Detection of HPV infection in urothelial carcinoma using RNAscope: Clinicopathological characterization.
Human papillomavirus (HPV) is a well-established mucosotropic carcinogen, but its impact on urothelial neoplasm is unclear. We aimed to clarify the clinical and pathological features of HPV-related urothelial carcinoma (UC). Tissue samples of 228 cases of UC were obtained from the bladder, upper and lower urinary tract, and metastatic sites to construct a tissue microarray. The samples were analyzed for the presence of HPV by a highly sensitive and specific mRNA in situ hybridization (RISH) technique (RNAscope) with a probe that can detect 18 varieties of high-risk HPV. We also conducted immunohistochemistry (IHC) for a major HPV capsid antibody and DNA-PCR. The HPV detection rates varied among the methods; probably due to low HPV copy numbers in UC tissues and the insufficient specificity and sensitivity of the IHC and PCR assays. The RISH method had the highest accuracy and identified HPV infection in 12 (5.2%) of the cases. The histopathological analysis of the HPV-positive UC showed six cases of usual type UC, five cases of UC with squamous differentiation (UC_SqD), and one case of micropapillary UC. The HPV detection rate was six-fold higher in the cases of UC_SqD than in the other variants of UC (odds ratio [OR] =8.9, p = 0.002). In addition, HPV infection showed a significant association with tumor grade (OR =9.8, p = 0.03) and stage (OR =4.7, p = 0.03) of UC. Moreover, the metastatic rate was higher in HPV-positive than in negative UC (OR =3.4). These data indicate that although the incidence of HPV infection in UC is low, it is significantly associated with squamous differentiation and poor prognosis. Furthermore, our observations show that RNAscope is an ideal method for HPV detection in UC compared with the other standard approaches such as IHC and PCR assays.


Highly Efficient Electroluminescence from Narrowband Green Circularly Polarized Multiple Resonance Thermally Activated Delayed Fluorescence Enantiomers.
Purely organic fluorescent materials that concurrently exhibit high efficiency, narrowband emission, and circularly polarized luminescence (CPL) remain an unaddressed issue despite their promising applications in wide color gamut- and 3D-display. Herein, the CPL optical property and multiple resonance (MR) effect induced thermally activated delayed fluorescence (MR-TADF) emission are integrated with high color purity and luminous efficiency together. Two pairs of highly efficient green CP-MR-TADF enantiomers, namely, (R/S)-OBN-2CN-BN and (R/S)-OBN-4CN-BN, are developed. The enantiomer-based organic light-emitting diodes (OLEDs) exhibit pure green emission with narrow full-width at half-maximums (FWHMs) of 30 and 33 nm, high maximum external quantum efficiencies (EQEs) of 29.4% and 24.5%, and clear circularly polarized electroluminescence (CPEL) signals with electroluminescence dissymmetry factors (gEL ) of +1.43 × 10-3 /-1.27 × 10-3 and +4.60 × 10-4 /-4.76 × 10-4 , respectively. This is the first example of a highly efficient OLED that exhibits CPEL signal, narrowband emission, and TADF concurrently.


Children of divorce: the differential diagnosis of contact refusal.
Contact refusal is a common phenomenon that can occur during the course of, or after, divorce, which affects the relationship between a child and the parent. This article defines the concept of contact refusal and discusses the importance of its recognition. The concept is further narrowed to focus on the child as the one refusing contact, not the parent, which can happen as well. Various types of contact refusals are illustrated in the article through clinical vignettes, and an approach to categorizing the various types of contact refusal is presented.


Automobile Shredder Residues in Italy: characterization and valorization opportunities.
At the moment Automobile Shredder Residue (ASR) is usually landfilled worldwide, but European draft Directive 2000/53/CE forces the development of alternative solutions, stating the 95%-wt recovery of an End of Life Vehicle (ELV) weight to be fulfilled by 2015. This work describes two industrial tests, each involving 250-300 t of ELVs, in which different pre-shredding operations were performed. The produced ASR materials underwent an extended characterization and some post-shredding processes, consisting of dimensional, magnetic, electrostatic and densimetric separation phases, were tested on laboratory scale, having as main purpose the enhancement of ASR recovery/recycling and the minimization of the landfilled fraction. The gathered results show that accurate depollution and dismantling operations are mandatory to obtain a high quality ASR material which may be recycled/recovered and partially landfilled according to the actual European Union regulations, with particular concern for Lower Heating Value (LHV), heavy metals content and Dissolved Organic Carbon (DOC) as critical parameters. Moreover post-shredding technical solutions foreseeing minimum economic and engineering efforts, therefore realizable in common European ELVs shredding plants, may lead to multi-purposed (material recovery and thermal valorization) opportunities for ASR reuse/recovery.


Addition of aerobic exercise to a weight loss program increases BMD, with an associated reduction in inflammation in overweight postmenopausal women.
Increased inflammation and weight loss are associated with a reduction in bone mineral density (BMD). Aerobic exercise may minimize the loss of bone and weight loss may contribute to a decrease in cytokines. We tested the hypothesis that aerobic exercise in combination with a weight loss program would decrease circulating concentrations of inflammatory markers, thus mediating changes in BMD. This was a nonrandomized controlled trial. Eighty-six overweight and obese postmenopausal women (50-70 years of age; BMI, 25-40 kg/m(2)) participated in a weight loss (WL; n = 40) or weight loss plus walking (WL + AEX; n = 46) program. Outcome measures included BMD and bone mineral content of the femoral neck and lumbar spine measured by dual energy X-ray absorptiometry, interleukin-6, tumor necrosis factor-alpha, soluble receptors of IL-6, and TNF-alpha (sTNFR1 and sTNFR2; receptors in a subset of the population), VO(2) max, fat mass, and lean mass. Weight decreased in the WL (p < 0.001) and WL + AEX (p < 0.001) groups. VO(2) max increased (p < 0.001) after WL + AEX. There was a 2% increase in femoral neck BMD in the WL + AEX group (p = 0.001), which was significantly different from the WL group. The change in sTNFR1 was significantly associated with the change in femoral neck BMD (p < 0.05). The change in VO(2) max was an independent predictor of the change in femoral neck BMD. Our findings suggest that the addition of aerobic exercise is recommended to decrease inflammation and increase BMD during weight loss in overweight postmenopausal women.


Green synthesis and characterization of silver nanoparticles using Pteris vittata extract and their therapeutic activities.
The bacterial infections have been substantially increasing with higher mortality and new regimens required for their management. The present work deals with the green synthesis of silver nanoparticles (AgNPs) using leaf extract of Pteris vittata at pH 9.0. The AgNPs showed a single absorption peak at 407 nm. The morphology of AgNPs was found to be spherical in shape analyzed by scanning electron micrographs. The X-ray diffraction studies revealed the face-centered cubic structure of AgNPs with a 17-nm average crystallite size. They showed the antimicrobial activity against Pseudomonas aeruginosa, and the cell growth was completely ceased at the minimum inhibitory concentration (MIC); 100 μg/mL, with rapidly decreased cell viability. This bactericidal effect was due to the enhancement of cell permeability caused by cell disruption. The AgNPs lead to show a promising antiquorum-sensing activity by inhibition of toxin protease and pyocyanin in P. aeruginosa by 88% and, 94% respectively, at the sub-MIC concentration (0.25× MIC). These results conclude that the green synthesis of AgNPs shows a promising antimicrobial and antivirulence activity against P. aeruginosa.


