Causality of injury and outcome in patients admitted in a major trauma center in North India.
Trauma in South Asia is an increasingly significant problem, particularly in light of increasing motorization. Societal changes are resulting in alterations in the epidemiology of trauma. To assess various epidemiological parameters that influence causation of injury in the patients admitted in a major trauma center in Northern India. Prospective, cross-sectional, Hospital based study from August 2008 to July 2009. A prospective study of 748 patients chosen by random assortment was carried out over a period of 1 year (August 2008 to July 2009) and following parameters were noted: Age group, sex, mode of trauma, type of injury, place where the trauma occurred and factors leading to injury. The length of stay of patients, Kampala trauma score (KTS) and mortality depending on the arrival time in emergency department was also noted. Data analysis was performed using SPSS Version 16. Overall trauma was most common in the age group 15-30 years (Mean age: 29.43 ± 16.87 years), with male constituting 85.29% of the total patients. It was observed that road side injuries were the most frequent (66.71%) site of injuries, whereas household injuries (23.66%), farm site (6.28%), work place (1.60) were the next most common modes of trauma. Mean time of presentation of injured patient was 2.53 ± 4.92 days. About 48.13% patients were admitted after more than 24 h after the injury. Two wheelers (32.09) were found to be the most common mode of injury. Maximum injuries (65.31%) occurred in the rural setting. The overall length of hospital stay ranged from 2 days to 178 days (median15.6 days). Mortality is more in patients who arrive in night (between 9 pm and 5 pm). We conclude that the majority of injuries are preventable and the epidemiological trends differ from that of developed countries. Therefore, preventive strategies should be made on the basis of these epidemiological trends.


Tissue-selective Estrogen Complex for Menopausal Hormone Therapy.
The first approved tissue-selective estrogen complex is a pairing of conjugated estrogen combined with the selective estrogen-receptor modulator, bazedoxifene. Advantages include relief of menopausal symptoms without the increased chance of bleeding or breast tenderness unlike with traditional estrogen-progestin therapy, which is associated with both bleeding and breast tenderness. Tissue-selective estrogen complex effects on relief of vasomotor symptoms, prevention of bone loss, improvement in vaginal symptoms, lack of significant cardiovascular effects beyond the expected 2-fold increase in venous thrombosis, neutral effect on breast, and protective effects on the endometrium are discussed.


Systematic review of corpus callosotomy utilizing MRI guided laser interstitial thermal therapy.
Corpus callosotomy is a palliative surgical option for patients with refractory epilepsy and frequent drop attacks, decreasing seizure frequency and severity by disconnecting the cerebral hemispheres. Though often successful, open surgery is not without risk. Corpus callosotomy by MRI-guided laser interstitial thermal therapy (MRgLITT) is a minimally invasive alternative to the standard open procedure. This report aims to present an illustrative case and systematically review the current literature on the surgical technique. A systematic review of the English literature through January 2019 was performed. Articles were searched by title utilizing the following key word combinations: "laser" and "callosotomy", "callosotomy" and "ablation", "laser" and "corpus", "callosotomy" and "thermal", and "stereotactic" and callosotomy". The articles recovered were then classified by level of evidence and summarized. Fifteen papers were reviewed, of which 6 met inclusion and exclusion criteria. All included studies were classified as level IV evidence. There was a total of 13 patients ranging from 13 months to 44 years old (mean 23.5 years old). The number of laser fibers utilized ranged from 1 to 3. Engel class I was achieved in 5 patients, II in 4, III in 2, IV in 1. Reported patient follow up was 4-39.7 months (mean 15.43). Corpus callosotomy utilizing MRI-guided laser interstitial thermal therapy results in improvement in seizure frequency and severity with minimal complications. Prospective trials are needed to compare its seizure control and long-term outcomes to that of standard open callosotomy.


Strong phonon scattering by layer structured PbSnS(2) in PbTe based thermoelectric materials.
The incorporation of PbSnS(2) in PbTe results in a tremendous reduction of the lattice thermal conductivity to 0.8 W/mK at room temperature, a reduction of almost 60% over bulk PbTe. Transmission electron microscopy reveals very high density displacement layers, misfit dislocations, and phase boundaries. Our thermal transport calculations based on modified Debye-Callaway model, well in agreement with the experimental measurements, reveal that the layer structured PbSnS(2) plays an important role in reducing the lattice thermal conductivity.


Context as a barrier: Impaired contextual processing increases the tendency to develop PTSD symptoms across repeated exposure to trauma.
Growing evidence links repeated traumatic exposure with impaired ability to process contextual information. Specifically, like individuals with PTSD, non-PTSD trauma-exposed individuals fail to react according to contextual demands. In the present study, we explored the process that underlies this impairment. First, we tested the ability of first responders to benefit from contextual primes to improve recognition. Second, we assessed its moderating role in the relationship between traumatic exposure and PTSD symptoms. Fifty-three active-duty firefighters and 33 unexposed civilians matched for age, gender, and years of education participated in the study. All participants completed the contextual priming paradigm, the CAPS-5 clinical interview, and the WAIS-IV vocabulary subtest and were assessed for depression and general traumatic exposure. Repeated traumatic exposure was assessed objectively using the fire-and-rescue-service tracking system. As predicted, we found that trauma-exposed individuals failed to use primes to facilitate rapid and accurate recognition of contextually related objects. Not only did contextual information not improve performance, but it achieved the opposite effect, manifested as negative priming. Hence, context appeared to be an obstacle for trauma-exposed individuals and delayed rapid and accurate recognition. Moreover, impaired ability to process contextual information predicted the tendency to develop PTSD symptoms across repeated exposure to trauma.


Status, use and impact of sharing individual participant data from clinical trials: a scoping review.
To explore the impact of data-sharing initiatives on the intent to share data, on actual data sharing, on the use of shared data and on research output and impact of shared data. All studies investigating data-sharing practices for individual participant data (IPD) from clinical trials. We searched the Medline database, the Cochrane Library, the Science Citation Index Expanded and the Social Sciences Citation Index via Web of Science, and preprints and proceedings of the International Congress on Peer Review and Scientific Publication. In addition, we inspected major clinical trial data-sharing platforms, contacted major journals/publishers, editorial groups and some funders. Two reviewers independently extracted information on methods and results from resources identified using a standardised questionnaire. A map of the extracted data was constructed and accompanied by a narrative summary for each outcome domain. 93 studies identified in the literature search (published between 2001 and 2020, median: 2018) and 5 from additional information sources were included in the scoping review. Most studies were descriptive and focused on early phases of the data-sharing process. While the willingness to share IPD from clinical trials is extremely high, actual data-sharing rates are suboptimal. A survey of journal data suggests poor to moderate enforcement of the policies by publishers. Metrics provided by platforms suggest that a large majority of data remains unrequested. When requested, the purpose of the reuse is more often secondary analyses and meta-analyses, rarely re-analyses. Finally, studies focused on the real impact of data-sharing were rare and used surrogates such as citation metrics. There is currently a gap in the evidence base for the impact of IPD sharing, which entails uncertainties in the implementation of current data-sharing policies. High level evidence is needed to assess whether the value of medical research increases with data-sharing practices.


Assessing attitudes about emergency contraception among urban, minority adolescent girls: an in-depth interview study.
The purpose of this work was to explore the knowledge, attitudes, and beliefs of urban, minority adolescent girls about intention to use emergency contraception pills and to identify barriers to emergency contraception pill use. We conducted an in-depth, semistructured interview study of healthy, urban-dwelling, English-speaking 15- to 19-year-old black adolescents seeking care in a children's hospital emergency department. Purposive sampling was used to recruit sexually active and nonsexually active adolescents and those with and without a history of pregnancy. Enrollment continued until saturation of key themes was achieved. Participants returned after their emergency department visit for a 1-hour interview. The interview consisted of semistructured questions based on the theory of planned behavior constructs: attitudes (including knowledge), subjective norms, and perceived behavioral control, as well as demographic data collection. Interviews were recorded and transcribed. Transcripts were coded by 2 members of the study team by using a modified grounded-theory method. Thirty interviews were required for saturation. Mean participant age was 16.4 years; 53% reported being sexually active, and 17% reported a history of pregnancy. Specific knowledge gaps exist about emergency contraception pills, including misconceptions about the recommended time frame for taking the medication. Several major themes were noted for each of the constructs. Intention to use emergency contraception pills is affected by the conflicting attitudes that the emergency contraception pill works faster than birth control pills and that those who use emergency contraception pills are irresponsible; family and friends are important influences and have uninformed but generally supportive opinions; and adolescents have a perception of limited behavioral control because of their young age and concerns about confidentiality. Urban, minority adolescent girls have misconceptions about emergency contraception pills, are affected by the opinions of those close to them, and express concern about specific barriers. These findings can inform specific interventions aimed at addressing the barriers to emergency contraception pill use that are of most importance to this population of young women.


Simplified Citrate Anticoagulation for CRRT Without Calcium Replacement.
Since 2012, citrate anticoagulation is the recommended anticoagulation strategy for continuous renal replacement therapy (CRRT). The main drawback using citrate as anticoagulant compared with heparin is the need for calcium replacement and the rigorous control of calcium levels. This study investigated the possibility to achieve anticoagulation while eliminating the need for calcium replacement. This was successfully achieved by including citrate and calcium in all CRRT solutions. Thereby the total calcium concentration was kept constant throughout the extracorporeal circuit, whereas the ionized calcium was kept at low levels enough to avoid clotting. Being a completely new concept, only five patients with acute renal failure were included in a short, prospective, intensely supervised nonrandomized pilot study. Systemic electrolyte levels and acid-base parameters were stable and remained within physiologic levels. Ionized calcium levels declined slightly initially but stabilized at 1.1 mmol/L. Plasma citrate concentrations stabilized at approximately 0.6 mmol/L. All postfilter ionized calcium levels were <0.5 mmol/L, that is, an anticoagulation effect was reached. All filter pressures were normal indicating no clotting problems, and no visible clotting was observed. No calcium replacement was needed. This pilot study suggests that it is possible to perform regional citrate anticoagulation without the need for separate calcium infusion during CRRT.


