Students' perception of stress in a baccalaureate-MD degree program.
The quality of student life in combined baccalaureate-M.D. degree programs has rarely been investigated although these programs address widely recognized problems in medical education. Through the use of an environmental stress inventory, 183 students' perceptions of the learning environment of a combined-degree program were examined. Students in that program rated few situations in their environment as stressful. Yet, they were significantly concerned about information overload and attendant time problems, just as their peers in 4-yr. schools were. Unlike their 4-yr. counterparts, however, they did not see relations with other students and faculty as problematic. Their scores on the inventory were best predicted at each year level by a combination of personal characteristics, notably living arrangements, sex, and to a lesser extent, introversion.


Rate stimulation of deoxyribonucleic acid synthesis after inhibition.
The degree to which the rate of deoxyribonucleic acid synthesis in thy- cultures of Escherichia coli is stimulated after a period of thymine starvation is shown to be a function of the concentration of thymine present as well as of the culture doubling time. Inhibition of deoxyribonucleic acid synthesis by nalidixic acid yields comparable results. Periods of thymine starvation exceeding one doubling time appear to cause an irreversible inactivation of a fraction of the replication forks in the culture.


Diet, smoking and exercise: interrelationships between adolescent health behaviours.
A questionnaire measuring smoking status, exercise and dietary behaviour was administered to 932 high school pupils during regular classroom periods. Pupils were taken from three year groups which included 327 year 8 (12-13 years), 313 year 9 (13-14 years) and 292 year 10 (14-15 years). Pupils also indicated whether they could recall classroom teaching on 15 food- and health-related issues. Scores were derived representing self-reported frequency of eating foods that were high in fat, and fresh fruits and vegetables. Smoking was found to be associated with lower levels of exercise, consumption of less fresh foods and greater consumption of fatty foods. In addition, consumption of fresh foods was found to be positively correlated with exercise. These findings have implications for the organization of school-based health education efforts and suggest that health education programmes need to adopt an integrated approach rather than treat health behaviours in isolation from each other.


Successful multidisciplinary treatment of the rare pathology of vulvar Crohn's disease.
A woman in her 50s with a medical history of rheumatoid arthritis (RA) and hypothyroidism presented with 3 months of vaginal pain and swelling. Physical examination showed vulvar oedema and erythema, ulcerations of the inferior vulva that extended to the buttocks and introitus with erythema and superficial erosions. MR pelvis showed a fibroid in the uterus but otherwise was unremarkable. Biopsies of the vagina showed extensive acute and chronic inflammation, necrosis and granulomas without concern for malignancy, which was consistent with a diagnosis of cutaneous Crohn's disease. MR enterography, upper endoscopy and colonoscopy revealed no gastrointestinal manifestations of Crohn's. She was treated initially with corticosteroids and metronidazole as well as vulvectomy and graft placement. Azathioprine was added to her regimen due to lack of response; however, despite 6 weeks of this therapy, the ulcerations did not heal thus infliximab was initiated. After 8 weeks the lesions had completely resolved.


Segment-specific associations between local haemodynamic and imaging markers of early atherosclerosis at the carotid artery: an in vivo human study.
Low and oscillatory wall shear stress (WSS) has long been hypothesized as a risk factor for atherosclerosis; however, evidence has been inferred primarily from model and post-mortem studies, or clinical studies of patients with already-developed plaques. This study aimed to identify associations between local haemodynamic and imaging markers of early atherosclerosis. Comprehensive magnetic resonance imaging allowed quantification of contrast enhancement (CE) (a marker of endothelial dysfunction) and vessel wall thickness at two distinct segments: the internal carotid artery bulb and the common carotid artery (CCA). Strict criteria were applied to a large dataset to exclude inward remodelling, resulting in 41 cases for which personalized computational fluid dynamic simulations were performed. After controlling for cardiovascular risk factors, bulb wall thickening was found to be weakly, but not significantly, associated with oscillatory WSS. CE at the bulb was significantly associated with low WSS (p < 0.001) and low flow helicity (p < 0.05). No significant associations were found for the CCA segment. Local haemodynamics at the bulb were significantly correlated with blood flow rates and heart rates, but not carotid bifurcation geometry (flare and curvature). Therefore low, but not oscillatory, WSS is an early independent marker of atherosclerotic changes preceding intimal thickening at the carotid bulb.


Early-stage compositional segregation in polymer-blend films.
The existence of a transient period during the surface enrichment of a binary polymer blend by one of its components has been suggested by previous theoretical and experimental studies as well as computer simulations. Taking advantage of the high depth resolution of neutron reflectivity and the slow dynamics of polymers near their glass transition, we investigate this early-stage surface compositional enrichment in a phase separating polymer blend for the first time. Two stages of surface enrichment layer growth are observed. A rapid local surface enrichment at the chain segmental level occurs first, followed by a slower growth of a diffuse layer having a scale on the order of the bulk correlation length and the radius of gyration of the surface enriching polymer chains.


Differential activity of Drosophila Hox genes induces myosin expression and can maintain compartment boundaries.
Compartments are units of cell lineage that subdivide territories with different developmental potential. In Drosophila, the wing and haltere discs are subdivided into anterior and posterior (A/P) compartments, which require the activity of Hedgehog, and into dorsal and ventral (D/V) compartments, needing Notch signaling. There is enrichment in actomyosin proteins at the compartment boundaries, suggesting a role for these proteins in their maintenance. Compartments also develop in the mouse hindbrain rhombomeres, which are characterized by the expression of different Hox genes, a group of genes specifying different structures along their main axis of bilaterians. We show here that the Drosophila Hox gene Ultrabithorax can maintain the A/P and D/V compartment boundaries when Hedgehog or Notch signaling is compromised, and that the interaction of cells with and without Ultrabithorax expression induces high levels of non-muscle myosin II. In the absence of Ultrabithorax there is occasional mixing of cells from different segments. We also show a similar role in cell segregation for the Abdominal-B Hox gene. Our results suggest that the juxtaposition of cells with different Hox gene expression leads to their sorting out, probably through the accumulation of non-muscle myosin II at the boundary of the different cell territories. The increase in myosin expression seems to be a general mechanism used by Hox genes or signaling pathways to maintain the segregation of different groups of cells.


Adequate disinfection of a split-septum needleless intravascular connector with a 5-second alcohol scrub.
Define optimum vascular catheter connector valve disinfection practices under laboratory and clinical conditions. Prospective observational clinical survey and laboratory assessment of disinfection procedures. All adult inpatients at an academic healthcare center. In the clinical setting, contamination of needleless connectors was assessed in 6 weekly prevalence surveys in which the connector valves from central venous catheters (CVCs) in situ were cultured by pressing the connector diaphragm to an agar plate. Before culture, valves were disinfected by scrubbing the diaphragm with a 70% isopropyl alcohol pledget for 0, 5, 10, 15, or 30 seconds. In the laboratory, the diaphragms on 150 unused sterile connector valves were inoculated with 10(3), 10(5), or 10(8) colony-forming units of Staphylococcus epidermidis and allowed to dry. After disinfection of the diaphragms by scrubbing with a 70% isopropyl alcohol pledget for 0, 5, 10, 15, or 30 seconds, the valves were sampled by pressing the diaphragm to an agar plate. In the clinical setting, 363 connector valves from patients with CVCs were sampled, and 66.7% of nondisinfected valves revealed bacterial contamination. After 5-second disinfection with an alcohol pledget, only 1 (1.4%) of 71 yielded microbial growth (P < .005). In the laboratory, at the 10(3) and 10(5) inoculum, all connector valves yielded sterile cultures when scrubbed for 5 or more seconds (P < .001). At the 10(8) inoculum, 2 (20%) of 10 connector valves yielded minimal growth of S. epidermidis. A 5-second scrub with a 70% isopropyl alcohol pledget yields adequate disinfection of a split-septum intravascular catheter connector valve under clinical and laboratory conditions.


Aprikalim reduces the Na+-Ca2+ exchange outward current enhanced by hyperkalemia in rat ventricular myocytes.
[corrected] Aprikalim, an adenosine triphosphate (ATP) sensitive K+ (K(ATP)) channel opener, attenuates the elevation of intracellular Ca2+ concentration ([Ca2+]i) and improves the contractile functions after hyperkalemic and hypothermic cardioplegia. There is evidence that cardioplegia increases the Na+-Ca2+ exchange activity without affecting Ca2+ influx through L-type Ca2+ channels or Ca2+ content in the sarcoplasmic reticulum, the intracellular Ca2+ store. We measured the Na+-Ca2+ exchange outward current with the patch-clamp technique in single rat ventricular myocytes exposed to hyperkalemia and hypothermia in the presence of aprikalim. The intracellular calcium concentration ([Ca2+]i) during cardioplegia, and the contractile function and [Ca2+]i transients induced by electrical stimulation or caffeine during rewarming and reperfusion in single ventricular myocytes were also determined. Contraction and [Ca2+]i were determined with video tracking and spectrofluorometry, respectively. Aprikalim, 100 micromol/L, the effect of which was blocked by glibamclamide, a K(ATP) inhibitor, significantly attenuated the hyperkalemia-elevated Na+-Ca2+ exchange current by 26% and 11% at 22 degrees C and 4 degrees C, respectively. Aprikalim also attenuated significantly the [Ca2+]i elevated during cardioplegia. Furthermore aprikalim significantly attenuated the reduction in amplitude and prolongation in duration of contraction of myocytes after cardioplegia. The effects of aprikalim mimicked those of nickle (Ni2+), a Na+-Ca2+ exchange blocker. The electrically or caffeine-induced [Ca2+]i transients were unaltered by cardioplegia or aprikalim. Aprikalim attenuates the Na+-Ca2+ exchange outward current elevated by hyperkalemia, which may attenuate the [Ca2+]i elevation during hyperkalemia and improve the contractile function after cardioplegia in the ventricular myocyte. The study provides further support that addition of a K(ATP) channel opener to the cardioplegic solution may produce beneficial effects in open heart surgery.


[Vertebral syndrome in multiple sclerosis: causes, clinical peculiarities and problems of differential diagnosis].
Presented is a review of the literature on the main causes of vertebral syndrome in multiple sclerosis (MS): dystrophic processes in spinal motor segments, disturbance of spinal static, development of functional blockade, osteoporosis, appearance of demyelinization foci in roots and the spinal cord, myelopathy, replacing foci by cavities. The authors report the results of clinical and MRI study of 115 patients with MS and single out some dissimilarities of vertebral syndrome in MS and dystrophic lesion of spinal cord as follows: in MS pain is long-term, non-intensive, without distinct periods of deterioration and improvement; muscle tonic disturbances are less pronounced but present on the level of all spinal compartments; intensity of root disorders is significantly less and location of clinical symptoms often does not correspond to the level of altered spinal motor segments. The Lermitt symptom and its analogs are described, the former being found in 14.7% of patients with remitting course, and their relation to the loci in the cervical part of the spinal cord is revealed. It is stressed that these loci could lead to an earlier onset of vertebral pain syndrome in patients with MS.


