Sequence diversity of Pseudomonas aeruginosa: impact on population structure and genome evolution.
Comparative sequencing of Pseudomonas aeruginosa genes oriC, citS, ampC, oprI, fliC, and pilA in 19 environmental and clinical isolates revealed the sequence diversity to be about 1 order of magnitude lower than in comparable housekeeping genes of Salmonella. In contrast to the low nucleotide substitution rate, the frequency of recombination among different P. aeruginosa genotypes was high, leading to the random association of alleles. The P. aeruginosa population consists of equivalent genotypes that form a net-like population structure. However, each genotype represents a cluster of closely related strains which retain their sequence signature in the conserved gene pool and carry a set of genotype-specific DNA blocks. The codon adaptation index, a quantitative measure of synonymous codon bias of genes, was found to be consistently high in the P. aeruginosa genome irrespective of the metabolic category and the abundance of the encoded gene product. Such uniformly high codon adaptation indices of 0.55 to 0.85 fit the ubiquitous lifestyle of P. aeruginosa.


Vibrational analysis of mononitrosyl complexes in hemerythrin and flavodiiron proteins: relevance to detoxifying NO reductase.
Flavodiiron proteins (FDPs) play important roles in the microbial nitrosative stress response in low-oxygen environments by reductively scavenging nitric oxide (NO). Recently, we showed that FMN-free diferrous FDP from Thermotoga maritima exposed to 1 equiv NO forms a stable diiron-mononitrosyl complex (deflavo-FDP(NO)) that can react further with NO to form N(2)O [Hayashi, T.; Caranto, J. D.; Wampler, D. A; Kurtz, D. M., Jr.; Moënne-Loccoz, P. Biochemistry 2010, 49, 7040-7049]. Here we report resonance Raman and low-temperature photolysis FTIR data that better define the structure of this diiron-mononitrosyl complex. We first validate this approach using the stable diiron-mononitrosyl complex of hemerythrin, Hr(NO), for which we observe a ν(NO) at 1658 cm(-1), the lowest ν(NO) ever reported for a nonheme {FeNO}(7) species. Both deflavo-FDP(NO) and the mononitrosyl adduct of the flavinated FPD (FDP(NO)) show ν(NO) at 1681 cm(-1), which is also unusually low. These results indicate that, in Hr(NO) and FDP(NO), the coordinated NO is exceptionally electron rich, more closely approaching the Fe(III)(NO(-)) resonance structure. In the case of Hr(NO), this polarization may be promoted by steric enforcement of an unusually small FeNO angle, while in FDP(NO), the Fe(III)(NO(-)) structure may be due to a semibridging electrostatic interaction with the second Fe(II) ion. In Hr(NO), accessibility and steric constraints prevent further reaction of the diiron-mononitrosyl complex with NO, whereas in FDP(NO) the increased nucleophilicity of the nitrosyl group may promote attack by a second NO to produce N(2)O. This latter scenario is supported by theoretical modeling [Blomberg, L. M.; Blomberg, M. R.; Siegbahn, P. E. J. Biol. Inorg. Chem. 2007, 12, 79-89]. Published vibrational data on bioengineered models of denitrifying heme-nonheme NO reductases [Hayashi, T.; Miner, K. D.; Yeung, N.; Lin, Y.-W.; Lu, Y.; Moënne-Loccoz, P. Biochemistry 2011, 50, 5939-5947 ] support a similar mode of activation of a heme {FeNO}(7) species by the nearby nonheme Fe(II).


Ratios of multijet Cross Sections in p p collisions at radical(s) = 1.8 TeV.
We report on a study of the ratio of inclusive three-jet to inclusive two-jet production cross sections as a function of total transverse energy in p&pmacr; collisions at a center-of-mass energy sqrt[s] = 1.8 TeV, using data collected with the D0 detector during the 1992-1993 run of the Fermilab Tevatron Collider. The measurements are used to deduce preferred renormalization scales in perturbative O(alpha(3)(s)) QCD calculations in modeling soft-jet emission.


Cerebral correlates of faking: evidence from a brief implicit association test on doping attitudes.
Direct assessment of attitudes toward socially sensitive topics can be affected by deception attempts. Reaction-time based indirect measures, such as the Implicit Association Test (IAT), are less susceptible to such biases. Neuroscientific evidence shows that deception can evoke characteristic ERP differences. However, the cerebral processes involved in faking an IAT are still unknown. We randomly assigned 20 university students (15 females, 24.65 ± 3.50 years of age) to a counterbalanced repeated-measurements design, requesting them to complete a Brief-IAT (BIAT) on attitudes toward doping without deception instruction, and with the instruction to fake positive and negative doping attitudes. Cerebral activity during BIAT completion was assessed using high-density EEG. Event-related potentials during faking revealed enhanced frontal and reduced occipital negativity, starting around 150 ms after stimulus presentation. Further, a decrease in the P300 and LPP components was observed. Source analyses showed enhanced activity in the right inferior frontal gyrus between 150 and 200 ms during faking, thought to reflect the suppression of automatic responses. Further, more activity was found for faking in the bilateral middle occipital gyri and the bilateral temporoparietal junction. Results indicate that faking reaction-time based tests alter brain processes from early stages of processing and reveal the cortical sources of the effects. Analyzing the EEG helps to uncover response patterns in indirect attitude tests and broadens our understanding of the neural processes involved in such faking. This knowledge might be useful for uncovering faking in socially sensitive contexts, where attitudes are likely to be concealed.


'Kindling theory' in arson: how dangerous are firesetters?
This article aims to review the literature on firesetters particularly looking at recidivism rates. The early literature described firesetters as dangerous individuals. This article reviews the more recent empirical data to examine if it supports the early literature. A literature review was performed examining papers which described firesetters with any reference to recidivism. These were divided into three broad categories based on where studies have been performed, namely in forensic psychiatric settings, the criminal justice system and general and psychiatric hospitals. The literature has been poorly focused and provides little help when assessing an individual firesetter. Risk factors associated with general criminology have been cited. The empirical literature cannot support the hypothesis that firesetters are inherently dangerous. More research should target different groups of firesetters and examining individual risk within that group with an aim of researching treatment for the different groups.


Electrophysiological interactions of isomers of cyclazocine with the phencyclidine antagonist metaphit in rat cerebellar Purkinje neurons.
Metaphit, 1-(1-(3-isothiocyanatophenyl) cyclohexyl) piperidine, an analog of phencyclidine (PCP) has been shown previously to selectively block PCP receptors and to irreversibly antagonize the depressant effect of PCP in cerebellum. In this study, we examined the electrophysiological interactions of metaphit and naloxone with stereoisomers of cyclazocine, an agent known to have analgesic and psychotomimetic activity in behavioral studies, effects that have been ascribed to opiate and PCP receptor activity. A dose-dependent and reversible slowing of Purkinje neuron discharge was seen with local application of (+)- or (-)-cyclazocine. We found that the blockade of (-)-cyclazocine effects required both high doses of naloxone and the presence of metaphit, whereas the responses to (+)-cyclazocine were blocked by metaphit alone on most cerebellar Purkinje neurons. These findings suggest that the depressant reaction of (+)-cyclazocine in cerebellar Purkinje neurons is primarily mediated through PCP receptors. (-)-Cyclazocine responses, on the other hand, appear to be due to activity at both PCP and kappa opioid receptors.


Feasibility of placebo-controlled clinical trials of antipsychotic compounds in Europe.
Placebo-controlled trials (PCTs) are still regulatory requirements for the licensing of new drugs. Most recent phase II and phase III PCTs of antipsychotics in schizophrenia have been conducted outside Europe. This development needs to be better understood. To ascertain the attitude of experienced European schizophrenia researchers to PCTs in acute and maintenance trials and identify national variations. A postal questionnaire to recognised schizophrenia researchers across Europe. In all, 115 (77%) questionnaires were returned from 11 countries. There was considerable variation between countries in willingness to conduct PCTs in both acute and maintenance trials. Only 30% (acute trials), respectively 39% (maintenance trials) of the respondents said that they would participate in a PCT. Over one-third of investigators with previous experience of PCTs would not contemplate them now. Many cited the attitude of local ethics committees as the reason for their reluctance. PCTs are difficult to conduct in Europe. There are potential problems with importing results from one health care context into a significantly different one. The ethical and practical issues need to be addressed by a broad stakeholder group involving the industry, universities, ethics committees and users groups.


Impairment-Based Rehabilitation Following Hip Arthroscopy: Postoperative Protocol for the HIP ARThroscopy International Randomized Controlled Trial.
Synopsis The number of hip arthroscopies for the management of femoroacetabular impingement syndrome and other hip intra-articular conditions has grown exponentially in the last decade. Postoperative rehabilitation is part of the treatment algorithm, although there is a lack of high-quality studies on the efficacy of both surgery and postoperative rehabilitation programs. It is known that impairments can be present up to 2 years after hip arthroscopy, with individuals exhibiting reduced function and quality of life when compared to those of similar age, highlighting a need to improve postoperative care. Postoperative rehabilitation programs aim to improve hip function; however, the description of interventions as well as criteria for progression are lacking in the literature. The aim of this clinical commentary was to present a targeted clinical rehabilitation approach for individuals undergoing hip arthroscopy. J Orthop Sports Phys Ther 2018;48(4):336-342. doi:10.2519/jospt.2018.8002.


Binding between elongation factor 1A and the 3'-UTR of Chinese wheat mosaic virus is crucial for virus infection.
The Chinese wheat mosaic virus (CWMV) genome consists of two positive-strand RNAs that are required for CWMV replication and translation. The eukaryotic translation elongation factor (eEF1A) is crucial for the elongation of protein translation in eukaryotes. Here, we show that silencing eEF1A expression in Nicotiana benthamiana plants by performing virus-induced gene silencing can greatly reduce the accumulation of CWMV genomic RNAs, whereas overexpression of eEF1A in plants increases the accumulation of CWMV genomic RNAs. In vivo and in vitro assays showed that eEF1A does not interact with CWMV RNA-dependent RNA polymerase. Electrophoretic mobility shift assays revealed that eEF1A can specifically bind to the 3'-untranslated region (UTR) of CWMV genomic RNAs. By performing mutational analyses, we determined that the conserved region in the 3'-UTR of CWMV genomic RNAs is necessary for CWMV replication and translation, and that the sixth stem-loop (SL-6) in the 3'-UTR of CWMV genomic RNAs plays a key role in CWMV infection. We conclude that eEF1A is an essential host factor for CWMV infection. This finding should help us to develop new strategies for managing CWMV infections in host plants.


