Pathology of Resin-Induced Gastrointestinal Damage: Report of 15 Cases and Review of Literature.
< strong > Objective: < /strong > Medication resins such as Kayexalate and Sevelamer used in the setting of chronic kidney disease for the correction of hyperkalemia and hyperphosphatemia are associated with gastrointestinal mucosal injury. In this study we describe the clinico-pathological features of Resin-induced gastrointestinal mucosal injury highlighting the histo-morphological appearances and differential diagnoses. The aim of this study is to increase the awareness of pathologists and clinicians alike to an under-reported etiology and pattern of intestinal mucosal injury related to medical resin therapy which may at times pose a clinical emergency. < strong > Material and Method: < /strong > The archives of the Department of Histopathology, Mubarak Al Kabir hospital were analyzed for cases of resin-induced gastrointestinal mucosal injury between 2013 and 2018. < strong > Results: < /strong > Of the 15 cases, Kayexalate crystals were identified in 7 cases, Sevelamer in 5 cases and both together were seen in 3 cases. Resin crystals were identified in the gastric antrum&duodenum (3 cases), colon (9 cases in the left colon, 2 cases in the right colon) and anal canal (1 case). The histological tissue reactions included mucosal necrosis (1 case), inflammatory polyps (2 cases), mucosal ulcerations with granulation tissue formation (10 cases), perforation (1 case) , and luminal crystals (1 case). < strong > Conclusion: < /strong > Accurate and timely recognition of the resin crystals in biopsy samples with clinical correlation is mandatory to avoid serious complications.


Impact of a hospital-wide huddle on device utilisation and infection rates: a community hospital's journey to zero.
Device utilisation ratios (DUR) correlate with device-associated complications and rates of infection. We implemented a hospital-wide Daily Interdisciplinary Safety Huddle (DISH) with infection control and device components. The aim of this study was to evaluate the impact of DISH on DURs and rates of infection for indwelling urinary catheters (IUC) and central venous catheters (CVC). A quasi-experimental study assessing DURs and rates of infection before and after implementation of DISH. At DISH, usage of IUC and CVC is reported by managers and the infection preventionist reviews indications and plans for removal. Data before and after implementation were compared. Paired T-test was used to assess for differences between both groups. DISH was successfully implemented at a community hospital. The average DUR for IUC in intensive care unit (ICU) and non-ICU settings was reduced from 0.56 to 0.35 and 0.27 to 0.12, respectively. CVC DUR decreased from 0.29 to 0.26 in the ICU and 0.14 to 0.12 in non-ICU settings. Catheter-associated urinary tract infections (CAUTIs) decreased by 87% and central line-associated bloodstream infections (CLABSIs) by 96%. DISH was associated with hospital-wide reductions in DUR and device-associated healthcare-associated infections. Reduction of CLABSIs and CAUTIs had estimated cost savings of $688,050. The impact was more profound in non-ICU settings. To our knowledge, an infection prevention hospital-wide safety huddle has not been reported in the literature. DISH increased device removal, accountability and promoted a culture of safety.


Complex I dysfunction redirects cellular and mitochondrial metabolism in Arabidopsis.
Mitochondrial complex I is a major avenue for reduced NAD oxidation linked to oxidative phosphorylation in plants. However, the plant enzyme has structural and functional features that set it apart from its counterparts in other organisms, raising questions about the physiological significance of this complex in plants. We have developed an experimental model in which rotenone, a classic complex I inhibitor, has been applied to Arabidopsis (Arabidopsis thaliana) cell suspension cultures in order to dissect early metabolic adjustments involved in cell acclimation to mitochondrial dysfunction. Rotenone induced a transitory decrease in cellular respiration (0-4 h after treatment). Cell respiration then progressively recovered and reached a steady state at 10 to 12 h after treatment. Complex I inhibition by rotenone did not induce obvious oxidative stress or cell death but affected longer term cell growth. Integrated analyses of gene expression, the mitochondrial proteome, and changes in primary metabolism indicated that rotenone treatment caused changes in mitochondrial function via alterations in specific components. A physical disengagement of glycolytic activities associated with the mitochondrial outer membrane was observed, and the tricarboxylic acid cycle was altered. Amino acid and organic acid pools were also modified by rotenone treatment, with a marked early decrease of 2-oxoglutarate, aspartate, and glutamine pools. These data demonstrate that, in Arabidopsis cells, complex I inhibition by rotenone induces significant remodeling of metabolic pathways involving the mitochondria and other compartments and point to early metabolic changes in response to mitochondrial dysfunction.


The antigenic structure of dengue type 1 virus envelope and NS1 proteins expressed in Escherichia coli.
The antigenic structures of the envelope protein, E, and the non-structural protein, NS1, of dengue type 1 virus (DEN1) have been studied in the form of recombinant fusion proteins expressed in Escherichia coli. Deletion analysis was used to identify two distinct antigenic domains in E that reacted with subsets of antiviral monoclonal antibodies (MAbs). Domain I of E extends from amino acid residues (aa) 76 to 93 of E; domain II extends from aa 293 to 402 and contains an essential disulphide bridge. MAbs also reacted with several determinants clustered near the N terminus of the NS1 protein (aa 57 to 126). Recombinant fusion proteins containing E. coli trpE sequences and most of the sequences for either E or NS1 were immunogenic in mice. The antibodies elicited by the E fusion protein reacted with a portion of the protein containing domain II, whereas antibodies elicited by the NS1 fusion protein did not react with the antigenic determinants defined by our MAbs.


Relationship of antibody to outcome in neonatal herpes simplex virus infections.
Neutralizing antibody titers to herpes simplex virus type 1 (HSV-1) and HSV-2 were measured at birth in normal infants and uninfected infants of mothers with genital HSV infections during pregnancy and at the onset of infection in 5 infants with mild infections and 11 infants with severe infections. Thirty-eight percent of premature and 29% of term infants had neutralization titers of <1:5. High titers ([unk]1:40) were found in 55% of infants of mothers with primary infections during pregnancy and in 76% of infants of mothers with recurrent infections. The mean titers to HSV-1 and -2 in 5 infected infants with mild infections were 1:56 and 1:65 at the time of onset of infection, whereas the mean titers in 11 infants with severe infections were 1:11 and 1:12. Six natally exposed infants who remained asymptomatic were also studied and had a mean titer to HSV-1 of 1:85 and to HSV-2 of 1:69. Therefore, infants with high titers of transplacentally derived antibody had a more favorable outcome than infants with lower titers. Ninety-five percent of the infants of mothers with recurrent infections had a Rawls index of more than 85, suggesting that the antibody response was to HSV-2. However, low levels of antibody with this type specificity failed to protect four infants from infection with HSV-2. Augmentation of the neutralization titer to HSV-2 by the amount of complement present in cord serum was less than twofold. The study suggests that the quantity of antibody derived transplacentally affects the outcome of infection after natal exposure to herpes simplex virus. Complete neutralization of virus by antibody may occur in some infants, and prolongation of the incubation period and modification of the infection may occur in others.


Disseminated intravascular coagulation: epidemiology, biomarkers, and management.
Disseminated intravascular coagulation (DIC) is a systemic activation of the coagulation system, which results in microvascular thrombosis and, simultaneously, potentially life-threatening haemorrhage attributed to consumption of platelets and coagulation factors. Underlying conditions, e.g. infection, cancer, or obstetrical complications are responsible for the initiation and propagation of the DIC process. This review provides insights into the epidemiology of DIC and the current understanding of its pathophysiology. It details the use of diagnostic biomarkers, current diagnostic recommendations from international medical societies, and it provides an overview of emerging diagnostic and prognostic biomarkers. Last, it provides guidance on management. It is concluded that timely and accurate diagnosis of DIC and its underlying condition is essential for the prognosis. Treatment should primarily focus on the underlying cause of DIC and supportive treatment should be individualised according to the underlying aetiology, patient's symptoms and laboratory records.


Cardiac surgery in infants with very low birth weight.
Congenital heart defects in low birth weight infants are typically managed with supportive therapy or palliative surgery, and definitive repair is delayed. However, the morbidity of such an approach has been shown to be high. Recent reports emphasize early surgical repair with good results in low birth weight and premature babies. However, there are no data on the outcomes in infants with very low birth weight (<1,500 g). Since 1990, the authors performed complete repair of congenital heart defects (other than isolated patent ductus arteriosus) in 20 infants weighing 1,500 g or less. Defects included aortic coarctation (n = 6), ventricular septal defect (n = 5), tetralogy of Fallot (n = 2), transposition of great arteries (n = 2), truncus arteriosus (n = 2), total anomalous pulmonary venous return (n = 1), double outlet right ventricle (n = 1), and pulmonary atresia with intact ventricular septum (n = 1). Preoperative morbidity was more common in patients who were referred late for corrective surgery. Modification of techniques of neonatal cardiopulmonary bypass were used. There were 2 early deaths (10%) caused by foot gangrene (n = 1), and pulmonary complications (n = 1). No patient had evidence of postbypass intracranial hemorrhage. At a median follow-up of 40 months, there was 1 late death, and 4 patients underwent a total of 5 surgical and catheter reinterventions. There was no evidence of neurological sequelae attributable to surgery. In most cases, delaying repair of congenital heart defects in low and very low birth weight infants does not confer any benefit and is associated with a higher incidence of preoperative morbidity. Complete repair of both simple and complex congenital heart lesions can be performed successfully in such patients with good early and medium-term results. Postoperative growth after repair approximates the normal growth curve for low birth weight infants without congenital heart disease. It is recommended that with few exceptions, such infants, especially when symptomatic, undergo early surgical correction rather than prolonged medical management or other forms of palliation.


Laudanosine and atracurium concentrations in a patient receiving long-term atracurium infusion.
Atracurium is sometimes used for muscle relaxation in patients undergoing mechanical ventilation. Use of atracurium in high doses or for a long period of time has raised the possibility of the accumulation of laudanosine, a breakdown product known to cause seizure activity in animals. The objective of this report was to see if laudanosine accumulation and seizure activity had occurred in a patient who had received a long-term, relatively high-dose infusion of atracurium. Case report. The patient received atracurium for 38 days, at rates ranging from 0.3 to 0.96 mg/kg/hr. An electroencephalogram (EEG) was done before the discontinuation of the infusion, and plasma concentrations of atracurium and laudanosine were measured at, and after, the termination of the atracurium infusion. The laudanosine elimination half-life was calculated. Intensive care unit. A 23-yr-old woman admitted with sickle cell crisis, complicated by acute chest syndrome, acute respiratory distress syndrome, and hepatic and renal failure. None. As expected, laudanosine concentrations were increased but were below the level reported to cause seizure activity in animals. Laudanosine elimination half-life was prolonged to 617 mins, which was consistent with previously reported values. The patient's EEG was normal, with no ictal pattern. Despite long-term use of high doses of atracurium infusion and the increased elimination half-life of laudanosine, only moderate accumulation of laudanosine occurred, and the EEG was normal. Hence, it appears unlikely that toxic concentrations of laudanosine would be reached, even in a critically ill patient.


