Morphological characterization of sprouting and intussusceptive angiogenesis by SEM in oral squamous cell carcinoma.
The word angiogenesis indicates the formation of new vascular segments from existing vessels such as capillaries and venules. Blood vessel formation in tumors is the result of rapid, disorganized vascular growth through two distinct mechanisms: sprouting and intussusceptive angiogenesis. The objective of this study was to elucidate the morphological aspects of these two vascular growth mechanisms in oral squamous cell carcinoma induced in hamster buccal pouch. Eight Syrian golden hamsters had their right buccal pouch treated with DMBA 0.5% and 10% carbamide peroxide for 90 days in order to produce squamous cell carcinoma in this site. Next, buccal pouches of the animals were submitted to the vascular corrosion technique and then analyzed by scanning electron microscopy. The vascular figures of sprouts were observed in the entire vascular network of the buccal pouches, as opposed to the intussusceptive angiogenesis that was predominantly observed in the sub-epithelial network. It was possible to differentiate the figures of sprouts from artifacts by the analysis of the blind ending of these structures. Intussusceptive angiogenesis was identified by the presence of holes trespassing the lumen of the capillaries. Vascular expansion occurred through intussusceptive angiogenesis in two ways: by the fusion of the pillars to form a new capillary and, by increasing the girth of the pillar to form meshes. The method of corrosion associated with scanning electron microscopy proved to be an excellent tool to study the two types of angiogenesis in oral squamous cell carcinoma in the hamster buccal pouch.


Intragenic suppression of gain-of-function mutations in the Escherichia coli mechanosensitive channel, MscL.
Mechanosensitive channels play an important role in protecting bacterial cells from osmotic downshock by serving as biological 'pressure release valves'. One of these channels, MscL, is found throughout the bacterial kingdom, but has been most studied in Escherichia coli. The E. coli MscL is a 136-amino-acid protein organized as a homopentamer with each subunit containing two transmembrane segments. Previous studies have shown that several residues, including V23 and G26, are essential for normal function of MscL; very severe gain-of-function phenotypes in which cell growth slows or is arrested can result from residue substitutions at these positions. Through random mutagenesis and growth selection, we have generated intragenic suppressors of the V23A and G26S mutations. The suppressor mutants have been characterized by growth phenotype, Western blot and patch clamp. Most of the mutations that render phenotypic suppression are located in the transmembrane domains with additional sites lying in the periplasmic loop. In contrast, only one mutation is found in the amino-terminal S1 domain, and none is found within the carboxyl-terminal domain. Not only have these findings revealed functional domains and subdomains critical for MscL function, but they also predict a pair of residues that interact directly during channel opening.


Cicatricial pemphigoid autoantibodies react with multiple sites on the BP180 extracellular domain.
Cicatricial pemphigoid (CP) is an autoimmune blistering disease that primarily affects mucosal tissues. Autoantibodies to laminin-5 have previously been detected in certain patients with a CP-like disease; however, individuals that exhibit this reactivity profile apparently represent a small subset of CP patients. In the present investigation, 0 of 18 CP sera showed reactivity with laminin-5 by immunoblotting. In contrast, 18 of 23 CP sera (78%) recognized a 180-kDa epidermal antigen that, by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, co-migrated with BP180, a hemidesmosomal glycoprotein associated with two other autoimmune blistering diseases, bullous pemphigoid and herpes gestationis. To investigate further the CP autoimmune response, various segments of human BP180 were expressed as bacterial fusion proteins and assayed by immunoblotting for reactivity with CP patients' sera. The results of this investigation demonstrated that the BP180 autoantigen is indeed a major target of CP autoantibodies. Further, two distinct CP-reactive sites were identified on the extracellular domain of the BP180 protein, one located in the non-collagenous (NC) 16A domain (at or near the previously defined autoantibody-reactive site recognized by bullous pemphigoid and herpes gestationis sera) and the other in the carboxy-terminal region of this protein. Sixteen of 23 CP sera (70%) reacted with one or both of these antigenic sites of BP180. Other immunologic data suggested that BP180 may harbor additional CP-reactive sites. In conclusion, there are now three bullous diseases, bullous pemphigoid, herpes gestationis, and cicatricial pemphigoid, that are known to be associated with an autoimmune response against the extracellular domain of the BP180 antigen.


Cost-utility analysis of disease-modifying drugs in relapsing-remitting multiple sclerosis in Iran.
Disease-modifying drugs (DMDs) are a significant expenditure for treating multiple sclerosis (MS). However, there is limited report on assessment of the cost-utility of DMDs compared with symptom management in the presence of long-term data. This study aimed to assess the lifetime cost-utility from the Iranian healthcare perspectives of 4DMDs relative to symptom management alone in patients with relapsing-remitting multiple sclerosis using evidence from long-term published studies. A Markov model was developed with patients transitioning through health states based on Kurtzke's expanded disability status scale.Patient costs included drug costs, other medical and lost worker productivity costs. Patient quality of life was considered in the form of utilities. Costs were valued in 2011 USD, and were discounted at 7.2% per annum. Various parameters and assumptions were tested in sensitivity analyses. Total costs per patient over the time horizon of a patient's lifetime were estimated at 20285, 144194, 299279, 251255 and 69796 USD for symptom management, Avonex, Betaferon, Rebif and CinnoVex, respectively. As a result, the incremental cost per quality adjusted life years (QALY) for patients receiving Avonex, Betaferon, Rebif and CinnoVex was 607397, 1374355, 1166515 and 1010429 USD, respectively, when compared with symptom management. The results were sensitive to changes in time horizon, disease progression and drug costs. DMDs in relapsing-remitting MS patients was associated with increased benefits compared with symptom management, albeit at higher costs. Because patients receiving Avonex incurred slightly higher QALYs than patients receiving other DMDs, treatment with Avonex dominates other DMDs in Iran.


Electroacupuncture improves rectal distension-induced delay in solid gastric emptying in dogs.
The aim of this study was to investigate the effects and mechanisms of electroacupuncture (EA) on rectal distension (RD)-induced delay in solid gastric emptying in dogs. Gastric emptying of solids was assessed in 12 dogs chronically implanted with a duodenal cannula by collecting samples at different time points from the cannula and measuring the dried weights of the samples. Bethanechol and atropine were used to qualitatively validate the method. In separate experiments, gastric emptying of solids was measured in a number of sessions: control, RD, RD + sham-EA, RD + EA of 6 mA, RD + EA of 3 mA, and RD + EA + naloxone. The method of gastric emptying by collecting and drying gastric chyme from the duodenal cannula was found to be accurate and reliable. Using the method, we found gastric emptying to be accelerated with bethanechol (70.01 ± 8.10% vs. 82.61 ± 4.15%, P = 0.04, vs. control) and delayed with atropine (4.31 ± 1.57%, P < 0.001, vs. control). RD substantially and significantly delayed gastric emptying. EA, but not sham-EA, attenuated delayed gastric emptying induced by RD (sham-EA: 48.79 ± 9.47% vs. EA: 74.28 ± 5.96%, P < 0.01). The effect was more potent with EA of 6 mA than EA of 3 mA and blocked by naloxone. EA is able to attenuate RD-induced delay in gastric emptying of solids, and this ameliorating effect may be mediated via the opioid pathway. EA may have a therapeutic potential for treating delayed gastric emptying attributed to lower gut distension.


Sex Differences in Vital Organ Support Provided to ICU Patients.
Critically ill women may receive less vital organ support than men but the mortality impact of this differential treatment remains unclear. We aimed to quantify sex differences in vital organ support provided to adult ICU patients and describe the relationship between sex, vital organ support, and mortality. In this retrospective observational study, we examined the provision of invasive ventilation (primary outcome), noninvasive ventilation, vasoactive medication, renal replacement therapy, extracorporeal membrane oxygenation (ECMO), or any one of these five vital organ supports in women compared with men. We performed logistic regression investigating the association of sex with each vital organ support, adjusted for illness severity, diagnosis, preexisting treatment limitation, year, and hospital. We performed logistic regression for hospital mortality adjusted for the same variables, stratified by vital organ support (secondary outcome). ICU admissions in the Australia and New Zealand Intensive Care Society Adult Patient Database 2018-2021. This registry records admissions from 90% of ICUs in the two nations. None. We examined 699,535 ICU admissions (43.7% women) to 199 ICUs. After adjustment, women were less likely than men to receive invasive ventilation (odds ratio [OR], 0.64; 99% CI, 0.63-0.65) and each other organ support except ECMO. Women had lower adjusted hospital mortality overall (OR, 0.94; 99% CI, 0.91-0.97). Among patients who did not receive any organ support, women had significantly lower adjusted hospital mortality (OR, 0.82; 99% CI, 0.76-0.88); among patients who received any organ support women and men were equally likely to die (OR, 1.01; 99% CI, 0.97-1.04). Women received significantly less vital organ support than men in ICUs in Australia and New Zealand. However, our findings suggest that women may not be harmed by this conservative approach to treatment.


Characterization of trimming Man9-mannosidase from pig liver. Purification of a catalytically active fragment and evidence for the transmembrane nature of the intact 65 kDa enzyme.
An alpha 1,2-mannosidase (Man9-mannosidase) involved in N-linked oligosaccharide processing has been purified about 16,000-fold from pig liver crude microsomes (microsomal fractions) by CM-Sepharose and DEAE-Sephacel chromatography, concanavalin A (Con A)-Sepharose chromatography and, as the key step of the procedure, affinity chromatography on immobilized N-5-carboxypentyl-l-deoxymannojirimycin (CP-dMM). On SDS/polyacrylamide-gel electrophoresis under reducing conditions, the isolated enzyme migrated as a single protein band with a molecular mass of 49 kDa. The enzyme does not bind Con A and is not susceptible to glycopeptidase F, indicating that it lacks N-linked oligosaccharides of the high-mannose or complex type. Purified Man9-mannosidase has a pH optimum close to 6.0 and requires bivalent cations for activity, with Ca2+ being most effective. The enzyme is inhibited strongly by basic sugar analogues of mannose such as 1-deoxymannojirimycin (dMM, Ki approximately 5 microM), N-methyl-dMM (Ki approximately 55 microM) and CP-dMM (Ki approximately 150 microM), whereas NN-dimethyl-dMM and the mannosidase II inhibitor swainsonine were hardly or not at all inhibitory. A homogeneous preparation of the 49 kDa enzyme cleaves specifically three of the four alpha 1,2-mannosidic linkages in the natural Man9-GlcNAc2 (M9) substrate. The relative rates by which the parent and intermediate structures are hydrolysed were found to be about 3:2:5 for M9, M8 and M7 respectively. The enzyme displays only marginal activity toward the remaining alpha 1,2-mannosidic linkages in the Man9-GlcNAc2 oligosaccharide (relative rate of M6 hydrolysis approximately 0.02) and is not active against nitrophenyl and methylumbelliferyl alpha-mannosides. This unique substrate specificity suggests that Man9-mannosidase processing differs from that catalysed by other trimming alpha 1,2-mannosidases hitherto reported. A polyclonal antibody raised against the denatured 49 kDa polypeptide not only recognizes a protein band of similar size in Western blots of crude microsomes, but also reacts strongly with a 65 kDa protein species. On trypsin treatment of detergent-solubilized microsomes, the 65 kDa protein is converted specifically into a stable 49 kDa fragment, indicating a precursor-product relationship between the two proteins. We conclude from this observation that the 65 kDa protein represents the intact form of Man9-mannosidase from which the 49 kDa enzyme which we have isolated has been generated, with retention of catalytic activity, by proteolysis during purification. Proteolytic studies with sealed microsomes suggest that the intact 65 kDa enzyme is a protein with a membrane-spanning domain, as well as a cytosolic polypeptide domain of size at least 3 kDa.