[Assessment of the immunological status of chondrosarcoma patients].
The immunological status was investigated in 40 patients with chondrosarcoma of clinical stages II and III. The radical operation was made in 40 patients, the polychemotherapy was applied to 10 of them in the early period and 3,6 and 12 months after the operation (sarcolysin, vincristine, carminomycin in generally accepted doses). A decrease in indices of the system of cellular and humoral immunity is established to occur in patients with chondrosarcoma. During a year after the operation the immunity indices restore gradually.


Five-level emergency triage systems: variation in assessment of validity.
Triage systems are scales developed to rate the degree of urgency among patients who arrive at EDs. A number of different scales are in use; however, the way in which they have been validated is inconsistent. Also, it is difficult to define a surrogate that accurately predicts urgency. This systematic review described reference standards and measures used in previous validation studies of five-level triage systems. We searched PubMed, EMBASE and CINAHL to identify studies that had assessed the validity of five-level triage systems and described the reference standards and measures applied in these studies. Studies were divided into those using criterion validity (reference standards developed by expert panels or triage systems already in use) and those using construct validity (prognosis, costs and resource use). A total of 57 studies examined criterion and construct validity of 14 five-level triage systems. Criterion validity was examined by evaluating (1) agreement between the assigned degree of urgency with objective standard criteria (12 studies), (2) overtriage and undertriage (9 studies) and (3) sensitivity and specificity of triage systems (7 studies). Construct validity was examined by looking at (4) the associations between the assigned degree of urgency and measures gauged in EDs (48 studies) and (5) the associations between the assigned degree of urgency and measures gauged after hospitalisation (13 studies). Particularly, among 46 validation studies of the most commonly used triages (Canadian Triage and Acuity Scale, Emergency Severity Index and Manchester Triage System), 13 and 39 studies examined criterion and construct validity, respectively. Previous studies applied various reference standards and measures to validate five-level triage systems. They either created their own reference standard or used a combination of severity/resource measures.


Age-Dependent Changes in the Effects of Androgens on Female Metabolic and Body Weight Regulation Systems in Humans and Laboratory Animals.
In recent years, the effects of androgens on metabolic and body weight regulation systems and their underlying mechanisms have been gradually revealed in females. In women and experimental animals of reproductive age, androgen excess can adversely affect metabolic functioning, appetite, and body weight regulation. In addition, excess androgens can increase the risk of metabolic disorders, such as obesity, insulin resistance, and diabetes. These unfavorable effects of androgens are induced by alterations in the actions of hypothalamic appetite-regulatory factors, reductions in energy expenditure, insulin resistance in skeletal muscle, and β-cell dysfunction. Interestingly, these unfavorable effects of androgens on metabolic and body-weight regulation systems are neither observed nor evident in ovariectomized animals and post-menopausal women, indicating that the adverse effects of androgens might be dependent on the estrogen milieu. Recent findings may provide novel sex- and age-specific strategies for treating metabolic diseases.


Emerging role of protein kinase C in energy homeostasis: A brief overview.
Protein kinase C-β (PKCβ), a member of the lipid-activated serine/threonine PKC family, has been implicated in a wide range of important cellular processes. Very recently, the novel role of PKCβ in the regulation of triglyceride homeostasis via regulating mitochondrial function has been explored. In this review, I aim to provide an overview of PKCβ regarding regulation by lipids and recently gained knowledge on its role in energy homeostasis. Alterations in adipose PKCβ expression have been shown to be crucial for diet-induced obesity and related metabolic abnormalities. High-fat diet is shown to induce PKCβ expression in white adipose tissue in an isoform- and tissue-specific manner. Genetically manipulated mice devoid of PKCβ are lean with increased oxygen consumption and are resistant to high-fat diet-induced obesity and hepatic steatosis with improved insulin sensitivity. Available data support the model in which PKCβ functions as a "diet-sensitive" metabolic sensor whose induction in adipose tissue by high-fat diet is among the initiating event disrupting mitochondrial homeostasis via intersecting with p66(Shc) signaling to amplify adipose dysfunction and have systemic consequences. Alterations in PKCβ expression and/or function may have important implications in health and disease and warrants a detailed investigation into the downstream target genes and the underlying mechanisms involved. Development of drugs that target the PKCβ pathway and identification of miRs specifically controlling PKCβ expression may lead to novel therapeutic options for treating age-related metabolic disease including fatty liver, obesity and type 2 diabetes.


Nosocomial respiratory tract infections in multiple trauma patients. Influence of level of consciousness with implications for therapy.
A prospective study of 161 multiple trauma patients was carried out to determine the incidence, the causative agents, and the outcome of nosocomial respiratory tract infections in this highly selected population. Thirty-eight (23.6 percent) patients developed a nosocomial pneumonia (NP). In addition, there were four superinfections in three patients, representing an incidence of 26 percent (42 of 161). Incidence of NP was significantly greater among comatose patients (42.2 vs 13.3 percent, p less than 0.05). Furthermore, purulent tracheobronchitis was diagnosed in six patients. The causative agent of NP was identified in 36 (85.7 percent) episodes by means of fiberoptic bronchoscopies with protected specimen brush sampling. Staphylococcus aureus (55.8 percent) was the predominant pathogen isolated in multiple trauma patients in coma (Glasgow coma score [GCS] below 9 during a period greater than 24 h), while aerobic Gram-negative bacilli were responsible for the majority of cases in the remaining population studied. The overall mortality rate was 19.8 percent, but only five deaths were related to NP. We conclude that nosocomial respiratory tract infections are a frequent problem in multiple trauma patients, especially in those with GCS below 9, although this complication is associated with a relatively low mortality. Among patients with GCS below 9, S aureus was a frequent finding; consequently, antimicrobial therapy in this population needs to be different than that for the remaining multiple trauma patients with NP.


[Routine use of of two internal mammary arteries for coronary bypass grafting--one year experience at the Tel Aviv Medical Center].
The skeletonized internal mammary artery (IMA) is longer, and its immediate spontaneous blood flow is greater than that of the pedicled IMA, thus providing increased versatility for complete, arterial myocardial revascularization without the use of saphenous vein grafts. From April 1996 to May 1997, 583 patients underwent coronary artery bypass grafting here and in 415 (71%) complete arterial revascularization was achieved using bilateral skeletonized IMA. The right gastroepiploic artery was used in 57 (13%); there were 329 males (79%) and 86 women (21%); average age was 64 (30-87) and 175 (36%) were older than 70; 131 (32%) were diabetics. Average number of grafts was 3.2 (range 2-6 grafts). At 30 days, 5 (1.2%) had died and there had been 6 perioperative infarcts (1.4%), 5 CVA's (1.2%), and 6 had sternal wound infections (1.4%). Up to 1-12 months of follow-up was achieved in 409 (99%). Late mortality was 1.4% (of which 3 were noncardiac). 394 (97%) were angina-free at latest follow-up. We conclude that arterial revascularization using bilateral skeletonized IMA is safe, as postoperative morbidity and mortality are low, even in old and diabetic patients.


Needlestick transmission of hepatitis C.
Hepatitis C virus (HCV) transmission following a needlestick is an important threat to health care workers. We present the case of a 29-year-old medical intern who sustained a needlestick injury from a source patient known to be infected with both human immunodeficiency virus and HCV. The case patient subsequently developed acute HCV infection. The optimal strategy for diagnosing HCV infection after occupational exposures has not been defined. At a minimum, HCV antibody and alanine aminotransferase testing should be done within several days of exposure (to assess if the health care worker is already infected with HCV) and 6 months after percutaneous, mucosal, or nonintact skin exposure to blood or infectious body fluids from an HCV-infected patient. Currently, it is not possible to prevent HCV infection after exposure. However, recent data suggest that early treatment of acute HCV infection with interferon alpha may be highly effective in preventing chronic HCV infection. These data underscore the importance of identifying persons with acute HCV infection and promptly referring them to experienced clinicians who can provide updated counseling and treatment.


Retrograde monosynaptic tracing reveals the temporal evolution of inputs onto new neurons in the adult dentate gyrus and olfactory bulb.
Identifying the connectome of adult-generated neurons is essential for understanding how the preexisting circuitry is refined by neurogenesis. Changes in the pattern of connectivity are likely to control the differentiation process of newly generated neurons and exert an important influence on their unique capacity to contribute to information processing. Using a monosynaptic rabies virus-based tracing technique, we studied the evolving presynaptic connectivity of adult-generated neurons in the dentate gyrus (DG) of the hippocampus and olfactory bulb (OB) during the first weeks of their life. In both neurogenic zones, adult-generated neurons first receive local connections from multiple types of GABAergic interneurons before long-range projections become established, such as those originating from cortical areas. Interestingly, despite fundamental similarities in the overall pattern of evolution of presynaptic connectivity, there were notable differences with regard to the development of cortical projections: although DG granule neuron input originating from the entorhinal cortex could be traced starting only from 3 to 5 wk on, newly generated neurons in the OB received input from the anterior olfactory nucleus and piriform cortex already by the second week. This early glutamatergic input onto newly generated interneurons in the OB was matched in time by the equally early innervations of DG granule neurons by glutamatergic mossy cells. The development of connectivity revealed by our study may suggest common principles for incorporating newly generated neurons into a preexisting circuit.


Effect of estradiol administration on splanchnic perfusion after trauma-hemorrhage and sepsis.
This review focuses on the latest mechanistic understanding of the effects of estradiol on the splanchnic circulation and the possibility of estradiol treatment as an adjunct for the treatment of trauma-hemorrhage and sepsis. Systemic hypotension induced by shock accompanies marked alterations in blood flow to various organs. Decreased splanchnic perfusion is frequently observed after insults, such as severe hemorrhage or sepsis, which leads to the destruction of the intestinal mucosal barrier and hepatic dysfunction. Studies suggest that estradiol acts as a facilitator of the intestinal blood flow via the increased production of nitric oxide, decreased production of vasoconstrictors, attenuated neutrophil adhesion, and decreased formation of oxygen free radicals. Trauma-hemorrhage results in decreased circulating blood volume. In contrast, sepsis is an inflammatory state mainly mediated by bacterial products. However, these divergent insults show similar pathophysiologic alterations in terms of the splanchnic circulation. Because estradiol effectively protects the organs from circulatory failure after various adverse circulatory conditions, many studies are being performed to clarify the molecular mechanism of estradiol action with regard to tissue circulation. Estradiol improves the macro- and microcirculation of the splanchnic organs by multiple mechanisms. Nonetheless, it remains unclear which mechanism plays the most important role in the treatment of trauma-hemorrhage and sepsis. Additional studies are required to elucidate the precise mechanism of estradiol action and to determine the usefulness of estradiol treatment for severe hemorrhage and sepsis in patients.