Cyclosporin A induces apoptosis in childhood acute lymphoblastic leukemia cells.
In an effort to identify novel antileukemic agents that can bypass the mechanisms of multidrug resistance, we found that cyclosporin A ([CyA] 5 mumol/L) produced a median cell kill of 69% (range, 47% to 85%) in seven B-lineage acute lymphoblastic leukemia (ALL) cell lines (OP-1, SUP-B15, KOPN-55bi, RS4;11, NALM6, REH, and 380) and three T-lineage ALL cell lines (MOLT4, CCRF-CEM, and CEM-C7) after 4 days of culture. At 10 mumol/L, median CyA toxicity was 99% (range, 88% to > 99%). CyA was equally toxic to both a multidrug-resistant cell line, CEM-VLB100, which overexpresses gp-170 P-glycoprotein, and one resistant to topoisomerase II inhibitors, CEM-VM1-5, which has a mutation in the topoisomerase II gene. CyA was also toxic to primary leukemic cells maintained in stroma-based culture, a system that substantially prolongs in vitro cell survival. Against lymphoblasts from 21 patients with B-lineage ALL, the compound (at 5 mumol/L) reduced the leukemic cell number by a median of 87% (range, 27% to > 99%) compared with results for parallel control cultures lacking CyA. Seven of these samples were from cases with unfavorable genetic features (e.g., Philadelphia-chromosome or MLL gene rearrangements); three were obtained at relapse. Against T lymphoblasts (from six patients), the median reduction in cell number was 79% (range, 30% to > 99%). At 10 mumol/L, the cell kill exceeded 97% in all cases studied. The mechanism of CyA cytotoxicity was found to be the activation of apoptosis, which was suppressed by phorbol myristate acetate but not by inhibitors of ceramide-mediated apoptosis, phosphatidyl inositol-3 kinase activity, or tyrosine kinase activity. These findings demonstrate high levels of CyA-induced toxicity against ALL cells at concentrations achievable in vivo, thus providing a strong rationale for clinical testing of this agent in patients with ALL.


Technology and College Student Mental Health: Challenges and Opportunities.
In recent years, there has been an increase in symptoms of depression, anxiety, eating disorders, and other mental illnesses in college student populations. Simultaneously, there has been a steady rise in the demand for counseling services. These trends have been viewed by some as a mental health crisis requiring prompt investigation and the generation of potential solutions to serve the needs of students. Subsequently, several studies linked the observed rise in symptoms with the ubiquitous rise in use of personal computing technologies, including social media, and have suggested that time spent on these types of technologies is directly correlated with poor mental health. While use of personal computing technologies has dramatically shifted the landscape in which college students connect with one another and appears to have some detriments to mental health, the same technologies also offer a number of opportunities for the enhancement of mental health and the treatment of mental illness. Here, we describe the challenges and opportunities for college student mental health afforded by personal computing technologies. We highlight opportunities for new research in this area and possibilities for individuals and organizations to engage with these technologies in a more helpful and wellness-promoting manner.


Virome and bacteriome: two sides of the same coin.
Although bacterial dysbiosis has been previously associated with carcinogenesis and HIV infection, the impact of the virome and these disease states has been less well studied. In this review, we will summarize what is known about the interplay between both the bacterial and the viral components of the microbiome on cancer and HIV pathogenesis. Bacterial dysbiosis has been associated with carcinogenesis such as colorectal cancer (CRC), hepatocellular carcinoma (HCC), lung cancer, breast cancer, and gastric cancer. The dysbiotic pathogenesis may be species-based or community-based and can have varying mechanisms of carcinogenesis. The human virome was also associated with certain cancers. Viruses, such as cytomegalovirus (CMV), Human herpesvirus 8 (HHV-8), human papilloma virus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), and Epstein-Barr virus (EBV), all had associations with cancers. It was also reported that an altered bacteriophage community may lead to carcinogenesis by allowing opportunistic, oncogenic bacteria to proliferate in a gastrointestinal biofilm. This mechanism shows the importance of analyzing the bacteriome and the virome concurrently as their interactions can provide insight into new mechanisms in the pathogenesis of not only cancer, but other diseases as well. The enteric bacteriome was shown to be distinctly altered in immunocompromised HIV-infected individuals, and highly active antiretroviral therapy (HAART) was shown to at least partially reverse the alterations that HIV causes in the bacteriome. Studies have shown that the progression to HIV is associated with changes in the plasma concentration of commensal viruses. HIV also acts synergistically with multiple other viruses, such as HPV, EBV, varicella zoster virus (VZV), and HHV-8. Although it has been shown that HIV infection leads to enteric virome expansion in humans, most of the research on HIV's effect on the virome was conducted in non-human primates, and there is a lack of research on the effect of HAART on the virome. Virome-wide analysis is necessary for identifying novel viral etiologies. There is currently a wealth of information on the bacteriome and its associations with cancer and HIV, but more research should be conducted on the virome's associations and reaction to HAART as well as the bacteriome-virome interactions that may play a major role in pathogenesis and recovery.


The discovery of the prokaryotic cytoskeleton: 25th anniversary.
The year 2017 marks the 25th anniversary of the discovery of homologues of tubulin and actin in prokaryotes. Before 1992, it was largely accepted that tubulin and actin were unique to eukaryotes. Then three laboratories independently discovered that FtsZ, a protein already known as a key player in bacterial cytokinesis, had the "tubulin signature sequence" present in all α-, β-, and γ-tubulins. That same year, three candidates for bacterial actins were discovered in silico. X-ray crystal structures have since confirmed multiple bacterial proteins to be homologues of eukaryotic tubulin and actin. Tubulin and actin were apparently derived from bacterial precursors that had already evolved a wide range of cytoskeletal functions.


Basolateral protrusion and apical contraction cooperatively drive Drosophila germ-band extension.
Throughout development, tissues undergo complex morphological changes, resulting from cellular mechanics that evolve over time and in three-dimensional space. During Drosophila germ-band extension (GBE), cell intercalation is the key mechanism for tissue extension, and the associated apical junction remodelling is driven by polarized myosin-II-dependent contraction. However, the contribution of the basolateral cellular mechanics to GBE remains poorly understood. Here, we characterize how cells coordinate their shape from the apical to the basal side during rosette formation, a hallmark of cell intercalation. Basolateral rosette formation is driven by cells mostly located at the dorsal/ventral part of the rosette (D/V cells). These cells exhibit actin-rich wedge-shaped basolateral protrusions and migrate towards each other. Surprisingly, the formation of basolateral rosettes precedes that of the apical rosettes. Basolateral rosette formation is independent of apical contractility, but requires Rac1-dependent protrusive motility. Furthermore, we identified Src42A as a regulator of basolateral rosette formation. Our data show that in addition to apical contraction, active cell migration driven by basolateral protrusions plays a pivotal role in rosette formation and contributes to GBE.


Genetic predisposition to gastrointestinal polyposis: syndromes, tumour features, genetic testing, and clinical management.
Gastrointestinal tract polyposis is characterised by the presence of multiple polyps, particularly in the colorectum, and encompasses both cancer predisposition genetic syndromes and non-syndromic clinical manifestations. The sources of the heterogeneity observed in polyposis syndromes relate to genetic cause, mode of inheritance, polyp burden and histological type, and spectrum and frequency of extracolonic manifestations. These features determine the clinical management of carriers, including strategies for cancer prevention and early detection, and oncological treatments. Despite substantial progress in identifying the genetic causes of polyposis, a large proportion of cases remain genetically unexplained. Although some of these cases might be due to lifestyle, environmental factors, or cancer treatments, it is likely that additional polyposis predisposition genes will be identified. This Review provides an overview of the known syndromes and genes, genetic testing, and clinical management of patients with polyposis, and recent advances and challenges in the field of gastrointestinal polyposis.


Over-expression of a pepper plastid lipid-associated protein in tobacco leads to changes in plastid ultrastructure and plant development upon stress.
Proteins homologous to fibrillin, a pepper plastid lipid-associated protein involved in carotenoid storage in fruit chromoplasts, have been recently identified in leaf chloroplasts from several species and shown to be induced upon environmental stress. To further investigate the role of the protein, transgenic Nicotiana tabacum plants over-expressing fibrillin using a constitutive promoter were generated. Transgenics grown under standard light intensities (300 micromol photons m-2 sec-1) were found to contain substantial amounts of fibrillin in flowers and leaves. In leaves, the protein was immunolocalized within chloroplasts in both stromal and thylakoid subfractions. No change was noticed in thylakoid structures from transgenics, but chloroplasts contained an increased number of plastoglobules organized in clusters. In petals, leucoplasts were also found to contain more agglutinated plastoglobules. The effects of environmental factors on fibrillin gene expression and protein localization were studied in tobacco leaves. Less fibrillin was present in plants grown under low light intensities, which can be explained by the involvement of a light-dependent splicing step in the control of fibrillin gene expression in leaves. Analysis of protein subfractions from plants subjected to drought or high light showed that both stresses resulted in fibrillin association with thylakoids. Whereas no growth difference between wild-type (WT) and transgenic plants was noticed under low light conditions, transgenics exhibit a longer main stem, enhanced development of lateral stems and accelerated floral development under higher light intensities. These data suggest that fibrillin-related proteins fulfil an important function in plant development in relation to environmental constraints.


Suprageneric taxa derived from Amblycoryphini sensu lato (Orthoptera: Tettigonioidea: Phaneropteridae: Phaneropterinae).
Based on the current description of the tribe Amblycoryphini some related genera have been excluded. These genera comprise two new tribes (Vossiini n. trib. and Plangiopsiini n. trib.) and a new generic group (Plangiae n. group). The main differences between the taxa described and the tribe Amblycoryphini are discussed, to understand the new proposed classification. Plangiopsis aedeps is placed in the genus Plangiola. This paper contributes to the knowledge of the tettigonid fauna from Africa and understanding of the taxonomy of neotropical Phaneropterinae.


