A randomized trial comparing myocardial salvage achieved by coronary stenting versus balloon angioplasty in patients with acute myocardial infarction considered ineligible for reperfusion therapy.
We assessed myocardial salvage achieved by reperfusion with percutaneous coronary interventions (PCI) and compared stenting with balloon angioplasty (PTCA) in patients with acute myocardial infarction (AMI) ineligible for thrombolysis. A substantial proportion of patients with AMI are currently considered ineligible for thrombolysis, and reperfusion treatment is frequently not recommended for them. It is not known whether these patients benefit from PCI. The Stent or PTCA for Occluded Coronary Arteries in Patients with Acute Myocardial Infarction Ineligible for Thrombolysis (STOPAMI-3) trial, a randomized, open-label study, included 611 patients with AMI who were ineligible for thrombolysis (lack of ST-segment elevation on the electrocardiogram, late presentation >12 h after symptom onset, and contraindications to thrombolysis). Patients were randomly assigned to receive either coronary artery stenting (n = 305) or PTCA (n = 306). Scintigraphic myocardial salvage index (proportion of the initial myocardial perfusion defect that was salvaged by reperfusion) was the primary end point of the study. A considerable myocardial salvage was achieved with both stenting and PTCA. In patients assigned to receive stenting, the median size of the salvage index was 0.54 (25th and 75th percentiles, 0.29 and 0.87), as compared with a median of 0.50 (25th and 75th percentiles, 0.26 and 0.82) in the group assigned to receive PTCA (p = 0.20). Mortality at six months was 8.2% in the group of patients assigned to receive stenting and 9.2% in the group of patients assigned to receive PTCA (p = 0.69). Patients with AMI who are currently considered ineligible for thrombolysis by conventional guidelines may greatly benefit from primary PCI. The benefit seems to be comparable when a strategy of stenting is compared with a strategy of PTCA in these patients.


Cumulative history recorded in the depth distribution of radiocesium in sediments deposited on a sandbar.
We collected sediments deposited on a sandbar from the surface to 20 cm in depth in the Abukuma River to clarify the history of radiocesium derived from the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident. We analyzed the (137)Cs concentration in the sediments from size-fractioned samples as well as bulk samples. The depth distribution of (137)Cs showed the highest concentration in the deepest sediment layer (18-20 cm) studied, which indicates that sediments with a lower (137)Cs concentration were transported and deposited on sediments having a higher (137)Cs concentration. At the same time, the depth distribution suggests a decrease in radioactivity in provenance areas of the sediments. Analysis of the size-fractioned sediments indicated that the three sediment layers at 4-6 cm, 16-18 cm and 18-20 cm intervals had similar size distribution of (137)Cs and grain size composition although the concentration levels of (137)Cs were different according to their bulk concentrations. The size distribution of (137)Cs also supported the possibility that the decrease in (137)Cs concentration in bulk sediments above 18 cm is due to a decrease in the level of radioactivity in the catchment area. A comparison of the size distribution of (137)Cs between the sediment layers above and below 18 cm suggested that the (137)Cs concentration in the transported fine sediment particles decreased more with time than the (137)Cs concentration in the coarse particles, reflecting the selective transport of the finer particles. The results of this study demonstrated that sediment layers deposited on a sandbar retained the cumulative history of the fluvial transport of radiocesium after the FDNPP accident.


Molecular topography and secondary structure comparisons of botulinum neurotoxin types A, B and E.
Botulinum neurotoxin (NT) serotypes A, B and E differ in microstructure and biological activities. The three NTs were examined for secondary structure parameters (alpha-helix, beta-sheet, beta-turn and random coil content) on the basis of circular dichroism; degree of exposed Tyr residues (second derivative spectroscopy) and state of the Trp residues (fluorescence and fluorescence quantum yield). The proteins are high in beta-pleated sheet content (41-44%) and low in alpha-helical content (21-28%). About 30-36% of the amino acids are in random coils. The beta-sheet contents in the NTs are similar irrespective of their structural forms (i.e. single or dichain forms) or level of toxicity. About 84%, 58% and 61% of Tyr residues of types A, B, and E NT, respectively, were exposed to the solvent (pH 7.2 phosphate buffer). Although the fluorescence emission maximum of Trp residues of type B NT was most blue shifted (331 nm compared to 334 for types A and E NT, and 346 nm for free tryptophan) the fluorescence quantum yields of types A and B were similar and higher than type E. In general the NTs have similar secondary (low alpha-helix and high beta-sheets) and tertiary (exposed tyrosine residues and tryptophan fluorescence quantum yield) structures. Within this generalized picture there are significant differences which might be related to the differences in their biological activities.


Metal-organic frameworks-derived manganese trioxide with uniformly loaded ultrasmall platinum nanoparticles boosting benzene combustion.
Four morphologies of metal-organic frameworks derived Mn2O3 were prepared by calcination of metal-organic frameworks self-assembled from metal ions and organic ligands and loaded with platinum. The catalyst showed excellent catalytic performance for benzene (T90% = 131 °C). ESR (electron spin resonance) test showed that due to the strong electron metal support interaction between Pt and Mn2O3, there were a large number of oxygen vacancies on the surface of the catalyst as active sites to promote the oxidation of benzene. The presence of a large number of Lewis acid sites on the catalyst surface was confirmed by Py-IP (Pyridine adsorption infrared spectroscopy) test. The intermediates of benzene catalytic oxidation are ethyl acetate, carboxylic acids and aldehydes, which can be verified by in-situ DRIFTS. In summary, the catalysts synthesized in this work provide a novel perspective for combining metal-organic frameworks-derived oxides and precious metals for the catalytic oxidation of volatile organic compounds.


Drug Screen Identifies Leflunomide for Treatment of Inflammatory Bowel Disease Caused by TTC7A Deficiency.
Mutations in the tetratricopeptide repeat domain 7A gene (TTC7A) cause intestinal epithelial and immune defects. Patients can become immune deficient and develop apoptotic enterocolitis, multiple intestinal atresia, and recurrent intestinal stenosis. The intestinal disease in patients with TTC7A deficiency is severe and untreatable, and it recurs despite resection or allogeneic hematopoietic stem cell transplant. We screened drugs for those that prevent apoptosis of in cells with TTC7A deficiency and tested their effects in an animal model of the disease. We developed a high-throughput screen to identify compounds approved by the US Food and Drug Administration that reduce activity of caspases 3 and 7 in TTC7A-knockout (TTC7A-KO) HAP1 (human haploid) cells and reduce the susceptibility to apoptosis. We validated the effects of identified agents in HeLa cells that stably express TTC7A with point mutations found in patients. Signaling pathways in cells were analyzed by immunoblots. We tested the effects of identified agents in zebrafish with disruption of ttc7a, which develop intestinal defects, and colonoids derived from biopsy samples of patients with and without mutations in TTC7A. We performed real-time imaging of intestinal peristalsis in zebrafish and histologic analyses of intestinal tissues from patients and zebrafish. Colonoids were analyzed by immunofluorescence and for ion transport. TTC7A-KO HAP1 cells have abnormal morphology and undergo apoptosis, due to increased levels of active caspases 3 and 7. We identified drugs that increased cell viability; leflunomide (used to treat patients with inflammatory conditions) reduced caspase 3 and 7 activity in cells by 96%. TTC7A-KO cells contained cleaved caspase 3 and had reduced levels of phosphorylated AKT and X-linked inhibitor of apoptosis (XIAP); incubation of these cells with leflunomide increased levels of phosphorylated AKT and XIAP and reduced levels of cleaved caspase 3. Administration of leflunomide to ttc7a-/- zebrafish increased gut motility, reduced intestinal tract narrowing, increased intestinal cell survival, increased sizes of intestinal luminal spaces, and restored villi and goblet cell morphology. Exposure of patient-derived colonoids to leflunomide increased cell survival, polarity, and transport function. In a drug screen, we identified leflunomide as an agent that reduces apoptosis and activates AKT signaling in TTC7A-KO cells. In zebrafish with disruption of ttc7a, leflunomide restores gut motility, reduces intestinal tract narrowing, and increases intestinal cell survival. This drug might be repurposed for treatment of TTC7A deficiency.


Preventable hospitalizations among older patients with cognitive impairments and dementia.
ABSTRACTObjectives:Dementia and cognitive impairment are associated with higher rates of complications and mortality during hospitalization in older patients. Moreover, length of hospital stay and costs are increased. In this prospective cohort study, we investigated the frequency of hospitalizations caused by ambulatory care-sensitive conditions (ACSCs), for which proactive ambulatory care might prevent the need for a hospital stay, in older patients with and without cognitive impairments. Prospective cohort study. Eight hospitals in Germany. A total of 1,320 patients aged 70 years and older. The Mini-Cog test has been used to assess cognition and to categorize patients in the groups no/moderate cognitive impairments (probably no dementia) and severe cognitive impairments (probable dementia). Moreover, lengths of hospital stay and complication rates have been assessed, using a binary questionnaire (if occurred during hospital stay or not; behavioral symptoms were adapted from the Cohen-Mansfield Agitation Inventory). Data have been acquired by the nursing staff who received a special multi-day training. Patients with severe cognitive impairments showed higher complication rates (including incontinence, disorientation, irritability/aggression, restlessness/anxiety, necessity of Tranquilizers and psychiatric consults, application of measures limiting freedom, and falls) and longer hospital stays (+1.4 days) than patients with no/moderate cognitive impairments. Both groups showed comparably high ACSC-caused admission rates of around 23%. The study indicates that about one-fourth of hospital admissions of cognitively normal and impaired older adults are caused by ACSCs, which are mostly treatable on an ambulatory basis. This implies that an improved ambulatory care might reduce the frequency of hospitalizations, which is of particular importance in cognitively impaired elderly due to increased complication rates.


Reduced body size of insular black-tailed deer is caused by slowed development.
Adult body size correlates strongly with fitness, but mean body sizes frequently differ among conspecific populations. Ultimate, fitness-based explanations for these deviations in animals typically focus on community-level or physiological processes (e.g., competition, thermoregulation). However, proximate mechanisms underlying adaptive body size adjustments remain poorly understood. Adjustments in adult body size may result from shifts in growth-related life-history traits, such as the length of time to achieve adult body size (i.e., growth period) and how quickly the body increases in size (i.e., growth rate). Since insular populations often demonstrate dramatic shifts in adult body size, island populations represent a natural experiment by which to test the proximate mechanisms of size change. Here, using dental eruption patterns, we show that a dwarfed population of black-tailed deer (Odocoileus hemionus columbianus) experiences significant heterochronic shifts relative to mainland conspecifics. Namely, juvenile development slowed, such that teeth erupted ≥ 1 year later, but cranial growth suggested no concurrent adjustments in skeletal growth period. Thus, slowed growth rate, shown here with teeth, combined with unchanged growth period resulted in dwarfism, consistent with ultimate predictions for insular, resource-limited populations. Therefore, selection on body size may act on life-history traits that influence body size, rather than acting on body size directly.


