Modulation of ultraviolet light-induced epidermal damage: beneficial effects of tocopherol.
Oxygen free radicals have been shown to result from and mediate deleterious effects of ultraviolet radiation on the skin. The purpose of this study was to determine if topical DL-alpha-tocopherol (vitamin E) could reduce ultraviolet-induced damage to the epidermis. Twenty mice were treated with either ethanol or a 1:1 mixture of tocopherol and ethanol. Treatments consisted of once-daily 0.1-ml topical applications for 1 week, followed by irradiation with 0.30 mW/cm2 of ultraviolet B irradiation. A statistically significant decrease in Schiff base formation was noted between tocopherol-treated animals and their controls. Histologic study revealed a statistically significant increase in epidermal thickness in tocopherol-treated skin versus controls or vehicle alone. The thicker epidermis was accompanied by the presence of parakeratosis, implicating increased proliferation as the cause of the increasing thickness. The number of sunburn cells was decreased by tocopherol treatment. Tocopherol protection from ultraviolet irradiation may have been due to both direct protection from free radicals and indirect protection by means of increased epidermal thickness. The demonstration of beneficial effects of tocopherol administration suggests that further studies in clinically relevant models to define optimal dosage, frequency of administration, vehicle, and quantitation of the possible protective effects afforded to Langerhans cells may be useful.


Impact of dietary level and ratio of n-6 and n-3 fatty acids on disease progression and mRNA expression of immune and inflammatory markers in Atlantic salmon (Salmo salar) challenged with Paramoeba perurans.
The aim of the study was to investigate the influence of dietary level and ratio of n-6/n-3 fatty acids (FA) on growth, disease progression and expression of immune and inflammatory markers in Atlantic salmon (Salmo salar) following challenge with Paramoeba perurans. Fish (80 g) were fed four different diets with different ratios of n-6/n-3 FA; at 1.3, 2.4 and 6.0 and one diet with ratio of 1.3 combined with a higher level of n-3 FA and n-6 FA. The diet with the n-6/n-3 FA ratio of 6.0 was included to ensure potential n-6 FA effects were revealed, while the three other diets were more commercially relevant n-6/n-3 FA ratios and levels. After a pre-feeding period of 3 months, fish from each diet regime were challenged with a standardized laboratory challenge using a clonal culture of P. perurans at the concentration of 1,000 cells L-1. The subsequent development of the disease was monitored (by gross gill score), and sampling conducted before challenge and at weekly sampling points for 5 weeks post-challenge. Challenge with P. perurans did not have a significant impact on the growth of the fish during the challenge period, but fish given the feed with the highest n-6/n-3 FA ratio had reduced growth compared to the other groups. Total gill score for all surfaces showed a significant increase with time, reaching a maximum at 21 days post-challenge and declined thereafter, irrespective of diet groups. Challenge with P. perurans influenced the mRNA expression of examined genes involved in immune and inflammatory response (TNF-α, iNOS, IL4-13b, GATA-3, IL-1β, p53, COX2 and PGE2-EP4), but diet did not influence the gene expression. In conclusion, an increase in dietary n-6/n-3 FA ratio influenced the growth of Atlantic salmon challenged with P. perurans; however, it did not alter the mRNA expression of immune genes or progression of the disease.


[Complications of enteral nutrition at home. Results of a multicentre trial].
In spite of the increasing number of home enteral nutrition (HEN) patients, only few articles had reported the frequency of complications related to this treatment. Our multicentric study analyzes the HEN complications in relation to access device and time of treatment. 92 HEN patients from 8 hospitals were randomly selected. Patients were distributed in relation to the time of treatment and access device (nasogastric tube and percutaneous or surgical gastrostomies). After an educational program, they were filled in an initial questionnaire and repeated it the days 15 and 30. They received a mean of 1650 Kcal of enteral solution. A total of 2760 HEN prospective days were analyzed. In prospective study 42% of patients had some complication (112 episodes). The most frequent were gastrointestinal (55%) and mechanical (29%); 0.16 complications of patient-year were registered. The most common complications were: extraction (15%), constipation (13%), vomiting (12%) and diarrhoea (10%). The gastrostomy group had more gastrointestinal complications. In retrospective evaluation, percutaneous gastrostomy group had the lowest ratio of complications and nasogastric tube group required more tube replacements (4 vs 2) and had 1.96 episodes/patient (percutaneous group 1.85 and surgical gastrostomy 3.1 episodes/patient). HEN is safe with low incidence of complications. An adequate educational program is very important and we expect, in the future, to establish an proper National Home Care System.


Frequency-modulated 50 kHz ultrasonic vocalizations: a tool for uncovering the molecular substrates of positive affect.
The evidence that frequency modulated (FM) 50 kHz ultrasonic vocalizations (USVs) reflect a positive emotional state in rats is reviewed. Positive emotional states in humans are measured by facial-vocal displays (e.g., Duchenne smiling and laughter), approach behavior, and subjective self-report of feeling states. In laboratory animals, only facial-vocal displays, along with approach behavior can be measured. FM 50 kHz USVs are uniquely elevated by hedonic stimuli and suppressed by aversive stimuli. Rates of FM 50 kHz USVs are positively correlated to the rewarding value of the eliciting stimulus. Additionally, playbacks of these vocalizations are rewarding. The neural and pharmacological substrates of 50 kHz USVs are consistent with those of human positive affective states. By experimentally eliciting FM 50 kHz USVs, the novel molecular underpinning of positive affect can be elucidated and may be similar to those in humans. In humans, positive emotional states confer resilience to depression and anxiety, as well as promote overall health. Using rough-and-tumble play induced hedonic USVs, we have identified insulin like growth factor I and the NR2B subunit of the NMDA receptor as playing a functional role in positive affective states. From this research, we have developed a promising new class of antidepressants that is entering phase II clinical trials for the treatment of depression.


Low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol and apolipoprotein B for cardiovascular care.
Some experts and consensus groups continue to argue that apolipoprotein B (apoB) should not be introduced broadly into clinical care. But, too often, the present approach to clinical care is not succeeding. An important reason for this failure, we believe, is that the conventional approach limits what the expert clinician can accomplish and is too complex, confusing, and contradictory for primary care physicians to apply effectively in their practise. There are four major reasons that apoB should be measured routinely in clinical care. First, apoB is a more accurate marker of cardiovascular risk than LDL-C or non-HDL-C. Second, the measurement of apoB is standardized whereas the measurements of LDL-C and non-HDL-C are not. Third, with apoB and a conventional lipid panel, all the lipid phenotypes can be simply and accurately distinguished. This will improve the care of the expert. Fourth, apoB, as the single measure to evaluate the success of therapy, would simplify the process of care for primary care physicians. By introducing apoB broadly into clinical care, the process of care will be improved for both the expert and the primary care physician, and this will improve the outcomes of care.


A characterisation of cyclic AMP release from monolayer cultures of normal human thyroid cells.
The thyrotrophin (TSH)-dependent and time-related release of cyclic AMP has been characterised in primary monolayer cultures of normal human thyroid cells. Accumulation of cyclic AMP within the incubation medium was detectable within 1 h of exposure of cultures to 5 mU TSH/ml, and increased throughout of subsequent 15 h incubation period, final levels attained being consistently in excess of the corresponding intracellular cyclic AMP levels. Accumulation of cyclic AMP in the incubation medium was dependent on TSH dose, for both short (1 h) and prolonged (16 h) incubations. Moreover, after incubation for 16 h, cyclic AMP levels in the incubation medium were significantly (P less than 0.01) in excess of intracellular levels for each dose of TSH tested above 0.2 mU/ml. In the absence of TSH, accumulation of cyclic AMP in the incubation medium remained low, after both 1 h and 16 h incubation periods. A consideration of these observations suggests that a bioassay based upon the cyclic AMP content of incubation medium samples should provide a more precise detection system for thyroid stimulators than those measuring the intracellular cyclic AMP response, and this has been demonstrated for a cell preparation in which the intracellular response to TSH was minimal.


Ca2+-RhoA signaling pathway required for polyamine-dependent intestinal epithelial cell migration.
Expression of voltage-gated K(+) (Kv) channel genes is regulated by polyamines in intestinal epithelial cells (IEC-6 line), and Kv channel activity is involved in the regulation of cell migration during early restitution by controlling membrane potential (E(m)) and cytosolic free Ca2+ concentration ([Ca2+](cyt)). This study tests the hypothesis that RhoA of small GTPases is a downstream target of elevated ([Ca2+](cyt)) following activation of K(+) channels by increased polyamines in IEC-6 cells. Depletion of cellular polyamines by alpha-difluoromethylornithine (DFMO) reduced whole cell K+ currents [I(K(v))] through Kv channels and caused membrane depolarization, which was associated with decreases in ([Ca2+](cyt)), RhoA protein, and cell migration. Exogenous polyamine spermidine reversed the effects of DFMO on I(K(v)), E(m), ([Ca2+](cyt)), and RhoA protein and restored cell migration to normal. Elevation of ([Ca2+](cyt)) induced by the Ca2+ ionophore ionomycin increased RhoA protein synthesis and stimulated cell migration, while removal of extracellular Ca2+ decreased RhoA protein synthesis, reduced protein stability, and inhibited cell motility. Decreased RhoA activity due to Clostridium botulinum exoenzyme C(3) transferase inhibited formation of myosin II stress fibers and prevented restoration of cell migration by exogenous spermidine in polyamine-deficient cells. These findings suggest that polyamine-dependent cell migration is partially initiated by the formation of myosin II stress fibers as a result of Ca2+-activated RhoA activity.


Effect of Exercise Interventions on Quality of Life in Patients With Lung Cancer: A Systematic Review of Randomized Controlled Trials.
Improving quality of life (QOL) is a key issue for patients with lung cancer. Exercise interventions could positively affect patients' QOL; however, there is no clear-cut understanding of the role of exercise in improving QOL in patients with lung cancer. The PubMed®, Embase®, Cochrane Library, and Web of Science electronic databases were searched from inception to September 6, 2019. 16 randomized controlled trials met the inclusion criteria. A qualitative synthesis method was used to identify the effect of exercise interventions on QOL in patients with lung cancer. This review indicates that exercise interventions may have beneficial effects on the QOL of patients with lung cancer. The effectiveness seems to be affected by the duration of the intervention, as well as exercise frequency, intensity, and adherence. Exercise interventions can be integrated into management plans for patients with lung cancer to improve their QOL. Healthcare providers should consider developing optimal exercise prescriptions to maximize the results for this population.


