Influence of ceramic veneer thickness and antagonist on impact stresses during dental trauma with and without a mouthguard assessed with finite element analysis.
Little is known about the effect of dental trauma and mouthguards (MG) on teeth with ceramic laminate veneers (CLV). The aim was to evaluate the influence of CLV thickness and the presence of a MG with and without antagonist tooth contact on impact stresses during dental trauma. Twelve 2D-finite element models of a head with maxillary structures and upper incisors, six with and six without antagonist tooth, were created in three CLV conditions: sound incisor (no CLV), 0.3 mm CLV, and 1.0 mm CLV. These were evaluated with and without a 4.0-mm ethylene-vinyl acetate MG, with and without an antagonist tooth. An impact analysis was performed in which the head frontally hits a rigid surface at a speed of 1 m/s (3.6 km/h). The results were analyzed using Critical modified von Mises (MPa). The mean of the 10% highest modified von Mises stresses in each structure was collected. MG presence substantially reduced impact stresses in the CLV and tooth structures. The contact of the antagonist tooth promoted better stress distribution and reduced the stress levels in the traumatized tooth. Critical stress areas were found in the palatal enamel, incisal enamel, labial cervical area, and enamel under the CLV for all models without MG. In the models with MG, the stresses reduced significantly. Critical modified von Mises stress showed that sound or prepared enamel experienced more critical impact stresses than 0.3 or 1.0-mm thick CLV. The use of 4.0 mm EVA mouthguard reduced the impact stress levels in models with 0.3-mm CLV and 1.0-mm CLV, similar to a sound tooth. The contact of an antagonist tooth and the MG better distributed the stresses and reduced the impact stress in the traumatized tooth.


Exopolysaccharides produced by Oenococcus oeni: From genomic and phenotypic analysis to technological valorization.
Oenococcus oeni (O. oeni), which is the main species that drives malolactic fermentation (FML), an essential step for wine microbial stabilization and quality improvement, is known to produce exopolysaccharides (EPS). Depending on the strain, these EPS can be soluble, remain attached to the cell or both. In the present study, fourteen strains were examined for eps gene content and EPS production capacities. Cell-linked and soluble heteropolysaccharides made of glucose, galactose and rhamnose, soluble β-glucan, and soluble dextran or levan were found, depending on the strain. The protective potential of either cell-linked heteropolysaccharides or dextrans produced was then studied during freeze drying of the bacterial strains.


Role of the military community mental health nurse.
To understand the role and effect of a community mental health nurse (CMHN) deployed to work with military personnel during sea-based operations. Semi-structured interviews were conducted to ascertain Royal Navy aircraft carrier military unit commanders' perceptions and experiences of the CMHN's role. Three mutually inclusive components are necessary to ensure successful integration of the CMHN: familiarity, trust and credibility. For CMHNs to function successfully and provide mental health care to sea-based military personnel, they need to demonstrate familiarity, trust and credibility. This will enhance uptake of mental health services among military personnel and ensure they are fit for service.


Breast Cancer-Related Lymphedema (BCRL) and Bioimpedance Spectroscopy: Long-Term Follow-Up, Surveillance Recommendations, and Multidisciplinary Risk Factors.
Early detection and intervention for breast cancer-related lymphedema (BCRL) significantly decreases progression to persistent BCRL (pBCRL). We aimed to provide long-term follow-up on our early detection with bioimpedance spectroscopy (BIS) and early home intervention demonstrating reduced pBCRL to guide surveillance recommendations. In total, 148 female patients with breast cancer who had axillary lymph node dissection (ALND) from November 2014 to December 2017 were analyzed. Baseline BIS measurements and postoperative follow-up occurred every 3 months for 1 year, biannual for 1 year, and then annually. An elevated BIS triggered evaluation and initiation of at-home interventions with reassessment for resolution versus persistent BCRL (pBCRL). High-risk factors and timing were analyzed. Mean follow-up was 55 months, and 65 (44%) patients had an abnormal BIS. Of these, 54 (82%) resolved with home intervention. The overall pBCRL rate was 8%. Average time to first abnormal BIS was 11.7 months. None of the stage 0 patients (0/34) and only 5/25 (20%) of stage 1 patients had pBCRL. All of stage 2 and stage 3 patients (7/7) had pBCRL. pBCRL correlated with number of positive nodes, percentage of positive nodes, stage of lymphedema at diagnosis, and recurring abnormal BIS measurements (p < 0.05). We have shown that patients undergoing ALND with early BCRL identified by BIS who performed home interventions had an 8% pBCRL rate. Patients at high risk for pBCRL should have routine surveillance starting at 9 months postoperatively to identify an opportunity for early intervention.


The impact of complete clearance and almost complete clearance of psoriasis on quality of life: a literature review.
Psoriasis is a chronic skin condition with systemic manifestations that have a detrimental impact on a patient's quality of life, affecting social, psychological, and sexual aspects of life. Complete clearance of lesions is a meaningful end goal of treatment; however, it is often difficult for patients to achieve. In this literature review, we summarized past studies that compared patients who achieved complete clearance to those who were almost clear to highlight the effect of complete clearance on psychological distress, social stigma, self-esteem, and interpersonal relationships in adult patients with psoriasis. A literature search was performed through the PubMed database using the keywords "clearance of psoriasis", "complete clearance of psoriasis", "psychological impact psoriasis", "social impact psoriasis", and "stigma of psoriasis". Age (< 18) and language (only articles written in English were included) were the only exclusion criteria to include adult patients only. The information was then collected and evaluated to compare complete clearance and almost complete clearance of psoriasis. Of the patients with complete skin clearance (sPGA of 0), 61.4-91.1% reported a Dermatology Life Quality Index (DLQI) of 0, indicating no detectable impact of psoriasis on quality of life, compared to 45.7-48.3% who were almost clear. Patients who were completely clear felt psoriasis had less of an effect on their leisure activities and daily living compared to patients who were almost clear. Patient perceptions of disease severity also differed between the two groups, with the majority (65.5%) of those achieving complete clearance reporting a Psoriasis Symptom Inventory (PSI) of 0, which is consistent with their disease being "not at all severe", compared to 32.6% of those who were almost but not completely clear. While patients with complete clearance achieve a DLQI of 0 at a higher rate than those who have only almost complete clearance, the difference in the mean DLQI between patients with sPGA of 0 (completely clear) and sPGA of 1 (almost clear) is less than the minimal clinically important difference (MCID of 3-5) of the DLQI.


Striking elevation of serum IgA, IgA-containing immune complexes, and IgA rheumatoid factor in clinically silent dermatitis herpetiformis.
We describe a patient with dermatitis herpetiformis with immunoglobulin A (IgA)-containing circulating immune complexes and IgA rheumatoid factor who presented with acute renal insufficiency; a renal biopsy specimen showed IgA nephropathy. The renal function and proteinuria spontaneously returned to normal despite markedly elevated levels of IgA-containing circulating immune complexes, IgA rheumatoid factor, and IgA antibodies to some environmental antigens. IgA1 was the predominant subclass. IgA2-containing immune complexes and IgM rheumatoid factor were not detected. Cultures of peripheral blood mononuclear cells produced increased quantities of IgA and IgA rheumatoid factor spontaneously and after pokeweed mitogen stimulation. These data indicate that renal function can improve and remain normal despite the presence of increased levels of IgA-containing circulating immune complexes and IgA rheumatoid factor.


Thromboelastometry: A contribution to perioperative free-flap management.
Microvascular tissue transfer is a fundamental part of reconstructive surgery. Different perioperative anticoagulation regimens exist, influencing hemostatic parameters. Since bleeding and thrombosis are major reasons for revision procedures and flap loss, current practice regarding anticoagulative treatment needs further refinement. Thromboelastometry has been demonstrated as worthwhile in the determination of alterations of the anticoagulation cascade. We evaluated this aspect of thromboelastometry for free flap surgery. Thirty-five patients undergoing free-flap surgery were enrolled in this study. Blood samples were obtained at three time points: at the beginning of surgery, at time of anastomosis and after 24 h. At each time point, thromboelastometry with special regard to clotting times for the intrinsic and extrinsic paths of coagulation was immediately performed. Global coagulation markers and clinical parameters were collected simultaneously. Hemostatic changes were deducible using thromboelastometry perioperatively. Measured parameters differed significantly over time (p < 0.05). Heparin therapy showed a significant effect on the measured slope of INTEM-clotting times (p < 0.001). Altered values of thromboelastometry suggested non-inferiority to standard testing. Neither standard testing nor thromboelastometry were capable of predicting adverse events such as thrombosis, bleeding or flap loss (p > 0.05). Thromboelastometry monitors hemostatic effects almost in real-time and could serve as a supplementary tool in microvascular tissue transfer once its use has been standardized. The utilization of thromboelastometry allows for assessment of the anticoagulation needs of individual patients undergoing free flap surgery, which is frequently accompanied by hemostatic changes in the perioperative setting. Our findings implicate further validation of thromboelastometry in free-flap surgery.


Willingness of Emerging Adults to Engage in Consensual Non-Monogamy: A Mixed-Methods Analysis.
Over the past decade, research on consensual non-monogamy (CNM) has increased. However, willingness to engage in CNM is an understudied phenomenon within this field. Because qualitative methods are rarely used to study this phenomenon, little is known about why individuals may or may not be willing to engage in CNM. Further, research on CNM has devoted little attention to the period of emerging adulthood. The current study used a mixed-methods approach to examine a sample of emerging adults' (ages 18-29; N = 549) willingness to engage in CNM. Results from a qualitative content analysis revealed three distinct groups (Unwilling, Willing, and Open-Minded), and several subthemes emerged within each group that help explain why emerging adults are willing to engage in CNM. Quantitative analyses examined the relationship between group membership and demographic characteristics, finding that a greater proportion of women and heterosexual participants were Unwilling. Results also indicated that a greater proportion of men were Willing, and a greater proportion of sexual minorities were Open-Minded. Group mean differences were examined using quantitative measures of CNM attitudes and willingness. The Unwilling group reported more negative attitudes towards CNM compared to the Open-Minded and Willing groups. Additionally, the Open-Minded group reported more negative attitudes compared to the Willing group. On the willingness to engage in CNM Scale, the Unwilling group had lower mean scores compared to the Willing and Open-Minded groups. The Willing group had higher mean scores compared to the Open-Minded group. Implications for CNM research and methodology are discussed.