Genes encoding ribonucleoside hydrolase 1 and 2 from Corynebacterium ammoniagenes.
Two kinds of nucleoside hydrolases (NHs) encoded by rih1 and rih2 were cloned from Corynebacterium ammoniagenes using deoD- and gsk-defective Escherichia coli. Sequence analysis revealed that NH 1 was a protein of 337 aa with a deduced molecular mass of 35,892 Da, whereas NH 2 consisted of 308 aa with a calculated molecular mass of 32 310 Da. Experiments with crude extracts of IPTG-induced E. coli CGSC 6885(pTNU23) and 6885(pTNI12) indicated that the Rih1 enzyme could catalyse the hydrolysis of uridine and cytidine and showed pyrimidine-specific ribonucleoside hydrolase activity. Rih2 was able to hydrolyse both purine and pyrimidine ribonucleosides with the following order of activity -- inosine>adenosine>uridine>guanosine>xanthosine>cytidine -- and was classified in the non-specific NHs family. rih1 and rih2 deletion mutants displayed a decrease in cell growth on minimal medium supplemented with pyrimidine and purine/pyrimidine nucleosides, respectively, compared with the wild-type strain. Growth of each mutant was substantially complemented by introducing rih1 and rih2, respectively. Furthermore, disruption of both rih1 and rih2 led to the inability of the mutant to utilize purine and pyrimidine nucleosides as sole carbon source on minimal medium. These results indicated that rih1 and rih2 play major roles in the salvage pathways of nucleosides in this micro-organism.


[ATP metabolism under conditions of radiation injury and the ways of its modification].
Content, methylation and an intensity of restoration of phosphoric components of ATP were studied in cross-striated muscles, brain and liver tissue of normal animals. These patterns were also studied in animals, subjected to irradiation: within 3 hrs after X-ray treatment (800 r); with subcutaneous administration of prozerine (0.5 mcg/kg) and nicotinic acid (20 microng/) 4 hrs before decapitation; and also in animals with vagus, cut off at the level of neck two weeks before irradiation. In different experimental conditions the character of regularity and interrelation between methylation and phosphorylation of ATP were established.


Intellectual disability rights and inclusive citizenship in South Africa: What can a scoping review tell us?
Intellectual disability (ID) is the most prevalent disability in the world. People with intellectual disability (PWID) frequently experience extreme violations of numerous human rights. Despite greater prevalence in South Africa than in high-income countries, most ID research currently comes from the Global North. This leaves us with few contextually sensitive studies to draw from to advance inclusive citizenship. Our scoping review aims to investigate pertinent ID rights issues in South Africa, synthesise quantitative and qualitative studies, and provide a synopsis of available evidence on which to base future work. We aim to clarify key concepts, address gaps in the literature and identify opportunities for further research. We followed strict eligibility criteria. Medical subject heading terms were entered into seven databases. Seven reviewers worked independently, two per paper. Quantitative and qualitative data extraction forms were designed. We followed Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines and registered a protocol. An inductive approach enabled a thematic analysis of selected studies. By following PRISMA guidelines, 82 studies were assessed for eligibility of which 59 were included. Ten sub-themes were integrated into four main themes: the right not to be discriminated against, the right to psychological and bodily integrity, the right to accommodating services and challenges to rights implementation. People with intellectual disability face compound difficulties when trying to assert their constitutionally entitled rights. This ongoing project requires serious commitment and action. Statutory obligations to nurture every South African's human rights naturally extend to PWID and their supporters who forge ahead in a disabling environment.


THEM6 is a prognostic biomarker for breast cancer and is associated with immune infiltration.
To characterize the implications of lipid metabolism-related gene thioesterase superfamily member 6 (THEM6) in breast cancer. Several databases including The Cancer Genome Atlas (TCGA) were utilized for our meticulous bioinformatics analysis. We further performed qRT-PCR, immunoblotting and IHC assays to validate the expression of THEM6 in various breast cancer cells and tissues. In addition, we have carried out relevant functional experiments to explore the regulatory role of THEM6 in vitro. Lipid metabolism-related genes are independent factors for overall survival. According to several databases, THEM6 was significantly more expressed in cancerous tissues of breast invasive carcinoma (BRCA) compared to its paracancerous tissues. Furthermore, THEM6 overexpression was correlated with poorer overall survival of BRCA patients, serving as a separate prognostic factor for BRCA. Biological functional analyses revealed that THEM6 was associated with tumor progression and pathogenesis. Finally, we discovered that in BRCA, THEM6 expression was linked to multiple immune cell types. qRT-PCR and Western blotting experiments demonstrated a general upregulation of THEM6 expression in breast carcinoma cells. IHC showed that THEM6 was expressed in both breast cancer tissues and para-cancer tissues, but its expression level was significantly higher in carcinoma tissues. In vitro studies indicated that THEM6 increased proliferation, invasion, and inhibited apoptosis of breast carcinoma cells, while also affecting the cell cycle and promoting cancer progression. Furthermore, THEM6 may influence macrophage recruitment and polarization in the tumor microenvironment by regulating CCL2 secretion, which in turn affects macrophage recruitment in the tumor microenvironment. Our findings indicate that the overexpression of THEM6, which is linked to the development of breast cancer, is a predictor of a poor prognosis and has an impact on the degree of immune cell infiltration. Therefore, THEM6 has the potential to be a valuable target for BRCA.


Automated emergent large vessel occlusion detection by artificial intelligence improves stroke workflow in a hub and spoke stroke system of care.
Emergent large vessel occlusion (ELVO) acute ischemic stroke is a time-sensitive disease. To describe our experience with artificial intelligence (AI) for automated ELVO detection and its impact on stroke workflow. We conducted a retrospective chart review of code stroke cases in which VizAI was used for automated ELVO detection. Patients with ELVO identified by VizAI were compared with patients with ELVO identified by usual care. Details of treatment, CT angiography (CTA) interpretation by blinded neuroradiologists, and stroke workflow metrics were collected. Univariate statistical comparisons and linear regression analysis were performed to quantify time savings for stroke metrics. Six hundred and eighty consecutive code strokes were evaluated by AI; 104 patients were diagnosed with ELVO during the study period. Forty-five patients with ELVO were identified by AI and 59 by usual care. Sixty-nine mechanical thrombectomies were performed.Median time from CTA to team notification was shorter for AI ELVOs (7 vs 26 min; p<0.001). Door to arterial puncture was faster for transfer patients with ELVO detected by AI versus usual care transfer patients (141 vs 185 min; p=0.027). AI yielded a time savings of 22 min for team notification and a 23 min reduction in door to arterial puncture for transfer patients. AI automated alerts can be incorporated into a comprehensive stroke center hub and spoke system of care. The use of AI to detect ELVO improves clinically meaningful stroke workflow metrics, resulting in faster treatment times for mechanical thrombectomy.


Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha.
The possibility that lipid-induced insulin resistance in human muscle is related to alterations in diacylglycerol (DAG)/protein kinase C (PKC) signaling was investigated in normal volunteers during euglycemic-hyperinsulinemic clamping in which plasma free fatty acid (FFA) levels were increased by a lipid/heparin infusion. In keeping with previous reports, rates of insulin-stimulated glucose disappearance (G(Rd)) were normal after 2 h but were reduced by 43% (from 52.7 +/- 8.2 to 30.0 +/- 5.3 micromol. kg(-1). min(-1), P < 0.05) after 6 h of lipid infusion. No changes in PKC activity or DAG mass were seen in muscle biopsy samples after 2 h of lipid infusion; however, at approximately 6 h, PKC activity and DAG mass were increased approximately fourfold, as were the abundance of membrane-associated PKC-betaII and -delta. A threefold increase in membrane-associated PKC-betaII was also observed at approximately 2 h but was not statistically significant (P = 0.058). Ceramide mass was not changed at either time point. To evaluate whether the fatty acid-induced insulin activation of PKC was associated with a change in the IkB kinase (IKK)/nuclear factor (NF)-kappaB pathway, we determined the abundance in muscle of IkappaB-alpha, an inhibitor of NF-kappaB that is degraded after its phosphorylation by IKK. In parallel with the changes in DAG/PKC, no change in IkappaB-alpha mass was observed after 2 h of lipid infusion, but at approximately 6 h, IkappaB-alpha was diminished by 70%. In summary, the results indicated that the insulin resistance observed in human muscle when plasma FFA levels were elevated during euglycemic-hyperinsulinemic clamping was associated with increases in DAG mass and membrane-associated PKC-betaII and -delta and a decrease in IkappaB-alpha. Whether acute FFA-induced insulin resistance in human skeletal muscle is caused by the activation of these specific PKC isoforms and the IKK-beta/IkappaB/NFkappaB pathway remains to be established.


Toxoplasma gondii serostatus is not associated with impaired long-term survival after heart transplantation.
Conflicting data have been reported about the effect of Toxoplasma serostatus on mortality after heart transplantation. Either a positive or a negative recipient Toxoplasma serostatus was found to be associated with increased mortality. We evaluated the effects of T. gondii infection on survival of our 582 cardiac allograft recipients operated upon between June 1984 and July 2011. The 258 Toxoplasma seronegative and 324 seropositive recipients differed in age, pretransplantation diagnosis, ischemia time, renal function, donor Toxoplasma serology, and maintenance immunosuppression. After a median follow-up time of 8.3 years (range, 0-26 years), 117 (45%) seronegative and 219 (67%) seropositive patients died. No difference was found in deaths due to cardiac allograft vasculopathy. After adjustment for all relevant clinical characteristics, the recipient Toxoplasma serostatus was not associated with mortality (hazard ratio, 1.21; 95% confidence interval [CI], 0.95-1.54). With the Toxoplasma serostatus combination donor negative/recipient negative as a reference, univariate hazard ratios for the Toxoplasma serostatus combinations were D+/R- 0.52 (95% CI, 0.37-0.73), D-/R+ 0.65 (95% CI, 0.40-1.05), and D+/R+ 0.78 (95% CI, 0.57-1.07). Multivariate analysis, however, showed that donor Toxoplasma serostatus was not independently associated with mortality. The Toxoplasma serostatus of both the recipient and donor appeared not to be independent risk factors for mortality after heart transplantation.


A pore-forming haemolysin from the hookworm, Ancylostoma caninum.
Hookworms feed on blood, but the mechanism by which they lyse ingested erythrocytes is unknown. Here we show that Ancylostoma caninum, the common dog hookworm, expresses a detergent soluble, haemolytic factor. Activity was identified in both adult and larval stages, was heat-stable and unaffected by the addition of protease inhibitors, metal ions, chelators and reducing agents. Trypsin ablated lysis indicating that the haemolysin is a protein. A closely migrating doublet of hookworm proteins with apparent molecular weights of 60-65 kDa bound to the erythrocyte membrane after lysis of cells using both unlabeled and biotinylated detergent-solubilised hookworm extracts. In addition, separation of detergent-soluble parasite extracts using strong cation-exchange chromatography, resulted in purification of 60-65 kDa proteins with trypsin-sensitive haemolytic activity. Erythrocytes lysed with particulate, buffer-insoluble worm extracts were observed using scanning electron microscopy and appeared as red cell ghosts with approximately 100 nm diameter pores formed in the cell membranes. Red blood cell ghosts remained visible indicating that lysis was likely caused by pore formation and followed by osmotic disruption of the cell.