Lean Mass and Body Fat Percentage Are Contradictory Predictors of Bone Mineral Density in Pre-Menopausal Pacific Island Women.
Anecdotally, it is suggested that Pacific Island women have good bone mineral density (BMD) compared to other ethnicities; however, little evidence for this or for associated factors exists. This study aimed to explore associations between predictors of bone mineral density (BMD, g/cm²), in pre-menopausal Pacific Island women. Healthy pre-menopausal Pacific Island women (age 16-45 years) were recruited as part of the larger EXPLORE Study. Total body BMD and body composition were assessed using Dual X-ray Absorptiometry and air-displacement plethysmography (n = 83). A food frequency questionnaire (n = 56) and current bone-specific physical activity questionnaire (n = 59) were completed. Variables expected to be associated with BMD were applied to a hierarchical multiple regression analysis. Due to missing data, physical activity and dietary intake factors were considered only in simple correlations. Mean BMD was 1.1 ± 0.08 g/cm². Bone-free, fat-free lean mass (LMO, 52.4 ± 6.9 kg) and age were positively associated with BMD, and percent body fat (38.4 ± 7.6) was inversely associated with BMD, explaining 37.7% of total variance. Lean mass was the strongest predictor of BMD, while many established contributors to bone health (calcium, physical activity, protein, and vitamin C) were not associated with BMD in this population, partly due to difficulty retrieving dietary data. This highlights the importance of physical activity and protein intake during any weight loss interventions to in order to minimise the loss of muscle mass, whilst maximizing loss of adipose tissue.


Consultation with health care professionals and influenza immunization among women in contact with young children.
Primary health providers serve an important role in providing and promoting annual influenza immunization to high-risk groups and their close contacts. The purpose of this analysis was to determine whether consultation with a medical professional increases the likelihood of receiving a flu shot among women who have given birth in the past five years and to determine whether this association differs by type of medical professional. Data were obtained from the Canadian Community Health Survey (2005), Cycle 3.1. Logistic regression was used to examine the association between receiving a flu shot in the past 12 months and consulting with family doctors, specialists, nurses, chiropractors, or homeopaths/naturopaths. Among the 6,925 women included in our sample, 1,847 (28.4%) reported receiving a flu shot in the past 12 months. After adjustment for socio-demographic characteristics and province of residence, women who received flu shots in the past 12 months were significantly more likely to consult with a family doctor (AOR 1.56, 95% CI 1.34-1.83) and significantly less likely to consult with a chiropractor (AOR 0.76, 95% CI 0.64-0.90) or a homeopath/naturopath (AOR 0.72, 95% CI 0.54-0.97) over the same time period. Consultation with family doctors was found to have the strongest association with annual flu shots among women in contact with young children, whereas consultation with alternative care providers was found to have an independent inverse association. Given the influenza-associated health risks for young children, medical professionals should promote immunization at the time of consultation for household contacts of young children, including pregnant women.


ReCAP: Comparison of Independent Error Checks for Oral Versus Intravenous Chemotherapy.
Intravenous (IV) chemotherapy is routinely delivered to patients in hospital settings, where safeguards such as independent checks and guidelines govern their administration. In contrast, oral chemotherapy, which is typically ordered in a cancer center but dispensed and administered in the community and home, respectively, is subject to fewer controls. Research in the United States has found that few safeguards in routine use for IV chemotherapy have been adopted for oral chemotherapy; however, less is known about the Canadian context. The objective of this study was to determine whether similar safeguards, in the form of independent checks, existed to identify potential errors related to both formulations. Human factors specialists conducted observations and interviews in cancer center clinics, a cancer center pharmacy, and four community pharmacies across Nova Scotia. Processes were analyzed to determine if an independent check was performed, which qualified provider completed the check, and at what point of the process the check occurred. A total of 57 systematic checks were identified for IV chemotherapy, whereas only six systematic checks were identified for oral chemotherapy. Community pharmacists were the only qualified professionals involved in independent systematic checking of oral chemotherapy, which occurred during ordering and dispensing. There is an enormous opportunity for pharmacists and other qualified professionals to take on an expanded role in improving patient safety for oral chemotherapy. Greater involvement of pharmacists, in both the clinic environment and the community, would facilitate increased systematic checking, which could improve patient safety related to oral chemotherapy.


Characterization of the interaction between the human DNA topoisomerase IIbeta-binding protein 1 (TopBP1) and the cell division cycle 45 (Cdc45) protein.
TopBP1 (topoisomerase IIbeta-binding protein 1) is a BRCT [BRCA1 (breast-cancer susceptibility gene 1) C-terminal]-domain-rich protein that is structurally and functionally conserved throughout eukaryotic organisms. It is required for the initiation of DNA replication and for DNA repair and DNA damage signalling. Experiments with fission yeast and Xenopus revealed that the TopBP1 homologues of these organisms are required for chromatin loading of the replication protein Cdc45 (cell division cycle 45). To improve our understanding of the physiological functions of human TopBP1, we investigated the interplay between human TopBP1 and Cdc45 proteins in synchronized HeLa-S3 cells. Using GST (glutathione transferase) pull-down and co-immunoprecipitation techniques, we showed a direct interaction between TopBP1 and Cdc45 in vitro and in vivo. The use of deletion mutants in GST pull-down assays identified the first and second as well as the sixth BRCT domains of TopBP1 to be responsible for the functional interaction with Cdc45. Moreover, the interaction between Cdc45 and the first and second BRCT domains of TopBP1 inhibited their transcriptional activation both in yeast and mammalian one-hybrid systems. Both proteins interacted exclusively at the G(1)/S boundary of cell cycle; only weak interaction could be found at the G(2)/M boundary. The overexpression of the sixth BRCT domain led to diminished loading of Cdc45 on to chromatin. These results suggest that human TopBP1 is involved in the formation of the initiation complex of replication in human cells and is required for the recruitment of Cdc45 to origins of DNA replication.


[Discussion on polysaccharide determination methods in new Chinese drug research].
According to existing problems in polysaccharide determination methods in new Chinese drug applications, the method suitability, chemical reference selection, components interference and method research were introduced. The author suggests that suitable determination method should be selected according to the structure and property of the polysaccharide, and validated. Some influent factors should be examined to assure the accuracy of the method, such as the stability and using amount of the visualizing reagent, visualizing time, maximum detection wavelength etc. Monosaccharide and other water soluble components should be removed from polysaccharide sample, and suitable reference substance and detection wavelength should be selected. It should pay attention to mutual interference of neutral and acidic saccharide, and use inhibitor to eliminate the interference. Because the slopes of the standard curves are different for different monosaccharide, it is proposed that the types and ratios of the monosaccharide in heteroglycan should be understood, and mixed reference substance solution in the ratio is prepared for determination.


Prescription drug and alcohol simultaneous co-ingestion in U.S. young adults: Prevalence and correlates.
Simultaneous co-ingestion of prescription medication (e.g., opioid, tranquilizer/sedative, stimulant) and alcohol is associated with overdose and elevated substance use, but no studies have examined prescription drug misuse (PDM) and alcohol co-ingestion in U.S. young adults (18-25 years), despite the high rates of PDM in this age group. We used the 2015-19 National Survey on Drug Use and Health (young adult N = 69,916) to examine prevalence of past-month PDM-alcohol co-ingestion, PDM characteristics, and sociodemographic, physical health, mental health, and substance use correlates. Logistic regression examined correlates, comparing those without past-year PDM, those with past-year but not past-month PDM, those with past-month PDM without alcohol co-ingestion, and those with past-month PDM and alcohol co-ingestion. An estimated 585,000 young adults engaged in any past-month PDM-alcohol co-ingestion, or between 32.7% (opioids) and 44.6% (tranquilizer/sedatives) of those who were engaged in past-month PDM. Co-ingestion varied by educational status and was more common in males and white or multiracial young adults. All PDM-involved groups had elevated odds of suicidal ideation and other psychopathology, but substance use and substance use disorder (SUD) odds were significantly higher in young adults with co-ingestion, versus all other groups. To illustrate, 41.1% with opioid-alcohol co-ingestion had multiple past-year SUDs, versus 2.0% in those without past-year PDM. Young adults with co-ingestion are particularly likely to have problematic alcohol use and higher rates of SUD. Counseling about the risks of PDM-alcohol co-ingestion and screening for co-ingestion among those at risk are warranted to limit poor outcomes. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Quantitative protein biomarker panels: a path to improved clinical practice through proteomics.
The utilisation of protein biomarker panels, rather than individual protein biomarkers, offers a more comprehensive representation of human physiology. It thus has the potential to improve diagnosis, prognosis and the differentiation of responders from nonresponders in the context of precision medicine. Although several proteomic techniques exist for measuring biomarker panels, the integration of proteomics into clinical practice has been limited. In this Commentary, we highlight the significance of quantitative protein biomarker panels in clinical medicine and outline the challenges that must be addressed in order to identify the most promising panels and implement them in clinical routines to realise their medical potential. Furthermore, we argue that the absolute quantification of protein panels through targeted mass spectrometric assays remains the most promising technology for translating proteomics into routine clinical applications due to its high flexibility, low sample costs, independence from affinity reagents and low entry barriers for its integration into existing laboratory workflows.


Safety and efficacy of lobectomy combined with off-pump coronary artery bypass grafting for lung cancer.
This study sought to assess the safety and efficacy of a lobectomy combined with off-pump coronary artery bypass grafting (OPCABG) among patients with lung cancer. Patients who underwent a simultaneous pulmonary lobectomy combined with OPCABG at Tianjin Chest Hospital from December 2010 to June 2019 and patients who underwent pulmonary lobectomy during the same period were selected at a ratio of 1:2 using a multi-factor propensity score for this study. The clinical data of each group during the operation and perioperative period were analyzed and compared, and the survival curves were drawn using the Kaplan-Meier method to compare the long-term survival of the patients. In the simultaneous-surgery group, no patients required a secondary thoracotomy for hemostasis and there were no perioperative deaths; however, 2 patients underwent a second intubation, 2 patients underwent a second debridement and suturing due to wound infection, 28 patients (76.3%) had pulmonary complications, and 10 patients (26.3%) had circulatory complications. The operation time, intraoperative blood loss, postoperative drainage volume, postoperative hospital stay, and complication rate were all higher in the simultaneous-surgery group than the lobectomy group. No significant difference was observed in the long-term survival rates between the 2 groups. The simultaneous surgery was safe and effective. Some differences existed in the data between the 2 groups during the perioperative period; however, the risk of complications after surgery was controllable.


