Prospective Endoscopic Activity Assessment for Eosinophilic Gastritis in a Multisite Cohort.
Eosinophilic gastritis (EG) is a chronic inflammatory disease of the stomach characterized by eosinophil-predominant gastric mucosal inflammation and gastrointestinal symptoms. The aim of this study was to prospectively evaluate endoscopic features in a large series of children and adults with EG to better understand the endoscopic manifestations and develop a standardized instrument for investigations. Data were prospectively collected as part of the Consortium for Eosinophilic Gastrointestinal Disease Researchers, a national collaborative network. Endoscopic features were prospectively recorded using a system specifically developed for EG, the EG Endoscopic Reference System (EG-REFS). Correlations were made between EG-REFS and clinical and histologic features. Of 98 patients with EG, 65 underwent assessments using EG-REFS. The most common findings were erythema (72%), raised lesions (49%), erosions (46%), and granularity (35%); only 8% of patients with active histology (≥30 eosinophils/high-power field) exhibited no endoscopic findings. A strong correlation between EG-REFS scores and physician global assessment of endoscopy severity was demonstrated (Spearman r = 0.84, P < 0.0001). The overall score and specific components of EG-REFS were more common in the antrum than in the fundus or body. EG-REFS severity was significantly correlated with active histology, defined by a threshold of ≥30 eosinophils/high-power field (P = 0.0002). Prospective application of EG-REFS identified gastric features with a strong correlation with physician global assessment of endoscopic activity in EG. Endoscopic features demonstrated greater severity in patients with active histology and a predilection for the gastric antrum. Further development of EG-REFS should improve its utility in clinical studies.


Cholinergic innervation of the smooth muscle cells in the choroid coat of the chick eye and its development.
The mechanical and pharmacological characteristics of the cholinergic activation of the smooth muscle in the choroidal coat of the chick eye have been assessed in tissues isolated from birds 1 d posthatching using histological, electrophysiological, and immunological techniques. The choroidal coat is innervated by a dense network of cholinergic nerves that make en passant synapses with smooth muscle. Thirty-hertz stimulation of these nerves initiates red blood cell (RBC) movement in the vessels of the choroidal coat, and this activation is blocked by muscarinic ACh receptor (AChR) antagonists. Force-transducer recordings of nerve-induced contractions of this tissue have a slow onset and relaxation time course similar to those of smooth muscle contractions. Furthermore, since nearly half the cholinergic neurons innervating the choroid die within a defined period during development, the onset and pharmacology of this innervation were studied during embryogenesis. With a neural cytoskeletal-like immunostain, we demonstrated that choroid axons are present in peripheral tissue by stage (St) 29. Extracellular electrical recordings made after choroid nerve stimulation allowed us to distinguish axon from muscle responses. These procedures permitted us to examine the time course of the innervation of the smooth muscle. However, to visualize the postsynaptic smooth muscle response, it was necessary to treat the isolated preparation with tetraethylammonium chloride (TEA). Accordingly, TEA-enhanced electrical smooth muscle responses to single-nerve stimuli could be recorded only after St 39. Treatment of the nerve-muscle preparation with prostigmine allowed the recording of TEA-enhanced electrical activity as early as St 36 (1 d after the beginning of the normal choroid neuron death period). This synaptic activation was completely blocked by atropine or quinuclidinyl benzylate (QNB), and was not affected by alpha bungarotoxin (alpha BTX), indicating that, as in the posthatching tissue, neuromuscular transmission is mediated by muscarinic receptors. These results show that cholinergic muscarinic activation of the choroidal coat can occur as early as St 36, but that it is not as efficient as transmission later in embryogenesis.


Heartless, a Drosophila FGF receptor homolog, is essential for cell migration and establishment of several mesodermal lineages.
A Drosophila FGF receptor homolog (DFGF-R2/DFRI) termed Heartless (Htl) is expressed in the embryonic mesoderm. The phenotypes of null mutant embryos demonstrated that Htl is a central player that is required for the development of several mesodermal lineages. No abnormalities in the primary specification of the mesoderm were observed. The first defects were seen as irregular migration and spreading of the mesoderm over the ectoderm. Subsequently, cell fates were not induced in several lineages including the visceral mesoderm, heart, and the dorsal somatic muscles. The defects in the induction of cell fates are likely to result from failure of the mesoderm to spread over the ectoderm and receive patterning signals. The defective spreading could be circumvented in htl mutant embryos by providing an ectopic Dpp patterning signal, leading to the formation of heart and dorsal muscle cells. Htl appears to be required also subsequently during the migration and morphogenesis of the different lineages. Expression of a dominant-negative htl construct after the initial induction of cell fates gave rise to aberrant migration and organization of the visceral mesoderm, heart, and somatic muscles. Thus, a common role for Htl in cell migration and tissue organization may account for the pleiotropic defects of the htl mutation.


Supporting transitions in medical career pathways: the role of simulation-based education.
Transitions, or periods of change, in medical career pathways can be challenging episodes, requiring the transitioning clinician to take on new roles and responsibilities, adapt to new cultural dynamics, change behaviour patterns, and successfully manage uncertainty. These intensive learning periods present risks to patient safety. Simulation-based education (SBE) is a pedagogic approach that allows clinicians to practise their technical and non-technical skills in a safe environment to increase preparedness for practice. In this commentary, we present the potential uses, strengths, and limitations of SBE for supporting transitions across medical career pathways, discussing educational utility, outcome and process evaluation, and cost and value, and introduce a new perspective on considering the gains from SBE. We provide case-study examples of the application of SBE to illustrate these points and stimulate discussion.


Understanding contributing factors to exoskeleton use-intention in construction: A decision tree approach using results from an online survey.
Work-related musculoskeletal disorders (WMSDs) are a major health concern in the construction industry. Occupational exoskeletons (EXOs) are a promising ergonomic intervention to help reduce WMSD risk. Their adoption, however, has been low in construction. To understand the contributing factors to EXO use-intention and assist in future decision-making, we built decision trees to predict responses to each of three EXO use-intention questions (Try, Voluntary Use, and Behavioral Intention), using online survey responses. Variable selection and hyperparameter tuning were used respectively to reduce the number of potential predictors and improve prediction performance. The importance of variables in each final tree was calculated to understand which variables had a greater influence. The final trees had moderate prediction performance. The root node of each tree included EXOs becoming standard equipment, fatigue reduction, or performance increase. Important variables were found to be quite specific to different decision trees. Practical implications of the findings are discussed.


Electrophysiological characteristics of the Marshall bundle in humans.
Marshall bundles (MBs) are the muscle bundles within the ligament of Marshall. This trial sought to the electrophysiological characteristics of the MB and the anatomical connections between MB and left atrium (LA) in patients with persistent atrial fibrillation (AF). We enrolled 72 patients (male:female 59:13, age 59.9 +/- 9.4 years) who underwent MB mapping and ablation for AF. MB mapping was done via an endocardial or epicardial approach during sinus rhythm and AF. Recordings were successful in 64 of 72 patients (89%). A single connection was noted in 11 of 64 patients between the MB and the coronary sinus (CS) muscle sleeves. The MB recordings showed distinct MB potentials with a proximal-to-distal activation pattern during sinus rhythm. During AF, organized passive activations and dissociated slow MB ectopic activities were commonly observed in this type of connection. Double connections to both CS and LA around left pulmonary veins were noted in 23 of 64 patients (36%). After the ablation of the distal connection, MB recording showed typical double potentials as in single connection. Multiple connections were noted in 30 of 64 patients (47%). During sinus rhythm, the earliest activation was in the middle of the MB. The activation patterns were irregular and variable in each patient. During AF, rapid and fractionated complex activations were noted in all patients of this group. We documented 3 different types of MB-LA connections. Rapid and fractionated activations were most commonly observed in the MB that had multiple LA connections.


[Cognitive traps: the case of omission in the genesis of work-related accidents].
This article discusses omissions in work-related accidents. The authors present James Reason's concepts on task characteristics which can increase the chance of operator omission. These ideas were applied to three accidents in which worker omission was given as the "cause" and "proof" of victim's guilt. Analysis of these accidents as a stepwise sequence of activities shows at least four of Reason's omissions characteristics. The expression "cognitive trap" is used to describe their simultaneous presence, and these omissions are highlighted as an organizational aspect requiring consideration in accident-prevention strategies.


[Depression and suicidal behavior of cancer inpatients: prevalence and associated factors].
To determine prevalence rates of depression and suicidal behavior among cancer inpatients and factors associated with these conditions. A total of 5357 patients consecutively admitted to a university hospital were assessed by means of the Hospital Anxiety and Depression Scale (HAD) and the suicide risk section of the Mini International Neuropsychiatric Interview (MINI). Univariate analyses adjusted for gender and age groups were performed with depression and suicide risk as dependent variables. Of those assessed, 675 had cancer. The prevalence rates for depression and suicide risk were 18.3% (95%CI = 15.4 - 21.4) and 4.7% (95%CI = 3.2 - 6.7) respectively. Depression was more frequently found in cancer bearers than in the other inpatients (13.2%; p = 0.0009). Female gender, low schooling level, long time of disease, pain, use of psychotropic drugs and suicide risk were associated with depression (p < 0.05). Pain and depression were associated with suicide risk. Because prevalence rates of depression and suicide risk are high among cancer inpatients, simple screening instruments and specific questions during interviews are needed to detect these clinical conditions.


Avian cathelicidins: paradigms for the development of anti-infectives.
The broad-spectrum defense system based on host defense peptides (HDPs) is evolutionary very old and many invertebrates rely on this system for protection from bacterial infections. However, in vertebrates the system remained important in spite of the superposition of a very sophisticated adaptive immune system. The cathelicidins comprise a major group of HDPs in mammals. About six years ago it was first described that cathelicidins are also present in birds. Here we review the properties and biological activities of the recently discovered avian cathelicidins and their potential to be used as a paradigm for the development of anti-infectives. Like the mammalian cathelicidins, avian cathelicidins exert direct antimicrobial activities but can also selectively boost host immune responses by regulation of cytokine production and recruitment of immune cells. In addition, it was found that chicken cathelicidins bind endotoxins and dampen the endotoxin-mediated inflammatory response. Molecular dissection has allowed identification of different structural elements involved in bacterial killing and immunomodulation. These studies have enabled the design of small HDP-based antibiotics with specific functions, i.e. having primarily immunomodulatory or antimicrobial activities. Since the immunomodulatory effects may, to a certain degree, be species-specific, we hypothesize that poultry-specific antibiotics can be developed based on avian cathelicidins.


