Testicular rupture following rubber bullet trauma case report.
Following civil unrest during 2020, physicians began to notice a variety of injuries resulting from crowd control weapons. While prior research emphasized ocular trauma, genitourinary complications of injuries have yet to be investigated. A previously healthy 27-year-old male presented to the emergency department due to sudden onset of severe left testicular pain following rubber bullet trauma. Physical exam showed extreme tenderness, abrasion, contusion, and edema of the left testicle with normal right testicle. Doppler ultrasound showed minimal blood flow to the superior pole with irregularity of the tunica albuginea. Surgery confirmed testicular rupture with a large tunical violation and extruded spermatic tubules. The testicle was thoroughly irrigated, non-viable tubules were debrided, and intraoperative ultrasound confirmed restoration of blood flow. Patient was discharged and instructed to follow-up should he face any fertility concerns in the future. Current crowd control guidelines state projectiles should be aimed at the lower abdomen or extremities; however, projectiles can cause testicular trauma which may lead to hypogonadism, infection, and psychological impact. Until there are changes to methods of crowd control, attendees should consider the use of athletic cups.


Palliative surgery versus medical management for bowel obstruction in ovarian cancer.
Ovarian cancer is the sixth most common cancer among women and is usually diagnosed at an advanced stage. Bowel obstruction is a common feature of advanced or recurrent ovarian cancer. Patients with bowel obstruction are generally in poor physical condition with a limited life expectancy. Therefore, maintaining their QoL with effective symptom control is the main purpose of the management of bowel obstruction. To compare the effectiveness and safety of palliative surgery (surgery performed to control the cancer, reduce symptoms and improve quality of life for those whose cancer is not able to be entirely removed) and medical management for bowel obstruction in women with ovarian cancer. We searched the Cochrane Gynaecological Cancer Group Trials Register, The Cochrane Central Register of Controlled trials (CENTRAL), Issue 1 2009, MEDLINE and EMBASE up to February 2009. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. Studies that compared palliative surgery and medical interventions, in adult women diagnosed with ovarian cancer who had either full or partial obstruction of the bowel. Randomised controlled trials (RCTs) and non-RCTs that used multivariable statistical adjustment for baseline case mix were eligible. Two review authors independently assessed whether potentially relevant studies met the inclusion criteria, abstracted data and assessed risk of bias. One non-randomised study was identified so no meta-analyses were performed. The search strategy identified 183 unique references of which 22 were identified as being potentially eligible on the basis of title and abstract. Only one study met our inclusion criteria and was included in the review. It analysed retrospective data for 47 women who received either palliative surgery (n = 27) or medical management with Octreotide (n = 20) and reported overall survival and perioperative mortality and morbidity. Women with poor performance status were excluded from surgery. Although six (22%) women who received surgery had serious complications of the operation and three (11%) died of complications, multivariable analysis found that women who received surgery had significantly (p < 0.001) better survival than women who received Octreotide, after adjustment for important prognostic factors. However, the magnitude of this effect was not reported. Quality of life (QoL) was not reported and adverse events were incompletely documented. We found only low quality evidence comparing palliative surgery and medical management for bowel obstruction in ovarian cancer. Therefore we are unable to reach definite conclusions about the relative benefits and harms of the two forms of treatment, or to identify sub-groups of women who are likely to benefit from one treatment or the other. However, there is weak evidence in support of surgical management to prolong survival.


Efficacy of a temperature-sensitive modified-live bovine herpesvirus type-1 vaccine against abortion and stillbirth in pregnant heifers.
To evaluate the efficacy of a commercially available temperature-sensitive modified-live bovine herpesvirus type-1 (BHV-1) vaccine against BHV-1 challenge-induced abortion and stillbirth. Prospective randomized control trial. 20 cycling, nonpregnant, BHV-1 seronegative heifers of various breeds and weights, 12 to 15 months old. Heifers were randomly assigned to a vaccinate (n = 10) or nonvaccinate control (n = 10) group. Seventeen to 26 days after members of the vaccinate group received a second dose of vaccine, all heifers were artificially inseminated. Heifers were challenged intravenously with Cooper strain BHV-1 between days 177 and 187 of gestation. Aborted fetuses and stillborn calves were necropsied, and tissues collected for histologic examination and virus isolation. Heifers, calves, and fetuses were tested for BHV-1 antibody throughout the study. The difference in number of abortions or stillbirths between vaccinated heifers (1/10) and control heifers (10/10) was significant (P < 0.003). Seven of 10 control heifers had a virus neutralization antibody titer to BHV-1 at abortion or stillbirth that declined or remained unchanged from their titer at a previous serologic evaluation (7 to 66 days earlier). Prebreeding vaccination of replacement heifers with modified-live BHV-1 vaccine provides fetal protection at 6 months of gestation (7 months after vaccination) and appears to be a reasonable precaution to control economic losses associated with BHV-1 infection. Abortions induced by BHV-1 are not necessarily associated with rising or markedly high virus neutralization antibody titers. These titers should be used cautiously when assessing the role of BHV-1 in bovine abortion and stillbirth.


Response rates to surveys with self-addressed, stamped envelopes versus a self-addressed label.
Return rates were studied for a survey on the perceived professional preparation of therapeutic recreation specialists by directors of college and university recreational therapy programs. Specifically, returns for surveys with self-addressed, stamped return envelopes enclosed were compared to those with self-adhering return address labels. Of the 75 surveys sent with a self-addressed, stamped return envelope, 42 responses (56%) were returned at a cost of $2.58 per respondent. Of the 72 surveys sent with a self-adhering return address label 43 responses (59.7%) were returned at a cost of $1.56 per response. While there was no significant difference in return rates, the self-adhering return address label was more cost effective than the self-addressed, stamped, return envelopes.


Pathways of glutamate catabolism among Fusobacterium species.
Glutamate is a major source of energy for Fusobacterium species but its mode of catabolism has not hitherto been elucidated. Cell suspensions of F. nucleatum and F. varium, as representative species from the oral cavity and gastrointestinal tract, respectively, both decarboxylated position-labelled glutamate but by different pathways. 14CO2 was released only from C-5 by F. nucleatum whereas F. varium decarboxylated glutamate at either C-1 or C-5. In both species, 2 mols of glutamate fermented yielded 2 mols of acetate and 1 mol of butyrate, suggesting the possibility of three metabolic pathways: the 2-oxoglutarate, mesaconate and 4-aminobutyrate pathways. Enzymes representative of the three pathways were assayed for in cell-free extracts of fusobacteria. All species tested possessed high levels of both glutamate dehydrogenase and 2-oxoglutarate reductase, indicating the presence of the 2-oxoglutarate pathway. Enzymes representative of the mesaconate pathway were detected in F. sulci, F. ulcerans, F. mortiferum and F. varium, while the latter two species also possessed the 4-aminobutyrate pathway. The pathways of glutamate catabolism therefore bore no relationship to the site of isolation of the fusobacteria tested but instead correlated with their chemotaxonomic properties. Thus, F. varium, F. mortiferum, F. ulcerans and F. sulci, which possess a peptidoglycan structure based on diaminopimelic acid, have either two or three pathways for glutamate catabolism whereas F. nucleatum and other species that have a lanthionine-based murein metabolized glutamate solely by the 2-oxoglutarate pathway.


A parameter optimization method for radial basis function type models.
This paper considers the nonlinear systems modeling problem for control. A structured nonlinear parameter optimization method (SNPOM) adapted to radial basis function (RBF) networks and an RBF network-style coefficients autoregressive model with exogenous variable model parameter estimation is presented. This is an off-line nonlinear model parameter optimization method, depending partly on the Levenberg-Marquardt method for nonlinear parameter optimization and partly on the least-squares method using singular value decomposition for linear parameter estimation. When compared with some other algorithms, the SNPOM accelerates the computational convergence of the parameter optimization search process of RBF-type models. The usefulness of this approach is illustrated by means of several examples.


Disability Severity and Home-Based Care Quality in Older Adults: The Mediating Effects of Social Support and Caregiver Competence.
The lack of adequate medical care, healthcare, and older adult care in remote, low-income, rural Kazakh areas of China is a particular concern that should be prioritized for improvement. This study was designed to explore the relationship between the variables of disability severity, social support, and caregiver competence and the quality of home-based care in a population of Kazakh older adults with disabilities and to analyze the path between severity of disability and quality of home-based care in this population. A cross-sectional survey was conducted on 335 Kazakh older adults with disabilities living in Xinjiang, China, and their primary informal caregivers. Disability severity was assessed using the Activities of Daily Living Scale, caregiver competence was assessed using the Family Caregiver Task Inventory, social support was assessed using the Social Support Rating Scale, and home-based care quality was assessed using the Family Caregiving Consequences Inventory Scale. Path analysis was used to check the effects of other variables on the quality of home-based care. Significant correlations were found among disability severity, caregiver competence, social support, and home-based care quality. Disability severity was shown to have a 29.28% direct effect on home-based care quality and a 70.72% indirect effect through social support and caregiver competence. The results of this study confirm that better social support and caregiver competence improves the quality of home-based care available to older adults with disabilities. Policymakers should give priority to improving the quality of care provided to community-dwelling older adults with severe disabilities. Furthermore, health management departments should provide informal caregiver training that teaches care and rehabilitation knowledge and skills to improve the competencies of caregivers.


[Dietary iron intake and deficiency in elite women volleyball players].
Volleyball practice requires repeated impacts on arms and feet caused by vertical jumps, falls, auctions, sudden and rapid changes of direction, which is why might raise us problems in the metabolism of iron (Fe) and the recommended intake of 18 mg/day (in the women in general), is not sufficient to meet the needs of the players of volleyball female (JVF). We analyzed the FS and IST of 10 JVF a team of Spanish SuperLeague (26.6 ± 5.9 years and height 178.05 ± 8.7 cm) in two moments of the season: Week 0 (pre-start of preseason) and week 11 (after 11 weeks of training and 6 games of the regular season). Also calculated Fe intake in this period with consumption frequency questionnaire developed and tested with food dietary records of 7 days. We observed that an intake of 25.8 mg/day of dietary Fe is not sufficient to prevent 30% of the JVF suffer pre-latent iron deficiency and 20% latent deficit (pre-anemia). It could be recommended conducting periodic blood analytical and a food education, teaching which foods containing a high content of Fe-type heme, and the factors that can interfere with absorption.


