Abciximab and excessive bleeding in patients undergoing emergency cardiac operations.
Abciximab (ReoPro; Eli Lilly and Co, Indianapolis, IN) is a monoclonal antibody that binds to the platelet glycoprotein IIb/IIIa receptor and produces powerful inhibition of platelet function. Clinical trials of abciximab in patients undergoing coronary angioplasty have demonstrated a reduction in thrombotic complications and have encouraged the widespread use of this agent. We have observed a substantial incidence of excessive bleeding among patients who receive abciximab and subsequently require emergency cardiac operations. The records of 11 consecutive patients who required emergency cardiac operations after administration of abciximab and failed angioplasty or stent placement were reviewed. The interval from the cessation of abciximab administration to operation was critical in determining the degree of coagulopathy after cardiopulmonary bypass. The median values for postoperative chest drainage (1,300 versus 400 mL; p < 0.01), packed red blood cells transfused (6 versus 0 U; p = 0.02), platelets transfused (20 versus 0 packs; p = 0.02), and maximum activated clotting time (800 versus 528 seconds; p = 0.01) all were significantly greater in the early group (cardiac operation < 12 hours after abciximab administration; n = 6) compared with the late (cardiac operation >12 hours after abciximab administration; n = 5) group. This report suggests that the antiplatelet agent abciximab is associated with substantial bleeding when it is administered within 12 hours of operation.


Optimal grafting methods for the small abdominal aorta.
Aortobifemoral bypass procedures were performed on 42 patients with the hypoplastic aortoiliac syndrome over an eight year period. During the first five years, 22 patients had either a 13 X 6.5 mm or a 14 X 7 mm knitted Dacron graft and served as historic controls for a second group of 20 others who had 14 X 7 mm grafts of expanded polytetrafluoroethylene (PTFE), during the last three years of the study. Although the two groups were neither concurrent nor randomized, they were nonetheless well matched with regard to age, sex, risk factors, indications for operations, distribution and severity of distal occlusive disease, and type of distal anastomosis. There was only one early graft limb occlusion in the PTFE group after a median follow-up of 14 months, compared to nine occlusions and one amputation in the Dacron group after a median follow-up of 26.2 months. The cumulative patency of the PTFE grafts was 95% at four years compared to only 52% for Dacron (p = 0.11). If the single postoperative occlusion which occurred in each group is excluded, then the difference in patency rates bordered on statistical significance (p = 0.06). Inclusion of the profunda femoris orifice in the distal anastomosis was also found to be an important factor contributing to long-term patency which approached statistical significance (p = 0.075). The configuration of the proximal aortic anastomosis (end to end vs. end to side), or the concomitant use of lumbar sympathectomy or the postoperative infusion of Dextran did not have a statistically significant influence on patency.(ABSTRACT TRUNCATED AT 250 WORDS)


Statistical determinants of success and complications of thrombolytic therapy for arterial occlusion of lower extremity.
In this prospective study, we have documented the limited usefulness of thrombolytic therapy in the management of all patients with arterial occlusion of the lower extremities. We have also emphasized the significant rate of recurrent thrombosis unless an underlying obstructive lesion is corrected surgically after clot dissolution. Because thrombolytic drugs can lyse clots of a duration of several weeks, we recommend consideration of fibrinolytic therapy for subacute graft occlusions and segmental arterial thromboses. In such instances, thrombolysis is likely to reveal a focal underlying lesion that is correctable by a limited anastomotic revision or balloon angioplasty. Without fibrinolytic therapy, these older occlusions generally require more extensive bypass grafting or graft replacement. In contrast, we are less enthusiastic about thrombolytic therapy for distal small vessel thrombosis or embolism because complete clot lysis was achieved in only one of five patients. The primary problems with regional arterial low dosage thrombolytic infusions are bleeding at the angiographic catheter entry site and distal thromboemboli of the lysing clot. These difficulties may discourage wide acceptance of fibrinolytic therapy. However, they can be minimized by careful technique. Although its usefulness is limited and complications are common, catheter directed arterial low dosage thrombolytic therapy can be an important initial step in the diagnosis and treatment of selected arterial occlusion of the lower extremities.


Rat liver microsomal palmitoyl-coenzyme A synthetase. Structural properties.
The structural properties of purified palmitoyl-CoA synthetase from rat liver microsomal material were investigated. The active enzyme has a molecular weight of 168000 and contains about 8.2mol of phospholipid bound/mol of enzyme protein, as well as bound fatty acids. Association of the active enzyme was shown to occur, without impairment of catalytic activity. The lowest-molecular-weight species obtained under denaturing conditions was 27000 daltons.


How to produce a pulsatile flow with low haemolysis?
It is evident that a pulsatile flow is important for blood circulation because the flow pulsatility can reduce the resistance of peripheral vessels. It is difficult, however, to produce a pulsatile flow with an impeller pump, since blood damage will occur when a pulsatile flow is produced. Further investigation has revealed that the main factor for blood damage is turbulence shear, which tears the membranes of red blood cells, resulting in free release of haemoglobin into the plasma, and consequently leads to haemolysis. Therefore, the question for developing a pulsatile impeller blood pump is: how to produce a pulsatile flow with low haemolysis? The authors have successively developed a pulsatile axial pump and a pulsatile centrifugal pump. In the pulsatile axial pump, the impeller reciprocates axially and rotates simultaneously. The reciprocation is driven by a pneumatic device and the rotation by a dc motor. For a pressure of 40 mm Hg pulsatility, about 50 mm axial reciprocating amplitude of the impeller is desirable. In order to reduce the axial amplitude, the pump inlet and the impeller both have cone-shaped heads, and the gap between the impeller and the inlet pipe changes by only 2 mm, that is the impeller reciprocates up to 2 mm and a pressure pulsatility of 40 mm Hg can be produced. As the impeller rotates with a constant speed, low turbulence in the pump may be expected. In the centrifugal pulsatile pump, the impeller changes its rotating speed periodically; the turbulence is reduced by designing an impeller with twisted vanes which enable the blood flow to change its direction rather than its magnitude during the periodic change of the rotating speed. In this way, a pulsatile flow is produced and the turbulence is minimized. Compared to the axial pulsatile pump, the centrifugal pulsatile pump needs only one driver and thus has more application possibilities. The centrifugal pulsatile pump has been used in animal experiments. The pump assisted the circulation of calves for several months without harm to the blood elements and the organ functions of the experimental animal. The experiments demonstrated that the pulsatile impeller pump is the most efficient pump for assisting heart recovery, because it can produce a pulsatile flow like a diaphragm pump and has no back flow as occurs in a non-pulsatile rotary pump; the former reduces the circulatory resistance and the latter increases the diastole pressure in aorta and thus increases the perfusion of coronary arteries of the natural heart.


Reading sentences of uniform word length: Evidence for the adaptation of the preferred saccade length during reading.
In the current study, the effect of removing word length variability within sentences on spatial aspects of eye movements during reading was investigated. Participants read sentences that were uniform in terms of word length, with each sentence consisting entirely of three-, four-, or five-letter words, or a combination of these word lengths. Several interesting findings emerged. Adaptation of the preferred saccade length occurred for sentences with different uniform word length; participants would be more accurate at making short saccades while reading uniform sentences of three-letter words, while they would be more accurate at making long saccades while reading uniform sentences of five-letter words. Furthermore, word skipping was affected such that three- and four-letter words were more likely, and five-letter words less likely, to be directly fixated in uniform compared to non-uniform sentences. It is argued that saccadic targeting during reading is highly adaptable and flexible toward the characteristics of the text currently being read, as opposed to the idea implemented in most current models of eye movement control during reading that readers develop a preference for making saccades of a certain length across a lifetime of experience with a given language. (PsycINFO Database Record


Association between plasma L-carnitine levels and mitochondrial DNA copy number.
Mitochondria are key cytoplasmic organelles in eukaryotic cells that generate adenosine triphosphate (ATP) through the electron transport chain and oxidative phosphorylation. Mitochondrial DNA (mtDNA) copy number (mtDNAcn) is considered a biomarker for both mitochondrial quantity and function as well as cellular oxidative stress level. Previous epidemiologic findings revealed that weight gain, higher body mass index (BMI), smoking, and high insulinemic potential of lifestyle were associated with lower leukocyte mtDNAcn. Carnitines are a group of compounds that play a critical role in energy production. We quantified the associations of plasma L-carnitine levels with leukocyte mtDNAcn. We then examined the association between mtDNAcn and L-carnitine (HMDB0000062) in 538 U.S. men without cancers, diabetes, or cardiovascular disease at blood collection from the Health Professionals Follow-Up Study (HPFS). We found a significant inverse association between L-carnitine and mtDNAcn (ρ = -0.1, P = 0.02). This implies that the carnitine metabolic pathway may be associated with mitochondrial function and oxidative stress.


Reflections on the cleft experience by South african adults: use of qualitative methodology.
This study explored the perceptions of a group of South African adults with repaired cleft lip, cleft palate, or both regarding their quality of life by considering the domains of communication, education, employment, family and marital life, social life, and emotional issues. An exploratory-descriptive, qualitative research design was employed. Individual, semistructured interviews were conducted in the homes of participants. Twenty adults with repaired cleft lip, cleft palate, or both aged between 18 and 50 years participated in the study. Participants were generally satisfied with their communicative abilities and perceived their speech to be intelligible. They also felt that speech therapy had improved the quality of their lives. Although they had experienced teasing during childhood, they did not feel that their cleft had affected their relationships with teachers and were generally satisfied with their educational attainments. Socially they reported being greatly affected by negative societal perceptions and prevailing cultural myths regarding etiology of clefts. Generally employment did not appear to be affected by the presence of a cleft. With regard to family life, participants reported being treated differently by parents in comparison with their siblings. For the majority of respondents, marital relationships and dating did not seem to be adversely affected. In terms of emotional factors, both positive and negative reactions were experienced in relation to the cleft. They also felt that the competent and compassionate care received from the multidisciplinary team had definitely enhanced the quality of their lives. These findings have important clinical implications for a multidisciplinary approach to treatment; counseling of patients and their families; education of the community regarding cleft lip, cleft palate, or both; and further research.