Maximum Ankle Plantarflexion and Dorsiflexion Allow for Optimal Arthroscopic Access to the Talar Dome: An Anatomic 3-Dimensional Radiography Study.
(1) to improve the comprehension of the topographical position of the talar dome beneath the inferior articular surface of the tibia and, (2) to illustrate the changes of possible access to the articular surface of the talar dome during arthroscopic treatment of talar osteochondral defects in an anatomical model. Twenty matched pairs (n = 40) of anatomical ankle specimen were used. All specimens were mounted in a standardized fashion, 3-dimensional radiography was performed in 4 defined positions (maximum dorsiflexion, neutral position, noninvasive distraction, and maximum plantarflexion). All radiographs were analyzed and statistically compared. Anterior accessibility was highest in maximum plantarflexion (medial: 49.20 ± 9.86%, lateral: 48.19 ± 8.85%), followed by non-invasive distraction (medial: 33.60 ± 7.96%, lateral: 31.98 ± 8.30%). Neutral position (medial: 19.34 ± 6.90%, lateral: 17.54 ± 6.63%) and dorsiflexion (medial: 15.36 ± 5.03%, lateral: 13.88 ± 4.33%) were not able to significantly increase accessibility. Posterior accessibility was greatest in maximum dorsiflexion (medial: 56.69 ± 9.65%, lateral: 46.82 ± 8.36%), followed by neutral position of the ankle joint (medial: 40.95 ± 8.28%, lateral: 31.06 ± 6.92%). Noninvasive distraction (medial: 31.41 ± 8.18%, lateral: 22.99 ± 7.63%) was still significantly better than plantarflexion (medial: 14.54 ± 5.10%, lateral: 13.89 ± 3.14%) and slightly increased accessibility to the talar dome. Medially, a central area of 5.89 ± 9.76% was accessible by maximum plantarflexion and maximum dorsiflexion from anterior and posterior, respectively, laterally a central blind spot of 4.99 ± 8.61% was detected. From an anatomical point of view, maximum joint positions of the ankle (i.e., plantarflexion and dorsiflexion) allow for better access to the talar dome in anterior and posterior ankle arthroscopy. Noninvasive distraction may increase accessibility in anterior approaches, but has no benefit from posterior. This study provides insight into the morphology of the ankle joint in a standardized laboratory setup and illustrates the influence of different surgically relevant ankle joint positions. The presented data allow for better preoperative planning for the arthroscopic treatment of talar osteochondral defects.


Looking, seeing and believing in autism: Eye movements reveal how subtle cognitive processing differences impact in the social domain.
Adults with High Functioning Autism Spectrum Disorders (ASD) viewed scenes with people in them, while having their eye movements recorded. The task was to indicate, using a button press, whether the pictures were normal, or in some way weird or odd. Oddities in the pictures were categorized as violations of either perceptual or social norms. Compared to a Typically Developed (TD) control group, the ASD participants were equally able to categorize the scenes as odd or normal, but they took longer to respond. The eye movement patterns showed that the ASD group made more fixations and revisits to the target areas in the odd scenes compared with the TD group. Additionally, when the ASD group first fixated the target areas in the scenes, they failed to initially detect the social oddities. These two findings have clear implications for processing difficulties in ASD for the social domain, where it is important to detect social cues on-line, and where there is little opportunity to go back and recheck possible cues in fast dynamic interactions. Autism Res 2016, 9: 879-887. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.


[Medical abortion using methotrexate and misoprostol. Efficacy and tolerability].
Medical abortion means interruption of early pregnancy (usually before 9-th gestational week) as a result of administration of abortifacient drugs without surgical intervention. To investigate the efficacy and tolerability of methotrexate plus misoprostol regimen as a method for early medical abortion < 49 days L.M.P. 50 mg methotrexate was administered orally to 20 women < 49 days L.M.P. followed by 800 mcg misoprostol vaginal and oral administration 3-7 days after the methotrexate. 19 Successful medical abortions (95%). One woman chose vacuum aspiration for termination of the abortion on day 3 of the induced bleeding. No serious side effects were observed after administration of the drugs. Medical abortion with methotrexate and misoprostol is safe and effective and can be offered to practicing gynecologists.


Plaque incision and fascia lata grafting in the surgical management of Peyronie's disease.
To assess the outcome of using modified human fascia lata (Tutoplast, Mentor Corp, Santa Barbara, CA, USA) in the surgical management of Peyronie's disease (PD), as the penile deformity associated with PD can be corrected by plaque incision and saphenous vein grafting (Lue procedure). In all, 14 patients (mean age 51 years, range 34-59) with PD had their penile deformity corrected by plaque incision and Tutoplast grafting. Three patients had a previous unsuccessful Nesbit operation. The mean (range) penile deformity before surgery was 67.2 (20-90) degrees and the mean follow-up was 31 (17-37) months. Using set criteria, 13 patients were satisfied (excellent or satisfactory) with the results of surgery. The penis was completely straight in 11 of 14 patients. One patient developed de novo erectile dysfunction after surgery. In 10 patients there was no penile shortening, whereas four reported penile shortening of >1 cm. Fascia lata Tutoplast grafts provide a reliable and well tolerated biomaterial for penile reconstruction in PD. The outcome of using Tutoplast is similar to that from saphenous vein but without the morbidity associated with the donor site. However, there remains a significant risk of penile shortening and development of erectile dysfunction.


Cyclin A-Cys41 does not undergo cell cycle-dependent degradation in Xenopus extracts.
Truncated cyclin A and cyclin B lacking the N-terminal domain comprising the 'destruction box' escape from proteolysis and arrest cells at metaphase. Mutation of a conserved arginine residue of the destruction domain makes cyclin B resistant to proteolysis. Here we show that mutation of the same residue also makes cyclin A resistant to proteolysis, in either of two situations in which the cyclin degradation pathway is turned on: (i) in Xenopus extracts of activated eggs where the degradation pathway has been permanently turned on by adding a recombinant undegradable cyclin B in which the arginine residue of the destruction box has been substituted by alanine; (ii) in extracts of metaphase II-arrested oocytes after Ca(2+)-dependent inactivation of the cytostatic factor (CSF).


The Effects in the Upper Airway of Heat and Exposure to Combustion Byproducts of Burning Materials on Larynx of Firefighters.
High exposure to heat and combustion byproducts is associated with health problems and an increased risk of cancer. To study the effects of heat and smoke derived from burning on the upper airway of firefighters. Thirteen firefighters underwent a 4-week training program in Compartment Fire Behavior Training simulators while working with live fire, heat, and smoke from pallets and oriented-strand board sheet burns. The firefighters were evaluated before exposure and at the end of the first and fourth weeks of training. The larynx was assessed by the Voice Handicap Index GRBASI scale, laryngoscopy, and peak expiratory flow. There was no change in Voice Handicap Index and GRBASI (only one in three speech therapists judged tension as worse by one point). Laryngoscopy showed alterations in one-third of the firefighters, with the most frequent being increased viscous mucus. Peak expiratory flow decreased significantly from 685 to 552 and 550 L/min in the first and fourth weeks, respectively. Although participants were protected from gases and smoke during the exercises, which proved to be very effective, the airway was slightly impacted by heat and combustion-derived byproducts.


Substrate and product stereoselectivity in monooxygenase-mediated drug activation and inactivation.
In this overview, stereoselective aspects of drug metabolism have been examined in a biochemical and pharmacodynamic perspective. From the facts and concepts presented, the conclusion to emerge is that the pharmacokinetic behaviour of mixtures of stereoisomers (e.g. racemates) is not always the simple addition of the behaviour of individual stereoisomers; as a consequence, stereoisomeric mixtures might display pharmacodynamic effects differing somewhat from those caused by the separate eutomers and distomers. In some circles, the notion of "isomeric ballast" is being mentioned with increasing regularity, leading almost fatally to the conclusion that eutomers should be purified from their distomeric ballast for therapeutic use. A number of examples discussed here show that in vitro and also in vivo, a racemate often displays a pharmacokinetic and pharmacodynamic behaviour which is not the mere addition of the behaviour of its separate enantiomers. This may seem as an additional argument for the therapeutic use of pure eutomers since a number of interactions are thus avoided. But does this imply that distomers must always be considered as detrimental ballast? Enforcing compulsory resolution of stereoisomeric mixtures, in particular racemates, would increase severalfold the cost of many drugs. This is a small price to pay if the benefit is an improved therapeutic index. But, to reword the question, would such a legislation automatically result in therapeutic benefits?


Lung cancer risk in a population-based cohort of patients hospitalized for asthma in Sweden.
It has been suggested that asthma increases the risk of lung cancer in males but not in females. However, previous studies may suffer from report bias and are based on a small numbers of cases. The objective of the present study was to assess the incidence of lung cancer in males and females using a nationwide Swedish cohort of asthma patients. Patients (n=92,986) aged > or = 20 yrs with a hospital-discharge diagnosis of asthma and who were alive and free from malignancy I yr after first hospitalization were followed-up, for incidence of lung cancer during the period 1965-1994 (average duration of follow-up, 8.5 yrs). Their incidence of lung cancer was compared with that of the national population. The authors observed 713 lung cancers (standardized incidence ratio (SIR) 1.58, 95% confidence interval (CI) 1.47-1.70). The SIR was 1.51 in males (95% CI 1.38-1.65, 492 cases) and 1.78 in females (95% CI 1.55-2.03, 221 cases). The SIR decreased with duration of follow-up and increased with calendar period and age at first hospitalization. The risk of lung cancer was higher for squamous cell and small cell carcinoma than for adenocarcinoma, and it was higher in patients with other diseases as the main diagnosis and in patients hospitalized in departments other than internal and respiratory medicine. It was confirmed that asthma patients are at increased risk of lung cancer, but there is no heterogeneity in risk between the sexes. Several indirect arguments point towards a noncausal explanation of these findings; in particular, confounding by tobacco smoking is a plausible explanation.


