A System for Anesthesia Drug Administration Using Barcode Technology: The Codonics Safe Label System and Smart Anesthesia Manager.
Many anesthetic drug errors result from vial or syringe swaps. Scanning the barcodes on vials before drug preparation, creating syringe labels that include barcodes, and scanning the syringe label barcodes before drug administration may help to prevent errors. In contrast, making syringe labels by hand that comply with the recommendations of regulatory agencies and standards-setting bodies is tedious and time consuming. A computerized system that uses vial barcodes and generates barcoded syringe labels could address both safety issues and labeling recommendations. We measured compliance of syringe labels in multiple operating rooms (ORs) with the recommendations of regulatory agencies and standards-setting bodies before and after the introduction of the Codonics Safe Label System (SLS). The Codonics SLS was then combined with Smart Anesthesia Manager software to create an anesthesia barcode drug administration system, which allowed us to measure the rate of scanning syringe label barcodes at the time of drug administration in 2 cardiothoracic ORs before and after introducing a coffee card incentive. Twelve attending cardiothoracic anesthesiologists and the OR satellite pharmacy participated. The use of the Codonics SLS drug labeling system resulted in >75% compliant syringe labels (95% confidence interval, 75%-98%). All syringe labels made using the Codonics SLS system were compliant. The average rate of scanning barcodes on syringe labels using Smart Anesthesia Manager was 25% (730 of 2976) over 13 weeks but increased to 58% (956 of 1645) over 8 weeks after introduction of a simple (coffee card) incentive (P < 0.001). An anesthesia barcode drug administration system resulted in a moderate rate of scanning syringe label barcodes at the time of drug administration. Further, adaptation of the system will be required to achieve a higher utilization rate.


Impact of an international nosocomial infection control consortium multidimensional approach on central line-associated bloodstream infection rates in adult intensive care units in eight cities in India.
To evaluate the impact of the International Nosocomial Infection Control Consortium (INICC) multidimensional infection control approach on central line-associated bloodstream infection (CLABSI) rates in eight cities of India. This was a prospective, before-and-after cohort study of 35650 patients hospitalized in 16 adult intensive care units of 11 hospitals. During the baseline period, outcome surveillance of CLABSI was performed, applying the definitions of the CDC/NHSN (US Centers for Disease Control and Prevention/National Healthcare Safety Network). During the intervention, the INICC approach was implemented, which included a bundle of interventions, education, outcome surveillance, process surveillance, feedback on CLABSI rates and consequences, and performance feedback. Random effects Poisson regression was used for clustering of CLABSI rates across time periods. During the baseline period, 9472 central line (CL)-days and 61 CLABSIs were recorded; during the intervention period, 80898 CL-days and 404 CLABSIs were recorded. The baseline rate was 6.4 CLABSIs per 1000 CL-days, which was reduced to 3.9 CLABSIs per 1000 CL-days in the second year and maintained for 36 months of follow-up, accounting for a 53% CLABSI rate reduction (incidence rate ratio 0.47, 95% confidence interval 0.31-0.70; p=0.0001). Implementing the six components of the INICC approach simultaneously was associated with a significant reduction in the CLABSI rate in India, which remained stable during 36 months of follow-up.


Tempered fractional Feynman-Kac equation: Theory and examples.
Functionals of Brownian and non-Brownian motions have diverse applications and attracted a lot of interest among scientists. This paper focuses on deriving the forward and backward fractional Feynman-Kac equations describing the distribution of the functionals of the space and time-tempered anomalous diffusion, belonging to the continuous time random walk class. Several examples of the functionals are explicitly treated, including the occupation time in half-space, the first passage time, the maximal displacement, the fluctuations of the occupation fraction, and the fluctuations of the time-averaged position.


Prevention of suppressed cell-mediated immunity in burned mice with histamine-2 receptor antagonist drugs.
Thermal injury has been shown to suppress many aspects of both specific and nonspecific immune responses. We investigated the effect of two histamine H-2 antagonist drugs on cell-mediated immunity in burned mice, utilizing a method of quantitating the degree of contact sensitivity elicited to the antigen. 2,4-dinitrofluorobenzene (DNFB). Following sensitization by painting the abdomen with DNFB, animals were challenged 5 days later by painting the ears; subsequent ear swelling is a sensitive and reproducible measure of cell-mediated immunity. We have previously demonstrated that burned mice are maximally immunosuppressed 10 to 14 days following burn injury. In the present study we found that daily intraperitoneal administration of appropriate doses of the H-2 antagonists cimetidine (2 and 10 mg/kg/day) and ranitidine (2 and 10 mg/kg/day) resulted in maintenance of normal cell-mediated immunity in burned animals. Neither a lower dose of ranitidine (0.2 mg/kg/day) nor higher doses of cimetidine (20 and 50 mg/kg/day) restored immunity, and diphenhydramine, an H-1 antagonist, had no effect. There was no augmentation of contact sensitivity in unburned mice treated with cimetidine. The immunorestorative effect is probably secondary to antagonism of histamine H-2 receptors on suppressor T lymphocytes, and may reflect increased suppressor cell activity in burned mice; however, other mechanisms may be involved.


The association between metabolic syndrome and restrictive ventilatory dysfunction in older persons.
The restrictive, but not the obstructive respiratory dysfunction, is associated with an increased risk of developing type 2 diabetes mellitus. Our aim was to verify in an elderly nondiabetic population whether a restrictive respiratory pattern was associated with a higher prevalence of metabolic syndrome and increased insulin resistance than were obstructive and normal respiratory patterns. We performed a cross-sectional study of 159 consecutive nondiabetic elderly persons attending two social centers. According to their spirometric pattern, volunteers were classified into the following categories: normal spirometry, obstructive (forced expiratory volume in 1 second/forced vital capacity<0.70), and restrictive pattern (forced vital capacity<80% predicted, forced expiratory volume in 1 second/forced vital capacity>or=0.70). Independent correlates of the metabolic syndrome were identified. The prevalence of metabolic syndrome was higher in restrictive (56%) than in both normal (21.4%, p=.001) and obstructive volunteers (12.9%, p=.001). Insulin resistance, as assessed by the log transformation of the HOmeostasis Model Assessment (HOMA), was higher in restrictive than in obstructive and normal volunteers (1+/-0.6 vs 0.3+/-0.6 and 0.5+/-0.5, p<.001). Restriction was an independent correlate of metabolic syndrome, also after adjustment for waist circumference and body mass index (odds ratio=3.23, 95% confidence interval, 1.23-8.48; p=.01). Restrictive, but not obstructive respiratory pattern, is associated with metabolic syndrome and insulin resistance, and does not only reflect a limitation of ventilation due to visceral obesity. Metabolic abnormalities likely mediate cardiovascular risk in patients with restrictive respiratory impairment.


Quality Assessment of Tc-99m Methylene Diphosphonate (MDP) Radiopharmaceutical Prepared Using Different Cold Kit Fractionation Methods.
Tc-99m Methylene diphosphonate (MDP) is prepared in house by labeling MDP cold kit. Each kit is a single time use vial and contains large amounts of reagent sufficient for preparing multiple doses. Therefore, several centers are adopting the practice of fractionating the MDP kit so that it can be used multiple times. The aim of the study was to evaluate the effect of kit fractionation on radiopharmaceutical property. The MDP kit was fractionated using two different approaches, namely, vial and syringe method. The quality of Tc-99m MDP prepared using these approaches was assessed and compared with that prepared by the conventional method. The image quality was evaluated in a total of 100 patients. The vial and syringe fractionated Tc-99m MDP showed >95% RCP till the 4th and 2nd days of fractionation, respectively. Percentage radiochemical purity deteriorated to 83.6% and 88% on the 8th day of fractionation in the vial and syringe method, respectively. No microbial growth was observed in any of these methods till the 8th day of fractionation. The reconstituted MDP solution during all preparations was clear and colorless in appearance with pH ranging from 6.5 to 7.5. The image contrast, contrast-to-noise, and signal-to-noise ratio were statistically similar in both methods compared to the conventional method until the 2nd day of fractionation. The image quality data showed no statistical difference among images of vial and syringe fractionated MDP as compared to the conventional unfractionated Tc-99m MDP. The observations revealed that if fractionated with utmost care, both methods yield almost similar results.


The effects of prophylactic tadalafil use on VEGF expression in the rabbit model of steroid-induced femoral head avascular necrosis.
The purpose of this study was to examine the effect of prophylactic tadalafil use on a steroid-induced femoral head avascular necrosis model in terms of microscopic, imaging, and molecular biological changes. Twenty-four New Zealand rabbits were divided into 3 equal groups. Eight rabbits were designated as the control group and did not receive treatment. Rabbits in group 1 (G1) received 0.1 mg/kg Escherichia coli lipopolysaccharide (LPS) intravenously and 40 mg/ kg methylprednisolone sodium succinate (MP) was administered intramuscularly for 3 days consecutively. Rabbits in group 2 (G2) were given 5 mg/kg tadalafil orally for 10 consecutive days. Starting on the eighth day, 0.1 mg/kg LPS was given, and following this 40 mg/kg MP injections were administered for 3 days. All animals were sacrificed 3 weeks after the final MP injection. Magnetic resonance imaging was performed, and bilateral femora were harvested. Half of the femoral head was stored for Vascular Endothelial Growth Factor (VEGF) examination with Western blot analysis. The other half was examined microscopically for the presence of osteonecrosis. In G1, 15 out of 16 hips (93%) of the 8 rabbits had osteonecrosis compared to 8 out of 12 hips (67%) of 6 rabbits in G2 (P > .05). The VEGF expression in G2 was significantly higher than in the control group and G1 (P < .05 and P < .001, respectively). There was no significant difference in VEGF expression between the control group and G1 (P > .05). This study has shown us that femoral head osteonecrosis can be reliably induced with LPS and corticosteroid, as described in the literature. Prophylactic tadalafil use did not decrease the occurrence of osteonecrosis significantly. However, it significantly increased VEGF expression in the femoral head independent of the effects of steroids and LPS.


