Magnetic anisotropy and planar topological Hall effect in SrMnxIr1-xO3films.
Strong Coulomb repulsion and spin-orbit coupling are known to give rise to exotic physical phenomena in transition metal oxides. Here, we report magnetic and transport characteristics of (001) oriented epitaxial SrMnxIr1-xO3thin films, having both 3dand 5delements on the perovskiteBsites. With the increase of Mn concentration, perpendicular magnetic anisotropy (PMA) decreases gradually in accompany with the magnetic easy axis tilting away from the out-of-plane [001] direction. X-ray absorption spectroscopy reveals that Mnegelectrons preferentially occupy thed3z2-r2orbital, which produces the observed PMA in the framework of spin-orbital coupling. A planar topological Hall effect appears in SrMnxIr1-xO3films withxabout 0.30 when the magnetic field is applied along the current, which is a result of the noncoplanar spin structure due to the competition among the PMA, the magnetic exchange interaction and the Zeeman energy. These results provide an example to show the subtle balance among complex competitions in materials with both strong correlation and spin-orbit coupling.


Preincubation of t-SNAREs with Complexin I Increases Content-Mixing Efficiency.
Complexin (Cpx) is a major regulator for Ca(2+)-triggered fast neuroexocytosis which underlies neuronal communication. Many psychiatric and neurological disorders accompany changes in the Cpx expression level, suggesting that abnormal Cpx levels may elicit aberrant cognitive symptoms. To comprehend how the changes in the Cpx level might affect neuronal communication, we investigated Ca(2+)-triggered exocytosis at various Cpx concentrations. Ca(2+)-triggered content-mixing between a single proteoliposome of t-SNARE and another single proteoliposome of v-SNARE plus Ca(2+)-sensor synaptotagmin 1 was examined with total internal reflection microscopy. We find that Cpx enhances Ca(2+)-triggered vesicle fusion with the yield changing from approximately 10% to 70% upon increasing Cpx from 0 to 100 nM. Unexpectedly, however, the fusion efficiency becomes reduced when Cpx is increased further, dropping to 20% in the micromolar range, revealing a bell-shaped dose-response curve. Intriguingly, we find that the rate of vesicle fusion is nearly invariant through the entire range of Cpx concentrations studied, suggesting that a reevaluation of the current Cpx clamping mechanism is necessary. Thus, our results provide insights into how delicately Cpx fine-tunes neuronal communication.


Clinical availability of urinary N-acetyl-beta-D-glucosaminidase index in dogs with urinary diseases.
Urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) was examined in healthy dogs and dogs with urinary diseases, and its clinical usefulness as an indicator of urinary diseases was discussed. Twenty-eight healthy dogs and 20 dogs with urinary diseases were used. Urinary NAG activity was measured using p-nitrophenyl N-acetyl-beta-D-glucosaminide as substrate, and expressed as units per gram of urinary creatinine (NAG index). Urinary NAG index in urine of healthy dogs was 3.2+/-2.4 U/g, and NAG index in the dogs with chronic renal failure or lower urinary tract infection accompanied by pyelonephritis was higher than that in healthy dogs. However, the dogs with lower urinary tract infection without pyelonephritis showed normal values of NAG index. Some dogs with diabetic mellitus showed elevated values of NAG index when control of blood sugar was not successful. Increase of NAG index was observed in some dogs with pyometra before increases of BUN and serum creatinine concentration. Therefore, NAG index in urine seems to be a good indicator for urinary diseases in dogs.


Prognostic value of pre-embolisation MRI features of uterine fibroids in uterine artery embolisation.
To evaluate the prognostic value of pretreatment pelvic magnetic resonance imaging (MRI) features in uterine artery embolisation (UAE) for symptomatic fibroids. MRI characteristics of 109 fibroids (≥3 cm) in 70 patients were analysed retrospectively. Imaging was performed 1.8±1.3 (SD) months before and 6.6±1.8 months after UAE. On pretreatment images, signal intensity (SI) of fibroids was compared with that of the myometrium and skeletal muscle on T1- and T2-weighted sequences; the contrast enhancement pattern and localisation of fibroids were also analysed. Fibroid volume reduction (VR) was assessed by control imaging. The numerical analogue quality-of-life score was obtained before and after UAE. Statistical analysis was performed using the Mann-Whitney U-test, Kruskal-Wallis test, and Wilcoxon signed-rank test. The mean fibroid volume decreased by 51.1±30.8% during the 6.6±1.8 months (p<0.001). Mean quality-of-life score improved by 48.2±27.6 points (p<0.001). The mean VR of submucosal fibroids (82.1±18.5%) was greater than that of intramural (49.4±30.7%) and subserosal (43±28.3%) fibroids (p<0.001 for both). Fibroids that were isointense/hyperintense to myometrium on T2-weighted images showed a better response than hypointense fibroids (63.7±25.8% versus 48.6±31.3%, respectively; p=0.041). On contrast-enhanced images, isointense/hyperintense fibroids showed a better VR than hypointense fibroids (61.3±27.4% versus 47.6±31.6%, respectively; p=0.035). Baseline fibroid volume of <50 cm3 was also associated with favourable imaging outcome (p=0.021). T2 SI compared to skeletal muscle and T1 SI compared to myometrium or skeletal muscle did not show association with VR. Localisation, T2 SI, contrast enhancement, and <50 cm3 fibroid volume were associated with better VR; these may help with treatment decisions.


[Blood pressure control after a one year follow-up in high risk subject screened in occupational medicine].
To identify factors predicting the success or the failure of intervention on blood pressure in a population estimated at high risks. The program "Coeur 2001" has analysed the absolute cardiovascular risk (ACVR Framingham) in 107 371 voluntary French railways employees. In the company, were considered at high risk (HR), subjects for whom risk was > or = to the 95th percentile of the distribution of the observed ACVR by age range: ACVR > or = 4.5% before 35 years, 12% between 35 and 45 years and 19% beyond 45 years, i.e. a total of 4 190 subjects. These subjects were warned about their risk and advised to choose and consult a physician. A two-year follow up was planned. Identical data (risk factors, ACVR, type of management and therapies) were collected during the first consultation with the occupational physician (T0), one year later (T1) and two years later (T2). Our work concerned 2376 employees at HR, consulting at T1. At T1, 54% of subjects were in the hight risk group (SHR) [48% when BP at T1 was < 140/90 mmHg and 62% when the BP was > or = 140/90 mmHg]. The mean decrease of the systolic BP (SBP) was 4 mmHg in the whole sample, 7.7 mmHg in subjects with normalised ACVR, and it remained stable in the group still at HR (-0.7 mmHg). At T0, blood pressure (BP) was > or = 140/90 mmHg in 55.8% of the patients and 38.4 at T1. This high BP was associated with higher frequency of diabetes (14 vs 7%) and overweight (BMI > or =30 kg/m2; 32.8 vs 19.7%). The percentage of treated hypertensive subjects had increased from 35 to 62% but one third of uncontrolled hypertensive subjects was treated by mono therapies at T1. To keep BP under control is a difficult task in routine medicine. At T1, despite a more aggressive treatment, 38% of subjects at high risk were still hypertensive subjects.


From Prediabetes to Type 2 Diabetes Mellitus in Women with Polycystic Ovary Syndrome: Lifestyle and Pharmacological Management.
Despite the very clear association between polycystic ovary syndrome (PCOS) and dysglycemia, few studies have explored the continuum of glycemic alterations leading from minor glucose abnormalities to overt diabetes. The purpose of this review is to trace the natural history of glycemic alteration in women with PCOS. We performed a literature review without time limit until August 2019. Inclusion criteria were studies addressing the association between impaired glucose tolerance or impaired fasting glucose or type 2 diabetes (T2D) and PCOS with at least an English abstract. The exclusion criteria were no PCOS or impaired glucose tolerance or impaired fasting glucose or T2D as outcome. The outcomes of interest were the onset of impaired glucose tolerance, impaired fasting glucose, T2D, and the progression from impaired glucose tolerance or impaired fasting glucose to T2D. Healthy diet and physical activity are the first-line therapy for PCOS. Treatment with metformin was associated with significant lower 2-hour postload glucose levels and with reduction in fasting glucose when compared to placebo. Thiazolidinediones were more effective in reducing fasting glucose levels compared to placebo. Metformin and pioglitazone treatments showed similar effects on fasting glucose levels. The sodium-glucose cotransporter-2 inhibitor empagliflozin did not show differences in metabolic parameters when compared to metformin. The combination therapy with metformin plus the glucagon-like peptide-1 receptor agonist liraglutide was associated with significant improvements in basal and postload glucose levels compared with only liraglutide. Likewise, a combination therapy with the dipeptidyl peptidase-4 inhibitor saxagliptin and metformin demonstrated superiority versus metformin in fasting glucose and oral glucose tolerance test normalization. Myo-inositol supplementation was associated with lower insulin levels, glucose levels, and insulin resistance when compared with placebo, metformin, or estrogen treatments. The use of insulin-sensitizing agents, such as metformin and inositols, along with lifestyle interventions may improve the metabolic profile in PCOS women.


Decreased Peripheral BDNF Levels and Cognitive Impairment in Late-Life Schizophrenia.
Objectives: There are relatively few studies on mechanisms of cognitive deficits in late-life schizophrenia (LLS). Brain-derived neurotrophic factor (BDNF), as an important neuroplastic molecule, has been reported to be involved in neurocognitive impairment in schizophrenia. This study aimed to examine whether peripheral BDNF levels were associated with cognitive deficits in LLS, which has not been explored yet. Methods: Forty-eight LLS patients and 45 age-matched elderly controls were recruited. We measured all participants on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) for cognition and serum BDNF levels. Psychopathological symptoms in patients were assessed by the Positive and Negative Syndrome Scale (PANSS). Results: The levels of BDNF in LLS patients were significantly lower than those in healthy controls (8.80 ± 2.30 vs. 12.63 ± 5.08 ng/ml, p < 0.001). The cognitive performance of LLS patients was worse than that of the controls on RBANS total score and scores of immediate memory, attention, language, and delayed memory (all p ≤ 0.005). BDNF was positively associated with attention in LLS patients (r = 0.338, p = 0.019). Conclusion: Our findings suggest that older patients with schizophrenia exhibit lower BDNF levels and more cognitive deficits than older controls, supporting the accelerated aging hypothesis of schizophrenia. Moreover, decreased BDNF is related to attention deficits, indicating that BDNF might be a candidate biomarker of cognitive impairments in LLS patients.