[Behaviour of the aortic lipoidosis in rats twenty months after stopping of an hyperlipidic diet (author's transl)].
48 rats were placed on an hyperlipidic diet (cholesterol, cholic acid, cholin, propylthiouracil), 23 were sacrificed at various intervals from the fourth up to the twelve month of the experiment. In the remaining 25 rats, the atherogenic regimen was replaced by a normal one. These animals were sacrificed one to twenty months after stopping of the experimental diet. Aortae of experimental and control animals were studied by means of histological and histochemical technics. All the animals developed hypercholesterolemia together with intima and media lipoidosis. None demonstrated any aortic cell proliferation. The only metabolic change of the smooth muscle cell was a progressive decrease in 5' nucleotidase, acid esterase and cholinesterase activities. The return to a normal diet involved the reversion of the serum cholesterol level to normal values and the disappearance of intima lipoidosis. The reduced enzymatic activities in the media returned to normal levels around the sixth month. The surfaces of the extracellular sudanophilic areas decreased. However, twenty months after stopping of the atherogenic diet, some lipids still persisted at the edges of the elastic fibres.


Flexible defense strategies: competition modifies investment in behavioral vs. morphological defenses.
Competition is predicted to affect the expression of inducible defenses, but because costs of behavioral and morphological antipredator defenses differ along resource gradients, its effects on defenses may depend on the traits considered. We tested the predictions from different defense models in tadpoles of the common frog Rana temporaria, which exhibit both types of defenses. In an outdoor experiment, we exposed the tadpoles to nonlethal predators (Aeshna dragonfly larvae) and to a gradient of intraspecific competition. Morphological responses did not follow any of the expected patterns, since investment in defense was not affected by resource level. Instead, tail depth decreased in the absence of predators. Behavioral defenses followed a state-dependent model. Overall, the defense strategy of the tadpoles revealed a shift from morphological and behavioral defenses at low tadpole density to morphological defense only at high density. This difference probably reflects the different efficiency of the defenses. Hiding is an effective means of defense, but it is unsustainable when resources are scarce. Morphological responses become more important with increasing density to compensate for the increase in behavioral risk-taking. Our results indicate that competition can strongly affect reaction norms of inducible defenses and highlight the importance of integrating ecological parameters that affect the cost-benefit balance of phenotypic plasticity.


Outcomes After Distal Radius Fracture Treatment With Percutaneous Wire Versus Plate Fixation: Meta-Analysis of Randomized Controlled Trials.
Multiple methods for surgical fixation of distal radius fractures exist, including percutaneous pinning with Kirschner wires and open reduction volar plating. Despite increased costs, the hypothesis of this study was that open reduction and volar plating does not provide improved outcomes over wire fixation. Following Transparent Reporting of Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a meta-analysis of randomized controlled trials was conducted comparing these two methods with regard to clinical outcomes, radiographic parameters, and complications. Seven trials with a total of 858 patients were included. Plating was not favored over pinning with regard to clinical outcomes and radiographic parameters. Pinning was associated with a higher superficial infection risk compared with plating, though the risk of repeat surgery was not different. It was concluded that Kirschner wire fixation, which may be associated with lower costs, is associated with similar clinical and radiographic outcomes when compared with volar plate fixation, although wire fixation is associated with higher superficial infection risk.


Relationship between endophenotype and phenotype in ADHD.
It has been hypothesized that genetic and environmental factors relate to psychiatric disorders through the effect of intermediating, vulnerability traits called endophenotypes. The study had a threefold aim: to examine the predictive validity of an endophenotypic construct for the ADHD diagnosis, to test whether the magnitude of group differences at the endophenotypic and phenotypic level is comparable, and to investigate whether four factors (gender, age, IQ, rater bias) have an effect (moderation or mediation) on the relation between endophenotype and phenotype. Ten neurocognitive tasks were administered to 143 children with ADHD, 68 non-affected siblings, and 120 control children (first-borns) and 132 children with ADHD, 78 non-affected siblings, and 113 controls (second-borns) (5 - 19 years). The task measures have been investigated previously for their endophenotypic viability and were combined to one component which was labeled 'the endophenotypic construct': one measure representative of endophenotypic functioning across several domains of functioning. The endophenotypic construct classified children with moderate accuracy (about 50% for each of the three groups). Non-affected children differed as much from controls at the endophenotypic as at the phenotypic level, but affected children displayed a more severe phenotype than endophenotype. Although a potentially moderating effect (age) and several mediating effects (gender, age, IQ) were found affecting the relation between endophenotypic construct and phenotype, none of the effects studied could account for the finding that affected children had a more severe phenotype than endophenotype. Endophenotypic functioning is moderately predictive of the ADHD diagnosis, though findings suggest substantial overlap exists between endophenotypic functioning in the groups of affected children, non-affected siblings, and controls. Results suggest other factors may be crucial and aggravate the ADHD symptoms in affected children.


Male pseudohermaphroditism due to steroid 5alpha-reductase 2 deficiency. Diagnosis, psychological evaluation, and management.
Sixteen subjects (from 10 Brazilian families) with male pseudohermaphroditism due to steroid 5alpha-reductase 2 deficiency have been evaluated in 1 clinic. The diagnoses were made on the basis of normal plasma testosterone values, normal or low plasma dihydrotestosterone levels and high testosterone/dihydrotestosterone ratios in the basal state in postpubertal subjects or after treatment with either human chorionic gonadotropin or testosterone in prepubertal subjects. The analysis of the ratios of etiocholanolone to androsterone in urine confirmed the diagnosis in all subjects who were tested, and the molecular basis of the underlying mutations was established in 9 of the families. Fourteen of the individuals were evaluated by the same psychologist. All subjects but 1 were given a female sex assignment at birth. Three of the subjects (1 the sibling of an individual who has undergone female to male social behavior) maintain a female social sex; they have been gonadectomized and treated with exogenous estrogens. Ten of 13 subjects of postpubertal age underwent a change of social sex from female to male, had surgical correction of the hypospadias, and were treated with high-dose testosterone esters by parenteral injection and subsequently with dihydrotestosterone cream. These regimens brought serum dihydrotestosterone levels to the normal male range (or above) but resulted only in limited growth of the prostate and penis and, in some, increase in body and facial hair and enhancement of libido and sexual performance. Treatment of the prepubertal boys with testosterone and/or dihydrotestosterone resulted in a doubling of penis size.


Tagging Continuous Labels for EEG-based Emotion Classification.
EEG-based emotion classification has long been a critical task in the field of affective brain-computer interface (aBCI). The majority of leading researches construct supervised learning models based on labeled datasets. Several datasets have been released, including different kinds of emotions while utilizing various forms of stimulus materials. However, they adopt discrete labeling methods, in which the EEG data collected during the same stimulus material are given a same label. These methods neglect the fact that emotion changes continuously, and mislabeled data possibly exist. The imprecision of discrete labels may hinder the progress of emotion classification in concerned works. Therefore, we develop an efficient system in this paper to support continuous labeling by giving each sample a unique label, and construct a continuously labeled EEG emotion dataset. Using our dataset with continuous labels, we demonstrate the superiority of continuous labeling in emotion classification through experiments on several classification models. We further utilize the continuous labels to identify the EEG features under induced and non-induced emotions in both our dataset and a public dataset. Our experimental results reveal the learnability and generality of the relation between the EEG features and their continuous labels.


Brain source localization based on fast fully adaptive approach.
In the electroencephalogram (EEG) or magnetoencephalogram (MEG) context, brain source localization (beamforming) methods often fail when the number of observations is small. This is particularly true when measuring evoked potentials, especially when the number of electrodes is large. Due to the nonstationarity of the EEG/MEG, an adaptive capability is desirable. Previous work has addressed these issues by reducing the adaptive degrees of freedom (DoFs). This paper develops and tests a new multistage adaptive processing for brain source localization that has been previously used for radar statistical signal processing application with uniform linear antenna array. This processing, referred to as the fast fully adaptive (FFA) approach, could significantly reduce the required sample support and computational complexity, while still processing all available DoFs. The performance improvement offered by the FFA approach in comparison to the fully adaptive minimum variance beamforming (MVB) with limited data is demonstrated by bootstrapping simulated data to evaluate the variability of the source location.


Positive Modulatory Interactions of NMDA Receptor GluN1/2B Ligand Binding Domains Attenuate Antagonists Activity.
N-methyl D-aspartate receptors (NMDAR) play crucial role in normal brain function and pathogenesis of neurodegenerative and psychiatric disorders. Functional tetra-heteromeric NMDAR contains two obligatory GluN1 subunits and two identical or different non-GluN1 subunits that include six different gene products; four GluN2 (A-D) and two GluN3 (A-B) subunits. The heterogeneity of subunit combination facilities the distinct function of NMDARs. All GluN subunits contain an extracellular N-terminal Domain (NTD) and ligand binding domain (LBD), transmembrane domain (TMD) and an intracellular C-terminal domain (CTD). Interaction between the GluN1 and co-assembling GluN2/3 subunits through the LBD has been proven crucial for defining receptor deactivation mechanisms that are unique for each combination of NMDAR. Modulating the LBD interactions has great therapeutic potential. In the present work, by amino acid point mutations and electrophysiology techniques, we have studied the role of LBD interactions in determining the effect of well-characterized pharmacological agents including agonists, competitive antagonists, and allosteric modulators. The results reveal that agonists (glycine and glutamate) potency was altered based on mutant amino acid sidechain chemistry and/or mutation site. Most antagonists inhibited mutant receptors with higher potency; interestingly, clinically used NMDAR channel blocker memantine was about three-fold more potent on mutated receptors (N521A, N521D, and K531A) than wild type receptors. These results provide novel insights on the clinical pharmacology of memantine, which is used for the treatment of mild to moderate Alzheimer's disease. In addition, these findings demonstrate the central role of LBD interactions that can be exploited to develop novel NMDAR based therapeutics.