High soluble CD30, CD25, and IL-6 may identify patients with worse survival in CD30+ cutaneous lymphomas and early mycosis fungoides.
Histopathology alone cannot predict the outcome of patients with CD30+ primary cutaneous lymphoproliferative disorders (CD30CLPD) and early mycosis fungoides (MF). To test the hypothesis that serum cytokines/cytokine receptors provide prognostic information in these disorders, we measured soluble CD30 (sCD30), sCD25, and selected cytokines in cell cultures and sera of 116 patients with CD30CLPD and 96 patients with early MF followed up to 20 years. Significant positive correlation was found between sCD30 levels and sCD25, CD40L, IL-6, and IL-8, suggesting that CD30+ neoplastic cells secrete these cytokines, but not Th2 cytokines. In vitro studies confirmed that sCD30, sCD25, IL-6, and IL-8 are secreted by CD30CLPD-derived cell lines. CD30CLPD patients with above normal sCD30 and sCD25 levels had worse overall and disease-related survivals, but only sCD30 retained significance in Cox models that included advanced age. High sCD30 also identified patients with worse survival in early MF. Increased IL-6 and IL-8 levels correlated with poor disease-related survival in CD30CLPD patients. We conclude that (1) neoplastic cells of some CD30CLPD patients do not resemble Th2 cells, and that (2) high serum sCD30, sCD25, IL-6, and perhaps IL-8 levels may provide prognostic information useful for patient management.


Complete cell killing by applying high hydrostatic pressure for acellular vascular graft preparation.
Pressure treatment has been developed in tissue engineering application. Although the tissue scaffold prepared by a ultrahydrostatic pressure treatment has been reported, an excessive pressure has a potential to disrupt a structure of extracellular matrix through protein denaturation. It is important to understand the suitable low-pressure condition and mechanisms for cell killing. In this study, cellular morphology, mitochondria activity, and membrane permeability of mammalian cells with various pressure treatments were investigated with in vitro models. When the cells were treated with a pressure of 100 MPa for 10 min, cell morphology and adherence were the same as an untreated cells. Dehydrogenase activity in mitochondria was almost the same as untreated cells. On the other hand, when the cells were treated with the pressure of more than 200 MPa, the cells did not adhere, and the dehydrogenase activity was completely suppressed. However, green fluorescence was observed in the live/dead staining images, and the cells were completely stained as red after above 500 MPa. That is, membrane permeability was disturbed with the pressure treatment of above 500 MPa. These results indicated that the pressure of 200 MPa for 10 min was enough to induce cell killing through inactivation of mitochondria activity.


The first amorphous and crystalline yttrium lactate: synthesis and structural features.
The synthesis and crystal structure of the first molecular yttrium lactate complex, Y(Lac)3(H2O)2, is reported, where the coordination sphere of yttrium is saturated with lactate ligands and water molecules, resulting in a neutral moiety. In Y(Lac)3(H2O)2, hydrogen bonding between α-hydroxy groups and water molecules allows for the formation of 2D layers. A subtle variation in synthetic conditions, i.e. a slight increase in pH (5.5 instead of 4.5) promoted the formation of a semi-amorphous fibrous material with a presumed chemical composition of Y4(OH)5(C3H5O3)7·6H2O. The flattened fibres in this material are responsible for its good flexibility and foldability.


The role of transmembrane domain 9 in substrate recognition by the fungal high-affinity glutathione transporters.
Hgt1p, a high-affinity glutathione transporter from Saccharomyces cerevisiae belongs to the recently described family of OPTs (oligopeptide transporters), the majority of whose members still have unknown substrate specificity. To obtain insights into substrate recognition and translocation, we have subjected all 21 residues of TMD9 (transmembrane domain 9) to alanine-scanning mutagenesis. Phe523 was found to be critical for glutathione recognition, since F523A mutants showed a 4-fold increase in Km without affecting expression or localization. Phe523 and the previously identified polar residue Gln526 were on the same face of the helix suggesting a joint participation in glutathione recognition, whereas two other polar residues, Ser519 and Asn522, of TMD9, although also orientated on the same face, did not appear to be involved. The size and hydrophobicity of Phe523 were both key features of its functionality, as seen from mutational analysis. Sequence alignments revealed that Phe523 and Gln526 were conserved in a cluster of OPT homologues from different fungi. A second cluster contained isoleucine and glutamate residues in place of phenylalanine and glutamine residues, residues that are best tolerated in Hgt1p for glutathione transporter activity, when introduced together. The critical nature of the residues at these positions in TMD9 for substrate recognition was exploited to assign substrate specificities of several putative fungal orthologues present in these and other clusters. The presence of either phenylalanine and glutamine or isoleucine and glutamate residues at these positions correlated with their function as high-affinity glutathione transporters based on genetic assays and the Km of these transporters towards glutathione.


Association between glutathione-S-transferase GSTP1 genotypes, GSTP1 over-expression, and outcome in epithelial ovarian cancer.
Ovarian cancer accounts for the majority of deaths from gynaecological malignancy, and polymorphisms in genes encoding the glutathione-S-transferase (GST) GSTP1 detoxifying enzymes may lead to variation in detoxification of carcinogens. We describe a study involving 81 women with invasive epithelial ovarian cancer. A number of important clinical variables and outcome data were obtained. GSTP1 genotyping was undertaken using PCR-based techniques, and GSTP1 expression was quantified using immunohistochemistry (IHC). A Cox's proportional hazard regression model was used to analyze the effects on outcome. We also independently examined 11 women with borderline or low malignant potential (LMP) tumors using IHC only. The mean age of the women was 61.5 years +/- 12 (1 SD) (range 36-88 years), the median overall survival was 26 months, and median progression free interval (PFI) 21 months. There was a significant association between GSTP1 (Val(104)/Val(104)) genotypes, and reduced survival (P = 0.05) and the GTP1 (Ile(104)/Val(104)) genotype appeared to have the best outcome (HR = 0.34, P = 0.045, 95% CI = 0.12-0.98). There was no significant association between the GSTP1 genotypes and any clinico-pathological parameters; there were also no associations between GSTP1 genotypes and response to postoperative chemotherapy. Specific nuclear GSTP1 over-expression was associated with less residual disease (P = 0.05); specific cytoplasmic GSTP1 over-expression with more favourable performance status (P = 0.014)). We found that 10/11 (91%) of the LMP (borderline) tumors over-expressed nuclear GSTP1 compared to only 52% of the invasive tumors (chi(2) ((1)) = 5.95, P = 0.015). There was no significant association between the level of GSTP1 expression and response to postoperative chemotherapy. The overall level of GSTP1 expression and the subcellular localization of GSTP1 expression were not associated with either survival or PFI. There was a significant association between the GSTP1 (Ile(104)/Ile(104)) genotypes and increased overall GSTP1 expression (P = 0.049), and the GSTP1 (Ile(104)/Val(104)) genotypes and reduced overall GSTP1 expression (P = 0.046). We speculate that GSTP1 Ile(104)/Val(104) genotypes are associated with improved outcome because the protein/enzyme, which is expressed, may provide a better balance between the effects of detoxification of carcinogens and the effects of metabolism of chemotherapy agents. In addition, over-expression of nuclear GSTP1 appears to be associated with more favorable ovarian tumor characteristics. In our preliminary study, we also reported a relationship between overall GSTP1 expression and certain GSTP1 genotypes. As far as we are aware, this is the first time that a relationship between the GSTP1 genotypes, GSTP1 expression and outcome has been described in ovarian cancer. Whether the genotype directly determines GSTP1 expression is at present unclear and the precise mechanism of this interaction is unknown.


Modeling the cost-effectiveness of a new treatment for MS (natalizumab) compared with current standard practice in Sweden.
To estimate the cost-effectiveness of a new treatment (natalizumab) for multiple sclerosis (MS) compared with current standard therapy with disease-modifying drugs (DMDs) in Sweden. A Markov model was constructed to illustrate disease progression based on functional disability (the Expanded Disability Status Scale (EDSS)). The effectiveness of natalizumab was based on a 2-year clinical trial in 942 patients (AFFIRM). The effectiveness of current DMDs was estimated from a matched sample of 512 patients in the Stockholm MS registry. Patients withdrawing from treatment were assumed to follow the disease course of 824 patients with relapsing-remitting disease at onset in the Ontario natural history cohort. Costs and utilities are based on a recent observational study in 1339 patients. All data sets were available at the patient level. Main results are presented from the societal perspective, over a 20-year time frame, in 2005 Euros (euro1 = 9.25 SEK). In the base case, treatment with natalizumab was less expensive and more effective than treatment with current DMDs. When only healthcare costs were considered, the cost per quality-adjusted life year gained with natalizumab was euro38 145. Results are sensitive only to the time horizon of the analysis and assumptions about effectiveness of natalizumab beyond the trial. This cost-effectiveness analysis used registry data, cohort and observational studies to extrapolate the efficacy findings of natalizumab from the AFFIRM clinical trial to measure effectiveness in clinical practice. The analysis results suggest that for the population considered, natalizumab provides an additional health benefit at a similar cost to current DMDs from a societal perspective.


The genetic control of apomixis: asexual seed formation.
Apomixis (asexual seed formation) is the result of a plant gaining the ability to bypass the most fundamental aspects of sexual reproduction: meiosis and fertilization. Without the need for male fertilization, the resulting seed germinates a plant that develops as a maternal clone. This dramatic shift in reproductive process has been documented in many flowering plant species, although no major seed crops have been shown to be capable of apomixis. The ability to generate maternal clones and therefore rapidly fix desirable genotypes in crop species could accelerate agricultural breeding strategies. The potential of apomixis as a next-generation breeding technology has contributed to increasing interest in the mechanisms controlling apomixis. In this review, we discuss the progress made toward understanding the genetic and molecular control of apomixis. Research is currently focused on two fronts. One aims to identify and characterize genes causing apomixis in apomictic species that have been developed as model species. The other aims to engineer or switch the sexual seed formation pathway in non-apomictic species, to one that mimics apomixis. Here we describe the major apomictic mechanisms and update knowledge concerning the loci that control them, in addition to presenting candidate genes that may be used as tools for switching the sexual pathway to an apomictic mode of reproduction in crops.