Anti-idiotypic antisera raised against monoclonal antibody specific for a p24 gag region epitope detects a common interspecies idiotype associated with anti-HIV responses.
One potential strategy for the control of human immunodeficiency virus (HIV) infection is immune network manipulation using anti-idiotypic antibodies: this study was undertaken to demonstrate experimentally the potential of such an approach which, in a more highly evolved form, could be used for the treatment of the acquired immune deficiency virus (AIDS) and related disorders. Anti-idiotypic antibodies were generated in rabbits against a murine monoclonal antibody identifying an epitope on the p24 gag core protein of HIV. After extensive absorption on affinity columns to remove isotype- and allotype-specific antibodies, the purified anti-idiotypic antibody preparation was shown to have specific complementarity with the immunizing mouse monoclonal antibody. This anti-idiotypic antibody was also shown to recognize a common idiotype associated with HIV-specific antibodies from both humans and chimpanzees infected with the AIDS virus. In addition a group of rats immunized with the anti-Id responded with significant antibody titers to recombinant derived p24 gag. These data indicate that at least a subpopulation of these polyclonal anti-Id antibodies structurally mimics an HIV gag region epitope and suggest that immunoregulation by anti-idiotypic antibodies may have therapeutic utility for the AIDS epidemic.


Effect of Brivaracetam on Efficacy and Tolerability in Patients With Brain Tumor-Related Epilepsy: A Retrospective Multicenter Study.
Background: Epilepsy is a common symptom of brain tumors and is often pharmacoresistent. Among new antiseizure medications (ASMs) Brivaracetam (BRV) has been approved as adjunctive treatment for focal seizures and it was tested in non-oncological patient populations. This is the first study that retrospectively explored efficacy and tolerability of BRV as add-on therapy in brain tumor-related epilepsy (BTRE) patients. Materials and Methods: We reviewed the medical records of 33 BTRE patients from six Italian epilepsy centers; charts included tumor history, diagnosis of BTRE, BRV added as first or second add-on for uncontrolled seizures and/or adverse events (AEs) of the previous ASMs, at least 1-month follow-up, seizure frequency, and AEs assessment. Results: Thirty-three patients (19 males, mean age: 57.6 years; 14 females, mean age: 42.4 years): 11 low grade gliomas, five high grade gliomas, six meningiomas, 10 glioblastomas, one primary cerebral lymphoma. Fourteen patients had focal aware seizures, nine focal unaware, seven focal to bilateral tonic-clonic seizures, three patients presented more than one seizure type: focal unaware with focal to bilateral tonic clonic seizures (two patients) and focal aware and unaware seizures (one patient). Mean seizure frequency in the month preceding BRV introduction: 7.0; at last follow-up: 2.0 (p = 0.001). Seven patients (21.2%) reported AEs (anxiety, agitation, fatigue, vertigo) and three of them (9.0%) required drug withdrawal due to psychiatric adverse events (PAEs). Three other patients withdrew BRV: one for scarce compliance (3.0%), two for uncontrolled seizures (6.0%). Conclusion: Our results showed that BRV could be a new therapeutic option effective in reducing seizures in BTRE patients, taking into account the incidence of PAEs in this particular population. Future and larger prospective studies are needed.


Animal Behavior Models: Increased Sensitivity to Stressors and Other Environmental Experiences after Prenatal Cocaine Exposurea.
Neural compensations occurring after prenatal cocaine exposure may often permit some functional recovery, although the cost of this reorganization may be a decrease in adaptability. As we have seen in our rodent model of prenatal cocaine exposure, latent deficits may become unmasked when offspring are exposed to cognitive and environmental demands and stressors. In adolescence and adulthood, offspring exposed gestationally to cocaine exhibit characteristic decreases in stress-induced immobility along with increases in aggression under the demands of social competition. Recently, we observed that cocaine-exposed offspring are also unusually sensitive to the long-term effects of early manipulation (noninvasive heart rate testing at 16 days of age). When tested in adulthood, cocaine-exposed offspring not receiving this early experience exhibited less immobility when tested in the presence of intermittent footshock or when subsequently examined in an open field as well as more locomotion in the open field than control offspring, findings reminiscent of previous work. By contrast, these effects were normalized (shock-induced immobility) or reversed (open field immobility and locomotion) in cocaine-exposed animals given the early experience. This marked susceptibility to the effects of early manipulation was less evident in control offspring and even in a group of stunted nutritional controls. Thus, cocaine-exposed offspring may exhibit increased sensitivity not only to environmental demands and stressors, but also to the potential moderating or beneficial effects of early experiences.


"As soon as the bat met the ball, I knew it was gone": outcome prediction, hindsight bias, and the representation and control of action in expert and novice baseball players.
A virtual-reality batting task compared novice and expert baseball players' ability to predict the outcomes of their swings as well as the susceptibility of these outcome predictions to hindsight bias--a measure of strength and resistance to distortion of memory for predicted action outcomes. During each swing the simulation stopped when the bat met the ball. Batters marked where on the field they thought the ball would land. Correct feedback was then displayed, after which batters attempted to remark the location they had indicated prior to feedback. Expert batters were more accurate than less-skilled individuals in the initial marking and showed less hindsight bias in the postfeedback marking. Furthermore, experts' number of hits in the previous block of trials was positively correlated with prediction accuracy and negatively correlated with hindsight bias. The reverse was true for novices. Thus the ability to predict the outcome of one's performance before such information is available in the environment is not only based on one's overall skill level, but how one is performing at a given moment.


Mouse Models for Atherosclerosis Research-Which Is My Line?
Atherosclerosis is one of the primary causes of cardiovascular disease and mortality. This chronic immunometabolic disease evolves during decades in humans and encompasses different organs and immune cell types, as well as local and systemic processes that promote the progression of the disease. The most frequently used animal model to study these atherogenic processes and inter-organ crosstalk in a short time frame are genetically modified mouse models. Some models have been used throughout the last decades, and some others been developed recently. These models have important differences in cholesterol and lipoprotein metabolism, reverse cholesterol transport pathway, obesity and diabetes as well as inflammatory processes. Therefore, the disease develops and progresses differently in the various mouse models. Since atherosclerosis is a multifaceted disease and many processes contribute to its progression, the choice of the right mouse model is important to study specific aspects of the disease. We will describe the different mouse models and provide a roadmap to facilitate current and future atherosclerosis researchers to choose the right model depending on their scientific question.


[New urodynamic data of sensory urgency in women].
Irritative bladder symptoms are common in females. Besides, micturition disorders are occasionally associated. Sensory urgency is one of the syndromes that include the symptoms. This entity is a urodynamic condition defined by the presence of pain or urgency during the filling phase without associated involuntary detrusor contractions. Although it is well defined urodynamically, the corresponding nosological entity is unknown. The objective of this study is to check if it has any relationship with the capability of the abdominal press to participate during micturition. We perform a transversal study comparing a group of 25 females (mean age 50.2 yr.) with the diagnosis of sensory urgency and a group of 48 patients paired by age. Urodynamic data from both groups were reviewed, and the existence of significant differences was determined for flowmetry, bladder capacity (cystometry), and participation of the abdominal press during voiding (voiding flow-detrusor pressure test). Patients with sensory urgency showed significantly lower maximum and mean flow rates than controls. Bladder capacity was similar in both groups, but bladder capacity at first desire to void was significantly lower in the sensory urgency group. No significant differences were observed between the groups on participation of the abdominal press. However, if the comparison was performed between the subgroup of patients with sensory urgency who also referred suprapubic pain during filling and controls, then there was a significantly higher participation of the abdominal press during voiding in this group. Data from this study are compatible with the hypothesis that sensory urgency is associated with bladder contractile capacity alterations. This association would be more evident in the group of patients in which sensory urgency is accompanied by hypogastric pain during filling, which could constitute a subgroup with higher progression risk.


Capillary network geometry and red cell distribution in hamster cremaster muscle.
Vascular geometry and red cell distribution were examined in 133 capillaries by means of intravital microscopy in the cremaster muscle of the pentobarbital-anesthetized hamster. Significant correlations (P less than 0.01) were found between diameter and flow, length and resistance, red cell transit time and flow, and red cell flux and hematocrit. Most unexpected was the lack of correlation (P greater than 0.2) between flow and resistance, length, or hematocrit. In addition, we analyzed the relation between blood flow and red cell flux at capillary bifurcations. The red blood cells had a slight (7%), but significant (P less than 0.025), tendency to enter the branch having either higher flow, red cell velocity, or pseudoshear rate (velocity/diameter). The net effect of the preferential red cell flow was to reduce mean capillary hematocrit from 13.7% prior to the bifurcation to 13.3% in the two branches. Finally, increasing the oxygen level of the superfusate above the muscle caused vasoconstriction and an increased heterogeneity of capillary red cell flux and hematocrit, decreasing the capacity for oxygen transport to the tissue.


Changes in Antiemetic Overuse in Response to Choosing Wisely Recommendations.
Antiemetics are used to prevent chemotherapy-induced nausea and vomiting in patients with cancer. Newer antiemetic agents (serotonin and neurokinin-1 receptor antagonists) have increased efficacy but are expensive. The American Society of Clinical Oncology's first guideline in the 2013 Choosing Wisely (CW) campaign discouraged overuse of expensive antiemetics in patients with low risk of chemotherapy-induced nausea and vomiting. However, little is known about patterns or trends in antiemetic overuse or whether any change has occurred with the publication of the CW recommendations. To estimate the baseline prevalence, trends, determinants, and costs of antiemetic overuse from January 1, 2008, through March 31, 2015. From January 1, 2008, through March 31, 2015, this observational study applied descriptive (univariate and bivariate) and multivariable logistic regression analyses to longitudinal health insurance enrollment and nationwide MarketScan insurance claims data for 678 220 privately insured patients receiving chemotherapy before and after the October 29, 2013, announcement of the CW guidelines. The baseline prevalence, trends, determinants, and costs of antiemetic overuse were estimated in cases stratified by risk for chemotherapy-induced nausea and vomiting. Antiemetic use, overuse measure, and expenses before and after the publication of the CW recommendation, with adjustment for patient and health care professional characteristics. The sample included 678 220 adults who started chemotherapy during the observation period. The average age of the sample was 59.5 years, with 58.2% (n = 394 724) female. Antiemetic overuse occurred in 24.1% (n = 163 451) of patients, with highest rates among those receiving intravenous chemotherapy with high chemotherapy-induced nausea and vomiting risk (32.4% [n = 106 795]). Compared with baseline before the CW, patients had 7.0% lower odds of antiemetic overuse (95% CI, 4.4%-9.5%) during the 6 months after the CW, but this decrease was transitory: the odds of antiemetic overuse were 7.4% (95% CI, 4.6%-10.2%) higher than baseline at 6 months after the CW. Low-risk intravenous chemotherapy agents had overuse that continued to decrease 6 months after the CW. Antiemetic overuse was associated with higher costs. Reducing antiemetic overuse could have paid for 6.1% (95% CI, 5.8%-6.4%) of the chemotherapy drug costs. Antiemetic overuse is prevalent and results in unnecessary spending associated with systemic chemotherapy treatment. Short-term decreases in antiemetic overuse were associated with the CW recommendation, but sustained decreases occurred in only one risk group.