Smart drugs and neuroenhancement: what do we know?
Introduction: Smart drugs are among the most common drugs used by students. It is estimated that they are second in incidence after cannabis. Although they are usually used for diseases such as attention deficit hyperactivity disorder (ADHD) and dementia, in most cases the use of smart drugs is illegal and without a prescription. Methodological issues: A systematic review was conducted according to PRISMA guidelines. SCOPUS, Medline (using PubMed as a search engine), Embase, Web of Sciences, and Google Scholar were used as search engines from January 1, 1980 to June 1, 2021 to evaluate the association between smart drugs and neuro-enhancement. A total of 4715 articles were collected. Of these, 295 duplicates were removed. A total of 4380 articles did not meet the inclusion criteria. In conclusion, 48 articles were included in the present systematic review. Results: Most of the studies were survey studies, 1 was a prospective longitudinal study, 1 was a cross-over study, and 1 was an experimental study in an animal model (rats). The largest group of consumers was school or university students. The most frequent reasons for using smart drugs were: better concentration, neuro enhancement, stress reduction, time optimization, increased wake time, increased free time, and curiosity. There are conflicting opinions, in fact, regarding their actual functioning and benefit, it is not known whether the benefits reported by consumers are due to the drugs, the placebo effect or a combination of these. The real prevalence is underestimated: it is important that the scientific community focus on this issue with further studies on animal models to validate their efficacy.


Macrophage Response to Allogeneic Adipose Tissue-Derived Stromal Cells in Hyaluronan-Based Hydrogel in a Porcine Vocal Fold Injury Model.
Adipose tissue-derived stromal cells (ASC) embedded in hyaluronan scaffold is a beneficial prophylactic treatment for vocal fold (VF) surgical scar. Here, we investigated the macrophage inflammatory response to allogeneic ASC-constructs and identified changes in lamina propria extracellular matrix. Pig ASC were characterized and transfected with GFP+ lentivirus. Thirty-three pigs underwent VF biopsies, and after 3 days, gel alone, gel+pASC, placebo, or pASC alone was injected into wound bed. Animals were sacrificed 3, 7, or 26 days post-injection. Flow cytometry; qPCR for NF-α, TGFβ, IL-10, IL-4, IFNγ, IL-12, FGF2, Col1A1, and HGF; and immunohistochemistry for collagen, elastin, HA, and fibronectin were performed to characterize macrophage phenotype, quantify cytokine transcription, analyze extracellular matrix remodeling, and track GFP+ cells. No significant differences were found in SWC3+/SWC9+ phenotype or mRNA expression between cells+gel, gel, or placebo. The ASC alone exhibited significantly greater collagen, gel alone resulted in significantly less hyaluronan, and gel+pASC significantly more fibronectin (all P < .05). The pASC-GFP+ were detected 26 days post-injection. The ASC-constructs were biocompatible; they did not influence the macrophage inflammatory response or provoke increases in collagen expression. Long-term engraftment was confirmed.


The potential clinical applications and prospects of microRNAs in lung cancer.
Lung cancer is the major cause of cancer deaths worldwide due to its late diagnosis and poor outcome. Understanding genomic medicine may widen our vision into the oncogenesis of lung cancer and may open the door to improvements in the clinical management of lung cancer. It is well known that almost half of all genes are regulated by microRNAs (miRNAs). This review focuses on the role of miRNAs in lung cancer and also touches on the value of miRNA-based novel therapies for lung cancers.


Local search methods based on variable focusing for random K-satisfiability.
We introduce variable focused local search algorithms for satisfiabiliity problems. Usual approaches focus uniformly on unsatisfied clauses. The methods described here work by focusing on random variables in unsatisfied clauses. Variants are considered where variables are selected uniformly and randomly or by introducing a bias towards picking variables participating in several unsatistified clauses. These are studied in the case of the random 3-SAT problem, together with an alternative energy definition, the number of variables in unsatisfied constraints. The variable-based focused Metropolis search (V-FMS) is found to be quite close in performance to the standard clause-based FMS at optimal noise. At infinite noise, instead, the threshold for the linearity of solution times with instance size is improved by picking preferably variables in several UNSAT clauses. Consequences for algorithmic design are discussed.


Novel Compound Heterozygous Variants in the CDC6 Gene in a Russian Patient with Meier-Gorlin Syndrome.
Meier-Gorlin syndrome (MGS) is a rare genetic syndrome inherited in an autosomal dominant or autosomal recessive manner. The disorder is characterized by bilateral microtia, absence or hypoplasia of the patella, and an intrauterine growth retardation as well as a number of other characteristic features. The cause of the disease is mutations in genes encoding proteins involved in the regulation of the cell cycle (ORC1, ORC4, ORC6, CDT1, CDC6, GMNN, CDC45L, MCM3, MCM5, MCM7, GINS2, and DONSON). Meier-Gorlin syndrome 5 due to mutations in the CDC6 gene is difficult to diagnose, and few clinical data have been described to date. Only one patient (male) with a missense mutation in a homozygous state has been previously reported. This report describes a new clinical case of Meier-Gorlin syndrome 5. This is also the first report of a Russian patient with Meier-Gorlin syndrome. The patient, a female, had extremely low physical development, neonatal progeroid appearance, lipodystrophy, thin skin, partial alopecia, cyanosis of the face, triangular face, microgenia, arachnodactyly, delayed bone age, hepatomegaly, hypoplasia of the labia majora, and hypertrophy of the clitoris in addition to known clinical signs. Differential diagnosis was performed with chromosomal abnormalities and Hutchinson-Gilford progeria. According to the results of sequencing of the clinical exome, the patient had two previously undescribed variants in the CDC6 gene, c.230A>G (p.(Lys77Arg)) and c.232C>T (p.(Gln78Ter)), NM_001254.3, in a compound heterozygous state. This case allows us to learn more about the clinical features and nature of MGS 5 and improve the speed of diagnostics and quality of genetic counseling for such families.


Doping porous silicon with erbium: pores filling as a method to limit the Er-clustering effects and increasing its light emission.
Er clustering plays a major role in hindering sufficient optical gain in Er-doped Si materials. For porous Si, the long-standing failure to govern the clustering has been attributed to insufficient knowledge of the several, concomitant and complex processes occurring during the electrochemical Er-doping. We propose here an alternative road to solve the issue: instead of looking for an equilibrium between Er content and light emission using 1-2% Er, we propose to significantly increase the electrochemical doping level to reach the filling the porous silicon pores with luminescent Er-rich material. To better understand the intricate and superposing phenomena of this process, we exploit an original approach based on needle electron tomography, EXAFS and photoluminescence. Needle electron tomography surprisingly shows a heterogeneous distribution of Er content in the silicon thin pores that until now couldn't be revealed by the sole use of scanning electron microscopy compositional mapping. Besides, while showing that pore filling leads to enhanced photoluminescence emission, we demonstrate that the latter is originated from both erbium oxide and silicate. These results give a much deeper understanding of the photoluminescence origin down to nanoscale and could lead to novel approaches focused on noteworthy enhancement of Er-related photoluminescence in porous silicon.


[Altered collagene characteristics and lysyl oxidase activity in lathyrism].
Experiments were carried out on rats with lathyrism, which was induced by adding semicarbazide (0.075%) into drinking water for 45 days. The data obtained show a 30% reduction in the body weight and an increase in.organ weight coefficients. Semicarbazide intake led to the pelvic limb paralysis, scoliosis, bone tissue degradation, cartilage growth, 46% decrease of the calcium level in the femur. It has been detected essential structural changes in extracellular matrix based on the collagen cross-links reduction. The activity of lysyl oxidase, a key enzyme for the collagen development, showed 5-fold decrease in the aorta tissues. The level of formaldehyde, a nonenzymic cross-links developer, has been measured in the liver tissue by the aldehyde trap (5,5-dimethyleyclohexane-1,3-dione) administration and then fluorimetric determination of formaldimedone. Under semicarbazide load, the formaldehyde level in the liver tissue was reduced by 47%. Therefore, semicarbazide influences not only the enzymic development of aldehyde groups in collagen, but the level of other aldehydes, which can cause cross-links. This experimental model of lathyrism is appropriate for investigation of the lysyl oxidase inhibitors effect on extracellular matrix.


Insomnia symptoms and subsequent cardiovascular medication: a register-linked follow-up study among middle-aged employees.
Sleep disturbances have been associated with an increased risk of cardiovascular disease outcomes. The associations of insomnia with hypertension and dyslipidaemia, the main modifiable cardiovascular risk factors, are less studied. We especially lack understanding on the longitudinal effects of insomnia on dyslipidaemia. We aimed to examine the associations of insomnia symptoms with subsequent prescribed medication for hypertension and dyslipidaemia using objective register-based follow-up data. Baseline questionnaire surveys among 40-60-year-old employees of the City of Helsinki, Finland, were conducted in 2000-2002 (n = 6477, response rate 67%, 78% women) and linked to a national register on prescribed reimbursed medication 5-7 years prior to and 5 years after baseline. Associations between the frequency of insomnia symptoms (difficulties in initiating and maintaining sleep, non-restorative sleep) and hypertension and dyslipidaemia medication during the follow-up were analysed using logistic regression analysis (odds ratios with 95% confidence intervals). Analyses were adjusted for pre-baseline medication, sociodemographic and work-related factors, health behaviours, mental health, and diabetes. Frequent insomnia symptoms were reported by 20%. During the 5-year follow-up, 32% had hypertension medication and 15% dyslipidaemia medication. Adjusting for age, gender and pre-baseline medication, frequent insomnia symptoms were associated with hypertension medication (odds ratio 1.57, 95% confidence interval 1.23-2.00) and dyslipidaemia medication (odds ratio 1.59, 95% confidence interval 1.19-2.12). Occasional insomnia symptoms were also associated with cardiovascular medication, though less strongly. Further adjustments had negligible effects. To conclude, insomnia should be taken into account in the prevention and management of cardiovascular disease and related risk factors.