Do organisms have an ontological status?
The category "organism" has an ambiguous status: is it scientific or is it philosophical? Or, if one looks at it from within the relatively recent field or sub-field of philosophy of biology, is it a central, or at least legitimate category therein, or should it be dispensed with? In any case, it has long served as a kind of scientific bolstering for a philosophical train of argument which seeks to refute the mechanistic or reductionist trend, which has been perceived as dominant since the 17th century, whether in the case of Stahlian animism, Leibnizian monadology, the neo-vitalism of Hans Driesch, or, lastly, of the "phenomenology of organic life" in the 20th century, with authors such as Kurt Goldstein, Maurice Merleau-Ponty, and Georges Canguilhem. In this paper I try to reconstruct some of the main interpretive stages or layers of the concept of organism in order to evaluate it critically. How might organism be a useful concept if one rules out the excesses of organismic biology and metaphysics? Varieties of instrumentalism and what I call the projective concept of organism are appealing, but perhaps ultimately unsatisfying.


Dual contacts between peptide agonist ligands and the secretin receptor directly established by photoaffinity labeling.
Structural analysis of secretin in solution has demonstrated extended helical domains within both amino- and carboxyl-terminal halves, with a possible turn in between. However, the conformation of this peptide as it resides in its binding site within the receptor has not been established. In the work reported here, we performed affinity labeling of the secretin receptor with radioiodinated secretin analogues having photolabile benzoyl-phenylalanine residues positioned in each half of the peptide. The probes had sites of covalent attachment in positions 6 and 22, and have been recently synthesized and characterized to represent high affinity agonist ligands. Both covalently labeled the secretin receptor in a saturable, specific, and efficient manner. After purification of the labeled receptor, we used a series of chemical and enzymatic cleavage techniques to define the domain of labeling. We complemented this by receptor mutagenesis, followed by additional cleavage and Edman degradation sequencing to refine our insights into the labeled residues. This has allowed us to demonstrate that sites of attachment were both within the extracellular aminoterminal domain of the receptor. Of particular interest, both probes labeled residues within the amino-terminal thirty residues at the distal end of the receptor. It will be particularly interesting to use these molecular approximations to model the binding domain of this important receptor.


Macronutrients, vitamins and minerals intake and risk of esophageal squamous cell carcinoma: a case-control study in Iran.
Although Iran is a high-risk region for esophageal squamous cell carcinoma (ESCC), dietary factors that may contribute to this high incidence have not been thoroughly studied. The aim of this study was to evaluate the effect of macronutrients, vitamins and minerals on the risk of ESCC. In this hospital-based case-control study, 47 cases with incident ESCC and 96 controls were interviewed and usual dietary intakes were collected using a validated food frequency questionnaire. Data were modeled through unconditional multiple logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI), controlling for age, sex, gastrointestinal reflux, body mass index, smoking history (status, intensity and duration), physical activity, and education. ESCC cases consumed significantly more hot foods and beverages and fried and barbecued meals, compared to the controls (p < 0.05). After adjusting for potential confounders, the risk of ESCC increased significantly in the highest tertiles of saturated fat [OR:2.88,95%CI:1.15-3.08], cholesterol [OR:1.53, 95%CI: 1.41-4.13], discretionary calorie [OR:1.51, 95%CI: 1.06-3.84], sodium [OR:1.49,95%CI:1.12-2.89] and total fat intakes [OR:1.48, 95%CI:1.09-3.04]. In contrast, being in the highest tertile of carbohydrate, dietary fiber and (n-3) fatty acid intake reduced the ESCC risk by 78%, 71% and 68%, respectively. The most cancer-protective effect was observed for the combination of high folate and vitamin E intakes (OR: 0.02, 95%CI: 0.00-0.87; p < 0.001). Controls consumed 623.5 times higher selenium, 5.48 times as much β-carotene and 1.98 times as much α-tocopherol as the amount ESCC cases consumed. This study suggests that high intake of nutrients primarily found in plant-based foods is associated with a reduced esophageal cancer risk. Some nutrients such as folate, vitamin E and selenium might play major roles in the etiology of ESCC and their status may eventually be used as an epidemiological marker for esophageal cancer in Iran, and perhaps other high-risk regions.


Neural correlates of effort-based behavioral inconsistency.
According to the theory of value-based decision making, subjects tend to choose the most valuable among a set of options. However, agents may not be consistent when facing the same decision several times. In this paper, Shannon's entropy (H) is employed as a measure of behavioral inconsistency: it is a central measure of information theory that, applied to decision making, allows the estimation of behavioral preferences among a set of options. We scanned (functional magnetic resonance imaging, fMRI) 24 young (18-25 year) subjects (14 female) while performing a decision-making task, where monetary rewards were devalued by physical effort (minutes running in the treadmill) and risk. Twenty different pairs of options were presented nine times each, and H was calculated for each pair and subject. Behavioral analyses showed that subjective value (SV) significantly explained agents' preferences only in pairs with a low inconsistent response. Averaged response time positively correlated with H, confirming entropy as an indicator of choice difficulty. Group analyses on fMRI data revealed a cluster in the paracingulate cortex as the neural correlate of H. Besides, BOLD signal in the posterior cingulate correlated with the SV of the pair only in consistent decisions, confirming that SV loses its explanatory power on highly inconsistent decisions. Finally, the anterior and central cingulate were especially recruited when predicting a secured effortless reward, compared with a secured reward that involved a maximum effort. Our study shows that different regions of the cingulate cortex are involved in choice inconsistency, SV and processing effort costs.


Sexual maturation and aging of adult male mealybug (Hemiptera: Pseudococcidae).
The physiological age of adult males of seven mealybug species was measured in relation to the elongation of the male pair of the waxy caudal filaments. These filaments begin to emerge after eclosion and reached their maximum length from 29.4-46.6 h. The studied males were divided into three age groups, expressed as percentages of the total waxy caudal filaments length. Attraction to a sex pheromone source was significantly higher in the oldest male group (maximum filaments growth) compared with youngest one. Only the oldest male group copulated successfully; few of the younger males tested displayed 'courtship' behavior towards conspecific virgin females. The calculated duration of the sexually active phase of the adult male life cycle varied among species ranging from 34.4 to 46.6 h. There were marked variations in the strength of attraction to a pheromone source according to time of day. There was a continuous decrease in sexual activity from morning to evening. Our findings reveal clear maturation periods for adult males of the seven studied species. The long immature phase of the adult male mealybug is probably also related to several physiological processes that are needed to complete male maturation. The most noticeable change is the elongation of the waxy caudal filaments. However, mating may be performed at any time ambient conditions are suitable. Whereas male mealybug flight towards a pheromone source is restricted to a few hours, the male may continue mating activity throughout its sexually active period.


Aetiological spectrum, injury characteristics and treatment outcome of head injury patients at Bugando Medical Centre in north-western Tanzania.
Head injury is considered as a major health problem that is a frequent cause of death and disability and makes considerable demands on health services. A cross-sectional study was conducted to determine the etiological spectrum, injury characteristics and treatment outcome of head injury patients at Bugando Medical Centre (BMC) in North-western Tanzania. Data were collected using a pre-tested, coded questionnaire and analyzed using SPSS programme. A total of 260 head injury patients (mean age=26.84 years) were studied. Males outnumbered females by a ratio of 1.5:1. Road traffic accidents (RTAs) were the most common cause of injury accounting for 49.2% of patients. Scalp injuries, cerebral concussion and skull fractures were the most common type of head injuries. Fifty-six (21.5%) patients had associated injuries of which musculoskeletal region (36.1%) was commonly affected. Most of patients (66.1%) sustained mild head injury. The majority of patients (75.8%) were treated conservatively and only 24.2% of patients needed surgical interventions. Most of patients (85.4%) had good recovery. The mean hospital stay (LOS) was 24.56 days and the mortality rate was 11.2%. Patients who had RTAs, penetrating head injuries, associated long bone fractures and those who were treated surgically were found to have significantly longer LOS (P< 0.001). Mortality was found to be significantly associated with extreme of age, presence of pre-morbid illness and associated injuries, admission Glasgow Coma Score < 9, systolic blood pressure < 90mmHg, injury severity core > or =16, longer duration of loss of consciousness, the need for intensive care unit admission and finding of space occupying lesion on computed tomography scan (P < 0.001). Head injuries resulting from RTAs remain a major public health problem in this part of Tanzania. Urgent preventive measures targeting at reducing the occurrence of RTAs is necessary to reduce the incidence of head injuries in this region.


Evaluation of early-phase [18F]-florbetaben PET acquisition in clinical routine cases.
In recent years several [18F]-labelled amyloid PET tracers have been developed and have obtained clinical approval. There is accumulating evidence that early (post injection) acquisitions with these tracers are equally informative as conventional blood flow and metabolism studies for diagnosis of Alzheimer's disease, but there have been few side-by-side studies. Therefore, we investigated the performance of early acquisitions of [18F]-florbetaben (FBB) PET compared to [18F]-fluorodeoxyglucose (FDG) PET in a clinical setting. All subjects were recruited with clinical suspicion of dementia due to neurodegenerative disease. FDG PET was undertaken by conventional methods, and amyloid PET was performed with FBB, with early recordings for the initial 10 min (early-phase FBB), and late recordings at 90-110 min p.i. (late-phase FBB). Regional SUVR with cerebellar and global mean normalization were calculated for early-phase FBB and FDG PET. Pearson correlation coefficients between FDG and early-phase FBB were calculated for predefined cortical brain regions. Furthermore, a visual interpretation of disease pattern using 3-dimensional stereotactic surface projections (3D-SSP) was performed, with assessment of intra-reader agreement. Among a total of 33 patients (mean age 67.5 ± 11.0 years) included in the study, 18 were visually rated amyloid-positive, and 15 amyloid-negative based on late-phase FBB scans. Correlation coefficients for early-phase FBB vs. FDG scans displayed excellent agreement in all target brain regions for global mean normalization. Cerebellar normalization gave strong, but significantly lower correlations. 3D representations of early-phase FBB visually resembled the corresponding FDG PET images, irrespective of the amyloid-status of the late FBB scans. Early-phase FBB acquisitions correlate on a relative quantitative and visual level with FDG PET scans, irrespective of the amyloid plaque density assessed in late FBB imaging. Thus, early-phase FBB uptake depicts a metabolism-like image, suggesting it as a valid surrogate marker for synaptic dysfunction, which could ultimately circumvent the need for additional FDG PET investigation in diagnosis of dementia.