CT enterography: technical and interpretive pitfalls.
CT enterography is a first-line test at many institutions to investigate potential small bowel disorders. While numerous articles have focused on the ability of CT enterography to diagnose and stage Crohn's disease, small bowel neoplasia, and malabsorptive or vascular disorders, this article reviews CT enterography limitations, technical and interpretive pitfalls, image review tactics, and complementary radiologic and endoscopic examinations to improve diagnostic accuracy. CT enterography limitations include its inability to demonstrate isolated mucosal abnormalities such as aphthous ulcers and its use of ionizing radiation. The most common technical pitfall of CT enterography is inadequate small bowel distention resulting from inadequate ingestion, gastric retention, or rapid small bowel transit of a large volume of neutral enteric contrast material. Additionally, segments of jejunum are frequently collapsed. Interpretive pitfalls commonly result from peristaltic contractions, transient intussusception and opaque intraluminal debris. Opaque debris is especially problematic during multiphasic CT enterography performed to identify potential small bowel sources of obscure gastrointestinal bleeding. False-negative examinations may result from inadequate radiation dose. Examinations complementary to CT enterography include small bowel follow through, enteroclysis, CT enteroclysis, MR enterography, MR enteroclysis, capsule endoscopy, and balloon-assisted endoscopy. Properly performed and accurately interpreted CT enterography contributes to the diagnosis and management of small bowel disease by itself and as a complement to other radiologic and optical small bowel imaging examinations.


RANK (TNFRSF11A) is epigenetically inactivated and induces apoptosis in gliomas.
Alterations of DNA methylation play an important role in gliomas. In a genome-wide screen, we identified a CpG-rich fragment within the 5' region of the tumor necrosis factor receptor superfamily, member 11A gene (TNFRSF11A) that showed de novo methylation in gliomas. TNFRSF11A, also known as receptor activator of NF-κB (RANK), activates several signaling pathways, such as NF-κB, JNK, ERK, p38α, and Akt/PKB. Using pyrosequencing, we detected RANK/TNFRSF11A promoter methylation in 8 (57.1%) of 14 diffuse astrocytomas, 17 (77.3%) of 22 anaplastic astrocytomas, 101 (84.2%) of 120 glioblastomas, 6 (100%) of 6 glioma cell lines, and 7 (100%) of 7 glioma stem cell-enriched glioblastoma primary cultures but not in four normal white matter tissue samples. Treatment of glioma cell lines with the demethylating agent 5-aza-2'-deoxycytidine significantly reduced the methylation level and resulted in increased RANK/TNFRSF11A mRNA expression. Overexpression of RANK/TNFRSF11A in glioblastoma cell lines leads to a significant reduction in focus formation and elevated apoptotic activity after flow cytometric analysis. Reporter assay studies of transfected glioma cells supported these results by showing the activation of signaling pathways associated with regulation of apoptosis. We conclude that RANK/TNFRSF11A is a novel and frequent target for de novo methylation in gliomas, which affects apoptotic activity and focus formation thereby contributing to the molecular pathogenesis of gliomas.


Olfactory discrimination of aliphatic odorants in South African fur seals (Arctocephalus pusillus).
Using a food-rewarded, two-choice, instrumental conditioning paradigm we assessed the ability of South African fur seals, Arctocephalus pusillus, to discriminate between members of five chemical classes of aliphatic odorants presumed to differ in their abundance in the marine chemical environment. We found that the fur seals were able to distinguish between 24 of the 25 odor pairs presented and thus have a well-developed ability to discriminate between structurally related odorants, that aliphatic n-acetic esters were significantly more poorly discriminated by the fur seals than aliphatic n-aldehydes and n-carboxylic acids, and a lack of correlations between discrimination performance and structural similarity of odorants in terms of differences in carbon chain length. These results suggest that the sense of smell may play an important and hitherto underestimated role in regulating the behavior of fur seals. Further, they support the notion that regular connections between the perceived quality of odorants and their molecular structural properties are not a general phenomenon but appear to be odorant class- and species-specific. Our data support the hypothesis that a species' chemical environment may affect its olfactory capabilities.


[Strategies to reduce the use of blood components in cardiovascular surgery].
The aim of this study is to evaluate the strategies adopted by our team to reduce the use of bloods components in patients undergoing cardiovascular surgical procedures. Between October 2005 and January 2007, 101 patients were operated. Fifty-one (50.5%) were male and 50 (49.5%) female. Patients' age ranged from 13 to 80 years (mean of 50.76 years). The strategy consisted in using antifibrinolytics and normovolemic hemodilution, and reinfusion of all the blood remaining in the CPB circuit. Mean use of blood components was 1.45 UI, red blood cells; 0.75 UI, fresh frozen plasma; 0.89 UI, cryoprecipitate, and 1.43 UI, platelet. Fifty-nine patients (58.4%) had not used blood components and 12 (11.9%) patients used more than 4 UI of red blood cells. In 27 patients (26.7%) whose CPB time was higher than 120 minutes, 17 (63%) needed hemotransfusion. However, 3 (2.97%) developed coagulopathy and 2 (1.98%) needed reoperation due to bleeding. Of the three patients who developed coagulopathy, two were in the elderly subgroup. In the presented series, the measures adopted succeeded in reducing the need of hemotransfusion in the postoperative period of thoracic surgery. Patients with CPB time higher than 120 minutes tended to need hemotransfusion. The association of surgery in elderly patients and CPB time over 120 minutes resulted in significantly greater use of blood components postoperatively.


Burden of elective early-term births in rural Appalachia.
Infants delivered at ≥ 37 weeks' gestation are considered full term, but research has demonstrated those born at 37 to 38 weeks (early term) have a higher risk for poor birth outcomes than deliveries at 39 to 41 weeks (full term). Despite this, many deliveries occur electively (scheduled, no medical indication) before 39 weeks. This study examined the risks of elective early-term delivery in a disadvantaged, rural sample and compared these results with national findings. Data were available for 638 rural women, recruited prenatally from three counties in rural southern Appalachia, who delivered electively at ≥ 37 weeks. Compared with electively delivered full-term infants, those delivered electively at early term were 7.7 times more likely to be low birth weight, 4.4 times more likely to have a neonatal intensive care unit admission, and 2.5 times more likely to develop jaundice. Those living furthest from the hospital were most likely to deliver electively at <39 weeks. Although rates of elective deliveries <39 weeks were no higher than national rates, adjusted odds ratios (aOR) of associated admission to a neonatal intensive care unit doubled (aOR 4.4 vs aOR 2.2). Results demonstrate that initiatives targeting early-term elective deliveries are needed in rural, disadvantaged regions.


Theoretical investigations on the structure and potential binding sites of antineoplaston A10 and experimental findings.
The essential biological importance of antineoplastons has motivated the present theoretical and experimental studies on the structure and potential binding sites of Antineoplaston A10, 3-phenylacetylamino-2,6-piperidinedione. Semi-empirical molecular orbital calculations SCF-LCAO-MO were performed using the MNDO method. The calculated molecular geometry of A10 is in very good agreement with the recently obtained X-ray structure of synthetic A10. Experimental investigations of the Raman spectra of A10 and its N,N-dideuterated derivative confirm the theoretical predictions concerning the structure and hydrogen bonding of A10. Analysis of calculated charge distribution reveals that the negative charges are localized on the ring nitrogen and on the exocyclic oxygen atoms of A10 and are similar to the corresponding charges computed for some pyrimidine bases. This indicates that Antineoplaston A10 may have similar binding sites. It is concluded that the mechanism of action of Antineoplaston A10 may in part be related to its structural and chemical resemblance with deoxythymidine and uridine. A10 may act as a nucleoside antagonist and interact very closely with adenosine units in nucleic acids and enzymes, which may interfere with protein synthesis in neoplastic cells.


Can women's network activities lead to improved health?
The aim of our study was to focus on women's networks in the Swedish county of Jämtland, and to analyse the relationship between network activities and the perceived health among the network participants, as well as participation in the community among its residents. Questionnaires were distributed to all 68 women's networks and 60 responded. The results show that the network activities correlate with an improved perception of health, as well as with increased participation in the community among the residents. The more support, influence, self-reliance and trust in the future experienced by the networks through their work, the better the health among the participants in the network. The greater the self-reliance, trust in the future, amount of network-related unpaid work and new jobs, the better the participation among the community residents. Despite its limitations, our study suggests that women's networks could have an important role in health promotion within the framework of the new public health. The network model, with its bottom-up strategy, could be useful in public health, provided that networking is not used to fill a gap when there are cuts in the public sector.


