups of three autumnal individuals (two males and a female or two females and a male) were placed in four experimental conditions (CB, CNB, TB and TNB), corresponding to interactions between environmental and social factors (n = 10 groups for each condition). Of the 40 groups only one initiated reproduction during the 18 weeks of cohabitation. Subsequently, animals were separated and isolated for 1 month and then paired with unfamiliar partners. Reproduction was monitored for an additional month, and 24 out of 39 females reproduced. In addition, of eight reproducing pairs placed in C conditions and 10 reproducing pairs maintained in T conditions, all but one pair continued reproduction. It was concluded that the delay in reproduction observed in autumnal individuals was the result of the social effects of living in groups as opposed to the environmental conditions of winter.


Amphipathic, alpha-helical antimicrobial peptides.
Gene-encoded antimicrobial peptides are an important component of host defense in animals ranging from insects to mammals. They do not target specific molecular receptors on the microbial surface, but rather assume amphipathic structures that allow them to interact directly with microbial membranes, which they can rapidly permeabilize. They are thus perceived to be one promising solution to the growing problem of microbial resistance to conventional antibiotics. A particularly abundant and widespread class of antimicrobial peptides are those with amphipathic, alpha-helical domains. Due to their relatively small size and synthetic accessibility, these peptides have been extensively studied and have generated a substantial amount of structure-activity relationship (SAR) data. In this review, alpha-helical antimicrobial peptides are considered from the point of view of six interrelated structural and physicochemical parameters that modulate their activity and specificity: sequence, size, structuring, charge, amphipathicity, and hydrophobicity. It begins by providing an overview of how these vary in peptides from different natural sources. It then analyzes how they relate to the currently accepted model for the mode of action of alpha-helical peptides, and discusses what the numerous SAR studies that have been carried out on these compounds and their analogues can tell us. A comparative analysis of the many alpha-helical, antimicrobial peptide sequences that are now available then provides further information on how these parameters are distributed and interrelated. Finally, the systematic variation of parameters in short model peptides is used to throw light on their role in antimicrobial potency and specificity. The review concludes with some considerations on the potentials and limitations for the development of alpha-helical, antimicrobial peptides as antiinfective agents.


Characteristics of catecholamine release from adrenal chromaffin cells cultured in medium containing ethanol--I. Spontaneous and K(+)-induced release.
Bovine adrenal chromaffin cells were dissociated and grown in primary culture for 9 days. Three days after plating, half the cultures were grown in a medium containing 200 mM ethanol and the other half in a control medium, for a further 6 days. The catecholamine content of the ethanol-treated cells was increased after 6 days of ethanol treatment, compared to control cells and there was a slight reduction in protein and DNA content. An enhanced spontaneous release of catecholamines was seen, which was Ca(2+)-dependent and was inhibited by cadmium but not by the organic dihydropyridine Ca2+ antagonist nitrendipine. The fraction of catecholamines released by K+ was also enhanced in ethanol-treated preparations, particularly at high K+ or Ca2+ concentrations. Release induced by K+ was sensitive to inhibition by both cadmium and organic dihydropyridine Ca2+ antagonists. The results show many similarities with changes observed in catecholaminergic transmission in rat brain during the development of ethanol physical dependence.


Prevalence, Incidence, and Associated Factors of Possible Sarcopenia in Community-Dwelling Chinese Older Adults: A Population-Based Longitudinal Study.
Purpose: This study aimed to assess the prevalence, incidence, and associated factors of possible sarcopenia in a nationwide representative sample of the community-dwelling older Chinese population. Methods:This study used the data of participants aged 60 years and over from the China Health and Retirement Longitudinal Study (CHARLS). Data on participants from three waves (2011-2015) of CHARLS were extracted. Possible sarcopenia was defined as low muscle strength or low physical performance, based on the Asian Working Group for Sarcopenia 2019 consensus. We first described baseline prevalence and four-year incidence of possible sarcopenia. Then multiple logistic regression and multivariable parametric proportional hazard model with Weibull distribution were used to examine the association of risk factors with baseline prevalence and four-year incidence of possible sarcopenia, respectively. Results:The prevalence of possible sarcopenia was 46.0%. The four-year incidence of possible sarcopenia was 11.9 per 100 person-years. Multivariable analysis revealed that advanced age and depressive symptoms were associated with increased prevalence of possible sarcopenia, while receiving education and moderate or high physical activity were associated with a lower risk of possible sarcopenia prevalence. For incidence, only advanced age was associated with an increased risk of possible sarcopenia incidence. Conclusion:Our study revealed the substantial burden of possible sarcopenia and related risk factors in community-dwelling settings in China. It highlighted the importance of early detection and intervention in this subclinical group for the prevention of sarcopenia.


Detection of Twin Pregnancies using Fetal Phonocardiogram.
Fetal phonocardiogram (fPCG), or the electronic recording of fetal heart sounds, is a safe and easily available signal that can be used to monitor fetal wellbeing. In the proposed work an attempt is made to identify twin pregnancies using fPCG data recorded from the fetus with 1/3rd power in octave band filtered output as features to train K-Nearest Neighbor (KNN) and support vector machine (SVM) classifiers. The SVM classifier with the quadratic kernel is able to identify singletons and twins with a positive predictive value of 100% and 79.1% respectively. The KNN classifier with k=10 neighbors is able to identify singletons and twins with a positive predictive value of 100% and 81.8% respectively.Clinical Relevance: Identifying twin pregnancies from singleton is an essential clinical protocol followed during late pregnancy as there may be complications like twin-twin transfusion syndrome, selective fetal growth restriction, and preterm labor in twin pregnancy [1], [2]. Ultrasound imaging is the most commonly used technique for twin pregnancy detection, though it is often not affordable or available in rural or low-income populations. Utilization of fPCG in such circumstances has immense clinical potential.


Metabolism-related proteins are differentially expressed according to the molecular subtype of invasive breast cancer defined by surrogate immunohistochemistry.
The purpose of this study was to investigate the expression of metabolism-related proteins such as Glut-1 and carbonic anhydrase IX (CAIX) according to breast cancer molecular subtype. We generated a tissue microarray of 276 breast cancer patients and performed immunohistochemical staining for known metabolism-related proteins, which were evaluated according to the molecular subtype. The expression of IGF-1, MIF, and HIF-1α was correlated with the HER-2 type (p < 0.05). Glut-1 overexpression and CAIX expression were associated with TNBC type, especially with basal-like type, high histologic grade, estrogen receptor negativity, and progesterone receptor negativity (p < 0.05). The expression of Glut-1 and CAIX was correlated with statistical significance (p < 0.001). We identified different patterns of expression of metabolism-related proteins according to the molecular subtypes of breast cancer defined by surrogate immunohistochemistry. Increased expression of HIF-1α, IGF-1, and MIF was noted in HER-2 type breast cancer and increased expression of Glut-1 and CAIX was noted in TNBC type breast cancer, especially in the basal-like subtype, which exhibited a glycolytic and acid-resistant tumor phenotype.


Rheumatoid arthritis disease activity and disability affect the risk of serious infection events in RADIUS 1.
To determine whether disease activity and disability independently correlate with serious infection event (SIE) risk in a large rheumatoid arthritis (RA) cohort. The associations between SIE and Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire-Disability Index (HAQ-DI) in the Rheumatoid Arthritis Disease-Modifying Antirheumatic Drug Intervention and Utilization Study (RADIUS 1) cohort were evaluated using the Andersen-Gill model (a proportional HR model allowing > 1 event per patient). Of 4084 patients with 347 SIE, 271 patients experienced ≥ 1 SIE. A 5-unit CDAI increase and 0.4-unit HAQ-DI increase corresponded to an increase in SIE risk with and without covariate adjustments. A 5-unit CDAI increase corresponded with a 7.7% increased SIE risk (adjusted HR 1.077, 95% CI 1.044-1.112, p < 0.0001) and a 0.4-unit HAQ-DI increase with a 30.1% increased risk (adjusted HR 1.301, 95% CI 1.225-1.381, p < 0.0001). Categorical analysis showed that more severe RA activity (even after controlling for disability) and disability were associated with an increased SIE risk. Increased RA disease activity and disability were each associated with a significantly increased SIE risk in the RADIUS 1 cohort, which could not be completely accounted for by disability.