Supraorbital Keyhole Approach: Lessons Learned from 106 Operative Cases.
The supraorbital keyhole approach through an eyebrow incision has been a potentially less invasive approach as an alternative to the standard pterional craniotomy. We aimed to review procedures for anterior and middle cranial fossa lesions and identify lessons learned from addressing various pathologies through this approach. We retrospectively reviewed 106 consecutive patients who underwent this approach. We documented patients' age, sex, pathology, clinical results, extent of tumor resection, complications, use of endoscope, and cosmetic results. Our series addressed a variety of pathologies. Male patients accounted for 55% of the cohort and mean age was 51.7 (2-79) years. Notably, 52% of patients underwent resection of extra-axial masses. Gross total resection was achieved in 74.4% of intra-axial lesions according to postoperative imaging. Two (1.9%) patients developed transient ptosis. One (0.9%) patient developed an allergic reaction to titanium. No cerebrospinal fluid fistula or rhinorrhea occurred. Three patients developed temporary diabetes insipidus after resection of parasellar lesions (2 craniopharyngiomas and 1 pituitary adenoma). In 14 patients with olfactory groove meningiomas, 6 (42.8%) suffered from absence or diminished olfaction postoperatively, and 2 (14.2%) developed postoperative anosmia. Five (38.5%) patients underwent a subsequent resection of recurrent glial tumors. Four weeks postoperatively, 95% of patients demonstrated acceptable cosmetic results. Cosmetic results for 6 (5%) patients were unavailable. The supraorbital keyhole approach may be safely used for various lesions within the anterior and middle cranial fossa. The effectiveness and limitations of this approach and possible complications are discussed. This is a valuable approach for selected patients.


CRISPR 2 PCR and high resolution melting profiling for identification and characterization of clinically-relevant Salmonella enterica subsp. enterica.
Nontyphoidal Salmonella spp. constitute a major bacterial cause of food poisoning. Each Salmonella serotype causes distinct virulence to humans. A small cohort study was conducted to characterize several aspects of Salmonella isolates obtained from stool of diarrheal patients (n = 26) admitted to Phayao Ram Hospital, Phayao province, Thailand. A simple CRISPR 2 molecular analysis was developed to rapidly type Salmonella isolates employing both uniplex and high resolution melting (HRM) curve analysis. CRISPR 2 monoplex PCR generated a single Salmonella serotype-specific amplicon, showing S. 4,[5],12:i:- with highest frequency (42%), S. Enteritidis (15%) and S. Stanley (11%); S. Typhimurium was not detected. CRISPR 2 HRM-PCR allowed further classification of S. 4,[5],12:i:- isolates based on their specific CRISPR 2 signature sequences. The highest prevalence of Salmonella infection was during the summer season (April to August). Additional studies were conducted using standard multiplex HRM-PCR typing, which confirmed CRISPR 2 PCR results and, using a machine-learning algorithm, clustered the majority of Salmonella serotypes into six clades; repetitive element-based (ERIC) PCR, which clustered the serotypes into three clades only; antibiogram profiling, which revealed the majority resistant to ampicillin (69%); and test for extended spectrum β-lactamase production (two isolates) and PCR-based detection of bla alleles. CRISPR 2 PCR provided a simple assay for detection and identification of clinically-relevant Salmonella serotypes. In conjunction with antibiogram profiling and rapid assay for β-lactamase producers, this approach should facilitate detection and appropriate treatment of Salmonellosis in a local hospital setting. In addition, CRISPR 2 HRM-PCR profiling enabled clustering of S. 4,[5],12:i:-isolates according to CRISPR 2 locus signature sequences, indicative of their different evolutionary trajectories, thereby providing a powerful tool for future epidemiological studies of virulent Salmonella serotypes.


Frequency and pattern of poisoning in adult and adolescent Kraków population in 2003 and 1983.
The pattern (frequency, type of exposure, toxic substance) of adolescent and adult poisonings in Kraków in 2003 is compared with 1983. The analysis includes data for poisoned patients treated at the Kraków Department of Clinical Toxicology and all on the spot fatal cases subjected to post-mortem autopsy and toxicological examinations at the Department of Forensic Medicine Jagiellonian University Medical College in both the years. As much as 4341 poisoning cases (2852 males; 1489 females) were treated in 2003 compared with 2132 (1078 males; 1054 females) in 1983. In 1983 in group of 154 poisoned persons who died at the place of accident there were 138 (89.6%) men and 16 (10.4%) women. In 2003 among 121 deaths at the scene there were 93 (76.9%) males and 28 (23.1%) females. Poisonings due to suicidal attempts decreased significantly from 53.6% in 1983 to 19% in 2003. Incidence of poisoning per 10 000 of general Kraków population increased from 36.17 in 1983 to 57 in 2003 or up to 65.7 if the population of adults and teenagers (above 15 years old) was only considered. Pharmaceuticals (40.6%) followed in frequency by ethanol (25%) and ethanol co-ingested with pharmaceuticals (12.2%) and carbon monoxide (10.6%) were the most common reasons for poisoning in 1983. In 2003 the most common cause of poisonings was ethanol (46.2%) followed by pharmaceuticals alone (25%) or co-ingested with ethanol (6.4%) and carbon monoxide (6.2%). An ingestion of mixed pharmaceuticals (55.1%) followed In frequency by non-barbiturate hypnotics and psychotropic drugs (26.3%) were a most common in 1983 whereas a non-barbiturate hypnotics and psychotropic drugs (34.4%) followed by mixed pharmaceuticals (32.9%) in 2003. A mortality both concerning only the people who died in hospital and also those who died on the spot (prior to any treatment) was significantly higher in 1983 compared with 2003.


Crystallization and preliminary X-ray diffraction of human interleukin-7 bound to unglycosylated and glycosylated forms of its alpha-receptor.
The interleukin-7 (IL-7) signaling pathway plays an essential role in the development, proliferation and homeostasis of T and B cells in cell-mediated immunity. Understimulation and overstimulation of the IL-7 signaling pathway leads to severe combined immunodeficiency, autoimmune reactions, heart disease and cancers. Stimulation of the IL-7 pathway begins with IL-7 binding to its alpha-receptor, IL-7R alpha. Protein crystals of unglycosylated and glycosylated complexes of human IL-7-IL-7R alpha extracellular domain (ECD) obtained using a surface entropy-reduction approach diffract to 2.7 and 3.0 A, respectively. Anomalous dispersion methods will be used to solve the unglycosylated IL-7-IL-7R alpha ECD complex structure and this unglycosylated structure will then serve as a model in molecular-replacement attempts to solve the structure of the glycosylated IL-7-alpha-receptor complex.


Aspirin or heparin or both for improving pregnancy outcomes in women with persistent antiphospholipid antibodies and recurrent pregnancy loss.
Aspirin and heparin are widely used as preventive strategy to reduce the high risk of recurrent pregnancy loss in women with antiphospholipid antibodies (aPL). This review supersedes a previous, out-of-date review that evaluated all potential therapies for preventing recurrent pregnancy loss in women with aPL. The current review focusses on a narrower scope because current clinical practice is restricted to using aspirin or heparins, or both for women with aPL in an attempt to reduce pregnancy complications. To assess the effects of aspirin or heparin, or both for improving pregnancy outcomes in women with persistent (on two separate occasions) aPL, either lupus anticoagulant (LAC), anticardiolipin (aCL) or aβ2-glycoprotein-I antibodies (aβ2GPI) or a combination, and recurrent pregnancy loss (two or more, which do not have to be consecutive). We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (3 June 2019), and reference lists of retrieved studies. Where necessary, we attempted to contact trial authors. Randomised, cluster-randomised and quasi-randomised controlled trials that assess the effects of aspirin, heparin (either low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH]), or a combination of aspirin and heparin compared with no treatment, placebo or another, on pregnancy outcomes in women with persistent aPL and recurrent pregnancy loss were eligible. All treatment regimens were considered. Two review authors independently assessed trials for inclusion criteria and risk of bias. Two review authors independently extracted data and checked them for accuracy and the certainty of the evidence was assessed using the GRADE approach. Eleven studies (1672 women) met the inclusion criteria; nine randomised controlled trials and two quasi-RCTs. The studies were conducted in the USA, Canada, UK, China, New Zealand, Iraq and Egypt. One included trial involved 1015 women, all other included trials had considerably lower numbers of participants (i.e. 141 women or fewer). Some studies had high risk of selection and attrition bias, and many did not include sufficient information to judge the risk of reporting bias. Overall, the certainty of evidence is low to very low due to the small numbers of women in the studies and to the risk of bias. The dose and type of heparin and aspirin varied among studies. One study compared aspirin alone with placebo; no studies compared heparin alone with placebo and there were no trials that had a no treatment comparator arm during pregnancy; five studies explored the efficacy of heparin (either UFH or LMWH) combined with aspirin compared with aspirin alone; one trial compared LMWH with aspirin; two trials compared the combination of LMWH plus aspirin with the combination of UFH plus aspirin; two studies evaluated the combination of different doses of heparin combined with aspirin. All trials used aspirin at a low dose. Aspirin versus placebo We are very uncertain if aspirin has any effect on live birth compared to placebo (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.71 to 1.25, 1 trial, 40 women, very low-certainty evidence). We are very uncertain if aspirin has any effect on the risk of pre-eclampsia, pregnancy loss, preterm delivery of a live infant, intrauterine growth restriction or adverse events in the child, compared to placebo. We are very uncertain if aspirin has any effect on adverse events (bleeding) in the mother compared with placebo (RR 1.29, 95% CI 0.60 to 2.77, 1 study, 40 women). The certainty of evidence for these outcomes is very low because of imprecision, due to the low numbers of women involved and the wide 95% CIs, and also because of risk of bias. Venous thromboembolism and arterial thromboembolism were not reported in the included studies. Heparin plus aspirin versus aspirin alone Heparin plus aspirin may increase the number of live births (RR 1.27, 95% CI 1.09 to 1.49, 5 studies, 1295 women, low-certainty evidence). We are uncertain if heparin plus aspirin has any effect on the risk of pre-eclampsia, preterm delivery of a live infant, or intrauterine growth restriction, compared with aspirin alone because of risk of bias and imprecision due to the low numbers of women involved and the wide 95% CIs. We are very uncertain if heparin plus aspirin has any effect on adverse events (bleeding) in the mother compared with aspirin alone (RR 1.65, 95% CI 0.19 to 14.03, 1 study, 31 women). No women in either the heparin plus aspirin group or the aspirin alone group had heparin-induced thrombocytopenia, allergic reactions, or venous or arterial thromboembolism. Similarly, no infants had congenital malformations. Heparin plus aspirin may reduce the risk of pregnancy loss (RR 0.48, 95% CI 0.32 to 0.71, 5 studies, 1295 women, low-certainty evidence). When comparing LMWH plus aspirin versus aspirin alone the pooled RR for live birth was 1.20 (95% CI 1.04 to 1.38, 3 trials, 1155 women). In the comparison of UFH plus aspirin versus aspirin alone, the RR for live birth was 1.74 (95% CI 1.28 to 2.35, 2 trials, 140 women). The combination of heparin (UFH or LMWH) plus aspirin during the course of pregnancy may increase live birth rate in women with persistent aPL when compared with aspirin treatment alone. The observed beneficial effect of heparin was driven by one large study in which LMWH plus aspirin was compared with aspirin alone. Adverse events were frequently not, or not uniformly, reported in the included studies. More research is needed in this area in order to further evaluate potential risks and benefits of this treatment strategy, especially among women with aPL and recurrent pregnancy loss, to gain consensus on the ideal prevention for recurrent pregnancy loss, based on a risk profile.