Persistent Psychological Well-being Predicts Improved Self-Rated Health Over 9-10 Years: Longitudinal Evidence from MIDUS.
Psychological well-being has been linked with better health, but mostly with cross-sectional evidence. Using MIDUS, a national sample of U.S. adults (N = 4,963), longitudinal profiles of well-being were used to predict in cross-time change over a 9-10 years in self-reported health. Well-being was largely stable, although adults differed in whether they had persistently high versus persistently low or moderate levels of well-being. After adjusting for sociodemographic factors, those with persistently high well-being reported better health (subjective health, chronic conditions, symptoms, functional impairment) across time compared to those with persistently low well-being. Further, persistently high well-being was protective of improved health especially among the educationally disadvantaged. The findings underscore the importance of intervention and educational programs designed to promote well-being for greater segments of society.


Management of osteosarcoma of the head and neck.
There is no clear consensus guideline that specifies the optimum course of treatment for adult head and neck osteosarcoma (HNO) because of its rarity. The review's goal is to examine the most recent research on the presentation, diagnosis, prognosis, and therapy of head and neck osteosarcoma. Due to overlapping symptoms with various benign disorders of the lower jaw and midface bone, these patients present with a noticeable delay. The greatest results for these malignancies can be achieved with surgery with sufficient margins. However, it may not be able to achieve sufficient margins in tumours of the midface and skull base, and the significance of adjuvant radiation/chemotherapy needs to be investigated. The use of adjuvant radiation in instances with an advanced stage, poor prognostic indicators, and inadequate resection is supported by evidence. Nonetheless, there are divergent opinions regarding the advantages of chemotherapy in adjuvant and neoadjuvant conditions, and further multicentric randomized control trials are required to provide robust evidence. Multimodality treatments seem to yield better results for advanced HNO with adverse features and incomplete resections.


Author Correction: Changes in climate patterns and their association to natural hazard distribution in South Tyrol (Eastern Italian Alps).
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


Anesthesia for dystocia and anesthesia of the equine neonate.
Equine anesthesia is complicated regardless of the procedure being performed. Anesthesia for the mare experiencing dystocia is complicated by the size of the fetus, positioning of the mare for the procedure, and concern over drug effect on the fetus through the neonatal period. Anesthesia of the neonate is complicated by multiple factors, specifically, sensitivity to the drugs administered. Ventilatory support, minimizing drugs administered, and minimizing anesthesia time are essential for a positive outcome.


Establishment and evaluation of a novel practical tool for the diagnosis of pre-sarcopenia in young people with diabetes mellitus.
Sarcopenia has been recognized as a third category of complications in people with diabetes. However, few studies focus on the reduction of skeletal muscle mass in young people with diabetes. The aim of this study was to investigate risk factors of pre-sarcopenia in young patients with diabetes and establish a practical tool to diagnose pre-sarcopenia in those people. Patients (n = 1246) enrolled from the National Health and Nutrition Examination Survey (NHANES) cycle year of 2011 to 2018 were randomly divided into the training set and validation set. The all-subsets regression analysis was used to select the risk factors of pre-sarcopenia. A nomogram model for the prediction of pre-sarcopenia in the diabetic population was established based on the risk factors. The model was evaluated by the area under the receiver operating characteristic curve for discrimination, calibration curves for calibration, and decision curve analysis curves for clinical utility. In this study, gender, height, and waist circumference were elected as predictive factors for pre-sarcopenia. The nomogram model presented excellent discrimination in training and validation sets with areas under the curve of 0.907 and 0.912, respectively. The calibration curve illustrated excellent calibration, and the decision curve analysis showed a wide range of good clinical utility. This study develops a novel nomogram that integrates gender, height, and waist circumference and can be used to easily predict pre-sarcopenia in diabetics. The novel screen tool is accurate, specific, and low-cost, highlighting its potential value in clinical application.


Partition of the Hodgkin-Huxley type model parameter space into the regions of qualitatively different solutions.
We have examined the problem of obtaining relationships between the type of stable solutions of the Hodgkin-Huxley type system, the values of its parameters and a constant applied current (I). As variable parameters of the system the maximal Na+(-gNa), K+(-gK) conductances and shifts (Gm, Gh, Gn) of the voltage-dependences have been chosen. To solve this problem it is sufficient to find points belonging to the boundary, partitioning the parameter space of the system into the regions of the qualitatively different types of stable solutions (steady states and stable periodic oscillations). Almost all over the physiological range of I, a type of stable solution is determined by the type of steady state (stable or unstable). Using this fact, the approximate solution of this problem could be obtained by analyzing the spectrum of eigenvalues of the Jacobian matrix for the linearized system. The families of the plan sections of the boundary have been constructed in the three-parameter spaces (I, -gNa, -gK), (I, Gm, Gh), (I, Gm, Gn).


Mapping from GenBank to MEDLINE.
GenBank has been based largely on literature that provides nucleic acid sequences. To find additional literature that is relevant to a given sequence, a search of MEDLINE can prove helpful. This paper documents some of the similarities between GenBank and MEDLINE that facilitate retrieval of documents from MEDLINE. In particular, techniques and examples are presented which take GenBank information and lead to MEDLINE information that supplements the GenBank information.


Design and implementation of software for assembly and browsing of 3D brain atlases.
Visualization software for three dimensional digital brain atlases present many challenges in design and implementation. These challenges include the design of an effective human interface, management of large data sets, display speed when slicing the data set for viewing/browsing, and the display of delineated volumes of interest (VOI). We present a software design, implementation and storage architecture that addresses these issues, allowing the user to navigate through a reconstructed volume quickly and smoothly, with an easy-to-use human interface. The software (macostat, for use with Macintosh OS) allows the user to rapidly display slices of the digital atlas at any arbitrary slicing angle, complete with delineated VOIs. The VOIs can be assigned colors of the user's choosing. The entire atlas, or selected portions, may be resliced with slices stored as individual image files, complete with delineations. These delineations may be transferred to corresponding sections of experimental materials using our analysis program (brain). The software may be obtained from the laboratory's web site: http://www.neuroterrain.org


Nitric-oxide reductase. Structure and properties of the catalytic site from resonance Raman scattering.
We have applied resonance Raman spectroscopy to investigate the properties of the dinuclear center of oxidized, reduced, and NO-bound nitric-oxide reductase from Paracoccus denitrificans. The spectra of the oxidized enzyme show two distinct nu(as)(Fe-O-Fe) modes at 815 and 833 cm(-1) of the heme/non-heme diiron center. The splitting of the Fe-O-Fe mode suggests that two different conformations (open and closed) are present in the catalytic site of the enzyme. We find evidence from deuterium exchange experiments that in the dominant conformation (833 cm(-1) mode, closed), the Fe-O-Fe unit is hydrogen-bonded to distal residue(s). The ferric nitrosyl complex of nitric-oxide reductase exhibits the nu(Fe(3+)-NO) and nu(N-O) at 594 and 1904 cm(-1), respectively. The nitrosyl species we detect is photolabile and can be photolyzed to generate a new form of oxidized enzyme in which the proximal histidine is ligated to heme b(3), in contrast to the resting form. Photodissociation of the NO ligand yields a five-coordinate high-spin heme b(3). Based on the findings reported here, the structure and properties of the dinuclear center of nitric- oxide reductase in the oxidized, reduced, and NO-bound form as well as its photoproduct can be described with certainty.


Effects of moderate dietary supplementations with n-3 fatty acids on macrophage and lymphocyte phospholipids and macrophage eicosanoid synthesis in the rat.
The effects of a moderate dietary intake of n-3 polyunsaturated fatty acids were determined on the eicosanoid synthesis by rat peritoneal macrophages: the availability of arachidonic acid (20:4 (n-6)) and eicosapentaenoic acid (20:5 (n-3] in the membrane phospholipids of peritoneal macrophages and splenic lymphocytes and the synthesis of the main eicosanoids were evaluated in parallel. The n-6/n-3 ratio was decreased from 13.5 in the control diet rich in 18:2(n-6) to about 2 by an addition of either linseed oil providing 18:3(n-3) (linseed oil diet) or fish oil providing 20:5(n-3) and 22:6(n-3) (fish oil diet). The dietary linoleic acid content was at least 3.5% of energy in each diet. In peritoneal macrophage and splenic lymphocyte membrane phospholipids, arachidonic acid content was significantly decreased with the linseed oil and fish oil diets. 20:5(n-3) content was significantly raised up in the linseed oil group (3-fold in macrophage phospholipids) and more strikely in the fish oil group (7-fold). In response to a stimulation by the calcium ionophore A23187, peritoneal macrophages released 6-ketoPGF1 alpha, TXB2, PGE2 and LTB4 and/or 5, but no or few peptidoleukotrienes. The linseed oil did not affect significantly the synthesis of these eicosanoids, except for LTB5, which was increased 2-fold. In contrast, the fish oil diet led to significant decreases in the productions of 6-ketoPGF1 alpha and PGE2 (-50%) and LTB4 (-40%) and to a 10-fold increase in the release of LTB5. TXB2 was also decreased (-35%), but not significantly. These results and the parallel evolutions of the two ratios 20:4(n-6)/20:5(n-3) and LTB4/LTB5 showed that eicosanoid synthesis is greatly dependent on the relative availability of the two substrates in competition.


Sister chromatid exchange in patients with viral disease.
Sister chromatid exchange (SCE) frequencies were studied in differentially stained chromosomes from lymphocytes of 17 patients with viral disease. The mean SCE score for the patients was 8.7 +/- 2.9 standard deviations. SCE scores were significantly elevated in the patients compared with the controls (p less than 0.01); however, variability in SCE means was observed in the patients. SCE elevations were also present in long term cultured Epstein Barr virus positive human B lymphocytes.


Mandibular distraction osteogenesis in the micrognathic neonate: a review for neonatologists and pediatricians.
In the past, severe neonatal upper airway obstruction secondary to micrognathia was managed with a tracheostomy. Although effective, tracheostomy can cause many short-term and long-term complications. More recently, mandibular distraction osteogenesis (MDO) has become a well-accepted surgical option in treating micrognathic newborns. Overall, MDO has been reported to be an effective intervention in alleviating the micrognathia-associated airway compromise. Furthermore, it seems to be well tolerated and has supplanted the need for tracheostomy in many patients. Neonatologists and pediatricians commonly care for these children, and therefore an up-to-date clinical narrative review regarding MDO is presented to increase the awareness of this relatively new surgical option.