Needs and priorities of young people with human immunodeficiency virus.
To ascertain the views of young people in the UK with human immunodeficiency virus (HIV) about their health care, and to compare these views with the perceptions of nurses involved in this sector and the current social policy response. Young people, aged 16 to 24 years, who have HIV and attend a specialist voluntary organisation and pre- and post-registration nurses attending an HIV care course were selected by convenience sampling. A cross-sectional survey was conducted by questionnaire. Hospital-based HIV clinics and services were the favoured source of care. There was consensus among the young people that care providers should be informative and approachable, and that care provision should include help to understand issues, such as pregnancy and contraception. Professionals involved in creating future social policy and commissioning services need to respond to young people's priorities and adapt to the patient's developing sexuality and the changing demographics of young people with HIV.


Risk scores predict atherosclerotic lesions in young people.
Atherosclerosis begins in childhood and progresses through young adulthood to form the lesions that cause coronary heart disease. These preclinical lesions are associated with coronary heart disease risk factors in young persons. The Pathobiological Determinants of Atherosclerosis in Youth study collected arteries and samples of blood and other tissues from persons aged 15 to 34 years who died of external causes and underwent autopsy in forensic laboratories. We measured the coronary heart disease risk factors and atherosclerotic lesions in the coronary arteries (CAs) (n = 1117) and the abdominal aorta (n = 1458). We developed risk scores, normalized so that a 1-unit increase was equivalent to a 1-year increase in age, to estimate the probability of advanced atherosclerotic lesions in the CAs and the abdominal aorta from age, sex, serum lipoprotein concentrations, smoking, hypertension, obesity, and hyperglycemia. Odds ratios for a 1-unit increase in the risk scores were 1.18 (95% confidence interval, 1.14-1.22) for the CAs and 1.29 (95% confidence interval, 1.23-1.35) for the abdominal aorta. These risk scores had good discrimination (c-indexes: 0.78 for the CAs and 0.84 for the abdominal aorta) and were calibrated. The presence of abdominal aortic lesions increased the likelihood of having CA lesions. Risk scores calculated from traditional coronary heart disease risk factors provide a tool for identifying young individuals with a high probability of having advanced atherosclerotic lesions.


Controversies regarding neonatal seizure recognition.
Recognition and classification of neonatal seizures remain problematic, particularly when clinicians rely only on clinical criteria. Physicians should utilize synchronized video-EEG-polygraphic recordings to correlate suspicious behaviors with electrographic seizures, to help limit misdiagnosis and overtreatment of either normal or abnormal nonepileptic behaviors. Since neonatal seizures, particularly status epilepticus, predict an increased risk for later epilepsy and other neurological sequelae, accurate diagnoses are needed for aggressive antiepileptic drug use in the NICU, as well as family counseling and anticipatory medical care after discharge. Neurophysiological documentation of neonatal seizures also must be integrated with an appreciation of pathophysiological mechanisms responsible for brain lesions that cause seizures. Maternal-fetal-placental diseases, as well as genetic vulnerabilities may be responsible for seizures long before diagnosis in the newborn period. Alternatively, the severity of seizures in neonates with perinatal asphyxia or other etiologies may be independently associated with brain injury. Seizures in the newborn are one of the few, neonatal neurological emergencies. While prompt diagnostic and therapeutic plans are necessary, unresolved medical issues continue to challenge the physician's evaluation of the newborn with suspected seizures (table I) [1-3]. Recognition of the seizure state remains the foremost challenge to overcome. Clinical and electroencephalographic manifestations of neonatal seizures vary dramatically from those of older children. This generalization is underscored by the brevity and subtlety of the clinical repertoire of the newborn's neurological examination. Environmental restrictions surrounding the sick infant in an intensive care setting, including confinement within an isolette, intubation and attachment to multiple catheters limit accessibility. Medication alters arousal and muscle tone, which further limit the clinician's ability to consider these clinical neurological signs as surrogate markers of underlying brain disorders. Brain injury from antepartum factors may later be expressed as neonatal seizures, as part of a postnatal, encephalopathic clinical picture which may only be precipitated by stress during the intrapartum and neonatal periods [4]. Alternatively, medical conditions during parturition or after birth may cause seizures, with coincident injury. For medication options to effectively treat seizures, new agents need to be designed for specific etiologies, timing of injury, and the unique cellular/molecular organization of the immature brain. This review addresses the challenges and controversies regarding neonatal seizure recognition in the context of current clinical practices. Experimental models of neonatal seizures elucidate the pathophysiological mechanisms and adverse consequences of seizures on brain development. Since 20% to 50% of children with neonatal seizures experience later epilepsy, diagnostic accuracy is essential [5, 6], particularly for the newborn who suffers a prolonged seizure state.


Factors determining resistance to beta-lactam combined with beta-lactamase inhibitors in Escherichia coli.
The influence of inoculum size, beta-lactamase hyperproduction (multicopy plasmid) and modifications in the outer membrane protein profile on the susceptibility of Escherichia coli to combinations of amoxycillin/clavulanate, amoxycillin/sulbactam, amoxycillin/tazobactam and piperacillin/tazobactam were studied. For all combinations the bacterial susceptibility was affected by factors determining an increase in beta-lactamase (inoculum size or hyperproduction). Clavulanic acid was the most efficient beta-lactamase inhibitor. The absence of the outer membrane proteins, OmpF and OmpC, did not significantly affect susceptibility to the combinations per se but when combined with the presence of beta-lactamase high MICs were observed. Seven out of eight amoxycillin/clavulanate resistant clinical isolates of E. coli had beta-lactamase hyperproduction and a decrease or absence of OmpF.


Cleft lip and palate surgery: 30 years follow-up.
Ten cleft lip and palate patients with complete unilateral (five patients) and bilateral (five patients) clefts were treated by a multidisciplinary team integrated by psychologists, surgeons, orthodontists, prosthodontists, pediatric dentists, and speech pathologists, to obtain ideal soft tissue and hard tissue continuity, facial symmetry, functional and esthetic dentitions, excellent nasal architecture, subtle, and hidden lip scars. No hypernasality and adequate social adaptation were found in the 30 years follow-up (20-30 years follow-up with an average of 25.5 years). The patients were treated in a pro-active fashion avoiding complications and related problems, executing the ideal surgical, dental, and speech therapy plan, based on a close follow-up over the entire period. Those patients treated at the right time required less surgeries and less salvaging maneuvers and presented complete dentitions with less dental prosthesis or dental implants and stable occlusions, than those who missed the ideal dental and surgical treatment opportunities. The focus of this article is the need of a close long-term follow-up to ensure an ideal patient's quality of life.


Ascidiidae Herdman, 1882 (Tunicata: Ascidiacea) on the Pacific coast of Panama.
The ascidian fauna of the Pacific coast of Panama is poorly known and only recently four species in the family Ascidiidae were reported on. Ascidia is the only known genus of Ascidiidae in Pacific Panama waters. In the present research, we describe a new species, Ascidia sideralis sp. nov., and we document the new occurrence of A. cf. gemmata and A. cf. liberata (both previously known to the West Pacific), A. archaia (a cosmopolitan species elsewhere in the Pacific), A. ceratodes (previously documented in the eastern N. Pacific), and A. sydneiensis (an Atlantic species on the east coast of Panama) in Pacific Panama waters. A tabular key for the identification of Ascidiidae on the American Pacific coast complements this study.


Dynamic Interactions in Synthetic Receptors: A Guest Exchange Saturation Transfer Study.
The accumulated knowledge regarding molecular architectures is based on established, reliable, and accessible analytical tools that provide robust structural and functional information on assemblies. However, both the dynamicity and low population of noncovalently interacting moieties within studied molecular systems limit the efficiency and accuracy of traditional methods. Herein, the use of a saturation transfer-based NMR approach to study the dynamic binding characteristics of an anion to a series of synthetic receptors derived from bambusuril macrocycles is demonstrated. The exchange rates of BF4 - are mediated by the side chains on the receptor (100 s-1 <kex <5000 s-1 ), which play a critical role in receptor-anion binding dynamics. The signal amplification obtained with this approach allows for the identification of different types of intermolecular interactions between the receptor and the anion, something that could not have been detected by techniques hitherto used to study molecular assemblies. These findings, which are supported by a computational molecular dynamic study, demonstrate the uniqueness and added value of this NMR method.


Self-administration of subcutaneous depot medroxyprogesterone acetate for contraception: feasibility and acceptability.
The objectives of the study were to assess feasibility, continuation rates and patient satisfaction with self-administration of subcutaneous depot medroxyprogesterone acetate (DMPA-SC). The study included 50 DMPA-seeking women between the ages of 18 and 49 years enrolled at two Florida Planned Parenthood health centers. Participants were taught self-injection during their initial study visit and, upon proficiency, self-injected one dose in clinic. Participants then injected a series of three more doses outside the health center over 9 months. Continuation rates, feasibility and acceptability were determined by analysis of four postinjection surveys. Continuation of DMPA-SC at injection 4 was 74% (95% confidence interval 62%-86%). Overall, survey responses from the three at-home injections indicated the method to be convenient (95%), easy (87%) and recommendable to others (94%). Twenty percent of injections were met with difficulty, most commonly cited as plunger resistance. No pregnancies occurred in study. Continuation was high with DMPA-SC self-injection. Participants reported injection to be easy and convenient and are likely to recommend self-administration to other women. Device issues are one potential deterrent.


Targeting the myeloid microenvironment in neuroblastoma.
Myeloid cells (granulocytes and monocytes/macrophages) play an important role in neuroblastoma. By inducing a complex immunosuppressive network, myeloid cells pose a challenge for the adaptive immune system to eliminate tumor cells, especially in high-risk neuroblastoma. This review first summarizes the pro- and anti-tumorigenic functions of myeloid cells, including granulocytes, monocytes, macrophages, and myeloid-derived suppressor cells (MDSC) during the development and progression of neuroblastoma. Secondly, we discuss how myeloid cells are engaged in the current treatment regimen and explore novel strategies to target these cells in neuroblastoma. These strategies include: (1) engaging myeloid cells as effector cells, (2) ablating myeloid cells or blocking the recruitment of myeloid cells to the tumor microenvironment and (3) reprogramming myeloid cells. Here we describe that despite their immunosuppressive traits, tumor-associated myeloid cells can still be engaged as effector cells, which is clear in anti-GD2 immunotherapy. However, their full potential is not yet reached, and myeloid cell engagement can be enhanced, for example by targeting the CD47/SIRPα axis. Though depletion of myeloid cells or blocking myeloid cell infiltration has been proven effective, this strategy also depletes possible effector cells for immunotherapy from the tumor microenvironment. Therefore, reprogramming of suppressive myeloid cells might be the optimal strategy, which reverses immunosuppressive traits, preserves myeloid cells as effectors of immunotherapy, and subsequently reactivates tumor-infiltrating T cells.


