Fusion of influenza virus in an intracellular acidic compartment measured by fluorescence dequenching.
The fusion of influenza virus with cultured cells has been investigated. The virus was labelled with the fluorescent probe octadecyl rhodamine B and fusion was monitored as fluorescence dequenching due to dilution of the probe from the viral into a cellular target membrane. Fusion with the plasma membrane does not occur, unless the extracellular pH is temporarily lowered. At neutral pH fusion occurs only after a lag phase of 10-15 min, the time required for virus internalization, and the reaction is inhibited by NH4Cl, indicating that it takes place in an intracellular acidic compartment, most likely the endosome. This suggests that influenza virus infects cells via the endocytic pathway.


Transfusion medicine in a developing country - alloantibodies to red blood cells in multi-transfused patients in Saudi Arabia.
Multiple transfusions are frequently complicated by alloimmunization. This retrospective study aims to determine whether alloimmunization could be accounted for by racial differences between donors and recipients. The development of alloantibodies were determined in 68 multi-transfused patients (thalassaemia, n=38) and (sickle cell anemia, n=30). The overall frequency of alloantibody formation in our patients is 22.06%. Thirteen patients received blood from the same ethnic group (Arab) and none developed antibodies, while of 47 patients who received multi-ethnic blood, 10 developed alloantibodies. Alloantibodies formation can be reduced by limiting the transfusion of RBC, collected from donors of the same ethnic origin.


Extranodal T- and NK-cell lymphomas.
Non-cutaneous extranodal NK/T cell lymphoproliferations constitute a heterogenous group of rare neoplasms, occurring primarily in the gastro-intestinal tract, nasal area, spleen, and liver. Their nomenclature refers to their usual clinical presentation and predilection for specific anatomic sites-i.e. extranodal NK/T-cell lymphoma, nasal-type, hepatosplenic T-cell lymphoma, primary intestinal T-cell lymphomas, indolent lymphoproliferative disorders of the gastrointestinal tract, and breast implant-associated anaplastic large cell lymphoma. Extranodal tissues may also be involved by T-cell leukemias, or other entities usually presenting as nodal diseases. Primary extranodal entities range from indolent to highly aggressive diseases. Here, we will review the clinicopathologic features of the pertinent entities including the recent advances in their molecular and genetic characterization, with an emphasis on the changes introduced in the 2022 International Consensus Classification of lymphoid neoplasms, and highlight the diagnostic criteria helpful to sort out the distinction with potential mimickers.


Low bone mineral density in Thai children with systemic lupus erythematosus: prevalence and risk factors.
Improvement of disease recognition and management has increased the survival of children with systemic lupus erythematosus (SLE), but has shifted the morbidity focus toward long-term complications, such as low bone mass and osteoporosis. Studies in adults with SLE show older age, chronic inflammation, and corticosteroid therapy are risk factors for low bone mineral density (BMD) and osteoporosis. To determine the prevalence of and identify risk factors associated with low BMD in Thai children with SLE. We conducted a retrospective review of demographic data and clinical variables for a cohort of 60 Thai children with SLE who underwent 2 dual-energy X-ray absorptiometry (DXA) at their initial examination and later follow-up. We considered a BMD z score ≤ -2.0 to indicate low BMD. Binary logistic regression was used to assess risk factors potentially associated with low BMD. The prevalence of low BMD at the first visit was 40% and increased to 55% over follow-up. We found a significantly decreased hip BMD z score (median difference -0.25, 95% confidence interval [CI] -0.40 to -0.05; P = 0.016) and lumbar BMD z score (median difference -0.49, 95% CI -0.69 to -0.28; P < 0.001) over time. The cumulative steroid dose tended to be higher for patients with low BMD (adjusted odds ratio [OR] = 1.08, 95% CI 1.00 to 1.17; P = 0.050). Low BMD has a 40% prevalence in Thai children newly diagnosed with SLE and progresses significantly over time. Higher cumulative corticosteroid dose tended to be associated with a low BMD, but we did not find a significant risk in this small sample.


Science, politics, and the GM debate in Europe.
Europe today stands at a crossroad, facing challenges but also opportunities. In its intent to make Europe a leading technology-based economy by 2010, the European Commission has identified biotechnology and genomics as fields for future growth, crucial for supporting the agricultural and food processing industry. Since first commercialization in 1996, GM crop areas have grown at double-digit rates, making this one of the most rapidly adopted technologies in agriculture. However, in contrast to other world areas and despite European Commission support, Europe has found itself 'bogged-down' in a polemic between opponents and supporters of plant biotechnology. As a result, planted areas have remained small. This stalemate is due to a lack of political leadership, especially at the Member State level, all the more surprising in light of European early development and competitive advantage with crop biotechnology. This situation proves once again that, for cutting-edge innovations, a solid science base alone is not sufficient. Acceptance or rejection of new technologies depends on interlinked political, economic, and societal factors that create a favorable or unfavorable situation at a given time. This article will look at GM crops in Europe and the role science and politics have played in the introduction of crop biotechnology.


Access to Trifluoromethylketones from Alkyl Bromides and Trifluoroacetic Anhydride by Photocatalysis.
Aliphatic trifluoromethyl ketones are a type of unique fluorine-containing subunit which play a significant role in altering the physical and biological properties of molecules. Catalytic methods to provide direct access to aliphatic trifluoromethyl ketones are highly desirable yet remain underdeveloped, partially owing to the high reactivity and instability of trifluoroacetyl radical. Herein, we report a photocatalytic synthesis of trifluoromethyl ketones from alkyl bromides with trifluoroacetic anhydride. The reaction features dual visible-light and halogen-atom-transfer catalysis, followed by an enabling radical-radical cross-coupling of an alkyl radical with a stabilized trifluoromethyl radical. The reaction provides straightforward access to aliphatic trifluoromethyl ketones from readily available and cost-effective alkyl halides and trifluoroacetic anhydride (TFAA).


Development of specific antibody patterns and clinical symptoms following Ockelbo virus infection.
Sixteen patients with symptoms typical for Ockelbo disease (rash, arthralgia, fever) were enrolled in a 2 1/2 year study, during which clinical symptoms were recorded and ELISA was employed to study specific IgM, IgG and IgG subclass development. Initially, all patients presented with rash and arthralgia, and five patients still suffered from joint symptoms at the end of the study period. Ockelbo virus specific IgM was detected during the first week post onset in 6 patients and in 15 patients by day 14. One patient failed to develop specific IgM and was later diagnosed with a human parvovirus B19 infection. All patients were IgM-negative 2 1/2 years post onset. Seroconversions or significant titer rises for specific total IgG were seen in 15 patients. IgG titers generally peaked within one year but in two patients maximum titers were seen 2 1/2 years post onset. Development of IgG1 followed that of total IgG, while IgG3, after an initial increase in all Ockelbo disease patients, remained at peak levels for one year in four patients, three of whom still had detectable IgG3 at the end of the study period. Ockelbo virus specific IgG2 or IgG4 was not detected in any of the patients.


Effects of engineered nanoparticles on the innate immune system.
Engineered nanoparticles (NPs) have broad applications in industry and nanomedicine. When NPs enter the body, interactions with the immune system are unavoidable. The innate immune system, a non-specific first line of defense against potential threats to the host, immediately interacts with introduced NPs and generates complicated immune responses. Depending on their physicochemical properties, NPs can interact with cells and proteins to stimulate or suppress the innate immune response, and similarly activate or avoid the complement system. NPs size, shape, hydrophobicity and surface modification are the main factors that influence the interactions between NPs and the innate immune system. In this review, we will focus on recent reports about the relationship between the physicochemical properties of NPs and their innate immune response, and their applications in immunotherapy.


Blood coagulation studies in patients with advanced carcinoma of the prostate treated with 2,6-cis-diphenylhexamethylcyclotetrasiloxane or estramustine-17-phosphate.
Two drugs, 2,6-cis-diphenylhexamethylcyclotetrasiloxane (Cisobitan) and estramustine-17-phosphate (Estracyt) were given to patients with poorly differentiated metastatic carcinoma of the prostate. The effect of the drugs on blood coagulation was investigated. Some parameters showed changes during the treatment: Antithrombin III decreased in the Estracyt treated patients to a level which might imply a thrombogenic effect. Fibrinogen decreased, whereas factor VIII showed no consistent change. Normotest changes appeared to correlate with liver damage whereas antithrombin III showed no change. Increased levels of fibrinogen degradation products and fibrinopeptide A (FPA) were more frequent in the group of deteriorating patients. However, the number of FPA analyses were too small for any definite conclusions regarding possible disseminated intravascular coagulation.


Discovery of WQ-3810: Design, synthesis, and evaluation of 7-(3-alkylaminoazetidin-1-yl)fluoro-quinolones as orally active antibacterial agents.
Novel 7-(3-alkylaminoazetidin-1-yl)fluoroquinolones were designed, synthesized, and evaluated for their antibacterial activities and oral absorption rates. Against Gram-negative bacteria, 10a-e, which have various alkyl groups containing different numbers of carbon atoms (C0-C3) at the C-7 alkylaminoazetidine position, showed potent and similar antibacterial activities, whereas the activity of 10f (C4, t-Bu) was significantly lower than those of 10a-e. Conversely, the oral absorption rates of 10a-e in rats increased depending on the number of carbon atoms in the alkyl groups; 10d (C3, n-Pr) and 10e (C3, i-Pr) had high oral absorption rates (>90% at 10 mg/kg). These results demonstrated that the introduction of alkyl groups onto C-7 aminoazetidine is useful for the improvement of the oral absorption rates of these drugs while maintaining their antibacterial activities. As a conclusion, from this series of fluoroquinolones, WQ-3810 (10e), having 3-isopropylaminoazetidine as the C-7 substituent, was identified as an orally active antibacterial agent with a potent in vitro activity.