Development aspects of renal beta-amino acid transport II. Ontogeny of uptake and efflux processes and effect of anoxia.
Renal cortex slices from newborn, 2-week, and 4-week-old Sprague-Dawley rats had reduced initial rates of taurine uptake compared to adult slices after short (less than 30 min) incubation periods. From birth onward, steady-state accumulation occurred by at least two sodium-dependent uptake systems. The first system had an "apparent Km1" = 0.1 mM and a Vmax varying from 1.8 to 5.1 mumoles/ml ICF/120 min at four ages. The second uptake mode had an apparent Km2 = 12-16 mM and a Vmax of 45 mumoles/ml ICF/120 min. Efflux of taurine was reduced in slices from younger animals possibly accounting for taurinuria. Only other beta-amino acids inhibited accumulation. Anoxia inhibited uptake at high concentration ( greater than 1.0 mM) at each age, but taurine accumulation at low concentrations ( less than 0.4 mM) was relatively protected from anoxia in neonatal ( less than 36 hr of age) tissue. Preincubation in taurine-free medium for 120 min enhanced low concentration, but not high concentration uptake in neonatal and 2-week slices. After preincubation in dibutyryl cyclic AMP (dbcAMP) enhanced uptake of taurine was found in adult cortex, but not in neonatal cortex. The ontogeny of renal taurine transport in cortex slices appeared to involve faster initial uptake rates and faster efflux as well as greater dependence on aerobic metabolism with maturation. Age-related differences in the response to preincubation and cyclic nucleotides were also indicative of maturation events in renal tubular amino acid transport.


Guidance on diagnosis, prevention and treatment of thromboembolic complications in COVID-19: a position paper of the Brazilian Society of Thrombosis and Hemostasis and the Thrombosis and Hemostasis Committee of the Brazilian Association of Hematology, Hemotherapy and Cellular Therapy.
Hemostatic abnormalities and thrombotic risk associated with coronavirus disease 2019 (COVID-19) are among the most discussed topics in the management of this disease. The aim of this position paper is to provide the opinion of Brazilian experts on the thromboprophylaxis and management of thrombotic events in patients with suspected COVID-19, in the sphere of healthcare in Brazil. To do so, the Brazilian Society of Thrombosis and Hemostasis (BSTH) and the Thrombosis and Hemostasis Committee of the Brazilian Association of Hematology, Hemotherapy and Cellular Therapy (ABHH) have constituted a panel of experts to carefully review and discuss the available evidence about this topic. The data discussed in this document was reviewed by May 9, 2020. Recommendations and suggestions reflect the opinion of the panel and should be reviewed periodically as new evidence emerges.


Vincenz Fukala (1847-1911) and the early history of clear-lens operations in high myopia.
Vincenz (Wincenty) Fukala, was born in 1847 in Zolkiew at Galicia in Poland, studied medicine and ophthalmology in Vienna in 1871. He was a pioneer in systematically extracting the clear crystalline lens in young patients with high myopia. He demonstrated the benefit to this group of increased visual acuity which enabled them to work and ophthalmologists gradually began to carry out surgery in high myopes worldwide. He persisted in operating despite the vigorous opposition of several authorities but, through sheer determination he convinced skeptics of the efficacy of his surgical method of lens dissection. He performed the first lens discission in 1887 and in 1894, he had successfully treated 44 patients. The late complication of retinal detachment, which was not understood until years later, eventually led surgeons to abandon the procedure until the recent improvements in both lenticular and retinal surgery techniques that led to better prognosis.


Cruveilhier-Baumgarten disease with associated splenic artery aneurysms.
Cruveilhier-Baumgarten Disease is a rare clinical entity. The distinction between C-B Disease and C-B syndrome rests solely on the liver morphology. In C-B Disease, the liver is morphologically normal. A case of a 27-year-old juvenile diabetic female with C-B Disease is presented. She manifested many of the metabolic and hemodynamic changes of cirrhosis including portal hypertension, encephalopathy, and a hyperdynamic cardiovascular state. There was also associated splenomegaly, hypersplenism, and splenic artery aneurysms. Splenectomy and splenic artery ligation were performed. Liver biopsies had normal morphology. The patient has had no recurrence of her symptoms. The pathogenesis of C-B Disease is unknown.


The influence of the extraction voltage on the energetic electron population of an electron cyclotron resonance ion source plasma.
An influence of the extraction voltage on the high energy slope of bremsstrahlung radiation spectra has been reported in ECRIS experiments, which is not well understood so far. In order to provide more detailed data on this effect, we have measured bremsstrahlung radiation spectra accompanying especially the evolution of highly charge ions (i.e., by monitoring the Ar(14+) charge state) as the extraction voltage is changed from 0 to 20 kV, in dedicated experiments at the Frankfurt 14 GHz-ECRIS.


ADVANCE: Towards near real-time monitoring of vaccination coverage, benefits and risks using European electronic health record databases.
The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private partnership aiming to develop and test a system for rapid benefit-risk (B/R) monitoring of vaccines using European electronic health record (eHR) databases. This proof-of-concept study aimed to test the feasibility of near real-time (NRT) monitoring of vaccination coverage, benefits and risks based on multiple European eHR databases, using acellular pertussis vaccination in children aged <6 years as test case. A qualitative feasibility assessment on NRT monitoring was carried out using a survey and face-to-face discussion with ADVANCE data partners. Subsequently, a dynamic cohort study was conducted containing two distinct observation periods: a first period to establish a baseline (Jan 2014 to Mar 2018) and a subsequent 3-month period to test the actual feasibility of weekly NRT monitoring, based on which data latencies were calculated. An interactive web-application was additionally developed to facilitate the visual monitoring of vaccination coverage, the vaccine preventable disease incidence rates (benefits) and the incidence rates of adverse events (risks). Nine databases from four countries (Denmark, Italy, Spain and UK) participated in the qualitative feasibility assessment. Of them, five databases took part in the dynamic cohort study, with 5 databases providing baseline data and 3 databases participating to the NRT monitoring, providing data extractions on an almost weekly basis. The median data latency (time between event date and data release date) was between 1 and 2 weeks except for the benefit and risk events in one of the databases (latency 16 weeks). Three European eHR databases successfully demonstrated the feasibility of providing data for weekly NRT monitoring, with short data latencies of 1-2 weeks for most events.


The influence path of caregivers' positive aspects, expressed emotion and coping style on behavioral and psychological symptoms of dementia.
To analyze the correlation and mechanism of action among caregivers' expressed emotion, positive aspects, coping style and the behavioral and psychological symptoms of people with dementia by using the theory of planned behavior as a framework. We investigated 193 pairs of people with dementia and caregivers to assess patients' behavioral and psychological symptoms, as well as caregivers' expressed emotion, positive aspects and coping style. Regression analysis and structural equation modeling were used. Dementia severity and psychotropic drug use were influencing factors of behavioral and psychological symptoms. Caregivers' positive aspects predicted expressed emotion and coping style, while expressed emotion predicted behavioral and psychological symptoms. Expressed emotion played a completely mediating role between caregivers' positive aspects and dementia patients' behavioral and psychological symptoms. Health care professionals should follow strict guidelines on medication, and focus on the caregiver's emotional state to reduce adverse effects on the person with dementia.


The Association of Penile Fracture and Female Sexual Abnormalities.
To study the effect of female sexual abnormalities on the etiology of penile fracture, which is an important urological emergency. The sexual function of the partners of patients with penile fracture (study group, n = 90) treated at our clinic and healthy women (control group, n = 90) were evaluated on a voluntary basis. In both groups, sexual function was evaluated with the Female Sexual Function Index (FSFI). Each substance of the FSFI was evaluated separately by comparing both groups and the effect on the development of penile fracture was investigated. There was no difference in demographic and clinical characteristics between the study and control groups. Evaluation of sexual function with FSFI revealed that the scores of vaginal lubrication, orgasm, satisfaction, and pain subscales were lower in the study group (p < .001). Among these subscales, anorgasmia was determined as the factor with the largest effect on the development of penile fracture (OR = 7.333, 95% CI = 2.666-20.166, p < .001). No correlation was found between the largest dimension of penile fracture and FSFI total and subscale scores in the study group. We believe that female vaginal dryness and dyspareunia in particular are factors which could cause the development of penile fracture during sexual intercourse. The treatment could prevent the development of penile fracture in the male.


Hand Function in a Population-Based Sample of Young Children with Unilateral or Bilateral Cerebral Palsy.
To describe aspects of hand function in a population-based sample of young children with clinical signs of unilateral or bilateral cerebral palsy (CP). A cross-sectional study with data from national CP registers in Norway. Manual ability was classified with the Manual Ability Classification System (MACS) or Mini-MACS. Hand use in bimanual activities was measured with the Assisting Hand Assessment (AHA) for unilateral CP or the newly developed Both Hands Assessment (BoHA) for bilateral CP. From 202 children, 128 (57 females) were included (Mini-MACS/MACS levels I-V, mean age 30.4 months; SD = 12.1). Manual abilities were distributed across levels I-III in unilateral CP and levels I-V in bilateral CP. Variations in AHA and BoHA units were large. One-way ANOVA revealed associations between higher AHA or BoHA units and Mini-MACS/MACS levels of higher ability (p < 0.01) and higher age (p < 0.04). Compared with young children with unilateral CP, children with bilateral CP showed greater variation in Mini-MACS/MACS levels, and both sub-groups showed large variations in AHA or BoHA units. The classifications and assessments used in this study are useful to differentiate young children's ability levels. Such information is important to tailor upper limb interventions to the specific needs of children with CP.


Prostate Stromal Tumor of Uncertain Malignant Potential: Case Report With 5-Year Follow-up.
Prostate stromal tumor of uncertain malignant potential is a term used to describe a specialized proliferation of stromal cells within the prostate. Most of these tumors tend to be benign, but some can present with local invasion or progress to prostatic stromal sarcoma with distant metastasis. We report a case of a 62-year-old male patient who presented to us with a diagnosis of stromal tumor of uncertain malignant potential. We have followed up the patient for 5 years with imaging, prostate-specific antigen checks, and annual prostate biopsies.


Partitioning of individual flexible polymers into a nanoscopic protein pore.
Polymer dynamics are of fundamental importance in materials science, biotechnology, and medicine. However, very little is known about the kinetics of partitioning of flexible polymer molecules into pores of nanometer dimensions. We employed electrical recording to probe the partitioning of single poly(ethylene glycol) (PEG) molecules, at concentrations near the dilute regime, into the transmembrane beta-barrel of individual protein pores formed from staphylococcal alpha-hemolysin (alphaHL). The interactions of the alpha-hemolysin pore with the PEGs (M(w) 940-6000 Da) fell into two classes: short-duration events (tau approximately 20 micro s), approximately 85% of the total, and long-duration events (tau approximately 100 micro s), approximately 15% of the total. The association rate constants (k(on)) for both classes of events were strongly dependent on polymer mass, and values of k(on) ranged over two orders of magnitude. By contrast, the dissociation rate constants (k(off)) exhibited a weak dependence on mass, suggesting that the polymer chains are largely compacted before they enter the pore, and do not decompact to a significant extent before they exit. The values of k(on) and k(off) were used to determine partition coefficients (Pi) for the PEGs between the bulk aqueous phase and the pore lumen. The low values of Pi are in keeping with a negligible interaction between the PEG chains and the interior surface of the pore, which is independent of ionic strength. For the long events, values of Pi decrease exponentially with polymer mass, according to the scaling law of Daoud and de Gennes. For PEG molecules larger than approximately 5 kDa, Pi reached a limiting value suggesting that these PEG chains cannot fit entirely into the beta-barrel.


