Multifunctional properties of the transmembrane LPxTG-motif protein derived from Limosilactobacillus reuteri SH-23.
The LPxTG-motif protein is an important transmembrane protein with high hydrophilicity and stability, as evidenced by its stress tolerance and adhesion ability. In this study, a novel LPxTG-motif protein with esterase activity (LEP) was expressed, and the multifunctional properties such as adhesion properties and esterase activity were also investigated. When cocultured with Limosilactobacillus reuteri (L. reuteri) SH-23, the adhesion ability of L. reuteri SH-23 to HT-29 cells was improved, and this adhesion was further found relating to the potential target protein Pyruvate kinase M1/2 (PKM) of HT-29 cells. In addition, as a multifunctional protein, LEP can promote the hydrolysis of bovine milk lipids with its esterase activity, and the activity was enhanced in the presence of Zn2+ and Mn2+ at pH 7. Furthermore, the polyunsaturated fatty acids (PUFA) such as linoleic acid and eicosapentaenoic acid were found to increase during the hydrolyzing process. These unique properties of LEP provide a comprehensive understanding of the adhesion function and PUFAs releasing properties of the multifunctional protein derived from L. reuteri SH-23 and shed light on the beneficial effect of this Lactobacillus strain on the colonization of the gastrointestinal tract.


The Effect of Nurses' Work-Life Balance on Work Engagement: The Adjustment Effect of Affective Commitment.
This study aimed to examine the effects of nurses' work-life balance (WLB), job demands and resources, and organizational attachment on their work engagement (WE). The second aim was to shed light on whether the relationships among WLB, job demands, resources, and WE are modulated by organizational attachment. In total, 425 nurses working in a university hospital responded to the questionnaire. The primary statistical analysis method was hierarchical multiple regression with WE as the dependent variable. In the model in which all variables were applied, affective commitment (AC) (β = 0.41), family-to-work positive spillover (β = 0.25), and number of children (β = 0.13) were found to have a significant association with WE. Family-to-work negative spillover (FWNS) and AC had significant interaction effects. The result suggests that when AC was low, WE tended to decline further due to FWNS; however, when AC was high, WE did not change due to the effect of FWNS. These results confirmed that to improve nurses' WE, hospital organizations should implement initiatives to facilitate WLB that considers nurses' household roles. Furthermore, high organizational attachment buffered the home's negative influence on work, thereby helping nurses work energetically.


Filamin concentration in cleavage furrow and midbody region: frequency of occurrence compared with that of alpha-actinin and myosin.
Affinity-purified rabbit antibody to purified chicken gizzard filamin was used in indirect immunofluorescence to localize filamin in dividing chick embryo cells. The antibody was shown to bind only chick embryo cell filamin when whole cell extracts were analyzed by the sensitive sodium dodecyl sulfate-polyacrylamide gel electrophoresis overlay technique described by Adair et al. (1978, J. Cell Biol. 790:281-285). The results show that filamin is located in stress fibers and membrane ruffles during interphase. As cells prophase, the condensing chromosomes are surrounded by diffuse antifilamin staining. No stress fibers are apparent. During metaphase and anaphase, the staining is bright but diffuse. There is often peripheral membrane staining. Filamin is not concentrated in the spindle region but neither is it excluded from the spindle. During cytokinesis, filamin is found highly concentrated in the cleavage furrow in 16 out of 100 cells examined. This frequency of concentration in the furrow is comparable to that observed for alpha-actinin (14%). Myosin concentration in the furrow is more frequent; it is observed in 37% of the cells examined. Neither myosin, alpha-actinin, nor filamin is observed concentrated in the furrow 100% of the time. We conclude that the results are consistent with, but not sufficient to prove, the hypothesis that alpha-actinin and filamin are essential components of the mechanism of cytokinesis.


Mechanical stimulation of single cells by reversible host-guest interactions in 3D microscaffolds.
Many essential cellular processes are regulated by mechanical properties of their microenvironment. Here, we introduce stimuli-responsive composite scaffolds fabricated by three-dimensional (3D) laser lithography to simultaneously stretch large numbers of single cells in tailored 3D microenvironments. The key material is a stimuli-responsive photoresist containing cross-links formed by noncovalent, directional interactions between β-cyclodextrin (host) and adamantane (guest). This allows reversible actuation under physiological conditions by application of soluble competitive guests. Cells adhering in these scaffolds build up initial traction forces of ~80 nN. After application of an equibiaxial stretch of up to 25%, cells remodel their actin cytoskeleton, double their traction forces, and equilibrate at a new dynamic set point within 30 min. When the stretch is released, traction forces gradually decrease until the initial set point is retrieved. Pharmacological inhibition or knockout of nonmuscle myosin 2A prevents these adjustments, suggesting that cellular tensional homeostasis strongly depends on functional myosin motors.


Efficacy and safety of sildenafil in men with serotonergic antidepressant-associated erectile dysfunction: results from a randomized, double-blind, placebo-controlled trial.
To evaluate the efficacy of short-term treatment with sildenafil citrate in men with serotonin reuptake inhibitor (SRI)-associated erectile dysfunction (ED). Men (aged>or=18 years) with major depressive disorder (MDD; DSM-IV criteria) in remission and taking SRIs who experienced SRI-associated ED were enrolled in this multicenter, 6-week, randomized, flexible-dose, double-blind, placebo-controlled trial. The primary study measures were questions 3 (Q3: frequency of penetration) and 4 (Q4: frequency of maintained erections after penetration) of the International Index of Erectile Function (IIEF) questionnaire. Secondary study measures were all other questions and domains of the IIEF, the Erectile Dysfunction Index of Treatment Satisfaction (EDITS), a global efficacy questionnaire (GEQ), and a patient-maintained event log of sexual activity. Patients receiving sildenafil (N=71) versus placebo (N=71) reported significantly higher mean+/-SE scores on Q3 (3.9+/-0.2 vs. 3.1+/-0.2, p=.003) and Q4 (3.7+/-0.2 vs. 2.8+/-0.2, p<.001) of the IIEF and significantly higher scores on all domains of the IIEF. Patients receiving sildenafil also reported significantly improved scores on all questions of the EDITS questionnaire (p<.02) and the GEQ (p<.0001) and an increased number of successful sexual intercourse attempts per week (p<.0001) compared with patients receiving placebo. All patients remained in MDD remission (score<or=10 on the Hamilton Rating Scale for Depression). Adverse events in patients taking sildenafil (vs. placebo) were headache (9% vs. 9%), dyspepsia (9% vs. 1%), anxiety (6% vs. 4%), and abnormal vision (3% vs. 0%). Short-term (6-week) administration of sildenafil was well tolerated and significantly improved erectile function and overall sexual satisfaction in men with ED associated with SRI therapy for MDD. Sildenafil may be successfully used to treat SRI-associated ED without interruption of antidepressant therapy.


New metal complexes with di(mono)acylhydrazidate molecules.
The simple hydrothermal self-assemblies between metal salts, organic polycarboxylic acids and N(2)H(4)·H(2)O, sometimes in the presence of phenanthroline (phen), created four di(mono)acylhydrazidate-coordinated compounds [Pb(2)(DPHKH)(2)(phen)(2)]·2H(2)O 1, [Cd(ODPTH)(phen)]·0.25H(2)O 2, [Pb(2)(MPTH)(4)(phen)(2)] 3, [Cd(2)(MPTH)(4)(phen)(2)]·H(2)O 4 as well as one diacylhydrazide molecule [H(2)(ODPTH)] 5 (DPHKH = 4,4'-diphthalhydrazidatoketone hydrazone, MPTH = 3-methylphthalhydrazidate, ODPTH = 4,4'-oxydiphthalhydrazidate). Note that the di(mono)acylhydrazidate molecules in the title compounds originated from the in situ acylation reactions between organic polycarboxylic acids and N(2)H(4)·H(2)O. Interestingly, another kind of ligand in situ reaction was found in the formation process of DPHKH in compound 1: the nucleophilic addition reaction of a ketone with N(2)H(4)·H(2)O.


Role of cytokines and major histocompatibility complex restriction in mouse resistance to infection with a natural recombinant strain (type I-III) of Toxoplasma gondii.
Herein we characterized various genetic markers and the biological behavior of a natural recombinant strain of Toxoplasma gondii (P-Br). From nine genetic markers analyzed, three (B1, ROP1, and SAG1) and three (cS10-A6, GRA6, and SAG3) markers belong to parasites from the type I and type III lineages, respectively. The SAG2 and L363 loci were shown to be type I-III chimera alleles. The cB2l-4 microsatellite marker showed a unique haplotype. The P-Br strain presented low virulence in the acute phase of infection and was cystogenic during the chronic infection. The interleukin 12/gamma interferon axis and inducible nitric oxide synthase were main determinants of resistance during the acute infection with the P-Br strain. As opposed to infection with the type II strain of T. gondii (ME-49), peroral infection with the P-Br strain led only to a light inflammatory infiltrate and no major lesions in the intestine of the C57BL/6 mice. In addition, the BALB/c (resistant to ME-49) and C57BL/6 (susceptible to ME-49) mice were shown, respectively, to be more susceptible and more resistant to cyst formation and toxoplasmic encephalitis when infected with the P-Br strain. Further, the C57BL/KsJ and DBA2/J congenic strains containing major histocompatibility complex (MHC) haplotype "d" were more resistant than the parental strains (C57BL/6 and DBA1/J), when infected with the ME-49 but not with the P-Br strain. Together, our results indicate that resistance to cyst formation and toxoplasmic encephalitis induced during infection with P-Br is not primarily controlled by the MHC haplotype d, as previously reported for type II strains of T. gondii.


Fine-tuning of microRNA-mediated repression of mRNA by splicing-regulated and highly repressive microRNA recognition element.
MicroRNAs are very small non-coding RNAs that interact with microRNA recognition elements (MREs) on their target messenger RNAs. Varying the concentration of a given microRNA may influence the expression of many target proteins. Yet, the expression of a specific target protein can be fine-tuned by alternative cleavage and polyadenylation to the corresponding mRNA. This study showed that alternative splicing of mRNA is a fine-tuning mechanism in the cellular regulatory network. The splicing-regulated MREs are often highly repressive MREs. This phenomenon was observed not only in the hsa-miR-148a-regulated DNMT3B gene, but also in many target genes regulated by hsa-miR-124, hsa-miR-1, and hsa-miR-181a. When a gene contains multiple MREs in transcripts, such as the VEGF gene, the splicing-regulated MREs are again the highly repressive MREs. Approximately one-third of the analysable human MREs in MiRTarBase and TarBase can potentially perform the splicing-regulated fine-tuning. Interestingly, the high (+30%) repression ratios observed in most of these splicing-regulated MREs indicate associations with functions. For example, the MRE-free transcripts of many oncogenes, such as N-RAS and others may escape microRNA-mediated suppression in cancer tissues. This fine-tuning mechanism revealed associations with highly repressive MRE. Since high-repression MREs are involved in many important biological phenomena, the described association implies that splicing-regulated MREs are functional. A possible application of this observed association is in distinguishing functionally relevant MREs from predicted MREs.