A Systematic Review of the Literature on Health and Wellness Coaching: Defining a Key Behavioral intervention in Healthcare.
Review the operational definitions of health and wellness coaching as published in the peer-reviewed medical literature. As global rates of preventable chronic diseases have reached epidemic proportions, there has been an increased focus on strategies to improve health behaviors and associated outcomes. One such strategy, health and wellness coaching, has been inconsistently defined and shown mixed results. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review of the medical literature on health and wellness coaching allowed for compilation of data on specific features of the coaching interventions and background and training of coaches. Eight hundred abstracts were initially identified through PubMed, with 284 full-text articles ultimately included. The majority (76%) were empirical articles. The literature operationalized health and wellness coaching as a process that is fully or partially patient-centered (86% of articles), included patient-determined goals (71%), incorporated self-discovery and active learning processes (63%) (vs more passive receipt of advice), encouraged accountability for behaviors (86%), and provided some type of education to patients along with using coaching processes (91%). Additionally, 78% of articles indicated that the coaching occurs in the context of a consistent, ongoing relationship with a human coach who is trained in specific behavior change, communication, and motivational skills. Despite disparities in how health and wellness coaching have been operationalized previously, this systematic review observes an emerging consensus in what is referred to as health and wellness coaching; namely, a patient-centered process that is based upon behavior change theory and is delivered by health professionals with diverse backgrounds. The actual coaching process entails goal-setting determined by the patient, encourages self-discovery in addition to content education, and incorporates mechanisms for developing accountability in health behaviors. With a clear definition for health and wellness coaching, robust research can more accurately assess the effectiveness of the approach in bringing about changes in health behaviors, health outcomes and associated costs that are targeted to reduce the global burden of chronic disease.


Transmesocolic approach for left side laparoscopic pyeloplasty: comparison with laterocolic approach in the initial learning period.
To evaluate the outcome of transmesocolic (TMC) laparoscopic pyeloplasty compared with conventional laterocolic procedure for surgeons with limited experience. We started laparoscopic pyeloplasty for ureteropelvic junction obstruction in 2009. Since then, 21 patients of left side disease have undergone this surgery in our institution. To access the left ureteropelvic junction, we used the conventional laterocolic approach in 9 patients, while the transmesocolic approach was used in the remaining 12 patients, and perioperative results and follow-up data were then compared. The mean operative time using the transmesocolic approach was significantly shorter than the conventional laterocolic approach (242 vs. 308 min, p=0.022). Furthermore, there was no complication or open conversion. Postoperative pain was significantly decreased in the TMC group (2.8 vs. 4.0 points, measured using the visual analogue scale on the first postoperative day, p=0.009). Postoperative complications were encountered in two patients. All patients were symptom-free after 1 year of follow-up, and radiologic success rates for each group were 92 and 89%, respectively. Direct exposure of the ureteropelvic junction via the mesocolon saves time during the colon mobilization procedure. The approach is safe and feasible even for surgeons with limited experience, and has success rates similar to those of the conventional laterocolic approach.


Structural Modeling of Cytokine-Receptor-JAK2 Signaling Complexes Using AlphaFold Multimer.
Homodimeric class 1 cytokine receptors include the erythropoietin (EPOR), thrombopoietin (TPOR), granulocyte colony-stimulating factor 3 (CSF3R), growth hormone (GHR), and prolactin receptors (PRLR). These cell-surface single-pass transmembrane (TM) glycoproteins regulate cell growth, proliferation, and differentiation and induce oncogenesis. An active TM signaling complex consists of a receptor homodimer, one or two ligands bound to the receptor extracellular domains, and two molecules of Janus Kinase 2 (JAK2) constitutively associated with the receptor intracellular domains. Although crystal structures of soluble extracellular domains with ligands have been obtained for all of the receptors except TPOR, little is known about the structure and dynamics of the complete TM complexes that activate the downstream JAK-STAT signaling pathway. Three-dimensional models of five human receptor complexes with cytokines and JAK2 were generated here by using AlphaFold Multimer. Given the large size of the complexes (from 3220 to 4074 residues), the modeling required a stepwise assembly from smaller parts, with selection and validation of the models through comparisons with published experimental data. The modeling of active and inactive complexes supports a general activation mechanism that involves ligand binding to a monomeric receptor followed by receptor dimerization and rotational movement of the receptor TM α-helices, causing proximity, dimerization, and activation of associated JAK2 subunits. The binding mode of two eltrombopag molecules to the TM α-helices of the active TPOR dimer was proposed. The models also help elucidate the molecular basis of oncogenic mutations that may involve a noncanonical activation route. Models equilibrated in explicit lipids of the plasma membrane are publicly available.


The diagnostic value of indeterminate lung lesions on staging chest computed tomographies in patients with colorectal cancer.
Selection of pulmonary staging modality in colorectal cancer surgery is controversial. Computed tomography (CT) clearly outperforms x-ray in terms of sensitivity, but findings of indeterminate lung lesions remain a problem. The aim of the present study was to evaluate the significance of such indeterminate lung findings in staging CT scans. The study comprises a retrospective analysis of 131 consecutive patients who underwent colorectal cancer surgery in 2004. A preoperative staging CT scan of the chest and abdomen was performed in all patients. Twenty-six patients (20%) had indeterminate lung findings. Four died postoperatively. The remaining 22 were followed for a median period of 26 months. In eight of the 22 patients (36%) lesions progressed. In one patient, the lesion turned out to be a primary lung cancer, in another a lymphoma. In the last six patients (27%), the lesions developed into colorectal cancer lung metastases within a median period of 15 months. These results were significantly different from those obtained in patients who had a normal CT, among whom only 6% developed lung malignancies in the follow-up period (p < 0.0001). The development of lung metastases was significantly related to positive nodal status at operation and elevated carcinoembryonic antigen (CEA) level at follow-up (p < 0.05). Approximately one quarter of the indeterminate lung lesions found on staging CT in colorectal cancer patients developed into metastases and one tenth into other lung malignancies, which were most often diagnosed in the second year after surgery. The development of lung metastases was significantly related to positive nodal disease and postoperative CEA elevation.


Mechanism of adenosine inhibition of catecholamine-induced responses in heart.
The properties of adenosine inhibition of catecholamine-induced responses were investigated, using an isolated rat heart preparation. Perfusion of hearts with 0.1 microM isoproterenol increased myocardial cAMP content 2.8-fold, activation of cAMP-dependent protein kinase 4.4-fold, phosphorylase a formation 3.4-fold, left ventricular pressure 1.8-fold, rate of ventricular pressure development 2.1-fold, and rate of ventricular relaxation 2.2-fold within 1 minute. When perfused with the isoproterenol, 10 microM adenosine reduced the catecholamine-produced increase in cAMP, cAMP-dependent protein kinase, and phosphorylase by 30-40%, and the elevation in left ventricular pressure and rate of ventricular pressure development by 40-70% within 40 seconds. More than 2 minutes were required for the nucleoside to significantly reduce the isoproterenol-elicited increase in the rate of ventricular relaxation. Perfusion of adenosine alone at concentrations from 0.1 to 10 microM were without effect on the above parameters. Theophylline at 50 microM had no effect alone on the above parameters but blocked the inhibitory actions of adenosine on the isoproterenol-induced responses. In the presence of 15 mM Mg++ adenosine reduced by approximately 56% the 2-fold increase in myocardial membrane adenylate cyclase activity produced by 1 microM isoproterenol without affecting basal or fluoride-stimulated activity. Adenosine also reduced the isoproterenol-induced increase in enzyme activity assayed at 1-2 mM Mg++, a level that more closely approximates the intracellular activity of the ion. The results suggest that physiological concentrations of adenosine attenuate the catecholamine-induced increase in cAMP content, cAMP-dependent protein kinase activation, phosphorylase a formation, and contractile parameters in the working heart, via reducing the beta-adrenergic activation of adenylate cyclase.


Microtubules and nucleoside diphosphate kinase. Comparison of kinetics of GTP- and CTP-induced assembly.
The kinetics of assembly of MAP2-tubulin microtubule protein were examined as a function of the GTP concentration in order to test the hypothesis that CTP-induced assembly results from the generation of GTP by nucleoside diphosphate kinase. These studies show that (a) there is no assembly below a minimum GTP concentration and that this represents a nucleation requirement, (b) the rate of elongation is inconsistent with a single assembly-species, and (c) the elongation rate increases markedly as the GTP concentration is raised, although GTP is not absolutely required for elongation. These assembly kinetics have been compared with those with increasing CTP concentrations, by using microtubule protein containing a very low nucleoside diphosphate kinase activity of known substrate specificity. Neither nucleation nor the observed rates of elongation can be attributed to the formation of GTP, either (a) in terms of the generation of free GTP and subsequent binding to tubulin or (b) by the direct charging of GDP bound to the tubulin exchangeable site. The results show that nucleoside diphosphate kinase is not required for CTP-induced microtubule assembly, and suggest that CTP directly effects microtubule assembly.