Low-frequency vibration treatment of bone marrow stromal cells induces bone repair in vivo.
To study the effect of low-frequency vibration on bone marrow stromal cell differentiation and potential bone repair in vivo. Forty New Zealand rabbits were randomly divided into five groups with eight rabbits in each group. For each group, bone defects were generated in the left humerus of four rabbits, and in the right humerus of the other four rabbits. To test differentiation, bones were isolated and demineralized, supplemented with bone marrow stromal cells, and implanted into humerus bone defects. Varying frequencies of vibration (0, 12.5, 25, 50, and 100 Hz) were applied to each group for 30 min each day for four weeks. When the bone defects integrated, they were then removed for histological examination. mRNA transcript levels of runt-related transcription factor 2, osteoprotegerin, receptor activator of nuclear factor κ-B ligan, and pre-collagen type 1 α were measured. Humeri implanted with bone marrow stromal cells displayed elevated callus levels and wider, more prevalent, and denser trabeculae following treatment at 25 and 50 Hz. The mRNA levels of runt-related transcription factor 2, osteoprotegerin, receptor activator of nuclear factor κ-B ligand, and pre-collagen type 1 α were also markedly higher following 25 and 50 Hz treatment. Low frequency (25-50 Hz) vibration in vivo can promote bone marrow stromal cell differentiation and repair bone injury.


Parenting stress among parents of children with congenital diaphragmatic hernia.
The aim of this study was to examine parental stress among parents of children with congenital diaphragmatic hernia (CDH). Between 2005 and 2009, a total of 51 children with CDH were treated at Astrid Lindgren Children's Hospital. The survival rate at discharge was 86% and long-term survival rate 80%. One parent each of the long-term survivors (41 children) was included in the present study, and 34 parents (83%) agreed to participate. Participants received the Swedish Parenthood Stress Questionnaire (SPSQ). The questionnaire was supplemented by data from case records. Parents of children with CDH, who had been supported by ECMO or had a long hospital stay, showed significantly higher overall parental stress. Mothers scored an overall higher parental stress compared with fathers. A prenatal diagnosis of CDH or lower parental educational level resulted in significantly higher parental stress in some of the factors. Parental stress in parents of children with CDH seems to increase with the severity of the child's malformation. Mothers tend to score higher parental stress than fathers.


Intermittent fluoxetine dosing in the treatment of women with premenstrual dysphoria.
Some women experience premenstrual mood symptoms that severely disrupt their lives and relationships. These women often require pharmacologic treatment. Selective serotonin reuptake inhibitors, particularly daily fluoxetine, have been proven superior to placebo in several randomized controlled trials. Twenty-four women with confirmed premenstrual dysphoric disorder (PMDD) and with a history of affective disorders or alcoholism were treated with fluoxetine 20 mg/day (continuous), and 24 women with PMDD and no psychiatric history were treated with fluoxetine 20 mg/day for 14 days premenstrually only (intermittent). Both groups received treatment for three menstrual cycles. Sixteen women (66.7%) in the continuous dosing group and 18 women (75.0%) in the intermittent group were classified as treatment responders. Intermittent dosing of fluoxetine seems to be effective and mostly free of side effects in women with PMDD and, therefore, may offer an attractive treatment option for a disorder that is itself intermittent.


Milk production and nitrogen utilization by dairy cows infused postruminally with sodium caseinate, soybean meal, or cottonseed meal.
Four Holstein cows with fistulated rumens were in a 4 X 4 Latin square design for us to determine effects of administering different sources of protein postruminally on milk production, milk composition, and efficiency of nitrogen utilization. Treatments consisted of postruminal infusion of 1) water, 2) sodium caseinate, 3) soybean meal, or 4) cottonseed meal. Milk yield (kg/day) and milk protein production (g/day) for the four treatments were: 1) 30.6, 1043; 2) 32.7, 1146; 3) 32.1, 1102; and 4) 31.1, 1087. Synthesis of milk protein increased during postruminal infusions of protein as indicated by the increased casein nitrogen fraction in milk. All protein infusions improved efficiency of use of absorbed nitrogen for synthesis of milk protein. Milk fat percentage and daily production of milk fat were not affected by treatments.


Improved pharmaceutical stability of a boronphenylalanine mannitol formulation for boron neutron capture therapy.
Boron neutron capture therapy (BNCT) is a radiotherapy based cancer treatment requiring the availability of a low energy thermal neutron beam and a boron containing drug. These requirements limit BNCT availability with the latter pharmaceutical issue related to the extremely short shelf-life and clinical acceptability of the current fructose based L-boronphenylalanine (BPA) formulation. Resolution of the formulation issues would remove this factor and therefore the stability of an alternative mannitol BPA formulation has been investigated. A mannitol BPA solution formulation was prepared and either lyophilised or stored as a solution at varying temperatures. After suitable periods the formulation was analysed by HPLC for BPA and degradation products. Lyophilised and solution mannitol BPA formulations exhibited a temperature and time dependent loss of BPA with concomitant increases in degradation products. Autoclaving the solution induced and accelerated degradation. A solution or lyophilised mannitol BPA formulation has a shelf-life of between 1 and 4 years respectively, a marked improvement over the current fructose formulation. Due to temperature dependent degradation the formulation cannot be terminally sterilised by autoclaving. The enhanced stability of the mannitol formulation removes the requirement for extemporaneous aseptic preparation of BPA just prior to treatment and eliminates one of the issues complicating the delivery of BNCT.


Human aging and progeria.
The notion that all aging is ultimately cell aging is a novel hypothesis and one with growing support. Recent studies in genetics and cell biology are consistent with this view. Criticism of the model is largely reflective of inadequate understanding of both the model itself and human pathology. Hutchinson-Gilford progeria is a segmental progeria that may well be an 'epigenetic mosaic' disease in which certain cell lines exhibit early cell senescence, while others are spared. The general cell senescence model of aging offers a consistent and elegant explanation of both human aging and progeria. More importantly, the model is not only testable but implies fundamental, novel and promising therapeutic avenues for both progeria and more typical age-related diseases.


A Soluble Precipitating Antigen From Hog Cholera Virus Propagated in Tissue Culture: I. Preparation and Characterization of the Antigen.
A precipitating hog cholera viral antigen was produced in a swine kidney tissue culture system. This antigen produced a single, sharp precipitin line with reference antiserum but no precipitin lines with nonimmune control sera. The precipitating antigen was present in the supernatant fluid after high-speed centrifugation, and was readily separated from infective virus by diethylaminoethyl cellulose (DEAE) chromatography. The antigen was found to be nondialyzable, stable to the action of chloroform and to storage at refrigeration temperature for at least 7 mo, but was inactivated at 56 C in 30 min.


Papillary carcinoma of the thyroid originating in a thyroglossal cyst. Report of a case and diagnostic criteria.
A 34-year-old female with papillary carcinoma of the thyroid originating in a thyroglossal cyst is described. The patient's chief complaint was a submental mass. The mass was 6 x 4 cm, elastic, soft, and smooth-surfaced. CT examination showed high-density areas in part of the interior of the mass. Resection of the mass was attempted with a diagnosis of thyroglossal cyst. Since papillary carcinoma of the thyroid was noted in the cyst by intraoperative frozen section pathological examination, primary carcinoma of the thyroid was suspected, and the thyroid and surrounding areas were examined. Since no abnormalities were noted in the thyroid, the thyroid was preserved. According to the following reasons, the tumor was considered to be primary papillary carcinoma of the thyroid arising in the thyroglossal cyst: (1) Scar formation was noted in the center of the tumor; (2) tumor cells partly infiltrated into the surrounding tissues, and (3) no tumor was noted in the thyroid. A definitive diagnosis of carcinoma arising in the thyroglossal cyst has required confirmation of the absence of carcinoma in the thyroid by total thyroidectomy. In the present case, however, total thyroidectomy was avoided, because no gross pathological changes were observed in the thyroid during the operation. This decision may be controversial both diagnostically and therapeutically, but we consider from our observation of the course that total thyroidectomy is not always necessary.


Biased agonism as a novel strategy to harness the proresolving properties of melanocortin receptors without eliciting melanogenic effects.
There is a need for novel approaches to control pathologies with overexuberant inflammatory reactions. Targeting melanocortin (MC) receptors represents a promising therapy for obesity and chronic inflammation, but lack of selectivity and safety concerns limit development. A new way to increase selectivity of biological effects entails the identification of biased agonists. In this study, we characterize the small molecule AP1189 as a biased agonist at receptors MC1 and MC3. Although not provoking canonical cAMP generation, AP1189 addition to MC1 or MC3, but not empty vector, transfected HEK293 cells caused ERK1/2 phosphorylation, a signaling responsible for the proefferocytic effect evoked in mouse primary macrophages. Added to macrophage cultures, AP1189 reduced cytokine release, an effect reliant on both MC1 and MC3 as evident from the use of Mc1r(-/-) and Mc3r(-/-) macrophages. No melanogenesis was induced by AP1189 in B16-F10 melanocytes. In vivo, oral AP1189 elicited anti-inflammatory actions in peritonitis and, upon administration at the peak of inflammation, accelerated the resolution phase by ∼3-fold. Finally, given the clinical efficacy of adrenocorticotropin in joint diseases, AP1189 was tested in experimental inflammatory arthritis, where this biased agonist afforded significant reduction of macroscopic and histological parameters of joint disruption. These proof-of-concept analyses with AP1189, an active oral anti-inflammatory and resolution-promoting compound, indicate that biased agonism at MC receptors is an innovative, viable approach to yield novel anti-inflammatory molecules endowed with a more favorable safety profile.