A stereotaxic method for small animals using experimentally determined reference profiles.
In bats conventional stereotaxic methods do not yield sufficient positional accuracy to allow reliable recordings and tracer injections in subnuclei of the auditory system. In a newly developed stereotaxic system experimentally measured patterns of skull profile lines are used to define the animal's brain position with an accuracy of +/- 100 microns. By combining the neurophysiological stereotaxic procedure with a standardization of the neuroanatomical processing of the brains, the location of recordings, stimulations or injections can be readily transformed into brain atlas coordinates. This facilitates the compilation and comparison of data within and among animals. The system is not restricted to use in bats and can be readily adapted to other experimental animals.


An intrinsic growth instability in isotropic materials leads to quasi-two-dimensional nanoplatelets.
Colloidal nanoplatelets are atomically flat, quasi-two-dimensional sheets of semiconductor that can exhibit efficient, spectrally pure fluorescence. Despite intense interest in their properties, the mechanism behind their highly anisotropic shape and precise atomic-scale thickness remains unclear, and even counter-intuitive for commonly studied nanoplatelets that arise from isotropic crystal structures (such as zincblende CdSe and lead halide perovskites). Here we show that an intrinsic instability in growth kinetics can lead to such highly anisotropic shapes. By combining experimental results on the synthesis of CdSe nanoplatelets with theory predicting enhanced growth on narrow surface facets, we develop a model that explains nanoplatelet formation as well as observed dependencies on time and temperature. Based on standard concepts of volume, surface and edge energies, the resulting growth instability criterion can be directly applied to other crystalline materials. Thus, knowledge of this previously unknown mechanism for controlling shape at the nanoscale can lead to broader libraries of quasi-two-dimensional materials.


Treatment of acute promyelocytic leukaemia with all-trans retinoic acid and arsenic trioxide: a paradigm of synergistic molecular targeting therapy.
To turn a disease from highly fatal to highly curable is extremely difficult, especially when the disease is a type of cancer. However, we can gain some insight into how this can be done by looking back over the 50-year history of taming acute promyelocytic leukaemia (APL). APL is the M3 type of acute myeloid leukaemia characterized by an accumulation of abnormal promyelocytes in bone marrow, a severe bleeding tendency and the presence of the chromosomal translocation t(15;17) or variants. APL was considered the most fatal type of acute leukaemia five decades ago and the treatment of APL was a nightmare for physicians. Great efforts have been made by scientists worldwide to conquer this disease. The first use of chemotherapy (CT) was unsuccessful due to lack of supportive care and cytotoxic-agent-related exacerbated coagulopathy. The first breakthrough came from the use of anthracyclines which improved the complete remission (CR) rate, though the 5-year overall survival could only be attained in a small proportion of patients. A rational and intriguing hypothesis, to induce differentiation of APL cells rather than killing them, was raised in the 1970s. Laudably, the use of all-trans retinoic acid (ATRA) in treating APL resulted in terminal differentiation of APL cells and a 90-95% CR rate of patients, turning differentiation therapy in cancer treatment from hypothesis to practice. The combination of ATRA with CT further improved the 5-year overall survival. When arsenic trioxide (ATO) was used to treat relapsed APL not only the patients but also the ancient drug were revived. ATO exerts dose-dependent dual effects on APL cells: at low concentration, ATO induces partial differentiation, while at relatively high concentration, it triggers apoptosis. Of note, both ATRA and ATO trigger catabolism of the PML-RARalpha fusion protein which is the key player in APL leukaemogenesis generated from t(15;17), targeting the RARalpha (retinoic acid receptor alpha) or promyelocytic leukaemia (PML) moieties, respectively. Hence, in treating APL both ATRA and ATO represent paradigms for molecularly targeted therapy. At molecular level, ATRA and ATO synergistically modulate multiple downstream pathways/cascades. Strikingly, a clearance of PML-RARalpha transcript in an earlier and more thorough manner, and a higher quality remission and survival in newly diagnosed APL are achieved when ATRA is combined with ATO, as compared to either monotherapy, making APL a curable disease. Thus, the story of APL can serve as a model for the development of curative approaches for disease; it suggests that molecularly synergistic targeted therapies are powerful tools in cancer, and dissection of disease pathogenesis or anatomy of the cancer genome is critical in developing molecular target-based therapies.


Down-regulation of TRPM8 in pulmonary arteries of pulmonary hypertensive rats.
Pulmonary hypertension (PH) is characterized by profound vascular remodeling and alterations in Ca(2+) homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Multiple transient receptor potential melastatin-related (TRPM) subtypes have been identified in vascular tissue. However, the changes in the expression and function of TRPM channels in pulmonary hypertension have not been characterized in detail. We examined the expression of TRPM channels and characterized the functions of the altered TRPM channels in two widely used rat models of chronic hypoxia (CH)- and monocrotaline (MCT)-induced PH. CH-exposed and MCT-treated rats developed severe PH and right ventricular hypertrophy, with a significant decrease in TRPM8 mRNA and protein expression in pulmonary arteries (PAs). The downregulation of TRPM8 was associated with significant reduction in menthol-induced cation-influx. Time-profiles showed that TRPM8 down-regulation occurred prior to the increase of right ventricular systolic pressure (RVSP) and right ventricular mass index (RVMI) in CH-exposed rats, but these changes were delayed in MCT-treated rats. The TRPM8 agonist menthol induced vasorelaxation in phenylephrine-precontracted PAs, and the vasorelaxing effects were significantly attenuated in PAs of both PH rat models, consistent with decreased TRPM8 expression. Downregulation of TRPM8 may contribute to the enhanced vasoreactivity in PH.


Failure of Sandwich Technique for Thoracoabdominal Aneurysm Treated with Custom-Made Fenestrated Endograft.
Custom-made fenestrated and branched endografts are considered the gold standard devices for thoracoabdominal repair, with lower perioperative mortality and morbidities than open surgical repair. Although they are not feasible in urgent and emergent settings, in which sandwich techniques are often necessary, custom-made devices can still be used as bail-out options to correct late complications such as high-flow endoleaks, as shown in this case report. A complex, symptomatic thoracoabdominal aneurysm, unsuitable for open repair, was treated by sandwich technique on the celiac trunk despite having a short distal neck. After the finding of a high-flow type IB endoleak during postoperative follow-up, reintervention was planned with a custom-made endograft with a distal scallop, to preserve patency of the superior mesenteric artery. The procedure achieved technical success, with complete exclusion of the aneurysm and patency of all the visceral arteries. Bail-out endovascular repair with custom-made endografts after failure of parallel graft repair of thoracoabdominal aneurysms is a valuable treatment option preventing the risks related to an open conversion.


Transcriptional regulation of styrene degradation in Pseudomonas putida CA-3.
The styrene degradative pathway in Pseudmonas putida CA-3 has previously been shown to be divided into an upper pathway involving the conversion of styrene to phenylacetic acid and a lower pathway for the subsequent degradation of phenylacetic acid. It is reported here that expression of the regulatory genes styS and styR is essential for transcription of the upper pathway, but not for degradation of the lower pathway inducer, phenylacetic acid. The presence of phenylacetic acid in the growth medium completely repressed the upper pathway enzymes even in the presence of styrene, the upper pathway inducer. This repression is mediated at the transcription level by preventing expression of the styS and styR regulatory genes. Finally, an examination was made of the various stages of the diauxic growth curve obtained when P. putida CA-3 was grown on styrene together with an additional carbon source and it is reported that catabolite repression may involve a different mechanism to transcriptional repression by an additional carbon source.


An RF dosimeter for independent SAR measurement in MRI scanners.
The monitoring and management of radio frequency (RF) exposure is critical for ensuring magnetic resonance imaging (MRI) safety. Commercial MRI scanners can overestimate specific absorption rates (SAR) and improperly restrict clinical MRI scans or the application of new MRI sequences, while underestimation of SAR can lead to tissue heating and thermal injury. Accurate scanner-independent RF dosimetry is essential for measuring actual exposure when SAR is critical for ensuring regulatory compliance and MRI safety, for establishing RF exposure while evaluating interventional leads and devices, and for routine MRI quality assessment by medical physicists. However, at present there are no scanner-independent SAR dosimeters. An SAR dosimeter with an RF transducer comprises two orthogonal, rectangular copper loops and a spherical MRI phantom. The transducer is placed in the magnet bore and calibrated to approximate the resistive loading of the scanner's whole-body birdcage RF coil for human subjects in Philips, GE and Siemens 3 tesla (3T) MRI scanners. The transducer loop reactances are adjusted to minimize interference with the transmit RF field (B1) at the MRI frequency. Power from the RF transducer is sampled with a high dynamic range power monitor and recorded on a computer. The deposited power is calibrated and tested on eight different MRI scanners. Whole-body absorbed power vs weight and body mass index (BMI) is measured directly on 26 subjects. A single linear calibration curve sufficed for RF dosimetry at 127.8 MHz on three different Philips and three GE 3T MRI scanners. An RF dosimeter operating at 123.2 MHz on two Siemens 3T scanners required a separate transducer and a slightly different calibration curve. Measurement accuracy was ∼3%. With the torso landmarked at the xiphoid, human adult whole-body absorbed power varied approximately linearly with patient weight and BMI. This indicates that whole-body torso SAR is on average independent of the imaging subject, albeit with fluctuations. Our 3T RF dosimeter and transducers accurately measure RF exposure in body-equivalent loads and provide scanner-independent assessments of whole-body RF power deposition for establishing safety compliance useful for MRI sequence and device testing.


