A Four-Center Retrospective Study of the Efficacy and Toxicity of Low-Dose Trimethoprim-Sulfamethoxazole for the Treatment of Pneumocystis Pneumonia in Patients without HIV Infection.
The dose of trimethoprim-sulfamethoxazole (TMP-SMX) for the treatment of Pneumocystis pneumonia (PCP) in patients without human immunodeficiency virus (HIV) infection has not been verified. The aim of this study was to investigate the efficacy and toxicity of a low-dose TMP-SMX regimen in such patients. A retrospective study was conducted in four hospitals. We reviewed the medical records of patients with PCP but not HIV (non-HIV-PCP) who were treated with TMP-SMX between 2003 and 2016. The patients were divided into conventional-dose (TMP, 15 to 20 mg/kg/day) and low-dose (TMP, <15 mg/kg/day) groups after patients who received high-dose (TMP, >20 mg/kg/day) treatment were excluded. Grouping was done according to a correction dose, which was based on renal function. Eighty-two patients had non-HIV-PCP. The numbers of patients who received high-, conventional-, and low-dose treatments were 5, 36, and 41, respectively. Kaplan-Meier analysis for death associated with PCP showed no statistically significant difference in survival rates between the conventional- and low-dose groups. Ninety-day cause-specific mortality rates were 25.0% and 19.5% in the conventional-dose and low-dose groups (P = 0.76), respectively. Adverse events that were graded as ≥3 according to the Common Terminology Criteria for Adverse Events (version 4.0) (National Cancer Institute, 2010) were 41.7% and 17.1% in the conventional-dose and low-dose groups (P = 0.02), respectively. Moreover, vomiting (P = 0.03) and a decrease in platelet count (P = 0.03) occurred more frequently in the conventional-dose group. Treatment of non-HIV-PCP with low-dose or conventional-dose TMP-SMX produces comparable survival rates; however, the low-dose regimen is better tolerated and associated with fewer adverse effects.


Conserved syntenic clusters of protein coding genes are missing in birds.
Birds are one of the most highly successful and diverse groups of vertebrates, having evolved a number of distinct characteristics, including feathers and wings, a sturdy lightweight skeleton and unique respiratory and urinary/excretion systems. However, the genetic basis of these traits is poorly understood. Using comparative genomics based on extensive searches of 60 avian genomes, we have found that birds lack approximately 274 protein coding genes that are present in the genomes of most vertebrate lineages and are for the most part organized in conserved syntenic clusters in non-avian sauropsids and in humans. These genes are located in regions associated with chromosomal rearrangements, and are largely present in crocodiles, suggesting that their loss occurred subsequent to the split of dinosaurs/birds from crocodilians. Many of these genes are associated with lethality in rodents, human genetic disorders, or biological functions targeting various tissues. Functional enrichment analysis combined with orthogroup analysis and paralog searches revealed enrichments that were shared by non-avian species, present only in birds, or shared between all species. Together these results provide a clearer definition of the genetic background of extant birds, extend the findings of previous studies on missing avian genes, and provide clues about molecular events that shaped avian evolution. They also have implications for fields that largely benefit from avian studies, including development, immune system, oncogenesis, and brain function and cognition. With regards to the missing genes, birds can be considered 'natural knockouts' that may become invaluable model organisms for several human diseases.


Two-year efficacy and safety of erenumab in participants with episodic migraine and 2-4 prior preventive treatment failures: results from the LIBERTY study.
To evaluate individual and group long-term efficacy and safety of erenumab in individuals with episodic migraine (EM) for whom 2-4 prior preventatives had failed. Participants completing the 12-week double-blind treatment phase (DBTP) of the LIBERTY study could continue into an open-label extension phase (OLEP) receiving erenumab 140 mg monthly for up to 3 years. Main outcomes assessed at week 112 were: ≥50%, ≥75% and 100% reduction in monthly migraine days (MMD) as group responder rate and individual responder rates, MMD change from baseline, safety and tolerability. Overall 240/246 (97.6%) entered the OLEP (118 continuing erenumab, 122 switching from placebo). In total 181/240 (75.4%) reached 112 weeks, 24.6% discontinued, mainly due to lack of efficacy (44.0%), participant decision (37.0%) and adverse events (AEs; 12.0%). The ≥50% responder rate was 57.2% (99/173) at 112 weeks. Of ≥50% responders at the end of the DBTP, 36/52 (69.2%) remained responders at ≥50% and 22/52 (42.3%) at >80% of visits. Of the non-responders at the end of the DBTP, 60/185 (32.4%) converted to ≥50% responders in at least half the visits and 24/185 (13.0%) converted to ≥50% responders in >80% of visits. Change from baseline at 112 weeks in mean (SD) MMD was -4.2 (5.0) days. Common AEs (≥10%) were nasopharyngitis, influenza and back pain. Efficacy was sustained over 112 weeks in individuals with difficult-to-treat EM for whom 2-4 prior migraine preventives had failed. Erenumab treatment was safe and well tolerated, in-line with previous studies. NCT03096834.


Biting activity and host preference of the malaria vectors Anopheles maculatus and Anopheles sawadwongporni (Diptera: Culicidae) in Thailand.
Adult mosquitoes in the Anopheles maculatus group were surveyed from different regions of Thailand and five different species were morphologically identified, including Anopheles maculatus, Anopheles sawadwongporni, Anopheles notanandai, Anopheles dravidicus, and Anopheles willmori. Blood-feeding activity and host preference of two species, Anopheles maculatus and Anopheles sawadwongporni, were observed during a one-year period at Pu Teuy Village, Sai Yok District, Kanchanaburi Province, west-central Thailand. Both species were more prevalent during the wetter period of the year and each had a greater predilection to feed on cattle than humans. Primary feeding activity occurred between 20:00-23:00 and a smaller peak at 01:00-03:00. Findings are discussed relative to the importance of these two vectors for malaria transmission in Pu Teuy.


Treatment data using a topical povidone-iodine antiseptic in patients with superficial skin abscesses.
The standard treatment of cutaneous abscesses in the emergency department is incision and drainage (I&D). The purpose of this investigation is to determine the feasibility of using a povodine-iodine topical antiseptic solution (PVP-I) as a clinical adjunct in the treatment of superficial skin abscesses after I&D, and the data is related to "Pilot Study to Evaluate the Adjunct Use of a Povidone-Iodine Topical Antiseptic in Patients with Soft Tissue Abscesses" [Olson et al., 2019]. The data aims to determine if the daily application of PVP-I in the wound cavity and as an antiseptic hand wash would confer any benefit over I&D alone. The primary outcome was clinical cure 7-10 days after I&D. The secondary outcomes were rate of new abscess development and spread of infection in household contacts (HC) within 30 days.


Cognitive impairment and anxiety are prevalent in kidney transplant recipients.
Cognitive impairment (CI) is common in end-stage kidney disease (ESKD), including kidney transplant recipients. Patients with cognitive problems may find it difficult to comply with medical recommendations after kidney transplantation (KT), which can be the cause of many complications, poorer prognosis, and increased hospitalization rates after transplantation. Additionally, some patients after KT may experience depression and anxiety, which are prevalent comorbidities in patients with ESKD. In this single-center, cross-sectional study, we included 56 consecutive adult patients after KT. Cognitive function were assessed using the Addenbrooke Cognitive Test III (ACE III). In addition, all patients were screened for depression and anxiety using the Hospital Anxiety and Depression Scale (HADS). The impact of immunosuppressive therapy and other disease-related variables on cognitive function were also assessed. A total of 56 KT patients, with a mean age of 50.3 ± 11.7 years, transplanted ≤ 35 months ago were included in the study. The prevalence of CI was 30%. Compared with cognitively unimpaired patients, patients with CI scored significantly lower in all cognitive domains. Furthermore, better cognitive functioning after KT was significantly associated with more years of schooling. We found no significant correlation between CI and age at assessment, duration of dialysis before KT, creatinine levels, creatinine clearance, uric acid levels, hemoglobin levels, comorbid cardiovascular diseases as well as immunosuppressive therapy. In addition, the prevalence of depression and anxiety in screening tests was 12.5% and 27%, respectively, and patients receiving higher daily dose of prednisone had higher HADS scores on both the depression and anxiety subscales (not statistically significant). Cognitive disorders is a relevant issue in kidney transplant recipients. There might be many factors, both before and after KT, that have a negative impact on cognition. Therefore, further research is needed to increase knowledge about the course and profile of cognitive function after KT.


Multicolor real-time polymerase chain reaction genotyping of six human platelet antigens using displacing probes.
Several genotyping methods for six clinically relevant human platelet antigens (HPAs) have been reported. A four-color real-time polymerase chain reaction (PCR) method using displacing probes for genotyping of the six HPAs is described. Primers and four differently fluorophor-labeled displacing probes were designed and synthesized to detect single-nucleotide polymorphisms responsible for each of the HPA-1, -2, -3, -4, -5, and -15 genotypes. Two HPA systems were analyzed in a single PCR procedure. After validation with samples of known genotypes, a total of 150 blood samples from healthy donors were genotyped. The results were compared with PCR with sequence-specific primers (SSP), PCR-restriction fragment length polymorphism (RFLP), and/or direct DNA sequencing. The frequencies of each HPA allele were calculated. Unequivocal real-time PCR genotyping results were obtained with minimal manual manipulation and carryover contamination. All 150 blood samples were correctly genotyped as confirmed by PCR-SSP, PCR-RFLP, and/or direct DNA sequencing. The allelic frequencies of HPA-1 through -5 and -15 among the Chinese population in Xiamen were comparable with those previously reported with Chinese living in other territories. For each specimen, genotyping of all six HPA biallelic systems was achieved in three tubes of PCR within 90 minutes and with material cost of no more than $1. Genotyping of HPA with real-time PCR using displacing probes is more rapid and reliable compared with PCR-SSP and PCR-RFLP methods and is more affordable than existing real-time PCR-based HPA genotyping assays. Thus, our approach is more suitable for routine HPA analysis and ideal for both urgent clinical testing and high-throughput screening.