Prevalence of hypertension among adolescents: systematic review and meta-analysis.
To estimate the prevalence of hypertension among adolescent Brazilian students. A systematic review of school-based cross-sectional studies was conducted. The articles were searched in the databases MEDLINE, Embase, Scopus, LILACS, SciELO, Web of Science, CAPES thesis database and Trip Database. In addition, we examined the lists of references of relevant studies to identify potentially eligible articles. No restrictions regarding publication date, language, or status applied. The studies were selected by two independent evaluators, who also extracted the data and assessed the methodological quality following eight criteria related to sampling, measuring blood pressure, and presenting results. The meta-analysis was calculated using a random effects model and analyses were performed to investigate heterogeneity. We retrieved 1,577 articles from the search and included 22 in the review. The included articles corresponded to 14,115 adolescents, 51.2% (n = 7,230) female. We observed a variety of techniques, equipment, and references used. The prevalence of hypertension was 8.0% (95%CI 5.0-11.0; I2 = 97.6%), 9.3% (95%CI 5.6-13.6; I2 = 96.4%) in males and 6.5% (95%CI 4.2-9.1; I2 = 94.2%) in females. The meta-regression failed to identify the causes of the heterogeneity among studies. Despite the differences found in the methodologies of the included studies, the results of this systematic review indicate that hypertension is prevalent in the Brazilian adolescent school population. For future investigations, we suggest the standardization of techniques, equipment, and references, aiming at improving the methodological quality of the studies.


Effect of the addition of vancomycin on the performance of an automated nonradioactive system for detection of mycobacteria.
A recently developed automated, nonradioactive system for the detection of mycobacteria (MB/BacT; Organon Teknika, Belgium) has provided good results, but the contamination rate was found to be higher than that obtained with the radiometric Bactec 460 system (Becton Dickinson, USA). In the present study, the effects of adding vancomycin (1 microg/ml) to the antibiotic mixture of the nonradioactive system were evaluated, and the performance of the system with versus without vancomycin was compared. Three hundred sputum samples were tested, using the radiometric system as the reference method. Mycobacteria were isolated from 47 (15.7%) samples. The nonradioactive system with and without vancomycin detected 42 and 43 strains, respectively; the time to detection was 1 day shorter with the medium without vancomycin (15.7 days vs. 14.3 days). The radiometric system detected 42 strains of mycobacteria in a mean detection time of 13.6 days. Contamination rates with the nonradioactive system were 6.7% in the medium without vancomycin and 2.7% in the medium with vancomycin. The latter figure was approximately the same as the contamination rate found with the radiometric system (2.3%). Our data suggest that the addition of vancomycin considerably reduces the number of contaminants in the MB/BacT medium without affecting the performance of the system.


Effect of temperature on growth and chemotactic behaviour of Campylobacter jejuni.
To determine the effect of two physiologically important temperatures on growth and chemotaxis in Campylobacter jejuni. Growth curves of Camp. jejuni were compared at 37 degrees C and 42 degrees C. Chemotaxis was compared at 37 degrees C and 42 degrees C by the disc and capillary assays. Student's t-test was applied to the results of the capillary assay to assess the significance in the difference between chemotaxis at the two temperatures. Both, the growth rate and chemotactic ability of the isolate, were found to be greater at 37 degrees C. Quorum sensing (related to population density), a regulation mechanism of virulence in micro-organisms, has been reported in Campylobacter. Chemotaxis is also a known virulence factor of Campylobacter. Both, growth (in terms of population density) and chemotaxis, being greater at 37 degrees C than at 42 degrees C, suggests that the physiological temperature of humans (37 degrees C) might be more favourable for the expression of virulence in Campylobacter than that of birds (42 degrees C). It is as yet not known why Campylobacter causes disease in humans but is avirulent in birds. This study suggests that the human body temperature is optimum for growth and chemotaxis in Campylobacter. There is scope for the study of temperature regulation of other virulence determinants of Campylobacter.


Renal complications of acquired immunodeficiency syndrome in children.
A low incidence of renal disease was noted in a retrospective analysis of pediatric patients with acquired immunodeficiency syndrome. Episodes of acute renal failure were attributable to dehydration or nephrotoxicity. One patient, however, had nephrosis with focal glomerular sclerosis. Focal sclerosis involving 10% to 20% of glomeruli was evident in autopsy tissue from three patients.


Generation and characterization of induced pluripotent stem cell lines from two patients with recessive dystrophic epidermolysis Bullosa.
Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a rare and severe genetic disease responsible for blistering of the skin and mucosa caused by a wide variety of mutations in COL7A1 encoding type VII collagen. We have generated Induced Pluripotent Stem Cells (iPSCs) from two RDEB patients' fibroblasts harboring homozygous recurrent mutations in COL7A1. Their pluripotent state was confirmed by gene and protein expression of stem cell markers OCT4, SOX2, TRA1/60 and SSEA4. Embryoid body formation followed by immunostaining and TaqMan scorecard analysis confirmed the capacity of RDEB iPSCs to differentiate into cell types from the three germ layers in vitro.


Precipitation and determination of the onset and course of schizophrenia by substance abuse--a retrospective and prospective study of 232 population-based first illness episodes.
Onset and lifetime prevalence of substance abuse were assessed retrospectively using the IRAOS interview in a population-based, controlled sample of 232 first episodes of schizophrenia (ABC sample). Subjects with schizophrenia were twice as likely as controls to have a lifetime history of substance abuse at the age of first admission (alcohol abuse: 23.7 versus 12.3%; drug abuse: 14.2 versus 7.0%). 88% of the patients with drug abuse took cannabis. The sequence of substance abuse and schizophrenia was studied on the timing of abuse onset and illness onset, the latter as based on various definitions: first sign of the disorder, first psychotic symptom and first admission. 62% of the patients with drug abuse and 51% of those with alcohol abuse began the habit before illness onset (=first sign of the disorder). Abuse onset and illness onset occurred highly significantly within the same month (drug abuse in 34.6%, alcohol abuse in 18.2%). Unexpectedly, no temporal correlation was found between abuse onset and the onset of the first psychotic episode. We concluded that a small proportion of schizophrenias might have been precipitated by substance--mainly cannabis--abuse. Long-term effects of early substance abuse were studied prospectively at six cross-sections over five years from first admission on in a subsample of 115 first episodes of schizophrenia. Abusers showed significantly more positive symptoms and a decrease in affective flattening compared with controls. Five-year outcome as based on treatment compliance, utilization of rehabilitative measures and rate of employment was also poorer for patients with than without early substance abuse.


The shape and free energy of a lipid bilayer surrounding a membrane inclusion.
Membrane inclusion interactions are studied within the scope of continuum theory. We show that the free energy functional for the membrane thickness can be rewritten as a constant times a dimensionless integral. For cylindrical inclusions, the resulting differential equation gives a thickness profile that depends on the radius of the cylinder and one single lipid property, a correlation length that is determined by the ratio of the thickness compressibility and bending moduli. The solutions decay in a non-monotonic fashion with one single observable minimum. A solution for planar geometry may either be explicitly constructed or obtained by letting the radius of the cylinder go to infinity. In dimensionless units the initial derivative of the thickness profile is universal and equal to -1/√2. In physical units, the derivative depends on the size of the hydrophobic mismatch as well as the membrane correlation length and will usually be fairly small but clearly non-zero. The line tension between the protein inclusion and a fluid phase membrane will depend on the hydrophobic mismatch and be of the order of 10 pN (larger for the gel phase). This results in free energy costs for the inclusion that will be up to tens of kJ/mol (in the fluid phase).


Survival associated with cerebrospinal fluid analysis in downer adult dairy cows: A retrospective study (2006-2014).
Threshold values for total nucleated cell count (TNCC) and protein concentration in cerebrospinal fluid (CSF) of downer dairy cows suggestive of a spinal cord lesion were recently published. Determine short- and long-term survival of downer cows that underwent CSF analysis using the reported threshold values. Evaluate the prognostic value of these threshold values to predict short- and long-term survival. Two hundred and fourteen downer adult dairy cows that underwent CSF analysis during hospitalization at the Centre Hospitalier Universitaire Vétérinaire (CHUV) of the Université de Montréal. Retrospective study. Medical records of downer adult dairy cows presented to the hospital between January 2006 and October 2014 for which CSF analysis results were available were studied. Short-term (discharge from hospital) and long-term (completion of lactation) survival were determined and compared in accordance with CSF TNCC and protein concentration, using a Chi-square test. Cows with CSF TNCC and/or protein concentration above the threshold values had a significantly lower short-term survival rate (P = .02). The odds of nonsurvival of cows with one or both CSF values above the threshold values was 2.16 times higher than the odds for cows with values under the threshold values. CSF TNCC >4.5 cells/μL had sensitivity and specificity of 17.3% (95% CI: 10.7%-25.7%) and 92.3% (95% CI: 85.4%-96.6%), respectively, for predicting short-term nonsurvival. CSF protein concentration >0.39 g/L had sensitivity and specificity of 20.9% (95% CI: 13.7%-29.7%) and 91.4% (95% CI: 84.2%-96.0%), respectively. CSF analysis above threshold values used in this study is associated with increased odds of short-term nonsurvival.


Clinical impact of NOTCH1 and/or FBXW7 mutations, FLASH deletion, and TCR status in pediatric T-cell lymphoblastic lymphoma.
Pediatric T-cell lymphoblastic lymphomas (T-LBL) are commonly treated on T-cell acute lymphoblastic leukemia (T-ALL) -derived protocols. Therapeutic stratification based on response to the prephase treatment and on minimal residual disease assessment is well established in T-ALL but is not easy to extrapolate to T-LBL. The identification of molecular prognostic markers at diagnosis in T-LBL could provide an alternative for early therapeutic stratification. Our study determines the frequency and prognostic value of NOTCH1/FBXW7 mutations (N/F(mut)), FLASH deletion at chromosome 6q, and TCR rearrangements in a prospective cohort of pediatric T-LBL. Pathologic samples were obtained at diagnosis for 54 patients treated according to the EuroLB02 protocol in France. N/F(mut) were identified by direct sequencing and allelic dosage was used to detect FLASH and TCRγ deletions, which were interpreted in conjunction with TCRγ, TCRβ, and TCRδ rearrangements. N/F(mut) were found in 55% of T-LBL patients, in whom they were associated with improved event-free survival (P < .01) and overall survival (P < .01). FLASH monoallelic deletions were observed in 18% of patients; they were predominantly N/F wild-type (six of nine) and tended to be of inferior prognosis (P = .09). Absence of biallelic TCRγ deletion (ABD) was seen in 7%, all of which were N/F(mut) and identified a poor prognosis group (P = .02). On multivariate analysis of N/F(mut), TCRγ ABD, and FLASH deletion, only N/F(mut) was an independent factor for good prognosis. Mutational status of NOTCH1/FBXW7 represents a promising marker for early therapeutic stratification in pediatric T-LBL.