Prevalence of Chronic Gastritis or Helicobacter pylori Infection in Adolescent Sleeve Gastrectomy Patients Does Not Correlate with Symptoms or Surgical Outcomes.
In adults undergoing gastric bypass surgery, it is routine practice to perform pre-operative testing for Helicobacter pylori infection. Evidence suggests that infection impairs anastomotic healing and contributes to complications. There currently are no data for adolescents undergoing bariatric procedures. Despite few patients with pre-operative symptoms, we noted occasional patients with H. pylori detected after sleeve gastrectomy. We reviewed our experience with our adolescent sleeve gastrectomy cohort to determine the prevalence of H. pylori infection, its predictive factors, and association with outcomes. We hypothesized that H. pylori infection would be associated with pre-operative symptoms, but not surgical outcomes. All patients undergoing sleeve gastrectomy at our hospital were included. We conducted a chart review to determine pre- or post-operative symptoms of gastroesophageal reflux disease GERD or gastritis, operative complications, and long-term anti-reflux therapy after surgery. Pathology reports were reviewed for evidence of gastritis and H. pylori infection. 78 adolescents had laparoscopic sleeve gastrectomy from January 2010 through July 2014. The prevalence of chronic gastritis was 44.9% (35/78) and 11.4% of those patients had H. pylori (4/35). Only one patient with H. pylori had pre-operative symptoms, and only 25.7% (9/35) of patients with pathology-proven gastritis had symptoms. One staple line leak occurred but this patient did not have H. pylori or gastritis. Mean patient follow-up was 10 (3-26) mos. There is a moderate prevalence of gastritis among adolescents undergoing sleeve gastrectomy, but only a small number of these patients had H. pylori infection. Neither the presence of chronic gastritis nor H. pylori infection correlated with symptoms or outcomes. Thus, in the absence of predictive symptomology or adverse outcome in those who are infected, we advocate for continued routine pathologic evaluation without the required need for pre-operative determination unless or until H. pylori infection is associated with adverse surgical outcomes.


The THERMOSENSITIVE MALE STERILE 1 Interacts with the BiPs via DnaJ Domain and Stimulates Their ATPase Enzyme Activities in Arabidopsis.
The Arabidopsis TMS1 encodes a heat shock protein identical to the Hsp40 protein AtERdj3A and plays important roles in the thermotolerance of pollen tubes and other plant tissues. Despite its importance to plant growth and reproduction, little has been known about its mechanisms underlying thermotolerance of plants. In this study, the relationship between TMS1 and the Hsp70 proteins, Binding Immunoglobulin Proteins (BiPs) was explored to understand the molecular mechanisms of TMS1 in thermotolerance of plants. The expression of TMS1 was induced not only by heat shock, but also by dithiothreitol (DTT) and L-azetidine-2-carboxylic acid (AZC), similarly to the three BiP genes, indicating that TMS1 may be involved in unfolded protein response (UPR). The firefly luciferase complementary imaging (LCI), GST pull-down and ATPase enzyme activity assays demonstrated that the DnaJ domain of TMS1 could interact with BiP1 and BiP3, and could stimulate their ATPase enzyme activities. In addition, the expression level of TMS1 was reduced in the bzip28 bzip60 double mutant. These results suggest that TMS1 may function at the downstream of bZIP28 and bZIP60 and be involved in termotolerance of plants, possibly by participating in refolding or degradation of unfolded and misfolded proteins through interaction with the BiPs.


Proposal of a new clinical protocol for evaluating fatigability in adult SMA patients.
Spinal Muscular Atrophy (SMA) is a genetic neuromuscular disease affecting the lower motor neuron, carrying a significant burden on patients' general motor skills and quality of life, characterized by a great variability in phenotypic expression. As new therapeutic options make their appearance on the scene, sensitive clinical tools and outcome measures are needed, especially in adult patients undergoing treatment, in which the expected clinical response is a mild improvement or stabilization of disease progression. Here, we describe a new functional motor scale specifically designed for evaluating the endurance dimension for the upper and lower limbs in adult SMA patients. The scale was first tested in eight control healthy subjects and then validated in ten adult SMA patients, proving intra- and inter-observer reliability. We also set up an evaluation protocol by using wearable devices including surface EMG and accelerometer. The endurance evaluation should integrate the standard clinical monitoring in the management and follow-up of SMA adult patients.


Biologically active mutants with deletions in the v-mos oncogene assayed with retroviral vectors.
We have constructed retroviral expression vectors by manipulation of the Moloney murine leukemia virus genome such that an exogenous DNA sequence may be inserted and subsequently expressed when introduced into mammalian cells. A series of N-terminal deletions of the v-mos oncogene was constructed and assayed for biological activity with these retroviral expression vectors. The results of the deletion analysis demonstrate that the region of p37mos coding region upstream of the third methionine codon is dispensable with respect to transformation. However, deletion mutants of v-mos which allow initiation of translation at the fourth methionine codon have lost the biological activity of the parental v-mos gene. Furthermore, experiments were also carried out to define the C-terminal limit of the active region of p37mos by the construction of premature termination mutants by the insertion of a termination oligonucleotide. Insertion of the oligonucleotide just 69 base pairs upstream from the wild-type termination site abolished the focus-forming ability of v-mos. Thus, we have shown the N-terminal limit of the active region of p37mos to be between the third and fourth methionines, while the C-terminal limit is within the last 23 amino acids of the protein.


Extra vertebrae in Ingres' La Grande Odalisque.
"La Grande Odalisque," a painting by Jean-Auguste Ingres (1780-1867), was throughout the 19th century notorious for its anatomical inaccuracy; in particular, the woman was said to have three lumbar vertebrae too many. This view was accepted by all art critics, but never tested and proven. We measured the length of the back and of the pelvis in human models, expressed the mean values in terms of head height, and transferred them to the painting. The deformation was found to be greater than originally assumed (five, rather than three, extra lumbar vertebrae), and to involve both the back and the pelvis. Ingres' paintings skilfully combine realism and symbolism. We suggest that the deformation may have been introduced for psychological reasons. By placing the harem woman's head further away from her pelvis the artist may have been marking the gulf between her thoughts (expressed by her aloof, resigned look) and her social role (symbolized by her deliberately lengthened pelvis).


Single-cell analysis by mass cytometry reveals metabolic states of early-activated CD8+ T cells during the primary immune response.
Memory T cells are thought to rely on oxidative phosphorylation and short-lived effector T cells on glycolysis. Here, we investigated how T cells arrive at these states during an immune response. To understand the metabolic state of rare, early-activated T cells, we adapted mass cytometry to quantify metabolic regulators at single-cell resolution in parallel with cell signaling, proliferation, and effector function. We interrogated CD8+ T cell activation in vitro and in response to Listeria monocytogenes infection in vivo. This approach revealed a distinct metabolic state in early-activated T cells characterized by maximal expression of glycolytic and oxidative metabolic proteins. Cells in this transient state were most abundant 5 days post-infection before rapidly decreasing metabolic protein expression. Analogous findings were observed in chimeric antigen receptor (CAR) T cells interrogated longitudinally in advanced lymphoma patients. Our study demonstrates the utility of single-cell metabolic analysis by mass cytometry to identify metabolic adaptations of immune cell populations in vivo and provides a resource for investigations of metabolic regulation of immune responses across a variety of applications.


Beyond Anion Template: Polyoxometalate as a Property Influencer in High-Nuclearity Silver Thiolate Cluster.
Two 48-nuclei silver nanocages with similar structures and compositions were synthesized by using Keggin-type polyoxometalates (POMs) BW12 and SiW11Ni as anionic templates. However, their photoluminescence and photocurrent properties showed obvious differences. These results suggest that POMs not only serve as anion templates in constructing silver clusters but also influence their properties.


[Evaluation of the visual evoked potentials in relation to the type of visual stimulation].
A classification of visual evoked potentials (VEP) in children and adults in response to various types of vision stimulation has been developed. Four major signs underlie this classification: (1) stimulation time frequency; (2) stimulation type; (3) mode of producing the visuals stimulus; (4) mono- or binocular presentation of the stimulus. One more sign can be added to classification: significant parameters of stimulation. Basing on this classification, the author describes the major VEP modalities and gives recommendations on the practical employment of these modalities.


Living Kidney Donor Knowledge of Provided Information and Informed Consent: The PRINCE Study.
Informed consent for living kidney donation is paramount, as donors are healthy individuals undergoing surgery for the benefit of others. The informed consent process for living kidney donors is heterogenous, and the question concerns how well they are actually informed. Knowledge assessments, before and after donor education, can form the basis for a standardized informed consent procedure for live kidney donation. In this prospective, a multicenter national cohort study conducted in all eight kidney transplant centers in The Netherlands, we assessed the current status of the informed consent practice for live donor nephrectomy. All of the potential living kidney donors in the participating centers were invited to participate. They completed a pop quiz during their first outpatient appointment (Cohort A). Living kidney donors completed the same pop quiz upon admission for donor nephrectomy (Cohort B). In total, 656 pop quizzes were completed (417 in Cohort A, and 239 in Cohort B). The average donor knowledge score was 7.0/25.0 (±3.9, range 0-18) in Cohort A, and 10.5/25.0 (±2.8, range 0-17.5) in Cohort B. Cohort B scored significantly higher on overall knowledge, preparedness, and the individual item scores (p < 0.0001), except for the long-term complications (p = 0.91). Donor knowledge generally improves during the live donor workup, but it is still quite disappointing. Long-term complications, especially, deserve more attention during living kidney donor education.