Severe fungal keratitis treated with subconjunctival fluconazole.
To assess the efficacy and safety of subconjunctival fluconazole treatment as an alternative therapy for severe fungal keratitis refractory to the conventional antifungal medical treatment. Prospective, interventional case series. This study included 13 eyes of 13 patients (mean age 49.6 years, range 28 to 75) with severe fungal keratitis that did not respond to initial therapy with topical and intravenous fluconazole plus oral itraconazole. All patients were injected with subconjunctival fluconazole 2%, up to 1.0 mL twice daily, for at least 5 days. If necessary, therapy was continued once daily for a maximum of 14 days after 5 days of injections. Six eyes were successfully treated after 5 days of subconjunctival injections of fluconazole. Seven patients required repeated injections for more than 5 days, but one of them finally underwent evisceration. The final visual acuity depended on the location of the remaining scar; in four cases, corneal transplantation was necessary. Neither local nor systemic toxic side effects were observed. Subconjunctival fluconazole could be effective for treatment of severe fungal keratitis and could be very useful to avoid surgical intervention at an acute stage of this infection. Although the efficacy of the various doses cannot be determined from this series, the dose used in this study seems to be safe and effective for fungal corneal ulcer with hypopyon.


Elevated Neuronal Excitability Due to Modulation of the Voltage-Gated Sodium Channel Nav1.6 by Aβ1-42.
Aberrant increases in neuronal network excitability may contribute to the cognitive deficits in Alzheimer's disease (AD). However, the mechanisms underlying hyperexcitability are not fully understood. Such overexcitation of neuronal networks has been detected in the brains of APP/PS1 mice. In the present study, using current-clamp recording techniques, we observed that 12 days in vitro (DIV) primary cultured pyramidal neurons from P0 APP/PS1 mice exhibited a more prominent action potential burst and a lower threshold than WT littermates. Moreover, after treatment with Aβ1-42 peptide, 12 DIV primary cultured neurons showed similar changes, to a greater degree than in controls. Voltage-clamp recordings revealed that the voltage-dependent sodium current density of neurons incubated with Aβ1-42 was significantly increased, without change in the voltage-dependent sodium channel kinetic characteristics. Immunohistochemistry and western blot results showed that, after treatment with Aβ1-42, expressions of Nav and Nav1.6 subtype increased in cultured neurons or APP/PS1 brains compared to control groups. The intrinsic neuronal hyperexcitability of APP/PS1 mice might thus be due to an increased expression of voltage-dependent sodium channels induced by Aβ1-42. These results may illuminate the mechanism of aberrant neuronal networks in AD.


3D printing of dolutegravir-loaded polylactide filaments as a long-acting implantable system for HIV treatment.
3D printing was used to prepare implantable systems or tablets loaded with dolutegravirto to explore their potential as long-acting implantables (LAIs). Our strategy relies on preparing a polylactide (PLA) filament loaded with the anti-HIV drug. Subsequently, 3D printing was performed under conditions that allowed the PLA to be simultaneously melted and the drug encapsulated within the printed strand. The dolutegravir release profiles indicated its sustained release for 47 days. Furthermore, neat and drug-loaded tablets were characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA), while their morphology was assessed by scanning electron microscopy (SEM). Finally, their biocompatibility was proved by MTT assay against ISO standards recommended L929 mouse and human Hs68 skin fibroblast cells. All the results indicated that the 3D printing of PLA-based tablets could produce customized medications with potential applications against HIV.


Sleep-wake pattern, chronotype and seizures in patients with epilepsy.
Although mounting evidence suggests that sleep and epilepsy are reciprocal and seizures influence circadian rhythms, sleep-wake pattern and seizure control have not been widely researched. This study aimed to investigate the association of sleep-wake pattern, sleep quality, and chronotype with seizures in patients with epilepsy (PWE). 160 consecutive PWE (aged 20-49 years, focal epilepsy, FE: generalized epilepsy, GE=127:33) and 130 age-gender matched healthy controls (HC) were enrolled. All subjects completed a sleep diary for more than 2 weeks, Pittsburgh Sleep Quality Index (PSQI), Epworth sleepiness scale (ESS), and the Morningness-Eveningness questionnaire (MEQ). Detailed seizure history was reviewed for the last 1 year. Sleep-wake patterns on workdays were different between PWE and HC (p<0.001), although PSQI, ESS, and MEQ did not differ. Social jetlag (difference of mid-sleep time between workdays and free days) was more evident in PWE (1.4h) than HC (0.7h, p<0.001). GE showed lower MEQ, later mid-sleep time on both workdays and free days, and larger social jetlag than FE. Higher seizure frequency was positively correlated with higher PSQI and ESS after adjusting for age, gender, and number of antiepileptic drugs (p<0.05). PWE with lower MEQ presented worse sleep quality. Contrary to HC, PWE maintained sleep-wake patterns more regularly during workdays and free days. GE patients reported more eveningness-preference; however, their sleep quality was not worse than FE. Although sleep quality may affect seizure frequency, sleep-wake patterns and chronotype were not related to seizures in PWE.


Partnership for productive development of biosimilar products: perspectives of access to biological products in the Brazilian market.
The manufacturing process for biological products is complex, expensive and critical to the final product, with an impact on their efficacy and safety. They have been increasingly used to treat several diseases, and account for approximately 50% of the yearly budget for the Brazilian public health system. As the patents of biological products expire, several biosimilars are developed. However, there are concerns regarding their efficacy and safety; therefore, the regulatory agencies establish rules to approve and monitor these products. In Brazil, partnership programs between national government-owned companies and private technology holders have been implemented, aiming at knowledge sharing, capacity-building and technological transfer. Such partnerships locally promote manufacturing of these strategic drugs at reduced costs to the public health system. These agreements offer mutual advantages to both the government and patent holders: for the former, a biotechnological development flow is established and enables potential cost reduction and self-sufficient production; whereas for the latter, exclusive sales of the product are ensured during technological transfer, for a fixed period.


Treatment of indolent B-Cell nonfollicular lymphomas: final results of the LL01 randomized trial of the Gruppo Italiano per lo Studio dei Linfomi.
To evaluate the effect of epirubicin on therapeutic response and survival in patients with indolent nonfollicular B-cell lymphomas (INFL) treated with pulsed high-dose chlorambucil. A total of 170 untreated patients with advanced/active INFL were randomly assigned to receive either eight cycles of high-dose chlorambucil (15 mg/m2/d) plus prednisone (100 mg/d) for 5 days (HD-CHL-P; arm A) or eight cycles of HD-CHL-P plus epirubicin 60 mg/m2 intravenous on day 1 (arm B). The responding patients were randomly assigned to either maintenance therapy with interferon alfa (IFNalpha-2a; 3 MU, three times weekly) for 12 months or observation. There were 160 assessable patients (82 males, 78 females; median age, 63 years; range, 33 to 77 years); 77 patients were assigned to arm A, and 83 were assigned to arm B. Induction therapy led to 47 complete responses (CRs; 29.4%) and 68 partial responses (PRs; 42.5%), with no significant difference between the two arms (60 CR + PR in arm A [77.9%] and 55 CR + PR in arm B [66.3%]; P =.07). After a median follow-up of 38 months (range, 2 to 103 months), there was no between-group difference in overall survival (OS; P =.45), failure-free survival (P =.07), or progression-free survival (PFS; P =.5). Eighty-eight patients were randomly assigned to either IFNalpha-2a (n = 43) or observation (n = 45), without any difference in 3-year PFS (44% and 42%, respectively). Univariate analysis showed that OS was influenced by age, anemia, serum lactate dehydrogenase levels, and International Prognostic Index distribution; multivariate analysis identified age and anemia as having influence on OS. HD-CHL-P treatment outcome in INFL patients was good (50% 3-year PFS, minimal toxicity, and low costs); epirubicin did not add any advantage. One-year IFNalpha maintenance treatment did not prolong response duration.


Evaluation of DNA Extraction Methods Developed for Forensic and Ancient DNA Applications Using Bone Samples of Different Age.
The efficient extraction of DNA from challenging samples, such as bones, is critical for the success of downstream genotyping analysis in molecular genetic disciplines. Even though the ancient DNA community has developed several protocols targeting small DNA fragments that are typically present in decomposed or old specimens, only recently forensic geneticists have started to adopt those protocols. Here, we compare an ancient DNA extraction protocol (Dabney) with a bone extraction method (Loreille) typically used in forensics. Real-time quantitative PCR and forensically representative typing methods including fragment size analysis and sequencing were used to assess protocol performance. We used four bone samples of different age in replicates to study the effects of both extraction methods. Our results confirm Loreille's overall increased gain of DNA when enough tissue is available and Dabney's improved efficiency for retrieving shorter DNA fragments that is beneficial when highly degraded DNA is present. The results suggest that the choice of extraction method needs to be based on available sample, degradation state, and targeted genotyping method. We modified the Dabney protocol by pooling parallel lysates prior to purification to study gain and performance in single tube typing assays and found that up to six parallel lysates lead to an almost linear gain of extracted DNA. These data are promising for further forensic investigations as the adapted Dabney protocol combines increased sensitivity for degraded DNA with necessary total DNA amount for forensic applications.


Complete Disruption of Autism-Susceptibility Genes by Gene Editing Predominantly Reduces Functional Connectivity of Isogenic Human Neurons.
Autism spectrum disorder (ASD) is phenotypically and genetically heterogeneous. We present a CRISPR gene editing strategy to insert a protein tag and premature termination sites creating an induced pluripotent stem cell (iPSC) knockout resource for functional studies of ten ASD-relevant genes (AFF2/FMR2, ANOS1, ASTN2, ATRX, CACNA1C, CHD8, DLGAP2, KCNQ2, SCN2A, TENM1). Neurogenin 2 (NGN2)-directed induction of iPSCs allowed production of excitatory neurons, and mutant proteins were not detectable. RNA sequencing revealed convergence of several neuronal networks. Using both patch-clamp and multi-electrode array approaches, the electrophysiological deficits measured were distinct for different mutations. However, they culminated in a consistent reduction in synaptic activity, including reduced spontaneous excitatory postsynaptic current frequencies in AFF2/FMR2-, ASTN2-, ATRX-, KCNQ2-, and SCN2A-null neurons. Despite ASD susceptibility genes belonging to different gene ontologies, isogenic stem cell resources can reveal common functional phenotypes, such as reduced functional connectivity.