Lactate activates the mitochondrial electron transport chain independently of its metabolism.
Lactate has long been considered a cellular waste product. However, we found that as extracellular lactate accumulates, it also enters the mitochondrial matrix and stimulates mitochondrial electron transport chain (ETC) activity. The resulting increase in mitochondrial ATP synthesis suppresses glycolysis and increases the utilization of pyruvate and/or alternative respiratory substrates. The ability of lactate to increase oxidative phosphorylation does not depend on its metabolism. Both L- and D-lactate are effective at enhancing ETC activity and suppressing glycolysis. Furthermore, the selective induction of mitochondrial oxidative phosphorylation by unmetabolized D-lactate reversibly suppressed aerobic glycolysis in both cancer cell lines and proliferating primary cells in an ATP-dependent manner and enabled cell growth on respiratory-dependent bioenergetic substrates. In primary T cells, D-lactate enhanced cell proliferation and effector function. Together, these findings demonstrate that lactate is a critical regulator of the ability of mitochondrial oxidative phosphorylation to suppress glucose fermentation.


Patients' Expectations on Spinal Cord Stimulation for Failed Back Surgery Syndrome: A Qualitative Exploration.
Spinal cord stimulation (SCS) is an effective therapy to reduce pain in patients who suffer from failed back surgery syndrome (FBSS). In order to inform patients optimally prior to this therapy, knowing their expectations is crucial. Thirteen patients suffering from FBSS and scheduled for SCS were interviewed using a semistructured protocol. Patients were interviewed either at home or at their treating hospital. Data from these interviews were analyzed using directed content analysis. In addition to the qualitative interviews, an adjusted Brief Pain Inventory questionnaire was used to quantify expectations. The expectations of patients with regard to SCS could be subdivided into 13 categories, which could be grouped into 6 general themes: (1) physical well-being, (2) social well-being, (3) material well-being, (4) emotional well-being, (5) development and activity, and (6) constraints of the procedure of SCS. These findings confirm patients' expectations about the improvement of their quality of life by SCS for FBSS. This indicates that assessing pain relief is not enough to adequately evaluate the effects of SCS. The small diversity within the studied population and the lack of patient-to-patient education are 2 possible limitations of this study. To improve education for patients prior to SCS surgery and to evaluate the effects of SCS, a multidimensional approach needs to be implemented. Possible disadvantages of SCS need to be discussed prior to the treatment.


Oldest record of Trimeniaceae from the early Cretaceous of northern Japan.
Molecular phylogenetic analyses have identified Trimeniaceae, a monotypic family distributed only in Oceania, as among the earliest diverging families of extant angiosperms. Therefore, the fossils of this family are helpful to understand the earliest flowering plants. Paleobotanical information is also important to track the historical and geographical pathways to endemism of the Trimeniaceae. However, fossils of the family were previously unknown from the Early Cretaceous, the time when the angiosperm radiated. In this study, we report a seed from the late Albian (ca. 100 million years ago) of Japan representing the oldest known occurrence of Trimeniaceae and discuss the character evolution and biogeography of this family. A structurally preserved seed was collected from the early Late Albian Hikagenosawa Formation of the Yezo Group, which was deposited in palaeolatitudes of 35 to 40 degrees N. The seed has a multilayered stony exotesta with alveolate surface, parenchymatous mesotesta, and operculate inner integument, which are characteristic to extant trimeniaceous seeds. However, the seed differs from extant seeds, i.e., in its well-developed endosperm and absence of antiraphal vascular bundle. Thus, the seed would be a new genus and species of Trimeniaceae. The fossil seed indicates that seed coat characters were conserved for 100 million years or more in Trimeniaceae. It also suggests that the antiraphal vascular bundle and perispermy originated secondarily in Trimeniaceae as previously inferred from the phylogeny and character distribution in the extant basalmost angiosperms. The fossil seed provides the first evidence that Trimeniaceae was distributed in a midlatitude location of the Northern Hemisphere during the Early Cretaceous, when angiosperms radiated extensively, supporting a hypothesis that the extant austral distribution is relict.


Bexarotene Reduces Production of CCL22 From Tumor-Associated Macrophages in Cutaneous T-Cell Lymphoma.
Bexarotene is a third-generation retinoid X receptor-selective retinoid that has been approved for use in the treatment of both early and advanced cutaneous T-cell lymphoma (CTCL). Although bexarotene has been used for decades in the treatment of CTCL, little is known about the mechanisms underlying its anti-tumor effects in CTCL patients. This study therefore focused on the immunomodulatory effects of bexarotene in vivo using an EL4 mouse T-cell lymphoma model, followed by investigation in CTCL patients treated with bexarotene. Intraperitoneal injection of bexarotene significantly decreased expressions of CCL22, CXCL5, CXCL10, and p19 in the tumor microenvironment. Based on those results, we then evaluated serum levels of CCL22, CXCL5, and CXCL10 in 25 patients with CTCL, revealing that CCL22 was significantly increased in advanced CTCL compared with early CTCL. Next, we evaluated serum levels of CCL22, CXCL5, and CXCL10 in CTCL patients treated with bexarotene. Serum levels of CCL22 were significantly decreased in 80% of CTCL patients who responded to bexarotene therapy. In addition, immunofluorescence staining revealed CD163+ M2 macrophages as the main source of CCL22. Moreover, bexarotene decreased the production of CCL22 by M2 macrophages generated from monocytes in vitro. Our findings suggest that the clinical benefits of bexarotene are partially attributable to suppressive effects on the production of CCL22 by M2-polarized tumor-associated macrophages.


A multicentre cross-sectional descriptive study evaluating the cardiovascular risk profile of preoperatively identified patients with hypertension.
The prevalence of hypertension in adults in South Africa (SA) is 35%. Hypertension is the most important modifiable risk factor for cardiovascular (CV) and chronic kidney disease (CKD) in sub-Saharan Africa. However, 49% of people are unaware of their blood pressure status. Screening for hypertension prior to surgery provides a unique opportunity to diagnose and treat affected individuals. Furthermore, assessing overall CV risk identifies patients at highest risk for complications, and improves the utilisation of scarce resources. To evaluate the CV risk profile of hypertensive patients in the adult population of the Western Cape Province presenting for elective non-cardiac, non-obstetric surgery. This report documents the CV risk profile of patients recruited to the HASS-2 study (Hypertension and Surgery Study 2), which was undertaken in seven Western Cape hospitals. Patients were screened for hypertension and pharmacological treatment was initiated or adjusted in patients with stages 1 and 2 disease. Stage 3 patients were referred to a physician. In the present substudy, patients with stages 1 and 2 hypertension were assessed for associated CV risk factors, the presence of target organ damage, and documented CV or kidney disease; they received an overall risk stratification according to the 2018 European Society of Cardiology and the European Society of Hypertension Guidelines. Sixty-one patients with stage 1 and 12 with stage 2 hypertension were analysed. Established CV disease was present in 13.7% of the study population, and CKD (eGFR <60 mL/min) in 10.8%. Seventy-one percent of the study group had a raised body mass index, and 55.9% underlying metabolic syndrome. Prediabetes and diabetes were present in 16.1% and 14.5%, respectively. According to the 2018 European guidelines, 34.7% were at moderate, 33.3% at high and 16.7% at very high risk for a CV event in the following 10 years. The perioperative period is a critical time during which surgeons, nurses and anaesthetists can influence patients' CV risk of adverse events. This involves appropriate screening, education and treatment. In this study population, nearly 9 out of 10 elective surgical patients with stage 1 or 2 hypertension had CV risk factors placing them at moderate to very high risk. The simultaneous assessment of these additional CV risk parameters, in addition to diagnosis and management of hypertension, may further decrease the health and financial burden in resource-limited facilities in SA, and improve CV outcomes.


Nonmuscle myosin 2 regulates cortical stability during sprouting angiogenesis.
Among the three nonmuscle myosin 2 (NM2) paralogs, NM 2A and 2B, but not 2C, are detected in endothelial cells. To study the role of NM2 in vascular formation, we ablate NM2 in endothelial cells in mice. Ablating NM2A, but not NM2B, results in reduced blood vessel coverage and increased vascular branching in the developing mouse skin and coronary vasculature. NM2B becomes essential for vascular formation when NM2A expression is limited. Mice ablated for NM2B and one allele of NM2A develop vascular abnormalities similar to those in NM2A ablated mice. Using the embryoid body angiogenic sprouting assay in collagen gels reveals that NM2A is required for persistent angiogenic sprouting by stabilizing the endothelial cell cortex, and thereby preventing excessive branching and ensuring persistent migration of the endothelial sprouts. Mechanistically, NM2 promotes focal adhesion formation and cortical protrusion retraction during angiogenic sprouting. Further studies demonstrate the critical role of Rho kinase-activated NM2 signaling in the regulation of angiogenic sprouting in vitro and in vivo.


Young adults' experiences and satisfaction with the transfer of care.
Transition of care of adolescents with chronic conditions is a critical area for clinicians. Patient-reported outcomes may provide important information on the quality of services. This cohort study examines young adults' experiences and satisfaction with the transfer to adult care and explores associations with patient characteristics. Follow-up of 518 young adults (18-25 years) with various chronic conditions who completed a Web-based survey in 2006 (response rate, 52%). Outcome measures were the 18-item On Your Own Feet Transfer Experiences Scale (α = .93) and satisfaction with the transfer process (visual analog scale). Associations with demographic and health care-related variables, health-related quality of life, and self-management were explored with stepwise multivariate modeling, using past (2006-T0) and current (2012-T1) variables. Of the respondents, 315 (65%) had transferred, while 10% was still in pediatric care and 25% was not in treatment anymore. Twenty percent rated their transfer as unsatisfactory, 50% felt prepared at the time of transfer, and 24% had met their adult-centered provider in advance. Men were more positive about their experiences and rated satisfaction higher than did women. Patient-centeredness of the adult health-care provider was the most important determinant for experiences (β = .29). Higher self-efficacy at T1 was associated with more positive experiences but not with higher satisfaction. The latter was higher for those transferred within the same hospital (β = .28). The On Your Own Feet Transfer Experiences Scale is a useful instrument to measure transfer experiences. The importance young adults attach to good relations with their new provider stresses the necessity of early involvement of and good collaboration with adult care.