[Chinese expert consensus on the diagnosis and treatment of herpes simplex keratitis (2023)].
As one of the common infectious corneal diseases, herpes simplex keratitis (HSK) has diverse clinical manifestations, is prone to recurrence, and can lead to blindness. In recent years, as new virus detection technologies, treatment drugs and surgical methods have emerged, there are more options for the diagnosis and treatment of HSK, but many problems still exist. In order to further standardize the clinical diagnosis and treatment of HSK and provide guidance and reference for clinical work, the Ocular Infection Group of Chinese Ophthalmologist Association has gathered relevant domestic experts, and reached this consensus on the diagnosis, treatment, and prevention of HSK through full discussion, on the basis of previous opinions, and in consideration of the latest research progress, relevant guidelines abroad and expert recommendations regarding the clinical care of patients with HSK.


Higher risk of offspring schizophrenia following antenatal maternal exposure to severe adverse life events.
Most societies believe that a mother's psychological state can influence her unborn baby. Severe adverse life events during pregnancy have been consistently associated with an elevated risk of low birth weight and prematurity. Such events during the first trimester have also been associated with risk of congenital malformations. To assess the effect in offspring of antenatal maternal exposure to an objective measure of stress on risk of adverse neurodevelopment, specifically schizophrenia. We hypothesized that the strongest relationship would be to maternal exposures during the first trimester. Population-based study. Denmark. In a cohort of 1.38 million Danish births from 1973 to 1995, mothers were considered exposed if 1 (or more) of their close relatives died or was diagnosed with cancer, acute myocardial infarction, or stroke syndrome up to 6 months before conception or during pregnancy. Offspring were followed up from their 10th birthday until their death, migration, onset of schizophrenia, or June 30, 2005; admissions were identified by linkage to the Central Psychiatric Register. Main Outcome Measure Schizophrenia. The risk of schizophrenia and related disorders was raised in offspring whose mothers were exposed to death of a relative during the first trimester (adjusted relative risk, 1.67 [95% confidence interval, 1.02-2.73]). Death of a relative during other trimesters or up to 6 months before pregnancy were not linked with a higher risk of schizophrenia. Our population-based study suggests that severe stress to a mother during the first trimester may alter the risk of schizophrenia in offspring. This finding is consistent with ecological evidence from whole populations exposed to severe stressors and suggests that environment may influence neurodevelopment at the feto-placental-maternal interface.


Identifying an O2 supply pathway in CO oxidation on Au/TiO2(110): a density functional theory study on the intrinsic role of water.
Au catalysis has been one of the hottest topics in chemistry in the last 10 years or so. How O2 is supplied and what role water plays in CO oxidation are the two challenging issues in the field at the moment. In this study, using density functional theory we show that these two issues are in fact related to each other. The following observations are revealed: (i) water that can dissociate readily into OH groups can facilitate O2 adsorption on TiO2; (ii) the effect of OH group on the O2 adsorption is surprisingly long-ranged; and (iii) O2 can also diffuse along the channel of Ti (5c) atoms on TiO2(110), and this may well be the rate-limiting step for the CO oxidation. We provide direct evidence that O2 is supplied by O2 adsorption on TiO2 in the presence of OH and can diffuse to the interface of Au/TiO2 to participate in CO oxidation. Furthermore, the physical origin of the water effects on Au catalysis has been identified by electronic structure analyses: There is a charge transfer from TiO2 in the presence of OH to O2, and the O2 adsorption energy depends linearly on the O2 charge. These results are of importance to understand water effects in general in heterogeneous catalysis.


Dietary cooked navy beans and their fractions attenuate colon carcinogenesis in azoxymethane-induced ob/ob mice.
Based on the protective effects of cooked dry bean consumption in a human intervention study, we evaluated which fraction of cooked dry beans is responsible for its cancer-preventive effects. Cooked navy beans (whole beans), the insoluble fraction (bean residue) or soluble fraction of the 60% (vol:vol) ethanol extract of cooked navy beans (bean extract), or a modified AIN-93G diet (16.6% fat including 12.9% lard) as control diet were fed to 160 male obese ob/ob mice after 2 azoxymethane injections. In comparison to control-fed mice, dysplasia, adenomas, or adenocarcinomas were detected in fewer mice on either bean fraction diet (percent reduction from control: whole beans 54%, P=0.10; bean residue 81%, P=0.003; bean extract 91%, P=0.007), and any type of colon lesions, including focal hyperplasia, were found in fewer mice on each of the 3 bean diets percent reduction from control: whole bean 56%, P=0.04; bean residue 67%, P=0.01; bean extract 87%, P=0.0003. These results suggest that both the soluble and the insoluble fraction of the extract contribute to the cancer-protective effect of cooked navy beans.


Glucocorticosteroids for primary biliary cirrhosis.
Primary biliary cirrhosis is a chronic progressive cholestatic liver disease of presumed autoimmune etiology, characterised by the destruction of small intrahepatic bile ducts and the eventual development of cirrhosis and liver failure. Its progression may be influenced by immunosuppression. Glucocorticosteroids are potent immunosuppressive agents, but they are associated with significant adverse effects, including osteoporosis. To systematically evaluate the beneficial and harmful effects of glucocorticosteroids versus placebo or no intervention for patients with primary biliary cirrhosis. The Cochrane Hepato-Biliary Controlled Trials Register,The Cochrane Library, MEDLINE, EMBASE, and the full text of the identified studies were searched until June 2004. The search strategy included terms for primary biliary cirrhosis and glucocorticosteroids (including the names of frequently used preparations). Previous research groups and manufacturers were contacted for additional references. No language restrictions were applied. Double-blind, single-blind, or unblinded randomised clinical trials evaluating any preparation of glucocorticosteroids versus placebo or no intervention in patients with primary biliary cirrhosis diagnosed by abnormal liver function tests and either anti-mitochondrial antibodies or histology were included. Additional agents were allowed if they were administered to both groups equally. The quality of the randomised clinical trials was evaluated by methodology components (generation of allocation sequence; allocation concealment; blinding; follow up). Analyses were performed according to the intention-to-treat method with missing data being accounted for by imputation. Only two underpowered trials (reporting 36 and 40 patients) were identified. These differed markedly in their inclusion criteria and treatment protocols. Both stated that they used placebo. However, allocation concealment was unclear. Only one trial reported any patient deaths. No significant improvement in mortality was identified (odds ratio (OR) 0.42, 95% confidence interval (CI) 0.10 to 1.76). Improvements in serum markers of liver inflammation and liver histology were identified. Potentially prognostically linked markers such as bilirubin and albumin were incompletely reported. Bone mineral density (weighted mean difference -2.84%, 95% CI -4.16 to -1.53) and the number of patients with any adverse event (OR 8.99, 95% CI 2.15 to 37.58) were significantly increased in the glucocorticosteroid group. There is insufficient data to support or reject the use of glucocorticosteroids for patients with primary biliary cirrhosis. It may be appropriate to consider a large prospective randomised clinical trial on this topic.


Juvenile-onset diabetes.
While information regarding the diagnosis of diabetes and acute care of the diabetic, i.e., management of ketoacidosis, is readily available, much less has been written about long-term management. In addition to a brief review of background information and recent developments in diabetes, some of the more common management problems are discussed from a practical viewpoint. Because an exhaustive review of diabetes is beyond the scope of this article, readers are referred to recent review articles for additional background information.


The expanding role of civil society in the global HIV/AIDS response: what has the President's Emergency Program For AIDS Relief's role been?
Civil society has been part of the HIV/AIDS response from the very beginning of the epidemic, often becoming engaged before national governments. Traditional roles of civil society--advocacy, activism, serving as government watchdog, and acting as community caretaker--have been critical to the response. In addition, civil society organizations (CSOs) play an integral part in providing world-class HIV prevention and treatment services and helping to ensure continuity of care. The President's Emergency Program for AIDS Relief (PEPFAR) has significantly increased the global scale-up of combination antiretroviral therapy reaching for more than 5 million people in developing countries, as well as implementation of effective evidence-based combination prevention approaches. PEPFAR databases in 5 countries and annual reports from a centrally managed initiative were mined and analyzed to determine the numbers and types of CSOs funded by PEPFAR over a 5-year period (2006-2011). Data are also presented from Uganda showing the overall resource growth in CSO working for HIV. Case studies document the evolution of 3 indigenous CSOs that increased the capacity to implement activities with PEPFAR funding. A legacy of PEPFAR has been the growth of civil society to address social and health issues as well as recognition by governments that partnerships with beneficiaries and civil society result in better outcomes. Scale-up of the global response could not have happened without the involvement of civil society and people living with HIV. This game changing partnership to jointly tackle the problems that countries face may well be the greatest benefit emerging from the HIV epidemic.


[Current status and issues in clinical use of opioids].
In Japan, 14 opioids with a variety of dosage forms, such as oral preparation, injection, transdermal patch, transmucosal and suppository are clinically available as analgesics, and their use properly depends on the type and degree of pain and patient condition. Fundamentally, strong opioids are restricted to only treatment of cancer pain, while the indication of fentanyl transdermal patch and oxycodone tamper resistant tablet has been expanded for the treatment of non-cancer chronic pain. In US, the additional indication of opioids to chronic pain has led to prolongation and generalization of opioid use, which may contribute to "opioid crisis" in which opioid-related death strikingly increased due to opioid abuse and overdose-induced respiratory depression. Currently, opioid-related abuse and death have not been evident in Japan, while abuse of antitussive opioids (codeine and dihydrocodeine) are recently seen as a problem, which may suggest the sense of guilt to abuse legally-uncontrolled drugs (ex. weak opioids, antitussives or hypnotics) may be low in Japanese. In this review, I will summarize current status and issues in clinical use of opioid analgesics, and will talk about the necessity and expectation for development of novel analgesics without serious adverse reactions such as addiction and respiratory depression.