Pharmacological characterization of two 5-hydroxytryptamine receptors coupled to adenylate cyclase in guinea pig hippocampal membranes.
Two 5-hydroxytryptamine (5-HT) receptors mediate stimulation of adenylate cyclase activity in membranes of adult guinea pig hippocampus. The two receptors were characterized with agonists and antagonists and with the aid of computerized curve-fitting procedures. Each receptor mediates about 50% of the maximal response to 5-HT. 5-HT is about 10-fold more potent in eliciting response through one cyclase-linked receptor (RH) than the other (RL). The concentrations of 5-HT that elicit half-maximal response through RH and RL are 43 +/- 6 nM and 414 +/- 53 nM, respectively. 5-Methoxytryptamine (5-MeOT) and 5-HT are approximately equipotent at each receptor. The agonists tryptamine and bufotenine are less potent than 5-HT at both receptors, and each is about 50-fold selective for RH. The two receptors are best discriminated by the agonists 5-carboxamidotryptamine (5-CONH2-T) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), both of which are selective for RH. 5-CONH2-T is about 7-fold more potent than 5-HT at RH. The rank order of agonist potencies at RH (5-CONH2-T greater than 8-OH-DPAT = 5-HT = 5-MeOT greater than bufotenine greater than tryptamine) differs from that at RL (5-HT = 5-MeOT greater than bufotenine greater than tryptamine = 5-CONH2-T greater than 8-OH-DPAT). Spiperone acts as a simple competitive antagonist at RH, with a dissociation constant of 20 nM, but it is at least 100-fold less potent as an antagonist at RL. The relatively low affinities of the selective 5-HT antagonists ketanserin and MDL 72222 for RH and RL indicate that neither receptor may be classified as the 5-HT2 or as the 5-HT3 (i.e., peripheral neuronal) type. The characteristics of RH suggest that it is a functional correlate of the 5-HT1A-binding site in brain. RL appears not to correspond to a known 5-HT-binding site, but it may be homologous to receptors that mediate 5-HT-stimulated adenylate cyclase activity in other systems such as infant rat colliculi. RH and RL may also mediate stimulation of adenylate cyclase activity by 5-HT in hippocampal membranes of adult rat.


Research progress of the effects of bisphenol analogues on the intestine and its underlying mechanisms: A review.
Bisphenol A (BPA) and its analogues have prompted rising concerns, especially in terms of human safety, due to its broad use and ubiquity throughout the ecosystem. Numerous studies reported various adverse effects of bisphenols, including developmental disorders, reproductive toxicity, cardiovascular toxicity, and so on. There is increasing evidence that bisphenols can enter the gastrointestinal tract. Consequently, it is important to investigate their effects on the intestine. Several in vivo and in vitro studies have examined the impacts of bisphenols on the intestine. Here, we summarized the literature concerning intestinal toxicity of bisphenols over the past decade and presented compelling evidence of the link between bisphenol exposure and intestinal disorders. Experiment studies revealed that even at low levels, bisphenols could promote intestinal barrier dysregulation, disrupt the composition and diversity of intestinal microbiota as well as induce an immunological response. Moreover, possible underlying mechanisms of these effects were discussed. Because of a lack of empirical data, the potential risk of bisphenol exposure in humans is still unidentified, particularly regarding intestinal disorders. Thus, we propose to conduct additional epidemiological investigations and animal experiments to elucidate the associations between bisphenol exposure and human intestinal health and reveal underlying mechanisms to develop preventative and therapeutic techniques.


Functional remodeling of gap junction-mediated electrical communication between adrenal chromaffin cells in stressed rats.
An increase in circulating catecholamine levels represents one of the mechanisms whereby organisms cope with stress. In the periphery, catecholamines mainly originate from the sympathoadrenal system. As we reported, in addition to the central control through cholinergic innervation, a local gap junction-delineated route between adrenal chromaffin cells contributes to catecholamine exocytosis. Here, we investigated whether this intercellular communication is modified when the hormonal demand is increased as observed during cold stress. Our results show that in cold exposed rats, gap-junctional communication undergoes a functional plasticity, as evidenced by an increased number of dye-coupled cells. Of a physiological interest is that this upregulation of gap-junctional coupling results in the appearance of a robust electrical coupling between chromaffin cells that allows the transmission of action potentials between coupled cells. This enhancement of gap-junctional communication parallels an increase in expression levels of connexin36 (Cx36) and connexin43 (Cx43) proteins. Both transcriptional and posttranslational mechanisms are involved because Cx36 transcripts are increased in stressed rats and the expression of the scaffolding protein zonula occludens-1, known to interact with both Cx36 and Cx43, is also upregulated. Consistent with an upregulated coupling extent in stressed rats, the cytosolic Ca(2+) concentration rises triggered in a single cell by an iontophoretic application of nicotine occur simultaneously in several neighboring cells. These results describe for the first time a functional plasticity of junctional coupling between adult chromaffin cells that should be crucial for adaptation to stress or sensitization to subsequent stressors.


Echocardiographic diagnosis of a right ventricular metastatic tumor.
Clinical and echocardiographic studies were done in a patient with a secondary right ventricular tumor. Stationary cardiac tumors produce differential diagnostic problems not associated with mobile cardiac tumors. In spite of limitations of specificity, positive diagnostic features do exist. This report emphasizes the usefulness as well as technical difficulties in assessing the presence of a secondary right ventricular tumor echocardiographically.


Coronary artery bypass graft outcome: the Trinidad and Tobago experience.
The study is retrospective review of the demographic, clinical, angiographic, and operative data of the first 205 consecutive CABG operations performed by Caribbean Heart Care at the Eric Williams Medical Sciences Complex (EWMSC), Trinidad and Tobago, between November 1993 and December 1997. The aim of the study was to determine the in-hospital and intermediate-term follow-up results. The mean age of patients was 59 +/- 10 years and 78% were male. Sixty-four per cent were of East Indian descent, whereas 16% were of African descent. Forty-eight per cent of the patients were hypertensive, 46% were diabetic, 33% had hyperlipidaemia, 20% had a recent history of cigarette smoking and 16% were obese. Sixty-five per cent had a positive family history of ischaemic heart disease. The average time interval between angiography and surgery was 2.3 months. At the time of angiography, 63.5% of patients had Canadian Cardiac Society (CCS) class 3 or 4 angina. The mean ejection fraction was 61 +/- 15%. Wall motion abnormalities were seen in 67% of patients. Significant stenoses of the left anterior descending artery, right circumflex artery, circumflex and ramus coronary arteries were present in 91%, 78%, 54% and 5%, respectively. Many patients (67%) had severe diffuse disease on angiography. The mean intensive care stay was 2.2 +/- 0.8 days. In-hospital mortality was 3.9% (8/205). The most frequent post-operative complication was haemorrhage (2.6%). Acute renal failure occurred in 2.1%; pulmonary collapse, 1.6%; stroke, 1% and cardiac arrest, 1%. Both sternal wound infections and systemic sepsis occurred in 0.5%. Intermediate-term follow-up data were obtained for 92% (189/205). The duration of follow-up ranged from 1 to 5 years (mean 3.7 years). During the follow-up period, 7 patients (3.4%) died. Angina severity was reduced from a mean CCS score of 2.61 +/- 0.95 before CABG to 1.22 +/- 0.55 at the time of follow-up (p < 0.0001). Overall 4-year mortality compared favourably with data from international studies. Among survivors, quality of life improved as evidenced by the reduction in the mean angina score.


Limitations in ROP Programs in 32 Neonatal Intensive Care Units in Five States in Mexico.
Retinopathy of prematurity (ROP) is the main cause of avoidable blindness in children in Mexico despite National ROP Guidelines and examination of preterm infants being a legal requirement. To assess coverage of ROP programs and their compliance with national guidelines. Thirty-two neonatal intensive care units (NICUs) in five of the largest states were visited. Staff were interviewed to collect information on their ROP programs which were defined as (1) compliant, if National Guidelines for screening and treatment were followed, (2) noncompliant, if other approaches were used, or (3) no program. Only 10 (31.2%) had fully compliant programs and 11 (34.4%) had no program. In the remaining 11 (34.4%) different screening criteria were used (7 units): screening was undertaken by an ophthalmologist in unsalaried time (4), was not undertaken in the NICU (2), and was undertaken by a neonatologist (1) and/or Avastin was used as first-line treatment (7). Poorer states had poorer programs. Despite legislation mandating eye examination of preterm births, many ROP programs in the largest cities in Mexico require improvement or need to be established. Prevention of blindness due to ROP needs to be prioritized in Mexico to control the epidemic of ROP blindness.


Robust Multiscale Identification of Apparent Elastic Properties at Mesoscale for Random Heterogeneous Materials with Multiscale Field Measurements.
The aim of this work is to efficiently and robustly solve the statistical inverse problem related to the identification of the elastic properties at both macroscopic and mesoscopic scales of heterogeneous anisotropic materials with a complex microstructure that usually cannot be properly described in terms of their mechanical constituents at microscale. Within the context of linear elasticity theory, the apparent elasticity tensor field at a given mesoscale is modeled by a prior non-Gaussian tensor-valued random field. A general methodology using multiscale displacement field measurements simultaneously made at both macroscale and mesoscale has been recently proposed for the identification the hyperparameters of such a prior stochastic model by solving a multiscale statistical inverse problem using a stochastic computational model and some information from displacement fields at both macroscale and mesoscale. This paper contributes to the improvement of the computational efficiency, accuracy and robustness of such a method by introducing (i) a mesoscopic numerical indicator related to the spatial correlation length(s) of kinematic fields, allowing the time-consuming global optimization algorithm (genetic algorithm) used in a previous work to be replaced with a more efficient algorithm and (ii) an ad hoc stochastic representation of the hyperparameters involved in the prior stochastic model in order to enhance both the robustness and the precision of the statistical inverse identification method. Finally, the proposed improved method is first validated on in silico materials within the framework of 2D plane stress and 3D linear elasticity (using multiscale simulated data obtained through numerical computations) and then exemplified on a real heterogeneous biological material (beef cortical bone) within the framework of 2D plane stress linear elasticity (using multiscale experimental data obtained through mechanical testing monitored by digital image correlation).


Depletion of norepinephrine, but not serotonin, reduces long-term potentiation in the dentate gyrus of rat hippocampal slices.
Long-term potentiation (LTP) in the hippocampus is a long-lasting enhancement of synaptic efficacy produced by a brief, high frequency repetitive stimulation of afferents. LTP has generated a great deal of interest as a candidate mechanism in learning and memory. A recent in vivo study has shown that depletion of norepinephrine (NE) or serotonin (5-hydroxytryptamine, 5-HT) reduced LTP in the dentate gyrus produced by stimulation of the perforant path. However, it was impossible to tell whether this resulted from depletion in the hippocampus, itself, or was secondary to depletion of other brain areas, and no comparison between hippocampal cell fields was done. Therefore, we have examined the effects of depletion of NE or 5-HT on LTP in the dentate and field CA1 of the isolated in vitro hippocampal slice preparation. We report here that NE depletion markedly reduces the occurrence and amplitude of LTP in the dentate, but not in field CA1. In contrast, depletion of 5-HT does not prevent occurrence of LTP in either area. Furthermore, pharmacologic data indicate that beta-receptor stimulation of adenylate cyclase is probably the mechanism of NE's action in the production of LTP in the dentate. These results suggest that endogenous hippocampal NE is more important to LTP in the dentate than is endogenous 5-HT.