A cascade of phase transitions in an orbitally mixed half-filled Landau level.
Half-filled Landau levels host an emergent Fermi liquid that displays instability toward pairing, culminating in a gapped even-denominator fractional quantum Hall ground state. While this pairing may be probed by tuning the polarization of carriers in competing orbital and spin degrees of freedom, sufficiently high quality platforms offering such tunability remain few. We explore the ground states at filling factor ν = 5/2 in ZnO-based two-dimensional electron systems through a forced intersection of opposing spin branches of Landau levels taking quantum numbers N = 1 and 0. We reveal a cascade of phases with distinct magnetotransport features including a gapped phase polarized in the N = 1 level and a compressible phase in N = 0, along with an unexpected Fermi liquid, a second gapped, and a strongly anisotropic nematic-like phase at intermediate polarizations when the levels are near degeneracy. The phase diagram is produced by analyzing the proximity of the intersecting levels and highlights the excellent reproducibility and controllability that ZnO offers for exploring exotic fractionalized electronic phases.


Effects of Antioxidant in Adjunct with Periodontal Therapy in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis.
This review investigated whether the adjunctive use of antioxidants with periodontal therapy improves periodontal parameters in patients with type 2 diabetes. A systematic and extensive literature search for randomized controlled trials (RCTs) conducted before April 2021 was performed on the PubMed, Cochrane Library, and Web of Science databases. The risk of bias was assessed using the Cochrane risk-of-bias tool. A meta-analysis was performed to quantitatively evaluate the clinical outcomes following periodontal therapy. After independent screening of 137 initial records, nine records from eight RCTs were included. The risk-of-bias assessment revealed that all RCTs had methodological weaknesses regarding selective bias, although other risk factors for bias were not evident. This meta-analysis of two RCTs showed that periodontal pocket depths were significantly reduced in the groups treated with combined non-surgical periodontal therapy and melatonin than in those treated with non-surgical periodontal therapy alone. The present systematic review and meta-analysis suggest that the adjunctive use of melatonin, resveratrol, omega-3 fatty acids with cranberry juice, propolis, and aloe vera gel with periodontal therapy significantly improves periodontal disease parameters in patients with type 2 diabetes, and melatonin application combined with non-surgical periodontal therapy might significantly reduce periodontal pocket depth. However, there are still limited studies of melatonin in combination with non-surgical periodontal therapy in Type 2 diabetic patients, and more well-designed RCTs are required to be further investigated.


Designing musical structures using a constrained optimization approach.
The paper discusses the application of numerical optimizing techniques to musical structures. It is shown that the natural tendency to emulate the instrument maker by optimizing the characteristic frequencies of the structure is not always the most appropriate strategy, and that in cases where one or more possible solutions exist it is more appropriate to specify the frequency requirements as a constraint. The strategy is illustrated using a xylophone bar.


Inflammatory activation is associated with a reduced glucocorticoid receptor alpha/beta expression ratio in monocytes of inpatients with melancholic major depressive disorder.
In this study, we used new technology to investigate whether a coherent pattern of enhanced expression of inflammatory and other immune activation genes in circulating monocytes is found in patients with major depression. Since a high inflammatory state of monocytes might be related to glucocorticoid resistance, we also included the genes for the two isoforms of the glucocorticoid receptor. For this study, we aimed at finding a similar coherent pattern of inflammatory and immune activation genes in monocytes of patients with MDD and recruited 47 medication-free melancholic MDD inpatients and 42 healthy controls. A quantitative-polymerase chain reaction (Q-PCR) monocyte gene expression analysis was performed using a panel of inflammatory-related genes previously identified as abnormally regulated in mood disorder patients. Selected serum cytokines/chemokines were assessed using a cytometric bead array. Depressive symptoms were analysed using Hamilton depression scores (HAMD). Thirty-four of the 47 monocyte inflammatory-related genes were significantly upregulated and 2 were significantly downregulated as compared to controls, the latter including the gene for the active GRα in particular in those with a high HAMD score. The reduced GRα expression correlated strongly to the upregulation of the inflammatory genes in monocytes. Serum levels of IL6, IL8, CCL2 and VEGF were significantly increased in patients compared to controls. Our data show the deregulation of two interrelated homoeostatic systems, that is, the immune system and the glucocorticoid system, co-occurring in major depression.


The impact of CHADS2 score on late stroke after the Cox maze procedure.
The Heart Rhythm Society, European Heart Rhythm Association, and European Cardiac Arrhythmia Society jointly recommend indefinite warfarin anticoagulation in patients with CHADS2 (congestive heart failure, hypertension, age, diabetes, and stroke) score of at least 2 who have undergone ablation for atrial fibrillation. This study determined the impact of CHADS2 score on risk of late stroke or transient ischemic attack after the performance of a surgical Cox maze procedure. A retrospective review of 433 patients who underwent a Cox maze procedure at our institution was conducted. Three months after surgery, warfarin was discontinued regardless of CHADS2 score if the patient showed no evidence of atrial fibrillation, was off antiarrhythmic medications, and had no other indication for anticoagulation. A follow-up questionnaire was used to determine whether any neurologic event had occurred since surgery. Follow-up was obtained for 90% of the study group (389/433) at a mean of 6.6 ± 5.0 years. Among these patients, 32% (125/389) had a CHADS2 score of at least 2, of whom only 40% (51/125) remained on long-term warfarin after surgery. Six patients had late neurologic events (annualized risk of 0.2%). Neither CHADS2 score nor warfarin anticoagulation was significantly associated with the occurrence of late neurologic events. Among the individual CHADS2 criteria, both diabetes mellitus and previous stroke or transient ischemic attack were predictive of late neurologic events. The risk of stroke or transient ischemic attack in patients after a surgical Cox maze procedure was low and not associated with CHADS2 score or warfarin use. Given the known risks of warfarin, we recommend discontinuation of anticoagulation 3 months after the procedure if the patient has no evidence of atrial fibrillation, has discontinued antiarrhythmic medications, and is without any other indication for systemic anticoagulation.


[Trial of the efficacy of health education programs on therapeutic compliance in arterial hypertension].
To analyse by means of a group session and postal support the efficacy of health education (HE) on compliance with therapy for light-to-moderate essential Hypertension. Controlled clinical trial with randomised distribution. Primary Care. 110 hypertense patients with new or uncontrolled Hypertension, for whom treatment with Trandolapril as a start or change of medication was indicated. The patients were split into two groups at random, with observation for six months after inclusion in the study and monthly attendance: 1) Control group (CG) of 55 patients who received HE from their family doctor; 2) Intervention group (IG) of 55 patients controlled. Patients were defined as compliant if their consumption was 80-110% of what was prescribed. The counting of pills was recorded. Percentages of compliant patients and mean compliance were analysed with the Chi squared and Student's t tests. 109 people completed, 77 of them women. Neither group differed as to age, sex, length of evolution, number of diseases or doses of drugs consumed. Intervening in HE with a group session and postal follow-up is an efficacious measure to improve therapeutic compliance in Hypertension cases.


Economic and biophysical limits to seaweed farming for climate change mitigation.
Net-zero greenhouse gas (GHG) emissions targets are driving interest in opportunities for biomass-based negative emissions and bioenergy, including from marine sources such as seaweed. Yet the biophysical and economic limits to farming seaweed at scales relevant to the global carbon budget have not been assessed in detail. We use coupled seaweed growth and technoeconomic models to estimate the costs of global seaweed production and related climate benefits, systematically testing the relative importance of model parameters. Under our most optimistic assumptions, sinking farmed seaweed to the deep sea to sequester a gigaton of CO2 per year costs as little as US$480 per tCO2 on average, while using farmed seaweed for products that avoid a gigaton of CO2-equivalent GHG emissions annually could return a profit of $50 per tCO2-eq. However, these costs depend on low farming costs, high seaweed yields, and assumptions that almost all carbon in seaweed is removed from the atmosphere (that is, competition between phytoplankton and seaweed is negligible) and that seaweed products can displace products with substantial embodied non-CO2 GHG emissions. Moreover, the gigaton-scale climate benefits we model would require farming very large areas (>90,000 km2)-a >30-fold increase in the area currently farmed. Our results therefore suggest that seaweed-based climate benefits may be feasible, but targeted research and demonstrations are needed to further reduce economic and biophysical uncertainties.


Intragenic CNTN4 copy number variants associated with a spectrum of neurobehavioral phenotypes.
Deletions and duplications involving the CNTN4 gene, which encodes for the contactin 4 protein, have been reported in children with autism spectrum disorder (ASD) and other neurodevelopmental phenotypes. In this study, we performed clinical and genetic characterization of three individuals from unrelated families with copy number variants (CNV) (one deletion and two duplications) within CNTN4. The patients exhibited cognitive delay (3/3), growth restriction (3/3), motor delay (2/3), and febrile seizure/epilepsy (2/3). In contrast to previous reports, all probands presented with speech apraxia or delay with no diagnosis of ASD. Parental studies for the proband with the deletion and one of the 2 probands with the duplication revealed paternal origin of the CNTN4 CNV. Interestingly, previously documented CNV involving this gene were mostly inherited from unaffected fathers, raising questions regarding reduced penetrance and potential parent-of-origin effect. Our findings are compared with previously reported patients and patients in the DECIPHER database. The speech impairment in the three probands suggests a role for CNTN4 in language development. We discuss potential factors contributing to phenotypic heterogeneity and reduced penetrance and attempt to find possible genotype-phenotype correlation. Larger cohorts are needed for comprehensive and unbiased phenotyping and molecular characterization that may lead to better understanding of the underlying mechanisms of reduced penetrance, variable expressivity, and potential parent-of-origin effect of copy number variants encompassing CNTN4.