The comparison of various oral hygiene strategies in neuromuscularly disabled individuals.
This study aims to investigate the effect of various oral hygiene strategies on the symptoms of inflammation in neuromuscularly disabled patients and to define the optimum hygiene method. Fifty-nine neuromuscularly disabled participants, suffering from cerebral palsy, were randomly divided into five groups as follows: Group M: manual toothbrush (n=14), Group E: electrically powered toothbrush (n=9), Group MC: manual toothbrush and chlorhexidine gluconate (CHX) spray (n=13), Group EC: electrically powered toothbrush and CHX spray (n=9), and Group C: CHX spray (n=14). The oral hygiene applications were provided by the parents and staff. At baseline and after 21 days the plaque index (PI), the gingival index (GI), and bleeding on probing (BOP) were recorded. In intra-group comparisons of the pre- and post-application scores, in all groups the PI and GI scores and BOP percentages, except in Group C, were found significantly different (p<0.05). There were significant differences among the post-application scores, between Group M and Group E and between Group C and Group E in PI scores; between Group C and Group E the difference in GI scores were found statistically significant (p<0.05). Although all oral hygiene strategies reduced plaque and gingival inflammation, the results of our study suggested the electrically powered toothbrush could be more recommendable to neuromuscularly disabled people in these strategies, while the combined procedures appeared to be neither beneficial nor favorable.


A population-based clinical study of allergic and non-allergic asthma.
The aim of this study was to describe differences between allergic and non-allergic asthma in a large community-based sample of Danish adolescents and adults. A total of 1,186 subjects, 14 to 44 years of age, who in a screening questionnaire had reported a history of airway symptoms suggestive of asthma and/or allergy, or who were taking any medication for these conditions were clinically examined. All participants were interviewed about respiratory symptoms, and furthermore skin test reactivity, lung function, and airway responsiveness were measured. A total of 489 individuals had clinical asthma of whom 61% had allergic asthma, whereas 39% had non-allergic asthma. Subjects with non-allergic asthma were more likely to be females, OR = 2.24 (1.32-3.72), p = 0.003, and to have cough as the predominant symptom, OR = 1.96, (1.19-3.23), p = 0.008, but were less likely to have AHR, OR = 0.40, (0.24-0.66), p < 0.001, food allergy, OR = 0.28, (0.11-0.73), p = 0.009, and symptoms of rhinitis, OR = 0.08 (0.05-0.14) compared with subjects with allergic asthma. Subjects with non-allergic asthma had had persistent symptoms within the last 4 weeks more often than subjects with allergic asthma (68% vs. 53%), p = 0.001. Non-allergic asthma accounts for two in every five cases of asthma in adults and constitutes symptomatically, and in terms of lung function, a more severe form of disease than allergic asthma.


Early intervention in Alzheimer's disease: a health economic study of the effects of diagnostic timing.
Intervention and treatment in Alzheimer's disease dementia (AD-dementia) can be cost effective but the majority of patients are not diagnosed in a timely manner. Technology is now available that can enable the earlier detection of cognitive loss associated with incipient dementia, offering the potential for earlier intervention in the UK health care system. This study aimed to determine to what extent the timing of an intervention affects its cost-effectiveness. Using published data describing cognitive decline in the years prior to an AD diagnosis, we modelled the effects on healthcare costs and quality-adjusted life years of hypothetical symptomatic and disease-modifying interventions. Early and standard interventions were assumed to have equal clinical effects, but the early intervention could be applied up to eight years prior to standard diagnosis. A symptomatic treatment which immediately improved cognition by one MMSE point and reduced in efficacy over three years, would produce a maximum net benefit when applied at the earliest timepoint considered, i.e. eight years prior to standard diagnosis. In this scenario, the net benefit was reduced by around 17% for every year that intervention was delayed. In contrast, for a disease-modifying intervention which halted cognitive decline for one year, economic benefits would peak when treatment effects were applied two years prior to standard diagnosis. In these models, the maximum net benefit of the disease modifying intervention was fifteen times larger than that of the symptomatic treatment. Timeliness of intervention is likely to have an important impact on the cost-effectiveness of both current and future treatments. Healthcare policy should aim to optimise the timing of AD-dementia diagnosis, which is likely to necessitate detecting and treating patients several years prior to current clinical practice.


Outdoor allergens.
Outdoor allergens are an important part of the exposures that lead to allergic disease. Understanding the role of outdoor allergens requires a knowledge of the nature of outdoor allergen-bearing particles, the distributions of their source, and the nature of the aerosols (particle types, sizes, dynamics of concentrations). Primary sources for outdoor allergens include vascular plants (pollen, fern spores, soy dust), and fungi (spores, hyphae). Nonvascular plants, algae, and arthropods contribute small numbers of allergen-bearing particles. Particles are released from sources into the air by wind, rain, mechanical disturbance, or active discharge mechanisms. Once airborne, they follow the physical laws that apply to all airborne particles. Although some outdoor allergens penetrate indoor spaces, exposure occurs mostly outdoors. Even short-term peak outdoor exposures can be important in eliciting acute symptoms. Monitoring of airborne biological particles is usually by particle impaction and microscopic examination. Centrally located monitoring stations give regional-scale measurements for aeroallergen levels. Evidence for the role of outdoor allergens in allergic rhinitis is strong and is rapidly increasing for a role in asthma. Pollen and fungal spore exposures have both been implicated in acute exacerbations of asthma, and sensitivity to some fungal spores predicts the existence of asthma. Synergism and/or antagonism probably occurs with other outdoor air particles and gases. Control involves avoidance of exposure (staying indoors, preventing entry of outdoor aerosols) as well as immunotherapy, which is effective for pollen but of limited effect for spores. Outdoor allergens have been the subject of only limited studies with respect to the epidemiology of asthma. Much remains to be studied with respect to prevalence patterns, exposure and disease relationships, and control.


Sleep in chronic obstructive lung disease.
Profound transient nocturnal hypoxemia is common during REM sleep in "blue bloaters" with chronic obstructive lung disease, these patients having hypoxemia and CO2 retention when awake, when breathing air. These hypoxemic episodes appear to be due to a combination of reduced ventilation in REM sleep with a possible increase in the maldistribution of ventilation to perfusion within the alveoli at that time, and a reduction in functional residual capacity. The episodes are associated with exacerbations of pulmonary vasoconstriction, which can be reversed by oxygen therapy throughout sleep. Cardiac arrhythmias and alterations in ST segments are also found in these patients during sleep when breathing air. It is probable that the severity of hypoxemia in REM sleep can be predicted from knowledge of the arterial PO2 when breathing air when awake in patients with COPD. If so, expensive sleep studies are not essential to indicate the presence of hypoxemia in sleep in these patients, but such studies may be required in obese patients, in those who snore, or those who complain of headache following nocturnal oxygen therapy to demonstrate the presence of the overlap syndrome, in which obstructive sleep apnea is combined with chronic obstructive lung disease in the same patient. Nocturnal oxygen therapy may be dangerous in such patients with the overlap syndrome but appears to cause little rise in PCO2, in patients with COPD and REM-associated hypoxemia alone. Hypoxemia and sleep quality can probably be improved by oxygen therapy in "blue bloaters," and this treatment can also reverse pulmonary hypertension in REM sleep. The new ventilatory stimulant almitrine can also correct hypoxemia, without disturbing sleep quality, but the effects of this drug on pulmonary vasoconstriction during REM sleep are as yet unknown.


Can morels (Morchella sp.) induce a toxic neurological syndrome?
Several cases of morel poisoning associated with neurological symptoms have been reported. The objective of this study was to describe this new mushroom poisoning syndrome. Retrospective study of morel poisonings collected in the French Poison Control Centers from 1976 to 2006. Cases were classified as neurological syndrome (NS; tremor or dizziness/inebriation or unsteadiness/ataxia +/- associated with gastrointestinal symptoms) or isolated gastrointestinal syndrome. 146 patients presented gastrointestinal syndrome (median time to onset: 5 h) and 129 presented NS (12 h) after morel consumption. Gastrointestinal (67%) and other neurological symptoms were also present (mainly ocular/vision disorders: 26%, paresthesia: 7%, drowsiness/confusion: 6%, and muscle disorders: 6%). These patients more frequently ingested a large quantity of morels. Confusion with Gyromitra was ruled out. The NS is very different from the common gastrointestinal syndrome occurring after ingestion of poorly cooked morels and is not limited to a cerebellar syndrome.


Potent intratype neutralizing activity distinguishes human immunodeficiency virus type 2 (HIV-2) from HIV-1.
HIV-2 has a lower pathogenicity and transmission rate than HIV-1. Neutralizing antibodies could be contributing to these observations. Here we explored side by side the potency and breadth of intratype and intertype neutralizing activity (NAc) in plasma of 20 HIV-1-, 20 HIV-2-, and 11 dually HIV-1/2 (HIV-D)-seropositive individuals from Guinea-Bissau, West Africa. Panels of primary isolates, five HIV-1 and five HIV-2 isolates, were tested in a plaque reduction assay using U87.CD4-CCR5 cells as targets. Intratype NAc in HIV-2 plasma was found to be considerably more potent and also broader than intratype NAc in HIV-1 plasma. This indicates that HIV-2-infected individuals display potent type-specific neutralizing antibodies, whereas such strong type-specific antibodies are absent in HIV-1 infection. Furthermore, the potency of intratype NAc was positively associated with the viral load of HIV-1 but not HIV-2, suggesting that NAc in HIV-1 infection is more antigen stimulation dependent than in HIV-2 infection, where plasma viral loads typically are at least 10-fold lower than in HIV-1 infection. Intertype NAc of both HIV-1 and HIV-2 infections was, instead, of low potency. HIV-D subjects had NAc to HIV-2 with similar high potency as singly HIV-2-infected individuals, whereas neutralization of HIV-1 remained poor, indicating that the difference in NAc between HIV-1 and HIV-2 infections depends on the virus itself. We suggest that immunogenicity and/or antigenicity, meaning the neutralization phenotype, of HIV-2 is distinct from that of HIV-1 and that HIV-2 may display structures that favor triggering of potent neutralizing antibody responses.