Pediatricians' opinions about the problems between the departments of pediatrics and child psychiatry and possible solutions.
The necessity of collaboration between the Departments of Pediatrics and Child Psychiatry is an accepted idea. However, relevant literature reveals that collaboration between the two departments is not satisfactory. Rearrangement of relations between the two departments in Hacettepe University Ihsan Doğramaci Children's Hospital has been designated a goal. An education program will be planned accordingly. A questionnaire was designed to determine 65 pediatricians' knowledge, thoughts, expectations and needs about collaboration between the two departments; all were working in Hacettepe University Children's Hospital, in inpatient services, outpatient clinics or emergency services. An education program for consultation-liaison activities has been constituted to achieve the desired results. Efficacy of the program was discussed considering the features and tendencies of the two departments.


Improved Socio-Emotional and Behavioral Functioning in Students with Autism Following School-Based Smartglasses Intervention: Multi-Stage Feasibility and Controlled Efficacy Study.
Background: Students with Autism Spectrum Disorder (ASD) commonly demonstrate prominent social communication deficits, symptoms of attention-deficit/hyperactivity disorder, and chronic irritability. These challenges hinder academic progress and frequently persist despite educational, behavioral, and medical interventions. An assistive smartglasses technology may aid these individuals, especially if the technology is efficacious in ecologically-valid school settings. This study explored the feasibility and efficacy of Empowered Brain, a computerized smartglasses intervention designed as a socio-emotional behavioral aid for students with ASD. Methods: This two-part six-week study involved four school children with ASD from a public elementary school. The study incorporated an initial three-week feasibility stage followed by a three-week controlled longitudinal efficacy stage. Both stages involved the use of a twice-daily socio-emotional intervention with the smartglasses. Educators completed pre-intervention and post-intervention Aberrant Behavioral Checklist (ABC) ratings at the start of the feasibility stage, and weekly during the efficacy stage. Primary outcome measures were improvements in the ABC subscales of irritability, hyperactivity, and social withdrawal. Results: Students in both feasibility and efficacy stages demonstrated improvements (decreases) in irritability, hyperactivity, and social withdrawal compared to a baseline period and control periods, respectively. Participants in the controlled efficacy stage demonstrated decreased ABC subscale scores of 90% for irritability, 41.6% for hyperactivity, and 45.6% for social withdrawal. An intervention exposure-response improvement in irritability and hyperactivity was found during the efficacy stage. Educators rated the technology as superior or vastly superior compared to other assistive technologies. Conclusion: A substantial number of school children with ASD demonstrate chronic and impairing cognitive and behavioral challenges. This study provides evidence that Empowered Brain, a smartglasses-based socio-emotional aid for autism, is both feasible and efficacious in improving symptoms of social withdrawal, irritability, and hyperactivity in students with autism. The improvement is demonstrated as part of a longitudinal school-based intervention. Further studies involving larger samples and incorporation of randomized controlled trial methodology are underway to further elucidate the impact of this technology.


Differentiation and central projections of peripheral sensory cells with action-potential block in Drosophila mosaics.
The ultrastructural differentiation and central projection of identified bristle mechanosensory neurons were examined in Drosophila mutants lacking action potentials. Two mutations, parats1 and napts, are known to block axonal conduction in centrally located neurons at high temperatures. Their effects on epithelial sensory cells, which are derived from imaginal disks during pupation, have not been determined. Furthermore, the parats1 napts double-mutant flies are lethal at all temperatures; thus the synergistic effect of these mutations on neurons has not yet been studied. It is possible to examine the above questions in genetic mosaics. By monitoring a reflex response involving identified bristle sensory cells, we found that the 2 mutations exert similar effects on these epithelial sensory cells as seen in central neurons. This also indicates that the action potential mechanisms in both epithelial sensory cells and central neurons are under similar genetic control. The parats1 napts double-mutant sensory cells in mosaics are nonfunctional at all temperatures, providing an opportunity to examine, at the single cell level, the development of neurons with activity block. Ultrastructural specializations typical of epithelial sensory cells were found in the double-mutant cells. Cobalt backfilling experiments showed that central projections of these nonfunctional sensory cells were not altered, as compared with the active contralateral sensory cells. Therefore, blockage of the action potential mechanism in individual sensory cells has no effect on their pathfinding and arborization.


Human antiviral B cell responses: Emerging lessons from hepatitis B and COVID-19.
Humoral immunity is a critical component of the coordinated response required to resolve viral infections and mediate protection following pathogen clearance or vaccination. A better understanding of factors shaping the memory B cell response will allow tailored development of efficient preventative vaccines against emerging acute viral infections, therapeutic vaccines, and immunotherapies for chronic viral infections. Here, we use recent data obtained by profiling antigen-specific B cell responses in hepatitis B as a framework to explore lessons that can be learnt from different viral infections about the diverse influences on humoral immunity. Hepatitis B provides a paradigm where successful B cell responses in resolved or vaccinated individuals can be contrasted to the failed response in chronic infection, while also exemplifying the degree to which B cell responses within infected individuals can differ to two antigens from the same virus. Drawing on studies in other human and murine infections, including emerging data from COVID-19, we consider the influence of antigen quantity and structure on the quality of the B cell response, the role of differential CD4 help, the importance of germinal center vs extrafollicular responses and the emerging concept that responses residing in non-lymphoid organs can participate in B cell memory.


[The relationship between the immunological efficacy of a dried meningococcal group-A polysaccharide vaccine and the molecular parameters of the group-A polysaccharide].
This work deals with the problem of relationship between the molecular parameters of group A meningococcal polysaccharide and its immunological effectiveness for laboratory animals and humans. The depolymerization of group A polysaccharide contained in the vaccine leads to a decrease in its capacity of inducing the production of hemagglutinating (19S and 7S) and bactericidal IgA antibodies in humans, as well as inducing an increase in the number of cells producing IgA antibodies in the spleen of immunized mice and the appearance of circulating IgA antibodies in their sera. As shown in this investigation, fully developed immune response to group A meningococcal vaccine may be achieved in humans only if the content of group A high-molecular polysaccharide in the vaccine is not less than 70%. Mice have been recommended as an experimental model for the prognostication of the effectiveness of meningococcal polysaccharide vaccines and for their control in the process of manufacture instead of currently used titration of bacteriolysins in the sera of immunized humans.


Learning and memory in adolescent psychiatric inpatients with major depression: a normative study of the California Verbal Learning Test.
Depressed adults have deficits in memory functions, especially on demanding tasks, but few studies of depressed adolescents have been published. In order to examine the extent of memory impairment and its diagnostic specificity, adolescent inpatients with DSM-III-R diagnoses of Major Depression (n = 56), Conduct Disorder (n = 42), or mixed Depression and Conduct Disorder (n = 22) were tested on the California Verbal Learning Test (CVLT) and compared to each other, to CVLT norms, and to previously published CVLT norms for adults with Major Depression. Adolescents with Major Depression performed below normative standards on all aspects of the CVLT, but did not have a specific profile of memory impairments that was different from the two comparison samples. Relative to norms for adult patients with Major Depression, adolescent females under performed across all CVLT measures, but males did not differ from adults Depression in adolescence is not associated with specific memory impairments, but adolescent females with depression may have more severe deficits than depressed adults.


Solution Combustion Synthesis: Towards a Sustainable Approach for Metal Oxides.
Solution combustion synthesis (SCS) has been widely used to produce simple and complex oxides with a desired morphology (size and shape). SCS is valuable due to low cost, simplicity and energy efficient synthesis. To guarantee the best molecular-level mixing of reactants in an aqueous or solvent-based solution some parameters need to be controlled, such as fuel type, metal cations precursors, stoichiometry ratio (φ), pH effect, atmosphere and initiation type. These determine the final properties of the oxide materials, providing the potential to reach different morphologies, which are essential for their final applications. This Review article focuses on the crucial parameters in SCS and how these affect the overall materials properties from nanostructures to thin films. To finalize, special attention is given to the application of SCS to form metal oxide thin films at low temperature and their application in thin film transistors (TFTs).