Convergence of nanotechnology and cancer prevention: are we there yet?
Nanotechnology is emerging as a promising modality for cancer treatment; however, in the realm of cancer prevention, its full utility has yet to be determined. Here, we discuss the potential of integrating nanotechnology in cancer prevention to augment early diagnosis, precision targeting, and controlled release of chemopreventive agents, reduced toxicity, risk/response assessment, and personalized point-of-care monitoring. Cancer is a multistep, progressive disease; the functional and acquired characteristics of the early precancer phenotype are intrinsically different from those of a more advanced anaplastic or invasive malignancy. Therefore, applying nanotechnology to precancers is likely to be far more challenging than applying it to established disease. Frank cancers are more readily identifiable through imaging and biomarker and histopathologic assessment than their precancerous precursors. In addition, prevention subjects routinely have more rigorous intervention criteria than therapy subjects. Any nanopreventive agent developed to prevent sporadic cancers found in the general population must exhibit a very low risk of serious side effects. In contrast, a greater risk of side effects might be more acceptable in subjects at high risk for cancer. Using nanotechnology to prevent cancer is an aspirational goal, but clearly identifying the intermediate objectives and potential barriers is an essential first step in this exciting journey.


Characterizing Emerging Canine H3 Influenza Viruses.
The continual emergence of novel influenza A strains from non-human hosts requires constant vigilance and the need for ongoing research to identify strains that may pose a human public health risk. Since 1999, canine H3 influenza A viruses (CIVs) have caused many thousands or millions of respiratory infections in dogs in the United States. While no human infections with CIVs have been reported to date, these viruses could pose a zoonotic risk. In these studies, the National Institutes of Allergy and Infectious Diseases (NIAID) Centers of Excellence for Influenza Research and Surveillance (CEIRS) network collaboratively demonstrated that CIVs replicated in some primary human cells and transmitted effectively in mammalian models. While people born after 1970 had little or no pre-existing humoral immunity against CIVs, the viruses were sensitive to existing antivirals and we identified a panel of H3 cross-reactive human monoclonal antibodies (hmAbs) that could have prophylactic and/or therapeutic value. Our data predict these CIVs posed a low risk to humans. Importantly, we showed that the CEIRS network could work together to provide basic research information important for characterizing emerging influenza viruses, although there were valuable lessons learned.


Aggression-related brain function assessed with the Point Subtraction Aggression Paradigm in fMRI.
The Point Subtraction Aggression Paradigm (PSAP) measures aggressive behavior in response to provocations. The aim of the study was to implement the PSAP in a functional neuroimaging environment (fMRI) and evaluate aggression-related brain reactivity including response to provocations and associations with aggression within the paradigm. Twenty healthy participants completed two 12-min PSAP sessions within the scanner. We evaluated brain responses to aggressive behavior (removing points from an opponent), provocations (point subtractions by the opponent), and winning points. Our results showed significant ventral and dorsal striatal reactivity when participants won a point and removed one from the opponent. Provocations significantly activated the amygdala, dorsal striatum, insula, and prefrontal areas. Task-related aggressive behavior was positively correlated with neural reactivity to provocations in the insula, the dorsal striatum, and prefrontal areas. Our findings suggest the PSAP within an fMRI environment may be a useful tool for probing aggression-related neural pathways. Activity in the amygdala, dorsal striatum, insula, and prefrontal areas during provocations is consistent with the involvement of these brain regions in emotional and impulsive behavior. Striatal reactivity may suggest an involvement of reward during winning and stealing points.


The increase with age of the components of the tissue factor coagulation pathway is gender-dependent.
To evaluate the influence of age and gender on the components of the tissue factor coagulation pathway, plasma levels of tissue factor pathway inhibitor (TFPI), activated factor VII (FVIIa) and factor VII coagulant activity (FVIIc) were measured in 160 normal individuals. The female (n = 82) and male (n = 78) part of the population were matched for age, which was equally distributed from 21 to 101 years. Mean levels of TFPI were lower and those of FVIIc higher in women than in men; there was no gender-related difference for FVIIa. Linear regression analysis showed a positive correlation between age and TFPI (r = 0.34, P = 0.0001), FVIIa (r = 0.36, P = 0.0001) and FVIIc (r = 0.40, P = 0.0001). For each measurement, the positive correlation with age was mainly contributed by the female part of the population (TFPI: r = 0.51, P = 0.0001; FVIIa: r = 0.47, P = 0.0001; FVIIc: r = 0.58, P = 0.0001), whereas there was no significant correlation between age and TFPI, FVIIa or FVIIc in males. The gender-related difference of the association of these measurements with age was confirmed by comparing men or women older than 55 years with those younger than 55 years. TFPI, FVIIa and FVIIc were much higher in the older women group (P < 0.0002), whereas in the male part of the population only FVIIc was slightly higher in the older group (P = 0.03). These results indicate that the increase with age of the components of the tissue factor pathway of blood coagulation is mainly contributed by the female part of the normal population.


Distinct Effects of Royal Jelly on Human Endothelial Cells Under High Glucose Condition.
To assess different effects of royal Jelly in protecting the human endothelial cells from high glucose level, human umbilical vein endothelial cells were exposed to various concentrations of royal jelly, from 0.625 to 10 mg/mL, at the presence of 5 and 30 mM glucose contents over a course of 72 h. In addition to cell viability assessment by conventional MTT assay, we also analyzed the feature of stemness by expression of Sox-2 and CD133 factors. Moreover, fatty acid profile, the expression of autophagy-related factor, namely microtubule-associated protein light chain 3 and activity of metalloproteinase 2 and 9 and were investigated. Royal jelly supplementation at the concentrations lower than 2.5 mg/mL did not influence the survival rate of cells and partially blunted the cytotoxic effects of 30 mM glucose. The expression of CD133 and Sox-2 factors were increased by royal jelly alone. Interestingly, an up-regulated expression of Sox-2 (58.8 ± 4%) coincided with a reduction in the levels of CD133 (15.1 ± 8.3%) in the combined treatment. We notified that the contents of palmitate and trans-palmitate as well as linoleate decreased by 30 mM glucose content while cis-palmitate levels increased when RJ returned them to near-normal levels (p < 0.05). The expression of autophagy marker was prominently induced in the presence of royal jelly in both conditions (p < 0.05). The glucose-induced activity of metalloproteinases was also reduced. Royal jelly is able to attenuate the abnormal status of 30 mM glucose condition in endothelial cells by different mechanisms.


[Diagnostic value of carcinoembryonic antigen in pleural fluid (author's transl)].
Of 30 unselected patients with pleural effusion of unknown cause 17 were subsequently found to have malignant disease of the pleura. In 11 of the 17 patients the concentration of carcinoembryonic antigen (CEA) in the pleural effusion was elevated to 4-60 ng/ml. In all 13 patients with pleural effusion of non-malignant cause the CEA concentration was normal (0-2 ng/ml). While the specificity of CEA antigen was 100% in the diagnosis of malignant pleural disease, its sensitivity was only about 65%. Since low CEA values in pleural effusion thus cannot exclude malignant disease with certainty, histological assessment of the pleural disease should be practised in every case where tumour is suspected, if necessary via thoracoscopy or thoracotomy.


Proximal ingrowth components.
The advantage of using a proximal ingrowth hip revision component is restoring physiologic load to the revision femur. Although first generation components had limited survivorship and diminished clinical outcomes, subsequent designs have proven much better with rates of aseptic loosening of 2% to 5%, and good clinical scores. Titanium is the favored substrate metal for these components because of its bone affinity and low modulus of elasticity. A series of 107 consecutive revisions of standard stems is presented using a calcar replacement long stem design with an overall 92.7% 11-year survivorship. Bone ingrowth was achieved in all but two components. Radiographic stress shielding was seen in 11.4% with 42.6% having some calcar healing. These implants can be used in most revision situations, but require sufficient proximal metaphysis of the femur to provide support of the component. Supplemental allograft may need to be used. These implants require a tight fit in the isthmus of the femur and fill of the proximal femur. Modularity makes achieving this easier, but monoblock designs also can be successful.


Dietary Quality and Perceived Barriers to Weight Loss among Older Overweight Veterans with Dysmobility.
Healthier diets are associated with higher muscle mass and physical performance which may reduce the risk of developing frailty and disability later in life. This study examined the dietary quality and self-reported weight loss barriers among older (>60 years), overweight (BMI ≥ 25 kg/m2) Veterans with dysmobility (low gait speed, impaired mobility diagnosis, or a comorbidity that results in impaired mobility). Habitual dietary intake and healthy eating index (HEI-2015) were assessed using 24-h recalls and compared to US nationally representative dietary intake data and national recommendations. The "MOVE!11" Patient Questionnaire assessed weight loss barriers. The sample (n = 28) was primarily male (93%), black (54%) and obese (BMI = 35.5 ± 5.4 kg/m2) adults aged 69.5 ± 7.0 years with two or more comorbidities (82%); 82% were prescribed four or more medications. Daily intakes (mean ± SD) were calculated for total energy (2184 ± 645 kcals), protein (0.89 ± 0.3 g/kg), fruits (0.84 ± 0.94 cup·eq.), vegetables (1.30 ± 0.87 cup·eq.), and HEI-2015 (52.8 ± 13.4). Veterans consumed an average of 11% less protein than the recommendation for older adults (1.0 g/kg/d) and consumed fewer fruits and vegetables than comparisons to national averages (18% and 21%, respectively). Mean HEI-2015 was 17% below the national average for adults >65 years, suggesting poor dietary quality among our sample. Top weight loss barriers were not getting enough physical activity, eating too much and poor food choices. This data suggests that dietary quality is suboptimal in older, overweight Veterans with disability and highlights the need to identify strategies that improve the dietary intake quality of older Veterans who may benefit from obesity and disability management.


Fine-scale variation within urban landscapes affects marking patterns and gastrointestinal parasite diversity in red foxes.
Urban areas are often considered to be a hostile environment for wildlife as they are highly fragmented and frequently disturbed. However, these same habitats can contain abundant resources, while lacking many common competitors and predators. The urban environment can have a direct impact on the species living there but can also have indirect effects on their parasites and pathogens. To date, relatively few studies have measured how fine-scale spatial heterogeneity within urban landscapes can affect parasite transmission and persistence.Here, we surveyed 237 greenspaces across the urban environment of Edinburgh (UK) to investigate how fine-scale variation in socio-economic and ecological variables can affect red fox (Vulpes vulpes) marking behavior, gastrointestinal (GI) parasite prevalence, and parasite community diversity.We found that the presence and abundance of red fox fecal markings were nonuniformly distributed across greenspaces and instead were dependent on the ecological characteristics of a site. Specifically, common foraging areas were left largely unmarked, which indicates that suitable resting and denning sites may be limiting factor in urban environments. In addition, the amount of greenspace around each site was positively correlated with overall GI parasite prevalence, species richness, and diversity, highlighting the importance of greenspace (a commonly used measure of landscape connectivity) in determining the composition of the parasite community in urban areas.Our results suggest that fine-scale variation within urban environments can be important for understanding the ecology of infectious diseases in urban wildlife and could have wider implication for the management of urban carnivores.