Telomerase reverse transcriptase promotes epithelial-mesenchymal transition and stem cell-like traits in cancer cells.
Telomerase activation through induction of telomerase reverse transcriptase (hTERT) contributes to malignant transformation by stabilizing telomeres. Clinical studies demonstrate that higher hTERT expression is associated with cancer progression and poor outcomes, but the underlying mechanism is unclear. Because epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) are key factors in cancer metastasis and relapse, and hTERT has been shown to exhibit multiple biological activities independently of its telomere-lengthening function, we address a potential role of hTERT in EMT and CSCs using gastric cancer (GC) as a model. hTERT overexpression promotes, whereas its inhibition suppresses, EMT and stemness of GC cells, respectively. Transforming growth factor (TGF)-β1 and β-catenin-mediated EMT was abolished by small interfering RNA depletion of hTERT expression. hTERT interacts with β-catenin, enhances its nuclear localization and transcriptional activity, and occupies the β-catenin target vimentin promoter. All these hTERT effects were independent of its telomere-lengthening function or telomerase activity. hTERT and EMT marker expression correlates positively in GC samples. Mouse experiments demonstrate the in vivo stimulation of hTERT on cancer cell colonization. Collectively, hTERT stimulates EMT and induces stemness of cancer cells, thereby promoting cancer metastasis and recurrence. Thus, targeting hTERT may prevent cancer progression by inhibiting EMT and CSCs.


Open-label non-randomized versus double-blind randomized antidepressive treatment: what are the advantages of clinical decision over randomization?
To study, whether and how the results from open and double-blind randomized trials on antidepressants differ. Seventy-one patients were included in a study comparing open, non-randomized, standardized treatment with paroxetine (PAROX) and amitriptyline (AMI) after a minimum of six drug-free days (OPEN). A second group of 56 patients received the same treatment under blind-randomized conditions (BLIND-RANDOM). The course of psychopathology as assessed by the Hamilton Depression Rating Scale was compared using repeated measurements ANOVA-(rm). While the rate of adverse events was higher in the BLIND-RANDOM compared to the OPEN condition, completer-analyses revealed no differences in psychopathological outcome. With similar clinical outcome BLIND-RANDOM trials of antidepressants may expose depressed patients to an increased risk of adverse events, when compared to OPEN conditions. However, the clinical outcome in study completers did not differ between the BLIND-RANDOM and the OPEN condition. Thus, the psychiatrist's choice may have impact on adverse events rather than on clinical outcome of antidepressant treatment.


Periarticular soft tissue calcification and ossification in the septic joint.
We encountered three infants who developed juxta-articular calcification adjacent to the anterolateral aspect of the ilium. All had had drainage of a septic hip using an anterior approach. Calcification was not found among five infants whose septic hips were drained using a posterior approach. Some surgeons who employ the anterior approach facilitate exposure of the joint capsule by elevation of the origins of the sartorius and rectus femoris muscles. We feel this juxta-articular calcification in this setting is a sequla of anterior surgical drainage of the hip in which there has been surgical elevation of the iliac periosteum. It does not imply an unfavorable outcome.


Regulatory B-cell induction by helminths: implications for allergic disease.
Chronic helminth infections are often associated with a reduced prevalence of inflammatory disorders, including allergic diseases. Helminths influence the host immune system by downregulating T-cell responses; the cytokine IL-10 appears to play a central role in this process. Over the last decade, evidence has emerged toward a new regulatory cell type: IL-10-producing B cells, capable of regulating immunity and therefore termed regulatory B cells. Initially, regulatory B cells have been described in autoimmunity models where they dampen inflammation, but recently they were also found in several helminth infection models. Importantly, regulatory B cells have recently been identified in humans, and it has been suggested that patients suffering from autoimmunity have an impaired regulatory B-cell function. As such, it is of therapeutic interest to study the conditions in which IL-10-producing B cells can be induced. Chronic helminth infections appear to hold promise in this context as emerging evidence suggests that helminth-induced regulatory B cells strongly suppress allergic inflammation. In this review, we will discuss the conditions under which regulatory B cells are present, leading to a state of tolerance, as well as the conditions where their absence or functional impairment leads to exacerbated disease. We will summarize their phenotypic characteristics and their mechanisms of action and elaborate on possible mechanisms whereby regulatory B cells can be induced or expanded, as this may open novel avenues for the treatment of inflammatory diseases, such as allergic asthma.


Metafrontier frameworks for studying hospital productivity growth and quality changes.
The objective of this study was to evaluate productivity growth and quality changes among different levels of accredited hospitals. This study used an attribute-incorporating Malmquist productivity index (MPI) under the metafrontier framework. This is the first attempt to compare productivity changes among hospitals operating under different production frontiers. The data consisted of 20 academic medical centers (AMCs), 61 metropolitan hospitals (MPs) and 112 local community hospitals (LCs) in Taiwan during the period 2007-2010. This study measured productivity growth and further identified technological gaps and catch-ups in different groups of hospitals with respect to the metafrontier. At the same time, comparisons of changes in quality among different levels of hospitals were also examined. We found that the sample hospitals of AMCs and MPs experienced productivity improvements mainly due to technological progress, but their efficiency and technology gap ratio (TGR) deteriorated. As for LCs, progress in technology along with improvements in their efficiency and TGR led to the highest productivity upgrade among the three groups of hospitals. We also found that the sample hospitals among the three groups showed improvements in quality. Moreover, hospitals in the local community group exhibited greater quality progress than the AMCs and MPs over the sample period. This paper presents a number of useful decompositions of the metafrontier MPI, which can provide useful insights into changes that are due to efficiency, quality improvements and/or technological changes in the healthcare sector.


The relationship of juvenile lumbar disc disease and Scheuermann's disease.
Between 1969 and 1979 five children were found to have lumbar disc disease and were evaluated for clinically unsuspected thoracic spine abnormalities. Of these five children, two had Scheuermann's disease and one had disc space narrowing associated with Schmorl's nodes. One other had narrowed disc spaces without bony defects, and one had a normal thoracic spine. A unitary concept of childhood lumbar disc disease, Schmorl's nodes and Scheuermann's disease is suggested.


A device that measures the pulling force and vector of delivering a baby.
I sought to demonstrate a new device that measures the pulling on an infant during a vaginal delivery. The Peisner Platform (US Patent 6,684,165; Canadian patent 2,436,154) utilizes Newton's Third Law to measure the force/vector of delivering a baby. Ten patients at term with a singleton fetus in the vertex presentation were recruited for this pilot study. The platform measured the forces/vectors on the fetal head during the delivery. The primary outcomes were the graphs of the force/vector on the fetus and duration of that force. The pulling force exerted on the fetus ranged from 31.7-135.4 N over 8-51 seconds. Force vectors were often negative early, and positive later. This new device, which measures the pulling force and vector of delivering a baby, has been successfully demonstrated.


[Acupuncture for headache].
Acupuncture is being increasingly used as one of the most important non-pharmacological therapies in treatment of chronic pain. Chronic headache, especially migraine and tension headache are diseases frequently encountered. In their treatment acupuncture is a method with very few side effects and is a remarkable alternative or addition in the whole concept of treatment. Open and placebo-controlled studies have shown that acupuncture reduces the frequency and intensity of headache in many patients, as well as the use of drugs. The success rates achieved of about 50-85% are comparable to the results of other methods. In the case of migraine, especially good results are archived by prophylactic treatment with acupuncture during the pain-free period. The concept of treatment depends on the basic rules of traditional Chinese medicine (TCM). Selection of the acupuncture points is primarily determined by the pain site. Long-term success could be confirmed by follow-up examinations six to eighteen months after end of the therapy.