[Preliminary assessment of ginkgo biloba (Ginkofar) in patients with dementia].
This preliminary open-label study was undertaken to assess the efficacy and tolerability of ginkgo biloba (Ginkofar) (manufactured by Biofarm Poznań) during a 6-month period in Alzheimer type dementia, vascular and mix dementia. Patients were required to have at entry a diagnosis of dementia Alzheimer type or vascular according to ICD-10 criteria. The presence of both types of dementia was classified as mix dementia. 30 patients were included into the study. Overall 27 patients entered treatment and completed a 6 months period. Results of clinical scales (IADL, Clock Test) during period of treatment (baseline, 3 months and 6 months) were stable. MMSE results demonstrated slight benefit. The results show that ginkgo biloba was well tolerated. The patients treated with Ginkofar remaining in the study demonstrate no clinically evident loss of cognitive function.


Potential of enzyme mimics in biomimetic sensors: a modified-cyclodextrin as a dehydrogenase enzyme mimic.
This paper reports the application of a dehydrogenase enzyme mimic as a biomimetic sensor. The model compound investigated was a beta-cyclodextrin (beta-CD) derivative with a nicotinamide group attached to the secondary face of a beta-CD (Fig. 1g). It was envisaged that the nicotinamide group would act as the electron transfer agent and that the cyclodextrin would provide a suitable hydrophobic cavity for the reaction to take place in. Ethanol, propranalol, dopamine and acetone were used as substrates in backgrounds of hydrophilic and hydrophobic anions. Electrochemical and fluorescence techniques were used to study the catalytic effects in solution. It was found that the size of the analyte and the hydrophobicity of the anion affected the catalytic activity of the dehydrogenase mimic. Catalytic effects were most enhanced with ethanol and dopamine in presence of larger and more strongly solvated anions, SO4(2-) and H2PO4- which are excluded from the cavity. The molecule was also immobilised in a sol-gel matrix and investigated as a sol-gel electrochemical biomimetic sensor. Concentration dependence with increasing aliquots of ethanol was observed. These results indicated that a re-usable biomimetic sensor is indeed feasible.


Cryptogenic organizing pneumonia. Characteristics of relapses in a series of 48 patients. The Groupe d'Etudes et de Recherche sur les Maladles "Orphelines" Pulmonaires (GERM"O"P).
Cryptogenic organizing pneumonia (COP) is a clinicopathologic syndrome characterized by rapid resolution with corticosteroids, but frequent relapses when treatment is tapered or stopped. We retrospectively studied relapses in 48 cases of biopsy-proven COP. One or more relapses (mean 2.4 +/- 2.2) occurred in 58%. At first relapse, 68% of patients were still under treatment for the initial episode. Compared with the no-relapse group, nine patients with multiple (>/= 3) relapses had longer delays between first symptoms and treatment onset (22 +/- 17 versus 11 +/- 8 wk, p = 0.02), and elevated gamma-glutamyltransferase (124 +/- 98 versus 29 +/- 13 IU/L, p = 0.001) and alkaline phosphatase (190 +/- 124 versus 110 +/- 68 IU/L, p = 0.04) levels. Relapses did not adversely affect outcome. Corticosteroid treatment side effects occurred in 25% of patients. Standardized treatment in 14 patients allowed a reduction of prednisone cumulated doses (p < 0.05) without affecting outcome or relapse rate. We conclude that: (1) delayed treatment increases the risk of relapses; (2) mild cholestasis identifies a subgroup of patients with multiple relapses; (3) relapses do not affect outcome, and prolonged therapy to suppress relapses appears unnecessary; (4) a standardized treatment allows a reduction in steroid doses.


Ric-8B interacts with G alpha olf and G gamma 13 and co-localizes with G alpha olf, G beta 1 and G gamma 13 in the cilia of olfactory sensory neurons.
Olfactory sensory neurons are able to detect odorants with high sensitivity and specificity. We have demonstrated that Ric-8B, a guanine nucleotide exchange factor (GEF), interacts with Galphaolf and enhances odorant receptor signaling. Here we show that Ric-8B also interacts with Ggamma13, a divergent member of the Ggamma subunit family which has been implicated in taste signal transduction, and is abundantly expressed in the cilia of olfactory sensory neurons. We show that Gbeta1 is the predominant Gbeta subunit expressed in the olfactory sensory neurons. Ric-8B and Gbeta1, like Galphaolf and Ggamma13, are enriched in the cilia of olfactory sensory neurons. We also show that Ric-8B interacts with Galphaolf in a nucleotide dependent manner, consistent with the role as a GEF. Our results constitute the first example of a GEF protein that interacts with two different olfactory G protein subunits and further implicate Ric-8B as a regulator of odorant signal transduction.


Primary and Recurrent Growing Teratoma Syndrome in Central Nervous System Nongerminomatous Germ Cell Tumors: Case Series and Review of the Literature.
The term "growing teratoma syndrome (GTS)" has been used as follows: patients with germ cell tumor (GCT) who present with enlarging original/metastatic masses during or after appropriate systemic chemotherapy despite normalized serum markers. In other words, the definition of the term GTS is not fully established. We analyzed and reviewed our case series regarding GTS that developed after the treatment of central nervous system (CNS) nongerminoatous germ cell tumors (NGGCTs). Our institutional review board approved this retrospective study. Between 2003 and 2018, we treated 16 patients (16 males; age ranging from 5.4 to 51.9 years, median 13.8) with CNS-NGGCT at our institution. We reviewed those patients and also reviewed the literature about GTS of CNS. We defined primary GTS (p-GTS) as the enlargement of cyst size and/or solid tumor occurred during treatment in the absence of marker elevation, and recurrent GTS (r-GTS) as the enlargement of teratoma after complete response of initial tumors. Among 16 patients with CNS-NGGCT, we surgically confirmed mature/immature teratoma components in 15 patients. Two patients underwent surgical removal of tumor before neoadjuvant therapy, and among the rest 14 patients, 6 developed p-GTS, and 2 patients underwent salvage surgery during chemo-/chemoradiotherapy. Those with histologic diagnosis of immature teratoma during salvage surgery had a shorter interval from the initiation of chemoradiotherapy compared with mature teratoma (P < 0.05). One patient developed r-GTS. In the literature review, most of the p-GTS consisted of enlargement with the multicystic component. Histologic diagnosis of immature teratoma during salvage surgery was observed in earlier stages of chemoradiotherapy (P < 0.05, log-rank test). Previous history of p-GTS might be a risk factor of r-GTS. The incidence of p-GTS, enlargement of the cystic component during treatment, is not rare. Physicians need to be aware of this important phenomenon.


Cytospora species from Populus and Salix in China with C. davidiana sp. nov.
Poplar and willow plantations have become widespread in China, in order to meet national economic and environmental needs. The emergence of several pathogens is enhanced by climatic change and associated human factors. Species of Cytospora are well-known pathogens on poplar and willow, and cause stem cankers and diebacks. In the present study, we conducted a survey of Cytospora species occurring on Populus spp. and Salix spp. in China. We used morphological examination and phylogenetic inferences, based on the DNA sequence data from the internal transcribed spacer regions (ITS1, 5.8S rDNA, and ITS2) and partial β-tubulin gene, to identify six Cytospora species occurring on poplar and willow. Five of these species belonged to known taxa, viz. Cytospora chrysosperma (asexual state of Valsa sordida), Cytospora translucens (asexual state of Leucostoma translucens), Cytospora fugax (asexual state of Valsa salicina), Cytospora atrocirrhata, and Cytospora kantschavelii. Our study yielded a new species, Cytospora davidiana sp. nov., on poplar. The new species is characterized by typical torsellioid conidiomata. An additional Cytospora sp. 1, which formed a distinct clade in the phylogenetic inferences, remains unnamed; the paucity of available materials prevented phenotypical characterization.


Increased plasma adrenomedullin in women with recurrent pregnancy loss.
To evaluate vascular changes and uterine perfusion in women with recurrent pregnancy loss. We measured plasma levels of adrenomedullin of 100 pregnant women in the midluteal phase of a nonpregnant cycle (control group: n = 62; recurrent pregnancy loss group: n = 38). We measured the pulsatility index (PI) in the uterine arteries by transvaginal pulsed Doppler ultrasonography at the same time. The plasma level of adrenomedullin in women with recurrent pregnancy loss (5.6 +/- 1.9, mean +/- standard deviation) was significantly higher (P >.001) than that in control women (3.6 +/- 1.7). Uterine arterial PI of women with recurrent pregnancy loss (2.70 +/- 0.47) was significantly higher (P >.001) than that in control women (2.09 +/- 0.39). Plasma level of adrenomedullin had a significant positive correlation with uterine arterial PI both in the control group (r =.58, P <.001) and in the recurrent pregnancy loss group (r =.78, P <.001). Both plasma adrenomedullin concentration (7.2 +/- 2.3) and uterine arterial PI (3.06 +/- 0.36) were significantly high in women with antiphospholipid antibodies. Plasma adrenomedullin may serve as a useful biochemical marker for recurrent pregnancy loss caused by impaired uterine perfusion.


The feasibility of web surveys for obtaining patient-reported outcomes from cancer survivors: a randomized experiment comparing survey modes and brochure enclosures.
Central cancer registries are often used to survey population-based samples of cancer survivors. These surveys are typically administered via paper or telephone. In most populations, web surveys obtain much lower response rates than paper surveys. This study assessed the feasibility of web surveys for collecting patient-reported outcomes via a central cancer registry. Potential participants were sampled from Utah Cancer Registry records. Sample members were randomly assigned to receive a web or paper survey, and then randomized to either receive or not receive an informative brochure describing the cancer registry. We calculated adjusted risk ratios with 95% confidence intervals to compare response likelihood and the demographic profile of respondents across study arms. The web survey response rate (43.2%) was lower than the paper survey (50.4%), but this difference was not statistically significant (adjusted risk ratio = 0.88, 95% confidence interval = 0.72, 1.07). The brochure also did not significantly influence the proportion responding (adjusted risk ratio = 1.03, 95% confidence interval = 0.85, 1.25). There were few differences in the demographic profiles of respondents across the survey modes. Older age increased likelihood of response to a paper questionnaire but not a web questionnaire. Web surveys of cancer survivors are feasible without significantly influencing response rates, but providing a paper response option may be advisable particularly when surveying older individuals. Further examination of the varying effects of brochure enclosures across different survey modes is warranted.