Management of postpartum pain.
Following the physiologic challenge of birth, many women will experience pain during the postpartum period. The goal is to achieve the right complement and dosing schedule of medications and nonpharmacologic comfort measures to successfully relieve pain, while at the same time allowing the woman to remain fully awake and aware to care for her newborn. Many of the common modalities used for nonpharmacologic pain relief in particular are based on anecdotal evidence, cultural ritual, or outdated studies. In this article, the most common sources of postpartum pain are reviewed as well as evidence-based pain management strategies, including both pharmacologic and nonpharmacologic methods.


InP-based pseudomorphic InAs/InGaAs triangular quantum well lasers with bismuth surfactant.
An InP-based 2.1 μm InAs/In0.53Ga0.47As triangular quantum well laser grown with Bi surfactant has shown improved performance in comparison to the device with the same structure but grown without Bi surfactant. Under continuous-wave driving operation, the output light power is increased from 32.6 to 37.5 mW at the same injecting current of 850 mA at 200 K. The external differential and internal quantum efficiencies for the laser with Bi surfactant are 18.4% and 41%, respectively, which are correspondingly higher than 13.1% and 31% for the reference device. Furthermore, a decreased internal loss from 20.9 to 17.6 cm-1 for the Bi surfactant laser is also observed. These results suggest that Bi surfactant is promising for further enhancing performances of strained quantum well laser diodes.


Histamine-containing cells in bronchial lavage fluid. I. Ultrastructural characterization and comparison with mast cells in three types of tissues of rhesus monkeys.
We have studied the ultrastructure of histamine-containing cells in the bronchial lavage of normal rhesus monkeys. These cells were recognized by the similarities of their specific cytoplasmic granules to those in tissue mast cells and basophilic leukocytes of other species. According to cell shape, two forms of bronchial lavage histamine-containing cells (BL-HCC) were observed. One was round and small, and the other pleomorphic and large. However, the subcellular structures, especially the specific cytoplasmic granules, were identical for both forms of HCC. With available evidence, we now consider both types of BL-HCC to be one cell species. The difference in cell shape may be an inherent variation within this cell population, or a reflection of the maturity of individual cells. Most BL-HCC had long slender pseudopods, and the majority of them were mononucleated. Some HCC appeared binucleated; multinucleated cells were not encountered. The ultrastructure of mast cells, in tissue fragments biopsied from three sites, was in many ways similar to that of BL-HCC, but there were clear morphological dissimilarities between these two cell groups. It is unlikely that tissue mast cells are the direct precursors of BL-HCC. Attempts to compare BL-HCC with blood basophilic leukocytes were unsuccessful due to the failure to detect the latter in monkey peripheral blood with electron microscopy in the present study. The possible origin of BL-HCC is discussed.


CYP2J subfamily cytochrome P450s in the gastrointestinal tract: expression, localization, and potential functional significance.
Our laboratory recently described a new human cytochrome P450 arachidonic acid epoxygenase (CYP2J2) and the corresponding rat homologue (CYP2J3), both of which were expressed in extrahepatic tissues. Northern analysis of RNA prepared from the human and rat intestine demonstrated that CYP2J2 and CYP2J3 mRNAs were expressed primarily in the small intestine and colon. In contrast, immunoblotting studies using a polyclonal antibody raised against recombinant CYP2J2 showed that CYP2J proteins were expressed throughout the gastrointestinal tract. Immunohistochemical staining of formalin-fixed, paraffin-embedded intestinal sections using anti-CYP2J2 IgG and avidin-biotin-peroxidase detection revealed that CYP2J proteins were present at high levels in nerve cells of autonomic ganglia, epithelial cells, intestinal smooth muscle cells, and vascular endothelium. The distribution of this immunoreactivity was confirmed by in situ hybridization using a CYP2J2-specific antisense RNA probe. Microsomal fractions prepared from human jejunum catalyzed the NADPH-dependent metabolism of arachidonic acid to epoxyeicosatrienoic acids as the principal reaction products. Direct evidence for the in vivo epoxidation of arachidonic acid by intestinal cytochrome P450 was provided by documenting, for the first time, the presence of epoxyeicosatrienoic acids in human jejunum by gas chromatography/mass spectrometry. We conclude that human and rat intestine contain an arachidonic acid epoxygenase belonging to the CYP2J subfamily that is localized to autonomic ganglion cells, epithelial cells, smooth muscle cells, and vascular endothelium. In addition to the known effects on intestinal vascular tone, we speculate that CYP2J products may be involved in the release of intestinal neuropeptides, control of intestinal motility, and/or modulation of intestinal fluid/electrolyte transport.


Histochemical localization of hydrochloric acid in the stomach of two teleost fishes.
The localization of hydrochloric acid in the gastric glands of Ophycephalus punctatus and Heteropneustes fossilis has been examined histochemically. The fishes were force-fed with the Prussian blue reagents in a test meal and the distribution of the precipitate was examined at regular intervals. Maximum amount of precipitate was observed in the lumen and at the mouth of the openings of the gastric glands 12 h after feeding in Ophiocephalus and at 18 h in Heteropneustes. Pepsinogen granules were distributed in all the cells lining the gastric glands. No histochemical difference was observed in the cells lining the gastric glands, and all the cells were capable of producing both HC1 and pepsinogen.


Effect of Regular Aerobic Training on Serum C-Reactive Protein and IL-6 Levels in Obese Women.
This study's objective was to evaluate interleukin-6 (IL-6) and C-reactive protein (CRP) responses and performance changes in obese women after 8 weeks of aerobic training with an intensity of 50 to 60% of their individual maximum oxygen uptake (VO2). A total of 18 sedentary women with an average age of 44.3 (± 1.9) years volunteered for this study. Over a period of 8 weeks, in 4 40-minute sessions per week, the participants walked at an exercise intensity that caused their heart rates to increase to levels corresponding to 50 to 60% of their VO2 peaks. Blood samples were collected from the participants, both when they were at rest and a couple of minutes after the end of the 1st exercise session. Sampling was repeated in the 4th and 8th weeks, before and after the last training sessions. The participants' body mass indices and weights decreased significantly by the end of the 8th week, while their maximum running speeds and VO2 peaks increased significantly. There were no differences in CRP or IL- 6 concentrations between the pre- and post-training sessions, but most of the participants' IL-6 levels dropped below 10 pg/ml after 8 weeks of training. Although no significant changes were observed in CRP or IL-6 concentrations, it is important to note that in response to aerobic training, the IL-6 levels of most of the participants fell to what is generally considered acceptable.


Alpha-T-catenin is expressed in human brain and interacts with the Wnt signaling pathway but is not responsible for linkage to chromosome 10 in Alzheimer's disease.
The gene encoding alpha-T-catenin, CTNNA3, is positioned within a region on chromosome 10, showing strong evidence of linkage to Alzheimer's disease (AD), and is therefore a good positional candidate gene for this disorder. We have demonstrated that alpha-T-catenin is expressed in human brain, and like other alpha-catenins, it inhibits Wnt signaling and is therefore also a functional candidate. We initially genotyped two single-nucleotide polymorphisms (SNPs) in the gene, in four independent samples comprising over 1200 cases and controls but failed to detect an association with either SNP. Similarly, we found no evidence for association between CTNNA3 and AD in a sample of subjects showing linkage to chromosome 10, nor were these SNPs associated with Abeta deposition in brain. To comprehensively screen the gene, we genotyped 30 additional SNPs in a subset of the cases and controls (n > 700). None of these SNPs was associated with disease. Although an excellent candidate, we conclude that CTNNA3 is unlikely to account for the AD susceptibility locus on chromosome 10.


The hydrophobic effect of nanoparticles composed of amphiphilic poly(γ-glutamic acid) on the degradability of the encapsulated proteins.
For the development of safe and effective next-generation vaccine carriers, their physicochemical properties (size, shape, surface charge, and hydrophobic/hydrophilic balance) are crucial to control their interactions (cellular uptake, intracellular degradability of the loaded antigen, and intracellular localization) with immune cells. Recently, the hydrophobicity of carriers affected the cellular uptake and immune response, which demonstrated that hydrophobicity is one of the most important factors to control the behaviors of the loaded antigens and carriers. In this study, we investigated the effect of the hydrophobicity of nanoparticles (NPs) composed of amphiphilic poly(γ-glutamic acid)-graft-phenylalanine ethyl ester (γ-PGA-Phe) with various grafting degrees of hydrophobic side chains on cellular uptake of the encapsulated antigens, their degradability, and their release behavior in the endosomal environment. These NPs could encapsulate proteins, and the degradability of the encapsulated proteins was changed by the hydrophobicity of NPs. On the other hand, the release behavior of the encapsulated proteins was not changed by the hydrophobicity of NPs. These results suggest that the intracellular behaviors of the encapsulated protein could be controlled by the hydrophobicity of NPs, and could result in the manipulation of the antigen-specific immune responses.


[Efficacy of quadropril (spirapril) vs capropril in treatment of essential hypertension].
To compare the efficacy of monotherapy with quadropril (spirapril) vs captopril in essential hypertension. 20 female patients aged 55 +/- 2 years with moderate hypertension (WHO classification) were included in the study. 16 patients had congestive heart failure stage II NYHA and 4 patients stage III NYHA. ECG and echocardiography were performed in all the patients. Two patient groups of 10 patients were treated for 6 weeks. Group 1 received 6 mg quadropril once daily. Group 2 received 25 mg captopril 3 times daily. The therapy was considered to be efficient if diastolic pressure (BP) was reduced to 90 +/- 5 mm Hg and systolic BP to 140 +/- 10 mm Hg from baseline values in the range of 210/120-170/100 mm Hg. The hypotensive effect of quadropril resulted in stabilisation of BP during the second week of therapy. A significant BP decrease was achieved at the end of 6 week therapy. Systolic BP fell from 178.8 +/- 3.2 to 145 +/- 5.6 mm Hd and diastolic BP from 109.7 +/- 1.2 to 92.4 +/- 1.7 mm Hg. Central and cardiac hemodynamic parameters improved. In one patient the condition improved from CHF stage III to stage II NYHA. No adverse effects were observed. A hypotensive effect of captopril reduced significantly systolic blood pressure from 182.1 +/- 2.7 to 150 +/- 4.6 mm Hg and diastolic BP from 110.4 +/- 1.1 to 100.1 +/- 1.9 mm Hg. Two patients developed adverse effects: cough and chest dyscomfort. Quadropril monotherapy showed to be more effective in diastolic BP decrease compared with captopril monotherapy and had advantages in one daily dose regimen, absence of the first dose effect and side effects.