Comparison of responses to artificial spawning of ruffe (Gymnocephalus cernua) specimens captured from their natural habitat to those produced in cultured conditions.
Although ruffe (Gymnocephalus cernua) are widely distributed in Eurasia, in some regions (i.e., North America) ruffe are considered an invasive species. There have been no reports on artificial reproduction of this species. A study, therefore, was conducted to evaluate reproduction of ruffe with results of specimens captured from their natural habitat and cultured (F1 generation) specimens being compared. Spawning specimens from both stocks were treated with hormonal preparations: carp pituitary homogenate (CPH), Ovopel, Ovaprim and human chorionic gonadotropin (hCG) and results were analyzed by comparing response to the specimens of control groups. Spermiation outcomes and sperm motility of the captured and cultured ruffe were similar and with all hormonal treatments, there was a slightly greater sperm motility (55.6 %-57.1 %) in comparison to specimens of control groups (46.7 %-47.1 %). For captured specimens, there was no asynchronous development of oocytes, whereas in cultured specimens 32 % of females had asynchronous development of oocytes. The ovulation rate in specimens of all treated groups was 100 %, whereas specimens in the control groups did not reproductively mature and have ovulations. The latency time from time of hormonal treatments to initiation of reproductive functions depended on the spawning agent used and oocyte maturation stage and there was the shortest latency after using CPH and the longest with hCG treatment. The embryo survival and hatching rates varied with use of different hormonal preparations to induce reproduction: greatest hatching rates with hCG treatment (86.4 %-88.9 %), followed by Ovaprim (78.2 %-80.2 %) and least hatching rate with Ovopel and CPH treatments (66.0 %-67.1 % and 64.0 %-66.0 %, respectively).


Hearing aid functioning in the preschool setting: stepping back in time?
In order for children with hearing impairment to receive maximum benefit from preschool programs, their amplification devices must be functioning appropriately. The purpose of this study, therefore, was to investigate the functionality of hearing aids in a preschool setting. Forty-four hearing aids worn by 24 preschool children, whose ages ranged from three to five years, (mean age=45.2 months, median age=48 months) from four state funded aural/oral habilitation preschools were evaluated using listening checks and visual examinations. Hearing aids passing both evaluations were given a pass rating and those failing one or more of the evaluations were given a fail rating. Causes of fail rates were documented. Over half of the hearing aids tested were determined to have at least one or more problems (n=27). These problems were detected using listening and visual checks. Failure rates based on basic listening and visual checks among the hearing aids examined in this study demonstrated no improvement over those reported in the 1970's. The results re-emphasize the need for a national dialogue on this topic.


Job Satisfaction and Associated Factors Among Health Care Professionals Working in Public Health Facilities in Ethiopia: A Systematic Review.
Job satisfaction is a feeling that measure cognitive and behavioral aspects of workers' towards their job. According to the World Health Organization report, it predicts that 40% of health care professionals' (nurses, midwives, and doctors) will leave their job as a result of job dissatisfaction. Studies were searched systematically using International databases from PubMed, Google Scholar, Cochrane Library, Embase, and CINAHL. The quality of searched articles assessed using the New Castle Ottawa scale for a cross-sectional study design. Statistical analysis was performed by using STATA version 14 software for window and systemic review carried out using a random effect method. The Preferred Reporting Item for Systematic Review and Meta-Analyses (PRISMA) guideline was followed for reporting results. From the total 1120 records screened, 8 studies with 4092 participants who fulfilled the inclusion criteria were included in this systematic review. The estimated pooled prevalence of job satisfaction of health care professionals in Ethiopia was 41.17%. About one in three health care professionals were satisfied. Therefore, the government and health institution should focus on strategies to promote health care professionals' of job satisfaction.


A review on algal biosorbents for heavy metal remediation with different adsorption isotherm models.
Biosorbent composites like chitin, alginate, moss, xanthene, and cotton can be derived from biotic species such as plants, algae, fungi, and bacteria which can be used for the exclusion of both organic and inorganic toxicants from sewage, industrial effluent, polluted soils, and many more. The use of composites in place of raw substrates like alginate and chitin increases the adsorption capacity as CS4CPL1 beads increase the adsorption capacity for copper and nickel from 66.7 mg/g and 15.3 mg/g in the case of alginate microsphere to 719.38 mg/g and 466.07 mg/g respectively. Biosorbent fabricated from algae Chlorella vulgaris having surface area of 12.1 m2/g and pore size of 13.7 nm owing to which it displayed a higher adsorption capacity for Pb 0.433 mmol/g indicating their potential as an efficient biosorbent material. This article contains detailed information related to heavy metals as well as biosorbent that includes different isotherms, kinetics, techniques to estimate heavy metal concentration, removal methods, and adverse health effects caused due to heavy metal pollution. Apart from the above recovery and reuse of biosorbent, correlation with the sustainable development goals has also been included.


Phosphodiesterase Inhibitors for Alzheimer's Disease: A Systematic Review of Clinical Trials and Epidemiology with a Mechanistic Rationale.
Preclinical studies, clinical trials, and reviews suggest increasing 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) with phosphodiesterase inhibitors is disease-modifying in Alzheimer's disease (AD). cAMP/protein kinase A (PKA) and cGMP/protein kinase G (PKG) signaling are disrupted in AD. cAMP/PKA and cGMP/PKG activate cAMP response element binding protein (CREB). CREB binds mitochondrial and nuclear DNA, inducing synaptogenesis, memory, and neuronal survival gene (e.g., brain-derived neurotrophic factor) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α). cAMP/PKA and cGMP/PKG activate Sirtuin-1, which activates PGC1α. PGC1α induces mitochondrial biogenesis and antioxidant genes (e.g.,Nrf2) and represses BACE1. cAMP and cGMP inhibit BACE1-inducing NFκB and tau-phosphorylating GSK3β. We review efficacy-testing clinical trials, epidemiology, and meta-analyses to critically investigate whether phosphodiesteraseinhibitors prevent or treat AD. Caffeine and cilostazol may lower AD risk. Denbufylline and sildenafil clinical trials are promising but preliminary and inconclusive. PF-04447943 and BI 409,306 are ineffective. Vinpocetine, cilostazol, and nicergoline trials are mixed. Deprenyl/selegiline trials show only short-term benefits. Broad-spectrum phosphodiesterase inhibitor propentofylline has been shown in five phase III trials to improve cognition, dementia severity, activities of daily living, and global assessment in mild-to-moderate AD patients on multiple scales, including the ADAS-Cogand the CIBIC-Plus in an 18-month phase III clinical trial. However, two books claimed based on a MedScape article an 18-month phase III trial failed, so propentofylline was discontinued. Now, propentofylline is used to treat canine cognitive dysfunction, which, like AD, involves age-associated wild-type Aβ deposition. Phosphodiesterase inhibitors may prevent and treat AD.


[Bone morphology following plate osteosynthesis as measured by axial tomography].
Previous examinations using computed tomography have shown that no geometrical changes in the cross-section was induced by the plate fixation; bone density was slightly reduced (10% in average) in the entire cross-section and not only next to the plate. A tomographic analysis is presented here about the quality and the amount of bone in the affected leg, compared to the contralateral one.