Nutritional situation in the world.
The paper describes the international nutrition problem, with references to previous crisis in the world. It is stated that the present situation cannot be compared to the historical famines in the past. The causes and magnitude of the problem are quite different. The information available on the nutritional situation in the world at present is scanty, erratic and contradictory. The criteria used for such evaluation is not uniform, and this is the reason of the differences in the estimation of the magnitude of the problem. According to the analysis of 101 surveys conducted in 59 developing countries during the last 10 years, in which more than 260,000 children below 5 years were examined the percentage of cases of severe forms of malnutrition was of 2.3% and of moderate forms of 18.8%. However there are some areas where severe forms represent 10 or 20% of children examined. Taking only the most representative surveys (25 out of 59) a rough estimation of the total number of malnoursihed children in developing countries gives the figure of 10 millions of severe forms and 90 millions of moderate forms. The paper makes references to mortality trends in developing countries compared with the trends observed in developed countries. It is the view of the author that the recent dramatic decline on mortality in developing countries is due more to public health action, particularly the existence of new drugs, than to any significant improvement in the standard of living, including nutrition. A distinction is made on the differences between the biological needs of nutrients and the social satisfaction produced by food intake. In fact the biological needs are much less than the average consumption of the affluent society. It is suggested that in order to raise the standards of nutrition in developing countries it would perhaps be necessary to moderate the excessive consumption among other things, of proteins of animal origin in developed countries. Finally the author strongly recommend to intensify the action on nutrition at international, national and family level.


Two-dimensional analysis of retinal information transfer.
A two-dimensional, time-dependent analysis of the mammalian retina is presented. A computer simulation of experimental data considers ganglion-cell activity as a two-dimensional process. The properties of the simulation model were examined with several input stimuli. Circular receptive fields enhance not only borders, but other spatial complexities, such as ends of lines and angles. The enhancement is remarkably insensitive to the shape of receptive fields. The processing of the input picture by on-center and off-center receptive fields is complementary but the division of labor varies with the task.


Harvest and group effects on pup survival in a cooperative breeder.
Recruitment in cooperative breeders can be negatively affected by changes in group size and composition. The majority of cooperative breeding studies have not evaluated human harvest; therefore, the effects of recurring annual harvest and group characteristics on survival of young are poorly understood. We evaluated how harvest and groups affect pup survival using genetic sampling and pedigrees for grey wolves in North America. We hypothesized that harvest reduces pup survival because of (i) reduced group size, (ii) increased breeder turnover and/or (iii) reduced number of female helpers. Alternatively, harvest may increase pup survival possibly due to increased per capita food availability or it could be compensatory with other forms of mortality. Harvest appeared to be additive because it reduced both pup survival and group size. In addition to harvest, turnover of breeding males and the presence of older, non-breeding males also reduced pup survival. Large groups and breeder stability increased pup survival when there was harvest, however. Inferences about the effect of harvest on recruitment require knowledge of harvest rate of young as well as the indirect effects associated with changes in group size and composition, as we show. The number of young harvested is a poor measure of the effect of harvest on recruitment in cooperative breeders.


Strategies for fertility preservation in young early breast cancer patients.
Diagnosis of breast cancer in young women poses a threat to fertility. Due to a recent trend of delaying pregnancy, an increasing number of breast cancer patients in reproductive age wish to bear children. Health care providers have the responsibility to know how to manage fertility issues in cancer survivors. Oncofertility counseling is of great importance to many young women diagnosed with cancer and should be managed in a multi-disciplinary background. Most of young breast cancer patients are candidate to receive chemotherapy, which could lead to premature ovarian failure. A baseline evaluation of ovarian reserve may help in considering the different fertility preservation options. The choice of the suitable strategy depends also on age, type of chemotherapy, partner status and patients' motivation. Various options are available, some established such as embryo and oocyte cryopreservation, some still experimental such as ovarian tissue cryopreservation and ovarian suppression with GnRHa during chemotherapy. An early referral to a reproductive specialist should be offered to patients at risk of infertility who are interested in fertility preservation.


Lymphocytic mastopathy mimicking breast malignancy: a case report.
Lymphocytic mastopathy affects both young and middle-aged women and is frequently associated with autoimmune diseases. Diagnosis is done by associating clinical (breast tissue thickening or hardened breast lump), radiological (increased breast density, presence of mass and calcifications), sonographic (nodule with posterior acoustic shadowing), histopathological (fibrosis and lymphocytic infiltrate) and immunohistochemical findings. Lymphocytic mastopathy is a benign entity that may mimic carcinoma. The authors report the case of a patient with lymphocytic mastopathy.


Improving Fairness in the Prediction of Heart Failure Length of Stay and Mortality by Integrating Social Determinants of Health.
Machine learning (ML) approaches have been broadly applied to the prediction of length of stay and mortality in hospitalized patients. ML may also reduce societal health burdens, assist in health resources planning and improve health outcomes. However, the fairness of these ML models across ethnoracial or socioeconomic subgroups is rarely assessed or discussed. In this study, we aim (1) to quantify the algorithmic bias of ML models when predicting the probability of long-term hospitalization or in-hospital mortality for different heart failure (HF) subpopulations, and (2) to propose a novel method that can improve the fairness of our models without compromising predictive power. We built 5 ML classifiers to predict the composite outcome of hospitalization length-of-stay and in-hospital mortality for 210 368 HF patients extracted from the Get With The Guidelines-Heart Failure registry data set. We integrated 15 social determinants of health variables, including the Social Deprivation Index and the Area Deprivation Index, into the feature space of ML models based on patients' geographies to mitigate the algorithmic bias. The best-performing random forest model demonstrated modest predictive power but selectively underdiagnosed underserved subpopulations, for example, female, Black, and socioeconomically disadvantaged patients. The integration of social determinants of health variables can significantly improve fairness without compromising model performance. We quantified algorithmic bias against underserved subpopulations in the prediction of the composite outcome for HF patients. We provide a potential direction to reduce disparities of ML-based predictive models by integrating social determinants of health variables. We urge fellow researchers to strongly consider ML fairness when developing predictive models for HF patients.


Periodontal diseases as bacterial infection.
The periodontal disease is conformed by a group of illnesses affecting the gums and dental support structures. They are caused by certain bacteria found in the bacterial plaque. These bacteria are essential to the onset of illness; however, there are predisposing factors in both the host and the microorganisms that will have an effect on the pathogenesis of the illness. Periodontopathogenic bacterial microbiota is needed, but by itself, it is not enough to cause the illness, requiring the presence of a susceptible host. These diseases have been classified as gingivitis, when limited to the gums, and periodontitis, when they spread to deeper tissues. Classification of periodontal disease has varied over the years. The one used in this work was approved at the International Workshop for a Classification of Periodontal Diseases and Conditions, held in 1999. This study is an overview of the different periodontal disease syndromes. Later, the systematic use of antibiotic treatment consisting of amoxicillin, amoxicillin-clavulanic acid, and metronidazole as first line coadjuvant treatment of these illnesses will be reviewed.


Longitudinal impedance of single frog muscle fibers.
The longitudinal impedance of single skeletal muscle fibers has been measured from1 to 10,000 Hz in an oil gap apparatus which forces current to flow longitudinally down the fiber. The impedance observed is purely resistive in some fibers from the semitendinosus muscle and in two fibers from the sartorius muscle. In other fibers from the semitendinosus muscle a small phase shift is observed. The mean value of the maximum phase shift observed from all fibers is 1.07 degrees. The artifacts associated with the apparatus and method are examined theoretically and it is shown that one of the likely artifacts could account for the small phase observed. It is concluded that the longitudinal impedance of skeletal muscle fibers is essentially resistive and that little, if any, longitudinal current crosses the membranes of the sarcoplasmic reticulum.


Fathers and mothers at play with their 2- and 3-year-olds: contributions to language and cognitive development.
Father-child and mother-child engagements were examined longitudinally in relation to children's language and cognitive development at 24 and 36 months. The study involved a racially/ethnically diverse sample of low-income, resident fathers (and their partners) from the National Early Head Start evaluation study (n=290). Father-child and mother-child engagements were videotaped for 10 min at home during semistructured free play, and children's language and cognitive status were assessed at both ages. Fathers' and mothers' supportive parenting independently predicted children's outcomes after covarying significant demographic factors. Moreover, fathers' education and income were uniquely associated with child measures, and fathers' education consistently predicted the quality of mother-child engagements. Findings suggest direct and indirect effects of fathering on child development.


True nature of the Curzon-Ahlborn efficiency.
The Curzon-Ahlborn efficiency has long served as the definite upper bound for the thermal efficiency at maximum output power, and has thus shaped the development of finite-time thermodynamics. In this paper, we repeal the ruling consensus according to which it has a genuine universal character that can be derived from linear irreversible thermodynamics. We demonstrate that the Curzon-Ahlborn efficiency should instead properly be associated with a particular case of nonlinear heat engines, and we derive a generalized expression for the efficiency at maximum power beyond the restrictive case of linear models.


[Pathological reactions of the erotic possession type].
The paper presents an analysis of the disorders with manifestations of non-delirious pathologic love as a response to the action of psychogenic factor on the basis of constitutional predisposition. By the results of the examination of 31 patients with prolonged psychogenic depressions, characterized by the phenomenon of erotic possession, 2 types of the pathologic reactions were distinguished: with a predominance of the possessed images and with a predominance of the delirious-like fantasies. Psycho-traumatic situations that reflected loss of significant relations (either real or imaginary) as a result of the divorce, broken relations, "love triangle", etc. were investigated. Estimation of the premorbid state in the patients allowed both to reveal accentuation in a sphere of love relationship and to single out a main mechanism of the development of pathologic reactions (by type of "key" experience) as well as to define typological differentiation of psychogenic by type of erotic possession taking into consideration the constitutional anomalies.