Role of hepatic fibrin in idiosyncrasy-like liver injury from lipopolysaccharide-ranitidine coexposure in rats.
Coadministration of nonhepatotoxic doses of the histamine 2-receptor antagonist ranitidine (RAN) and bacterial lipopolysaccharide (LPS) results in hepatocellular injury in rats, the onset of which occurs in 3 to 6 hours. This reaction resembles RAN idiosyncratic hepatotoxicity in humans. Early fibrin deposition occurs in livers of rats cotreated with LPS/RAN. Accordingly, we tested the hypothesis that the hemostatic system contributes to liver injury in LPS/RAN-treated rats. Rats were given either LPS (44.4 x 10(6) EU/kg) or its vehicle, then RAN (30 mg/kg) or its vehicle 2 hours later. They were killed 2, 3, 6, 12, or 24 hours after RAN treatment, and liver injury was estimated from serum alanine aminotransferase activity. A modest elevation in serum hyaluronic acid, which was most pronounced in LPS/RAN-cotreated rats, suggested altered sinusoidal endothelial cell function. A decrease in plasma fibrinogen and increases in thrombin-antithrombin dimers and in serum concentration of plasminogen activator inhibitor-1 occurred before the onset of liver injury. Hepatic fibrin deposition was observed in livers from LPS/RAN-cotreated rats 3 and 6 hours after RAN. Liver injury was abolished by the anticoagulant heparin and was significantly attenuated by the fibrinolytic agent streptokinase. Hypoxia, one potential consequence of sinusoidal fibrin deposition, was observed in livers of LPS/RAN-treated rats. In conclusion, the results suggest that the hemostatic system is activated after LPS/RAN cotreatment and that fibrin deposition in liver is important for the genesis of hepatic parenchymal cell injury in this model.


[Modern technologies of diagnosis and combined surgical treatment in liver tumors].
Modern technologies used at St. Petersburg Central Research Institute of Roentgenology and Radiotherapy of Russia's Ministry of Health in the diagnosis and treatment of malignant and benign liver cancers are surveyed in the paper. Apart from routine examinations, like ultrasound scanning, computer tomography, MRT, angiography, the below new technologies were widely used: multi-stratum spiral computer tomography, special MRT techniques and positron-emission tomography. The new methods enabled us to diagnose the tumor and its extension, to choose an optimal intervention technique, to make an objective assessment of the results and to correct the treatment strategy. Preoperative embolization of the portal-vein branches in the damaged hepatic lobe and postoperative adjuvant local chemotherapy of the hepatic artery and portal vein belong to the new combined surgical treatment scheme. The method of combined arterial-portal chemoembolization, used in unresectable malignant hepatic pathologies, extends the survival of patients by 3-5 times. Ferromagnetic embolization presupposes the administration of ferromagnetic, through the arterial bed or direct puncture, into the tumor with a subsequent SHF-current treatment which brings about a selective tumor hyperthermia without heating the normal hepatic parenchyma. Arterial embolization combined with local injection sclerotherapy in hemangiomas of the liver provides for a complete regeneration of benign tumors and can be regarded as a low-trauma alternative to liver resection. The use of new methods of diagnosis and treatment expands the possibilities of surgical care for patients with hepatic neoplasms and essentially improves the treatment results.


Nonclassical Monocytes in Health and Disease.
Monocytes are innate blood cells that maintain vascular homeostasis and are early responders to pathogens in acute infections. There are three well-characterized classes of monocytes: classical (CD14+CD16- in humans and Ly6Chi in mice), intermediate (CD14+CD16+ in humans and Ly6C+Treml4+ in mice), and nonclassical (CD14-CD16+ in humans and Ly6Clo in mice). Classical monocytes are critical for the initial inflammatory response. Classical monocytes can differentiate into macrophages in tissue and can contribute to chronic disease. Nonclassical monocytes have been widely viewed as anti-inflammatory, as they maintain vascular homeostasis. They are a first line of defense in recognition and clearance of pathogens. However, their roles in chronic disease are less clear. They have been shown to be protective as well as positively associated with disease burden. This review focuses on the state of the monocyte biology field and the functions of monocytes, particularly nonclassical monocytes, in health and disease.


Colloid-templated multisectional porous polymeric fibers.
A fabrication method for porous polymeric fibers (PPFs) is reported. We show that a multisectional colloidal crystal can be assembled within a microcapillary by alternating dipping into colloidal solutions of varying size. Subsequent infiltration with curable polymer and washing with suitable solvents results in porous fibers with a cylindrical cross section. Along the length of the fiber, alternating sections of controlled length, pore size, and pore size distribution exist. These fibers present interesting materials for neural scaffolding, catalysis, and possibly photonics if produced with a high degree of crystallinity. The surface pores and bulk porosity of the fibers are characterized by variable-pressure scanning electron microscopy (vp-SEM). Careful analysis shows that the surface pores vary with the colloidal template diameter and polymer infiltration time.


Congenital laryngeal cyst in infancy. A rare cause of life-threatening stridor.
An unusual cause of life-threatening stridor in infancy due to a congenital lateral saccular cyst of the larynx in association with an upper respiratory infection is presented. The literature is reviewed. The histopathogenesis, classification, clinical manifestations, and therapeutical principles of congenital laryngeal cysts are discussed. As almost 50% of the reported cases of congenital laryngeal cysts were diagnosed at autopsy, the gravity and importance of early recognition of these lesions must be stressed to the pediatrician and otolaryngologist.


En bloc total sacrectomy performed in a single stage through a posterior approach.
Total sacrectomies are performed for extensive en bloc tumor resections. Exposure traditionally combines a posterior approach with a laparotomy to facilitate vascular control. We present a case of a total en bloc sacrectomy performed entirely through the posterior approach, thereby avoiding the need for a laparotomy. A 57-year-old man presented with sacral pain and loss of bowel and bladder function. A large sacral mass was identified and submitted to biopsy. Results were consistent with an osteoblastoma, although osteosarcoma could not be excluded on pathological examination. The patient was taken to the operating room for a total sacrectomy and en bloc resection of the mass. Lateral iliac osteotomies were performed, followed by an L5-S1 discectomy and resection of the annulus, thus mobilizing the sacrum. Gradual distraction of the interspace coupled with upward traction of the sacrum provided an anterior exposure through which the internal iliac vessels were controlled, dissected, and divided. A combined transperineal approach completed the posterior dissection and the tumor was delivered en bloc. Lumbopelvic reconstruction was performed simultaneously. With the use of interspace distraction and sacral elevation to facilitate vascular control, a total sacrectomy was performed without the need for the anterior exposure of a laparotomy.


The primacy of the good midwife in midwifery services: an evolving theory of professionalism in midwifery.
Theory is the acknowledged foundation to practise methodology, professional identity and growth of formalized knowledge. It has been noted that practice must not only be evidence-based but also theory-based. Hence, midwifery must be theory based because theories serve as a broad framework for practice and may also articulate the goals of a profession and core values. In this paper, an evolving theory on the empowerment of childbearing women is introduced, where the midwife's professionalism is central. The theory is synthesized from nine datasets and scholarly work, and then more than three hundred studies were reviewed for clarification and confirmation. According to the theory, the midwife's professionalism is constructed from five main aspects: The professional midwife cares for the childbearing woman and her family. This caring within the professional domain is seen as the core of midwifery. The professional midwife is professionally competent. This professional competence must always have primacy for the sake of safety of woman and child. The professional midwife has professional wisdom and knows how to apply it. Professional wisdom is a new concept used to denote the interplay of knowledge and experience. The professional midwife has interpersonal competence, is capable of empowering communication and positive partnership with the woman and her family. The professional midwife develops herself both personally and professionally, which is the prerequisite for true professionalism. This evolving theory must be regularly reconstructed in the light of current knowledge within midwifery. It is an attempt to identify and articulate the processes and components of the art and science of midwifery practice in an endeavour of continuing the discipline's development by assisting in the understanding and practice of creating further theoretical discourse, processes and products for midwifery practice. The theory has implications for midwifery education and practice.


Rheumatoid arthritis synovium contains two subsets of CD83-DC-LAMP- dendritic cells with distinct cytokine profiles.
Dendritic cells (DCs) have been proposed to play a pivotal role in the initiation and perpetuation of rheumatoid arthritis (RA) by presentation of arthritogenic antigens to T cells. We investigated the in vivo characteristics of two major DC subsets, myeloid DCs (mDCs) and plasmacytoid DCs (pDCs), in RA synovial tissue (ST) by measuring their frequency, phenotype, distribution, and cytokine expression. ST was obtained by arthroscopy from 20 RA, 8 psoriatic arthritis, and 10 inflammatory osteoarthritis patients. Levels of CD1c(+) mDCs and CD304(+) pDCs present in ST were quantified by digital image analysis, and their distribution was assessed by double immunolabeling with antibodies against CD3 and CD8. The maturation status and cytokine profile of mDCs and pDCs were quantified by double-immunofluorescence microscopy. In RA patients, the number of CD304(+) pDCs exceeded that of CD1c(+) mDCs, with the majority of infiltrating DCs being CD83(-) or DC-LAMP(-). Synovial pDC numbers were especially increased in RA patients who were positive for rheumatoid factor and anti-citrullinated peptide antibody. mDCs and pDCs were localized adjacent to lymphocyte aggregates. In ST from RA patients, both mDCs and pDCs expressed interleukin (IL)-15. IL-18 and interferon (IFN)-alpha/beta were mainly expressed by pDCs whereas IL-12p70 and IL-23p19 expression was predominant in mDCs. These data characterize the phenotypes of mDCs and pDCs in inflammatory synovitis and define for the first time the cytokine expression profile of these DC subsets.


Participation of women and sex analyses in late-phase clinical trials of new molecular entity drugs and biologics approved by the FDA in 2007-2009.
Biological sex differences may contribute to differential treatment outcomes for therapeutic products. This study tracks women's participation in late-phase clinical trials (LPCTs), where efficacy and safety of drugs and biologics are evaluated, of new molecular entity (NME) drugs and biologics approved by the U.S. Food and Drug Administration (FDA) in 2007-2009. Furthermore, presentations of sex-based analyses were assessed from the FDA reviews. New drug applications (NDAs) and biologics license applications (BLAs) were accessed from the U.S. FDA database and evaluated for women's participation in LPCTs. Sex-based analyses for efficacy and safety contained in FDA reviews were surveyed. Ratios for women's LPCT participation (PROPORTION OF STUDY SUBJECTS) to their proportion in the disease population were calculated for each approved therapeutic product and grouped into therapeutic categories. Sex-specific (n=5) and pediatric (n=3) drug applications were excluded. Women's participation in LPCTs was 39%, 48%, and 42% in NDAs (n=50) and 49%, 62%, and 58% in BLAs (n=11) for 2007, 2008, and 2009, respectively. Sixty-four percent of NDAs and 91% of BLAs had participation to proportion ratios of ≥0.80. Seventy-four percent of NDA reviews and 64% of BLA reviews included safety and efficacy sex analysis. Ninety-six percent of NDA reviews and 100% of BLA reviews included efficacy sex analysis. Women's participation in LPCTs averaged 43% for NDAs and 57% for BLAs in 2007-2009 and varied widely by indication. As a comparison, the 2001 U.S. Government Accountability Office (GAO) reported 52% of women's participation for drug clinical trials in1998-2000 and an FDA study reported 45% for BLAs approved from 1995 to 1999. This study showed that sex-analysis of both safety and efficacy in NDA has increased to 74% since the GAO report of 72%, while those for BLAs increased to 64% from 37% reported for therapeutic biologics approved in 1995-1999. Knowledge of disease prevalence and participation in clinical trials provides an understanding of recruitment and retention patterns of patients in these trials.