Endogenous vasopressin affects postural control of blood pressure in man.
1. Six healthy volunteers received intravenous infusions of isotonic (0.9% NaCl) and hypertonic (3% NaCl) saline on separate days. There were no significant changes in blood pressure or forearm blood flow, despite an increase in plasma arginine vasopressin (AVP) during hypertonic saline. 2. Immediately and 10 min after passive tilting to 50 degrees, mean forearm blood flow fell by 17.1 and 14.3% compared with the values in the supine position during isotonic saline and by 40.3 and 43.3% during hypertonic saline. Forearm vascular resistance rose by 23.6 and 17.8% with isotonic saline and by 80.2 and 88.2% with hypertonic saline for the two readings in the tilted compared with the supine position. 3. Tilting was associated with a 14.9 and 12.1% rise in diastolic blood pressure immediately and 10 min after assuming this position during hypertonic saline, and a rise of 6.4% in mean arterial pressure. 4. The results from this study are similar to those obtained previously, when small amounts of AVP were infused. They provide further evidence that AVP may have a physiological role in the postural regulation of blood pressure.


A Genotype-Phenotype Correlation Study of SHV β-Lactamases Offers New Insight into SHV Resistance Profiles.
The SHV β-lactamases (BLs) have undergone strong allele diversification that has changed their substrate specificities. Based on 147 NCBI entries for SHV alleles, in silico mathematical models predicted 5 positions as relevant for the β-lactamase inhibitor (BLI)-resistant (2br) phenotype, 12 positions as relevant for the extended-spectrum BL (ESBL) (2be) phenotype, and 2 positions as related solely to the narrow-spectrum (2b) phenotype. These positions and six additional positions described in other studies (including one promoter mutation) were systematically substituted and investigated for their substrate specificities in a BL-free Escherichia coli background, representing, to our knowledge, the most comprehensive substrate and substitution analysis for SHV alleles to date. An in vitro analysis confirmed the essentiality of positions 238 and 179 for the 2be phenotype and of position 69 for the 2br phenotype. The E240K and E240R substitutions, which do not occur alone in known 2br SHV variants, led to a 2br phenotype, indicating a latent BLI resistance potential of these substitutions. The M129V, A234G, S271I, and R292Q substitutions conferred latent resistance to cefotaxime. In addition, seven positions that were found not always to be associated with the ESBL phenotype resulted in increased resistance to ceftaroline. We also observed that coupling of a strong promoter (IS26) to an A146V mutant with the 2b phenotype resulted in highly increased resistance to BLIs, cefepime, and ceftaroline but not to third-generation cephalosporins, indicating that SHV enzymes represent an underestimated risk for empirical therapies that use piperacillin-tazobactam or cefepime to treat different infectious diseases caused by Gram-negative bacteria.


CD4+ T cells specific for glycoprotein B from cytomegalovirus exhibit extreme conservation of T-cell receptor usage between different individuals.
Antigen-specific CD8(+) cytotoxic T cells often demonstrate extreme conservation of T-cell receptor (TCR) usage between different individuals, but similar characteristics have not been documented for CD4(+) T cells. CD4(+) T cells predominantly have a helper immune role, but a cytotoxic CD4(+) T-cell subset has been characterized, and we have studied the cytotoxic CD4(+) T-cell response to a peptide from human cytomegalovirus glycoprotein B presented through HLA-DRB*0701. We show that this peptide elicits a cytotoxic CD4(+) T-cell response that averages 3.6% of the total CD4(+) T-cell repertoire of cytomegalovirus-seropositive donors. Moreover, CD4(+) cytotoxic T-cell clones isolated from different individuals exhibit extensive conservation of TCR usage, which indicates strong T-cell clonal selection for peptide recognition. Remarkably, this TCR sequence was recently reported in more than 50% of cases of CD4(+) T-cell large granular lymphocytosis. Immunodominance of cytotoxic CD4(+) T cells thus parallels that of CD8(+) subsets and suggests that cytotoxic effector function is critical to the development of T-cell clonal selection, possibly from immune competition secondary to lysis of antigen-presenting cells. In addition, these TCR sequences are highly homologous to those observed in HLA-DR7(+) patients with CD4(+) T-cell large granular lymphocytosis and implicate cytomegalovirus as a likely antigenic stimulus for this disorder.


Isotropic fractionator: a simple, rapid method for the quantification of total cell and neuron numbers in the brain.
Stereological techniques that estimate cell numbers must be restricted to well defined structures of isotropic architecture and therefore do not apply to the whole brain or to large neural regions. We developed a novel, fast, and inexpensive method to quantify total numbers of neuronal and non-neuronal cells in the brain or any dissectable regions thereof. It consists of transforming highly anisotropic brain structures into homogeneous, isotropic suspensions of cell nuclei, which can be counted and identified immunocytochemically as neuronal or non-neuronal. Estimates of total cell, neuronal, and non-neuronal numbers can be obtained in 24 h and vary by <10% among animals. Because the estimates obtained are independent of brain volume, they can be used in comparative studies of brain-volume variation among species and in studies of phylogenesis, development, adult neurogenesis, and pathology. Applying this method to the adult rat brain, we show, for example, that it contains approximately 330 million cells, of which 200 million are neurons, and almost 70% of these are located in the cerebellum alone. Moreover, contrary to what is commonly assumed in the literature, we show that glial cells are not the majority in the rat brain.


[Interpretation of varicella serology in pregnancy].
Chickenpox during pregnancy may result in a severe, in some cases fatal, generalized infection of the newborn. Pregnant women with unknown Varicella-Zoster-virus (VZV) immunity, who have had contact with an individual infected by chickenpox, should be tested immediately for specific antibodies to VZV. The interpretation of test results may be difficult under certain circumstances. This problem is discussed using individual case studies.


Live-Cell Imaging at the Nanoscale with Bioconjugatable and Photoactivatable Fluorophores.
Optical diffraction fundamentally limits the spatial resolution of conventional fluorescence images to length scales that are, at least, 2 orders of magnitude longer than the dimensions of individual molecules. As a result, the development of innovative probes and imaging schemes to overcome diffraction is very much needed to enable the investigation of the fundamental factors regulating cellular functions at the molecular level. In this context, the chemical synthesis of molecular constructs with photoactivatable fluorescence and the ability to label subcellular components of live cells can have transformative implications. Indeed, the fluorescence of the resulting assemblies can be activated with spatiotemporal control, even in the intracellular environment, to permit the sequential localization of individual emissive labels with precision at the nanometer level and the gradual reconstruction of images with subdiffraction resolution. The implementation of these operating principles for subdiffraction imaging, however, is only possible if demanding photochemical and photophysical requirements to enable photoactivation and localization as well as stringent structural requisites to allow the covalent labeling of intracellular targets in live cells are satisfied. Because of these complications, only a few synthetic photoactivatable fluorophores with appropriate performance for live-cell imaging at the nanoscale have been developed so far. Significant synthetic efforts in conjunction with spectroscopic analyses are still very much needed to advance this promising research area further and turn photoactivatable fluorophores into the imaging probes of choice for the investigation of live cells.


Competition Sensing Changes Antibiotic Production in Streptomyces.
One of the most important ways that bacteria compete for resources and space is by producing antibiotics that inhibit competitors. Because antibiotic production is costly, the biosynthetic gene clusters coordinating their synthesis are under strict regulatory control and often require "elicitors" to induce expression, including cues from competing strains. Although these cues are common, they are not produced by all competitors, and so the phenotypes causing induction remain unknown. By studying interactions between 24 antibiotic-producing strains of streptomycetes, we show that strains commonly inhibit each other's growth and that this occurs more frequently if strains are closely related. Next, we show that antibiotic production is more likely to be induced by cues from strains that are closely related or that share secondary metabolite biosynthetic gene clusters (BGCs). Unexpectedly, antibiotic production is less likely to be induced by competitors that inhibit the growth of a focal strain, indicating that cell damage is not a general cue for induction. In addition to induction, antibiotic production often decreases in the presence of a competitor, although this response was not associated with genetic relatedness or overlap in BGCs. Finally, we show that resource limitation increases the chance that antibiotic production declines during competition. Our results reveal the importance of social cues and resource availability in the dynamics of interference competition in streptomycetes.IMPORTANCE Bacteria secrete antibiotics to inhibit their competitors, but the presence of competitors can determine whether these toxins are produced. Here, we study the role of the competitive and resource environment on antibiotic production in Streptomyces, bacteria renowned for their production of antibiotics. We show that Streptomyces cells are more likely to produce antibiotics when grown with competitors that are closely related or that share biosynthetic pathways for secondary metabolites, but not when they are threatened by competitor's toxins, in contrast to predictions of the competition sensing hypothesis. Streptomyces cells also often reduce their output of antibiotics when grown with competitors, especially under nutrient limitation. Our findings highlight that interactions between the social and resource environments strongly regulate antibiotic production in these medicinally important bacteria.


Cognitive impairment and potential biological and psychological correlates of neuropsychological performance in recently orchiectomized testicular cancer patients.
The aim of this study was to determine the prevalence of cognitive impairment (CI) in newly diagnosed and orchiectomized testicular cancer (TC) patients prior to systemic treatment, and to explore biological and psychological correlates. Sixty-six TC patients were compared with 25 healthy men on neuropsychological tests and a measure of cognitive complaints. CI status and a global composite score (representing overall neuropsychological performance) were calculated for each participant. Possible psychological (depression, anxiety, stress, and post-traumatic stress symptoms) and biological (cortisol, IL-6, TNF-α, and CRP) correlates and predictors of patients' cognitive functioning were explored. TC patients had lower scores on 6 out of 11 neuropsychological outcomes (p < 0.01) in processing speed, attention, and working memory, verbal learning and memory, and verbal fluency. Prevalence of CI among TC patients was 58%, significantly exceeding the frequency in healthy men (p < 0.01). Patients' cortisol levels predicted overall neuropsychological performance (p = 0.04). Cognitive complaints were associated with IL-6 (p = 0.02) and all psychological distress measures (p < 0.001). The prevalence of CI in recently orchiectomized TC patients was unexpectedly high with patients performing more poorly than healthy controls on a majority of neuropsychological outcomes. Cortisol is a potential predictor of neuropsychological performance in TC patients prior to cytotoxic treatment.