Bootstrap approach for constructing confidence intervals for population pharmacokinetic parameters. I: A use of bootstrap standard error.
In population pharmacokinetic studies, one of the main objectives is to estimate population pharmacokinetic parameters specifying the population distributions of pharmacokinetic parameters. Confidence intervals for population pharmacokinetic parameters are generally estimated by assuming the asymptotic normality, which is a large-sample property, that is, a property which holds for the cases where sample sizes are large enough. In actual clinical trials, however, sample sizes are limited and not so large in general. Likelihood functions in population pharmacokinetic modelling include a multiple integral and are quite complicated. We hence suspect that the sample sizes of actual trials are often not large enough for assuming the asymptotic normality and that the asymptotic confidence intervals underestimate the uncertainties of the estimates of population pharmacokinetic parameters. As an alternative to the asymptotic normality approach, we can employ a bootstrap approach. This paper proposes a bootstrap standard error approach for constructing confidence intervals for population pharmacokinetic parameters. Comparisons between the asymptotic and bootstrap confidence intervals are made through applications to a simulated data set and an actual phase I trial.


A study of three enzymes acting on glucose in the lens of different species.
1. The activities of three enzymes which act on glucose, namely hexokinase, aldose reductase and glucose dehydrogenase, were measured in extracts of eye lens from cow, calf, rabbit, rat and guinea pig, and in human cataractous lenses. 2. The K(m) (glucose) of these three enzymes in extracts of cow lens was found to be 0.12mm, 28mm and 690mm respectively. 3. The physiological importance of hexokinase, aldose reductase and glucose dehydrogenase in the lens of normal and diabetic animals is discussed.


[An amebic liver abscess; early suspicion, late detection].
Two men aged 38 and 26 years developed symptoms including pain in the (upper) abdomen, malaise and fever 1.5-5 months after visiting the Caribbean. It was only after repeated ultrasonography that liver abscesses were observed. Adequate treatment was instituted and the patients recovered. The diagnosis of 'amoebic abscess of the liver' is usually based on the clinical presentation, the serological findings and characteristic observations at ultrasonography. However, if patients are seen at an early stage of development of the abscess, the serological findings may be negative and the ultrasonographic findings normal; consequently these findings do not justify exclusion of the diagnosis.


Effects of polyamine analogues on prostatic adenocarcinoma cells in vitro and in vivo.
The overall purpose of this study was to determine the potential usefulness of 1,19-di-(ethylamino)-5,10,15-triazononadecane (BE-4-4-4-4) in the treatment of prostate cancer using in vitro and in vivo models. More specifically the objectives were: (1) to determine the in vitro and in vivo sensitivity of human and rat prostate cancer cells to two polyamine analogues N1,N11-di(ethyl)norspermine (DENSPM) and BE-4-4-4-4; (2) to determine whether the mechanism of cell kill occurred through an apoptotic pathway; and (3) to determine the toxicity associated with therapeutic doses of BE-4-4-4-4 using an animal model. In order to determine the ability of these drugs to cause in vitro cytotoxicity, colony-forming assays were performed utilizing the well-characterized Dunning rat prostate cancer cell lines AT3.1, AT6.1 and AT6.3, and the androgen-insensitive human prostate cancer cell lines DU145, DuPro-1 and TSU-Pr1. Apoptotic cell death was determined using DNA laddering and DAPI staining of nuclei. The antitumor activity of BE-4-4-4-4 was evaluated by treatment of DuPro- and PC-3 xenograft tumors in nude mice. BE-4-4-4-4 was shown to be approximately 4 to 86 times more cytotoxic in clonogenic assays than DENSPM in both rat and human prostate carcinoma cell lines. Cells treated with cytotoxic doses of DENSPM or BE-4-4-4-4 showed no signs of apoptosis using either DNA laddering or DAPI staining of nuclei. There was a significant inhibition of DuPro-1 tumors for animals treated with BE-4-4-4-4 compared with control animals. Equitoxic doses of BE-4-4-4-4 resulted in greater tumor inhibition than DENSPM, although the difference was not significant. After treatment with therapeutic doses of BE-4-4-4-4, histopathologic evaluation indicated minimal to mild necrosis and inflammation in the kidneys on days 15 and 22 following treatment. On day 35, there was no necrosis or regeneration present in the kidney, indicating that the toxicity was transient and that regeneration of epithelial cells was complete with apparent return to normalcy. These initial studies demonstrate that BE-4-4-4-4 is cytotoxic against rat and human prostate cancer cells in culture and effective against DuPro-1 xenografts in nude mice. Polyamine analogues, such as DENSPM or BE-4-4-4-4, should be considered for clinical use in the treatment of prostate adenocarcinomas.


Extensive structure-activity studies of lactam derivatives of MT-II and SHU-9119: their activity and selectivity at human melanocortin receptors 3, 4, and 5.
The melanocortin system is involved in the regulation of several diverse physiologic pathways. Recently we have demonstrated that replacing His6 by Pro6 in the well-known antagonist SHU-9119 resulted in a potent agonist at the hMC5R (EC50 = 0.072 nm) with full antagonist activity at the hMC3R and the hMC4R. We have designed, synthesized, and pharmacologically characterized a series of peptide analogs of MT-II and SHU-9119 at the human melanocortin receptors MC3R, MC4R and MC5R. All these peptides were modified at position 6 with a Pro instead of a His residue. In this study, we have identified new scaffolds which are antagonists at the hMC4R and hMC3R. Additionally, we have discovered a new selective agonist at the hMC4R, Ac-Nle-c[Asp-Pro-D-Phe-Arg-Trp-Lys]-Pro-Val-NH2 (6, PG-931) which will be useful in further biologic investigations of the hMC4R. PG-931 was about 100-fold more selective for the hMC4R vs. the hMC3R (IC50 = 0.58 and 55 nm, respectively). Some of these new analogs have exceptional biologic potencies at the hMC5R and will be useful in further efforts to differentiate the substructural features responsible for selectivity at the hMC3R, hMC4R, and hMC5R.


Dermatologic aspects of sports medicine.
The skin is the barrier between the athlete and the sports milieu and is subjected to many insults. The purpose of this article is to review traumatic injuries to the cutaneous infections, environmental injuries, and exacerbation of preexisting dermatoses, which occur in sports enthusiasts. Emphasis will be placed on prevention and early therapeutic intervention.


Total correction of Fallot's tetralogy.
Eighty-six patients with Fallot's tetralogy underwent total correction; 80% of them were less than 15 years old. Twenty-five patients were operated upon with primary intracardiac repair, while 61 had undergone some form of palliative heart surgery previously. A patch of woven Dacron was used in the outflow tract reconstruction in 9 cases. The total mortality was 28%, 11 of the 23 deaths were presumed to be caused by low cardiac output, arrhythmia and cardiac arrest. The 62 patients surviving surgery have continuously had a good result and are without disability. The reasons for the relatively high mortality in this series, as well as the controversy concerning the one-stage or the two-stage approach for repair of Fallot's tetralogy, are briefly discussed.


Matrix metalloproteinase processing of PTHrP yields a selective regulator of osteogenesis, PTHrP1-17.
Parathyroid hormone-related protein (PTHrP) is a critical regulator of bone resorption and augments osteolysis in skeletal malignancies. Here we report that the mature PTHrP1-36 hormone is processed by matrix metalloproteinases to yield a stable product, PTHrP1-17. PTHrP1-17 retains the ability to signal through PTH1R to induce calcium flux and ERK phosphorylation but not cyclic AMP production or CREB phosphorylation. Notably, PTHrP1-17 promotes osteoblast migration and mineralization in vitro, and systemic administration of PTHrP1-17 augments ectopic bone formation in vivo. Further, in contrast to PTHrP1-36, PTHrP1-17 does not affect osteoclast formation/function in vitro or in vivo. Finally, immunoprecipitation-mass spectrometry analyses using PTHrP1-17-specific antibodies establish that PTHrP1-17 is indeed generated by cancer cells. Thus, matrix metalloproteinase-directed processing of PTHrP disables the osteolytic functions of the mature hormone to promote osteogenesis, indicating important roles for this circuit in bone remodelling in normal and disease contexts.


Silicone breakdown and capsular synovial metaplasia in textured-wall saline breast prostheses.
Saline-filled prostheses are currently the only type of prostheses available for cosmetic use in the United States because of concerns raised about the possibility of systemic toxicity of silicone-filled artificial mammary implants. Although the approved implants are saline-filled, their potential to release silicone particles from the shells has not been systematically evaluated. We performed microscopic examination of the pericapsular tissue of 54 patients with textured-surface implants and compared these with 51 patients with smooth-walled implants over a 2-year period. The capsules that had formed around virtually all textured-surface implants had silicone fragments present either in extracellular spaces, in vacuolated histiocytes, or in the form of foreign-body granulomas in surrounding fibroadipose tissue but not in capsules associated with smooth-walled implants. In 87 percent of samples of pericapsular tissue from textured saline implants, the contact surface displayed exuberant reactive synovial metaplasia, a histologic pattern not previously described with these devices. Our findings suggest that smooth-walled prostheses are associated with less silicone fragmentation than textured devices in the peri-implant tissue capsules that tend to form around artificial surfaces used for this purpose.


[Long-Term Prognosis of Patients with Biliary Tract Cancer Undergoing Pancreaticoduodenectomy].
We divided the patients with biliary tract cancer who underwent pancreaticoduodenectomy(PD)at our hospital into the 5-year recurrence-free and recurrence groups and investigated the prognostic factors. Additionally, we investigated the efficacy of adjuvant chemotherapy in patients with and without lymph node (LN) metastasis. There was no significant difference between the two groups for patient characteristics and perioperative factors. However, patients with LN metastasis tended to have a higher recurrence rate. For patients without LN metastasis, the median overall survival(OS)was not significantly different between the patients who received and did not receive adjuvant chemotherapy. For patients with LN metastasis, although it was not significantly different(p=0.234), the OS of patients who received adjuvant therapy was more than 3 times than that of patients who did not(58.6 months and 18.4 months, respectively). For patients with biliary tract cancer who underwent PD, positive LN metastasis may be a poor prognostic factor, and adjuvant therapy may possibly improve prognosis.