Meningitis.
Based on strong evidence, blood cultures usually recover the causative organism of bacterial meningitis in children not pretreated with antibiotics. Based on moderate evidence, pretreatment does not adversely affect the cerebrospinal fluid cell count, but it decreases the positive test result for cerebrospinal fluid culture, especially for meningococcal meningitis. Based on some research evidence as well as consensus, children with suspected bacterial meningitis and no clinical signs of brain herniation do not need neuroimaging as part of their initial clinical evaluation. Dexamethasone adjunctive therapy in children with pneumococcal meningitis is controversial. Some experts recommend neuroimaging toward the end of therapy for all neonates with bacterial meningitis. Based on some research evidence as well as consensus, home intravenous antimicrobial therapy may be an option in selected cases of pediatric bacterial meningitis.


Use of food label information by urban consumers in India - a study among supermarket shoppers.
To study consumer knowledge and use of food labels. A cross-sectional study employing both quantitative and qualitative methods. Intercept interviews were conducted with 1832 consumers at supermarket sites selected using a stratified random sampling procedure. This information was triangulated with twenty-one focus group discussions. New Delhi and Hyderabad, two metro-cities from north and south India. Adolescent (10-19 years), adult (20-59 years) and elderly (≥60 years) consumers. While the national urban literacy rate is 84 %, about 99 % of the study participants were educated. About 45 % reported that they buy pre-packaged foods once weekly and about a fifth buy them every day. Taste, quality, convenience and ease of use are the main reasons for buying pre-packaged foods. Although 90 % of consumers across the age groups read food labels, the majority (81 %) looked only for the manufacturing date or expiry/best before date. Of those who read labels, only a third checked nutrition information and ingredients. Nutrient information on labels was not often read because most consumers either lacked nutrition knowledge or found the information too technical to understand. About 60 % read quality symbols. A positive association was found between education level and checking various aspects of food labels. Women and girls concerned about 'fat' and 'sugar' intake read the nutrition facts panel. The intention of promoting healthy food choices through use of food labels is not being completely met. Since a majority of people found it difficult to comprehend nutrition information, there is a need to take up educational activities and/or introduce new forms of labelling.


Analysis of fibronectin, plasminogen activators and plasminogen in tear fluid as markers of corneal damage and repair.
Corneal damage of various origins initiates a series of processes which lead to repair but also tend to perpetuate the damage; healing thus depends on the prevalence of repair over progression processes. The plasminogen/plasmin system has an important impact on this process, particularly by degrading the extracellular matrix components with resulting interference of the repair processes. This paper presents the immunoblotting analysis of fibronectin, tissue and urokinase-type plasminogen activators and plasminogen/plasmin in the tear fluid of control subjects and patients affected by various ocular pathologies (corneal ulcers, thermal or chemical burns, herpetic keratitis). A significant modification was noted in the protein profiles of fibronectin, tissue and urokinase-type plasminogen activators and plasminogen/plasmin in the cases of corneal ulcers and thermal or chemical burns relative to the pattern observed in the control subjects, while in cases of herpetic keratitis, only plasminogen/plasmin showed slight variations. The altered protein patterns gradually normalized during therapeutic treatment and, at remission, coincided with those of the control subjects.


Effects of vitamin B12 on human circadian body temperature rhythm.
To clarify the effect of vitamin B12 on the human circadian clock, five healthy male adults participated in two constant routine procedures, 2 or 3 weeks apart. In one, subjects received intravenous saline injections (placebo trial) and in the other, intravenous injections of methylcobalamin (MB12) (drug trial). Intravenous administration of MB12 increased rectal temperature in the later hours of the daytime during the constant routine. The activity did not change between treatments in any period during the constant routine. During the later hours of the constant routine, alertness assessed with visual analog scale was higher in the drug trial than in the placebo trial. The period in which drug treatment produced greater alertness almost coincided with that in which MB12 elevated rectal temperature. These results may provide evidence of an effect of vitamin B12 on the circadian clock.


Fatigue and cognitive symptoms in patients with diabetes: relationship with disease phenotype and insulin treatment.
Neurobehavioral symptoms are frequently reported in patients with diabetes. Nevertheless, the characterization of the specific symptom dimensions that develop in diabetic patients with respect to disease phenotype and treatment status remains obscure. This study comparatively assessed fatigue symptoms and cognitive performance using a dimensional approach in 21 patients with insulin-treated type 1 diabetes, 24 type 2 diabetic patients either insulin-free or undergoing insulin treatment for at least six months, and 15 healthy subjects. Specific dimensions of fatigue were assessed using the Multidimensional-Fatigue-Inventory (MFI). Cognitive performance on tests of choice reaction time, pattern recognition memory and spatial planning was evaluated using the Cambridge-Neuropsychological-Automated-Battery (CANTAB). Body mass index (BMI) and glycated-hemoglobin (HbA1C) concentrations were collected, as well as information on diabetes complications and disease duration. Patients with type 2 diabetes, regardless of insulin treatment status, exhibited higher scores of fatigue, primarily in the dimensions of general and physical fatigue as well as reduced activity. Cognitive alterations, in the form of longer reaction times and impaired spatial planning, were also detected in type 2 diabetic patients treated with insulin. These alterations were overall unrelated to glucose control, as reflected in HbA1C levels, and were not explained by complications and duration of diabetes. No specific alteration was measured in type 1 diabetic patients who exhibited fatigue scores and cognitive performance comparable to healthy participants. While associated with fatigue, increased BMI did not significantly account for the relationship of type 2 diabetes with general fatigue and physical fatigue. BMI, however, modulated the association of type 2 diabetes with reduced activity and the association of insulin-treated type 2 diabetes with psychomotor slowing. These findings reveal specific fatigue and cognitive symptoms in patients with type 2 diabetes and suggest the involvement of differential pathophysiological processes.


New information on drug resistance: implications for the adjuvant treatment of breast cancer.
We would suggest on the basis of our analysis that drug resistance still appears to represent a plausible explanation for drug treatment failure in adjuvant breast chemotherapy. It may not be the only factor, but, if present, clearly has to be circumvented if treatment results are to be improved. Since it seems most unlikely that a new wonder drug for breast cancer will emerge in the next few years, then it is to our existing armamentarium of antineoplastic agents that we will have to turn for improved therapeutic results. Fundamental questions will need to be asked about what indeed are the most appropriate agents to be used in combination chemotherapy protocols for this disease and what are the optimal dose ratios. Our own institutional experience in a number of areas has suggested that many chemotherapeutic protocols that are widely used represent significant underdosing and that achieving optimal results requires pushing therapeutic agents closer to the reasonable limits of tolerance. Enhanced techniques for patient support during programs of more intensive chemotherapy are now available, and it has also been our experience that patients tolerate briefer, intensive programs of chemotherapy better than they do protracted, less intensive protocols. The role of new drug combinations that incorporate synergistic or significant biochemical modulation effects (i.e., platinum-etoposide, 5-fluorouracil-leucovorin) need to be examined in the context of the management of breast cancer. We appear to have reached something of a plateau with existing protocols and approaches, and it is time to move ahead.


The effect of heating by microwave irradiation and by conventional heating on the aldehyde concentration in aqueous glutaraldehyde solutions.
The effect of short time heating of aqueous solutions of glutaraldehyde (GA) on relative aldehyde concentration was determined using spectrophotometric analysis. Because free monomeric GA absorbs U.V. light at 280 nm, whereas the alpha, beta polymeric forms absorb at 235 nm, the purity of GA solutions can be expressed as the ratio: A 235 nm/A 280 nm (purification index, P.I.). Heating of 4 ml aliquots of 0.85% distilled aqueous GA solution resulted in an increase of the absorption at 280 nm which is correlated positively with temperature. No increase of absorption at 235 nm was found when solutions were kept at 40 degrees C for several hours. The increase of absorption at 280 nm is caused by a rapid decyclization of hemiacetals producing an increase in free aldehyde concentration. No major differences in absorption were found between the solutions heated by microwave and by conventional heating. However, because microwave irradiation is known to produce an homogeneous rise in temperature, especially in bulky samples, it is expected that the results of fixation procedures will improve by the combined effect of higher temperature and enhanced diffusion rates of the fixating species.


Effects of pain and audiovisual stimulation on the opioid-induced depression of the hypoxic ventilatory response.
Normoxic and hypoxic ventilation are influenced by chemoreceptor and nonchemoreceptor drives. Although inhalational anesthetics blunt hypoxic ventilation, this effect is reversed by audiovisual stimulation but not by pain. Opioids reduce both normoxic and hypoxic ventilation, but their interaction with pain and audiovisual stimulation has not been fully reported. Isocapnic, acute hypoxic ventilatory responses (AHRs) were measured in 11 volunteers. AHR and normoxic ventilation were measured under the following conditions: (1) eyes closed, no audio stimulation (low wakefulness); (2) low wakefulness conditions plus painful thermal stimulation; and (3) playing a computer game (high wakefulness), each with and without remifentanil infusion. The average (+/- sd) remifentanil dose was 0.035 +/- 0.012 microg x kg x min(-1). Both normoxic and hypoxic ventilation were significantly reduced by the remifentanil infusion under all three conditions. The AHR values under low wakefulness conditions were 0.33 +/- 0.19 and 0.89 +/- 0.49 l x min(-1) x sat(-1) with and without remifentanil, respectively (P < 0.05). High wakefulness significantly increased AHR with and without remifentanil, whereas low wakefulness with pain did not. However, high wakefulness with remifentanil did not increase the AHR back to what was observed during low wakefulness without remifentanil. The computer game was a more potent stimulus than pain in countering the depressant effect of remifentanil on AHR. Although the effect of high wakefulness was more attenuated than was previously observed with respect to inhalational anesthetics, the significance of these findings is underlined by the more clinically relevant scenario of what is experienced in the face of opioid administration.


Large enhancement of thermoelectric effects in multiple quantum dots in a serial configuration due to Coulomb interactions.
In the present work we theoretically study Seebeck effect in a set of several quantum dots in a serial configuration coupled to nonmagnetic conducting electrodes. We focus on the combined effect of intra-dot Coulomb interactions between electrons and the number of dots on the thermopower (S) and the thermoelectric figure of merit (ZT) of the considered transport junction within the Coulomb blockade regime. We show that a strong enhancement of the bothSand ZT may occur when the chemical potential of electrodes is situated within the Coulomb gap in the electron transmission spectrum thus indicating a possibility of significant increase of the efficiency of heat-to-electric energy conversion. The enhancement becomes more pronounced when the number of dots increases.