Machine learning-based model for predicting major adverse cardiovascular and cerebrovascular events in patients aged 65 years and older undergoing noncardiac surgery.
Few evidence-based prediction models have been developed for predicting major adverse cardiovascular and cerebrovascular events (MACCE) in patients aged 65 years or older undergoing noncardiac surgery. In this study, we aimed to analyze the risk factors for perioperative MACCE in patients aged 65 years or older undergoing noncardiac surgery and construct a prediction model. In this nested case-control study, a total of 342 Chinese patients who were aged ≥ 65 years and underwent medium- or high-risk noncardiac surgery in our hospital were included. There were 84 cases with MACCE (the MACCE group) and 258 without MACCE (the control group). Univariable logistic regression analysis was performed to identify the risk factors for MACCE. Least absolute shrinkage and selection operator (LASSO) regression was used to screen the variables. Nomogram was constructed using the selected variables. Machine learning methods, including Decision Tree, XGBoost, Support Vector Machine, K-nearest Neighbor, and Neural network, was used to establish, validate, and compare the performance of different prediction models. A prediction model based on nine variables, including age ≥ 85 years, history of ischemic chest pain, symptoms of decompensated heart failure, high-risk surgery, intraoperative minimum systolic blood pressure, postoperative systolic blood pressure, Cr levels over 2.0 mg/dL, left ventricular ejection fraction, and perioperative blood transfusion, was constructed. This LASSO logistic regression model showed good discriminatory ability to predict MACCE (area under the curve = 0.89; 95% confidence interval, 0.818 - 0.963) and fit to the test set (Hosmer-Lemeshow, χ2 = 7.4053, P = 0.4936). The decision curve analysis showed a positive net benefit of the new model. Compared with logistic regression model, the XGBoost model showed better prediction ability (area under the curve = 0.903). A preoperative prediction model based on five variables, including age ≥ 85 years, symptoms of decompensated heart failure, ischemic chest pain, high-risk type of surgery and Cr levels over 2.0 mg/dL was also constructed. This model showed good discriminatory ability to predict MACCE before surgery (area under the curve = 0.720 [95% CI, 0.591-0.848]. Both models compared with the modified RCRI score had improvement in reclassification. By analyzing Chinese patients aged ≥ 65 years undergoing medium- or high-risk noncardiac surgery, the risk factors for perioperative MACCE were identified. Then, simple prediction models were constructed and validated, which showed good prediction performance and may be used as a decision-making assistant tool for clinicians. These findings provide a basis for preventing and improving the perioperative management of MACCE.


Plasma levels of zinc, copper, copper/zinc ratio, and activity of carbonic anhydrase in equine piroplasmosis.
We have determined the plasma concentrations of copper, zinc, copper/zinc ratio, and carbonic anhydrase activity in horses infected with Babesia equi. The study was conducted in 14 horses with the disease and 10 healthy animals that served as controls. The infection was confirmed by the clinical manifestations of the disease and by Giemsa staining of thin blood smears showing the parasites inside red blood cells. The horses with piroplasmosis had lower plasma levels of zinc, elevated copper, and increased activity of carbonic anhydrase. Consequently, the copper/zinc ratio was also higher than in the healthy controls.


Detecting Eye Disease Using Vision Transformers Informed by Ophthalmology Resident Gaze Data.
We showcase two proof-of-concept approaches for enhancing the Vision Transformer (ViT) model by integrating ophthalmology resident gaze data into its training. The resulting Fixation-Order-Informed ViT and Ophthalmologist-Gaze-Augmented ViT show greater accuracy and computational efficiency than ViT for detection of the eye disease, glaucoma.Clinical relevance- By enhancing glaucoma detection via our gaze-informed ViTs, we introduce a new paradigm for medical experts to directly interface with medical AI, leading the way for more accurate and interpretable AI 'teammates' in the ophthalmic clinic.


Clinical and translational studies of a phase II trial of the novel oral Akt inhibitor perifosine in relapsed or relapsed/refractory Waldenstrom's macroglobulinemia.
Waldenström's macroglobulinemia (WM) is a rare, low-grade lymphoproliferative disorder. Based on preclinical studies, we conducted a phase II clinical trial testing the efficacy and safety of the Akt inhibitor perifosine in patients with relapsed/refractory WM. Thirty-seven patients were treated with oral perifosine (150 mg daily) for six cycles. Stable or responding patients were allowed to continue therapy until progression. The median age was 65 years (range, 44-82). The median number of prior therapy lines was two (range, one to five). Of the 37 patients, 4 achieved partial response (11%), 9 minimal response (24%), and 20 showed stable disease (54%). The median progression-free survival was 12.6 months. Additionally, beta2 microglobulin of >3.5 mg/dL was associated with poor event-free survival (P = 0.002). Perifosine was generally well tolerated; adverse events related to therapy were cytopenias (grade 3-4, 13%), gastrointestinal symptoms (grade 1-2, 81%), and arthritis flare (all grades, 11%). Translational studies using gene expression profiling and immunohistochemistry showed that perifosine inhibited pGSK activity downstream of Akt, and inhibited nuclear factor kappaB activity. Perifosine resulted in at least a minimal response in 35% of patients and a median progression-free survival of 12.6 months in patients with relapsed or relapsed/refractory WM, as well as in vivo inhibition of pGSK activity. The results of this study warrant further evaluation of perifosine in combination with rituximab or other active agents in patients with WM.


Plasticity versus canalization: population differences in the timing of shade-avoidance responses.
The reliability of environmental cues and costs of a fixed phenotype are two factors determining whether selection favors phenotypic plasticity or environmental specialization. This study examines the relationship between these two factors and the evolution of plant competitive strategies (plastic vs. fixed morphologies). In natural plant populations, shifts in light quality associated with foliar shade reliably indicate the presence of neighbors. These cues mediate plastic stem-elongation responses that often increase competitive ability and access to light. Using experimental light treatments (full sun, neutral shade, and foliar shade), genetic differences among populations of Abutilon theophrasti (velvetleaf) in average elongation and plasticity to foliar-shade cues were examined. Six populations, two from each of three site types (fields in continuous corn cultivation, fields undergoing corn-soy rotation, and weedy sites), were exposed to the light treatments at two stages in their life history. At the seedling stage, populations derived from cornfield sites exhibited higher, average elongation than populations from either rotating corn-soy fields or weedy areas. Because seedling elongation may delay shading of velvetleaf by corn, population differences may reflect adaptive responses to directional selection imposed by competitive conditions. However, the effects of simulated foliar shade on elongation were three times as great as the average population differences, and these comparatively higher levels of elongation were associated with an allocation cost. These results are consistent with the hypothesis that phenotypic plasticity may limit the evolution of specialists; reliable environmental cues enable individuals to facultatively adopt highly elongated, costly phenotypes in crowded patches while avoiding the costs of that phenotype in less crowded microsites. At later life-history stages, populations experiencing competition with corn exhibited lower plasticity to light quality than populations derived from weedy areas. Elongation at later nodes is maladaptive in cornfields because velvetleaf is ultimately incapable of overtopping corn; individuals that elongate therefore experience the cost of allocating to stems but fail to improve leaf exposure. The decreased responsiveness of cornfield populations to light quality is consistent with theoretical predictions in which reduced plasticity is favored when environmental cues fail to mediate an adaptive response.


Use of Corneal Topography in Pediatric Ophthalmology.
To introduce the topic of pediatric keratoconus, highlighting the importance of routine corneal topography and tomography in children and adolescents from predisposed groups. To attempt to ensure the early detection of keratoconus and its subclinical form, enabling early treatment, which brings better expected postoperative results. Material and methods: Using the corneal tomograph Pentacam AXL we examined children and adolescents with astigmatism equal or greater than 2 diopters (in at least one eye) and patients with at least one risk factor such as eye rubbing in the case of allergic pathologies, positive family history of keratoconus or certain forms of retinal dystrophy. In total, we included 231 eyes (116 patients), of which 54 were girls and 62 were boys. The Belin-Ambrósio deviation index parameter was evaluated, in which we classified a total of 41 eyes as subclinical keratoconus and 12 eyes as clinical keratoconus. Next, the corneal maps were evaluated individually, in which we included a total of 15 eyes as subclinical keratoconus and 6 eyes as clinical keratoconus. In our group, compared to the control group, subclinical and clinical keratoconus occurred most often in the group of patients with astigmatism and in the group of so-called "eye rubbers". After individual evaluation, keratoconus occurred more frequently in boys than in girls in our cohort. Most patients with keratoconus are diagnosed when there is a deterioration of visual acuity and changes on the anterior surface of the cornea. Corneal topography and tomography allows us to monitor the initial changes on the posterior surface of the cornea, and helps us to detect the subclinical form of keratoconus and the possibility of its early treatment. Therefore, it is important to determine which groups are at risk and groups in which corneal topography and tomography should be performed routinely.


Adhesion-related proteins E-cadherin, P-cadherin, CD44, and CD44v6, and antimetastatic protein nm23H1 in complete hydatidiform moles in relation to invasion potential.
Cell adhesion has an essential role in regulating metastasis, and loss of cell adhesion is a classic feature of invasion. There is currently a great deal of interest in the role of adhesion proteins and the antimetastatic protein nm23H1 in the progression of cancer. However, reports on the expression of these proteins in complete hydatidiform moles (CHMs) are limited. In the present study, expression of the adhesion molecules E-cadherin, P-cadherin, CD44, and CD44v6, and the antimetastatic protein nm23H1 was assessed in relation to the invasive potential of CHMs. This is the first report on the expression of these proteins in CHMs. Immunohistochemical assessment was carried out in CHMs (105 cases including 15 cases of invasive moles) and compared with that of gestational age-matched normal placentae (95 cases). The expression of the adhesion proteins ranged from mild to moderate intensity with a general down-regulation in the molar trophoblasts, the down-regulation in CD44 and CD44V6 being highly significant. No relation was, however, noticed with the invasiveness or the persistence of the disease. nm23H1 protein, on the other hand, was significantly down-regulated in the molar trophoblasts with none of the invasive lesions showing intense expression. The study thus suggests down-regulation of adhesion proteins, especially that of CD44 and CD44v6, to be an early step in the transformation to molar placenta with reduced expression of nm23H1 conferring an invasive potential to the trophoblasts.