A tipping point in refreezing accelerates mass loss of Greenland's glaciers and ice caps.
Melting of the Greenland ice sheet (GrIS) and its peripheral glaciers and ice caps (GICs) contributes about 43% to contemporary sea level rise. While patterns of GrIS mass loss are well studied, the spatial and temporal evolution of GICs mass loss and the acting processes have remained unclear. Here we use a novel, 1 km surface mass balance product, evaluated against in situ and remote sensing data, to identify 1997 (±5 years) as a tipping point for GICs mass balance. That year marks the onset of a rapid deterioration in the capacity of the GICs firn to refreeze meltwater. Consequently, GICs runoff increases 65% faster than meltwater production, tripling the post-1997 mass loss to 36±16 Gt-1, or ∼14% of the Greenland total. In sharp contrast, the extensive inland firn of the GrIS retains most of its refreezing capacity for now, buffering 22% of the increased meltwater production. This underlines the very different response of the GICs and GrIS to atmospheric warming.


Cost-effectiveness of cardiovascular imaging for stable coronary heart disease.
To assess the cost-effectiveness of management strategies for patients presenting with chest pain and suspected coronary heart disease (CHD): (1) cardiovascular magnetic resonance (CMR); (2) myocardial perfusion scintigraphy (MPS); and (3) UK National Institute for Health and Care Excellence (NICE) guideline-guided care. Using UK data for 1202 patients from the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease 2 trial, we conducted an economic evaluation to assess the cost-effectiveness of CMR, MPS and NICE guidelines. Health outcomes were expressed as quality-adjusted life-years (QALYs), and costs reflected UK pound sterling in 2016-2017. Cost-effectiveness results were presented as incremental cost-effectiveness ratios and incremental net health benefits overall and for low, medium and high pretest likelihood of CHD subgroups. CMR had the highest estimated QALY gain overall (2.21 (95% credible interval 2.15, 2.26) compared with 2.07 (1.92, 2.20) for NICE and 2.11 (2.01, 2.22) for MPS) and incurred comparable costs (overall £1625 (£1431, £1824) compared with £1753 (£1473, £2032) for NICE and £1768 (£1572, £1989) for MPS). Overall, CMR was the cost-effective strategy, being the dominant strategy (more effective, less costly) with incremental net health benefits per patient of 0.146 QALYs (-0.18, 0.406) compared with NICE guidelines at a cost-effectiveness threshold of £15 000 per QALY (93% probability of cost-effectiveness). Results were similar in the pretest likelihood subgroups. CMR-guided care is cost-effective overall and across all pretest likelihood subgroups, compared with MPS and NICE guidelines.


The complex HLA-E-nonapeptide in Behçet disease.
The knowledge of the aetiology of Behçet disease (BD), an immune-mediated vasculitis, is limited. HLA-B, mainly HLA-B51, and HLA-A molecules are associated with disease, but the ultimate cause of this association remains obscure. There is evidence that NK cells participate in the etiopathology of BD. NK cells have activator and inhibitor surface receptors, like the KIR and the NKG2 families. Classical HLA-class I molecules (A, B and C) are keys in the activity control of the NK because they are KIR ligands. Most NKG2 receptors bind HLA-E, which presents only nonapeptides derived from the signal peptide of other class-I molecules. This study investigates the contribution of the pair HLA-E and ligand, nonapeptide derived from the 3-11 sequence of the signal peptides of class I classical molecules, to the susceptibility to BD. We analyzed the frequency of the HLA-derivated nonapeptide forms in 466 BD patients and 444 controls and an HLA-E functional dimorphism in a subgroup of patients and controls. Results: In B51 negative patients, the frequency of VMAPRTLLL was lower (70.4% versus 80.0% in controls; P=0.006, Pc=0.04, OR=0.60, 95%CI 0.41-0.86), and the frequency of VMAPRTLVL was higher (81.6% versus 71.4% in controls; P=0.004, Pc=0.03, OR=1.78, 95%CI 1.20-2.63). In homozygosity, VMAPRTLLL is protective, and VMAPRTLVL confers risk. The heterozygous condition is neutral. There were no significant differences in the distribution of the HLA-E dimorphism. Our results explain the association of BD with diverse HLA-A molecules, reinforce the hypothesis of the involvement of the NK cells in the disease and do not suggest a significant contribution of the HLA-E polymorphism to disease susceptibility.


XMU-MP-1 induces growth arrest in a model human mini-organ and antagonises cell cycle-dependent paclitaxel cytotoxicity.
XMU-MP-1 is an inhibitor of the Hippo pathway kinases MST1/2 and has been shown to promote the downstream activation of the pro-proliferative, pro-regenerative and anti-apoptotic transcriptional regulator YAP1. We tested whether XMU-MP-1 can activate YAP1 in a model human mini-organ, namely the hair follicle, to determine whether it can be pharmacologically exploited to promote regeneration in the hair follicle as a novel strategy to treat pathological hair loss disorders. XMU-MP-1 treatment inhibited MOB1 phosphorylation but did not increase active YAP1 in the hair follicle. Rather than promote proliferation, XMU-MP-1 serendipitously decreased the number of Ki-67+, EdU+ and phospho histone H3+ hair matrix keratinocytes and antagonised the cytotoxic effects of paclitaxel. XMU-MP-1 perturbs epithelial cell cycle progression in a model human mini-organ. This may arise as an off-target effect, especially when XMU-MP-1 has been described to strongly inhibit 21 additional kinases beyond MST1/2. Therefore, whilst these effects may be dependent on tissue context, researchers should exercise caution when interpreting the effects of XMU-MP-1, especially in tissues with actively proliferating cell populations.


[Urinary trehalase activity during normal pregnancy: tubular dysfunctions].
By measuring urinary trehalase which is localized in renal brush borders, we examined whether tubular dysfunction occurred or not during and after normal pregnancy. Urinary trehalase activity in 1st trimester, 2nd trimester, and 3rd trimester was increased significantly as compared with the controls (=non-pregnant women) (p less than 0.01). After delivery, urinary trehalase activity in puerperal 5th day was decreased to the level of the 1st trimester, and the activity of puerperal on the 30th day was in the range of the control value. Urinary beta 2-microglobulin (beta 2-MG) in the 1st trimester and 2nd trimester was not increased significantly as compared with the controls. Urinary beta 2-MG in the 3rd trimester, however, was significantly higher than that in the controls. After delivery, the value for beta 2-MG in puerperal on the 5th day was not decreased significantly as compared with the 3rd trimester, and in puerperal on the 30th day, urinary beta 2-MG was decreased to the control value. Urinary N-acetyl-beta-D-glucosaminidase (NAG) in the 3rd trimester was significantly higher than that in the controls (p less than 0.01) and in the 1st trimester (p less than 0.02). After delivery, a significant decrease was observed in urinary NAG between 5th puerperal day and the 3rd trimester. Moreover, urinary NAG on the 30th puerperal day was the level of the controls. On the basis of these results, it is inferred that tubular dysfunction is observed during normal pregnancy.


Dietary protein intake and bone health.
Considerable attention has recently focused on dietary protein's role in the mature skeleton. The aim was to conduct a systematic review evaluating the effects of dietary protein intake alone on bone health measures in adults (Bone Mineral Density (BMD) and bone biomarkers. Searches across 3 databases were conducted through February 2019 including randomized controlled trials (RCT's) and prospective cohort studies examining the effects of ''high versus low'' protein intake. Studies in various populations are currently limited, varying doses and dietary compositions were used or prescribed, respectively, and there was medium risk of bias among the RCTs and the cohort studies examined. Moderate evidence suggested that higher protein intake may have protective effect on lumbar spine (LS) bone mineral density (BMD) compared with lower protein intake but no effect on total hip (TH), femoral neck (FN), or total body BMD or bone biomarkers. Current evidence shows no adv erse effects of higher protein intakes. Although there were positive trends on BMD at most bone cites, only the LS showed moderate evidence to support benefits of higher protein intake. Studies were heterogeneous. High-quality, long-term studies are needed to clarify dietary protein's role in bone health.


Reconstruction of skin cancer defects of the auricle.
This article reviews the results of reconstruction of surface defects of the auricle after removal of skin cancer, and discusses the results of the delayed reconstruction method of care and modalities of treatment. Fifty-four patients with 62 defects involving various locations on the auricle were treated. Management included direct closure, secondary epithelization, full thickness skin grafts, local flaps using direct advancement, and rotational advancement flaps using one or more stages. Nine defects were treated by direct closure with adjacent tissue, 12 defects healed by secondary epithelization, and 13 patients were treated with a full thickness skin graft. Twenty-eight defects were reconstructed with local flaps, which included the direct advancement, rotational flaps, transposition, and subcutaneous island flaps. No infections occurred. Many options are available for reconstruction of auricular defects which yield acceptable results. Factors to consider before choosing a reconstructive format include size, location, and depth of the defect, patient medical history, smoking, and esthetic concerns. This review exposed that patients easily accept the "delayed" method of reconstruction. Delaying allows the surgeon time to research options for care and allows the patient choices of secondary epithelization and significantly reduced costs of care.


Motivational Interviewing Case Management (MICM) for Persons on Probation or Parole Entering Sober Living Houses.
The failure of incarceration as a response to drug offenses has resulted in new policies supporting community-based alternatives. One challenge has been finding appropriate housing for persons on probation and parole. Sober living houses (SLHs) are alcohol- and drug-free living environments that are increasingly being used as housing options for these individuals. The current study examined 6- and 12-month outcomes for 330 persons on probation or parole who entered 49 SLHs. Residents in 22 houses (n = 149 individuals) were randomly assigned to receive a "Motivational Interviewing Case Management" (MICM) intervention and residents in the other 27 houses (n = 181 individuals) received SLH residency as usual. At 6-and 12-month follow-up, both study conditions showed significant improvement relative to baseline on substance abuse, criminal justice, HIV risk, and employment outcomes. For persons who attended at least one MICM session, there were better criminal justice outcomes compared to the SLH as usual group.