Pharmacological therapies, lifestyle choices and nitric oxide deficiency: a perfect storm.
Over the past 10 years, despite a slight increase in life expectancy and a decrease in all causes of deaths, the percentage of the US population with heart disease, cancer, diabetes, hypertension and obesity has increased. So even though Americans are living longer, they are plagued by increasing incidences of morbidities. This trend is also reflective of the global population, where 17.3 million people died from cardiovascular disease in 2008, and an estimated 23.6 million are expected to die from this disease in 2030. Whereas access to medical care and management of certain diseases has improved, it is clear that the incidence and treatment of chronic disease has not kept pace. The discovery of nitric oxide (NO) production in the human body is a relatively new advancement of modern medicine. Unfortunately, NO is still not at the forefront of therapy. In the clinical setting, there are no standard laboratory diagnostics for NO status and no prescription therapies to safely and effectively restore NO homeostasis, despite being recognized as the earliest indicator for a number of different chronic diseases. This review will reveal how many modern therapies and western lifestyles actually lead to a decrease in NO homeostasis in patients, from pediatrics to geriatrics. The findings outlined here highlight why nitric oxide homeostasis should be accounted for and considered in the treatment of patients and in the development of new therapies. Understanding NO homeostasis in each patient and how treatments and procedures affect NO homeostasis should allow for better medical care and improved outcomes.


Associations between heart rate variability, peripheral inflammatory markers and major depressive disorder.
Measures for the irregularity of the heartbeat, for example respiratory sinus arrhythmia, have been implicated as a measure for restorative functions of the vegetative nervous system. In the current observational study, we investigated 265 subjects, 70 of whom had a lifetime history of major depression, with a plethysmographic heartbeat monitor, blood sampling, as well as a range of psychiatric questionnaires. Subjects with a history of MDE had significantly reduced respiratory sinus arrhythmia (RSA) as compared to never-depressed controls; in the whole sample, higher RSA went with lower anxiety/fear variables, especially in subscores related to cardiac symptoms as well as being afraid of dying. A reduced RSA was also associated with an increased concentration of cytokines (TNFa, IL1a, IL6, IFNg) and thyroid-stimulating hormone in the serum, pointing to a possible triangular relationship between immune system, vegetative nervous system, and emotional dysregulation. We used a plethysmographic device for the measurement of heartbeat instead of an electrocardiogram, and had a single time point only. This data corroborate the idea that a disequilibrium of the vegetative nervous, especially if accompanied by a dysregulation system in immune function, can increase the risk for depression. Conversely, vagal stimulation and anti-inflammatory treatments may support the treatment with antidepressants.


Mechanistic basis for receptor-mediated pathological α-synuclein fibril cell-to-cell transmission in Parkinson's disease.
The spread of pathological α-synuclein (α-syn) is a crucial event in the progression of Parkinson's disease (PD). Cell surface receptors such as lymphocyte activation gene 3 (LAG3) and amyloid precursor-like protein 1 (APLP1) can preferentially bind α-syn in the amyloid over monomeric state to initiate cell-to-cell transmission. However, the molecular mechanism underlying this selective binding is unknown. Here, we perform an array of biophysical experiments and reveal that LAG3 D1 and APLP1 E1 domains commonly use an alkaline surface to bind the acidic C terminus, especially residues 118 to 140, of α-syn. The formation of amyloid fibrils not only can disrupt the intramolecular interactions between the C terminus and the amyloid-forming core of α-syn but can also condense the C terminus on fibril surface, which remarkably increase the binding affinity of α-syn to the receptors. Based on this mechanism, we find that phosphorylation at serine 129 (pS129), a hallmark modification of pathological α-syn, can further enhance the interaction between α-syn fibrils and the receptors. This finding is further confirmed by the higher efficiency of pS129 fibrils in cellular internalization, seeding, and inducing PD-like α-syn pathology in transgenic mice. Our work illuminates the mechanistic understanding on the spread of pathological α-syn and provides structural information for therapeutic targeting on the interaction of α-syn fibrils and receptors as a potential treatment for PD.


Growth in Cushing syndrome.
Pre- and post-operative growth was analysed in eight children with Cushing syndrome. Six children had Cushing's disease; three of them were treated by bilateral adrenalectomy and three by transphenoidal pituitary adenectomy. One child had an adrenocortical adenoma and another primary adrenocortical nodular dysplasia. The typical cushingoid habitus was not always present during hypercortisolism. In contrast, abnormal deceleration of longitudinal growth and increase in relative weight were constant. The slowing of growth started 0.2-5.1 years before diagnosis. In four children these changes concurred. In three others the excessive weight gain preceded the slowing of growth, by 2.5-7.0 years. In one patient the deceleration appeared first; this was a girl with concomitant coeliac disease. This pattern of growth change occurring before (normal slowing of growth in) late puberty should raise the possibility of hypercortisolism. There was a suggestion of a better growth recovery in Cushing disease after pituitary adenectomy than after bilateral adrenalectomy.


Determination of mercury and methylmercury in hair of the Czech children's population.
The developed method for mercury speciation analysis has been validated and used for the biomonitoring study of mercury species in human hair. Statistical evaluation proved the reliability of simplified determination of inorganic mercury (difference between total mercury and methylmercury). The results of the validation showed that the method is very well suitable for the determination of both species of mercury in hair for biomonitoring purposes. Non-exposed schoolchildren from three areas in the western and central part of the Czech Republic were chosen as the target group. Tenth of a microgram per gram of the total mercury were generally found in the analyzed hair; values higher than 1 microg g(-1) were detected only exceptionally. Comparable results were obtained for two western areas and differed significantly from those for the third area located in the central part of the Czech Republic. In the areas examined, the mean methylmercury contents amounted to 23-46% of the total mercury in the hair. The results confirm an assumption that exposure to mercury does not pose a significant risk to the population in the Czech Republic.


Prognostic variables in head and neck cancer. Tumor site, stage, nodal status, differentiation, and immune status.
Currently the best prognostic indicator of cancer response is that of staging by the American Joint Commission Staging System. This system is most helpful in state I and in stage IV patients as a prognosticator. Caution must be exercised in oral cavity stage I cancers which tend to be more threatening and where further staging techniques should be used. The major need for careful prognostic indicators beyond simple staging is clearly evident in the stage II and stage III group. In this group, the histologic criteria of Jakobsson, the nuclear criteria suggested by Holm, and the immunologic staging parameters discussed here will hopefully better predict survival, and more importantly, guide therapy. Finally, the role of induction chemotherapy as a prognostic indicator itself has great potential and is currently being heavily investigated.


Alginate scaffolds improve functional recovery after spinal cord injury.
In this systematic review and meta-analysis, the use of alginate for the repair of the damaged spinal cord was investigated. After an extensive search of databases including MEDLINE, SCOPUS, EMBASE and Web of Science, an initial screening was performed based on inclusion and exclusion criteria. The full text of related articles was reviewed and data mining was performed. Data were analyzed by calculating the mean of ratios between treated and untreated groups using STATA software. Subgroup analysis was also performed due to heterogeneity. Articles were subjected to quality control and PRISMA guidelines were followed. Twelve studies and 17 experiments were included in the study. After SCI, alginate hydrogel had a moderate effect on motor function recovery (SMD = 0.64; 95% CI 0.28-1.00; p < 0.0001) and alginate scaffolds loaded with drugs, growth factors, or cells on the SCI group compared with untreated SCI animals showed has a strong effect in the treatment of SCI (SMD = 2.82; 95% CI 1.49-4.145; p < 0.0001). Treatment with drug/cell in combination with alginate was more strongly significant compared to the groups treated with drug/cell alone (SMD = 4.55; 95% CI 1.42-7.69; p < 0.0001). Alginate alone or in combination therapy when used as an implant, had a more significant effect than injection. These findings suggest that alginate is an efficient scaffold for functional recovery and even a much better scaffold for drug/cell delivery after SCI.