[Fusarium meningoencephalitis in the late puerperium: A case report].
Fusarium infection in the central nervous system is a rare pathology generally reported in patients with hematological malignancies. A patient with Fusarium meningoencephalitis during the late postpartum period is presented. The patient's main symptom was holocranial headache with poor response to analgesics, adding dysarthria and blurred vision. Initially, it was classified as aseptic meningitis due to the absence of bacterial isolation, however, 8 weeks after the onset of the symptoms, Fusarium development was obtained in cerebrospinal fluid cultures. Targeted treatment with liposomal amphotericin and voriconazole was established, with partial improvement at first; however, at 16 weeks from the onset of the clinical picture, the patient presented sudden deterioration of alertness, an ischemic area was found in the occipital lobe by imaging study, which quickly led the patient to a fatal outcome. Despite the fact that in recent years Fusarium spp infection has been detected more frequently in the population, the treatment is still not well established, making management of the Central Nervous System a challenge.


The learning curve of one anastomosis gastric bypass and its impact as a preceding procedure to Roux-en Y gastric bypass: initial experience of one hundred and five consecutive cases.
The aim of this study was to assess the learning curve of one anastomosis gastric bypass (OAGB-MGB) at the start of a low volume bariatric unit and analyze its impact as a preceding procedure to Roux-en Y gastric bypass (RYGB). From January 2014 to December 2017, all patients who underwent bariatric surgeries in our teaching hospital that were performed by the same surgeon were enrolled. The first 47 patients who underwent OAGB-MGB were assigned to group A. RYGB has been offered as a treatment option since July 2016; thereafter, 26 patients who underwent OAGB-MGB and 32 patients who underwent RYGB at the same time interval were assigned to group B and group C, respectively. Baseline characteristics, perioperative outcomes and percentage of total weight loss (%TWL) up to 12 months postoperatively were collected and analyzed between groups. Compared to the patients in group C, those in groups A and B were older (39.4 yrs. and 42.2 yrs., respectively, vs. 34.2 yrs.; p = 0.021) and predominantly male (48.9 and 73.1%, respectively vs. 40.6%; p = 0.04), and they had a higher body mass index (41.8 kg/m2 and 43.3 kg/m2, respectively vs. 37.7 kg/m2; p = 0.002) and a higher incidence of hypertension (44.7 and 61.5%, respectively vs. 21.9%; p = 0.008). In addition, the operation time was significantly reduced (118.2 min and 115.8 min, respectively vs. 153.1 min; p < 0.001), and the length of stay was shortened (3.0 days and 2.9 days, respectively vs. 3.4 days; p = 0.002) in groups B and C compared to group A. No mortality, conversion or leakage was reported throughout the study period. The 30-day complication rate was decreased in group C compared to groups A and B (0% vs. 6.4 and 7.7%, respectively; p = 0.307). The %TWL at the 12-month follow-up was 36.3, 30.9 and 28.3% for groups A, B and C, respectively (p < 0.001). Our study verified the early emergence of a learning curve effect for OAGB-MGB, and the proficiency acquired can be transferred to subsequent practice for RYGB in terms of acceptable operation time and length of stay without an increase in complications.


[Endocrine disruptors: hormone-active chemicals from the environment: a risk to humans?].
Many substances from the technical and natural environment can cause damage to the endocrine system. Animal tests show that so-called endocrine disruptors (ED), such as pesticides, fungicides, plasticizers (phthalates), bisphenol A (BPA), and organotin compounds can interfere with the endocrine system. In humans, it is difficult to attribute such changes to specific ED. Nevertheless, in vitro studies with human cells and tissues clearly show that ED are able to interfere with endogenous hormones, i. e. affecting the steroid hormone metabolism and intracellular signaling. Several clinical studies show that humans are also affected, including reproductive disorders like reduction of spermatogenesis, decreased testosterone production or malformation of the genitals or induction of tumors like mammary carcinoma. Facing the body of reports documenting the effects of ED, the European Union supported--inter alia--COMPRENDO, a project addressing risk assessment of particular ED in human and wildlife species, while the FDA supports the industry's actions to stop producing BPA-containing baby bottles and infant feeding cups. Some ED show an u-shaped dose response curve and specific ED have effects at levels dramatically lower than thought relevant to traditional toxicology, a phenomenon termed "Low Dose Impact". Further research is needed to clarify whether the observed findings represent associations or causal results.


The association of genotype-based inbreeding coefficient with a range of physical and psychological human traits.
Across animal species, offspring of closely related mates exhibit lower fitness, a phenomenon called inbreeding depression. Inbreeding depression in humans is less well understood because mating between close relatives is generally rare and stigmatised, confounding investigation of its effect on fitness-relevant traits. Recently, the availability of high-density genotype data has enabled quantification of variation in distant inbreeding in 'outbred' human populations, but the low variance of inbreeding detected from genetic data in most outbred populations means large samples are required to test effects, and only a few traits have yet been studied. However, it is likely that isolated populations, or those with a small effective population size, have higher variation in inbreeding and therefore require smaller sample sizes to detect inbreeding effects. With a small effective population size and low immigration, Northern Finland is such a population. We make use of a sample of ∼5,500 'unrelated' individuals in the Northern Finnish Birth Cohort 1966 with known genotypes and measured phenotypes across a range of fitness-relevant physical and psychological traits, including birth length and adult height, body mass index (BMI), waist-to-hip ratio, blood pressure, heart rate, grip strength, educational attainment, income, marital status, handedness, health, and schizotypal features. We find significant associations in the predicted direction between individuals' inbreeding coefficient (measured by proportion of the genome in runs of homozygosity) and eight of the 18 traits investigated, significantly more than the one or two expected by chance. These results are consistent with inbreeding depression effects on a range of human traits, but further research is needed to replicate and test alternative explanations for these effects.


[TOPICAL ISSUES OF FUNCTIONING AND DEVELOPMENT OF THE SINGLE MARKET OF MEDICINES OF THE EURASIAN ECONOMIC UNION].
Currently, the Eurasian Economic Union regulates all stages of the circulation of medicines, including their development, preclinical research, clinical trials, industrial production, pharmacy manufacture, sale, storage, transportation, medical use, return to the manufacturer or supplier and destruction. Legal regulation of medicines in the EEU is carried out at several levels: at the level of the legislation of the EEU and at the level of the national legislation of each of the member states. As part of the formation of a common market for medicines in the EEU countries, more than seventy regulatory legal acts were adopted. The article analyzes the regulatory framework governing the functioning of the common market of medicines of the member states of the Eurasian Economic Union, considers the registration of medicines under the uniform rules of the Union, the functioning of a unified information system and the approval of.


Stapling procedure for hemorrhoids versus conventional haemorrhoidectomy.
Forty patients admitted at the Saudi German Hospital were randomly assigned to Milligan-Morgan haemorrhoidectomy (n = 20) or the circular stapled procedure. Under general anesthesia patients underwent standardized haemorrhoidectomy or had a circumferential doughnut of rectal mucosa and submucosa above the dentate line excised and closed with a standard circular end to end stapling device. All patients received the same preoperative and postoperative analgesic and laxative regimens. Patients completed linear analogue pain charts each day and were interviewed at 1, 3, and 12 weeks postoperatively. Summary measures of average pain experience were calculated from 10 cm linear analogue pain scores and were used as the primary outcome measure. The stapled group was found to have shorter anesthesia time (9-25 minutes, median 18) versus (15-35 minutes, median 22). Average pain in the stapled group was significantly lower than it was in the Milligan-Morgan group (0.2-7.6, median 2.1) versus (3.1-8.5, median 6.5). Hospital stay and time to first bowel motion were not significantly different between both groups. Return to normal activity was significantly shorter in the stapled group (3-60 days, median 17) versus (14-90 days, median 34). Early and late complications, patient assessed symptom control, and functional outcome appear to be similar after short term follow up.


High-throughput, quantitative enzyme kinetic analysis in microdroplets using stroboscopic epifluorescence imaging.
Droplet-based microfluidic systems offer a range of advantageous features for the investigation of enzyme kinetics, including high time resolution and the ability to probe extremely large numbers of discrete reactions while consuming low sample volumes. Kinetic measurements within droplet-based microfluidic systems are conventionally performed using single point detection schemes. Unfortunately, such an approach prohibits the measurement of an individual droplet over an extended period of time. Accordingly, we present a novel approach for the extensive characterization of enzyme-inhibitor reaction kinetics within a single experiment by tracking individual and rapidly moving droplets as they pass through an extended microfluidic channel. A series of heterogeneous and pL-volume droplets, containing varying concentrations of the fluorogenic substrate resorufin β-d-galactopyranoside and a constant amount of the enzyme β-galactosidase, is produced at frequencies in excess of 150 Hz. By stroboscopic manipulation of the excitation laser light and adoption of a dual view detection system, "blur-free" images containing up to 150 clearly distinguishable droplets per frame are extracted, which allow extraction of kinetic data from all formed droplets. The efficiency of this approach is demonstrated via a Michaelis-Menten analysis which yields a Michaelis constant, Km, of 353 μM. Additionally, the dissociation constant for the competitive inhibitor isopropyl β-d-1-thiogalactopyranoside is extracted using the same method.


Childhood adversity and personality disorders: results from a nationally representative population-based study.
Although, a large population-based literature exists on the relationship between childhood adversity and Axis I mental disorders, research on the link between childhood adversity and Axis II personality disorders (PDs) relies mainly on clinical samples. The purpose of the current study was to examine the relationship between a range of childhood adversities and PDs in a nationally representative sample while adjusting for Axis I mental disorders. Data were from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; n=34,653; data collection 2004-2005); a nationally representative sample of the United States population aged 20 years and older. The results indicated that many types of childhood adversity were highly prevalent among individuals with PDs in the general population and childhood adversity was most consistently associated with schizotypal, antisocial, borderline, and narcissistic PDs. The most robust childhood adversity findings were for child abuse and neglect with cluster A and cluster B PDs after adjusting for all other types of childhood adversity, mood disorders, anxiety disorders, substance use disorders, other PD clusters, and sociodemographic variables (Odd Ratios ranging from 1.22 to 1.63). In these models, mood disorders, anxiety disorders, and substance use disorders also remained significantly associated with PD clusters (Odds Ratios ranging from 1.26 to 2.38). Further research is necessary to understand whether such exposure has a causal role in the association with PDs. In addition to preventing child maltreatment, it is important to determine ways to prevent impairment among those exposed to adversity, as this may reduce the development of PDs.