Cost-utility analysis of lifestyle interventions to prevent type 2 diabetes in women with prior gestational diabetes.
To compare estimated costs and health outcomes of lifestyle interventions for the prevention of type 2 diabetes mellitus in women who had gestational diabetes. An age-specific Markov model was applied comparing costs and quality-adjusted life years (QALYs) of three alternatives: 'doing nothing'; an annual reminder system (ARS) with an awareness campaign ('ARS-awareness'); and an ARS with an intensive lifestyle intervention ('ARS-ILS'). A healthcare payer perspective was adopted, the time horizon was 30 years and the setting was Flanders (Belgium). Sensitivity analyses were performed. 'ARS-awareness' was extendedly dominated. Per 10 000 participants, 'ARS-ILS' cost €13 210 256 more and gained 496 QALYs compared with 'doing nothing' (26 632 €/QALY), with a 63% probability of being cost effective, given a cost effectiveness threshold of 35 000 €/QALY. A scenario analysis showed that 'ARS-ILS' for 15 years only offered to women with prediabetes (compared with 'doing nothing') has an 89.5% likelihood of being dominant. 'ARS-ILS' may be the preferred intervention. However, the probability of being cost effective was low. Based on further scenario analyses, we recommend healthcare decision makers to consider the application of a more intensive alternative, focused on the highest risk profiles and with a shorter intervention duration.


Serological Responses in Cattle following Booster Vaccination against Serotypes 4 and 8 Bluetongue Virus with Two Bivalent Commercial Inactivated Vaccines.
Since the outbreak of bluetongue in Northern Europe in 2006, numerous outbreaks involving several serotypes have been observed. Since 2008, compulsory or voluntary vaccination campaigns with inactivated vaccines have been carried out to eradicate these serotypes. In France, serotypes 8 and 4 have been enzootic since 2017, and currently, the majority of vaccinations take place in the context of animal movements, to comply with the regulations of the importing countries. Several vaccine manufacturers have developed inactivated vaccines against serotypes 4 and 8 (mono or bivalent). In this study, we investigated and compared the serological responses to a booster vaccination with two different bivalent inactivated vaccines (BTVPUR suspension injectable® 4 + 8, Boehringer Ingelheim or SYVAZUL ® BTV 4 + 8, Biové) following a primary vaccination with BTVPUR® 4 + 8 in the previous year. The results show that using an alternative vaccine for booster vaccination is at least as effective as using the homologous vaccine. Indeed, the antibody response against BTV-8 is higher in the case of a heterologous vaccination and identical for BTV-4. This information could allow more flexibility in the choice of vaccines used for booster vaccination, particularly in cases where homologous vaccines are in short supply or unavailable.


Treatment of testicular cancer: a new and improved model.
Testicular cancer has become a model for a curable neoplasm. Prior to the advent of cisplatin combination chemotherapy, standard chemotherapy consisted of dactinomycin, alone or in combination with chlorambucil and methotrexate. Disseminated germ cell tumors were chemosensitive to these older regimens, with a 50% objective response rate and a 10% to 20% complete remission rate; however, the cure rate was only 5% to 10%. In 1974, we began our initial cisplatin plus vinblastine plus bleomycin (PVB) chemotherapy. Thirty-three of 47 patients with disseminated germ cell tumors treated from 1974 to 1976 achieved a complete remission (CR), and an additional five (11%) were rendered disease-free with post-PVB resection of teratoma or carcinoma. Twenty-seven (57%) of these patients are continuously disease-free with a minimal follow-up of 13 + years. Thus, cisplatin-based chemotherapy produced a one-log increase in the cure rate compared with dactinomycin. A subsequent phase III study performed from 1976 to 1978 demonstrated that the vinblastine dosage could be reduced 25% from 0.4 mg/kg to 0.3 mg/kg with a reduction in toxicity but without any decrement in therapeutic efficacy. A third-generation PVB study from 1978 to 1981 documented that optimal cure rates were achieved with 12 weeks of induction therapy with PVB and that long-term maintenance therapy with vinblastine was unnecessary. In 1978, we initiated salvage therapy with cisplatin plus etoposide (VP-16) in patients not cured with PVB, and 25% of these patients were subsequently cured with this regimen. This represented the first time an adult solid tumor had been cured with a second-line regimen. In 1983, we began studies with third-line therapy with cisplatin plus ifosfamide combination chemotherapy, and even in this refractory setting, approximately 20% of patients are curable. From 1981 to 1984, we compared cisplatin plus VP-16 plus bleomycin (PVP16B) with PVB as first-line chemotherapy. There was a significant reduction in neuromuscular toxicity favoring the VP-16 arm, and furthermore, 78% of these patients were continuously disease-free compared with 66% with PVB. Approximately 75% of patients with disseminated germ cell tumors will be cured with PVP16B, and an additional 10% are curable with salvage chemotherapy. This represents the highest cure rate in any adult malignancy.


New family with HSPB8-associated autosomal dominant rimmed vacuolar myopathy.
We clinically and molecularly characterize a new family with autosomal dominant rimmed vacuolar myopathy (RVM) caused by mutations in the HSPB8 gene. We performed whole-exome and whole-genome sequencing in the family. Western blot and immunocytochemistry were used to analyze 3 patient fibroblasts, and findings were compared with their age- and sex-matched controls. Affected patients have distal and proximal myopathy, with muscle biopsy showing rimmed vacuoles, muscle fiber atrophy, and endomysial fibrosis typical of RVM. Muscle MRI showed severe relatively symmetric multifocal fatty degenerative changes of the lower extremities. We identified a duplication of C at position 515 of the HSPB8 gene (c.515dupC) by whole-genome sequencing, which caused a frameshift with a predicted alternate stop codon p.P173SFS*43 in all affected individuals, resulting in an elongated protein product. Western blot and immunocytochemistry studies revealed reduced expression of heat shock protein beta 8 in patient fibroblasts compared with control fibroblasts, in addition to disrupted autophagy pathology. We report a novel family with autosomal dominant RVM caused by the c.515dupC mutation of the HSPB8 gene, causing a translational frameshift that results in an elongated protein. Understanding the mechanism for the RVM pathology caused by mutated chaperone will permit novel targeted strategies to alter the natural history progression. As next-generation sequencing becomes more available, additional myopathic families will be identified with HSPB8 mutations.


Genetic background of apparently idiopathic sporadic cerebellar ataxia.
Disease-causing mutations have been identified in various entities of autosomal dominant ataxia and in Friedreich's ataxia. However, no molecular pathogenic factor is known to cause idiopathic cerebellar ataxias. We investigated the CAG/CTG trinucleotide repeats causing spinocerebellar ataxia types 1, 2, 3, 6, 7, 8 and 12, and the GAA repeat of the frataxin gene in 124 patients apparently suffering from idiopathic sporadic ataxia, including 20 patients with the clinical diagnosis of multiple system atrophy. Patients with a positive family history, a typical Friedreich phenotype, or symptomatic ataxia were excluded. Genetic analyses uncovered the most common Friedreich mutation in 10 patients with an age at onset between 13 and 36 years. The SCA6 mutation was present in nine patients with disease onset between 47 and 68 years of age. The CTG repeat associated with SCA8 was expanded in three patients. One patient had SCA2 attributable to a de novo mutation from a paternally transmitted, intermediate allele. We did not identify the SCA1, SCA3, SCA7 or SCA12 mutation in idiopathic sporadic ataxia patients. No trinucleotide repeat expansion was detected in the MSA subgroup. This study has revealed the genetic basis in 19% of apparently idiopathic ataxia patients. SCA6 is the most frequent mutation in late onset cerebellar ataxia. The frataxin trinucleotide expansion should be investigated in all sporadic ataxia patients with onset before age 40, even when the phenotype is atypical for Friedreich's ataxia.


The association between somatic and psychological discomfort and health-related quality of life according to the elderly and non-elderly.
Symptoms and discomfort are common complaints in primary care settings. It has been postulated that the physical symptoms are informative index in estimating Health-related quality of life (HRQOL). Thus, we conducted a community-based cross-sectional study to assess the relationship between somatic and psychological discomfort and HRQOL in elderly and non-elderly people. A total of 2467 participants were recruited in 2013 from a population of 17,066 rural residents aged 20 or older. Information on demographic characteristics, somatic and psychological discomfort symptoms, and HRQOL was collected. Two months after the baseline survey, we conducted a repeated survey to assess changes in the discomfort symptoms and HRQOL. We evaluated associations of the discomfort symptoms with HRQOL using multiple linear regression and mixed model. EuroQol-Visual Analogue Scale (EQ-VAS), index of HRQOL, was correlated with fatigue, pain, sleep disturbances, indigestion, and anxiety/depression, after adjusting for covariates. However, the factors most significantly associated with EQ-VAS differed between the elderly and non-elderly. Pain was the most important factor contributing to EQ-VAS in the elderly, whereas depression and anxiety were the predominant factors in the non-elderly. These relationships were replicated in the repeated measurements to assess the change of symptoms and change of EQ-VAS. Our study suggests that somatic and psychological discomfort symptoms are associated with HRQOL. The main factors related to HRQOL vary according to age and large prospective studies and clinical trials are needed to clarify the association between specific symptoms and HRQOL according to the age.


Homology modeling of human Fyn kinase structure: discovery of rosmarinic acid as a new Fyn kinase inhibitor and in silico study of its possible binding modes.
Tyrosine phosphorylation represents a unique signaling process that controls metabolic pathways, cell activation, growth and differentiation, membrane transport, apoptosis, neural, and other functions. We present here the three-dimensional structure of Fyn tyrosine kinase, a Src-family enzyme involved in T-cell receptor signal transduction. The structure of Fyn was modeled for homology using the Sybyl-Composer suite of programs for modeling. Procheck and Prosa II programs showed the high quality of the obtained three-dimensional model. Rosmarinic acid, a secondary metabolite of herbal plants, was discovered as a new Fyn kinase inhibitor using immunochemical and in silico methods. Two possible binding modes of rosmarinic acid were evaluated here, i.e., near to or in the ATP-binding site of kinase domain of Fyn. Enzyme kinetic experiments revealed that Fyn is inhibited by a linear-mixed noncompetitive mechanism of inhibition by rosmarinic acid. This indicates that rosmarinic acid binds to the second "non-ATP" binding site of the Fyn tyrosine kinase.