Hypoxanthine: a low molecular weight factor essential for growth of erythrocytic Plasmodium falciparum in a serum-free medium.
A low molecular weight factor in a basal medium essential for erythrocytic Plasmodium falciparum development in a serum-free medium using a cell growth-promoting factor derived from adult bovine serum was detected. The factor was hypoxanthine. The optimal hypoxanthine concentration for parasite growth was between 15 and 120 microM. The contribution of hypoxanthine to increased parasite growth was clearly evident in cultures on day 4. Among various low molecular weight supplements tested, adenine, adenosine, AMP, ATP, cyclic AMP, guanine, guanosine, inosine, inosine monophosphate, xanthine, NAD, NADH, NADP, NADPH and deoxyguanosine triphosphate showed a similar effect to that of hypoxanthine in the serum-free culture system. On the other hand, the addition of uric acid, FAD, thymidine, uridine, orotic acid, deoxythymidine triphosphate, deoxycytidine triphosphate, deoxyadenosine triphosphate, ribose-1-phosphate, or ethanolamine was not beneficial to the parasite growth. The results presented here will not only be of practical value, but will provide important information about the developmental requirements of the parasite.


[Comparison of Effectiveness of Gefitinib, Erlotinib, and Afatinib in Advanced Non-small Cell Lung Cancer Patients with EGFR Mutation Positive in Indonesian Population].
EGFR-tyrosine kinase inhibitors (EGFR-TKIs) were used to treat non-small cell lung cancer (NSCLC) patients with EGFR mutation positive. This study aims to compare the effectiveness of first line TKIs; gefitinib, erlotinib, and afatinib in the treatment of advanced stage NSCLC patients with EGFR mutation positive in the Indonesian population. A retrospective cohort study of 88 NSCLC patients with EGFR mutation positive treated with gefitinib (n=59), erlotinib (n=22), and afatinib (n=7) was performed in national cancer hospital in Indonesia.Inclusion criteria were stage IIIb or IV NSCLC with adenocarcinoma subtype. Subjects less than 18 years or with a history of other malignancy were excluded. Outcomes were treatment response, progression-free survival (PFS), and mortality rate. Complete response, partial response, and stable disease were shown in 1.1%, 35.2%, and 31.8% of subjects, respectively. There were 31.8% of subjects developed progressive disease during treatment. Regarding EGFR mutation positive profile, a total of 56.8% subjects had deletion in exon 19, 42% subjects had mutation in exon 21, and rare mutation in exon 18 was found in 3.4% of total subjects. Demography and clinical characteristics had no significant association with the risk of progressive disease. The median PFS of subjects was 11 months (95%CI: 6.8-15.2 months). There was no statistical difference of PFS between treatment groups. CONCLUSIONS: Gefitinib, erlotinib, and afatinib have similar effectiveness in advanced stage NSCLC with EGFR mutation positive. Afatinib tends to be associated with longer PFS but further investigation is required.


Figure-ground organization in the visual cortex: does meaning matter?
Figure-ground organization in the visual cortex is generally assumed to be based partly on general rules and partly on specific influences of object recognition in higher centers as found in the temporal lobe. To see if shape familiarity influences figure-ground organization, we tested border ownership-selective neurons in monkey V1/V2 with silhouettes of human and monkey face profiles and "nonsense" silhouettes constructed by mirror-reversing the front part of the profile. We found no superiority of face silhouettes compared with nonsense shapes in eliciting border-ownership signals overall. However, in some neurons, border-ownership signals differed strongly between the two categories consistently across many different profile shapes. Surprisingly, this category selectivity appeared as early as 70 ms after stimulus onset, which is earlier than the typical latency of shape-selective responses but compatible with the earliest face-selective responses in the inferior temporal lobe. Although our results provide no evidence for a delayed top-down influence from object recognition centers, they indicate sophisticated shape categorization mechanisms that are much faster than generally assumed. NEW & NOTEWORTHY A long-standing question is whether low-level sensory representations in cortex are influenced by cognitive "top-down" signals. We studied figure-ground organization in the visual cortex by comparing border-ownership signals for face profiles and matched nonsense shapes. We found no sign of "face superiority" in the population border-ownership signal. However, some neurons consistently differentiated between the face and nonsense categories early on, indicating the presence of shape classification mechanisms that are much faster than previously assumed.


Harmonic Focus Versus Conventional Electrocautery for Femoral Artery Exposure: a "Direct" Comparison on the Same Patients.
Surgical access complications during endovascular aneurysm repair (EVAR) are reported relatively frequent. HARMONIC FOCUS® (HF; Ethicon Endo-Surgery Inc., Cincinnati, Ohio, USA) is a device developed to improve bleeding control and reduce heat-related damage stemming from surgical preparation. The aim of this study was to evaluate outcomes and safety of HF versus conventional haemostasis with electrocautery, both techniques used in the same patient. Five patients developed bilateral wound's thickening (13.9%) demonstrated at the CT scan, two of whom had no clinical manifestation while in three cases the thickening was associated with lymphocele (4.54%), 2 of which were in the side where the EC was used (5.5%), and 1 case (2.7%), in the HF applied side. One isolated lymphocele occurred at the left groin (2.7%) (tables n.2-3). A Fisher's exact test was conducted between EC and HF on the occurrence of wound healing complications (3/36 for EC and 1/36 for HF) that resulted statistically significant at p<0.05. Focus Harmonic Scalpel has certain advantages than conventional haemostasis in avoiding surgical access complications.


Ventilatory control and carbon dioxide response in preterm infants with idiopathic apnea.
Idiopathic apnea in preterm infants, more than 30 weeks of gestation, after the first week of life is uncommon and poorly understood. To study ventilatory control in these infants we measured minute ventilation, respiratory frequency, tidal volume, end-tidal oxygen pressure and carbon dioxide pressure, and transcutaneous oxygen pressure before and during the fifth minute of breathing 4% carbon dioxide in air. Nine healthy preterm infants and eight infants with three or more episodes of apnea (greater than or equal to 20 s) in 24 hours were studied during active sleep. We found that infants with apnea had a significantly increased alveolar carbon dioxide pressure while respiratory frequency, minute ventilation, and slope were significantly decreased. Alveolar-transcutaneous oxygen gradients were essentially unchanged. These preterm infants with apnea have a decreased carbon dioxide sensitivity. They have a decreased minute ventilation primarily as a result of decreased respiratory frequency and their alveolar-transcutaneous oxygen gradient is normal. Our findings suggest that the major deficit in these infants is a central disturbance in the regulation of breathing.


Treatment approaches for dual diagnosis clients in England.
Dual diagnosis (DD, co-occurrence of substance use and mental health problems) prevalence data in England are limited to specific regions and reported rates vary widely. Reliable information on actual service provision for dual diagnosis clients has not been collated. Thus a national survey was carried out to estimate dual diagnosis prevalence in treatment populations and describe the service provision available for this client population in drug/alcohol (DAS) and mental health services (MHS). A questionnaire was sent to managers of 706 DAS and 2374 MHS. Overall, 249 (39%) DAS and 493 (23%) MHS participated in the survey. In both DAS and MHS, around 32% of clients were estimated to have dual diagnosis problems. However, fewer than 50% of services reported assessing clients for both problem areas. Regarding specific treatment approaches, most services (DAS: 88%, MHS: 87%) indicated working jointly with other agencies. Significantly fewer services used joint protocols (DAS: 55%, MHS: 48%) or shared care arrangements, including access to external drug/alcohol or mental health teams (DAS: 47%, MHS: 54%). Only 25% of DAS and 17% of MHS employed dual diagnosis specialists. Dual diagnosis clients constitute a substantial proportion of clients in both DAS and MHS in England. Despite recent policy initiatives, joint working approaches tend to remain unstructured.


Oceanographic boundaries constrain microbial diversity gradients in the South Pacific Ocean.
Marine microbes along with microeukaryotes are key regulators of oceanic biogeochemical pathways. Here we present a high-resolution (every 0.5° of latitude) dataset describing microbial pro- and eukaryotic richness in the surface and just below the thermocline along a 7,000-km transect from 66°S at the Antarctic ice edge to the equator in the South Pacific Ocean. The transect, conducted in austral winter, covered key oceanographic features including crossing of the polar front (PF), the subtropical front (STF), and the equatorial upwelling region. Our data indicate that temperature does not determine patterns of marine microbial richness, complementing the global model data from Ladau et al. [Ladau J, et al. (2013) ISME J 7:1669-1677]. Rather, NH4+, nanophytoplankton, and primary productivity were the main drivers for archaeal and bacterial richness. Eukaryote richness was highest in the least-productive ocean region, the tropical oligotrophic province. We also observed a unique diversity pattern in the South Pacific Ocean: a regional increase in archaeal and bacterial diversity between 10°S and the equator. Rapoport's rule describes the tendency for the latitudinal ranges of species to increase with latitude. Our data showed that the mean latitudinal ranges of archaea and bacteria decreased with latitude. We show that permanent oceanographic features, such as the STF and the equatorial upwelling, can have a significant influence on both alpha-diversity and beta-diversity of pro- and eukaryotes.


Characterization of FOXO1, 3 and 4 transcription factors in ovaries of fetal, prepubertal and adult rhesus macaques.
The phosphoinositide 3-kinase/AKT (protein kinase B) signaling pathway negatively regulates follicle activation via the forkhead box O (FOXO) transcription factor in rodents. FOXO3 knockout mice exhibit global activation of primordial follicles leading to early depletion of ovarian follicles and subsequent infertility. Whether a similar mechanism for follicle activation exists in the primate ovary is unclear. In the current study, protein localization of FOXO1, 3, and 4 as well as their upstream regulator, AKT/p-AKT, was examined in rhesus macaque ovaries of three developmental stages: fetal, prepubertal, and adult. FOXO1 protein is expressed in granulosa cells of fetal, prepubertal, and adult ovaries. FOXO3 is distributed sparsely in the mitotically active germ cells, but its expression decreases following follicle formation in the macaque fetal ovary. In addition, FOXO3 is seldom with interanimal variation in the prepubertal ovary and is absent in the adult ovary. FOXO4 is nondetectable in fetal ovaries, although it is expressed in some theca cells of antral follicles and some stromal cells in prepubertal and adult ovaries. Our results suggest that the regulation and/or function of FOXO3 in the primate primordial follicle may differ than that of the rodent. Nevertheless, AKT/p-AKT is expressed in macaque primordial oocytes, suggesting that similar upstream events but different downstream effects may regulate primordial follicle activation in nonhuman primates compared to rodents. Elucidation of the mechanism responsible for follicle activation in primates will be crucial for understanding primary ovarian insufficiency, improving female fertility, and applying techniques for in vitro maturation of follicles for fertility preservation in cancer survivors.