How do general practices respond to a pandemic? Protocol for a prospective qualitative study of six Australian practices.
The COVID-19 pandemic has transformed healthcare systems worldwide. Primary care providers have been at the forefront of the pandemic response and have needed to rapidly adjust processes and routines around service delivery. The pandemic provides a unique opportunity to understand how general practices prepare for and respond to public health emergencies. We will follow a range of general practices to characterise the changes to, and factors influencing, modifications to clinical and organisational routines within Australian general practices amidst the COVID-19 pandemic. This is a prospective case study of multiple general practices using a participatory approach for design, data collection and analysis. The study is informed by the sociological concept of routines and will be set in six general practices in Melbourne, Australia during the 2020-2021 COVID-19 pandemic. General practitioners associated with the Monash University Department of General Practice will act as investigators who will shape the project and contribute to the data collection and analysis. The data will include investigator diaries, an observation template and interviews with practice staff and investigators. Data will first be analysed by two external researchers using a constant comparative approach and then later refined at regular investigator meetings. Cross-case analysis will explain the implementation, uptake and sustainability of routine changes that followed the commencement of the pandemic. Ethics approval was granted by Monash University (23950) Human Research Ethics Committees. Practice reports will be made available to all participating practices both during the data analysis process and at the end of the study. Further dissemination will occur via publications and presentations to practice staff and medical practitioners.


Prevalence and heritability of obsessive-compulsive spectrum and anxiety disorder symptoms: A survey of the Australian Twin Registry.
While past twin studies indicate moderate levels of heritability of "obsessive-compulsive related" and anxiety disorder symptoms, no single study has reported such estimates in the same twin population nor examined potential genetic sex differences. We assessed symptoms of obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, hypochondriasis, panic disorder, social phobia and generalized anxiety disorder in 2,495 adult twins (1,468 female). Prevalence estimates for the corresponding symptom measures were determined using empirically derived cut-off scores. Twin resemblance was assessed by Pearson correlations and biometrical model-fitting analyses, incorporating sex-specific effects, using OpenMx. Prevalence estimates ranged from 1.6% in the symptoms of generalized anxiety to 16.9% for social phobia. Female twins demonstrated significantly higher prevalence rates across all domains with the exception of obsessive-compulsive symptoms. Additive genetic factors accounted for a moderate proportion of the total liability to each symptom domain. Evidence suggesting qualitative genetic sex differences (i.e., distinct genetic influences between genders) was observed for body dysmorphic concern and panic symptoms, while quantitative differences were observed for hoarding and social phobia symptoms, indicating stronger heritability in females. Novel findings in this study include the observation of probable genetic sex differences in liability towards hoarding symptoms and dysmorphic concern, as well as the lack of such differences in hypochondriasis. The trend towards qualitative sex differences in panic symptoms has some intuitive appeal with regard to biological-experimental models of panic.


Fast high-resolution prospective motion correction for single-voxel spectroscopy.
To develop a fast high-resolution image-based motion correction method using spiral navigators with multislice-to-volume registration. A semi-LASER sequence was modified to include a multislice spiral navigator for prospective motion correction (∼305 ms including acquisition, processing, and feedback) as well as shim and frequency navigators for prospective shim and frequency correction (∼100 ms for each). MR spectra were obtained in the prefrontal cortex in five healthy subjects at 3 T with and without prospective motion and shim correction. The effect of key navigator parameters (number of slices, image resolution, and excitation flip angle) on registration accuracy was assessed using simulations. Without prospective motion and shim correction, spectral quality degraded significantly in the presence of voluntary motion. In contrast, with prospective motion and shim correction, spectral quality was improved (metabolite linewidth = 6.7 ± 0.6 Hz, SNR= 67 ± 9) and in good agreement with baseline data without motion (metabolite linewidth = 6.9 ± 0.9 Hz, SNR = 73 ± 9). In addition, there was no significant difference in metabolites concentrations measured without motion and with prospective motion and shim correction in the presence of motion. Simulations showed that the registration precision was comparable when using three navigator slices with 3 mm resolution and when using the entire volume (all slices) with 8 mm resolution. The proposed motion correction scheme allows fast and precise prospective motion and shim correction for single-voxel spectroscopy at 3 T. With 3 mm resolution, only a few navigator slices are necessary to achieve excellent motion correction performance.


A test of ecologically dependent postmating isolation between sympatric sticklebacks.
Ecological speciation occurs when reproductive isolation evolves ultimately as a result of divergent natural selection between populations inhabiting different environments or exploiting alternative resources. I tested a prediction of the ecological model concerning the fitness of hybrids between two young, sympatric species of threespine sticklebacks (Benthics and Limnetics). The two species are ecologically and morphologically divergent: the Benthic is adapted to feeding on invertebrates in the littoral zone of the lake whereas the Limnetic is adapted to feeding on zooplankton in the open water. The growth rate of two types of hybrids, the Benthic backcross and the Limnetic backcross, as well as both parent species, was evaluated in enclosures in both parental habitats in the lake. The use of backcrosses is ideal because a comparison of their growth rates in the two habitats estimates an ecologically dependent component of their fitness while controlling for any intrinsic genetic incompatibilities that may exist between the Benthic and Limnetic genomes. The backcross results revealed a striking pattern of ecological dependence: in the littoral zone, Benthic backcrosses grew at approximately twice the rate of Limnetic backcrosses, while in the open water, Limnetic backcrosses grew at approximately twice the rate of Benthic backcrosses. Such a reversal of relative fitness of the two cross-types in the two environments provides strong evidence that divergent natural selection has played a central role in the evolution of postmating isolation between Benthics and Limnetics. Although the rank order of growth rates of all cross-types in the littoral zone was Benthic > Benthic backcross > Limnetic backcross > Limnetic, neither backcross differed significantly from the parent from which it was mainly derived. Implications of this result are discussed in terms of ecological speciation and possible introgressive hybridization between the species. Results in the open water were less clear and were not fully consistent with the ecological model of speciation, mainly as a result of the low growth rate of Limnetics. However, analysis of the diet of the fish in the open water suggests that these enclosures may not have been fully successful at replicating the food regimes characteristic of this habitat.


[Approach and reconstruction in the operative treatment of tumors of the tongue, epiglottis, floor of the mouth and pharynx].
This paper explains a new way of a temporary splitting of the lower jaw and the reconstruction of the tongue and the floor of the mouth. The described way of the temporary splitting of the lower jaw allows to maintain the nerve and results in better suppositions for the reposition and osteosynthesis. For the reconstruction of the tongue and the floor of the mouth, an island flap is reommended. The flap consists of the musculus sternocleidomastoideus, pedicled inferiorly in its cranial part of the skin. The skin taking extends over the insertion of the muscle up to the beginning of the hairy part. With this flap it is possible to cover even large defects in the floor of the mouth and its taking does scarcely bother the patient. Thus, in many cases the flap gives the suppositions to maintain the lower jaw.


All-trans-retinoic acid treatment and retinoic acid receptor alpha gene rearrangement in acute promyelocytic leukemia: a model for differentiation therapy.
All-trans-retinoic acid (ATRA), a vitamin A derivative, is a safe and effective drug in the obtention of complete remission in acute promyelocytic leukemia (APL). ATRA is able to activate the maturation of malignant cells from patients with APL either in vitro or in vivo. Complete remission was obtained without any feature of aplastic phase and the severe bleeding diathesis rapidly disappeared. The major adverse effect is the occurrence of hyperleukocytosis which is prevented by the addition of chemotherapy. A progressive acquired resistance appears during ATRA treatment and prolonged event free survival time is obtained after consolidation with cytotoxic drugs. In APL the retinoic acid receptor alpha gene is rearranged and fused with a novel gene called PML. The hybrid PML-RAR product could have a role in the leukemogenesis blocking the effect of the normal RAR on target genes. Retinoic acid exerts a differentiating effect either by the induction of a normal activity of the aberrant product in the presence of pharmacological concentration, or by an over-expression of the normal allele. The results obtained by cellular and molecular biology gave opportunities to confirm the diagnosis, to follow the assessment of the minimal residual disease and to understand the acquired resistance.


Effects of a Low-Fat Vegan Diet on Gut Microbiota in Overweight Individuals and Relationships with Body Weight, Body Composition, and Insulin Sensitivity. A Randomized Clinical Trial.
Diet modulates gut microbiota and plays an important role in human health. The aim of this study was to test the effect of a low-fat vegan diet on gut microbiota and its association with weight, body composition, and insulin resistance in overweight men and women. We enrolled 168 participants and randomly assigned them to a vegan (n = 84) or a control group (n = 84) for 16 weeks. Of these, 115 returned all gut microbiome samples. Gut microbiota composition was assessed using uBiome Explorer™ kits. Body composition was measured using dual energy X-ray absorptiometry. Insulin sensitivity was quantified with the predicted clamp-derived insulin sensitivity index from a standard meal test. Repeated measure ANOVA was used for statistical analysis. Body weight decreased in the vegan group (treatment effect -5.9 kg [95% CI, -7.0 to -4.9 kg]; p < 0.001), mainly due to a reduction in fat mass (-3.9 kg [95% CI, -4.6 to -3.1 kg]; p < 0.001) and in visceral fat (-240 cm3 [95% CI, -345 to -135 kg]; p < 0.001). PREDIcted M, insulin sensitivity index (PREDIM) increased in the vegan group (treatment effect +0.83 [95% CI, +0.48 to +1.2]; p < 0.001). The relative abundance of Faecalibacterium prausnitzii increased in the vegan group (+5.1% [95% CI, +2.4 to +7.9%]; p < 0.001) and correlated negatively with changes in weight (r = -0.24; p = 0.01), fat mass (r = -0.22; p = 0.02), and visceral fat (r = -0.20; p = 0.03). The relative abundance of Bacteroides fragilis decreased in both groups, but less in the vegan group, making the treatment effect positive (+18.9% [95% CI, +14.2 to +23.7%]; p < 0.001), which correlated negatively with changes in weight (r = -0.44; p < 0.001), fat mass (r = -0.43; p < 0.001), and visceral fat (r = -0.28; p = 0.003) and positively with PREDIM (r = 0.36; p < 0.001), so a smaller reduction in Bacteroides fragilis was associated with a greater loss of body weight, fat mass, visceral fat, and a greater increase in insulin sensitivity. A low-fat vegan diet induced significant changes in gut microbiota, which were related to changes in weight, body composition, and insulin sensitivity in overweight adults, suggesting a potential use in clinical practice.


Platinum-based drugs and hydrogel: a promising anti-tumor combination.
Platinum-based drugs are widely used as first-line anti-tumor chemotherapy agents. However, they also have nonnegligible side effects due to the free drugs in circulation. Therefore, it is necessary to develop efficient and safe delivery systems for better tumor cell targeting. Hydrogel is a promising anti-tumor drug carrier that can form a platinum/hydrogel combination system for drug release, which has shown better anti-tumor effects in some studies. However, there is a lack of systematic summary in this field. This review aims to provide a comprehensive overview of the platinum/hydrogel combination system with the following sections: firstly, an introduction of platinum-based drugs; secondly, an analysis of the platinum/hydrogel combination system; and thirdly, a discussion of the advantages of the hydrogel-based delivery system. We hope this review can offer some insights for the development of the platinum/hydrogel combination system for better cancer therapy.