Contributions of RNA secondary structure and length of the thymidine tract to transcription termination at the thr operon attenuator.
The thr operon of Escherichia coli is regulated by an attenuation mechanism in which regulated transcription termination occurs in response to the levels of charged tRNAthr and tRNAile. Transcription of the thr operon regulatory region in vitro produces a 162-base transcript that is terminated efficiently at the attenuator. The attenuator sequence is similar to other rho-independent terminators. It contains a G + C region of dyad symmetry followed by a run of 9 A + T residues. We have characterized in detail the sequence requirements for efficient transcription termination in vitro. Using a set of point mutations in the G + C region of dyad symmetry of the thr attenuator, we have characterized the effects of these mutations on the efficiency of transcription termination. The efficiency was reduced in all of the mutants analyzed with the greatest effect being an approximate 20% decrease in termination. In some instances the electrophoretic mobilities of the terminated transcripts on 8% polyacrylamide, 8 M urea gels were shifted substantially relative to the wild type-terminated transcript, but the sites of transcription termination were altered by only a few base pairs. We also constructed a set of deletions removing consecutive thymidines which follow the G + C-rich region of dyad symmetry. Removal of 1 or 3 of the 9 thymidine residues had no effect on termination efficiency in vitro or in vivo. Removal of four to six thymidines caused a linear decrease in the efficiency of termination. When only one or two thymidines were present in the template, termination was completely abolished. These results indicate that both the integrity of the RNA stem and the length of the consecutive thymidine residues are important signals recognized by RNA polymerase during transcription of the thr operon regulatory region.


Porous Silicon Nanoparticles Embedded in Poly(lactic-co-glycolic acid) Nanofiber Scaffolds Deliver Neurotrophic Payloads to Enhance Neuronal Growth.
Scaffolds made from biocompatible polymers provide physical cues to direct the extension of neurites and to encourage repair of damaged nerves. The inclusion of neurotrophic payloads in these scaffolds can substantially enhance regrowth and repair processes. However, many promising neurotrophic candidates are excluded from this approach due to incompatibilities with the polymer or with the polymer processing conditions. This work provides one solution to this problem by incorporating porous silicon nanoparticles (pSiNPs) that are pre-loaded with the therapeutic into a polymer scaffold during fabrication. The nanoparticle-drug-polymer hybrids are prepared in the form of oriented poly(lactic-co-glycolic acid) nanofiber scaffolds. We test three different therapeutic payloads: bpV(HOpic), a small molecule inhibitor of phosphatase and tensin homolog (PTEN); an RNA aptamer specific to tropomyosin-related kinase receptor type B (TrkB); and the protein nerve growth factor (NGF). Each therapeutic is loaded using a loading chemistry that is optimized to slow the rate of release of these water-soluble payloads. The drug-loaded pSiNP-nanofiber hybrids release approximately half of their TrkB aptamer, bpV(HOpic), or NGF payload in 2, 10, and >40 days, respectively. The nanofiber hybrids increase neurite extension relative to drug-free control nanofibers in a dorsal root ganglion explant assay.


Sensor-measured sedentariness and physical activity are differentially related to fluid and crystallized abilities in aging.
Aerobic exercise and physical activity (PA) are known to benefit cognition in adulthood. However, a typical older adult spends most of the day sedentary or in light PA, behaviors that are typically poorly captured by questionnaires. To better understand the associations between time spent in different intensities of lifestyle PA and cognition, we measured average time spent daily in sedentariness, light, and moderate to vigorous PA using hip-worn sensors (ActiGraph accelerometers). We studied baseline data from 228 cognitively normal adults (Age 60-80) who took part in a clinical trial (clinical study identifier: NCT01472744). Fluid (processing speed, memory, and reasoning) and crystallized abilities (vocabulary knowledge) were assessed with the Virginia Cognitive Aging Battery. Adjusting for age, sex, and several modifiable socioeconomic, physical and functional health factors, time spent daily in moderate to vigorous PA was positively related with fluid abilities (perceptual speed and reasoning). Furthermore, we found that those spending more time sedentary performed better on vocabulary knowledge and reasoning tasks. In contrast, time spent in light PA was not related to either fluid or crystallized abilities. Our results add to the previous literature by providing the first sensor-based evidence that crystallized and fluid abilities in older age may be associated with engagement in different intensities of daily activity. Moreover, our findings suggest that the behavior of moderate to vigorous PA is at least as important in relation to cognition as the desirable long-term physiological effects of higher intensity PA and exercise. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Auracyanin B structure in space group P6(5).
The structure of auracyanin B, a 'blue' copper protein produced by Chloroflexus aurantiacus, has previously been solved and refined in the hexagonal space group P6(4)22 with a single molecule in the asymmetric unit. The protein has now been crystallized in space group P6(5), with unit-cell parameters a = b = 115.9, c = 108.2 A. In the new crystal form, the asymmetric unit contains four protein molecules. The structure has been solved by molecular replacement and refined at 1.9 A resolution. The final residuals are R = 19.2% and R(free) = 21.9%. In relation to the earlier crystal structure, the doubling of the unit-cell volume and the lower symmetry are explained by small rotations of the molecules with respect to one another.


[Modern approaches to the therapy of biliary system diseases].
The therapeutic efficacy of duspatalin was evaluated in 72 patients with chronic cholecystitis and dyskinesia of the biliary tract (BT). Supplementation of duspatalin to the combined therapy in the patients with chronic cholecystitis shown to exert a pronounced therapeutic effect. This caused positive changes in clinical symptoms and BT function and quality of life, diminished the lithogenic properties of bile.


Primary fibroblasts from CSPα mutation carriers recapitulate hallmarks of the adult onset neuronal ceroid lipofuscinosis.
Mutations in the co- chaperone protein, CSPα, cause an autosomal dominant, adult-neuronal ceroid lipofuscinosis (AD-ANCL). The current understanding of CSPα function exclusively at the synapse fails to explain the autophagy-lysosome pathway (ALP) dysfunction in cells from AD-ANCL patients. Here, we demonstrate unexpectedly that primary dermal fibroblasts from pre-symptomatic mutation carriers recapitulate in vitro features found in the brains of AD-ANCL patients including auto-fluorescent storage material (AFSM) accumulation, CSPα aggregates, increased levels of lysosomal proteins and lysosome enzyme activities. AFSM accumulation correlates with CSPα aggregation and both are susceptible to pharmacological modulation of ALP function. In addition, we demonstrate that endogenous CSPα is present in the lysosome-enriched fractions and co-localizes with lysosome markers in soma, neurites and synaptic boutons. Overexpression of CSPα wild-type (WT) decreases lysotracker signal, secreted lysosomal enzymes and SNAP23-mediated lysosome exocytosis. CSPα WT, mutant and aggregated CSPα are degraded mainly by the ALP but this disease-causing mutation exhibits a faster rate of degradation. Co-expression of both WT and mutant CSPα cause a block in the fusion of autophagosomes/lysosomes. Our data suggest that aggregation-dependent perturbation of ALP function is a relevant pathogenic mechanism for AD-ANCL and supports the use of AFSM or CSPα aggregation as biomarkers for drug screening purposes.


Influence of water content on RF and microwave dielectric behavior of foods.
The importance of dielectric properties of food materials is discussed with respect to their influence on the heating of materials by radio-frequency and microwave energy and their use for rapid, nondestructive sensing of quality characteristics of such materials. Data are presented graphically showing the frequency and temperature dependence of the dielectric constant and loss factor of wheat, fresh chicken breast meat, several fresh fruits, and apple juice, representing food materials with a wide range of moisture content. The influence of moisture or water content on the dielectric behavior of these materials is discussed, and that behavior is explained in terms of dipolar relaxation and ionic conduction.


Randomised placebo-controlled trial of combination ACE inhibitor and beta-blocker therapy to prevent cardiomyopathy in children with Duchenne muscular dystrophy? (DMD Heart Protection Study): a protocol study.
Although cardiologists were 'late-comers' to the multidisciplinary team-contributing to the complex care of patients with Duchenne muscular dystrophy (DMD), they now recognise the importance of systematic cardiac surveillance and timely therapy to prolonged survival in patients with DMD. Empirical deployment of cardioactive medications has already improved outcomes, but the evidence base for clinical decision making is weak. Fundamental questions remain as to whether prophylactic therapy is justified and convincingly superior to prompt deployment of the same therapies once left ventricular (LV) dysfunction is detected. Even if it were, at what age should therapy be introduced and with what specific drugs? We are conducting a multicentre, parallel group, randomised, placebo-controlled study of combination therapy with an ACE inhibitor (perindopril) and a beta-blocker (bisoprolol) in boys with DMD aged 5-13 years, with normal LV function by echocardiographic criteria at the time of recruitment. Boys are being followed-up for a minimum of 3 years and a maximum of 5 years and undergo repeat assessments of LV function, heart rate and ECG, forced expiratory volume in the 1 s and forced vital capacity, adverse event reporting and quality of life at 6 monthly intervals.The primary outcome is change in LV function between active and placebo-treated participants over the course of the study. The study was approved by 'NRES Committee East Midlands - Derby'. The results will be disseminated through manuscript publications, an international workshop and presentations to scientific meetings and parent forums. The study seeks to establish the evidence for prophylactic heart therapies for children with DMD, define the optimum age for their introduction and identify any safety concerns. The protocol describes the design of an ongoing multicentre, double-blind, randomised placebo-controlled study to establish the evidence for the use of prophylactic heart therapies in children with DMD, define the optimum age for their introduction and identify any safety concerns. EudraCT2007-005932-10 and ISRCTN50395346; Pre-results.


Mating skew in Barbary macaque males: the role of female mating synchrony, female behavior, and male-male coalitions.
A fundamental question of sexual selection theory concerns the causes and consequences of reproductive skew among males. The priority of access (PoA) model (Altmann, Ann NY Acad Sci 102:338-435, 1962) has been the most influential framework in primates living in permanent, mixed-sex groups, but to date it has only been tested with the appropriate data on female synchrony in a handful of species. In this paper, we used mating data from one large semi-free ranging group of Barbary macaques: (1) to provide the first test of the priority-of-access model in this species, using mating data from 11 sexually active females (including six females that were implanted with a hormonal contraceptive but who showed levels of sexual activity comparable to those of naturally cycling females) and (2) to determine the proximate mechanism(s) underlying male mating skew. Our results show that the fit of the observed distribution of matings with sexually attractive females to predictions of the PoA model was poor, with lower-ranking males mating more than expected. While our work confirms that female mating synchrony sets an upper limit to monopolization by high-ranking individuals, other factors are also important. Coalitionary activity was the main tactic used by males to lower mating skew in the study group. Coalitions were expressed in a strongly age-related fashion and allowed subordinate, post-prime males to increase their mating success by targeting more dominant, prime males. Conversely, females, while mating promiscuously with several males during a given mating cycle, were more likely to initiate their consortships with prime males, thus reducing the overall effectiveness of coalitions. We conclude that high-ranking Barbary macaque males have a limited ability to monopolize mating access, leading to a modest mating skew among them.