Intravenous administration of oxytocin in rats acutely decreases deprivation-induced chow intake, but it fails to affect consumption of palatable solutions.
Despite its limited ability to cross the blood-brain barrier, peripherally administered oxytocin (OT) acutely decreases food intake, most likely via the brainstem and hypothalamic mechanisms. Studies performed to date have focused mainly on the effects of subcutaneous or intraperitoneal OT on the consumption of only solid calorie-dense diets (either standard or high-fat), whereas it is unknown whether, similarly to central OT, peripherally administered peptide reduces intake of calorie-dilute and non-caloric palatable solutions. In this project, we established that 0.1μg/kg intravenous (IV) OT is the lowest anorexigenic dose, decreasing deprivation-induced standard chow intake by ca. 40% in rats and its effect does not stem from aversion. We then used this dose in paradigms in which effects of centrally acting OT ligands on consumption of palatable solutions had been previously reported. We found that IV OT did not change episodic intake of individually presented palatable solutions containing 10% sucrose, 0.1% saccharin, combined 10% sucrose-0.1% saccharin or 4.1%. Intralipid and it failed to affect daily scheduled consumption of a sucrose solution in non-deprived rats. In a two-bottle choice test, IV OT did not shift animals' preference from sucrose to Intralipid. Finally, OT injected IV prior to the simultaneous presentation chow and a sucrose solution in food-deprived rats significantly decreased chow intake, whereas sugar water consumption remained unchanged. We conclude that IV OT reduces deprivation-induced chow intake without causing aversion, but the dose effective in decreasing energy-driven consumption of high-calorie food fails to affect consumption of palatable calorie-dilute solutions.


Coffee consumption is associated with response to peginterferon and ribavirin therapy in patients with chronic hepatitis C.
High-level coffee consumption has been associated with reduced progression of pre-existing liver diseases and lower risk of hepatocellular carcinoma. However, its relationship with therapy for hepatitis C virus infection has not been evaluated. Patients (n=885) from the lead-in phase of the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial recorded coffee intake before retreatment with peginterferon α-2a (180 μg/wk) and ribavirin (1000-1200 mg/day). We assessed patients for early virologic response (2 log10 reduction in level of hepatitis C virus RNA at week 12; n=466), and undetectable hepatitis C virus RNA at weeks 20 (n=320), 48 (end of treatment, n=284), and 72 (sustained virologic response; n=157). Median log10 drop from baseline to week 20 was 2.0 (interquartile range [IQR], 0.6-3.9) among nondrinkers and 4.0 (IQR, 2.1-4.7) among patients that drank 3 or more cups/day of coffee (P trend<.0001). After adjustment for age, race/ethnicity, sex, alcohol, cirrhosis, ratio of aspartate aminotransferase to alanine aminotransferase, the IL28B polymorphism rs12979860, dose reduction of peginterferon, and other covariates, odds ratios for drinking 3 or more cups/day vs nondrinking were 2.0 (95% confidence interval [CI]: 1.1-3.6; P trend=.004) for early virologic response, 2.1 (95% CI: 1.1-3.9; P trend=.005) for week 20 virologic response, 2.4 (95% CI: 1.3-4.6; P trend=.001) for end of treatment, and 1.8 (95% CI: 0.8-3.9; P trend=.034) for sustained virologic response. High-level consumption of coffee (more than 3 cups per day) is an independent predictor of improved virologic response to peginterferon plus ribavirin in patients with hepatitis C.


Enhancing RPE Cell-Based Therapy Outcomes for AMD: The Role of Bruch's Membrane.
Age-related macular degeneration (AMD) is the leading cause of legal blindness in older people in the developed world. The disease involves damage to the part of the retina responsible for central vision. Degeneration of retinal pigment epithelial (RPE) cells, photoreceptors, and choriocapillaris may contribute to visual loss. Over the past decades, scientists and clinicians have tried to replace lost RPE cells in patients with AMD using cells from different sources. In recent years, advances in generating RPE cells from stem cells have been made and clinical trials are currently evaluating the safety and efficiency of replacing the degenerated RPE cell layer with stem cell-derived RPE cells. However, the therapeutic success of transplantation of stem cell-derived RPE cells may be limited unless the transplanted cells can adhere and survive in the long term in the diseased eye. One hallmark of AMD is the altered extracellular environment of Bruch's membrane to which the grafted cells have to adhere. Here, we discuss recent approaches to overcome the inhibitory environment of the diseased eye and to enhance the survival rate of transplanted RPE cells. Our aim is to highlight novel approaches that may have the potential to improve the efficacy of RPE transplantation for AMD in the future.


Repetition blindness is immune to the central bottleneck.
The attentional blink (AB) and repetition blindness (RB) phenomena refer to subjects' impaired ability to detect the second of two different (AB) or identical (RB) target stimuli in a rapid serial visual presentation stream if they appear within 500 msec of one another. Despite the fact that the AB reveals a failure of conscious visual perception, it is at least partly due to limitations at central stages of information processing. Do all attentional limits to conscious perception have their locus at this central bottleneck? To address this question, here we investigated whether RB is affected by online response selection, a cognitive operation that requires central processing. The results indicate that, unlike the AB, RB does not result from central resource limitations. Evidently, temporal attentional limits to conscious perception can occur at multiple stages of information processing.


Glucocorticoids impair oocyte competence and trigger apoptosis of ovarian cells via activating the TNF-α system.
Mechanisms by which female stress and particularly glucocorticoids impair oocyte competence are largely unclear. Although one study demonstrated that glucocorticoids triggered apoptosis in ovarian cells and oocytes by activating the FasL/Fas system, other studies suggested that they might induce apoptosis through activating other signaling pathways as well. In this study, both in vivo and in vitro experiments were conducted to test the hypothesis that glucocorticoids might trigger apoptosis in oocytes and ovarian cells through activating the TNF-α system. The results showed that cortisol injection of female mice (1.) impaired oocyte developmental potential and mitochondrial membrane potential with increased oxidative stress; (2.) induced apoptosis in mural granulosa cells (MGCs) with increased oxidative stress in the ovary; and (3.) activated the TNF-α system in both ovaries and oocytes. Culture with corticosterone induced apoptosis and activated the TNF-α system in MGCs. Knockdown or knockout of TNF-α significantly ameliorated the pro-apoptotic effects of glucocorticoids on oocytes and MGCs. However, culture with corticosterone downregulated TNF-α expression significantly in oviductal epithelial cells. Together, the results demonstrated that glucocorticoids impaired oocyte competence and triggered apoptosis in ovarian cells through activating the TNF-α system and that the effect of glucocorticoids on TNF-α expression might vary between cell types.


Carfentanil on the darknet: Potential scam or alarming public health threat?
In an age of global insecurity, highly potent synthetic drugs have become a major public health issue. Their online advertisement and sale are facilitated by surface web, darknet markets and social media fuelling substance abuse and addiction, as well as various types of new criminal activities and their growth in sophistication. This study presents a systematic analysis of the darknet sale of one of the most potent synthetic opioids: Carfentanil. With an equianalgesic potency of 10.000 times a unit of morphine, its toxicity is comparable to traditional nerve agents, and it has been previously used as a chemical weapon, causing human fatalities. Digital trace data was collected retrospectively from all the darknet marketplaces, which have been active in the past five years. Data on vendors offering Carfentanil on Agartha, Empire and Yakuza marketplaces were analysed with regard to items sold and sellers' features as these were the only active markets at the time of search. Searches were carried out in the English language only. 63 Cartfentanil vendors operating on 19 darknet marketplaces were identified. Contacts and payments were facilitated with end-to-end encryption messaging mobile applications and content-expiring messages. Although it is known that Agartha is a scam market, and no operative sellers were found on Yakuza, several sellers promoting Carfentanil sales were active in the Empire marketplace with a number of transaction ranging from 4 to 1223. The availability of highly potent drugs such as Carfentanil on the darknet requires the urgent development of novel scientific methods and tools able to monitor and to predict such new threats, while informing policymaking and protecting the health and the security of citizens.


Residential placement for veterans with addiction: American Society of Addiction Medicine criteria vs. a veterans homeless program.
The goal of this study was to compare placements of patients with addiction undertaken by a) a unidimensional, protocol-driven, independent "permanent" housing "wet" program versus b) a multidimensional, patient-individualized, contingency-based housing approach. The sample consisted of eight veterans in a single team's panel admitted to a housing program and eight matched veterans on the verge of homelessness placed by the team according to the American Society of Addiction Medicine (ASAM) criteria. The two groups (matched for sex, race-ethnicity, and age [SD, 5 years]) were similar on demography, substance disorder, and psychiatric comorbidity. Measures consisted of a) description of the placements, b) 12-month postplacement outcomes using a 12-item scale, and c) a Drug Abuse Research Project-based 10-item scale to assess recovery processes at two 6-month preplacement and two 6-month postplacement intervals. The veterans in the housing program escalated drinking and/or drug use; all were readdicted by the end of 12 months after placement. In the ASAM-criteria group, five of the eight patients had brief slips lasting 2 days or less, but none were readdicted at 12 months. The housing program group experienced five nontrivial outcomes: three imprisonments for felonies, one life-threatening medical complication, and one death. In conclusion, the findings support close monitoring and relevant contingencies using the ASAM criteria in the treatment of substance use disorder.


K562 cells resistant to phorbol 12-myristate 13-acetate-induced growth arrest: dissociation of mitogen-activated protein kinase activation and Egr-1 expression from megakaryocyte differentiation.
The K562 cell line undergoes megakaryocytic differentiation in response to phorbol 12-myristate 13-acetate (PMA) stimulation. This event correlates with mitogen-activated protein kinase activation, cell cycle arrest, and expression of the Egr-1 transcription factor. We have isolated K562 cells that are resistant to the growth-inhibitory action of PMA. Molecular characterization demonstrates that PMA resistance is downstream from PMA-induced activation of the mitogen-activated protein kinase pathway. Although the levels of Egr-1 expression and cyclic AMP-responsive element-binding protein phosphorylation are comparable in wild-type and PMA-resistant clones in response to PMA, the expression of megakaryocytic cell surface marker CD41 is detected only in the wild-type cells. The lack of differentiation of the PMA-resistant clones correlates with a failure of the PMA-treated cells to induce dephosphorylation and down-regulation of the retinoblastoma protein. These cells may provide a useful model system to distinguish those events that are connected to cell cycle arrest from those involved in the differentiation program initiated by PMA.