Evaluation of outcome by race in early-stage non-small cell lung cancer.
Most studies of outcome by race in cancer have shown that blacks have a shorter survival compared to whites, both overall and within each TNM stage. We endeavored to evaluate the difference in survival by race in US military veterans treated for early stage non-small cell lung cancer (NSCLC). This retrospective analysis of overall survival by race, looking at all-cause mortality in a group of consecutively treated veterans with stage I-II NSCLC, was carried out at a 1,000-bed tertiary care Department of Veterans Affairs Medical Center. The study included 143 white and 45 black patients treated with curative intent for stage I-II NSCLC between January 1982 through August 1994. Nineteen patients received radiotherapy alone for their treatment while the remaining 169 underwent a complete surgical resection. There were no significant differences in patient characteristics for important prognostic variables. An overall survival analysis of all-cause mortality found no significant difference between the two groups. With equal access to health care, as is available for eligible patients in Department of Veterans Affairs Medical Centers, racial differences in lung cancer treatment outcome may be diminished or eliminated.


Expression of the SLAM family of receptors adapter EAT-2 as a novel strategy for enhancing beneficial immune responses to vaccine antigens.
Recent studies have shown that activation of the signaling lymphocytic activation molecule (SLAM) family of receptors plays an important role in several aspects of immune regulation. However, translation of this knowledge into a useful clinical application has not been undertaken. One important area where SLAM-mediated immune regulation may have keen importance is in the field of vaccinology. Because SLAM signaling plays such a critical role in the innate and adaptive immunity, we endeavored to develop a strategy to improve the efficacy of vaccines by incorporation of proteins known to be important in SLAM-mediated signaling. In this study, we hypothesized that coexpression of the SLAM adapter EWS-FLI1-activated transcript 2 (EAT-2) along with a pathogen-derived Ag would facilitate induction of beneficial innate immune responses, resulting in improved induction of Ag-specific adaptive immune responses. To test this hypothesis, we used rAd5 vector-based vaccines expressing murine EAT-2, or the HIV-1-derived Ag Gag. Compared with appropriate controls, rAd5 vectors expressing EAT-2 facilitated bystander activation of NK, NKT, B, and T cells early after their administration into animals. EAT-2 overexpression also augments the expression of APC (macrophages and dendritic cells) surface markers. Indeed, this multitiered activation of the innate immune system by vaccine-mediated EAT-2 expression enhanced the induction of Ag-specific cellular immune responses. Because both mice and humans express highly conserved EAT-2 adapters, our results suggest that human vaccination strategies that specifically facilitate SLAM signaling may improve vaccine potency when targeting HIV Ags specifically, as well as numerous other vaccine targets in general.


The views of first time mothers completing an intervention to reduce postpartum weight retention: A qualitative evaluation of the mums OnLiNE study.
maternal postpartum weight retention (PPWR) has implications for short and long term weight-related health of both the mother and child. Little is known about how mothers perceive they may be best supported to achieve a healthy postpartum weight and healthy lifestyle behaviours. Evaluating existing postpartum weight focussed intervention strategies is an important step in the planning of future programs aimed at supporting new mothers. to describe the perspectives of women who completed the mums OnLiNE pilot intervention, regarding the acceptability and effectiveness of a program which aimed to limit PPWR and promote healthy diet and physical activity behaviours in new mothers. descriptive qualitative research methods utilising semi-structured interview questions to explore new mothers' views regarding their participation in the mums OnLiNE intervention were used. All women who completed the intervention were invited to participate in one-on-one interviews via telephone. Interviews were digitally recorded and transcribed verbatim. Data were analysed utilising thematic analysis for common, emerging themes. twelve women participated in the interviews. Six main themes including program usefulness, intervention components, walking, self-monitoring, barriers and challenges and future recommendations described women's views of the mums OnLiNE intervention. Women felt well supported being part of the program and their reported awareness of healthy eating increased. Telephone support was the most valued and helpful component of the intervention and the smartphone application for self-monitoring was used more often than the website. Walking was by far the most preferred activity as it was considered enjoyable and achievable and some reported that their incidental walking increased as a result of being part of the program. Lack of time and motivation were the main barriers to participation in the program. Suggestions for future programs included encouraging group support and mother-baby exercise sessions. women perceived the mums OnLiNE intervention to be useful in promoting a healthy lifestyle and valued the support provided. Whilst barriers to participation in healthy lifestyle programs exist, well planned interventions which consider time constraints of new mothers, utilize one-on-one support and offer social engagement with other new mothers may further support women in their attainment of healthy postpartum weight and lifestyle behaviours.


A Recovery-Oriented Care Approach: Weighing the Pros and Cons of a Newly Built Mental Health Facility.
The current study adopted a recovery-oriented care approach by emphasizing patients' perspectives and experiences regarding changes to a newly built mental health facility. The inpatient entrance, or "portal," intended to balance the aims of recovery-oriented care with minimizing risk. A mixed-methods study of the portal's pros and cons was conducted, according to four themes: (a) autonomy versus inconvenience; (b) safety and security versus stigma; (c) unit door versus portal operating costs; and (d) privacy versus community integration. Focus groups engaging with patients (N = 39) indicated that the design effectively supported recovery-oriented care. Patients did not find the portal to be stigmatizing or triggering and valued the safety and privacy it created, and visitors also generally had a positive experience. Survey responses (N = 101) from portal users were also positive about the new design. The study findings suggest that the pros outweighed the cons of the new design. [Journal of Psychosocial Nursing and Mental Health Services, 54(2), 39-48.].


Adenoviral delivery of CTLA4Ig into myeloid dendritic cells promotes their in vitro tolerogenicity and survival in allogeneic recipients.
Dendritic cells (DC) are highly specialized antigen-presenting cells (APC) that initiate and modulate immune responses. They are essential for naive T cell activation, but may also play roles both in central and peripheral tolerance. Blockade of costimulatory pathways that provide the crucial second signal for lymphocyte activation is one strategy to augment the potential tolerogenicity of DC. Here, in vitro propagated DC were transduced using an adenoviral (Ad) vector to express the gene encoding cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA4lg), which blocks interaction of CD80 and CD86 on DC with CD28 on T cells. Supernatants of AdCTLA4lg-transduced DC strikingly inhibited mixed leukocyte reactions (MLR) induced by non-transduced DC. Whereas transduction of marker genes (LacZ or enhanced green fluorescence protein (EGFP)) did not alter their potent allostimulatory activity, DC transduced with CTLA4lg exhibited striking reductions in cell surface staining for CD86, but not MHC class II, and were poor stimulators of T cell proliferation and cytotoxic T lymphocyte (CTL) responses. In addition, they induced alloantigen-specific T cell hyporesponsiveness. They were detected, following local injection, in significantly increased numbers in the lymphoid tissue of unmodified allogeneic recipients. This is the first report of the functional properties of DC genetically engineered to express CTLA4lg.


MicroRNA-146a as a Prognostic Biomarker for Esophageal Squamous Cell Carcinoma.
MicroRNAs including miR146a have a regulatory role on the expression of genes and act with binding to 3'-UTR region of the genes. Cyclooxygenase-2 (COX-2) is involved in carcinogenesis as an inflammatory marker, and microRNA-146a (miR-146a) as a negative regulatory factor. We aimed to evaluate miR146a expression as a prognostic or diagnostic biomarker for esophageal squamous cell carcinoma (ESCC) and also an association between miR146a and COX2 expression. We quantified the level of miR-146a and COX-2 expression in cancerous and adjacent normal tissue samples obtained from 34 patients with ESCC, using real-time-PCR. Statistical analyses were conducted using one-sample t-test. Receiver-operating characteristic (ROC) curve and Kaplan-Meier analysis were applied to assay miR146a as a diagnostic and prognostic marker, respectively, during 4 years of the study. Furthermore, the Cox regression model was performed to assay the hazard ratio (HR). The association between miR-146a and COX2 expression level in ESCC patients was evaluated by nonparametric Spearman's rho analysis. The results revealed a reduction of miR-146a expression in 50% of cancerous tissue when compared with adjacent normal regions (P-value=0.127). COX-2 expression in 80% of ESCC patients was higher than in the controls (P-value=0.001). Overall, in 60% of cases, direct association was seen between microRNA-146a and COX-2 expression level (correlation coefficient= 0.438, P-value=0.011). COX2 can be considered as a diagnostic biomarker (AUC=0.834, sensitivity=72%, specificity =83%, P-value<0.0001) but miR146a cannot be considered as a diagnostic biomarker (AUC=0.553, sensitivity=88%, specificity =28%, P-value=0.453). Survival analysis by Kaplan-Meier method showed miR146a and COX2 expression can be probably considered as prognostic biomarkers for ESCC because patients with high expression of miR146a had 7 months shorter life span and patients with low expression of COX2 had 8 months shorter life span. COX2 expression is a diagnostic biomarker. MiR-146a and COX2 expression can probably be considered as prognostic biomarkers for survival in ESCC.


Staged heterogeneity learning to identify conformational B-cell epitopes from antigen sequences.
The broad heterogeneity of antigen-antibody interactions brings tremendous challenges to the design of a widely applicable learning algorithm to identify conformational B-cell epitopes. Besides the intrinsic heterogeneity introduced by diverse species, extra heterogeneity can also be introduced by various data sources, adding another layer of complexity and further confounding the research. This work proposed a staged heterogeneity learning method, which learns both characteristics and heterogeneity of data in a phased manner. The method was applied to identify antigenic residues of heterogenous conformational B-cell epitopes based on antigen sequences. In the first stage, the model learns the general epitope patterns of each kind of propensity from a large data set containing computationally defined epitopes. In the second stage, the model learns the heterogenous complementarity of these propensities from a relatively small guided data set containing experimentally determined epitopes. Moreover, we designed an algorithm to cluster the predicted individual antigenic residues into conformational B-cell epitopes so as to provide strong potential for real-world applications, such as vaccine development. With heterogeneity well learnt, the transferability of the prediction model was remarkably improved to handle new data with a high level of heterogeneity. The model has been tested on two data sets with experimentally determined epitopes, and on a data set with computationally defined epitopes. This proposed sequence-based method achieved outstanding performance - about twice that of existing methods, including the sequence-based predictor CBTOPE and three other structure-based predictors. The proposed method uses only antigen sequence information, and thus has much broader applications.