Multiplier method for prediction of adult height in patients with achondroplasia.
To date, the only way to predict adult height in achondroplastic dwarves has been to consult a growth chart. The purpose of this study was to ascertain whether the multiplier method of predicting adult height at skeletal maturity in healthy persons can be applied to persons with achondroplasia. Previous studies have shown that the multiplier method can be applied to lower limb length, upper limb length, total height, foot length, and foot height. It is therefore reasonable to suggest that the growth pattern for total height in achondroplastic dwarves might also be characterized by a multiplier. Total height multipliers for achondroplastic dwarves ("achondroplasia height multipliers") were calculated from two separate databases by dividing height at maturity by height at each respective age for both genders. Little variability was found among multipliers for each age and among multipliers calculated from different databases. Upper torso (sitting height) multipliers and lower limb multipliers were also derived for achondroplastic dwarves. Lower limb and total height growth rates were slower in achondroplastic dwarves compared with healthy persons. However, sitting height multipliers for achondroplastic dwarves were closely related to sitting height multipliers for healthy persons. Because these findings showed that the multiplier values were independent of population and percentile, the multiplier method may be a valid method for quickly predicting height at any age for achondroplastic dwarves.


Following ligand migration pathways from picoseconds to milliseconds in type II truncated hemoglobin from Thermobifida fusca.
CO recombination kinetics has been investigated in the type II truncated hemoglobin from Thermobifida fusca (Tf-trHb) over more than 10 time decades (from 1 ps to ∼100 ms) by combining femtosecond transient absorption, nanosecond laser flash photolysis and optoacoustic spectroscopy. Photolysis is followed by a rapid geminate recombination with a time constant of ∼2 ns representing almost 60% of the overall reaction. An additional, small amplitude geminate recombination was identified at ∼100 ns. Finally, CO pressure dependent measurements brought out the presence of two transient species in the second order rebinding phase, with time constants ranging from ∼3 to ∼100 ms. The available experimental evidence suggests that the two transients are due to the presence of two conformations which do not interconvert within the time frame of the experiment. Computational studies revealed that the plasticity of protein structure is able to define a branched pathway connecting the ligand binding site and the solvent. This allowed to build a kinetic model capable of describing the complete time course of the CO rebinding kinetics to Tf-trHb.


Osteosarcoma of jaws: Challenges in diagnosis.
Osteosarcoma (OS) accounts for about 20% of all sarcomas with gnathic involvement seen in about 6%-10% of all OSs. The clinical presentation of OSs in the jaws is different from that of long bones as swelling is the most common complaint in patients with jaw OS followed by pain. The histopathologic variables seen are more favorable in OSs of jaws. Low-grade tumors are Stage I, high-grade tumors are Stage II and metastatic tumors (regardless of grade) are Stage III. A 17-year-old male patient reported with a complaint of the presence of an intra-oral growth gradually increasing in size in the right buccal mucosa region soft tissue enveloping the occlusal aspect of the right mandibular second molar. Extraorally swelling was present on the right side of the face for 4 months. Radiographically, there was a radiolucency from the distal aspect of right Mandibular second molar extending into the ramus region of the mandible with ill-defined borders. Hemi-mandibulectomy was done with the removal of the right mandible from the premolar region to condyle and coronoid processes. Microscopic evaluation of the sections after hematoxylin and eosin staining revealed interlacing fascicles of spindle-shaped cells arranged in a biphasic pattern and some areas of attempted bone formation evident in deeper sections. Tumor was an osteoblastic variety consisting of tumor osteoid surrounded by bizarrely arranged fibroblast-like cells. It showed positive staining with α-smooth muscle actin and Vimentin, suggesting a malignant tumor of mesenchymal cells with high myofibroblastic activity. Our case had small-cell histology; therefore, differential diagnosis was important.


Arthroscopic meniscal surgery: a national society treatment guideline and consensus statement.
The aim of the British Association for Surgery of the Knee (BASK) Meniscal Consensus Project was to develop an evidence-based treatment guideline for patients with meniscal lesions of the knee. A formal consensus process was undertaken applying nominal group, Delphi, and appropriateness methods. Consensus was first reached on the terminology relating to the definition, investigation, and classification of meniscal lesions. A series of simulated clinical scenarios was then created and the appropriateness of arthroscopic meniscal surgery or nonoperative treatment in each scenario was rated by the group. The process was informed throughout by the latest published, and previously unpublished, clinical and epidemiological evidence. Scenarios were then grouped together based upon the similarity of clinical features and ratings to form the guideline for treatment. Feedback on the draft guideline was sought from the entire membership of BASK before final revisions and approval by the consensus group. A total of 45 simulated clinical scenarios were refined to five common clinical presentations and six corresponding treatment recommendations. The final guideline stratifies patients based upon a new, standardized classification of symptoms, signs, radiological findings, duration of symptoms, and previous treatment. The 2018 BASK Arthroscopic Meniscal Surgery Treatment Guidance will facilitate the consistent identification and treatment of patients with meniscal lesions. It is hoped that this guidance will be adopted nationally by surgeons and help inform healthcare commissioning guidance. Validation in clinical practice is now required and several areas of uncertainty in relation to treatment should be a priority for future high-quality prospective studies. Cite this article: Bone Joint J 2019;101-B:652-659.


DC-SCRIPT Regulates IL-10 Production in Human Dendritic Cells by Modulating NF-κBp65 Activation.
The balance between tolerance and immunity is important for the outcome of an infection or cancer, and dendritic cells (DCs) are key regulators of this balance. DC-specific transcript (DC-SCRIPT) is a protein expressed by DCs and has been demonstrated to suppress both TLR-mediated expression of IL-10 and glucocorticoid receptor-mediated transcription of glucocorticoid-induced leucine zipper (GILZ). Because GILZ is known to promote IL-10 production, we investigated whether these two processes are linked. Dual-knockdown and inhibition experiments demonstrated that neither GILZ nor glucocorticoid receptor play a role in TLR-induced IL-10 production after DC-SCRIPT knockdown. The NF-κB pathway is another route involved in IL-10 production after DC activation. Strikingly, inhibition of NF-κB led to a decreased TLR-mediated IL-10 production in DC-SCRIPT knockdown DCs. Moreover, DC-SCRIPT knockdown DCs showed enhanced phosphorylation, acetylation, and IL10 enhancer binding of the NF-κB subunit p65. These data demonstrate that besides nuclear receptor regulation, DC-SCRIPT also modulates activation of NF-κBp65 after TLR activation in human DCs.


Increased burn patient survival with individualized dosages of gentamicin.
The clinical effect of measuring serum gentamicin concentrations and individualizing each patient's dosage regimen was determined 105 burn patients with severe gram-negative sepsis. Thirty-nine patients (conventionally dosed group) received the recommended dosage regimen of 3 to 5 mg/kg/day from 1972 to 1974. From 1974 to 1976, serum concentrations were measured in 66 patients (individually dosed group), and each patient's dose was individually calculated to obtain therapeutic serum concentrations. All patients had normal renal function prior to initiation of gentamicin therapy. For each group, 16 independent variables were compared that may have influenced treatment response. The patients in the individually dosed group required an average dose of 7.4 mg/kg/day to achieve therapeutic concentrations, compared to the average dose of 4.4 mg/kg/day for the patients receiving conventional doses (P less than 0.001). An abrupt increase in patient survival occurred with the implementation of individualized regimens. Patient survival rates for the entire hospital course were 33% and 64% for the conventionally dosed and individually dosed groups, respectively (P less than 0.005). Survival rates for the first septic episode were 51.3% and 86.4%, respectively (P less than 0.001). Individualized gentamicin regimens, age, percent burn, and sex were the statistically significant variables related to patient survival for the first episode of sepsis. Age, percent burn, individualized dosing, complications during hospitalization, and a positive blood culture were significant factors related to patient survival for the entire hospital course. These data confirm the need for measuring serum gentamicin concentrations and adjusting dosages to ensure therapeutic levels and maximal efficacy of gentamicin in burn patients.


Inflammatory fibroid polyp of the esophagus.
The case of a 76-year-old woman with a submucosal tumor of the esophagus, whose principal symptoms were dysphagia and epigastric/retrosternal pain, is reported here. Endoscopy, barium swallow and a CAT scan all pointed to extramucosal localization. The lesion was located in the lower esophagus lying on the stomach fundus. An ulcer in the region of the cardia complicated the tumor. Two sets of conventional biopsies failed to detect malignancy, only inflammation and intestinal metaplasia were seen in the specimens of the mucosa surrounding the ulcer. The endoscopic ultrasonographic findings were an indistinct margin, hypoechogenicity, homogeneous appearance and location within the second and third echographic layer. The surgical resection of the tumor was complemented by an anterior partial fundoplication. The histologic study revealed an inflammatory fibroid polyp, which is a rare, benign, non-capsulated submucosal lesion composed mainly of loose connective tissue and vessels, with an eosinophilic inflammatory component. This lesion is seldom found in the esophagus.


Diet of Paranthropus boisei in the early Pleistocene of East Africa.
The East African hominin Paranthropus boisei was characterized by a suite of craniodental features that have been widely interpreted as adaptations to a diet that consisted of hard objects that required powerful peak masticatory loads. These morphological adaptations represent the culmination of an evolutionary trend that began in earlier taxa such as Australopithecus afarensis, and presumably facilitated utilization of open habitats in the Plio-Pleistocene. Here, we use stable isotopes to show that P. boisei had a diet that was dominated by C(4) biomass such as grasses or sedges. Its diet included more C(4) biomass than any other hominin studied to date, including its congener Paranthropus robustus from South Africa. These results, coupled with recent evidence from dental microwear, may indicate that the remarkable craniodental morphology of this taxon represents an adaptation for processing large quantities of low-quality vegetation rather than hard objects.