Investigation of dense fine speckled pattern and anti-dense fine speckled 70 antibody by a single step assay.
The indirect immunofluorescence (IIF) method is the gold standard for identifying anti-nuclear antibodies (ANAs). It is recommended that ANA, including the dense fine speckled (DFS) pattern, should be verified with a highly specific confirmatory test after a sensitive screening test. Although methods such as ELISA and LIA are often used to confirm the presence of anti-DFS70 antibodies, new IIF methods have been developed in recent years to prevent the difficulties in the recognition of the DFS pattern and to carry out the confirmatory test in a single step. In this study, we evaluated CytoBead (Generic Assays, Germany) test, which contained both HEp-2 cell substrate and beads coated with DFS70 antigen in one well, in comparison to the routine two-step test strategy. Five hundred forty-one samples were studied by conventional IIF assay, LIA, and CytoBead assay; 264 samples were studied by ELISA. The Bead component of the CytoBead test was found to be reliable as a confirmational test when compared with ELISA and LIA (total agreement values were 85.6% and 87.6%, respectively). The CytoBead ANA DFS70 might be a promising test in the future, allowing both screening and confirmation in a single step, saving time and being easier than two-step testing.


Toxic and recovery effects of copper on Caenorhabditiselegans by various food-borne and water-borne pathways.
Copper pollutions are typical heavy metal contaminations, and their ability to move up food chains urges comprehensive studies on their effects through various pathways. Currently, four exposure pathways were prescribed as food-borne (FB), water-borne plus clean food (WCB), water-food-borne (WFB) and water-borne (WB). Caenorhabditiselegans was chosen as the model organism, and growth statuses, feeding abilities, the amounts of four antioxidant enzymes, and corresponding recovery effects under non-toxic conditions with food and without food were investigated. Based on analysis results, copper concentrations in exposure were significantly influenced by the presence of food and its uptake by C.elegans. Both exposure and recovery effects depended on exposure concentrations and food conditions. For exposure pathways with food, feeding abilities and growth statuses were generally WFB<WCB≤FB (p<0.05). The antioxidant activities were up-regulated in the same order. Meanwhile, the exposure pathway without food (WB) caused non-up-regulated antioxidant activities, and had the best growth statuses. For recoveries with food, growth statuses, feeding abilities and the inductions of the antioxidant enzymes were all WB≈WFB<WCB<FB (p<0.05). For recoveries without food, the order of growth statuses remained WB>FB>WCB>WFB (p<0.05), while the antioxidant activities were all inhibited in a concentration-dependent fashion. In conclusion, contaminated food was the primary exposure pathway, and various pathways caused different responses of C.elegans.


Effects of high-fat diet and age on the blood lipidome and circulating endocannabinoids of female C57BL/6 mice.
Alterations in lipid metabolism play a significant role in the pathogenesis of obesity-associated disorders, and dysregulation of the lipidome across multiple diseases has prompted research to identify novel lipids indicative of disease progression. To address the significant gap in knowledge regarding the effect of age and diet on the blood lipidome, we used shotgun lipidomics with electrospray ionization-mass spectrometry (ESI-MS). We analyzed blood lipid profiles of female C57BL/6 mice following high-fat diet (HFD) and low-fat diet (LFD) consumption for short (6weeks), long (22weeks), and prolonged (36weeks) periods. We examined endocannabinoid levels, plasma esterase activity, liver homeostasis, and indices of glucose tolerance and insulin sensitivity to compare lipid alterations with metabolic dysregulation. Multivariate analysis indicated differences in dietary blood lipid profiles with the most notable differences after 6weeks along with robust alterations due to age. HFD altered phospholipids, fatty acyls, and glycerolipids. Endocannabinoid levels were affected in an age-dependent manner, while HFD increased plasma esterase activity at all time points, with the most pronounced effect at 6weeks. HFD-consumption also altered liver mRNA levels of PPARα, PPARγ, and CD36. These findings indicate an interaction between dietary fat consumption and aging with widespread effects on the lipidome, which may provide a basis for identification of female-specific obesity- and age-related lipid biomarkers.


Operative repair of retroglandular hypospadias.
The operative repair of retroglandular hypospadias should be individualized. In some cases only resection of hooded foreskin and meatotomy are required. In a small number of properly selected cases a one-stage operation may be performed. In most cases a three-stage repair was carried out by the authors.


Complementary effects of dapagliflozin and lobeglitazone on metabolism in a diet-induced obese mouse model.
Thiazolidinedione, an insulin sensitizer, has beneficial effects on glucose metabolism; however, there are concerns regarding weight gain and heart failure. Sodium-glucose co-transporter 2 (SGLT2) inhibitors can reduce body weight, increase diuresis, and play a protective role in heart failure. We examined the complementary effects of dapagliflozin, an SGLT2 inhibitor, and lobeglitazone, a thiazolidinedione, in high-fat diet (HFD)-induced obese mice. We treated HFD-induced obese mice with vehicle, dapagliflozin, lobeglitazone, and their combination for 12 weeks. Oral glucose tolerance and insulin tolerance tests were performed after 12-week treatment, and body composition was measured by dual-energy X-ray absorptiometry before and after treatment. We analyzed oxygen consumption rate (OCR) using 3T3-L1 cells after treatment of β-hydroxybutyrate and/or lobeglitazone. Treatment with a combination of dapagliflozin and lobeglitazone resulted in a significant decrease in postprandial hyperglycemia compared with dapagliflozin monotherapy, but not compared with lobeglitazone monotherapy. The addition of dapagliflozin to lobeglitazone treatment did not attenuate weight gain compared with lobeglitazone monotherapy in this study. However, this combination prevented the increase of organ weight of liver and heart, and OCR in 3T3-L1 cells was increased after treatment with a combination of β-hydroxybutyrate and lobeglitazone compared to lobeglitazone monotherapy. We confirmed the beneficial effect of lobeglitazone on glucose metabolism; however, we did not find any beneficial effect of dapagliflozin on body weight in HFD-induced obese mice. However, the protective effects of dapagliflozin and lobeglitazone combined therapy on the liver, heart, energy consumption, and β-cell senescence are worth investigating in clinical trials.


Distinct dynamics of lipid accumulation by porcine cumulus cells during in vitro maturation with follicular fluid of low and high fatty acid contents.
Follicular fluid (FF) is a complex biological medium providing a fully balanced microenvironment for the oocyte. The standard medium for in vitro maturation of porcine oocytes contains 10% of FF which due to its unknown and inconstant composition is a source of a significant variation. This study aimed to investigate whether follicular fluids of significantly different fatty acid contents (standardized follicular fluid) supplemented to porcine IVM media affects lipid metabolism of porcine oocytes and cumulus cells. Two categories of FF from cyclic gilts containing high (H) and low (L) FA content was added to IVM medium for oocytes from prepubertal gilts. Altogether, 521 cumulus oocyte-complexes (oocytes and corresponding cumulus cells) were analyzed for mRNA expression of 7 genes regulating lipid metabolism and selected traits of the lipid droplets (LD). The applied FFs of different FA levels exerted distinct effects on oocytes and cumulus cells (CCs). During IVM oocytes tended to utilize the lipids as demonstrated by the reduced LD number and lipid fluorescence, whereas cumulus cells accumulated lipids as indicated by the increase in LD number, the occupied area and fluorescence level. Changes in cumulus cells were independent of the FA content in the follicular fluid which means an efficient lipid accumulation during IVM. Final analysis including the effect of FA level on LD traits in oocytes and corresponding CCs revealed two distinct patterns. COCs matured in FF of high FA content were characterized by elevated dynamics of lipid accumulation in CCs and stable lipid content in oocytes. In the case of FF with low FA content, CCs accumulated lipids at a significantly lower rate whereas lipid level in oocytes was reduced. The alterations observed in the LD parameters were not accompanied by changes in oocyte nuclear maturation and in transcript level of any from the 7 analyzed genes. In conclusion, fatty acid content of the follicular fluid supplemented to porcine IVM medium affects lipid metabolism in cumulus cells of the maturing oocyte and application of a standardized FF may help to improve the quality of porcine oocytes matured in vitro.


Effects of pretreatment methods and leaching methods on jujube wine quality detected by electronic senses and HS-SPME-GC-MS.
Conventional analysis, electronic senses and HS-SPME-GC-MS were applied to evaluate the effects of pretreatment methods and leaching methods on jujube wine quality. Significant differences (p < 0.05) in the levels of alcohol content, color, taste and aroma were observed among all the jujube wine samples, in which the pulp and pectase fermented jujube wine was the best among all. Moreover, rather than taste, aroma is the most significantly (p < 0.05) affected. In regard to aroma, a total of 182 volatile compounds were identified by HS-SPME-GC-MS. It was found that the blended-into-pulp treatment and the leached-by-pectase treatment had notable positive effects on jujube wine. The pulp and pectase fermented jujube wines exhibited the highest concentration of total volatile compounds as well as alcohols, esters, acids and aldehydes. Thus, the optimal pretreatment method and leaching method for jujube wine fermentation are blended-into-pulp and leached-by-pectase respectively.


Src activation generates reactive oxygen species and impairs metabolism-secretion coupling in diabetic Goto-Kakizaki and ouabain-treated rat pancreatic islets.
Na(+)/K(+)-ATPase inhibition by ouabain suppresses ATP production by generating reactive oxygen species (ROS) and impairs glucose-induced insulin secretion from pancreatic islets. To clarify the signal-transducing function of Na(+)/K(+)-ATPase in decreasing ATP production by the generation of ROS in pancreatic islets, the involvement of Src was examined. In addition, the significance of Src activation in diabetic islets was examined. Isolated islets from Wistar rats and diabetic Goto-Kakizaki (GK) rats (a model for diabetes) were used. ROS was measured by 5-(and 6)-chloromethyl-2',7'-dichlorofluorescein fluorescence using dispersed islet cells. After lysates were immunoprecipitated by anti-Src antibody, immunoblotting was performed. Ouabain caused a rapid Tyr(418) phosphorylation, indicating activation of Src in the presence of high glucose. The specific Src inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) restored the ouabain-induced decrease in ATP content and the increase in ROS production. Both PP2 and ROS scavenger restored the impaired insulin release and impaired ATP elevation in GK islets, but had no such effect in control islets. PP2 reduced the high glucose-induced increase in ROS generation in GK islet cells but had no effect on that in control islet cells. Moreover, ouabain had no effect on ATP content and ROS production in the presence of high glucose in GK islets. These results indicate that Src plays a role in the signal-transducing function of Na(+)/K(+)-ATPase, in which ROS generation decreases ATP production in control islets. Moreover, ROS generated by Src activation plays an important role in impaired glucose-induced insulin secretion in GK islets, in which Src is endogenously activated independently of ouabain.