SUPPRESSION OF SEX-RATIO MEIOTIC DRIVE AND THE MAINTENANCE OF Y-CHROMOSOME POLYMORPHISM IN DROSOPHILA.
Like several other species of Drosophila, D. quinaria is polymorphic for X-chromosome meiotic drive; matings involving males that carry a "sex-ratio" X chromosome (XSR ) result in the production of strongly female-biased offspring sex ratios (Jaenike 1996). A survey of isofemale lines of D. quinaria from several populations reveals that there is genetic variation for partial suppression of this meiotic drive. Crossing experiments show that there is Y-linked, and probably autosomal, variation for suppression of drive. Y-linked suppressors of X-chromosome drive have now been described in several species of Diptera. I develop a simple model for the maintenance of Y-chromosome polymorphism in species polymorphic for X-linked meiotic drive. One interesting feature of this model is that, if there is a stable Y-chromosome polymorphism, then the equilibrium frequency of the standard and sex-ratio X chromosomes is determined solely by Y-chromosome parameters, not by the fitness effects of the different X chromosomes on their carriers. This model suggests that Y-chromosome polymorphism may be easier to maintain than previously thought, and I hypothesize that karyotypic variation in Y chromosomes will be found to be associated with suppression of sex-ratio meiotic drive in other species of Drosophila.


Ten-year changes in breast cancer knowledge, attitudes, and practices in Native Hawaiian women.
Compared to women in other ethnic groups, Native Hawaiian women have the highest breast cancer mortality rates in the state of Hawai'i. Nationally, the five-year relative survival rate for Native Hawaiian women is 9% shorter than for Caucasians and all races. This poor outcome has been attributed, in part, to late-stage detection of cancer in Native Hawaiians, and data suggest that breast cancer screening rates for Native Hawaiian women are relatively low. This study examined breast cancer knowledge, attitudes, and practices (KAP) among Native Hawaiian women, reached through their friendship, community, and organizational networks. Response to an initial KAP survey in 1989-1990 was rewarded by a voucher for a free mammogram. Participation in both the survey (n = 903) and mammogram offer (n = 496) was high. The initial, Time 1 participants were resurveyed in 1999-2000, yielding a sample of 117 women who completed KAP surveys at both time points. After 10 years, changes in women's knowledge and attitudes were minimal. However, remarkable improvements in breast health practices were seen, with 62% of women reporting compliance with American Cancer Society guidelines for mammogram screening in 1999-2000, compared to only 14% in 1989-1990. Findings suggest that breast health practices can be improved through appropriate outreach; encouragement by health professionals; and policies and programs that increase access and affordability.


Is suicide preventable.
Among 500 cases of suicide analyzed in Stockholm, fewer than a third were associated with depression. Most forms of psychiatric disease were represented. Nevertheless, most persons give some warning before attempting suicide, and these warnings should be the signal for preventive action. Centers with trained personnel could prevent many suicides, if the potential victims were recognized and referred early enough. Laymen too should be educated to recognize potential suicide and help avert it.


Atypical Viral Infections in Gastroenterology.
Enteric viruses are commonly found obligate parasites in the gastrointestinal (GI) tract. These viruses usually follow a fecal-oral route of transmission and are characterized by their extraordinary stability as well as resistance in high-stress environments. Most of them cause similar symptoms including vomiting, diarrhea, and abdominal pain. In order to come in contract with mucosal surfaces, these viruses need to pass the three main lines of defense: mucus layer, innate immune defenses, and adaptive immune defenses. The following atypical gastrointestinal infections are discussed: SARS-CoV2, hantavirus, herpes simplex virus I, cytomegalovirus, and calicivirus. Dysbiosis represents any modification to the makeup of resident commensal communities from those found in healthy individuals and can cause a patient to become more susceptible to bacterial and viral infections. The interaction between bacteria, viruses, and host physiology is still not completely understood. However, with growing research on viral infections, dysbiosis, and new methods of detection, we are getting closer to understanding the nature of these viruses, their typical and atypical characteristics, long-term effects, and mechanisms of action in different organ systems.


Protective actions of Rubus coreanus ethanol extract on collagenous extracellular matrix in ultraviolet-B irradiation-induced human dermal fibroblasts.
Solar ultraviolet (UV) irradiation leads to distinct changes in the skin connective tissues by degradation of collagen, which is a major structural component in the extracellular matrix. UV irradiation induces the production of matrix metalloproteinases (MMP) capable of attacking native fibrillar collagen and responsible for inhibiting the construction of collagenous extracellular matrix. In this study, we attempted to investigate the protective actions of Rubus coreanus ethanol extract (RCE) on the MMP production and the consequent procollagen/collagen degradation in UV-B-irradiated human dermal fibroblasts. The analytical data showed that Rubus coreanus ethanol extract was mostly comprised of cyanidin 3-rutinoside. Pre-treatment of fibroblasts with this extract inhibited UV-B-induced production of MMP-1, MMP-8 and MMP-13 in dose-dependent manners. In addition, Western blot analysis and immunocytochemical staining assay revealed that RCE markedly augmented the cellular levels of procollagen/collagen declined in UV-B-exposed dermal fibroblasts. These results demonstrate that RCE blocks UV-B-induced increase of the collagen degradation by inhibiting MMP production. Thus, RCE may act as an agent inhibiting excessive dermal collagen degradation leading to the skin photoaging.


Lupus nephritis. Clinicopathological correlation.
To classify all renal biopsies of lupus nephritis patients presenting in the last 10 years, according to the modified World Health Organization (WHO) classification using the facilities of light, fluorescent, and electron microscopy. To assess the activity and chronicity indices of renal biopsies according to the National Institute of Health protocol, and to correlate the histological findings with the clinical features of the patients presented up to the time of biopsy. Seventy-eight patients with lupus nephritis, biopsied over 10 years between January 1995 to December 2005 in King Abdul-Aziz University Hospital, Jeddah, Kingdom of Saudi Arabia were reviewed by 2 histopathologists with the assistance of a nephrologist. The predominant histological type was WHO class IV. Patients of this class were more commonly associated with microhematuria, elevated proteinuria, and renal insufficiency. Active and chronic lesions were more likely to occur in patients of class III/IV. These patients were also more likely to have evidence of clinical renal disease than patients in class II. There was a significant association between nephrotic syndrome and class V lupus nephritis. Although the clinical and pathological correlation demonstrated a significant relationship between underlying histopathology and the clinical course of the patient, however, the biopsy findings did not uniformly correlate with the clinical features. Moreover, the status prediction of lupus nephritis patients based on clinical information alone was significantly enhanced by information obtained from renal biopsy.


[Treatment of fulminant hepatitis with highly reliable artificial liver support and administration of interferon].
We treated 10 patients with viral fulminant hepatitis (FH) and subacute hepatitis (SH) by highly reliable artificial liver support (ALS), the combination of plasma exchange (PE) and hemodiafiltration (HDF) using polymethyl methacrylate (PMMA) membrane. All patients regained clear consciousness by the ALS. Even the patients with long term hepatic failure up to for 108 days were sustained in a favorable clinical condition. Five patients finally survived. Interferon was administered to one case with type B FH with positive HBeAg, four cases with NANB FH and SH who were assumed to have persistent viral replication. Two of them showed favorable clinical responses and definite liver regeneration was confirmed. The intensive liver support which can sustain patient with severe fulminant hepatic failure accompanied by the administration interferon is believed to be the most effective treatment for FH and SH especially caused by NANB virus in our country.


Impact of flavonoids on thyroid function.
Flavonoids are polyphenolic compounds of natural occurrence produced by plants that are largely consumed both for therapeutic purposes and as food. Experimental data have shown that many flavonoids could inhibit thyroperoxidase activity, decreasing thyroid hormones levels thus increasing TSH and causing goiter. In humans, infants fed with soy formula have been shown to develop goiter. However, in post-menopausal women soy intake did not affect thyroid function. In thyroid tumor cell line, flavonoids were shown to inhibit cell growth, but they can also decrease radioiodine uptake, that could reduce the efficacy of radioiodine therapy. Flavonoids could also affect the availability of thyroid hormones to target tissues, by inhibiting deiodinase activity or displacing T4 from transthyretin. Thus, flavonoids have been shown to interfere with many aspects of the thyroid hormones synthesis and availability in in vivo and in vitro models. In the present article, we review and synthesize the literature on the effects of flavonoids on thyroid and discuss the possible relevance of these effects for humans.


Inward rectifier K+ channel Kir2.3 is localized at the postsynaptic membrane of excitatory synapses.
Classical inwardly rectifying K+ channels (Kir2.0) are responsible for maintaining the resting membrane potential near the K+ equilibrium potential in various cells, including neurons. Although Kir2.3 is known to be expressed abundantly in the forebrain, its precise localization has not been identified. Using an antibody specific to Kir2.3, we examined the subcellular localization of Kir2.3 in mouse brain. Kir2.3 immunoreactivity was detected in a granular pattern in restricted areas of the brain, including the olfactory bulb (OB). Immunoelectron microscopy of the OB revealed that Kir2.3 immunoreactivity was specifically clustered on the postsynaptic membrane of asymmetric synapses between granule cells and mitral/tufted cells. The immunoprecipitants for Kir2.3 obtained from brain contained PSD-95 and chapsyn-110, PDZ domain-containing anchoring proteins. In vitro binding assay further revealed that the COOH-terminal end of Kir2.3 is responsible for the association with these anchoring proteins. Therefore, the Kir channel may be involved in formation of the resting membrane potential of the spines and, thus, would affect the response of N-methyl-D-aspartic acid receptor channels at the excitatory postsynaptic membrane.


Would male hormonal contraceptives affect cardiovascular risk?
The aim of hormonal male contraception is to prevent unintended pregnancies by suppressing spermatogenesis. Hormonal male contraception is based on the principle that exogenous administration of androgens and other hormones such as progestins suppress circulating gonadotropin concentrations, decreasing testicular Leydig cell and Sertoli cell activity and spermatogenesis. In order to achieve more complete suppression of circulating gonadotropins and spermatogenesis, a progestin has been added testosterone to the most recent efficacy trials of hormonal male contraceptives. This review focusses on the potential effects of male hormonal contraceptives on cardiovascular risk factors, lipids and body composition, mainly in the target group of younger to middle-aged men. Present data suggest that hormonal male contraception can be reasonably regarded as safe in terms of cardiovascular risk. However, as all trials have been relatively short (< 3 years), a final statement regarding the cardiovascular safety of hormonal male contraception, especially in long-term use, cannot be made. Older men with at high risk of cardiovascular event might not be good candidates for hormonal male contraception. The potential adverse effects of hormonal contraceptives on cardiovascular risk appear to depend greatly on the choice of the progestin in regimens for hormonal male contraceptives. In the development of prospective hormonal male contraception, data on longer-term cardiovascular safety will be essential.