Donor transmitted and de novo cancer after liver transplantation.
Cancers in solid organ recipients may be classified as donor transmitted, donor derived, de novo or recurrent. The risk of donor-transmitted cancer is very low and can be reduced by careful screening of the donor but cannot be abolished and, in the United Kingdom series is less than 0.03%. For donors with a known history of cancer, the risks will depend on the nature of the cancer, the interventions given and the interval between diagnosis and organ donation. The risks of cancer transmission must be balanced against the risks of death awaiting a new graft and strict adherence to current guidelines may result increased patient death. Organs from selected patients, even with high-grade central nervous system (CNS) malignancy and after a shunt, can, in some circumstances, be considered. Of potential donors with non-CNS cancers, whether organs may be safely used again depends on the nature of the cancer, the treatment and interval. Data are scarce about the most appropriate treatment when donor transmitted cancer is diagnosed: sometimes substitution of agents and reduction of the immunosuppressive load may be adequate and the impact of graft removal should be considered but not always indicated. Liver allograft recipients are at increased risk of some de novo cancers, especially those grafted for alcohol-related liver disease and hepatitis C virus infection. The risk of lymphoproliferative disease and cancers of the skin, upper airway and bowel are increased but not breast. Recipients should be advised to avoid risk behavior and monitored appropriately.


Exercise enhances placental labyrinth trophoblast development by activation of PGC-1α and FNDC5/irisin.
Placental chorion/labyrinth trophoblasts are energy demanding which is met by the mitochondrial oxidative phosphorylation. Exercise enhances placental development and mitochondrial biogenesis, but the underlying mechanisms remain poorly understood. To address, female C57BL/6 J mice were randomly assigned into two groups: a control (CON) group and an exercise (EX) group. All animals were acclimated to treadmill exercise for one week before mating, but only the EX group was subjected to daily exercise during pregnancy from embryonic day (E) 1.5 to E16.5. Placenta was collected at E18.5 for biochemical and histochemical analyses, and primary trophoblast cells were isolated from the E18.5 placenta for further analyses. Data showed the exercise during pregnancy promoted the expression of syncytiotrophoblast cell markers, indicating trophoblast cell differentiation, which was closely associated with elevated mitochondrial biogenesis and oxidative metabolism in the E18.5 placenta. In addition, exercise during pregnancy activated PGC-1α, which was associated with upregulated placental α-ketoglutarate (α-KG) and the expression of isocitrate dehydrogenases (IDHs) and ten-eleven translocations (TETs), facilitating DNA demethylation of the Pgc1a promoter. Furthermore, exercise upregulated FNDC5 expression and the secretion of its cleaved form, irisin, which is known to activate PGC-1α. These data suggest that exercise-induced activation of PGC-1α, via epigenetic modifications, is responsible for promoting mitochondrial energy metabolism and chorion/labyrinth trophoblast development.


Measurement of electrical current density distribution in a simple head phantom with magnetic resonance imaging.
Knowledge of the influence of the human skull on the electrical current (d.c.) distribution within the brain tissue could prove useful in measuring impedance changes inside the human head. These changes can be related to physiological functions. The studies presented in this paper examine the current density distribution in a simple phantom consisting of a saline filled tank (to simulate scalp and brain) and a ring made of dental grade plaster of Paris (to simulate the human skull). Images of the distribution of the d.c. density of the phantom with and without the plaster of Paris ring were produced using a magnetic resonance imaging technique. These images indicate that the skull is likely to produce a more uniform d.c. density within the brain.


Mathematical modeling and experimental validation of chemotaxis under controlled gradients of methyl-aspartate in Escherichia coli.
Escherichia coli has evolved an intracellular pathway to regulate its motion termed as chemotaxis so as to move towards a favorable environment such as regions with higher concentration of nutrients. Chemotaxis is a response to temporal and spatial variation of extracellular ligand concentration and randomness in motion induced by collisions with solvent molecules. Previous studies have reported average drift velocities for a given gradient and do not measure drift velocities as a function of time and space. To address this issue, a novel experimental technique was developed to quantify the motion of E. coli cells to varying concentrations and gradients of methyl-aspartate so as to capture the spatial and temporal variation of the drift velocity. A two-state receptor model accounting for the intracellular signaling pathway predicted the experimentally observed increase in drift velocity with gradient and the subsequent adaptation. Our study revealed that the rotational diffusivity induced by the extracellular environment is crucial in determining the drift velocity of E. coli. The model predictions matched with experimental observations only when the response of the intracellular pathway was highly ultra-sensitive to overcome the extracellular randomness. The parametric sensitivity of the pathway indicated that the dissociation constant for the binding of the ligand and the rate constants of the methylation/demethylation of the receptor are key to predict the performance of the chemotactic behavior. The study also indicates a possible role of oxygen in the chemotaxis response and that the response to a ligand may have to account for effects of oxygen.


India's ban on antimicrobial fixed-dose combinations: winning the battle, losing the war?
India, the country with the largest market availability of antimicrobial fixed-dose combinations (FDCs), banned certain antimicrobial FDCs in September 2018. Our objective was to examine the impact of Government ban on the sales of antimicrobial FDCs. The sales patterns of 14 of the 26 banned antimicrobial FDCs were analyzed using monthly private sector drug sales data from IQVIA (a comprehensive and nationally representative drug sales database) between January 2018 and December 2019. We carried out descriptive analyses to evaluate the trend in sales over time for banned and non-banned antimicrobial FDCs using cumulative sales volumes. Overall, the cumulative sales volume of banned antimicrobial FDCs declined by 75% between January and September 2018 and the same months of 2019, although some banned FDCs continued to be available in significant volumes. The effectiveness of the ban was offset by several pathways. First, the sales of combinations containing moieties belonging to the same drug-classes as the antimicrobials in the banned FDCs increased after the ban. Second, while certain formulations of particular combinations were banned, the sales of other non-banned formulation of these combinations increased. Third, in some cases, products containing new non-antimicrobial components added to the banned combinations remained available. While sales of the banned antimicrobial FDCs decreased in 2019, we identified several mechanisms that counterbalanced the ban, including implementation failure, rising sales of congeners, and products with additional non-antimicrobial components.


RUSC2 and WDR47 oppositely regulate kinesin-1-dependent distribution of ATG9A to the cell periphery.
Autophagy-related protein 9 (ATG9) is a transmembrane protein component of the autophagy machinery that cycles between the trans-Golgi network (TGN) in the perinuclear area and other compartments in the peripheral area of the cell. In mammalian cells, export of the ATG9A isoform from the TGN into ATG9A-containing vesicles is mediated by the adaptor protein 4 (AP-4) complex. However, the mechanisms responsible for the subsequent distribution of these vesicles to the cell periphery are unclear. Herein we show that the AP-4-accessory protein RUSC2 couples ATG9A-containing vesicles to the plus-end-directed microtubule motor kinesin-1 via an interaction between a disordered region of RUSC2 and the kinesin-1 light chain. This interaction is counteracted by the microtubule-associated protein WDR47. These findings uncover a mechanism for the peripheral distribution of ATG9A-containing vesicles involving the function of RUSC2 as a kinesin-1 adaptor and WDR47 as a negative regulator of this function.


Improvement of grayscale representation of the horizontally scanning holographic display.
The horizontally scanning holographic display has increased viewing angle and display screen size as compared to conventional holographic displays. Elementary holograms, which are generated by a high-speed SLM and projected by an anamorphic imaging system, are aligned horizontally by a galvano mirror. When the frame rate of the SLM is high, the width of the elementary holograms becomes several times as large as their horizontal display pitch so that several sets of elementary holograms can be displayed. A laser is modulated to illuminate different elementary hologram sets by different laser powers. The grayscale representation of reconstructed images is improved by properly designing the elementary hologram sets and the illumination laser powers.


ELK4 Promotes Cell Cycle Progression and Stem Cell-like Characteristics in HPV-associated Cervical Cancer by Regulating the FBXO22/PTEN Axis
Cervical cancer (CC) is a prevalent gynecological carcinoma, and patients infected with human papillomavirus (HPV) have a higher morbidity rate. To explore the effects of ETS-like transcription factor 4 (ELK4) in patients with HPV+ CC. In vitro cell lines and human-sample study. The ELK4 levels in human tissue (65 HPV+ CC tissue and 25 HPV− normal cervical tissue) and cell lines (human cervical epithelial immortalized cell line H8 and CC cell lines HeLa [HPV18], CaSki [HPV16], and SiHa [HPV−]) were quantified using qRT-PCR and western blot assay. ELK4 knockdown transfection was effective and confirmed by western blotting. The MTT and EDU assays were used to evaluate cell viability and proliferation, respectively. Flow cytometry was used to detect the CC cell cycle stage. Stem cell markers, such as cluster of differentiation 133 (CD133), CD44, and aldehyde dehydrogenase 1, and the cervicospheres formed were measured. ChIP-qPCR and luciferase activity experiments were used to assess the bond between ELK4 and F-box protein 22 (FBXO22). ELK4 was highly expressed in the HPV+ CC tissue. CC cells with ELK4 knockdown had lower viability and proliferation than the control cells. ELK4 knockdown blocked the progression of the cell cycle from G1 to S phase. ELK4 knockdown suppressed the stem cell-like characteristics of the HPV+ CC cells. ELK4 bonded with the FBXO22 promoter, inhibiting the levels of phosphatase and tensin homolog (PTEN). ELK4 facilitated cell cycle progression and stem cell-like characteristics by regulating the FBXO22/PTEN axis. Thus, ELK4 could be a potential therapeutic target to arrest the progress of HPV-associated CC.