Micro RNA 146a gene variant / TNF-α / IL-6 / IL-1 β; A cross-link axis inbetween oxidative stress, endothelial dysfunction and neuro-inflammation in acute ischemic stroke and chronic schizophrenic patients.
This work was purposed to speculate the possible association of rs2910164hsa-miR-146a C>G gene single nucleotide polymorphism in the pathogenesis of schizophrenia and subsequently their relevance to neuro-inflammatory, vascular and oxidative stress pathways as acute ischemic stroke (AIS) risk factors in chronic schizophrenic patients. 450 subjects, 150 healthy controls (group I), 150 chronic schizophrenic patients without any evidences of stroke (group II) and 150 chronic schizophrenic patients with AIS (group III) were included. Genotypes (CC, CG&GG) for hsa-mir-146a gene polymorphism were identified using polymerase chain reaction-restriction fragment length polymorphism PCR-RFLP technique. Tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), interleukin 1β (IL-1 β), plasminogen activator-inhibitor 1 (PAI-1), thrombomodulin (TM) and 8-Hydroxy-2-deoxyguanosine (8-OHdG) serum levels were immunoassayed. Complete lipid profile was estimated. The CG and GG hsa-miR-146a genotypes were associated with increased risk of both schizophrenia and AIS in schizophrenic patients with thrombomodulin levels decrement in group II& III. On the other side, the risk genotypes were associated significantly with positive and negative syndrome scale PANSS scores, TNF-α, IL-6, IL-1 β, PAI-1, and 8-OHdG increment levels in both groups II & III. By contrast, the CG and GG hsa-miR-146a genotypes did not affect the neuro-inflammatory and oxidative stress markers in healthy controls. These findings illustrate a new mechanism strengthening the occurrence of oxidative stress and DNA damage as a result of the neuro-inflammatory and endothelial dysfunction status originated from the hsa-miR-146a C>G gene single nucleotide polymorphism, thus, confirming their role in the pathogenesis of schizophrenia and its AIS risk.


Development and testing of a green fluorescent protein-based bacterial biosensor for measuring bioavailable arsenic in contaminated groundwater samples.
A green fluorescent protein (GFP)-based bacterial biosensor for the detection of bioavailable As(III), As(V), and Sb(III) was developed and characterized. The biosensor strain Escherichia coli DH5alpha (pVLAS1) was developed based on the expression of gfp under the control of the ars promoter and the arsR gene of Staphylococcus aureus plasmid pI258. Strain DH5alpha (pVLAS1) responded mainly to As(III), As(V), and Sb(III), with the lowest detectable concentrations being 0.4, 1, and 0.75 microM, respectively, during a 2-h exposure and 0.1 microM for all three metal ions with an 8-h induction period. To assess its applicability for analyzing environmentally relevant samples, the biosensor was field-tested on shallow-well groundwater for which contaminant levels were known. Our results demonstrate that the nonpathogenic bacterial biosensor developed in the present study is useful and applicable in determining the bioavailability of arsenic with high sensitivity in contaminated groundwater samples, and they suggest a potential for its inexpensive application in field-ready tests.


Households' perception of climate change and human health risks: a community perspective.
Bangladesh has been identified as one of the most vulnerable countries in the world concerning the adverse effects of climate change (CC). However, little is known about the perception of CC from the community, which is important for developing adaptation strategies. The study was a cross-sectional survey of respondents from two villages--one from the northern part and the other from the southern part of Bangladesh. A total of 450 households were selected randomly through multistage sampling completed a semi-structure questionnaire. This was supplemented with 12 focus group discussions (FGDs) and 15 key informant interviews (KIIs). Over 95 percent of the respondents reported that the heat during the summers had increased and 80.2 percent reported that rainfall had decreased, compared to their previous experiences. Approximately 65 percent reported that winters were warmer than in previous years but they still experienced very erratic and severe cold during the winter for about 5-7 days, which restricted their activities with very destructive effect on agricultural production, everyday life and the health of people. FGDs and KIIs also reported that overall winters were warmer. Eighty point two percent, 72.5 percent and 54.7 percent survey respondents perceived that the frequency of water, heat and cold related diseases/health problems, respectively, had increased compared to five to ten years ago. FGDs and KIIs respondents were also reported the same. Respondents had clear perceptions about changes in heat, cold and rainfall that had occurred over the last five to ten years. Local perceptions of climate variability (CV) included increased heat, overall warmer winters, reduced rainfall and fewer floods. The effects of CV were mostly negative in terms of means of living, human health, agriculture and overall livelihoods. Most local perceptions on CV are consistent with the evidence regarding the vulnerability of Bangladesh to CC. Such findings can be used to formulate appropriate sector programs and interventions. The systematic collection of such information will allow scientists, researchers and policy makers to design and implement appropriate adaptation strategies for CC in countries that are especially vulnerable.


Characterization of Complex Drug Formulations Using Cryogenic Scanning Electron Microscopy (Cryo-SEM).
The physicochemical properties of complex drug formulations, including liposomes, suspensions, and emulsions, are important for understanding drug release mechanisms, quality control, and regulatory assessment. It is ideal to characterize these complex drug formulations in their native hydrated state. This article describes the characterization of complex drug formulations in a frozen-hydrated state using cryogenic scanning electron microscopy (cryo-SEM). In comparison to other techniques, such as optical microscopy or room-temperature scanning electron microscopy, cryo-SEM combines the advantage of studying hydrated samples with high-resolution imaging capability. Detailed information regarding cryo-fixation, cryo-fracture, freeze-etching, sputter-coating, and cryo-SEM imaging is included in this article. A multivesicular liposomal complex drug formulation is used to illustrate the impact of different cryogenic sample preparation conditions. In addition to drug formulations, this approach can also be applied to biological samples (e.g., cells, bacteria) and soft-matter samples (e.g., hydrogels). © Published 2022. This article is a U.S. Government work and is in the public domain in the USA. Basic Protocol 1: Cryo-fixation to preserve the native structure of samples using planchettes Alternate Protocol: Cryo-fixation to preserve the native structure of biological samples on sapphire disks Basic Protocol 2: Sample preparation for cross-sectional cryo-SEM imaging Basic Protocol 3: Cryo-SEM imaging and microanalysis.


Dual atrio-ventricular nodal pathways and atrial fibrillation.
The determinants of the ventricular rate during atrial fibrillation were studied in a group of eleven patients demonstrating dual A-V nodal pathways during atrial stimulation. The shortest R-R interval and the mean ventricular cycle length during at least 1 min of pacing-induced atrial fibrillation were compared: a) to the effective and functional refractory period of the fast pathway; b) to the effective refractory period of the slow pathway determined during atrial stimulation, at two or more different basic cycle lengths of pacing; and c) to the shortest cycle length during atrial stimulation followed by 1:1 A-V conduction. A group of 8 patients not demonstrating dual A-V nodal pathway-curves during atrial stimulation was used as a control. In both groups the shortest R-R interval during atrial fibrillation was best predicted by the shortest cycle length followed by 1:1 A-V conduction during atrial stimulation. The mean ventricular cycle length during atrial fibrillation was not accurately predicted by any of the variables studied. The similar results in patients with and without dual A-V nodal pathways suggest that concealed conduction from one to another A-V nodal pathway does not play a role in determining the ventricular response during atrial fibrillation in patients with dual A-V nodal pathways.


Spinal cord compression of neoplastic origin: surgical experience using a common clinical language.
To assess the value of a common clinical language in a multidisciplinary tumour board for spinal metastasis, using both the Rades score and the Spinal Instability Neoplastic Score (SINS) for multidisciplinary decision-making. Retrospective study of 60 consecutive patients treated surgically for MSCC. The indication for surgery was done in a multidisciplinary board, basically according to SINS and RADES scores. Three prognostic groups were defined according to the Rades score: poor (Rades 1: 20-30 points), intermediate (Rades 2: 31-35), and good (Rades 3: 36-45). The 2-year overall survival (OS) rate was 50%, with median survival of 19 months. By Rades prognostic group (1, 2, 3), median OS was 6 months, 15 months, and not reached, respectively. OS rates at 6 months (Rades 1, 2, 3) were 51, 69, and 74.1%, respectively. Within the Rades 1 group, 6-month survival in patients with new-onset cancer was 68 vs. 40% in those with a known primary. The overall complication rate ≥ grade 3 was 23.3% (n = 14). In patients who underwent urgent surgery (< 48 h), the complication rate was 45.5% (5/11) versus 18.3% (9/49) in the planned surgeries. Our findings supports the utility of using a common language in multidisciplinary tumour board for spinal metastasis. The 2-year OS rate in this series was 50%, which is the highest OS reported to date in this population. In the poor prognosis subgroup (Rades 1), OS at 6 months was higher in patients with new-onset cancer versus those with a known primary (68 vs. 40%). These findings suggest that surgery should be the first treatment option in patients with MSCC as first symptom of cancer although a predicted poor prognosis.


Novel biological effects of alloferon and its selected analogues: structure-activity study.
The subject of this paper is a search for new biological properties of alloferon (H-His-Gly-Val-Ser-Gly-His-Gly-Gln-His-Gly-Val-His-Gly-OH) and a series of its analogues. The studies on structure/activity relationship in alloferon, the synthesis of a series of 28 analogues were performed. The analogues were modified at position 1 or 6, and other were oligopeptides with a shortened peptide sequence. Biological effects of the peptides were evaluated by the pro-apoptotic action in vivo on haemocytes of Tenebrio molitor and in the cardiotropic test in vitro on the heart of T. molitor and Zophobas atratus. In the in vivo bioassays, new biological activities of alloferon and its analogues were discovered. In haemocytotoxic bioassay, alloferon strongly induces T. molitor haemocytes to undergo apoptosis at a dose of 10 nM. Moreover, [Phe(p-NH2)(1)]-, [Tyr(6)]- and [1-10]-alloferon exhibit a two-fold increase of caspases activation in comparison with the alloferon. However, alloferon and its analogues show a weak cardiostimulatory activity in Z. atratus but the heart of T. molitor is not sensitive to these peptides. The results obtained here suggest that alloferon plays pleiotropic functions in insects.