New high-throughput screening protease assay based upon supramolecular self-assembly.
We previously demonstrated that the supramolecular self-assembly of cyanines could be useful for developing fluorescent enzymatic assays. We took that concept a step further by synthesizing a covalent adduct of the tetrapeptide Asp-Glu-Val-Asp (DEVD) and a cyanine (DEVD-cyanine). The DEVD-cyanine due to its canonical sequence was recognized and hydrolyzed by the proteases, Caspase-3 and -7 in 96- or 384-microwell plate reactions. The catalytically liberated cyanine self-assembled upon scaffolds of carboxymethylamylose (CMA), carboxymethylcellulose (CMC), or a mixture of CMA and CMC resulting in a J aggregate exhibiting bright fluorescence at a 470 nm emission wavelength (optimum signal/background using excitation wavelengths of 415-440 nm). The fluorescence intensity increased with enzyme and substrate concentrations or reaction time and exhibited classical saturation profiles of a rectangular hyperbola. Saturation of the reaction was at 30 U/mL (1 microg/mL) Caspase-3 and 250 microM DEVD-cyanine. The reaction kinetics was linear between 1 and 20 min and saturated at 60 min. The affinity constant (Km) for DEVD-cyanine was approximately 23 microM, similar to those of previously reported values for other DEVD substrates of Caspase-3. Maximal fluorescence emission was observed by using a mixture of CMA and CMC scaffolds at 65 and 35 microM, respectively. The reaction kinetics of Caspase-7 executed in a 384-well plate was similar to the reaction kinetics of Caspase-3 conducted in a 96-well plate. We believe that this is the first demonstration of a cyanine liberated from a covalent adduct due to protease action, leading to supramolecular self-assembly and the detection of protease activity.


HIV-1 Vif protein binds the editing enzyme APOBEC3G and induces its degradation.
The viral infectivity factor (Vif) encoded by HIV-1 neutralizes a potent antiviral pathway that occurs in human T lymphocytes and several leukemic T-cell lines termed nonpermissive, but not in other cells termed permissive. In the absence of Vif, this antiviral pathway efficiently inactivates HIV-1. It was recently reported that APOBEC3G (also known as CEM-15), a cytidine deaminase nucleic acid-editing enzyme, confers this antiviral phenotype on permissive cells. Here we describe evidence that Vif binds APOBEC3G and induces its rapid degradation, thus eliminating it from cells and preventing its incorporation into HIV-1 virions. Studies of Vif mutants imply that it contains two domains, one that binds APOBEC3G and another with a conserved SLQ(Y/F)LA motif that mediates APOBEC3G degradation by a proteasome-dependent pathway. These results provide promising approaches for drug discovery.


Performances on the NBME I, II, and III by medical students in the problem-based learning and conventional tracks at the University of New Mexico.
Problem-based learning curricula are growing in popularity, and questions have been raised about the appropriateness of standardized examinations, such as the National Board of Medical Examiners (NBME) Parts I, II, and III examinations, for assessing students in these new curricula. Data on students' performances on the NBME I were analyzed for 508 graduates of the conventional track and 167 graduates of the problem-based Primary Care Curriculum (PCC) track at the University of New Mexico School of Medicine from the classes of 1983-1992; on NBME II, for 447 and 144 graduates, respectively (classes of 1983-1991); and on NBME III, for 313 and 100 graduates, respectively (classes of 1983-1989). The analyses also included data on the students' total Medical College Admission Test (MCAT) scores, undergraduate science grade-point averages (SGPAs), and admission subgroups within tracks. The statistical methods included analysis of covariance, Student's t-test, and the Fisher exact test. The students who had requested the PCC track but had been randomized into the conventional track had the highest mean scores on all the study variables (for 34 students, 521 on the NBME I, and for 19 students, 551 on the NMBE III). The high-risk students who had requested but had not been accepted into the PCC track seemed to benefit from the highly structured conventional track with regard to their NMBE I performances (467 for 18 students). The PCC students--both those who had been randomized into the PCC and those who had been selected into the PCC--had significantly lower mean scores on the NBME I (455 for 85 students and 463 for 82 students compared with 505 for the 439 students who chose the conventional track), but significantly higher mean scores on the NBME III (521 for 38 students and 522 for 62 students compared with 483 for the seven high-risk students and 487 for the 276 students who chose the conventional track). For both tracks, strong relationships were found among the scores on the three NBME examinations. For the PCC students, significantly weaker relationships were found between mean SGPAs and mean scores on the NBME I, II, and III. For both tracks, MCAT scores, especially in the lowest and highest ranges, were most predictive of performances on the NBME I and II. In the short run, the more teacher-centered and structured conventional curriculum better prepared the students for the NBME I, while in the long run, the more student-centered problem-based curriculum better prepared the students for the NBME III:


MPP+ induced apoptotic cell death in SH-SY5Y neuroblastoma cells: an electron microscope study.
PD is a common, late-onset neurodegenerative disorder that results in part from the gradual loss of dopaminergic neurons in the substantia nigra pars compacta. The neurotoxin MPTP can induce PD-like clinical symptomatology and neuropathological destruction and, thus, has been used as a PD model. The human neuroblastoma cell line SH-SY5Y possesses many of the qualities of human neurons and, as such, has served as a model for them. Apoptosis is the mode of cell death induced in SH-SY5Y cells by MPTP, and this was confirmed with nick end labeling and bisbenzimide staining. Transmission electron microscopic analysis of the ultrastructural changes occurring in neurotoxin exposed SH-SY5Ys revealed many morphological characteristics consistent with apoptosis. These changes included plasmalemmal blebbing, altered cytosolic density, nuclear condensation and fragmentation, pronounced vacuole formation, ribosomal dispersion, and the disappearance of the golgi complex, microtubules, and smooth endoplasmic reticulum. Limited amounts of rough endoplasmic reticulum and mitochondria exhibited normal morphology throughout the apoptotic changes but then were disrupted during secondary necrotic changes. The in vitro induction of apoptosis by a parkinsonism neurotoxin might be reflective of the mechanisms of in vivo nigral degeneration occurring during PD.


Generation of Fragment Angular Momentum in Fission.
A recent analysis of experimental data [J. Wilson et al., Nature (London) 590, 566 (2021)NATUAS0028-083610.1038/s41586-021-03304-w] found that the angular momenta of nuclear fission fragments are uncorrelated. Based on this finding, the authors concluded that the spins are therefore determined only after scission has occurred. We show here that the nucleon-exchange mechanism, as implemented in the well-established event-by-event fission model freya, while agitating collective rotational modes in which the two spins are highly correlated, nevertheless leads to fragment spins that are largely uncorrelated. This counterexample invalidates the conclusion in [J. Wilson et al.] that uncorrelated spins must necessarily have been generated after scission (a potentious conclusion that would rule out all models that generate the fragment spins prior to scission). Furthermore, it was reported [J. Wilson et al.] that the mass dependence of the average fragment spin has a sawtooth structure. We demonstrate that such a behavior naturally emerges when shell and deformation effects are included in the moments of inertia of the fragments at scission.


A difficult laparoscopic cholecystectomy that requires conversion to open procedure can be predicted by preoperative ultrasonography.
A prospective study was conducted from March 1999 to April 2000 that included 73 patients who underwent elective laparoscopic cholecystectomy for uncomplicated gallstone disease. The study was conducted at one surgical unit in the Department of Surgery and Department of Radio-diagnosis and one surgical unit in the Department of Surgery, Maulana Azad Medical College and the associated Lok Nayak Hospital, which is the largest referral hospital in northern India and is located in the capital of India. A preoperative ultrasound was performed just prior to surgery, and 4 ultrasonographic parameters were analyzed. namely gallbladder wall thickness, contracted gallbladder, impaction of gallstones at the neck of the gallbladder, and common bile duct stones. The surgical findings were objectively graded as difficult or easy laparoscopic cholecystectomy according to 5 operative parameters, namely total time taken for the surgery, time taken to dissect gallbladder bed, spillage of stones, tear of gallbladder during dissection, and conversion to the open procedure. Of the 73 cases, 17 (23.3%) were conversions to the open procedure. Of the 21 (28.76%) cases predicted to be difficult, 17 (23.3%) were technically difficult, of which 13 (17.8%) were converted to the open procedure. Of the 52 (71.23%) cases predicted to be easy on ultrasonography, only 7 (9.38%) were found to be difficult on surgery, of which only 4 (5.48%) had to be converted to the open procedure. Based on our results, we conclude that preoperative ultrasonography is of great value in selecting patients preoperatively for laparoscopic cholecystectomy and minimizing complications and conversion to the open procedure.


[National recommendations on pediatric donation].
Despite being an international reference in donation and transplantation, Spain needs to improve pediatric donation, including donation after the circulatory determination of death. The present article, a summary of the consensus report prepared by the Organización Nacional de Trasplantes and the Spanish Pediatrics Association, intends the facilitation of donation procedures in newborns and children and the analysis of associated ethical dilemma. The ethical basis for donation in children, the principles of clinical assessment of possible donors, the criteria for the determination of death in children, intensive care management of donors, basic concepts of donation after the circulatory determination of death and the procedures for donation in newborns with severe nervous system's malformation incompatible with life, as well as in children receiving palliative care are commented. Systematically considering the donation of organs and tissues when a child dies in conditions consistent with donation is an ethical imperative and must become an ethical standard, not only because of the need of organs for transplantation, but also to ensure family centered care.


Effect of naloxone on feedback regulation of small bowel transit by fat.
Studies were carried out in 7 healthy male volunteers to investigate whether the delay in small bowel transit time, induced by the infusion of fat emulsions into the human ileum, was mediated by endogenous opioids. The effect of ileal infusion of intralipid on small bowel transit time of a 100-ml solution containing 13.3 g of lactulose was studied during intravenous infusion of either saline or naloxone (20 micrograms/kg X h) in saline. During intravenous infusion of saline, ileal infusion of fat significantly delayed small bowel transit time of the head of the lactulose infusion (ileal intralipid vs. saline; 249 +/- 46 vs. 44 +/- 8 min; mean +/- SEM; p less than 0.01). Intravenous infusion of naloxone, however, abolished the delay in small bowel transit time induced by ileal infusion of intralipid in 5 of 7 subjects (intravenous naloxone; ileal intralipid vs. saline; 89 +/- 26 vs. 46 +/- 8 min; p greater than 0.2). Intravenous naloxone had no effect on small bowel transit time when saline was infused into the ileum. This result suggests that endogenous opioids may be involved in the feedback regulation of small bowel transit by ileal intralipid.