In Situ Structural Observation of a Substrate- and Peroxide-Bound High-Spin Ferric-Hydroperoxo Intermediate in the P450 Enzyme CYP121.
The P450 enzyme CYP121 from Mycobacterium tuberculosis catalyzes a carbon-carbon (C-C) bond coupling cyclization of the dityrosine substrate containing a diketopiperazine ring, cyclo(l-tyrosine-l-tyrosine) (cYY). An unusual high-spin (S = 5/2) ferric intermediate maximizes its population in less than 5 ms in the rapid freeze-quenching study of CYP121 during the shunt reaction with peracetic acid or hydrogen peroxide in acetic acid solution. We show that this intermediate can also be observed in the crystalline state by EPR spectroscopy. By developing an on-demand-rapid-mixing method for time-resolved serial femtosecond crystallography with X-ray free-electron laser (tr-SFX-XFEL) technology covering the millisecond time domain and without freezing, we structurally monitored the reaction in situ at room temperature. After a 200 ms peracetic acid reaction with the cocrystallized enzyme-substrate microcrystal slurry, a ferric-hydroperoxo intermediate is observed, and its structure is determined at 1.85 Å resolution. The structure shows a hydroperoxyl ligand between the heme and the native substrate, cYY. The oxygen atoms of the hydroperoxo are 2.5 and 3.2 Å from the iron ion. The end-on binding ligand adopts a near-side-on geometry and is weakly associated with the iron ion, causing the unusual high-spin state. This compound 0 intermediate, spectroscopically and structurally observed during the catalytic shunt pathway, reveals a unique binding mode that deviates from the end-on compound 0 intermediates in other heme enzymes. The hydroperoxyl ligand is only 2.9 Å from the bound cYY, suggesting an active oxidant role of the intermediate for direct substrate oxidation in the nonhydroxylation C-C bond coupling chemistry.


Tiny Piezoelectric Multi-Layered Actuators with Application in a Compact Camera Module-Design, Fabrication, Assembling and Testing Issues.
Piezoelectric actuators with multi-layer structures have largely gained attention from academic and industry experts. This is due to its distinctive advantages of fast response time, huge generative force and the inherent good planar electromechanical coupling factor, as well as other mechanical qualities. Typically, lead zirconate titanate (PZT) is one of the most represented piezoelectric ceramic materials that have been used for multi-layer piezoelectric actuators. Piezoelectric multi-layered actuators (PMLAs) were developed vigorously in the past decades due to the emergence of portable devices, such as smartphones with a highly compact camera module (CCM) and an image stabilizer (IS). This study reviewed the progress made in the field of PMLA applications, with a particular focus on the miniaturized dimensions and associated generated output force, speed and maximum output power requirement for various loads. Several commercial attempts, such as Helimorph, Lobster and the two-degrees-of-freedom ultrasonic motor (USM), were investigated. The proposed simple bimorph and multi-layer bimorph USMs experimentally showed thrust as high as 3.08 N and 2.57 N with good free speed and structural thicknesses of 0.7 and 0.6 mm, respectively. When compared with the other 14 reported linear USMs, they ranked as the top 1 and 2 in terms of the thrust-to-volume ratio. The proposed design shows great potential for cellphone camera module application, especially in moving sensor image stabilization. This study also provided outlooks for future developments for piezoelectric materials, configurations, fabrication and applications.


Is the absence of the ossific nucleus prognostic for avascular necrosis after closed reduction of developmental dysplasia of the hip?
The presence of the ossific nucleus before reduction of developmental dysplasia of the hip may reduce the rate of avascular necrosis. Forty-eight hips in 45 children who underwent successful closed reduction had at least a 2-year follow-up. Medical records were reviewed for sex, side, Pavlik harness, traction, age at reduction, adductor tenotomy, cast duration, length of follow-up, and subsequent surgery. Prereduction radiographs were reviewed for presence or absence of the ossific nucleus. Avascular necrosis was noted as present if there was evidence of Bucholz and Ogden type II, III, or IV on the postreduction radiographs. Avascular necrosis was noted postreduction in 17 hips. Adductor tenotomy may reduce the rate of avascular necrosis following closed reduction. Delaying closed reduction until the presence of the ossific nucleus can be detected radiographically may reduce the rate of avascular necrosis. The presence of avascular necrosis increases the need for subsequent surgery.


Survey of resistance of Pseudomonas aeruginosa from UK patients with cystic fibrosis to six commonly prescribed antimicrobial agents.
Respiratory infection with Pseudomonas aeruginosa is very common in patients with cystic fibrosis (CF) but antimicrobial resistance rates of CF isolates across the UK are largely unknown. The susceptibility of 417 CF patient isolates of P aeruginosa from 17 hospitals to six commonly prescribed antibiotics were examined. Isolates were tested by an agar break point dilution method and E-tests according to British Society of Antimicrobial Chemotherapy guidelines. Genotyping of isolates was performed by XbaI DNA macrorestriction and pulsed field gel electrophoresis. 38% of isolates were susceptible to all of the agents tested; almost half were resistant to gentamicin compared with ceftazidime (39%), piperacillin (32%), ciprofloxacin (30%), tobramycin (10%), and colistin (3%). Approximately 40% were resistant to two or more compounds with ceftazidime in combination with gentamicin, piperacillin or ciprofloxacin being the most common cross resistances. Resistance rates were generally similar to those reported recently from the USA and Germany. A selection of resistant isolates proved to be predominantly genotypically distinct by XbaI DNA macrorestriction but six pairs from three centres had similar genotypes. The level of resistance to front line antipseudomonal agents, with the exception of colistin, is disturbingly high. The prudent use of antimicrobial drugs and closer monitoring of accumulation of resistant strain populations should be actively considered.


Therapeutic approaches in multiple sclerosis: lessons from failed and interrupted treatment trials.
The therapy for multiple sclerosis (MS) has changed dramatically over the past decade. Recent immunobiological findings and current pathophysiological concepts together with advances in biotechnology, improvements in clinical trial design and development of magnetic resonance imaging have led to a variety of evaluable therapeutic approaches in MS. However, in contrast to the successfully introduced and established immunomodulatory therapies (e.g. interferon-beta and glatiramer acetate), there have been a remarkable number of therapeutic failures as well. Despite convincing immunological concepts, impressive data from animal models and promising results from phase I/II studies, the drugs and strategies investigated showed no benefit or even turned out to have unexpectedly severe adverse effects. Although to date there is no uniformly accepted model for MS, there is agreement on the significance of inflammatory events mediated by autoreactive T cells in the CNS. These can be modified therapeutically at the individual steps of a hypothetical pathogenetic cascade. Crucial corners like: the prevalence and peripheral activation of CNS-autoreactive T cells in the periphery;adhesion and penetration of T cells into the CNS;local activation and proliferation and;de- and remyelination processes can be targeted through their putative mediators. Like a 'specificity pyramid', therapeutic approaches therefore cover from general immunosuppression up to specific targeting of T-cell receptor peptide major histocompatibility (MHC) complex. We discuss in detail clinical MS trials that failed or were discontinued for other reasons. These trials include cytokine modulators [tumour necrosis factor (TNF)-alpha antagonists, interleukin-10, interleukin-4, transforming growth factor-beta2], immunosuppressive agents (roquinimex, gusperimus, sulfasalazine, cladribine), inducers of remyelination [intravenous immunoglobulins (IVIg)], antigen-derived therapies [oral tolerance, altered peptide ligands (APL), MHC-Peptide blockade], T cell and T-cell receptor directed therapies (T cell vaccination, T-cell receptor peptide vaccination), monoclonal antibodies against leucocyte differentiation molecules (anti-CD3, anti-CD4), and inactivation of circulating T cells (extracorporeal photopheresis). The main conclusions that can be drawn from these 'negative' experiences are as follows. Theoretically promising agents may paradoxically increase disease activity (lenercept, infliximab), be associated with unforeseen adverse effects (e.g. roquinimex) or short-term favourable trends may reverse with prolonged follow-up (e.g. sulfasalzine). One should not be too enthusiastic about successful trials in animal models (TNFalpha blockers; oral tolerance; remyelinating effect of IVIg) nor be irritated by non-scientific media hype (deoxyspergualine; bone marrow transplantation). More selectivity can imply less efficacy (APL, superselective interventions like T-cell receptor vaccination) and antigen-related therapies can stimulate rather than inhibit encephalitogenic cells. Failed strategies are of high importance for a critical revision of assumed immunopathological mechanisms, their neuroimaging correlates, and for future trial design. Since failed trials add to our growing understanding of multiple sclerosis, 'misses' are nearly as important to the scientific process as the 'hits'.


Effect of x-ray tube parameters and iodine concentration on image quality and radiation dose in cerebral pediatric and adult CT angiography: a phantom study.
The aim of the present phantom study was to investigate the effect of x-ray tube parameters and iodine concentration on image quality and radiation dose in cerebral computed tomographic (CT) angiographic examinations of pediatric and adult individuals. Four physical anthropomorphic phantoms that represent the average individual as neonate, 1-year-old, 5-year-old, and 10-year-old children and the RANDO phantom that simulates the average adult individual were used. Cylindrical vessels were bored along the brain-equivalent plugs of each physical phantom. To simulate the brain vasculature, vessels of 0.6, 1, 2, and 3 mm in diameter were created. These vessels were filled with contrast medium (CM) solutions at different iodine concentrations, that is, 5.6, 4.2, 2.7, and 1.4 mg I/mL. The phantom heads were scanned at 120, 100, and 80 kV. The applied quality reference tube current-time product values ranged from a minimum of 45 to a maximum of 680. The CT acquisitions were performed on a 16-slice CT scanner using the automatic exposure control system. Image quality was evaluated on the basis of image noise and contrast-to-noise ratio (CNR) between the contrast-enhanced iodinated vessels and the unenhanced regions of interest. Dose reduction was calculated as the percentage difference of the CT dose index value at the quality reference tube current-time product and the CT dose index at the mean modulated tube current-time product. Image noise that was measured using the preset tube current-time product settings varied significantly among the different phantoms (P < 0.0001). Hounsfield unit number of iodinated vessels was linearly related to CM concentration (r² = 0.907) and vessel diameter (r² = 0.918). The Hounsfield unit number of iodinated vessels followed a decreasing trend from the neonate phantom to the adult phantom at all kilovoltage settings. For the same image noise level, a CNR improvement of up to 69% and a dose reduction of up to 61% may be achieved when CT acquisition is performed at 80 kV compared with 120 kV. For the same CNR, a reduction by 25% of the administered CM concentration may be achieved when CT acquisition is performed at 80 kV compared with 120 kV. In cerebral CT angiographic studies, appropriate adjustment of the preset tube current-time product settings is required to achieve the same image noise level among participants of different age. Cerebral CT angiography at 80 kV significantly improves CNR and significantly reduces radiation dose. Moreover, at 80 kV, a considerable reduction of the administered amount of the CM may be reached, thus reducing potential risks for contrast-induced nephropathy.