Targeted silencing of SOX2 by an artificial transcription factor showed antitumor effect in lung and esophageal squamous cell carcinoma.
SOX2 is a transcription factor essential for early mammalian development and for the maintenance of stem cells. Recently, SOX2 was identified as a lineage specific oncogene, recurrently amplified and activated in lung and esophageal squamous cell carcinoma (SCC). In this study, we have developed a zinc finger-based artificial transcription factor (ATF) to selectively suppress SOX2 expression in cancer cells and termed the system ATF/SOX2. We engineered the ATF using six zinc finger arrays designed to target a 19 bp site in the SOX2 distal promoter and a KOX transcriptional repressor domain. A recombinant adenoviral vector Ad-ATF/SOX2 that expresses ATF/SOX2 suppressed SOX2 at the mRNA and protein levels in lung and esophageal SCC cells expressing SOX2. In these kinds of cells, Ad-ATF/SOX2 decreased cell proliferation and colony formation more effectively than the recombinant adenoviral vector Ad-shSOX2, which expresses SOX2 short hairpin RNA (shSOX2). Ad-ATF/SOX2 induced the cell cycle inhibitor CDKN1A more strongly than Ad-shSOX2. Importantly, the ATF did not suppress the cell viability of normal human cells. Moreover, Ad-ATF/SOX2 effectively inhibited tumor growth in a lung SCC xenograft mouse model. These results indicate that ATF/SOX2 would lead to the development of an effective molecular-targeted therapy for lung and esophageal SCC.


Testing the Pragmatic Effectiveness of a Consumer-Based Mindfulness Mobile App in the Workplace: Randomized Controlled Trial.
Mental health and sleep problems are prevalent in the workforce, corresponding to costly impairment in productivity and increased health care use. Digital mindfulness interventions are efficacious in improving sleep and mental health in the workplace; however, evidence supporting their pragmatic utility, potential for improving productivity, and ability to reduce employer costs is limited. This pragmatic, cluster randomized controlled trial aimed to evaluate the experimental effects of implementing a commercially available mindfulness app-Calm-in employees of a large, multisite employer in the United States. Outcomes included mental health (depression, anxiety, and stress), sleep (insomnia and daytime sleepiness), resilience, productivity impairment (absenteeism, presenteeism, overall work impairment, and non-work activity impairment), and health care use (medical visit frequency). Employees were randomized at the work site to receive either the Calm app intervention or waitlist control. Participants in the Calm intervention group were instructed to use the Calm app for 10 minutes per day for 8 weeks; individuals with elevated baseline insomnia symptoms could opt-in to 6 weeks of sleep coaching. All outcomes were assessed every 2 weeks, with the exception of medical visits (weeks 4 and 8 only). Effects of the Calm intervention on outcomes were evaluated via mixed effects modeling, controlling for relevant baseline characteristics, with fixed effects of the intervention on outcomes assessed at weeks 2, 4, 6, and 8. Models were analyzed via complete-case and intent-to-treat analyses. A total of 1029 employees enrolled (n=585 in the Calm intervention group, including 101 who opted-in to sleep coaching, and n=444 in waitlist control). Of them, 192 (n=88 for the Calm intervention group and n=104 for waitlist) completed all 5 assessments. In the complete-case analysis at week 8, employees at sites randomized to the Calm intervention group experienced significant improvements in depression (P=.02), anxiety (P=.01), stress (P<.001), insomnia (P<.001), sleepiness (P<.001), resilience (P=.02), presenteeism (P=.01), overall work impairment (P=.004), and nonwork impairment (P<.001), and reduced medical care visit frequency (P<.001) and productivity impairment costs (P=.01), relative to the waitlist control. In the intent-to-treat analysis at week 8, significant benefits of the intervention were observed for depression (P=.046), anxiety (P=.01), insomnia (P<.001), sleepiness (P<.001), nonwork impairment (P=.04), and medical visit frequency (P<.001). The results suggest that the Calm app is an effective workplace intervention for improving mental health, sleep, resilience, and productivity and for reducing medical visits and costs owing to work impairment. Future studies should identify optimal implementation strategies that maximize employee uptake and large-scale implementation success across diverse, geographically dispersed employers. ClinicalTrials.gov NCT05120310; https://clinicaltrials.gov/ct2/show/NCT05120310.


Innate immune responses in oral mucosa.
It is speculated that more than 400 bacterial species reside in the oral cavity. Some cause inflammation (e.g. periodontitis), understanding of which requires examination of innate immunity in the oral cavity. Oral mucosal cells such as epithelial cells are thought to act as a physical barrier against the invasion of pathogenic organisms, but they have an ability to produce inflammatory cytokines and express adhesion molecules. Oral epithelial cells are refractory to many bacterial components although they express Toll-like receptors/MyD88, and acquire responsiveness after priming with IFN-gamma. When the cells are stimulated with lipopolysaccharide (LPS) and neutrophil protease (PR3) after IFN-gamma priming, the cells produce bio-active IL-18, which is critical to Th1 and Th2 responses. PR3 itself is able to activate the cells through G protein-coupled protease-activated receptor-2 on the cell surface. These results suggest that innate immune responses of oral epithelial cells to bacterial components are regulated in the inflammatory process. In addition, saliva contains abundant bio-active CD14 from salivary glands in a soluble form, although LPS-binding protein was below detectable levels, suggesting that saliva CD14 is important for the maintenance of oral health.


Human Embryonic Stem Cell-Derived Immature Midbrain Dopaminergic Neurons Transplanted in Parkinsonian Monkeys.
Human embryonic stem cells (hESCs) differentiate into specialized cells, including midbrain dopaminergic neurons (DANs), and Non-human primates (NHPs) injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine develop some alterations observed in Parkinson's disease (PD) patients. Here, we obtained well-characterized DANs from hESCs and transplanted them into two parkinsonian monkeys to assess their behavioral and imaging changes. DANs from hESCs expressed dopaminergic markers, generated action potentials, and released dopamine (DA) in vitro. These neurons were transplanted bilaterally into the putamen of parkinsonian NHPs, and using magnetic resonance imaging techniques, we calculated the fractional anisotropy (FA) and mean diffusivity (MD), both employed for the first time for these purposes, to detect in vivo axonal and cellular density changes in the brain. Likewise, positron-emission tomography scans were performed to evaluate grafted DANs. Histological analyses identified grafted DANs, which were quantified stereologically. After grafting, animals showed signs of partially improved motor behavior in some of the HALLWAY motor tasks. Improvement in motor evaluations was inversely correlated with increases in bilateral FA. MD did not correlate with behavior but presented a negative correlation with FA. We also found higher 11C-DTBZ binding in positron-emission tomography scans associated with grafts. Higher DA levels measured by microdialysis after stimulation with a high-potassium solution or amphetamine were present in grafted animals after ten months, which has not been previously reported. Postmortem analysis of NHP brains showed that transplanted DANs survived in the putamen long-term, without developing tumors, in immunosuppressed animals. Although these results need to be confirmed with larger groups of NHPs, our molecular, behavioral, biochemical, and imaging findings support the integration and survival of human DANs in this pre-clinical PD model.


KIT-positive gastrointestinal stromal tumor in a 22-year-old male chimpanzee (Pan troglodites).
Gastrointestinal stromal tumors (GIST), KIT-positive and KIT signaling driven or platelet-derived growth factor receptor alpha (PDGFRA) signaling driven mesenchymal tumors, are poorly known in nonhuman primates. Availability of KIT- and PDGFRA-inhibitor drug imatinib mesylate has greatly raised the interest for these tumors. At necropsy of a 22-year-old male chimpanzee, a round, firm 2-cm intramural tumor was incidentally found in the midbody of the stomach and diagnosed as a GIST. Histologically, the mass was composed of spindle to polygonal epithelioid cells arranged in short to intermediate-length, interlacing streams, bundles, and nodular whorls often separated by hyalinized eosinophilic matrix. The mitotic rate was a maximum 1/50 high-power field. Immunohistochemically, the tumor cells were diffusely positive for KIT and CD34, focally positive for alpha-smooth muscle actin, and negative for muscle specific actin, desmin, S-100 protein, synaptophysin, and glial fibrillary acidic protein. Because the majority of human GISTs have gain-of-function KIT or PDGFRA mutations, genomic sequences of KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 from this chimpanzee GIST were polymerase chain reaction amplified and sequenced. However, no mutation was identified in the analyzed "mutational hot spots." This study is the first extensive histomorphologic, immunohistochemical, and molecular genetic analysis of a chimpanzee GIST. More cases of nonhuman primate GISTs should be analyzed to discover the clinicopathologic spectrum of GISTs in these species.


[Study of specific interactions of amino acid esters with the synthetic polynucleotides poly(A) x 2 poly(U), poly(A) x poly(U) and poly(A) by thermal denaturation].
The interactions of amino acid esters with poly(A)x2poly(U) and poly(A)xpoly(U) have been investigated by means of thermal denaturation of these polynucleotides. The esters under consideration raised the melting point, revealing the preferable binding to helical polynucleotide structures. The melting point shifts demonstrate the following sequence of the stabilities of these complexes: Arg greater than Lys much greater than His greater than Met greater than Ser greater than Gly. The same stability order is observed when studying the polynucleotide renaturation in the presence of esters. This order coincides with that previously obtained for the nucleotide base--amino acid ester complexes excepting basic amino acid esters. The ester interactions with poly(A) and poly(U) also reveal the specificity of monomer--monomer interactions. Some dynamic contributions into the studied specificity are also discussed.