Validation of two short versions of the Zarit Burden Interview in the palliative care setting: a questionnaire to assess the burden of informal caregivers.
Several validated outcome measures, among them the Zarit Burden Interview (ZBI), are valid for measuring caregiver burden in advanced cancer and dementia. However, they have not been validated for a wider palliative care (PC) setting with non-cancer disease. The purpose was to validate ZBI-1 (ultra-short version and proxy rating) and ZBI-7 short versions for PC. In a prospective, cross-sectional study with informal caregivers of patients in inpatient (PC unit, hospital palliative support team) and outpatient (home care team) PC settings of a large university hospital, content validity and acceptability of the ZBI and its structural validity (via confirmatory factor analysis (CFA) and Rasch analysis) were tested. Reliability assessment used internal consistency and inter-rater reliability and construct validity used known-group comparisons and a priori hypotheses on correlations with Brief Symptom Inventory, Short Form-12, and Distress Thermometer. Eighty-four participants (63.1% women; mean age 59.8, SD 14.4) were included. Structural validity assessment confirmed the unidimensional structure of ZBI-7 both in CFA and Rasch analysis. The item on overall burden was the best item for the ultra-short version ZBI-1. Higher burden was recorded for women and those with poorer physical health. Internal consistency was good (Cronbach's α = 0.83). Inter-rater reliability was moderate as proxy ratings estimated caregivers' burden higher than self-ratings (average measures ICC = 0.51; CI = 0.23-.69; p = 0.001). The ZBI-7 is a valid instrument for measuring caregiver burden in PC. The ultra-short ZBI-1 can be used as a quick and proxy assessment, with the caveat of overestimating burden.


Novel tissue-derived biomimetic scaffold for regenerating the human nucleus pulposus.
Numerous scaffold formulations have been investigated to support the regeneration of nucleus pulposus (NP) tissue for use as an early-stage therapy for intervertebral disc degeneration. Particular attention has focused on recreating the biochemical and mechanical properties of the native NP via the incorporation of exogenous extracellular matrix (ECM) components or synthetic surrogates. In the present study, we describe a novel approach to develop a tissue engineering (TE) scaffold comprised acellular porcine NP ECM. Complete decellularization of porcine NP was successfully achieved using a combination of chemical detergents, ultrasonication, and treatment with nucleases. Resulting NP scaffolds were devoid of host-cell remnants and the porcine antigen alpha-Gal. Native NP ECM components including aggrecan/chondroitin-6-sulfate and collagens types II, IX, and XI were found in physiologically relevant ratios within the NP scaffold. NP scaffold swelling capacity and unconfined mechanical properties were not significantly different from porcine NP tissue. Furthermore, NP scaffolds were conducive to repopulation with human adipose-derived stem cells as cell viability and proliferative capacity were maintained. These results demonstrate the successful decellularization of porcine NP and the resultant formation of a biomimetic scaffold exhibiting potential utility for TE the human NP.


Paediatric procedural sedation and analgesia by emergency physicians in a country with a recent establishment of emergency medicine.
Paediatric patients receive less procedural sedation and analgesia (PSA) in the emergency department compared with adults, especially in countries where emergency medicine is at an early stage of development. The objectives of this study were to evaluate the adverse events and efficacy of paediatric PSA in a country with a recent establishment of emergency medicine and to describe which factors aided implementation. This is a prospective, multicentre, observational study of paediatric patients undergoing PSA by the first trained emergency physicians (EPs) in The Netherlands. A standardized data collection form was used at all participating hospitals to collect data on adverse events, amnesia, pain scores, and procedure completion. A survey was used to interpret which factors had aided PSA implementation. We recorded 351 paediatric PSA. The mean age was 9.5 years (95% confidence interval: 9.1-10.0). Esketamine was most frequently used (42.4%), followed by propofol (34.7%). The adverse event rate was low (3.0%). Amnesia was present in 86.8%. The median pain score was 2 (out of 10) for patients without amnesia. Procedures were successfully completed in 93.9% of the cases. Paediatric PSA provided by the first EPs in The Netherlands showed appropriate levels of sedation and analgesia with a high rate of procedure completion and a low rate of adverse events. Our paper suggests that EPs provided with a proper infrastructure of mentorship, training and guidelines can implement effective paediatric PSA.


The origin and dynamic evolution of chemical information transfer.
Although chemical communication is the most widespread form of communication, its evolution and diversity are not well understood. By integrating studies of a wide range of terrestrial plants and animals, we show that many chemicals are emitted, which can unintentionally provide information (cues) and, therefore, act as direct precursors for the evolution of intentional communication (signals). Depending on the content, design and the original function of the cue, there are predictable ways that selection can enhance the communicative function of chemicals. We review recent progress on how efficacy-based selection by receivers leads to distinct evolutionary trajectories of chemical communication. Because the original function of a cue may channel but also constrain the evolution of functional communication, we show that a broad perspective on multiple selective pressures acting upon chemicals provides important insights into the origin and dynamic evolution of chemical information transfer. Finally, we argue that integrating chemical ecology into communication theory may significantly enhance our understanding of the evolution, the design and the content of signals in general.


DRG Voltage-Gated Sodium Channel 1.7 Is Upregulated in Paclitaxel-Induced Neuropathy in Rats and in Humans with Neuropathic Pain.
Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect experienced by cancer patients receiving treatment with paclitaxel. The voltage-gated sodium channel 1.7 (Nav1.7) plays an important role in multiple preclinical models of neuropathic pain and in inherited human pain phenotypes, and its gene expression is increased in dorsal root ganglia (DRGs) of paclitaxel-treated rats. Hence, the potential of change in the expression and function of Nav1.7 protein in DRGs from male rats with paclitaxel-related CIPN and from male and female humans with cancer-related neuropathic pain was tested here. Double immunofluorescence in CIPN rats showed that Nav1.7 was upregulated in small DRG neuron somata, especially those also expressing calcitonin gene-related peptide (CGRP), and in central processes of these cells in the superficial spinal dorsal horn. Whole-cell patch-clamp recordings in rat DRG neurons revealed that paclitaxel induced an enhancement of ProTx II (a selective Nav1.7 channel blocker)-sensitive sodium currents. Bath-applied ProTx II suppressed spontaneous action potentials in DRG neurons occurring in rats with CIPN, while intrathecal injection of ProTx II significantly attenuated behavioral signs of CIPN. Complementarily, DRG neurons isolated from segments where patients had a history of neuropathic pain also showed electrophysiological and immunofluorescence results indicating an increased expression of Nav1.7 associated with spontaneous activity. Nav1.7 was also colocalized in human cells expressing transient receptor potential vanilloid 1 and CGRP. Furthermore, ProTx II decreased firing frequency in human DRGs with spontaneous action potentials. This study suggests that Nav1.7 may provide a potential new target for the treatment of neuropathic pain, including chemotherapy (paclitaxel)-induced neuropathic pain.SIGNIFICANCE STATEMENT This work demonstrates that the expression and function of the voltage-gated sodium channel Nav1.7 are increased in a preclinical model of chemotherapy-induced peripheral neuropathy (CIPN), the most common treatment-limiting side effect of all the most common anticancer therapies. This is key as gain-of-function mutations in human Nav1.7 recapitulate both the distribution and pain percept as shown by CIPN patients. This work also shows that Nav1.7 is increased in human DRG neurons only in dermatomes where patients are experiencing acquired neuropathic pain symptoms. This work therefore has major translational impact, indicating an important novel therapeutic avenue for neuropathic pain as a class.


Dynamic study of supratentorial gliomas with L-methyl-11C-methionine and positron emission tomography.
The regional kinetics of intravenously injected L-methyl-11C-methionine (11C-L-methionine) in the brain was investigated by positron emission tomography (PET) in 14 patients with gliomas. In both tumor and unaffected brain the tracer uptake reached a nearly constant level in 5 min or less. The ratio between the uptake of 11C-L-methionine by high-grade tumors and the uptake by unaffected brain was 1.9-4.8. In two cases of low-grade astrocytoma the ratio was 0.8-1.0. High uptakes of 11C-L-methionine occurred in gliomas even in the absence of blood-brain barrier defects as observed by other methods. This indicates that besides active transport of amino acid, a larger extracellular space in tumor as compared with unaffected brain tissue may also contribute to the increased uptake of 11C-L-methionine--derived radioactivity. In some patients delineation of the tumors was improved by use of PET with 11C-L-methionine as compared with computed tomography, angiography, and, in some instances, PET with 68Ga-EDTA. PET with 11C-L-methionine permits better evaluation of the tumor extent and may affect preoperative grading.


Study of Hepatitis E Virus-4 Infection in Human Liver-Chimeric, Immunodeficient, and Immunocompetent Mice.
The hepatitis E virus (HEV) is responsible for 20 million infections worldwide per year. Although, HEV infection is mostly self-limiting, immunocompromised individuals may evolve toward chronicity. The lack of an efficient small animal model has hampered the study of HEV and the discovery of anti-HEV therapies. Furthermore, new HEV strains, infectious to humans, are being discovered. Human liver-chimeric mice have greatly aided in the understanding of HEV, but only two genotypes (HEV-1 and HEV-3) have been studied in this model. Moreover, the immunodeficient nature of this mouse model does not allow full investigation of the virus and all aspects of its interaction with the host. Recent studies have shown the susceptibility of regular and nude Balb/c mice to a HEV-4 strain (KM01). This model should allow the investigation of the interplay between HEV and the adaptive immune system of its host, and potential immune-mediated complications. Here, we assess the susceptibility of human liver-chimeric and non-humanised mice to a different HEV-4 strain (BeSW67HEV4-2008). We report that humanised mice could be readily infected with this isolate, resulting in an infection pattern comparable to HEV-3 infection. Despite these results and in contrast to KM01, non-humanised mice were not susceptible to infection with this viral strain. Further investigation, using other HEV-4 isolates, is needed to conclusively determine HEV-4 tropism and mouse susceptibility.


Anti-diabetic activity of canophyllol from Cratoxylum cochinchinense (Lour.) Blume in type 2 diabetic mice by activation of AMP-activated kinase and regulation of PPARγ.
In the present study, the potential anti-diabetic activity of canophyllol (CNPL) and its mechanisms were investigated in vitro and in vivo. CNPL is a predominant friedelane-type triterpene extracted from young leaves of Cratoxylum cochinchinense ("Huang Niu Tea"). In vitro, CNPL increased GLUT4 translation in a L6-myotube model to 2.60-fold, and glucose uptake to 1.71-fold levels relative to untreated L6 myotubes. Moreover, compound C, an inhibitor of AMP-activated protein kinase (AMPK), completely suppressed the CNPL-induced GLUT4 translocation. In vivo, serum insulin levels, hyperglycemia, as well as other blood indexes of the KK-Ay diabetic mice were improved by a four-week oral administration of CNPL. Examination of its possible anti-diabetic mechanism showed that CNPL promoted the expression of p-AMPKα and GLUT4 in L6 myotubes. In KK-Ay mice treated with CNPL, GLUT4 expression was increased in skeletal muscle and white adipose tissue, and the levels of p-AMPKα were increased in the liver, skeletal muscle and white adipose tissue. Moreover, CNPL stimulated the expression of PPARγ to decrease and inhibited the activity of ACC by stimulating its phosphorylation in both liver and white adipose tissue, thereby indicating that CNPL also improved lipid metabolism disorders. Altogether, these results show that CNPL may improve glucose tolerance, reduce hyperglycemia, normalize insulin secretion, and ameliorate lipid metabolism disorders. The diverse anti-diabetic effects of CNPL may be attributed to the regulation of GLUT4, PPARγ, AMPK phosphorylation and ACC phosphorylation.