Surgical Therapy for Perihilar Cholangiocarcinoma: State of the Art.
Surgical therapy still offers the only chance of long-term survival for patients with perihilar cholangiocarcinoma (pCCA). The aim of this narrative review is to summarize the current standards and challenges in the surgical treatment of pCCA. After imaging and defining resectability, the first step towards optimal surgical treatment is optimizing biliary drainage and preventing cholangitis, followed by securing adequate future liver remnant volume and/or function. The main goal of resection for pCCA is achieving radical resection and ultimately long-term survival. In order to achieve radical resection, several points will be addressed (e.g., vascular resection and reconstruction, intraoperative frozen sections, right versus left hemihepatectomy, and the usefulness of preoperative [chemo]therapy). In order to optimize long-term outcomes for patients with pCCA, collaboration between leading centers should be increased. In addition, this collaboration is necessary to design large prospective randomized controlled trials, as the incidence of pCCA is low and the number of resectable patients is even lower. Currently, most results are based on small retrospective cohort studies resulting in low evidence. In order to properly investigate how to improve long-term survival, we need to set up trials to confirm the results of small series suggesting the positive effect of preoperative chemotherapy and extended lymph node resection.


Druggability modification strategies of the diarylpyrimidine-type non-nucleoside reverse transcriptase inhibitors.
Drug discovery of human immunodeficiency virus (HIV) is a hot field in medicinal chemistry community for many years. The diarylpyrimidines (DAPYs) are the second-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) targeting reverse transcriptase, playing a great irreplaceable role in HIV transcriptional therapy. However, fast-growing drug-resistant mutations as nonnegligible challenge are still unpredictably appeared in the clinical practice, leading to deactivate or reduce the existing drugs. In the last 20 years, more and more novel DAPY derivatives have developed with the purpose to counter the mutants. Nevertheless, most of them have dissatisfactory pharmacokinetics (PK) or poor antiviral activity toward resistant mutant strains. In this article, we will analyze the NNRTI derivatives with promising druggability, and summarize a series of druggability modification strategies to improve the antiviral activity, reduce toxicity and improve the PK properties in recent years. The prospects of DAPYs and the directions for future efforts will be discussed.


A comparison of referral patterns and characteristics of patients with first episode symptomatic genital HSV-1 and HSV-2 infections in Sheffield.
To ascertain factors associated with HSV-1 and HSV-2 isolates in patients attending a genitourinary medicine clinic with symptomatic first episode genital herpes (FEGH). Retrospective study. A total of 606 females and 333 males presenting with culture positive FEGH between 1990-94. Department of Genitourinary Medicine, Royal Hallamshire Hospital, Sheffield, UK. Group comparison of referral patterns, demographic data, prior and concurrent episodes of STD, recent partner change. HSV-1 infected patients of either sex were more likely to be general practitioner (GP) referred, to be white, and less likely to have had preceding STD episodes. Recent sexual partner change had occurred significantly more often in HSV-2 infected females but there was no similar difference between HSV-1 and HSV-2 infected males. The relative HSV-1:HSV-2 isolate ratio in FEGH is influenced by the referral patterns. HSV-1 isolates predominate in patients presenting to GPs who refer the patients to GUM clinics for accurate diagnosis, counselling, follow up and screening for other STDs.


Nitric oxide emission from tobacco leaves and cell suspensions: rate limiting factors and evidence for the involvement of mitochondrial electron transport.
Quantitative data on nitric oxide (NO) production by plants, and knowledge of participating reactions and rate limiting factors are still rare. We quantified NO emission from tobacco (Nicotiana tabacum) wild-type leaves, from nitrate reductase (NR)- or nitrite reductase (NiR)-deficient leaves, from WT- or from NR-deficient cell suspensions and from mitochondria purified from leaves or cells, by following NO emission through chemiluminescence detection. In all systems, NO emission was exclusively due to the reduction of nitrite to NO, and the nitrite concentration was an important rate limiting factor. Using inhibitors and purified mitochondria, mitochondrial electron transport was identified as a major source for reduction of nitrite to NO, in addition to NR. NiR and xanthine dehydrogenase appeared to be not involved. At equal respiratory activity, mitochondria from suspension cells had a much higher capacity to produce NO than leaf mitochondria. NO emission in vivo by NiR-mutant leaves (which was not nitrite limited) was proportional to photosynthesis (high in light +CO(2), low in light -CO(2), or in the dark). With most systems including mitochondrial preparations, NO emission was low in air (and darkness for leaves), but high under anoxia (nitrogen). In contrast, NO emission by purified NR was not much different in air and nitrogen. The low aerobic NO emission of darkened leaves and cell suspensions was not due to low cytosolic NADH, and appeared only partly affected by oxygen-dependent NO scavenging. The relative contribution of NR and mitochondria to nitrite-dependent NO production is estimated.


Charge Asymmetry Suppresses Coarsening Dynamics in Polyelectrolyte Complex Coacervation.
Mixing solutions of oppositely charged macromolecules can result in liquid-liquid phase separation into a polymer-rich coacervate phase and a polymer-poor supernatant phase. Here, we show that charge asymmetry in the constituent polymers can slow down the coarsening dynamics, with an apparent growth exponent that deviates from the well-known 1/3 for neutral systems and decreases with increasing degrees of charge asymmetry. Decreasing solvent quality accelerates the coarsening dynamics for asymmetric mixtures but slows down the coarsening dynamics for symmetric mixtures. We rationalize these results by examining the interaction potential between merging droplets.


Outcome of the Joint Council of Thoracic Surgery Education's Early Review Course Project.
The Joint Council on Thoracic Surgical Education was formed in 2008 to improve cardiothoracic education. Resident learning has been a concern as reflected in declining passing rates on the American Board of Thoracic Surgery examinations. The Joint Council on Thoracic Surgical Education piloted a program to determine whether early exposure to a cardiothoracic curriculum through participation in a board review course would improve learning. The purpose of this paper is to report the results of this project. Residents from the incoming classes of traditional 5-2 or 5-3 cardiothoracic training programs were randomly selected to attend a 3-day board review course (University of Utah) in September of their first year. For the 2012 and 2013 classes of cardiothoracic residents, we asked all incoming residents to take the prior spring in-training examination in July of their first year and then take the in-training examination in the spring of their first year. We combined the results of the incoming class of 2012 and 2013 and analyzed the results. There were 171 residents who participated in either 2012 or 2013. There were 38 residents (78.9% were men) who attended the board review course and 133 (79.7% men) who did not. Questionnaires completed by the program directors and the residents who took the review course showed a favorable opinion of the program. The number of correct answers on the in-training examination, the percentage correct, and the percentile rank score increased more for the residents who took the review course, but was not statistically significant. When only the general thoracic surgery questions were analyzed, there was a statistically significant increase in the rank change between residents who attended the review course and residents who did not (8.4% increase versus 2.0% decrease, respectively; p = 0.042, Student t test). This pilot study established for the first time the baseline level of knowledge of incoming residents assessed by the in-training examination. Participation in a board review type course early in the residency training program may increase learning by cardiothoracic residents, but there was not a clear statistical difference between the two groups. The program was viewed as favorable by both the participating residents and the program directors.


Efficacy of an indicated prevention strategy on sickness absence and termination of the employment contract: a 5-year follow-up study.
It was shown that an indicated prevention strategy (IPS), based on screening and early intervention, can considerably decrease future risk of long-term sickness absence (LTSA>28 days) over one year. Given the nature of the interventions, the potential of an effect extending beyond the original one year of follow-up might be present. This study aims to determine the efficacy of this IPS on LTSA and termination of employment contract over five years by extended follow up of IPS trials. Company records on sickness absence and termination of employment contract over five years were used from two randomized controlled trials (RCT) on the efficacy of the IPS (RCT I employees at high-risk for LTSA: intervention: N=263; RCT II high-risk employees with concurrent mild depressive complaints: intervention: N=139). Survival analysis was used to model time until the first LTSA episode and termination of employment contract. RCT I showed a decrease of 43.2 days of sickness absence (P=0.05) and a lower 5-year risk of LTSA in the intervention, as compared to the control group [hazard ratio (HR) 0.61, 95% confidence interval (CI) 0.41-0.90], however no considerable impact on employment contract (HR 0.85, 95% CI 0.54-1.35) (intention-to-treat, ITT). For RCT II, we found no large difference in days of SA and no difference in LTSA risk over five years (HR 1.31, 95% CI 0.70-2.47), whereas the risk of termination of the employment contract was lower (HR 0.62, 95% CI 0.39-0.99) (ITT). Effects of the IPS were observed over five years, albeit differential between the two approaches. A combination of elements of both interventions might lead to optimal results but needs further study.


Hemograms and microscopic lesions of herring gulls during captivity.
Herring gulls (Larus argentatus) kept in captivity for a maximum of 28 days developed marked heterophilia and nonregenerative anemia. These hematologic findings remained abnormal throughout captivity. Concurrently, severe amyloid deposition was seen in vessel walls of the spleen and in other tissues, and vacuolar degeneration of catecholamine-producing cells of the adrenal glands was found in gulls necropsied at various intervals. Behavioral signs of stress were seen in the early stages of captivity, but were not seen in most gulls after day 3. Clinical signs referable to the microscopic lesions were not observed in this study. Therefore, gulls brought into captivity appear to adapt behaviorally, but maintain severe microscopic lesions and an abnormal hemogram.