ATM-depletion in breast cancer cells confers sensitivity to PARP inhibition.
Mutations in the DNA damage response (DDR) factors, breast cancer 1 (BRCA1) and BRCA2, sensitize tumor cells to poly(ADP-ribose) polymerase (PARP) inhibitors. The ataxia telangiectasia mutated (ATM) kinase is a key DDR protein whose heterozygous germline mutation is a moderate-risk factor for developing breast cancer. In this study, we examined whether ATM inactivation in breast cancer cell lines confers sensitivity to PARP inhibitors. Wild-type BRCA1/2 breast cancer cells (i.e., MCF-7 and ZR-75-1 lines) were genetically manipulated to downregulate ATM expression then assayed for cytostaticity/cytotoxicity upon treatment with PARP inhibitors, olaparib and iniparib. When ATM-depleted cells and their relative controls were treated with olaparib (a competitive PARP-1/2 inhibitor) and iniparib (a molecule originally described as a covalent PARP-1 inhibitor) a different response to the two compounds was observed. ATM-depletion sensitized both MCF-7 and ZR-75-1 cells to olaparib-treatment, as assessed by short and long survival assays and cell cycle profiles. In contrast, iniparib induced only a mild, ATM-dependent cytostatic effect in MCF-7 cells whereas ZR-75-1 cells were sensitive to this drug, independently of ATM inactivation. These latest results might be explained by recent observations indicating that iniparib acts with mechanisms other than PARP inhibition. These data indicate that ATM-depletion can sensitize breast cancer cells to PARP inhibition, suggesting a potential in the treatment of breast cancers low in ATM protein expression/activity, such as those arising in mutant ATM heterozygous carriers.


Are "accidental" gun deaths as rare as they seem? A comparison of medical examiner manner of death coding with an intent-based classification approach.
Unintentional firearm death is often considered a nearly negligible proportion of overall gun death. These rates are based on medical examiner (ME) and coroner death classifications, which affect derived epidemiologic data and subsequent prevention measures. The aim of this study was to compare the proportion of pediatric unintentional gun deaths in Miami-Dade County based on manner of death coding by the ME with an intent-based classification of child gun deaths. ME and police records for all pediatric firearm fatalities in Miami-Dade County from 1994 to 1998 were reviewed. The ME's assignment of manner of death as homicide, suicide, or accident was compared with an intent-based classification of intentional homicide, intentional suicide, and unintentional firearm death based on expressed or implied evidence of intent to harm. There were 123 pediatric firearm deaths in Miami-Dade County from 1994 to 1998. A significant difference between ME coding and the intent-based classification was found for homicide (94 vs 78) but not for suicide. A significant difference was also found between the ME's coding for "accident" and the investigator's classification of "unintentional" firearm death (4 vs 26). The incidence of unintentional pediatric firearm deaths is significantly underreported by the Miami-Dade County ME when the classification of "accidental" firearm death is used. Reviewing the manner of death classification criteria or establishing an intent code on official death documentation is recommended. Furthermore, clinicians should be aware that the true incidence of unintentional gun death may be higher than that reported as accidental.


Opioids and alpha-2-agonists for analgesia and sedation in newborn infants: protocol of a systematic review.
Hospitalized newborn infants may require analgesia and sedation either for the management of procedural pain, during or after surgery, and other painful conditions. The benefits and harms of opioids administered at different doses and routes of administration have been reported in numerous trials and systematic reviews. The use of alpha-2-agonists such as clonidine and dexmedetomidine in newborn infants is more recent, and they might be prescribed to reduce the total amount of opioids which are thought to have more side effects. Moreover, alpha-2-agonists might play an important role in the management of agitation and discomfort. We will conduct a systematic review and meta-analysis on the use of opioids, alpha-2-agonists, or the combination of both drugs. We will include randomized controlled trials to assess benefits and harms and observational studies to assess adverse events and pharmacokinetics; preterm and term infants; studies on any opioids or alpha-2-agonists administered for any indication and by any route except spinal, intraosseous, or administration for nerve blocks and wound infusions. The use of opioids or alpha-2-agonists will be compared to no intervention; placebo with normal saline or other non-sedative, non-analgesic drug; control with oral sugar solution or non-pharmacological intervention; same drug of different dose or route; or a different drug (not limiting to opioids and alpha-2-agonists) or combinations of such drugs. The primary outcomes for this review will be all-cause mortality during initial hospitalization and hypotension requiring medical therapy. We will conduct a search in the following databases: The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, Embase, and CINAHL. Two review authors will independently screen records for inclusion, undertake data abstraction using a data extraction form and assess the risk of bias of all included trials using the Cochrane "Risk of bias" tool. This systematic review will summarize and update our knowledge about neonatal analgesia and sedation including pharmacokinetics/pharmacodynamics, and provide a platform for developing evidence-based guidelines that we can immediately apply to our clinical practice. PROSPERO 2020 CRD42020170852.


Short report: case of gnathostomiasis in Beijing, China.
A 59-year-old woman sought treatment of for creeping eruption and erythematous plaques associated with high fever and systemic symptoms. She had a history of eating undercooked freshwater fish raised in Beijing 10 days before admission and reported no travel during the previous year. Blood examination showed eosinophila and ultrasonography detected multiple hypoechoic areas in the liver and spleen. Western blot test detected specific antibodies to the larvae of Gnathostoma spinigerum. Cutaneous and visceral larva migrations associated with G. spinigerum were diagnosed. Twenty-three cases in 12 provinces have been reported in the Chinese literature but none have been reported in English.


Big Data for Nutrition Research in Pediatric Oncology: Current State and Framework for Advancement.
Recognition and treatment of malnutrition in pediatric oncology patients is crucial because it is associated with increased morbidity and mortality. Nutrition-relevant data collected from cancer clinical trials and nutrition-specific studies are insufficient to drive high-impact nutrition research without augmentation from additional data sources. To date, clinical big data resources are underused for nutrition research in pediatric oncology. Health-care big data can be broadly subclassified into three clinical data categories: administrative, electronic health record (including clinical data research networks and learning health systems), and mobile health. Along with -omics data, each has unique applications and limitations. We summarize the potential use of clinical big data to drive pediatric oncology nutrition research and identify key scientific gaps. A framework for advancement of big data utilization for pediatric oncology nutrition research is presented and focuses on transdisciplinary teams, data interoperability, validated cohort curation, data repurposing, and mobile health applications.


Nanoparticle-mediated expression of a Wnt pathway inhibitor ameliorates ocular neovascularization.
The deficiency of very low-density lipoprotein receptor resulted in Wnt signaling activation and neovascularization in the retina. The present study sought to determine whether the very low-density lipoprotein receptor extracellular domain (VLN) is responsible for the inhibition of Wnt signaling in ocular tissues. A plasmid expressing the soluble VLN was encapsulated with poly(lactide-co-glycolide acid) to form VLN nanoparticles (VLN-NP). Nanoparticles containing a plasmid expressing the low-density lipoprotein receptor extracellular domain nanoparticle were used as negative control. MTT, modified Boyden chamber, and Matrigel (™) assays were used to evaluate the inhibitory effect of VLN-NP on Wnt3a-stimulated endothelial cell proliferation, migration, and tube formation. Vldlr(-/-) mice, oxygen-induced retinopathy, and alkali burn-induced corneal neovascularization models were used to evaluate the effect of VLN-NP on ocular neovascularization. Wnt reporter mice (BAT-gal), Western blotting, and luciferase assay were used to evaluate Wnt pathway activity. Our results showed that VLN-NP specifically inhibited Wnt3a-induced endothelial cell proliferation, migration, and tube formation. Intravitreal injection of VLN-NP inhibited abnormal neovascularization in Vldlr(-/-), oxygen-induced retinopathy, and alkali burn-induced corneal neovascularization models, compared with low-density lipoprotein receptor extracellular domain nanoparticle. VLN-NP significantly inhibited the phosphorylation of low-density lipoprotein receptor-related protein 6, the accumulation of β-catenin, and the expression of vascular endothelial growth factor in vivo and in vitro. Taken together, these results suggest that the soluble VLN is a negative regulator of the Wnt pathway and has antiangiogenic activities. Nanoparticle-mediated expression of VLN may thus represent a novel therapeutic approach to treat pathological ocular angiogenesis and potentially other vascular diseases affected by Wnt signaling.


Reforming pharmaceutical industry-physician financial relationships: lessons from the United States, France, and Japan.
This article compares the means that the United States, France, and Japan use to oversee pharmaceutical industry-physician financial relationships. These countries rely on professional and/or industry ethical codes, anti-kickback laws, and fair trade practice laws. They restrict kickbacks the most strictly, allow wide latitude on gifts, and generally permit drug firms to fund professional activities and associations. Consequently, to avoid legal liability, drug firms often replace kickbacks with gifts and grants. The paper concludes by proposing reforms that address problems that persist when firms replace kickbacks with gifts and grants based on the experience of the three countries.


Review: functional properties of kefir.
Kefir is a unique cultured dairy product due to combined lactic acid and alcoholic fermentation of lactose in milk. Kefir is produced by microbial activity of "kefir grains" which have a relatively stable and specific balance of lactic acid bacteria and yeast. Due to the claimed health benefits of kefir which include reduction of lactose intolerance symptoms, stimulation of the immune system, lowering cholesterol, and antimutagenic and anticarcinogenic properties, kefir has become an important functional dairy food and consequently, research on kefir has increased in the past decade. In the following review, recent studies on the functional properties of kefir are reviewed.


Trapping flocking particles with asymmetric obstacles.
Asymmetric obstacles can be exploited to direct the motion and induce sorting of run-and-tumble particles. In this work, we show that flocking particles which follow the Vicsek model aligning rules experience collective trapping in the presence of a wall of funnels made of chevrons, concentrating at the opposite side of the wall of funnels to run-and-tumble particles. Flocking particles can be completely trapped or exhibit a dynamical trapping behaviour; these two regimes open the door to the design of a system with two perpendicular flows of active particles. This systematic study broadens our understanding of the emergence of collective motion of microorganisms in confined environments and directs the design of new microfluidic devices able to control these collective behaviours.