A novel microtubule-associated protein from mammalian nerve shows ATP-sensitive binding to microtubules.
We report the isolation of a protein from mammalian nerve which shows ATP-sensitive binding to microtubules and ATPase activity. This protein, which we have designated HMW4, was prepared from bovine spinal nerve roots by microtubule affinity and ATP-induced release, and was further purified by sucrose density gradient centrifugation. It is a high molecular weight protein with a denatured Mr of 315,000, a Stokes radius of 90 A, and a sedimentation value of approximately 19S. It can be resolved electrophoretically from the well-characterized bovine brain microtubule-associated proteins (MAPs) and also appears to be distinct from MAP 1C. HMW4 has a vanadate-sensitive and azide-insensitive ATPase activity which averages 20 nmol Pi/min per mg protein and is different from dynein and myosin ATPases. HMW4 prepared on sucrose gradients exhibits binding to MAP-free microtubules in the absence of ATP which is reduced by ATP addition. Assayed by darkfield microscopy, HMW4 causes bundling of MAP-free microtubules which is reversed by ATP addition.


Low-dose estradiol spray: a novel treatment for vasomotor instability in postmenopausal women.
This article describes a novel transdermal estradiol spray developed for the treatment of menopausal vasomotor instability. The spray delivers estradiol directly into the subcutaneous microcirculation achieving the advantages of estradiol patches, creams and gels but with minimal skin reaction, patient inconvenience or cosmetic shortcomings associated with transdermal methods. In the one published Phase III clinical trial, postmenopausal women (n = 454) with eight or more moderate-to-severe hot flashes per day applied each morning, one, two or three estradiol 90 microl sprays (each containing estradiol 1.53 mg) versus matching placebo sprays. There was a significant decrease in hot flash frequency and intensity at weeks 4 and 12 compared with corresponding placebo groups (p < 0.010). The systemic estradiol delivery rates at week 12 were approximately 0.021, 0.029 and 0.040 mg/day for the 1-, 2- and 3-spray doses, respectively. There were common adverse events similar to those previously reported with transdermal estradiol, except for skin irritation, which was very low. The spray is a well-tolerated, cosmetically attractive and convenient method of delivering low-dose, transdermal estradiol.


Cortical tuber count: a biomarker indicating neurologic severity of tuberous sclerosis complex.
The relationship between the number of cortical tubers observed by magnetic resonance imaging (MRI) and the severity of cerebral dysfunction of tuberous sclerosis patients has been examined in a meta-analysis of the published literature. The literature review has identified five independent studies for examining the association. These studies consistently reveal that the cortical tuber count detected on MRI scans is increased among those with more severe cerebral disease. Severity of the cerebral dysfunction is measured by the seizure status and its control and by the developmental status and the level of mental retardation. Meta-analysis demonstrates that within a study population, the MRI-detected cortical tuber count is six times more likely to be above the median count for tuberous sclerosis patients with severe cerebral dysfunction (poor seizure control or moderate-severe retardation or both) than more mildly affected tuberous sclerosis patients. Similarly, across studies, moderately to severely affected patients are five times more likely to have greater than seven MRI-detected cortical tubers than those more mildly affected. These associations are both statistically significant and strong. The cortical tuber count is a biomarker that reasonably predicts the severity of cerebral dysfunction of tuberous sclerosis. Cortical tubers of tuberous sclerosis form in the early gestational period. The embryologic disruption determining the clinical severity of the cortical dysfunction of tuberous sclerosis is set in the early gestational period.


[Analysis and classification of hospital emergencies through Ambulatory Patient Groups].
To assess the feasibility and results of application of Ambulatory Patient Groups (APG) patient's classification system to the case-mix of patients seen at the Emergency Departments (ED) of 6 Barcelona metropolitan area hospitals. Development of a minimum discharge data set specific for the Emergency Departments (CMBDAU). Gathering of relevant variables from a random sample of patients seen at the ED using the ED discharge reports. Use of the APG classification system to those episodes. A total of 11.188 episodes were codified and grouped with the APG system. Fifteen diagnostics identified 25% of all episodes. Nearly 50% of all procedures performed at the ED were common and simple procedures. Fifteen APG's grouped 50% of all cases seen at the ED. The ED Uniform Discharge Data Set (CMBDAU) developed is a valid instrument for describing the case-mix seen at the ED, and its grouping by means of the APG system provides consistent and meaningful results. The widespread use of systems like APG in the ED requires a former validation of relative weights assigned in the US system. The availability of human and technical resources must also be assessed, in order to guarantee the quality and sustainability of such a system.


Experiences in anti-tuberculosis treatment in patients with multiple previous treatments and its impact on drug resistant tuberculosis epidemics.
Tuberculosis (TB) patients with a history of multiple anti-TB treatments are the 'neglected' group to the free anti-TB treatment policy in China. To understand the experiences of TB patients with multiple previous treatments with regard to bacteriological diagnosis and treatment regimens, especially for second-line anti-TB drugs, and how this might influence the risks of multidrug and extensively drug-resistant TB (M/XDR-TB). A cross-sectional study was conducted in 10 county/district TB clinics in five provinces of China. The study participants were TB patients that had at least two previous treatment episodes that lasted longer than 1 month each. Face-to-face interviews and drug susceptibility testing (DST) were conducted with the consenting participants. A total of 328 TB patients were recruited. The proportion of multidrug-resistant tuberculosis (MDR-TB) was 58.2% in the 287 DST-confirmed patients. Forty-two percent of the patients did not complete their first treatment course. About 23.8% of the participants had a history of taking second-line drugs, and more than 77.8% of them were treated in county TB dispensaries where only sputum microscopy was applied. Multivariate analysis found that the use of second-line drugs was significantly associated with frequency of previous treatments (p<0.01), but not with drug resistance profiles of patients. Patients with multiple previous treatments are at extremely high risk of MDR-TB in China. The unregulated use of second-line drugs bring about the threat of XDR-TB epidemic. DST-guided treatment and strict regulations of anti-TB treatment should be assured for the high-risk TB patients for the prevention and control of M/XDR-TB.


Is Structured Exercise Performed with Supplemental Oxygen a Promising Method of Personalized Medicine in the Therapy of Chronic Diseases?
This systematic review aimed to explore the literature to identify in which types of chronic diseases exercise with supplemental oxygen has previously been utilized and whether this type of personalized therapy leads to superior effects in physical fitness and well-being. Methods: Databases (PubMed/MEDLINE, CINHAL, EMBASE, Web of knowledge and Cochrane Library) were searched in accordance with PRISMA. Eligibility criteria included adult patients diagnosed with any type of chronic diseases engaging in supervised exercise training with supplemental oxygen compared to normoxia. A random-effects model was used to pool effect sizes by standardized mean differences (SMD). Results: Out of the identified 4038 studies, 12 articles were eligible. Eleven studies were conducted in chronic obstructive pulmonary disease (COPD), while one study included coronary artery disease (CAD) patients. No statistical differences were observed for markers of physical fitness and patient-reported outcomes on well-being between the two training conditions (SMD -0.10; 95% CI -0.27, 0.08; p = 0.26). Conclusions: We found that chronic exercise with supplemental oxygen has mainly been utilized for COPD patients. Moreover, no superior long-term adaptations on physical fitness, functional capacity or patient-reported well-being were found, questioning the role of this method as a personalized medicine approach. Prospero registration: CRD42018104649.


Increased salt- and nisin-sensitivity of pressure-injured bioluminescent Listeria monocytogenes.
Suspensions of a bioluminescent (luxAB) transformant of Listeria monocytogenes in pH 7.0 phosphate buffer were pressurised and the effect of the pressure treatment was monitored by plate counting. When the bacteria were suspended in NaCl- and nisin-free buffer the number of colony forming units (CFU) decreased by 3 and 6 log cycles after 300 MPA for 10 and 30 min, respectively. Supplementing the plating medium with 5% NaCl did not influence the colony forming capacity of non-pressurised cells, however, CFU of residual populations after respective treatments of 300 MPa for 10 and 30 min were reduced by a further 2 and 3.5 log cycles in case of salt containing plates. Nisin-addition to the plating medium caused less than one log unit decrease in the CFU of the non-pressurised population. However, the CFU of 10 min-pressurised sample was 4 log cycles less in the nisin-containing plates than in the nisin-free ones, whereas no colonies were formed in the nisin-containing plates even when 1 ml was inoculated from the originally 10(10) CFU/ml population after 300 MPa for 30 min. The luciferase activities (bioluminescence intensities) decreased concomitant with the reduction of the viable cell counts, however, they were approx. 0.6-0.8 log units less in the presence of 5% NaCl in the pressurised suspension than those expected from the previously established linear correlation between the logarithmic light outputs and the logarithmic viable cell counts.


Acute Eosinophilic Pneumonia. Causes, Diagnosis, and Management.
Acute eosinophilic pneumonia (AEP) is an uncommon acute respiratory illness of varying severity that includes presentation as acute respiratory distress syndrome with fatal outcome. AEP may be idiopathic, but identifiable causes include smoking and other inhalational exposures, medications, and infections. The pathogenesis of AEP is poorly understood but likely varies depending on the underlying cause. Airway epithelial injury, endothelial injury, and release of IL-33 are early events that subsequently promote eosinophil recruitment to the lung; eosinophilic infiltration and degranulation appear to mediate subsequent lung inflammation and associated clinical manifestations. Crucial for the diagnosis are the demonstration of pulmonary eosinophilia in the BAL fluid and the exclusion of other disease processes that can present with acute pulmonary infiltrates. Although peripheral blood eosinophilia at initial presentation may be a clue in suggesting the diagnosis of AEP, it may be absent or delayed, especially in smoking-related AEP. Optimal management of AEP depends on the recognition and elimination of the underlying cause when identifiable. The cessation of the exposure to the inciting agent (e.g., smoking), and glucocorticoids represent the mainstay of treating AEP of noninfectious origin. If AEP is recognized and treated in a timely manner, the prognosis is generally excellent, with prompt and complete clinical recovery, even in those patients manifesting acute respiratory failure.