Bridging the gap between primary and secondary care: use of a clinical pathway for the investigation and management of deep vein thrombosis.
Clinical processes that span the boundary between primary and secondary care often suffer from poor standardization of practice and lines of communication. One example is the clinical management of suspected deep vein thrombosis (DVT). Making or excluding the diagnosis can be complex. Tools to investigate DVT were not available to family physicians so patients had to be referred to the hospital emergency department and endure a long wait which could exacerbate the condition. In addition, urgent referrals to the ultrasound department disrupted the scheduled list of patients. A team of stakeholders including all relevant specialties and professions from primary and secondary care was established. After reviewing the literature and interviewing those involved in delivering care, an evidence-based scoring system to calculate the clinical probability of a DVT was adopted and introduced as part of a clinical pathway from primary to secondary care. Its introduction was based on the Plan, Do, Study, Act (PDSA) cycle. In the first year after the introduction of the clinical pathway, 70% of family physicians had used it and were very satisfied. Patients found it efficient (75%) with 96% very satisfied or satisfied. The waiting time in the emergency department fell from a mean of 379 minutes to 285 minutes. Although the incidence of initial investigations (D-Dimer tests) increased by 42%, the proportion of patients undergoing a subsequent ultrasound test found to have a DVT was unchanged (14%). This suggested the level of suspicion of a DVT in the community had risen. Referrals to the hospital's DVT clinic increased by 14% overall, driven partly by a large increase in those who had come from the new clinical pathway from primary care. Key lessons include the importance of including all relevant stakeholders and the benefits of using PDSA to make rapid changes during implementation. We are now seeking to extend the use of the clinical pathway to other hospitals and more family physicians. In addition, the clinical pathway approach will be applied to other conditions and interventions. We have demonstrated how a multidisciplinary group of stakeholders in a clinical care process can develop and introduce a clinical pathway that allows smooth transit of patients over the barriers between different sectors of the health care system and between independent disciplines. We have also demonstrated the use of untapped non-physician potential in the system to safely facilitate patient care.


Unusual findings in brain biopsies of two patients with acute magnetic resonance imaging lesions associated with focal seizures.
Patients with focal seizures often have magnetic resonance imaging (MRI) abnormalities in the brain region of their presumed seizure focus. Neoplasms, ischemic infarctions, inflammatory processes, and other specific pathologic entities have been diagnosed by biopsies of such MRI abnormalities. Two patients with this presentation had brain lesion biopsies with a leading presumptive diagnosis of glial neoplasm but were found to have indistinct histopathology. Each patient was initially seen with focal seizures (right parietal region, right hippocampus) corresponding with focally increased T2 signal on MRI. In both patients, the preoperative clinical suspicion was for neoplastic or inflammatory processes. Several weeks after seizure onset, craniotomy in patient 1 and stereotactic needle biopsy in patient 2 revealed mild gliosis with reactive vascular changes and perivascular hemosiderin deposition, not diagnostic of but compatible with venous congestion (or possibly venous thrombosis). Postoperatively, patient 1 had brief sensory seizures that stopped 5 months after surgery, whereas subsequent seizures did not develop in patient 2. Both patients had normalization of their MRI (except for postoperative changes) and have remained seizure free. We describe two patients who had brain biopsies of striking focal increased T2 signal MRI abnormalities associated with seizures. Pathologic findings contradicted our preoperative suspicions (neoplasm or inflammatory process), compatible with (but not conclusive for) subacute venous congestion/thrombosis. These findings indicate that patients with seizures may have an associated discrete intraaxial MRI lesion that is not neoplastic. To our knowledge, this is the first report of focal seizure-associated MRI lesions with biopsy findings compatible with venous congestion/thrombosis.


Extradural haemangiolipoma in the spinal canal. Two cases presenting during pregnancy.
Extradural spinal haemangiolipomas are very rare but they account for forty per cent of all lipomas in this position. The two cases described here were middleaged women who both had a paraparesis during their pregnancy which remitted after parturition. Both tumours were in the thoracic region on the posterior surface of the dura. The histological appearances were those of a lipoma with a definite capillary component. The pathogenesis of the relapsing and remitting paraplegia and its relationship with pregnancy is probably multi-factorial. It is proposed that both blood volume and extra-cellular fluid volume changes occurring during pregnancy may be responsible for the fluctuating cord compression. Similarly the hypothesis is put forward that due to the vascularity of the tumour it exerts a "steal" phenomenon over the blood supply to the adjacent cord. Also, because of its vascularity, the tumour could have a pulsatile compressive effect on the cord.


A study of the impact of VNS on health care utilisation in England.
To compare hospital service use before and after VNS therapy implantation in a sample of drug-resistant people with epilepsy. The before and after study was performed using anonymised Hospital Episode Statistics (HES) data from one year before to 3 years after implantation in 321 patients from data collected between April 2009 to July 2011. Episodes relating to out-patient clinic, Accident and Emergency (A&E) department attendance, hospital admissions and length of stay were collected and compared. Descriptive statistics are used to summarise patient demographics, patient pathways and resource usage before and after VNS implantation. Means and proportions were reported on continuous variables, proportion and frequency on categorical variables. Trends of activity over time were determined using before and after VNS comparisons and tested with the Wilcoxon Signed-rank (WSR) test. The summary statistics indicate a drop in resource use in terms of in-patient bed-days (21% decrease), elective in-patient episodes (7% decrease) and non-elective in-patient episodes (14% decrease). There was an increase in the quarterly average out-patient appointments by 12%. The A&E attendance outcome recorded a mean increase in quarterly attendances of 9% but a slight decrease when subject to a signed rank test. These contradictory results should therefore be treated with caution. VNS Therapy may be associated with an overall reduction in health service resource use.


CD13 expression in B cell malignancies is a hallmark of plasmacytic differentiation.
The diagnosis of Waldenström Macroglobulinaemia (WM)/lymphoplasmacytic lymphoma (LPL) remains one of exclusion because other B-cell lymphoproliferative disorders (B-LPD), such as marginal zone lymphoma (MZL), can fulfil similar criteria, including MYD88 L265P mutation. It has been suggested that expression of the myeloid marker CD13 (also termed ANPEP) is more frequent in LPL than in other B-LPD and has also been described on normal and malignant plasma cells. Here, CD13 expression was tested in a cohort of 1037 B-LPD patients from 3 centres by flow cytometry. The percentage of CD13-expressing cells was found to be variable among B-LPD but significantly higher in WM/LPL (median 31% vs. 0% in non-WM/LPL, P < 0·001). In multivariate linear regression, CD13 expression remained significantly associated with a diagnosis of WM/LPL (P < 0·001). A cut-off value of 2% of CD19+ cells co-expressing CD13 yielded the best diagnostic performance for WM/LPL assertion. This was further improved by association with the presence or absence of IgM paraprotein. Finally, given that previously published transcriptomic data revealed no difference in CD13 (also termed ANPEP) mRNA between normal and pathological B-cells, the hypothesis of some post-transcriptional regulation must be favoured. These results suggest that testing for CD13 expression in routine flow cytometry panels could help to discriminate WM/LPL from other B-LPD.


Entomophthoramycosis: A diagnostically challenging presentation of liver space-occupying lesion.
Entomophthoramycosis, a rare fungal infection, can mimic various clinical entities. We present a case of entomophthoramycosis affecting a 3-year-old male masquerading as liver tumour, diagnosed on stereotactic biopsy and later on resected specimen. He improved following partial hepatectomy and antifungal therapy. A high index of suspicion and heightened awareness regarding its unique morphological characteristics are required for appropriate management.


VEGF receptor signal transduction - A brief update.
Vascular endothelial growth factor (VEGF) signal transduction through receptor tyrosine kinases VEGF receptor-1, -2 and -3 is of crucial importance for monocytes/macrophages, blood vascular endothelial and lymphatic endothelial cells both in physiology and in a number of pathologies notably cancer. This brief review summarizes the current status of VEGF receptor signaling with emphasis on in vivo data.


Clinicopathologic correlations of silent corticotroph adenomas of the pituitary: report of four cases and literature review.
Silent corticotroph adenomas (SCA) are rare pituitary tumors with histologic hallmarks of corticotroph differentiation, including ACTH immunoreactivity, but lacking clinical evidence of Cushing's syndrome. We report on four female patients, aged 19-66 years, each presenting with a nonfunctional macroadenoma. Leading symptoms were headache in two cases and visual field deficits in one. One patient was incidentally diagnosed while undergoing cranial MRI for an unrelated condition. Three patients had marked obesity; none of them presented constitutional signs of Cushing's syndrome. Serum cortisol levels were moderately elevated in the two patients systematically tested in this respect. Marginal to moderate hyperprolactinemia was present in two cases. Two patients also were shown to be deficient in either gonadotroph or thyrotroph axis, while a third had a combined insufficiency of both gonadotroph and thyrotroph axis. MRI scans revealed intratumoral hemorrhage and/or cystic change in three cases, as well as tumor-related occlusive hydrocephalus in one. The latter patient was biopsied only, while the remaining underwent gross total resection. Histologically, all four lesions were diagnosed as SCA subtype I displaying intense immunoreactivity for ACTH. In three tumors, scattered cells coexpressed PRL as well. In addition, Crooke's hyaline change was noted in a significant number of tumor cells and in residual non-neoplastic corticotrophs in one case each. With MIB-1 labeling indices of 1-3%, none of the tumors qualified as atypical adenoma. We conclude that SCAs are more likely to be discovered as expansile tumors, whose advanced local space-occupying character at surgery rather than an inherently aggressive growth potential may negatively influence the clinical outcome. Subtle morphologic evidence of corticotroph suppression in residual pituitary adjacent to tumor lends further support to literature data indicating minimal or intermittent functional activity in this tumor type.


[Structure and function of biological membranes (author's transl)].
Biological membranes are essentially asymmetric two-dimensional solutions of proteins in a bimolecular lipid layer. The overall structure and many physical properties of biological membranes can be explained by the fact that membrane proteins and membrane lipids contain hydrophilic as well as hydrophobic domains. Most biological properties of the membrane are determined by the membrane proteins which can catalyze directional processes. With the membrane protein cytochrome oxidase it will be demonstrated how the three-dimensional arrangement of membrane proteins can be studied by chemical, fluorometric, and electron optical methods. However, it is in most cases still impossible to explain the function of a membrane on the basis of its molecular architecture.


Mecillinam (FL 1060), a 6beta-amidinopenicillanic acid derivative: in vitro evaluation.
Mecillinam (formerly called FL 1060), a novel 6beta-amidinopenicillanic acid derivative, showed markedly higher activity than ampicillin against clinical isolates of Enterobacteriaceae. The mode of action of mecillinam is different from that of ampicillin and consequently no intrinsic cross-resistance between the two antibiotics was observed. Mecillinam is inactivated by beta-lactamases but is generally more stable than ampicillin; thus an apparent cross-resistance exists for strong beta-lactamase producers. The protein binding was low and the activity was relatively independent of pH between 5.5 and 8.0. Slow-growing, insensitive variants of Escherichia coli could be selected but these were not stable. The frequency of insensitive variants was affected by the sodium chloride concentration in the medium.