A study of Two Clinical Performance Scores: Assessing the Psychometric Characteristics of a Combined Score Derived from Clinical Evaluation Forms and OSCEs.
Background/Purpose - It is important to improve the quality of clinical skill assessments. In addition to using the OSCE, the clinical skills of medical students are assessed with clinical evaluation forms (CEFs). The purpose of this study is to examine the psychometric characteristics of an OSCE/CEF composite score. Methods - This study included 2 medical student classes from a large medical school. Students completed approximately 12 OSCEs and were rated over 33 times on a CEF. The reliability of the CEF and OSCE were estimated. A correlation between the mean OSCE score and the mean CEF was calculated and corrected for attenuation. Classical methods were used to examine composite score reliability. Results - For both classes there was a statistically significant correlation between the CEF and OSCE (r = .27 & .42, p = .003 & .0001). The disattenuated correlations were .44 and .68. Weighting the OSCE in the composite score as high as .4 was associated with only a small decrease in composite reliability. Conclusion - These results demonstrate that assessment information based on simulated and actual patient encounters can be combined into a composite. Since a composite score may provide a more valid measure of clinical performance, this study supports using a combined CEF and OSCE measure.


Effects of nutritionally induced metabolic acidosis with or without glutamine infusion on acid-base balance, plasma amino acids, and plasma nonesterified fatty acids in sheep.
This study characterized the effects of nutritionally induced metabolic acidosis with or without Gln infusion on acid-base balance, plasma AA, and plasma NEFA in sheep. In a randomized complete block design with a 2 x 2 factorial arrangement of treatments, 24 fully fleeced sheep (Rideau-Arcott, 63.6 +/- 5.9 kg of BW) were fed a control supplement (CS; 300 g/d of canola meal) or an acidosis supplement (AS; 300 g/d of NutriChlor; HCl-treated canola meal), offered twice daily at 0700 and 1100 h. Sheep were infused at 1400 h daily with 0.3 g of L-glutamine per kg of BW or saline via jugular vein catheters for 7 d. The sheep were individually housed and limit-fed a basal diet of dehydrated alfalfa pellets (1.75 kg/d; 90% DM, 22% CP, and 1.2 Mcal of NE(g)/kg on a DM basis) offered twice daily at 1000 and 1300 h. Blood and urine was sampled daily between 1100 and 1130 h, and blood samples were analyzed for hematocrit, plasma pH, gases, strong ions, AA, and NEFA, whereas urine was analyzed for pH. The AS reduced (P < 0.01) DMI, urine and plasma pH, blood urea, partial pressure of CO(2), strong ion difference, and plasma HCO(3)(-), and increased (P < 0.01) plasma K(+), Ca(2+), and Cl(-). The AS with saline infusion increased (P <or= 0.03) partial pressure of O(2) and plasma glucose, whereas AS with Gln infusion reduced (P < 0.01) partial pressure of O(2) and plasma glucose. The AS increased (P < 0.01) plasma lysine and reduced (P < 0.01) plasma taurine. Glutamine infusion increased (P = 0.04) plasma leucine with the CS treatment but had no effect (P = 0.89) with the AS treatment. Plasma 16:0, 18:2n-6, 18:3n-3, 20:4n-6, and total NEFA were increased and 18:0 was decreased (P < 0.001) in AS sheep compared with CS sheep. Infusion of Gln decreased (P < 0.05) 16:0, 18:2n-6, 18:3n-3, 20:4n-6, and total NEFA compared with saline infusion. Plasma cis-9, trans-11 CLA was elevated (P = 0.001) in AS sheep, whereas plasma cis-9, trans-11 CLA, regardless of the diets, was decreased (P < 0.02) with Gln infusion. These results show that despite some improvement in overall mobilization of NEFA, Gln infusion did not ameliorate the negative responses associated with metabolic acidosis.


Enhancement of epithelial sodium channel expression in renal cortical collecting ducts cells by advanced glycation end products.
The epithelial sodium channel (ENaC) is a complex, and the alphaENaC subunit has a crucial role in sodium uptake induced by aldosterone in the distal nephron. Although experimental animal models of diabetes have demonstrated up-regulation of alphaENaC expression in renal cortical collecting duct (CCD) cells, the molecular mechanism remains unclear. Advanced glycation end products (AGEs) are by-products of long-term hyperglycaemia and comprise a significant pathogenic factor in diabetic nephropathy. We hypothesize that AGEs play a role in regulating alphaENaC gene expression. Mouse CCD cells (mpkCCDcl(4)) were cultured with AGE to determine the effects of AGE on alphaENaC expression and sodium uptake. Gene expressions of ENaC were measured by real-time PCR and sodium uptake was measured with fluorescent dye as a sodium indicator (SBFI-AM). This study analysed mitogen-activated protein kinases signalling pathways by western blotting. Cells co-transfected with plasmids of the alphaENaC promoter carrying a luciferase reporter and plasmids expressing wild-type or mutant serum- and glucocorticoid-induced kinase 1 (Sgk1) mRNA were stimulated with AGE to identify the signalling pathway. The AGEs, stimulated in a time- and dose-dependent manner, enhanced alphaENaC mRNA expression and sodium uptake in mpkCCDcl(4) cells. The AGEs also significantly stimulated Sgk1 mRNA and Sgk1 activity in a time- and dose-dependent manner. Co-transfected with plasmid expressing mutant Sgk1 significantly limited stimulated alphaENaC promoter-driven luciferase activity by AGEs in mpkCCDcl(4) cells. Experimental results indicate that AGEs induced alphaENaC expression and increased sodium uptake in renal CCD cells. The mechanism through which AGEs activate alphaENaC expression may be via activation of Sgk1 in mpkCCDcl(4) cells.


In Vitro Static and Fatigue Behavior of Ceramic Occlusal Veneers Using CAD/CAM.
To evaluate fracture resistance of occlusal veneers made of glass-ceramic and zirconia with and without fatigue. Occlusal overlays (N=80; n=10 per group) were milled out of CAD/CAM materials, namely: a)LD:Lithium disilicate glass ceramic, b)LDS:Lithium-disilicate- strengthened aluminosilicate glass ceramic, c)ZLT:Zirconium dioxide ceramic and d)ZMT:Zirconium dioxide ceramic. The overlays were cemented on polymeric duplicates, randomly distributed to aging or non-aging conditions and loaded until fracture. Ultimate catastrophic failure strength(Fmax) and Initial crack formation load(Finitial) values were analysed using two-way ANOVA. For Finitial, material type and aging and their interaction resulted in significant values (p =⟨0.001). Finitial mean±SD values ranged from ZMTa (593 N ±205 N) to LDSb (118 N ±42 N). As for Fmax, the material type significantly affected the outcome (p⟨0.001), while aging type did not show an influence (p=0.795). The non-aged Fmax specimens values presented were: LDSa (877 N ±253 N)⟨LDa (2029 N ±412 N)⟨ZLTa (2049 N ±379 N)⟨ZMTa (2144 N ±333 N), LDSa being significantly lower (p⟨0.001). The aged Fmax values were: LDSb (1313 N ±599 N)⟨ ZLTb (1715 N ±453 N)⟨ZMTb (2018 N ±300 N)⟨LDb (2134 N ±289 N). LDS yielded significantly lower Fmax values without and non-significant less favourable results with aging. The mechanical properties following aging and lack of additional firing makes LDS an interesting restorative material for clinical application.


Modulation of growth-stimulating and antitumor activity of macrophages by BCG and cyclophosphamide.
Recently it has been shown that some tumours require macrophage-derived growth factors for in vitro and in vivo proliferation, as well as tumour growth stimulation by macrophages. Furthermore, it has been reported that several biological response modifiers (BRM) stimulated some growth factor production in macrophages. In the present study we tried to define whether some BRM can modulate production of macrophage-derived growth factors for stimulating tumour cells. Results obtained indicate that: 1) growth stimulating activity of macrophages may be co-expressed with antitumor activity; 2) growth stimulating activity could prevail over antitumor effects in the outcome of tumour cell/macrophage interaction in vitro; 3) Some BRM and antitumor drugs can modulate the balance between antitumor and growth stimulating activity of macrophages. It is therefore proposed that growth factors modulation assessment is necessary for new BRM characterization.


Supportive care for patients with gastrointestinal cancer.
Supportive care has traditionally been given to optimise the comfort of patients and their ability to function, as well as to minimise the side-effects of anti-cancer treatments. The scope of modern comprehensive supportive care however is broadening and covers not only specific palliative treatment but non-tumour specific treatment such as social, psychological and spiritual support. In oncology, best supportive care (BSC) has been used as a comparator arm of randomised controlled trials in chemotherapy. However the BSC arm is usually not well defined and its evaluation is therefore difficult because of the heterogeneity of the definitions. A systematic review was undertaken of the evidence from all RCTs of gastrointestinal cancers (includes gastrointestinal/gastric, colorectal/colon cancer but excludes pancreatic cancer trials) which include a BSC/SC arm. 1. To examine the effectiveness/outcomes of best supportive care interventions versus cancer therapies for gastrointestinal cancer trials;2. To determine whether trials containing best supportive care include a definition of this. Electronic databases, grey literature sources, citation searching and reference checking, handsearches of journals and discussion with experts were used to identify potentially eligible trials from both published and unpublished sources. RCTs comparing BSC/SC versus anticancer therapies in patients with gastrointestinal cancers. Four RCTs were found and reviewed. Because of the heterogeneity of studies, a meta-analysis was not attempted. Data was extracted from the included papers and the quality of each included study was assessed using the Jadad 1996 and Rinck 1997 methods of assessing the quality of RCTs. Data from four trials (483 patients) were included. Due to the heterogeneity of studies (in terms of populations studied, the interventions used, the variety of outcomes and assessments used) it was not possible to make direct comparisons between the studies. The primary outcome in all four trials was survival, in spite of patients with advanced/metastatic gastrointestinal cancer having a poor prognosis, and the interventions being primarily palliative. Overall the results show that for most of the trials included in this review, certain forms of chemotherapy plus supportive care improve both survival and quality of life in patients with gastrointestinal cancer (gastric and colorectal cancers) compared to receiving supportive care alone. Trials involving BSC/SC in patients with advanced gastrointestinal cancer require careful evaluation. Oncologists and researchers alike should strive for improvements in trial design and reporting. Future trials should focus on clearer definitions of supportive care. The EORTC definition of supportive care can be used as a guide. BSC/SC trials should use standardised validated outcome measures for symptom control, quality of life, toxicity and other useful palliative measures.