The non-receptor tyrosine kinase Pyk2 modulates acute locomotor effects of cocaine in D1 receptor-expressing neurons of the nucleus accumbens.
The striatum is critical for cocaine-induced locomotor responses. Although the role of D1 receptor-expressing neurons is established, underlying molecular pathways are not fully understood. We studied the role of Pyk2, a non-receptor, calcium-dependent protein-tyrosine kinase. The locomotor coordination and basal activity of Pyk2 knock-out mice were not altered and major striatal protein markers were normal. Cocaine injection increased Pyk2 tyrosine phosphorylation in mouse striatum. Pyk2-deficient mice displayed decreased locomotor response to acute cocaine injection. In contrast, locomotor sensitization and conditioned place preference were normal. Cocaine-activated ERK phosphorylation, a signaling pathway essential for these late responses, was unaltered. Conditional deletion of Pyk2 in the nucleus accumbens or in D1 neurons reproduced decreased locomotor response to cocaine, whereas deletion of Pyk2 in the dorsal striatum or in A2A receptor-expressing neurons did not. In mice lacking Pyk2 in D1-neurons locomotor response to D1 agonist SKF-81297, but not to an anticholinergic drug, was blunted. Our results identify Pyk2 as a regulator of acute locomotor responses to psychostimulants. They highlight the role of tyrosine phosphorylation pathways in striatal neurons and suggest that changes in Pyk2 expression or activation may alter specific responses to drugs of abuse, or possibly other behavioral responses linked to dopamine action.


Melanoma cell-cell interactions are mediated through heterophilic Mel-CAM/ligand adhesion.
Mel-cell adhesion molecule (CAM), also known as MUC18 and CD146, is a novel member of the immunoglobulin supergene family. Mel-CAM was first identified as an integral membrane glycoprotein in human melanoma and is also abundantly expressed by endothelial cells of various origins. In a previous study (I. M. Shih et al., Cancer Res., 54: 2514-2520, 1994), we showed that Mel-CAM is a cell-cell adhesion molecule with a possible role in melanoma invasion and metastasis. Here, we define the molecular mechanism responsible for cell-cell adhesion of Mel-CAM and demonstrate its role in melanoma-endothelial cell interactions. Most of human melanoma cells, including Mel-CAM-negative SBcl-2 cells, adhered to nitrocellulose-immobilized Mel-CAM produced by baculovirus recombinants. This adhesion can be blocked by full-length Mel-CAM or polyclonal antiserum against Mel-CAM. Adhesion is not affected by the presence of EDTA, truncated Mel-CAM extracellular domain, or heparan sulfate proteoglycan. In cell aggregation assays, Mel-CAM-negative SBcl-2 cells cluster with U937TM cells (U937 transfected with Mel-CAM cDNA) but not with control nontransfectants, suggesting that SBcl-2 cells express the ligand for Mel-CAM. SBcl-2 cells also form heterotypic aggregates with Mel-CAM-positive human endothelial cells but not with Mel-CAM-negative but ligand-positive smooth muscle cells. Taken together, our results show that Mel-CAM mediates cell-cell adhesion through heterophilic adhesion to an as yet unidentified ligand present on melanoma but not on endothelial cells. Thus, melanoma-endothelial interactions during metastasis may occur through this novel mechanism.


Disposition of atovaquone in humans.
Atovaquone is an antiprotozoal compound with good in vitro stability against metabolic inactivation. Previous human studies which did not involve radiolabelling had not accounted for a substantial proportion of the dose. The possible metabolism of atovaquone in men was examined in a radiolabelling study involving four healthy male volunteers. Radioactivity was eliminated almost exclusively via the feces. All radioactivity in plasma, urine, and feces was accounted for by atovaquone, with no evidence of metabolites. Radiolabelled atovaquone was administered to a patient with an indwelling biliary tube after surgery. Biliary radioactivity was approximately 10- to 40-fold higher than that in plasma and was accounted for by atovaquone. Atovaquone is not significantly metabolized in humans but is excreted into bile against a high concentration gradient.


[Seasonal changes in the endocrine cells of the gastric epithelium of Rana temporaria].
By means of the light and electron microscopy methods histotopography, quantity and ultramicroscopic organization of endocrine cells (EC) have been studied in gastric epithelium of the frog (Rana temporaria) during various periods of its life: hibernation, awakening, active life. At all the periods of life 8 types of EC are revealed. Depending on the season, certain changes both in their amount and ultrastructural organization are observed. Decreasing amount of EC is noted during hibernation and their increase in spring during awakening and in summer. Quantity of enterochromaffin cells is not subjected to seasonal fluctuations. This is explained by the fact that in hibernation these cells are also at their active functional state, since they produce serotonin necessary for maintaining deep hypothermia, specific for hibernating animals.


Variant histology as a significant predictor of survival after radical nephroureterectomy in patients with upper urinary tract urothelial carcinoma.
To investigate the effect of variant histology (VH) on survival after radical nephroureterectomy in patients with upper urinary tract urothelial carcinoma (UTUC) and the effect of adjuvant chemotherapy on the survival of patients with UTUC with VH. A total of 452 patients who underwent radical nephroureterectomy for UTUC without neoadjuvant chemotherapy in our institution between 1991 and 2012 were retrospectively analyzed. We performed a comparative analysis between pure UTUC and UTUC with VH groups. The Kaplan-Meier method was used to calculate survival estimates for cancer-specific survival (CSS) and overall survival (OS), and log-rank test was used to conduct comparisons between the groups. Univariate and multivariate Cox-proportional hazard regression analyses were performed to evaluate significant variables associated with CSS and OS. UTUC with VH was present in 41 (9.1%) patients. UTUC with VH showed aggressive clinicopathological features in comparison with pure UTUC. The Kaplan-Meier curves showed significantly decreased 5-year CSS and OS (both, P<0.001) in UTUC with VH group. Multivariate analysis revealed that VH was an independent predictor of CSS (P<0.001) and OS (P<0.002). The Kaplan-Meier curves also showed significantly decreased 5-year CSS and OS in UTUC with the VH group compared to the pure UTUC group in patients who received adjuvant chemotherapy. We found that UTUC with VH harbored aggressive biologic features, and VH was an independent prognostic factor for CSS and OS on both univariate and multivariate analyses. In addition, UTUC with VH group had poorer survival outcomes than pure UTUC group in patients who received adjuvant chemotherapy. Consequently, adjuvant treatment modalities other than adjuvant chemotherapy should be considered in this group.


Molecular subtyping methods for Listeria monocytogenes.
Conventional, phenotypic, and DNA-based subtyping methods allow differentiation of Listeria monocytogenes beyond the species and subspecies level. Bacterial subtyping methods not only improve our ability to detect and track human listeriosis outbreaks, but also provide tools to track sources of L. monocytogenes contamination throughout the food system. The use of subtyping methods also provides an opportunity to better understand the population genetics, epidemiology, and ecology of L. monocytogenes. The last 5 years have seen tremendous advancements in the development of sensitive, rapid, automated, and increasingly easy-to-use molecular subtyping methods for L. monocytogenes. This review highlights key aspects of different L. monocytogenes subtyping methods and provides examples of their application in public health, food safety, population genetics, and epidemiology. A significant focus is on the application of subtyping methods to define L. monocytogenes subtypes and clonal groups, which may differ in phenotypic characteristics and pathogenic potential.


Sodium butyrate inhibits aerobic glycolysis of hepatocellular carcinoma cells via the c-myc/hexokinase 2 pathway.
Aerobic glycolysis is a well-known hallmark of hepatocellular carcinoma (HCC). Hence, targeting the key enzymes of this pathway is considered a novel approach to HCC treatment. The effects of sodium butyrate (NaBu), a sodium salt of the short-chain fatty acid butyrate, on aerobic glycolysis in HCC cells and the underlying mechanism are unknown. In the present study, data obtained from cell lines with mouse xenograft model revealed that NaBu inhibited aerobic glycolysis in the HCC cells in vivo and in vitro. NaBu induced apoptosis while inhibiting the proliferation of the HCC cells in vivo and in vitro. Furthermore, the compound inhibited the release of lactate and glucose consumption in the HCC cells in vitro and inhibited the production of lactate in vivo. The modulatory effects of NaBu on glycolysis, proliferation and apoptosis were related to its modulation of hexokinase 2 (HK2). NaBu downregulated HK2 expression via c-myc signalling. The upregulation of glycolysis in the HCC cells induced by sorafenib was impeded by NaBu, thereby enhancing the anti-HCC effect of sorafenib in vitro and in vivo. Thus, NaBu inhibits the expression of HK2 to downregulate aerobic glycolysis and the proliferation of HCC cells and induces their apoptosis via the c-myc pathway.


Effect of short-term fasting on the lipolytic response to theophylline.
We investigated the hypothesis that the increase in lipolysis that occurs in short-term (86-h) fasting is due to a decreased inhibitory influence of adenosine. In normal volunteers who fasted for 14 and 86 h, the response to adenosine receptor blockade was assessed by the infusion of theophylline at a rate sufficient to produce plasma concentrations (30 microM) that blocked adenosine receptors but that were well below the threshold for inhibition of phosphodiesterase. Lipolysis was assessed by determining the rate of appearance of glycerol using D-5-glycerol infusion. Fatty acid flux was also determined by means of [1-13C]palmitate infusion, and total fatty acid oxidation was determined by indirect calorimetry. There was a mild stimulatory effect of theophylline on lipolysis at 14 h. After the subjects fasted for 86 h, theophylline infusion caused a much greater increase in both lipolysis and fatty acid oxidation. These results suggest that the inhibitory effect of adenosine on lipolysis is increased during short-term fasting.


A breast cancer prediction model incorporating familial and personal risk factors.
Many factors determine a woman's risk of breast cancer. Some of them are genetic and relate to family history, others are based on personal factors such as reproductive history and medical history. While many papers have concentrated on subsets of these risk factors, no papers have incorporated personal risk factors with a detailed genetic analysis. There is a need to combine these factors to provide a better overall determinant of risk. The discovery of the BRCA1 and BRCA2 genes has explained some of the genetic determinants of breast cancer risk, but these genes alone do not explain all of the familial aggregation of breast cancer. We have developed a model incorporating the BRCA genes, a low penetrance gene and personal risk factors. For an individual woman her family history is used in conjuction with Bayes theorem to iteratively produce the likelihood of her carrying any genes predisposing to breast cancer, which in turn affects her likelihood of developing breast cancer. This risk was further refined based on the woman's personal history. The model has been incorporated into a computer program that gives a personalised risk estimate.