Fanconi anemia: prenatal diagnosis in 30 fetuses at risk.
We report our experience, since 1978, with prenatal diagnosis in fetuses at risk for Fanconi anemia. Amniotic fluid cells from 30 fetuses from 24 families were monitored for baseline and diepoxybutane-induced chromosomal breakage. Seven of the fetuses at risk were diagnosed as affected; baseline and diepoxybutane-induced breakage ranged from 0.18 to 0.45 and 0.69 to 0.96 breaks per cell, respectively. The range of baseline and diepoxybutane-induced chromosomal breakage in amniocytes from the 23 pregnancies at risk that were diagnosed prenatally as unaffected ranged from 0 to 0.08 and 0 to 0.13 breaks per cell, respectively. Four of these cases were also diagnosed as normal on the basis of chromosomal breakage studies in cells obtained by chorionic villus sampling. The range of baseline and diepoxybutane-induced breakage in cells from five control fetuses was 0 to 0.05 and 0 to 0.10 breaks per cell, respectively. Of the pregnancies diagnosed as affected, two were carried to term, whereas five were terminated. One newborn and two abortuses had congenital malformations including abnormalities of the thumb and radius. The other affected live-born infant, now 5 1/2 years old, has severe growth retardation and pancytopenia. No Fanconi anemia-associated malformations were found in any of the other fetuses or newborns studied. In all cases in which tissue was available for study, diagnoses were confirmed by chromosome breakage studies. This method thus permits reliable detection of Fanconi anemia.


The diagnosis and management of psychogenic non-epileptic seizures in the UK Armed Forces.
Psychogenic non-epileptic seizures (PNES) is a disorder that mimics epilepsy, but does not have the associated organic changes or abnormal neuronal discharge foci in the brain. In this article the diagnosis, management and clinical considerations of managing this condition in the UK Armed Forces are considered. The occupational and operational considerations for the military environment are also discussed.


PDX1, a key factor in pancreatic embryogenesis, can exhibit antimetastatic activity in pancreatic ductal adenocarcinoma.
Background: In cancer biology, metastasizing is one of the most poorly studied processes. Pancreatic ductal adenocarcinoma (PDAC) is characterized by early metastasis, which is the leading cause of death. The PDX1 protein is crucial for the development of cancer, and its low levels are characteristic of the most aggressive PDAC tumors. The PDX1 is a mediator of initiation and progression of PDAC. However, further studies are needed to elucidate the role of PDX1 in the cancer metastasis. Purpose: To confirm the hypothesis that PDX1 in PDAC plays suppressor role of epithelial-mesenchymal transition (EMT), and to study its possible ability to inhibit metastasis. Methods: A PDX1-overexpressing PDAC cell line was obtained by lentiviral transduction of PANC-1 cells. PDX1 overexpression was confirmed by RT-PCR and Western blotting. Effects of PDX1 ectopic expression on cell proliferation and motility were determined in PANC-1 cells using MTS, cell cycle analysis, transwell and wound-healing assay. EMT genes expression was analyzed in PDX1-overexpressing and Control PANC-1. Finally, the migration potential of pancreatic cancer cells expressing PDX1 was evaluated using a zebrafish embryo model. Results: The motility of human PDAC cells PANC-1 considerably decreased at ectopic expression of PDX1. The decreased expression of ZEB1, the key factor of EMT, and almost unchanged expression of the genes that characterize the epithelial state suggest a decrease in the EMT ability. Suppression of PDX1 expression by siRNA knockdown restored the PANC1 motility. Conclusion: The results obtained suggest a possible therapeutic use of PDX1 delivery into PDAC patients with a reduced or absent expression of PDX1 in the most aggressive tumors.


Ultrastructural studies of human lymphoid cells. mu and J chain expression as a function of B cell differentiation.
J chain expression was examined as a function of the stage in differentiation along the B cell axis in humans. Intracellular distribution of J and mu chains in leukemic HLA-DR+ null and pre-B cells, and in normal B cells stimulated with pokeweed mitogen (PWM) was determined by immunoelectron microscopy and radioimmunoassay (RIA). J chain was detected in leukemic null and pre-B cells on free and membrane-bound ribosomes in the cytoplasm, or on perinuclear cisternae. Mu chain was found on free ribosomes and ribosomal clusters in leukemic pre-B cells but was absent in the leukemic null cells. In pre-B cell lines, mu chain was seen within rough endoplasmic reticulum (RER) and the Golgi apparatus whereas J chain was not detected in these organelles. However, both mu and J chain were detected in RER and the Golgi apparatus of immature and mature plasma cells induced by PWM stimulation of normal peripheral blood lymphocytes. Low levels of J chain were also detected by RIA in lysates of leukemic null and pre-B cells. Most of the intracellular J chain became detectable after reduction and alkylation of cell lysates, and free J chain was not found in the culture supernatants. The amount of intracellular and secreted immunoglobulin-bound J chain increased dramatically after PWM stimulation of peripheral blood lymphocytes. The majority of J chain-positive cells seen over an 8 d culture interval were lymphocytes and lymphoblasts, while mu chain was found primarily in plasma cells. These results suggest that J chain expression precedes mu chain synthesis during B cell differentiation and that a combination of the two chains for secretion is not initiated until the onset of plasma cells maturation.


Synthesis, activity, and their relationships of 2,4-diaminonicotinamide derivatives as EGFR inhibitors targeting C797S mutation.
The C797S mutation is one of the major factors behind resistance to the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Herein, we describe the discovery of the 2,4-diaminonicotinamide derivative 5j, which shows potent inhibitory activity against EGFR del19/T790M/C797S and L858R/T790M/C797S. We also report the structure-activity relationship of the 2,4-diaminonicotinamide derivatives and the co-crystal structure of 5j and EGFR del19/T790M/C797S.


Quality Improvement Initiatives Need Rigorous Evaluation: The Case of Pressure Ulcers.
The Partnership for Patients (PfP) and the Agency for Healthcare Research and Quality (AHRQ) have reported a 23.5% decline in hospital-acquired pressure ulcers (HAPU) over 4 years resulting in a cumulative cost savings of more than $10 billion and 49 000 averted deaths, claiming that this significant decline may have been spurred in part by Medicare payment incentives associated with severe (stage 3 or 4) HAPUs. Hospitals with a high rate of severe HAPUs have a payment penalty imposed, creating a financial disincentive to report severe HAPUs, possibly contributing to the magnitude of the reported decline. Despite the financial disincentive to report, the number of severe HAPUs found in claims data over the corresponding 4-year period did not decline but instead remained unchanged. The results from claims data, combined with some flaws in estimating HAPUs, call into question the validity of the decline in HAPUs reported by PfP and AHRQ.


The early biochemical and hormonal profile of patients with long bone fractures at risk of fat embolism syndrome.
Free fatty acids (FFA) are believed to play a role in the genesis of the fat embolism syndrome (FES). Levels of plasma FFA, glucose, insulin, and the stress hormones cortisol, growth hormone, prolactin, glucagon, and catecholamines were measured on admission to hospital in: a) 14 patients with long bone fractures at risk of developing FES, b) 14 patients with soft-tissue injuries of comparable severity, and c) 20 healthy fasting subjects. The findings were similar in both groups of injured patients and in keeping with the hormonal and substrate responses to the stress of trauma; plasma FFA levels were raised but in neither group was the rise pronounced. Plasma FFA levels of the fracture patients were only moderately higher than the values of the healthy fasting subjects. These findings suggest that mobilized FFA from peripheral adipose tissue are not important in the genesis of the FES, but do not exclude a role for FFA derived mainly from hydrolysis of triglyceride emboli in the lung.


[Trauma and carcinoma--cause and corollary of osteomyelitis (author's transl)].
The fact that the hematogenic osteomyelitis can be cured, if a treatment with antibiotics is done early, confines the very difficult question about the correlation between trauma and hematogenous osteomyelitis to exceptional cases. Under certain conditions which have to be described in a more precise way, the trauma sometimes takes the form of an activating partial factor among the variety of causes of the hematogenous osteomyelitis, but is never the only producing cause. Fistulous chronic osteomyelitites are subject to a malignant degeneration at a specified frequency of up to 0.5%. Since an early diagnosis can seldom be made at an intra-osseus carcinoma localization, the demand for prophylactic measures is justified.


Pharmacogenetics/genomics of membrane transporters in cancer chemotherapy.
Inter-individual variability in drug response and the emergence of adverse drug reactions are main causes of treatment failure in cancer therapy. Recently, membrane transporters have been recognized as an important determinant of drug disposition, thereby affecting chemosensitivity and -resistance. Genetic factors contribute to inter-individual variability in drug transport and targeting. Therefore, pharmacogenetic studies of membrane transporters can lead to new approaches for optimizing cancer therapy. This review discusses genetic variations in efflux transporters of the ATP-binding cassette (ABC) family such as ABCB1 (MDR1, P-glycoprotein), ABCC1 (MRP1), ABCC2 (MRP2) and ABCG2 (BCRP), and uptake transporters of the solute carrier (SLC) family such as SLC19A1 (RFC1) and SLCO1B1 (SLC21A6), and their relevance to cancer chemotherapy. Furthermore, a pharmacogenomic approach is outlined, which using correlations between the growth inhibitory potency of anticancer drugs and transporter gene expression in multiple human cancer cell lines, has shown promise for determining the relevant transporters for any given drugs and predicting anticancer drug response.