Ferrihydrite nanoparticles insights: Structural characterization, lactate dehydrogenase binding and virtual screening assay.
The binding between the enzyme lactate dehydrogenase (LDH) and ferrihydrite nanoparticles (Fh-NPs) was investigated by means of small-angle neutron scattering (SANS), Fourier-transform infrared (FTIR) spectroscopy, fluorescence and Förster resonance energy transfer (FRET) and molecular docking. Fh-NPs - LDH compounds of dimensions under 100 nm are formed. The conformational changes and the mechanism of interaction between LDH and Fh-NPs simple and doped with Cu and Co, and the effect of these NPs on the thermal denaturation of LDH were monitored. The quenching mechanism is static, the binding occurring with moderate affinity, being mainly driven by hydrogen bonding and van der Waals forces. FRET occurs at a minimal distance of 2.55 nm. Thermal denaturation of LDH in the presence of simple and doped Fh-NPs shows that the thermodynamic parameters of protein unfolding are significantly changed with temperature. The denaturation temperature of LDH shifts to higher values in the presence of all Fh-NPs, than in the case of simple LDH. The docking approach estimates the energy corresponding to the best fit of the ferrihydrite in the LDH binding site near Trp. These results have direct implications on the uses of the complex of LDH with Fh-NPs in various biochemical, biological, or clinical applications.


Stroke Risk Stratification and its Validation using Ultrasonic Echolucent Carotid Wall Plaque Morphology: A Machine Learning Paradigm.
Stroke risk stratification based on grayscale morphology of the ultrasound carotid wall has recently been shown to have a promise in classification of high risk versus low risk plaque or symptomatic versus asymptomatic plaques. In previous studies, this stratification has been mainly based on analysis of the far wall of the carotid artery. Due to the multifocal nature of atherosclerotic disease, the plaque growth is not restricted to the far wall alone. This paper presents a new approach for stroke risk assessment by integrating assessment of both the near and far walls of the carotid artery using grayscale morphology of the plaque. Further, this paper presents a scientific validation system for stroke risk assessment. Both these innovations have never been presented before. The methodology consists of an automated segmentation system of the near wall and far wall regions in grayscale carotid B-mode ultrasound scans. Sixteen grayscale texture features are computed, and fed into the machine learning system. The training system utilizes the lumen diameter to create ground truth labels for the stratification of stroke risk. The cross-validation procedure is adapted in order to obtain the machine learning testing classification accuracy through the use of three sets of partition protocols: (5, 10, and Jack Knife). The mean classification accuracy over all the sets of partition protocols for the automated system in the far and near walls is 95.08% and 93.47%, respectively. The corresponding accuracies for the manual system are 94.06% and 92.02%, respectively. The precision of merit of the automated machine learning system when compared against manual risk assessment system are 98.05% and 97.53% for the far and near walls, respectively. The ROC of the risk assessment system for the far and near walls is close to 1.0 demonstrating high accuracy.


[Spontaneous and induced permeability of the tight junctions in the bladder epithelium of the frog Rana temporaria].
The spontaneous and induced alterations in paracellular permeability of the isolated frog urinary bladder were studied. For estimation of the tight junction (TJ) permeability, a fluorescent dye uranine was used. No morphological or functional evidences for the TJ opening were found in the autumn-winter period, both in the control and after the osmotic flow stimulation by 25 mg/ml pituitrine (P) or serosal mannitol (200 mM). In the spring, a spontaneous uranine efflux through the bladder wall from the mucosal solution was found in parallel with an increase in the basal water flow and a decrease in the responses of the bladder to P and serosal hypertonicity. At the same time, the intercellular substance remained to be a barrier for water. In the autumn-winter the TJ opening could be induced by adding sulfhydryl reagents, p-chloromercury-phenyl-sulfonic acid (PCMPS) or N-ethylmaleimide (NEM), to the serosal solution. However, NEM was effective only when added to the mucosal solution. The uranine efflux induced by sulfhydryl reagents was accompanied with a marked hydroosmotic flow in parallel with a diminished sensitivity to P, the barrier properties of intercellular substances were lost. As evidenced by electron microscopy, PCMPS induced a gradual destruction of TJ structures, while certain cytoplasmic structures were not affected. The uranine efflux in the autumn-winter frogs could be induced by an artificial osmotic gradient after preincubation of the bladders in the isotonic solution with P. Some possible intracellular mechanisms causing both spontaneous and induced alterations in the TJ permeability are discussed.


Reviewing and Content Analysis of Persian Language Mobile Health Apps for COVID-19 Management.
The present study aimed to systematically search in app stores and intended to carry out content analysis of free Persian mobile health apps in the management of COVID-19 and, ultimately determine the relationship between the popularity and quality of these apps. According to a researcher-made checklist including five axes of ease of use, privacy, data sharing, education, and monitoring, four app markets such as Myket, Bazzar, Google Play and App Store were searched from May 2021 up to now. The findings showed that all selected apps performed well in terms of ease of use and privacy but they needed to be improved in terms of education, monitoring, and data sharing. Also, there was no significant relationship between the popularity and quality of these apps. Owing to the high penetration rate of smartphones in Iran and the low popularity of COVID-19 apps, government, developers, and investors are required to improve the quality of apps and their marketing.


Evaluation of the comorbidity burden in patients with ankylosing spondylitis using a large US administrative claims data set.
Comorbidities among US patients with ankylosing spondylitis (AS) are inadequately understood. This study compared the prevalence and incidence of comorbidities between patients with AS and matched controls using national claims databases. Adults enrolled in the MarketScan Commercial and Medicare databases with ≥ 1 inpatient or ≥ 2 non-rule-out outpatient diagnoses of AS between January 1, 2012 and December 31, 2014 were included. Patients had to have ≥ 1 AS diagnosis in 2013; the first AS diagnosis in 2013 was assigned as the index date. Control patients without AS were matched to AS patients on age, geographic region, index calendar year, and sex. Comorbidities were evaluated in AS patients and matched controls during the baseline and follow-up periods (before and after the index date, respectively). Hazard ratios of developing new comorbidities were estimated using Cox proportional hazard models adjusted for patients' characteristics. A total of 6679 patients with AS were matched to 19,951 control patients. In addition to extra-articular manifestations of AS (inflammatory bowel disease [IBD], psoriasis, uveitis), a higher proportion of AS patients had asthma, cardiovascular disease, depression, dyslipidemia, gastrointestinal ulcers, malignancies, multiple sclerosis, osteoporosis, sleep apnea, and spinal fractures during the baseline period than matched controls. After AS diagnosis, a higher proportion of patients developed newly diagnosed cases of cardiovascular diseases, depression, osteoporosis, spinal fracture, IBD, psoriasis, and uveitis than matched controls. In this real-world, US claims-based study, patients with AS were shown to have significantly more comorbidities than matched controls.


Effectiveness of regular weighing, weight target setting and feedback by community midwives within routine antenatal care in preventing excessive gestational weight gain: randomised controlled trial.
Many pregnant women gain excess weight during pregnancy which increases the health risks to the mother and her baby. Interventions to prevent excess weight gain need to be given to the whole population to prevent excess weight gain. The aim of this study was to assess the effectiveness of a simple and brief intervention embedded withinroutine antenatal care to prevent excessive gestation weight gain. Six hundred and ten pregnant women (between 10-14 weeks gestation), aged ≥18 years with a body mass index (BMI) ≥18.5 kg/m2, planned to receive community midwife led care or shared care at the time of recruitment are eligible to take part in the study. Women will be recruited from four maternity centres in England. Community midwives complete a short training module before delivering the intervention. In the intervention, midwives weigh women, set maximum weight limits for weight gain at each antenatal appointment and ask women to monitor their weight at home. Themaximum weight limit is adjusted by the midwife at each antenatal appointment if women have exceeded their maximum weight gain limit set at their previous appointment. The intervention will be compared with usual antenatal care. The primary outcome is the proportion of women per group who exceed the Institute of Medicine guidelines for gestational weight gain at 38 weeks of pregnancy according to their early pregnancy BMI category. The proposed trial will test a brief intervention comprising regular weighing, target setting and monitoring ofweight during pregnancy that can be delivered at scale as part of routine antenatal care. Using the professional expertise of community midwives, but without specialist training in weight management, the intervention will incur minimal additionalhealthcare costs, and if effective at reducing excess weight gain, is likely to be very cost effective. Current controlled trials ISRCTN67427351. Date assigned 29/10/2014.


Serotyping of adenoviruses on conjunctival scrapings by PCR and sequence analysis.
To detect and identify adenovirus (Ad), we investigated hypervariable regions (HVRs) of Ad by using a combination of PCR and direct sequencing (PCR-sequence) method. Primers for nested PCR to amplify the conserved region in the hexon protein containing HVRs were designed based on hexon gene sequences derived from GenBank. These two primer sets amplified a DNA fragment of 7 HVRs from 16 prototypes of Ad, which were divided into five subgenera, including seven serotypes that are the predominant causative agents of acute conjunctivitis in Japan, and from 31 recent conjunctival scraping specimens from patients with adenoviral conjunctivitis. HVR DNA sequences were determined by means of universal sequence primers. Analysis of the predicted amino acid homology of HVRs among Ad prototypes suggested three regions, HVR4, -5, and -7, to be candidates for the neutralization epitopes. The clinical serotype of specimens was determined by the PCR-sequence method with reference to these three HVRs. The serotype determined according to this method was identical to that obtained by culture isolation and the neutralization test (NT) in all scraping samples, whereas the results of this method did not match PCR and restriction fragment length polymorphism (PCR-RFLP) analysis in five samples. It took only three days to detect Ad and to identify the serotype, in contrast to culture isolation-NT, which took at least 2 weeks. These findings indicate that our newly developed PCR-sequence method is applicable for the detection and serotyping of human Ads.