Radioactive impact in sediments from an estuarine system affected by industrial wastes releases.
A big fertilizer industrial complex and a vast extension of phosphogypsum piles (12 km2), sited in the estuary formed by the Odiel and Tinto river mouths (southwest of Spain), are producing an unambiguous radioactive impact in their surrounding aquatic environment through radionuclides from the U-series. The levels and distribution of radionuclides in sediments from this estuarine system have been determined. The analyses of radionuclide concentrations and activity ratios have provided us with an interesting information to evaluate the extension, degree and routes of the radioactive impact, as well as for the knowledge of the different pathways followed for the radioactive contamination to disturb this natural system. The obtained results indicate that the main pathway of radioactive contamination of the estuary is through the dissolution in its waters of the radionuclides released by the industrial activities and their later fixation on the particulate materials. Tidal activity also plays an important role in the transport and homogenization along the estuary of the radioactivity released from the fertilizer plants.


Resection of bilateral massive Achilles tendon xanthomata with reconstruction using vascularized iliotibial tract: A case report and literature review.
Cerebrotendinous xanthomatosis is a rare autosomal recessive metabolic disease. Surgical treatment is only indicated when the xanthoma becomes large, painful, and irritable with shoe wear. Reconstruction of the large defect following resection challenging, especially with resection of the entire Achilles tendon. We report a case of bilateral Achilles tendon defects of 16 cm following resection of bilateral Achilles tendon xanthomata, with reconstruction using vascularized iliotibial tract. The patient had a good functional outcome with well-preserved strength and cosmesis. Reconstruction of a total Achilles tendon defect using Vascularized iliotibial tract is safe and effective.


Liver toxicity profile in gold-treated Egyptian rheumatoid arthritis patients.
The objective was to evaluate the rationale for liver needle biopsy versus blood liver functional tests in monitoring the incidence of hepatotoxicity in Egyptian rheumatoid arthritic patients treated with gold compounds. Forty patients (12 males, 28 females) were randomly selected out of 258 Egyptian rheumatoid arthritic patients treated with sodium auro-thiomalate during the past 4 years. The minimum duration of treatment was 40 weeks. The methods used were firstly, liver function tests (serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminase, total serum bilirubin and total serum albumin) before, weekly during and after administration of sodium auro-thiomalate. Secondly, a needle liver biopsy was conducted by using the tru-cut needle. Then liver histology was graded according to Roenigk for grading liver toxicity. Viral hepatitis markers (hepatitis B surface antigen, anti-hepatitis C virus were done for monitoring viral hepatitis. Finally, the liver tissue contents of heavy metals were counted in the cases that showed grade IIIB histological changes. The results showed that none of the studied cases developed any clinically significant liver disease during the course of chrysotherapy. Blood liver function tests were of normal value throughout the course of drug administration. According to Roenigk grading, 20 patients (50%) showed grade I liver changes, and the other 20 patients showed liver changes of grades II and III (four grade II, eight grade IIIA, and another eight grade IIIB). None of the patients showed grade IV liver changes. It was concluded that blood liver tests are not the most sensitive methods to detect hepatotoxicity in gold-receiving Egyptian rheumatoid arthritic patients. Needle liver biopsy is not superior in detecting liver toxicity, compared with routine laboratory liver function tests, because of its complications. Rheumatoid arthritic patients with a potential risk of clinically significant liver disease should not be exposed to the risk of gold salt therapy. Pretreatment HLA-DR genetic typing may be a good detector for rheumatoid arthritic patients with potential risk of hepatotoxicity.


Why have child pedestrian death rates fallen?
Pedestrian injuries are a leading cause of childhood mortality and disability. Over the past two decades in Britain child pedestrian death rates have fallen despite large increases in traffic volume. In this paper Roberts examines the likely reasons for this decline. He argues that neither prevention programmes nor improvements in medical care are a plausible explanation and that the decline is most likely the result of a substantial reduction in children's traffic exposure. He believes, however, that restricting children's traffic exposure exacerbates socioeconomic differentials in childhood mortality and denies children their right to mobility. Roberts is convinced that one answer is for British transport policy to be aimed at providing mobility equitably rather than struggling to meet the ever increasing demands of car travel.


Menopause occurs late in life in the captive chimpanzee (Pan troglodytes).
Menopause in women occurs at mid-life. Chimpanzees, in contrast, continue to display cycles of menstrual bleeding and genital swelling, suggestive of ovulation, until near their maximum life span of about 60 years. Because ovulation was not confirmed hormonally, however, the age at which chimpanzees experience menopause has remained uncertain. In the present study, we provide hormonal data from urine samples collected from 30 female chimpanzees, of which 9 were old (>30 years), including 2 above the age of 50 years. Eight old chimpanzees showed clear endocrine evidence of ovulation, as well as cycles of genital swelling that correlated closely with measured endocrine changes. Endocrine evidence thus confirms prior observations (cyclic anogenital swelling) that menopause is a late-life event in the chimpanzee. We also unexpectedly discovered an idiopathic anovulation in some young and middle-aged chimpanzees; this merits further study. Because our results on old chimpanzees validate the use of anogenital swelling as a surrogate index of ovulation, we were able to combine data on swelling and urinary hormones to provide the first estimates of age-specific rates of menopause in chimpanzees. We conclude that menopause occurs near 50 years of age in chimpanzees as it does in women. Our finding identifies a basic difference between the human and chimpanzee aging processes: female chimpanzees can remain reproductively viable for a greater proportion of their life span than women. Thus, while menopause marks the end of the chimpanzee's life span, women may thrive for decades more.


A cavity loadlock apparatus for next-generation quantum optics experiments.
Cavity quantum electrodynamics (QED), the study of the interaction between quantized emitters and photons confined in an optical cavity, is an important tool for quantum science in computing, networking, and synthetic matter. In atomic cavity QED, this approach typically relies upon an ultrahigh vacuum chamber that hosts a cold trapped atomic ensemble and an optical cavity. Upgrading the cavity necessitates a months-long laborious process of removing external optics, venting, replacing the resonator, baking, and replacing optics, constituting a substantial bottleneck to innovation in resonator design. In this work, we demonstrate that the flexibility of optical cavities and the quick turnaround time in switching between them can be restored with the vacuum loadlock technique-reducing the cycle time to install a cavity, bake it, and transport it into the science chamber for days, achieving 3 × 10-10 Torr pressure in the science chamber. By reducing vacuum limitations, this approach is particularly powerful for labs interested in quickly exploring novel optic cavities or any other atomic physics relying on in-vacuum optics.


Ca2+-activation characteristics of single fibres from chemically skinned rat muscle incubated with glucose-6-phosphate.
In this study we examined the effects of 3-24 h of incubation of chemically skinned rat fast-twitch muscle with the glycolytic metabolite glucose 6-phosphate (G6-P) on the contractile properties and myosin ATPase activity in single muscle fibres, and on the carbohydrate content of myosin heavy chains (MHCs). Exposure of the permeabilised muscle to 10 mM G6-P for 24 h at 22+/-1 degrees C in a rigor solution containing protease inhibitors and a reducing agent (dithiothreitol, DTT) significantly decreased maximum Ca(2+)-activated force output by 31%, lowered the Ca2+ threshold for contraction by 0.1 pCa units and produced shallower force-pCa curves compared with controls. Furthermore, under these conditions, G6-P-treated muscle displayed lower myofibrillar MgATPase activity and a markedly higher carbohydrate content of MHCs, as identified with an immunoblot protocol for glycoprotein detection. Shorter incubations under the same conditions or 24-h incubations with 5 mM G6-P generally resulted in smaller changes in the contractile activation parameters. These findings suggest that reducing sugars acting as metabolic intermediates in the glycolytic pathway can have important non-energy-related effects on the contractile activation characteristics of mammalian skeletal muscle. These effects are consistent with the glycation of muscle proteins, in particular that of the MHC.


Association of polygenic scores for depression and neuroticism with perceived stress in daily life during a long-lasting stress period.
Genetic factors contribute significantly to interindividual differences in the susceptibility to stress-related disorders. As stress can also be conceptualized as environmental exposure, controlled gene-environment interaction (GxE) studies with an in-depth phenotyping may help to unravel mechanisms underlying the interplay between genetic factors and stress. In a prospective-longitudinal quasi-experimental study, we investigated whether polygenic scores (PGS) for depression (DEP-PGS) and neuroticism (NEU-PGS), respectively, were associated with responses to chronic stress in daily life. We examined law students (n = 432) over 13 months. Participants in the stress group experienced a long-lasting stress phase, namely the preparation for the first state examination for law students. The control group consisted of law students without particular stress exposure. In the present manuscript, we analyzed perceived stress levels assessed at high frequency and in an ecologically valid manner by ambulatory assessments as well as depression symptoms and two parameters of the cortisol awakening response. The latter was only assessed in a subsample (n = 196). No associations between the DEP-PGS and stress-related variables were found. However, for the NEU-PGS we found a significant GxE effect. Only in individuals experiencing academic stress a higher PGS for neuroticism predicted stronger increases of perceived stress levels until the exam. At baseline, a higher NEU-PGS was associated with higher perceived stress levels in both groups. Despite the small sample size, we provide preliminary evidence that the genetic disposition for neuroticism is associated with stress level increases in daily life during a long-lasting stress period.


Magnetic resonance imaging of the ovary.
Magnetic resonance imaging (MRI) of the pelvis can characterize a wide variety of ovarian lesions. We discuss MRI strategies for identification and characterization of ovarian neoplasms and correlate MRI findings with lesion gross pathological and histopathological structure.


Mind-Body Therapies in Individuals With Dementia: An Integrative Review.
Mind-body therapies frequently derive from Eastern philosophies and are becoming increasingly popular. These therapies, such as meditation, yoga, tai chi, qigong, biofield therapies, and guided imagery, have many reported benefits for improving symptoms and physiological measures associated with various chronic diseases. However, clinical research data concerning the effectiveness of these practices in individuals with dementia have not been evaluated using a synthesis approach. Thus, an integrative review was conducted to evaluate studies examining the efficacy of mind-body therapies as supportive care modalities for management of symptoms experienced by individuals with dementia. Findings from the studies reviewed support the clinical efficacy of mind-body practices in improving behavioral and psychological symptoms exhibited by individuals with dementia. [Res Gerontol Nurs. 2017; 10(6):288-296.].