Acute clostridial enteritis--or pig-bel?
Acute postprandial gastric dilatation and associated clostridial enteritis necroticans is a well recognised but unusual clinical condition. Non-pathological overeating, gastric distension, and clostridial enteritis, termed pig-bel, has been reported in Papua, New Guinea. A similar condition (Darmbrand) was reported from Germany after the second world war, but it is not a condition seen in our society today. Gastric dilatation alone may be seen in individuals with anorexia nervosa, who may occasionally indulge in episodes of overeating (bulimia). We wish to report a case of gastric dilatation associated with a fulminating enteritis, and discuss the similarities with enteritis necroticans (pig-bel).


Effect of micro-environment modification and polymer type on the in-vitro dissolution behavior and in-vivo performance of amorphous solid dispersions.
This study investigates the effects of micro-environment modification and polymer type on the in-vitro dissolution behavior and in-vivo performance of micro-environment pH modifying solid dispersions (pHM-SD) for the poorly water-soluble model drug Toltrazuril (TOL). Various pHM-SDs were prepared using Ca(OH)2 as a pH-modifier in hydrophilic polymers, including polyethylene glycol 6000 (PEG6000), polyvinylpyrrolidone k30 (PVPk30) and hydroxypropyl methylcellulose (HPMC). Based on the results of physicochemical characterizations and in-vitro dissolution testing, the representative ternary (Ca(OH)2:TOL:PEG6000/HPMC/PVPk30=1:8:24, w/w/w) and binary (TOL:PVPk30=1:3, w/w) solid dispersions were selected and optimized to perform in-vivo pharmacokinetic study. The micro-environment pH modification improved the in-vitro water-solubility and in-vivo bioavailability of parent drug TOL. Furthermore, the addition of alkalizers not only enhanced the release and absorption of prototype drug, but also promoted the generation of active metabolites, including toltrazuril sulfoxide (TOLSO) and toltrazuril sulfone (TOLSO2). The in-vitro dissolution profiles and in-vivo absorption, distribution and metabolism behaviors of the pHM-SDs varied with polymer type. Moreover, in-vivo bioavailability of three active pharmaceutical ingredients increased with an increase in in-vitro dissolution rates of the drug from the pHM-SDs prepared with various polymers. Therefore, a non-sink in-vitro dissolution method can be used to predict the in-vivo performance of pHM-SDs formulated with various polymers with trend consistency. In-vitro and in-vivo screening procedures revealed that the pHM-SD composed of Ca(OH)2, TOL and PVPk30 at a weight ratio of 1:8:24, of which the safety was adequately proved via histopathological examination, may be a promising candidate for providing better clinical outcomes.


Novel amino-carbonitrile-pyrazole identified in a small molecule screen activates wild-type and ΔF508 cystic fibrosis transmembrane conductance regulator in the absence of a cAMP agonist.
Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF transmembrane conductance regulator (CFTR) Cl⁻ channel. We developed a phenotype-based high-throughput screen to identify small-molecule activators of human airway epithelial Ca²⁺-activated Cl⁻ channels (CaCCs) for CF therapy. Unexpectedly, screening of ∼110,000 synthetic small molecules revealed an amino-carbonitrile-pyrazole, C(act)-A1, that activated CFTR but not CaCC Cl⁻ conductance. C(act)-A1 produced large and sustained CFTR Cl⁻ currents in CFTR-expressing Fisher rat thyroid (FRT) cells and in primary cultures of human bronchial epithelial (HBE) cells, without increasing intracellular cAMP and in the absence of a cAMP agonist. C(act)-A1 produced linear whole-cell currents. C(act)-A1 also activated ΔF508-CFTR Cl⁻ currents in low temperature-rescued ΔF508-CFTR-expressing FRT cells and CF-HBE cells (from homozygous ΔF508 patients) in the absence of a cAMP agonist, and showed additive effects with forskolin. In contrast, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770) and genistein produced little or no ΔF508-CFTR Cl⁻ current in the absence of a cAMP agonist. In FRT cells expressing G551D-CFTR and in CF nasal polyp epithelial cells (from a heterozygous G551D/Y1092X-CFTR patient), C(act)-A1 produced little Cl⁻ current by itself but showed synergy with forskolin. The amino-carbonitrile-pyrazole C(act)-A1 identified here is unique among prior CFTR-activating compounds, as it strongly activated wild-type and ΔF508-CFTR in the absence of a cAMP agonist. Increasing ΔF508-CFTR Cl⁻ conductance by an "activator," as defined by activation in the absence of cAMP stimulation, provides a novel strategy for CF therapy that is different from that of a "potentiator," which requires cAMP elevation.


Compassionate love as a mechanism linking sacred qualities of marriage to older couples' marital satisfaction.
Previous work has underscored the robust links between sanctification of marriage and marital outcomes, and recent developments in the literature suggest that compassionate love, which is important for intimate relationships, may act as a mediator of that relationship. Accordingly, the current study used actor-partner interdependence models to examine the relationship between a spiritual cognition (i.e., perceived sacred qualities of marriage) and marital satisfaction, and to determine whether that relationship is mediated by compassionate love, in a sample of older married couples (N = 64). Results revealed that wives' greater sacred qualities of marriage were significantly and positively linked to marital satisfaction on the part of both spouses, and that these links were partially mediated by couples' reports of compassionate love. These findings highlight the importance of moving beyond simply establishing the existence of the link between global markers of involvement of religion and marriage to understanding how specific spiritual cognitions may foster better relationship quality, especially among older couples.


Chronic exposure to cannabinoids during adolescence causes long-lasting behavioral deficits in adult mice.
Regular use of marijuana during adolescence enhances the risk of long-lasting neurobiological changes in adulthood. The present study was aimed at assessing the effect of long-term administration of the synthetic cannabinoid WIN55212.2 during adolescence in young adult mice. Adolescent mice aged 5 weeks were subjected daily to the pharmacological action of WIN55212.2 for 3 weeks and were then left undisturbed in their home cage for a 5-week period and finally evaluated by behavioral testing. Mice that received the drug during adolescence showed memory impairment in the Morris water maze, as well as a dose-dependent memory impairment in fear conditioning. In addition, the administration of 3 mg/kg WIN55212.2 in adolescence increased adult hippocampal AEA levels and promoted DNA hypermethylation at the intragenic region of the intracellular signaling modulator Rgs7, which was accompanied by a lower rate of mRNA transcription of this gene, suggesting a potential causal relation. Although the concrete mechanisms underlying the behavioral observations remain to be elucidated, we demonstrate that long-term administration of 3 mg/kg of WIN during adolescence leads to increased endocannabinoid levels and altered Rgs7 expression in adulthood and establish a potential link to epigenetic changes.


The Atkins Diet as a possible trigger for an ICU admission: a case report.
A case of initial presentation and diagnosis of hereditary coproporphyria is described, following a patient's first seizure in the surgical ward, where she had been admitted for investigation of abdominal pains. The frequency of seizures, motor neuropathy and florid visual hallucinations worsened over the subsequent days, until the definitive investigations revealed the diagnosis and specific therapies were instituted. The acute porphyrias, a rare group of conditions caused by deficiencies in enzymes involved in haem biosynthesis, are associated with significant morbidity and occasional mortality. Consideration of the diagnosis, combined with appropriate supportive and specific therapies can reduce the duration of the crisis and lessen the rates of morbidity and mortality associated with these conditions.


Longitudinal examination of objectively-measured physical activity and sedentary time among children with and without significant movement impairments.
Children with Developmental Coordination Disorder (DCD) tend to be less active than typically-developing (TD) children. Current evidence, however, is based on cross-sectional and self-reported activity, and little is known about sedentary time among children with significant movement impairments such as DCD. The current study examines the longitudinal patterns of objectively measured physical activity and sedentary time in children with and without possible DCD (pDCD). Data is from a longitudinal nested case-control study, with 103 participants (n=60 males ages=12 and 13 at baseline). Participants averaging ⩽16th percentile on the Movement Assessment Battery for Children were considered having significant movement impairments and pDCD (n=49). All participants wore accelerometers for seven days. There were significant main effects for time (Estimate=-23.98, p<.01) and gender (Estimate=59.86, p<.05) on total physical activity, and time spent being sedentary (Estimate=15.58, p<.05). Significant main effects for pDCD (Estimate=-5.38, p<.05) and gender (Estimate=26.89, p<.01), and time by gender interaction (Estimate=-7.50, p<.05) were found for moderate-to-vigorous physical activity (MVPA). Sedentary time did not differ between children with and without DCD. Results suggest children with pDCD engaged in less MVPA compared to TD children. Consistent patterns of MVPA over time, however, suggest that the divergence in MVPA occurs earlier in childhood. Further longitudinal research following a younger cohort is necessary to identify the specific point that differences in MVPA emerge.


DNA repair in xeroderma pigmentosum cells treated with combinations of ultraviolet radiation and N-acetoxy-2-acetylaminofluorene.
We used three techniques to examine excision repair in human cells treated with ultraviolet radiation, N-acetoxy-2-acetylaminofluorene, and a combination of the two. The three techniques gave similar results. Two types of human cells were used: (a) excision repair proficient (normal human fibroblasts and xeroderma pigmentosum variants); and (b) excision repair deficient (xeroderma pigmentosum C, D, and E). Saturation doses were determined and used for combined treatments with both agents. We observed two patterns of repair: (a) in repair-proficient cells total repair was additive; and (b) in repair-deficient cells total repair was much less than additive (usually less than that repair was much less than additive (usually less than that observed for separate treatments) and N-acetoxy-2-acetylaminofluorene inhibited excision of pyrimidine dimers. We conclude that, in the first group of cells, pathways for repair of ultraviolet radiation- and N-acetoxy-2-acetylaminofluorene-induced lesions are not identical and, in the second group of cells, there is an inhibitory effect exerted by major or minor products of each agent on the repair enzyme(s) of the other.