Adherence to recommended treatments for early invasive breast cancer: decisions of women attending surgeons in the breast cancer audit of Australia and New Zealand.
The study aim was to determine the frequency with which women decline clinicians' treatment recommendations and variations in this frequency by age, cancer and service descriptors. The study included 36,775 women diagnosed with early invasive breast cancer in 1998-2005 and attending Australian and New Zealand breast surgeons. Rate ratios for declining treatment were examined by descriptor, using bilateral and multiple logistic regression analyses. Proportional hazards regression was used in exploratory analyses of associations with breast cancer death. 3.4% of women declined a recommended treatment of some type, ranging from 2.6% for women under 40 years to 5.8% for those aged 80 years or more, and with parallel increases by age presenting for declining radiotherapy (p<0.001) and axillary surgery (p=0.006). Multiple regression confirmed that common predictors of declining various treatments included low surgeon case load, treatment outside major city centres, and older age. Histological features suggesting a favourable prognosis were often predictive of declining various treatments, although reverse findings also applied with women with positive nodal status being more likely to decline a mastectomy and those with larger tumours more likely to decline chemotherapy. While survival analyses lacked statistical power due to small numbers, higher risks of breast cancer death were suggested, after adjusting for age and conventional clinical risk factors, (1) for women not receiving breast surgery for unstated reasons (RR=2.29; p<0.001); and (2) although not approaching statistical significance p≥ 0.200), for women declining radiotherapy (RR=1.22), a systemic therapy (RR1.11), and more specifically, chemotherapy (RR=1.41). Women have the right to choose their treatments but reasons for declining recommendations require further study to ensure that choices are well informed and clinical outcomes are optimized.


In vivo antitumour potential of camel's milk against hepatocellular carcinoma in rats and its improvement of cisplatin renal side effects.
Camel milk (CM) is recommended for liver disease patients in Egypt for a strong belief that it has a curative effect. The effect of consumption of CM with or without chemotherapeutic drug cisplatin was evaluated on induced hepatocarcinogenesis in rats. Wistar male rats (56) were divided into eight groups (7 rats each). Group I was control. Hepatocarcinogenesis was initiated by a single dose of intraperitoneal injection of diethylnitrosamine (DENA) (200 mg/kg BW) and promoted by phenobarbitone (500 ppm) in drinking water in groups V, VI, VII and VIII. Treatment started from 28th till 38th week using CM (5 mL/day) and/or cisplatin (5 mg/kg/3 weeks) in groups II, III IV, VI, VII and VIII. Biochemical analysis, lipid peroxidation and superoxide dismutase (SOD) activity in liver tissue were performed. Histopathology of liver and kidney and immunohistochemistry of placental glutathione-S-transferase (P-GST) in liver were performed and analyzed using image analysis. Albumin concentration and SOD activity were 3.13 ± 0.23 and 311.45 ± 41.71 in group VII (DENA & cisplatin), whereas they were 4.3 ± 0.15 and 540.5 ± 29.94 in group VII (DENA, CM and cisplatin). The mean area of altered hepatocellular foci and P-GST altered foci decreased in group VI (DENA and CM) (1049.6 ± 174.78 and 829.1 ± 261) and group VIII (cisplatin and CM) (1615.12 ± 436 and 543.9 ± 127) compared to group V (DENA only) (4173.74 ± 510.7 and 3169.49 ± 538.61). Cisplatin caused chronic interstitial nephritis, which was slightly alleviated in group VIII (CM and cisplatin). CM had an antioxidant effect and together with cisplatin managed to decrease hepatocarcinogenesis.


Repair of BHK cell surface ganglioside GM3 after its degradation by extracellular sialidase.
Treatment of BHK fibroblasts with V. cholerae sialidase for 20 min caused the breakdown of about 70% of total cellular ganglioside GM3 and the production of an approximately equivalent amount of lactosylceramide. On removal of the enzyme, a slow resynthesis of GM3 from lactosylceramide was observed, equivalent to about 5-6%/h of the degraded GM3. Resynthesis of degraded surface ganglioside has not previously been observed, but its magnitude is similar to previous measurements of the rate of protein resialylation after sialidase treatment. This suggests that resialylation of both lipid and protein is limited by vesicular transport of plasma membrane components through the trans-Golgi network [TGN] where sialyltransferase is thought to be localized. In contrast, resynthesis of sphingomyelin which has been degraded at the cell surface by exogenous sphinogomyelinase is about five times faster than resynthesis of GM3 and may involve non-vesicular transport of ceramide.


Elderly persons' social network and need for social support after their first myocardial infarction.
Social network and social support are phenomena suggested to be of importance to successful recovery from myocardial infarction. However, very few studies have been carried out, especially among the elderly, focusing on their social network and its ability to provide adequate support after myocardial infarction. The aim of this study was to examine elderly persons' social network and need for social support three months after their first myocardial infarction. The sample consisted of 128 persons between 65 and 94 years of age who answered a questionnaire. The results showed that the subjects, even the oldest ones, had an available social network and that they were satisfied with the support it provided. There was an increased need for social support after the myocardial infarction, especially for emotional support and appraisal, but also for instrumental aid and information. Despite these positive results indicating that elderly persons with myocardial infarction have a social network, whose members provide them with support, there may be a need for support also from persons outside this network. Assessment of social network characteristics and the need for social support as well as the provision of adequate information about additional support networks are important tasks for all health professionals.


Cerebral metabolites in HIV-infected children followed for 10 months with 1H-MRS.
Previous studies have shown that HIV-infected children have abnormal cerebral metabolites, measured by proton MR spectroscopy (1H MRS), but the stability of these measurements over time has not been described in HIV-infected children. The authors recently reported a study of cerebral metabolites in 20 HIV-infected children (6 to 16 years of age); the current study followed 12 of these children (10.0 years +/- 3.7 years) and repeated the MR spectroscopy at 24.1 +/- 3.7 weeks and 42.2 +/- 3.5 weeks following the entry time with repeated neuropsychological testing. 1H MR spectra were acquired at 1.5 T (GE Signa, PRESS localization, repetition time = 3,000 msec, echo time = 30 msec). Five brain regions were studied: right frontal white matter, left frontal white matter, right basal ganglia, right hippocampus, and midfrontal gray matter. The concentrations of N-acetylaspartate (NAA), choline (CHO), creatine (CR), and myo-inositol (mI) and the ratio of each metabolite to CR were determined. There were no changes in the metabolite concentrations or metabolite/CR ratios at the three time periods. Similarly, during this follow-up period, HIV-positive children showed no changes in clinical signs, HIV viral loads, CD4%, or CD4 counts, except for improved spatial memory with repeat testing. In a clinically and neurologically stable group of HIV-infected children, cerebral metabolites were stable over a 10-month time period, suggesting that it is possible to assess changes in cerebral metabolites as a measure of cerebral health, but longer follow-up in a larger sample is needed.


Developmental tightening of cerebellar cortical synaptic influx-release coupling.
Tight coupling between Ca(2+) channels and the sensor for vesicular transmitter release at the presynaptic active zone (AZ) is crucial for high-fidelity synaptic transmission. It has been hypothesized that a switch from a loosely coupled to a tightly coupled transmission mode is a common step in the maturation of CNS synapses. However, this hypothesis has never been tested at cortical synapses. We addressed this hypothesis at a representative small cortical synapse: the synapse connecting mouse cerebellar cortical parallel fibers to Purkinje neurons. We found that the slow Ca(2+) chelator EGTA affected release significantly stronger at immature than at mature synapses, while the fast chelator BAPTA was similarly effective in both groups. Analysis of paired-pulse ratios and quantification of release probability (pr) with multiple-probability fluctuation analysis revealed increased facilitation at immature synapses accompanied by reduced pr. Cav2.1 Ca(2+) channel immunoreactivity, assessed by quantitative high-resolution immuno-electron microscopy, was scattered over immature boutons but confined to putative AZs at mature boutons. Presynaptic Ca(2+) signals were quantified with two-photon microscopy and found to be similar between maturation stages. Models adjusted to fit EGTA dose-response curves as well as differential effects of the Ca(2+) channel blocker Cd(2+) indicate looser and less homogenous coupling at immature terminals compared with mature ones. These results demonstrate functionally relevant developmental tightening of influx-release coupling at a single AZ cortical synapse and corroborate developmental tightening of coupling as a prevalent phenomenon in the mammalian brain.


Efficacy and safety of beta-arteether and alpha/beta-arteether for treatment of acute Plasmodium falciparum malaria.
One hundred thirty-eight adult patients with acute Plasmodium falciparum malaria were randomized to receive either beta-arteether or alpha/beta-arteether. The drugs were administered in the dose of 150 mg once a day intramuscularly for three consecutive days in hospitalized patients. After one week of hospitalization, patients were followed-up for three weeks after release from the hospital. There was no statistically significant difference between cure rates, mean fever clearance time (FCT), mean parasite clearance time (PCT), and occurrence of side effects in either group. The cure rate was 97.14% for beta-arteether and 97.01 for alpha/beta-arteether (P = 0.9660). The mean PCT was 38.49 hours for beta-arteether and 36.90 hours for alpha/beta-arteether (P = 0.6054), and the mean FCT was 37.27 hours for beta-arteether and 37.9 hours for alpha/beta-arteether (P = 0.8718). Both arteether formulations were safe and efficacious in reducing the clinical symptoms of acute falciparum malaria. There was also rapid clearance of parasitemia with both formulations. Thus, either beta-arteether or alpha/beta-arteether can be used in the treatment of acute falciparum malaria.


[The central gray substance of the midbrain: the role of corticosteroids in the analgesic effect].
The effect of stimulation of periaqueductal gray matter on pain threshold and blood corticosteroids was studied in anesthetized rats. The stimulation with 30-50-microA current resulted in an increase of analgesia and blood corticosteroids. An increase of current intensity up to 100 microA resulted in a decreasing corticosteroid level and analgetic effect. The magnitude and duration of the analgesia were decreased after blocking the pituitary-adrenocortical system. The corticosteroids seem to induce analgesia after stimulation of periaqueductal gray matter stimulation.


Communication Matters: A Long-Term Follow-up Study of Child Savings Account Program Participation.
As they are a long-term policy instrument, the results of many child savings account (CSA) programs take decades to realize. Because of this, important questions regarding the long-term impacts of the programs, as well as participants' perceptions regarding the programs' long-term impacts, are unanswered. In this study, we present findings from a qualitatively driven complex mixed methods follow-up of the first large CSA demonstration project, the quasi-experimental Michigan Saving for Education, Entrepreneurship, and Downpayment (SEED) program. We asked SEED account-holding and non-account-holding families how they communicated about college, saving for college, and future educational attainment, nearly ten years after the CSA demonstration project ended. In a novel approach, we conducted separate semi-structured interviews with dyads of parents and children, combining that information with survey data and account balance monitoring data, ultimately gaining a multidimensional picture of how families with and without SEED accounts were approaching planning for post-secondary education right before the transition to adulthood. We found that: (1) the vast majority of account-holding families did not make withdrawals from their SEED accounts, (2) recent family communication about the SEED accounts was related to the specificity of a child's post-secondary plans, (3) there were tensions between college aspirations and the concrete steps needed to get there, and (4) families voiced concerns regarding the substantial barriers to post-secondary education. These findings point to both the promises and challenges of CSAs that newly developed programs might want to consider.