Characterization of immune cell subsets during the active phase of multiple sclerosis reveals disease and c-Jun N-terminal kinase pathway biomarkers.
Autoimmune activation and deregulated apoptosis of T lymphocytes are involved in multiple sclerosis (MS). c-Jun N-terminal kinase (JNK) plays a role in T-cell survival and apoptosis. The aim of this work was to investigate the role of the JNK-dependent apoptosis pathway in relapsing-remitting MS (RRMS). The immunomodulatory effect of AS602801, a JNK inhibitor, was firstly evaluated on activated peripheral blood mononuclear cells (PBMCs) from healthy volunteers (HVs) and secondly in unstimulated purified CD4+, CD8+ and CD11b+ cells from RRMS patients and HVs. Moreover JNK/inflammation/apoptosis related genes were investigated in RRMS and HV samples. In activated PBMCs from HVs, we showed that AS602801 blocked T-lymphocyte proliferation and induced apoptosis. In RRMS CD4+ and CD8+ cells, AS602801 induced apoptosis genes and expression of surface markers, while in RRMS CD11b+ cells it induced expression of innate immunity receptors and co-stimulatory molecules. Untreated cells from RRMS active-phase patients significantly released interleukin-23 (IL-23) and interferon-gamma (IFN-γ) and expressed less apoptosis markers compared to the cells of HVs. Moreover, gene expression was significantly different in cells from RRMS active-phase patients vs. HVs. By comparing RRMS PBMCs in the active and stable phases, a specific genomic signature for RRMS was indentified. Additionally, CASP8AP2, CD36, ITGAL, NUMB, OLR1, PIAS-1, RNASEL, RTN4RL2 and THBS1 were identified for the first time as being associated to the active phase of RRMS. The analysis of the JNK-dependent apoptosis pathway can provide biomarkers for activated lymphocytes in the active phase of RRMS and a gene expression signature for disease status. The reported results might be useful to stratify patients, thereby supporting the development of novel therapies.


Facilitated dynamics of an active polymer in 2D crowded environments with obstacles.
Understanding the behaviors of a single active chain in complex environments is not only an interesting topic in non-equilibrium physics but also has applicative implications in biological/medical engineering. In this work, by using molecular simulations, we systematically study the dynamical and conformational behaviors of an active polymer in crowded environments, i.e., a single active chain confined in 2D space with randomly arranged obstacles. We found that the competition between the chain's activity and rigidity in the presence of obstacles leads to many interesting dynamical and conformational states, such as the diffusive expanded state, the diffusive collapsed state, and the localized collapsed state. Importantly, we found a counter-intuitive phenomenon, i.e., crowded environments facilitate the diffusion of the active polymer within a large parameter space. As the crowdedness (packing fraction of obstacles) increases, the parameter space in which crowding-enhanced diffusion occurs still remains. This abnormal dynamics is attributed to a structural reason that the obstacles prevent active chains from collapsing. Our findings capture some generic features of active polymers in complex environments and provide insights into the design of novel drug delivery systems.


Photonic Circuits with Time Delays and Quantum Feedback.
We study the dynamics of photonic quantum circuits consisting of nodes coupled by quantum channels. We are interested in the regime where the time delay in communication between the nodes is significant. This includes the problem of quantum feedback, where a quantum signal is fed back on a system with a time delay. We develop a matrix product state approach to solve the quantum stochastic Schrödinger equation with time delays, which accounts in an efficient way for the entanglement of nodes with the stream of emitted photons in the waveguide, and thus the non-Markovian character of the dynamics. We illustrate this approach with two paradigmatic quantum optical examples: two coherently driven distant atoms coupled to a photonic waveguide with a time delay, and a driven atom coupled to its own output field with a time delay as an instance of a quantum feedback problem.


Photon upconversion in supramolecular gel matrixes: spontaneous accumulation of light-harvesting donor-acceptor arrays in nanofibers and acquired air stability.
Efficient triplet-triplet annihilation (TTA)-based photon upconversion (UC) is achieved in supramolecular organogel matrixes. Intense UC emission was observed from donor (sensitizer)-acceptor (emitter) pairs in organogels even under air-saturated condition, which solved a major problem: deactivation of excited triplet states and TTA-UC by molecular oxygen. These unique TTA-UC molecular systems were formed by spontaneous accumulation of donor and acceptor molecules in the gel nanofibers which are stabilized by developed hydrogen bond networks. These molecules preorganized in nanofibers showed efficient transfer and migration of triplet energy, as revealed by a series of spectroscopic, microscopic, and rheological characterizations. Surprisingly, the donor and acceptor molecules incorporated in nanofibers are significantly protected from the quenching action of dissolved molecular oxygen, indicating very low solubility of oxygen to nanofibers. In addition, efficient TTA-UC is achieved even under excitation power lower than the solar irradiance. These observations clearly unveil the adaptive feature of host gel nanofiber networks that allows efficient and cooperative inclusion of donor-acceptor molecules while maintaining their structural integrity. As evidence, thermally induced reversible assembly/disassembly of supramolecular gel networks lead to reversible modulation of the UC emission intensity. Moreover, the air-stable TTA-UC in supramolecular gel nanofibers was generally observed for a wide combination of donor-acceptor pairs which enabled near IR-to-yellow, red-to-cyan, green-to-blue, and blue-to-UV wavelength conversions. These findings provide a new perspective of air-stable TTA-UC molecular systems; spontaneous and adaptive accumulation of donor and acceptor molecules in oxygen-blocking, self-assembled nanomatrixes. The oxygen-barrier property of l-glutamate-derived organogel nanofibers has been unveiled for the first time, which could find many applications in stabilizing air-sensitive species in aerated systems.


Exploring the minimally frustrated energy landscape of unfolded ACBP.
The unfolded state of globular proteins is not well described by a simple statistical coil due to residual structural features, such as secondary structure or transiently formed long-range contacts. The principle of minimal frustration predicts that the unfolded ensemble is biased toward productive regions in the conformational space determined by the native structure. Transient long-range contacts, both native-like and non-native-like, have previously been shown to be present in the unfolded state of the four-helix-bundle protein acyl co-enzyme binding protein (ACBP) as seen from both perturbations in nuclear magnetic resonance (NMR) chemical shifts and structural ensembles generated from NMR paramagnetic relaxation data. To study the nature of the contacts in detail, we used paramagnetic NMR relaxation enhancements, in combination with single-point mutations, to obtain distance constraints for the acid-unfolded ensemble of ACBP. We show that, even in the acid-unfolded state, long-range contacts are specific in nature and single-point mutations affect the free-energy landscape of the unfolded protein. Using this approach, we were able to map out concerted, interconnected, and productive long-range contacts. The correlation between the native-state stability and compactness of the denatured state provides further evidence for native-like contact formation in the denatured state. Overall, these results imply that, even in the earliest stages of folding, ACBP dynamics are governed by native-like contacts on a minimally frustrated energy landscape.


Physical optimization of quantum error correction circuits with spatially separated quantum dot spins.
We propose an efficient protocol for optimizing the physical implementation of three-qubit quantum error correction with spatially separated quantum dot spins via virtual-photon-induced process. In the protocol, each quantum dot is trapped in an individual cavity and each two cavities are connected by an optical fiber. We propose the optimal quantum circuits and describe the physical implementation for correcting both the bit flip and phase flip errors by applying a series of one-bit unitary rotation gates and two-bit quantum iSWAP gates that are produced by the long-range interaction between two distributed quantum dot spins mediated by the vacuum fields of the fiber and cavity. The protocol opens promising perspectives for long distance quantum communication and distributed quantum computation networks.


A review of Cloud computing technologies for comprehensive microRNA analyses.
Cloud computing revolutionized many fields that require ample computational power. Cloud platforms may also provide huge support for microRNA analysis mainly through disclosing scalable resources of different types. In Clouds, these resources are available as services, which simplifies their allocation and releasing. This feature is especially useful during the analysis of large volumes of data, like the one produced by next generation sequencing experiments, which require not only extended storage space but also a distributed computing environment. In this paper, we show which of the Cloud properties and service models can be especially beneficial for microRNA analysis. We also explain the most useful services of the Cloud (including storage space, computational power, web application hosting, machine learning models, and Big Data frameworks) that can be used for microRNA analysis. At the same time, we review several solutions for microRNA and show that the utilization of the Cloud in this field is still weak, but can increase in the future when the awareness of their applicability grows.


Importance of the heart borders as a fluoroscopic clue for cardiac tamponade.
Every catheter laboratory is equipped with an X-ray system designed to provide fluoroscopic imaging of the heart. Although cardiac catheters are well visualized in all X-ray imaging, the soft tissue of myocardium is not. Therefore the imaging of the cardiac chambers is indirect through relation to the cardiac silhouette. However, fluoroscopy can be used to detect complications from the invasive procedures in the cardiac catheterization laboratory, such as cardiac tamponade where the excursion of the cardiac silhouette decreases, and visceral and parietal pericardium are seen separated by the blood of accumulation in the pericardial cavity. Even if a transthoracic or intracardiac echocardiography guidance is immediately available, early fluoroscopic detection of tamponade should be remembered during the invasive procedures in the cardiac catheterization laboratory.


Laparoscopic Appendectomy in Children With Perforated Appendicitis: A Meta-Analysis.
The purpose of this meta-analysis was to compare the influence of different surgical procedures on perforated appendicitis in pediatric population. Studies were identified through a computerized literature search of Pubmed, Embase, Ovid, the Cochrane Colorectal Cancer Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials, the Cochrane Library database, and Web of Science. Two reviewers independently assessed the quality of each study and abstracted outcome data. Data were extracted comparing laparoscopic appendectomy (LA) and open appendectomy (OA) in pediatric population with regard to several postoperative variables. We synthesized published data using fixed-effect models, expressing results as relative risk (RR). Nine eligible studies were included which came from various medical centers all over the world. Statistically significant differences between "LA" and "OA" groups were found for wound infection (RR=0.88), intra-abdominal abscess (RR=1.38), and bowel obstruction (RR=0.79). Our meta-analysis found that LA is associated with lower incidence of wound infections and bowel obstruction, but the rate of intra-abdominal abscess was higher than OA.