Sensitive high-pressure liquid chromatographic assay for amphotericin B which incorporates an internal standard.
We developed a rapid, sensitive, high-pressure liquid chromatographic (HPLC) procedure which incorporates a commercially available internal standard, 1-amino-4-nitronaphthalene, to measure amphotericin B in serum. Recovery was quantitative (greater than or equal to 90%), and the standard curve was linear from 0.04 to at least 10.0 micrograms/ml. The reproducibility of the assay was good, with intrarun coefficients of variation from 2.0 to 6.8% and interrun coefficients of variation from 4.9 to 10.0%. Comparison by linear regression analysis of the HPLC assay with an agar well diffusion bioassay gave a correlation coefficient of 0.942, with the HPLC assay exhibiting greater precision and sensitivity. No interference was encountered from over 20 drugs and three amphotericin B analogs. However, serum specimens that contained high concentrations of conjugated bilirubin (greater than 3 mg/dl) produced interfering peaks in both this assay and other previously reported HPLC assays for amphotericin B. We also describe a solid-phase extraction procedure which effectively removes this interference and uses an alternative internal standard (N-acetyl amphotericin B).


Low-field MRI: An MR physics perspective.
Historically, clinical MRI started with main magnetic field strengths in the ∼0.05-0.35T range. In the past 40 years there have been considerable developments in MRI hardware, with one of the primary ones being the trend to higher magnetic fields. While resulting in large improvements in data quality and diagnostic value, such developments have meant that conventional systems at 1.5 and 3T remain relatively expensive pieces of medical imaging equipment, and are out of the financial reach for much of the world. In this review we describe the current state-of-the-art of low-field systems (defined as 0.25-1T), both with respect to its low cost, low foot-print, and subject accessibility. Furthermore, we discuss how low field could potentially benefit from many of the developments that have occurred in higher-field MRI. In the first section, the signal-to-noise ratio (SNR) dependence on the static magnetic field and its impact on the achievable contrast, resolution, and acquisition times are discussed from a theoretical perspective. In the second section, developments in hardware (eg, magnet, gradient, and RF coils) used both in experimental low-field scanners and also those that are currently in the market are reviewed. In the final section the potential roles of new acquisition readouts, motion tracking, and image reconstruction strategies, currently being developed primarily at higher fields, are presented. Level of Evidence: 5 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2019.


Mitochondrial-associated endoplasmic reticulum membranes (MAM) form innate immune synapses and are targeted by hepatitis C virus.
RIG-I is a cytosolic pathogen recognition receptor that engages viral RNA in infected cells to trigger innate immune defenses through its adaptor protein MAVS. MAVS resides on mitochondria and peroxisomes, but how its signaling is coordinated among these organelles has not been defined. Here we show that a major site of MAVS signaling is the mitochondrial-associated membrane (MAM), a distinct membrane compartment that links the endoplasmic reticulum to mitochondria. During RNA virus infection, RIG-I is recruited to the MAM to bind MAVS. Dynamic MAM tethering to mitochondria and peroxisomes then coordinates MAVS localization to form a signaling synapse between membranes. Importantly, the hepatitis C virus NS3/4A protease, which cleaves MAVS to support persistent infection, targets this synapse for MAVS proteolysis from the MAM, but not from mitochondria, to ablate RIG-I signaling of immune defenses. Thus, the MAM mediates an intracellular immune synapse that directs antiviral innate immunity.


Basal Ganglia volumes in patients with Gilles de la Tourette syndrome.
Despite strong circumstantial evidence that the pathophysiology of Gilles de la Tourette syndrome (TS) involves structural and functional disturbances of the basal ganglia, inconsistent findings from relatively small in vivo TS imaging studies have supported contradictory conclusions concerning the role of abnormal anatomical characteristics of the basal ganglia in the pathophysiology of TS. Basal ganglia volumes were measured on high-resolution magnetic resonance images acquired for 154 children and adults with TS and 130 healthy control subjects. Repeated-measures analyses tested hypotheses concerning regional specificity, age effects, and abnormal asymmetries in the basal ganglia of subjects with TS. Subjects with prior neuroleptic exposure had larger basal ganglia volumes and were excluded from further statistical analyses. Caudate nucleus volumes were significantly (P =.008) smaller in children and adults with TS. Lenticular nucleus volumes also were smaller in adults with TS and in children with TS who were diagnosed as having comorbid obsessive-compulsive disorder. Regional anatomical asymmetries did not differ across groups. Regional volumes did not correlate significantly with the severity of tic, obsessive-compulsive disorder, or attention-deficit/hyperactivity disorder symptoms. Reduced caudate nucleus volumes may be a good candidate marker for a trait abnormality in the structure of the basal ganglia in persons with TS. Smaller lenticular nucleus volumes may be an additional marker for the presence of comorbid obsessive-compulsive disorder and for the persistence of tic symptoms into adulthood. Brain regions other than the basal ganglia may have greater clinical relevance in determining the severity of tic symptoms.


Early physiological and morphological changes in the remnant kidney of living donors.
In order to describe the early functional and morphological changes in the remnant kidney of living donors, a retrospective study was carried out at the Cayetano Heredia Hospital. Data from 55 individuals was included. Clinical and demographic data were obtained from the clinical records, as well as data for creatinine clearance, proteinuria, blood pressure and renal dimensions at 1, 2, 3, 6 and 12 months after kidney donation. The mean age was 40.88 (±9.84) years; 80% were women and the mean body mass index was 25.68 (±3.5) kg/m2. Linear and quadratic models were used to study physiological and morphological variables. During the follow-up time, glomerular filtration rate, proteinuria, diastolic blood pressure, and kidney length showed significant changes (p < 0.05).


Knowledge of Adult Sexual Orientation Influences Perceptions of Adult-Child Interactions.
Child sexual abuse (CSA) is a highly prevalent concern that carries lifelong consequences for the survivor. Many instances of CSA may be prevented when people correctly recognize precursory behaviors to abuse; however, research has shown that people's biases color their perceptions of behavior. Past research demonstrated sexual and gender minority adults are more likely to erroneously be seen as predators and face harsher consequences compared to straight adults. The current study examined how knowledge of adults' sexual orientation influenced perceptions regarding the nature of adult-child interactions. Participants in the current study read a series of vignettes describing interactions between adults and children where the adult sexual orientation (straight male, gay male) and the gender of the child (male, female) were manipulated. Participants then indicated whether they believed the behavior to be predatory or innocuous. Participants were less likely to recognize dangerous behaviors when the adult was described as a straight man interacting with a male child, suggesting that harmful adult-child interactions are more likely to go undetected in these instances.


Age-Friendly as Tranquilo Ambiente: How Sociocultural Perspectives Shape the Lived Environment of Latinx Older Adults.
Researchers have increasingly considered the importance of age-friendly communities to improve the health and well-being of older adults. Studies have primarily focused on the built environment, such as community infrastructure, older adult behavior, and environmental expectations. Less is known about the role of cultural characteristics in shaping perceptions of age-friendly environments, especially among racial and ethnic minorities. Using an ethnographic methodological approach, including participant observation in a Latinx community near New York City and 72 semistructured interviews, this study examines how older Latinxs characterize age-friendly communities. Latinx older adults described their community as age-friendly through the concept Tranquilo Ambiente, translated as a calm or peaceful environment. More specifically, Tranquilo Ambiente includes (a) a sense of perceived personal safety, (b) ethnic and social connectedness, and (c) spatial and cultural accessibility. This study extends prior research that has largely considered structural or economic components to show how culture may also influence the well-being of older Latinxs, even if living in an underresourced area. The concept of Tranquilo Ambiente demonstrates that both structural and cultural environmental factors influence older Latinxs' understandings of age-friendly communities. By utilizing a sociocultural lens, this research highlights how Latinx older adults benefit from an environment that supports their physical (e.g., well-lit and newly paved streets), social (e.g., city hall senior center), and cultural (e.g., events and programs that promote cultural heritage) needs.