The ideal timing for experimental cleft lip creation.
Cleft lip and palate (CLP) is the most common congenital defect of the face. Many animal models have been utilized to study embryogenesis and pathogenesis of CLP, including the development of secondary anomalies and consequent deformities. However, the ideal gestational age for surgical creation of lip or palate defects in rat models has never been determined. The aim of the present study is to improve the experimental model utilizing rat fetuses, defining the most appropriate timing for creation of the lip defect model. The study was composed of three groups of fetuses undergoing surgical creation of a lip defect at the left side of the superior lip at 17.5, 18.5, and 19.5 days of gestation. Fetuses were harvested at 21.5 days of gestation (term = 22 days) and underwent macroscopic and microscopic analyses. We found that the most appropriate moment for lip defect creation was at 19.5 days, given the presence of lip depression at the site of the defect and asymmetry and retraction associated with interruption of the lip and complete reepithelialization of the borders of the defect.


Functional domains of the yeast chromatin protein Sin1p/Spt2p can bind four-way junction and crossing DNA structures.
Sin1p/Spt2p is a yeast chromatin protein that, when mutated or deleted, alters the transcription of a family of genes presumably by modulating local chromatin structure. In this study, we investigated the ability of different domains of this protein to bind four-way junction DNA (4WJDNA) since 4WJDNA can serve as a model for bent double helical DNA and for the crossed structure formed at the exit and entry of DNA to the nucleosomes. Sequence alignment of Sin1p/Spt2p homologues from 11 different yeast species showed conservation of several domains. We found that three domains of Sin1p/Spt2p fused to glutathione S-transferase can each bind independently in a structure-specific manner to 4WJDNA as measured in a gel mobility shift assay. A feature common to these domains is a cluster of positively charged amino acids. Modification of this cluster resulted in either abolishment of binding or a change in the binding properties. One of the domains tested clearly bound superhelical DNA, although it failed to induce bending in a circularization assay. Poly-l-lysine, which may be viewed as a cluster of positively charged amino acids, bound 4WJDNA as well. Phenotypic analysis showed that disruption of any of these domains resulted in suppression of a his4-912delta allele, indicating that each domain has functional significance. We propose that Sin1p/Spt2p is likely to modulate local chromatin structure by binding two strands of double-stranded DNA at their crossover point.


Apolipoprotein A-I exchange is impaired in metabolic syndrome patients asymptomatic for diabetes and cardiovascular disease.
We tested the hypothesis that HDL-apolipoprotein A-I exchange (HAE), a measure of high-density lipoprotein (HDL) function and a key step in reverse cholesterol transport (RCT), is impaired in metabolic syndrome (MetSyn) patients who are asymptomatic for diabetes and cardiovascular disease. We also compared HAE with cell-based cholesterol efflux capacity (CEC) to address previous reports that CEC is enhanced in MetSyn populations. HAE and ABCA1-specific CEC were measured as tests of HDL function in 60 MetSyn patients and 14 normolipidemic control subjects. Predictors of HAE and CEC were evaluated with multiple linear regression modeling using clinical markers of MetSyn and CVD risk. HAE was significantly reduced in MetSyn patients (49.0 ± 10.9% vs. 61.2 ± 6.1%, P < 0.0001), as was ABCA1-specific CEC (10.1 ± 1.6% vs. 12.3 ± 2.0%, P < 0.002). Multiple linear regression analysis identified apoA-I concentration as a significant positive predictor of HAE, and MetSyn patients had significantly lower HAE per mg/dL of apoA-I (P = 0.004). MetSyn status was a negative predictor of CEC, but triglyceride (TG) was a positive predictor of CEC, with MetSyn patients having higher CEC per mg/dL of TG, but lower overall CEC compared to controls. MetSyn patients have impaired HAE that contributes to reduced capacity for ABCA1-mediated CEC. MetSyn status is inversely correlated with CEC but positively correlated with TG, which explains the contradictory results from earlier MetSyn studies focused on CEC. HAE and CEC are inhibited in MetSyn patients over a broad range of absolute apoA-I and HDL particle levels, supporting the observation that this patient population bears significant residual cardiovascular disease risk.


The psychosocial characteristics and needs of patients presenting with orofacial injury.
Individuals with orofacial injury presenting to urban trauma centers in the United States tend to be disproportionately socioeconomically disadvantaged, young, adult, ethnic minority men. Most injuries are assaultive in origin, suggesting poor impulse control and maladaptive social behaviors. Compared with matched control populations, patients with orofacial injuries are more likely to report higher levels of substance use behaviors and to manifest greater levels of hostility, anxiety, and depression. Although they have significantly greater current and lifetime need for mental health service and social service, actual use of social services is low. The underlying psychosocial characteristics of many patients with orofacial injury, along with unmet service needs, render them vulnerable for posttrauma psychological sequelae and may compromise functional outcomes and recovery.


Structural basis of transcription-translation coupling and collision in bacteria.
Prokaryotic messenger RNAs (mRNAs) are translated as they are transcribed. The lead ribosome potentially contacts RNA polymerase (RNAP) and forms a supramolecular complex known as the expressome. The basis of expressome assembly and its consequences for transcription and translation are poorly understood. Here, we present a series of structures representing uncoupled, coupled, and collided expressome states determined by cryo-electron microscopy. A bridge between the ribosome and RNAP can be formed by the transcription factor NusG, which stabilizes an otherwise-variable interaction interface. Shortening of the intervening mRNA causes a substantial rearrangement that aligns the ribosome entrance channel to the RNAP exit channel. In this collided complex, NusG linkage is no longer possible. These structures reveal mechanisms of coordination between transcription and translation and provide a framework for future study.


New and resurrected Hawaiian species of pilo (Coprosma, Rubiaceae) from the island of Maui.
Two species of Coprosma (Rubiaceae) J.R.Forst. & G.Forst. are described from the island of Maui of the Hawaiian Archipelago. A newly described taxon, Coprosma cordicarpa J.Cantley, Sporck-Koehler, & M.Chau, sp. nov. is locally common in medium to high elevation dry forests and shrublands of leeward East Maui. The second taxon is resurrected from the synonymy of Coprosma foliosa A.Gray as Coprosma stephanocarpa Hillebr. and occurs in mesic to wet rainforests of both East and West Maui. Both taxa are segregated from Coprosma foliosa, with which they share similar morphological characters. A conspicuous and persistent calyx of the fruit and various floral characters most easily differentiate both taxa from other Hawaiian taxa. The newly described Coprosma cordicarpa is further distinguished from Coprosma stephanocarpa by a central constriction of the fruit with a depressed apex, which gives it a characteristic heart shape. Furthermore, the taxa are largely separated phenologically, ecologically, and geographically. Descriptions, conservation status, and specimens examined for the new species are included.


Novel application of PBBM to justify impact of faster dissolution on safety and pharmacokinetics - a case study and utility in regulatory justifications.
Physiologically based biopharmaceutics modelling (PBBM) was recognised as potential approach for biopharmaceutics applications. However, PBBM to justify safety is an unexplored area.In this manuscript, we elucidated PBBM application for safety justification. Product DRL is a generic extended release tablet containing an anti-epileptic narrow therapeutic index (NTI) drug. During dossier review, regulatory agency requested to evaluate the impact of faster dissolution profiles observed during stability on safety aspects. In order to justify, PBBMbased strategy was adapted.Model was validated and population simulations were performed for reference and test formulations and the predictions matched with clinical outcome. The model was found to be sensitive to dissolution changes and hence applied for the prediction of stability batches exhibiting faster dissolution profiles, virtually generated profiles at lower and upper specifications. The maximum predicted plasma levels were well below the reported safety levels, thereby demonstrating safety of the product.Overall, a novel application of PBBM to justify safety was demonstrated. Similar justifications using PBBM and linking with safety can be adopted where safety can be impacted due to aggravated dissolution profiles. Such justifications have potential to avoid clinical safety studies and helps in faster approval of drug product.


To sell or not to sell; the differences between regulatory and community demands regarding access to antibiotics in rural Ghana.
In Ghana, there is extensive over-the-counter dispensing of antibiotics, resulting in high levels of inappropriate use, and an increase in antibiotic resistance. Regulations prevent Licenced Chemical Sellers (LCS, Over-the-Counter Medicine Sellers) from selling antibiotics other than Cotrimoxazole. In practice, however, these sellers sell a variety of antibiotics. This paper aims to provide insight into the differences between regulatory and community demands on the sale of antibiotics, and to explore how these differences in demand could be resolved to facilitate safe and appropriate use of antibiotics in rural Ghana. A total of 32 in-depth interviews were conducted in the Kintampo North and South Districts in Ghana; 16 among antibiotic suppliers, predominantly LCS, and 16 among community members. Six focus group discussions were also conducted among 40 community members. Data were coded using Nvivo 10 and thematically analyzed in line with study objectives. The results are presented as narratives with quotes to illustrate the findings. Generally, antibiotic suppliers were aware that regulations prevent LCS from selling antibiotics except Cotrimoxazole. However, LCS sell all types of antibiotics because of community demand, economic motivations of LCS, and the poor implementation of regulations that are intended to prevent them from selling these medications. Factors that influence community demand for antibiotics include previous knowledge of effectiveness of some antibiotics, delays in seeking care at health facilities, financial constraints, and distance to health facilities. LCS suggested that they should be trained and allowed to sell some types of antibiotics instead of being prevented completely from selling. Community members also suggested that Community-based Health Planning and Services (CHPS) compounds should be equipped to dispense antibiotics. The sale of antibiotics by LCS at the community level is influenced by both structural and individual contextual factors. There is a need to educate community members on the appropriate access and use of antibiotics in rural Ghana. In addition, rather than enforcing rules that go against practice, it may be more effective to regulate the sale of antibiotics by LCS and train them to make their dispensing more appropriate. CHPS compound could also be equipped to dispense some antibiotics to improve appropriate antibiotic access at the community level.