Evaluation of Family and Community Social Network Characteristics Among High-Risk Family Members to Improve Cancer-Related Health Behaviors.
To evaluate the effects of social network characteristics of individuals with a family history of cancer on the use of cancer-related services (e.g., screening, genetic counseling/testing). 170 family members of individuals with the most common hereditary or familial cancers. Data collection occurred between March and September 2021 using an online survey. Having strong within-immediate family relationships and family members who underwent more screening procedures was associated with increased breast cancer screening, and having more family members with cancer was associated with colorectal cancer screening. Having a large family, having family members who underwent screening for more cancers, and having strong social cohesion among families were associated with an increased rate of genetic testing. Nurses working with families affected by cancer should focus on strategies to strengthen relationships among family members to improve knowledge of cancer screening and available genetic services.


Erysipelas in a black and red tamarin.
Erysipelothrix rhusiopathiae was isolated in large numbers from the kidneys and was visualized histologically in the kidneys, heart muscle, skeletal muscle, selected lymph nodes, and the submandibular salivary glands of a black and red tamarin (Saguinus nigricollis) following an acute fatal illness. Sites (heart valves, joints) usually associated with disease mediated by E rhusiopathiae appeared uninvolved.


Suspected facial eczema in sheep in the central Orange Free State.
Facial eczema is known to occur in the Humansdorp district of the Cape Province. During June 1982-January 1984, 5 outbreaks of hepatogenous photosensitivity occurred in sheep in central districts of the Orange Free State. In one of these outbreaks a diagnosis of suspected facial eczema was made histologically.


[Comparison of oral administration and intramuscular injection of thymus preparations on the leukopoiesis test in rats and some of the preventive possibilities emerging from the results].
Considering the fact that all immunologic processes consume energy, we have been attempting for more than a decade to combine immunostimulating measures with such for increasing the energetic state. This basic resulted in designing several modern variants of the Oxygen Multistep Immunostimulation. In order to make this method broadly applicable to public health care, its protocol had to be simplified in such a way that it can easily be applied also to outpatients at a reasonable expenditure of time. Such a program is described here among other variants. Its concept is based on measurements of leukopoiesis in rats after administration of thymus extract. The test system used revealed that oral administration of the thymus extract taken from specified dragées was of at least the same effect as intramuscular injection. The simplified variant of the Oxygen Multistep Immunostimulation which can be practised ambulantly within a short time, consists of the administration of thymus dragées and the 15-min-oxygen multistep quick procedure of the Oxygen Multistep Therapy. It is demonstrated by comparison of photographs of a case report the precancerous skin lesions can be unprimed by this simple treatment within 10 months. The finding indicates that along these lines a permanently effective cancer prevention might become practicable. Furthermore, it is supposed that the simple treatment schedule described should be of benefit in preventive medicine and gerontology as well, in order to fight illness in general and to reduce the disposition to diseases having a bad prognosis particularly in old age.


Spectrum and prevalence of vasculopathy in pediatric neurofibromatosis type 1.
To describe the spectrum and associated clinical features of peripheral and cerebral vasculopathy in pediatric patients with neurofibromatosis type 1, children seen at a single center from 2000 to 2010 with appropriate imaging studies were identified. Scans were assessed for vascular disease by 2 pediatric neuroradiologists. Of 181 children, 80 had pertinent imaging studies: 77 had brain imaging, 6 had peripheral imaging, and 3 had both. Vasculopathy was identified in 14/80 children (18%, minimum prevalence of 14/181; 8%). Of those with vascular abnormalities, 2/14 had peripheral vasculopathy (1% minimum prevalence) and 12/14 had cerebrovascular abnormalities (7% minimum prevalence). No associations were found between vasculopathy and common clinical features of neurofibromatosis type 1, including optic pathway glioma, plexiform neurofibroma, skeletal abnormalities, attention-deficit hyperactivity disorder (ADHD), or suspected learning disability. Both peripheral and cerebral vasculopathy are important complications of pediatric neurofibromatosis type 1 and should be considered in the management of this complex disease.


Effect of eucapnic hypoxia on bronchomotor tone and on the bronchomotor response to dry air in asthmatic subjects.
Because hypoxia has been shown to cause bronchoconstriction and to potentiate bronchomotor responsiveness in animals, we investigated whether hypoxia has similar effects in subjects with asthma. We measured specific airway resistance (SRaw; the mean of 5 sequential readings taken 30 s apart) before and immediately after each of 15 asthmatic subjects breathed a mixture of 8% O2 in N2 until hemoglobin saturation (SaO2; by ear oximetry) fell to 80% or less for at least 2 min. We maintained end-tidal CO2 at resting levels, the temperature of the inspirate at 22.0 +/- 1.1 degrees C, and the dew point at 18.5 +/- 1.6 degrees C (mean +/- SD). The SaO2 fell to 70 +/- 8%; minute ventilation rose to 28.4 +/- 8.5 L/min, and heart rate rose by 27 +/- 6 beats/min. The SRaw did not increase significantly in the group (baseline SRaw, 6.61 +/- 2.36; posthypoxia SRaw, 6.69 +/- 2.21 L X cm H2O/L/s) or in any subject. To determine if hypoxia increases bronchomotor responsiveness, we also compared the responses to eucapnic hyperpnea with dry air and with dry gas mixtures of 7 to 10% O2 in N2 in a randomized, double-blind sequence in 9 of the subjects. We measured SRaw in each subject before and after stepwise increases in minute ventilation, for 3 min at each level, until SRaw doubled or until the subject's maximal voluntary ventilation was achieved. The SaO2 fell to 82% or less at each level of ventilation with the hypoxic gas mixture. The 2 stimulus-response curves thus obtained did not differ in any subject.(ABSTRACT TRUNCATED AT 250 WORDS)


Expression of the coat protein of potato virus X from a dicistronic mRNA in transgenic potato plants.
Transgenic potato plants were generated which express a dicistronic mRNA corresponding to the 8 kDa protein and coat protein (CP) genes of potato virus X (PVX). Northern blot analysis of RNA isolated from these plants indicated that both the 8 kDa protein and the CP are translated from this dicistronic mRNA. Expression of both of these proteins in transgenic plants was demonstrated by Western blot analysis, and suggests that translation of CP takes place either by initiation by internal entry of ribosomes or by a termination/reinitiation mechanism. CP was detected in protoplasts electroporated with RNA transcripts of the dicistronic construct in the presence or absence of a stable hairpin structure at the 5' terminus, suggesting that the former model is more likely. Similar results were obtained when a DNA fragment containing the PVX CP leader sequence was placed between two reporter genes in the transient assay system. These results suggest that potexvirus CP expression may take place from the genomic RNA as well as from the subgenomic RNA.


Projected impact of population aging on non-communicable disease burden and costs in the Kingdom of Saudi Arabia, 2020-2030.
The number of people aged greater than 65 years per 100 people aged 20-64 years is expected to almost double in The Kingdom of Saudi Arabia (KSA) between 2020 and 2030. We therefore aimed to quantify the growing non-communicable disease (NCD) burden in KSA between 2020 and 2030, and the impact this will have on the national health budget. Ten priority NCDs were selected: ischemic heart disease, stroke, type 2 diabetes, chronic obstructive pulmonary disease, chronic kidney disease, dementia, depression, osteoarthritis, colorectal cancer, and breast cancer. Age- and sex-specific prevalence was projected for each priority NCD between 2020 and 2030. Treatment coverage rates were applied to the projected prevalence estimates to calculate the number of patients incurring treatment costs for each condition. For each priority NCD, the average cost-of-illness was estimated based on published literature. The impact of changes to our base-case model in terms of assumed disease prevalence, treatment coverage, and costs of care, coming into effect from 2023 onwards, were explored. The prevalence estimates for colorectal cancer and stroke were estimated to almost double between 2020 and 2030 (97% and 88% increase, respectively). The only priority NCD prevalence projected to increase by less than 60% between 2020 and 2030 was for depression (22% increase). It is estimated that the total cost of managing priority NCDs in KSA will increase from USD 19.8 billion in 2020 to USD 32.4 billion in 2030 (an increase of USD 12.6 billion or 63%). The largest USD value increases were projected for osteoarthritis (USD 4.3 billion), diabetes (USD 2.4 billion), and dementia (USD 1.9 billion). In scenario analyses, our 2030 projection for the total cost of managing priority NCDs varied between USD 29.2 billion - USD 35.7 billion. Managing the growing NCD burden in KSA's aging population will require substantial healthcare spending increases over the coming years.


p53 N-terminus-targeted protein kinase activity is stimulated in response to wild type p53 and DNA damage.
The p53 tumour suppressor protein plays a central role in the cellular defence against agents which cause genetic damage. The activity of p53 is regulated at different levels and is subject to multi-site phosphorylation by a variety of different protein kinases. In this paper we have characterised p53 N-terminus-targeted protein kinase (p53NK) activities, present in a range of cell lines, following fractionation of cellular lysates by ion exchange chromatography on HiTrap Q and Mono Q resins. Three peaks of p53NK activity were observed following fractionation of HeLa cell lysates; these activities were each able to catalyse phosphorylation of up to three residues (serines 4, 6 and 9 in murine p53) within the N-terminus of the p53 protein. Similarly, multiple p53NK activities were detected in the MethAp53(ts) cell line (which expresses the valine 135 temperature-sensitive p53 protein). Strikingly, when these cells were shifted from 38 degrees C (the non-permissive temperature) to 28 degrees C, at which the p53 adopts a wild type conformation, a fivefold stimulation of kinase activity was detected. Moreover, when the DNA damage-inducing drugs etoposide or camptothecin were added to the cells, a further stimulation of kinase activity was observed following growth at 28 degrees C, but not 38 degrees C. These data are consistent with a regulatory model in which p53 is sensitive to stress or DNA damage through phosphorylation at its N-terminus.