Endogenous mitochondrial oxidative stress in MnSOD-deficient mouse embryonic fibroblasts promotes mitochondrial DNA glycation.
The accumulation of somatic mutations in mitochondrial DNA (mtDNA) induced by reactive oxygen species (ROS) is regarded as a major contributor to aging and age-related degenerative diseases. ROS have also been shown to facilitate the formation of certain advanced glycation end-products (AGEs) in proteins and DNA and N(2)-carboxyethyl-2'-deoxyguanosine (CEdG) has been identified as a major DNA-bound AGE. Therefore, the influence of mitochondrial ROS on the glycation of mtDNA was investigated in primary embryonic fibroblasts derived from mutant mice (Sod2(-/+)) deficient in the mitochondrial antioxidant enzyme manganese superoxide dismutase. In Sod2(-/+) fibroblasts vs wild-type fibroblasts, the CEdG content of mtDNA was increased from 1.90 ± 1.39 to 17.14 ± 6.60 pg/μg DNA (p<0.001). On the other hand, the CEdG content of nuclear DNA did not differ between Sod2(+/+) and Sod2(-/+) cells. Similarly, cytosolic proteins did not show any difference in advanced glycation end-products or protein carbonyl contents between Sod2(+/+) and Sod2(-/+). Taken together, the data suggest that mitochondrial oxidative stress specifically promotes glycation of mtDNA and does not affect nuclear DNA or cytosolic proteins. Because DNA glycation can change DNA integrity and gene functions, glycation of mtDNA may play an important role in the decline of mitochondrial functions.


Assessing the utility of a distress screening tool at capturing sexual concerns in a gyne-oncology follow-up clinic.
Communication and assessment of sexual health within cancer care is poor despite high rates of sexual dysfunction in cancer survivors. Screening for distress programs have been implemented, as a standardized part of cancer care across Canada, with the aim of increasing identification and improving access to support. Alberta Health Services uses a general distress screening form, containing the Canadian Problem Checklist, which includes a list of possible problems, one of which is "intimacy/sexuality." Theoretically, the discreet nature of the screening for distress form may reduce patient discomfort in disclosing sexual concerns verbally, and therefore help health care providers identify patients requiring intervention. This study aims to determine the adequacy of this distress screening tool in identifying gynecological cancer patients who have an intimacy/sexuality concern. A chart review was conducted on all follow-up visits in a gyne-oncology clinic over 1 year. Each patient's chart was reviewed to determine the prevalence of the distress screening form completion, prevalence of the "intimacy/sexuality" item being checked, and documentation of actions taken to address any reported intimacy/sexuality problems. Seven hundred thirty patient visits were recorded during this period with completed distress screening forms found on 79.0% (n = 577) of charts. Only 6% of the patients indicated an intimacy/sexuality concern on this form. Of those, only one third had documentation that their problem was addressed. These results call into question the utility of the intimacy/sexuality item on the Canadian Problem Checklist to identify gynecological cancer patients who have sexual concerns. Furthermore, even among those patients who indicated concerns, there is evidence that their problems are rarely addressed. Providers need to directly inquire with patients about their sexual health.


Migraine equivalent as a cause of episodic vertigo.
There are many transient neurologic disturbances associated with various types of migraine. Visual symptoms, such as scintillating scotomata are most common, but somatosensory, motor, cranial nerve, and brain stem symptoms also occur. Among the brain stem symptoms, vestibular manifestations are quite common and include nonspecific dizziness, disequilibrium, vertigo, and motion intolerance. Auditory symptoms are less common. These transient neurologic symptoms can precede the headache as an aura, can occur during the headache, or, uncommonly, can immediately follow the headache. It is also well documented that the neurologic symptoms can occur in the period between headaches, a situation termed "migraine equivalent." Migraine equivalents usually occur in patients who have experienced typical migraine headaches earlier in life or who have migraine headaches at times other than when they experience equivalent symptoms. Rarely, typical migraine equivalent symptoms precede the development of the headaches by months or years, or occur in individuals who never develop headaches. Five patients with migraine equivalent symptoms that include vertigo are presented. The vertigo was the dominant symptom in some cases and was accompanied by nausea and vomiting. Differentiation from peripheral labyrinthine disorders is difficult, but a personal or family history of migraine, the temporal association of the neuro-otologic symptoms with other migraine equivalent symptoms, a characteristic pattern of occurrence of the symptoms, and a positive response to antimigrainous therapy are features that strengthen the diagnosis of a migraine equivalent phenomenon.


Efficacy of direct hemoperfusion for the removal of phenobarbital through blood concentration analysis.
Phenobarbital overdose can cause coma and even death. The consciousness disturbance is often prolonged due to its long half-life. In this study, we investigated the efficacy of direct hemoperfusion (DHP) for the removal of phenobarbital by measuring the blood levels of phenobarbital. Study subjects included five patients with phenobarbital poisoning who were transferred to our hospital. Direct hemoperfusion was carried out in three of the five patients (six times in total), and the elimination rate was calculated by measuring the blood levels before and after DHP. Furthermore, the disappearance rate of phenobarbital without DHP was calculated in all five patients (seven times in total) for comparison with the elimination rate. The elimination rate of phenobarbital with DHP was significantly higher than the disappearance rate without DHP.. This study suggests that early introduction of DHP should be considered as a treatment option for phenobarbital poisoning.


Immune Checkpoint Inhibitors in Older Adults.
Cancer is primarily a disease of older adults. The treatment of advanced stage tumors usually involves the use of systemic agents that may be associated with significant risk of toxicity, especially in older patients. Immune checkpoint inhibitors are newcomers to the oncology world with improved efficacy and better safety profiles when compared to traditional cytotoxic drugs. This makes them an attractive treatment option. While there are no elderly specific trials, this review attempts to look at the current available data from a geriatric oncology perspective. We reviewed data from phase III studies that led to newly approved indications of checkpoint inhibitors in non-small cell lung cancer, melanoma, and renal cell cancer. Data were reviewed with respect to response, survival, and toxicity according to three groups: <65 years, 65-75 years, and >75 years. Current literature does not allow one to draw definitive conclusions regarding the role of immune checkpoint inhibitors in older adults. However, they may offer a potentially less toxic but equally efficacious treatment option for the senior adult oncology patient.


Updates in Drug Treatment of Severe Hypertriglyceridemia.
To provide an insight into the new pharmacological options for the treatment of severe hypertriglyceridemia (sHTG). sHTG is difficult to treat. The majority of the traditional pharmacological agents available have limited success in both robustly decreasing triglyceride levels and/or in reducing the incidence of acute pancreatitis (AP), the most severe complication of sHTG. Therapeutic options with novel mechanisms of action have been developed, such as antisense oligonucleotides (ASO) and small interfering RNA (siRNA) targeting APOC3 and ANGPTL3. The review discusses also 2 abandoned drugs for sHTG treatment, evinacumab and vupanorsen. The ASO targeting APOC3, volanesorsen, is approved for use in patients with familial chylomicronemia syndrome (FCS) in Europe. Olezarsen, an N-acetylgalactosamine (GalNAc)-conjugated ASO with the same target, seems to have a better safety and efficacy profile. siRNA targeting APOC3 and ANGPTL3, namely ARO-APOC3 and ARO-ANG3, are also promising for the treatment of sHTG. However, the ultimate clinical goal of any sHTG treatment, the decrease in the risk of AP, has not been definitively achieved till now by any pharmacotherapy, either approved or in development.


Morphometric features and glycoconjugate pattern of rabbit intestine are affected by particle size of pelleted diets.
Feed particle size effects on morphology and glycoconjugate pattern was investigated in the rabbit intestine. Rabbits fed with fine particles (2 mm) displayed more irregularly shaped, higher duodenal villi and deeper crypts in distal colon as well as higher number of goblet cells than coarse (8 mm) fed ones. Brush border expressed: (i) in duodenum, neutral/sulfated glycoconjugates and glycans binding MAL II, SNA, Con A than KOH-sialidase-PNA and DBA reactivity in fine and coarse fed rabbits, respectively, (ii) in cecum, mainly sulfoglycans in coarse fed rabbits, MAL II and PNA staining in all samples, and (iii) in distal colon few sulfoglycans and MAL II reactivity. Enterocytes bound MAL II in duodenum, Con A in cecum, DBA, and Con A in distal colon of all rabbits, SNA in distal colon of coarse fed ones. Brunner's glands displayed high presence of acidic/sulfated mucins in fine fed rabbits, neutral glycoconjugates and reactivity with MAL II, SNA, PNA, KOH-sialidase-PNA, and Con A in all rabbits. Goblet cells exhibited: (i) in duodenum neutral and sulfomucins as well as MAL II and KOH-sialidase-PNA staining, than SNA and DBA in fine and coarse fed rabbits, respectively, (ii) in cecum sulfated glycans, MAL II, SNA, KOH-sialidase-PNA, DBA reactivity, and (iii) in distal colon acidic/sulfomucins, MAL II and SNA staining, and DBA reactivity in fine fed specimens. Crypt cells exhibited neutral and PNA reactive glycoconjugates in the cecum. In the distal colon also acidic/sulfated glycans, and MAL II, KOH-sialidase-PNA, DBA; SNA staining showed weaker reactivity in fine fed rabbits, which bound Con A.


Pharmacokinetic properties of bromide in dogs after the intravenous and oral administration of single doses.
Bromide (20 mg kg-1) was administered intravenously and orally to normal beagle dogs. The mean (SD) apparent elimination half life (t1/2 beta) after oral administration (46 +/- 9 days) was not significantly different from the mean t1/2 beta after intravenous administration (37 +/- 10 days). The mean total body clearance was 9.0 +/- 3.9 ml day-1 kg-1 and the mean apparent volume of distribution was 0.45 +/- 0.07 litre kg-1. The mean area under the serum concentration time curve (AUC) was significantly smaller after oral administration than after intravenous administration, and from a comparison of the two values the oral bioavailability of bromide was estimated to be 46 per cent. Assuming this degree of bioavailability, the daily dose of bromide necessary to maintain serum bromide concentrations within the therapeutic range of 1000 to 2000 mg litre-1 recommended for epileptic dogs was estimated to be approximately 21 mg kg-1. The intravenous loading dose of sodium bromide necessary to reach minimal therapeutic serum bromide concentrations was predicted to be 570 +/- 90 mg kg-1.


