A human estrogen receptor (ER)alpha mutation with differential responsiveness to nonsteroidal ligands: novel approaches for studying mechanism of ER action.
Estrogens, acting through the estrogen receptors (ERs), play crucial roles in regulating the function of reproductive and other systems under physiological and pathological conditions. ER activity in regulating target genes is modulated by the binding of both steroidal and synthetic nonsteroidal ligands, with ligand binding inducing ERs to adopt various conformations that control their interactions with transcriptional coregulators. Previously, we developed an intramolecular folding sensor with a mutant form of ERalpha (ER(G521T)) that proved to be essentially unresponsive to the endogenous ligand 17beta-estradiol, yet responded very well to certain synthetic ligands. In this study, we have characterized this G521T-ER mutation in terms of the potency and efficacy of receptor response toward several steroidal and nonsteroidal ligands in two different ways: directly, by ligand effects on mutant ER conformation (by the split-luciferase complementation system), and indirectly, by ligand effects on mutant ER transactivation. Full-length G521T-ER shows no affinity for estradiol and does not activate an estrogen-responsive reporter gene. The synthetic pyrazole agonist ligand propyl-pyrazole-triol is approximately 100-fold more potent than estradiol in inducing intramolecular folding and reporter gene transactivation with the mutant ER, whereas both ligands have high potency on wild-type ER. This estradiol-unresponsive mutant ER can also specifically highlight the agonistic property of the selective ER modulator, 4-hydroxytamoxifen, by reporter gene transactivation, even in the presence of estradiol, and it can exert a dominant-negative effect on estrogen-stimulated wild-type ER. This system provides a model for ER-mutants that show differential ligand responsiveness to gene activation to gain insight into the phenomenon of hormone resistance observed in endocrine therapies of ER-positive breast cancers.


Activity of essential oils and individual components against acetyl- and butyrylcholinesterase.
We have tested acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of nineteen essential oils obtained from cultivated plants, namely one from Anethum graveolens L. (organic fertilizer), two from Foeniculum vulgare Mill. collected at fully-mature and flowering stages (organic fertilizer), two from Melissa officinalis L. (cultivated using organic and chemical fertilizers), two from Mentha piperita L. and M. spicata L. (organic fertilizer), two from Lavandula officinalis Chaix ex Villars (cultivated using organic and chemical fertilizers), two from Ocimum basilicum L. (green and purple-leaf varieties cultivated using only organic fertilizer), four from Origanum onites L., O. vulgare L., O. munitiflorum Hausskn., and O. majorana L. (cultivated using organic fertilizer), two from Salvia sclarea L. (organic and chemical fertilizers), one from S. officinalis L. (organic fertilizer), and one from Satureja cuneifolia Ten. (organic fertilizer) by a spectrophotometric method of Ellman using ELISA microplate-reader at 1 mg/ml concentration. In addition, a number of single components widely encountered in most of the essential oils [gamma-terpinene, 4-allyl anisole, (-)-carvone, dihydrocarvone, (-)-phencone, cuminyl alcohol, cumol, 4-isopropyl benzaldehyde, trans-anethole, camphene, iso-borneol, (-)-borneol, L-bornyl acetate, 2-decanol, 2-heptanol, methyl-heptanol, farnesol, nerol, iso-pulegol, 1,8-cineole, citral, citronellal, citronellol, geraniol, linalool, alpha-pinene, beta-pinene, piperitone, iso-menthone, menthofurane, linalyl oxide, linalyl ester, geranyl ester, carvacrol, thymol, menthol, vanilline, and eugenol] was also screened for the same activity in the same manner. Almost all of the essential oils showed a very high inhibitory activity (over 80%) against both enzymes, whereas the single components were not as active as the essential oils.


AIDS knowledge and educational needs of technical university students in Turkey.
AIDS is a main health problem of the recent century and is now considered a very important cause for mortality and morbidity among young people. The aim of this research is to determine the Turkish university students knowledge, sexual risk behavior, attitude towards AIDS and educational needs concerning AIDS. A cross-sectional exploratory design is utilized in this study. One thousand four hundred and twenty-seven university new registrants from the Middle East Technical University participated and answered a 32-item self-administered questionnaire. The questionnaire addressed sociodemographics, sexual risk behavior, self-assessed knowledge on HIV transmission and AIDS, attitudes towards AIDS infection and AIDS patient, source of information and need for AIDS course. The response rate was 84%. Two hundred and seventy-one (19%) participants had sexual intercourse. Eighty-one (30%) participants reported condom use during the last encounter. Seven hundred and twenty-four (51%) stated they knew "very much" about AIDS. Students of faculty of engineering (n=384, 69%), economic and administrative sciences (n=115, 55%), and architecture (n=42, 52%) declared they knew "very much" on AIDS and had a higher frequency as the students from the faculty of arts and sciences (n=119, 43%) and education (n=64, 40%). Television was reported as the major source of information about AIDS (n=871, 61%). Students in faculty of education had lower scores than others (P=0.01). Almost all students stated that there should be a course on AIDS in their curriculum. Educational and medical institutions are the minor information sources for students at universities. Therefore, schools have to integrate new courses on AIDS and sexual health in their curricula, physicians caring for these students have to take more time for health education.


Human age-related cataract and lens epithelial cell death.
To evaluate the importance of lens epithelial cell death in age-related cataract. To determine whether the large percentage of terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL)-positive lens epithelial cells previously reported in human capsulotomy specimens results from apoptosis or necrosis. Capsulotomy specimens from patients who had undergone cataract surgery and epithelia from cataractous lenses of eye bank eyes were compared with epithelia from noncataractous lenses of eye bank eyes. DNA fragmentation was assayed using the TUNEL method. Cell membrane integrity was tested using a fluorescent stain for DNA, BOBO-3, that is excluded from living cells. Cell proliferation was assayed by labeling with 5-bromo-2'-deoxyuridine (BrdU). The number of cells in different regions of the lens epithelium was measured by digital imaging and computerized counting of nuclei after staining with methyl green. TUNEL-positive cells were sometimes detected adjacent to denuded regions of capsulotomy specimens, especially when epithelia were not fixed immediately after surgery. TUNEL-stained cells usually stained with BOBO-3, indicating loss of plasma membrane integrity. No BrdU-labeled cells were detected in capsulotomy specimens. Cell density in cataractous lens epithelia was similar to that in normal lens epithelia. In cataractous lenses from eye bank eyes, cell density in the region of the epithelium overlying the cataract was higher than cell density in the region of the epithelium overlying the transparent part of the lens. No correlation was found between cell density and cataract severity or between cell density and age. TUNEL staining of lens epithelial cells in capsulotomy specimens most likely results from necrotic cell death caused by damage during or soon after cataract surgery. Loss of cells from the lens epithelium, by apoptosis or other mechanisms of cell death, does not seem to play a major role in age-related cataract formation.


Timing of blunt force injuries in long bones: the effects of the environment, PMI length and human surrogate model.
Timing of blunt force trauma in human bone is a critical forensic issue, but there is limited knowledge on how different environmental conditions, the duration of postmortem interval (PMI), different bone types and different animal models influence fracture morphology. This study aims at evaluating the influence of the type of postmortem environment and the duration of the postmortem period on fracture morphology, for distinguishing perimortem from postmortem fractures on different types of long bones from different species. Fresh limb segments from pig and goat were sequentially left to decompose, under 3 different environmental circumstances (surface, buried and submerged), resulting in sets with different PMI lengths (0, 28, 56, 84, 112, 140, 168 and 196 days), which were then fractured. Fractured bones (total=325; pig tibia=110; pig fibula=110; goat metatarsals=105) were classified according to the Fracture Freshness Index (FFI). Climatic data for the experiment location was collected. Statistical analysis included descriptive statistics, correlation analysis between FFI and PMI, Mann-Whitney U tests comparing FFI medians for different PMI's and linear regression analysis using PMI, pluviosity and temperature as predictors for FFI. Surface samples presented increases in FFI with increasing PMI, with positive correlations for all bone types. The same results were observed in submerged samples, except for pig tibia. Median FFI values for surface samples could distinguish bones with PMI=0 days from PMI≥56 days. Buried samples presented no significant correlation between FFI and PMI, and nonsignificant regression models. Regression analysis of surface and submerged samples suggested differences in FFI variation with PMI between bone types, although without statistical significance. Adding climatic data to surface regression models resulted in PMI no longer predicting FFI. When comparing different animal models, linear regressions suggested greater increases in FFI with increasing PMI in pig, compared to goat, in both surface and submerged environments, although statistically not significant. No differences were found between environments except for buried vs. submerged goat samples and surface vs. buried/submerged tibia pig samples. FFI showed a weak association with PMI and it seems to be affected by various factors, such as different bone types, decomposition environments and climatic factors. Nonetheless, the FFI shows promising discriminating power during the early postmortem period. The apparent variation between bone types from different species suggests that extrapolations to humans can be challenging.


Association of Ureaplasma urealyticum in the placenta with perinatal morbidity and mortality.
We investigated the presence of ureaplasmas, mycoplasmas, chlamydiae, fungi, aerobic and anaerobic bacteria, and cytomegalovirus in fetal membranes and evaluated their association with perinatal morbidity and mortality. We cultured 801 placentas from three groups of subjects (144 who died in the perinatal period, 452 neonates admitted to the intensive-care unit, and 205 controls). Ureaplasma urealyticum, Mycoplasma hominis, or both were isolated from 21 per cent of placentas of premature and term infants who died in the perinatal period, 25 per cent of those admitted to intensive care, and 11 per cent of controls. Gestational age and birth weight were inversely related to isolation of ureaplasma, and chorioamnionitis was positively related to isolation. The presence of ureaplasmas in the placenta suggests the transcervical migration of these microorganisms from the lower genitourinary tract. These data show a strong association between ureaplasma infection of the placenta and low birth weight of the neonate and suggest that the association is causal.