Arrhythmia Variant Associations and Reclassifications in the eMERGE-III Sequencing Study.
Sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing can identify carriers of pathogenic or likely pathogenic (P/LP) variants. However, the extent to which these variants are associated with clinically meaningful phenotypes before or after return of variant results is unclear. In addition, the majority of discovered variants are currently classified as variants of uncertain significance, limiting clinical actionability. The eMERGE-III study (Electronic Medical Records and Genomics Phase III) is a multicenter prospective cohort that included 21 846 participants without previous indication for cardiac genetic testing. Participants were sequenced for 109 Mendelian disease genes, including 10 linked to arrhythmia syndromes. Variant carriers were assessed with electronic health record-derived phenotypes and follow-up clinical examination. Selected variants of uncertain significance (n=50) were characterized in vitro with automated electrophysiology experiments in HEK293 cells. As previously reported, 3.0% of participants had P/LP variants in the 109 genes. Herein, we report 120 participants (0.6%) with P/LP arrhythmia variants. Compared with noncarriers, arrhythmia P/LP carriers had a significantly higher burden of arrhythmia phenotypes in their electronic health records. Fifty-four participants had variant results returned. Nineteen of these 54 participants had inherited arrhythmia syndrome diagnoses (primarily long-QT syndrome), and 12 of these 19 diagnoses were made only after variant results were returned (0.05%). After in vitro functional evaluation of 50 variants of uncertain significance, we reclassified 11 variants: 3 to likely benign and 8 to P/LP. Genome sequencing in a large population without indication for arrhythmia genetic testing identified phenotype-positive carriers of variants in congenital arrhythmia syndrome disease genes. As the genomes of large numbers of people are sequenced, the disease risk from rare variants in arrhythmia genes can be assessed by integrating genomic screening, electronic health record phenotypes, and in vitro functional studies. URL: https://www. gov; Unique identifier; NCT03394859.


Renal vulnerability to drug toxicity.
Drug-induced kidney disease occurs primarily in patients with underlying risk factors. A number of factors enhance the vulnerability of the kidney to the nephrotoxic effects of drugs and toxins. They are broadly categorized as patient-specific, kidney-related, and drug-related factors. One, two, or all three of the factor categories can act to promote various forms of renal injury. Importantly, all compartments of the kidney can be affected and result in one or more classic clinical renal syndromes. These include acute kidney injury, various tubulopathies, proteinuric renal disease, and chronic kidney disease. Recognizing risk factors that increase renal vulnerability to drug-induced kidney disease is the first step in reducing the renal complications of drugs and toxins.


TNF-α antagonist use and risk of hospitalization for infection in a national cohort of veterans with rheumatoid arthritis.
Medications used to treat rheumatoid arthritis (RA) may confer an increased risk of infection. We conducted a retrospective cohort study of veterans with RA followed in the United States Department of Veterans Affairs health care system from October 1998 through September 2005. Risk of hospitalization for infection associated with tumor necrosis factor (TNF)-α antagonists therapy was measured using an extension of Cox proportional hazards regression, adjusting for demographic characteristics, comorbid illnesses, and other medications used to treat RA. A total of 20,814 patients met inclusion criteria, including 3796 patients who received infliximab, etanercept, or adalimumab. Among the study cohort, 1465 patients (7.0%) were hospitalized at least once for infection. There were 1889 hospitalizations for infection. The most common hospitalized infections were pneumonia, bronchitis, and cellulitis. Age and several comorbid medical conditions were associated with hospitalization for infection. Prednisone (hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.88-2.43) and TNF-α antagonist use (HR, 1.24; 95% CI, 1.02-1.50) were associated with hospitalization for infection, while the use of disease-modifying antirheumatic drugs (DMARDs) other than TNF-α antagonists was not. Compared to etanercept, infliximab was associated with risk for hospitalization for infection (HR, 1.51; 95% CI, 1.14-2.00), while adalimumab use was not (HR, 0.95; 95% CI, 0.68-1.33). In all treatment groups, rate of hospitalization for infection was highest in the first 8 months of therapy. We conclude that patients with RA who are treated with TNF-α antagonists are at higher risk for hospitalization for infection than those treated with other DMARDs. Prednisone use is also a risk factor for hospitalization for infection.


The need to accelerate access to new drugs for multidrug-resistant tuberculosis.
Approximately half a million people are thought to develop multidrug-resistant tuberculosis annually. Barely 20% of these people currently receive recommended treatment and only about 10% are successfully treated. Poor access to treatment is probably driving the current epidemic, via ongoing transmission. Treatment scale-up is hampered by current treatment regimens, which are lengthy, expensive, poorly tolerated and difficult to administer in the settings where most patients reside. Although new drugs provide an opportunity to improve treatment regimens, current and planned clinical trials hold little promise for developing regimens that will facilitate prompt treatment scale-up. In this article we argue that clinical trials, while necessary, should be complemented by timely, large-scale, operational research that will provide programmatic data on the use of new drugs and regimens while simultaneously improving access to life-saving treatment. Perceived risks - such as the rapid development of resistance to new drugs - need to be balanced against the high levels of mortality and transmission that will otherwise persist. Doubling access to treatment and increasing treatment success could save approximately a million lives over the next decade.


Learning temporal statistics for sensory predictions in mild cognitive impairment.
Training is known to improve performance in a variety of perceptual and cognitive skills. However, there is accumulating evidence that mere exposure (i.e. without supervised training) to regularities (i.e. patterns that co-occur in the environment) facilitates our ability to learn contingencies that allow us to interpret the current scene and make predictions about future events. Recent neuroimaging studies have implicated fronto-striatal and medial temporal lobe brain regions in the learning of spatial and temporal statistics. Here, we ask whether patients with mild cognitive impairment due to Alzheimer's disease (MCI-AD) that are characterized by hippocampal dysfunction are able to learn temporal regularities and predict upcoming events. We tested the ability of MCI-AD patients and age-matched controls to predict the orientation of a test stimulus following exposure to sequences of leftwards or rightwards orientated gratings. Our results demonstrate that exposure to temporal sequences without feedback facilitates the ability to predict an upcoming stimulus in both MCI-AD patients and controls. However, our fMRI results demonstrate that MCI-AD patients recruit an alternate circuit to hippocampus to succeed in learning of predictive structures. In particular, we observed stronger learning-dependent activations for structured sequences in frontal, subcortical and cerebellar regions for patients compared to age-matched controls. Thus, our findings suggest a cortico-striatal-cerebellar network that may mediate the ability for predictive learning despite hippocampal dysfunction in MCI-AD.


Direct measurement of sequence-dependent transition path times and conformational diffusion in DNA duplex formation.
The conformational diffusion coefficient, D, sets the timescale for microscopic structural changes during folding transitions in biomolecules like nucleic acids and proteins. D encodes significant information about the folding dynamics such as the roughness of the energy landscape governing the folding and the level of internal friction in the molecule, but it is challenging to measure. The most sensitive measure of D is the time required to cross the energy barrier that dominates folding kinetics, known as the transition path time. To investigate the sequence dependence of D in DNA duplex formation, we measured individual transition paths from equilibrium folding trajectories of single DNA hairpins held under tension in high-resolution optical tweezers. Studying hairpins with the same helix length but with G:C base-pair content varying from 0 to 100%, we determined both the average time to cross the transition paths, τtp, and the distribution of individual transit times, PTP(t). We then estimated D from both τtp and PTP(t) from theories assuming one-dimensional diffusive motion over a harmonic barrier. τtp decreased roughly linearly with the G:C content of the hairpin helix, being 50% longer for hairpins with only A:T base pairs than for those with only G:C base pairs. Conversely, D increased linearly with helix G:C content, roughly doubling as the G:C content increased from 0 to 100%. These results reveal that G:C base pairs form faster than A:T base pairs because of faster conformational diffusion, possibly reflecting lower torsional barriers, and demonstrate the power of transition path measurements for elucidating the microscopic determinants of folding.


Caffeine protects against MPTP-induced blood-brain barrier dysfunction in mouse striatum.
The blood-brain barrier (BBB) is important physiologically. Pathologically, BBB disruption has been implicated in a wide spectrum of neurological disorders including Parkinson's disease (PD). Recent studies indicate that caffeine is protective against PD, but by poorly understood mechanisms. Using a MPTP neurotoxin model of PD we tested the hypothesis that the protective actions of caffeine were because of, at least in part, preventing MPTP-induced BBB dysfunction. FVB mice were pre-treated with caffeine (10 mg/kg, i.p.) or saline for 7 days prior to initiation of neurotoxin treatments; during the 7 days of neurotoxin treatment, caffeine or saline continued to be administered 10 min before each dose of MPTP (20 mg/kg, i.p.). Striatum (and for some studies hippocampus and cerebral cortex as well) were evaluated for BBB leakage, tight junction protein expression levels, integrity of dopaminergic neurons, and activation of astrocytes and microglia using immunostaining, immunoblotting and real-time PCR techniques. We found that caffeine blocked MPTP-induced decreases in numbers of tyrosine hydroxylase-positive dopaminergic neurons, increases in leakage of Evan's blue dye and FITC-albumin in striatum but not in cerebral cortex or hippocampus, decreases in levels of the tight junction proteins occludin and ZO-1, and increases in reactive gliosis. Our results suggest that caffeine might protect against PD and PD-like features in animal models, in part, by stabilizing the BBB.


Melatonin Attenuates Arsenic-Induced Neurotoxicity in Rats Through the Regulation of miR-34a/miR-144 in Sirt1/Nrf2 Pathway.
Arsenic (As) exposure is known to cause several neurological disorders through various molecular mechanisms such as oxidative stress, apoptosis, and autophagy. In the current study, we assessed the effect of melatonin (Mel) on As-induced neurotoxicity. Thirty male Wistar rat were treated daily for 28 consecutive days. As (15 mg/kg, gavage) and Mel (10 and 20 mg/kg, i.p.) were administered to rats. Morris water maze test was done to evaluate learning and memory impairment in training days and probe trial. Oxidative stress markers including MDA and GSH levels, SOD activity, and HO-1 levels were measured. Besides, the levels of apoptosis (caspase 3, Bax/Bcl2 ratio) and autophagy markers (Sirt1, Beclin-1, and LC3 II/I ratio) as well as the expression of miR-144 and miR-34a in cortex tissue were determined. As exposure disturbed learning and memory in animals and Mel alleviated these effects. Also, Mel recovered cortex pathological damages and oxidative stress induced by As. Furthermore, As increased the levels of apoptosis and autophagy proteins in cortex, while Mel (20 mg/kg) decreased apoptosis and autophagy. Also, Mel increased the expression of miR-144 and miR-34a which inhibited by As. In conclusion, Mel administration attenuated As-induced neurotoxicity through anti-oxidative, anti-apoptotic, and anti-autophagy mechanisms, which may be recommended as a therapeutic target for neurological disorders.