Shaping of Peripheral T Cell Responses by Lymphatic Endothelial Cells.
Lymph node stromal cells (LNSCs) have newly been promoted to the rank of new modulators of T cell responses. The different non-hematopoietic cell subsets in lymph node (LN) were considered for years as a simple scaffold, forming routes and proper environment for antigen (Ag)-lymphocyte encountering. Deeper characterization of those cells has recently clearly shown their impact on both dendritic cell and T cell functions. In particular, lymphatic endothelial cells (LECs) control lymphocyte trafficking and homeostasis in LNs and limit adaptive immune responses. Therefore, the new role of LECs in shaping immune responses has drawn the attention of immunologists. Striking is the discovery that LECs, among other LNSCs, ectopically express a large range of peripheral tissue-restricted Ags (PTAs), and further present PTA-derived peptides through major histocompatibility class I molecules to induce self-reactive CD8+ T cell deletional tolerance. In addition, both steady-state and tumor-associated LECs were described to be capable of exogenous Ag cross-presentation. Whether LECs can similarly impact CD4+ T cell responses through major histocompatibility class II restricted Ag presentation is still a matter of debate. Here, we review and discuss our current knowledge on the contribution of Ag-presenting LECs as regulators of peripheral T cell responses in different immunological contexts, including autoimmunity and cancer.


Increasing influenza immunization rates among healthcare providers in an ambulatory-based, University Healthcare Setting☆.
Despite its 'best practice' status as an intervention to combat healthcare-related influenza, many healthcare personnel (HCP) do not seek vaccinations themselves. The objective of this study was to achieve the Healthy People [HP] 2020's influenza vaccination goal of 90% among our HCP. The study utilized the model for improvement, consisting of Plan-Do-Study-Act (PDSA) cycles. Each influenza season served as a PDSA cycle until the HP 2020 vaccination goal was achieved. The quality improvement (QI) study was conducted over four influenza seasons (i.e. 2014-15; 2015-16; 2016-17 and 2017-18). The study's setting was an ambulatory-based, university health center within a suburban university located in central New Jersey. Adapting the National Vaccine Advisory Committee's definition of HCP, clinical and non-clinical staff members (n = 110) participated in the QI-study. QI-interventions were centered on staff education/outreach, improved accessibility to influenza vaccines and frequent communication to staff over several PDSA cycles. The QI-interventions significantly increased our overall vaccination coverage on our influenza vaccination status survey from 70.2% (2011-14 influenza seasons; n = 102) to 84.9% (2014-15 influenza season; n = 93) in PDSA 1, and 91.1% (2015-16 influenza season; n = 90) in PDSA cycle 2 (χ2 = 309.53, P < 0.001). Vaccination rates remained above the 90% performance goal during our quality control/assurance measuring periods (i.e. the 2016-18 influenza seasons). This study demonstrates that influenza vaccination coverage can significantly improve among HCP through the application of concurrent and multifaceted QI-interventions.


Cigarette smoking in New Zealand: Results from the 1976 population census.
The 1976 New Zealand Census included information about 2 201 178 persons over 15 years. Thirty-eight percent of men and 31 percent of women smoked cigarettes regularly. The peak age for male smoking is from 45-49 years and in men aged 35 to 39 years more than half (55 percent) smoke more than 20 cigarettes a day. In the youngest age group (15 to 19 years) more girls than boys are cigarette smokers. Sixteen percent of the population (353 627) stated that they have given up regular cigarette smoking. Smoking is least prevalent in Nelson, Marlborough and Canterbury, while the greatest percentage of smokers are found in the East Coast of the North Island and Southland. Except for Southland, there are significantly more smokers in the younger age groups (16 to 24 years) in the North Island than in the South Island. Cigarette smoking in New Zealand is probably less prevalent than in the past and the figures compare favourably with those of other countries. However, the high levels of smoking among young people, particularly women, is a major health problem.


In vivo evidence that the stromelysin-3 metalloproteinase contributes in a paracrine manner to epithelial cell malignancy.
Stromelysin-3 (ST3; Basset, P., J.P. Bellocq, C. Wolf, I. Stoll, P. Hutin, J.M. Limacher, O.L. Podhajcer, M.P. Chenard, M.C. Rio, P. Chambon. 1990. Nature. 348:699-704) is a matrix metalloproteinase (MMP) expressed in mesenchymal cells located close to epithelial cells, during physiological and pathological tissue remodeling processes. In human carcinomas, high ST3 levels are associated with a poor clinical outcome, suggesting that ST3 plays a role during malignant processes. In this study we report the ST3 gene inactivation by homologous recombination. Although ST3 null mice (ST3-/-) were fertile and did not exhibit obvious alterations in appearance and behavior, the lack of ST3 altered malignant processes. Thus, the suppression of ST3 results in a decreased 7, 12-dimethylbenzanthracene-induced tumorigenesis in ST3-/- mice. Moreover, ST3-/- fibroblasts have lost the capacity to promote implantation of MCF7 human malignant epithelial cells in nude mice (P < 0.008). Finally, we show that this ST3 paracrine function requires extracellular matrix (ECM)-associated growth factors. Altogether, these findings give evidence that ST3 promotes, in a paracrine manner, homing of malignant epithelial cells, a key process for both primary tumors and metastases. Therefore, ST3 represents an appropriate target for specific MMP inhibitor(s) in future therapeutical approaches directed against the stromal compartment of human carcinomas.


Machine learning uncovers the Pseudomonas syringae transcriptome in microbial communities and during infection.
Pseudomonas syringae pv. tomato DC3000 is a model plant pathogen that infects tomatoes and Arabidopsis thaliana. The current understanding of global transcriptional regulation in the pathogen is limited. Here, we applied iModulon analysis to a compendium of RNA-seq data to unravel its transcriptional regulatory network. We characterize each co-regulated gene set, revealing the activity of major regulators across diverse conditions. We provide new insights on the transcriptional dynamics in interactions with the plant immune system and with other bacterial species, such as AlgU-dependent regulation of flagellar genes during plant infection and downregulation of siderophore production in the presence of a siderophore cheater. This study demonstrates the novel application of iModulons in studying temporal dynamics during host-pathogen and microbe-microbe interactions, and reveals specific insights of interest.


Predicting discharge location of hip fracture patients; the new discharge of hip fracture patients score.
This paper reports on the development and validity of a new instrument, called the discharge of hip fracture patients score (DHP), that predicts at admission the discharge location in patients living in their own home prior to hip fracture surgery. A total of 310 patients aged 50 years and above were included. Risk factors for discharge to an alternative location (DAL) were analysed with a multivariable regression analysis taking the admission variables into account with different weights based on the estimates. The score ranged from 0-100 points. The cut-off point for DAL was calculated using a ROC analysis. Reliability of the DHP was evaluated. Risk factors for DAL were higher age, female gender, dementia, absence of a partner and a limited level of mobility. The cut-off point was set at 30 points, with a sensitivity of 83.8%, a specificity of 64.7% and positive predictive value of 79.2%. The DHP is a valid, simple and short instrument to be used at admission to predict discharge location of hip fracture patients.


Membrane-bound interleukin-21 and CD137 ligand induce functional human natural killer cells from peripheral blood mononuclear cells through STAT-3 activation.
Natural killer (NK) cell adoptive transfer is a promising approach for cancer immunotherapy; however, its development has been hindered by the lack of efficient methods to produce large numbers of functional NK cells. In this study, we engineered the leukaemia cell line K562 to express CD137 ligand (CD137L) and membrane-bound interleukin (mbIL)-21 on the cell surface, and used these cells to expand NK cells from the peripheral blood mononuclear cells. We found that purity of the NK cells (CD3(-) CD56(+) /CD16(+) ) increased from less than 30% to above 95% after a 3-week expansion and proliferation of the cells was sustained for more than 8 weeks. The surface expression of NK cell activating and inhibitory receptors, except for NKp80, was clearly increased with the expansion, and NK cell-mediated killing activity was also enhanced significantly. However, these changes in both phenotype and function were clearly reversed by JSI-124, a specific signal transducer and activator of transcription-3 (STAT-3) inhibitor. Taken together, data showed that the combination of mbIL-21 and CD137L could efficiently induce the formation of functional human NK cells from peripheral blood mononuclear cells, and STAT-3 inhibition could impair this induction. Therefore, STAT-3 activation may benefit human NK cell proliferation and cytotoxicity, and provide valuable clinical applications in NK cell immunotherapy against viral infectious diseases and cancers.


Dynamical Quantum Cherenkov Transition of Fast Impurities in Quantum Liquids.
The challenge of understanding the dynamics of a mobile impurity in an interacting quantum many-body medium comes from the necessity of including entanglement between the impurity and excited states of the environment in a wide range of energy scales. In this Letter, we investigate the motion of a finite mass impurity injected into a three-dimensional quantum Bose fluid as it starts shedding Bogoliubov excitations. We uncover a transition in the dynamics as the impurity's velocity crosses a critical value that depends on the strength of the interaction between the impurity and bosons as well as the impurity's recoil energy. We find that in injection experiments, the two regimes differ not only in the character of the impurity velocity abatement but also exhibit qualitative differences in the Loschmidt echo, density ripples excited in the Bose-Einstein condensate, and momentum distribution of scattered bosonic particles. The transition is a manifestation of a dynamical quantum Cherenkov effect and should be experimentally observable with ultracold atoms using Ramsey interferometry, rf spectroscopy, absorption imaging, and time-of-flight imaging.


Three-dimensional printing in adult cardiovascular medicine for surgical and transcatheter procedural planning, teaching and technological innovation.
Three-dimensional (3D)-printing technologies in cardiovascular surgery have provided a new way to tailor surgical and percutaneous treatments. Digital information from standard cardiac imaging is integrated into physical 3D models for an accurate spatial visualization of anatomical details. We reviewed the available literature and analysed the different printing technologies, the required procedural steps for 3D prototyping, the used cardiac imaging, the available materials and the clinical implications. We have highlighted different materials used to replicate aortic and mitral valves, vessels and myocardial properties. 3D printing allows a heuristic approach to investigate complex cardiovascular diseases, and it is a unique patient-specific technology providing enhanced understanding and tactile representation of cardiovascular anatomies for the procedural planning and decision-making process. 3D printing may also be used for medical education and surgical/transcatheter training. Communication between doctors and patients can also benefit from 3D models by improving the patient understanding of pathologies. Furthermore, medical device development and testing can be performed with rapid 3D prototyping. Additionally, widespread application of 3D printing in the cardiovascular field combined with tissue engineering will pave the way to 3D-bioprinted tissues for regenerative medicinal applications and 3D-printed organs.