Defining the next generation journal: The NLM-Elsevier interactive publications experiment.
A unique collaborative project to identify interactive enhancements to conventional-print journal articles, and to evaluate their contribution to readers' learning and satisfaction. It was hypothesized that (a) the enhanced article would yield more knowledge acquisition than the original article; (b) the interactivity aspects of the enhanced article would measurably contribute to the acquisition of knowledge; and (c) the enhancements to the original article would increase reader acceptance. Fifteen SNMA medical students, assumed to have a greater generational familiarity and comfort level with interactive electronic media, reviewed 12 articles published in three Elsevier clinical and basic science journals. They used the Student National Medical Association's asynchronous online discussion forum over a four month period to suggest desired enhancements to improve learning. "Prognostic Factors in Stage T1 Bladder Cancer", published in the journal Urology was selected by the investigators as presenting the best opportunity to incorporate many of the students' suggested interactive and presentational enhancements in the limited timeframe available prior to the established test date. Educational, statistical, and medical consultants assisted in designing a test protocol in which 51 second to fourth year medical students were randomly assigned to experimental and control conditions, and were administered either the original or enhanced interactive version of the article on individual computer workstations. Test subjects consisted of 23 participants in the control group (8 males, 15 females) and 28 participants in the experimental group (9 males, 19 females). All subjects completed pre- and post-test instruments which measured their knowledge gain on 30 true-false and multiple-choice questions, along with 7 Likert-type questions measuring acceptance of the articles' format. Time to completion was recorded with the experimental group taking 22 min on average compared to 18 min for the controls; pre- and post-test times were 6 and 7 min, respectively. Statistical comparisons were based on change scores using either the Student t-test or the Two Way Analysis of Variance or Covariance. Significance was set at α = 0.05 or better. on the dependent measure of knowledge acquisition showed no difference overall on the 30 questions, but learning gain was statistically significant for the subset of 10 questions that measured gain on content that was accessible by the user-invoked interactive features of the enhanced article. Further analyses revealed significant interactions by student year and gender. Second year students (11 in the control group, 8 in the experimental group) were the best performers in terms of knowledge acquisition from both articles. The female medical students received a larger learning gain from journal enhancements and interactivity components than their male counterparts. Acceptance overall was greater for the experimental group who rated the experience more favorably than the controls. Failure to consider human factors such as gender and learning style may obscure underlying differences and their impact on the interactive aspects of scientific publications. Preliminary findings suggest the need for further study to include a heavier focus on interactivity apart from presentational enhancements; a more rigorous treatment of time as a specific variable; and an expanded experimental design that evaluates acquisition, understanding, integration and acceptance as dependent measures.


How is self-regulated learning documented in e-portfolios of trainees? A content analysis.
It is assumed that portfolios contribute to self-regulated learning (SRL). Presence of these SRL processes within the documentation kept in portfolios is presupposed in common educational practices, such as the assessment of reflective entries. However, questions can be asked considering the presence of SRL within portfolios. The aim of this study was to gain insight into the documentation of SRL processes within the electronic (e)-portfolio content of medical trainees. SRL consists of numerous processes, for this study the focus was on self-assessment via reflection and feedback, goal-setting and planning, and monitoring, as these are the processes that health professions education research mentions to be supported by portfolios. A database containing 1022 anonymous e-portfolios from General Practitioner trainees was used to provide descriptive statistics of the various available e-portfolio forms. This was followed by a quantitative content analysis of 90 e-portfolios, for which, a codebook was constructed to rate the documentation of the included SRL processes. The numbers of forms in the e-portfolios varied to a great extent. Content analysis showed a limited documentation of reflective entries, and available entries mainly described events and experiences without explanations and context. Feedback was generally limited to comments on what went well and lacked specificity, context and suggestions for future action. Learning goals and plans were short of specificity, but did contain challenging topics and different goals were compatible with each other. 75% of the e-portfolios showed (limited) signs of monitoring. The e-portfolio content showed limited documentation of SRL processes. As documentation of SRL requires time and asks for a high level of introspection and writing skills, one cannot expect documentation of SRL processes to appear in e-portfolio content without efforts.


Accuracy and repeatability of 3 apex locators in locating root canal perforations: an ex vivo study.
This study was an ex vivo evaluation of the accuracy and repeatability of 3 electronic apex locators (EALs) in locating simulated root canal perforations. Thirty-five human teeth were used. Perforations were placed 5 mm from the apex of each specimen. A #15 K-file was attached to a micrometer, and the specimens were fixed in a mounting model. The EALs were connected to the files, and electronic measurements of the simulated perforations were obtained. This procedure was repeated, the files were cemented in place, and x-rays were obtained to evaluate the distances between the measurement files and the simulated perforations. The obtained results were compared with the corresponding control lengths. Three investigators evaluated the distance of the file position in relation to the perforation for each specimen. The 3 investigators reached consensus regarding these measurements. Statistical analyses of the results revealed that the EAL reliabilities in the exact detections of the root canal perforations were 97.1% for the Mini Apex Locator, 100% for the Root SW, and 91.4% for the Root ZX II. Analysis of variance revealed that the accuracies of the 3 devices were not different (P > .05). The results also indicated high levels of repeatability for each of the 3 EALs (intraclass correlation coefficients: 0998, 0.999, and 0.999 for the Mini Apex Locator, Root SW, and Root ZX II, respectively). It was concluded that each of these 3 EALs provided excellent ex vivo accuracy in locating root perforations and that all tested devices possess excellent ex vivo repeatability.


Histopathology associated with angiostrongylosis in Akodon species (Rodentia: Sigmodontinae) from Sierra de la Ventana, Buenos Aires, Argentina.
Angiostrongylus is a metastrongylid nematode genus that includes species found in carnivores, rodents, and occasionally primates (including humans). About 100 species of wild sigmodontine rodents occur in Argentina, 16 of which are species of Akodon. The lungs of Akodon azarae and Akodon dolores from Sierra de la Ventana, Buenos Aires, Argentina, were examined, and 2 of 10 A. dolores specimens were positive for angiostrongylosis, showing macroscopic lesions of verminous pneumonia. Adults found were identified as Angiostrongylus morerai. Histopathology of the lungs revealed multiple nodules in the interstitium, alveoli, and vessels, resulting in interstitial fibrosis and the destruction of small capillaries and arterioles. Since extensive pathology in the lung was noted here from only 2 adults, it is probable that heavier infections may cause mortality in their hosts. This is the first record of this nematode species from A. dolores , expanding its geographic distribution to the southwest of Buenos Aires Province, and the first description of the histopathology of larval angiostrongylosis in a wild rodent from South America.


In Vivo Imaging of Tumor Metabolism and Acidosis by Combining PET and MRI-CEST pH Imaging.
The vast majority of cancers exhibit increased glucose uptake and glycolysis regardless of oxygen availability. This metabolic shift leads to an enhanced production of lactic acid that decreases extracellular pH (pHe), a hallmark of the tumor microenvironment. In this way, dysregulated tumor pHe and upregulated glucose metabolism are linked tightly and their relative assessment may be useful to gain understanding of the underlying biology. Here we investigated noninvasively the in vivo correlation between tumor 18F-FDG uptake and extracellular pH values in a murine model of HER2+ breast cancer. Tumor extracellular pH and perfusion were assessed by acquiring MRI-CEST (chemical exchange saturation transfer) images on a 3T scanner after intravenous administration of a pH-responsive contrast agent (iopamidol). Static PET images were recorded immediately after MRI acquisitions to quantify the extent of 18F-FDG uptake. We demonstrated the occurrence of tumor pHe changes that report on acidification of the interstitial fluid caused by an accelerated glycolysis. Combined PET and MRI-CEST images reported complementary spatial information of the altered glucose metabolism. Notably, a significant inverse correlation was found between extracellular tumor pH and 18F-FDG uptake, as a high 18F-FDG uptake corresponds to lower extracellular pH values. These results show how merging the information from 18F-FDG-uptake and extracellular pH measurements can improve characterization of the tumor microenvironment. Cancer Res; 76(22); 6463-70. ©2016 AACR.


Rosmarinic acid inhibits TCR-induced T cell activation and proliferation in an Lck-dependent manner.
Lck is a T cell-restricted Src family protein tyrosine kinase that plays pivotal roles in TCR-mediated signaling. We aimed to identify novel agents that could disrupt the molecular interaction of the Src homology 2-domain of Lck (Lck SH2) with its binding partners, with the expectation that this would impair TCR signaling and generate immunosuppression. Large-scale screening of plant extracts indicated that rosmarinic acid (RosA) in extracts of Prunella vulgaris consistently inhibits the interaction between Lck SH2 and a peptide containing its consensus binding sequence (pYEEI). The inhibitory effect of RosA was specific for SH2 domains of Src family protein tyrosine kinase. RosA inhibited TCR-induced-Ca(2+) mobilization and IL-2 promoter activation but not phorbol 12-myristate 13-acetate/ionomycin-induced IL-2 promoter activation, indicating its point of inhibition at the membrane proximal site of TCR signaling. Furthermore, RosA inhibited TCR-induced splenocyte proliferation as well as one-way MLR at an IC(50) of 25-50 microM and inhibited cytokine expression such as IL-2 and IFN-gamma. Here, we first report RosA as an inhibitor of TCR-signaling and subsequent T cell proliferation.


Clinical experience with a new norgestimate-containing oral contraceptive.
Research in the area of oral contraception currently focuses on the development of selective progestogens that combine targeted progestational and antiovulatory activity with a minimal potential for androgenicity. The present dual-center study was conducted to investigate the efficacy, tolerability, and safety of a new monophasic oral contraceptive (OC) containing 250 micrograms norgestimate in combination with 35 micrograms ethinyl estradiol (Ortho-Cyclen or Cilest). Ninety-seven healthy women of childbearing age participated in the study: 37 received the new norgestimate/ethinyl estradiol combination OC as primary therapy and 31 were switched over from other OCs. The norgestimate/ethinyl estradiol formulation was well tolerated and was associated with excellent cycle control. After six cycles of use, there were no statistically significant differences in the incidence of spotting or breakthrough bleeding compared with baseline, nor were there any significant changes in the incidence of headache, nausea, or mastalgia. Body weights remained constant for the duration of the study, as did systolic and diastolic blood pressures. Of particular note was the absence of any statistically significant alterations in metabolic parameters, including blood glucose or lipoprotein levels. These findings are consistent with the results of several other European studies and indicate that the norgestimate/ethinyl estradiol combination OC combines superior cycle control with minimal risk of androgenic side effects.