A novel cuproptosis-related prognostic gene signature in adrenocortical carcinoma.
Adrenocortical carcinoma (ACC) is an aggressive and rare malignant tumor associated with poor outcomes. Cuproptosis, a new pattern of cell death, relies on mitochondrial respiration and is associated with protein lipoylation. Increasing evidence has demonstrated the potential roles of cuproptosis in several tumor entities. However, the relationship between cuproptosis and ACC remains unclear. In total, 10 cuproptosis-related genes (CRGs) of patients with ACC were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases and differential expression analysis of CRGs was analyzed. Functional enrichment of the CRGs was performed and protein-protein interaction analysis was utilized to explore the association between the CRGs. Cuproptosis-related risk score (CRRS) was constructed by Lasso Cox regression and validated. In the current study, the alteration and expression patterns of 10 CRGs in TCGA-ACC datasets were analyzed. We identified different expression patterns of CRGs in ACCs, discovered strong associations between CRGs and ACCs, and found that the CRGs were associated with immune infiltration in ACCs. A CRRS was created thereafter to predict overall survival (OS). CRRS = (0.083103718) *FDX1 + (-0.278423862) *LIAS+(0.090985682) *DLAT+(-0.018784047) *PDHA1 + (0.297218951) *MTF1 + (0.310197964) *CDKN2A. Patients were divided into high- and low-risk groups based on their CRRS, and independent prognostic factors were investigated. Finally, CDKN2A and FDX1 were found to be independent prognostic predictors of patients with ACC. CDKN2A and FDX1 are independent prognostic predictors of patients with ACC. Cuproptosis may play a role in the development of ACC, providing a new perspective on therapeutic strategies related to CRGs for cancer prevention and treatment.


Patient-perceived outcomes in the treatment of stress urinary incontinence: focus on urethral injection therapy.
Intervention for stress urinary incontinence (SUI) is generally focused on minimizing urinary leakage. However, the overall impact of SUI therapy on patients' quality of life is, arguably, more important than leakage outcomes. We performed a literature search to investigate the effect of urethral injection therapy on quality of life. Significant quality-of-life improvements have been observed with a number of injectable agents, while there is a distinct lack of correlation between subjective and objective outcomes. Two studies comparing urethral injection therapy with surgical intervention found superior objective efficacy with surgery, but no significant differences in quality-of-life improvements. Personal goals of patients undergoing urethral injection are yet to be explored, but there may be willingness to trade a lower success rate in favor of a more minor treatment procedure. In conclusion, quality-of-life improvements after urethral injection appear significant and comparable to those obtained with surgery. Further study of patients' own perceptions, pre- and posttreatment, would be valuable.


A distinct subgroup of chronic inflammatory demyelinating polyneuropathy with CNS demyelination and a favorable response to immunotherapy.
To explore subclinical central nervous system (CNS) involvement in chronic inflammatory demyelinating polyneuropathy (CIDP), we recorded somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs) using transcranial magnetic stimulation, to measure central sensory conduction time (CSCT) and central motor conduction time (CMCT) and examined brain and spinal cord MRI in patients with probable CIDP based on the American Academy of Neurology AIDS Task Force criteria. Eighteen patients with probable CIDP (12 males and 6 females; mean age at examination+/-SD, 45.8+/-17.0 years; range, 17-72) were included in the study. Of the 13 patients who underwent SEPs, one had prolonged CSCT (8%) and of the 13 who underwent MEPs, four had abnormal CMCT (31%). Cranial MRI revealed five of 18 patients had abnormal scans, only one of which showed multiple ovoid periventricular lesions suggestive of demyelination while none showed any intramedullary lesion on spinal cord MRI. Thus, 6 of the 18 patients were considered to have subclinical demyelinative CNS involvement which had lower disability on Global Neurological Disability Score (GNDS) (p=0.0061), a male preponderance (0.0537) and a larger compound muscle action potential (CMAP) amplitude in the median nerve (p=0.005) than those without. The decrease of GNDS with immunologic therapies was nearly significant in the former (p=0.0556) but not in the latter. The results of the present study suggest that subclinical CNS involvement in CIDP is not uncommon in Japanese patients and that CIDP with subclinical CNS involvement is more demyelinative thus responsive to immunotherapies while those without have more axonal damage and less responsive to immunotherapies.


Case-control geographic clustering for residential histories accounting for risk factors and covariates.
Methods for analyzing space-time variation in risk in case-control studies typically ignore residential mobility. We develop an approach for analyzing case-control data for mobile individuals and apply it to study bladder cancer in 11 counties in southeastern Michigan. At this time data collection is incomplete and no inferences should be drawn - we analyze these data to demonstrate the novel methods. Global, local and focused clustering of residential histories for 219 cases and 437 controls is quantified using time-dependent nearest neighbor relationships. Business address histories for 268 industries that release known or suspected bladder cancer carcinogens are analyzed. A logistic model accounting for smoking, gender, age, race and education specifies the probability of being a case, and is incorporated into the cluster randomization procedures. Sensitivity of clustering to definition of the proximity metric is assessed for 1 to 75 k nearest neighbors. Global clustering is partly explained by the covariates but remains statistically significant at 12 of the 14 levels of k considered. After accounting for the covariates 26 Local clusters are found in Lapeer, Ingham, Oakland and Jackson counties, with the clusters in Ingham and Oakland counties appearing in 1950 and persisting to the present. Statistically significant focused clusters are found about the business address histories of 22 industries located in Oakland (19 clusters), Ingham (2) and Jackson (1) counties. Clusters in central and southeastern Oakland County appear in the 1930's and persist to the present day. These methods provide a systematic approach for evaluating a series of increasingly realistic alternative hypotheses regarding the sources of excess risk. So long as selection of cases and controls is population-based and not geographically biased, these tools can provide insights into geographic risk factors that were not specifically assessed in the case-control study design.


Activated alpha beta-CD8+, but not alpha alpha-CD8+, TCR-alpha beta+ murine intestinal intraepithelial lymphocytes can mediate perforin-based cytotoxicity, whereas both subsets are active in Fas-based cytotoxicity.
CD8 single-positive (CD8+) T cells in murine intestinal intraepithelial lymphocytes (iIEL) consist of alpha alpha-CD8+ and alpha beta-CD8+ subpopulations. Cytotoxicity represents an important function of peripheral CD8+ T cells, so we examined perforin-granzymebased and Fas-based cytotoxicity of activated CD8+ TCR-alpha beta+ iIEL subsets. We found that allospecific CTL activity was induced from alpha beta-CD8+ iIEL but not from alpha alpha-CD8+ iIEL even when allospecific TCR were present on the iIEL, as demonstrated by using 2C TCR transgenic mice. On the other hand, both CD8+ iIEL subsets proliferated upon allostimulation with a lower responder frequency than CD8+ LN cells. The alpha alpha-CD8+ TCR-alpha beta+ iIEL appeared to lose their ability to perform perforin-based killing after activation through TCR because fresh cells lysed P815 cells coated with anti-TCR beta-chain (TCR-beta) mAb, whereas cells activated by plate-bound anti-TCR mAb did not. Of interest, both activated CD8+ TCR-alpha beta+ iIEL subsets, but not fresh cells, were able to mediate Fas-based killing when triggered with PMA and CA2+ ionophore.


Loss of 13q14-q21 and gain of 5p14-pter in the progression of leiomyosarcoma.
Leiomyosarcomas of soft tissues are an aggressive group of tumors with a high incidence of recurrence. Little is known about the molecular genetic changes associated with clinical outcome. Therefore, we studied 28 leiomyosarcoma samples of similar grade using comparative genomic hybridization and DNA flow cytometry and identified a difference in survival time associated with ploidy status and the number of chromosomal aberrations. The average survival time was shown to decrease with increase in chromosomal aberrations identified using comparative genomic hybridization. The average survival time was shorter in the near-tetraploid group than in the diploid and triploid group. Gain of 5p14-pter was significantly more common in near-tetraploid tumors. The survival time of patients with near-tetraploidy together with gain of 5p14-pter was reduced, and 50% died within the 1st year. Furthermore, loss of 13q14-q21 was significantly more frequent in the <5-year than in the >5-year survival group (P =.01). These results suggest that 13q14-q21 loss and 5p14-pter gain at diagnosis could be used to identify patients with leiomyosarcoma who are likely to have a shorter survival time and who might benefit from early treatment intensification.


Development of locus specific sub-clone separation by fluorescence in situ hybridization in suspension in chronic lymphocytic leukemia.
Intra-tumor genetic heterogeneity is a hallmark of cancer. The ability to monitor and analyze these sub-clonal cell populations can be considered key to successful treatment, particularly in the modern era of targeted therapies. Although advances in sequencing technologies have significantly improved our ability to analyze the mutational landscape of tumors, this utility is reduced when considering small, but clinically significant sub-clones, that is, those representing <10% of the tumor burden. We have developed a high-throughput method that utilizes a 17-probe labeled bacterial artificial chromosome contig to quantify sub-clonal populations of cells based on deletion of a single locus. Chronic lymphocytic leukemia (CLL) cells harboring deletion of the short arm of chromosome 17 (del17p), an important prognostic marker for CLL were used to demonstrate the technique. Sub-clones of del17p cells were quantified and isolated from heterogeneous CLL populations using fluorescence in situ hybridization in suspension (FISH-IS) and the locus specific probe set. Using the combination of FISH-IS with the locus-specific probe set enables automated analysis of tens of thousands of cells, accurately quantifying and isolating cells carrying a del17p. Based on the fluorescence intensity of 17p probes, 17p (TP53) deleted cells were identified and sorted using flow cytometric techniques, and enrichment was demonstrated using single nucleotide polymorphism analysis. The ability to separate sub-clones of cells based on genetic heterogeneity, independent of the clone size, highlights the potential application of this method not only in the diagnostic and prognostic setting, but also as an unbiased approach to enable further detailed genetic analysis of the sub-clone with deep sequencing approaches. © 2017 International Society for Advancement of Cytometry.


3-(1H-Indol-3-yl)-2-(2-nitro-benzene-sulfonamido)-propanoic acid including an unknown solvate.
In the title compound, C(17)H(15)N(3)O(6)S, which crystallized with highly disordered methanol and/or water solvent mol-ecules, the dihedral angle between the the indole and benzene ring systems is 5.3 (2)°, which allows for the formation of intra-molecular π-π stacking inter-actions [centroid-centroid separations = 3.641 (3) and 3.694 (3) Å] and an approximate overall U-shape for the mol-ecule. In the crystal, dimers linked by pairs of N(s)-H⋯O(c) (s = sulfonamide and c = carboxyl-ate) hydrogen bonds generate R(2) (2)(10) loops, whereas N(i)-H⋯π (i = indole) inter-actions lead to chains propagating in [100] or [010]. Together, these lead to a three-dimensional network in which the solvent voids are present as inter-secting (two-dimensional) systems of [100] and [010] channels. The title compound was found to contain a heavily disordered solvent mol-ecule, which could be methanol or water or a mixture of the two. Due to its uncertain nature and the unresolvable disorder, the data were processed with the SQUEEZE option in PLATON [Spek (2009 ▶). Acta Cryst. D65, 148-155], which revealed 877.8 Å(3) of solvent-accessible volume per unit cell and 126 electron-units of scattering density or 109.7 Å(3) (16 electron units) per organic mol-ecule.. This was not included in the calculations of overall formula weight, density and absorption coefficient.