Scoping review of the relationship between xerostomia and voice quality.
This scoping review aims to synthesize all of the currently available information on how xerostomia correlates with vocal function and the mechanisms that underpin it. Our scoping review used PubMed, Scopus, Embase, and Web of Science databases to review articles published between January 1999 and July 2022 in accordance with the PRISMA-ScR guidelines. In addition to the academic databases, we also conducted a manual search of Google Scholar. Further investigation was conducted on studies that examined the relationship between xerostomia and vocal function. Of the 682 initially identified articles, 21 met our inclusion criteria. Among the included studies, two articles (n = 2) revealed the mechanistic relationship between xerostomia and vocal function. Most studies (n = 12) focused on xerostomia secondary to other underlying conditions or treatments, among which radiotherapy and Sjögren's syndrome were commonly investigated. Seven studies (n = 7) provided details about common vocal parameters measured in studies of xerostomia and the voice. The literature currently lacks publications regarding the relationship between xerostomia and vocal function. Most of the studies included in this review were about xerostomia secondary to other conditions or medical treatments. Therefore, the impacts on the voice that were observed were very multifaceted and the role of xerostomia alone in phonation could not be ascertained. Nevertheless, it is clear that dryness in the mouth plays some role in vocal function and further research should focus on clarifying and finding the underlying mechanism behind this relationship by incorporating high-speed imaging and cepstral peak prominence analyses.


Improved synthesis of 2,2'-dibromo-9,9'-spirobifluorene and its 2,2'-bisdonor-7,7'-bisacceptor-substituted fluorescent derivatives.
Pure 2,2'-Dibromo-9,9'-spirobifluorene was synthesized by a method that did not involve troublesome dibromination of 9,9'-spirobifluorene or Sandmeyer reaction of 2,2'-diamino-9,9'-spirobifluorene. A series of donor-acceptor orthogonally substituted 9,9'-spirobifluorene was subsequently prepared showing rich variation of fluorescence in solution and in solid state. [reaction: see text]


Chlamydia trachomatis contains a protein similar to the Legionella pneumophila mip gene product.
A 27kDa Chlamydia trachomatis L2 protein was characterized by the use of monoclonal antibodies and by two-dimensional gel electrophoresis. The protein was shown to be located in the membrane of reticulate bodies as well as elementary bodies. Its synthesis could be detected from 10 hours post-infection. Cloning and sequence analysis of the distal part of the gene revealed an open reading frame of 175 amino acids. Comparison of the deduced amino acid sequence with the NBRF data base revealed significant homology between the 27 kDa chlamydial membrane protein and the product of the macrophage infectivity potentiator (mip) gene of Legionella pneumophila.


Light-switchable diphtherin transgene system combined with losartan for triple negtative breast cancer therapy based on nano drug delivery system.
Breast cancer is a common malignancy in women. The abnormally dense collagen network in breast cancer forms a therapeutic barrier that hinders the penetration and anti-tumor effect of drugs. To overcome this hurdle, we adopted a therapeutic strategy to treat breast cancer which combined a light-switchable transgene system and losartan. The light-switchable transgene system could regulate expression of the diphtheria toxin A fragment (DTA) gene with a high on/off ratio under blue light and had great potential for spatiotemporally controllable gene expression. We developed a nanoparticle drug delivery system to achieve tumor microenvironment-responsive and targeted delivery of DTA-encoded plasmids (pDTA) to tumor sites via dual targeting to cluster of differentiation-44 and αvβ3 receptors. In vivo studies indicated that the combination of pDTA and losartan reduce the concentration of collagen type I from 5.9 to 1.9 µg/g and decreased the level of active transforming growth factor-β by 75.0% in tumor tissues. Moreover, deeper tumor penetration was achieved, tumor growth was inhibited, and the survival rate was increased. Our combination strategy provides a novel and practical method for clinical treatment of breast cancer.


Prostatic capsule- and seminal-sparing cystectomy for bladder carcinoma: initial results for selected patients.
To evaluate the oncological outcome and functional results of prostate-sparing cystectomy (PSC), proposed for treating bladder cancer, used since 1999 in our institution in an attempt to preserve male sexuality and to increase continence after cystectomy. Between January 1999 and December 2001, 111 men were candidates for cystectomy; 42 were selected for a prostatic capsule- and seminal-sparing cystectomy with orthotopic urinary diversion. All patients had clinically organ-confined tumours (clinical stage </= T2, N0M0). The first stage of the procedure was a transurethral resection of the prostate to exclude the involvement of transitional cell carcinoma (TCC) in the prostate. Eight patients were excluded from PSC because they had TCC (seven) or prostate adenocarcinoma (one). The mean age of the remaining 34 patients was 61 years and all underwent PSC. After a mean follow-up of 26 months, seven patients (21%) had a recurrence; one developed a local recurrence, there were widespread metastases in six (18%), and five had histologically confirmed organ-confined tumour (T1-2N0M0). Rates for daytime and night-time continence were 90% and 85%, and in 29 patients potency was unchanged. These early results suggest that PSC is not equivalent to radical cystoprostatectomy for bladder cancer control, despite marked improvements in the functional results. Moreover, in carefully selected patients this approach appears to dramatically increase an unusually high metastasis rate. Therefore, the indications for PSC should be either clearly well defined or abandoned in these patients.


Patient-Identified Markers of Quality Care: Improving HIV Service Delivery for Older African Americans.
Over 50% of new AIDS/HIV diagnoses are older adults and disproportionately African American people. Longstanding health inequities, driven by the enduring nature of systemic racism, pose challenges to obtaining optimal HIV services. Patient experiences and identities shape the health care experience, yet patient voices are often minimized, including their assessment of quality HIV care. Understanding these markers of care, including facilitators of and barriers to care and engagement, may help enhance the patient voice, potentially improving service delivery and eradicating HIV healthcare disparities. Using a convergent mixed method design, our study identifies patient-identified markers of quality care among older African Americans (N = 35). Measurements of global stress, HIV stigma, and engagement in care were collected, and in-depth qualitative interviews explored the symbols of quality care as well as facilitators of and barriers to care. We identified widespread participant awareness and recognition of quality care, the detection of facilitators and barriers across individual, clinic, and community levels. Facilitators of care include diet, health, relationships, community support, and compassionate HIV care. Barriers to care include health comorbidities, economic, food, and housing insecurity, lack of transportation, and structural racism. Our findings illuminate how the prominence of barriers to care often uproot facilitators of care, creating impediments to HIV service delivery as patients transition through the HIV care continuum. We offer implications for practice and policy, as well as recommendations for reducing structural barriers to care by enhancing the patient voice and for aligning services toward compassionate and inclusive care.


Psychiatric morbidity in social workers' clients. A comparison between an inner-city area and a small town.
The rate of psychiatric disorder in a social services sample in a small town was compared to the rate in an inner-city sample. Nearly 40% of respondents in the small town had a positive General Health Questionnaire score and 37% had case status (ID greater than 5) on the Present State Examination. Most of these were cases of neurotic depression and were generally recognised as such by the social workers. The type of intervention undertaken by social workers differed in the two settings. Small-town social workers were more likely to offer advice, guidance, exploration and mobilisation of resources. The small-town social workers were more likely to have success in helping their clients with problems of social isolation and marital disharmony than were their inner-city counterparts. Mental illness problems, however, showed less improvement than in the inner-city sample, with over one-third of the small-town cases remaining unwell throughout the 12-month follow-up. Both previous psychiatric history and current depression were indicators of a poor outcome. The present findings provide further support for the argument that unless there is close collaboration between social workers, the medical profession, and health care teams, people who present their problems to social services are unlikely to have their mental health problems addressed adequately.