Incisional hernia at the site of a stoma.
Incisional hernia at the site where a patient had previously had a stoma has not been clearly studied. The aim of this study is to determine the incidence and associated factors that may lead to an incisional hernia related to the reversal of an intestinal stoma. An analysis was made of 70 cases of intestinal reconnection. All patients received Cefotaxime or Ceftazidime during anaesthesia induction and two more doses at 1-8 h in the post-operative period. In all of the cases, closure of the stoma site was effected as a primary closure using no. 1 polyglycolic acid continuous suture. There followed wound lavage with iodopovidone, and the skin was closed with simple sutures using polypropylene 3/0. No drain was left in situ in any of the cases. The study considered the following aspects: demographic characteristics of the study group; illnesses giving rise to the need for stoma formation; the stoma site itself; clinical aspects, including body mass index (BMI); the incidence of incisional hernia; and any complications involving the surgical wound. At this hospital, the cause of requiring treatment with stoma formation was diverticular disease of the colon principally, and the age of the patients varied from 36 to 87 years (median 61). The incidence of incisional hernia at the stoma site was 22 cases (31.4%), presenting equally in both sexes and with greater frequency under the following circumstances: during the first year of follow-up and in patients with concomitant illnesses, principally diabetes. Local complications involving the surgical wound occurred in six cases (8.5%). The incidence of incisional hernia at the stoma site was found to be 31.4% in this study, which is a high incidence of hernias with simple repair.


SOLVx therapeutics vaccine - Activate T-cell immunity using broad surveillance epitope strategy against mutant strains SARS-COV2.
Highly mutable Coronavirus-19 continuously reconstructs its genome and renders prophylactic vaccines ineffective. The objective of the present study was to demonstrate the anti-viral efficacy and safety of the SOLVx therapeutics vaccine. The peptides were designed with Neo7Logix R&D and synthesized with Genescript GLP laboratory with 95 % purity. BALB/C mice were used to develop the HCoV-229E mutant coronavirus model and viral mRNA confirmation in the lung tissue was assessed with qPCR. Mice were euthanized and effects of treatment on various parameters (Viral mRNA in lungs, cytokine levels, PBMC differentiation, hematological and biochemical) were assessed with respective biological samples. Immuno-typing analysis of PBMCs by flowcytometry showed marked increase in T cell subsets, % of B cells and NK cell population in mice treated with SOLVx (Series 1) in a dose dependent manner. Serum immunoglobulin G, and M levels were increased significantly (P < 0.001). In the peptide treatment groups, there was a dose dependent statistically significant decrease in IL-6, IL-10 and TNF-α levels (P < 0.001). IFN-γ was elevated in treatment group significantly (P < 0.001). In conclusion, the qPCR results suggested that the SOLVx vaccine (Series 1) reduced the SARS-COV2 virus infectivity in a dose dependent manner. The humoral, cellular and functional activity of the SOLVx showed that it worked through multi-mechanistic targeting the virus evolution, offering immune response, defense and eradication of the SARS-COV2 virus.


Molecular features and immunological properties of lactate dehydrogenase C4 isozymes from mouse and rat testes.
With the use of a computer graphics system, spacefilling models of mouse and rat testis lactate dehydrogenase C4 (LDH-C4) isozymes were constructed from amino acid sequence and published x-ray diffraction data. Thirty-two residues that differ between the mouse and rat LDH-C4 sequences are also displayed on the monomeric and tetrameric lactate dehydrogenase molecules. Immunological properties of mouse and rat LDH-C4 isozymes are compared and related to these 32 differences. Possible relationships between the structure, especially the amino acid sequence, and the unique enzymatic properties of LDH-C4 isozymes are also discussed.


Identification of galloylated propelargonidins and procyanidins in buckwheat grain and quantification of rutin and flavanols from homostylous hybrids originating from F. esculentumxF. homotropicum.
The flavonoid rich grain of buckwheat (Fagopyrum esculentum Moench, Fam. Polygonaceae) is of high nutritional value. With the aim to improve its agronomic productivity, cultivars were crossed with the wild species F. homotropicum which, however, differs in its flavonoid content. The intention of this work was to determine the flavonoid composition in developed interspecific hybrids and to elucidate the proanthocyanidin structures. Seven compounds were purified from methanol extracts of buckwheat (Fagopyrum esculentum Moench) grains by Sephadex LH-20 column chromatography. Beside the procyanidin epicatechin-[4-8]-epicatechin-3-O-(3,4)-dimethylgallate the following propelargonidins were identified: epiafzelechin-[4-6]-epicatechin, epiafzelechin-[4-8]-epiafzelechin-[4-8]-epicatechin, epiafzelechin-[4-8]-epicatechin-3-O-(3,4-dimethyl)-gallate, epiafzelechin-[4-8]-epiafzelechin-[4-8]-epicatechin-3-O-(3,4-dimethyl)-gallate, epiafzelechin-[4-8]-epicatechin-3-O-4-methyl-gallate and epiafzelechin-[4-8]-epicatechin-p-OH-benzoate on the basis of HPLC and LC-MS/MS.


Subepidermal Calcinosis Cutis of Ear: Case Report with Review of Literature.
Subepidermal Calcified Nodule of Ear is an uncommon lesion which is a type of Idiopathic Calcinosis Cutis. It is characterised by calcium deposits in an otherwise normal tissue with no underlying defects in Calcium or phosphorus homeostasis. With an unknown etiopathogenesis, it is usually seen in the paediatric age group. Final diagnosis need a clinicopathological correlation and it underlines the importance of post operative lab investigations which the patient must undergo to rule out any other underlying pathology. We present case of an 8 year old girl with subepidermal calcified nodule of left ear auricle which is a rare occurrence.


Medical management of radiation enteritis--an algorithmic guide.
An algorithmic guide to the differential diagnosis and management of late radiation enteritis is proposed. The proposition is based on physiological principles and clinical experience rather than on published reports. Too few patients with late radiation enteritis are seen in most oncology centres for a large prospective trial of the algorithm to be set up, but we hope it will stimulate further investigation.


A correlated morphometric and biochemical study of estrogen-induced vitellogenesis in male Rana pipiens.
Adult male Rana pipiens were administered estradiol-17 beta to induce vitellogenesis. Liver and blood were taken from control animals and experimental animals on Days 1, 2, 4, 8, 12, 16, and 120 following hormone treatment. Stereological analysis of livers showed that mitochondrial structural parameters remained constant while rough endoplasmic reticulum (RER) parameters increased significantly by 4 days and to more than four times control, or 120-day levels, by 8-16 days. Liver RNA concentration increased 2.5-fold and in parallel with RER, while liver protein and DNA concentrations did not change. Increases in total plasma protein and plasma vitellogenin (Vg) lagged behind increases in liver RER and RNA. Of the total plasma protein, Vg constituted 6% by 4 days, 40% by 12-16 days and less than 2% by 120 days. The half-life of plasma Vg was estimated to be no greater than 22 days. These studies provide the first quantitative correlations between ultrastructural and biochemical changes occurring in frog tissues following estrogen administration.


Statins and cancer: current and future prospects.
Statins are inhibitors of 3-hydroxy-methylglutaryl (HMG) CoA reductase. They exhibit effects beyond cholesterol reduction, including anticancer activity. This review presents the effects of statins in vitro and their possible molecular anticancer mechanisms and critically discusses the data regarding the role of statins in cancer prevention. Finally, this review focuses on the use of statins combined with other chemotherapeutics to increase the effectiveness of cancer treatments. Despite rare and inconclusive clinical data, the preclinical results strongly suggest that such combined treatment could be a promising new strategy for the treatment of certain tumor types.


Modeling the role of land conversion on the spread of an epizootic disease.
Land conversion and the resulting contact between domesticated and wild species has arguably been the single largest contributor to the emergence of novel epizootic and zoonotic diseases in the past century. An unintended consequence of these interactions is zoonotic or epizootic disease spillovers from wild species to humans and their domesticates. Disease spillovers are edge effects of land conversion and are sensitive to the size and shape of converted areas. We combine spatial metrics from landscape ecology with theoretical epidemiological models to understand how the size and shape of land conversion affect epizootic and zoonotic disease transmission of single and two species populations. We show that the less compact the converted area, and the greater the depth of the contact zone, the more rapidly will an introduced disease spread through the domesticated population.


Descriptive epidemiology of epilepsy in the U.S. population: A different approach.
Determine prevalence and incidence of epilepsy within two health insurance claims databases representing large sectors of the U.S. A retrospective observational analysis using Commercial Claims and Medicare (CC&M) Supplemental and Medicaid insurance claims data between January 1, 2007 and December 31, 2011. Over 20 million continuously enrolled lives of all ages were included. Our definition of a prevalent case of epilepsy was based on International Classification of Diseases, Ninth Revision, Clinical Modification-coded diagnoses of epilepsy or seizures and evidence of prescribed antiepileptic drugs. Incident cases were identified among prevalent cases continuously enrolled for ≥ 2 years before the year of incidence determination with no epilepsy, seizure diagnoses, or antiepileptic drug prescriptions recorded. During 2010 and 2011, overall age-adjusted prevalence estimate, combining weighted estimates from all datasets, was 8.5 cases of epilepsy/1,000 population. With evaluation of CC&M and Medicaid data separately, age-adjusted prevalence estimates were 5.0 and 34.3/1,000 population, respectively, for the same period. The overall age-adjusted incidence estimate for 2011, combining weighted estimates from all datasets, was 79.1/100,000 population. Age-adjusted incidence estimates from CC&M and Medicaid data were 64.5 and 182.7/100,000 enrollees, respectively. Incidence data should be interpreted with caution due to possible misclassification of some prevalent cases. The large number of patients identified as having epilepsy is statistically robust and provides a credible estimate of the prevalence of epilepsy. Our study draws from multiple U.S. population sectors, making it reasonably representative of the U.S.-insured population.