Transcriptomic effects-based monitoring for endocrine active chemicals: assessing relative contribution of treated wastewater to downstream pollution.
The present study investigated whether a combination of targeted analytical chemistry information with unsupervised, data-rich biological methodology (i.e., transcriptomics) could be utilized to evaluate relative contributions of wastewater treatment plant (WWTP) effluents to biological effects. The effects of WWTP effluents on fish exposed to ambient, receiving waters were studied at three locations with distinct WWTP and watershed characteristics. At each location, 4 d exposures of male fathead minnows to the WWTP effluent and upstream and downstream ambient waters were conducted. Transcriptomic analyses were performed on livers using 15,000 feature microarrays, followed by a canonical pathway and gene set enrichment analyses. Enrichment of gene sets indicative of teleost brain-pituitary-gonadal-hepatic (BPGH) axis function indicated that WWTPs serve as an important source of endocrine active chemicals (EACs) that affect the BPGH axis (e.g., cholesterol and steroid metabolism were altered). The results indicated that transcriptomics may even pinpoint pertinent adverse outcomes (i.e., liver vacuolization) and groups of chemicals that preselected chemical analytes may miss. Transcriptomic Effects-Based monitoring was capable of distinguishing sites, and it reflected chemical pollution gradients, thus holding promise for assessment of relative contributions of point sources to pollution and the efficacy of pollution remediation.


Biochemical basis of resistance to multiple contaminations in the native and invasive populations of Dreissena polymorpha.
The zebra mussel Dreissena polymorpha (Pallas, 1771) is an invasive species and a valuable bioindicator in the inland waters. Nevertheless, the biochemical reasons for the unique competitiveness of zebra mussels are not clear. This study aimed to compare the native and invasive populations of D. polymorpha in their ability to withstand the same multiple environmental challenges (i.e. chemical: microplastics and caffeine; physical: temperatures). The specimens from the invasive population in west Ukraine (Tn) and native population at lower streams of river Dnipro (south Ukraine, Kh) were sampled in the August of 2021 y. Molluscs from both populations were treated simultaneously with microplastics (MP, 1 mg L-1, pore size 2 μm); caffeine (Caf, 20.0 μg L-1) at 18 °C, elevated temperature (25 °C) and MP and Caf combinations at 18 °C and 25 °C for 14 days. Untreated molluscs exposed at 18 °C represented control groups. A set of the 20 markers of oxidative stress, biotransformation, detoxification and apoptosis were assayed in the total soft tissues. From the two controls, Kh-group indicated lower stressful impact. However, both populations increased caspase-3 and GST activities and lysosomal instability in most exposures, and cholinesterase and phenoloxidase activities under the heating and combine exposures, indicating the remarkable properties to respond to new challenges and synergistic effect of mixtures. Inter-population differences were related to the metallothionein, cathepsin D, cytochrome P540 and oxidative stress responses that reflect population-dependent adverse outcome pathways. The discriminant analysis separated two populations with a substantially lesser magnitude of responses in the invasive population as a sign of higher resistance.


[The ratio of sex hormone production by the ovaries and the adrenal cortex in different phases of the rat estrous cycle].
The biosynthesis of estradiol and testosterone was found to occur mainly in the ovaries (4-5 and 10-20 times more than in the adrenals during diestrus and proestrus, resp.). Estron and androstendion were produced equally in both glands. The estrogens and androgens were found to act as synergists in the stimulation of biosynthetic processes in the uterus. Their level in peripheral blood reflects less fully the character of hormonal function of the ovaries than study of these steroids in the incubates of the ovaries. The biosynthesis of progesterone in adrenals exceeds 2-3-fold that in the ovaries. No changes on production of this hormone depending on the cycle phase, were found.


Improvement on moiré technique for in-plane deformation measurements.
A technique to improve the sensitivity of in-plane deformation measurements on transparent and reflective specimens under tension or compression is described. The principle of this technique is that of moiré fringe multiplication. Experiments with 20-cycle/mm gratings yielded results having eighteen times the sensitivity of the conventional moiré technique. One fringe shift of each moiré fringe corresponded to an in-plane deformation of 2.7 microm.


Disease specific signature of circulating miR-150-5p and miR-21-5p in myasthenia gravis patients.
Reliable biological markers for patients with the autoimmune neuromuscular disorder myasthenia gravis (MG) are lacking. We determined whether levels of the circulating immuno-microRNAs miR-150-5p and miR-21-5p were elevated in sera from clinically heterogeneous MG patients, with and without immunosuppression, as compared to healthy controls and patients with other autoimmune disorders. Sera from 71 MG patients and 55 healthy controls (HC) were analyzed for the expression levels of miR-150-5p and miR-21-5p with qRT-PCR. Sera were also assayed from 23 patients with other autoimmune disorders (AID; psoriasis, Addison's and Crohn's diseases). 34 MG patients had no immunosuppressive drug treatment (MG-0) and 37 patients were under stable immunosuppressive drug treatment since ≥ 6 months (MG+IMM). Serum levels of miR-150-5p and miR-21-5p were higher in the MG-0 patients compared to HC (p<0.0001). Further, miR-150-5p levels were 41% lower and miR-21-5p levels were 25% lower in the MG+IMM compared to MG-0 (p=0.0051 and 0.0419). In the AID patients, mean miR-150-5p and miR-21-5p were comparable with healthy controls (p=0.66). The immuno-microRNAs miR-150-5p and miR-21-5p show a disease specific signature, which suggests these microRNAs as possible biological autoimmune markers of MG.


Gambling near-misses enhance motivation to gamble and recruit win-related brain circuitry.
"Near-miss" events, where unsuccessful outcomes are proximal to the jackpot, increase gambling propensity and may be associated with the addictiveness of gambling, but little is known about the neurocognitive mechanisms that underlie their potency. Using a simplified slot machine task, we measured behavioral and neural responses to gambling outcomes. Compared to "full-misses," near-misses were experienced as less pleasant, but increased desire to play. This effect was restricted to trials where the subject had personal control over arranging their gamble. Near-miss outcomes recruited striatal and insula circuitry that also responded to monetary wins; in addition, near-miss-related activity in the rostral anterior cingulate cortex varied as a function of personal control. Insula activity to near-misses correlated with self-report ratings as well as a questionnaire measure of gambling propensity. These data indicate that near-misses invigorate gambling through the anomalous recruitment of reward circuitry, despite the objective lack of monetary reinforcement on these trials.


Comparing the Effect of Intranasal Lidocaine 4% with Peppermint Essential Oil Drop 1.5% on Migraine Attacks: A Double-Blind Clinical Trial.
Prevalence of migraine, as a chronic neurovascular disorder, was approximately 10.3 and 23.1% among men and women, respectively, mostly in people younger than 40 years old. Migraine is prevalent in different geographic areas worldwide. The present study was designed to compare the impact of intranasal lidocaine 4% and peppermint essential oil drop 1.5% on migraine attacks. In this double-blind, parallel, randomized controlled trial, 120 adult patients with a diagnosis of migraine based on the International Headache Society criteria were treated with intranasal lidocaine drop 4% or peppermint essential oil drop 1.5% or placebo. Patients expressed their symptoms 5 and 15 min after dripping, and if they still had a headache after 15 min, they were given the second dose. Patients with a second dose of medication, 15 min later recorded their headache rate. All patients recorded their symptoms after 30 min. Symptoms of the patients were followed by a researcher through the phone and in-person after 2 months. Then, the questionnaires were filled. In the present study, there was a significant difference among groups in headache intensity after treatment (P < 0.001). In 40% of the patients in the peppermint oil and lidocaine groups, the intensity of headache decreased. In the placebo group, fewer patients responded highly to the treatment, whereas 41.5% of patients in the lidocaine group and 42.1% of patients in the peppermint oil group responded to the treatment considerably. Concerning the findings of the present study, nasal application of peppermint oil caused considerable reduction in the intensity and frequency of headache and relieved majority of patients' pain similar to lidocaine. On the basis of findings of this study, it can be concluded that nasal menthol, such as lidocaine, can be used to relieve migraine headaches.


American Hepato-Pancreato-Biliary Association: who are we and where are we going?
The American Hepato-Pancreato-Biliary Association (AHPBA) was initiated in 1994 following the first World Congress of the International Hepato-Pancreato-Biliary Association (IHPBA), which was held in Boston. Presently, the AHPBA has more than 500 dues-paying members whose median age is in the mid-40s. More than 90% of members reside in North America. Approximately 80% of members have completed a fellowship in transplantation, hepato-pancreato-biliary surgery and/or research, surgical oncology, gastroenterology, or laparoscopy. Approximately 90% have a faculty appointment with 80% of these being full-time faculty. More than half of the average AHPBA member's time is spent in patient care, but approximately 45% of time is divided equally among research, teaching, and administration. Approximately 85% of members perform biliary, 75% hepatic, and 45% pancreatic surgery, whereas 25% perform liver and pancreatic transplantation. Nearly 90% are members of the American College of Surgeons, two thirds The Society for Surgery of the Alimentary Tract, 60% the Association for Academic Surgery, and 40% the IHPBA. The AHPBA's vision is to be the leading American association devoted to hepato-pancreato-biliary education, research, surgical training, and patient care and to serve as the American chapter of the IHPBA. The AHPBA mission is as follows: (1) to disseminate knowledge of hepato-pancreato-biliary disease, techniques, and research; ( 2) to facilitate clinical trials in hepato-pancreato-biliary disease; (3) to coordinate advanced training in hepato-pancreato-biliary surgery; and (4) to foster excellence in the care of patients with hepato-pancreato-biliary disease. The AHPBA has strategic initiatives to increase membership, bring value to a journal affiliation, and enhance its education, research, and training missions through multiple collaborations and better communication.