Fine mapping of an Alzheimer disease-associated gene encoding beta-amyloid protein.
We have sublocalized an Alzheimer Disease-associated gene, which encodes for cerebrovascular beta-amyloid protein, to the region from the centromere through the proximal half of band 21q21 using both somatic cell and in situ mapping techniques. In addition we found repeatedly significant but weaker hybridization of the beta-amyloid protein probe to the short arm of chromosome 20. 794 cells were analyzed from whole blood, lymphoblastoid and skin cultures. The latter two types of cultures had parts of the 21st chromosome translocated to other chromosomes facilitating sublocalization.


Evaluation of the safety and efficacy of suction-tip forceps, a new tool for laparoscopic surgery, for gastric cancer.
Laparoscopic surgery is a minimally invasive surgery; however, obstacles to its functional optimization remain. Surgical ports can accommodate only one instrument at a time so complex exchange manipulations are necessary during surgery which increases operation times and patient risk. We developed a new laparoscopic instrument that functions as both forceps and a suction tube, which renders intraoperative tool exchange unnecessary. This pilot study was undertaken to evaluate the safety and efficacy of this novel dual-function device in laparoscopic surgery for gastric cancer. This single-center pilot study assessed patient safety during and after laparoscopic distal gastrectomy for gastric cancer with the suction-forceps using intraoperative video and clinical follow-up, respectively. To evaluate instrument efficacy, we measured the time interval between the start of any bleeding and the start of aspiration ("suction access time") and compared this time with that of a conventional surgical setup. In total 15 patients participated, with all procedures being successful. No excess tissue damage occurred during surgery. Suction access time was significantly shorter in cases of bleeding when the suction-tip forceps were used for aspiration (2.01 seconds) compared to an ordinary suction tube (12.5 seconds; P < .01). These findings suggest that our new suction-tip forceps are a useful, safe, and efficacious operative tool. This surgical innovation may considerably simplify gastric laparoscopic surgery. This pilot study was registered with Japan Clinical Trial Registration on 22 June 2017 (registration number: UMIN000027879).


WITHDRAWN: Are high heart rate variability and parasympathetic activity a key for wellness?
This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.


Degeneration of human photosensitive retinal ganglion cells may explain sleep and circadian rhythms disorders in Parkinson's disease.
Parkinson's disease (PD) patients often suffer from non-motor symptoms like sleep dysregulation, mood disturbances or circadian rhythms dysfunction. The melanopsin-containing retinal ganglion cells are involved in the control and regulation of these processes and may be affected in PD, as other retinal and visual implications have been described in the disease. Number and morphology of human melanopsin-containing retinal ganglion cells were evaluated by immunohistochemistry in eyes from donors with PD or control. The Sholl number of intersections, the number of branches, and the number of terminals from the Sholl analysis were significantly reduced in PD melanopsin ganglion cells. Also, the density of these cells significantly decreased in PD compared to controls. Degeneration and impairment of the retinal melanopsin system may affect to sleep and circadian dysfunction reported in PD pathology, and its protection or stimulation may lead to better disease prospect and global quality of life of patients.


Optimizing assessors' mental workload in rater-based assessment: a critical narrative review.
Rater-based assessment has resulted in high cognitive demands for assessors within the education of health professionals. Rating quality may be influenced by the mental workload required of assessors to complete rating tasks. The objective of this review was to explore interventions or strategies aimed at measuring and reducing mental workload for improvement in assessment outcomes in health professions education. A critical narrative review was conducted for English-language articles using the databases PubMed, EMBASE, and Google Scholar from conception until November 2018. To be included, articles were eligible if they reported results of interventions aimed at measuring or reducing mental workload in rater-based assessment. A total of six articles were included in the review. All studies were conducted in simulation settings (OSCEs or videotaped interactions). Of the four studies that measured mental workload, none found any reduction in mental workload as demonstrated by objective secondary task performance after interventions of assessor training or reductions in competency dimension assessment. Reductions in competency dimensions, however, did result in improvements in assessment quality across three studies. The concept of mental workload in assessment in medical education needs further exploration, including investigation into valid measures of assessors' mental workload. It appears that adjusting raters' focus may be a valid strategy to improve assessment outcomes. Future research should be designed to inform how to best reduce load in assessments to improve quality, while balancing the type and quantity of data needed for judgments.


Haemophilus influenzae causes purulent salpingitis.
We describe two patients with laparoscopically diagnosed, severe acute salpingitis who had nontypable Haemophilus influenzae isolated directly from the fallopian tubes. Nontypable H. influenzae should be recognized as an important genital pathogen.


A spinal haematoma occurring in the subarachnoid as well as in the subdural space in a patient treated with anticoagulants.
A 75-year-old man on anticoagulant therapy suddenly experienced an excruciating back pain and subsequently developed a paraplegia. At operation a subarachnoid and a subdural haematoma were found, extending between the levels of the vertebrae T3 and L2. This extremely rare combination of haematomas may have been caused either by rupture of a small vessel in the arachnoid membrane or by rupture of the arachnoid membrane itself, secondary to a massive haemorrhage in the subarachnoid space.


Semaphorin 3 C enhances putative cancer stemness and accelerates peritoneal dissemination in pancreatic cancer.
Semaphorins, axon guidance cues in neuronal network formation, have been implicated in cancer progression. We previously identified semaphorin 3 C (SEMA3C) as a secreted protein overexpressed in pancreatic ductal adenocarcinoma (PDAC). We, therefore, hypothesized that SEMA3C supports PDAC progression. In this study, we aimed to investigate the clinical features of SEMA3C, especially its association with chemo-resistance and peritoneal dissemination. In resected PDAC tissues, we assessed the relationship between SEMA3C expression and clinicopathological features by immunohistochemistry. In vitro studies, we have shown invasion assay, pancreatosphere formation assay, colony formation assay, cytotoxicity assay, and activation of SEMA3C downstream targets (c-Met, Akt, mTOR). In vivo, we performed a preclinical trial to confirm the efficacy of SEMA3C shRNA knockdown and Gemcitabine and nab-Paclitaxel (GnP) in an orthotopic transplantation mouse model and in peritoneal dissemination mouse model. In resected PDAC tissues, SEMA3C expression correlated with invasion and peritoneal dissemination after surgery. SEMA3C promoted cell invasion, self-renewal, and colony formation in vitro. We further demonstrated that SEMA3C knockdown increased Gem-induced cytotoxicity by suppressing the activation of the Akt/mTOR pathway via the c-Met receptor. Combination therapy with SEMA3C knockdown and GnP reduced tumor growth and peritoneal dissemination. SEMA3C enhances peritoneal dissemination by regulating putative cancer stemness and Gem resistance and activates phosphorylation of the Akt/mTOR pathway via c-Met. Our findings provide a new avenue for therapeutic strategies in regulating peritoneal dissemination during PDAC progression.


Assessment of risk factors for cystic periventricular leukomalacia.
Periventricular leukomalacia (PVL) is an important cause of cerebral palsy in premature infants, and cystic PVL is the most serious form of the disease. The risk factors for cystic PVL in singleton fetuses at a gestational age of <35 weeks are unclear. This study included 2013 singleton birth infants delivered at a gestational age of <35 weeks in Kagoshima City Hospital between 2006 and 2017. The findings for 30 infants with cystic PVL were compared with those for 63 matched control infants by gestational age and birth weight. The cystic PVL was associated with increased incidence of recurrent late deceleration (L/D) (43.4% vs. 15.9%, P = 0.004) and loss of variability (LOV) (10.0% vs. 0.0%, P = 0.03) in fetal heart rate monitoring and late-onset circulatory dysfunction (LCD) (33.3% vs. 11.1%, P = 0.02). Logistic regression analysis revealed that recurrent L/D (odds ratio [OR] = 3.57, 95% confidence interval [CI]: 1.29-10.15, P = 0.01) and LCD (OR = 3.41, 95% CI: 1.09-11.04, P = 0.03) were risk factors associated with cystic PVL. LOV was not included in the multivariate analysis as there were too few cases in both the cystic PVL and control groups. Recurrent L/D, LOV and LCD are strongly associated with cystic PVL. In cases of fetal acidosis related to recurrent L/D or loss of variability, cystic PVL may occur.


Effect of interaction of volatile anesthetics and high hydrostatic pressure on central neurons.
Autoactive neurons in the central nervous system of Helix and Aplysia were studied after exposure to several volatile anesthetics and under compression by mineral oil. Voltage clamp studies reveal that halothane will eliminate the slow inward current that underlies oscillatory activity in burster neurons, while high pressure shifts the negative resistance region of the current without causing its elimination. Simultaneous application of the anesthetic and pressure results in the loss of inward current over a time course similar to that of halothane application alone. It is concluded that in this system, pressure and anesthetics are not acting antagonistically at the site in the membrane that controls slow wave conductances.


COVID-19: A Cloud with a Silver Lining for Renewable Energy?
COVID-19 has led to an unprecedented reduction in demand for energy for transportation and electricity, a crash in prices and employment in the fossil fuel industries and record-breaking reductions in global carbon emissions. This paper discusses whether this "demand destruction" could spell the beginning of the end for fossil fuels or a temporary recession and the imperative to recover from the current crisis by "building back better" and not the same as before. There are encouraging signs for the renewable energy industry that could make COVID-19 a cloud with a silver lining; whether this is the case will depend not only on the technological realities and social response to the crisis but also on political will and foresight.


Influence of lead poisoning on ultrastructural changes in the body wall of Eisenia foetida (Savigny), Oligochaeta. II. Long action of different concentration of lead on ultrastructural changes in the cells of the body wall.
The studies were performed on earthworms collected from March to September in the vicinity of Katowice. The earthworms were breed in Petri dishes on soil to which lead nitrate was added in the following concentrations 0.025, 0.10, 0.50 mg/g of soil. For the performed studies small specimen were taken from behind the citellum in which was lead histochemically evaluated. Tissue specimen taken from the citellum of the experimental animals were investigated in electronmicroscope. It has been found that lead accumulates in the sarcoplasm of the muscle fibres but not in the cell organells. Lead concentrations in the cells appear as regular crystals with membranaceous cover. The lead compounds used in the experiments does not provoke structural changes in the contractile elements of the muscle fibres, they induce only some deformations of mitochondria and hyperactivity of the glandular cells of the epithelium.