Global burden of non-optimal temperature attributable stroke: The long-term trends, population growth and aging effects.
Since the 20th century, the world has undergone climate change, population growth and population aging, which may result in alterations in the epidemiology of non-optimal temperature-associated strokes. We employed multiple methodologies and data from the global burden of disease 2019 to unveil the long-term curvilinear trends in strokes attributed to non-optimal temperature and the impact of aging and population growth on its changing epidemiology. From 1990 to 2019, the age-standardized DALYs rate (ASDR) of strokes attributable to low temperature had been decreasing, but from 2016, the continued downward trend in ASDR disappeared and began to remain stable. On the contrary, the ASDR of strokes attributable to high temperature continued to increase. The high socio-demographic index (SDI) region experienced the fastest decreased trend. The disease burden of stroke attributable to low temperature is increased by aging in 178 countries (87.25%), compared with 130 (63.73%) for high temperature. After excluding aging and population growth, the DALY rate for strokes attributed to high temperature was increasing in 87 countries and territories (42.64%). The disease burden of strokes attributed to low temperature is far greater than that of high temperature in absolute figures. However, globally, there is a significant trend toward an increase in strokes attributed to high temperature. Social development has largely offset the burden of strokes attributed to low temperature, but most regions of the world are equally affected by strokes attributed to high temperature. Simultaneously, in the framework of climate change, aging is also largely hindering stroke prevention efforts.


Molecular Characterization of Influenza C Viruses from Outbreaks in Hong Kong SAR, China.
In 2014, the Centre for Health Protection in Hong Kong introduced screening for influenza C virus (ICV) as part of its routine surveillance for infectious agents in specimens collected from patients presenting with symptoms of respiratory viral infection, including influenza-like illness (ILI). A retrospective analysis of ICV detections up to week 26 of 2019 revealed persistent low-level circulation, with two outbreaks having occurred in the winters of 2015 to 2016 and 2017 to 2018. These outbreaks occurred at the same time as, and were dwarfed by, seasonal epidemics of influenza types A and B. Gene sequencing studies on stored ICV-positive clinical specimens from the two outbreaks have shown that the hemagglutinin-esterase (HE) genes of the viruses fall into two of the six recognized genetic lineages (represented by C/Kanagawa/1/76 and C/São Paulo/378/82), with there being significant genetic drift compared to earlier circulating viruses within both lineages. The location of a number of encoded amino acid substitutions in hemagglutinin-esterase fusion (HEF) glycoproteins suggests that antigenic drift may also have occurred. Observations of ICV outbreaks in other countries, with some of the infections being associated with severe disease, indicates that ICV infection has the potential to have significant clinical and health care impacts in humans.IMPORTANCE Influenza C virus infection of humans is common, and reinfection can occur throughout life. While symptoms are generally mild, severe disease cases have been reported, but knowledge of the virus is limited, as little systematic surveillance for influenza C virus is conducted and the virus cannot be studied by classical virologic methods because it cannot be readily isolated in laboratories. A combination of systematic surveillance in Hong Kong SAR, China, and new gene sequencing methods has been used in this study to assess influenza C virus evolution and provides evidence for a 2-year cycle of disease outbreaks. The results of studies like that reported here are key to developing an understanding of the impact of influenza C virus infection in humans and how virus evolution might be associated with epidemics.


Role of the lectin pathway of complement in hematopoietic stem cell transplantation-associated endothelial injury and thrombotic microangiopathy.
Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) is a life-threatening syndrome that occurs in adult and pediatric patients after hematopoietic stem cell transplantation. Nonspecific symptoms, heterogeneity within study populations, and variability among current diagnostic criteria contribute to misdiagnosis and underdiagnosis of this syndrome. Hematopoietic stem cell transplantation and associated risk factors precipitate endothelial injury, leading to HSCT-TMA and other endothelial injury syndromes such as hepatic veno-occlusive disease/sinusoidal obstruction syndrome, idiopathic pneumonia syndrome, diffuse alveolar hemorrhage, capillary leak syndrome, and graft-versus-host disease. Endothelial injury can trigger activation of the complement system, promoting inflammation and the development of endothelial injury syndromes, ultimately leading to organ damage and failure. In particular, the lectin pathway of complement is activated by damage-associated molecular patterns (DAMPs) on the surface of injured endothelial cells. Pattern-recognition molecules such as mannose-binding lectin (MBL), collectins, and ficolins-collectively termed lectins-bind to DAMPs on injured host cells, forming activation complexes with MBL-associated serine proteases 1, 2, and 3 (MASP-1, MASP-2, and MASP-3). Activation of the lectin pathway may also trigger the coagulation cascade via MASP-2 cleavage of prothrombin to thrombin. Together, activation of complement and the coagulation cascade lead to a procoagulant state that may result in development of HSCT-TMA. Several complement inhibitors targeting various complement pathways are in clinical trials for the treatment of HSCT-TMA. In this article, we review the role of the complement system in HSCT-TMA pathogenesis, with a focus on the lectin pathway.


Regenerative cells for transplantation in hepatic failure.
Human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells have an enormous potential; however, their potential clinical application is being arrested due to various limitations such as teratoma formation followed by tumorigenesis, emergent usage, and the quality control of cells, as well as safety issues regarding long-term culture are also delaying their clinical application. In addition, human ES cells have two crucial issues: immunogenicity and ethical issues associated with their clinical application. The efficient generation of human iPS cells requires gene transfer, yet the mechanism underlying pluripotent stem cell induction has not yet been fully elucidated. Otherwise, although human adult regenerative cells including mesenchymal stem cells have a limited capacity for differentiation, they are nevertheless promising candidates for tissue regeneration in a clinical setting. This review highlights the use of regenerative cells for transplantation in hepatic failure.


If you're happy and you know it: neural correlates of self-evaluated psychological health and well-being.
Psychological health and well-being have important implications for individual and societal thriving. Research underscores the subjective nature of well-being, but how do individuals intuit this subjective sense of well-being in the moment? This pre-registered study addresses this question by examining the neural correlates of self-evaluated psychological health and their dynamic relationship with trial-level evaluations. Participants (N = 105) completed a self-evaluation task and made judgments about three facets of psychological health and positive functioning-self-oriented well-being, social well-being and ill-being. Consistent with pre-registered hypotheses, self-evaluation elicited activity in the default mode network, and there was strong spatial overlap among constructs. Trial-level analyses assessed whether and how activity in a priori regions of interest-perigenual anterior cingulate cortex (pgACC), ventromedial prefrontal cortex (vmPFC) and ventral striatum-were related to subjective evaluations. These regions explained additional variance in whether participants endorsed or rejected items but were differentially related to evaluations. Stronger activity in pgACC was associated with a higher probability of endorsement across constructs, whereas stronger activity in vmPFC was associated with a higher probability of endorsing ill-being items, but a lower probability of endorsing self-oriented and social well-being items. These results add nuance to neurocognitive accounts of self-evaluation and extend our understanding of the neurobiological basis of subjective psychological health and well-being.


Spectrum of rhodopsin mutations in French autosomal dominant rod-cone dystrophy patients.
PURPOSE. To identify the prevalence of rhodopsin (RHO) mutations in French patients with autosomal dominant rod-cone dystrophies (adRPs). Methods. Detailed phenotypic characterization was performed, including precise family history, best corrected visual acuity with the ETDRS chart, slit lamp examination, kinetic and static perimetry, full-field and multifocal electroretinography (ERG), fundus autofluorescence imaging (FAF), and optical coherence tomography (OCT). For genetic diagnosis, genomic DNA of 79 families was isolated by standard The coding exons and flanking intronic regions of RHO were PCR amplified, purified, and sequenced in the index patient. RESULTS. Of this French adRP sample, 16.5% carried an RHO mutation. Three different families showed a novel mutation (p. Leu88Pro, p.Met207Lys and p.Gln344Pro), while ten unrelated families showed recurrent, previously published mutations (p.Asn15Ser, p.Leu131Pro, p.Arg135Trp, p.Ser334GlyfsX21 and p.Pro347Leu). All mutations co-segregated with the phenotype within a family, and the novel mutations were not identified in control samples. CONCLUSIONS. This study revealed that the prevalence of RHO mutations in French adRP patients is in accordance with that in other studies from Europe. Most of the changes identified herein reflect recurrent mutations, within which p.Pro347Leu substitution is the most prevalent. Nevertheless, almost one fourth of the changes are novel, indicating that, although RHO is the first gene implicated and probably the most studied gene in RP, it is still important performing mutation analysis in RHO to detect novel changes. The detailed phenotype-genotype analyses in all available family members deliver the basis for therapeutic approaches in those families.


Feasibility of a supervised and home-based tailored exercise intervention in head and neck cancer patients during chemoradiotherapy.
Chemoradiotherapy (CRT) for head and neck cancer (HNC) is associated with high toxicity that adversely affects physical functioning, body composition, fatigue, quality of life and treatment outcomes. Exercise interventions during treatment might counteract these negative effects. We therefore assessed the feasibility of an exercise programme for HNC patients during CRT. Forty patients were offered a tailored 10-week endurance and resistance training with supervised and home-based sessions. Feasibility endpoints were (1) adherence (main outcome): ≥60% attendance; (2) recruitment: ≥30%; (3) retention rate: ≥85% and (4) compliance rate: ≥60%. Physical performance, muscle strength, body composition, quality of life and fatigue were assessed pre- and post-intervention. Overall adherence was 54%. The recruitment rate was 36%, and the retention rate was 65%. Compliance to the supervised intervention protocol was 66%. Statistically significant decreases were found in mean grip strength, fat-free mass and clinically relevant deteriorations on several domains of quality of life, and fatigue subscales were found. We conclude that this exercise programme for HNC patients during CRT in its current form is feasible for only a minority of patients. We suggest adaptations to improve adherence and retention rates for a definitive multicentre trial. This study is registered at the Netherlands Trial Register (NTR7305), 6 June 2018, retrospectively registered.