Grain setting defect1, encoding a remorin protein, affects the grain setting in rice through regulating plasmodesmatal conductance.
Effective grain filling is one of the key determinants of grain setting in rice (Oryza sativa). Grain setting defect1 (GSD1), which encodes a putative remorin protein, was found to affect grain setting in rice. Investigation of the phenotype of a transfer DNA insertion mutant (gsd1-Dominant) with enhanced GSD1 expression revealed abnormalities including a reduced grain setting rate, accumulation of carbohydrates in leaves, and lower soluble sugar content in the phloem exudates. GSD1 was found to be specifically expressed in the plasma membrane and plasmodesmata (PD) of phloem companion cells. Experimental evidence suggests that the phenotype of the gsd1-Dominant mutant is caused by defects in the grain-filling process as a result of the impaired transport of carbohydrates from the photosynthetic site to the phloem. GSD1 functioned in affecting PD conductance by interacting with rice ACTIN1 in association with the PD callose binding protein1. Together, our results suggest that GSD1 may play a role in regulating photoassimilate translocation through the symplastic pathway to impact grain setting in rice.


Modes of metal toxicity and impaired branchial ionoregulation in rainbow trout exposed to mixtures of Pb and Cd in soft water.
Models such as the Biotic Ligand Model (BLM) predict how natural organic matter (NOM) and competing ions (e.g., Ca(2+), H(+) and Na(+)) affect metal bioavailability and toxicity in aquatic organisms. However, such models focus upon individual metals, not metal mixtures. This study determined whether Pb and Cd interact at the gill of rainbow trout (Oncorhynchus mykiss) when trout were exposed to environmentally relevant concentrations of these metals (Cd<100 nmol L(-1); Pb<500 nmol L(-1)) in soft (<100 micromol Ca(2+)L(-1)), moderately acidic (pH 6.0) water. The 96-h LC50 for Pb was 482 nmol L(-1), indicating that Pb was one-order of magnitude more toxic in soft, acidic water than in harder, circumneutral pH waters. The LC50 for Cd alone was also low, 6.7 nmol L(-1). Surprisingly, fish acclimated to soft water had multiple populations of Pb-gill and Cd-gill binding sites. A low capacity, high affinity population of Pb-gill binding sites had a B(max) of 18.2 nmol g(-1) wet weight (ww) and apparent K(Pb-gill)=7.05, but a second low affinity population could not be saturated up to free Pb concentrations approaching 4000 nmol L(-1). Two populations of Cd-gill binding sites were characterized: a high affinity, low capacity population with an apparent K(Cd-gill)=7.33 and B(max)=1.73 nmol g(-1) ww, and a low affinity, high capacity population with an apparent K(Cd-gill)=5.86, and B(max)=13.7 nmol g(-1) ww. At low concentrations, Cd plus Pb accumulation was less than additive because Cd out-competed Pb for gill binding sites, which were likely apical Ca(2+)-channels. While disturbances to Ca(2+) influx were caused by Cd alone, Pb alone had no effect. However, Pb exacerbated Cd-induced disturbances to Ca(2+) influx demonstrating that, although Pb- plus Cd-gill binding was less than additive due to competition, the effects (ionic disturbances) were more than additive (synergistic). Pb was also likely binding to intracellular targets, such as branchial carbonic anhydrase, which led to inhibited Na(+) influx. This ionic disturbance was exacerbated by Cd. We conclude that exposure to environmentally relevant concentrations of Pb plus Cd results in less than additive metal-gill binding in soft, moderately acidic waters. However, ionic disturbances caused by Cd plus Pb are greater than additive, and this may ultimately increase the toxicity of Cd-Pb mixtures to fishes. Our findings suggest that it may be necessary to re-evaluate water quality criteria and assumptions of the BLM for fish exposed to mixtures of Pb and Cd in the acidic, soft waters found in the Canadian Shield, Scandinavia and other sensitive regions.


Intermittent hypoxia increases ventilation and Sa(O2) during hypoxic exercise and hypoxic chemosensitivity.
The purpose of this study was 1) to test the hypothesis that ventilation and arterial oxygen saturation (Sa(O2)) during acute hypoxia may increase during intermittent hypoxia and remain elevated for a week without hypoxic exposure and 2) to clarify whether the changes in ventilation and Sa(O2) during hypoxic exercise are correlated with the change in hypoxic chemosensitivity. Six subjects were exposed to a simulated altitude of 4,500 m altitude for 7 days (1 h/day). Oxygen uptake (VO2), expired minute ventilation (VE), and Sa(O2) were measured during maximal and submaximal exercise at 432 Torr before (Pre), after intermittent hypoxia (Post), and again after a week at sea level (De). Hypoxic ventilatory response (HVR) was also determined. At both Post and De, significant increases from Pre were found in HVR at rest and in ventilatory equivalent for O2 (VE/VO2) and Sa(O2) during submaximal exercise. There were significant correlations among the changes in HVR at rest and in VE/VO2 and Sa(O2) during hypoxic exercise during intermittent hypoxia. We conclude that 1 wk of daily exposure to 1 h of hypoxia significantly improved oxygenation in exercise during subsequent acute hypoxic exposures up to 1 wk after the conditioning, presumably caused by the enhanced hypoxic ventilatory chemosensitivity.


Relationship between sleep duration and body mass index depends on age.
Sleep duration is associated with obesity and cardiometabolic disease. It is unclear, though, how these relationship differs across age groups. Data from 2007 to 2008 National Health and Nutrition Examination Survey (NHANES) were used, including respondents aged 16+ with complete data (N = 5,607). Sleep duration and age were evaluated by self-report, and body mass index (BMI) was assessed objectively. Sleep duration was evaluated continuously and categorically [very short (≤4 h), short (5-6 h), and long (≥9 h) versus average (7-8 h)]. Age was also evaluated continuously and categorically [adolescent (16-17 years), young adult (18-29 years), early middle age (30-49 years), late middle age (50-64 years), and older adult (≥65 years)]. There was a significant interaction with age for both continuous (Pinteraction = 0.014) and categorical (Pinteraction = 0.035) sleep duration. A pseudo-linear relationship was seen among the youngest respondents, with the highest BMI associated with the shortest sleepers and the lowest BMI associated with the longest sleepers. This relationship became U-shaped in middle-age, and less of a relationship was seen among the oldest respondents. These findings may provide insights for clinical recommendations and could help to guide mechanistic research regarding the sleep-obesity relationship.


Are Self-Efficacy and Weight Perception Associated With Physical Activity and Sedentary Behavior in Hispanic Adolescents?
Little is known about the correlates of physical activity and sedentary behavior in Hispanic adolescents. This study examined at baseline and 2-year follow-up: (1) the relationship between self-efficacy for physical activity and physical activity, (2) the association of weight perception with physical activity and sedentary behavior, and (3) whether sex moderated these associations. Hispanic adolescents ( N = 483 at baseline; age 15-17 years; 55.1% girls) completed questionnaires that assessed their self-efficacy for physical activity, weight perception, and time spent in physical activity and sedentary behavior. Multiple-group path analyses were conducted to examine the proposed relationships and determine whether they were moderated by sex. Models controlled for body mass index, weight loss intention, participation on a sports team, language spoken at home, parental education, and country of birth. Self-efficacy was related to time spent in physical activity in boys ( b = .35, p < .001) and girls ( b = .41, p < .001) at baseline, but not 2 years later. No association was found for weight perception and time spent in physical activity and sedentary behavior. Post hoc analyses for overweight participants at baseline showed that weight perception was associated with time spent watching television. Overall, the findings suggest that self-efficacy is an important correlate, but not a predictor, of physical activity among Hispanic adolescents. Including strategies to address and enhance self-efficacy for physical activity in lifestyle interventions may increase adherence to physical activity recommendations and help reduce the high prevalence of obesity in this population.


The time course of metabolites in human plasma after 6-[(18)F]fluoro-l-m-tyrosine administration.
For the investigation of intracerebral dopamine metabolism, 6-[(18)F]fluoro-l-m-tyrosine (FmT) has been proposed as an alternative tracer that, unlike 6-[(18)F]fluoro-l-dopa, is not subjected to O-methylation. We have studied the time course of FmT and its labelled metabolites in plasma after intravenous injection into humans, employing a method that we have developed and validated to analyze labelled metabolites of FmT in plasma. The study population comprised 38 subjects, 14 of whom were taking an aromatic amino acid decarboxylase inhibitor (carbidopa), and obtained arterialized venous blood samples at various times after an intravenous injection of between 185 and 370 MBq of FmT. The major metabolite of FmT present in plasma was 6-[(18)F]fluoro-3-hydroxyphenylacetic acid. The time course of the fraction of radioactivity in plasma attributable to FmT was fitted well by the decay of two exponential functions. The fast component of the decay accounted for 40%-50% of the radioactivity and had a half-life of about 5 min. The slow component of the decay had a half-life of about 6 h in the subjects not taking carbidopa and 20 h in the patients taking carbidopa. When the total available FmT was calculated for each individual subject and expressed as a proportion of total radioactivity, this quantity did not differ significantly from that determined from the corresponding population mean. There was significantly more (15% on average) FmT available over the course of the 2-h experiment in the group pretreated with carbidopa. Our results demonstrate that the major metabolite in plasma after an intravenous injection of FmT is 6-[(18)F]fluoro-3-hydroxyphenylacetic acid. The clearance of FmT from plasma compares well with the clearance of intravenously administered levodopa. Carbidopa increases significantly the availability of FmT in plasma. These results verify, in a large number of human subjects, earlier analyses of FmT metabolism in other species. We validate a population-derived approach that can adequately describe the time course of FmT in plasma, alleviating the need for metabolite analysis.


[Is ironic meaning activated before considering common ground?].
This study used an on-line method to explore whether the perception of irony occurs before considering common ground between speaker and listener. In Experiment 1 and 2, the shared common ground between the speaker and the listener was manipulated, and a meaningfulness-decision task was conducted immediately after the presentation of ironical utterances. The results showed that a priming effect was obtained only when common ground was shared by the speaker and the listener when utterances were presented with long duration (1800 ms). When utterances were presented with a short duration (1000 ms), however, priming effects were obtained regardless of the common ground. In Experiment 3, no priming effect was obtained when the contexts were presented without the utterances. The results suggest that ironic meaning is activated from an egocentric perspective at an early stage of processing and is inhibited at a later stage if it is not intended.