Discordant uterine artery velocity waveforms as a predictor of subsequent miscarriage in early viable pregnancies.
Our purpose was to determine whether an abnormal uterine perfusion pattern was associated with subsequent pregnancy loss after fetal cardiac activity was documented. Pulsatility indexes of both the right and left uterine arteries were obtained by transvaginal color Doppler ultrasonography in 318 consecutive viable pregnancies between 6 and 12 weeks' gestation. The Delta uterine artery pulsatility index value, expressed as the highest uterine artery pulsatility index value minus the lowest value, was calculated for each pregnancy. Women were subsequently classified as having continuing pregnancies or pregnancy loss before 20 weeks' gestation. To predict subsequent pregnancy loss, Doppler findings were adjusted for maternal age, history of previous abortion, presence of subchorionic hematoma, embryonic bradycardia, and gestational age by means of multivariate logistic regression analysis. Twenty-four pregnancies (8%) were spontaneously aborted before 20 weeks' gestation. Both Delta uterine artery pulsatility index (odds ratio 2.9, 95% confidence interval 1.5-5.8) and history of previous abortion (odds ratio 3.1, 95% confidence interval 1.2-8.2) were significantly associated with pregnancy loss in the multivariate logistic regression analysis. The sensitivity and specificity of the multivariate logistic regression model to predict abortion were 75% and 85%, respectively, significantly higher than the diagnostic performances of qualitative and quantitative variables considered individually. Discordant uterine artery pulsatility indexes in the first trimester were strongly associated with subsequent pregnancy loss. This suggests that uterine ischemia may be implicated in certain cases of early pregnancy loss after documentation of fetal cardiac activity during the first trimester.


Pharmacological preconditioning of ATP-sensitive potassium channel openers on acute urinary retention-induced bladder dysfunction in the rat.
What's known on the subject? and What does the study add? Acute urinary retention (AUR) and catheterization for AUR (AURC) or drainage of the urine is a well established cause of bladder dysfunction. Previously, we reported that the induction of AURC significantly reduced contractile responses to both carbachol and KCl compared with a control group, and that this reduction was prevented by nicorandil and cromakalim in a dose-dependent manner; however, although we reported a possible beneficial effect of nicorandil and cromakalim on bladder dysfunction caused by AURC, its molecular mechanism is still unknown. Our study establishes that nicorandil and cromakalim, but not glibenclamide, prevent AURC-induced bladder dysfunction via up-regulation of both K(IR)6.1 and K(IR)6.2 with a subsequent decrease in oxidative stress and decreased induction of apoptosis in the bladder. To investigate whether ATP-sensitive potassium (K(ATP)) channel openers prevent bladder injury after acute urinary retention (AUR) and subsequent catheterization for AUR (AURC) in the rat. Eight-week-old male Sprague-Dawley rats were divided into five groups: a sham-operated control group, an AUR group, and three AUR groups treated with: nicorandil (10 mg/kg); cromakalim (300 µg/kg); or glibenclamide (5 mg/kg). AUR was induced by intravesical infusion of 3.0 mL of saline via cystostomy with simultaneous clamping of the penile urethra and, after 30 min of AUR, the bladder was allowed to drain for 60 min. After the experimental period, bladder function was assessed using organ bath techniques (carbachol and KCl), and by measuring tissue levels of 8-isoprostane, a marker of oxidative stress. The participation levels of K(ATP) channel pores were investigated using ELISA and real-time PCR methods, respectively. The degree of apoptosis was estimated using the TUNEL method in the bladder smooth muscle and epithelium. The AURC group showed significantly decreased contractile responses to carbachol and KCl, and significant increases in tissue 8-isoprostane levels and apoptosis index in the epithelium compared with the control group. Nicorandil and cromakalim, but not glibenclamide, significantly prevented these AURC-induced alterations. The expressions of K(IR)6.1 and K(IR)6.2 mRNAs were significantly up-regulated by the induction of AURC. Nicorandil and cromakalim, but not glibenclamide, significantly up-regulated expressions of K(IR)6.1 and K(IR)6.2 mRNAs in the bladder compared with the AUR group. Our data indicate that nicorandil and cromakalim, but not glibenclamide, prevent AURC-induced bladder dysfunction via activation of K(ATP) channels, with a subsequent decrease in oxidative stress and decreased induction of apoptosis.


Eclampsia in association with partial molar pregnancy and congenital abnormalities.
A case of eclampsia in association with partial molar pregnancy is described. Cytogenetic analysis confirmed a 69,XXX karyotype, and pathologic examination of the fetus showed a meningomyelocele, exomphalos, incomplete intestinal rotation, and cerebral ventricular dilatation.


A convenient radiometric assay for flavin-containing monooxygenase activity.
A rapid, convenient assay to determine the activity of the flavin-containing monooxygenase is described. The method is based on direct analysis of quenched incubation mixtures by thin-layer chromatography and utilizes tritiated dimethylaniline as the substrate. The synthesis of the radiolabeled substrate is described. The usefulness of dimethylaniline N-oxide formation as a measure of flavin-containing monooxygenase activity was assessed using the purified hog liver enzyme, hog liver microsomes, and liver microsomes from untreated and phenobarbital-pretreated rats.


Differential cytotoxicity and sonosensitization by sanazole: effect of cell type and acoustic parameters.
Although sanazole has been used as a hypoxic radiosensitizer, we recently reported on its ability to sensitize U937 cells to hyperthermia and X-irradiation under aerobic conditions, enhancing apoptotic cell death following the combined treatment. The current study was undertaken to evaluate the effect of sanazole as a sonosensitizer under previously studied acoustic conditions of different pulse repetition frequencies, using two cell lines representative of solid tumours and haematopoietic cancers. Cells were treated with different doses of sanazole. Flow-cytometric analysis and DNA fragmentation assay were carried out at different times, and morphological features were also inspected. For ultrasound treatment, cells were pre-incubated with a non-cytotoxic dose of sanazole for 30 min before exposure. Evaluation of cell killing and a parallel examination of intracellular oxidative stress levels in both cell lines were performed using flow cytometry. Sanazole alone displayed selective cytotoxic effects towards solid tumour-derived cancer cells, resulting in complete cell death after 24 h of treatment, and enhanced the ultrasound-induced cell killing 6 h post-treatment. The enhancement seemed to be mediated by an additive increase in intracellular oxidative stress levels. Sanazole seems to be an efficient cytotoxic agent for the treatment of solid tumours and a promising sonosensitizer under aerobic conditions.


Risk and resource factors for depressive symptoms during adolescence and emerging adulthood - A 5-year follow-up using population-based data of the BELLA study.
Depression is one of the most common mental disorders in adolescents and young adults worldwide, and causes a high burden for both individuals and society. The present study aims to investigate the role of risk and resource factors for depressive symptoms during adolescence and emerging adulthood in a German population-based cohort. Within the longitudinal BELLA study, data on risk and resource factors were collected among n = 632 children and adolescents aged 11 to 17 years. Depressive symptoms were measured five years later. Multivariate linear regression models served to investigate effects of risk and resource factors on depressive symptoms. Regression models were stratified by gender. Moreover, we explored potential interaction effects. A negative mother-child relationship predicted depressive symptoms in girls, whereas school stress served as a risk factor in boys. Peer competence was associated with fewer depressive symptoms in girls, and family cohesion was identified as a resource factor in boys. In addition, few moderating effects of resource factors on the association between risk factors and depressive symptoms were found. As the BELLA study is a population-based observational study, we only identified associations between risk and resource factors and no cause-effect relationships. Findings provide evidence of gender-specific risk and resource factors for depression. Individuals who are exposed to risk factors must be monitored during the transition into adulthood. Gender-sensitive prevention and early intervention programs are needed.


Activity profiling of aminopeptidases in cell lysates using a fluorogenic substrate library.
Aminopeptidases are exopeptidases that process peptide bonds at the N-terminus of protein substrates, and they are involved in controlling several metabolic pathways. Due to their involvement in diseases such as cancer or rheumatoid arthritis, their presence can also be used as a predictive biomarker. Here, we used a library of fluorogenic substrates containing natural and unnatural amino acids to reliably measure the aminopeptidase N (APN) activity in cell lysates obtained from human, pig and rat kidneys. We compared our results to the substrate specificity profile of isolated APN. Our data strongly support the observation that fluorogenic substrates can be successfully used to identify aminopeptidases and to measure their activity in cell lysates. Moreover, in contrast to assays using single substrates, which can result in overlapping specificity due to cleavage by several aminopeptidases, our library fingerprint can provide information about single enzymes.


Knowledge of biosimilars and perceptions of the naming conventions for biosimilar products in clinical practice in the United States.
Biosimilar therapies and their naming conventions are both relatively new to the drug development market and in clinical practice. We studied the use of the four-letter naming convention in practice and the knowledge, perceptions, and preferences of US health care providers. A survey was distributed among health care professionals with a history of utilizing biosimilars in clinical practice to measure key knowledge and the presence of discernable naming trends. Differences in responses across pre-hypothesized subgroups were tested for statistical significance. Of the 506 surveys emailed, 83 (16%) people responded. Overall, there was poor knowledge about the key concepts surrounding biosimilars. For example, only 52% of respondents correctly identified that biosimilars were not the same as the generic drug; however, frequent use correlated with superior knowledge across all groups. In reference to naming preferences, 67% of all respondents indicated that they commonly use the brand name to distinguish biosimilars in clinical practice and a majority of them (85%) indicated that the brand name was easier to remember than the nonproprietary name with the four-letter suffix. An unexpected number of neutral responses was documented. Notably, more than half of respondents (68%) indicated a neutral response when asked if the four-letter suffix promoted medical errors. There remains a knowledge gap with regard to biosimilars, and lack of consensus on how the naming convention is and should be utilized in clinical practice. The data also suggest that effective biosimilar education could aid in promoting familiarity with the naming convention among health care providers.


Therapeutic effects of antibacterial treatment for intractable skin diseases in Helicobacter pylori-positive Japanese patients.
In order to understand the pathogenic relationship between Helicobacter pylori (H. pylori) and skin diseases, we examined the serum levels of IgG antibody against H. pylori and then performed gastroscopic examinations in Japanese patients with chronic skin diseases. These H. prylori-positive patients were treated with antibacterial eradication therapy, and therapeutic efficacy was evaluated. A total of 198 patients who were resistant to conventional therapies were randomly selected. They included 50 cases with chronic urticaria, 32 with pruritus cutaneous, 74 with atopic dermatitis, 15 with nummular dermatitis, 17 with prurigo chronica multiformis, 6 with psoriasis vulgaris, and 4 with erythroderma. Positive anti-H. pylori antibody was detected in 102 out of these 198 patients; more than half of the ones with chronic urticaria, pruritus cutaneous, nummular dermatitis, and prurigo chronica multiformis had positive antibodies. Gastroscopy was then performed in 48 cases with positive antibodies. Eradication therapy was effective in 60% of the patients with chronic urticaria, in 58% with pruritus cutaneous, in 54% with nummular dermatitis, and in 50% with prurigo chronica multiformis. In chronic skin diseases, persistent infection with H. pylori may be an eruption trigger and may cause deterioration of the disease into an in tractable and chronic form.