Bioautographic visualization of aminoacylase-1: assignment of the structural gene ACY-1 to chromosome 3 in man.
A bioautographic assay was developed for the visualization of aminoacylase-1 (N-acylamino acid aminohydrolase, ACY-1; EC 18.104.22.168) after zone electrophoresis. Bioautography and species differences in electrophoretic mobility of ACY-1 made it possible to investigate the chromosome assignment of the gene for human ACY-1 using human--mouse somatic cell hybrids. Human ACY-1 segregated concordantly with beta-galactosidase-A (beta GALA; EC 18.104.22.168) but showed discordant segregation with 32 other markers representing 23 linkage groups. The beta GALA gene has been previously assigned to chromosome 3. From this evidence and confirming chromosome analyses, ACY-1 has been assigned to chromosome 3. A genetic polymorphism in the electrophoretic mobility of ACY was observed in mouse strains, demonstrating that this enzyme can be mapped in genetic crosses of Mus musculus.


Analysis of Volumetric Perfusion Quantitative Parameters Using CS-VIBE Breast Dynamic Contrast Enhanced MR Imaging.
To evaluate the diagnostic performance of three-dimensional volume of interest (3D-VOI) perfusion quantitative parameters using CS-VIBE DCE-MRI and investigate the relationship of the prognostic factors. The volumetric perfusion quantitative parameters of Ktrans, Kep, Ve, Vp, of 124 pathologically proven breast masses in 93 patients were obtained using the two-compartment extended Tofts model. Also, the perfusion parameters of AUC, TTP, Emax, wash-in, and washout were automatically calculated using post-processing software. The relationship between the perfusion quantitative parameters and lesion size, pathology, and prognostic factors of malignancy was evaluated. Ktrans and Kep were significantly higher in the malignant than the benign lesions (p < 0.001), and the AUROC of Ktrans and Kep was 0.802 and 0.815, respectively. The area under the DCE curve, TTP, Emax, wash-in, and wash-out were significantly different between the benign and malignant lesions (p < 0.05). In multiple linear regression analysis, Ktrans and Kep were significantly different between benign and malignant tumors. Malignant tumors larger than 2cm were significantly different from those smaller than 2cm in Ktrans, Kep, Vp, area under the DCE curve, TTP, Emax, and wash-in values (p < 0.05). TTP was significantly lower in higher Ki-67 index (p < 0.05). Perfusion quantitative parameters may be applied as a feasible imaging biomarker to discriminate malignant from benign tumors. In malignant lesions, perfusion parameters were not associated with histopathological results but only in tumor size.


Differential effects of progesterone on COX-2 and Mn-SOD expressions are associated with histone acetylation status of the promoter region in human endometrial stromal cells.
Progesterone differently regulates TNFα-induced gene expression of cyclooxygenase-2 (COX-2) and manganese superoxide dismutase (Mn-SOD) in human endometrial stromal cells (ESC). The present study investigated the mechanisms by which TNFα and progesterone affect the expressions of COX-2 and Mn-SOD in ESC. ESC were incubated with TNFα and progesterone. COX-2 and Mn-SOD mRNA expression was determined by real-time RT-PCR. Nuclear factor (NF)-κB binding to the promoter region or histone acetylation status of the NF-κB response element was analyzed by a chromatin immunoprecipitation assay. TNFα increased COX-2 and Mn-SOD mRNA levels. Progesterone (10(-6) M) suppressed TNFα-induced COX-2 mRNA expression, whereas TNFα-induced Mn-SOD expression was not inhibited by progesterone. The inhibitory effect of progesterone was abolished by knockdown of progesterone receptors by small interfering RNA. Chromatin immunoprecipitation assay revealed that TNFα increased NF-κB binding at both the COX-2 promoter and the Mn-SOD enhancer and that progesterone inhibited only the NF-κB binding at the COX-2 promoter. The histone acetylation level of the NF-κB response element of the Mn-SOD enhancer was lower than that of the COX-2 promoter. However, when histone acetylation was induced by histone deacetylase inhibitors, progesterone inhibited the TNFα-induced NF-κB binding to the Mn-SOD enhancer. TNFα increased COX-2 and Mn-SOD expression via NF-κB activation. Progesterone inhibited COX-2 expression by inhibiting the binding of NF-κB to its response element but did not inhibit TNFα-induced Mn-SOD expression. The gene-specific action of progesterone may be due to the difference in chromatin structure at the NF-κB response elements in the COX-2 promoter and Mn-SOD enhancer.


The role of fibreoptic bronchoscopy in the management of respiratory burns.
We found that fibreoptic bronchoscopy was a useful, simple, safe and accurate method in the diagnosis of inhalation injury, determining the type, the site and the extent of damage sustained. The most common mucosal damage was erythema and oedema of the supraglottic and glottic tissues, though in a few cases more severe and extensive injury was seen. Death seemed to be determined largely by the extent of skin burn but since there did not appear to be a close relationship between the severity of skin burn and the presence of inhalation burn, we suggest that the two types of injuries be evaluated separately. The main therapeutic role lies in the assessment and anticipation of imminent upper airway obstruction caused by oedema of the supraglottic tissues and the glottis. Endotracheal intubation could then be carried out promptly. Changes in clinical features and laboratory results were too slow to be of use in the prediction of upper airway obstruction, but could be indirect indicators of lower and peripheral airway injury.


Evaluation of textile dye degradation due to the combined action of enzyme horseradish peroxidase and hydrogen peroxide.
The kinetic parameters of the oxidant action of the combination of enzyme horseradish peroxidase (HRP) with hydrogen peroxide in the degradation of methylene blue dye were investigated. Twenty-one percent of color removal was obtained at pH 5.0 and temperature of 30 °C. Under these conditions, the kinetic parameters K m and V max of enzymatic reactions were determined for hydrogen peroxide in the absence of methylene blue dye (K m = 17.3 mM; V max = 1.97 mM/min) and in the presence of methylene blue dye (K m = 0.27 mM, V max = 0.29 μM/min). By means of analysis of phosphorescence, the presence of reactive oxygen species was detected in the form of singlet oxygen through the redox reaction between HRP and hydrogen peroxide. The existence of this reactive species is directly dependent on the concentration of hydrogen peroxide in the aqueous solution.


Purification and identification of a BMP-like factor from bovine serum.
Myogenic differentiation is suppressed in vitro by unknown factors present in fetal bovine serum (FBS). We found that specific inhibitors of bone morphogenetic proteins (BMPs) stimulated myogenic differentiation even in the presence of 20% FBS, which in turn activated specific BMP signaling. Moreover, these specific BMP inhibitors blocked maturation of osteoblastic cells induced by FBS, indicating that BMP-like factor(s) in serum regulate both myogenic and osteoblastic differentiation. The factor identified had an apparent molecular weight (Mw) of over 100kDa on a Superdex 200 column for molecular sieving HPLC, but an apparent Mw of 33kDa on SDS-PAGE under non-reducing conditions. Analysis of a purified preparation from FBS (5L) by liquid chromatography-tandem mass spectrometry revealed the presence of an amino acid sequence conserved between mature human and murine BMP-4. This is the first study to show that BMP-4 is present in FBS as a large complex.