Evaluation of energetic metabolism in the rat brain after meningitis induction by Klebsiella pneumoniae.
Bacterial meningitis is an infection of the central nervous system characterised by strong inflammatory response. The brain is highly dependent on ATP, and the cell energy is obtained through oxidative phosphorylation, a process which requires the action of various respiratory enzyme complexes and creatine kinase (CK) as an effective buffering system of cellular ATP levels in tissues that consume high energy. Evaluate the activities of mitochondrial respiratory chain complexes I, II, III, IV and CK activity in hippocampus and cortex of the Wistar rat submitted to meningitis by Klebsiella pneumoniae. Adult Wistar rats received either 10 µl of sterile saline as a placebo or an equivalent volume of K. pneumoniae suspension. The animals were killed in different times at 6, 12, 24 and 48 h after meningitis induction. Another group was treated with antibiotic, starting at 16 h and continuing daily until their decapitation at 24 and 48 h after induction. In the hippocampus, the meningitis group without antibiotic treatment, the complex I was increased at 24 and 48 h, complex II was increased at 48 h, complex III was inhibited at 6, 12, 24 and 48 h and in complex IV all groups with or without antibiotic treatment were inhibited after meningitis induction, in the cortex there was no alteration. Discussion Although descriptive, our results show that antibiotic prevented in part the changes of the mitochondrial respiratory chain. The meningitis model could be a good research tool to study the biological mechanisms involved in the pathophysiology of the K. pneumoniae meningitis.


Generation of Suicide Gene-Modified Chimeric Antigen Receptor-Redirected T-Cells for Cancer Immunotherapy.
Chimeric antigen receptor (CAR)-redirected T-cells are a powerful tool for the treatment of several type of cancers; however, they can cause several adverse effects including cytokine release syndrome, off-target effects resulting in potentially fatal organ damage or even death. Particularly, for CAR T-cells redirected toward acute myeloid leukemia (AML) antigens myelosuppression can be a challenge. The previously validated inducible Caspase9 (iC9) suicide gene system is one of the approaches to control the infused cells in vivo through its activation with a nontherapeutic chemical inducer of dimerizer (CID). We performed a preclinical validation using a model of CD33+ AML, and generated iC9 CAR T-cells co-expressing a CAR targeting the AML-associated antigen CD33 and a selectable marker (ΔCD19). ΔCD19 selected (sel.) iC9-CAR.CD33 T-cells were effective in controlling leukemia growth in vitro, and could be partially eliminated (76%) using a chemical inducer of dimerization that activates iC9. Moreover, to completely eliminate residual cells, a second targeted agent was added. Future plans with these methods are to investigate the utility of iC9-CAR.CD33 T-cells as part of the conditioning therapy for an allogeneic hematopoietic stem cell transplant. Additional strategies that we are currently validating include (1) the modulation of the suicide gene activation, using different concentrations of the inducing agent(s), to be able to eliminate CAR T-cells modified by a regulatable gene, ideally aiming at preserving a proportion of the infused cells (and their antitumor activity) for mild to moderate toxicities, or (2) the co-expression of an inhibitory CAR aiming at sparing normal cells co-expressing an antigen not shared with the tumor.


Evaluation of left ventricular short- and long-axis function in severe mitral regurgitation using 2-dimensional strain echocardiography.
Few data exist on the changes in left ventricular (LV) short- and long-axis function and their usefulness as markers of LV contractile function in patients with chronic, severe mitral regurgitation (MR). We studied 59 patients who had severe MR with an ejection fraction > or =50% and 34 healthy controls. Speckle tracking imaging was performed to measure peak systolic radial (SR(R)), circumferential (SR(C)), and longitudinal strain rates (SR(L)). In all patients, the peak rate of LV pressure rise (peak dP/dt) was measured using a micromanometer-tipped catheter. The patients were subdivided into patients with preserved (group 1, peak dP/dt > or =1,300 mm Hg/s [n = 30]) and depressed (group 2 [n = 29]) contractile function. SR(L) was significantly depressed in groups 1 and 2 when compared with the control group, but there was no difference between groups 1 and 2. In contrast, SR(R) and SR(C) were depressed only in group 2, whereas there were no differences between the control group and group 1. SR(R) and SR(C) correlated well with peak dP/dt (r = 0.71, P <.001 and r = -0.63, P <.001, respectively), whereas SR(L) did not. These findings suggest that LV long-axis function becomes depressed earlier than short-axis function in the chronic remodeling process. Left ventricular short-axis function is a useful marker of LV contractility in patients with chronic, severe MR. Left ventricular long-axis function becomes depressed earlier in the chronic remodeling process. Therefore, evaluation of short-axis as well as long-axis function might be important for better assessment of LV contractile function in these patients.


Genomic sequence of a mutant strain of Caenorhabditis elegans with an altered recombination pattern.
The original sequencing and annotation of the Caenorhabditis elegans genome along with recent advances in sequencing technology provide an exceptional opportunity for the genomic analysis of wild-type and mutant strains. Using the Illumina Genome Analyzer, we sequenced the entire genome of Rec-1, a strain that alters the distribution of meiotic crossovers without changing the overall frequency. Rec-1 was derived from ethylmethane sulfonate (EMS)-treated strains, one of which had a high level of transposable element mobility. Sequencing of this strain provides an opportunity to examine the consequences on the genome of altering the distribution of meiotic recombination events. Using Illumina sequencing and MAQ software, 83% of the base pair sequence reads were aligned to the reference genome available at Wormbase, providing a 21-fold coverage of the genome. Using the software programs MAQ and Slider, we observed 1124 base pair differences between Rec-1 and the reference genome in Wormbase (WS190), and 441 between the mutagenized Rec-1 (BC313) and the wild-type N2 strain (VC2010). The most frequent base-substitution was G:C to A:T, 141 for the entire genome most of which were on chromosomes I or X, 55 and 31 respectively. With this data removed, no obvious pattern in the distribution of the base differences along the chromosomes was apparent. No major chromosomal rearrangements were observed, but additional insertions of transposable elements were detected. There are 11 extra copies of Tc1, and 8 of Tc2 in the Rec-1 genome, most likely the remains of past high-hopper activity in a progenitor strain. Our analysis of high-throughput sequencing was able to detect regions of direct repeat sequences, deletions, insertions of transposable elements, and base pair differences. A subset of sequence alterations affecting coding regions were confirmed by an independent approach using oligo array comparative genome hybridization. The major phenotype of the Rec-1 strain is an alteration in the preferred position of the meiotic recombination event with no other significant phenotypic consequences. In this study, we observed no evidence of a mutator effect at the nucleotide level attributable to the Rec-1 mutation.


Intraoperative cardiac arrest: A 10-year study of patients undergoing tumorous surgery in a tertiary referral cancer center in China.
Intraoperative cardiac arrest (IOCA) is a lethal complication of noncardiac surgery. According to several reports, immediate survival after IOCA is approximately 50%. In this study, a retrospective case analysis was performed to determine the incidence of IOCA, the potential causes of cardiac arrest, and the risk factors of no resuscitation in patients undergoing tumorous surgery.The medical records of surgery patients who experienced cardiac arrest during the intraoperative period between 2005 and 2014 were reviewed. The general conditions of the patients with IOCA were compared between the successfully resuscitated group and the unresuscitated group.Fifteen patients with IOCA among 142,853 patients undergoing tumorous surgery were reviewed during the study period. Immediate survival after IOCA was 60%. Hospital survival was 46.7%. The incidence of IOCA decreased during 2010 to 2014 when compared with the rate during 2005 to 2009 (P < .05). The risk factors affecting the success of resuscitation after IOCA included American Society of Anesthesiologists Physical Status (ASA PS) classification ≥ III (P < .05) and preoperative tachycardia (heart rate ≥100/min, P < .05). The methods of anesthesia had no effects on the results of resuscitation.The incidence of IOCA in patients undergoing tumorous surgery was 1.05 per 10,000 anesthesia. The overall mortality of IOCA was 0.56/10,000. The frequency of IOCA decreased within 10 years. There was no cardiac arrest primarily attributable to anesthesia over this study period. The risk factors leading to unsuccessful resuscitation after IOCA were ASA PS classification ≥ III and preoperative tachycardia.


Panniculectomy and supraumbilical vertical midline incisions in morbidly obese gynecologic oncology patients.
We reviewed the outcomes of panniculectomy and supraumbilical vertical midline incisions in morbidly obese women undergoing gynecologic operations. Medical records were reviewed for 62 morbidly obese women with a large dependent pannus who underwent gynecologic operations on the Gynecologic Oncology Service at the State University of New York at Stony Brook between May 1990 and July 1997. Thirty-five patients underwent panniculectomy and 27 had a supraumbilical vertical midline incision, forming the study groups. The patient charts were abstracted for demographic, perioperative, and postoperative data. For the entire study population, the average age was 56 years, the mean body mass was 128.6 kg, and the mean Quetelet Index was 48.3 kg/m2. The mean operative time and estimated blood loss were similar for both groups. Eight percent of the patients had urologic injuries, evenly distributed between the groups. Postoperative infections, wound breakdowns, and hospital stay were greater for the panniculectomy group than for the supraumbilical vertical midline incision group (p < 0.05). Uniform use of subcutaneous closed-suction drains (since 1995) was associated with a significant reduction in the incidence of wound breakdowns and a shorter hospital stay in the panniculectomy group. Panniculectomy and supraumbilical vertical midline incision provide reasonable peritoneal access with acceptable rates of postoperative complications for morbidly obese women undergoing gynecologic operations.


Serologic response to Helicobacter pylori among children and teenagers in northern Chile.
The serologic response to Helicobacter pylori was determined in 388 children and teenagers living in Iquique, Chile by using an IgG enzyme-linked immunosorbent assay. Serum antibody levels, as measured by optical density, correlated strongly with age. Increases in the mean antibody level were seen primarily after age five, with rates of seropositivity increasing to > or = 70% among teenagers. The reasons for this age-related pattern of acquisition of infection remain to be determined.


Detection of T lymphocytes with a second-site mutation in skin lesions of atypical X-linked severe combined immunodeficiency mimicking Omenn syndrome.
X-linked severe combined immunodeficiency (XSCID) is caused by mutations of the common gamma chain (gammac) and usually characterized by the absence of T and natural killer (NK) cells. Here, we report an atypical case of XSCID presenting with autologous T and NK cells and Omenn syndrome-like manifestations. The patient carried a splice-site mutation (IVS1+5G>A) that caused most of the mRNA to be incorrectly spliced but produced normally spliced transcript in lesser amount, leading to residual gammac expression and development of T and NK cells. The skin biopsy specimen showed massive infiltration of revertant T cells. Those T cells were found to have a second-site mutation and result in complete restoration of correct splicing. These findings suggest that the clinical spectrum of XSCID is quite broad and includes atypical cases mimicking Omenn syndrome, and highlight the importance of revertant mosaicism as a possible cause for variable phenotypic expression.