Epidermal growth factor receptor signaling-dependent calcium elevation in cumulus cells is required for NPR2 inhibition and meiotic resumption in mouse oocytes.
In preovulatory ovarian follicles, the oocyte is maintained in meiotic prophase arrest by natriuretic peptide precursor C (NPPC) and its receptor natriuretic peptide receptor 2 (NPR2). LH treatment results in the decrease of NPR2 guanylyl cyclase activity that promotes resumption of meiosis. We investigated the regulatory mechanism of LH-activated epidermal growth factor (EGF) receptor signaling on NPR2 function. Cumulus cell-oocyte complex is cultured in the medium with 30 nM NPPC to prevent oocyte spontaneous maturation. In this system, EGF could stimulate oocyte meiotic resumption after 4 hours of incubation. Further study showed that EGF elevated intracellular calcium concentrations of cumulus cells and decreased cGMP levels in cumulus cells and oocytes, and calcium-elevating reagents ionomycin and sphingosine-1-phosphate mimicked the effects of EGF on oocyte maturation and cGMP levels. EGF-mediated cGMP levels and meiotic resumption could be reversed by EGF receptor inhibitor AG1478 and the calcium chelator bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid, tetra(acetoxymethyl)-ester. EGF also decreased the expression of Npr2 mRNA in cumulus cells, which may not be involved in meiotic resumption, because the block of NPR2 protein de novo synthesis by cycloheximide had no effect on NPPC and EGF-mediated oocyte maturation. However, EGF had no effect on oocyte maturation when meiotic arrest was maintained in the present of cGMP analog 8-bromoadenosine-cGMP. These results suggest that EGF receptor signaling induces meiotic resumption by elevating calcium concentrations of cumulus cells to decrease NPR2 guanylyl cyclase activity.


ESHRD: deconvolution of brain homogenate RNA expression data to identify cell-type-specific alterations in Alzheimer's disease.
We describe herein a bioinformatics approach that leverages gene expression data from brain homogenates to derive cell-type specific differential expression results. We found that differentially expressed (DE) cell-specific genes were mostly identified as neuronal, microglial, or endothelial in origin. However, a large proportion (75.7%) was not attributable to specific cells due to the heterogeneity in expression among brain cell types. Neuronal DE genes were consistently downregulated and associated with synaptic and neuronal processes as described previously in the field thereby validating this approach. We detected several DE genes related to angiogenesis (endothelial cells) and proteoglycans (oligodendrocytes). We present a cost- and time-effective method exploiting brain homogenate DE data to obtain insights about cell-specific expression. Using this approach we identify novel findings in AD in endothelial cells and oligodendrocytes that were previously not reported. We derived an enrichment score for each gene using a publicly available RNA profiling database generated from seven different cell types isolated from mouse cerebral cortex. We then classified the differential expression results from 3 publicly accessible Late-Onset Alzheimer's disease (AD) studies including seven different brain regions.


Phytoestrogens in soy-based infant foods: concentrations, daily intake, and possible biological effects.
Exposure to estrogenic compounds may pose a developmental hazard to infants. Soy products, which contain the phytoestrogens, genistein and daidzein, are becoming increasingly popular as infant foods. To begin to evaluate the potential of the phytoestrogens in these products to affect infants, we measured total genistein and daidzein contents of commercially available soy-based infant formulas, infant cereals, dinners, and rusks. We also assayed phytoestrogens in dairy-based formulas and in breast milk from omnivorous or vegetarian mothers. In most cases, the glucoside forms of the phytoestrogens were hydrolyzed before separation by HPLC. Mean (+/-SEM) total genistein and daidzein contents in four soy infant formulas were 87+/-3 and 49+/-2 microg/g, respectively. The phytoestrogen content of cereals varied with brand, with genistein ranging from 3-287 microg/g and daidzein from 2-276 microg/g. By contrast, no phytoestrogens were detected in dairy-based infant formulas or in human breast milk, irrespective of the mother's diet (detection limit = 0.05 microg/ml). When fed according to the manufacturer's instruction, soy formulas provide the infant with a daily dose rate of total isoflavones (i.e., genistein + daidzein) of approximately 3 mg/kg body weight, which is maintained at a fairly constant level between 0-4 months of age. Supplementing the diet of 4-month-old infants with a single daily serving of cereal can increase their isoflavone intake by over 25%, depending on the brand chosen. This rate of isoflavone intake is much greater than that shown in adult humans to alter reproductive hormones. Since the available evidence suggests that infants can digest and absorb dietary phytoestrogens in active forms and since neonates are generally more susceptible than adults to perturbations of the sex steroid milieu, we suggest that it would be highly desirable to study the effects of soy isoflavones on steroid-dependent developmental processes in human babies.


Hyaluronan accumulates with high-fat feeding and contributes to insulin resistance.
Increased deposition of specific extracellular matrix (ECM) components is a characteristic of insulin-resistant skeletal muscle. Hyaluronan (HA) is a major constituent of the ECM. The hypotheses that 1) HA content is increased in the ECM of insulin-resistant skeletal muscle and 2) reduction of HA in the muscle ECM by long-acting pegylated human recombinant PH20 hyaluronidase (PEGPH20) reverses high-fat (HF) diet-induced muscle insulin resistance were tested. We show that muscle HA was increased in HF diet-induced obese (DIO) mice and that treatment of PEGPH20, which dose-dependently reduced HA in muscle ECM, decreased fat mass, adipocyte size, and hepatic and muscle insulin resistance in DIO mice at 10 mg/kg. Reduced muscle insulin resistance was associated with increased insulin signaling, muscle vascularization, and percent cardiac output to muscle rather than insulin sensitization of muscle per se. Dose-response studies revealed that PEGPH20 dose-dependently increased insulin sensitivity in DIO mice with a minimally effective dose of 0.01 mg/kg. PEGPH20 at doses of 0.1 and 1 mg/kg reduced muscle HA to levels seen in chow-fed mice, decreased fat mass, and increased muscle glucose uptake. These findings suggest that ECM HA is a target for treatment of insulin resistance.


[Mitosis in the tubular epithelium of allotransplanted dog kidney during the early periods following transplantation].
Cells dividing by mitosis were revealed in the tubular epithelium of 5 of 23 allografted kidneys of mongrel dogs. These mitoses were localized in the proximal and distal convoluted tubules (88 and 21 mitoses, respectively). Four pathological mitoses among 29 dividing epithelial cells were revealed 3 and 5 days after the operation, whereas no pathological mitoses were found among 80 mitoses of the kidneys present in the recipient's organism for 1 and 2 days. No mitoses were observed in the tubular epithelium of control kidneys (in the unoperated dogs).


Cognition in action: imaging brain/body dynamics in mobile humans.
We have recently developed a mobile brain imaging method (MoBI), that allows for simultaneous recording of brain and body dynamics of humans actively behaving in and interacting with their environment. A mobile imaging approach was needed to study cognitive processes that are inherently based on the use of human physical structure to obtain behavioral goals. This review gives examples of the tight coupling between human physical structure with cognitive processing and the role of supraspinal activity during control of human stance and locomotion. Existing brain imaging methods for actively behaving participants are described and new sensor technology allowing for mobile recordings of different behavioral states in humans is introduced. Finally, we review recent work demonstrating the feasibility of a MoBI system that was developed at the Swartz Center for Computational Neuroscience at the University of California, San Diego, demonstrating the range of behavior that can be investigated with this method.


Validity and reliability of resiliency measures trialled for the evaluation of a preventative Resilience-promoting social-emotional curriculum for remote Aboriginal school students.
We aimed to test the reliability and validity of two brief measures of resilience adopted for the evaluation of a preventative social-emotional curriculum implemented for Aboriginal middle school students from socially disadvantaged remote communities in Australia's Northern Territory. The questionnaires chosen were intended to measure psychological resilience and socio-cultural resilience as complementary dimensions of the capacity to cope in circumstances of significant life stress and risk of self-harm. Confirmatory factor analysis (CFA) was conducted to assess construct validity of the 10-item Connor-Davidson Resilience Scale (CD-RISC-10), a measure of psychological resilience, and the 12-item Child and Youth Resilience Measure (CYRM-12), a measure of socio-cultural resilience, with a sample of 520 students. Associations between resilience and psychological distress and emotional and behavioural difficulty were analysed in relation to life stressors to assess criterion validity of the scales. CFA provided support for the validity of the respective constructs. There was good fit for both scales. However, assessment of criterion validity of the scales suggested that the adapted measure of socio-cultural resilience (CYRM-12NT) showed higher reliability and a clearer indication of predictive validity than the measure of psychological resilience (CD-RISC-10). The CYRM-12NT appears to be a more useful measure of resilience among Aboriginal youth exposed to significant life stress and disadvantage. However, both measures may require further development to enhance their validity and utility among potentially at-risk adolescents in socially, culturally and linguistically diverse remote Aboriginal communities.


Design and validation of two optical beacons for guidewire localization in breast-conserving surgery.
Stereotactically placed guidewires are used for indicating the location of a nonpalpable carcinoma in breast-conserving surgery. Pathologists use the end of the embedded guidewire to guide sectioning during intraoperative margin assessment, but they do not currently have a tool to indicate the location of the guidewire end for informed sectioning. We present analysis and experimental testing of two optical methods for localizing the end of an embedded fiber-optic guidewire: the first uses irradiance emitted from the fiber to indicate the location of the guidewire end, while the second system uses the fiber optic to create a photoacoustic pulse for localization. Both systems locate the end of the guidewire within ±5 mm, which ensures that the lesion of interest is bisected during sectioning. The accuracy of the irradiance-based beacon is influenced by standard margin paints, so the photoacoustic beacon proved more useful under current tissue-handling protocols.


The Parkinson's disease protein LRRK2 impairs proteasome substrate clearance without affecting proteasome catalytic activity.
Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common known cause of Parkinson's disease (PD). The clinical features of LRRK2 PD are indistinguishable from idiopathic PD, with accumulation of α-synuclein and/or tau and/or ubiquitin in intraneuronal aggregates. This suggests that LRRK2 is a key to understanding the aetiology of the disorder. Although loss-of-function does not appear to be the mechanism causing PD in LRRK2 patients, it is not clear how this protein mediates toxicity. In this study, we report that LRRK2 overexpression in cells and in vivo impairs the activity of the ubiquitin-proteasome pathway, and that this accounts for the accumulation of diverse substrates with LRRK2 overexpression. We show that this is not mediated by large LRRK2 aggregates or sequestration of ubiquitin to the aggregates. Importantly, such abnormalities are not seen with overexpression of the related protein LRRK1. Our data suggest that LRRK2 inhibits the clearance of proteasome substrates upstream of proteasome catalytic activity, favouring the accumulation of proteins and aggregate formation. Thus, we provide a molecular link between LRRK2, the most common known cause of PD, and its previously described phenotype of protein accumulation.