Gomco circumcision in the office in patients heavier than 5.5 Kg and/or older than 3 months.
Although most pediatric urologists do not perform clamp circumcisions in boys older than 3 months or heavier than 5.5 kg, there are no universally accepted guidelines on the optimal patient age or weight. To compare outcomes of office circumcision within and outside these traditional patient parameters. This is a retrospective review of circumcisions performed by a single surgeon from 2019 to 2022. Demographics reviewed include age and weight at time of circumcision, gestational weeks at birth, as well as post-procedure: bleeding, planned and unplanned visits, adhesions/concealment, and interventions related to the circumcision. "Active Bleeding" was defined as bleeding occurring after discharge requiring intervention with pressure, sutures, or cautery. "All Bleeding" included Active Bleeding, and cases where bleeding was controlled at home with pressure, stopped by the time of arrival at clinic or emergency department, and immediate bleeding after circumcision controlled before discharge. During the study period, 773 Gomco circumcisions were performed. A total of 603 patients (78%) had post-procedure evaluation 2 weeks after circumcision. 574 patients (74%) were less than 5.5 kg and 199 (26%) over. Only age corrected for gestation was used in the study: 658 (85%) were younger than 3 months and 115 (15%) older. There was no significant difference in Active Bleeding based on weight (p = 0.3819) or age (p = 0.2798), and no difference in All Bleeding based on weight (p = 0.2072). There was a significant difference (p = 0.0258) in All Bleeding based on age. There was also a significant difference in unexpected visits based on weight (p = 0.0258) and age (p = 0.0131). With regards to adhesions, there was no statistical significant differences when comparing weight or age. However, older and heavier boys had significantly more concealment (5% vs <1%). Our study showed Active Bleeding rates 0.5-0.9% higher in the older and heavier group, although the difference did not reach statistical significance. We found a significantly increased rate of unexpected post-procedure visits of around 3.5-4.7% in those patients older than 3 months and heavier than 5.5 kg. Also, post -procedure concealment was significantly increased in the older and heavier boys. Modifications of the dressing for high risk groups could reduce the risk of bleeding, and efforts on pre-circumcision education of the families might ameliorate unexpected visits. Exlcuding patients with hidden penis or performing penoscrotal skin tacking at the time of the gomco circumcision could decrease concealment rates in the higher risk patients. Gomco clamp circumcision is safe in patients over 5.5 kg and older than 3 months, with a less than 1% higher risk of bleeding, which in the current study was controlled without the need for general anesthesia or transfusions. Broadening the inclusion criteria for office clamp circumcisions could reduce costs and make the procedure available to patients who cannot afford to have the surgery under general anesthesia.


Guidelines and Quality Standards in the Care of Children with Epilepsy.
To provide quality care for children with epilepsy there is a continuing need to synthesize clinical research into forms that reflect best clinical practice. The design of evidence-based guidelines allows the gathering of this information together. This review discusses the components needed to analyze published data and produce recommendations for clinical management. Guideline implementation should be seen as an essential component that is integrated into guideline development. Robust clinical practice guidelines can also form the basis of defining quality standards that in turn should allow the development and measurement of clinical outcomes that lead to direct improvements in patient care.


Impact of posttraumatic stress disorder of World War II on the next generation.
A clinical survey examined the experiences of children who grew up in families in which a father suffered from posttraumatic stress disorder as a result of combat experience in World War II. Although the data did not permit rigorous epidemiological or definitive etiological conclusions, the survey did reveal that some offspring of World War II combat veterans demonstrate long-term, transgenerational effects from their father's combat trauma. Although the children's conscious knowledge of the veteran's combat experience and the impact of the veteran on the affective life of his family and on his children varied among the five families studied, the continuing legacy of wartime trauma was apparent in the adult lives of many of these offspring.


Ketoconazole inhibition of testicular secretion of testosterone and displacement of steroid hormones from serum transport proteins.
In vivo perfusion of canine testes with ketoconazole inhibited the stimulation of testosterone production by human chorionic gonadotropin in a dose-dependent manner. Ketoconazole also selectively displaced steroids from serum-binding globulins. Dihydrotestosterone and estradiol binding to sex hormone-binding globulin were inhibited by ketoconazole. Cortisol binding to corticosteroid-binding globulin was unaffected. The concentrations of ketoconazole that inhibited human chorionic gonadotropin stimulation of testicular androgen production and displaced sex steroids from sex hormone-binding globulin were in the range of blood levels found in patients on higher therapeutic dosage regimens. Suppression of testicular testosterone synthesis and displacement of estrogens from sex hormone-binding globulin may decrease the androgen/estrogen ratio of the blood and contribute to the development of gynecomastia that has been reported in some ketoconazole-treated patients.


Semimetallic dense hydrogen above 260 GPa.
Being the lightest and the most abundant element in the universe, hydrogen is fascinating to physicists. In particular, the conditions of its metallization associated with a possible superconducting state at high temperature have been a matter of much debate in the scientific community, and progress in this field is strongly correlated with the advancements in theoretical methods and experimental techniques. Recently, the existence of hydrogen in a metallic state was reported experimentally at room temperature under a pressure of 260-270 GPa, but was shortly after that disputed in the light of more experiments, finding either a semimetal or a transition to an other phase. With the aim to reconcile the different interpretations proposed, we propose by combining several computational techniques, such as density functional theory and the GW approximation, that phase III at ambient temperature of hydrogen is the Cmca-12 phase, which becomes a semimetal at 260 GPa . From phonon calculations, we demonstrate it to be dynamically stable; calculated electron-phonon coupling is rather weak and therefore this phase is not expected to be a high-temperature superconductor.


Push-out strength of translucent fibre posts cemented using a dual-curing technique or a light-curing self-adhering material.
To compare by means of a push-out test the interfacial strength of a dual-curing resin cement and a light-curing self-adhering resin composite when used in translucent fibre post cementation. Thirty-four extracted human premolars with single canals were selected and root filled. Translucent fibre posts (RelyX Fiber Post) were luted into the root canal using two resinous luting systems (n = 17). Dual-Curing Technique (DC): the specimens were treated with Excite DSC and RelyX ARC, which were light-cured simultaneously through the post for 60 s. Light-Curing Self-Adhering Technique (LCSA): the specimens were treated with Vertise Flow, which was light-cured through the post for 60 s. The specimens were sectioned transversally into six slices to perform the push-out test at the coronal, middle and apical regions of the root canals. Data were analysed by two-way anova. All specimens were analysed by stereomicroscopy and SEM to determine fracture patterns. There were no significant differences between the DC and LCSA techniques (P = 0.703) in any of the canal regions. Root region was not a significant factor for push-out values (P = 0.255) and group-region interactions were not significant (P = 0.740). For the DC technique, the majority of the fracture patterns (73.3%) were adhesive at the interface between dual-curing resin cement and adhesive. For the LCSA technique, the majority of the fracture patterns (71.7%) were adhesive at the interface between light-curing self-adhering resin composite and dentine. The interfacial strength between light-curing self-adhering resin composite and root canal walls is equivalent to the interfacial strength between dual-curing cement and root canal walls.


SLICC classification criteria for juvenile systemic lupus erythematosus: a cross sectional study.
to verify the sensitivity and specificity of the criteria for systemic lupus erythematosus, proposed by the Systemic Lupus International Collaborating Clinics (SLICC) and compare it to the ACR lupus criteria, in a pediatric population. this is an observational cohort study, with a descriptive analysis of data from a Pediatric Rheumatology center, including 23 patients with Juvenile Systemic Lupus Erythematosus (jSLE) and a control group of 24 patients with Juvenile Idiopathic Arthritis (JIA), both groups recently diagnosed and virgin of treatment. Information on signs and symptoms was obtained on the diagnostic consult, and the ACR and SLICC criteria were applied to both groups. Statistical analysis on descriptive data was performed, presenting them in absolute and relative frequency and calculating sensitivity and specificity for each set of criteria. by comparing the ACR and SLICC criteria, we obtained higher sensitivity and accuracy using the SLICC criteria (100% and 97.9%, respectively) and equal specificity. Individually, the positive ANA criterion had 100% sensitivity but only 58.3% specificity in both classifications. The other criteria showed low sensitivity and high specificity when individually analyzed; renal disorder, leukopenia or lymphopenia, positive anti-DNA antibody and low complement level were the only criteria with sensitivity above 50%. Arthritis was the least specific criterion. our results were similar to previous studies with both children and adults, and classification criteria should be used with caution. The SLICC criteria showed high sensitivity and specificity for the classification of jSLE.


Lyme borreliosis in the southern United States: a review.
Lyme borreliosis (Lyme disease) is the most often reported arthropod transmitted disease in humans in the U.S.A. Although it has been reported from 43 states, cases are especially abundant in the mid-Atlantic and northeastern regions. Borrelia burgdorferi, the etiologic agent, is transmitted primarily by the western blacklegged tick (Ixodes pacificus) in far western North America, and by the blacklegged tick (Ixodes scapularis) in eastern North America. Although Lyme disease cases have been reported from southern states, some researchers doubt the presence of B. burgdorferi or of human Lyme disease in the south. However, new data show that B. burgdorferi is widely distributed in the south and that strains are genetically more varied than in the north. Moreover, B. burgdorferi enzootic cycles appear to be more complex and more tick species are identified as vectors of the spirochete in the southern states.


Characterizing Time Irreversibility in Disordered Fermionic Systems by the Effect of Local Perturbations.
We study the effects of local perturbations on the dynamics of disordered fermionic systems in order to characterize time irreversibility. We focus on three different systems: the noninteracting Anderson and Aubry-André-Harper (AAH) models and the interacting spinless disordered t-V chain. First, we consider the effect on the full many-body wave functions by measuring the Loschmidt echo (LE). We show that in the extended or ergodic phase the LE decays exponentially fast with time, while in the localized phase the decay is algebraic. We demonstrate that the exponent of the decay of the LE in the localized phase diverges proportionally to the single-particle localization length as we approach the metal-insulator transition in the AAH model. Second, we probe different phases of disordered systems by studying the time expectation value of local observables evolved with two Hamiltonians that differ by a spatially local perturbation. Remarkably, we find that many-body localized systems could lose memory of the initial state in the long-time limit, in contrast to the noninteracting localized phase where some memory is always preserved.