Thyrotropin Levels in Patients with Coronavirus Disease 2019: Assessment during Hospitalization and in the Medium Term after Discharge.
The objectives of this study were (1) to compare TSH levels between inpatients with critical versus non-critical coronavirus disease 19 (COVID-19), and (2) to describe the status of TSH levels three months after hospitalization. We collected data on adult patients hospitalized with COVID-19 at Amiens University Hospital. We compared TSH levels between inpatients with critical (intensive care unit admission and/or death) versus non-critical COVID-19. Thereafter, survivors were invited to return for a three-month post-discharge visit where thyroid function tests were performed, regardless of the availability of TSH measurement during hospitalization. Among 448 inpatients with COVID-19, TSH assay data during hospitalization were available for 139 patients without prior thyroid disease. Patients with critical and non-critical forms of COVID-19 did not differ significantly with regard to the median (interquartile range) TSH level (0.96 (0.68-1.71) vs. 1.27 mIU/L (0.75-1.79), p = 0.40). Abnormal TSH level was encountered in 17 patients (12.2%); most of them had subclinical thyroid disease. TSH assay data at the three-month post-discharge visit were available for 151 patients without prior thyroid disease. Only seven of them (4.6%) had abnormal TSH levels. Median TSH level at the post-discharge visit was significantly higher than median TSH level during hospitalization. Our findings suggest that COVID-19 is associated with a transient suppression of TSH in a minority of patients regardless of the clinical form. The higher TSH levels three months after COVID-19 might suggest recovery from non-thyroidal illness syndrome.


Effect of rubber flooring on dairy cattle stepping behavior and muscle activity.
Use of compressible flooring, such as rubber, has increased on dairy farms. Rubber improves locomotion and is well used by cattle in preference experiments that combine walking and standing. Previous work has found that rubber is particularly beneficial for lame animals, perhaps because a softer material is particularly useful when a single hoof is compromised. The goal of this work was to evaluate the effect of flooring while standing, because cattle in freestall housing spend 40 to 50% of their time engaged in this behavior. In a 2 × 2 design, cows (n = 16) were evaluated on 4 standing surfaces that varied in terms of both floor type (concrete or rubber) and presentation [same floor under all 4 legs (all 4 legs on either concrete or rubber) or a rough surface under only one hind leg and the other 3 legs on concrete or rubber] in a crossover design. Surface electromyograms were used to evaluate muscle fatigue, total activity, and movement of muscle activity between legs during 1 h of standing. Muscle fatigue was evaluated in 2 contexts: (1) static contractions when cows continuously transferred weight to each hind leg, before and after 1 h of standing, and (2) dynamic contractions associated with steps during 1 h on treatment surfaces. In addition, stepping rate, time between each consecutive step, and the latency to lie down after testing were measured. No interaction between floor type and presentation was found. Presentation had a significant effect; when one hind leg was on a rough surface, cattle took 1.7 times more steps with this leg and the non-rough hind leg had 1.2 times more muscle activity, compared with when all 4 legs were on the same surface. These changes are consistent with movement away from concrete with protrusions. When standing on rubber, muscle-activity movements among legs remained stable (0.6-0.7 movements per min) over 1 h but increased on concrete (0.6-0.9 movements per min), indicating that, like humans, cattle may sway to counteract effects of standing. However, additional work, including measurements of blood flow in the leg, is needed to fully understand the biological implications of these changes. Overall, the rubber flooring tested had little effect on standing behavior.


Thymosin fraction 5 does not accelerate reconstitution of immunologic reactivity after human marrow grafting.
More than 1 year is required for immunologic function to recover following human marrow grafting. In an attempt to shorten the time required for immunologic reconstitution, 14 patients were treated with thymosin fraction 5 after transplantation. Two died before administration of thymosin could be completed. In the remaining 12 patients, immunologic studies were compared to those of patients who were transplanted but did not receive thymosin. While five patients had transient elevation of in vitro lymphocyte blastogenesis during thymosin treatment, results of other immunologic studies from patients treated with thymosin were similar to those from patients not treated. The subsequent development of graft-versus-host disease, major or minor infection, and leukaemic relapse was not different between the groups. Six patients are alive and five are well without problems; one has chronic graft-versus-host disease. We conclude that thymosin fraction 5 administered as described was not toxic. Although modifying some immunological parameters, thymosin did not appear to alter the incidence of graft-versus-host disease, infection or leukaemic relapse or to accelerate immunologic reconstitution.


The phosphatidylinositol 3-kinase/AKT signal transduction pathway plays a critical role in the expression of p21WAF1/CIP1/SDI1 induced by cisplatin and paclitaxel.
The cyclin-dependent kinase inhibitor p21WAF1/CIP1/SD11 (p21) plays a crucial role in DNA repair, cell differentiation, and apoptosis through regulation of the cell cycle. A2780 human ovarian carcinoma cells, which are sensitive to cisplatin and paclitaxel, express wild-type p53 and exhibit a p53-mediated increase in p21 in response to the chemotherapeutic agents. Here, we demonstrate that phosphatidylinositol 3-kinase (PI3K) and its downstream targets serine/threonine kinases AKT1 and AKT2 (AKT), are required for the full induction of p21 in A2780 cells treated with cisplatin or paclitaxel. Inactivation of the PI3K/AKT signal transduction pathway either by its specific inhibitor LY294002 or by expression of dominant negative AKT inhibited p21 expression but had no inhibitory effect on the expression of the proapoptotic protein BAX by cisplatin and paclitaxel treatment. In addition, overexpression of wild-type or constitutively active AKT in A2780 cells sustained the regulation of p21 induction or increased the level of p21 expression, respectively. Experiments with additional ovarian carcinoma cell lines revealed that PI3K is involved in the expression of p21 induced by cisplatin or paclitaxel in OVCAR-10 cells, which have wild-type p53, but not in OVCAR-5 cells, which lack functional p53. These data indicate that the PI3K/AKT signal transduction pathway mediates p21 expression and suggest that this pathway contributes to cell cycle regulation promoted by p53 in response to drug-induced stress. However, inactivation of PI3K/AKT signaling did not result in significant alteration of the drug sensitivity of A2780 cells, suggesting that the cell death induced by cisplatin or paclitaxel proceeds independently of cell protective effects of PI3K and AKT.


Cryopreservation of the model alga Ectocarpus (Phaeophyceae).
The brown alga Ectocarpus has recently become the first fully sequenced multicellular alga and is an important biological model. Due to the large and growing number of Ectocarpus strains isolated and maintained by the research community, including increasing numbers of mutants, there is an urgent need for developing reliable, cost-effective long-term maintenance techniques. We report here that cryopreservation constitutes an attractive option in this respect, using a simple two-step protocol employing combined DMSO 10 percent (v/v) and sorbitol 9 percent (w/v) as cryoprotectants. This model organism appears to be remarkably robust and post-cryo recovery has been observed in all strains tested in this study. Cultures can be regenerated by the germination of cryopreserved zooids (spores), or the recovery of vegetative cells. In the latter case, dividing surviving cells may grow into the cell lumen of a neighbouring dead cell, eventually regenerating a phenotypically normal thalloidal structure.


Laparoscopic Versus Open Resection of Gastric Gastrointestinal Stromal Tumors Larger Than 5 cm: A Single-Center, Retrospective Study.
The technical feasibility and oncological safety of laparoscopic surgery for gastric gastrointestinal stromal tumors (GISTs) larger than 5 cm has not been adequately studied. Therefore, we performed this retrospective study to investigate the clinical outcomes of gastric GIST patients treated with laparoscopic surgery compared with those who underwent open surgery. We retrospectively evaluated the outcomes of 48 consecutive patients who underwent gastric resection for gastric GISTs larger than 5 cm. The patients were divided into 2 groups based on the surgery performed: the laparoscopic resection group (LAPG) and the open resection group (OG). We assessed all available patient data, including baseline information, tumor characteristics, surgical outcomes, pathological results, postoperative complications, and long-term patient survival. The 2 groups had similar baseline data. No differences were found in tumor size, location, mitotic count, and risk grade according to Fletcher's risk classification. The LAPG was superior to the OG in blood loss, time to first flatus, time to oral intake, and length of postoperative hospital stay. Perioperative complications, recurrence rate, and long-term survival, however, did not differ significantly between the groups. The mean operation time in the LAPG was 28 minutes longer than that in the OG. In patients with primary gastric GISTs larger than 5 cm, laparoscopic resection is a technically feasible and oncologically safe surgery when performed by experienced surgeons.


Mitochondrial complex II prevents hypoxic but not calcium- and proapoptotic Bcl-2 protein-induced mitochondrial membrane potential loss.
Mitochondrial membrane potential loss has severe bioenergetic consequences and contributes to many human diseases including myocardial infarction, stroke, cancer, and neurodegeneration. However, despite its prominence and importance in cellular energy production, the basic mechanism whereby the mitochondrial membrane potential is established remains unclear. Our studies elucidate that complex II-driven electron flow is the primary means by which the mitochondrial membrane is polarized under hypoxic conditions and that lack of the complex II substrate succinate resulted in reversible membrane potential loss that could be restored rapidly by succinate supplementation. Inhibition of mitochondrial complex I and F(0)F(1)-ATP synthase induced mitochondrial depolarization that was independent of the mitochondrial permeability transition pore, Bcl-2 (B-cell lymphoma 2) family proteins, or high amplitude swelling and could not be reversed by succinate. Importantly, succinate metabolism under hypoxic conditions restores membrane potential and ATP levels. Furthermore, a reliance on complex II-mediated electron flow allows cells from mitochondrial disease patients devoid of a functional complex I to maintain a mitochondrial membrane potential that conveys both a mitochondrial structure and the ability to sequester agonist-induced calcium similar to that of normal cells. This finding is important as it sets the stage for complex II functional preservation as an attractive therapy to maintain mitochondrial function during hypoxia.