Phenological synchrony between a butterfly and its host plants: Experimental test of effects of spring temperature.
Climate-driven changes in the relative phenologies of interacting species may potentially alter the outcome of species interactions. Phenotypic plasticity is expected to be important for short-term response to new climate conditions, and differences between species in plasticity are likely to influence their temporal overlap and interaction patterns. As reaction norms of interacting species may be locally adapted, any such climate-induced change in interaction patterns may vary among localities. However, consequences of spatial variation in plastic responses for species interactions are understudied. We experimentally explored how temperature affected synchrony between spring emergence of a butterfly, Anthocharis cardamines, and onset of flowering of five of its host plant species across a latitudinal gradient. We also studied potential effects on synchrony if climate-driven northward expansions would be faster in the butterflies than in host plants. Lastly, to assess how changes in synchrony influence host use we carried out an experiment to examine the importance of the developmental stage of plant reproductive structures for butterfly oviposition preference. In southern locations, the butterflies were well-synchronized with the majority of their local host plant species across temperatures, suggesting that thermal plasticity in butterfly development matches oviposition to host plant development and that thermal reaction norms of insects and plants result in similar advancement of spring phenology in response to warming. In the most northern region, however, relative phenology between the butterfly and two of its host plant species changed with increased temperature. We also show that the developmental stage of plants was important for egg-laying, and conclude that temperature-induced changes in synchrony in the northernmost region are likely to lead to shifts in host use in A. cardamines if spring temperatures become warmer. Northern expansion of butterfly populations might possibly have a positive effect on keeping up with host plant phenology with more northern host plant populations. Considering that the majority of insect herbivores exploit multiple plant species differing in their phenological response to spring temperatures, temperature-induced changes in synchrony might lead to shifts in host use and changes in species interactions in many temperate communities.


The Association of Unfairness with Mental and Physical Health in a Multiethnic Sample of Adults: Cross-sectional Study.
Two psychosocial constructs that have shown consistent associations with negative health outcomes are discrimination and perceived unfairness. The current analyses report the effects of discrimination and unfairness on medical, psychological, and behavioral outcomes from a recent cross-sectional survey conducted in a multiethnic sample of adults in Michigan. A cross-section survey was collected using multiple approaches: community settings, telephone-listed sample, and online panel. Unfairness was assessed with a single-item previously used in the Whitehall study, and everyday discrimination was assessed with the Williams 9-item scale. Outcomes included mental health symptoms, past-month cigarette use, past-month alcohol use, past-month marijuana use, lifetime pain medication use, and self-reported medical history. A total of 2238 usable surveys were collected. In bivariate analyses, higher unfairness values were significantly associated with lower educational attainment, lower age, lower household income, and being unmarried. The highest unfairness values were observed for African American and multiracial respondents followed by Middle Eastern or North African participants. Unfairness was significantly related to worse mental health functioning, net adjustment for sociodemographic variables, and everyday discrimination. Unfairness was also related to self-reported history of depression and high blood pressure although, after including everyday discrimination in the model, only the association with depression remained significant. Unfairness was significantly related to 30-day marijuana use, 30-day cigarette use, and lifetime opiate use. Our findings of a generally harmful effect of perceived unfairness on health are consistent with prior studies. Perceived unfairness may be one of the psychological pathways through which discrimination negatively impacts health. Future studies examining the relationships we observed using longitudinal data and including more objective measures of behavior and health status are needed to confirm and extend our findings.


Disentangling the interrelations between hopelessness, loneliness, and suicidal ideation.
We attempted to disentangle the interrelations between hopelessness, loneliness, and suicidal ideation, by comparing two conceptually driven models of their relationships, prospectively among 234 undergraduates, using a series of multiple regression/correlation equations. Model 1 framed loneliness as a risk factor for future suicidality that operates via its influence on hopelessness (the mediational view). Model 2 viewed hopelessness as a source variable that is predictive of both loneliness and suicidality, and postulated no relation between loneliness and suicidality beyond hopelessness. Model 2 received support, whereas Model 1 did not. We discuss the implications of our findings for the nomological status of hopelessness and loneliness as correlates of suicidality, and for exploration of the structural interrelations of suicide-related variables in general.


Towards a bioethics of innovation.
In recent years, it has become almost axiomatic that biomedical research and clinical practice should be 'innovative'-that is, that they should be always evolving and directed towards the production, translation and implementation of new technologies and practices. While this drive towards innovation in biomedicine might be beneficial, it also raises serious moral, legal, economic and sociopolitical questions that require further scrutiny. In this article, we argue that biomedical innovation needs to be accompanied by a dedicated 'bioethics of innovation' that attends systematically to the goals, process and outcomes of biomedical innovation as objects of critical inquiry. Using the example of personalised or precision medicine, we then suggest a preliminary framework for a bioethics of innovation, based on the research policy initiative of 'Responsible Innovation'. We invite and encourage critiques of this framework and hope that this will provoke a challenging and enriching new bioethical discourse.


Wildfire smoke exposure during pregnancy and perinatal, obstetric, and early childhood health outcomes: A systematic review and meta-analysis.
Maternal exposure to air pollution during pregnancy is associated with adverse birth outcomes, although less is known for wildfire smoke. This systematic review evaluated the association between maternal exposure to wildfire smoke during pregnancy and the risk of adverse perinatal, obstetric, and early childhood health outcomes. We searched CINAHL Complete, Ovid/EMBASE, Ovid/MEDLINE, ProQuest, PubMed, Scopus, Web of Science, and Google Scholar to identify relevant epidemiological observational studies indexed through September 2023. The screening of titles, abstracts, and full-texts, and data extraction was performed by pairs of independent reviewers. Our systematic search yielded 28,549 records. After duplicate removal, we screened 14,010 studies, identifying 31 for inclusion in the present review. Data extraction highlighted high methodological heterogeneity between studies, including a lack of geographic variation. Approximately 56.5% and 16% originated in the United States and Brazil, respectively, and fewer in other countries. Among the studies, wildfire smoke exposure during pregnancy was assessed using distance of residence from wildfire-affected areas (n = 15), measurement of air pollutant concentration during wildfires (n = 11), number of wildfire records (n = 3), aerosol index (n = 1), and geographic hot spots (n = 1). Pooled meta-analysis for birthweight and low birthweight were inconclusive, likely due to low number of methodologically homogenous studies. However, the reviewed studies provided suggestive evidence for an increased risk of birthweight reduction, low birthweight, preterm birth, and other adverse health outcomes. This review identified 31 studies evaluating the impacts of maternal wildfire smoke exposure on maternal, infant, and child health. Although we found suggestive evidence of harm from exposure to wildfire smoke during pregnancy, more methodologically homogenous studies are required to enable future meta-analysis with greater statistical power to more accurately evaluate the association between maternal wildfire smoke and adverse birth outcomes and also other health outcomes.


Possibilities for unexplained chronic illnesses among reserve units deployed in Operation Desert Shield/Desert Storm.
Because Armed Forces Reserve members, especially combat support units, were rapidly mobilized during Operation Desert Shield/Desert Storm, they were at higher risk for anxiety and stress-related disorders. Personnel in reserve units in the military force structure are at greater risk for psychologic stress due to rapid mobilization and demobilization, which allows minimal time to process adverse experiences or fears. The unexpected disruption of families and careers and resulting financial pressures are magnified in older age groups who have increased personal and family commitments. Personnel in combat support units are at greatest risk when they lack necessary training, cohesion, and leadership. Prevention efforts in reserve units should involve education regarding the potential for activation and associated disruption of family and career plans. Support networks for reserve families should be encouraged. Additional training in an appropriate context regarding risks of biologic and chemical exposure, with the goal of developing confidence in training and equipment, should be stressed. Finally, group processing before demobilization and recall within 90 days of return to emphasize unit cohesion and readjustment to civilian life may be of benefit.


The Mediation Effect of Self-Report Physical Activity Patterns in the Relationship between Educational Level and Cognitive Impairment in Elderly: A Cross-Sectional Analysis of Chilean Health National Survey 2016-2017.
The aims of this cross-sectional study were (i) to determine the association of educational level attained with cognitive impairment and (ii) to investigate the mediating effect of different self-report physical activity (PA) patterns in a large sample of older Chileans. A sample of 1571 older adults from the National Chilean Survey (2016-2017) was included. The educational level attained, PA levels, mode of commuting, sedentary time, and leisure-time PA were self-reported through validated questionnaires. Cognitive impairment was determined by Mini-Mental State Examination (modified version). Association between educational level attained and cognitive impairment was examined using logistic regression models. Counterfactual mediation models were used to test the mediating effect of self-reported PA patterns. A lower educational level was consistently associated with higher odds of cognitive impairment (OR range 2.846 to 2.266, all p < 0.001), while leisure-time PA was the only PA pattern that partially mediated this association (proportion mediated 8.0%). In conclusion, leisure-time PA was the solely PA pattern that partially mediated the association between the educational level and cognitive impairment. The rest self-reported PA patterns did not modify this association.