Erythrocytosis Following Testosterone Therapy.
A rapid increase in awareness of androgen deficiency has led to substantial increases in prescribing of testosterone therapy (TTh), with benefits of improvements in mood, libido, bone density, muscle mass, body composition, energy, and cognition. However, TTh can be limited by its side effects, particularly erythrocytosis. This review examines the literature on testosterone-induced erythrocytosis and polycythemia. To review the available literature on testosterone-induced erythrocytosis, discuss possible mechanisms for pathophysiology, determine the significance of formulation, and elucidate potential thromboembolic risk. A literature review was performed using PubMed for articles addressing TTh, erythrocytosis, and polycythemia. Mechanism, pharmacologic contribution, and risk of testosterone-induced erythrocytosis. For men undergoing TTh, the risk of developing erythrocytosis compared with controls is well established, with short-acting injectable formulations having the highest associated incidence. Potential mechanisms explaining the relation between TTh and erythrocytosis include the role of hepcidin, iron sequestration and turnover, erythropoietin production, bone marrow stimulation, and genetic factors. High blood viscosity increases the risk for potential vascular complications involving the coronary, cerebrovascular, and peripheral vascular circulations, although there is limited evidence supporting a relation between TTh and vascular complications. Short-acting injectable testosterone is associated with greater risk of erythrocytosis compared with other formulations. The mechanism of the pathophysiology and its role on thromboembolic events remain unclear, although some data support an increased risk of cardiovascular events resulting from testosterone-induced erythrocytosis. Ohlander SJ, Varghese B, Pastuszak AW. Erythrocytosis Following Testosterone Therapy. Sex Med Rev 2018;6:77-85.


Total colpocleisis with high levator plication for the treatment of advanced pelvic organ prolapse.
Our purpose was (1). to report long-term objective and subjective outcome data after total colpocleisis with high levator plication and (2). to compare operative morbidity of total colpocleisis in patients with prior versus concurrent hysterectomy. The medical records of patients who underwent total colpocleisis with high levator plication between August 1, 1988, and December 31, 2000, were retrospectively reviewed. Patient characteristics, operative data, and objective outcome measures including pelvic organ prolapse staging measurements were obtained from subject records. Subjective outcome measures were obtained by a standardized telephone survey. A t test was used to compare continuous variables between patients who underwent prior versus concurrent hysterectomy. The Fisher exact test was used to test for association between patient group and each categorical variable. During the 12-year study period, 92 subjects underwent total colpocleisis with high levator plication. Of the 92 subjects, 90 (97.8%) underwent concurrent operations and 37 (40.2%) underwent simultaneous hysterectomy. With objective cure defined as absence of prolapse to the hymen, 90 subjects (97.8%) were objectively cured after a median follow-up of 12 months (range, 0-64 months). Of 62 subjects available for telephone follow-up, 56 (90.3%) reported being satisfied or very satisfied with how the surgery cured their prolapse after a median follow-up of 24 months (range, 13-161 months). Concurrent hysterectomy was associated with statistically significant increases in absolute change in hematocrit (9.5% without vs 11.9% with hysterectomy) and transfusion requirement (12.7% without vs 35.1% with hysterectomy). There was no significant difference in surgical complications between groups. Total colpocleisis is an effective operation for the treatment of advanced pelvic organ prolapse. Concurrent hysterectomy is associated with higher blood loss and transfusion requirements.


Applications and Perceptions of Date Labeling of Food.
Open dating of food products has been practiced for decades, and has been key to achieving stock rotation at retail and providing information to consumers. The open date provides a simple communication tool, which may be based on product quality and/or food safety as determined by the manufacturer or retailer. Date marking is generally open but it can be closed (code intended for managing product at retail, and for recall and traceability), and the terminology and applications vary widely around the world. The variation in date labeling terms and uses contributes to substantial misunderstanding by industry and consumers and leads to significant unnecessary food loss and waste, misapplication of limited resources, unnecessary financial burden for the consumer and the food industry, and may also lead to potential food safety risk in regards to perishable foods. A "use by" or similar date cannot be relied on to indicate or guarantee food safety because absolute temperature control of food products throughout the food supply chain cannot be assured. This paper provides an introduction to the issue of food product date labeling and addresses its history in the United States, different terms used and various practices, U.S. and international frameworks, quality compared with safety, adverse impacts of misconceptions about date labeling, and advantages of technological innovations. Collaboration to develop a simple workable solution to address the challenges faced by stakeholders would have tremendous benefit. Conclusions include a call to action to move toward uniformity in date labeling, thereby decreasing confusion among stakeholders and reducing food waste.


Comprehensibility of patient education literature.
A survey of the mental health information literature available in NSW was made using the Flesch Formula for Reading Ease. It was found that ten out of thirteen were written at a level of complexity unintelligible to up to 60% of the general public. The literature is therefore falling far short of its potential. It is recommended that a serious attempt be made to write pamphlets in Plain English style. This process should include a Reading Ease estimation.


A hospital-based cross-sectional study to develop an estimation formula for 2-h post-challenge plasma glucose for screening impaired glucose tolerance.
To create and validate an estimation formula for 2-h post-challenge plasma glucose (2-hPG) as an alternative to oral glucose tolerance test (OGTT) for impaired glucose tolerance (IGT) screening. 380 Japanese subjects (57.6% males, aged 58.5 (14.0); mean (SD) years) undergoing OGTT were included in this hospital-based cross-sectional study mainly at Kyoto University Hospital between 2000 and 2011. We determined the main predictive variables of 2-hPG from clinical variables and separated the subjects randomly into two groups: a derivation group to construct an estimation formula of 2-hPG on the basis of predictive variables and a validation group to evaluate the accuracy of the formula. Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) were highly correlated with 2-hPG measured by OGTT. Multiple linear regression analysis showed that estimated 2-hPG (e2-hPG) was calculated by the formula: e2-hPG = 1.66 × FPG (mmol/l) + 1.63 × HbA1c (%)-10.11 (R(2), coefficient of determination=60.2%). When the cut-off value was set to the diagnostic criteria of IGT, 7.8 mmol/l of e2-hPG, sensitivity, specificity, and negative predictive value (NPV) were 83.3%, 44.1%, and 74.3%, respectively. When the cut-off value was set lower (7.2 mmol/l), these values were 94.4%, 30.5%, and 85.7%, respectively. The area under the receiver operating characteristic (ROC) curve was 0.68. This high-sensitive estimation formula may be a useful alternative to OGTT for IGT screening. For the levels ≤ 7.2 mmol/l, this formula may also be useful in cross-sectional study to identify people whose glucose tolerance is normal.


The Success of Thread-embedding Therapy in Generating Hair Re-growth in Mice Points to Its Possibly Having a Similar Effect in Humans.
Recently, thread-embedding therapy (TET) has been widely applied in Korean medicine for cosmetic purposes such as reducing skin wrinkles. An inserted thread was reported to have induced continuous stimulation, followed by support for connective tissue regeneration. However, the potential role of TET in hairgrowth has not yet been reported. We designed this study to evaluate whether TET has a hair-growth-promoting effect. C57 black 6 (C57BL/6) mice were divided into three groups: normal saline-treated, minoxidil-treated, and thread-embedded groups. Normal saline or 5% minoxidil was topically sprayed on the dorsal skin of the mice once a day for 16 days. Medical threads were embedded into the dorsal skin of the mice in a single application. Hair growth activity was evaluated by using dermoscopic and microscopic observations. Sections of the dorsal skin were stained with hematoxylin and eosin. Expressions of bromodeoxyuridine (BrdU), proliferating cell nuclear antigen (PCNA), fibroblast growth factor-7 (FGF-7), and fibroblast growth factor-5 (FGF-5) were detected by using immunohistochemical staining. A reverse transcription-polymerase chain reaction (RT-PCR) analysis was adopted to measure the messenger RNA (mRNA) expressions of FGF-7 and FGF-5. TET enhanced anagen development in the hair follicles of C57BL/6 mice. The expressions of BrdU and PCNA, both of which imply active cellular proliferation, were increased by using TET. Moreover, TET increased the expression of FGF-7, an anagen-inducing growth factor, while decreasing the expression of FGF-5, an anagen-cessation growth factor, both at the protein and the mRNA levels. TET enhanced hair re-growth in C57BL/6 mice. TET regulated the expressions of anagen-associated growth factors and activated the proliferation of hair follicular cells in depilated skin lesions. Considering its long-lasting effect, TET may be a good alternative therapeutic for the treatment of alopecia.


Pharmaceuticals, hormones, and other organic wastewater contaminants in U.S. streams, 1999-2000: a national reconnaissance.
To provide the first nationwide reconnaissance of the occurrence of pharmaceuticals, hormones, and other organic wastewater contaminants (OWCs) in water resources, the U.S. Geological Survey used five newly developed analytical methods to measure concentrations of 95 OWCs in water samples from a network of 139 streams across 30 states during 1999 and 2000. The selection of sampling sites was biased toward streams susceptible to contamination (i.e. downstream of intense urbanization and livestock production). OWCs were prevalent during this study, being found in 80% of the streams sampled. The compounds detected represent a wide range of residential, industrial, and agricultural origins and uses with 82 of the 95 OWCs being found during this study. The most frequently detected compounds were coprostanol (fecal steroid), cholesterol (plant and animal steroid), N,N-diethyltoluamide (insect repellant), caffeine (stimulant), triclosan (antimicrobial disinfectant), tri(2-chloroethyl)phosphate (fire retardant), and 4-nonylphenol (nonionic detergent metabolite). Measured concentrations for this study were generally low and rarely exceeded drinking-water guidelines, drinking-water health advisories, or aquatic-life criteria. Many compounds, however, do not have such guidelines established. The detection of multiple OWCs was common for this study, with a median of seven and as many as 38 OWCs being found in a given water sample. Little is known about the potential interactive effects (such as synergistic or antagonistic toxicity) that may occur from complex mixtures of OWCs in the environment. In addition, results of this study demonstrate the importance of obtaining data on metabolites to fully understand not only the fate and transport of OWCs in the hydrologic system but also their ultimate overall effect on human health and the environment.


Characterization of ghrelin receptor activity in a rat pituitary cell line RC-4B/C.
Ghrelin, a 28 amino acid, octanoylated peptide, is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). In addition to various endocrine functions, including stimulation of GH release, ghrelin has been characterized as an important regulator of energy homeostasis. Ghrelin administration has been shown to increase adiposity in rodents and stimulate food intake in humans. Studies suggest that these orexigenic effects are mediated primarily through GHS-R expression in hypothalamic and pituitary neuronal pathways. In this context, GHS-R has been recognized as a potential target for the treatment of GH deficiency and body weight disorders. Cell lines provide convenient in vitro systems to identify and characterize potential pharmacophores and to analyze GHS-R functional activity. While recombinant cell lines that overexpress GHS-R have served as effective research tools for these studies, such cell lines may differ in signaling response to ghrelin compared with hypothalamic or pituitary cells expressing GHS-R. We show here that a cell line derived from a rat anterior pituitary adenoma, RC-4B/C, expresses endogenous GHS-R as judged by reverse transcriptase-PCR. In a Ca(2+)mobilization assay, RC-4B/C cells demonstrate a dose-dependent increase in intracellular [Ca(2+)] on stimulation with rat ghrelin and a related peptide agonist, hexarelin (EC(50), 1.0 nM and 1.7 nM respectively), but are unresponsive to treatment with inactive des-octanoyl rat ghrelin. A subclone, RC-4B/C.40, with a more robust and stable ghrelin response, was isolated from the parental population of cells to allow further analysis of GHS-R signal transduction. Using pertussis toxin and the phospholipase C inhibitor U-73122, we show that ghrelin signals through the Gq pathway in the RC-4B/C.40 cells. We also demonstrate that the ghrelin-induced rise of intracellular [Ca(2+)] in RC-4B/C.40 cells involves initial Ca(2+)release from intracellular stores followed by a sustained elevation that occurs via influx of extracellular Ca(2+) through ion channels. In addition, unlike observations reported in recombinant cell systems, the RC-4B/C.40 cells do not exhibit a high level of GHS-R constitutive activity as determined in a phosphatidylinositol hydrolysis assay. Overall, the data presented here suggest that the RC-4B/C parental and RC-4B/C.40 cells provide novel in vitro systems for the characterization of GHS-R pharmacophores and ghrelin signaling.