The control of chick myoblast fusion by ion channels operated by prostaglandins and acetylcholine.
Chick myoblast fusion in culture was investigated using prostanoid synthesis inhibitors to delay spontaneous fusion. During this delay myoblast fusion could be induced by prostaglandin E1 (PGE1), by raising extracellular potassium and by addition of carbachol. Carbachol-induced fusion, but not PGE-induced fusion, was prevented by the acetylcholine receptor blocker alpha-bungarotoxin. Fusion induced by any of these agents was prevented by the Ca channel blockers lanthanum and D600. The threshold for potassium-induced fusion was 7-8 mM; maximal fusion occurred at 16-20 mM. Low extracellular potassium inhibited spontaneous fusion. Intracellular potassium in fusion competent myoblasts was 101 m-moles/l cell. Calcium flux measurements demonstrated that high potassium increased calcium permeability in fusion-competent myoblasts. A 30-s exposure to high potassium or PGE1 was sufficient to initiate myoblast fusion. Anion-exchange inhibitors (SITS and DIDS) delayed spontaneous myoblast fusion and blocked fusion induced by PGE1 but not carbachol. Blocking the acetylcholine receptor shifted the dose-response relation for PGE-induced fusion to higher concentrations. PGE1-induced fusion required chloride ions; carbachol-induced fusion required sodium ions. Provided calcium channels were available, potassium always induced fusion. We conclude that myoblasts possess at least three, independent pathways, each of which can initiate myoblast fusion and that the PGE-activated pathway and the acetylcholine receptor-activated pathway act synergistically. We suggest that fusion competent myoblasts have a high resting membrane potential and that fusion is controlled by depolarization initiated directly (potassium), by an increase in permeability to chloride ions (PGE), or by activation of the acetylcholine receptor (carbachol); depolarization triggers a rise in calcium permeability. The consequent increase in intracellular calcium initiates myoblast fusion.


Pilot study of submucosal radiofrequency for epistaxis in hereditary hemorrhagic telangiectasia.
To assess the safety and efficacy of submucosal radiofrequency (RF) treatment for hereditary hemorrhagic telangiectasia (HHT) with mild or moderate epistaxis. We carried out a prospective pilot study of 16 consecutive patients with HHT-related epistaxis from June 2010 to April 2012. Under local anesthesia, RF was applied to one or both sides of the nose from the columella beneath the septal mucosal (50 joules per puncture). Patients were sent a questionnaire at least six months after the procedure. RF under local anesthesia was well tolerated, according to visual analog scale scores. Neither crusting nor pain was reported one week after the intervention. The frequency of epistaxis per day and per month was significantly lower after RF. The duration of bleeding also decreased from more than 10 minutes to less than 5 minutes in two thirds of patients. Thirteen of the 16 patients were satisfied with the technique and would request it for subsequent procedures to treat repeated bleeding. Submucosal RF treatment for HHT is a safe, well tolerated procedure with significant efficacy in the short term. It should be considered as an alternative technique for managing HHT-related epistaxis, although long-term results remain to be evaluated.


Predictors of self-harm emergency department visits in adolescents: A statewide longitudinal study.
This study investigated patient- and area-level characteristics associated with adolescent emergency department (ED) patients' risk of subsequent ED visits for self-harm. Retrospective analysis of adolescent patients presenting to a California ED in 2010 (n = 480,706) was conducted using statewide, all-payer, individually linkable administrative data. We examined associations between multiple predictors of interest (patient sociodemographic factors, prior ED utilization, and residential mobility; and area-level characteristics) and odds of a self-harm ED visit in 2010. Patients with any self-harm in 2010 were followed up over several years to assess predictors of recurrent self-harm. Self-harm patients (n = 5539) were significantly more likely than control patients (n = 16,617) to have prior histories of ED utilization, particularly for mental health problems, substance abuse, and injuries. Residential mobility also increased risk of self-harm, but racial/ethnic minority status and residence in a disadvantaged zipcode decreased risk. Five-year cumulative incidence of recurrent self-harm was 19.3%. Admission as an inpatient at index visit, Medicaid insurance, and prior ED utilization for psychiatric problems or injury all increased recurrent self-harm risk. A range of patient- and area-level characteristics observable in ED settings are associated with risk for subsequent self-harm among adolescents, suggesting new targets for intervention in this clinical context.


The house dust mite allergen, Dermatophagoides pteronyssinus, promotes type 2 responses by modulating the balance between IL-4 and IFN-gamma.
A common property of allergens is their potential to generate type 2 cytokine responses. To understand the mechanisms involved in this phenomenon, we have evaluated the polarizing potential of a major allergen, Dermatophagoides pteronyssinus 1 (Der p 1), in an heterologous immunization system using the glutathione S-transferase of the parasite Schistosoma mansoni (Sm28-GST) as immunogen. In previous studies, we showed that immunization with the Sm28-GST emulsified in CFA induced a nonpolarized immune response. In contrast, when alum was used as adjuvant, a type 2 immune response was induced against Sm28-GST. Using this experimental model, we examined whether the administration of Der p 1 together with Sm28-GST influenced the nonpolarized and/or the Th2 profiles induced by the CFA or the alum immunization, respectively. Our results showed that the introduction of Der p 1 in the CFA immunization protocol was associated with diminished anti-Sm28-GST IgG2a Ab titers, reduced IFN-gamma mRNA expression, and frequency of IFN-gamma-producing cells. In contrast, the introduction of Der p 1 in the alum protocol did not affect IL-4 or Ig isotype responses. The effect of Der p 1 was specific, since coimmunization with tetanus toxin fragment C did not affect the profile of the response against Sm28-GST. Furthermore, inactivation of Der p 1 reduced its ability to modify the immune response profile, suggesting that its protease activity played an important role in deviating the immune response. Our results suggest that the Der p 1 has the ability to modify the profile of an immune response by modulating the balance between the polarizing cytokines IL-4 and IFN-gamma.


Vegan regimen with reduced medication in the treatment of bronchial asthma.
Thirty-five patients who had suffered from bronchial asthma for an average of 12 yr, all receiving long-term medication, 20 including cortisone, were subject to therapy with vegan food for 1 yr. In almost all cases, medication was withdrawn or drastically reduced. There was a significant decrease in asthma symptoms. Twenty-four patients (69%) fulfilled the treatment. Of these, 71% reported improvement at 4 months and 92% at 1 yr. There was a significant improvement in a number of clinical variables; for example, vital capacity, forced expiratory volume at one sec and physical working capacity, as well as a significant change in various biochemical indices as haptoglobin, IgM, IgE, cholesterol, and triglycerides in blood. Selected patients, with a fear of side-effects of medication, who are interested in alternative health care, might get well and replace conventional medication with this regimen.


Computational Tools for Interpreting Ion Channel pH-Dependence.
Activity in many biological systems is mediated by pH, involving proton titratable groups with pKas in the relevant pH range. Experimental analysis of pH-dependence in proteins focusses on particular sidechains, often with mutagenesis of histidine, due to its pKa near to neutral pH. The key question for algorithms that predict pKas is whether they are sufficiently accurate to effectively narrow the search for molecular determinants of pH-dependence. Through analysis of inwardly rectifying potassium (Kir) channels and acid-sensing ion channels (ASICs), mutational effects on pH-dependence are probed, distinguishing between groups described as pH-coupled or pH-sensor. Whereas mutation can lead to a shift in transition pH between open and closed forms for either type of group, only for pH-sensor groups does mutation modulate the amplitude of the transition. It is shown that a hybrid Finite Difference Poisson-Boltzmann (FDPB) - Debye-Hückel continuum electrostatic model can filter mutation candidates, providing enrichment for key pH-coupled and pH-sensor residues in both ASICs and Kir channels, in comparison with application of FDPB alone.


High prevalence of epilepsy in two rural onchocerciasis endemic villages in the Mahenge area, Tanzania, after 20 years of community directed treatment with ivermectin.
Epilepsy is a neurological disorder with a multitude of underlying causes, which may include infection with Onchocerca volvulus, the parasitic worm that causes human onchocerciasis. A survey carried out in 1989 revealed a high prevalence of epilepsy (1.02% overall, ranging from 0.51 to 3.71% in ten villages) in the Mahenge area of Ulanga district, an onchocerciasis endemic region in south eastern Tanzania. This study aimed to determine the prevalence and incidence of epilepsy following 20 years of onchocerciasis control through annual community directed treatment with ivermectin (CDTI). The study was conducted in January 2017 in two suburban and two rural villages in the Mahenge area. Door-to-door household visits were carried out by trained community health workers and data assistants to screen for persons suspected of having epilepsy, using a standardised questionnaire. Persons with suspected epilepsy were then interviewed and examined by a neurologist for case verification. Onchocerciasis associated epilepsy was defined as epilepsy without an obvious cause, with an onset of seizures between the ages of 3-18 years in previously healthy children. In each village, fifty males aged ≥20 years were tested for onchocerciasis antibodies using an OV16 rapid test and were examined for presence of onchocerciasis nodules. Children aged 6-10 years were also tested using OV16 tests. 5117 individuals (median age 18.5 years, 53.2% female) from 1168 households were screened. 244 (4.8%) were suspected of having epilepsy and invited for neurological assessment. Prevalence of epilepsy was 2.5%, with the rural villages having the highest rate (3.5% vs 1.5%), P < 0.001. Overall incidence of epilepsy was 111 cases (95% CI: 73-161) per 100 000 person-years, while that of onchocerciasis associated epilepsy was 131 (95% CI: 70-223). Prevalence of OV16 antibodies in adult males and among children 6-10 years old was higher in rural villages than in suburban villages (76.5% vs 50.6, and 42.6% vs 4.7% respectively), (P < 0.001), while overall prevalence of onchocerciasis nodules was 1.8%. This survey revealed a high prevalence and incidence of epilepsy in two rural onchocerciasis endemic villages in the Mahenge area. Despite 20 years of CDTI, a high prevalence of OV16 antibodies in children aged 6-10 years suggests on-going O. volvulus transmission. Reasons for the persistence of on-going parasite transmission in the Mahenge area need to be investigated.