Hotspots and main drivers of fecal pollution in Neusiedler See, a large shallow lake in Central Europe.
To minimize the risk of negative consequences for public health from fecal pollution in lakes, the continuous surveillance of microbiological water quality parameters, alongside other environmental variables, is necessary at defined bathing sites. Such routine surveillance may prove insufficient to elucidate the main drivers of fecal pollution in a complex lake/watershed ecosystem, and it may be that more comprehensive monitoring activities are required. In this study, the aims were to identify the hotspots and main driving factors of fecal pollution in a large shallow Central European lake, the Neusiedler See, and to determine to what degree its current monitoring network can be considered representative spatially. A stochastic and geostatistical analysis of a huge data set of water quality data (~ 164,000 data points, representing a 22-year time-series) of standard fecal indicator bacteria (SFIB), water quality and meteorological variables sampled at 26 sampling sites was conducted. It revealed that the hotspots of fecal pollution are exclusively related to sites with elevated anthropogenic activity. Background pollution from wildlife or diffuse agricultural run-off at more remote sites was comparatively low. The analysis also showed that variability in the incidence of SFIB was driven mainly by meteorological phenomena, above all, temperature, number of sunny hours, and wind (direction and speed). Due to antagonistic effects and temporal undersampling, the influence of precipitation on SFIB variance could not be clearly determined. Geostatistical analysis did reveal that the current spatial sampling density is insufficient to cover SFIB variance over the whole lake, and that the sites are therefore in the most part representative of local phenomena. Suggestions for the future monitoring and managing of fecal pollution are offered. The applied statistical approach may also serve as a model for the study of other such areas, and in general indicate a method for dealing with similarly large and spatiotemporally heterogeneous datasets.


Pharmacodynamics of florfenicol for calf pneumonia pathogens.
The antimicrobial properties of florfenicol were investigated for the bovine respiratory tract pathogens, Mannheimia haemolytica and Pasteurella multocida. Three in vitro indices of efficacy and potency were determined; minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and in vitro time-kill curves for six pathogenic strains of each organism. Each was monitored in two matrices, Mueller Hinton broth (MHB) and calf serum. MBC:MIC ratios were low, 1.8 : 1 for M haemolytica in both MHB and serum and 2.4 : 1 and 2.1 : 1 for P multocida in MHB and serum, respectively. The killing action of florfenicol had the characteristics of concentration dependency against M haemolytica and codependency (on time and concentration) against P multocida. Modelling of the time-kill data after 24 hours exposure was undertaken to quantify three levels of activity for the ratio, area under concentration-time curve over 24 hours (AUC24h)/MIC; bacteriostatic action (no change in bacterial count), 3log10 reduction and 4log10 reduction in bacterial count. Mean AUC24h/MIC values for P multocida in MHB (and serum) were 22.0 (23.3) hour, 34.5 (39.9) hour and 45.8 (50.4) hour, respectively. Similar numerical values were obtained for M haemolytica. For both bacterial species, interstrain variability was low; coefficients of variation ( per cent) in serum for 3log10 and 4log10 reductions in count were, respectively, 14.3 and 24.1 for P multocida and 7.8 and 11.4 for M haemolytica. These data form a rational basis for dosage selection for treatment of calf pneumonia caused by M haemolytica or P multocida.


Human papillomavirus type 16 in intraepithelial neoplasia (bowenoid papulosis) and coexistent invasive carcinoma of the vulva.
Tissues from two cases of bowenoid papulosis of the vulva with coexistent invasive squamous cell carcinoma were evaluated for the presence of human papillomaviruses (HPVs) and for nuclear DNA content. In both cases, HPV type 16 and nuclear aneuploidy were found in bowenoid papulosis as well as in invasive carcinoma. Patterns of hybridization suggested that the viral genome was integrated into the cellular genome in both bowenoid papulosis tissues as well as in invasive carcinoma tissues. These observations suggest that lesions designated as bowenoid papulosis may have invasive cancer potential. The term vulvar intraepithelial neoplasia seems to be more appropriate for HPV-16-containing aneuploid, intraepithelial lesions of the vulva.


Model-guided fieldwork: practical guidelines for multidisciplinary research on wildlife ecological and epidemiological dynamics.
Infectious disease ecology has recently raised its public profile beyond the scientific community due to the major threats that wildlife infections pose to biological conservation, animal welfare, human health and food security. As we start unravelling the full extent of emerging infectious diseases, there is an urgent need to facilitate multidisciplinary research in this area. Even though research in ecology has always had a strong theoretical component, cultural and technical hurdles often hamper direct collaboration between theoreticians and empiricists. Building upon our collective experience of multidisciplinary research and teaching in this area, we propose practical guidelines to help with effective integration among mathematical modelling, fieldwork and laboratory work. Modelling tools can be used at all steps of a field-based research programme, from the formulation of working hypotheses to field study design and data analysis. We illustrate our model-guided fieldwork framework with two case studies we have been conducting on wildlife infectious diseases: plague transmission in prairie dogs and lyssavirus dynamics in American and African bats. These demonstrate that mechanistic models, if properly integrated in research programmes, can provide a framework for holistic approaches to complex biological systems.


High-permeability criterion for BCS classification: segmental/pH dependent permeability considerations.
The FDA classifies a drug substance as high-permeability when the fraction of dose absorbed (F(abs)) in humans is 90% or higher. This direct correlation between human permeability and F(abs) has been recently controversial, since the β-blocker sotalol showed high F(abs) (90%) and low Caco-2 permeability. The purpose of this study was to investigate the scientific basis for this disparity between permeability and F(abs). The effective permeabilities (P(eff)) of sotalol and metoprolol, a FDA standard for the low/high P(eff) class boundary, were investigated in the rat perfusion model, in three different intestinal segments with pHs corresponding to the physiological pH in each region: (1) proximal jejunum, pH 6.5; (2) mid small intestine, pH 7.0; and (3) distal ileum, pH 7.5. Both metoprolol and sotalol showed pH-dependent permeability, with higher P(eff) at higher pH. At any given pH, sotalol showed lower permeability than metoprolol; however, the permeability of sotalol determined at pH 7.5 exceeded/matched metoprolol's at pH 6.5 and 7.0, respectively. Physicochemical analysis based on ionization, pK(a) and partitioning of these drugs predicted the same trend and clarified the mechanism behind these observed results. Experimental octanol-buffer partitioning experiments confirmed the theoretical curves. An oral dose of metoprolol has been reported to be completely absorbed in the upper small intestine; it follows, hence, that metoprolol's P(eff) value at pH 7.5 is not likely physiologically relevant for an immediate release dosage form, and the permeability at pH 6.5 represents the actual relevant value for the low/high permeability class boundary. Although sotalol's permeability is low at pH 6.5 and 7.0, at pH 7.5 it exceeds/matches the threshold of metoprolol at pH 6.5 and 7.0, most likely responsible for its high F(abs). In conclusion, we have shown that, in fact, there is no discrepancy between P(eff) and F(abs) in sotalol's absorption; the data emphasize that, if a compound has high fraction of dose absorbed, it will have high-permeability, not necessarily in the jejunum, but at some point along the relevant intestinal regions.


Off-label and unlicensed medication use and associated adverse drug events in a pediatric emergency department.
The study objectives were to (1) determine the types and frequency of off-label (OL) or unlicensed (UL) medications used in a pediatric emergency department (PED) and before admission, (2) describe OL/UL-associated adverse drug events (ADEs) resulting in admission to the PED and those occurring during patient care in PED, and (3) determine the outcomes of these ADEs. Medical records of patients 18 years or younger admitted to the PED over a 5-month period were reviewed. Off-label/UL use of medications was determined based on Food and Drug Administration-approved labeling. The Adverse Drug Reaction Probability Scale was used to determine ADE causality. Data were analyzed using descriptive statistics. A total of 2191 patients with 6675 medication orders were evaluated. About 26.2% (n = 1712) of medication orders were considered as OL/ UL use; 70.5% (n = 1208) of these medications were ordered as part of treatment in the PED, and the remaining 29.5% (n = 504) were home medications before their PED evaluation. Inhaled bronchodilators (30.4%), antimicrobials (14.8%), and antihistamines/antiemetics (9.1%) were the most common OL/UL medication classes. The frequency of ADEs among licensed medication use was greater compared with OL/UL use by 2-fold. Reported overall rate of ADEs was 0.6% (n = 40). Of these 40 ADEs, 5 resulted from the use of an OL/UL medication, 3 from home medication use, and 2 from PED-prescribed medications. The frequency of reported ADEs associated with OL/UL medications was less than the frequency of ADEs from licensed medication use, with overall ADE frequency of less than 1%.


Statistical modeling for Bayesian extrapolation of adult clinical trial information in pediatric drug evaluation.
Children represent a large underserved population of "therapeutic orphans," as an estimated 80% of children are treated off-label. However, pediatric drug development often faces substantial challenges, including economic, logistical, technical, and ethical barriers, among others. Among many efforts trying to remove these barriers, increased recent attention has been paid to extrapolation; that is, the leveraging of available data from adults or older age groups to draw conclusions for the pediatric population. The Bayesian statistical paradigm is natural in this setting, as it permits the combining (or "borrowing") of information across disparate sources, such as the adult and pediatric data. In this paper, authored by the pediatric subteam of the Drug Information Association Bayesian Scientific Working Group and Adaptive Design Working Group, we develop, illustrate, and provide suggestions on Bayesian statistical methods that could be used to design improved pediatric development programs that use all available information in the most efficient manner. A variety of relevant Bayesian approaches are described, several of which are illustrated through 2 case studies: extrapolating adult efficacy data to expand the labeling for Remicade to include pediatric ulcerative colitis and extrapolating adult exposure-response information for antiepileptic drugs to pediatrics.


Direct detection of Mycobacterium tuberculosis complex in nonrespiratory specimens by Gen-Probe Amplified Mycobacterium Tuberculosis Direct Test.
The Gen-Probe Amplified Mycobacterium Tuberculosis Direct Test (AMTDT) was adapted for the detection of Mycobacterium tuberculosis complex in 224 nonrespiratory specimens from 188 patients. The sensitivity and specificity of the AMTDT for such specimens, after resolution of discrepant results, were 85.7 and 100%, respectively. Pretreatment of nonrespiratory specimens with sodium dodecyl (lauryl) sulfate is mandatory to obtain consistent and reproducible AMTDT results. The use of 500 microliters of decontaminated specimen improves the sensitivity of the test. Because the AMTDT detects stable rRNA from noncultivable bacilli, it is not useful for monitoring patients receiving treatment.