Nocturnal Hypertension and Left Ventricular Diastolic Dysfunction in Patients With Diabetes With the Absence of Heart Failure: Prospective Cohort HSCAA Study.
Diabetes is an important risk factor for heart failure (HF) and is associated with left ventricular (LV) diastolic dysfunction. However, diabetic comorbid conditions, such as nocturnal hypertension, as predictors of diastolic dysfunction are not known in the absence of an HF period. The present study was conducted as the longitudinal examination of the predictive value of nocturnal hypertension profiles on the progression of LV diastolic dysfunction in patients with and without diabetes without HF. 422 subjects (154 diabetes and 268 nondiabetes) in the absence of HF were followed for 36.8±18.2 months. The relationships among the patterns of nocturnal hypertension and the outcome of LV diastolic dysfunction, defined as an increase in E/e'>14, were investigated in the patients with and without diabetes. The interaction effect of the diabetes status and the patterns of nocturnal hypertension on the hazard rate of the occurrence of E/e'>14 was statistically significant (P=0.017). Kaplan-Meier analysis results revealed that patients with diabetes with nondipper (P=0.021 versus dipper) and riser (P=0.006 versus dipper) had a greater risk for a diastolic dysfunction event. Furthermore, multivariable Cox proportional hazards analysis revealed that nondipper (hazard ratio, 4.56 [95% CI, 1.49-13.96]; P=0.007) and riser (hazard ratio, 3.89 [95% CI, 1.31-11.57]; P=0.014) patterns were associated with elevated risk of the outcome of LV diastolic dysfunction. In contrast, no similar significant associations were found in patients without diabetes. During the absence of HF periods, nocturnal hypertension is an important predictor for the progression of LV diastolic dysfunction in patients with diabetes.


Role of CYP2E1 in ethanol-induced oxidant stress, fatty liver and hepatotoxicity.
Several pathways contribute to mechanisms by which ethanol induces oxidant stress. While some studies support a role for cytochrome P450 2E1 (CYP2E1), others do not. There is a need to develop oral models of significant ethanol-induced liver injury and to evaluate the possible role of CYP2E1 in ethanol actions in such models. We evaluated chronic ethanol-induced liver injury, steatosis and oxidant stress in wild-type (WT) mice, CYP2E1 knockout (KO) mice and in humanized CYP2E1 knockin (KI) mice, where the human 2E1 was added back to mice deficient in the mouse 2E1. WT mice and CYP2E1 KO and KI mice (both provided by Dr. F. Gonzalez, NCI) were fed a high-fat Lieber-DeCarli liquid diet for 3 weeks; pair-fed controls received dextrose. Ethanol produced fatty liver and oxidant stress in WT mice, but liver injury (transaminases, histopathology) was minimal. Ethanol-induced steatosis and oxidant stress were blunted in the KO mice (no liver injury) but restored in the KI mice. Significant liver injury was produced in the ethanol-fed KI mice with elevated transaminases and necrosis. This liver injury in the KI mice was associated with elevated oxidant stress and elevated levels of the human CYP2E1 compared to levels of the mouse 2E1 in WT mice. Activation of JNK was observed in the ethanol-fed KI mice compared to the other groups. Fatty liver in WT and KI mice was associated with lower levels of lipolytic PPAR-α. No such changes were found in the ethanol-fed KO mice. These results show that CYP2E1 plays a major role in ethanol-induced fatty liver and oxidant stress. Restoring CYP2E1 in the CYP2E1 KO mice restores ethanol-induced fatty liver and oxidant stress.


A large and unusually thick-shelled turtle egg with embryonic remains from the Upper Cretaceous of China.
Turtle eggs containing embryos are exceedingly rare in the fossil record. Here, we provide the first description and taxonomic identification, to our knowledge, of a fossilized embryonic turtle preserved in an egg, a fossil recovered from the Upper Cretaceous Xiaguan Formation of Henan Province, China. The specimen is attributed to the Nanhsiungchelyidae (Pan-Trionychia), an extinct group of large terrestrial turtles (possibly the species Yuchelys nanyangensis). The egg is rigid, spherical, and is one of the largest and thickest shelled Mesozoic turtle eggs known. Importantly, this specimen allowed identification of other nanhsiungchelyid egg clutches and comparison to those of Adocidae, as Nanhsiungchelyidae and Adocidae form the basal extinct clade Adocusia of the Pan-Trionychia (includes living soft-shelled turtles). Despite the differences in habitat adaptations, nanhsiungchelyids (terrestrial) and adocids (aquatic) shared several reproductive traits, including relatively thick eggshells, medium size clutches and relatively large eggs, which may be primitive for trionychoids (including Adocusia and Carrettochelyidae). The unusually thick calcareous eggshell of nanhsiungchelyids compared to those of all other turtles (including adocids) may be related to a nesting style adaptation to an extremely harsh environment.


HCSD: the human cancer secretome database.
The human cancer secretome database (HCSD) is a comprehensive database for human cancer secretome data. The cancer secretome describes proteins secreted by cancer cells and structuring information about the cancer secretome will enable further analysis of how this is related with tumor biology. The secreted proteins from cancer cells are believed to play a deterministic role in cancer progression and therefore may be the key to find novel therapeutic targets and biomarkers for many cancers. Consequently, huge data on cancer secretome have been generated in recent years and the lack of a coherent database is limiting the ability to query the increasing community knowledge. We therefore developed the Human Cancer Secretome Database (HCSD) to fulfil this gap. HCSD contains >80 000 measurements for about 7000 nonredundant human proteins collected from up to 35 high-throughput studies on 17 cancer types. It has a simple and user friendly query system for basic and advanced search based on gene name, cancer type and data type as the three main query options. The results are visualized in an explicit and interactive manner. An example of a result page includes annotations, cross references, cancer secretome data and secretory features for each identified protein.


Subunit structure of factor VIII antigen synthesized by cultured human endothelial cells.
Cultured human endothelial cells were labeled with (3H)leucine, and the radioactive Factor VIII antigen present in the postculture medium was isolated by double anitbody immunoprecipitation and characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis after reduction with dithiothreitol. The Factor VIII antigen synthesized by cultured endothelial cells was found to contain the same single polypeptide subunit (mol wt 225,000) present in plasma Factor VIII antigen. These results suggest that in vivo, the endothelial cell is a major site of synthesis of circulating Factor VIII antigen.


Partial foot amputations in the combat wounded.
Throughout the current conflicts in Afghanistan and Iraq, there have been more than 1100 combat-related major limb amputations, with approximately 80% involving the lower extremity. There is, however, a paucity of data regarding the number of amputations below the level of the ankle. Although not as common, partial foot amputations, in the appropriate setting, offer a way to improve function and decrease energy consumption when compared to proximal amputations. Sound surgical tenets are prerequisite for successful outcomes when performing a distal amputation. Maintaining a robust soft tissue envelope allowing for tension-free wound closure is paramount in determining the feasibility of a partial foot amputation. Careful consideration of tendon balancing is also of utmost importance in avoiding common complications of contracture and deformity. Partial foot amputations present a viable surgical option for successful outcomes and maximization of patient function in the combat injured when certain criteria are met.


Expected role of medical technologists in diabetes mellitus education teams.
The expected role of medical technologists within diabetes mellitus education teams was surveyed. In addition to items regarding laboratory examinations and results themselves, good communication with patients and education team members was highly required. When medical technologists sufficiently follow this role, it would aid patients to cope with life with diabetes mellitus.


The lipid-teichoic acid complex in the cytoplasmic membrane of Streptococcus faecalis N.C.I.B. 8191.
1. A lipid-teichoic acid complex was isolated from Streptococcus faecalis N.C.I.B. 8191. The covalent nature of the linkage between teichoic acid and lipid was established. 2. The complex exhibits macromolecular properties in solution, and ultracentrifugation studies show that these are due to micelle formation. 3. From chemical studies it is concluded that the teichoic acid is a poly(glycerol phosphate) in which some of the glycerol hydroxyl groups possess kojibiosyl [2-O-alpha-d-glucopyranosyl-(1-->2)-alpha-d- glucopyranosyl] substituents, together with d-alanine ester residues. 4. The lipid is 1-kojibiosyl diglyceride, already known as a membrane component of this organism, with probably a phosphatidyl substituent. The phosphatidyl kojibiosyl diglyceride is attached to the teichoic acid through a phosphodiester linkage, and the chain of the teichoic acid contains 28-35 units. 5. Although the complex represents the whole of the membrane teichoic acid in this organism, only about 12% of the membrane glycolipid is associated with teichoic acid. 6. Two phosphatidyl glycolipids, closely resembling that bearing the teichoic acid, were isolated from the lipids of the organism and were partly characterized.