Combination therapy with arsenic trioxide, all-trans retinoic acid, and chemotherapy in acute promyelocytic leukemia patients with various relapse risks.
To improve the recovery rate of high-risk patients with acute promyelocytic leukemia (APL), we used all-trans retinoic acid (ATRA)/arsenic trioxide (ATO)/daunorubicin combination in remission induction, daunorubicin and cytarabine in consolidation, and ATRA/ATO/methotrexate ± 6-mercaptopurine in maintenance treatment of APL patients with various risks for relapse. Our results showed a high complete remission rate of 95.3%. Excluding the cases of early-death, no significant differences in event-free survival were observed between the intermediate-risk and high-risk group (p = 0.393) and the low-risk and high-risk group (p = 0.162). In addition, there were no significant differences between the groups in cumulative incidence of central nervous system relapse. In conclusion, our results suggest that APL patients benefit from combination ATO/ATRA/chemotherapy, and that this regimen is especially beneficial for patients with high-risk prognostic factors.


Resting saliva volume as a risk factor for hypogeusia: A retrospective study.
The causes of hypogeusia include zinc deficiency, systemic illness, and consumption of drugs. Notably, patients with oral cavity diseases such as oral candidiasis and salivary gland hypofunction may present with risk factors that remain unreported. Hence, this study aimed to investigate the relationship between age, sex, smoking status, serum zinc concentration, oral candidiasis, saliva volume, and taste function in patients with hypogeusia. Overall, 335 participants who complained of taste abnormalities underwent a taste test. Based on the recognition threshold value, the participants were classified as normal individuals (recognition threshold of 1 and 2) and patients with hypogeusia (recognition threshold of ≥3). The clinical characteristics, including resting saliva volume (RSV) and stimulated saliva volume (SSV), were compared, and a multivariate logistic regression analysis focusing on RSV was performed. Patients with hypogeusia had a lower RSV than normal individuals for all tastes, but not for SSV. Based on the results of regression analysis, RSV was identified as an independent predictor of hypogeusia for salty and bitter tastes. Moreover, the proportion of patients with decreased RSV increased as the number of taste qualities exceeding the reference recognition threshold increased. Furthermore, a decrease in RSV was associated with an increase in the recognition threshold for salty and bitter tastes. Based on the results of the present study, moisturizing the oral cavity may be useful against hypogeusia.


Biotherapy and treatment of adult primary chronic rhinosinusitis with nasal polyps: Cellular and molecular bases.
The present article reviews the molecular and cellular mechanisms involved in the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwCRSwNP) and underlying the action mechanisms of biotherapies. Biotherapy uses substances naturally produced by the organism or their specific antagonists targeting a proinflammatory mechanism. CRSwCRSwNP is a form of chronic rhinosinusitis (CRS), which is classically subdivided in to 2 types according to the presence of polyps. In recent years, the concept of endotypes emerged, with a more exhaustive definition of the types of CRS according to inflammatory mechanism, with a view to developing personalized treatments. CRSwNP pathophysiology is poorly understood. Polyps arise from a primary epithelial lesion in a context of chronic local inflammation, mainly type 2 in Europe, implicating eosinophils, IgE, Th2 cytokines (IL-4/IL-13, IL-5) and T and B cells. Biotherapy seems promising in CRSwNP. The present review details the various pathophysiological pathways underlying the action mechanisms of biotherapies, and the various published studies, assessing efficacy and mode of action in the treatment of CRSwNP.


Comparison of microbial colonization rates between central venous catheters and peripherally inserted central catheters.
Central venous catheters (CVCs) and peripherally inserted central catheters (PICCs), have been widely used as intravascular devices in critically ill patients. However, they might evoke complications, such as catheter colonization that has been considered as predisposing factor for central line-associated bloodstream infections (CLABSIs). Although numerous studies have compared the risk of bloodstream infections between PICCs and CVCs, comparative studies on their colonization rates are limited. The episodes of catheter colonization in critically ill patients with CVCs or PICCs were retrospectively analysed during a two-year period in a Greek tertiary care hospital and colonization rates, microbial profiles and antimicrobial susceptibility patterns were compared. Clinical and laboratory data of consecutive hospitalized critically-ill patients who underwent PICC and CVC placement between May 2017-May 2019 were analysed. All catheters were examined by the semiquantitative culture technique for bacterial pathogens, either as a routine process after catheter removal or after suspicion of infection. Species identification and antimicrobial resistance patterns were determined by the Vitek2 automated system. During the survey period a total of 122/1187 (10.28%) catheter colonization cases were identified among CVCs and 19/639 (2.97%) cases among PICCs (p = 0.001). The colonization rate was 12.48/1000 catheter-days for the CVC group and 1.71/1000 catheter-days for the PICC group (p < 0.001). The colonization rate per 1000 catheter-days due to multidrug-resistant organisms (MDROs) was 3.85 in all study cases, 7.26 (71/122) in the CVC group and 0.63 (7/19) in the PICC group (p < 0.001). Within the CVC group, the most common microorganism isolated was MDR Acinetobacter baumannii (n = 38, 31.1%) followed by MDR Klebsiella pneumoniae (n = 20, 16.4%). In the PICC group, the predominant microorganism isolated was Candida spp. (n = 5, 23.8%) followed by MDR K. pneumoniae and MDR A. baumannii in equal numbers (n = 3, 14.2%). PICC lines were associated with significantly lower colonization rates comparing to the CVC ones. In addition, patterns of microbial colonization revealed a trend over the predominance of MDR gram-negatives in CVCs suggesting that PICCs might be a safer alternative for prolonged inpatient intravascular access. Prevention programs directed by local microbial ecology may diminish catheter colonization rates and CLABSIs.


Response of the pearl oyster Pinctada margaritifera to cadmium and chromium: Identification of molecular biomarkers.
This study was designed to identify in the pearl oyster Pinctada margaritifera, used as a bio-accumulator, molecular biomarkers for the presence of heavy metals in the lagoon environment. Pearl oysters were exposed to 2 concentrations (1 and 10μgL-1) of cadmium (Cd) and chromium (Cr) compared to a control. Twelve target genes encoding proteins potentially involved in the response to heavy metal contamination with antioxidant, detoxification or apoptosis activities were selected. P. margaritifera accumulated Cd but not Cr, and mortality was related to the amount of Cd accumulated in tissues. In response to Cd-Cr contamination, metallothionein (MT) was significantly up-regulated by Cd-Cr at both concentrations, while 7 others (SOD, CAT, GPX, GSTO, GSTM, CASP, MDR) were down-regulated. Based on the development of these molecular tools, we propose that the pearl oyster, P. margaritifera, could be used as a sentinel species for heavy metal contamination in the lagoons of tropical ecosystems.


E3 Ubiquitin Ligase RNF125 Suppresses Immune Escape in Head and Neck Squamous Cell Carcinoma by Regulating PD-L1 Expression.
Head and neck squamous cell carcinoma (HNSCC) is a lethal malignancy. Given the essential roles of E3 ligases in cancer immunotherapies, this paper explored the effect of E3 ubiquitin ligase ring finger protein 125 (RNF125) on immune escape in HNSCC. After delivering overexpressed (oe)-RNF125, interferon-gamma, or oe-programmed death-ligand 1 (PD-L1) into HNSCC cells and cell culture with carboxyfluorescein succinimidyl ester-labeled CD8+ T cells, RNF125 and PD-L1 levels were determined via RT-qPCR and Western blot, with HNSCC cell behaviors assessed via colony formation assay, Transwell assays and flow cytometry, and inflammatory factors measured via ELISA. PD-L1 ubiquitination level and PD-L1's interaction with RNF125 were analyzed via co-immunoprecipitation. The in vivo action of RNF125 on HNSCC was validated via nude mouse tumorigenicity assay. Briefly, RNF125 was weakly expressed in HNSCC cells. RNF125 overexpression inhibited immune escape of HNSCC cells, evidenced by decreased TSCCA cell proliferation, migration, and invasion, increased CD8+ T cell proliferation, and elevated IL-2 and TNF-α levels. RNF125 downregulated PD-L1 in TSCCA cells and facilitated PD-L1 ubiquitinational degradation. PD-L1 overexpression partially abated RNF125-mediated suppression on TSCCA cell immune escape. Moreover, RNF125 suppressed tumorigenesis and tumor growth in vivo. Overall, RNF125 promoted PD-L1 ubiquitinational degradation, hence inhibiting immune escape in HNSCC.


Does tent caterpillar attack reduce the food quality of red alder foliage?
We assayed the quality of red alder trees for western tent caterpillar growth and survival to test the hypothesis that caterpillar feeding stimulates plant defenses in both attacked and adjacent trees. Three years of high tent caterpillar density were necessary before deterioration in foliage quality occurred, and even then only foliage from trees which were almost completely defoliated in the current year reduced the growth of caterpillars. Both tent size and mean egg mass size increased after the second year of high density which indicates that good conditions still existed for tent caterpillars after 2 to 3 years of heavy feeding.Egg masses which were moved to areas where trees had not recently supported a high caterpillar population produced significantly smaller tents than endemic controls in 1982. Therefore the small tent and egg mass size of the high density population in 1982 was inherent to the insects rather than modified by food source. In 1983 the tents from introduced egg masses were as large as naturally occurring tents.If lightly attacked trees within areas of high caterpillar density are better defended against insect attack, this does not show up in their ability to support caterpillar growth and survival. We found no evidence to support the hypothesis that trees communicate insect attack and stimulate chemical defenses in adjacent trees. Reduced foliage quality seems to be a result of extensive insect damage rather than a defense against insect damage.