The Usefulness of Phospholipase A2 Receptor and IgG4 Detection in Differentiation Primary Membranous Nephropathy From Secondary Membranous Nephropathy in Renal Biopsy.
Membranous nephropathy (MGN) is the most common cause of the nephrotic syndrome in adults. Most cases of MGN are primary, but secondary MGN are frequently encountered. Determination of secondary MGN is crucial for initiation of appropriate treatment. The diagnostic performance of the phospholipase A2 receptor (PLA2R) and immunoglobulin G4 (IgG4) detection based on immunohistochemistry were evaluated using biopsy tissues of 59 primary and 56 secondary MGN cases for discrimination between primary MGN and secondary MGN. The PLA2R and IgG4 detection based on immunohistochemistry were dominantly positive in primary MGN cases. Sensitivity and specificity values for identification of primary MGN were 83% and 88% for PLA2R, and 76% and 86% for IgG4. Both PLA2R and IgG4 positivity showed a high specificity of 96.4% for identifying primary MGN. A meta-analysis was performed for analysis of the diagnostic accuracy of histologic PLA2R and IgG4 deposition for differentiation of primary from secondary MGN. The overall sensitivity, specificity, and area under curve of summary receiver operating characteristics were 76%, 86%, 0.93 for histologic PLA2R deposition, and 80%, 69%, 0.82 for histologic IgG4 deposition. PLA2R and IgG4 detection based on immunohistochemistry can be useful for differentiation of primary MGN from secondary MGN.


A bony connection signals laryngeal echolocation in bats.
Echolocation is an active form of orientation in which animals emit sounds and then listen to reflected echoes of those sounds to form images of their surroundings in their brains. Although echolocation is usually associated with bats, it is not characteristic of all bats. Most echolocating bats produce signals in the larynx, but within one family of mainly non-echolocating species (Pteropodidae), a few species use echolocation sounds produced by tongue clicks. Here we demonstrate, using data obtained from micro-computed tomography scans of 26 species (n = 35 fluid-preserved bats), that proximal articulation of the stylohyal bone (part of the mammalian hyoid apparatus) with the tympanic bone always distinguishes laryngeally echolocating bats from all other bats (that is, non-echolocating pteropodids and those that echolocate with tongue clicks). In laryngeally echolocating bats, the proximal end of the stylohyal bone directly articulates with the tympanic bone and is often fused with it. Previous research on the morphology of the stylohyal bone in the oldest known fossil bat (Onychonycteris finneyi) suggested that it did not echolocate, but our findings suggest that O. finneyi may have used laryngeal echolocation because its stylohyal bones may have articulated with its tympanic bones. The present findings reopen basic questions about the timing and the origin of flight and echolocation in the early evolution of bats. Our data also provide an independent anatomical character by which to distinguish laryngeally echolocating bats from other bats.


A community of practice to address system-based issues and promote clinical leadership among trainee medical officers in a large public health service: an evaluation of a trainee-led forum.
Clinical leadership is necessary to improve the performance of large public hospitals. Trainee medical officers (TMOs) are important stakeholders in organisation-wide initiatives that affect the medical workforce and support clinician engagement. This case study describes the development of a representative body known as the 'TMO Forum' within the Central Adelaide Local Health Network as a mechanism to promote engagement between medical trainees and the hospital executive to facilitate escalation and discussion of system-based issues. Over the past 8 years, this group has evolved into a community of practice with steady and sustained growth since inception. Trainees have fostered relationships with the executive, and have engaged in leadership and quality improvement initiatives. Here we explore the evolution, value and barriers to success of the TMO Forum. Our discussion is supplemented with findings from anonymous online evaluation surveys of both the TMO and executive stakeholder groups. We propose that initiatives such as the described may offer reciprocal benefits to both constituent groups regarding communication, and that the development of a dedicated community of practice will enhance engagement of TMOs in health service improvement initiatives and advocacy. However, there are obstacles to overcome in order to attract a greater number of trainees and maximise the benefits from this initiative.


Reducing risk, increasing protective factors: findings from the Caribbean Youth Health Survey.
To identify the prevalence of health-compromising behaviors, and the risk and protective factors associated with them among youth in the Caribbean, and to predict the likelihood of these outcomes given the presence or absence of the risk and protective factors. Analyses were done on the results of a 1997-98 survey of over 15,500 young people in nine countries of the Caribbean Community. The four health-compromising behaviors studied included violence involvement, sexual intercourse, tobacco use, and alcohol use. Logistic regression was used to identify the strongest risk and protective factors, and also to create models for predicting the outcomes given combinations of the risk and protective factors. Rage was the strongest risk factor for every health-compromising behavior for both genders, and across all age groups, and school connectedness was the strongest protective factor. For many of the outcomes studied, increased protective factors were associated with as much or more reduction of involvement in health-compromising behaviors than a decrease in risk factors. This research suggests the importance of strengthening the protective factors in the lives of vulnerable youth not just reducing risk.


Update on the evaluation of pediatric idiopathic intracranial hypertension.
Papilledema associated with idiopathic intracranial hypertension (IIH) may result in irreversible, progressive visual loss. The development of tools for the evaluation of pediatric patients with IIH is particularly relevant as many patients may not be able to comply with the detailed clinical evaluation utilized in adults for the treatment and management of this disease. The purpose of this review is to summarize relevant articles on the diagnostic tools used in evaluation and management of pediatric IIH. Studies suggest that characteristic pediatric IIH MRI findings include empty sella turcica, decreased pituitary gland size, optic nerve tortuosity, perioptic subarachnoid space enlargement, posterior globe flattering, and intraocular protrusion of the optic nerve head. On optical coherence tomography (OCT), increased retinal nerve fiber layer and macular thickness may be observed in children with IIH compared with controls. The retinal nerve fiber layer thickness seems to coincide with the severity of papilledema and may be more sensitive than funduscopy for detecting optic nerve head elevation. Research on ultrasound of the optic nerve shows increased size of the optic nerve sheath diameter in pediatric IIH patients, and this may correlate with increased opening pressure on lumbar puncture. There appears to be characteristic findings on MRI, OCT, and ultrasound studies in pediatric IIH patients. Although ultrasound is rarely used for monitoring these patients nowadays, MRI and OCT can be useful in the evaluation and management of these individuals.


Transposon-dependent induction of Vincent van Gogh's sunflowers: exceptions revealed.
The radiate sunflower inflorescence is composed by zygomorphic ray flowers and actinomorphic disk flowers. Studies performed on mutants identify HaCYC2c, a CYCLOIDEA (CYC)-like gene, as one of the key players controlling flower symmetry in sunflower. turf and tub mutants are characterized by a shift from zygomorphic to actinomorphic ray flowers, caused by insertion of transposable elements (TEs) in HaCYC2c gene. In dbl or Chry mutants, an insertion upstream the coding region of HaCYC2c causes the ectopic expression of the gene and the shift from actinomorphic to zygomorphic disk flowers. We focused on Chry2 mutant: a 1034 bp insertion placed 558 bp before the start codon of HaCYC2c was identified. The insertion is a truncated version of a CACTA TE. Unexpectedly, phenotypic and genetic co-segregation analysis in F2 and F3 progenies derived from the crosses Chry2 × turf and turf × Chry2 demonstrated that CACTA insertion is not always sufficient to alter the expression of HaCYC2c gene and generate Chry2 phenotype. F3 plants homozygous for the CACTA insertion displayed either HaCYC2c transcription pattern identical to wild-type plants or a normal heterogamous inflorescence. Stated these results, we conclude that a much more complex regulatory system stays behind the Chry2 phenotype.


Mass transfer studies on biological denitrification in fluidized bed bioreactor.
A fluidized bed bioreactor has been used to carry out biological denitrification in the present work as it offers many advantages over other types of reactors. Plastic beads of low density (1055 kg/m3) were used as fluidizing media with Pseudomonas stuzeri, a denitrifying microorganism immobilized on them. The denitrification rate under different operating conditions was studied. The results of experimental results were used to simulate a biofilm model. The effect of initial concentration of nitrate, liquid flow rate and biofilm thickness on biomass concentration of reactor was studied. The concentration of nitrate at biofilm surface was found by iteration. Knowing the concentration at biofilm surface, the external mass transfer coefficient for the process was calculated for each run. The effect of parameters like liquid flow rate and biofilm thickness on external mass transfer coefficient was studied. A functional relationship between Sherwood, Reynolds and Schmidt numbers was established.


Short-Term Fructose Feeding Induces Inflammation and Oxidative Stress in the Hippocampus of Young and Adult Rats.
The drastic increase in the consumption of fructose encouraged the research to focus on its effects on brain physio-pathology. Although young and adults differ largely by their metabolic and physiological profiles, most of the previous studies investigated brain disturbances induced by long-term fructose feeding in adults. Therefore, we investigated whether a short-term consumption of fructose (2 weeks) produces early increase in specific markers of inflammation and oxidative stress in the hippocampus of young and adult rats. After the high-fructose diet, plasma lipopolysaccharide and tumour necrosis factor (TNF)-alpha were found significantly increased in parallel with hippocampus inflammation, evidenced by a significant rise in TNF-alpha and glial fibrillar acidic protein concentrations in both the young and adult groups. The fructose-induced inflammatory condition was associated with brain oxidative stress, as increased levels of lipid peroxidation and nitro-tyrosine were detected in the hippocampus. The degree of activation of the protein kinase B, extracellular signal-regulated kinase 1/2, and insulin receptor substrate 1 pathways found in the hippocampus after fructose feeding indicates that the detrimental effects of the fructose-rich diet might largely depend on age. Mitochondrial function in the hippocampus, together with peroxisome proliferator-activated receptor gamma coactivator 1-alpha content, was found significantly decreased in fructose-treated adult rats. In vitro studies with BV-2 microglial cells confirmed that fructose treatment induces TNF-alpha production as well as oxidative stress. In conclusion, these results suggest that unbalanced diet, rich in fructose, may be highly deleterious in young people as in adults and must be strongly discouraged for the prevention of diet-associated neuroinflammation and neurological diseases.