Polyphenol inhibition of benzo[a]pyrene-induced oxidative stress and neoplastic transformation in an in vitro model of carcinogenesis.
While dietary polyphenols are widely recognized for cancer-preventing characteristics, the relative effectiveness and mechanisms of action of different polyphenols is not clear. In the present study, we investigated the protective effects of six different polyphenols against benzo[a]pyrene (B[a]P)-induced oxidative stress and neoplastic transformation in the Bhas 42 cell carcinogenesis assay. All of the polyphenols completely prevented the increased intracellular ROS generation by B[a]P at 12 h, and most inhibited after 3 days. B[a]P increased mitochondrial superoxide generation at 12 h, which was inhibited by the anthocyanins and berberine. B[a]P increased expression of genes related to oxidative stress and inflammation (Nrf2, UCP2, and TNF-α) after 24 h. Polyphenols strongly inhibited the increase in TNF-α and also several polyphenols inhibited the increase in UCP2. At 21 days after 72 h treatment, B[a]P produced a large increase in the number of neoplastic colonies. This transformation was inhibited by most polyphenols, and strongly by resveratrol. In summary, all tested polyphenols were able to inhibit B[a]P-induced increases in markers of oxidative stress and inflammation, and to inhibit cellular transformation, with resveratrol being notable for the strongest preventive effect on cell transformation. The results support a role for dietary polyphenols in protecting against B[a]P-induced carcinogenesis.


Aspergillus specific nested PCR from the site of infection is superior to testing concurrent blood samples in immunocompromised patients with suspected invasive aspergillosis.
Invasive aspergillosis (IA) is a severe complication in immunocompromised patients. Early diagnosis is crucial to decrease its high mortality, yet the diagnostic gold standard (histopathology and culture) is time-consuming and cannot offer early confirmation of IA. Detection of IA by polymerase chain reaction (PCR) shows promising potential. Various studies have analysed its diagnostic performance in different clinical settings, especially addressing optimal specimen selection. However, direct comparison of different types of specimens in individual patients though essential, is rarely reported. We systematically assessed the diagnostic performance of an Aspergillus-specific nested PCR by investigating specimens from the site of infection and comparing it with concurrent blood samples in individual patients (pts) with IA. In a retrospective multicenter analysis PCR was performed on clinical specimens (n = 138) of immunocompromised high-risk pts (n = 133) from the site of infection together with concurrent blood samples. 38 pts were classified as proven/probable, 67 as possible and 28 as no IA according to 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group consensus definitions. A considerably superior performance of PCR from the site of infection was observed particularly in pts during antifungal prophylaxis (AFP)/antifungal therapy (AFT). Besides a specificity of 85%, sensitivity varied markedly in BAL (64%), CSF (100%), tissue samples (67%) as opposed to concurrent blood samples (8%). Our results further emphasise the need for investigating clinical samples from the site of infection in case of suspected IA to further establish or rule out the diagnosis.


[The molecular genetic diagnostic of Gaucher disease type I].
The Gaucher disease is a hereditary enzymopathy underlaid by deficiency of activity of acidic beta-glycosidase, a lysosomal enzyme participating in degradation of products of cell metabolism. The actual study was carried out to characterize genotypes of patients with Gaucher disease in the Russian Federation. The study group consisted of sampling of 122 adult patients with Gaucher disease type I. The technique of allele-specific polymerase chain reaction in real time was applied to screening for detection of four most frequent mutations of gene of acidic beta-glycosidase (N370S, 84GG, L444P, IVS2+ 1). The results of molecular genetic studies demonstrated that in Russian patients the most frequent is mutation N370S and genotype N370S/other mutation. The second allele is presented by mutation not included into number of most frequent mutations of gene of acidic beta-glycosidase.


Digital Resilience Through Training Protocols: Learning To Identify Fake News On Social Media.
We explore whether training protocols can enhance the ability of social media users to detect fake news, by conducting an online experiment (N = 417) to analyse the effect of such a training protocol, while considering the role of scepticism, age, and level of education. Our findings show a significant relationship between the training protocol and the ability of social media users to detect fake news, suggesting that the protocol can play a positive role in training social media users to recognize fake news. Moreover, we find a direct positive relationship between age and level of education on the one hand and ability to detect fake news on the other, which has implications for future research. We demonstrate the potential of training protocols in countering the effects of fake news, as a scalable solution that empowers users and addresses concerns about the time-consuming nature of fact-checking.


Test-Retest Reliability of Graph Theoretic Metrics in Adolescent Brains.
Graph theory analysis of structural brain networks derived from diffusion tensor imaging (DTI) has become a popular analytical method in neuroscience, enabling advanced investigations of neurological and psychiatric disorders. The purpose of this study was to investigate (1) the effects of edge weighting schemes and (2) the effects of varying interscan periods on graph metrics within the adolescent brain. We compared a binary (B) network definition with three weighting schemes: fractional anisotropy (FA), streamline count, and streamline count with density and length correction (SDL). Two commonly used global and two local graph metrics were examined. The analysis was conducted with two groups of adolescent volunteers who received DTI scans either 12 weeks apart (16.62 ± 1.10 years) or within the same scanning session (30 min apart) (16.65 ± 1.14 years). The intraclass correlation coefficient was used to assess test-retest reliability and the coefficient of variation (CV) was used to assess precision. On average, each edge scheme produced reliable results at both time intervals. Weighted measures outperformed binary measures, with SDL weights producing the most reliable metrics. All edge schemes except FA displayed high CV values, leaving FA as the only edge scheme that consistently showed high precision while also producing reliable results. Overall findings suggest that FA weights are more suited for DTI connectome studies in adolescents.


Prostaglandin E2 desensitizes cAMP-mediated pepsinogen secretion in chief cells.
To evaluate whether pretreatment with prostaglandin E2 (PGE2) could desensitize pepsinogen secretion in chief cells from guinea pig, chief cells were pretreated with 10 microM PGE2 for up to 30 min. Desensitization of subsequent PGE2-stimulated secretion was maximal after 15 min, averaging only 29 +/- 9% (SE) of pepsinogen secretion in control cells stimulated with 10 microM PGE2. Desensitization was half-maximal with 30 nM PGE2. PGE2 pretreatment at 4 degrees C did not cause desensitization. In cells pretreated with 10 microM PGE2 for 15 min and then given 60 min to recover, responsiveness increased to 79 +/- 7% of that for control cells stimulated with PGE2. Thus the desensitization was reversible. Pretreatment with PGD2 and PGF2a did not alter subsequent PGE2-mediated secretion. PGE2-induced desensitization was heterologous but mediator specific because pepsinogen secretion was reduced in response to adenosine 3',5'-cyclic monophosphate (cAMP)-mediated agents (secretin and vasoactive intestinal peptide) but not Ca(2+)-mediated agents (CCK-8, gastrin, or carbachol). Pretreating chief cells with 10 microM PGE2 did not significantly alter cAMP generation in response to PGE2, secretin, or 3-isobutyl-1-methylxanthine, suggesting that desensitization was not mediated by an alteration in the receptor-coupled adenylate cyclase system. Because PGE2 pretreatment also desensitized pepsinogen secretion induced by the synthetic cAMP analogues 8-BrcAMP and 2'-O-monobutyryl-8-BrcAMP, it is likely that the ability of PGE2 to desensitize pepsinogen secretion in chief cells isolated from guinea pig is due to a mechanism distal to generation of cAMP.


[Treatment of varicose veins of the lower extremities with vistarin and varicocide under ambulatory conditions].
Injection-sclerosing treatment of primary varicosity of superficial veins of the lower extremities was employed in 250 patients, 200 of them being treated with vistrin and 50-with varicocide injections. The treatment was conducted under outpatient conditions. Vistarin was found to show a greater therapeutic efficacy as compared with varicocide. Late results were studied in 152 patients treated with vistarin injections and in 150 of them a good functional and cosmetic effect was gained.


Effects of Berry curvature on the collective modes of ultracold gases.
Topological energy bands have important geometrical properties described by the Berry curvature. We show that the Berry curvature changes the hydrodynamic equations of motion for a trapped Bose-Einstein condensate, and causes significant modifications to the collective mode frequencies. We illustrate our results for the case of two-dimensional Rashba spin-orbit coupling in a Zeeman field. Using an operator approach, we derive the effects of Berry curvature on the dipole mode in very general settings. We show that the sizes of these effects can be large and readily detected in experiment. Collective modes therefore provide a sensitive way to measure geometrical properties of energy bands.


Mechanical factors and the regulation of perfusion through atelectatic lung in pigs.
The role of mechanical interdependence in the perfusion of atelectatic lung was studied in two ways: a) regional hemodynamics were compared before (control) and after the development of lobar and sublobar atelectasis, and b) the effect of thoracotomy on regional hemodynamics was assessed. With lobar atelectasis mean lobar blood flow and vascular conductance decreased to 60% of control. Sublobar atelectasis caused mean sublobar blood flow and vascular conductance to decrease to 6% of control. Opening the chest after production of lobar atelectasis caused blood flow to fall to 50% of control. When sublobar atelectasis was produced in the open chest, sublobar blood flow decreased to 25% of control measurements made prior to thoracotomy. We conclude that with a closed chest, sublobar vascular distortion mediated by mechanical interdependence may be an important mechanism responsible for the differences in hemodynamic responses to atelectasis between lobes and sublobar regions.


In vivo the environmental pollutants lead and mercury induce oligoclonal T cell responses skewed toward type-2 reactivities.
An oligoclonal utilization of Vbetas has been reported for pathogenesis of several autoimmune diseases, anti-tumorigenic activity, and superantigen-regulation of thymic T cell development. Altered ratios of Th1 and Th2 cells also are observed in immunodysregulations, leading to impaired cell-mediated immunity with an increased incidence of infectious disease or cancer and/or aberrant immunity that could culminate with an autoimmune disease. Lead (Pb) and mercury (Hg) are known pollutants with immunodisrupting activities; Hg is known to cause autoimmune glomerulonephritis. Both metals are known to suppress host resistance to pathogens. To further evaluate the manner by which these metals cause in vivo immunomodulation, their in vivo effects on Vbeta expression were evaluated along with the Th1 and Th2 frequency. Exposure of BALB/c mice to PbCl2 or HgCl2 induced an oligoclonal response with increases of Vbeta 5+, Vbeta 7+, and Vbeta 13+ CD4+ splenic, but not thymic, T cells. A significantly skewed frequency of Pb-induced splenic Th2 cells expressing Vbeta 7 or Vbeta 13 over Th1 cells was determined by limiting dilution analysis, but this Th2 predominance was not observed with CD4+ T cells expressing Vbeta 8. DO11.10 transgenic mouse exposed to Pb and antigen also demonstrated a skewed type-2 response evidenced by significantly increased IgE levels, lowered IFN-gamma levels, and increased IgG1 and lowered IgG2a anti-OVA levels. Even in the absence of specific T cell responses to a Pb-induced antigen, due to the restricted T cell specificity in the transgenic mouse model, Pb still was able to skew the response toward type-2 reactivity. However, this skewing occurred only in the presence of antigen. Therefore, the Pb-induced oligoclonal T cell response in BALB/c mice which must be initiated by self-antigens and was predominately type-2 may be responsible for autoantibody production and the detrimental health effects associated with Pb exposure.