Regulation of cardiac calcium channel current and contractile activity by the dihydropyridine Bay K 8644 is voltage-dependent.
Pharmacological studies have provided considerable information about the molecular structure of ion channels in the membranes of excitable cells. Two classes of drugs, the local anesthetics and the biotoxins, have been used to study sodium channels in nerve, skeletal muscle, and cardiac cells, and tetraethylammonium ion and many of its derivatives have provided structural information about potassium channels in nerve. More recently, organic compounds that block calcium channels (calcium channel antagonists) have begun to be used to probe calcium channels in cardiac and smooth muscle cells (see). One group of calcium channel blockers, the dihydropyridines, has provided considerable information on the structure and function of these channels on the basis of electrophysiological and binding studies. Slight modification of the structure of one of these dihydropyridines, nifedipine, has led to the discovery of a group of compounds that are presumed to act by increasing the influx of Ca2+ into cardiac and smooth muscle cells. One of these novel compounds, Bay K 8644 (methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5 carboxylate) has been reported to act at the same receptor site as the calcium channel antagonist nifedipine, but enhances contractile activity of the perfused heart and aortic strips. Because activation of contraction in cardiac muscle is closely linked to calcium entry via voltage-dependent calcium channels (see for review) these results suggested that Bay K 8644 might act on these channels.


Osteoclast differentiation requires TAK1 and MKK6 for NFATc1 induction and NF-kappaB transactivation by RANKL.
Osteoclast (Oc) differentiation is fundamentally controlled by receptor activator of nuclear factor kappaB ligand (RANKL). RANKL signalling targets include mitogen-activated protein kinases (MAPKs), nuclear factor kappaB (NF-kappaB), and nuclear factor of activated T cells (NFAT)c1. In this study, we found that p38 MAPK upstream components transforming growth factor-beta-activated kinase 1 (TAK1), MKK3, and MKK6 increased by RANKL in an early stage of osteoclastogenesis from primary bone marrow cells, which led to enhanced p38 activation. Retroviral transduction of dominant-negative (DN) forms of TAK1 and MKK6, but not that of MKK3, reduced Oc differentiation. Transduction of TAK1-DN and MKK6-DN and treatment with the p38 inhibitor SB203580 attenuated NFATc1 induction by RANKL. TAK1-DN, MKK6-DN, and SB203580, but not MKK3-DN, also suppressed RANKL stimulation of NF-kappaB transcription activity in a manner dependent on p65 phosphorylation on Ser-536. These results indicate that TAK1 and MKK6 constitute the p38 signalling pathway to participate to Oc differentiation by RANKL through p65 phosphorylation and NFATc1 induction, and that MKK6 and MKK3 have differential roles in osteoclastogenesis from bone marrow precursors.


Simulation in obstetrics and gynecology.
Simulation is a practical and safe approach to the acquisition and maintenance of task-oriented and behavioral skills across the spectrum of medical specialties, including obstetrics and gynecology. Since the 1990s, the profession of obstetrics and gynecology has come to appreciate the value of simulation and major steps are being taken toward incorporating this technique into specialty-specific training, evaluation, and credentialing programs. This article provides an overview of simulators and simulation in health care and describes the scope of their current use and anticipated applications in the field of obstetrics and gynecology.


Restoration of blood pressure by centrally injected U-46619, a thromboxane A(2) analog, in hemorrhaged hypotensive rats: investigation of different brain areas.
In the present study, we investigated the cardiovascular effects of centrally injected U-46619, a thromboxane A(2) (TXA(2)) analog, and the central and peripheral mechanisms of these effects in hemorrhagic shock conditions. Hemorrhage was performed by withdrawing a total volume of 2.1 ml of blood/100 g body weight over a period of 10 min. Injections were made into the lateral cerebral ventricle (LCV), nucleus tractus solitarius (NTS), rostral ventrolateral medulla (RVLM) and paraventricular nucleus of hypothalamus (PVN). U-46619 (0.1, 1 and 2 microg) increased blood pressure and reversed hypotension in hemorrhagic shock. The pressor effect was dose- and time-dependent in all investigated brain areas. Heart rate changes were not significantly different in all groups. Pretreatment of rats with an injection of SQ-29548 (4 or 8 microg), a TXA(2) receptor antagonist, into the LCV, NTS, RVLM and PVN completely blocked the pressor effect of U-46619 (1 microg) injected into respective brain areas. Hemorrhage itself increased plasma adrenaline, noradrenaline, vasopressIN levels and renin activity. U-46619 (1 microg) injected into the LCV, PVN, RVLM and NTS produced additional increases in these hormone levels and in renin activity. Intravenous pretreatments of rats with prazosin (0.5 mg/kg), an alpha(1)-adrenoceptor antagonist, [beta-mercapto-beta,beta-cyclopentamethylenepropionyl(1), O-Me-Tyr(2),Arg(8)]- vasopressin (10 microg/kg), a vasopressin V(1)-receptor antagonist, or saralasin (250 microg/kg), an angiotensin II receptor antagonist, in hemorrhaged rats partially blocked the pressor response to U-46619 (1 microg) injected into the LCV, PVN, RVLM and NTS. Results show that centrally administered U-46619, a TXA(2) analog, increases blood pressure and reverses hypotension in hemorrhagic shock. Activation of central TXA(2) receptors mediates the pressor effect of the drug. Furthermore, the increases in plasma adrenaline, noradrenaline, vasopressin levels and renin activity are involved in these effects.


Description of regional mitral annular nonplanarity in healthy human subjects: a novel methodology.
Finite-element analysis demonstrates that the nonplanar shape of the mitral annulus diminishes mitral leaflet stress. It has therefore been postulated that repair with annuloplasty rings that maintain the nonplanar shape of the annulus could increase repair durability. Although the global nonplanarity of the mitral annulus has been adequately characterized, design of such a ring requires a quantitative description of regional annular geometry. By using real-time 3-dimensional echocardiography in conjunction with available image processing software, we developed a methodology for describing regional annular geometry and applied it to the characterization of the normal human mitral annulus. Five healthy volunteers underwent mitral valve imaging with real-time 3-dimensional echocardiography. Regional annular height was calculated at 36 evenly spaced intervals. Maximal annular height/commissural width ratio was found to occur at the midpoint of the anterior annulus in all cases. These values averaged 26% +/- 3.1%, whereas those for the midposterior annulus averaged 18% +/- 3.0%. The average commissural width was 35.2 +/- 6.0 mm. Although substantial spatial heterogeneity was observed, regional annular height at a given rotational position was highly conserved among subjects when normalized to commissural width. These quantitative imaging and analytic techniques demonstrate that the normal human mitral annulus is regionally heterogeneous in its nonplanarity, and they establish a means of describing annular geometry at a regional level. With wider application, these techniques may be used both to characterize pathologic annular geometry and to optimize the design of mitral valve annuloplasty devices.


Association between skin immune-related adverse events (irAEs) and multisystem irAEs during PD-1/PD-L1 inhibitor monotherapy.
Patients treated with immune checkpoint inhibitors (ICIs) often develop immune-related adverse events (irAEs) in various organs of the body. However, the patient factors associated with the development of multisystem irAEs are not well known. Skin irAEs most frequently occur and appear early after ICI treatment initiation. They may be a predictive marker for the development of multisystem irAEs, and their occurrence should be evaluated. Data of patients receiving ICI monotherapy for lung cancer, melanoma, and head and neck cancer treatment were retrospectively evaluated (n = 207); the single irAE development group (n = 69) was compared with the multisystem irAE development group (n = 37). The primary endpoint was the comparison of the incidence of skin irAEs between the two groups. Skin, thyroid, and hepatic irAEs were associated with the development of multisystem irAEs (odds ratio: 3.30, 95% confidence interval: 1.27-8.52, p = 0.01 for skin; 5.07, 2.09-12.3, p = 0.0003 for thyroid; 10.63, 1.19-94.7, p = 0.03 for hepatic). Skin irAEs were the most common type (65.0% of total participants) and appeared earlier than other irAEs, except for gastrointestinal and ocular irAEs (median time to onset of skin irAEs: 7.5 weeks). Skin irAEs occurred more frequently in the multisystem irAE group (81.0%) than in the single irAE group (56.5%, p = 0.02). Skin irAEs can be a useful predictive marker for multisystem irAE development due to ICI treatment. Consequently, patients with skin irAEs should be treated and monitored for other types of irAEs.


Preferential expression of hPGFS in primary SCCHN and tumour cell lines derived from respiratory and digestive organs.
Identifying overexpressed genes in tumours is a critical step for tumour diagnosis, prognosis, and treatment. Using differential display polymerase chain reaction, sequence analysis, and gene Blast searches, we discovered that human prostaglandin F synthase (hPGFS) was upregulated in squamous cell carcinoma of the head and neck (SCCHN). Northern blot analysis indicated that up to a 16-fold increase in the level of hPGFS expression was detected in 40.5% (15 out of 37) of SCCHN primary tumours. The increased expression of hPGFS in SCCHN was primarily detected in SCC of larynx and hypopharynx (59%, P<0.05). Using the same primary tissue samples, increased levels of epidermal growth factor receptor (EGFR) expression were detected in only 32% of tumour tissues, suggesting hPGFS may have the potential to become a drug target or molecular marker for SCCHN. To determine if the increased level of hPGFS expression came from tumour cells, we determined the level of hPGFS expression in SCCHN tumour cell lines. A high level of hPGFS expression was detected in four out of five tumour SCCHN cell lines. To determine if upregulation of hPGFS is SCCHN-specific, hPGFS expression was analysed in 59 tumour cell lines derived from different types of tumours. The expression of hPGFS was increased from two- to 500-fold in a large portion of cell lines derived from lung (five out of nine), colon (five out of seven) as well as head and neck cancer (four out of five). These data link hPGFS expression to tumours located in the respiratory and digestive organs.


n-3 fatty acids and revascularization procedures.
Largely initiated by studies among Greenland Eskimos in the early 1970s, great attention has been given to the possible effects of the very long chain n-3 polyunsaturated fatty acids (PUFA) in a variety of cardiovascular disease states. A series of possibly positive effects on pathogenetic mechanisms in cardiovascular disease has evolved from laboratory studies in cell cultures and animals as well as in humans, focusing mainly on eicosanoid metabolism with reduced activities of platelets and leucocytes, reduced plasma triglycerides and, antiarrhythmic effects in the myocardium. A rationale for a positive effect of very long chain n-3 PUFA in the secondary prophylaxis after revascularization procedures obviously also exists. The positive clinical effects based on prospectively randomized trials are summarized as follows. After coronary artery bypass grafting (CABG), the SHOT study showed statistically significant reduction in angiographic vein graft occlusion in 610 patients after 1 yr with supplementation of 3.4 g/d of highly concentrated very long chain n-3 PUFA. The reduction in occlusion rates was significantly related to the change in the n-3 PUFA concentration in serum phospholipids during the study period with the occlusion rate in the upper quartile of such changes at only approximately 50% of that in the lower quartile. These results were also clearly related to the presence of angina pectoris and occurrence of myocardial infarction after 1 yr. Several studies were conducted in patients after percutaneous transluminal coronary angioplasty (PTCA). By 1993, two meta-analyses indicated a positive effect on the restenosis rate, a significant problem after otherwise successful PTCA. During the late 1990s, three large prospective randomized placebo-controlled angiographic studies were conducted with very long n-3 PUFA 5.1-8.0 g/d, all with completely negative results. Today, therefore, very long chain n-3 PUFA supplementation cannot be recommended to reduce the incidence of restenosis after PTCA. All studies were performed without stenting of the coronary lesion. In the very special revascularization procedure of heart transplantation, evolving hypertension and accelerated atherosclerosis have been major clinical problems. In other studies, positive effects by supplementation with very long chain n-3 PUFA (3.4-5.7 g/d) were obtained on the surrogate end points coronary vasoreactivity to acetylcholine and hypertension, respectively. On the basis of the presently available literature from clinical studies, recommendations for supplementation with very long chain n-3 PUFA can be given to patients after venous CABG (up to 3.4 g/d), and after heart transplantation (3.4-5.7 g/d) but not to patients after traditional PTCA. In fact, data from substudies suggested the possibility that large doses (5.1 g/d) of very long chain n-3 PUFA might be contraindicated because they induce a proinflammatory state in patients under oxidative stress.