A surface-eroding poly(1,3-trimethylene carbonate) coating for fully biodegradable magnesium-based stent applications: toward better biofunction, biodegradation and biocompatibility.
Biodegradable magnesium-based materials have a high potential for cardiovascular stent applications; however, there exist concerns on corrosion control and biocompatibility. A surface-eroding coating of poly(1,3-trimethylene carbonate) (PTMC) on magnesium (Mg) alloy was studied, and its dynamic degradation behavior, electrochemical corrosion, hemocompatibility and histocompatibility were investigated. The PTMC coating effectively protected the corrosion of the Mg alloy in the dynamic degradation test. The corrosion current density of the PTMC-coated alloy reduced by three orders and one order of magnitude compared to bare and poly(ε-caprolactone) (PCL)-coated Mg alloy, respectively. Static and dynamic blood tests in vitro indicated that significantly fewer platelets were adherent and activated, and fewer erythrocytes attached on the PTMC-coated surface and showed less hemolysis than on the controls. The PTMC coating after 16 weeks' subcutaneous implantation in rats maintained ~55% of its original thickness and presented a homogeneously flat surface demonstrating surface erosion, in contrast to the PCL coated control, which exhibited non-uniform bulk erosion. The Mg alloy coated with PTMC showed less volume reduction and fewer corrosion products as compared to the controls after 52 weeks in vivo. Excessive inflammation, necrosis and hydrogen gas accumulation were not observed. The homogeneous surface erosion of the PTMC coating from exterior to interior (surface-eroding behavior) and its charge neutral degradation products contribute to its excellent protective performance. It is concluded that PTMC is a promising candidate for a surface-eroding coating applied to Mg-based implants.


Mitochondrial membrane cholesterol, the voltage dependent anion channel (VDAC), and the Warburg effect.
Normal cells of aerobic organisms synthesize the energy they require in the form of ATP via the process of oxidative phosphorylation. This complex system resides in the mitochondria of cells and utilizes oxygen to produce a majority of cellular ATP. However, in most tumors, especially those with elevated cholesterogenesis, there is an increased reliance on glycolysis for energy, even in conditions where oxygen is available. This aerobic glycolysis (the Warburg effect) has far reaching ramifications on the tumor itself and the cells that surround it. In this brief review, we will discuss how abnormally high membrane cholesterol levels can result in a subsequent deficiency of oxidative energy production in mitochondria from cultured Morris hepatoma cells (MH-7777). We have identified the voltage dependent anion channel (VDAC) as a necessary component of a protein complex involved in mitochondrial membrane cholesterol distribution and transport. Work in our laboratory demonstrates that the ability of VDAC to influence mitochondrial membrane cholesterol distribution may have implications on mitochondrial characteristics such as oxidative phosphorylation and induction of apoptosis, as well as the propensity of cancer cells to exhibit a glycolytic phenotype.


Comparison of a double-textured prototype manual toothbrush with 3 branded products. A professional brushing study.
The consensus has been that there is no one superior design of manual toothbrush for plaque removal, despite, in some cases, encouraging findings from laboratory studies. The user appears the major variable and may mask differences in brush efficacy. The aim of this study was to compare 2 new double-filament texture brushes with 3 established brands for plaque removal, under standardised conditions of professional brushing. The study was a blind, randomised crossover design, balanced for residual effects. A panel of 15 subjects suspended tooth cleaning for 3 days. On day 4, plaque was scored from 6 sites per tooth before and after a 2-min professional toothbrushing. A washout period of at least 3 days was allowed between study periods. Overall plaque removal was 50% with no significant differences between brushes, a 3% absolute difference in average total mouth plaque separating brushes. However, at upper- and mid-buccal sites, a not significant 8% and a significant 9% difference, respectively, in plaque removal were recorded in favour of one of the prototype brushes, and at the mid-lingual site, there was a non-significant 10% difference in favour of one branded brush. Other sites were cleaned similarly by all brushes except for reduced plaque removal from buccal compared to lingual surfaces and interproximal compared to mid-surface sites. Highly significant subject differences in plaque removal were noted which may be relevant to inherent anatomical difficulties in tooth cleaning for some individuals. Period effects were not significant, supporting the consistency in brushing by the professional brusher. The method appeared capable of detecting small benefits of brush design. However, the benefits reported must be taken within the context of an overall lack of difference between brushes. The method could be used to set and record a minimum level of efficacy for toothbrushes.


Attitudes of health service providers: The perspective of people with disabilities in the Kumasi Metropolis of Ghana.
Awareness of disability issues has gained considerable interest by advocacy groups in recent years. However, it is uncertain whether attitudes and perceptions of all service providers and society have adjusted accordingly towards the health care of people with disabilities. This study sought to examine the attitudes of health providers from the perspective of people with disabilities in the Kumasi Metropolis. A cross-sectional study using semi-structured questionnaires was conducted with people with disabilities (with physical, hearing and visual impairments,) in the Kumasi Metropolis. The study used a multi-stage sampling involving cluster and simple random sampling to select 255 respondents split amongst the following five clusters of communities; Oforikrom, Subin, Asewase, Tafo and Asokwa. Data were analysed using STATA 14 and presented in descriptive and inferential statistics. The study found that 71% of the respondents faced some form of discrimination including the use of derogatory remarks, frustration and unavailable required services on the basis of their disability, the type of services they need and the location. Women were 3.89 times more likely to face discrimination; Adjusted odds ratio (AOR) = 3.89 (95% confidence interval [CI]; 1.41, 10.76), and visually impaired was more likely to be discriminated at the facility compared with physical disability; AOR = 5.05 (95% CI; 1.44, 17.65). However, respondents with some educational qualification and those who stayed with their family members were less likely to face discrimination; AOR = 0.08 (95% CI; 0.01, 0.39). The study recommends the provision of in-service training for service providers to update their knowledge on disability issues and improve access to services for people with disabilities.


The role of prostacyclin and thromboxane in sepsis and septic shock.
Prostacyclin, or prostaglandin I2 (PGI2), and thromboxane A2 (TXA2) are potent, endogenously produced, vasoactive substances that have been implicated as mediators in the pathophysiologic nature of septic shock. We investigated the contribution and production of PGI2 and TXA2 in sepsis and septic shock, using an intact rabbit model and an in vitro rabbit isolated cardiac perfusion model. Continuous hemodynamic monitoring of both experimental models, along with serial radioimmunoassays of the metabolites of PGI2 and TXA2, indicated that myocardial depression is a common finding in subjects with septic shock and that septic shock causes a suppression of PGI2 production while augmenting TXA2 production. In addition, PGI2 and TXA2 were mediators of some cardiovascular changes in septic shock but were themselves not the toxic factor(s) responsible for the associated myocardial depression.


Hepatectomy for hepatocellular carcinoma: toward zero hospital deaths.
The authors report on the surgical techniques and protocol for perioperative care that have yielded a zero hospital mortality rate in 110 consecutive patients undergoing hepatectomy for hepatocellular carcinoma (HCC). The hepatectomy results are analyzed with the aim of further reducing the postoperative morbidity rate. In recent years, hepatectomy has been performed with a mortality rate of <10% in patients with HCC, but a zero hospital mortality rate in a large patient series has never been reported. At Queen Mary Hospital, Hong Kong, the surgical techniques and perioperative management in hepatectomy for HCC have evolved yearly into a final standardized protocol that reduced the hospital mortality rate from 28% in 1989 to 0% in 1996 and 1997. Surgical techniques were designed to reduce intraoperative blood loss, blood transfusion, and ischemic injury to the liver remnant in hepatectomy. Postoperative care was focused on preservation and promotion of liver function by providing adequate tissue oxygenation and immediate postoperative nutritional support that consisted of branched-chain amino acid-enriched solution, low-dose dextrose, medium-chain triglycerides, and phosphate. The pre-, intra-, and postoperative data were collected prospectively and analyzed each year to assess the influence of the evolving surgical techniques and perioperative care on outcome. Of 330 patients undergoing hepatectomy for HCC, underlying cirrhosis and chronic hepatitis were present in 161 (49%) and 108 (33%) patients, respectively. There were no significant changes in the patient characteristics throughout the 9-year period, but there were significant reductions in intraoperative blood loss and blood transfusion requirements. From 1994 to 1997, the median blood transfusion requirement was 0 ml, and 64% of the patients did not require a blood transfusion. The postoperative morbidity rate remained the same throughout the study period. Complications in the patients operated on during 1996 and 1997 were primarily wound infections; the potentially fatal complications seen in the early years, such as subphrenic sepsis, biliary leakage, and hepatic coma, were absent. By univariate analysis, the volume of blood loss, volume of blood transfusions, and operation time were correlated positively with postoperative morbidity rates in 1996 and 1997. Stepwise logistic regression analysis revealed that the operation time was the only parameter that correlated significantly with the postoperative morbidity rate. With appropriate surgical techniques and perioperative management to preserve function of the liver remnant, hepatectomy for HCC can be performed without hospital deaths. To improve surgical outcome further, strategies to reduce the operation time are being investigated.


Computed tomography derived anatomical predictors of vascular access complications following transfemoral transcatheter aortic valve implantation: A systematic review.
Vascular complications after percutaneous transfemoral transcatheter aortic valve implantation (TAVI) are associated with adverse clinical outcomes and remain a significant challenge. The purpose of this review is to synthesize the existing evidence regarding the iliofemoral artery features predictive of vascular complications after TAVI on pre-procedural contrast-enhanced multidetector computed tomography (MDCT). A systematic search was performed in Embase and Medline (Pubmed) databases. Studies of patients undergoing transfemoral TAVI with MDCT were included. Studies with only valve-in-valve TAVI, planned surgical intervention and those using fluoroscopic assessment were excluded. Data on study cohort, procedural characteristics and significant predictors of vascular complications were extracted. We identified 23 original studies involving 8697 patients who underwent TAVI between 2006 and 2020. Of all patients, 8514 (97.9%) underwent percutaneous transfemoral-TAVI, of which 8068 (94.8%) had contrast-enhanced MDCT. The incidence of major vascular complications was 6.7 ± 4.1% and minor vascular complications 26.1 ± 7.8%. Significant independent predictors of major and minor complications related to vessel dimensions were common femoral artery depth (>54 mm), sheath-to-iliofemoral artery diameter ratio (>0.91-1.19), sheath-to-femoral artery diameter ratio (>1.03-1.45) and sheath-to-femoral artery area ratio (>1.35). Substantial iliofemoral vessel tortuosity predicted 2-5-fold higher vascular risk. Significant iliofemoral calcification predicted 2-5-fold higher risk. The iliac morphology score was the only hybrid scoring system with predictive value. Independent iliofemoral predictors of access-site complications in TAVI were related to vessel size, depth, calcification and tortuosity. These should be considered when planning transfemoral TAVI and in the design of future risk prediction models.