Presence of biofilm containing viable multiresistant organisms despite terminal cleaning on clinical surfaces in an intensive care unit.
Despite recent attention to surface cleaning and hand hygiene programmes, multiresistant organisms (MROs) continue to be isolated from the hospital environment. Biofilms, consisting of bacteria embedded in exopolymeric substances (EPS) are difficult to remove due to their increased resistance to detergents and disinfectants, and periodically release free-swimming planktonic bacteria back into the environment which may may act as an infection source. To establish whether reservoirs of MROs exist in the environment as biofilms. Following terminal cleaning, equipment and furnishings were removed aseptically from an intensive care unit (ICU) and subjected to culture and scanning electron microscopy (SEM). Samples were placed in 5 mL of tryptone soya broth, sonicated for 5 min before plate culture on horse blood agar, Brillance MRSA and Brilliance VRE agar plates. Samples for SEM were fixed in 3% glutaraldehyde and hexamethyldisilizane (HMDS) prior to sputter-coating with gold and examination in an electron microscope. Biofilm was demonstrated visually on the sterile supply bucket, the opaque plastic door, the venetian blind cord, and the sink rubber, whereas EPS alone was seen on the curtain. Viable bacteria were grown from three samples, including MRSA from the venetian blind cord and the curtain. Biofilm containing MROs persist on clinical surfaces from an ICU despite terminal cleaning, suggesting that current cleaning practices are inadequate to control biofilm development. The presence of MROs being protected within these biofilms may be the mechanism by which MROs persist within the hospital environment.


Gut Microbiota for Health: How Can Diet Maintain A Healthy Gut Microbiota?
The human intestinal tract is colonized by a resilient integrated ecosystem represented by a complex consortium of trillions of microbes [...].


Neuromyelitis optica spectrum disorders with a benign course. Analysis of 544 patients.
Neuromyelitis optica spectrum disorders (NMOSD) most commonly cause severe disability which is related to disease attacks. However, some patients retain good neurological function for a long time after disease onset. To determine the frequency, demographic and the clinical features of good outcome NMOSD, and analyze their predictive factors. We selected patients who met the 2015 International Panel for NMOSD diagnostic criteria from seven MS Centers. Assessed data included age at disease onset, sex, race, number of attacks within the first and three years from onset, annualized relapsing rate (ARR), total number of attacks, aquaporin-IgG serum status, presence of cerebrospinal fluid (CSF)-specific oligoclonal bands (OCB) and the Expanded Disability Status Scale (EDSS) score at the last follow-up visit. NMOSD was classified as non-benign if patients developed sustained EDSS score >3.0 during the disease course, or benign if patients had EDSS score ≤3.0 after ≥15 years from disease onset. Patients with EDSS <3.0 and disease duration shorter than 15 years were not qualified for classification. We compared the demographic and clinical characteristics of benign and non-benign NMOSD. Logistic regression analysis identified predictive factors of outcome. There were 16 patients with benign NMOSD (3% of the entire cohort; 4.2% of those qualified for classification; and 4.1% of those who tested positive for aquaporin 4-IgG), and 362 (67.7%) with non-benign NMOSD, whereas 157 (29.3%) did not qualify for classification. All patients with benign NMOSD were female, 75% were Caucasian, 75% tested positive for AQP4-IgG, and 28.6% had CSF-specific OCB. Regression analysis showed that female sex, pediatric onset, and optic neuritis, area postrema syndrome, and brainstem symptoms at disease onset, as well as fewer relapses in the first year and three years from onset, and CSF-specific OCB were more commonly found in benign NMOSD, but the difference did not reach statistical significance. Conversely, non-Caucasian race (OR: 0.29, 95% CI: 0.07-0.99; p = 0.038), myelitis at disease presentation (OR: 0.07, 95% CI: 0.01-0.52; p <0.001), and high ARR (OR: 0.07, 95% CI: 0.01-0.67; p = 0.011) were negative risk factors for benign NMOSD. Benign NMOSD is very rare and occurs more frequently in Caucasians, patients with low ARR, and those who do not have myelitis at disease onset.


CCK 8 analgesia and hyperalgesia after intrathecal administration in the rat: comparison with CCK-related peptides.
The C-terminal octapeptide of cholecystokinin (CCK 8) was administered intrathecally to rats. Doses in the nanogram range produced weak but significant antinociception in the paw pressure test five minutes after injection whereas microgram doses of CCK 8 produced hyperalgesia. The CCK 8-induced analgesia or hyperalgesia was not seen in the tail flick test and was not associated with motor incapacitation or any other noticeable side effects. The C-terminal tetrapeptide of CCK (CCK 4) and pentagastrin were found to be ineffective in all tests but caerulein and molluscan cardioexcitatory neuropeptide (FMRF-amide), like CCK 8, produced antinociception in the paw pressure test.


Mechanisms of O2 transport in Andean dogs.
Using previously inserted catheters, 11 dogs native to high altitude (7.5-23 kg bwt) were studied standing and unsedated in Cerro de Pasco, Peru at 4350 meters. Hemoglobin (Hb), hematocrit (Hct), O2 and CO2 contents, PO2, PCO2 and pH were measured in simultaneously obtained arterial and mixed venous blood samples. Blood pressures were measured in the pulmonary artery and the left ventricle and cardiac output (Q) was determined by dye dilution. Moderately higher values for Hb and Hct were found in these dogs. Hb-O2 affinity was no different than that found in sea level dogs: the P50 in the Andean dogs was 31.6 mm Hg at 38 degrees C and pH of 7.4. Because of the low barometric pressure at 4350 m (458 mmHg) the partial pressures of oxygen in inspired and in alveolar air were lower than at sea level: 84.3 and 56.4 mm Hg, respectively. PAO2 and PVO2, were 55.5 and 32.9 mm Hg while the SAO2 and SVO2 were 79.5 and 50.7%, respectively. Marked hyperventilation was observed (PACO2, 25.6 mm Hg) however, pH was normal. Cardiac output was normal (average 162 plus or minus 39 ml/min/kg). Moderate pulmonary arterial hypertension was observed in the presence of normal left ventricular end diastolic pressure suggesting increased pulmonary vascular resistance.


Phytochemical and pharmacological properties of Myristica fragrans Houtt.: an updated review.
Myristica fragrans Houtt. (Myristicaceae), an aromatic evergreen tree, is well known as a commercial source of mace (aril) and nutmeg (seed), which have long been widely used as spices in the culinary field. In addition, various parts of M. fragrans have been used in folk medicine for treating several diseases. Since its extensive uses in the culinary sector and folk medicine, M. fragrans has long attracted a great deal of attention from pharmacologists and chemists. Numerous studies have indicated that M. fragrans contains diverse phytochemicals such as lignans, neolignans, diphenylalkanes, phenylpropanoids, and terpenoids, which exhibit many of pharmacological activities. Among them, macelignan (1), meso-dihydroguaiaretic acid (2), myristicin (111), and malabaricone C (Mal C, 104) are the most active compounds. The aim of this review is to comprehensively summarize the phytochemical and pharmacological properties of M. fragrans that have reported to date.


Second trimester abortion: single dose intra-amniotic injection of prostaglandin F2alpha with intravenous oxytocin augmentation.
One hundred-sixty mid-trimester pregnancies were terminated by intra-amniotic injection of Prostaglandin F2alpha with concomitant intravenous oxytocin. Only four of 77 nulliparas and one of 83 multiparas required a second prostaglandin injection. Mean injection-abortion interval was 22.8 hours, and 17.0 hours respectively. This difference between groups was statistically significant. Four nulliparas sustained uterine trauma, a high incidence suggesting that this method may be ill-advised in these women. Because of the predictable short injection-abortion interval in the multipara, this method can be combined conveniently with surgical sterilization.


Spontaneous cure of domestic pigs experimentally infected by Trypanosoma brucei gambiense. Implications for the control of sleeping sickness.
The existence of a pig reservoir for human African trypanosomosis (HAT) due to Trypanosoma brucei gambiense complicates the fight against this disease. This study, reports results obtained from pigs, which were inoculated with the blood of a person, suffering from HAT in Cameroon. The pigs were reared and kept in the shelter from all contact with Glossina, and monitored for 188 days. The seroconversion was checked by agglutination assays for trypanosomosis (CATT 1.3 and LATEX/T.b.gambiense). The parasitemia was measured by quantitative buffy coat method (QBC) and by polymerase chain reaction method (PCR). In addition, growth was recorded as well as blood counting and blood formulas. The results showed that the pigs were trypanotolerant and cure themselves in less than 6 months. It is concluded that sterilisation of this reservoir could be achieved by tsetse-control measures in 1 year. It confirms the strategy to complement screening and treatment of HAT with tsetse fly control measures.


BACE2 deficiency impairs expression and function of endothelial nitric oxide synthase in brain endothelial cells.
Beta-site amyloid precursor protein (APP)-cleaving enzyme 2 (BACE2) is highly expressed in cerebrovascular endothelium. Notably, BACE2 is one of the most downregulated genes in cerebrovascular endothelium derived from patients with Alzheimer's disease. The present study was designed to determine the role of BACE2 in control of expression and function of endothelial nitric oxide synthase (eNOS). Genetic downregulation of BACE2 with small interfering RNA (BACE2siRNA) in human brain microvascular endothelial cells (BMECs) significantly decreased expression of eNOS and elevated levels of eNOS phosphorylated at threonine residue Thr495, thus leading to reduced production of nitric oxide (NO). BACE2siRNA also suppressed expression of APP and decreased production and release of soluble APPα (sAPPα). In contrast, adenovirus-mediated overexpression of APP increased expression of eNOS. Consistent with these observations, nanomolar concentrations of sAPPα and APP 17mer peptide (derived from sAPPα) augmented eNOS expression. Further analysis established that γ-aminobutyric acid type B receptor subunit 1 and Krüppel-like factor 2 may function as downstream molecular targets significantly contributing to BACE2/APP/sAPPα-induced up-regulation of eNOS. In agreement with studies on cultured human endothelium, endothelium-dependent relaxations to acetylcholine and basal production of cyclic GMP were impaired in cerebral arteries of BACE2-deficient mice. We propose that in the brain blood vessels, BACE2 may function as a vascular protective protein.


Photoassisted Biodegradation of Irradiated Organics in Simulated Nuclear Wastewater.
The extent of dehalogenation and degradation of toxic aromatic compounds in a nuclear wastewater was evaluated using a two-stage system consisting of a photolytic reactor followed by a biological reactor. Experiments were performed by varying the initial 4-chlorophenol (4-CP) concentration from 50 to 1000 mg/L. The UV pretreatment stage improved the overall efficiency of biodegradation of the recalcitrant compound by facilitating degradability in the biological stage. Removal efficiencies greater than 98% were achieved at 4-CP feed concentrations < 50 mg/L. Adding an H2O2 dose of 0.1 mg/L as an oxidant further improved biodegradation under optimum operating conditions for the entire system. Some known aromatic compound degraders such as Pseudomonas aeruginosa and Pseudomonas mendocina were detected in the consortium using the 16S rRNA genetic fingerprint technique. To the authors' knowledge, this is the first study on biodegradation of halogenated aromatic compounds that are copollutants of metallic radionuclides in radioactive wastewater.