Regulation of Hippocampal Synaptic Function by the Metabolic Hormone, Leptin: Implications for Health and Neurodegenerative Disease.
The role of the endocrine hormone leptin in controlling energy homeostasis in the hypothalamus are well documented. However the CNS targets for leptin are not restricted to the hypothalamus as a high density of leptin receptors are also expressed in several parts of the brain involved in higher cognitive functions including the hippocampus. Numerous studies have identified that in the hippocampus, leptin has cognitive enhancing actions as exogenous application of this hormone facilitates hippocampal-dependent learning and memory, whereas lack or insensitivity to leptin results in significant memory deficits. Leptin also markedly influences some of the main cellular changes that are involved in learning and memory including NMDA-receptor dependent synaptic plasticity and glutamate receptor trafficking. Like other metabolic hormones, there is a significant decline in neuronal sensitivity to leptin during the ageing process. Indeed, the capacity of leptin to modulate the functioning of hippocampal synapses is substantially reduced in aged compared to adult tissue. Clinical studies have also identified an association between circulating leptin levels and the risk of certain neurodegenerative disorders such as Alzheimer's disease (AD). In view of this, targeting leptin and/or its receptor/signaling mechanisms may be an innovative approach for developing therapies to treat AD. In support of this, accumulating evidence indicates that leptin has cognitive enhancing and neuroprotective actions in various models of AD. Here we assess recent evidence that supports an important regulatory role for leptin at hippocampal CA1 synapses, and we discuss how age-related alterations in this hormonal system influences neurodegenerative disease.


Predicting brain age with deep learning from raw imaging data results in a reliable and heritable biomarker.
Machine learning analysis of neuroimaging data can accurately predict chronological age in healthy people. Deviations from healthy brain ageing have been associated with cognitive impairment and disease. Here we sought to further establish the credentials of 'brain-predicted age' as a biomarker of individual differences in the brain ageing process, using a predictive modelling approach based on deep learning, and specifically convolutional neural networks (CNN), and applied to both pre-processed and raw T1-weighted MRI data. Firstly, we aimed to demonstrate the accuracy of CNN brain-predicted age using a large dataset of healthy adults (N = 2001). Next, we sought to establish the heritability of brain-predicted age using a sample of monozygotic and dizygotic female twins (N = 62). Thirdly, we examined the test-retest and multi-centre reliability of brain-predicted age using two samples (within-scanner N = 20; between-scanner N = 11). CNN brain-predicted ages were generated and compared to a Gaussian Process Regression (GPR) approach, on all datasets. Input data were grey matter (GM) or white matter (WM) volumetric maps generated by Statistical Parametric Mapping (SPM) or raw data. CNN accurately predicted chronological age using GM (correlation between brain-predicted age and chronological age r = 0.96, mean absolute error [MAE] = 4.16 years) and raw (r = 0.94, MAE = 4.65 years) data. This was comparable to GPR brain-predicted age using GM data (r = 0.95, MAE = 4.66 years). Brain-predicted age was a heritable phenotype for all models and input data (h2 ≥ 0.5). Brain-predicted age showed high test-retest reliability (intraclass correlation coefficient [ICC] = 0.90-0.99). Multi-centre reliability was more variable within high ICCs for GM (0.83-0.96) and poor-moderate levels for WM and raw data (0.51-0.77). Brain-predicted age represents an accurate, highly reliable and genetically-influenced phenotype, that has potential to be used as a biomarker of brain ageing. Moreover, age predictions can be accurately generated on raw T1-MRI data, substantially reducing computation time for novel data, bringing the process closer to giving real-time information on brain health in clinical settings.


[Euglycemic ketosis in an adolescent with type 1 diabetes on insulin and dapaglifozin: Case report].
Dapagliflozin, an insulin-independent sodium-glucose cotransporter 2 inhibitor (SGLT2-I) induces glycosuria and reduces hyperglycemia in adults with type 2 diabetes. To present an "euglycemic" diabetic ketosis in an adolescent with type 1 diabetes (T1D) receiving dapagliflozin, to alert about the risk of a drug not approved in children nor in T1D. A 17 years old adolescent with T1D during 9 years, was started on dapagliflozin 10 mg / day to reduce insulin dose and weight. During 11 months on treatment, capillaries ketones were undetectable and she exhibited a reduction in body mass index 23.9 to 21.1 kg/m2, basal insulin 40 to 17 U, glycated hemoglobin 8.3 to 7.5%, capillary glucose 175 to 161 mg/dl and glucose variability (standard deviation) 85 to 77. Suddenly nausea and vomits appeared. The patient was on an insulin pump and well calibrated continuous glucose monitoring, showing stable glucose levels under 200 mg/dl, and an insulin bolus was delivered. Vomiting without hyperglycemia persisted; three hours later, she was severely dehydrated and fainting, with ketones 4.6 nmol/l and glucose 224 mg/dl. She received IV saline fluids, ondansetron, carbohydrates and several insulin boluses. Hydration and general condition improved soon, however despite several insulin doses, ketosis continued for 24 hours. It is remarkable that the pump was working well and the cannula was not changed. After the ketosis was resolved, she continued using the same cannula with good metabolic control. Euglycemic ketosis is a life-threatening condition that must be suspected.


Staphylocoagulase-binding region in human prothrombin.
A staphylocoagulase-binding region in human prothrombin was studied by utilizing several fragments prepared from prothrombin by limited proteolysis. Bovine prothrombin, prethrombin 1, prethrombin 2, and human diisopropylphosphorylated alpha-thrombin strongly inhibited formation of the complex ("staphylothrombin") between human prothrombin and staphylocoagulase, but bovine prothrombin fragment 1 and fragment 2 had no effect on the complex formation, indicating that the binding region of human prothrombin for staphylocoagulase is located in the prethrombin 2 molecule. To identify further the staphylocoagulase-binding region, human alpha-thrombin was cleaved into the NH2-terminal large fragment (Mr = 26,000) and the COOH-terminal fragment (Mr = 16,000) by porcine pancreatic elastase. Of these fragments, the COOH-terminal fragment, which includes Asn-200 to the COOH-terminal end of the alpha-thrombin molecule, partially inhibited the complex formation between staphylocoagulase and human prothrombin. In contrast, the NH2-terminal large fragment did not show any inhibitory effect on the staphylothrombin formation. These results suggest that the staphylocoagulase interacts with human prothrombin through the COOH-terminal region of alpha-thrombin B chain. Other plasma proteins, factor X, factor IX, protein C, protein S, protein Z, all of which are structurally similar to prothrombin, did not inhibit the staphylothrombin formation at all, indicating that a specific interaction site with staphylocoagulase is contained only in the prothrombin molecule.


A biopersistence study following exposure to chrysotile asbestos alone or in combination with fine particles.
In designing a study to evaluate the inhalation biopersistence of a chrysotile asbestos that was used as a component of a joint-compound, a feasibility study was initiated to evaluate the short-term biopersistence of the chrysotile alone and of the chrysotile in combination with the sanded reformulated joint-compound. Two groups of Wistar rats were exposed to either 7RF3 chrysotile (Group 2) or to 7RF3 chrysotile combined with aerosolized sanded joint-compound (Group 3). In addition, a control group was exposed to filtered-air. The chrysotile used in the Ready Mix joint compound is rapidly removed from the lung. The chrysotile alone exposure group had a clearance half-time of fibers L > 20 microm of 2.2 days; in the chrysotile plus sanded exposure group the clearance half-time of fibers L > 20 microm was 2.8 days. However, across all size ranges there was approximately an order of magnitude decrease in the mean number of fibers remaining in the lungs of Group 3 as compared to Group 2 despite similiar aerosol exposures. Histopathological examination showed that the chrysotile exposed lungs had the same appearance as the filtered-air controls. This study uniquely illustrates that additional concurrent exposure to an aerosol of the sanded joint-compound, with large numbers of fine-particles depositing in the lungs, accelerates the recruitment of macrophages, resulting in a tenfold decrease in the number of fibers remaining in the lung. The increased number of macrophages in the chrysotile/sanded joint exposure group was confirmed histologically, with this being the only exposure-related histological finding reported.


Soybean nodule autoregulation receptor kinase phosphorylates two kinase-associated protein phosphatases in vitro.
The NARK (nodule autoregulation receptor kinase) gene, a negative regulator of cell proliferation in nodule primordia in several legumes, encodes a receptor kinase that consists of an extracellular leucine-rich repeat and an intracellular serine/threonine protein kinase domain. The putative catalytic domain of NARK was expressed and purified as a maltose-binding or a glutathione S-transferase fusion protein in Escherichia coli. The recombinant NARK proteins showed autophosphorylation activity in vitro. Several regions of the NARK kinase domain were shown by mass spectrometry to possess phosphoresidues. The kinase-inactive protein K724E failed to autophosphorylate, as did three other proteins corresponding to phenotypically detected mutants defective in whole plant autoregulation of nodulation. A wild-type NARK fusion protein transphosphorylated a kinase-inactive mutant NARK fusion protein, suggesting that it is capable of intermolecular autophosphorylation in vitro. In addition, Ser-861 and Thr-963 in the NARK kinase catalytic domain were identified as phosphorylation sites through site-directed mutagenesis. The genes coding for the kinase-associated protein phosphatases KAPP1 and KAPP2, two putative interacting components of NARK, were isolated. NARK kinase domain phosphorylated recombinant KAPP proteins in vitro. Autophosphorylated NARK kinase domain was, in turn, dephosphorylated by both KAPP1 and KAPP2. Our results suggest a model for signal transduction involving NARK in the control of nodule development.


Development of the male germline stem cell niche in Drosophila.
Stem cells are found in specialized microenvironments, or "niches", which regulate stem cell identity and behavior. The adult testis and ovary in Drosophila contain germline stem cells (GSCs) with well-defined niches, and are excellent models for studying niche development. Here, we investigate the formation of the testis GSC niche, or "hub", during the late stages of embryogenesis. By morphological and molecular criteria, we identify and follow the development of an embryonic hub that forms from a subset of anterior somatic gonadal precursors (SGPs) in the male gonad. Embryonic hub cells form a discrete cluster apart from other SGPs, express several molecular markers in common with the adult hub and organize anterior-most germ cells in a rosette pattern characteristic of GSCs in the adult. The sex determination genes transformer and doublesex ensure that hub formation occurs only in males. Interestingly, hub formation occurs in both XX and XY gonads mutant for doublesex, indicating that doublesex is required to repress hub formation in females. This work establishes the Drosophila male GSC niche as a model for understanding the mechanisms controlling niche formation and initial stem cell recruitment, as well as the development of sexual dimorphism in the gonad.