The second sphere and the story of no story.
The author discusses Roy Schafer's ideas of the second self and second reality, as well as his consistent theme of storyteller and story. The latter theme is also explored in the context of more recent psychoanalytic influences, such as Bionian thought, trauma theory, the French approach, and the interpersonal perspective. To illustrate the idea of the nonstory in today's clinical encounters, the author presents two clinical vignettes.


Leupaxin is a novel LIM domain protein that forms a complex with PYK2.
We have identified a novel cytoplasmic protein, leupaxin, that is preferentially expressed in hematopoietic cells and is most homologous to the focal adhesion protein, paxillin. Leupaxin possesses two types of protein interaction domains. There are four carboxyl-terminal LIM domains in leupaxin that share 70% amino acid identity and 80% similarity with those in paxillin. Paxillin LIM domains mediate localization to focal contacts. In the amino-terminal region of leupaxin there are three short stretches of approximately 13 amino acids that share 70-90% similarity with paxillin LD motifs. Paxillin LD motifs have been implicated in focal adhesion kinase (FAK) and vinculin binding resulting in the localization of FAK to focal adhesions. Leupaxin is expressed in cell types, such as macrophage, that lack FAK. We demonstrate here that leupaxin associates with a second FAK family member, PYK2. As leupaxin and PYK2 are both preferentially expressed in leukocytes they may therefore form a cell type-specific signaling complex. We also demonstrate that leupaxin is a substrate for a tyrosine kinase in lymphoid cells and thus may function in and be regulated by tyrosine kinase activity. Leupaxin is thus a phosphotyrosine protein with LD and LIM binding motifs most homologous to paxillin that may assemble and regulate PYK2 signaling complexes in leukocytes.


[Gastric vascular lesions in cirrhosis: gastropathy and antral vascular ectasia].
Portal hypertensive gastropathy (GHP) is a complication of portal hypertension usually associated with liver cirrhosis. The pathogenesis is unclear but the presence of portal hypertension is an essential factor for its development. GHP may be asymptomatic or present as gastrointestinal bleeding or iron deficiency anemia. Endoscopic lesions vary from a mosaic pattern to diffuse red spots; the most common location is the fundus. Treatment is indicated when there is acute or chronic bleeding, as secondary prophylaxis. There is insufficient evidence to recommend primary prophylaxis in patients who have never bled. Drugs that decrease portal pressure, such as non-cardioselective beta-blockers, and/or endoscopic ablative treatments, such as argon-beam coagulation, may be used. The role of transarterial intrahepatic portosystemic shunt) or bypass surgery has been insufficiently analyzed. Antral vascular ectasia (EVA) is a rare entity in liver cirrhosis, whose pathophysiology is still unknown. Clinical presentation is similar to that of GHP and endoscopy usually shows red spots in the antrum. Biopsy is often required to differentiate EVA from GHP. There is no effective medical therapy, so endoscopic ablative therapy and, in severe cases, antrectomy are recommended.


An aspergilloma caused by Aspergillus flavus.
Chronic pulmonary aspergillosis is broad term encompassing chronic cavitary, chronic fibrosing pulmonary aspergillosis and aspergilloma. All affect patients with structural lung diseases and many have subtle genetic immune defects. Almost all cases are caused by Aspergillus fumigatus. Here we report a patient with an aspergilloma which had Aspergillus flavus recovered from a surgical specimen and serum containing detectable precipitating antibody.


Rates and Routes of Hysterectomy for Benign Indications in Austria 2002 - 2014.
Rates and routes of hysterectomy have implications for quality, costs and training. This study analyzed rates of benign hysterectomy and surgical approaches for benign hysterectomy in Austria from 2002 to 2014. This was a population-based retrospective observational study of coding data from all acute care hospitals (public and private) in Austria. Main outcome measures were numbers of women undergoing hysterectomy for benign indications in Austria per year and the route of hysterectomy for benign indications. The number of benign hysterectomies performed per year declined from 10 675 in 2002 to 7747 in 2014, a decline of 27%. The use of vaginal hysterectomy was stable (53% and 47%, respectively). Use of laparoscopic techniques increased (5% in 2002, 32% in 2014) whereas use of abdominal hysterectomy decreased (41% and 20%, respectively). Numbers of benign hysterectomies performed per year in Austria declined substantially between 2002 and 2014. Use of vaginal hysterectomy was stable at about 50%, whereas increased use of laparoscopic techniques was associated with lower rates of open hysterectomy.


Immune status of children with obstructive sleep apnea/hypopnea syndrome.
We aimed to evaluate the immune status of children with obstructive sleep apnea/hypopnea syndrome (OSAHS). Fifty children with OSAHS having the symptoms of "snoring, mouth breathing and suffocating during sleep", who were admitted in our hospital from May 2014 to May 2016, were randomly selected. Another 52 healthy, age- and gender-matched children were enrolled as control subjects after taking informed consent. After admission, the peripheral venous blood was collected. T cell subsets and cytokines were analyzed by flow cytometry. Immunoglobulin and complement levels were detected by immunoassay analyzer. The percentage of CD8+ T lymphocytes in children with OSAHS was (26.47 ± 1.52)% which was significantly higher than that of control group ((21.94 ± 1.92)%) (P<0.05). OSAHS group had a significantly lower CD4+/CD8+ ratio (1.24 ± 0.12) than that of control group (1.45 ± 0.11) (P<0.05). The two groups had similar percentages of CD3+ and CD4+ T lymphocytes (P>0.05). OSAHS group had significantly higher serum levels of IL-4, IL-6, IL-10 and IFN-γ than those of control group (P<0.05), but their IL-2 and TNF-α levels were similar (P>0.05). The serum IgA and C3 levels of OSAHS group significantly exceeded those of control group (P<0.05), but their IgG, IgM and C4 levels were similar (P>0.05). Children with OSAHS had increased percentage of CD8+ T lymphocytes and decreased CD4+/CD8+ ratio, suggesting this group had poor immune function. Increase in humoral immune-related indices IL-4, IL-6, IL-10 and IFN-γ indicated the occurrence of oxidative stress and systemic inflammatory status.


Long non‑coding RNA HOTAIR promotes burn wound healing by regulating epidermal stem cells.
Local transplantation of epidermal stem cells (ESCs) exerts a therapeutic effect on burn wounds. However, cell viability can impede their clinical application. HOX antisense intergenic RNA (HOTAIR) is involved in regulating adult tissue stem cells, as well as in developmental patterning and pluripotency. However, little is known about its role in regulating ESCs. The present study was performed to investigate the effects of HOTAIR in the modulation of ESCs and wound repair. Firstly, reverse transcription‑quantitative PCR was used to detect the relative expression of HOTAIR during burn wound healing in mice to determine whether HOTAIR is associated with wound healing. Subsequently, ESCs derived from mouse skin were transfected with a lentiviral vector to overexpress or knockdown HOTAIR. The effects of HOTAIR on cell proliferation and differentiation were measured by 5‑bromodeoxyuridine and MTT assays, and by assessing NANOG mRNA expression. Lastly, mice with burns were administered a subcutaneous injection of HOTAIR‑overexpressing ESCs. Images were captured and histological analyses were performed to evaluate wound healing. The results revealed that the expression of HOTAIR gradually increased and peaked at day 7 post‑burn and maintained at relatively high levels until day 14 post‑burn during wound healing. Furthermore, overexpression of HOTAIR promoted ESC proliferation and maintained the stem cell state in vitro. By contrast, suppression of HOTAIR inhibited cell proliferation and cell stemness. It was also identified that HOTIR‑overexpressing ESCs accelerated re‑epithelialization and facilitated burn wound repair. In conclusion, the present findings confirmed an essential role of HOTAIR in the regulation of ESC proliferation and stemness. Therefore, targeting HOTAIR in ESCs may be a potentially promising therapy for burn wound healing.


Impact of Michelangelo prosthetic hand: Findings from a crossover longitudinal study.
This work explores the functional and psychosocial impact of the multigrip Michelangelo (M) prosthetic hand. Transradial myoelectric prosthesis users (6 men, median age: 47 y) participated in a crossover longitudinal study. A multifactorial assessment protocol was applied before the application of M and after 3 mo (functional assessment) and 6 mo (psychosocial assessment) of home use. Functional assessment included both practical tests (i.e., Southampton Hand Assessment Procedure [SHAP], Box and Blocks Test [BBT], and Minnesota Manual Dexterity Test [MMDT]) and self-report functional scales. Psychosocial assessment consisted of a clinical interview and a battery of self-report questionnaires concerning current anxious-depressive symptoms and health-related quality of life, body image concerns, adjustment and satisfaction with prosthesis, social support, coping style, and personality. Increased manual dexterity was observed after 3 mo based on improvements in the SHAP, BBT, and MMDT. Two important themes emerged from the clinical interviews at the 6 mo follow-up: (1) the enhanced functionality and (2) the "like a real hand" aspect of the M, which further increased prosthesis integration to the Self. A few patients expressed concerns about M dimension, noise, and weight. The M appeared to restore hand function and natural appearance. The present findings provide preliminary evidence, and additional studies are needed.


Evaluation of common genetic variants in pre-microRNA in susceptibility and prognosis of esophageal cancer.
Genetic variants in micro-RNAs (miRNA) have been shown to affect progression, diagnosis, and prognosis of various malignancies; however, their role in esophageal squamous cell carcinoma (ESCC) susceptibility is controversial. Therefore, we aimed to determine role of common genetic variants in cancer related pre-miRNA in susceptibility and survival outcome of north Indian ESCC patients. We genotyped four common polymorphisms in pre-miRNA: mir-196a-2C>T, mir-146aG>C, mir-499T>C, and mir-423C>A in 289 incident ESCC cases (including 153 follow-up cases) and 309 controls using PCR/PCR RFLP-based methods. Binary logistic regression was applied for risk estimation, while Kaplan-Meier and Cox Regression tests were performed for survival analysis. We observed that none of the pre-miRNA genetic variants were associated with ESCC or its clinical phenotypes independently, however, combined risk genotypes of four pre-miRNA polymorphisms increased risk of ESCC in dose-response manner (Ptrend = 0.011). Specifically, patients with 2-4 risk genotypes of pre-miRNA polymorphisms had 1.4-fold higher risk of ESCC compared to patients with 0-1 risk genotypes (OR = 1.43, 95% CI = 1.02-1.09, P-value = 0.037). The risk was more pronounced in ESCC cases with upper-third esophageal tumors. Moreover, cumulative but not independent effect of risk genotypes of pre-miRNA polymorphisms was observed on survival outcome of ESCC patients. Cases with 2-4 risk genotypes had significantly lower median survival (11.60 vs. 30.2 months) and 2.3-fold greater hazard of death compared to patients with 0-1 risk genotypes. In conclusion, the four studied common pre-miRNA polymorphisms cumulatively affect susceptibility and survival of ESCC patients in north Indian population. © 2012 Wiley Periodicals, Inc.