Telepathology at the Armed Forces Institute of Pathology: A Retrospective Review of Consultations From 1996 to 1997.
- Telepathology is the practice of pathology at a distance, transmitting images using telecommunication methods for second opinion and/or diagnostic assistance, or for educational purposes. It may be the only means of consultation for some pathologists. - To retrospectively review and evaluate a subset of telepathology consultations from June 1996 to March 1997, and to determine the concordance between the telepathology diagnosis of the contributor and pathologists at the Armed Forces Institute of Pathology (AFIP), Washington, District of Columbia, as well as the concordance between the telepathology diagnosis and the glass slide diagnosis, when available. - Photocopies of de-identified telepathology reports from the AFIP during a 15-month period between June 1996 and March 1997 were reviewed. Contributor versus telepathology diagnosis was graded as 1 (complete agreement), 2 (partial agreement), 3 (disagreement; usually a diagnosis of benign versus malignant), and deferred. Data were analyzed using descriptive statistical methods. - Of the 262 cases, 194 (74%) were in complete agreement with the contributor's diagnosis, 34 of 262 (13%) were in minor disagreement, and 21 of 262 (8%) were in major disagreement. Diagnoses were deferred in 5% (13 of 262) of cases. - Using commercial off-the-shelf technology and despite telecommunication challenges during that time, the AFIP demonstrated that telepathology could be conducted reliably.


Problems in exposure assessment of fluoride in drinking water.
We developed a source documentation approach that identified fluoride content of drinking water at the state or local level to estimate fluoride concentrations from public water systems. We then compared estimates from this approach with estimates obtained from a single source, the 1992 Centers for Disease Control and Prevention (CDC) Fluoridation Census. We used residential histories from a case-control study. For each residence we attempted to determine fluoride concentrations using the 1992 CDC Fluoridation Census. For the source documentation method we utilized multiple sources from state and local contacts to verify and collect additional data. We compared the fluoride estimates obtained by the two methods. When fluoride values were found using both methods, there was good correlation (Kendall's tau = 0.85; 95% confidence interval = 0.79, 0.90) and concordance was 96 percent. We obtained over 99 percent of the fluoride values needed using source documentation as compared to 49 percent of the values needed when we used a single publication. When fluoride values were missing using the 1992 CDC Fluoridation Census, 21 percent had source documentation estimates of at least 0.7 ppm. Researchers need to consider limitations of using a secondary data source to estimate fluoride in drinking water, particularly in studies where exposure to fluoride is the primary exposure of interest.


The nurse's role in office hysteroscopy.
In recent years, hysteroscopy has been developed to provide physicians with direct visibility of the uterine cavity. Using carbon dioxide gas as a distending medium, office hysteroscopy has few side effects for women. It is also more cost effective than outpatient surgery. The nurse's role is pivotal in simplifying office hysteroscopy through empathetic preparation and support of women, careful planning, procurement of necessary items, and finally, conscientious care of the instruments.


Role of alpha-synuclein in autophagy modulation of primary human T lymphocytes.
It has been demonstrated that α-synuclein can aggregate and contribute to the pathogenesis of some neurodegenerative diseases and it is capable of hindering autophagy in neuronal cells. Here, we investigated the implication of α-synuclein in the autophagy process in primary human T lymphocytes. We provide evidence that: (i) knocking down of the α-synuclein gene resulted in increased autophagy, (ii) autophagy induction by energy deprivation was associated with a significant decrease of α-synuclein levels, (iii) autophagy inhibition by 3-methyladenine or by ATG5 knocking down led to a significant increase of α-synuclein levels, and (iv) autophagy impairment, constitutive in T lymphocytes from patients with systemic lupus erythematosus, was associated with abnormal accumulation of α-synuclein aggregates. These results suggest that α-synuclein could be considered as an autophagy-related marker of peripheral blood lymphocytes, potentially suitable for use in the clinical practice.


Prospective Randomized Trial of Standard Left Anterolateral Thoracotomy Versus Modified Bilateral Clamshell Thoracotomy Performed by Emergency Physicians.
Resuscitative thoracotomy is a time-sensitive, lifesaving procedure that may be performed by emergency physicians. The left anterolateral thoracotomy (LAT) is the standard technique commonly used in the United States to gain rapid access to critical intrathoracic structures. However, the smaller incision and subsequent limited exposure may not be optimal for the nonsurgical specialist to complete time-sensitive interventions. The modified bilateral anterior clamshell thoracotomy (MCT) developed by Barts Health NHS Trust clinicians at London's Air Ambulance overcomes these inherent difficulties, maximizes thoracic cavity visualization, and may be the ideal technique for the nonsurgical specialist. The aim of this study is to identify the optimal technique for the nonsurgical-specialist-performed resuscitative thoracotomy. Secondary aims of the study are to identify technical difficulties, procedural concerns, and physician preferences. Emergency medicine staff and senior resident physicians were recruited from an academic Level I trauma center. Subjects underwent novel standardized didactic and skills-specific training on both the MCT and LAT techniques. Later, subjects were randomized to the order of intervention and performed both techniques on separate fresh, nonfrozen human cadaver specimens. Success was determined by a board-certified surgeon and defined as complete delivery of the heart from the pericardial sac and subsequent 100% occlusion of the descending thoracic aorta with a vascular clamp. The primary outcome was time to successful completion of the resuscitative thoracotomy technique. Secondary outcomes included successful exposure of the heart, successful descending thoracic aortic cross clamping, successful procedural completion, time to exposure of the heart, time to descending thoracic aortic cross-clamp placement, number and type of iatrogenic injuries, correct anatomic structure identification, and poststudy participant questionnaire. Sixteen emergency physicians were recruited; 15 met inclusion criteria. All participants were either emergency medicine resident (47%) or emergency medicine staff (53%). The median number of previously performed training LATs was 12 (interquartile range 6 to 15) and the median number of previously performed MCTs was 1 (interquartile range 1 to 1). The success rates of our study population for the MCT and LAT techniques were not statistically different (67% versus 40%; difference 27%; 95% confidence interval -61% to 8%). However, staff emergency physicians were significantly more successful with the MCT compared with the LAT (88% versus 25%; difference 63%; 95% CI 9% to 92%). Overall, the MCT also had a significantly higher proportion of injury-free trials compared with the LAT technique (33% versus 0%; difference 33%; 95% CI 57% to 9%). Physician procedure preference favored the MCT over the LAT (87% versus 13%; difference 74%; 95% CI 23% to 97%). Resuscitative thoracotomy success rates were lower than expected in this capable subject population. Success rates and procedural time for the MCT and LAT were similar. However, the MCT had a higher success rate when performed by staff emergency physicians, resulted in less periprocedural iatrogenic injuries, and was the preferred technique by most subjects. The MCT is a potentially feasible alternative resuscitative thoracotomy technique that requires further investigation.


Does hypertension or a previous myocardial infarction influence the blood pressure and heart rate responses to changes in body position? Results from a study with serial measurements in the supine and standing positions in 60-year-old men.
An age-related attenuation of the normal increase in diastolic blood pressure and heart rate upon standing has previously been observed in man. Whether this is due to ageing as such, or a consequence of a higher prevalence of cardiovascular disease in older compared to younger subjects, is unclear. This population-based study was conducted to address this question. It was carried out in three groups of 60-year-old men: (i) with hypertension (n = 75), (ii) with a previous myocardial infarction (n = 39), and (iii) without any of these diseases, thus constituting a control group (n = 41). Blood pressure and heart rate were assessed during three 7-min periods (supine-standing-supine), using an unbiased non-invasive method. The cardiovascular responses were both qualitatively and quantitatively similar in all three groups, i.e. the increases in diastolic blood pressure and heart rate upon standing, and decreases upon laying down, were of a similar magnitude. In conclusion, 60-year-old men with hypertension or a previous myocardial infarction had blood pressure and heart rate responses similar to those of men of the same age who did not have these diseases. This indicates that the attenuated response previously reported in older compared to younger people is not explained by the higher prevalence of these cardiovascular diseases in the elderly, but is merely an age-dependent characteristic.


Postural control during sit-to-stand movement and its relationship with upright position in children with hemiplegic spastic cerebral palsy and in typically developing children.
The purpose of this study was to compare postural control in typically developing (TD) children and children with cerebral palsy (CP) during the sit-to-stand (STS) movement and to assess the relationship between static (during static standing position) and dynamic postural control (during STS movement) in both groups. The center of pressure (CoP) behavior of 23 TD children and 6 children with spastic hemiplegic CP (Gross Motor Function Classification System [GMFCS] I and II) was assessed during STS movement performance and during static standing conditions with the use of a force plate. The data obtained from the force plate were used to calculate CoP variables: anteroposterior (AP) and mediolateral (ML) amplitudes of CoP displacement and the area and velocity of CoP oscillation. According to the Mann-Whitney test, children with CP exhibited higher CoP values in all of the analyzed variables during the beginning of STS movement. Pearson's correlation verified a positive correlation between the CoP variables during both static conditions and the performance of STS movement. Children with spastic hemiplegic CP present major postural oscillations during the beginning of STS movement compared with typical children. Moreover, the observed relationship between postural control in static and dynamic conditions reveals the importance of body control in the static position for the performance of functional activities that put the body in motion, such as STS movement.


Active GSK3β and an intact β-catenin TCF complex are essential for the differentiation of human myogenic progenitor cells.
Wnt-β-catenin signalling is essential for skeletal muscle myogenesis during development, but its role in adult human skeletal muscle remains unknown. Here we have used human primary CD56Pos satellite cell-derived myogenic progenitors obtained from healthy individuals to study the role of Wnt-β-catenin signalling in myogenic differentiation. We show that dephosphorylated β-catenin (active-β-catenin), the central effector of the canonical Wnt cascade, is strongly upregulated at the onset of differentiation and undergoes nuclear translocation as differentiation progresses. To establish the role of Wnt signalling in regulating the differentiation process we manipulated key nodes of this pathway through a series of β-catenin gain-of-function (GSK3 inhibition and β-catenin overexpression) or loss-of-function experiments (dominant negative TCF4). Our data showed that manipulation of these critical pathway components led to varying degrees of disruption to the normal differentiation phenotype indicating the importance of Wnt signalling in regulating this process. We reveal an independent necessity for active-β-catenin in the fusion and differentiation of human myogenic progenitors and that dominant negative inhibition of TCF4 prevents differentiation completely. Together these data add new mechanistic insights into both Wnt signalling and adult human myogenic progenitor differentiation.