[Acute promyelocytic leukaemia].
Acute promyelocytic leukaemia (APL) is a subtype of acute myeloid leukaemia (AML) with unique biological and clinical features and unique therapeutic requirements. The article provides a brief description of the development, pathophysiology, diagnosis and treatment of APL. The article is based on the authors' own experience and reviews of key articles and national and international guidelines. The disease is caused by a single genetic event, namely the translocation t(15;17), which gives rise to the oncoprotein PML-RARA. Clinical and morphological characteristics arouse suspicion of the disease, and the diagnosis is verified by detecting the translocation. At the time of diagnosis most patients have severe coagulopathy and the predominant clinical manifestation is bleeding. Early mortality is due to severe haemorrhage, usually intracranial. Early treatment start with all-trans retinoic acid (ATRA) on suspicion of APL is essential to reduce this early mortality. ATRA is also an important part of continued treatment, in combination with anthracycline-based chemotherapy and possibly arsenic. After this treatment, the prognosis for disease-free long-term survival is > 90%. There are also safe and effective treatment options for elderly patients with complex comorbidities. With APL it is particularly important to start disease-targeting therapy in the form of ATRA quickly because of the high risk of serious haemorrhages and high early mortality. If serious haemorrhages are avoided, the prognosis is very good.


Inhibitory effect of carnosine and N-acetyl carnosine on LPS-induced microglial oxidative stress and inflammation.
Chronic inflammation and oxidative stress have been implicated in the pathogenesis of neurodegenerative diseases. A growing body of research focuses on the role of microglia, the primary immune cells in the brain, in modulating brain inflammation and oxidative stress. One of the most abundant antioxidants in the brain, particularly in glia, is the dipeptide carnosine, beta-alanyl-L-histidine. Carnosine is believed to be involved in cellular defense such as free radical detoxification and inhibition of protein cross-linking. The more stable N-acetyl derivative of carnosine has also been identified in the brain. The aim of the present study was to examine the role of carnosine and N-acetyl carnosine in the regulation of lipopolysaccharide (LPS)-induced microglial inflammation and oxidative damage. In this study, BV2 microglial cells were stimulated with bacterial LPS, a potent inflammatory stimulus. The data shows that both carnosine and N-acetyl carnosine significantly attenuated the LPS-induced nitric oxide synthesis and the expression of inducible nitric oxide synthase by 60% and 70%, respectively. By competitive spectrophotometric measurement and electrospray mass spectrometry analysis, we demonstrated a direct interaction of N-acetyl carnosine with nitric oxide. LPS-induced TNFalpha secretion and carbonyl formation were also significantly attenuated by both compounds. N-acetyl carnosine was more potent than carnosine in inhibiting the release of the inflammatory and oxidative stress mediators. These observations suggest the presence of a novel regulatory pathway through which carnosine and N-acetyl carnosine inhibit the synthesis of microglial inflammatory and oxidative stress mediators, and thus may prove to play a role in brain inflammation.


Gas chromatographic kinetic study of carbon monoxide oxidation over platinum-rhodium alloy catalysts.
The kinetics for the oxidation of carbon monoxide in the presence of excess oxygen over Pt-Rh alloy catalysts were studied by using the reversed-flow gas chromatography technique. Suitable mathematical analysis equations were derived by means of which the rate constants for the oxidation reaction of carbon monoxide, as well as for the adsorption and desorption of the reactant CO on the catalysts pure Pt, 75 atom% Pt+25 atom% Rh, 50 atom% Pt+50 atom% Rh, 25 atom% Pt+75 atom% Rh and pure Rh supported on SiO2 were determined. All the catalysts show a maximum rate constant for the production of CO2 at a characteristic temperature close to that found in the literature. The rate constants for the adsorption of CO increase generally with increasing temperature, while those for the desorption decrease with increasing temperature. From the variation of the rate constants with temperature activation energies for the oxidation reaction and adsorption of CO were determined, which are sensitive to the composition of the catalytic surface. The appearance of CO2 and carbon, when introducing pure CO into the column with the catalysts, verified a partial dissociative adsorption (e.g., disproportionation) of CO on the catalysts used. The latter indicates a mechanism for the CO oxidation through a partial dissociative adsorption of CO followed by the reaction of adsorbed CO molecules with adsorbed O atoms.


Unresponsive cutaneous leishmaniasis and HIV co-infection: report of three cases.
Cutaneous leishmaniasis (CL) is a vector borne disease caused by various species of Leishmania parasite. CL is endemic in the Thar desert of Rajasthan state and Himachal Pradesh in India. Immune suppression caused by human immunodeficiency virus (HIV) infection is associated with atypical clinical presentation of CL which responds poorly to the standard treatment and causes frequent relapses. We are reporting three cases of localized and disseminated CL due to Leishmania tropica which failed to respond to conventional intralesional/intramuscular sodium stibogluconate (SSG) injections. Initially, we did not think of HIV infection because CL is endemic in this region. When patients did not respond to SSG injections, we performed enzyme-linked immunosorbent assay (ELISA) tests for HIV and they turned out to be HIV positive. Our report showed that CL is emerging as an opportunistic infection associated with HIV/AIDS and may be the first manifestation in HIV positive patients in an endemic area.


Interactional synchrony: signals, mechanisms and benefits.
Many group-living animals, humans included, occasionally synchronize their behavior with that of conspecifics. Social psychology and neuroscience have attempted to explain this phenomenon. Here we sought to integrate results around three themes: the stimuli, the mechanisms and the benefits of interactional synchrony. As regards stimuli, we asked what characteristics, apart from temporal regularity, prompt synchronization and found that stimulus modality and complexity are important. The high temporal resolution of the auditory system and the relevance of socio-emotional information endow auditory, multimodal, emotional and somewhat variable and adaptive sequences with particular synchronizing power. Looking at the mechanisms revealed that traditional perspectives emphasizing beat-based representations of others' signals conflict with more recent work investigating the perception of temporal regularity. Timing processes supported by striato-cortical loops represent any kind of repetitive interval sequence fairly automatically. Additionally, socio-emotional processes supported by posterior superior temporal cortex help endow such sequences with value motivating the extent of synchronizing. Synchronizing benefits arise from an increased predictability of incoming signals and include many positive outcomes ranging from basic information processing at the individual level to the bonding of dyads and larger groups.


Recovery of DNA from Low-Melting-Temperature Agarose Gels: Organic Extraction.
In this protocol, DNA fragments are separated according to size by electrophoresis through low-melting-temperature agarose, and then recovered by melting the agarose and extracting with phenol:chloroform. The protocol works best for DNA fragments ranging in size from 0.5 to 5.0 kb. Yields of DNA fragments outside this range are usually lower, but often are sufficient for many purposes.


Scallops visually respond to the size and speed of virtual particles.
The unique eyes of scallops are abundant along the right and left valve mantle margins. These eyes form images by reflection off a concave spherical mirror, and give scallops an angular resolution of around 2 degrees , far better than the 13-40 degrees angular resolution provided by the eyes of other bivalves. It has been argued that bivalve mantle eyes primarily act as predator detectors, but behavioral studies have suggested that vision may serve additional purposes in scallops. By placing specimens of the bay scallop Argopecten irradians (Lamarck 1819) in a tank with 5-10 cm s(-1) flow, showing them simulated images of moving particles, and recording their behavior, we tested whether visual cues may influence feeding behavior in these animals. We found that scallops opened their anterior mantle gapes significantly more often when they were shown 1.5x1.5 mm virtual particles (with angular sizes of 3.4 degrees ) than when they were shown 0.6x0.6 mm particles (1.4 degrees ; P<0.001) or no particles at all (P<0.05). We also found that scallops opened their anterior mantle gapes significantly more often when they were shown virtual particles moving at 2.5 cm s(-1) (P<0.01) or 5 cm s(-1) (P<0.05) than when they were shown particles moving at 10 cm s(-1). Because scallops must open their anterior mantle gapes to feed, our findings suggest that these animals may visually detect the size and speed of moving particles and use this information to help identify favorable feeding conditions.


Hematologic and cytogenetic findings in eleven chronic myelogenous leukemia patients treated with imatinib mesylate at a tertiary care hospital.
To evaluate the response of Imatinib mesylate in patients with myeloid leukemia in chronic accelerated and blast phase. Eleven patients with established diagnosis of chronic myeloid leukemia were treated with Imatinib mesylate. Adverse events were documented with regular follow ups. Hematological and cytogenetic responses were assessed according to established criteria. Patients with zero percent Philadelphia positive metaphases were labeled as complete cytogenetic response while patients with 1% to 35% Philadelphia positive metaphases were termed as partial responders. Of 11 cases there were 7 males and 4 females with a mean age of 39.5 years and median age 51 years (range 21-69). Male to female ratio was 7:4. Median follow-up was 34 weeks (range 8-78). Four patients were in blast crisis, 1 in accelerated phase and remaining six patients were in chronic phase. All patients achieved hematological response. Cytogenetic response was present in six patients, 3 were responders and the remaining were non responders. Two patients achieved complete cytogenetic response and one patient had partial cytogenetic response. Both patients with complete cytogenetic response relapsed in twelve weeks time. Imatinib mesylate is a drug with curative potential and can be used as a first line drug in the management of CML, however at present the cure rate is unknown.


A plasmid-borne blaOXA-58 gene confers imipenem resistance to Acinetobacter baumannii isolates from a Lebanese hospital.
We investigated the basis of the carbapenem resistance of 17 multidrug-resistant Acinetobacter baumannii clinical isolates collected from 2004 to 2005 at the Saint George University Hospital in Beirut, Lebanon. A. baumannii isolates were clonally related and were susceptible to colistin and trimethoprim-sulfamethoxazole, susceptible or intermediate to ampicillin-sulbactam and meropenem, and resistant to all other antimicrobials. Conjugation experiments demonstrated that resistance to imipenem could be transferred along with a plasmid containing the carbapenem-hydrolyzing oxacillinase bla(OXA-58) gene. The plasmid that we called pABIR was 29,823 bp in size and showed a novel mosaic structure composed of two origins of replication, four insertion sequence (IS) elements, and 28 open reading frames. The bla(OXA-58) gene was flanked by IS18 and ISAba3 elements at the 5' and 3' ends, respectively. The production of the carbapenem-hydrolyzing oxacillinase OXA-58 was apparently the only mechanism for carbapenem resistance in A. baumannii isolates causing the outbreak at the Lebanese Hospital.