Unusual Escherichia coli PBP 3 Insertion Sequence Identified from a Collection of Carbapenem-Resistant Enterobacteriaceae Tested In Vitro with a Combination of Ceftazidime-, Ceftaroline-, or Aztreonam-Avibactam.
Carbapenemase-producing Enterobacteriaceae isolates (n = 110) from health care centers in central Indiana (from 2010 to 2013) were tested for susceptibility to combinations of avibactam (4 μg/ml) with ceftazidime, ceftaroline, or aztreonam. MIC50/MIC90 values were 1/2 μg/ml (ceftazidime-avibactam), 0.5/2 μg/ml (ceftaroline-avibactam), and 0.25/0.5 μg/ml (aztreonam-avibactam.) A β-lactam MIC of 8 μg/ml was reported for the three combinations against one Escherichia coli isolate with an unusual TIPY insertion following Tyr344 in penicillin-binding protein 3 (PBP 3) as the result of gene duplication.


Latent difference score approach to longitudinal trauma research.
In this article, the authors introduce a latent difference score (LDS) approach to analyzing longitudinal data in trauma research. The LDS approach accounts for internal sources of change in an outcome variable, including the influence of prior status on subsequent levels of that variable and the tendency for individuals to experience natural change (e.g., a natural decrease in posttraumatic stress disorder [PTSD] symptoms over time). Under traditional model assumptions, the LDSs are maximally reliable and therefore less likely to introduce biases into model testing. The authors illustrate the method using a sample of children who experienced significant burns or other injuries to examine potential influences (i.e., age of child-adolescent at time of trauma and ongoing family strains) on PTSD symptom severity over time.


High population densities of Macrolophus pygmaeus on tomato plants can cause economic fruit damage: interaction with Pepino mosaic virus?
The zoophytophagous predator Macrolophus pygmaeus Rambur (Hemiptera: Miridae) is a successful biocontrol agent against several pest species in protected tomato crops. This predator is considered to be harmless for the crop. However, in recent years, Heteroptera feeding punctures on tomato fruit in Belgian and Dutch greenhouses have been misinterpreted as Pepino mosaic virus (PepMV) symptoms. In this study, three hypotheses were tested: (1) M. pygmaeus causes fruit damage that increases with population density and surpasses economic thresholds; (2) the presence of prey or alternative prey reduces the damage; (3) an infection of the tomato plants by PepMV triggers or aggravates M. pygmaeus fruit damage. At increasing M. pygmaeus densities, the severity of fruit damage increased from a few dimples towards yellowish discoloration and deformed fruits. A correlation with an infection with PepMV was found. The severity of the symptoms was independent of the presence of prey. A minimum economic density threshold was estimated at 0.32 M. pygmaeus per leaf. M. pygmaeus can cause economic damage to tomato fruits at densities common in practice. An infection of the plants with PepMV enhances fruit symptoms significantly. Interacting plant defence responses are most likely the key to explaining this, although confirmation is required. © 2015 Society of Chemical Industry.


Omeprazole induces NAD(P)H quinone oxidoreductase 1 via aryl hydrocarbon receptor-independent mechanisms: Role of the transcription factor nuclear factor erythroid 2-related factor 2.
Activation of the aryl hydrocarbon receptor (AhR) transcriptionally induces phase I (cytochrome P450 (CYP) 1A1) and phase II (NAD(P)H quinone oxidoreductase 1 (NQO1) detoxifying enzymes. The effects of the classical and nonclassical AhR ligands on phase I and II enzymes are well studied in human hepatocytes. Additionally, we observed that the proton pump inhibitor, omeprazole (OM), transcriptionally induces CYP1A1 in the human adenocarcinoma cell line, H441 cells via AhR. Whether OM activates AhR and induces the phase II enzyme, NAD(P)H quinone oxidoreductase 1 (NQO1), in fetal primary human pulmonary microvascular endothelial cells (HPMEC) is unknown. Therefore, we tested the hypothesis that OM will induce NQO1 in HPMEC via the AhR. The concentrations of OM used in our experiments did not result in cytotoxicity. OM activated AhR as evident by increased CYP1A1 mRNA expression. However, contrary to our hypothesis, OM increased NQO1 mRNA and protein via an AhR-independent mechanism as AhR knockdown failed to abrogate OM-mediated increase in NQO1 expression. Interestingly, OM activated Nrf2 as evident by increased phosphoNrf2 (S40) expression in OM-treated compared to vehicle-treated cells. Furthermore, Nrf2 knockdown abrogated OM-mediated increase in NQO1 expression. In conclusion, we provide evidence that OM induces NQO1 via AhR-independent, but Nrf2-dependent mechanisms.


Lower Extremity Bypass Surgery on Patients Transferred from Other Hospitals is Associated with Increased Morbidity and Mortality.
Despite advances in endovascular surgery, lower extremity arterial bypass remains the gold standard treatment for severe, symptomatic peripheral arterial disease (PAD). Patients who are transferred to other hospitals have generally complex medical problems compared to those patients who are directly admitted from home. The purpose of this study is to identify factors associated with an interfacility transfer in patients with PAD and compare the postoperative outcomes of these patients to those who are directly admitted to the hospital. The 2013 lower extremity revascularization-targeted American College of Surgeons (ACS-National Surgical Quality Improvement Program [NSQIP]) database and generalized 2013 general and vascular surgery ACS-NSQIP Participant Use File were used for this study. Patient, diagnosis, and procedure characteristics of patients undergoing lower extremity bypass surgery were assessed. Multivariate logistic regression analysis was used to determine independent risk factors for transfer to another hospital. A total of 2,646 patients (65% male, 35% female) were identified in the NSQIP database that underwent lower extremity open revascularization during the year 2013. A total of 287 patients (11%) were transferred from other institutions: acute care hospital inpatient (4%), nursing home/chronic care/intermediate care (3%), outside emergency department (3%), and other (1%). Factors associated with increased risk of interfacility transfer included need for emergency surgery (odds ratio [OR]: 5.51, P < 0.05), infected wounds (OR: 2.77, P < 0.05), and age >85 years (OR: 2.24, P < 0.05). Postoperative outcome associated with transfer was mortality <30 days postop (OR: 1.96) and length of stay >30 days (OR: 2.04; P < 0.05). Multiple factors affect an interfacility transfer of patients including advanced age, need for emergency procedure, contaminated wounds. Patients who are transferred from another institution for a lower extremity bypass surgery are at a substantially higher risk for postoperative morbidity and mortality.


Removal of unexpected schwannoma with superficial parotidectomy using modified-Blair incision and superficial musculoaponeurotic system folding: A case report.
When a firm facial mass in the cheek region is associated with a high index of clinical suspicion of its being of parotid gland origin, preventive parotidectomy is invariably performed. We report a rare case of a schwannoma that was suspected to be of parotid gland origin in a patient, who underwent successful surgical management using a modified-Blair incision and superficial musculoaponeurotic system (SMAS) layer folding method. A 27-year-old woman presented to the hospital for evaluation of a firm, fixed, non-tender mass (2.5 cm × 3.5 cm), located anterior to the right ear, of 1 year's duration. Contrast-enhanced facial computed tomography revealed a well-encapsulated, low-density mass adherent to the superficial lobe of the right parotid gland, with a high index of clinical suspicion of an accessory parotid gland mass. The patient was scheduled to undergo resection of the mass and superficial parotidectomy. She underwent surgery using a modified-Blair incision, and the SMAS layer was folded posteriorly to reconstruct the defect. Histopathological examination confirmed the diagnosis of a schwannoma., and we observed no postoperative complications such as hematoma, infection, or abnormal facial expressions. The incision scar was unnoticeable 2 mo postoperatively, and the facial contour was maintained without any differences between the affected and unaffected sides. We used a modified-Blair incision and SMAS layer folding method to achieve aesthetically good results following resection of a rare schwannoma with superficial parotidectomy in the cheek region.


In vitro and in vivo evaluation of the estrogenic, androgenic, and progestagenic potential of two cyclic siloxanes.
The purpose of these experiments was to determine the potential estrogenic, androgenic, and progestagenic activity of two cyclic siloxanes, octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5). Receptor-binding experiments and a luciferase reporter gene assay were used to determine if the materials were able to bind and activate either the estrogen receptors (ERs) or progesterone receptors (PRs)-alpha or beta. The rat uterotrophic assay (RUA) for estrogenic activity and the Hershberger assay for androgenic activity were utilized as the in vivo assays. For the ER-binding studies, D4 was shown to bind to ERalpha but not to ERbeta. D5 did not bind to either of the two receptors. D4 activated the reporter gene at 10 microM, while D5 was considered negative in the estrogen reporter gene assay. Neither material was a ligand for the PRs. Both the RUA and Hershberger assays were conducted using whole-body inhalation of the two materials for 16 h/day. D4 resulted in a small but significant increase in both wet and blotted uterine weight as well as increases in both luminal and glandular epithelial cell height in both Sprague Dawley and Fischer 344 rats. D5 was negative in both rat strains, indicating that D5 does not possess estrogenic activity. Neither material possessed any significant antiestrogenic activity. Both materials were negative in the Hershberger assay indicating that neither material possesses any significant androgenic activity. Our studies have shown that D4 exhibits a low affinity for ERalpha in vitro and a weakly estrogenic response in vivo.


Comparison of short and long-term treatment with synthetic LH-releasing hormone and clomiphene citrate in male hypothalamic hypogonadism.
The effects of short and long-term treatment with clomiphene citrate and with synthetic LH-releasing hormone (LHRH) on gonadotropin release were studied in 5 male patients with hypothalamic hypogonadism. Neither short-term treatment with clomiphene citrate (50 mg or 200 mg daily for 4 days) nor long-term treatment (25 mg or 100 mg for 30-62 days) was effective in increasing serum LH and FSH in any patients. On the other hand, 5 cases showed slight or no rise in LH after administration of a single dose of 100 mug LH-releasing hormone (LHRH) and higher rises after administration of 400 mug. Four cases who were given 200 mug LHRH daily for 3 weeks showed an increasing response of serum LH and reached maximal LH levels at 2 weeks, followed by no further increase. In two of the four cases serum LH level reached normal adult male ranges. There was no increase of serum testosterone during LHRH treatment. These results suggest that long-term treatment with synthetic LHRH may be effective for gonadotropin restoration in some patients with hypothalamic hypogonadism in which long-term treatment of clomiphene citrate was shown to be ineffective.