Immunochemical study of antigenic specificity in delayed hypersensitivity. IV. The production of unresponsiveness to delayed hypersensitivity with a single antigenic determinant.
Injections of various conjugates of arsanilic acid into newborn guinea pigs produced a specific tolerance in respect to subsequent development of hapten-specific delayed hypersensitivity. In general, larger polyvalent conjugates produced longer lasting and more profound suppression of delayed sensitivity than did the smaller ones. Carrier injections alone were ineffective. At lower doses of conjugate, breakthrough of tolerance occurred first with animals immunized with the heterologous carrier conjugate. The duration of tolerance produced by injection of monovalent conjugates into neonates is in contrast to the transient inhibition produced by the same conjugates in previously sensitized animals, suggesting that different target cells may be involved in these two phenomena.


Interrelationships between sex and dietary lysine on growth performance and carcass composition of finishing boars and gilts.
The main goals of this study were to determine whether boars and gilts respond differently to the standardized ileal digestible lysine to net energy ratio (SID Lys:NE) and model the response to optimize growth performance. A total of 780 finishing pigs, 390 boars and 390 gilts [Pietrain NN × (Landrace × Large White)], with an initial individual body weight of 70.4 ± 9.2 for boars and 68.7 ± 8.0 kg for gilts, were used in a 41-d dose-response experiment. Pens (13 pigs per pen) were randomly allocated to a dietary treatment (2.64, 3.05, 3.46, 3.86, 4.27 g SID Lys/Mcal NE) by block and sex, with six replicates per treatment and sex. Two isoenergetic diets (2,460 kcal NE/kg), representing the extreme SID Lys:NE, were formulated and then mixed. Pigs were individually weighed at days 0, 22, and 41, when the experiment finished. The differential effect of SID Lys:NE on growth performance and carcass composition between sexes was analyzed with orthogonal polynomial contrasts to compare the linear and quadratic trends in each sex. In addition, broken-line linear (BLL) models to optimize average daily gain (ADG), including average daily feed intake (ADFI) as a covariate, were fitted when possible. As expected, boars had a greater ADG and feed efficiency (G:F; P < 0.001) than gilts, but there was no evidence of differences in ADFI (P = 0.470). Increasing SID Lys:NE had a greater linear impact on boars ADG (P = 0.087), G:F (P = 0.003), and carcass leanness (P = 0.032). In contrast, gilts showed a greater linear increase in SID Lys intake per kg gain (P < 0.001) and feed cost per kg gain (P = 0.005). The best fitting BLL models showed that boars maximized ADG at 3.63 g SID Lys/Mcal NE [95% confidence interval (CI): (3.32 to 3.94)], although another model with a similar fit, compared with the Bayesian information criterion, reported the optimum at 4.01 g SID Lys/Mcal NE [95% CI: (3.60, 4.42)]. The optimum to maximize ADG for gilts was estimated at 3.10 g SID Lys/Mcal NE [95% CI: (2.74, 3.47)]. Thus, the present study confirmed that boars and gilts have a different linear response to SID Lys:NE, explained by the greater protein deposition potential of boars. Likewise, BLL models indicated that boars require a higher SID Lys:NE to maximize ADG from 70 to 89 kg. These results suggest that split feeding of finishing boars and gilts could be beneficial in terms of both performance and cost return.


Treatment with Trichuris suis soluble products during monocyte-to-macrophage differentiation reduces inflammatory responses through epigenetic remodeling.
Helminths have strong immunoregulatory properties that may be exploited in treatment of chronic immune disorders, such as multiple sclerosis and inflammatory bowel disease. Essential players in the pathogenesis of these diseases are proinflammatory macrophages. We present evidence that helminths modulate the function and phenotype of these innate immune cells. We found that soluble products derived from the Trichuris suis (TsSP) significantly affect the differentiation of monocytes into macrophages and their subsequent polarization. TsSPs reduce the expression and production of inflammatory cytokines, including IL-6 and TNF, in human proinflammatory M1 macrophages. TsSPs induce a concomitant anti-inflammatory M2 signature, with increased IL-10 production. Furthermore, they suppress CHIT activity and enhance secretion of matrix metalloproteinase 9. Short-term triggering of monocytes with TsSPs early during monocyte-to-macrophage differentiation imprinted these phenotypic alterations, suggesting long-lasting epigenetic changes. The TsSP-induced effects in M1 macrophages were completely reversed by inhibiting histone deacetylases, which corresponded with decreased histone acetylation at the TNF and IL6 promoters. These results demonstrate that TsSPs have a potent and sustained immunomodulatory effect on human macrophage differentiation and polarization through epigenetic remodeling and provide new insights into the mechanisms by which helminths modulate human immune responses.-Hoeksema, M. A., Laan, L. C., Postma, J. J., Cummings, R. D., de Winther, M. P. J., Dijkstra, C. D., van Die, I., Kooij, G. Treatment with Trichuris suis soluble products during monocyte-to-macrophage differentiation reduces inflammatory responses through epigenetic remodeling.


Risk Factors for Lymph Node Metastasis and Recurrence in T1 Colorectal Cancer: Analysis of 801 Patients in a Single Institute.
To identify risk factors for lymph node metastasis and postoperative recurrence of pT1 colorectal cancer by clinicopathological study of surgically resected cases. In 801 patients with pT1 colorectal cancer who underwent surgical resection with lymph node dissection between April 2007 and January 2021, we evaluated clinicopathological factors (age, gender, BMI, serum CEA level, tumor localization, additional resection after endoscopic treatment, operation time, blood loss, histological type, tumor size, vascular invasion, and central lymph node dissection). We performed univariate and multivariate analyses to examine risk factors for lymph node metastasis. We also examined risk factors for recurrence in 583 patients up to December 2017. Lymph node metastasis was observed in 100/801 patients (12.5%). Multivariate analysis of lymph node metastasis showed that patients with positive lymphatic invasion (odds ratio 2.57, 95% CI 1.62-4.04, P < .0001), positive venous invasion (odds ratio 2.31, 95% CI 1.48-3.61, P = .0002), and histologically poorly differentiated type (odds ratio 4.54, 95% CI 1.35-15.2, P = .014) were identified as risk factors. Postoperative recurrence was observed in 18/580 patients (3.1%). Risk factors for postoperative recurrence were also examined, including preoperative endoscopic treatment (odds ratio 3.59, 95% CI 1.18-10.9, P = .024), positive venous invasion (odds ratio 3.63, 95% CI 1.22-10.8, P = .021), positive lymph node metastasis (odds ratio 4.91, 95% CI 1.10-21.8, P = .037) were extracted as risk factors. In this study, venous invasion, lymphatic invasion, and histologically poorly differentiated type were identified as risk factors for lymph node metastasis in T1 colorectal cancer, and positive venous invasion, positive lymph node metastasis, and preoperative endoscopic treatment were identified as risk factors for recurrence. We hope that large prospective study will lead to the development of a more specific treatment strategy, including endoscopic treatment and additional surgical resection.


Comparison of Mismatch Repair Status Between Primary and Matched Metastatic Sites in Patients With Colorectal Cancer.
Differences between the features of primary cancer and matched metastatic cancer have recently drawn attention in research. This study investigated the concordance in microsatellite instability (MSI) and mismatch repair (MMR) status between primary and corresponding metastatic colorectal cancer (CRC). Consecutive patients with metastatic CRC who had both primary and metastatic tumors diagnosed at our institution in January 2008 through December 2016 were identified. Immunohistochemistry was used to test the MMR status of both primary and matched metastatic tumors, and PCR analysis was performed to test MSI in patients with deficient MMR (dMMR) status. A total of 369 patients were included. Of the 46 patients with MSI-high primary tumors, 37 (80.4%) also had MSI-high metastatic tumors, whereas 9 (19.6%) had microsatellite stable (MSS) metastatic tumors. A high concordance was found in patients with liver, lung, or distant lymph node metastases. Interestingly, the discrepancy was more likely to be limited to peritoneal (5/20) or ovarian (4/4) metastasis (chi-square test, P<.001). These organ-specific features were also found in the pooled analysis. Along with the change of MSI-high in primary cancer to MSS in metastatic cancer, lymphocyte infiltration decreased significantly (P=.008). However, the change did not influence survival; the median overall survival of MSI-high and MSS metastatic tumors was 21.3 and 21.6 months, respectively (P=.774). The discrepancy rate was 1.6% for patients with proficient MMR primary tumors. For patients with dMMR primary tumors, the concordance of MSI and MMR status in primary CRC and corresponding metastatic cancer is potentially organ-specific. High concordance is found in liver, lung, and distant lymph node metastases, whereas discrepancy is more likely to occur in peritoneal or ovarian metastasis. Rebiopsy to evaluate MSI-high/dMMR status might be needed during the course of anti-PD-1 therapy in cases of peritoneal or ovarian metastasis.


Surface properties of adipocyte lipid-binding protein: Response to lipid binding, and comparison with homologous proteins.
Adipocyte lipid-binding protein (ALBP) is one of a family of intracellular lipid-binding proteins (iLBPs) that bind fatty acids, retinoids, and other hydrophobic ligands. The different members of this family exhibit a highly conserved three-dimensional structure; and where structures have been determined both with (holo) and without (apo) bound lipid, observed conformational changes are extremely small (Banaszak, et al., 1994, Adv. Prot. Chem. 45, 89; Bernlohr, et al., 1997, Annu. Rev. Nutr. 17, 277). We have examined the electrostatic, hydrophobic, and water accessible surfaces of ALBP in the apo form and of holo forms with a variety of bound ligands. These calculations reveal a number of previously unrecognized changes between apo and holo ALBP, including: 1) an increase in the overall protein surface area when ligand binds, 2) expansion of the binding cavity when ligand is bound, 3) clustering of individual residue exposure increases in the area surrounding the proposed ligand entry portal, and 4) ligand-binding dependent variation in the topology of the electrostatic potential in the area surrounding the ligand entry portal. These focused analyses of the crystallographic structures thus reveal a number of subtle but consistent conformational and surface changes that might serve as markers for differential targeting of protein-lipid complexes within the cell. Most changes are consistent from ligand to ligand, however there are some ligand-specific changes. Comparable calculations with intestinal fatty-acid-binding protein and other vertebrate iLBPs show differences in the electrostatic topology, hydrophobic topology, and in localized changes in solvent exposure near the ligand entry portal. These results provide a basis toward understanding the functional and mechanistic differences among these highly structurally homologous proteins. Further, they suggest that iLBPs from different tissues exhibit one of two predominant end-state structural distributions of the ligand entry portal.