Organotypic cultures as tools for optimizing central nervous system cell therapies.
Stem cell therapy is a promising treatment for neurological disorders such as cerebral ischemia, Parkinson's disease and Huntington's disease. In recent years, many clinical trials with various cell types have been performed often showing mixed results. Major problems with cell therapies are the limited cell availability and engraftment and the reduced integration of grafted cells into the host tissue. Stem cell-based therapies can provide a limitless source of cells but survival and differentiation remain a drawback. An improved understanding of the behaviour of stem cells and their interaction with the host tissue, upon implantation, is needed to maximize the therapeutic potential of stem cells in neurological disorders. Organotypic cultures made from brain slices from specific brain regions that can be kept in culture for several weeks after injecting molecules or cells represent a remarkable tool to address these issues. This model allows the researcher to monitor/assess the behaviour and responses of both the endogenous as well as the implanted cells and their interaction with the microenvironment leading to cell engraftment. Moreover, organotypic cultures could be useful to partially model the pathological state of a disease in the brain and to study graft-host interactions prior to testing such grafts for pre-clinical applications. Finally, they can be used to test the therapeutic potential of stem cells when combined with scaffolds, or other therapeutic enhancers, among other aspects, needed to develop novel successful therapeutic strategies or improve on existing ones.


Thermoelectric La-doped SrTiO3 epitaxial layers with single-crystal quality: from nano to micrometers.
High-quality thermoelectric La0.2Sr0.8TiO3 (LSTO) films, with thicknesses ranging from 20 nm to 0.7 μm, have been epitaxially grown on SrTiO3(001) substrates by enhanced solid-source oxide molecular-beam epitaxy. All films are atomically flat (with rms roughness < 0.2 nm), with low mosaicity (<0.1°), and present very low electrical resistivity (<5 × 10-4 Ω cm at room temperature), one order of magnitude lower than standard commercial Nb-doped SrTiO3 single-crystalline substrate. The conservation of transport properties within this thickness range has been confirmed by thermoelectric measurements where Seebeck coefficients of approximately -60 μV/K have been recorded for all films. These LSTO films can be integrated on Si for non-volatile memory structures or opto-microelectronic devices, functioning as transparent conductors or thermoelectric elements.


Fzr/Cdh1 Promotes the Differentiation of Neural Stem Cell Lineages in Drosophila.
How stem cells and progenitors balance between self-renewal and differentiation is a central issue of stem cell biology. Here, we describe a novel and essential function of Drosophila Fzr/Cdh1, an evolutionary conserved protein, during the differentiation of neural stem cell (NSC) lineages in the central nervous system. We show that Fzr, a known co-activator of Anaphase Promoting Complex/Cyclosome (APC/C) ubiquitin ligase, promotes the production of neurons from neural progenitors called ganglion mother cells (GMCs). However, knockdown of APC/C subunit Ida or another APC/C co-activator CDC20 does not similarly impair GMC-neuron transition. We also observe a concomitant loss of differentiation factor Prospero expression and ectopic accumulation of mitotic kinase Polo in fzr mutant clones, strongly supporting the impairment of GMC to neuron differentiation. Besides functioning in GMCs, Fzr is also present in NSCs to facilitate the production of intermediate neural progenitors from NSCs. Taken together, Fzr plays a novel function in promoting differentiation programs during Drosophila NSC lineage development. Given that human Fzr is inactivated in multiple types of human cancers including brain tumors and that Fzr regulates neurotoxicity in various models of neurodegenerative diseases, our study on the role of Fzr in turning off proliferation in neuronal cells may provide insights into how Fzr deficits may contribute to human neurodegenerative diseases and tumors.


Magnon-drag thermopile.
Thermoelectric effects in spintronics are gathering increasing attention as a means of managing heat in nanoscale structures and of controlling spin information by using heat flow. Thermal magnons (spin-wave quanta) are expected to play a major role; however, little is known about the underlying physical mechanisms involved. The reason is the lack of information about magnon interactions and of reliable methods to obtain it, in particular for electrical conductors because of the intricate influence of electrons. Here, we demonstrate a conceptually new device that enables us to gather information on magnon-electron scattering and magnon-drag effects. The device resembles a thermopile formed by a large number of pairs of ferromagnetic wires placed between a hot and a cold source and connected thermally in parallel and electrically in series. By controlling the relative orientation of the magnetization in pairs of wires, the magnon drag can be studied independently of the electron and phonon-drag thermoelectric effects. Measurements as a function of temperature reveal the effect on magnon drag following a variation of magnon and phonon populations. This information is crucial to understand the physics of electron-magnon interactions, magnon dynamics and thermal spin transport.


Hierarchical molecular events driven by oocyte-specific factors lead to rapid and extensive reprogramming.
Nuclear transfer to oocytes is an efficient way to transcriptionally reprogram somatic nuclei, but its mechanisms remain unclear. Here, we identify a sequence of molecular events that leads to rapid transcriptional reprogramming of somatic nuclei after transplantation to Xenopus oocytes. RNA-seq analyses reveal that reprogramming by oocytes results in a selective switch in transcription toward an oocyte rather than pluripotent type, without requiring new protein synthesis. Time-course analyses at the single-nucleus level show that transcriptional reprogramming is induced in most transplanted nuclei in a highly hierarchical manner. We demonstrate that an extensive exchange of somatic- for oocyte-specific factors mediates reprogramming and leads to robust oocyte RNA polymerase II binding and phosphorylation on transplanted chromatin. Moreover, genome-wide binding of oocyte-specific linker histone B4 supports its role in transcriptional reprogramming. Thus, our study reveals the rapid, abundant, and stepwise loading of oocyte-specific factors onto somatic chromatin as important determinants for successful reprogramming.


A Systematic Review of the Safety of Blocking the IL-1 System in Human Pregnancy.
Blockade of the interleukin-1 (IL-1) pathway has been used therapeutically in several inflammatory diseases including arthritis and cryopyrin-associated periodic syndrome (CAPS). These conditions frequently affect women of childbearing age and continued usage of IL-1 specific treatments throughout pregnancy has been reported. IL-1 is involved in pregnancy complications and its blockade could have therapeutic potential. We systematically reviewed all reported cases of IL-1 blockade in human pregnancy to assess safety and perinatal outcomes. We searched several databases to find reports of specific blockade of the IL-1 pathway at any stage of pregnancy, excluding broad spectrum or non-specific anti-inflammatory intervention. Our literature search generated 2439 references of which 22 studies included, following extensive review. From these, 88 different pregnancies were assessed. Most (64.8%) resulted in healthy term deliveries without any obstetrical/neonatal complications. Including pregnancy exposed to Anakinra or Canakinumab, 12 (15.0%) resulted in preterm birth and one stillbirth occurred. Regarding neonatal complications, 2 cases of renal agenesis (2.5%) were observed, and 6 infants were diagnosed with CAPS (7.5%). In conclusion, this systematic review describes that IL-1 blockade during pregnancy is not associated with increased adverse perinatal outcomes, considering that treated women all presented an inflammatory disease associated with elevated risk of pregnancy complications.


A highly invasive subpopulation of MDA-MB-231 breast cancer cells shows accelerated growth, differential chemoresistance, features of apocrine tumors and reduced tumorigenicity in vivo.
The acquisition of an invasive phenotype is a prerequisite for metastasization, yet it is not clear whether or to which extent the invasive phenotype is linked to other features characteristic of metastatic cells. We selected an invasive subpopulation from the triple negative breast cancer cell line MDA-MB-231, performing repeated cycles of preparative assays of invasion through Matrigel covered membranes. The invasive sub-population of MDA-MB-231 cells exhibits stronger migratory capacity as compared to parental cells confirming the highly invasive potential of the selected cell line. Prolonged cultivation of these cells did not abolish the invasive phenotype. ArrayCGH, DNA index quantification and karyotype analyses confirmed a common genetic origin of the parental and invasive subpopulations and revealed discrete structural differences of the invasive subpopulation including increased ploidy and the absence of a characteristic amplification of chromosome 5p14.1-15.33. Gene expression analyses showed a drastically altered expression profile including features of apocrine breast cancers and of invasion related matrix-metalloproteases and cytokines. The invasive cells showed accelerated proliferation, increased apoptosis, and an altered pattern of chemo-sensitivity with lower IC50 values for drugs affecting the mitotic apparatus. However, the invasive cell population is significantly less tumorigenic in orthotopic mouse xenografts suggesting that the acquisition of the invasive capacity and the achievement of metastatic growth potential are distinct events.


Protocol for sorting and culturing of mouse early erythroid progenitor BFU-E cells.
Techniques allowing the long-term culture of the burst-forming unit of erythroid (BFU-E) progenitor cells are essential for understanding erythropoiesis. Here, we present a protocol for sorting mouse BFU-E cells and culturing them in a medium that promotes BFU-E cell expansion. We describe steps for isolating BFU-E cells from mouse fetal livers by combining magnetic microbeads with flow cytometry and culturing BFU-E cells with a specific expansion media. This approach can enhance the production of BFU-E cells. For complete details on the use and execution of this protocol, please refer to Li et al..1.


Predictive value of pretransplant inflammatory markers in renal allograft survival and rejection in children.
Pretransplant (pre-Tx) inflammation has been associated with acute rejection (AR) in adult Tx recipients. Our study was performed to determine whether a single pre-Tx serum C-reactive protein (CRP), Neopterin (Neo), and IL-12 determination could predict outcome in pediatric renal Tx recipients. Pre-Tx sera from 51 children transplanted between 1985 and 2000 were analyzed for serum CRP, Neo, and IL-12 for correlation with Tx-related variables. Endpoints were graft loss and AR. Kaplan-Meier and log-rank statistics were used to compare rejection-free and overall graft survival at different quartiles for each marker. Cox regression analysis was performed to determine the independent effects of various pre-Tx variables on the endpoints. The mean age of the children at Tx was 11 years. The mean CRP, Neo, and IL-12 were 1.3 mg/L, 1.78 ng/mL and 123 pg/mL, respectively. At last-follow-up (mean 4.9 years after Tx), 50% of the children had experienced AR and 29% had lost their grafts. The mean CRP, Neo, and IL-12 were not different between the patients with versus without AR or graft loss (P > .4 for all). Neither rejection-free survival nor graft survival was affected by CRP, Neo, or IL-12 quartiles (log-rank test). Cox regression analysis demonstrated no predictive value of any marker on the outcomes. Unlike adults, a single pre-Tx determination of inflammatory markers was not predictive of AR or graft loss in children. The pathogenesis of AR may be different in children with a lesser contribution of alloantigen-independent factors such as chronic infections.