Perturbation of glutathione by a central action of morphine.
A series of studies were conducted in order to further characterize the previously reported effect of morphine to diminish hepatocellular concentrations of glutathione (GSH) in mice. Naive ICR mice administered morphine (i.p.) in doses up to 1000 mg/kg had diminished hepatic GSH concentrations, with a maximum depletion of approximately 50% occurring at doses of 250 mg/kg or greater. No such effect from an acute challenge with morphine was observed in morphine-tolerant mice. The intracerebro-ventricular administration of the opioid receptor antagonist naltrexone (250 micrograms) completely blocked the hepatic GSH depression resulting from the systemic (i.p.) administration of morphine (100 mg/kg). When morphine (100 micrograms) was administered by the i.c.v. route, GSH concentrations in liver and plasma were significantly altered while heart and kidney were unchanged. Variable responses to i.c.v. morphine were obtained in spleen, stomach and lung. The depression of hepatic GSH was found not to be a consequence of morphine-induced hypoxia or hypothermia, and could not be attributed to intracellular oxidation of GSH.


Interleukin-6-174 Promoter Polymorphism and Susceptibility to Hepatitis B Virus Infection as a Risk Factor for Hepatocellular Carcinoma in Iran.
Hepatitis B virus (HBV) is a major risk factor for hepatocellular carcinoma (HCC). Cytokines play an important role in the regulation of immune responses and defense against viral infections. Human interleukin 6 (IL6) is a multifunctional cytokine that participates in these processes. The aim of this study was to assess the IL6-174 gene polymorphism in patients with chronic hepatitis B virus (HBV) infection as compared with healthy controls in an Iranian population. Totals of 297 HBV patients and 368 control individuals were evaluated. Genomic DNA was extracted from peripheral blood and the SSP-PCR (sequence specific primer-polymerase chain reaction) method was applied for genotyping. The frequencies of genotypes C/C, G/G and C/G in HBV cases were 4.7%, 34.3%, 60.9% and in controls were 12.8%, 39.7% and 47.6%, respectively. The frequencies of G and C allele in patients and controls were 78.1%, 21.9% and 67.4%, 32.6 % respectively. There was a significant difference in the frequencies of G/G genotype (CI=1.8-7.1, OR=3.47, P=0.00001) and G allele (CI=1.34-2.23, OR=1.72, P=0.0001) between HBV patients and the control group. These findings suggest that the IL6-174 C/G genotype and the G allele are strongly associated with susceptibility to HBV infection. Demographic information showed that most of the subjects were male (74.4%). According to high frequency of G/G genotype in male participants (63.1%) men probably are more susceptible to hepatitis than women.


Functional Adaptation of the Fibrocartilage and Bony Trabeculae at the Attachment Sites of the Anterior Cruciate Ligament.
The direct insertion of an enthesis is composed of uncalcified fibrocartilage (FC) and calcified FC, believed to function as buffers for multidirectional forces applied to the ligament. This study was performed to investigate the relationship between the FC thickness and bony trabecular orientation of the anterior cruciate ligament (ACL) on both the femoral and tibial sides. Six cadavers were examined (age at death: 73-92 years). Both femoral and tibial insertions of the ACL were harvested and used to make 0.5 mm interval semi-serial sections. Microdigital images were taken and used to measure the maximum thickness of both the uncalcified FC and Calcified FC. Two-dimensional discrete Fourier analysis was also performed to determine the orientation angle and orientation intensity of bony trabeculae directly under the FC. The mean thicknesses of the uncalcified FC at the femoral and tibial insertions were 0.98 mm and 0.49 mm, respectively. The mean thicknesses of the calcified FC were 0.47 mm and 0.38 mm, respectively. There was a significant difference in the uncalcified FC thickness, but not in the calcified FC thickness. The bony trabeculae showed a prominent orientation parallel to the ACL fiber on both sides, but it was more intense on the tibial side than on the femoral side. The trabecular orientation was prominent in the proximal-posterior part of the femoral side and in the anteromedial part of the tibial side, suggesting that mechanical stress is greater in these parts. The dominant bony trabecular angle was 69.0° on the femoral side and 59.8° on the tibial side when the tidemark was set at 0°. These findings suggest that the femoral side receives multidirectional stresses, while relatively unidirectional stress is loaded on the tibial side. Furthermore, stress is considered to be greater in the proximal-posterior part of the femoral insertion and in the anteromedial part of the tibial insertion. At the time of ACL reconstruction, attention should be paid to assign a robust portion of the graft to the posterior part of the femoral insertion and anteromedial part of the tibial insertion. Clin. Anat., 33:988-996, 2020. © 2019 Wiley Periodicals, Inc.


Differential migratory response of U-2 OS osteosarcoma cell to the various forms of platelet-derived growth factor.
U-2 OS osteosarcoma cells are mesenchymal-derived transformed cells spontaneously expressing both platelet-derived growth factor (PDGF) A- and B-chain genes, and releasing PDGF AA dimers in culture. Using modified Boyden chemotactic chambers, platelet-purified PDGF was shown to be a chemoattractant for U-2 OS cells. More specifically, U-2 OS cells migrated in the presence of PDGF AB and BB dimers but not in the presence of PDGF AA dimers. This pattern of response was similar to that observed with human fibroblasts and this similarity is consistent with the fact that U-2 OS cells express PDGF receptor alpha- and beta-subunits in a similar fashion to human fibroblasts.


Changes in ACh levels in the rat brain during subacute administration of diisopropylfluorophosphate.
Rats were treated with diisopropylfluorophosphate (DFP) acutely and daily for 14 days. The total, free, and bound acetylcholine (ACh) levels were monitored in striatum, hippocampus, and frontal cortex after DFP administration. Thirty minutes after daily administration of DFP, the total and free ACh levels were significantly increased and remained constant after each successive dose. The bound ACh levels in striatum and frontal cortex were also significantly increased; however, they were comparable to control levels after the 14th injection of DFP. The total ACh levels 30 min after a challenge dose of 2 mg/kg DFP in saline and DFP subacutely treated rats were significantly increased in hippocampus (34 and 76%) and frontal cortex (49 and 64%) and were not significantly different between the two groups. However, the level of total ACh in striatum was increased less in the tolerant rats (10%) than in the acutely treated rats (36%). The levels of free and bound ACh after acute administration of 2 mg/kg DFP were markedly increased in three brain regions. After subacute administration, the levels of bound ACh were significantly increased in hippocampus (84%) and frontal cortex (40%); however, that in striatum did not change. The increase in the bound ACh level in the subacute treatment group was less than that in acutely treated rats in all three brain regions; however, the duration of the elevation of the free ACh in striatum was shorter in subacutely treated rats. These results suggest that the presynaptic cholinergic storage sites for ACh might be changed during subacute administration of DFP.


Crystal structure of sarcoplasmic reticulum Ca2+-ATPase (SERCA) from bovine muscle.
The SERCA pump, a membrane protein of about 110kDa, transports two Ca(2+) ions per ATP hydrolyzed from the cytoplasm to the lumen of the sarcoplasmic reticulum. In muscle cells, its ability to remove Ca(2+) from the cytosol induces relaxation. The transport mechanism employed by the enzyme from rabbit muscle has been extensively studied, and several crystal structures representing different conformational states are available. However, no structure of the pump from other sources is known. In this paper we describe the crystal structure of the bovine enzyme, crystallized in the E1 conformation and determined at 2.9Å resolution. The overall molecular model is very similar to that of the rabbit enzyme, as expected by the high amino acid sequence identity. Nevertheless, the bovine enzyme has reduced catalytic activity with respect to the rabbit enzyme. Subtle structural modifications, in particular in the region of the long loop that protrudes into the SR lumen connecting transmembrane α-helices M7 and M8, may explain the difference.


Comparison of non-invasive imaging modalities in presurgical evaluation of temporal lobe epilepsy patients: a multicenter study.
Intractable drug-resistant magnetic resonance imaging (MRI) negative epilepsy in one of the complicated issues in neurology. Epilepsy surgery is beneficial treatment of intractable seizures, but precise localization of epileptogenic zone is a major concern. Thirty-four MRI negative drug-resistant epilepsy patients underwent video electroencephalography (EEG), positron emission tomography (PET) scan, and voxel-based morphometry (VBM) MRI from 2014 to 2019. Then, the findings of PET scan and VBM were compared with semiology and long-term electrophysiology. Cohen's kappa-coefficient (k) test was utilized to measure the agreement between our modalities. Among 34 patients with age ranging from 8 to 49 (mean: 29.00 ± standard deviation: 10.35), 19 were male (55.9%) and 15 were female (44.1%). Twenty-one patients (61.76%) had right temporal, 12 patients (35.3%) had left and one patient had bilateral temporal ictal focus according to video EEG. Inter-rater agreement analysis showed that the kappa index between video EEG and PET scan was of almost acceptable (more than 0.4) and there was poor agreement between video EEG and VBM (kappa index = 0.099). PET is highly concordant with video EEG in temporal lobe epilepsy (TLE) and has a considerable agreement in localizing epileptogenic zone while VBM is less.


Missense mutations outside the catalytic domain of the ABO glycosyltransferase can cause weak blood group A and B phenotypes.
Only little is known about the impact of amino acid substitutions outside an enzyme's active site on A and B transferase activity. A panel of blood group A- and B-specific plasmids containing the six known missense mutations of the coding sequence upstream of exon 6 of the ABO gene were constructed. HeLa cells were used to transfect ABO expression plasmids. Expression of ABO variants containing single or multiple missense mutations in HeLa cells resulted in a significant decrease in the percentage of antigen-expressing cells (up to 29%) and in mean fluorescence intensity (MFI; up to 50%) compared to transfection with ABO*A101 or ABO*B101. Coexpression of the respective antithetical wild-type construct (ABO*A101 and ABO*B101, respectively) further reduced cell surface expression of variant ABO constructs in regard to the percentage of expressing cells (up to 53% decrease) and MFI (up to 59% decrease). Weak A and B subgroups can arise from transferases with amino acid changes in the N-terminal domain, particularly in AB phenotypes, where normal A1 or B1 glycosyltransferases compete for the same substrates.


Porous cyclopentadiene unit-incorporated graphitic carbon nitride nanosheets for efficient photocatalytic oxidation of recalcitrant organic micropollutants in wastewater.
For the purpose of searching for efficient photocatalysts to deal with recalcitrant organic micropollutants in wastewater, here an in-situ supramolecule self-assembly-thermal polymerization strategy is developed to prepare a series of porous cyclopentadiene (CPD) unit-incorporated g-C3N4 ultrathin nanosheets (CCPD-g-C3N4). The CCPD-g-C3N4 demonstrate CPD unit doping level-dependent and remarkably enhanced visible-light photocatalytic oxidation efficiency towards two organic micropollutants, acetaminophen and methylparaben, in which the optimized CCPD-g-C3N4-2 shows 6.1 and 3.5 times higher acetaminophen and methylparaben degradation rate than bulk g-C3N4; moreover, CCPD-g-C3N4-2 is still robust and efficient in the treatment of five mixed organic micropollutants in pharmaceutical wastewater, and the satisfactory micropollutant removal efficiency is obtained in a wide pH window and the presence of high concentrations of inorganic anions and cations as well as dissolved organic matters. Theoretical calculation combined with experimental test reveal that CCPD-g-C3N4 can significantly reduce ecological risk of the target pollutant after the photocatalytic degradation reaction. Such enhanced photocatalytic oxidation efficiency is dominated by the accelerated charge carrier separation dynamics and extended visible-light response region due to the incorporation of CPD units, which finally lead to the generation of abundant reactive oxygen species to degrade and mineralize target micropollutants efficiently.