Trends of the Global, Regional, and National Incidence of Measles, Vaccine Coverage, and Risk Factors in 204 Countries From 1990 to 2019.
Measles is a highly contagious disease that has caused global morbidity and mortality. Though great progress has been made in measles elimination, the resurgence of measles has been observed in recent years. As extant literature were mainly confined to data of local area, we conducted a systematic analysis to explore the trends of the incidence of measles, coverage rate, and the risk factors from 1990 to 2019 on global, regional, and national levels. Data on cases of incidence, age standardized rate (ASR), vaccine coverage, and risk factors of measles were retrieved from the Global Burden of Disease (GBD) Study 2019 database. Estimated averaged percentage change (EAPC) of ASR was calculated to quantify the trends of measles incidence. Pearson correlation was applied to assess the association of EAPC and measles-containing vaccine coverage rate with socio-demographic index (SDI) in 2019, and the correlation between ASR and measles-containing vaccine coverage rate. Globally, there was a significant decrease in the number (84.18%) and ASR (6.13%, 95% CI: 5.41-6.84%) of measles incidence from 1990 to 2019. More than 80% of incidence cases were attributed to children under 5 and the proportion was highest in low SDI region. Countries and territories with low ASRs are mostly clustered in North America, Southern Latin America, and Western Europe, whereas those with high ASRs are mainly clustered in Africa, East Asia, and South Asia. Lower SDI was associated with higher ASR and lower vaccine coverage rate. The more the SDI value was further away from 0.6, the smaller the absolute value did EAPC have. Child wasting accounted for the most measles-related death cases, followed by child underweight, child stunting, and vitamin A deficiency. Measles eradication is feasible, but urgently demands political commitment, financial support, and public engagement. In the context of COVID-19 pandemic and the global resurgence of measles, surveillance systems and routine immunization programs should be improved, while vaccine hesitancy needs to be addressed.


Concurrent intramedullary spinal cord and intracranial tuberculomas.
Tubeculosis commonly involves the nervous system, but involvement of spinal cord in the form of intramedullary tuberculoma is rare and concurrent occurrence of cranial and intramedullary tuberculomas is extremely rare. We report a case of concurrent occurrence of intramedullary tuberculoma with multiple intracranial tuberculomas in a young girl from Islamabad, who presented with one month history of paraplegia and with a sensory level at T6. MRI spine showed a well circumscribed lesion opposite T6, which was diagnosed as intramedullary tuberculoma. On cranial imaging, she was found to have multiple round contrast enhancing lesions which were diagnosed as intracranial tuberculomas based on their typical MRI findings. She had complete recovery with conventional treatment of ATT and steroids, without any surgical intervention. The follow-up MRI of patient showed disappearance and complete resolution of most of the lesions.


Global Health Security Agenda Implementation: A Case for Community Engagement.
In today's interconnected world, infectious diseases can spread rapidly within and between countries. The 2014-2016 Ebola epidemic in Guinea, Liberia, and Sierra Leone underscored the inability of countries with limited capacities and weak public health systems to respond effectively to outbreaks. To mitigate future health threats, nations and international organizations launched the Global Health Security Agenda (GHSA) to accelerate compliance with the WHO's International Health Regulations, so as to enhance global protection from infectious disease threats. To advance GHSA's mandate to build capacity to prevent, detect, and respond to infectious diseases, and thereby contain threats at their source, community engagement is needed. This article advocates for community engagement in GHSA implementation, using examples from 3 GHSA action packages. A country's ability to prevent a local disease outbreak from becoming an epidemic often rests with the level of knowledge about the situation and the actions taken at the community level.


Non-covalent polyvalent ligands by self-assembly of small glycodendrimers: a novel concept for the inhibition of polyvalent carbohydrate-protein interactions in vitro and in vivo.
Polyvalent carbohydrate-protein interactions occur frequently in biology, particularly in recognition events on cellular membranes. Collectively, they can be much stronger than corresponding monovalent interactions, rendering it difficult to control them with individual small molecules. Artificial macromolecules have been used as polyvalent ligands to inhibit polyvalent processes; however, both reproducible synthesis and appropriate characterization of such complex entities is demanding. Herein, we present an alternative concept avoiding conventional macromolecules. Small glycodendrimers which fulfill single molecule entity criteria self-assemble to form non-covalent nanoparticles. These particles-not the individual molecules-function as polyvalent ligands, efficiently inhibiting polyvalent processes both in vitro and in vivo. The synthesis and characterization of these glycodendrimers is described in detail. Furthermore, we report on the characterization of the non-covalent nanoparticles formed and on their biological evaluation.


DEPRESSIVE EPISODE INCIDENCE IN PATIENTS WITH CHRONIC HEPATITIS C TREATED WITH PEGYLATED INTERFERON AND RIBAVIRIN.
The effectiveness of antiviral therapy with pegylated interferon and ribavirin for chronic hepatitis C is far from ideal and presents several adverse events. Among such events, there is the depressive episode that can even lead to treatment discontinuity. Analyze the incidence of depressive episodes in patients with chronic hepatitis C treated with pegylated interferon (IFN-PEG) and ribavirin, as well as the possible factors associated with its occurrence and its impact on patients' sustained virological response. People with chronic hepatitis C undergoing antiviral therapy were interviewed at the baseline, at the 4th, 12th, 24th and 48th treatment weeks and 4 weeks after the end of it, using the HADS scale for tracking the depressive episode. Patients with HADS ≥9 were subjected to Beck Depression Inventory (BDI-II) to grade the episode. Clinical, sociodemographic, laboratorial and histological variables were obtained to identify factors related to the onset of depression. The sustained virological response rate (negative HCV-RNA 6 months after end of therapy) was compared among patients with and without depressive symptoms. The study comprised 32 patients, most men (59%) with mean age of 54±11.13 years old. Genotype non-1 was prevalent (56%) and 81% of the patients were non-cirrhotic. The depressive episode was diagnosed in 25% of the patients and the peak incidence was found in the 12th treatment week. The depressive episode was moderate in 87% of the patients and only one patient abandoned the treatment. None of the analyzed factors was associated with depressive episode onset. A trend was observed in female patients ( P =0.08). The sustained virological response rate was of 75% and 67% in patients with and without depressive episode, respectively ( P =0.66). The incidence of depressive episodes in patients with chronic hepatitis C undergoing antiviral therapy was of 25% and the 12th treatment week was the most critical one. The presence of depressive episode did not affect the sustained virological response rate.


The haematic thiamine level in the course of alcoholic neuropathy.
The specific roles of ethanol and malnutrition in the pathogenesis of neurological disorders of chronic alcoholism remain unclear. We measured plasmatic thiamine levels and erythrocyte transketolase activity in 30 alcoholics with peripheral neuropathy and in 4 with a Wernicke-Korsakoff (W-K) syndrome. Thiamine levels in the first group were comparable to those of normal subjects while a significantly lower concentration was found in W-K syndrome. Transketolase activity was lower for both groups in comparison with normal subjects. We suggest that a defect in thiamine utilization is involved in peripheral neuropathy of alcoholics, rather than a lack of thiamine itself.


Purification and characterization of Desulfovibrio vulgaris (Hildenborough) hydrogenase expressed in Escherichia coli.
Hydrogenase from Desulfovibrio vulgaris (Hildenborough) is a heterologous dimer of molecular mass 46 + 13.5 kDa. Its two structural genes have been cloned on a 4664-base-pair fragment of known sequence in the vector pUC9. Expression of hydrogenase polypeptides in Escherichia coli transformed with this plasmid is poor (approximately 0.1% w/w of total protein). Deletion of up to 1.9 kb of insert DNA brings the gene encoding for the large subunit in close proximity to the lac promotor of pUC9 and results in a 50-fold increased expression of hydrogenase polypeptides in E. coli. The protein formed is inactive and was purified in order to delineate its defect. Complete purification was achieved with a procedure similar to that used for the isolation of active hydrogenase from D. vulgaris H. The derived protein is also an alpha beta dimer and electron-paramagnetic resonance studies indicate the presence of the electron-transferring ferredoxin-type iron-sulfur clusters. In contrast to the native protein from D. vulgaris H, these can only be reduced with dithionite, not with hydrogen, indicating that the hydrogen-binding active centre which also contains an iron-sulfur cluster is missing.


Apex predator and the cyclic competition in a rock-paper-scissors game of three species.
This work deals with the effects of an apex predator on the cyclic competition among three distinct species that follow the rules of the rock-paper-scissors game. The investigation develops standard stochastic simulations but is motivated by a procedure which is explained in the work. We add the apex predator as the fourth species in a system that contains three species that evolve following the standard rules of migration, reproduction, and predation, and study how the system evolves in this new environment, in comparison with the case in the absence of the apex predator. The results show that the apex predator engenders the tendency to spread uniformly in the lattice, contributing to destroy the spiral patterns, keeping biodiversity but diminishing the average size of the clusters of the species that compete cyclically.


[Mechanism of thymosin beta 10 inhibiting the apoptosis and prompting proliferation in A549 cells].
Thymosin beta 10 (Tβ10) is one of β-thymosin family members, has a highly conserved polar 5 kDa peptides. This peptide is now regarded to be a small actin-binding protein and thereby induce depolymerization of the intracellular F-actin networks. Alteration of Tβ10 expression may alter the balance of cell growth, cell death, cell attachment and cell migration. Tβ10 also affects cell metastasis as well as proliferation, apoptosis and vascularization of cancer cells. But function of Tβ10 appear to be rather different between cancer cells, and the molecular mechanisms of β-thymosins to regulate cell apoptosis and proliferation in NSCLC (non-small cell lung cancer) cell lines are unclear. In this study, we used lung adenocarcinoma cell line A549, added Tβ10 or down-regulated the expression of Tβ10. We observed the change of apoptosis, proliferation and cell cyclin ability in A549 and the mechanisms underline them were also identified. After A549 was treated with 100 ng/mL recombinant human Tβ10 or siTβ10, apoptosis rate of A549 and cell cycle distribution were detected by flow cytometry (FCM). CCK-8 assay was employed to determine the proliferation of A549. The mRNA level of P53, Caspase-3, Cyclin A and Cyclin E were determined by real-time PCR. The protein level of P53, Caspase-3, Cyclin A and Cyclin E were detected by Western blot. Add Tβ10 can inhibit the apoptosis and prompt the proliferation of A549. It can also increase the cell rates of S-phrase and G2/M-phrase, decrease the expression of P53 and Caspase-3, but increase the expression of Cyclin A and Cyclin E. Interferance of Tβ10 can prompt the apoptosis and inhibit the proliferation of A549. It can also increase the cell rates of G0/G1-phrase, increase the expression of P53 and Caspase-3, but decrease the expression of Cyclin A and Cyclin E. In lung cancer cell line, Tβ10 can inhibit the apoptosis by increase P53, drive cells into the S and G2/M-phase, prompt cell proliferation by increase the expression of Cyclin A and Cyclin E. Tβ10 may become a potential biomarker and therapy target for non-small cell lung cancer.