High promutagen activating capacity of yeast microsomes containing human cytochrome P-450 1A and human NADPH-cytochrome P-450 reductase.
Yeast Saccharomyces cerevisiae strains have been constructed that co-express cDNAs coding for the human cytochrome P-450 enzymes CYP1A1 or CYP1A2 in combination with human NADPH-cytochrome P-450 reductase (oxidoreductase). Microsomal fractions prepared from the strains were able to efficiently activate various drugs to Salmonella mutagens. These experiments demonstrated that a functional interaction occurred between the respective human enzymes in the yeast microsomes. For every drug tested, the microsomes containing CYP enzymes and oxidoreductase were 2- to 4-fold better in activation than the corresponding microsomes that contained CYP alone. Interestingly, co-expression of CYP1A2 with oxidoreductase resulted in a decrease of 7-ethoxyresorufin-O-deethylase activity, a problem which is related to this specific substrate. Using the microsomes, it was demonstrated that aflatoxin B1 was activated to a mutagen not only by CYP1A2 but also by CYP1A1. In contrast, benzo[a]pyrene was exclusively activated by CYP1A1 whereas CYP1A2 was inactive. The drug 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) was activated by CYP1A2 and to a lesser extent by CYP1A1. A strong substrate specificity was observed with the two structurally related heterocyclic arylamines 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) and 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx). MeIQx was activated efficiently by both CYP enzymes, whereas MeIQ was only activated by CYP1A2 and not by CYP1A1. The fact that microsomes from vector transformed control strains were unable to activate any of the drugs studied underlines the suitability of these microsomes for metabolic studies. Moreover, the presence of suitable marker genes in the yeast strains will enable us to study mitotic recombination and gene conversion events induced by drugs that require metabolic activation.


[The value of a new digital laser card for image/report documentation and transmission].
The capabilities of a patient-oriented digital optical laser-card for the documentation of the image/report unit and for image transmission were assessed. 150 conventional X-rays covering the fields of urology (n = 50), traumatology (n = 50) and orthopaedics (n = 50) were digitised using a CCD scanner and subsequently transmitted to an Image-Transfer Medium (ITM) and to an optical laser-card. The image quality for the detection of relevant diagnostic parameters was evaluated by 4 radiologists and one clinician of the corresponding specialty. Based upon a total of 4740 decision readings for each method, it was found that the optical laser-card reduced the image quality significantly (p < 0.01) in comparison to the digitised ITM images in all fields. Thus, a primary diagnostic statement cannot be made based upon the images of the optical card. However, concomitant documentation of the image and opinion on the card may be used for the transmission of the radiological report, especially to external referring institutions.


Disease-specific versus generic measurement of health-related quality of life in insulin-dependent diabetic patients.
The health-related quality of life of 170 adult insulin-dependent diabetic patients was measured cross-sectionally to compare a disease-specific instrument, Diabetes Quality of Life (DQOL) questionnaire, and two generic instruments, the Duke Health Profile (DUKE) and the General Health Perceptions Questionnaire (GHP). The generic measures provided as much or more information about health-related quality of life as the disease-specific instrument. This was demonstrated both by comparison of the DQOL with the DUKE and GHP and by comparison of the disease-specific with the generic components of a modified version of the DQOL. Patients with the diabetic complication of nephropathy had increased worry over their health and lower general health perceptions. Neither the duration of diabetes nor the intensity of insulin therapy, however, was found to have a statistically significant effect on any of the health-related quality of life scores. Nondiabetic factors, such as the comorbidity, nondiabetic medications, marital status, social relationships, and family arguments were found to be predictors of health-related quality of life more often than the diabetic factors duration of diabetes, complications, and intensity of insulin therapy. These analyses suggest the clinical value of using generic questionnaires to measure health-related quality of life and psychosocial factors to identify nondiabetic problems that might respond to intervention, thereby potentially enhancing the effect of diabetes-specific therapy.


Metallic carbon nanotube-based saturable absorbers for holmium-doped fiber lasers.
In 2003, carbon nanotubes opened a new field of research on nanomaterial-based mode-locked fiber lasers. They maintain popularity in the ultrafast laser community due to their broadband operation, relatively high damage threshold, and tunable optical properties. Here we show that metallic carbon nanotube-based thin film fabricated by vacuum filtration technique can be used as a saturable absorber in holmium-doped fiber laser operating in anomalous and normal dispersion regimes. Scaling the absorbers modulation depth by adjusting the film thickness was observed. The Fourier transform limited 6.65 nm wide optical solitons in anomalous dispersion regime were generated. Utilizing stretched-pulse regime greatly improves the laser performance - 212 fs pulses reach the energy of 3.79 nJ.


"Say-stay" identification and psychoacoustic performance of hearing-impaired listeners.
Controversy exists over the extent to which psychoacoustic abilities explain speech perception. The present study addressed this issue by assessing the contribution of psychoacoustic abilities to speech identification by hearing-impaired listeners. Speech stimuli and nonspeech analogs were presented to normal-hearing and hearing-impaired listeners with varying degrees of hearing loss. Phonemic judgments for synthetic versions of "say-stay" stimuli were evaluated as a function of first formant onset frequency and of silence duration between the /s/ noise and the vocalic portion. Three psychoacoustic measures were obtained: glide onset frequency discrimination, gap detection in noise, and gap detection in speechlike composite signals. Although the resulting difference limens increased with increasing hearing loss, the acoustic cues to the speech contrast were available to all listeners. Nonetheless, the response patterns to the speech stimuli varied among groups in a manner that was not explained by the psychoacoustic results. Thus, although hearing-impaired listeners were able to detect and discriminate essential acoustic cues for speech, the perceptual organization of speech stimuli appeared to differ with degree of loss. Alternative explanations for the findings are considered, including the possible effect of hearing loss on auditory/linguistic experience.


First chemical feature-based pharmacophore modeling of potent retinoidal retinoic acid metabolism blocking agents (RAMBAs): identification of novel RAMBA scaffolds.
The first three-dimensional (3D) pharmacophore model was developed for potent retinoidal retinoic acid metabolism blocking agents (RAMBAs) with IC(50) values ranging from 0.0009 to 5.84nM. The seven common chemical features in these RAMBAs as deduced by the Catalyst/HipHop program include five hydrophobic groups (hydrophobes), and two hydrogen bond acceptors. Using the pharmacophore model as a 3D search query against NCI and Maybridge conformational Catalyst formatted databases; we retrieved several compounds with different structures (scaffolds) as hits. Twenty-one retrieved hits were tested for RAMBA activity at 100nM concentration. The most potent of these compounds, NCI10308597 and HTS01914 showed inhibitory potencies less (54.7% and 53.2%, respectively, at 100nM) than those of our best previously reported RAMBAs VN/12-1 and VN/14-1 (90% and 86%, respectively, at 100nM). Docking studies using a CYP26A1 homology model revealed that our most potent RAMBAs showed similar binding to the one observed for a series of RAMBAs reported previously by others. Our data shows the potential of our pharmacophore model in identifying structurally diverse and potent RAMBAs. Further refinement of the model and searches of other robust databases is currently in progress with a view to identifying and optimizing new leads.


Characterization of a hepatitis C virus-like particle vaccine produced in a human hepatocyte-derived cell line.
An effective immune response against hepatitis C virus (HCV) requires the early development of multi-specific class 1 CD8+ and class II CD4+ T-cells together with broad neutralizing antibody responses. We have produced mammalian-cell-derived HCV virus-like particles (VLPs) incorporating core, E1 and E2 of HCV genotype 1a to produce such immune responses. Here we describe the biochemical and morphological characterization of the HCV VLPs and study HCV core-specific T-cell responses to the particles. The E1 and E2 glycoproteins in HCV VLPs formed non-covalent heterodimers and together with core protein assembled into VLPs with a buoyant density of 1.22 to 1.28 g cm-3. The HCV VLPs could be immunoprecipited with anti-ApoE and anti-ApoC. On electron microscopy, the VLPs had a heterogeneous morphology and ranged in size from 40 to 80 nm. The HCV VLPs demonstrated dose-dependent binding to murine-derived dendritic cells and the entry of HCV VLPs into Huh7 cells was blocked by anti-CD81 antibody. Vaccination of BALB/c mice with HCV VLPs purified from iodixanol gradients resulted in the production of neutralizing antibody responses while vaccination of humanized MHC class I transgenic mice resulted in the prodution of HCV core-specific CD8+ T-cell responses. Furthermore, IgG purified from the sera of patients chronically infected with HCV genotypes 1a and 3a blocked the binding and entry of the HCV VLPs into Huh7 cells. These results show that our mammalian-cell-derived HCV VLPs induce humoral and HCV-specific CD8+ T-cell responses and will have important implications for the development of a preventative vaccine for HCV.


Formative design and evaluation of patient-delivered partner therapy informational materials and packaging.
To develop and evaluate instructional and packaging materials for patient-delivered partner therapy (PDPT). 64 patients participated from an urban US sexually transmitted infection (STI) clinic. The research comprised three phases: individual interviews to elicit attitudes and beliefs regarding PDPT and to assess the understanding of key STI-related concepts and terminology; the development and rapid validation of prototype instructional and packaging materials for PDPT and interviews to assess the effectiveness, acceptability and usability of the prototype materials. Thematic qualitative data analysis was used to examine interview responses. Participants were willing to deliver and receive PDPT and several potentially important related beliefs were identified. Participants indicated substantial unfamiliarity with words associated with STI treatment and some variability in definitions of sex partners. PDPT informational materials differentially affected participant willingness to receive (positively) and deliver (negatively) PDPT, positively influenced self-efficacy and understanding and were perceived as easy to use. PDPT creates complex challenges for education, motivation and communication. Issues such as appropriate vocabulary and interpersonal trust may be amplified when responsibility for a medical procedure-dispensation of treatment-is shifted to patients. STI PDPT implementation can be augmented with effective, high-quality informational and packaging materials; however, several challenges exist.


Deficiency in macrophage-stimulating protein results in spontaneous intestinal inflammation and increased susceptibility toward epithelial damage in zebrafish.
Several genome-wide association studies have identified the genes encoding for macrophage-stimulating protein (MSP) and its receptor RON (Recepteur d'Origine Nantais) as possible susceptibility factors in inflammatory bowel disease. While it has been shown that the MSP-RON signaling pathway is involved in tissue injury responses, current mouse models for MSP and RON deficiency have not clearly demonstrated a role of MSP-RON signaling in the context of intestinal inflammation. In this study, we report that the recently identified zebrafish Msp mutant (msp(t34230)) develops spontaneous intestinal inflammation over time. From 14 to 28 weeks postfertilization Msp-deficient zebrafish show intestinal eosinophilia, increased intestinal expression of inflammatory marker mmp9, and activation of intestinal goblet cells. Moreover, these Msp mutant zebrafish are more susceptible toward ethanol-induced epithelial damage, which resulted in increased infiltration and proliferation of immune cells within the lamina propria and prolonged intestinal proinflammatory cytokine responses in some mutant fish. In light of the recent development of many tools to visualize, monitor, and genetically modify zebrafish, these Msp-deficient zebrafish will enable in-depth in vivo analysis of epithelial and macrophage-specific MSP-RON signaling in the context of intestinal inflammation.