Online Clinical Teaching: A Simple Model to Facilitate Students' Communication and Clinical Reasoning Skills on Distance Learning e-Platform.
This article was migrated. The article was marked as recommended. One of the most important outcomes expected from clinical teaching is to develop an adequate level of clinical reasoning skills among the students. This largely depends on the efficient retrieval of information from the patients, desirably in the way of direct history taking and physical examination. Communication skills play a vital role in making this activity maximally effective. In any situation when the direct contact between students and patients becomes restricted or compromised, a suitable alternative seems to appear to be a 'felt need' to support the students remain active and engaged in a similar kind of learning. During this ongoing pandemic, an online teaching model was devised to instruct a group of undergraduate medical students which appeared to be promising to facilitate their clinical reasoning (CR) and communication skills (CS) in a virtual environment. There is scope to make it more effective and to get it incorporated into our clinical curriculum as a part of its regular e-learning component. Out of a total of five weeks of online clinical posting, the initial two to three weeks' period was spent on teaching the very basics of the subject such as clinical anatomy, pathophysiology, and the most common and most important clinical conditions. This was then followed by the online history-taking sessions where the students played the roles of both simulated patients and student-doctors. The whole session was directly supported and supervised by a clinical instructor who offered constructive feedback at the various levels of the session. The method was well-accepted by the students, and it helped them develop confidence in terms of knowledge and skills that they later translated into their real workplace training effectively.


Regulatory mechanisms and therapeutic potential of microglial inhibitors in neuropathic pain and morphine tolerance.
Microglia are important cells involved in the regulation of neuropathic pain (NPP) and morphine tolerance. Information on their plasticity and polarity has been elucidated after determining their physiological structure, but there is still much to learn about the role of this type of cell in NPP and morphine tolerance. Microglia mediate multiple functions in health and disease by controlling damage in the central nervous system (CNS) and endogenous immune responses to disease. Microglial activation can result in altered opioid system activity, and NPP is characterized by resistance to morphine. Here we investigate the regulatory mechanisms of microglia and review the potential of microglial inhibitors for modulating NPP and morphine tolerance. Targeted inhibition of glial activation is a clinically promising approach to the treatment of NPP and the prevention of morphine tolerance. Finally, we suggest directions for future research on microglial inhibitors.


A Health Care Transition Curriculum for Primary Care Residents: Identifying Goals and Objectives.
The transition from pediatric to adult health care is a vulnerable period for youth with special health care needs. Although successful transitions are recognized as critical for improving adult outcomes and reducing health care utilization and cost, an educational gap in health care transitions for physicians persists. Our aim with this project was to develop a national health care transition residency curriculum for primary care physicians, using an expert-based, consensus-building process. Medical professionals with expertise in health care transition were recruited to participate in a survey to assist in the development of a health care transition curriculum for primary care physicians. By using a modified Delphi process, curricular goals and objectives were drafted, and participants rated the importance of each objective, feasibility of developing activities for objectives, and appropriateness of objectives for specified learners. Mean and SDs for each response and percent rating for the appropriateness of each objective were calculated. Fifty-six of 246 possible respondents participated in round 1 of ratings and 36 (64%) participated in the second round. Five goals with 32 associated objectives were identified. Twenty-five of the 32 objectives (78%) were rated as being appropriate for "proficient" learners, with 7 objectives rated as "expert." Three objectives were added to map onto the Got Transition guidelines. The identified goals and objectives provide the foundation and structure for future curriculum development, facilitating the sharing of curricular activities and evaluation tools across programs by faculty with a range of expertise.


[Knee endoprosthesis: sports orthopedics possibilities and limitations].
Many patients would like to resume some sport activities after total knee replacement; however, most recommendations are based on subjective opinion rather than scientific evidence. The following paper presents a literature review of sports after total knee replacement and includes recommendations which are based on biomechanical laws. Most total knee designs show increased conformity near full extension. Beyond a certain knee flexion angle, the conformity ratio decreases due to a reduced femoral radius. Therefore, these designs accept higher loads near full extension than in flexion. In order to recommend suitable physical activities after total knee replacement, both the load and the knee flexion angle of the peak load must be considered. It has been shown that power walking and cycling produce the lowest polyethylene inlay stress of a total knee replacement and seem to be the least demanding endurance activities. Jogging and downhill walking show high inlay stress levels and should be avoided. Hence, for mountain hiking, patients are advised to avoid descents or at least use skipoles and walk slowly downhill to reduce the load on the knee joint. It must also be mentioned that any activity represents additional wear, which may affect the long-term results of total knee replacements. Further clinical studies are necessary to validate the biomechanical investigations.


Functions of the extracellular matrix and matrix degrading proteases during tumor progression.
Cell interactions with extracellular matrices are important to pathological changes that occur during cell transformation and tumorigenesis. Several extracellular matrix proteins including fibronectin, thrombospondin-1, laminin, SPARC, and osteopontin have been suggested to modulate tumor phenotype by affecting cell migration, survival, or angiogenesis. Likewise, proteases including the matrix metalloproteinases (MMPs) are understood to not only facilitate migration of cells by degradation of matrices, but also to affect tumor formation and growth. We have recently demonstrated an in vivo role for the RGD-containing protein, osteopontin, during tumor progression, and found evidence for distinct functions in the host versus the tumor cells. Because of the compartmentalization and temporal regulation of MMP expression, it is likely that MMPs may also function dually in host stroma and the tumor cell. In addition, an important function of proteases appears to be not only degradation, but also cleavage of matrix proteins to generate functionally distinct fragments based on receptor binding, biological activity, or regulation of growth factors.


[Analysis on clinical and epidemioloical characteristics of measles in hospitalized children in Shanghai in 2012].
To investigate the main factors that influence measles morbidity and the genotype of measles virus, so as to provide evidence for scientific decision making to further control the prevalence of measles. A retrospective analysis included 182 children in Children's Hospital of Fudan University, diagnosed with measles from January 1, 2012 to December 31. The clinical and epidemiological characteristics, including the gender, age, the incidence of seasonal trends, measles vaccine vaccination history, contact history and other clinical manifestations, laboratory test results, and so on were analyzed. And the reverse transcription PCR (RT-PCR) was adopted to detect sputum specimens from suspected patients with measles,who were selected randomly,the sequence of the part of the PCR products was analyzed. (1) Clinical and epidemiological data: Totally were 182 children with measles (125 males, 57 females) were enrolled into this study. The age of the patients ranged from 3 months to 89 months, 127 cases were younger than 9 months (69. 8%). The prevalence season was from April to August, while the peak month was April and May (22. 5%, 23. 1%). Among 182 hospitalized children, only 11 cases underwent measles vaccination (6. 0%), and among them 5 cases were within 2 weeks before disease onset. A total of 167 cases (91. 8%) had not been vaccinated, most of whom were immigrants, and the measles vaccination history of the remaining 4 cases were unknown. There was a positive correlation between the measles vaccination ratio in children of the floating population (8. 45%, 6/71) and the settled children (29.4%, 5/17, χ =8. 11 P =0. 004). In total, 24 cases (13. 2%) had definite measles exposure history, with 153 cases (84. 1%) of unknown origin,5 cases (2.7%) without any history of contact. (2) Clinical manifestations: All the 182 patients had fever (100%) and obvious rashes (100%), among them 145 cases had body temperature higher than 39 °C (79. 7%). The fever period ranged from 2 to 38 days. Among 182 hospitalized children,165 cases (90. 7%) had typical measles,17 cases had atypical measles. Among the 17 cases, two had severe measles, one had heterotypic measles. (3) The common complica tions: 96 cases had pneumonia (52. 8%), 80 had laryngitis (44. 0%), 38 had bronchitis (20. 9%),15 had hepatic dysfunction (8. 2%), 11 had myocardial damage (6. 0%), 3 had febrile seizures (1. 6%), and no patient had encephalitis. Of the 96 cases with pneumonia, 92 received sputum test; 38 were sputum culture positive (41%). The dominant pathogens were Streptococcus pneumoniae(11/38,29%), Haemophilus influenzae (6/ 38,16%), Moraxella catarrhalis (4/38, 11%), Escherichia coli (4/38, 11%), Candida albicans (4/38, 11%), Mycoplasma pneumoniae (4/38, 11%) and Staphylococcus aureus (3/38, 8%). (4) The H1a genotype was the only one genotype in the detected sequence of 54 measles virus strains. Measles was more often seen in the children under the age of 9 months from the floating population. The morbidity peak month was from April to May in Shanghai. The H1a genotype was the only one genotype. We should try to improve vaccination coverage rate in the children who are at the age for vaccination, so as to prevent measles outbreak.


Effects of caffeine on the electrical and mechanical activity of guinea-pig ureter smooth muscle.
The effects of caffeine on the electrical and mechanical activity of the guinea-pig ureter smooth muscle were studied. Under untreated conditions caffeine mainly showed inhibitory action on the ureter, inhibiting the evoked action potentials and phasic contractions as well as potassium contracture. Caffeine was also found to suppress the low-Na contracture of Na-loaded ureter muscle. It is established that Na-loaded tissue is able to generate transient contracture in response to caffeine application at 37 degrees C. These caffeine contractures could be evoked under completely removed [Ca2+]0 and in the presence of high doses of Ca-channel blockers (nifedipine, diltiazem, Mn ions) and could be reversibly blocked by tetracaine, procaine and benzocaine. Caffeine contractures could also be produced by the ureter muscle placed in isotonic K-solution. Cooling significantly potentiated low-Na, potassium and caffeine contractures of the ureter muscle. Filling of the store is totally dependent on the entry of Ca ions from the extracellular Ca2+ store sites which sequester Ca ions entering the cell on either Na-Ca exchange or via voltage operated Ca channels.


Sex Differences in Attention and Attitude Toward Infant and Sexual Images.
Reproduction in mammals includes two general categories of behaviors: mating and parenting. Historically and cross-culturally, men invest more than women in mating; women invest more than men in parenting. Sex differences in attention and attitude toward mating and parenting stimuli have rarely been assessed together despite theoretical interest. To evaluate these differences simultaneously in a naturalistic setting, 582 study participants (459 women, 123 men) were presented with sexual and infant images, online in the privacy of their home, at three time periods spanning several weeks for a more reliable result. Attention was measured by covertly recording viewing time of images using Qualtrics software, and attitude was measured via self-report after each viewing session. Men reported a more positive attitude than women toward the sexual images; women reported a more positive attitude than men toward the infant images. Women viewed the infant images marginally longer than did men, and the infant-to-sexual viewing ratio was larger for women. The sexual-to-infant viewing ratio was larger for men than for women. Unexpectedly, both genders viewed the sexual images longer than the infant images, with no significant gender difference in the sexual image viewing time. The results suggest that women and men may give equal attention to visual sexual stimuli despite self-reported sex differences in interest. The possibly underestimated valence of visual sexual stimuli for women is discussed.