[The multiple organ failure syndrome (MOFS) and septic states].
The multiple organic failure syndrome (MOFS or MOF) is the result of a hyperergic and chaotic activation of the unspecific immune (inflammatory) system. It may be elicited, either as a consequence of hypodynamic shock phenomena with initial tissular lesions caused by a diseased peripheral vascular bed, characteristic of states of shock, or as the result of an inflammatory aseptic or septic focus occurring in the process of transformation of tissular territories diseased under the action of various factors (traumatic, thermic, immune etc.). The local inflammatory process sets in motion a series of elements of the immune apparatus, such as: polynuclear neutrophilic leucocytes, macrophages, complement, which lead, when they begin to exert an hyperergic action, to the cascade activation of these elements also outside the focus of lesion, generating disseminated lesions at the level of organs and systems of organs. The lesions have an aleatory character and affect variously organs and territories, leading finally to insufficiency phenomena with clinical expression: renal failure, pulmonary failure, encephalopathy, shock digestive tract, intravascular disseminated coagulation, state of shock initially hyperdynamic and afterwards hypodynamic, metabolic disturbances etc. The specific manifestations, the symptomatology, the therapy and the prognosis of the syndrome are described.


Tricuspid Valve Repair for Infective Endocarditis with Periannular Involvement: Complete Valve Reconstruction.
Background and aim of the study: Tricuspid valve (TV) infective endocarditis (TVIE) is uncommon and is mainly cured with medical treatment. When surgery is indicated, the appropriate surgical option remains to be determined. The study aim was to determine whether valve reconstruction using autologous pericardium is a safe and efficacious procedure to treat TVIE. Methods: A retrospective review was conducted of patients who underwent surgery for acute isolated TVIE with periannular involvement. Radical debridement was performed to provide a safe ground for pericardium implantation. Untreated pericardial patches were prepared and sutured to the remaining part of the debrided annulus. Neochordae were fashioned with polytetrafluoroethylene sutures attached to the free edge of the pericardial neoleaflet. Results: A total of 448 patients underwent TV surgery between September 2007 and May 2013 at the authors' center. Nine patients (six males, three females; mean age 28 ± 4.9 years) underwent TV repair with pericardium for isolated TVIE. All male patients were intravenous drug users, and the three female patients had infected central venous catheters. Microbiology confirmed growth of Staphylococcus aureus alone in three cases, S. aureus and Candida sp. in two cases, methicillin-resistant S. aureus in one case, and Pseudomonas aeruginosa in one case. The culture was negative in two cases. There was no inhospital mortality, and the mean follow up was 16.4 ± 14.1 months. The latest follow up echocardiography revealed moderate tricuspid regurgitation in nine patients. Two non-cardiac-related deaths occurred, but there were no cases of recurrent endocarditis or reoperation. Conclusion: Valve reconstruction utilizing autologous pericardium and neochordae could be used with acceptable results in isolated TVIE cases with periannular involvement.


Hereditary and environmental determinants of growth in height in a longitudinal sample of children and youth of Guatemalan and European ancestry.
The effects of hereditary and environmental factors upon the growth in stature of children living in Guatemala City has been studied. Heights at yearly examinations were fitted, by individual, to a double logistic curve in samples of Guatemalan and European children attending a private school in Guatemala City. These two samples differed genetically yet shared the same environment. Their growth was compared, by a multivariate analysis of the parameterized curves, to that of children from the Berkeley Growth Study, genetically similar to the European sample, yet living in different environments. The European children in Guatemala grew, before adolescence, more similar to Guatemalan and differed significantly from the Berkeley sample children. However, the amount of growth during the adolescent years experienced by the European children was similar to that of the Berkeley sample and differed from their Guatemalan counterparts.


Trimethoprim-sulphamethoxazole does not affect the pharmacokinetics of sirolimus in renal transplant recipients.
The influence of the trimethoprim-sulphamethoxazole combination on the steady-state pharmacokinetics of sirolimus, a potent macrocyclic immunosuppressant, was studied in renal transplant recipients. Fifteen kidney transplant recipients were treated with sirolimus 8-23 mg m(-2) in combination with azathioprine and prednisolone from the day of transplantation. Whole blood sirolimus AUC and C(max) were determined on days 6 and 7 after transplantation. On day 7, sirolimus was coadministered with the first dose of trimethoprim (80 mg) and sulphamethoxazole (400 mg). On day 6, the mean (95% confidence interval) whole blood sirolimus AUC((0-24 h)) was 1040 (846, 1234) ng ml(-1) and mean C(max) was 109 (88, 129) ng ml(-1). Corresponding values on day 7 were AUC((0-24 h)) 1060 (826, 1293) ng ml(-1) and C(max) mean 107 (87, 127) ng ml(-1). The mean difference in the dose-corrected AUC((0-24 h)) was 0.40% (-9.4, +10). A single dose of trimethoprim-sulphamethoxazole does not affect the pharmacokinetics of sirolimus in renal transplant patients.


What's the risk? Identifying potential human pathogens within grey-headed flying foxes faeces.
Pteropus poliocephalus (grey-headed flying foxes) are recognised vectors for a range of potentially fatal human pathogens. However, to date research has primarily focused on viral disease carriage, overlooking bacterial pathogens, which also represent a significant human disease risk. The current study applied 16S rRNA amplicon sequencing, community analysis and a multi-tiered database OTU picking approach to identify faecal-derived zoonotic bacteria within two colonies of P. poliocephalus from Victoria, Australia. Our data show that sequences associated with Enterobacteriaceae (62.8% ± 24.7%), Pasteurellaceae (19.9% ± 25.7%) and Moraxellaceae (9.4% ± 11.8%) dominate flying fox faeces. Further colony specific differences in bacterial faecal colonisation patterns were also identified. In total, 34 potential pathogens, representing 15 genera, were identified. However, species level definition was only possible for Clostridium perfringens, which likely represents a low infectious risk due to the low proportion observed within the faeces and high infectious dose required for transmission. In contrast, sequences associated with other pathogenic species clusters such as Haemophilus haemolyticus-H. influenzae and Salmonella bongori-S. enterica, were present at high proportions in the faeces, and due to their relatively low infectious doses and modes of transmissions, represent a greater potential human disease risk. These analyses of the microbial community composition of Pteropus poliocephalus have significantly advanced our understanding of the potential bacterial disease risk associated with flying foxes and should direct future epidemiological and quantitative microbial risk assessments to further define the health risks presented by these animals.


A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency.
The Ehlers-Danlos syndrome is a heritable connective-tissue disorder caused by defects in fibrillar-collagen metabolism. Mutations in the type V collagen genes account for up to 50 percent of cases of classic Ehlers-Danlos syndrome, but many other cases are unexplained. We investigated whether the deficiency of the tenascins, extracellular-matrix proteins that are highly expressed in connective tissues, was associated with the Ehlers-Danlos syndrome. We screened serum samples from 151 patients with the classic, hypermobility, or vascular types of the Ehlers-Danlos syndrome; 75 patients with psoriasis; 93 patients with rheumatoid arthritis; and 21 healthy persons for the presence of tenascin-X and tenascin-C by enzyme-linked immunosorbent assay. We examined the expression of tenascins and type V collagen in skin by immunohistochemical methods and sequenced the tenascin-X gene. Tenascin-X was present in serum from all normal subjects, all patients with psoriasis, all patients with rheumatoid arthritis, and 146 of 151 patients with the Ehlers-Danlos syndrome. Tenascin-X was absent from the serum of the 5 remaining patients with Ehlers-Danlos syndrome, who were unrelated. Tenascin-X deficiency was confirmed in these patients by analysis of skin fibroblasts and by immunostaining of skin. The expression of tenascin-C and type V collagen was normal in these patients. All five of these patients had hypermobile joints, hyperelastic skin, and easy bruising, without atrophic scarring. Tenascin-X mutations were identified in all tenascin-X-deficient patients; one patient had a homozygous tenascin-X gene deletion, one was heterozygous for the deletion, and three others had homozygous truncating point mutations, confirming a causative role for tenascin-X and a recessive pattern of inheritance. Tenascin-X deficiency causes a clinically distinct, recessive form of the Ehlers-Danlos syndrome. This finding indicates that factors other than the collagens or collagen-processing enzymes can cause the syndrome and suggests a central role for tenascin-X in maintaining the integrity of collagenous matrix.


Red clover (Trifolium pratense L.) isoflavones: root phenolic compounds affected by biotic and abiotic stress factors.
Phenolic compounds have recently received considerable attention for their ability to protect plant and human cells from oxidative stress-induced damage. Red clover (Trifolium pratense L.) is a rich source of isoflavonoids with multiple potential protective functions. The aim of this study was to identify and characterise phenolic compounds in red clover roots by high-performance liquid chromatography and mass spectrometry and to study the effects of stress factors and growth stage on root phenolics. A total of 28 phenolic compounds were tentatively identified in red clover roots. The most abundant phenolics in pot-grown roots were formononetin glycoside malonate (G-M) (1.51-4.26 mg g(-1)), formononetin (2.21-3.57 mg g(-1)) and biochanin A (1.73-2.17 mg g(-1)), whereas field-grown roots were rich in formononetin-G-M (3.90-4.27 mg g(-1)), maackiain-G-M (2.35-3.02 mg g(-1)) and pseudobaptigenin-G-M (1.80-2.58 mg g(-1)). Concentrations were affected by the growth stage. Ozone exposure slightly affected the total phenolic content in roots and also had minor effects on individual compounds. Elevated ozone, cultivation regime and growth stage affected the levels of phenolics in red clover roots, suggesting sensitivity of root phenolics to biotic and abiotic stress conditions. The high levels of phenolics found in roots even in late autumn may be utilised in many applications.


[Factors family background of mothers involved in having a premature baby].
Level of prematurity is an objective criterion for determining the health welfare of the population. Several family background factors of the mother increases the risk of preterm birth child - family status, unwanted pregnancy, etc. Pregnancy among unmarried women and unwanted pregnancy are associated with a higher risk of giving premature baby. Aim of this study is a survey and analysis of factors of family background of the mother (family status and unplanned pregnancy) and their influence on the birth of a premature baby. The survey found nearly three times higher risk OR = 2,83 95 % CI (1,7-4,7) for the birth of a premature baby among unmarried mothers compared to married women, and twice as high proportion of unplanned pregnancy mothers of preterm infants - 20.7% compared to terminfants-10.4%.