Evolution of cellular HIV DNA levels in virologically suppressed patients switching to dolutegravir/lamivudine versus maintaining a triple regimen: a prospective, longitudinal, matched, controlled study.
To assess the impact of switching to dolutegravir plus lamivudine maintenance therapy on the HIV cellular reservoir size. This was a prospective, longitudinal, matched, controlled study. We enrolled virologically suppressed patients on stable three-drug ART who switched at baseline (BL) to dolutegravir/lamivudine (DT group) or maintained triple therapy (TT group); subjects in the TT group were matched 1:1 with those in the DT group according to age, gender, years since HIV diagnosis, years on ART and anchor drug. Total blood-associated HIV DNA levels were assessed by droplet digital PCR at BL and after 48 weeks (T48). Results were expressed as log10 HIV DNA copies/106 leucocytes. We enrolled 40 patients in the DT group and 40 in the TT group; the two groups were homogeneous for all main characteristics except nadir CD4 cell count. At BL, HIV DNA levels were comparable between the DT and TT groups: 2.27 (IQR 1.97-2.47) and 2.26 (IQR 2.05-2.61) log10 HIV DNA copies/106 leucocytes, respectively. Change in HIV DNA load from BL to T48 was -0.105 (IQR -0.384 to 0.121, P = 0.041) in the DT group and -0.132 (IQR -0.362 to 0.046, P = 0.005) in the TT group, with a comparable decline observed between the two groups (P = 0.821). A higher HIV DNA decline was associated with higher BL CD4/CD8 ratio. Maintenance therapy with dolutegravir/lamivudine had the same impact as the triple regimen on HIV DNA levels after 48 weeks of treatment. These data seem to support the effectiveness of a dolutegravir/lamivudine dual regimen in controlling the magnitude of the cellular reservoir (www.clinicaltrials.gov, number NCT02836782).


Classification of the hearing impaired for independent living using the Vineland Adaptive Behavior Scale.
Training hearing-impaired persons in independent living skills has become a focus of education and rehabilitation programs for the hearing impaired. Yet, few programs and assessment instruments are designed to evaluate a person's potential for acquiring independent living skills. In this study, the Vineland Adaptive Behavior Scale was used to classify 118 hearing-impaired persons in groups based on their ability to be trained in independent living skills. Cluster analysis was used to group the subjects according to four domains: communication, daily living, socialization, and maladaptive behavior. The results indicate that the behavior scale can be used to classify hearing-impaired persons according to their ability to acquire independent living skills. The cluster analysis resulted in three groups. The persons in the lowest group did not have the most severe hearing losses, but they were more likely to have additional handicaps. This suggests that additional handicaps may be more important than degree of hearing loss in determining whether hearing-impaired persons can acquire independent living skills.


Cardiac rehabilitation in a family practice setting.
In January 1978, a cardiac rehabilitation program was begun at Fort Ord, California. The program is unique in being designed and run by family physicians. In the Medical Intensive Care Unit, the patient with a myocardial infarction is started on a graduated exercise program and a structured course concerning heart disease. Eight weeks after the infarction, the patient is asked to join an out-patient exercise class meeting three times a week. The patient's progress is followed by serial treadmill and blood tests. After training for six months, the patients have shown an increase in exercise tolerance and a decrease in incidence of readmission for cardiac disease. Most importantly, the patients have become actively involved in their own treatment.


Randomized multicenter trial on the effect of radiotherapy for plantar Fasciitis (painful heel spur) using very low doses--a study protocol.
A lot of retrospective data concerning the effect of radiotherapy on the painful heel spur (plantar fasciitis) is available in the literature. Nevertheless, a randomized proof of this effect is still missing. Thus, the GCGBD (German cooperative group on radiotherapy for benign diseases) of the DEGRO (German Society for Radiation Oncology) decided to start a randomized multicenter trial in order to find out if the effect of a conventional total dose is superior compared to that of a very low dose. In a prospective, controlled and randomized phase III trial two radiotherapy schedules are to be compared:standard arm: total dose 6.0 Gy in single fractions of 1.0 Gy applied twice a weekexperimental arm: total dose 0.6 Gy in single fractions of 0.1 Gy applied twice a week (acting as a placebo)Patients aged over 40 years who have been diagnosed clinically and radiologically to be suffering from a painful heel spur for at least six months can be included. Former trauma, surgery or radiotherapy to the heel are not allowed nor are patients with a severe psychiatric disease or women during pregnancy and breastfeeding. According to the statistical power calculation 100 patients have to be enrolled into each arm. After having obtaining a written informed consent a patient is randomized by the statistician to one of the arms mentioned above. After radiotherapy, the patients are seen first every six weeks, then regularly up to 48 months after therapy, they additionally receive a questionnaire every six weeks after the follow-up examinations. The effect is measured using several target variables (scores): Calcaneodynia-score according to Rowe et al., SF-12 score, and visual analogue scale of pain. The most important endpoint is the pain relief three months after therapy. Patients with an inadequate result are offered a second radiotherapy series applying the standard dose (equally in both arms). This trial protocol has been approved by the expert panel of the DEGRO as well as by the Ethics committee of the Saarland Physicians' Chamber. The trial is supported by a HOMFOR grant (Saarland University Research Grant). Current controlled trials ISRCTN94220918.


Assessment of myocardial perfusion by videodensitometry in the canine model.
Assessment of the functional severity of coronary stenoses has become increasingly important as the intrinsic limitations of coronary angiography have been documented. Videodensitometric coronary flow reserve has been proposed as a means to assess the physiologic significance of a coronary stenosis in humans. This study compared videodensitometric assessment of coronary flow with microsphere quantitation in the closed chest canine model. In five dogs, flow rates were assessed at baseline, after vasodilation with adenosine, after vasoconstriction with vasopressin and during rapid cardiac pacing. The videodensitometric peak density, time to one-half peak density and washout time (time from peak to one-half peak density) were compared at each flow state with flow assessed by microsphere injection. Reproducibility of videodensitometric measurements from two different coronary injections during the same flow state was best with peak density (r = 0.94). Videodensitometric flow ratios (flow state under study to flow at rest) using peak density demonstrated a fair correlation with flow ratios by microsphere (r = 0.81). There was poor correlation between flow ratios when time to one-half peak or washout time was used. Videodensitometric flow measurements used in vivo to assess a wide range of drug-induced coronary flows may not accurately reflect coronary flow measured by microsphere.


An outbreak of cutaneous abscesses caused by Panton-Valentine leukocidin-producing methicillin-susceptible Staphylococcus aureus among gold mine workers, South Africa, November 2017 to March 2018.
We aimed to describe an outbreak of cutaneous abscesses caused by Panton-Valentine leukocidin (PVL)-producing methicillin-susceptible Staphylococcus aureus (MSSA) among gold mine workers. In February 2018, we retrospectively reviewed a random sample of 50 medical records from 243 cases and conducted face-to-face interviews using a structured questionnaire. Pus aspirates were sent to the National Institute for Communicable Diseases from prospectively-identified cases (November 2017-March 2018). Nasopharyngeal swabs were collected during a colonisation survey in February 2018. Staphylococcus aureus isolates were screened with a conventional PCR for lukS/F-PV. Pulsed-field gel electrophoresis (PFGE) was performed to determine the genetic relatedness among the isolates. A sample of isolates were selected for whole genome sequencing (WGS). We conducted an assessment on biological risks associated with mining activities. From January 2017 to February 2018, 10% (350/3582) of mine workers sought care for cutaneous abscesses. Forty-seven medical files were available for review, 96% were male (n = 45) with a mean age of 43 years (SD = 7). About 52% (24/46) were involved in stoping and 28% (13/47) worked on a particular level. We cultured S. aureus from 79% (30/38) of cases with a submitted specimen and 14% (12/83) from colonisation swabs. All isolates were susceptible to cloxacillin. Seventy-one percent of S. aureus isolates (30/42) were PVL-PCR-positive. Six PFGE clusters were identified, 57% (21/37) were closely related. WGS analysis found nine different sequence types. PFGE and WGS analysis showed more than one cluster of S. aureus infections involving closely related isolates. Test reports for feed and product water of the mine showed that total plate counts were above the limits of 1000 cfu/ml, coliform counts > 10 cfu/100 ml and presence of faecal coliforms. Best practices were poorly implemented as some mine workers washed protective clothing with untreated water and hung them for drying at the underground surface. PVL-producing MSSA caused an outbreak of cutaneous abscesses among underground workers at a gold mining company. To our knowledge, no other outbreaks of PVL-producing S. aureus involving skin and soft tissue infections have been reported in mining facilities in South Africa. We recommend that worker awareness of infection prevention and control practices be strengthened.


Inorganic pyrophosphate is located primarily in the mitochondria of the hepatocyte and increases in parallel with the decrease in light-scattering induced by gluconeogenic hormones, butyrate and ionophore A23187.
1. The effects of a variety of hormones on the PPi content and light-scattering of isolated rat liver cells was studied. 2. The basal PPi content was about 130 pmol/mg of cell protein, and increased after hormone addition, in parallel with a decrease in light-scattering which we have observed previously [Quinlan, Thomas, Armston & Halestrap (1983) Biochem. J. 214, 395-404]. 3. The mean increases in PPi content with the agonists shown (as pmol/mg of protein) were: 0.1 microM-glucagon, 25; 20 microM-phenylephrine, 30; 25 nM-vasopressin, 127; glucagon + phenylephrine, 115; glucagon + vasopressin, 382; 100 microM-ADP, 50; 15 microM-A23187, 72; 1 mM-butyrate, 80. 4. In the absence of extracellular Ca2+, vasopressin had little effect on either the PPi content or the light-scattering of hepatocytes. 5. The magnitude of the increase in PPi content correlated with that of the decrease in light-scattering irrespective of the stimulating agent, provided that the PPi did not exceed 300 pmol/mg of protein. Above this value little additional change in light-scattering was observed. 6. Subcellular fractionation showed that over 90% of the cellular PPi was intramitochondrial in both control and stimulated cells. 7. The data support the conclusions of previous experiments using isolated liver mitochondria [Davidson & Halestrap (1987) Biochem. J. 246, 715-723] that hormones increase the mitochondrial matrix volume through a Ca2+-induced rise in matrix [PPi]. 8. It is further proposed that this increase in mitochondrial [PPi] allows entry of ADP into the mitochondria in exchange for PPi and is therefore responsible for the increase in total mitochondrial adenine nucleotides observed after hormone treatment.