B-90063, a novel endothelin converting enzyme inhibitor isolated from a new marine bacterium, Blastobacter sp. SANK 71894.
A novel endothelin-converting enzyme (ECE) inhibitor, B-90063, was isolated from the culture supernatant of the newly discovered marine bacterium Blastobacter sp. SANK 71894. Based on spectral analyses and chemical reactions, the structure of B-90063 was determined to be bis[6-formyl-4-hydroxy-2-(2'-n-pentyloxazol-4'-yl)-4-pyridon -3-yl]-disulfide (1a). Human and rat ECEs were inhibited more potently by B-90063, with respective IC50 values of 1.0 and 3.2 microM, than were other neutral endopeptidases such as NEP and type-I and -IV collagenases. B-90063 also inhibited the binding of ET-1 to rat ET(A) and bovine ET(B) receptors, though its antagonistic activities were weak. B-90063, thus, may abolish the physiological actions of endothelins through the ECE inhibitory and receptor antagonistic mechanisms.


Biomarker counseling, disclosure of diagnosis and follow-up in patients with mild cognitive impairment: A European Alzheimer's disease consortium survey.
Mild cognitive impairment (MCI) is associated with an increased risk of further cognitive decline, partly depending on demographics and biomarker status. The aim of the present study was to survey the clinical practices of physicians in terms of biomarker counseling, management, and follow-up in European expert centers diagnosing patients with MCI. An online email survey was distributed to physicians affiliated with European Alzheimer's disease Consortium centers (Northern Europe: 10 centers; Eastern and Central Europe: 9 centers; and Southern Europe: 15 centers) with questions on attitudes toward biomarkers and biomarker counseling in MCI and dementia. This included postbiomarker counseling and the process of diagnostic disclosure of MCI, as well as treatment and follow-up in MCI. The response rate for the survey was 80.9% (34 of 42 centers) across 20 countries. A large majority of physicians had access to biomarkers and found them useful. Pre- and postbiomarker counseling varied across centers, as did practices for referral to support groups and advice on preventive strategies. Less than half reported discussing driving and advance care planning with patients with MCI. The variability in clinical practices across centers calls for better biomarker counseling and better training to improve communication skills. Future initiatives should address the importance of communicating preventive strategies and advance planning.


Tropomyosin distinguishes between the two actin-binding sites of villin and affects actin-binding properties of other brush border proteins.
The intestinal epithelial cell brush border exhibits distinct localizations of the actin-binding protein components of its cytoskeleton. The protein interactions that dictate this subcellular organization are as yet unknown. We report here that tropomyosin, which is found in the rootlet but not in the microvillus core, can bind to and saturate the actin of isolated cores, and can cause the dissociation of up to 30% of the villin and fimbrin from the cores but does not affect actin binding by 110-kD calmodulin. Low speed sedimentation assays and ultrastructural analysis show that the tropomyosin-containing cores remain bundled, and that 110-kD calmodulin remains attached to the core filaments. The effects of tropomyosin on the binding and bundling activities of villin were subsequently determined by sedimentation assays. Villin binds to F-actin with an apparent Ka of 7 X 10(5) M-1 at approximate physiological ionic strength, which is an order of magnitude lower than that of intestinal epithelial cell tropomyosin. Binding of villin to F-actin presaturated with tropomyosin is inhibited relative to that to pure F-actin, although full saturation can be obtained by increasing the villin concentration. Villin also inhibits the binding of tropomyosin to F-actin, although not to the same extent. However, tropomyosin strongly inhibits bundling of F-actin by villin, and bundling is not recovered even at a saturating villin concentration. Since villin has two actin-binding sites, both of which are required for bundling, the fact that tropomyosin inhibits bundling of F-actin under conditions where actin is fully saturated with villin strongly suggests that tropomyosin's and one of villin's F-actin-binding sites overlap. These results indicate that villin and tropomyosin could compete for actin filaments in the intestinal epithelial cell, and that tropomyosin may play a major role in the regulation of microfilament structure in these and other cells.


THE RESPONSE OF SINGLE VISUAL SENSE CELLS TO LIGHTS OF DIFFERENT WAVE LENGTHS.
The effect of various wave lengths of visible light in the stimulation of single visual sense cells has been studied by means of the single fiber preparation from the eye of Limulus. Oscillographic records were made of the impulse discharge in a single optic nerve fiber in response to stimulation of the attached sense cell by lights of different wave lengths. Wratten monochromatic filters supplied the means for obtaining the different spectral lights; the total intensity supplied to the eye being determined by a thermopile and galvanometer. With lights of approximately equal energy content the strongest response occurs to the green region of the spectrum. The response, however, does not vary qualitatively with wave length. By the proper adjustment of intensity, responses can be obtained which are identical, impulse for impulse, for all the spectral lights used. Moreover the ratios of the intensities for the various wave lengths necessary to produce a constant response do not vary with the intensity level of the stimulating lights; there is no Purkinje effect. The single visual sense cell can gauge brightness but cannot distinguish wave length. The reciprocals of the intensities necessary to produce a constant response when plotted against wave length give the visibility curve for the single sense cell. This curve is symmetrical about a maximum at lambda520mmicro, falling off to low values in the red and violet. It closely resembles the visibility curve for human rod vision. Bundles from the optic nerve containing several active fibers whose impulses can be distinguished by differences in form and magnitude or whose attached sense cells can be located and illuminated independently were used to determine whether there is any differential sensitivity among sense cells in the same eye for different regions of the spectrum. Such a differential sensitivity has been found to exist in the eye of Limulus and may be considered a peripheral mechanism of color vision.


Prevalence of Growth Restriction at Birth for Newborns With Congenital Heart Defects: A Population-Based Prospective Cohort Study EPICARD.
Background and Objectives: Congenital heart defects (CHD) and growth restriction at birth are two major causes of childhood and adult morbidity and mortality. The aim of this study was to assess the overall risk of growth restriction at birth, as measured by its imperfect proxy small (< 10th percentile) for gestational age (SGA), for newborns with CHD. Methods: Using data from a population-based cohort of children born with CHD, we assessed the risk of growth restriction at birth using SGA and severe SGA (3rd percentile). To compare the odds of SGA and severe SGA across five specific major CHD, we used ordinal logistic regression using isolated, minor (non-operated) ventricular septal defect (VSD) as the control group. Results: The overall proportion of SGA for "isolated" CHD (i.e., those not associated with other anomalies) was 13% (95% CI, 12-15%), which is 30% higher than what would be expected in the general population (i.e., 10%). The risk of severe SGA was 5% (95% CI, 4-6%) as compared with the expected 3% in the general population. There were substantial differences in the risk of overall SGA and more so severe SGA across the different CHD. The highest risk of SGA occurred for Tetralogy of Fallot (adjusted OR 2.7, 95% CI, 1.3-5.8) and operated VSD (adjusted OR 2.1, 95% CI, 1.1-3.8) as compared with the control group of minor (non-operated) VSD. Conclusion: The overall risks of both SGA and severe SGA were higher in isolated CHD than what would be expected in the general population with substantial differences across the subtypes of CHD. These results may provide a clue for understanding the underlying mechanisms of the relation between alterations in fetal circulation associated with different types of CHD and their effects on fetal growth.


To adapt or go extinct? The fate of megafaunal palm fruits under past global change.
Past global change may have forced animal-dispersed plants with megafaunal fruits to adapt or go extinct, but these processes have remained unexplored at broad spatio-temporal scales. Here, we combine phylogenetic, distributional and fruit size data for more than 2500 palm (Arecaceae) species in a time-slice diversification analysis to quantify how extinction and adaptation have changed over deep time. Our results indicate that extinction rates of palms with megafaunal fruits have increased in the New World since the onset of the Quaternary (2.6 million years ago). In contrast, Old World palms show a Quaternary increase in transition rates towards evolving small fruits from megafaunal fruits. We suggest that Quaternary climate oscillations and concurrent habitat fragmentation and defaunation of megafaunal frugivores in the New World have reduced seed dispersal distances and geographical ranges of palms with megafaunal fruits, resulting in their extinction. The increasing adaptation to smaller fruits in the Old World could reflect selection for seed dispersal by ocean-crossing frugivores (e.g. medium-sized birds and bats) to colonize Indo-Pacific islands against a background of Quaternary sea-level fluctuations. Our macro-evolutionary results suggest that megafaunal fruits are increasingly being lost from tropical ecosystems, either due to extinctions or by adapting to smaller fruit sizes.


Epilepsy of infancy with migrating focal seizures: three patients treated with the ketogenic diet.
We present three patients with epilepsy of infancy with migrating focal seizures treated with the ketogenic diet. Between February 1, 2012 and January 31, 2014, three patients who met the diagnostic criteria for migrating focal seizures in infancy at our department were placed on the ketogenic diet and followed for a minimum of seven months. Two of the three children responded well to the ketogenic diet. One of these patients became seizure-free and his neuropsychological performance also significantly improved. The other child had a seizure reduction of 75% to 99% with only weekly seizures and moderate psychomotor improvement. For these two patients who responded well to the ketogenic diet, hospital admission was not required. The remaining patient had a seizure reduction of less than 50%. Tolerability of the diet was good in all three patients. Early treatment with the ketogenic diet should be considered for epilepsy of infancy with migrating focal seizures to control seizures and status epilepticus, and avoid progressive cognitive impairment.


A Genome-Wide Association Study for Calving Interval in Holstein Dairy Cows Using Weighted Single-Step Genomic BLUP Approach.
The aim of the present study was to identify genomic region(s) associated with the length of the calving interval in primiparous (n = 6866) and multiparous (n = 5071) Holstein cows. The single nucleotide polymorphism (SNP) solutions were estimated using a weighted single-step genomic best linear unbiased prediction (WssGBLUP) approach and imputed high-density panel (777 k) genotypes. The effects of markers and the genomic estimated breeding values (GEBV) of the animals were obtained by five iterations of WssGBLUP. The results showed that the accuracies of GEBVs with WssGBLUP improved by +5.4 to +5.7, (primiparous cows) and +9.4 to +9.7 (multiparous cows) percent points over accuracies from the pedigree-based BLUP. The most accurate genomic evaluation was provided at the second iteration of WssGBLUP, which was used to identify associated genomic regions using a windows-based GWAS procedure. The proportion of additive genetic variance explained by windows of 50 consecutive SNPs (with an average of 165 Kb) was calculated and the region(s) that accounted for equal to or more than 0.20% of the total additive genetic variance were used to search for candidate genes. Three windows of 50 consecutive SNPs (BTA3, BTA6, and BTA7) were identified to be associated with the length of the calving interval in primi- and multiparous cows, while the window with the highest percentage of explained genetic variance was located on BTA3 position 49.42 to 49.52 Mb. There were five genes including ARHGAP29, SEC24D, METTL14, SLC36A2, and SLC36A3 inside the windows associated with the length of the calving interval. The biological process terms including alanine transport, L-alanine transport, proline transport, and glycine transport were identified as the most important terms enriched by the genes inside the identified windows.