Identification of genes related to immune enhancement caused by heterologous ChAdOx1-BNT162b2 vaccines in lymphocytes at single-cell resolution with machine learning methods.
The widely used ChAdOx1 nCoV-19 (ChAd) vector and BNT162b2 (BNT) mRNA vaccines have been shown to induce robust immune responses. Recent studies demonstrated that the immune responses of people who received one dose of ChAdOx1 and one dose of BNT were better than those of people who received vaccines with two homologous ChAdOx1 or two BNT doses. However, how heterologous vaccines function has not been extensively investigated. In this study, single-cell RNA sequencing data from three classes of samples: volunteers vaccinated with heterologous ChAdOx1-BNT and volunteers vaccinated with homologous ChAd-ChAd and BNT-BNT vaccinations after 7 days were divided into three types of immune cells (3654 B, 8212 CD4+ T, and 5608 CD8+ T cells). To identify differences in gene expression in various cell types induced by vaccines administered through different vaccination strategies, multiple advanced feature selection methods (max-relevance and min-redundancy, Monte Carlo feature selection, least absolute shrinkage and selection operator, light gradient boosting machine, and permutation feature importance) and classification algorithms (decision tree and random forest) were integrated into a computational framework. Feature selection methods were in charge of analyzing the importance of gene features, yielding multiple gene lists. These lists were fed into incremental feature selection, incorporating decision tree and random forest, to extract essential genes, classification rules and build efficient classifiers. Highly ranked genes include PLCG2, whose differential expression is important to the B cell immune pathway and is positively correlated with immune cells, such as CD8+ T cells, and B2M, which is associated with thymic T cell differentiation. This study gave an important contribution to the mechanistic explanation of results showing the stronger immune response of a heterologous ChAdOx1-BNT vaccination schedule than two doses of either BNT or ChAdOx1, offering a theoretical foundation for vaccine modification.


[Nitrogen exchange in the large intestine of ruminants. 4. Exchange and isotope balance of intracecally administered 14C- and 15N-urea in sheep with simultaneous intracecal dose of a partly hydrolyzed straw meal].
Two experiments were performed with wethers (Body weight 34 to 44 kg) receiving a ration rich in crude fibre at maintenance level. The animals were fitted with ileocaecal cannulas into which 14C-, 15N-labelled urea together with digesta was introduced hourly for a 24 hours period (V1; 2 animals). In experiment two (V2; 3 animals) in addition HCl-partly hydrolysed straw meal was introduced. After ureolytic degradation the intracaecal applied urea entered mainly the intermediary metabolism. The resulting ammonia was resynthesized to urea without any time lag. The rate constant for the increase in 15N labelling of urea was 3.2 d-1 in both experiments. Urea leaves the plasma with half lives of 10.6 (V1) and 5.2 (V2) hours. More than 60% of the applied urea were excreted with urine. Formed 14CO2 appeared at proportions of 66% (V2) and 71% (V1) in the respiration gases. Both, the decline of the 14C-activity in blood plasma and the specific 14C-activity of CO2 in the respiration gases after the end of the labelling period do not follow a kinetic of first order. The 15N-labelling of the NH3-N in ileal digesta was very high and reached plateau values similar with those of plasma urea (2.54 vs. 2.56 atom-% 15N-excess). A direct entry of plasma urea into the small intestine was concluded.


NMDA-induced apoptosis in mixed neuronal/glial cortical cell cultures: the effects of isoflurane and dizocilpine.
In animal models of severe ischemia, it has not been uniformly observed that anesthetics are protective. However, anesthetics have not been evaluated in the presence of a mild excitotoxic insult. We hypothesized that in the presence of a mild excitotoxic insult, 3 microm N-methyl-D-aspartate (NMDA), isoflurane may prevent apoptotic cell death. Primary mixed neuronal/glial cultures were prepared from fetal rat brains. Mature cultures were exposed to dissolved isoflurane [0 mM, 0.4 mM (1.8 minimum alveolar concentration) or 1.6 mM (7 minimum alveolar concentration)] or dizocilpine (10 microM), and NMDA (0 or 3 microM) at 37 degrees C for 30 minutes. Apoptosis was assessed using terminal-deoxy-nucleotidyl end-nick labeling oligonucleosomal DNA fragmentation enzyme-linked immunosorbent assay, and caspases-3 and -9 activation assays. NMDA (3 muM) induced apoptosis in mixed neuronal/glial cell cultures. Apoptosis induced by 3 microm NMDA was caspase-3 but not caspase-9 mediated. In the presence of a mild excitotoxic insult, this investigation showed an attenuation of apoptotic cell death by dizocilpine, but not isoflurane.


Primary pulmonary lymphoepithelioma-like carcinoma: A case report of pathological complete response (pCR) by neoadjuvant treatment.
Primary pulmonary lymphoepithelioma-like carcinoma (PPLELC) is a rare subtype of non-small cell lung cancer (NSCLC). It is predominantly reported in East Asia and currently there is no standard treatment for this disease. We report a case of stage IV PPLELC that achieved pathological complete response (pCR) by neoadjuvant treatment. The patient was a 46-year-old male who developed hemoptysis for about 20 ml of volume accompanied by cough and sputum after physical labor. Contrast enhanced chest CT scanning showed occupation of left lower hilar area and left pleural effusion. Combined with medical history and auxiliary examination, the patient was formally diagnosed stage IV lymphoepithelioma-like carcinoma of the left lower lung (T3N0M1a pleura). The patient was given Sintilimab combined with gemcitabine + nedaplatin chemotherapy (GP) regimen for four cycles with 3 weeks as a cycle, supplemented with antiemetics and stomach protection drugs to reduce chemotherapy-related side effects. After 4 cycles of treatment, the patient's left lung lesion has been markedly reduced and the left pleural effusion has also been significantly absorbed. Remarkably, surgical biopsies found no cancer cells in the lesion site and postoperative pathology showed complete pathological remission (pCR). We reported a case of PPLELC that is sensitive to neoadjuvant treatment, showing excellent effectiveness and safety and achieving pCR.


Discontinuous replication of colicin E1 plasmid deoxyribonucleic acid.
The plasmid pML 21, which was found to contain approximately 49% of the Col E1 genome was used to determine the template origin of single-stranded deoxyribonucleic acid (DNA) fragments (4 to 32% of the Col E1 units length) associated with Col E1 dna replicative intermediates. The results of DNA hybridization competition experiments indicate that the single-stranded fragments derive from the full length of the Col E1 DNA template as expected for Okazaki fragments and the plasmid pML 21 contains the replication origin of Col E1 DNA.


Impact of exercise training on oxidative stress in individuals with a spinal cord injury.
Individuals with a spinal cord injury (SCI) have an increased cardiovascular risk. We hypothesize that (anti)oxidative imbalance is associated with the increased cardiovascular risk in SCI, while exercise can reverse this status. The aim of the study is to compare baseline levels of oxidative stress and antioxidative capacity between individuals with SCI and able-bodied (AB) subjects, and to assess acute and long-term effects of functional electrical stimulation (FES) exercise on oxidative stress and antioxidative capacity in SCI. Venous blood was taken from subjects with an SCI (n = 9) and age- and gender-matched AB subjects (n = 9) to examine oxidative stress through malondialdehyde (MDA) levels, while superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzyme levels represented anti-oxidative capacity. Subsequently, subjects with an SCI performed an 8-week FES exercise training period. Blood was taken before and after the first exercise bout and after the last FES session to examine the acute and chronic effect of FES exercise, respectively. Baseline levels of MDA, SOD and GPx were not different between individuals with SCI and AB subjects. SCI demonstrated a correlation between initial fitness level and MDA (R = -0.83, P = 0.05). MDA, SOD and GPx levels were neither altered by a single FES exercise bout nor by 8 weeks FES training. In conclusion, although individuals with an SCI demonstrate a preserved (anti)oxidative status, the correlation between fitness level and (anti)oxidative balance suggests that higher fitness levels are related to improved (anti)oxidative status in SCI. Nonetheless, the FES exercise stimulus was insufficient to acutely or chronically change (anti)oxidative status in individuals with an SCI.


Developing and sustaining human resources in the health supply chain in Ethiopia: barriers and enablers.
The health supply chain is often the weakest link in achieving the health-related Millennium Development Goals and universal health coverage, requiring trained professionals who are often unavailable. In Ethiopia there have been recent developments in the area of health supply chain management. The aim of this study was to explore the current status of the development of human resources in health supply chain management in Ethiopia and to identify important factors affecting this development. A series of face-to-face interviews with key stakeholders was carried out in 2014. The interviews were conducted using a semi-structured interview guide. The interview guide comprised 51 questions. A qualitative analysis of transcripts was made. A total of 25 interviews were conducted. Three themes were identified: General changes: recognition, commitment and resources, Education and training, and Barriers and enablers. Results confirm the development of human resources in health supply chain management in many areas. However, several problems were identified including lack of coordination, partly due to the large number of stakeholders; reported high staff mobility; and a lack of overall strategy regarding the job/career structures necessary for maintaining human resources. Rural areas have a particular set of problems, including in transportation of goods and personnel, attracting and keeping personnel, and in communication and access to information. Ethiopia is on the way to developing a nationwide viable system for health supply chain management. However, there are still challenges. Short-term challenges include the importance of highlighting strategies and programs for human resources in health supply chain management. In the long term, commitments to financial support must be obtained. A strategy is needed for the further development and sustainability of human resources in the health supply chain in Ethiopia.


Antibacterial activity of labdane diterpenoids from Stemodia foliosa.
As part of a continuing interest in exploring the chemistry of Brazilian medicinal plants, three new labdane diterpenoids, 6alpha-acetoxymanoyl oxide (1), 6alpha-malonyloxymanoyl oxide (2), and 6alpha-malonyloxy-n-butyl ester manoyl oxide (3), together with the known betulinic acid, lupeol, sitosterol, and stigmasterol, were isolated from the aerial parts of Stemodia foliosa. The structures of 1-3 were established on the basis of interpretation of spectroscopic data, including HRESIMS, and 1D and 2D NMR techniques. All compounds were tested against a bacteria panel consisting of Staphylococcus aureus, Bacillus cereus, B. subtilis, B. anthracis, Micrococcus luteus, Mycobacterium smegmatis, and M. phlei. Compound 2 showed moderate activity against these strains, with MIC values in the range 7-20 microg/mL.