Cognitive deficits in bipolar disorder: from acute episode to remission.
Considerable evidence demonstrates that neuropsychological deficits are prevalent in bipolar disorder during both acute episodes and euthymia. However, it is less clear whether these cognitive disturbances are state- or trait-related. We here present the first longitudinal study employing a within-subject pre- and post-testing examining acutely admitted bipolar patients (BP) in depression or mania and during euthymia, aiming to identify cognitive performance from acute illness to remission. Cognitive performance was measured during acute episodes and repeated after at least 3 months of remission. To do so, 55 BP (35 depressed, 20 hypo-/manic) and 55 healthy controls (HC) were tested with a neuropsychological test battery (attention, working memory, verbal memory, executive functioning). The results showed global impairments in acutely ill BP compared to HC: depressed patients showed a characteristic psychomotor slowing, while manic patients had severe deficits in executive functioning. Twenty-nine remitted BP could be measured in the follow-up (dropout rate 48 %), whose cognitive functions partially recovered, whereas working memory and verbal memory were still impaired. However, we found that subthreshold depressive symptoms and persisting sleep disturbances in euthymic BP were associated with reduced speed, deficits in attention and verbal memory, while working memory was correlated with psychotic symptoms (lifetime). This result indicates working memory as trait related for a subgroup of BP with psychotic symptoms. In contrast, attention and verbal memory are negatively influenced by state factors like residual symptoms, which should be more considered as possible confounders in the search of cognitive endophenotypes in remitted BP.


Prevalence and prognostic impact of microembolic signals in arterial sources of embolism. A systematic review of the literature.
To compile available studies using microembolic signal (MES) detection by transcranial Doppler sonography in varying sources of arterial brain embolism. We investigated prevalences of MES and whether MES detection is of proven use for risk stratification. Studies reporting prevalences of MES and the risk of cerebral ischemic events were pooled for patients with symptomatic or asymptomatic carotid stenosis, intracranial artery stenosis, cervical artery dissection, and aortic embolism. MES were reported in 43% of 586 patients with symptomatic and in 10% of 1066 patients with asymptomatic carotid stenosis. Presence of one MES indicated an increased risk of future events [odds ratio (OR): 7.5, 95% confidence interval (CI): 3.6-15.4, p<0.0001 for symptomatic, and OR: 13.4, 95% CI: 6.5-27.4, p<0.0001 for asymptomatic disease). MES were reported in 25% of 220 patients with symptomatic vs. 0% of 86 patients with asymptomatic intracranial stenosis (p<0.0001), Of 82 patients with cervical artery dissection presenting with TIA or stroke, 50% had MES compared with 13% of 16 patients with local symptoms (p=0.006), In patients with aortic embolism, patients with plaques >or= 4 mm more frequently had MES compared with patients with smaller plaques (p=0.04), Data were insufficient to reliably predict future events in patients with intracranial stenosis, cervical artery dissection, and aortic embolism. MES are a frequent finding in varying sources of arterial brain embolism, MES detection is useful for risk stratification in patients with carotid stenosis.


[Determination gentiopicrin in biyanqingdu granulae by SPE-HPLC].
The purpose was to develop SPE-HPLC method for the assay of gentiopicrin in Biyanqingdu Granulae. Separation was performed on a hypersil ODS(2) column (250 mm x 4.6 mm, 5 microm). The mobile phase consisted of methanol: water (30:70, v/v). The flow rate was 1 ml/min. The UV detect wavelength was set at 275nm. Gentiopicrin had a good linear relation in the range of 0. 02235 - 0. 1676 mg/ml, the average recovery was 98.1% with RSD 1.7%. The method is simple, sensitive and rapid and it can be applied to determine the content of Biyanqingdu Granulae.


Behavior of metal implants used in ENT surgery in 7 Tesla magnetic resonance imaging.
Magnetic resonance imaging (MRI) has become increasingly important as an imaging technique in cross-sectional imaging of head and neck diseases. To investigate whether MRI examinations can be performed without risk in patients with metal implants even at higher field strengths, we examined different materials in 7 Tesla MRI. Implants near sensory organs like the middle ear or eye are of particular interest here. Using the 7 Tesla research MRI for small animals, we tested implants made of various metals like titanium, gold, gold/platinum, platinum/iridium, gold-plated silver, PTFE and stainless steel for heating, translocation and rotation according to a standardized protocol. A fiber optic temperature probe measured the heating of the implant before, during and after MRI scanning. None of the implants showed significant heating. The gold-plated stainless steel ventilation tube was the only implant to markedly change its position already in the Petri dish. Of the remaining implants, a trachea support ring, a nose dilatator and the wire from the ventilation tubes moved during vibration of the Petri dish. With exception of two implants, all implants changed positions in the water bath. In the swim test, the gold implants showed the least movement of all the implants. In this study, the properties of the non-ferromagnetic implant materials differed in the 7 Tesla MRI. Stainless steel ventilation tubes, the trachea support ring and the nose dilatator were not suited for the 7 Tesla MRI system, because they changed their position during MRI. In the case of ventilation tubes with a steel wire, the wire should be removed before MRI to prevent injury to the external auditory canal. There was a tendency for the pure gold implants to move less in the 7 Tesla MRI than all other tested materials. General statements cannot be made about the MRI suitability of different implants. Every implant should be individually examined to confirm its definitive MRI compatibility. Particularly, middle ear implants warrant special attention here due to their closeness to the oval window.


Impact of the COVID-19 Pandemic on Epidemiology of Antibiotic Resistance in an Intensive Care Unit (ICU): The Experience of a North-West Italian Center.
The SARS-CoV-2 pandemic caused an increase in intensive care unit (ICU) hospitalizations with a rise in morbidity and mortality; nevertheless, there is still little evidence on the impact of the pandemic on antibiotic resistance in ICUs. This is a retrospective, monocentric epidemiological study. The aim of the study was to describe and analyze the impact of the SARS-CoV-2 pandemic on ICU bacterial resistance patterns. All bacteria isolated from all patients admitted to the E.O. Galliera ICU from January 2018 to December 2022 were included. Antibiotic resistance (AR) profiles were evaluated. A total of 1021 microorganisms were identified, of which 221 (12.47%) had a resistance pattern (resistant organisms; ROs). In this time, there were 1679 patients with a total of 12,030 hospitalization days. The majority of microorganisms were Gram-negative (79.66% in 2018, 77.29% in 2019, 61.83% in 2020, 62.56% in 2021, and 60.75% in 2022), but an increase in Gram-positive microorganisms was observed (20.34 to 39.25% between 2018 and 2022). The prevalence of AR was 19.44% in 2018, 11.54% in 2019, 38.04% in 2020, 34.15% in 2021, and 39.29% in 2022 for Gram-positive microorganisms and 19.86% in 2018, 13.56% in 2019, 18.12% in 2020, 12.41% in 2021, and 12.31% in 2012 for Gram-negative microorganisms. The incidence of ROs showed a COVID-19-related increase in 2020-2021, followed by a lowering trend since 2021, and a new increase in 2022. Possible explanations are antibiotic overtreatment and a decrease in containment measures. An interesting finding was the cumulative lowering trend of carbapenem-resistant K. pneumoniae and P. aeruginosa, probably due to different patient features.


[Interstitial deletion in the long arm of chromosome 7].
An interstitial deletion of 7q (q31.2-q32.3) is reported. Main features of this boy included facial dysmorphy, psychomotor retardation and absence of language.


Synaptic abnormalities of mice lacking toll-like receptor (TLR)-9.
Motor, sensory, and autonomic abnormalities are reported for toll-like receptor 9 (TLR9) knock-out (KO) mice. However, a physiological role of TLR9 in the nervous system is largely unknown. Since altered synaptic transmission can contribute to sensory and motor abnormalities, we evaluated neuromuscular junction (NMJ) function and morphology of TLR9 KO mice. Triangularis sterni nerve-muscle preparations were dissected from TLR9 KO and age-matched control mice. Two-electrode voltage clamp of the motor endplate revealed that the amplitude and frequency of miniature end plate currents (mEPCs) for TLR9 KO NMJs were significantly greater than control. In contrast, mean endplate current (EPC, 1Hz) amplitude was equivalent to control. The ratio of mean EPC to mean mEPC amplitude indicated a decline of quantal content (m) for TLR9 KO NMJs. Furthermore, m declined more rapidly than control in response to 50-Hz stimulus trains. A rightward shift of the mEPC amplitude distribution suggested formation of vesicles containing larger amounts of acetylcholine (ACh). Staining with rhodamine α-bungarotoxin revealed a significant decline of endplate size in TLR9 KO mice. This alteration may result from ACh-induced decline of acetylcholine receptor (AChR) expression resulting from increased frequency and amplitude of mEPCs. At the same time, excessive spontaneous vesicular ACh release may initiate retrograde suppression of excitation-secretion coupling. These data suggest a novel role of TLR9 in the development of the NMJ.


Purification and characterization of a novel glutathione S-transferase from Atactodea striata.
A novel GST isoenzyme was purified from hepatopancreas cytosol of Atactodea striata with a combination of affinity chromatography and reverse-phase HPLC. The molecular weight of the enzyme was determined to be 24 kDa by SDS-PAGE electrophoresis and 48 kDa by gel chromatography, in combination with GST information from literature revealed that the native enzyme was homodimeric with a subunit of M(r) 24 kDa. The purified enzyme, exhibited high activity towards 1-chloro-2,4-dinitrobenzene (CDNB) and 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl). Kinetic analysis with respect to CDNB as substrate revealed a K(m) of 0.43 mM and V(max) of 0.24 micromol/min/mg and a specific activity of 108.9 micromol/min/mg. The isoelectric point of the enzyme was 5.5 by isoelectric focusing and its optimum temperature was 38 degrees C and the enzyme had a maximum activity at approximately pH 8.0. The amino acid composition was also determined for the purified enzyme.