Following the water? Landscape-scale temporal changes in bat spatial distribution in relation to Mediterranean summer drought.
Understanding how the spatial distribution of ecological resources shapes species' diversity and abundance in human-modified landscapes is a central theme in conservation biology. However, studies often disregard that such patterns may vary over time, thereby potentially missing critical environmental constraints to species persistence. This may be particularly important in highly mobile species such as bats, which are able to track temporal variations in spatial resource distribution. Here we test the hypothesis that bats in Mediterranean landscapes are strongly affected by the progressive reduction in water availability during the seasonal summer drought. We analyzed the effects of landscape composition and structure on bat diversity and activity, during pregnancy, lactation, and postlactation periods, and identified the most influential variables within and across periods. Water bodies showed the strongest positive effect on bats, followed by riparian habitats and areas with steeper (>30%) slopes. However, while during pregnancy, there were only small landscape effects, these increased during lactation and postlactation, highlighting a progressively stronger association with water habitats during the summer drought. The spatial projection of habitat models showed that the landscape distribution of bat diversity and activity hotspots changed markedly over time. During pregnancy, the spatial pattern of hotspot distribution was weakly defined, while during lactation and particularly postlactation, there was a concentration of hotspots along permanently flowing watercourses. Our study highlights that permanently flowing watercourses are critical for bat conservation in Mediterranean landscapes, calling for measures to counteract their ongoing degradation due in particular to climate change, water abstraction and damming. More generally, our study underlines the importance of considering the temporal dimension in habitat selection studies, without which there is the risk of overlooking the importance of habitats that are key for species persistence only at certain times of the year.


Speed of visual acuity for vertical eye-movements with a change of accommodation.
Speed of visual acuity was measured for Landolt-C targets presented above and below the line of sight as the targets were moved from 2.4 m to 0.6 m from the observer. Target recognition was faster for a downward than an upward eye movement. There was no difference in response times for the up and down eye-movements when the fixation and target distances were the same.


Thinking Out of the Box: A Green and Social Climate Fund Comment on "Politics, Power, Poverty and Global Health: Systems and Frames".
Solomon Benatar's paper "Politics, Power, Poverty and Global Health: Systems and Frames" examines the inequitable state of global health challenging readers to extend the discourse on global health beyond conventional boundaries by addressing the interconnectedness of planetary life. Our response explores existing models of international cooperation, assessing how modifying them may achieve the twin goals of ensuring healthy people and planet. First, we address why the inequality reducing post World War II European welfare model, if implemented state-by-state, is unfit for reducing global inequality and respecting environmental boundaries. Second, we argue that to advance beyond the 'Westphalian,' human centric thinking integral to global inequality and climate change requires challenging the logic of global economic integration and exploring the politically infeasible. In conclusion, we propose social policy focused changes to the World Trade Organisation (WTO) and a Green and Social Climate Fund, financed by new global greenhouse gas charges, both of which could advance human and planetary health. Recent global political developments may offer a small window of opportunity for out of the box proposals that could be advanced by concerted and united advocacy by global health activists, environmental activists, human rights activists, and trade unions.


[Characteristics of reassociation of DNA in polytene chromosome preparations of malaria mosquito].
Analysis of DNA reassociation in polytene chromosome preparations of malarial mosquito is presented. It was shown that reassociation of highly repeated DNA sequences takes place during the first two hours. Then, middle repeated DNA sequences are reassociating at the third hour. Reassociation of different DNA sequences is going during the fourth and fifth hours.


Diagnosis of Wilson Disease and Its Phenotypes by Using Artificial Intelligence.
WD is caused by ATP7B variants disrupting copper efflux resulting in excessive copper accumulation mainly in liver and brain. The diagnosis of WD is challenged by its variable clinical course, onset, morbidity, and ATP7B variant type. Currently it is diagnosed by a combination of clinical symptoms/signs, aberrant copper metabolism parameters (e.g., low ceruloplasmin serum levels and high urinary and hepatic copper concentrations), and genetic evidence of ATP7B mutations when available. As early diagnosis and treatment are key to favorable outcomes, it is critical to identify subjects before the onset of overtly detrimental clinical manifestations. To this end, we sought to improve WD diagnosis using artificial neural network algorithms (part of artificial intelligence) by integrating available clinical and molecular parameters. Surprisingly, WD diagnosis was based on plasma levels of glutamate, asparagine, taurine, and Fischer's ratio. As these amino acids are linked to the urea-Krebs' cycles, our study not only underscores the central role of hepatic mitochondria in WD pathology but also that most WD patients have underlying hepatic dysfunction. Our study provides novel evidence that artificial intelligence utilized for integrated analysis for WD may result in earlier diagnosis and mechanistically relevant treatments for patients with WD.


[Use of antipsychotics during pregnancy and lactation].
When a pregnant or lactating woman is treated with an antipsychotic drug, the maternal need of antipsychotics must be weighed against possible risks to the fetus/infant. Published articles on the use of antipsychotics during pregnancy and lactation were identified by Medline and Embase searches. An overview is presented. Available data do not indicate a clinically significant increased risk of congenital malformations after use of first-generation antipsychotics in pregnancy. However, use in the third trimester increases the risk of extrapyramidal symptoms in the newborn. Epidemiological studies do not indicate long-term effects on psychomotor development or cognitive abilities. For second-generation antipsychotics, data are generally very sparse. The excretion in breast milk of first-generation high potency antipsychotics is generally low and no negative effects have been documented after use in monotherapy. For second-generation antipsychotics, data are sparse or lacking. First-generation antipsychotics do not appear to be teratogenic. If antipsychotics are used in the third trimester, the neonate should be observed for extrapyramidal symptoms. When the use of a first-generation antipsychotic is indicated in a lactating woman, the favourable effects of lactation will most likely in the majority of cases exceed the theoretical risk of detrimental drug effects in the infant. Nevertheless, efforts should always be made to minimise drug exposure to the fetus or suckling infant.


Interactions between the PTS regulation domains of the BglG transcriptional antiterminator from Escherichia coli.
The E. coli BglG protein inhibits transcription termination within the bgl operon in the presence of beta-glucosides. BglG represents a family of transcriptional antiterminators that bind to RNA sequences, which partially overlap rho-independent terminators, and prevent termination by stabilizing an alternative structure of the transcript. The activity of BglG is determined by its dimeric state, which is modulated by reversible phosphorylation catalyzed by BglF, a PTS permease. Only the non-phosphorylated BglG dimer binds to RNA and allows read-through of transcription. BglG is composed of three domains: an RNA-binding domain followed by two domains, PRD1 and PRD2 (PTS regulation domains), which are similar in their sequence and folding. Based on the three-dimensional structure of dimeric LicT, a BglG homologue from Bacillus subtilis, the interactions within the dimer are PRD1-PRD1 and PRD2-PRD2. We have shown before that PRD2 mediates homodimerization very efficiently. Using genetic systems and in vitro techniques that assay and characterize protein-protein interactions, we show here that the PRD1 dimerizes very slowly, but once it does, the homodimers are stable. These results support our model that formation of BglG dimers initiates with PRD2 dimerization followed by zipping up of two BglG monomers to create the active RNA-binding domain. Moreover, our results demonstrate that PRD1 and PRD2 heterodimerize efficiently in vitro and in vivo. The affinity among the PRDs is in the following order: PRD2-PRD2 > PRD1-PRD2 > PRD1-PRD1. The interaction between PRD1 and PRD2 offers an explanation for the requirement of conserved residues in PRD1 for the phosphorylation of PRD2 by BglF.


Using Asynchronous Exergames to Encourage an Active Ageing Lifestyle: Solitaire Fitness Study Protocol.
A healthy and active lifestyle can significantly improve the well-being and quality of life; however, some elderly people struggle to stay motivated and engaged with any form of exercise. The project Elaine (Elderly, AI and New Experiences) addresses this problem by seeking to improve the quality of life of the elderly through exergames. Currently, the project explores a novel approach in the field of health informatics called asynchronous exergaming. This approach, a new trend in games in the health domain, allows the elderly to workout at their own pace, and in their own time, with their physical activity linked asynchronously to a game. This paper presents the study protocol for Solitaire Fitness, a new asynchronous exergame developed by the team. The game aims at increasing the motivation of the elderly to engage in physical exercise whilst helping to maintain their cognitive abilities. It also describes the protocol for the trial. The result of this research has the potential to benefit elderly that need nudging to be motivated to exercise, health care providers treating people with sedentary lifestyles and researchers investigating ways to encourage the elderly to exercise.


HEALTHY intervention: fitness, physical activity, and metabolic syndrome results.
This study aimed to assess the effect of the HEALTHY intervention on the metabolic syndrome (Met-S), fitness, and physical activity levels of US middle-school students. Cluster randomized controlled trial conducted in 42 (21 intervention) US middle schools. Participants were recruited at the start of sixth grade (2006) when baseline assessments were made, with post-assessments made 2.5 yr later at the end of eighth grade (2009). The HEALTHY intervention had four components: 1) improved school food environment, 2) physical activity and eating educational sessions, 3) social marketing, and 4) revised physical education curriculum. Met-S risk factors, 20-m shuttle run (fitness), and self-reported moderate to vigorous physical activity (MVPA) were assessed at each time point. Ethnicity and gender were self-reported. Obesity status (normal weight, overweight, or obese) was also assessed. At baseline, 5% of the participants were classified with Met-S, with two-thirds of the males and one-third of the females recording below average baseline fitness levels. Control group participants reported 96 min of MVPA at baseline with 103 min reported by the intervention group. There were no statistically significant (P < 0.05) differences in Met-S, fitness, or MVPA levels at the end of the study after adjustment for baseline values and confounders. There were no differences in any ethnic, obesity, or ethnic × obesity subgroups for either gender. The HEALTHY intervention had no effect on the Met-S, fitness, or physical activity levels. Approaches that focus on how to change physical activity, fitness, and Met-S using nonschool or perhaps in addition to school based components need to be developed.