Short QT syndrome. Genotype-phenotype correlations.
The short QT syndrome is a new congenital entity associated with familial atrial fibrillation and/or sudden death or syncope. Three different gain-of-function mutations in genes encoding for cardiac potassium channels (KCNH2, KCNQ1, and KCNJ2) have been identified up to now to cause short QT syndrome. The syndrome is characterized electrocardiographically by a shortened QTc interval less than 300 to 320 milliseconds and a lack of adaptation during increasing heart rates. During programmed electrical stimulation, atrial and ventricular effective refractory periods are shortened, and in a high percentage, ventricular tachyarrhythmias are inducible. Sudden cardiac death occurs in all age groups and even in newborns. Therapy for choice seems to be the implantable cardioverter-defibrillator because of the high incidence of sudden death. However, ICD therapy may be associated with an increased risk of inappropriate therapies for T wave oversensing, which, however, can be resolved by reprogramming ICD detection algorithms. The impact of sotalol, ibutilide, flecainide, and quinidine on QT prolongation has been evaluated. But only quinidine effectively suppressed gain-of-function in IKr, along with prolongation of the QT interval. Furthermore, in patients with a mutation in HERG (SQT1), quinidine rendered ventricular tachyarrhythmias noninducible and restored the QT interval/heart rate relationship toward a reference range. It may serve as an adjunct to ICD therapy or as possible alternative treatment especially for children and newborns.


Synthesis and preliminary biological evaluations of 5'-substituted derivatives of uridine as glycosyltransferase inhibitors.
New derivatives of uridine which contain a b-ketoenol motif were synthesized, characterized and biologically tested. Synthesized compounds 1-4 showed no activity against bovine milk β-1,4-galactosyltransferase I at concentrations up to 2.0 mM and were not active against Candida albicans and Aspergilus fumigatus up to the maximum tested concentration of 1,000 µg/mL.


Anti-Tumor Activity vs. Normal Cell Toxicity: Therapeutic Potential of the Bromotyrosines Aerothionin and Homoaerothionin In Vitro.
Novel strategies to treat cancer effectively without adverse effects on the surrounding normal tissue are urgently needed. Marine sponges provide a natural and renewable source of promising anti-tumor agents. Here, we investigated the anti-tumor activity of Aerothionin and Homoaerothionin, two bromotyrosines isolated from the marine demosponge Aplysina cavernicola, on two mouse pheochromocytoma cells, MPC and MTT. To determine the therapeutic window of these metabolites, we furthermore explored their cytotoxicity on cells of the normal tissue. Both metabolites diminished the viability of the pheochromocytoma cell lines significantly from a concentration of 25 µM under normoxic and hypoxic conditions. Treatment of MPC cells leads moreover to a reduction in the number of proliferating cells. To confirm the anti-tumor activity of these bromotyrosines, 3D-pheochromocytoma cell spheroids were treated with 10 µM of either Aerothionin or Homoaerothionin, resulting in a significant reduction or even complete inhibition of the spheroid growth. Both metabolites reduced viability of normal endothelial cells to a comparable extent at higher micromolar concentration, while the viability of fibroblasts was increased. Our in vitro results show promise for the application of Aerothionin and Homoaerothionin as anti-tumor agents against pheochromocytomas and suggest acceptable toxicity on normal tissue cells.


Phenotypes and genotypes in non-consanguineous and consanguineous primary microcephaly: High incidence of epilepsy.
Primary microcephaly (PM) is defined as a significant reduction in occipitofrontal circumference (OFC) of prenatal onset. Clinical and genetic heterogeneity of PM represents a diagnostic challenge. We performed detailed phenotypic and genomic analyses in a large cohort (n = 169) of patients referred for PM and could establish a molecular diagnosis in 38 patients. Pathogenic variants in ASPM and WDR62 were the most frequent causes in non-consanguineous patients in our cohort. In consanguineous patients, microarray and targeted gene panel analyses reached a diagnostic yield of 67%, which contrasts with a much lower rate in non-consanguineous patients (9%). Our series includes 11 novel pathogenic variants and we identify novel candidate genes including IGF2BP3 and DNAH2. We confirm the progression of microcephaly over time in affected children. Epilepsy was an important associated feature in our PM cohort, affecting 34% of patients with a molecular confirmation of the PM diagnosis, with various degrees of severity and seizure types. Our findings will help to prioritize genomic investigations, accelerate molecular diagnoses, and improve the management of PM patients.


The effect of incubation temperature on recovery of mesophilic bacteria from broiler chicken carcasses subjected to temperature abuse.
The optimum temperature to recover mesophilic organisms from temperature-abused broiler chicken carcasses was determined. Twenty broiler carcasses were collected from a commercial processing plant in each of three trials. Ten carcasses were sampled immediately (Day 0 control); 8 carcasses were sampled after holding at 3 C for 3 d, temperature abusing at 25 C for 12 h, and holding them at 3 C for an additional 3 d (temperature abused); and the remaining 2 carcasses were sampled after holding at 3 C for 7 d (Day 7 control). Whole carcass rinses were analyzed using total aerobic plate counts (TPC) and impedimetric detection times (DT) at incubation temperatures of 41, 42, 43, and 44 C. Total plate counts decreased (P < .05) and DT increased (P < .05), at all incubation temperatures tested, for carcasses held under refrigeration (Day 7 control). This demonstrates that mesophilic bacteria, rather than psychrotrophic bacteria, are being enumerated, because psychrotrophs increase on chicken skin upon cold storage. Total plate count was greater (P < .05) and DT was significantly lower for temperature-abused vs Day 7 control birds (5.7 vs 3.6 log10 cfu/mL and 3.7 vs 6.5 h), respectively. These results indicate that temperature-abused carcasses can be microbiologically distinguished from nonabused controls at all incubation temperatures tested. Recovery of mesophiles was optimal at 41 and 42 C for TPC and 41, 42, and 43 C for DT. Because there were no differences between DT at 41, 42, and 43 C, and because 42 C has been successfully used in the past, either 42 C or 43 C can be used when determining DT.


Toys, sociocognitive traits, and occupations: Italian children's endorsement of gender stereotypes.
In a sample of 136 Italian children ages 8 to 12 years (M = 9.6, SD = 1.2; 68 boys, 68 girls), gender stereotypes related to gender-typed toys, traits, and occupational choices were examined, using the forced-choice technique between a male and a female silhouette. Stereotypy was established considering boys' and girls' choices for the 70%-100% range. Differences in gender stereotyping for age and sex of participants were verified. Analysis indicated children attributed toys prevalently connected with aesthetic aspect and domestic activities to the female silhouette, while technology, warfare, locomotion, and construction toys were attributed to the male. Children attributed physical and verbal aggressiveness and dominance to the male silhouette; the female profile was exclusively characterized by sweetness. The occupational stereotypical male model was structured in both practical-manual activities and of highly cultural and specialist relevance, while for the female model the number of activities, mainly of a domestic type, were reduced. Significant main effect of sex of children was found, but no significant age-related differences in the three domains. Results were discussed within the framework of gender-stereotype theories.


Host-directed therapy for bacterial infections -Modulation of the phagolysosome pathway.
Bacterial infections still impose a significant burden on humanity, even though antimicrobial agents have long since been developed. In addition to individual severe infections, the f fatality rate of sepsis remains high, and the threat of antimicrobial-resistant bacteria grows with time, putting us at inferiority. Although tremendous resources have been devoted to the development of antimicrobial agents, we have yet to recover from the lost ground we have been driven into. Looking back at the evolution of treatment for cancer, which, like infectious diseases, has the similarity that host immunity eliminates the lesion, the development of drugs to eliminate the tumor itself has shifted from a single-minded focus on drug development to the establishment of a treatment strategy in which the de-suppression of host immunity is another pillar of treatment. In infectious diseases, on the other hand, the development of therapies that strengthen and support the immune system has only just begun. Among innate immunity, the first line of defense that bacteria encounter after invading the host, the molecular mechanisms of the phagolysosome pathway, which begins with phagocytosis to fusion with lysosome, have been elucidated in detail. Bacteria have a large number of strategies to escape and survive the pathway. Although the full picture is still unfathomable, the molecular mechanisms have been elucidated for some of them, providing sufficient clues for intervention. In this article, we review the host defense mechanisms and bacterial evasion mechanisms and discuss the possibility of host-directed therapy for bacterial infection by intervening in the phagolysosome pathway.


Programme of the 21st European Conference on Eye Movements.
About ECEM ECEM was initiated by Rudolf Groner (Bern), Dieter Heller (Bayreuth at the time) and Henk Breimer (Tilburg) in the 198 to provide a forum for an interdisciplinary group of scientists interested in eye movements. Since the inaugural meeting in Bern, the conference has been held every two years in different venues across Europe until 2021, when it was planned to take place in Leicester but was cancelled due to the COVID pandemic. It was decided to hold the meeting in Leicester in August 2022 instead, and as an in person meeting rather than an online or hybrid event. Incidentally, the present meeting is the third time the conference has come to the English East Midlands, now in Leicester following previous meetings in the neighbouring cities of Derby and Nottingham. The sites of previous ECEMs and webpages can be found here..


Immobilization of Chlamydomonas reinhardtii CLH1 on APTES-Coated Magnetic Iron Oxide Nanoparticles and Its Potential in the Production of Chlorophyll Derivatives.
Recombinant Chlamydomonas reinhardtii chlorophyllase 1 (CrCLH1) that could catalyze chlorophyll hydrolysis to chlorophyllide and phytol in vitro was successfully expressed in Escherichia coli. The recombinant CrCLH1 was immobilized through covalent binding with a cubic (3-aminopropyl) triethoxysilane (APTES) coating on magnetic iron oxide nanoparticles (MIONPs), which led to markedly improved enzyme performance and decreased biocatalyst costs for potential industrial application. The immobilized enzyme exhibited a high immobilization yield (98.99 ± 0.91 mg/g of gel) and a chlorophyllase assay confirmed that the immobilized recombinant CrCLH1 retained enzymatic activity (722.3 ± 50.3 U/g of gel). Biochemical analysis of the immobilized enzyme, compared with the free enzyme, showed higher optimal pH and pH stability for chlorophyll-a hydrolysis in an acidic environment (pH 3-5). In addition, compared with the free enzyme, the immobilized enzyme showed higher activity in chlorophyll-a hydrolysis in a high temperature environment (50-60 °C). Moreover, the immobilized enzyme retained a residual activity of more than 64% of its initial enzyme activity after 14 cycles in a repeated-batch operation. Therefore, APTES-coated MIONP-immobilized recombinant CrCLH1 can be repeatedly used to lower costs and is potentially useful for the industrial production of chlorophyll derivatives.