Aberrant patterns of X chromosome inactivation in bovine clones.
In mammals, epigenetic marks on the X chromosomes are involved in dosage compensation. Specifically, they are required for X chromosome inactivation (XCI), the random transcriptional silencing of one of the two X chromosomes in female cells during late blastocyst development. During natural reproduction, both X chromosomes are active in the female zygote. In somatic-cell cloning, however, the cloned embryos receive one active (Xa) and one inactive (Xi) X chromosome from the donor cells. Patterns of XCIhave been reported normal in cloned mice, but have yet to be investigated in other species. We examined allele-specific expression of the X-linked monoamine oxidase type A (MAOA) gene and the expression of nine additional X-linked genes in nine cloned XX calves. We found aberrant expression patterns in nine of ten X-linked genes and hypomethylation of Xist in organs of deceased clones. Analysis of MAOA expression in bovine placentae from natural reproduction revealed imprinted XCI with preferential inactivation of the paternal X chromosome. In contrast, we found random XCI in placentae of the deceased clones but completely skewed XCI in that of live clones. Thus, incomplete nuclear reprogramming may generate abnormal epigenetic marks on the X chromosomes of cloned cattle, affecting both random and imprinted XCI.


Cancer Research in the Arab World: A review of publications from seven countries between 2000-2013.
This review aimed to examine trends in cancer research in the Arab world and identify existing research gaps. A search of the MEDLINE® database (National Library of Medicine, Bethesda, Maryland, USA) was undertaken for all cancer-related publications published between January 2000 and December 2013 from seven countries, including Bahrain, Kuwait, Iraq, Lebanon, Morocco, Palestine and Sudan. A total of 1,773 articles were identified, with a significant increase in yearly publications over time (P <0.005). Only 30.6% of the publications included subjects over the age of 50 years old. There was a dearth of cross-sectional/correlational studies (8.8%), randomised controlled trials (2.4%) and systematic reviews/meta-analyses (1.3%). Research exploring cancer associations mainly considered social and structural determinants of health (27.1%), followed by behavioural risk factors (14.1%), particularly tobacco use. Overall, more cancer research is needed in the Arab world, particularly analytical studies with high-quality evidence and those focusing on older age groups and associations with physical activity and diet.


Hematological Alterations after Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.
Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have benefits for survival in some cancers with peritoneal metastasis. Hematologic toxicity described rate is 2 to 38%. Patients admitted to an intensive care unit (ICU) after CRS and HIPEC over 78 months. The data recorded were demographic characteristics, the severity of illness, complete blood samples, the type of cancer and extension, HIPEC drug and temperature, ICU and hospital stay and mortality, bleeding, and the need for transfusion of blood products. Of the 96 patients included, 77.1% presented hematological complications: 8.3% leukopenia (<4000/mm3 leucocytes), 66.7% anemia (hemoglobin < 10 mg/dL), and 22.9% coagulopathy (INR < 1.5, or/and aPTT < 45 s, or/and platelet count < 100,000/mm3, or/and <100 mg/dL of serum fibrinogen). Leukopenia was higher in ovarian cancer or those treated with doxorubicin. Females with anemia, ovarian cancer, and those treated with cisplatin or doxorubicin had longer ICU stays. Bleeding complications were low-corrected in a conservative manner. The median ICU stay was 5 (4.0-5.0) days. The ICU mortality rate was 1.0%. In our study, 77.1% of patients treated with CRS and HIPEC developed hematological complications during the postoperative period; the majority of them were not severe and resolved spontaneously, without an effect on mortality or hospital stay.


Evaluation of cytotoxic properties of a cyclopamine glucuronide prodrug in rat glioblastoma cells and tumors.
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Activation of the developmental hedgehog (Hh) pathway is observed in GBM, particularly in the so-called glioma stem cells (GSCs). An inhibitor of this pathway is the steroidal alkaloid cyclopamine, an antagonist of the Hh coreceptor Smoothened (SMO). To limit the toxicity of cyclopamine toward Hh-dependent non-tumor cells, our group previously reported the synthesis of a prodrug (called 1b), designed to deliver cyclopamine in the presence of β-glucuronidase, an enzyme found in the necrotic area of GBM. Here, we aimed to analyze the in vitro, ex vivo, and in vivo cytotoxic properties of this prodrug in the C6 rat GBM cells. In the presence of β-glucuronidase, the activated prodrug 1b was toxic and downregulated expression of Gli1, a Hh target gene, in C6 cells and C6-GSCs, but not in normal rat astrocytes in which the Hh pathway is weakly activated. In the absence of β-glucuronidase, prodrug 1b displayed no obvious toxicity toward rat brain tissue explants while cyclopamine clearly affected brain tissue viability. When administered to rats bearing fluorescent C6-derived GBM, the prodrug 1b reduced the tumor density more efficiently than cyclopamine. Prodrug 1b thus appears as a promising concept to optimize confinement of cyclopamine cytotoxicity within the tumors, with more limited effects in the surrounding normal brain tissue.


Analysis of differentially expressed genes and microRNAs in alcoholic liver disease.
The purpose of this study was to screen differentially expressed genes and microRNAs in order to find a new target for the accurate diagnosis and effective therapy of alcoholic liver disease (ALD) at the gene and microRNA levels. The total RNA of liver tissues was extracted from four groups of patients, ten subjects each. Microarrays were utilized to detect differentially expressed genes and microRNAs. According to gene values, significance levels and false discovery rate with a random variance model, gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, node genes and key microRNAs in networks were obtained and analyzed. A total of 878 differentially expressed genes and 26 microRNAs were found. In co-expression genetic networks, node genes modulating the network were Acyl-coenzyme A synthetase-3 (ACSF3), Frizzled-5 (FZD5), LOC727987 and C1orf222. In microRNA-gene networks, the key microRNAs were hsa-miR-570, hsa-miR-122, hsa-miR-34b, hsa-miR-29c, hsa-miR-922 and hsa-miR-185, which negatively regulated approximately 79 downstream target genes. In the course of ALD, we found 4 differentially expressed node genes and analyzed ACSF3 and FZD5. ACSF3 was significantly upregulated, and was involved in fatty acid and lipid metabolism and accelerated liver injury. These two genes were involved in fatty acids and lipid metabolism. FZD5 was downregulated and reduced the synthesis of membrane transport protein in the hepatic membrane and the membrane stability, and accelerated the liver cell apoptosis process. Six key microRNAs regulated numerous biological functions such as the immune response, the inflammatory response and glutathione metabolism. This finding provides valuable insight into the diagnosis and treatment of ALD.


Synthesis and structure-activity relationships of peptidyl alpha-keto heterocycles as novel inhibitors of prolyl endopeptidase.
The preparation and in vitro prolyl endopeptidase (PEP) inhibitory activity of a series of alpha-keto heterocyclic compounds is described. The design is based on the introduction of alpha-keto heterocycles at the C-terminal end of substrate-like peptides. Many of the compounds including those substituted with thiazole, benzothiazole, benzoxazole, imidazole, and pyridine groups exhibit IC50 potencies of PEP inhibition at nanomolar levels. Structure-activity studies of the C-terminal heterocyclic groups indicate the importance of an sp2 nitrogen atom at a beta-position from the adjoining ketone carbonyl group. This heterocyclic nitrogen atom would provide a critical hydrogen-bond interaction with the histidine residue of the catalytic triad in PEP. Our inhibitors would extend the generality of the alpha-keto heterocycle design to another serine protease.


Extremely small amounts of B[a]P residues remobilised in long-term contaminated soils: A strong case for greater focus on readily available and not total-extractable fractions in risk assessment.
There is a lack of understanding about the potential for remobilisation of polycyclic aromatic hydrocarbons (PAHs) residues in soils, specifically after the removal of readily available fractions, and the likelihood to cause harm to human and environmental health. Sequential solvent extractions, using butanol (BuOH), dichloromethane/acetone, and methanolic saponification were used to investigate the time-dependent remobilisation of B[a]P residues in aged soils, after removal of readily available or total-extractable fractions. After 120 d of aging, BuOH-remobilised B[a]P were small or extremely small ranging from 2.3 ± 0.1 mg/kg to 4.5 ± 0.5 mg/kg and from 0.9 ± 0.0 mg/kg to 1.0 ± 0.1 mg/kg, after removal of readily available and total-extractable fractions, respectively. After removal of readily available fractions, the remobilisation rates of B[a]P residues were constant over 5 re-equilibration times, as shown by first-order kinetics. The amounts of B[a]P remobilised significantly (p < 0.05) decreased with aging, particularly in hard organic carbon-rich soils. After 4 years of aging, BuOH- and total-remobilised B[a]P were generally < 5% of the initially spiked 50 mg/kg. Based on the findings of this study, the potential or significant potential for B[a]P NERs in soils to cause significant harm to human and environmental health are minimal.


Ethical dilemmas of cervical cancer screening.
Cervical screening presents several ethical dilemmas to family physicians. The author reviews the risks associated with screening, costs versus benefits of running a screening program, and the issues surrounding patient autonomy and patient coercion. Is saving one life worthwhile, and at what cost? Cervical screening programs are imperative in family practice, but only if harm to the patient is minimized and ethical objections are addressed.


Nicotinic acetylcholine receptors containing subunits alpha3 and alpha5 in rat nociceptive dorsal root ganglion neurons.
Nociceptive primary afferent neurons carry nicotinic acetylcholine receptors (nAChRs). Using RTPCR, mRNAs for all alpha-subunits have been identified in rat dorsal root ganglia (DRG) (Genzen et al., 2001; Lips et al., 2002), but the responses of nociceptive neurons to nicotine are not uniform and the cellular distribution of nAChRs within DRG, in general, and among functionally different subtypes of primary afferent neurons, in particular, are only partially resolved (Rau et al., 2005). These diverse actions might suggest the presence of various nAChR isoforms that are operative under different conditions. The present study was aimed to extend previous studies on nAChRs that contain subunits alpha4, alpha7, and alpha10 in providing data for alpha3- and alpha5-subunit-containing nAChRs (Haberberger et al., 2004; Papadopolou et al., 2004). To this end, calcium-imaging and double-labeling immunofluorescence with nAChR alpha-subunit-specific antibodies, in combination with markers for nociceptive neurons (TRPV1, I-B4), were applied.