Use of weak acids to determine the bulk diffusion limitation of H+ ion conductance through the gramicidin channel.
The addition of 2 M formic acid at pH 3.75 increased the single channel H+ ion conductance of gramicidin channels 12-fold at 200 mV. Other weak acids (acetic, lactic, oxalic) produce a similar, but smaller increase. Formic acid (and other weak acids) also blocks the K+ conductance at pH 3.75, but not at pH 6.0 when the anion form predominates. This increased H+ conductance and K+ block can be explained by formic acid (HF) binding to the mouth of the gramicidin channel (Km = 1 M) and providing a source of H+ ions. A kinetic model is derived, based on the equilibrium binding of formic acid to the channel mouth, that quantitatively predicts the conductance for different mixtures of H+, K+, and formic acid. The binding of the neutral formic acid to the mouth of the gramicidin channel is directly supported by the observation that a neutral molecule with a similar structure, formamide (and malonamide and acrylamide), blocks the K+ conductance at pH 6.0. The H+ conductance in the presence of formic acid provides a lower bound for the intrinsic conductance of the gramicidin channel when there is no diffusion limitation at the channel mouth. The 12-fold increase in conductance produced by formic acid suggests that greater than 90% of the total resistance to H+ results from diffusion limitation in the bulk solution.


Spectrum of pulmonary fungal pathogens, associated risk factors, and anti-fungal susceptibility pattern among persons with presumptive tuberculosis at Gombe, Nigeria.
Pulmonary mycosis (PM) poses a great diagnostic challenge due to the lack of pathognomonic and radiological features, especially in the absence of mycology laboratory tests. This study was aimed to isolate, phenotypically identify, determine the prevalence of pulmonary fungal pathogens and antifungal susceptibility pattern of isolates of presumptive tuberculosis (PTB) patients attending Federal Teaching Hospital (FTH) Gombe, Nigeria. After ethical approval, three consecutive early morning sputa were collected from 216 participants with presumptive of PTB attending FTH Gombe, between May 2, 2017 and May 30, 2018. Samples were processed using standard mycological staining, microscopy, sugar biochemistry, and antifungal susceptibility test protocols. Sociodemographic variables and risk factors of pulmonary fungal infection were assessed through structured questionnaires. Pulmonary fungal infection was defined by the positive culture in at least two sputa. PTB was defined by Genexpert® nested polymerase chain reaction. Of the 216 participants, 19.9% had PTB and 73.6% had pulmonary fungal pathogens. Among the isolated pulmonary fungal pathogens, Aspergillus fumigatus made the highest occurrence, while 6.5% had PTB-fungal co-infection. No significant association existed between the prevalence of PM with age and sex of participants (P < 0.05). Cigarette smoking (adjusted odds ratio [aOR] = 15.9 [95% confidence interval (CI): 0.9-268.8]), prolong antibiotic use (aOR = 77.9 [95% CI: 4.7-1283]) and possession of domestic pet (aOR = 77.9 [95% CI: 4.7-1283]) were significant risk factors of PM (P < 0.05). Penicillium citrinum, Mucor spp. and Aspergillus flavus are more susceptible to voriconazole, and Candida albicans was found to be more susceptible to Nystatin. Of the 159 fungal isolates, 92.5% were resistant to fluconazole. Findings from this study revealed high level pulmonary fungal pathogens, especially among PTB patients. A majority of fungal isolates were resistant to fluconazole. It's recommended that persons should do away with or minimize risk factors for pulmonary fungal pathogens identified in this study.


Trans-10,cis-12, not cis-9,trans-11, conjugated linoleic acid inhibits G1-S progression in HT-29 human colon cancer cells.
Commercial preparations of conjugated linoleic acid (CLA) contain both positional and geometric isomers of octadecadienoic acid, with cis-9,trans-11 CLA (c9t11) and trans-10,cis-12 CLA (t10c12) as the principal isomers. We showed previously that CLA reduced the incidence of colon tumors in rats treated with 1,2-dimethylhydrazine. In addition, our previous in vitro studies showed that t10c12 inhibited the growth of HT-29 and Caco-2 human colon cancer cells, whereas c9t11 had no effect on cell growth. In the present study, to examine the effects of the CLA isomers on cell cycle and cell cycle regulatory proteins, we treated HT-29 cells with various concentrations (0-4 micromol/L) of the individual CLA isomers. A DNA flow cytometric analysis revealed that t10c12 induced a G1 arrest, whereas c9t11 had no effect on the cell cycle. Western blot analysis of total cell lysates revealed no alteration in the protein expression of cyclin A, cyclin D, cyclin E, cyclin-dependent kinase (CDK) 2, or CDK4 due to t10c12 treatment. However, t10c12 substantially increased the protein expression and mRNA accumulation of the CDK inhibitor p21(CIP1/WAF1). The t10c12 isomer increased the association of p21(CIP1/WAF1) with CDK2 and proliferating cell nuclear antigen, but decreased the levels of phosphorylated retinoblastoma protein (Rb), with an increase in the levels of hypophosphorylated Rb protein. An in vitro kinase assay using histone H1 as a substrate showed that the activities of CDK2 were significantly decreased by t10c12. These results indicate that t10c12 exerts its growth inhibitory effects in colon cancer cells through the induction of G1 cell cycle arrest. The induction of p21(CIP1/WAF1) may be one of the mechanisms by which t10c12 inhibits cell cycle progression in HT-29 cells.


Teashirt 3 is necessary for ureteral smooth muscle differentiation downstream of SHH and BMP4.
Ureteric contractions propel foetal urine from the kidney to the urinary bladder. Here, we show that mouse ureteric smooth muscle cell (SMC) precursors express the transcription factor teashirt 3 (TSHZ3), and that Tshz3-null mutant mice have congenital hydronephrosis without anatomical obstruction. Ex vivo, the spontaneous contractions that occurred in proximal segments of wild-type embryonic ureter explants were absent in Tshz3 mutant ureters. In vivo, prior to the onset of hydronephrosis, mutant proximal ureters failed to express contractile SMC markers, whereas these molecules were detected in controls. Mutant embryonic ureters expressed Shh and Bmp4 transcripts as normal, with appropriate expression of Ptch1 and pSMAD1/5/8 in target SM precursors, whereas myocardin, a key regulator for SMC differentiation, was not expressed in Tshz3-null ureters. In wild-type embryonic renal tract explants, exogenous BMP4 upregulated Tshz3 and myocardin expression. More interestingly, in Tshz3 mutant renal tract explants, exogenous BMP4 did not improve the Tshz3 phenotype. Thus, Tshz3 is required for proximal ureteric SMC differentiation downstream of SHH and BMP4. Furthermore, the Tshz3 mutant mouse model of ;functional' urinary obstruction resembles congenital pelvi-ureteric junction obstruction, a common human malformation, suggesting that TSHZ, or related, gene variants may contribute to this disorder.


The influence of working conditions and individual factors on the incidence of neck and upper limb symptoms among professional computer users.
To assess the influence of working conditions and individual factors on the incidence of neck and upper limb symptoms among professional computer users. The study is a prospective cohort study with an observation period of 10 months. A baseline questionnaire about symptoms in the neck, shoulder and arm/hand during previous month, individual factors, work content, physical and psychosocial work-related exposures was answered by 1,283 computer operators (response rate 84%). Incidence data were collected by ten monthly questionnaires regarding the occurrence of symptoms categorized into three gross body regions: neck, shoulders and arms/hands. A case, in the specific gross body region, was defined as a subject who was classified as non-symptomatic in that region at baseline or during minimum one follow-up period and later reported symptoms (>or=3 days). Univariable and multivariable incidence rate ratios with 95% confidence intervals for first occurrence of neck, shoulder and arm/hand cases, respectively, were calculated with Cox regression analysis. The incidence rate was 67, 41 and 47 cases per 100 person years for neck, shoulder and arm/hand symptoms, respectively. In the multivariable analyses, comfort of the computer work environment and gender were related to the incidence of symptoms in all body regions (RR = 1.5-1.9 for low comfort and 1.8-2.1 for females, respectively). Duration of mouse use predicted arm/hand symptoms (RR = 1.7 for >or=3 h/day) and job strain (high demands and low decision latitude) predicted neck symptoms (RR = 1.6 and 2.2 for medium and high strain, respectively). Additionally, age was related to neck and shoulder symptoms. Preventive strategies to reduce neck and upper limb symptoms among computer users should include measures to reduce mouse use, to increase the comfort of the work environment and to reduce job strain. Although the effect estimates were relatively weak to moderate, preventive measures may have a marked impact on the incidence of neck and upper limb symptoms in the general population because of the widespread use of computers in working life as well as at home.


Undetected antisense tRNAs in mitochondrial genomes?
The hypothesis that both mitochondrial (mt) complementary DNA strands of tRNA genes code for tRNAs (sense-antisense coding) is explored. This could explain why mt tRNA mutations are 6.5 times more frequently pathogenic than in other mt sequences. Antisense tRNA expression is plausible because tRNA punctuation signals mt sense RNA maturation: both sense and antisense tRNAs form secondary structures potentially signalling processing. Sense RNA maturation processes by default 11 antisense tRNAs neighbouring sense genes. If antisense tRNAs are expressed, processed antisense tRNAs should have adapted more for translational activity than unprocessed ones. Four tRNA properties are examined: antisense tRNA 5' and 3' end processing by sense RNA maturation and its accuracy, cloverleaf stability and misacylation potential. Processed antisense tRNAs align better with standard tRNA sequences with the same cognate than unprocessed antisense tRNAs, suggesting less misacylations. Misacylation increases with cloverleaf fragility and processing inaccuracy. Cloverleaf fragility, misacylation and processing accuracy of antisense tRNAs decrease with genome-wide usage of their predicted cognate amino acid. These properties correlate as if they adaptively coevolved for translational activity by some antisense tRNAs, and to avoid such activity by other antisense tRNAs. Analyses also suggest previously unsuspected particularities of aminoacylation specificity in mt tRNAs: combinations of competition between tRNAs on tRNA synthetases with competition between tRNA synthetases on tRNAs determine specificities of tRNA amino acylations. The latter analyses show that alignment methods used to detect tRNA cognates yield relatively robust results, even when they apparently fail to detect the tRNA's cognate amino acid and indicate high misacylation potential.