Modulation of Kv4.2 channels by a peptide isolated from the venom of the giant bird-eating tarantula Theraphosa leblondi.
In order to find new peptide inhibitors for voltage-dependent potassium (Kv) channels, we examined the effects of venom from Theraphosa leblondi on Kv channel-mediated currents with the whole-cell patch-clamp technique. Both A-type currents in cultured hippocampal neurons and A-type currents recorded from HEK 293 cells transiently expressing recombinant Kv4.2 channels were selectively inhibited by T. leblondi venom. No venom activity was observed on recombinant Kv1.3, Kv1.4, Kv2.1 or Kv3.4 channels. We purified and sequenced three novel homologous peptides from this venom, which are related to previously identified Kv4 channel-specific peptide inhibitors and were named T. leblondi toxin (TLTx) 1, 2 and 3. The mode of action of TLTx1 on recombinant Kv4.2 channels was studied in more detail. TLTx1 inhibited Kv4.2-mediated currents with an IC50 of approximately 200 nM, and macroscopic current inactivation was slowed in the presence of TLTx1. Notably, TLTx1 also caused a shallower voltage dependence of Kv4.2 peak conductance and a shift of the activation midpoint to more positive potentials (DeltaV1/2 = +35 mV). TLTx1 caused a noticable slowing of Kv4.2 activation kinetics, and Kv4.2 deactivation kinetics were accelerated by TLTx1 as infered from Rb+ tail current measurements. Chimeric Kv2.1(4.2L3-4) channels, in which the linker region between S3 and S4 of the TLTx1-insensitive Kv2.1 channel was replaced by the corresponding Kv4.2 domain, were sensitive to TLTx1. Apparently, TLTx1 can act as a gating modifier of Kv4.2 channels.


[Effect of beditine on the cerebral circulation and various metabolic parameters].
Beditin, or 2-(2-amino-4-thiazolyl)-1,4-benzodioxane hydrochloride, is a new benzodioxane derivative possessing antihypoxant and alpha 2-adrenoreceptor blocker properties. In contrast to idazoxan, a well-known alpha 2-adrenoreceptor blocker, beditin (3 mg/kg) significantly increases the circulation rate and decreases the blood vessel resistance in various brain structures of rats and cats without considerably changing their systemic hemodynamic indices. Upon a one-side ligation of the common carotid artery in rats, beditin prevented a sharp increase in the lactate dehydrogenase activity and a growth in the content of free ammonia in the brain, which are characteristic of the ischemic states. The ammonia-eliminating effect of beditin is related to an increase in the glutamate dehydrogenase activity in the reductive amination reaction.


Predominant role for C5b-9 in renal ischemia/reperfusion injury.
Previous work has indicated that complement is a mediator of ischemia/reperfusion (I/R) injury. To investigate the components of complement responsible for this effect, we examined a model of renal I/R injury in C3-, C4-, C5-, and C6-deficient mice. We occluded the renal arteries and veins (40-58 minutes) and, after reperfusion (0-72 hours), assessed renal structural and functional injury. C3-, C5-, and C6-deficient mice were protected from renal I/R injury, whereas C4-deficient mice were not protected. C6-deficient mice treated with antibody to block C5a generation showed no additional protection from I/R injury. Reconstitution with C6 alone restored the I/R injury in C6-deficient mice. Tubular epithelial cells were the main structures damaged by complement-mediated attack, and, in contrast, the renal vessels were spared. Neutrophil infiltration and myeloperoxidase activity were reduced in C-deficient mouse kidney, but by a similar extent in C3-deficient and C6-deficient mice. We conclude that the membrane attack complex of complement (in which C5 and C6 participate) may account for the effect of complement on mouse renal I/R injury. Neither C5a-mediated neutrophil infiltration nor the classic pathway, in which C4 participates, appears to contribute to I/R injury in this model. By contrast with other organs, such as the heart, the primary effect of complement in the ischemic area is on the parenchymal cell rather than the vascular endothelial cell. The membrane attack complex of complement is a potential target for prevention of I/R injury in this model.


ROC and LROC analyses of the effects of lesion contrast, size, and signal-to-noise ratio on detectability in PET images.
Image quality in PET is typically assessed using measures such as contrast recovery, noise variation, and signal-to-noise ratio (SNR). However, these criteria do not directly reflect performance in the clinical use of the images. Lesion detection is a critical task in the clinical interpretation of many PET studies. A receiver operating characteristic (ROC) study is an accepted method for quantitatively evaluating detection performance with respect to factors that influence image quality. ROC and localization ROC (LROC) analyses were conducted to investigate the effects of lesion contrast, SNR, and size on detectability of hot lesions in PET images. A thorax phantom was imaged with spheres of 3 sizes simulating lesions (0.45, 1.0, and 1.9 mL). The relative activity in the lesions and the total number of counts acquired were each varied by factors of 2 to ascertain the effects of contrast and SNR, respectively. Measured attenuation correction and a standard reconstruction protocol were used. Three nuclear medicine physicians and 6 medical physicists participated as readers, rating each image and indicating the suspected lesion location. The area under the calculated ROC and LROC curves (Az and Az,LROC) were used as measures of detection performance. Detection performance was shown to increase from virtually random (Az approximately 0.5, Az,LROC approximately 0.2) to superior (Az > 0.9, Az,LROC > 0.9) as lesion contrast was increased by 50% and as lesion SNR was doubled. Detection performance was not seen to vary when comparison was made using image-based measures alone. This study quantitatively shows that moderate increases in the image-based measures of lesion contrast and SNR give a relatively large increase in the task-based measure of lesion detection as measured by ROC and LROC analyses. Thus, techniques that give modest increases in lesion contrast or SNR are expected to improve detection. Results will be useful in evaluating improvement in detection for various reconstruction, acquisition, and data analysis methods that enhance contrast or noise performance.


The Dark-Purple Tea Cultivar 'Ziyan' Accumulates a Large Amount of Delphinidin-Related Anthocyanins.
Recently, we developed a novel tea cultivar 'Ziyan' with distinct purple leaves. There was a significant correlation between leaf color and anthocyanin pigment content in the leaves. A distinct allocation of metabolic flow for B-ring trihydroxylated anthocyanins and catechins in 'Ziyan' was observed. Delphinidin, cyanidin, and pelargonidin (88.15 mg/100 g FW in total) but no other anthocyanin pigments were detected in 'Ziyan', and delphinidin (70.76 mg/100 g FW) was particularly predominant. An analysis of the catechin content in 'Ziyan' and eight other cultivars indicated that 'Ziyan' exhibits a preference for synthesizing B-ring trihydroxylated catechins (with a proportion of 74%). The full-length cDNA sequences of flavonoid pathway genes were isolated by RNA-Seq coupled with conventional TA cloning, and their expression patterns were characterized. Purple-leaved cultivars had lower amounts of total catechins, polyphenols, and water extract than ordinary non-anthocyanin cultivars but similar levels of caffeine. Because dark-purple-leaved Camellia species are rare in nature, this study provides new insights into the interplay between the accumulations of anthocyanins and other bioactive components in tea leaves.


Multiplication and haemadsorbing activity of infectious salmon anaemia virus in the established Atlantic salmon cell line.
Infectious salmon anaemia virus (ISAV), which previously had never been isolated in any of the commercially available established fish cell lines, was successfully propagated in the continuous cell line Atlantic salmon (AS). The yield of infectious ISAV increased with the incubation time of virus-inoculated cells, demonstrated by in vivo infectivity trials in groups of Atlantic salmon. Trypsin treatment of the virus was not necessary for primary infection of AS cells with salmon-grown ISAV. The infection was non-cytopathic, but it was possible to detect virus-infected cells by a haemadsorption centre assay using Atlantic salmon erythrocytes. Pleomorphic enveloped virus particles were seen by transmission electron microscopy of infected AS cells. Elongated forms were observed, but spherical particles with diameters of 90-130 nm were commonest. Growth of ISAV was inhibited by actinomycin D but not by 5-bromo-2-deoxyuridine treatment, which indicates that ISAV may be an aquatic orthomyxovirus.


Decolorization of a mixture of textile dyes using Bjerkandera sp. BOL-13.
The white-rot fungus Bjerkandera sp. BOL-13 was evaluated regarding decolorization of four textile dyes Reactive blue 21, Reactive black 5, Reactive orange 13 and Reactive yellow 206. Experiments were performed in batch and continuous modes. The total dye concentration in all experiments was 100 mg l(-1). The results of the batch experiments showed that the fungus decolorized all dyes but at different rates. There was, however, an increase in the ultraviolet (UV) absorbance when a medium with a low concentration of nitrogen was used. No increase in UV range was observed when the nitrogen concentration was increased. A continuous experiment was performed to study the decolorization of a mixture of three of the dyes Reactive blue 21, Reactive black 5 and Reactive orange 13. Scanning of inlet and outlet samples showed that the absorbance at the peaks in the visible range decreased by 60-66%. The UV absorbance of the outlet increased during the first days of operation after which it decreased again to reach the same level as the inlet. The hydraulic retention time in the reactor was 3 days. The medium containing the higher nitrogen concentration was used in the continuous experiment.


TCR signaling promotes formation of an STS1-Cbl-b complex with pH-sensitive phosphatase activity that suppresses T cell function in acidic environments.
T cell responses are inhibited by acidic environments. T cell receptor (TCR)-induced protein phosphorylation is negatively regulated by dephosphorylation and/or ubiquitination, but the mechanisms underlying sensitivity to acidic environments are not fully understood. Here, we found that TCR stimulation induced a molecular complex of Cbl-b, an E3-ubiquitin ligase, with STS1, a pH-sensitive unconventional phosphatase. The induced interaction depended upon a proline motif in Cbl-b interacting with the STS1 SH3 domain. STS1 dephosphorylated Cbl-b interacting phosphoproteins. The deficiency of STS1 or Cbl-b diminished the sensitivity of T cell responses to the inhibitory effects of acid in an autocrine or paracrine manner in vitro or in vivo. Moreover, the deficiency of STS1 or Cbl-b promoted T cell proliferative and differentiation activities in vivo and inhibited tumor growth, prolonged survival, and improved T cell fitness in tumor models. Thus, a TCR-induced STS1-Cbl-b complex senses intra- or extra-cellular acidity and regulates T cell responses, presenting a potential therapeutic target for improving anti-tumor immunity.


[Lipid composition of Halobacterium cells and bacteriorhodopsin isolated from them].
The phospholipids qualitative and quantitative compositions were determined in halobacteria cells and in bacteriorodopsin isolated from them. The phospholipid composition of the cells and bacteriorodopsin is established to be unstable and to depend on the cells cultivation conditions and the culture strain.