Use of a long distally fixed intramedullary stem to treat a periprosthetic femoral fracture following total hip arthroplasty using a thrust plate hip prosthesis: A case report.
The thrust plate hip prosthesis (TPP; Zimmer, Winterthur, Switzerland) is a hip prosthesis that is no longer in production. Few reports have focused on periprosthetic fractures following total hip arthroplasty (THA) with the use of a TPP. We report a 57-year-old woman with a periprosthetic femoral fracture 13 years after THA with the use of a TPP. A plain radiograph showed a displaced subtrochanteric fracture of the right femur just below the distal tip of the lateral plate without implant loosening. She underwent revision surgery with a long distally fixed intramedullary stem in conjunction with a plate and cable system. Three months after surgery, bone union was confirmed using radiography and the patient was clinically asymptomatic. We encountered three major problems while planning surgical treatment, these being, discontinuation of the TPP system, loss of proximal femoral cancellous bone, and difficulties with the type of subtrochanteric fracture. After considering these problems, we planned revision surgery using a long distally fixed intramedullary stem in conjunction with a plate and cable system. This case shows that sufficient implant preparation based on precise preoperative planning is necessary to obtain good clinical results for the surgical treatment of periprosthetic femoral fractures following THA with the use of a TPP.


Profile of stroke in a teaching university hospital in the western region.
An epidemiological study of stroke on patients admitted at King Abdul Aziz University hospital to determine the pattern of stroke, clinical presentation, risk factors and the outcome of the stroke in Saudis and non Saudis. Case records of patients admitted with stroke between (January 1997 to January 2000) at King Abdul Aziz University Hospital which is a teaching hospital affiliated to Ministry of Education, provides health care to multinational population of mixed socioeconomic status. The diagnosis was established by radiological assessment either by computerized tomography scan or magnetic resonance imaging. Pattern of stroke, clinical presentations, risk factors and the outcome of stroke and other relevant data were documented. A total of 71 patients were admitted with stroke during the period of the study with incidence of 3% of total admission to the medical unit. The mean age was 63 years with male: female ratio of 3.4:1. Cerebral infarction was recorded in 80% of the cases. The most common presentation of stroke in Saudis were ischamic in 77% and hemorrhagic in 20.5%. Where as in non-Saudis, it was 85% and 7%. Intra cerebral hemorrhage was recorded in 15% of patients, while the subaraichnoid hemorrhage only in 1%. Ruptured aneurysm diagnosed by cerebral angiogram attributed to the cause of subarachnoid hemorrhage. Hypertension was the most important risk factor for ischamic and hemorrhagic stroke, as other risk factors were hyperlipidemia, diabetes mellitus, ischemic heart disease, atrial fibrillation and smoking. Death was the eventual outcome of stoke in 31% of patients, septicemia contributed to 35% of deaths, 77% of cerebral stokes were treated with aspirin, only 2 cases were treated by ticlopdine. Average hospital stay was 63 days, while 6 patients stayed longer than 600 days. Stroke is a common neurological problem among patients admitted at King Abdul Aziz University Hospital and the pattern of stroke is similar to those reported from other parts of Saudi Arabia and other Arab countries. There was a high incidence of thrombotic stroke in our study. Hemorrhage was rare in our study especially subarachniod hemorrhage. Hypertension was the most common risk factor, so emphasis should be made on strict control of blood pressure in the community to reduce the incidence of stroke. Since long hospital stay was observed in our study, we recommend establishment of more nursing homes and rehabilitation centers for stoke patients aiming to decrease the burden on the teaching hospital.


Associations Between Marital Discord and Depressive Symptoms: A Cross-Cultural Analysis.
The objectives of this study were to investigate actor and partner effects of the association between marital discord and depressive symptoms in a sample of 4,779 couples from 11 European countries that were divided into three groups (i.e., Northern, Central, Southern Europe), and evaluate the potential gender and cross-cultural invariance of this association. Actor-partner interdependence models were used to analyze the cross-sectional associations between self-reported perceived marital conflict and depressive symptoms. Marital conflict was significantly and positively associated with self-reported depressive symptoms for husbands and wives (actor effects), as well as with partner-reported depressive symptoms (partner effects). Pooling across cultural groups, no significant difference in the magnitude of actor or partner effects based on gender was found. The magnitude of the actor effects varied across cultural groupings only for women: a significantly weaker association existed for women residing in Northern Europe relative to women in Central or Southern Europe. These results suggest that marital discord is a reliable correlate of depressive symptoms for European couples and that the magnitude of the positive association varies by culture for women. Should these results be replicated longitudinally, couple-based interventions may be indicated to reduce marital discord and prevent and treat depression in Europe.


A protein-bound polysaccharide immunomodulator, PSK, does not suppress the conversion from 1-(2-tetrahydrofuryl)-5-fluorouracil to 5-fluorouracil in patients with gastric cancer.
Effects of the immunomodulator PSK on the metabolism of 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) to 5-fluorouracil (5-FU) were examined in 10 patients with advanced gastric cancer and who had undergone curative resection. PSK is a protein-bound preparation, extracted from Coriolus versicolor and belongs to Basidiomycetes. The 5-FU concentration in the plasma was 0.024 micrograms/ml at 15 min after the intravenous injection of 400 mg of tegafur and the area under the curve of 5-FU was 0.58 micrograms.h/ml. Following administration of PSK, 3 g/day for 8-14 months, there was no change in the plasma level of 5-FU, in any patient. As the clinical dose of PSK had no apparent influence on the metabolism of tegafur to 5-FU, the combination of PSK and tegafur can be prescribed to treat patients with advanced gastric cancer.


Cocaine perturbs mitovesicle biology in the brain.
Cocaine, an addictive psychostimulant, has a broad mechanism of action, including the induction of a wide range of alterations in brain metabolism and mitochondrial homeostasis. Our group recently identified a subpopulation of non-microvesicular, non-exosomal extracellular vesicles of mitochondrial origin (mitovesicles) and developed a method to isolate mitovesicles from brain parenchyma. We hypothesised that the generation and secretion of mitovesicles is affected by mitochondrial abnormalities induced by chronic cocaine exposure. Mitovesicles from the brain extracellular space of cocaine-administered mice were enlarged and more numerous when compared to controls, supporting a model in which mitovesicle biogenesis is enhanced in the presence of mitochondrial alterations. This interrelationship was confirmed in vitro. Moreover, cocaine affected mitovesicle protein composition, causing a functional alteration in mitovesicle ATP production capacity. These data suggest that mitovesicles are previously unidentified players in the biology of cocaine addiction and that target therapies to fine-tune brain mitovesicle functionality may be beneficial to mitigate the effects of chronic cocaine exposure.


Prospective randomized study on the efficacy of blue light in the treatment of psoriasis vulgaris.
Blue light has no known toxic effects on human skin, but reduces the proliferative capacity of keratinocytes in vitro. We therefore investigated the efficacy of blue light in the treatment of psoriasis vulgaris (PV). Forty patients with mild to moderate PV and bilateral plaques were assigned to two groups. Group 1 (n = 20) received irradiation at home with blue light (light-emitting diode, LED, emission maximum: 420 nm) once daily for 4 weeks. In parallel, group 2 (n = 20) performed irradiations with another blue light device (LED emission maximum: 453 nm). The contralateral control plaques remained untreated in both groups. Thirty-seven patients completed the trial. The main study parameter, the difference of Local Psoriasis Severity Index (LPSI) scores of the irradiated plaques compared to the control plaques, showed statistically significant improvement after 4 weeks of treatment in both groups [group 1 (420 nm): n = 17, p = 0.04; group 2 (453 nm): n = 20, p = 0.04]. Accordingly, plaque status as assessed by both the physicians and the patients improved continuously during the 4 weeks of treatment and steadily declined thereafter. Blue light appears to be a promising treatment modality in PV that warrants further evaluation in larger studies.


Ginkgetin induces apoptosis via activation of caspase and inhibition of survival genes in PC-3 prostate cancer cells.
Ginkgetin is a natural biflavonoid isolated from leaves of Ginkgo biloba L. Though it was known to have anti-inflammatory, anti-influenza virus, anti-fungal activity, osteoblast differentiation stimulating activity and neuro-protective effects, the underlying antitumor mechanism of ginkgetin still remains unclear. Thus, in the present study, anti-cancer mechanism of ginkgetin was elucidated in human prostate cancer PC-3 cells. Ginkgetin suppressed the viability of PC-3 cells in a concentration-dependent manner and also significantly increased the sub-G1 DNA contents of cell cycle in PC-3 cells. Ginkgetin activated caspase-3 and attenuated the expression of survival genes such as Bcl-2, Bcl-xL, survivin and Cyclin D1 at protein and mRNA levels. Consistently, pan-caspase inhibitor Z-DEVD-fmk blocked sub G1 accumulation and cleavages of PRAP and caspase 3 induced by ginkgetin in PC-3 cells. Overall, these findings suggest that ginkgetin induces apoptosis in PC-3 cells via activation of caspase 3 and inhibition of survival genes as a potent chemotherapeutic agent for prostate cancer treatment.


Acid-catalyzed reactions of epoxides for atmospheric nanoparticle growth.
Although new particle formation accounts for about 50% of the global aerosol production in the troposphere, the chemical species and mechanism responsible for the growth of freshly nucleated nanoparticles remain largely uncertain. Here we show large size growth when sulfuric acid nanoparticles of 4-20 nm are exposed to epoxide vapors, dependent on the particle size and relative humidity. Composition analysis of the nanoparticles after epoxide exposure reveals the presence of high molecular weight organosulfates and polymers, indicating the occurrence of acid-catalyzed reactions of epoxides. Our results suggest that epoxides play an important role in the growth of atmospheric newly nucleated nanoparticles, considering their large formation yields from photochemical oxidation of biogenic volatile organic compounds.