Derailing the aspartate pathway of Mycobacterium tuberculosis to eradicate persistent infection.
A major constraint for developing new anti-tuberculosis drugs is the limited number of validated targets that allow eradication of persistent infections. Here, we uncover a vulnerable component of Mycobacterium tuberculosis (Mtb) persistence metabolism, the aspartate pathway. Rapid death of threonine and homoserine auxotrophs points to a distinct susceptibility of Mtb to inhibition of this pathway. Combinatorial metabolomic and transcriptomic analysis reveals that inability to produce threonine leads to deregulation of aspartate kinase, causing flux imbalance and lysine and DAP accumulation. Mtb's adaptive response to this metabolic stress involves a relief valve-like mechanism combining lysine export and catabolism via aminoadipate. We present evidence that inhibition of the aspartate pathway at different branch-point enzymes leads to clearance of chronic infections. Together these findings demonstrate that the aspartate pathway in Mtb relies on a combination of metabolic control mechanisms, is required for persistence, and represents a target space for anti-tuberculosis drug development.


Polyethylenimine Coated Graphene Oxide Nanoparticles for Targeting Mitochondria in Cancer Cells.
Mitochondrion, the powerhouse of the cells, controls bioenergetics, biosynthesis, metabolism, and signaling. Consequently, it has become an unorthodox target for cancer therapeutics. However, specific targeting of mitochondria into subcellular milieu in cancer cells remains a major challenge. To address this, we have engineered polyethylenimine cloaked positively charged self-assembled graphene oxide nanoparticle (PEI-GTC-NP) comprising topotecan and cisplatin concurrently. These PEI-GTC-NPs effectively homed into mitochondria in HeLa cervical cancer cells at 6 h and impaired mitochondria leading to reactive oxygen species generation followed by remarkably improved cancer cell death. This platform can be used for specific subcellular organelle targeting for future cancer therapy.


Contactless micromanipulation of small particles by an ultrasound field excited by a vibrating body.
A method is presented to position and displace micron-sized particles of a diameter between 10 and 100 microm without contact to solid instruments. An ultrasound field is utilized for this purpose. It is excited in a fluid-filled gap between a harmonically vibrating body and a rigid plane surface of an arbitrary other body, e.g., an object slide or a wafer. In this ultrasound field a force field is established, which acts on the particles suspended in the fluid and moves them to certain positions. The advantage of the method is that it is possible to manipulate single particles or many particles in parallel on any surface, for example, on a structured wafer. Theoretical calculations of the force field and experimental results including three principles to displace particles with micrometer accuracy are shown. The method might be used for microassembly or cell manipulation and treatment.


The prostate cancer detection rates of CEUS-targeted versus MRI-targeted versus systematic TRUS-guided biopsies in biopsy-naïve men: a prospective, comparative clinical trial using the same patients.
The current standard for Prostate Cancer (PCa) detection in biopsy-naïve men consists of 10-12 systematic biopsies under ultrasound guidance. This approach leads to underdiagnosis and undergrading of significant PCa while insignificant PCa may be overdiagnosed. The recent developments in MRI and Contrast Enhanced Ultrasound (CEUS) imaging have sparked an increasing interest in PCa imaging with the ultimate goal of replacing these "blind" systematic biopsies with reliable imaging-based targeted biopsies. In this trial, we evaluate and compare the PCa detection rates of multiparametric (mp)MRI-targeted biopsies, CEUS-targeted biopsies and systematic biopsies under ultrasound guidance in the same patients. After informed consent, 299 biopsy-naïve men will undergo mpMRI scanning and CEUS imaging 1 week prior to the prostate biopsy procedure. During the biopsy procedure, a systematic transrectal 12-core biopsy will be performed by one operator blinded for the imaging results and targeted biopsy procedure. Subsequently a maximum of 4 CEUS-targeted biopsies and/or 4 mpMRI-targeted biopsies of predefined locations determined by an expert CEUS reader using quantification techniques and an expert radiologist, respectively, will be taken by a second operator using an MRI-US fusion device. The primary outcome is the detection rate of PCa (all grades) and clinically significant PCa (defined as Gleason score ≥7) compared between the three biopsy protocols. This trial compares the detection rate of (clinically significant) PCa, between both traditional systematic biopsies and targeted biopsies based on predefined regions of interest identified by two promising imaging technologies. It follows published recommendations on study design for the evaluation of imaging guided prostate biopsy techniques, minimizing bias and allowing data pooling. It is the first trial to combine mpMRI imaging and advanced CEUS imaging with quantification. The Dutch Central Committee on Research Involving Human Subjects registration number NL52851.018.15, registered on 3 Nov 2015. Clinicaltrials.gov database registration number NCT02831920 , retrospectively registered on 5 July 2016.


Perceived stress, internal resources, and social support as determinants of mental health among young adults.
Mental health is a central determinant of quality of life. While psychiatric morbidity of populations has been studied extensively, the role of perceived stress, social support, and internal resources as determinant of health is still poorly understood. We surveyed 2000 randomly selected university students. Perceived stress was measured by the Brief Encounter Psychosocial Instrument, social support by the Duke-UNC Functional Social Support Questionnaire, internal resources (mastery and self-esteem) by a brief version of the Pearlin coping questionnaire. Linear regression models were used to explore the relationships between these variables and mental health, based on the SF-12 health survey. After two reminders, 1257 students answered the questionnaire. In bivariate analysis, mental health was negatively associated with stress and positively associated with internal resources and social support (all p-values < 0.001). In multiple regression analysis, internal resources were positively associated with mental health, and buffered the negative impact of stress on mental health. Internal resources and stress mediated the positive impact of social support on mental health. Our data confirm that perceived stress is an important risk factor for low mental health and suggest that mastery and self-esteem are important protective factors of mental health among young adults.


Comparison between colloid preload and crystalloid co-load in cesarean section under spinal anesthesia: a randomized controlled trial.
Hypotension is a common problem during spinal anesthesia for cesarean delivery. Intravenous fluid loading is used to correct preoperative dehydration and reduce the incidence and severity of hypotension. Different fluid regimens have been studied but colloid preload and crystalloid co-load have not been compared. In this randomized double-blind study, 210 patients scheduled for elective cesarean section under spinal anesthesia were randomly allocated to receive either 6% hydroxyethyl starch 130/0.4 500 mL before spinal anesthesia (colloid preload) or Ringer's acetate solution 1000 mL administered rapidly starting with intrathecal injection (crystalloid co-load). Maternal hypotension (systolic blood pressure <80% of baseline or <90 mmHg) and severe hypotension (systolic blood pressure <80 mmHg) were treated with 5 and 10mg ephedrine boluses, respectively. The primary outcome was the incidence of hypotension. Secondary outcomes included the incidence of severe hypotension, total ephedrine dose, nausea and vomiting and neonatal outcome assessed by Apgar scores and umbilical artery blood gas analysis. Data analysis was performed on 205 patients; 103 in the colloid preload group and 102 in the crystalloid co-load group. There were no significant differences in the incidence of hypotension (52.4% vs. 42.2%; P=0.18) or severe hypotension (15.5% vs. 9.8%; P=0.31) between colloid preload and crystalloid co-load groups, respectively. The median [range] ephedrine dose was 5 [0-45]mg in the colloid preload group and 0 [0-35]mg in the crystalloid co-load group (P=0.065). There were no significant differences in maternal nausea or vomiting or neonatal outcomes between groups. The use of 1000 mL crystalloid co-load has similar effect to 500 mL colloid preload in reducing the incidence of hypotension after spinal anesthesia for elective cesarean delivery. Neither technique can totally prevent hypotension and should be combined with vasopressor use.


Fabrication and characterization of whispering-gallery-mode resonators made of polymers.
High-quality whispering-gallery-mode resonators made of polymethylmethacrylate (PMMA) are fabricated by simple mechanical turning and polishing according to a technique used by Ilchenko et al. to produce crystalline whispering-gallery-mode resonators with high quality factors (Q-factors). The high-Q PMMA resonators are investigated in two wavelength regimes: in the near infrared between the wavelengths 1470 and 1580 nm and at the wavelength 635 nm. The Q-factor in the infrared regime is limited by material absorption to 3 x 10(5) At 635 nm the Q-factor is limited by surface scattering only and reaches 4 x 10(7), which is a new record for polymers.


[Content of arachidonic acid metabolites in blood and saliva of children with bronchial asthma].
The rise of the thromboxane B2, leukotriene B4 and prostaglandin F2a concentration in the blood and saliva of children was revealed during the attack of the bronchial asthma. At the same time the content of the prostaglandin E2 and prostacyclin in these biological fluids was reduced. The level of the eicosanoids in the examined liquids was correlated with the severity of bronchial asthma proceeding and with the adrenal glands function, which activity was also reduced.


Antiviral effects of artesunate on JC polyomavirus replication in COS-7 cells.
The human JC polyomavirus (JCPyV) causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). A growing number of patients with induced or acquired immunosuppression are at risk for infection, and no effective antiviral therapy is presently available. The widely used antimalarial drug artesunate has shown broad antiviral activity in vitro but limited clinical success. The aim of this study was to investigate the effect of artesunate on JCPyV replication in vitro. The permissivity for JCPyV MAD-4 was first compared in four cell lines, and the monkey kidney cell line COS-7 was selected. Artesunate caused a concentration-dependent decrease in the extracellular JCPyV DNA load 96 h postinfection, with a 50% effective concentration (EC50) of 2.9 μM. This effect correlated with a decreased expression of capsid protein VP1 and a reduced release of infectious viral progeny. For concentrations of <20 μM, transient reductions in cellular DNA replication and proliferation were seen, while for higher concentrations, some cytotoxicity was detected. A selective index of 16.6 was found when cytotoxicity was calculated based on cellular DNA replication in the mock-infected cells, but interestingly, cellular DNA replication in the JCPyV-infected cells was more strongly affected. In conclusion, artesunate is efficacious in inhibiting JCPyV replication at micromolar concentrations, which are achievable in plasma. The inhibition at EC50 probably reflects an effect on cellular proteins and involves transient cytostatic effects. Our results, together with the favorable distribution of the active metabolite dihydroartemisinin to the central nervous system, suggest a potential use for artesunate in patients with PML.