Transparent functional nanocomposite films based on octahedral metal clusters: synthesis by electrophoretic deposition process and characterization.
Transparent optical thin films have recently attracted a growing interest for functional window applications. In this study, highly visible transparent nanocomposite films with ultraviolet (UV)-near-infrared (NIR)-blocking capabilities are reported. Such films, composed of Mo6 and Nb6 octahedral metal atom clusters (MC) and polymethylmethacrylate polymer (PMMA), were prepared by electrophoretic deposition on indium tin oxide-coated glass (ITO glass). PMMA was found to improve both the chemical and physical stability of Mo6 and Nb6 MCs, resulting in a relatively homogeneous distribution of the clusters within the PMMA matrix, as seen by microstructural observations. The optical absorption spectrum of these transparent MC@polymer nanocomposite films was marked by contributions from their Mo6 and Nb6-based clusters (absorption in the UV range) and from the ITO layer on silica glass (absorption in the NIR range). Mo6@PMMA nanocomposite films also exhibited excellent photoluminescence properties, which were preserved even after exposure to 50°C at a relative humidity of 70% for one month. These films cumulate high transparency in the visible range with remarkable UV-NIR blocking properties and represent interesting candidates for functional glass application.


Polyurethane Adhesives Based on Oxyalkylated Kraft Lignin.
Lignin-based polyol was obtained via oxyalkylation reaction with propylene carbonate using eucalyptus kraft lignin isolated from the industrial cooking liquor by the Lignoboost® procedure. This lignin-based polyol (LBP) was used without purification in the preparation of polyurethane (PU) adhesives combined with polymeric 4,4'-methylenediphenyl diisocyanate (pMDI). A series of adhesives were obtained by varying the NCO/OH ratio of PU counterparts (pMDI and LBPs) and their performance was evaluated by gluing wood pieces under predefined conditions. The adhesion properties of the novel PU adhesive were compared with those of a commercial PU adhesive (CPA). The occurrence and extent of curing reactions and changes in the polymeric network of PA were monitored by Fourier transform infrared spectroscopy (FTIR) and dynamic mechanical analysis. Although the lap shear strength and glass transition temperature of the lignin-based PU adhesives have increased steadily with the NCO/OH ratio ranging from 1.1-2.2, chemical aging resistance can be compromised when the NCO/OH is very low. It was found that the lignin-based PU adhesive with an NCO/OH ratio of 1.3 showed better chemical resistance and adhesion efficiency than CPA possibly because the NCO/OH in the latter is too high as revealed by FTIR spectroscopy. Despite some lower thermal stability and shorter gelation time of lignin-based PU than CPA, the former revealed great potential to reduce the use of petroleum-derived polyols and isocyanates with potential application in the furniture industry as wood bonding adhesive.


[Some aggregation parameters in the bulbar vessels used for assessing the clinical course of retinopathy in patients with essential hypertension and diabetes mellitus].
The aggregation status of the blood in the bulbar vessels was assessed by computer analyzer system of television images of the eye (CASTIE) in 10 patients with hypertensive angiosclerosis, 22 with diabetic proliferative retinopathy, and 15 patients without vascular abnormalities. The aggregation gradients of intravascular bloodflow in the venules were increased and aggregation coefficients in the bulbar veins decreased in the patients with vascular diseases of the retina, this indicating disorders of blood aggregation. CASTIE helps assess the degree of disorders in blood aggregation at the level of the intravascular and parietal bloodflow and single out the groups at risk of developing thrombotic complications of the retina among the patients with essential hypertension and diabetes mellitus.


A ventricular assist device as a bridge to recovery, decision making, or transplantation in patients with advanced cardiac failure.
Despite many advances in the management of patients with heart failure, acute cardiogenic shock and progressive congestive heart failure remain serious problems with dismal prognoses. Both temporary and permanent mechanical support has been gaining wide clinical application in this patient population. Although mechanical circulatory support technology is rapidly evolving, this approach is associated with multiple issues such as the optimal duration of temporary support, ideal timing to bridge these patients to a long-term device, and selection of the right device for the right patient. The currently available devices are categorized into two major groups: temporary and long-term devices (including destination therapy). Heart failure is a dynamic condition, and the therapeutic approach may need to be modified depending on the patient's condition. Furthermore, the patient's preexisting morbidity, age, socioeconomic status, and family support are confounding factors that need to be considered when making such decisions. Clinical trials including prospective studies, as well as meticulous analysis of existing data, may help develop universal guidelines to select the right device. This manuscript will review the most widely used ventricular assist devices.


Resonance energy transfer approaches in molecular pharmacology and beyond.
A satellite workshop entitled 'Use of resonance energy transfer (RET) approaches to study signal transduction: conceptual and methodological considerations' was held during a recent Molecular Pharmacology Gordon Conference in Ventura (USA). In this article, we summarize the principal trends of the field that were discussed during the workshop. Consensus guidelines for obtaining reliable information from RET-based experiments are also presented.


Rearrangement of nicotinic receptor alpha subunits during formation of the ligand binding sites.
Muscle nicotinic acetylcholine receptors (AChRs) are pentamers that contain two alpha subunits a beta, gamma (or epsilon), and delta subunit. In this paper, we have characterized subunit processing and folding events leading to formation of the two AChR ligand binding sites. alpha subunit residues, 187-199, which are part of overlapping ACh and alpha-bungarotoxin (Bgt) binding sites on AChRs, were assayed using a monoclonal antibody (mAb) specific for these residues. We found that this region was inaccessible to the mAb early during AChR assembly but became accessible as the first of two Bgt binding sites formed later during assembly, indicating that the region changes conformation as the Bgt binding site appears. Without previous reduction, 20% of the alpha subunits could be alkylated by bromoacetylcholine bromide as the first ACh binding site formed, which further indicated that the disulfide bond between cysteines 192 and 193 does not form until the first ACh binding site appears soon after Bgt binding site formation. When alpha subunits were mutated to add a glycosylation site at residue 187, the number of Bgt binding sites increased threefold, AChRs assembled more efficiently, and 2.5-fold more AChRs reached the cell surface. Our results indicate that binding site formation involves a rate-limiting rearrangement of the alpha subunit that exposes the 187-199 region to the endoplasmic reticulum lumen and determines when cysteines 192 and 193 disulfide bond.


Interactions of native and non-native lady beetle species (Coleoptera: Coccinellidae) with aphid-tending ants in laboratory arenas.
Interactions between lady beetles and the European fire ant (Myrmica rubra L.) tending potato aphids [Macrosiphum euphorbiae (Thomas)] were compared in the laboratory. Lady beetle species native to North America (Coccinella trifasciata perplexa Mulsant, Coleomegilla maculata lengi Timberlake, Hippodamia convergens Guérin-Méneville) and non-native species of Palearctic origin [Coccinella septempunctata L., Harmonia axyridis (Pallas), Hippodamia variegata (Goeze), Propylea quatuordecimpunctata L.)] were evaluated. Harmonia axyridis consumed a significantly greater number of aphids compared with all other species but C. septempunctata. Ant stings affected H. variegata and C. septempunctata to a greater extent than other species. Ants showed a significantly greater amount of aggression toward H. convergens and H. variegata compared with P. quatuordecimpunctata. P. quatuordecimpunctata, C. trifasciata, and H. axyridis reacted significantly less to ants compared with H. variegata, H. convergens, C. maculata, and C. septempunctata. Differences in interactions with natural enemies may explain, in part, the successful establishment of some non-native coccinellids in new habitats.


[Emergency management of convulsions and prevention of status epilepticus with rectal diazepam administered by parents].
The parents of 17 children with a history of convulsions, were shown how to administer liquid diazepam through the rectum using a 1 mL insulin syringe, in order to alleviate a convulsion at home or any where ever this may occur. Eight of the children had suffered from repetitive and/or prolonged non-temperature related convulsions, four had epileptic status and five had suffered from simple fever related convulsions, complicated in four and in a convulsive status in 1; the number of fever-related convulsions ranged between 1 and 6 per child and those non temperature related ranged from one daily to once a month. The observation of the children was done in an 88 month period (between 1 and nine months per child, averaging 5.2 months). In seven of the children, it was required of the parents to administer rectal diazepam a total of 90 times (fluctuating between 2 and 25 doses per child), with no complications, a dose of 0.5 mg/kg was administered in those patients whose convulsions lasted over 5 minutes or more. In 75 occasions, the convulsion stopped within a period of 2 to 5 minutes, in 12 other times there was a need for repeated dosages and in 2 occasions, a third doses was needed. Only in one occasion was hospital management needed. Therefore, we conclude that the administration of rectal diazepam by parents--at home--is a useful and secure method to prevent prolonged convulsions and the epileptic status; it gives parents security and tranquility using an instrument which can be used in any circumstance therefore reducing anguish and the cost of hospital care.(ABSTRACT TRUNCATED AT 250 WORDS)


Charcot-Leyden Crystals Activate the NLRP3 Inflammasome and Cause IL-1β Inflammation in Human Macrophages.
Charcot-Leyden crystals (CLCs) are Galectin-10 protein crystals that can form after eosinophils degranulate. CLCs can appear and persist in tissues from patients with eosinophilic disorders, such as asthma, allergic reactions, and fungal and helminthic infections. Despite abundant reports of their occurrence in human disease, the inflammatory potential of CLCs has remained unknown. In this article, we show that CLCs induce the release of the proinflammatory cytokine IL-1β upon their phagocytosis by primary human macrophages in vitro. Chemical inhibition and small interfering RNA knockdown of NLRP3 in primary human macrophages abrogated their IL-1β response to CLCs. Using C57BL/6 ASC-mCitrine transgenic inflammasome reporter mice, we showed that the instillation of CLCs into the lungs promoted the assembly of ASC complexes in infiltrating immune cells (neutrophils and inflammatory monocytes) and resulted in IL-1β accumulation into the bronchoalveolar lavage fluid. Our findings reveal that CLCs are recognized by the NLRP3 inflammasome, which may sustain inflammation that follows eosinophilic inflammatory processes.