Environmental Regulation, Promotion Pressure of Officials, and Enterprise Environmental Protection Investment.
This study expands on the impact of local government environmental regulation on enterprise environmental protection investment. Furthermore, it analyzes the influence promotion pressure of officials has on the scale of enterprise environmental investment. The results show that the environmental protection investment of companies in China is generally insufficient. The attitude of companies toward environmental protection is passive under the policy regulation. The environmental supervision of the government is also still at a low level. Both of these observations are far from the intentions of the government. There is a U-shaped relationship between the pressure of official promotion and the scale of enterprise environmental protection investment. Only when the pressure of official promotion exceeds a certain limit can it positively stimulate enterprises to invest in environmental protection. Environmental regulation also exerts a threshold effect on the environmental protection investment by enterprises. This research provides a new way to understand the decision-making behavior of local officials and the environmental protection responsibility of enterprises. This study provides recommendations for improving the environment appraisal and government supervision system in China.


Trapped modes in an infinite or semi-infinite tube with a local enlargement.
Trapped modes in a hard cylindrical tube with a local axisymmetric enlargement or bulge and filled with a uniform acoustic medium is studied. The governing Helmholtz equation in the cylindrical coordinate system is employed to deal with this problem through the domain decomposition method and matching technique. The trapped modes and the corresponding frequencies less than the threshold frequency or cut-off frequency are derived. It is found that in addition to the fundamental mode, the second- and higher-order trapped modes exist and depend on the geometry parameters of the local bulge. The effects of the bulge radius and width on the frequencies are discussed. The local bulge leads to a decrease of the frequencies and the corresponding vibration mode is localized near the bulge. A multimodal analysis is made and frequency band gap of generalized trapped modes is also studied. A frequency band gap depends on the radius of a bulge and is independent of its width. The obtained results can be extended to analyze bound states in quantum wires.


KLF9-dependent ROS regulate melanoma progression in stage-specific manner.
Although antioxidants promote melanoma metastasis, the role of reactive oxygen species (ROS) in other stages of melanoma progression is controversial. Moreover, genes regulating ROS have not been functionally characterized throughout the entire tumor progression in mouse models of cancer. To address this question, we crossed mice-bearing knock-out of Klf9, an ubiquitous transcriptional regulator of oxidative stress, with two conditional melanocytic mouse models: BrafCA mice, where BrafV600E causes premalignant melanocytic hyperplasia, and BrafCA/Pten-/- mice, where BrafV600E and loss of Pten induce primary melanomas and metastases. Klf9 deficiency inhibited premalignant melanocytic hyperplasia in BrafCA mice but did not affect formation and growth of BrafCA/Pten-/- primary melanomas. It also, as expected, promoted BrafCA/Pten-/- metastasis. Treatment with antioxidant N-acetyl cysteine phenocopied loss of Klf9 including suppression of melanocytic hyperplasia. We were interested in a different role of Klf9 in regulation of cell proliferation in BrafCA and BrafCA/Pten-/- melanocytic cells. Mechanistically, we demonstrated that BRAFV600E signaling transcriptionally upregulated KLF9 and that KLF9-dependent ROS were required for full-scale activation of ERK1/2 and induction of cell proliferation by BRAFV600E. PTEN depletion in BRAFV600E-melanocytes did not further activate ERK1/2 and cell proliferation, but rendered these phenotypes insensitive to KLF9 and ROS. Our data identified an essential role of KLF9-dependent ROS in BRAFV600E signaling in premalignant melanocytes, offered an explanation to variable role of ROS in premalignant and transformed melanocytic cells and suggested a novel mechanism for suppression of premalignant growth by topical antioxidants.


Heritable modifiers of the tumor microenvironment influence nanoparticle uptake, distribution and response to photothermal therapy.
We report the impact of notch-DLL4-based hereditary vascular heterogeneities on the enhanced permeation and retention (EPR) effect and plasmonic photothermal therapy response in tumors. Methods: We generated two consomic rat strains with differing DLL4 expression on 3rd chromosome. These strains were based on immunocompromised Salt-sensitive or SSIL2Rγ- (DLL4-high) and SS.BN3IL2Rγ- (DLL4-low) rats with 3rd chromosome substituted from Brown Norway rat. We further constructed three novel SS.BN3IL2Rγ- congenic strains by introgressing varying segments of BN chromosome 3 into the parental SSIL2Rγ- strain to localize the role of SSIL2Rγ- DLL4 on tumor EPR effect with precision. We synthesized multimodal theranostic nanoparticles (TNPs) based on Au-nanorods which provide magnetic resonance imaging (MRI), X-ray, and optical contrasts to assess image guided PTT response and quantify host specific therapy response differences in tumors orthotopically xenografted in DLL4-high and -low strains. We tested recovery of therapy sensitivity of PTT resistant strains by employing anti-DLL4 conjugated TNPs in two triple negative breast cancer tumor xenografts. Results: Host strains with high DLL4 allele demonstrated slightly increased tumor nanoparticle uptake but consistently developed photothermal therapy resistance compared to tumors in host strains with low DLL4 allele. Tumor micro-environment with low DLL4 expression altered the geographic distribution of nanoparticles towards closer proximity with vasculature which improved efficacy of PTT in spite of lower overall TNP uptake. Targeting TNPs to tumor endothelium via anti-DLL4 antibody conjugation improved therapy sensitivity in high DLL4 allele hosts for two triple negative human breast cancer xenografts. Conclusions: Inherited DLL4 expression modulates EPR effects in tumors, and molecular targeting of endothelial DLL4 via nanoparticles is an effective personalized nanomedicine strategy.


Persistence and adverse events of biological treatment in adult patients with juvenile idiopathic arthritis: results from BIOBADASER.
Biologic therapy has changed the prognosis of patients with juvenile idiopathic arthritis (JIA). The aim of this study was to examine the pattern of use, drug survival, and adverse events of biologics in patients with JIA during the period from diagnosis to adulthood. All patients included in BIOBADASER (Spanish Registry for Adverse Events of Biological Therapy in Rheumatic Diseases), a multicenter prospective registry, diagnosed with JIA between 2000 and 2015 were analyzed. Proportions, means, and SDs were used to describe the population. Incidence rates and 95% CIs were calculated to assess adverse events. Kaplan-Meier analysis was used to compare the drug survival rates. A total of 469 patients (46.1% women) were included. Their mean age at diagnosis was 9.4 ± 5.3 years. Their mean age at biologic treatment initiation was 23.9 ± 13.9 years. The pattern of use of biologics during their pediatric years showed a linear increase from 24% in 2000 to 65% in 2014. Biologic withdrawal for disease remission was higher in patients who initiated use biologics prior to 16 years of age than in those who were older (25.7% vs 7.9%, p < 0.0001). Serious adverse events had a total incidence rate of 41.4 (35.2-48.7) of 1000 patient-years. Patients younger than 16 years old showed significantly increased infections (p < 0.001). Survival and suspension by remission of biologics were higher when these compounds were initiated in patients with JIA who had not yet reached 16 years of age. The incidence rate of serious adverse events in pediatric vs adult patients with JIA treated with biologics was similar; however, a significant increase of infection was observed in patients under 16 years old.


Gastrointestinal tissue engineering.
Tissue engineering is an emerging discipline that combines engineering principles and the biological sciences toward the development of functional replacement tissue. Virtually every tissue in the body has been investigated and tremendous advances have been made in many areas. This article focuses on the gastrointestinal tract and reviews the current status of bioengineering gastrointestinal tissues, including the esophagus, stomach, small intestine and colon. Although progress has been achieved, there continues to be significant challenges that need to be addressed.


Ultra-thin boundary layer for high-accuracy simulations of light propagation.
The modified Born series method is currently one of the most efficient methods available for simulating light scattering in large inhomogeneous media. However, to achieve high accuracy, the method requires thick gradually absorbing layers around the simulation domain. Here, we introduce new boundary conditions, combining a padding-free acyclic convolution with an ultra-thin boundary layer. Our new boundary conditions minimize the wrap-around and reflection artefacts originating from the edges of the simulation domain, while also greatly reducing the computational costs and the memory requirements of the method. Our GPU-accelerated Matlab implementation is available on GitHub.


[Quality assessment in neonatology].
After discussing some general factors influencing the result of medical care at all (socio-economic conditions, biological factors), the difficulties of neonatal quality control compared with the assessment of quality in obstetric care are pointed out (greater variability of the data, evaluation of long-term effects). In addition to the obstetric system of data collection a similar evaluation of neonatal data is recommended to be introduced and definitions for general use are given. The recommendations are based on own investigations of the predictive value of some data gained within the perinatal period (history, physical examination, laboratory tests etc.). The high expenditures of personnel and equipment, at present, don't allow a nationwide introduction of such records. But in future perinatal centers should collect their data in an unique way according to this recommendations for comparing the efficiency of perinatal care in voluntary programs of quality control. The experiences collected by those analyses will be of great value concerning planning the design of a nationwide data recording system in perinatal medicine.


Screening for potential -α -Glucosidase inhibitors in Coptis chinensis franch extract using ultrafiltration LC-ESI-MSn.
Naturally existing -α -glucosidase inhibitors from traditional herbal medicines have attracted considerable interest to treat type 2 diabetes mellitus (T2DM). Hundreds of herbs have been reported to have the potential to inhibit -α -glucosidase. However, most common methods to examine the inhibitors of -α -glucosidase are usually time-consuming. In the current study, the screening of -α -glucosidase ligands from Coptis chinensis Franch extract was undertaken by ultrafiltration liquid chromatography coupled to electrospray ionization tandem mass spectrometry (ultrafiltration LC-ESI-MS(n)). Resultantly, the enzyme inhibition studies showed that Coptis chinensis Franch extract carries the strongest -α -glucosidase inhibitory activity among the five kinds of Chinese herbal extracts. Subsequently, five compounds that could bind to -α -glucosidase in the Coptis chinensis Franch extract were found using ultrafiltration liquid chromatography, and their structures were identified by ESI-MS(n) to be coptisine, epiberberine, jatrorrhizine, berberine, palmatine. Cumulatively, these results were anticipated to be encouraging for applying the Coptis chinensis Franch extracts as efficient anti-diabetic drug candidates.


Soluble interleukin-2 receptor: a new marker in pancreatic adenocarcinoma?
An increase in soluble Interleukin-2 receptor has been observed in several lymphoproliferative diseases and in certain solid neoplasms. Little is known, however, of the serum levels of this marker in pancreatic cancer. We studied the behaviour of the soluble Interleukin-2 receptor in 32 patients with pancreatic cancer versus 17 patients with alcoholic chronic pancreatitis and 24 healthy controls. The results obtained showed a significant statistical difference (Student's "t"-test and Mann Whitney U test) between pancreatic cancer on one hand and chronic pancreatitis plus healthy controls on the other (p < 0.0001).