Interleukin-24 inhibits influenza A virus replication in vitro through induction of toll-like receptor 3 dependent apoptosis.
New anti-viral agents and strategies are urgently needed to fight rapidly mutating viruses, as vaccine programs cannot react fast enough to prevent pandemics. Recently, we have shown that interleukin-24 (IL-24) sensitizes tumor cells to toll-like receptor 3 (TLR3) mediated apoptosis. As influenza A virus stimulates the TLR3 receptor, we hypothesized that IL-24 might also exert an anti-viral effect. This study demonstrates that IL-24 reduces the titer of different influenza A virus subtypes independently of type I interferon in an apoptosis dependent manner. The anti-viral effect of IL-24 correlated with caspase-3 activation and could be blocked by a pan-caspase inhibitor and by small interfering RNA (siRNA) directed towards TLR3. Surprisingly, caspase-3 activation in influenza A virus/IL-24-stimulated cells correlated with the down-regulation of the B-cell lymphoma 2 (Bcl-2) family member myeloid cell leukemia 1 (Mcl-1). Correspondingly, knockdown of Mcl-1 by siRNA enhanced caspase activation in influenza A virus infected cells and was furthermore linked to a reduction of viral titers. We conclude that IL-24 exerts an anti-viral role selectively purging virally infected cells by leading to a down-regulation of Mcl-1. Our findings might therefore represent the first step towards a new rational concept in the development of anti-viral strategies based on the induction of apoptosis.


No evidence for a role of xenotropic murine leukaemia virus-related virus and BK virus in prostate cancer of German patients.
Prostate cancer is one of the most prevalent types of cancer in men. Controversial data exist concerning the role of BKPyV and the xenotropic murine leukaemia virus-related gammaretrovirus (XMRV) in prostate cancer development. We therefore assessed the association between prostate cancer and viral infections. We could detect BKPyV in only 1 out of 85 prostate cancer samples, whereas none of the tissue samples showed evidence for XMRV positivity. Lack of detection of BKPyV and XMRV in prostate cancer tissues suggests that these viruses do not play a role in the pathogenesis of this type of cancer.


Dress, posture, and setting as additive factors in subjective probabilities of rape.
Subjects indicated the likelihood that a female, photographed in eight situations, would be raped. The situations were created by the Cartesian product of her dress (seductive/nonseductive), posture (aggressive/nonaggressive), and setting (inside/outside). The three variables combined additively with the highest subjective probability of rape associated with the seductive/nonaggressive/outside condition.


Antigenic and immunogenic spectrum of foot-and-mouth disease vaccine strain O1 Campos against representative viruses of topotypes that circulated in Asia over the past decade.
Identifying vaccine strains to control outbreaks of foot-and-mouth disease virus that could spread to new regions is essential for contingency plans. This is the first report on the antigenic/immunogenic relationships of the South American O1/Campos vaccine strain with representative isolates of the three currently active Asian type O topotypes. Virus neutralization tests using O1/Campos post-vaccination sera derived from cattle and pigs predicted for both species acceptable cross-protection, even after single vaccination, established by r1 values and by expectancy of protection using monovalent or polyvalent vaccines. The results indicate that effective oil vaccines containing the O1/Campos strain can be used against Asian isolates, expanding the scope of O1/Campos strain included in vaccine banks to control emergencies caused by Asian viruses, even on single-dose vaccination, and to cover the need of effective vaccines in Asia during systematic vaccination.


1-Butyl-3-methylimidazolium methane sulfonate ionic liquid corrosion inhibitor for mild steel alloy: Experimental, optimization and theoretical studies.
The current research reports the performance of 1-butyl-3-methylimidazolium methane sulfonate ([C4MIM][OMs](IL)) as effective corrosion inhibitor for mild steel in 1 M H2SO4 electrolyte. For proper evaluation, weight loss, electrochemical study, theoretical modeling and optimization techniques were used. Weight loss and electrochemical methods shows that the inhibition performance of [C4MIM][OMs] on the metal surface strengthens as the concentration increases. Maximum inhibition efficiency of 85.71%, 92.5% and 91.1% at 0.8 g L-1 concentration of [C4MIM][OMs] were obtained from the weight loss, polarization and impedance studies, respectively. In addition, response surface methodology (RSM) a statistical tool was used for modeling and optimization of the empirical data. The RSM model validates the empirical findings. Also, DFT/MD-simulation investigations evidenced that [C4MIM][OMs] forms a barrier film on the mild steel surface. The result shows that the synthesized [C4MIM][OMs] could open up opportunities in corrosion and materials protection for sustainability.


Emerging Bladder Cancer Biomarkers and Targets of Therapy.
Bladder cancer is a heterogeneous disease characterized by complex networks of molecular alterations and gene expression. This review summarizes some of the recent genomic studies that have further advanced the understanding of the pathways driving bladder cancer, highlighting several important biomarkers and potential targeted therapeutic strategies that are now in clinical trials. In addition, noninvasive techniques to evaluate biomarkers in patients' urine and serum for early detection and surveillance are discussed.


Nonclosure of rectourethral fistula during posterior sagittal anorectoplasty: Our experience.
To study the effect of nonclosure of rectourethral (RU) fistula and to do a comparative analysis of the complications with and without nonclosure of RU fistula during posterior sagittal anorectoplasty (PSARP) in anorectal malformation cases (ARM). A total of 68 cases of ARM were included in the study group, of which 34 cases were those in whom RU fistula was not closed (group A) during PSARP. Another 34 successive cases were included in study group B in whom the RU fistula was closed as is conventionally done by using interrupted sutures. Comparatively, group A had none or minimum urological complications as compared to Group B. RU fistula closure is not mandatory during PSARP and nonclosure avoids urological complications. It especially avoids urethral complications, which are 100% preventable.


Black-white differences in serum Lp(a) lipoprotein levels.
Serum Lp(a) lipoprotein was determined in 81 black and 81 white healthy men and women matched for sex and age. The results show a highly significant increase of Lp(a) concentrations in blacks as compared to whites, and confirm the notion that Lp(a) lipoprotein levels are race-dependent. Whether high values of Lp(a) play an atherogenic role in blacks remains to be established in further studies.


[Cutaneous leishmaniasis in the military hospital Moulay Ismaïl of Meknes (Morocco): about 49 cases diagnosed between 2005 and 2011].
An increase in the number of cases of cutaneous leishmaniasis has been observed, in recent years, in Morocco. We tried, through a series of 49 cases collected from the dermatology department at the military hospital Moulay Ismail of Meknes, to clarify the epidemiological, clinical and evolutionary aspects of the reported cases. We recorded for each patient: age, sex, geographic origin and the period before consultation. We have also noted the number of lesions, their location, and their clinical aspects. Finally, we recorded results of direct examination in search of the parasite, treatment and post treatment evolution. The sex ratio was 11. The average age was 35.6 years. The average period of consultation was 3.8 months. Eighty-six percent of cases (n=42) were from the region extending from south to south-east of the atlas. The average number of lesions per patient was 4.46 (from 1 to 40). Thirty-seven percent of cases (n=18) had single lesions and 63% (n=31) multiple lesions. There was a polymorphism of clinical aspects of lesions with predominant of ulcerative crusting aspects observed in 55.1% of cases (n=27). Face localization was observed in 20.4% of cases (n=10). Ninety-two percent of cases (n=45) had involvement of the upper limbs and/or lower. Direct examination was positive in 65% of cases (n=32). The treatment was based on meglumine antimoniate associated in three quarters of cases with cryotherapy using liquid nitrogen. The outcome was favorable for all patients. We observed an increase in the number of cases in 2011 and especially those with multiple lesions followed by a decline in 2011.


Molecular detection and diversity of medium-chain-length polyhydroxyalkanoates-producing bacteria enriched from activated sludge.
Knowledge of the species composition of complex bacterial communities is still very limited. The main objectives of this study were to identify medium-chain-length polyhydroxyalkanoates (mcl-PHAs)-producing bacteria from activated sludge fed with methanol as well as to characterize their PHA operon. The identification was based on PCR amplification of mcl-PHA synthase gene fragments. In the analysed sample, four isolates possessing mcl-PHA synthesis systems were distinguished. The results of a 16S rDNA sequence analysis revealed that three strains belonged to Pseudomonas species and the fourth one was characterized as Comamonas testosteroni. The results of this study indicate that the PCR-RFLP approach is an excellent way to identify mcl-PHA-synthesizing micro-organisms. The discovery of 4 genetic variants, among the 20 analysed, demonstrates that microbial diversity of activated sludge is high and thus offers a great opportunity for the discovery of novel gene forms. An important discovery of this study is that C. testosteroni could harbour mcl-PHA operon. Moreover, the results obtained indicate that PHAs synthesis ability can be spread by horizontal gene transfer. The results of a comparative phylogenetic analysis revealed that mcl-PHA-synthesizing bacteria can be divided into Pseudomonas fluorescens and Pseudomonas aeruginosa groups.


The effects of S9 mix from rat oesophagus, salivary gland, and liver on the mutagenicity of the rat oesophageal carcinogen N-nitroso-N-methylaniline in the Salmonella typhimurium assay.
The present study examines the feasibility of using the Salmonella typhimurium plate-incorporation assay of Ames for detecting target-organ specificity with N-nitroso-N-methylaniline (NMA), a compound for which the target site for tumour formation in the rat is the oesophagus. Thus it was anticipated that the oesophagus would bioactivate this compound. The compound has been investigated using S9 from Aroclor- and NMA-induced rat oesophagus, salivary gland and liver in the presence and absence of the co-mutagen, norharman. No response to NMA was seen with oesophageal S9 even though benzo[a]pyrene produced a dose-related increase in revertants in strain TA98 and TA100. No response to NMA was seen with salivary-gland S9. However, a response was produced with Aroclor-induced rat-liver S9 in the presence of norharman and with NMA-induced rat-liver S9 in the absence of norharman.