Personalized health care in 2013: a status report on the impact of genomics.
This issue of the NCMJ describes the impact that genomics has had on the practice of medicine in the decade since the full sequencing of the human genome was completed in 2003. Specifically, it reports on how genomics is affecting health care delivery, describes the concept of personalized health care, and discusses the role that genomics plays in such care. The commentaries and sidebars that follow highlight the opportunities and challenges of bringing genomics into clinical practice. Reading these articles will hopefully give clinicians and others a better understanding of the benefits and limitations of genomic technologies. Emerging capabilities, resulting in part from genomic research, are providing an opportunity to move health care from a reactive, disease-focused model to one that is personalized, predictive, proactive, precise, and patient-centered. Genomics and related technologies have already changed many approaches to care, particularly in the field of oncology, and I believe they will help to transform our overall approach to the delivery of health care. With the rapidly accumulating capabilities being developed and the focus on patient-centered and personalized care, I expect that the practice of medicine will become proactive and personalized within the next decade.


Evaluation of the excretory urogram in adult enuresis.
Excretory urograms in 216 primary enuretic adult males aged between 18 and 20 years were retrospectively evaluated. In no patient was there a finding considered relevant to the complaint. It is considered that, in the absence of urinary infection or other urological complaint in a patient with normal neurological status, excretory urography is a non-contributory examination in the investigation of adult male enuresis.


Unveiling the complex configurational landscape of the intralayer cavities in a crystalline carbon nitride.
The in-depth understanding of the reported photoelectrochemical properties of the layered carbon nitride, poly(triazine imide)/LiCl (PTI/LiCl), has been limited by the apparent disorder of the Li/H atoms within its framework. To understand and resolve the current structural ambiguities, an optimized one-step flux synthesis (470 °C, 36 h, LiCl/KCl flux) was used to prepare PTI/LiCl and deuterated-PTI/LiCl in high purity. Its structure was characterized by a combination of neutron/X-ray diffraction and transmission electron microscopy. The range of possible Li/H atomic configurations was enumerated for the first time and, combined with total energy calculations, reveals a more complex energetic landscape than previously considered. Experimental data were fitted against all possible structural models, exhibiting the most consistency with a new orthorhombic model (Sp. Grp. Ama2) that also has the lowest total energy. In addition, a new Cu(i)-containing PTI (PTI/CuCl) was prepared with the more strongly scattering Cu(i) cations in place of Li, and most closely matching with the partially-disorder structure in Cmc21. Thus, a complex configurational landscape of PTI is revealed to consist of a number of ordered crystalline structures that are new potential synthetic targets, such as with the use of metal-exchange reactions.


The critical role of IL-15 in the antitumor effects mediated by the combination therapy imatinib and IL-2.
The synergistic antitumor effects of the combination therapy imatinib mesylate (IM) and IL-2 depended upon NK1.1- expressing cells and were associated with the accumulation of CD11c(int)B220(+)NK1.1(+) IFN-producing killer dendritic cells (IKDC) into tumor beds. In this study, we show that the antitumor efficacy of the combination therapy was compromised in IL-15 and IFN-type 1R loss-of-function mice. IL-15Ralpha was required for the proliferation of IKDC during IM plus IL-2 therapy. Trans-presentation of IL-15/IL-15Ralpha activated IKDC to express CCR2 and to respond to type 1 IFN by producing CCL2. Moreover, the antitumor effects of the combination therapy correlated with a CCL2-dependent recruitment of IKDC, but not B220(-) NK cells, into tumor beds. Altogether, the IL-15-driven peripheral expansion and the CCL-2-dependent intratumoral chemoattraction of IKDC are two critical parameters dictating the antitumor efficacy of IM plus IL-2 in mice.


Nonvolatile Memristive Effect in Few-Layer CrI3 Driven by Electrostatic Gating.
The potential of memristive devices for applications in nonvolatile memory and neuromorphic computing has sparked considerable interest, particularly in exploring memristive effects in two-dimensional (2D) magnetic materials. However, the progress in developing nonvolatile, magnetic field-free memristive devices using 2D magnets has been limited. In this work, we report an electrostatic-gating-induced nonvolatile memristive effect in CrI3-based tunnel junctions. The few-layer CrI3-based tunnel junction manifests notable hysteresis in its tunneling resistance as a function of gate voltage. We further engineered a nonvolatile memristor using the CrI3 tunneling junction with low writing power and at zero magnetic field. We show that the hysteretic transport observed is not a result of trivial effects or inherent magnetic properties of CrI3. We propose a potential association between the memristive effect and the newly predicted ferroelectricity in CrI3 via gating-induced Jahn-Teller distortion. Our work illuminates the potential of 2D magnets in developing next-generation advanced computing technologies.


Broad phenotypic cross-resistance to elvitegravir in HIV-infected patients failing on raltegravir-containing regimens.
The failure of raltegravir (RAL) is generally associated with the selection of mutations at integrase position Y143, Q148, or N155. However, a relatively high proportion of failures occurs in the absence of these changes. Here, we report the phenotypic susceptibilities to RAL and elvitegravir (EVG) for a large group of HIV-infected patients failing on RAL-containing regimens. Plasma from HIV-infected individuals failing on RAL-containing regimens underwent genotypic and phenotypic resistance testing (Antivirogram v2.5.01; Virco). A control group of patients failing on other regimens was similarly tested. Sixty-one samples were analyzed, 40 of which belonged to patients failing on RAL-containing regimens. Full RAL susceptibility was found in 20/21 controls, while susceptibility to EVG was diminished in 8 subjects, with a median fold change (FC) of 2.5 (interquartile range [IQR], 2.1 to 3.1). Fourteen samples from patients with RAL failures showed diminished RAL susceptibility, with a median FC of 38.5 (IQR, 10.8 to 103.2). Primary integrase resistance mutations were found in 11 of these samples, displaying a median FC of 68.5 (IQR, 23.5 to 134.3). The remaining 3 samples showed a median FC of 2.5 (IQR, 2 to 2.7). EVG susceptibility was diminished in 19/40 samples from patients with RAL failures (median FC, 7.71 [IQR, 2.48 to 99.93]). Cross-resistance between RAL and EVG was high (R(2) = 0.8; P < 0.001), with drug susceptibility being more frequently reduced for EVG than for RAL (44.3% versus 24.6%; P = 0.035). Susceptibility to RAL and EVG is rarely affected in the absence of primary integrase resistance mutations. There is broad cross-resistance between RAL and EVG, which should preclude their sequential use. Resistance to EVG seems to be more frequent and might be more influenced by integrase variability.


Impairment of autonomically mediated heart rate control in patients with cardiac dysfunction.
Patients with cardiac disorders have defective parasympathetic control of heart rate. To evaluate the possibility of similar changes in sympathetic control of heart rate, we compared reflex chronotropic responses to 80 degree upright tilt and nitroglycerin-induced hypotension in 31 cardiac patients and 7 normal individuals before and after partial parasympathetic blockade with atropine. Tilting revealed an attenuation of the normal heart rate increase in patients; the magnitude of this defect was greatest in patients with more severe symptoms (class III) and evidence of left ventricular dysfunction (the heart rate increase averaged 25 plus or minus 3 beats/min in normal subjects, 12 plus or minus 2 beats/min in class I-II patients, and 7 plus or minus 1 beats/min in class III patients). Class III symptoms due to mechanical causes (mitral stenosis), however, were not associated with this defect. A marked reduction in heart rate rise with hypotension was seen only in those class III patients without mitral stenosis (0.4 plus or minus 0.1 beats min-minus 1 mm Hg-minus 1 vs. 3.0 plus or minus 0.5 beats min-minus 1 mm Hg-minus 1 in normal subjects). This abnormality also persisted after atropine administration, thus confirming a defect in the sympathetic as well as the parasympathetic component of baroreceptor-mediated reflex heart rate control in patients with cardiac dysfunction. Infusions of isoproterenol produced equivalent rises in heart rate in patients and normal individuals, excluding a reduction in beta-receptor responsiveness as a cause of impaired sympathetic influence. Norepinephrine depletion, however, is a well-recognized concomitant of cardiac failure. It is possible that the reduction in sympathetically mediated heart rate responses results in part from depletion of the sympathetic neurotransmitter.


[Individual anatomical variability of the cerebellar nuclei].
While studying the cerebellar grey nuclei in serial horizontal sections performed at the distance of 0.5 mm from each other, a considerable individual variability was revealed. For example, the denticulate nucleus, which has greater dimentions than other cerebellar nuclei, was present in all preparations in all three planes. The emboliform nucleus, which has smaller dimentions than the denticulate nucleus, varied within greater limits in all three planes, and it was rather difficult to find its permanent zone of presence. The spherical nucleus was of small dimentions and has a wide range of individual variability, therefore, it was not possible to demonstrate its permanent place in all preparations of all three planes. The tegmental nucleus, as small as the spherical nucleus in its dimentions, was permanently demonstrated only in the medial-sagittal plane, and in two other planes its position varied-within wide range.


A survey of fully haploidentical hematopoietic stem cell transplantation in adults with high-risk acute leukemia: a risk factor analysis of outcomes for patients in remission at transplantation.
Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is an alternative treatment to patients with high-risk acute leukemia lacking a human leukocyte antigen-matched donor. We analyzed 173 adults with acute myeloid leukemia (AML) and 93 with acute lymphoblastic leukemia (ALL) who received a haplo-HSCT in Europe. All grafts were T cell-depleted peripheral blood progenitor cells from a direct family or other related donor. At transplantation, there were 25 patients with AML in CR1 (complete remission 1), 61 in more than or equal to CR2, and 87 in nonremission, and 24 with ALL in CR1, 37 in more than or equal to CR2, and 32 in nonremission. Median follow-up was 47 months in AML and 29 months in the ALL groups. Engraftment was observed in 91% of the patients. Leukemia-free survival at 2 years was 48% plus or minus 10%, 21% plus or minus 5%, and 1% for patients with AML undergoing transplantation in CR1, more than or equal to CR2, and nonremission, and 13% plus or minus 7%, 30% plus or minus 8%, and 7% plus or minus 5% in ALL patients, respectively. In conclusion, haplo-HSCT can be an alternative option for the treatment of high-risk acute leukemia patients in remission, lacking a human leukocyte antigen-matched donor.


[Patient's point of view on surgical innovations: for less traumatic surgery and enhanced recovery].
Surgical innovations (associating LESS, NOTES, robotics, images software and Fast-track surgery) will allow a less and less invasive surgery. While these advances could be view as surgical or industrial marketing, or compared to the laparoscopic revolution, they simply answer patients' demand in a society changing its standard regarding: medical care, body image, recovery and rehabilitation. We will in this paper, according to results of a Google Survey analyzing population expectations of surgery, evaluate the interest of these surgical innovations. While, these innovations at least in part answers patients expectation, their therapeutic validity will have to be proved. It is our job, to foresee the future of surgery in accordance with health care system needs and patients expectation for adequate implementation of these innovations.