UK science during rapid change.
When Ottoline Leyser was appointed as the chief executive of UK Research and Innovation (UKRI) in 2020, she acquired a front-row seat for some extraordinary events in United Kingdom and European politics. She took charge of UKRI-which was forged from multiple agencies to unify government-funded research in all fields-after Brexit and during a time of bold moves in the reorganization of science in the UK, continuous turnover in the UK government, and formidable challenges in coordinating with European science. She sat down with me for a candid talk about these matters and a refreshing willingness to explain the issues.


Evaluating metagenomics tools for genome binning with real metagenomic datasets and CAMI datasets.
Shotgun metagenomics based on untargeted sequencing can explore the taxonomic profile and the function of unknown microorganisms in samples, and complement the shortage of amplicon sequencing. Binning assembled sequences into individual groups, which represent microbial genomes, is the key step and a major challenge in metagenomic research. Both supervised and unsupervised machine learning methods have been employed in binning. Genome binning belonging to unsupervised method clusters contigs into individual genome bins by machine learning methods without the assistance of any reference databases. So far a lot of genome binning tools have emerged. Evaluating these genome tools is of great significance to microbiological research. In this study, we evaluate 15 genome binning tools containing 12 original binning tools and 3 refining binning tools by comparing the performance of these tools on chicken gut metagenomic datasets and the first CAMI challenge datasets. For chicken gut metagenomic datasets, original genome binner MetaBat, Groopm2 and Autometa performed better than other original binner, and MetaWrap combined the binning results of them generated the most high-quality genome bins. For CAMI datasets, Groopm2 achieved the highest purity (> 0.9) with good completeness (> 0.8), and reconstructed the most high-quality genome bins among original genome binners. Compared with Groopm2, MetaBat2 had similar performance with higher completeness and lower purity. Genome refining binners DASTool predicated the most high-quality genome bins among all genomes binners. Most genome binner performed well for unique strains. Nonetheless, reconstructing common strains still is a substantial challenge for all genome binner. In conclusion, we tested a set of currently available, state-of-the-art metagenomics hybrid binning tools and provided a guide for selecting tools for metagenomic binning by comparing range of purity, completeness, adjusted rand index, and the number of high-quality reconstructed bins. Furthermore, available information for future binning strategy were concluded.


Non-viral vector as vaccine carrier.
Over the last several years, advances in gene-based delivery technology arising from the field of gene therapy have helped revitalize the field of vaccine development. Genetic vaccination encoding antigen from bacteria, virus, and cancer has shown promise in protective humoral and cellular immunity; however, the potential disadvantages of naked DNA vaccine have reduced the value of the approach. To optimize antigen delivery efficiency as well as vaccine efficacy, the non-viral vector as vaccine carrier, for example, the cationic liposome, has shown particular benefits to circumvent the obstacles that both peptide/protein- and gene-based vaccines have encountered. Liposome-mediated vaccine delivery provides greater efficacy and safer vaccine formulation for the development of vaccine for human use. The success of the liposome-based vaccine has been demonstrated in clinical trials and further human trials are also in progress.


The effects of cisplatin and other divalent platinum compounds on glucose metabolism and pancreatic endocrine function.
Three divalent platinum compounds, cis-dichlorodiammineplatinum (cis-DDP), trans-dichlorodiammineplatinum (trans-DDP), and ammonium tetrachloroplatinate, were examined for their effects on glucose metabolism in male F-344 rats. Rats were treated with a single iv dose of cis-DDP (0, 2.5, or 5 mg/kg), trans-DDP (0, 5, 7.5, or 15 mg/kg) or tetrachloroplatinate (0, 6, or 18 mg/kg). Glucose tolerance was evaluated 2, 4, 7, and 14 days following platinum treatment by serially measuring plasma glucose before and following an ip glucose load. Administration of 5 mg/kg cis-DDP impaired glucose tolerance on Days 2 and 4, but not on Days 7 and 14. Plasma immunoreactive glucagon (IRG) was elevated at all times following cis-DDP treatment and thus was not correlated with the transient impairment in glucose tolerance. Plasma immunoreactive insulin (IRI) response to a glucose load was deficient relative to the degree of hyperglycemia in cis-DDP-treated (5 mg/kg) animals on Days 2 and 4. However, neither histopathological damage of the pancreas nor pancreatic stores of IRI were affected by cis-DDP treatment. In contrast to cis-DDP, equimolar or greater than equimolar doses of trans-DDP or tetrachloroplatinate did not significantly affect glucose tolerance at any time examined. These results indicate that cis-DDP-mediated glucose intolerance is unique to the geometry of the complex and is related to properties other than the presence of a divalent platinum atom. Furthermore, glucose intolerance following cis-DDP treatment appears to be related to a relative deficiency in insulin secretion.


Reduced drug accumulation as a major mechanism of acquired resistance to cisplatin in a human ovarian carcinoma cell line: circumvention studies using novel platinum (II) and (IV) ammine/amine complexes.
Acquired resistance to cisplatin (cis-diamminedichloroplatinum (II)) has been generated in vitro in the 41M human ovarian carcinoma cell line, established from a previously untreated patient. Three cisplatin-resistant variants were selected at approximately 2, 4 and 6-fold resistance (in terms of 50% inhibitory concentrations), in order to study the underlying mechanisms of acquired cisplatin resistance. Compared to the parent line, platinum accumulation following exposure to equimolar concentrations of cisplatin was on average (across the entire concentration range) 2.9, 3.6 and 4.8-fold lower in the 41McisR2, 41McisR4 and 41McisR6 cell lines, respectively. Thus the difference in uptake corresponded closely with their resistance factor in the three resistant variants. Moreover, a significant reduction in platinum accumulation was observed as early as 5 min after exposure to cisplatin in the 41M vs 41McisR6 cell lines. Platinum accumulation was similar in all cell lines following exposure to equitoxic concentrations (2 h IC50) of cisplatin. Enhanced efflux of drug was not observed between the 41M and 41McisR6 cells. In addition, there was no difference in intracellular glutathione (GSH) levels. Our previous studies have shown no indication of metallothionein involvement and the decrease in cisplatin uptake in the 41McisR6 cells was reflected by a similar reduction in DNA interstrand cross-links (ISC) formation. These results suggest that the mechanism of acquired resistance to cisplatin in the 41McisR6 cell line may be predominantly due to reduced drug uptake. The 41McisR6 cells were not found to be cross-resistant to ouabain, a postulated specific inhibitor of sodium-potassium adenosine triphosphatase (Na+, K(+)-ATPase), suggesting that decreased cisplatin accumulation in these cells is probably not regulated by alterations in their Na+, K(+)-ATPase levels, and Na+ potential across the plasma membrane. Cellular accumulation of a novel class of platinum (IV) ammine/cyclohexylamine dicarboxylates, which exhibit enhanced cytotoxicity over cisplatin and completely circumvent resistance to cisplatin in the 41McisR line, was also examined. The data suggests that increased accumulation of these compounds, as a result of their enhanced lipophilicity, could account for the dramatic increase in their potency over cisplatin.


Droplet formation assay for investigating phase-separation mechanisms of RNA Pol II transcription and CTCF functioning.
Clustering of RNA polymerase II carboxy-terminal domain (CTD) and CTCF DNA-binding domains (DBDs) have been viewed as emerging mechanisms of transcription regulation and three-dimensional chromatin organization. In this protocol, we address the need for a quantitative means of investigating phase-separation mechanisms of Pol II transcription and CTCF functioning. We describe steps for protein purification, droplet formation, and automeasuring droplet properties. We then detail quantification during Pol II CTD and CTCF DBD clustering and outline their limitations. For complete details on the use and execution of this protocol, please refer to Wang et al. (2022)1 and Zhou et al. (2022).2.