Efficacy of anti-TNF dosing interval lengthening in adolescents and young adults with inflammatory bowel disease in sustained remission (FREE-study): protocol for a partially randomised patient preference trial.
Anti-tumour necrosis factor (TNF) therapy has greatly improved treatment outcomes in patients with inflammatory bowel disease (IBD), but long-term use is associated with cutaneous reactions, susceptibility to infections and frequent injections or hospital visits. Several non-controlled studies have demonstrated that dose reduction is feasible for a subset of patients, provided that early detection of a disease flare is possible. Here, we aim to compare the effectiveness of interval lengthening with standard dosing in maintaining remission in young patients with IBD. In this international, prospective, non-inferiority, partially randomised patient preference trial, we aim to recruit 148 patients aged 12-25 years with luminal Crohn's disease or ulcerative colitis in sustained remission (ie, three consecutive in-range faecal calprotectin (FC) results or recently confirmed endoscopic remission). In the interventional arm, the dosing interval will be lengthened from 8 to 12 weeks for infliximab users and from 2 to 3 weeks for adalimumab users. In the control group, standard dosing will be continued. Rapid tests will be performed for FC every 4 weeks and for anti-TNF trough levels every 12 weeks. The primary outcome is the cumulative incidence of out-of-range FC results at 48-week follow-up. Secondary endpoints include time to get out-of-range FC results, cumulative incidence of adverse effects, proportion of patients progressing to loss of response and identification of predictors of successful interval lengthening. The protocol has been approved by the Medical Ethics Review Committee of the University Medical Centre Groningen and is pending at the other participating centres. Results will be disseminated in peer-reviewed journals and presented at scientific meetings. EudraCT number: 2020-001811-26; ClinicalTrials.gov Identifier: NCT04646187. Protocol version 4, date 17 September 2021.


The relative capabilities of the upper and lower visual hemifields.
Visual performance is better in the lower visual hemifield than in the upper field for many classes of stimuli. The origin of this difference is unclear. One theory associates it with finer-grained attention in the lower field, an idea consistent with a change in relative efficacy with task difficulty. The first experiment in this study confirmed a lower hemifield advantage for discriminating a range of stimuli, including those that differ in contrast, hue, and motion. An identical paradigm revealed an upper field advantage when stimuli differed in their apparent distances from the observer. Presentations of stimuli in the upper or lower hemifield were interlaced to reduce the likelihood of possible artifacts or biases. A second experiment varied the difficulty of these discriminations, showing that difficulty does not determine field preference. Thus, an attentional mechanism is not a likely explanation for these preferences.


Arginine-based surfactants alter the rheological and in-plane structural properties of stratum corneum model membranes.
Amino acid-based surfactants have been proposed as skin permeation enhancers. In this work, we investigated the potentiality of two arginine-based amphiphiles as permeation enhancers by studying their interaction with stratum corneum (SC) model lipid membranes. Nα-benzoyl arginine decyl- and dodecylamide were tested in comparison with the classical enhancer, oleic acid, and the non-enhancer, stearic acid. Two complementary approaches were used: lipid monolayers, taken as models of the unit film layer of SC, and atomistic molecular dynamics simulations. The arginine-based amphiphiles studied were able to be incorporated into the SCM membrane and alter its rheological and structural properties by disordering the lipid chains, enhancing membrane elasticity, and thinning the overall membrane. They also affected the lateral structure of heterogeneous SC membranes at the nanoscale by relaxing and rounding the domain borders. Our work shows that the alteration observed of the overall rheological and structural properties of the SC membranes appears to be a shared ability for several amphiphilic permeation enhancers. Our results encourage future exploration of those amphiphiles as skin permeation enhancers.


Breast cancer in transgender women: A case report.
The risk of breast cancer in transgender women continues to be a topic of debate in the medical literature. Studies have theorized an increased risk in transgender women taking feminizing hormone therapy on the basis of established risk factors and histological characteristics in cisgender men and established increased risk in cisgender women on hormone replacement therapy. Historically, testing this theory has been challenging due to a relative lack of cases and large-scale, long-term studies reported in the literature. Studies to date have been contradictory, and a lack of medical consensus has led to inconsistencies in establishing universally accepted standards of care, including guidelines for screening. We hope to contribute to the ongoing discussion by presenting a case report of a transgender woman who had taken feminizing hormone therapy intermittently over 40 years and was subsequently diagnosed with breast cancer.


Synergistic effects of nitrogen and CO2 enrichment on alpine grassland biomass and community structure.
Global environmental change is altering the Earth's ecosystems. However, much research has focused on ecosystem-level responses, and we know substantially less about community-level responses to global change stressors. Here we conducted a 6-yr field experiment in a high-altitude (4600 m asl) alpine grassland on the Tibetan Plateau to explore the effects of nitrogen (N) addition and rising atmospheric CO2 concentration on plant communities. Our results showed that N and CO2 enrichment had synergistic effects on alpine grassland communities. Adding nitrogen or CO2 alone did not alter total community biomass, species diversity or community composition, whereas adding both resources together increased community biomass, reduced species diversity and altered community composition. The observed decline in species diversity under simultaneous N and CO2 enrichment was associated with greater community biomass and lower soil water content, and driven by the loss of species characterised simultaneously by tall stature and small specific leaf area. Our findings point to the co-limitation of alpine plant community biomass and structure by nitrogen and CO2 , emphasising the need for future studies to consider multiple aspects of global environmental change together to gain a more complete understanding of their ecological consequences.


Cloning, purification, crystallization and X-ray analysis of the Escherichia coli pyrimidine nucleoside hydrolase YeiK.
The E. coli yeiK gene product is homologous to members of the nucleoside hydrolase family of enzymes, the physiological role of which in bacteria is still unknown. Here, the cloning, expression in milligram quantities and enzymatic characterization of YeiK as a pyrimidine-specific nucleoside hydrolase is reported. Crystals of YeiK diffract X-rays to a resolution of 1.7 A and belong to the triclinic crystal system in space group P1, with unit-cell parameters a = 44.81, b = 85.71, c = 90.68 A, alpha = 112.95, beta = 101.95, gamma = 85.92 degrees.


Hurricane Sandy: Impact on Emergency Department and Hospital Utilization by Older Adults in Lower Manhattan, New York (USA).
On October 29th, 2012, Hurricane Sandy caused a storm surge interrupting electricity with disruption to Manhattan's (New York, USA) health care infrastructure. Beth Israel Medical Center (BIMC) was the only fully functioning major hospital in lower Manhattan during and after Hurricane Sandy. The impact on emergency department (ED) and hospital use by geriatric patients in lower Manhattan was studied. The trends of ED visits and hospitalizations in the immediate post-Sandy phase (IPS) during the actual blackout (October 29 through November 4, 2012), and the extended post-Sandy phase (EPS), when neighboring hospitals were still incapacitated (November 5, 2012 through February 10, 2013), were analyzed with baseline. The analysis was broken down by age groups (18-64, 65-79, and 80+ years old) and included the reasons for ED visits and admissions. During the IPS, there was a significant increase in geriatric visits (from 11% to 16.5% in the 65-79 age group, and from 6.5% to 13% in the 80+ age group) as well as in hospitalizations (from 22.7% to 25.2% in the 65-79 age group, and from 17.6% to 33.8% in the 80+ age group). However, these proportions returned to baseline during the EPS. The proportions of the categories "dialysis," "respiratory device," "social," and "syncope" in geriatric patients in ED visits were significantly higher than younger patients. The increases of the categories "medication," "dialysis," "respiratory device," and "social" represented two-thirds of absolute increase in both ED visits and admissions for the 65-79 age group, and half of the absolute increase in ED visits for the 80+ age group. The categories "social" and "respiratory device" peaked one day after the disaster, "dialysis" peaked two days after, and "medication" peaked three days after in ED visit analysis. There was a disproportionate increase in ED visits and hospitalizations in the geriatric population compared with the younger population during the IPS. The primary factor of the disproportionate impact on the geriatric population appears to be from indirect effects of the hurricane, mainly due to the subsequent power outages, such as "dialysis," "respiratory device," and "social." Further investigation by chart review may provide more insights to better aid with future disaster preparedness.


Dissection of human allostimulatory determinants with cloned T cells: stimulation inhibition by monoclonal antibodies TU22, 34, 35, 36, 37, 39, 43, and 58 against distinct human MHC class II molecules.
Alloantigenic determinants causing secondary lymphoproliferative responses of primed T cells were investigated by blocking stimulation with monoclonal antibodies TU22, 34, 35, 36, 37, 39, 43, and 58 binding differentially to HLA-DR and SB or MB associated molecules. In particular, the use of cloned and functionally defined T cell responders greatly facilitated the assignment of stimulator-level inhibition caused by these antibodies. Thus, a novel way of functional "mapping" for stimulatory epitopes for sets of clones with restimulation specificities associated with HLA-D, SB, MB, or hitherto unidentified class II determinants is presented here. This considerably helps to elucidate the distinct immunoregulatory roles of the three major class II alloantigen systems thus far defined.