Partial reconstitution of 60S ribosomal subunits from yeast.
Ribosomal 60S subunits active in polyphenylalanine synthesis can be reconstituted from core particles lacking 20-40% of the total protein. These core particles were obtained by treatment of yeast 60S subunits with dimethylmaleic anhydride, a reagent for protein amino groups. Upon reconstitution a complementary amount of split proteins is incorporated into the ribosomal particles, which have the sedimentation coefficient of the original subunits. Ribosomal protein fractions obtained by extraction with 1.25 M NH4Cl, 4 M LiCl, 7 M LiCl, or 67% acetic acid, are much less efficient in the reconstitution of active subunits from these core particles than the corresponding released fraction prepared with dimethylmaleic anhydride. Attempts to reconstitute active subunits from protein-deficient particles obtained with 1.25 M NH4Cl plus different preparations of ribosomal proteins, including the fraction released with dimethylmaleic anhydride, were unsuccessful. Therefore, under our conditions, of the disassembly procedures assayed only dimethylmaleic anhydride allows partial reconstitution of active 60S subunits.


Synthesis, Characterization, and Reactivity of the Group 11 Hydrido Clusters [Ag6H4(dppm)4(OAc)2] and [Cu3H(dppm)3(OAc)2].
The group 11 hydride clusters [Ag6H4(dppm)4(OAc)2] (1) and [Cu3H(dppm)3(OAc)2] (2) (dppm = 1,1-bis(diphenylphosphino)methane) were synthesized in moderate yields from the reaction of M(OAc) (M = Ag, Cu) with Ph2SiH2, in the presence of dppm. Complex 1 is the first structurally characterized homometallic polyhydrido silver cluster to be isolated. Both 1 and 2 catalyze the hydrosilylation of (α,β-unsaturated) ketones. Notably, this represents the first example of hydrosilylation with an authentic silver hydride complex.


MicroRNA expression in preimplantation mouse embryos from Ped gene positive compared to Ped gene negative mice.
The mouse preimplantation embryo development (Ped) gene product, Qa-2, influences the rate of preimplantation embryonic development and overall reproductive success. Here we investigated the expression pattern of two microRNAs, miR-125a and miR-125b, known to be involved in development in lower organisms, in preimplantation embryos from the two-cell, four-cell, eight-cell, morula, and blastocyst stages of development from the congenic B6.K1 (Ped negative) and B6.K2 (Ped positive) strains of mice. B6.K1 and B6.K2 congenic mice differ only in the absence (B6.K1) or presence (B6.K2) of the genes encoding Qa-2 protein. We analyzed the expression of miR-125a and miR-125b in B6.K1 and B6.K2 preimplantation embryos by using real-time PCR. We found no variability in miR-125b expression at any developmental stage in both strains. However, miR-125a expression increased during development in both strains and was ten times higher in Ped negative (B6.K1) embryos than in Ped positive (B6.K2) embryos by the blastocyst stage of development. Our results show that the absence of the Ped gene profoundly affects the level of a miRNA (miR-125a) known to regulate early development. The implication is that miR-125a is likely involved in the regulation of timing of early development in mice.


Nonclinical safety assessment of epigenetic modulatory drugs: Current status and industry perspective.
Pharmaceutic products designed to perturb the function of epigenetic modulators have been approved by regulatory authorities for treatment of advanced cancer. While the predominant effort in epigenetic drug development continues to be in oncology, non-oncology indications are also garnering interest. A survey of pharmaceutical companies was conducted to assess the interest and concerns for developing small molecule direct epigenetic effectors (EEs) as medicines. Survey themes addressed (1) general levels of interest and activity with EEs as therapeutic agents, (2) potential safety concerns, and (3) possible future efforts to develop targeted strategies for nonclinical safety assessment of EEs. Thirteen companies contributed data to the survey. Overall, the survey data indicate the consensus opinion that existing ICH guidelines are effective and appropriate for nonclinical safety assessment activities with EEs. Attention in the framework of study design should, on a case by case basis, be considered for delayed or latent toxicities, carcinogenicity, reproductive toxicity, and the theoretical potential for transgenerational effects. While current guidelines have been appropriate for the nonclinical safety assessments of epigenetic targets, broader experience with a wide range of epigenetic targets will provide information to assess the potential need for new or revised risk assessment strategies for EE drugs.


Estimates of the Public Health Impact of a Pediatric Vaccination Program Using an Intranasal Tetravalent Live-Attenuated Influenza Vaccine in Belgium.
Our objectives were to estimate the public health outcomes of vaccinating Belgian children using an intranasal tetravalent live-attenuated influenza vaccine (QLAIV) combined with current coverage of high-risk/elderly individuals using the trivalent inactivated vaccine. We used a deterministic, age-structured, dynamic model to simulate seasonal influenza transmission in the Belgian population under the current coverage or after extending vaccination with QLAIV to healthy children aged 2-17 years. Differential equations describe demographic changes, exposure to infectious individuals, infection recovery, and immunity dynamics. The basic reproduction number (R 0) was calibrated to the observed number of influenza doctor visits/year. Vaccine efficacy was 80 % (live-attenuated) and 59-68 % (inactivated). The 10-year incidence of symptomatic influenza was calculated with different coverage scenarios (add-on to current coverage). Model calibration yielded R 0 = 1.1. QLAIV coverage of 75 % of those aged 2-17 years averted 374,000 symptomatic cases/year (57 % of the current number), 244,000 of which were among adults (indirect effect). Vaccinating 75 % of those aged 2-11 years and 50 % of those aged 12-17 years averted 333,200 cases/year (213,000 adult cases/year). Vaccinating only healthy children aged 2-5 years generated direct protection but limited indirect protection, even with 90 % coverage (40,800 averted adult cases/year; -8.4 %). Targeting all children averted twice as many high-risk cases as targeting high-risk children only (8485 vs. 4965/year with 75 % coverage). Sensitivity analyses showed the robustness of results. The model highlights the direct and indirect protection benefits when vaccinating healthy children with QLAIV in Belgium. Policies targeting only high-risk individuals or the youngest provide limited herd protection, as school-age children are important influenza vectors in the community.


Anomalous origin of the left coronary artery from the pulmonary trunk with multiple valvar incompetence.
A 63-year-old woman, operated upon for anomalous origin of the left coronary artery from the pulmonary trunk, developed complaints of dyspnea several years later. Echocardiography and angiography showed incompetence of all four cardiac valves. Possible causes of the multiple valvar incompetence are discussed.


Differential expression of RNA and protein of the three pore-forming subunits of the amiloride-sensitive epithelial sodium channel in taste buds of the rat.
Salt taste signals from the rat anterior tongue are probably transduced via epithelial sodium channels (ENaCs) residing in the apical cellular pole of taste cells. The signals are blocked by mucosal amiloride in low microM concentrations. In contrast, the rat vallate papilla does not contribute to amiloride-blockable salt taste. Two approaches were used to probe for the three subunits of ENaC in the anterior and posterior tongue of the rats in sodium balance. (a) Immunohistochemistry with antibodies against ENaC subunits and against amiloride binding sites. In the anterior tongue, reactivity for alpha-, beta-, and gamma-subunits was present in taste buds and lingual epithelium. In the posterior tongue vallate papilla, reactivity for alpha-subunit and for amiloride binding sites was easily demonstrable, whereas that for beta-subunit and especially for gamma-subunit was weaker than in the anterior tongue. (b) RT-PCR techniques were used to probe for the presence of ENaC subunit mRNA. In isolated taste buds of the anterior tongue, mRNA of all three subunits was found, whereas in isolated taste buds of the vallate papilla only mRNA of the alpha-subunit was easily detectable. That of beta- and gamma-subunits was much less abundant. RNA of all three subunits was abundant only in taste buds of the anterior tongue. Therefore, subsets of elongated taste cells do express ENaC, but regional differences exist in the transcription and expression of subunits. The regional differences suggest that amiloride-sensitive salt taste, which requires all three subunits, is present in the anterior but not the posterior tongue of rats, as functional studies indicate.


Dysregulation of early gene response to a mixed meal in skeletal muscle in obesity and type 2 diabetes.
Obesity- and type 2 diabetes mellitus-induced changes in the expression of protein-coding genes in human skeletal muscle were extensively examined at baseline (after an overnight fast). We aimed to compare the early transcriptomic response to a typical single meal in skeletal muscle of metabolically healthy subjects and obese individuals without and with type 2 diabetes. Transcriptomic response (RNA-seq) to a mixed meal (nutritional drink, ∼25 kJ/kg of body mass) was examined in the vastus lateralis muscle (1 h after a meal) in 7 healthy subjects and 14 obese individuals without or with type 2 diabetes. In all obese individuals, the transcriptome response to a meal was dysregulated (suppressed and altered) and associated with different biological processes compared with healthy control. To search for potential transcription factors regulating transcriptomic response to a meal, the enrichment of transcription factor-binding sites in individual promoters of the human skeletal muscle was examined. In obese individuals, the transcriptomic response is associated with a different set of transcription factors than that in healthy subjects. In conclusion, metabolic disorders are associated with a defect in the regulation of mixed meal/insulin-mediated gene expression-insulin resistance in terms of gene expression. Importantly, this dysregulation occurs in obese individuals without type 2 diabetes, i.e., at the first stage of the development of metabolic disorders.NEW & NOTEWORTHY In skeletal muscle of metabolically healthy subjects, a typical single meal normalized to body mass induces activation of various transcription factors, expression of numerous receptor tyrosine kinases associated with the insulin signaling cascade, and transcription regulators. In skeletal muscle of obese individuals without and with type 2 diabetes, this signaling network is poorly regulated at the transcriptional level, indicating dysregulation of the early gene response to a mixed meal.


Lethal hepatopathy and leukodystrophy caused by a novel mutation in MPV17 gene: description of an alternative MPV17 spliced form.
It has recently been reported that mutations in MPV17 gene may be causative of mtDNA depletion syndrome (MDS). Patients with this alteration presented with severe liver failure, hypoglycemia, growth retardation and neurological symptoms during the first year of life. We report on the clinical, biochemical and molecular findings of a patient presenting with lethal hepatopathy, polyneuropathy, neurological regression and leukodystrophy associated with mutations in MPV17. Mitochondrial respiratory chain activities were low in liver and within reference values in muscle. However, levels of mtDNA were markedly reduced both in muscle and liver. A novel homozygous mutation in MPV17, c.70+5G>A (IVS1+5G>A), was identified. This intronic change causes the full-length cDNA loss, probably due to loss of strength of the splice donor site of exon 1. Western blot analysis, performed in liver homogenates, further corroborates these results as the amount of patient's protein was highly reduced, or almost absent, compared with that of controls. We also identified an additional alternative spliced form in controls and in the patient, due to exon 2 skipping, that has not previously been reported.