Type IV collagen, laminin, and fibronectin promote the adhesion and migration of rabbit lens epithelial cells in vitro.
To assess the ability of basement membrane and extracellular matrix proteins to promote rabbit lens epithelial cell adhesion and migration, which may play a role in the development of secondary cataract. Rabbit lens epithelial cells were isolated and grown in tissue culture for use in standardized assays to study adhesion and migration of rabbit lens epithelial cells in response to type IV collagen, laminin, fibronectin, and ovalbumin. Under these conditions, the adhesion of rabbit lens epithelial cells to surfaces coated with varying concentrations of type IV collagen, laminin, and fibronectin was shown to be dependent on concentration. Rabbit lens epithelial cells did not adhere to ovalbumin-coated surfaces at any concentration tested. Type IV collagen promotes maximal in vitro adhesion of rabbit lens epithelial cells at lower coating concentrations in comparison to laminin and fibronectin. In cell migration experiments, fibronectin promoted maximal migration at lower concentrations in comparison with laminin and type IV collagen. This was shown both in haptotaxis experiments (the migration of cells to surfaces coated with protein) and in chemotaxis experiments (the migration of cells to attractants in solution). Lens epithelial cells did not migrate in response to ovalbumin under the conditions of this study. The results of these studies indicate that adhesion and migration of lens epithelial cells occurs in response to the lens capsule proteins type IV collagen and laminin and in response to fibronectin, a protein found in the lens during embryologic development. Because fibronectin plays a role in the embryologic development of the lens but is not normally present in the adult lens, the possible introduction of fibronectin into the eye after surgery may play a critical role in the posterior migration of lens epithelial cells and the development of posterior capsular opacification or secondary cataract.


Barx2 is expressed in satellite cells and is required for normal muscle growth and regeneration.
Muscle growth and regeneration are regulated through a series of spatiotemporally dependent signaling and transcriptional cascades. Although the transcriptional program controlling myogenesis has been extensively investigated, the full repertoire of transcriptional regulators involved in this process is far from defined. Various homeodomain transcription factors have been shown to play important roles in both muscle development and muscle satellite cell-dependent repair. Here, we show that the homeodomain factor Barx2 is a new marker for embryonic and adult myoblasts and is required for normal postnatal muscle growth and repair. Barx2 is coexpressed with Pax7, which is the canonical marker of satellite cells, and is upregulated in satellite cells after muscle injury. Mice lacking the Barx2 gene show reduced postnatal muscle growth, muscle atrophy, and defective muscle repair. Moreover, loss of Barx2 delays the expression of genes that control proliferation and differentiation in regenerating muscle. Consistent with the in vivo observations, satellite cell-derived myoblasts cultured from Barx2(-/-) mice show decreased proliferation and ability to differentiate relative to those from wild-type or Barx2(+/-) mice. Barx2(-/-) myoblasts show reduced expression of the differentiation-associated factor myogenin as well as cell adhesion and matrix molecules. Finally, we find that mice lacking both Barx2 and dystrophin gene expression have severe early onset myopathy. Together, these data indicate that Barx2 is an important regulator of muscle growth and repair that acts via the control of satellite cell proliferation and differentiation.


MEPicides: α,β-unsaturated Fosmidomycin N-Acyl Analogs as Efficient Inhibitors of Plasmodium falciparum 1-Deoxy-d-xylulose-5-phosphate reductoisomerase.
Malaria, a mosquito-borne disease caused by several parasites of the Plasmodium genus, remains a huge threat to global public health. There are an estimated 0.5 million malaria deaths each year, mostly among African children. Unlike humans, Plasmodium parasites and a number of important pathogenic bacteria employ the methyl erythritol phosphate (MEP) pathway for isoprenoid synthesis. Thus, the MEP pathway represents a promising set of drug targets for antimalarial and antibacterial compounds. Here, we present new unsaturated MEPicide inhibitors of 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR), the second enzyme of the MEP pathway. A number of these compounds have demonstrated robust inhibition of Plasmodium falciparum DXR, potent antiparasitic activity, and low cytotoxicity against HepG2 cells. Parasites treated with active compounds are rescued by isopentenyl pyrophosphate, the product of the MEP pathway. With higher levels of DXR substrate, parasites acquire resistance to active compounds. These results further confirm the on-target inhibition of DXR in parasites by the inhibitors. Stability in mouse liver microsomes is high for the phosphonate salts, but remains a challenge for the prodrugs. Taken together, the potent activity and on-target mechanism of action of this series further validate DXR as an antimalarial drug target and the α,β-unsaturation moiety as an important structural component.


Clinical outcomes of MR-guided laser interstitial thermal therapy corpus callosum ablation in drug-resistant epilepsy: a systematic review and meta-analysis.
The goal of this systematic review and meta-analysis was to provide an updated analysis of studies investigating outcomes, morbidity, and mortality associated with MR-guided laser interstitial thermal therapy (MRgLITT) corpus callosum ablation (CCA). Study inclusion criteria for screening required that studies report on human subjects only, including patients aged 1-52 years diagnosed with drug-resistant epilepsy who underwent CCA. Sixteen articles published between 2016 and 2023 were included for the systematic review and analysis, including 4 case reports, 11 case series, and 1 case-control study. Altogether, 85 pediatric and adult patients undergoing CCA were included in the systematic review (46 patients younger and 39 patients older than 21 years). The main outcome of seizure freedom was measured using the decrease in the frequency of atonic seizures following surgery, percentage of atonic seizure freedom following surgery, and percentage of overall seizure freedom following surgery. These measurements were made using data from the last follow-up for patients with at least 6 months of follow-up post-CCA. The extent of CCA differed across the pooled cohorts, including anterior two-thirds CCA (38.89%, n = 35) and posterior one-third CCA for completion of a prior partial CCA (22.22%, n = 20), complete CCA (27.78%, n = 25), or CCA of residual white matter in the case of subtotal initial ablation (5.56%, n = 5). Overall, 12.94% of the patients undergoing CCA experienced operational complications. The most common operative complications across 90 CCA operations were probe malpositioning (n = 6), hemorrhage (n = 5), off-target extension of splenium ablation to the thalamus (n = 1), infection (n = 1), and postoperative CSF leak (n = 1). Neurological deficits following CCA were reported as transient in 18.82% and permanent in 4.71% of patients across all studies. The most common neurological deficits were disconnection syndrome (n = 4) or transient hemiplegia (supplementary motor area-like syndrome; n = 4). The 6-month overall seizure freedom rate was 18.87% of 53 patients, and the atonic seizure freedom rate was 46.28% of 52 patients postoperatively. CCA resulted in an average decrease in atonic seizure rate from 8.30 to 1.65 atonic seizures per day (average decrease 80.12%). CCA is associated with an acceptable complication profile, and most patients experience a meaningful reduction in target seizure semiologies. Accurate MRgLITT probe placement is likely important for maximizing CCA while avoiding collateral damage. Avoidable complications of CCA include off-target ablation (and associated deficits), hemorrhage, and future surgery for residual CCA to palliate continued seizures.


Borderline Dravet syndrome: a useful diagnostic category?
The term "borderline" severe myoclonic epilepsy of infancy (SMEIB) has been used to designate patients in whom myoclonic seizures or generalized spike and wave activity are absent. It has also been used loosely to indicate mild forms of the syndrome. It is now acknowledged that the course and outcome of patients with SMEIB are the same as in the core syndrome. The rate of patients exhibiting SCN1A gene mutations is also similar, and it has been observed that the same mutations can cause both typical and "borderline" forms, indicating causal homogeneity. Defining a borderline form of a syndrome would mean setting the criteria of semiology and severity whereby a given phenotype falls within and outside the core syndrome. Such process has never been made for Dravet syndrome and is of course unrealistic in view its polymorphic expression. The eponym Dravet syndrome has been preferred to designate a syndrome spectrum that also embraces SMEIB. Therefore the term "borderline" Dravet syndrome is improper. The definition "mild form" of Dravet syndrome would certainly be more suitable to indicate those patients exhibiting a less severe or incomplete form of the syndrome. Variability in severity favors the concept that SCN1A loss of function causes a spectrum of epilepsy phenotypes in which seizures, often prolonged and precipitated by fever, are the prominent feature and schematic subdivisions would be inappropriate, at least in the early stages. An initial definition of SCN1A gene-related epilepsy would perhaps be more suitable when a mutation of this gene is ascertained and the clinical picture is still ill defined.


Synthesis and Antibacterial Activity of Novel Triazolo[4,3-a]pyrazine Derivatives.
Infectious diseases pose a major challenge to human health, and there is an urgent need to develop new antimicrobial agents with excellent antibacterial activity. A series of novel triazolo[4,3-a]pyrazine derivatives were synthesized and their structures were characterized using various techniques, such as melting point, 1H and 13C nuclear magnetic resonance spectroscopy, mass spectrometry, and elemental analysis. All the synthesized compounds were evaluated for in vitro antibacterial activity using the microbroth dilution method. Among all the tested compounds, some showed moderate to good antibacterial activities against both Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli strains. In particular, compound 2e exhibited superior antibacterial activities (MICs: 32 μg/mL against Staphylococcus aureus and 16 μg/mL against Escherichia coli), which was comparable to the first-line antibacterial agent ampicillin. In addition, the structure-activity relationship of the triazolo[4,3-a]pyrazine derivatives was preliminarily investigated.


BMI and headache among women: results from 11 epidemiologic datasets.
To evaluate the association between BMI (kg/m(2)) and headaches among women. Cross-sectional analysis of 11 datasets identified after searching for all large publicly available epidemiologic cohort study datasets containing relevant variables. Datasets included National Health Interview Survey (NHIS): 1997-2003, the first National Health Examination and Nutrition Survey, Alameda County Health Study (ACHS), Tecumseh Community Health Study (TCHS), and Women's Health Initiative (WHI). The women (220,370 in total) were aged 18 years or older and had reported their headache or migraine status. Using nonlinear regression techniques and models adjusted for age, race, and smoking, we found that increased BMI was generally associated with increased likelihood of headache or severe headache among women. A BMI of approximately 20 was associated with the lowest risk of headache. Relative to a BMI of 20, mild obesity (BMI of 30) was associated with roughly a 35% increase in the odds for experiencing headache whereas severe obesity (BMI of 40) was associated with roughly an 80% increase in odds. Results were essentially unchanged when models were further adjusted for socioeconomic variables, alcohol consumption, and hypertension. Being diagnosed with migraine showed no association with BMI. Among US women, a BMI of approximately 20 (about the 5th percentile) was associated with the lowest likelihood of headache. Consistently across studies, obese women had significantly increased risk for headache. By contrast, the risk for diagnosed migraine headache per se was not obviously related to BMI. The direction of causation and mechanisms of action remain to be determined.