Extended spectrum -lactamases (ESBL) - an emerging threat to clinical therapeutics.
Extended spectrum -lactamases (ESBLs) are plasmid mediated, TEM and SHV derived enzymes, first isolated in Western Europe in mid 1980s, most commonly in Klebsiella spp., followed by Escherichia coli. These enzymes are capable of hydrolyzing broad spectrum cephalosporins and monobactams but inactive against cephamycins and imipenem. In addition, ESBL producing organisms exhibit coresistance to many other classes of antibiotics resulting in limitation of therapeutic option. Several risk factors have been suggested. A variety of classification schemes have been developed. Recently, Bush-Jacoby-Medeiros scheme integrated functional and molecular characteristics. ESBLs have serine at their active site and attack the amide bond in the lactam ring of antibiotics causing their hydrolysis. Because of inocolum effect and substrate specificity their detection is a major challenge. Two indicators of ESBLs are eight fold reduction in MIC and potentiation of the inhibitor zone of third generation cephalosporin in the presence of clavulanic acid. Incidence of these organisms is being continuously increasing through out the world with limited treatment alternatives. It becomes necessary to know the prevalence of these organisms and to formulate treatment policy. Moreover, restricted use of the third generation cephalosporins lead to withdrawal of selective pressure and use of lactam and -lactamase inhibitor combinations may exert reverse mutation on these enzymes.


Characterization of Carotenoid-protein Complexes and Gene Expression Analysis Associated with Carotenoid Sequestration in Pigmented Cassava (Manihot Esculenta Crantz) Storage Root.
Carotenoid-protein complex (CPC) was isolated from chromoplast-enriched suspensions of cassava storage root (CSR) using size exclusion chromatography and characterized. Peptide sequences (LC_MS/MS spectrum) obtained from CPC and their corresponding proteins were obtained using publically available databases. Small Heat Shock Proteins (sHSPs) were the most abundant proteins identified in the CPC. Western blot analysis showed that Fribrillin and Or-protein were present in chromoplast-enriched suspensions of yellow root but not in the complex or white root. Results from qRT-PCR helped identify an isoform of HSP21 possessing four single point mutations in the intense yellow CSR that may be responsible for increased sequestration of b-carotene.


Working memory contributions to reinforcement learning impairments in schizophrenia.
Previous research has shown that patients with schizophrenia are impaired in reinforcement learning tasks. However, behavioral learning curves in such tasks originate from the interaction of multiple neural processes, including the basal ganglia- and dopamine-dependent reinforcement learning (RL) system, but also prefrontal cortex-dependent cognitive strategies involving working memory (WM). Thus, it is unclear which specific system induces impairments in schizophrenia. We recently developed a task and computational model allowing us to separately assess the roles of RL (slow, cumulative learning) mechanisms versus WM (fast but capacity-limited) mechanisms in healthy adult human subjects. Here, we used this task to assess patients' specific sources of impairments in learning. In 15 separate blocks, subjects learned to pick one of three actions for stimuli. The number of stimuli to learn in each block varied from two to six, allowing us to separate influences of capacity-limited WM from the incremental RL system. As expected, both patients (n = 49) and healthy controls (n = 36) showed effects of set size and delay between stimulus repetitions, confirming the presence of working memory effects. Patients performed significantly worse than controls overall, but computational model fits and behavioral analyses indicate that these deficits could be entirely accounted for by changes in WM parameters (capacity and reliability), whereas RL processes were spared. These results suggest that the working memory system contributes strongly to learning impairments in schizophrenia.


Porcine aromatases: studies on tissue-specific, functionally distinct isozymes from a single gene?
Aromatase cytochrome P450 (P450arom) is expressed in a variety of tissues. Pigs express P450arom as bilaminar blastocysts in utero, and thereafter in the gonads, adrenal glands and placenta. Our studies also demonstrate the existence of porcine isozymes of P450arom which differ substantially in their amino acid composition and function. The placental isoform, most similar to P450arom in other mammals, consists of 503 amino acids. The ovarian isoform, expressed in both theca and granulosa cells, is a 501 amino acid protein exhibiting less than 20% of the activity of the placental isozyme. Furthermore, it is inhibited not only by CGS16949A but also by etomidate which does not inhibit the placental P450arom. Partial sequences generated by the rapid amplification of the cDNA ends (RACE) procedure indicate that the expression of a third isoform in the blastocyst is switched to the placental isozyme during differentiation of the fetal membranes. In addition, these transcripts, and others from the theca, granulosa, testes, adrenal glands and placenta demonstrate differences in the 5'-untranslated region (putative exon I) suggestive of tissue-specific alternative splicing. An identical 5'-untranslated sequence was obtained from transcripts expressed in the theca and granulosa. Testes and adrenal transcripts also have identical 5' ends, which differ substantially from the ovarian sequence. Blastocyst and placenta 5'-untranslated sequences differ from each other and from those expressed in the gonads and adrenals. Several tissue-specific transcripts thus encode porcine P450arom. Interestingly, distinct 5' sequences exist for ovarian and testes P450arom mRNAs, suggesting different promoters and therefore regulation in the male and female gonads. The molecular origins of the functional isoforms and the tissue-specific transcripts are uncertain, however partial genomic sequence and other genetic analyses suggest the existence of multiple genes. However, sequence alignment of the placental and ovarian isoforms indicates complete conservation of putative exon III, so that complex splicing remains a possibility. Clearly, the regulation of P450arom expression is more complex in the pig than in other vertebrates investigated to date.


Ethanol exposure suppresses bone marrow-derived dendritic cell inflammatory responses independent of TLR4 expression.
Acute alcohol (ethanol) exposure is linked with increased susceptibility to infection and increased mortality in trauma and burn patients. Dendritic cells (DCs) are central mediators in innate and adaptive immune responses, and they play a role in the presentation of pathogens to adaptive immune cells. We investigated the effects of acute ethanol exposure on bone marrow-derived DC (BM-DC) responses. Total bone marrow cells, obtained from 8 to 10 week old C57BL/6 male mice, were cultured in the presence of granulocyte/monocyte-colony stimulating factor and interleukin (IL)-4 for 7 days. BM-DCs were harvested and treated with increasing doses of ethanol (50, 100, and 250 mM) at the time of, or 3 h before, lipopolysaccharide (LPS). After LPS, supernatants were collected for cytokine measurement, and cells were harvested for flow cytometry. Concurrent acute ethanol exposure and LPS treatment resulted in a dose-dependent suppression of IL-6, IL-12p40, IL-23, and IL-10. In addition, ethanol exposure before LPS dysregulated the IL-12p40/IL-23 balance and more profoundly suppressed IL-6 and IL-10 secretion by BM-DCs, as compared with cells concurrently treated with ethanol and LPS. Ethanol treatment did not affect either toll-like receptor (TLR)4 or TLR2 expression. In summary, our study demonstrates that acute ethanol exposure suppresses BM-DC LPS-induced responses, irrespective of affecting TLR4 or TLR2 expression.


[Radiobiological pitfalls of new techniques in radiotherapy].
Radiotherapy techniques in the last decade evolved to the stage where the potential dose distribution significantly differs from earlier practices. Rotational IMRT, robotic radiotherapy or proton radiotherapy enables extremely precise dose delivery to target volumes, on the other hand, these techniques can yield a number of problems. As for photon radiotherapy, this concerns primarily the effect of large volume irradiation with doses of 0.10.5 Gy. In this range, the hypersensitivity to low doses and the bystander effect may play an important role. Proton therapy is upredictable in its radiobiological effect at the end of the Bragg curve and there is also uncertainty about the peaks exact location. These effects should be taken into account when choosing among the irradiation techniques or when applying tolerance doses to critical organs in clinical practice, especially in younger patients with long survival expectation.


Textural properties of gelling system of low-methoxy pectins produced by demethoxylating reaction of pectin methyl esterase.
After deesterification of commercial pectins with a pectin methyl esterase (PME), their gelling properties were characterized using instrumental texture analysis. The final degree of esterification (DE) of the high- and low-methoxy pectins reached approximately 6% after the PME treatment, while deesterification of low-methoxy amidated pectin stopped at 18% DE. Furthermore, DE of high-methoxy pectin was tailored to be 40%, which is equivalent to the DE of commercial low-methoxy pectin. As a result, significant changes in molecular weight (Mw) distribution were observed in the PME-treated pectins. The texture profile analysis showed that PME modification drastically increased hardness, gumminess, and chewiness, while decreasing cohesiveness and adhesiveness of the pectin gels (P < 0.05). The pectin gel with relatively high peak molecular weight (Mp, 3.5 x 10(5)) and low DE (6), which was produced from high-methoxy pectin, exhibited the greatest hardness, gumminess, chewiness, and resilience. The hardness of low-methoxy amidated pectin increased over 300% after PME deesterification, suggesting that the effects of amide substitution could be reinforced when DE is even lower. The partial least square regression analysis indicated that the Mw and DE of the pectin molecule are the most crucial factors for hardness, chewiness, gumminess, and resilience of gel matrix.


Efficient geometric integrators for nonadiabatic quantum dynamics. I. The adiabatic representation.
Geometric integrators of the Schrödinger equation conserve exactly many invariants of the exact solution. Among these integrators, the split-operator algorithm is explicit and easy to implement but, unfortunately, is restricted to systems whose Hamiltonian is separable into kinetic and potential terms. Here, we describe several implicit geometric integrators applicable to both separable and nonseparable Hamiltonians and, in particular, to the nonadiabatic molecular Hamiltonian in the adiabatic representation. These integrators combine the dynamic Fourier method with the recursive symmetric composition of the trapezoidal rule or implicit midpoint method, which results in an arbitrary order of accuracy in the time step. Moreover, these integrators are exactly unitary, symplectic, symmetric, time-reversible, and stable and, in contrast to the split-operator algorithm, conserve energy exactly, regardless of the accuracy of the solution. The order of convergence and conservation of geometric properties are proven analytically and demonstrated numerically on a two-surface NaI model in the adiabatic representation. Although each step of the higher order integrators is more costly, these algorithms become the most efficient ones if higher accuracy is desired; a thousand-fold speedup compared to the second-order trapezoidal rule (the Crank-Nicolson method) was observed for a wavefunction convergence error of 10-10. In a companion paper [J. Roulet, S. Choi, and J. Vaníček, J. Chem. Phys. 150, 204113 (2019)], we discuss analogous, arbitrary-order compositions of the split-operator algorithm and apply both types of geometric integrators to a higher-dimensional system in the diabatic representation.