Differential impact of disfiguring facial features on overt and covert attention.
Observers can form negative impressions about faces that contain disfiguring features (e.g., scars). Previous research suggests that this might be due to the ability of disfiguring features to capture attention - as evidenced by contrasting observers' responses to faces with or without disfiguring features. This, however, confounds the effects of salience and perceptual interpretation, i.e. whether the feature is seen as integral to the face, or separate from it. Furthermore, it remains unclear to what extent disfiguring features influence covert as well as overt attention. We addressed these issues by studying attentional effects by photographs of unfamiliar faces containing a unilateral disfigurement (a skin discoloration) or a visually similar control feature that was partly occluding the face. Disfiguring and occluding features were first matched for salience (Experiment 1). Experiments 2 and 3 assessed the effect of these features on covert attention in two cueing tasks involving discrimination of a (validly or invalidly cued) target in the presence of, respectively, a peripheral or central distractor face. In both conditions, disfigured and occluded faces did not differ significantly in their impact on response-time costs following invalid cues. In Experiment 4 we compared overt attention to these faces by analysing patterns of eye fixations during an attractiveness rating task. Critically, faces with disfiguring features attracted more fixations on the eyes and incurred a higher number of recurrent fixations compared to faces with salience-matched occluding features. Together, these results suggest a differential impact of disfiguring facial features on overt and covert attention, which is mediated both by the visual salience of such features and by their perceptual interpretation.


Gene duplication, genome duplication, and the functional diversification of vertebrate globins.
The functional diversification of the vertebrate globin gene superfamily provides an especially vivid illustration of the role of gene duplication and whole-genome duplication in promoting evolutionary innovation. For example, key globin proteins that evolved specialized functions in various aspects of oxidative metabolism and oxygen signaling pathways (hemoglobin [Hb], myoglobin [Mb], and cytoglobin [Cygb]) trace their origins to two whole-genome duplication events in the stem lineage of vertebrates. The retention of the proto-Hb and Mb genes in the ancestor of jawed vertebrates permitted a physiological division of labor between the oxygen-carrier function of Hb and the oxygen-storage function of Mb. In the Hb gene lineage, a subsequent tandem gene duplication gave rise to the proto α- and β-globin genes, which permitted the formation of multimeric Hbs composed of unlike subunits (α(2)β(2)). The evolution of this heteromeric quaternary structure was central to the emergence of Hb as a specialized oxygen-transport protein because it provided a mechanism for cooperative oxygen-binding and allosteric regulatory control. Subsequent rounds of duplication and divergence have produced diverse repertoires of α- and β-like globin genes that are ontogenetically regulated such that functionally distinct Hb isoforms are expressed during different stages of prenatal development and postnatal life. In the ancestor of jawless fishes, the proto Mb and Hb genes appear to have been secondarily lost, and the Cygb homolog evolved a specialized respiratory function in blood-oxygen transport. Phylogenetic and comparative genomic analyses of the vertebrate globin gene superfamily have revealed numerous instances in which paralogous globins have convergently evolved similar expression patterns and/or similar functional specializations in different organismal lineages.


Different effects of nifedipine and amlodipine on circulating catecholamine levels in essential hypertensive patients.
To compare the acute and chronic effects of nifedipine retard (NPA), nifedipine gastrointestinal therapeutic system (NGITS) and amlodipine at trough and peak plasma concentrations of drug on blood pressure and heart rate, and on plasma norepinephrine and epinephrine levels in patients with mild-to-moderate hypertension (diastolic blood pressure 95-115 mmHg). After 3-4 weeks' placebo treatment, patients of both sexes were randomly allocated to be administered 10 or 20 mg NPA twice a day, 30 or 60 mg NGITS once a day, and 5 or 10 mg amlodipine once a day for 6 weeks. Initially, for the first 2 weeks, the lowest dose of each drug was used, but higher doses were administered after 2 weeks if sitting diastolic blood pressure was > 90 mmHg. Patients were evaluated after administration of the first dose and after 6 weeks' therapy in a hospital setting. Blood samples were taken for high-performance liquid chromatography measurement of catecholamine and drug levels at various intervals for a period covering trough to peak drug level ranges. Administration of all three drugs reduced clinic blood pressure to the same level after 6 weeks' therapy, but heart rate was increased slightly only with amlodipine (P < 0.05). Administration of NPA reduced blood pressure more abruptly whereas administrations of NGITS and amlodipine induced smoother falls after acute and chronic treatments: a significant increase in heart rate was observed with amlodipine after chronic treatment. Both acute and chronic treatments with NPA (n = 19) increased norepinephrine levels (P < 0.01) transiently (2-4 h). In contrast, administration of NGITS (n = 22) did not increase norepinephrine levels and even induced a slight but significant decrease in norepinephrine levels 5-6 h after chronic treatments. Although administration of amlodipine (n = 22) did not increase norepinephrine levels transiently either after acute or after chronic administration, it did induce a sustained rise in basal norepinephrine levels by more than 50% after chronic therapy (P < 0.01). Plasma epinephrine levels were not increased by any of the treatments and even a slight decrease was observed 4 h after administration of a dose following chronic treatments with NGITS and amlodipine (P < 0.05). The transient increase in norepinephrine levels observed with NPA and the sustained increases in norepinephrine levels observed after chronic treatment with amlodipine suggest that sympathetic activation occurs with those two drugs. The lack of increase in norepinephrine levels after administration of NGITS suggests that this formulation does not activate the sympathetic system. The lowering of epinephrine levels after administrations of NGITS and amlodipine suggests that inhibition of release of epinephrine by the adrenal medulla occurs with longer-acting dihydropyridine formulations.


AlphaB-crystallin in the trabecular meshwork is inducible by transforming growth factor-beta.
Because in glaucomatous eyes transforming growth factor-beta (TGF-beta) and alphaB-crystallin are increased in the anterior eye segment, the effect of TGF-beta1 and TGF-beta2 on the expression of alphaB-crystallin and its corresponding mRNA was studied in human trabecular meshwork (TM) cells. Monolayer cultures of "cribriform" and "corneoscleral" TM cells of 5 human donors (12-73 years of age) were treated with either 1.0 ng/ml TGF-beta1, TGF-alpha2, or 5 X 10(-7) dexamethasone (DEX) for 12 to 96 hours. Induction of alphaB-crystallin and the related mRNA was investigated by western and northern blot analyses. For comparison, human foreskin fibroblasts (HFF) and NIH 3T3 cells were treated in the same way as the TM cells. An increase of alphaB-crystallin mRNA was observed after treatment of TM cells with TGF-beta1 and TGF-beta2, whereas DEX had no effect. In the cribriform TM cells with a high basal level, the enhancement ranged between 2 and 3 times; whereas in the corneoscleral TM cells alphaB-crystallin mRNA increased between 5 and 6 times. Using western blot analysis, the increase of alphaB-crystallin expression in the cribriform TM cells was only small compared with the significant increase in the corneoscleral TM cells. Treatment of HFF and NIH 3T3 cells with TGF-beta did not induce alphaB-crystallin mRNA. This is the first time to show that alphaB-crystallin is not only induced by stress factors but also by TGF-beta in TM cell cultures. The difference in induction of mRNA and protein seems to be dependent on alphaB-crystallin concentration before treatment.


Recent evolution of the NF-κB and inflammasome regulating protein POP2 in primates.
Pyrin-only protein 2 (POP2) is a small human protein comprised solely of a pyrin domain that inhibits NF-κB p65/RelA and blocks the formation of functional IL-1β processing inflammasomes. Pyrin proteins are abundant in mammals and several, like POP2, have been linked to activation or regulation of inflammatory processes. Because POP2 knockout mice would help probe the biological role of inflammatory regulation, we thus considered whether POP2 is common in the mammalian lineage. BLAST searches revealed that POP2 is absent from the available genomes of not only mice and rats, but those of other domestic mammals and New World monkeys as well. POP2 is however present in the genome of the primate species most closely related to humans including Pan troglodytes (chimpanzees), Macaca mulatta (rhesus macaques) and others. Interestingly, chimpanzee POP2 is identical to human POP2 (huPOP2) at both the DNA and protein level. Macaque POP2 (mqPOP2), although highly conserved is not identical to the human sequence; however, both functions of the human protein are retained. Further, POP2 appears to have arisen in the mammalian genome relatively recently (~25 mya) and likely derived from retrogene insertion of NLRP2. Our findings support the hypothesis that the NLR loci of mammals, encoding proteins involved in innate and adaptive immunity as well as mammalian development, have been subject to recent and strong selective pressures. Since POP2 is capable of regulating signaling events and processes linked to innate immunity and inflammation, its presence in the genomes of hominids and Old World primates further suggests that additional regulation of these signals is important in these species.