Auto-transplanted mesenchymal stromal cell fate in periodontal tissue of beagle dogs.
Mesenchymal stromal cells (MSC) possess multilineage differentiation potential and characteristics of self-renewal. It has been reported that MSC can acquire characteristics of cells in the periodontal ligament (PDL) in vitro. Moreover, the transplantation of MSC has been shown to be a promising strategy for treating periodontal defects. However, little is known about the fate of MSC in periodontal tissue in vivo. The aim of this study was to trace the paths of MSC after transplantation into periodontal tissues in vivo. MSC labeled with bromodeoxyuridine (BrdU) were transplanted into periodontal defects of beagle dogs. Six weeks after surgery, the animals were killed and decalcified specimens were prepared. Migration and differentiation of MSC were detected by single/double immunohistochemistry and a combination of immunohistochemistry and in situ hybridization. BrdU-labeled MSC were observed distributing into periodontal tissue that included alveolar bone, PDL, cementum and blood vessels and expressing surface markers typical of osteoblasts and fibroblasts. Cumulatively, our data suggest that MSC migrate throughout periodontal tissue and differentiate into osteoblasts and fibroblasts after transplantation into periodontal defects at 6 weeks in vivo, and have the potential to regenerate periodontal tissue.


Dietary intake among young adolescents in Ontario: associations with vegetarian status and attitude toward health.
This study aimed to describe the dietary intakes of adolescent vegetarians and omnivores and determine if, and how, attitude toward personal health related to food consumption. Among grade 9 students in Ontario, Canada (n = 630), vegetarian status and estimated consumption of foods and food groups were determined by food frequency questionnaire. Personal health was self-categorized as very important (the "health conscious") or somewhat/not important (the "non-health conscious"). The prevalence of vegetarianism was 6.5% (CI = 4.6-8.4%) among females and 1.0% (CI = 0.2-1.8%) among males. Health-conscious omnivores consumed more grain, vegetables and fruit, and milk product than non-health-conscious omnivores (P < 0.05). Health-conscious vegetarians ingested more grain products, vegetables and fruit, and meat and alternatives than non-health-conscious vegetarians (P < 0.05). Among non-health-conscious vegetarians, none consumed two daily servings of meat and alternatives compared to 60.5% of non-health-conscious omnivores (P < 0.001). Among health-conscious vegetarians, milk product consumption was lower than that of health-conscious omnivores (P = 0.015). Large proportions of both vegetarian and omnivore adolescents consumed suboptimal diets. Health consciousness had value as an indicator of dietary adequacy and may be useful as a rudimentary screen for problematic dietary consumption patterns.


Effects of tunicamycin on protein glycosylation and development inVolvox carteri.
The involvement of protein glycosylation in regulation of the development of the multicellular green alga,Volvox carteri, was studied using the antibiotic, tunicamycin. Three specific developmental processes were found to be affected by the antibiotic: reproductive cell maturation; establishment of polar cellular organization during embryogenesis and release of progeny spheroids from the parental spheroids. Tunicamycin inhibited the transfer of GlcNAc-1-phosphate to dolichyl phosphate which is catalyzed byVolvox membrane preparations. Changes in the glycosylation of several secreted and cellular glycoproteins were observed when proteins were labelled with radioactive amino acids and sugars in the absence and presence of tunicamycin and then electrophoresed on sodium dodecylsulfate-polyacrylamide slab gels. The levels of a few secreted proteins were reduced in tunicamycin treated cultures and one protein band appeared exclusively in the treated cells. Tunicamycin treatment also altered the electrophoretic mobility of radio-iodinated surface macromolecules. Binding of concanavalin A by tunicamycin treatedVolvox spheroids was drastically reduced. It is there-fore likely that the aberrant development results from inhibition of protein glycosylation and the consequent changes in the structure of the cellular, secreted and surface glycoproteins.


T cell lymphoblastic lymphoma/leukemia within an adrenocorticotropic hormone and thyroid stimulating hormone positive pituitary adenoma: A cytohistological correlation emphasizing importance of intra-operative squash smear.
We present a rare case of primary pituitary T cell lymphoma/leukemia (T-LBL) in association with adrenocorticotropic hormone (ACTH) and thyroid stimulating hormone (TSH) expressing pituitary adenoma in a 55-year-old woman highlighting the importance of intra-operative squash smears examination. The patient presented with complaints of headache, diminution of vision and recent onset altered sensorium. MRI revealed a mass lesion in the sellar-suprasellar region with non-visualization of pituitary gland separately, extending to involve adjacent structures diagnosed as invasive pituitary macroadenoma. Intra-operative tissue was sent for squash smear examination. The cytology showed a tumor comprising of sheets of immature lymphoid cells intermixed with clusters of pituitary acinar cells with many mitoses and tingible body macrophages. A diagnosis of presence of immature lymphoid cells within the pituitary was offered and differentials of infiltration by lymphoma cells from systemic disease versus primary central nervous lymphoma-like lymphoma arising in the pituitary adenoma were considered. Later paraffin section examination and immunohistochemistry corroborated with the squash findings and a final diagnosis of primary pituitary T cell lymphoma/leukemia in association with ACTH and TSH expressing pituitary adenoma was made. To date, only six cases of primary pituitary T cell lymphomas, including three T-LBL cases, have been reported. This is the seventh case and first one additionally describing cytohistological correlation and importance of intra-operative cytology.


Methylation of the c-myc gene changes during aging process of mice.
The degree of methylation at c-myc proto-oncogene was found to change during aging process of mice by the use of methylation-sensitive restriction enzymes. The spleen DNA showed hypomethylation as mice aged, while hypermethylation was observed in the liver DNA. The brain DNA on the contrary revealed no appreciable difference between young and old mice. When the DNAs were examined at actin and dihydrofolate reductase (DHFR), no significant change was observed. It suggests that an age-related change of oncogene structure may be one of the factors which are related to an age-associated increase of cancer incidence rate.


Characterization of calpain-mediated proteolysis of GluR1 subunits of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors in rat brain.
Previous results have indicated that GluR1 subunits of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors are targets of calpain. In the present study, we determined the effects of calpain treatment of synaptic membranes on GluR1 subunits using western blots with antibodies directed against the C-terminal (C-Ab) and the N-terminal (N-Ab) domains of the proteins, and compared them with the effects of calcium treatment of frozen-thawed brain sections. Calpain treatment of synaptic membranes resulted in a large decrease in the GluR1 band (105 kDa) labeled with C-Ab and in the formation of a doublet band labeled with N-Ab due to the appearance of a new species of GluR1 (98 kDa). These effects were blocked almost completely by calpain inhibitors. Calpain-induced changes in GluR1 immunological properties were not associated with modifications of [3H]AMPA or 6-cyano-7-[3H]nitroquinoxaline-2,3-dione ([3H]CNOX) binding. Treatment of frozen-thawed brain sections with concentrations of calcium as low as 0.2 mM resulted in a large decrease in the 105-kDa GluR1 band and in the concurrent appearance of the 98-kDa band. This treatment was associated with increased [3H]-AMPA and [3H]CNOX binding. These results suggest that there exist several types/states of GluR1 subunits exhibiting different sensitivities to calpain. Our data also indicate the existence of additional calcium-dependent processes regulating the characteristics of receptors in intact tissues.


Complete Genome Sequence of a Porcine Polyomavirus from Nasal Swabs of Pigs with Respiratory Disease.
Metagenomic sequencing of pooled nasal swabs from pigs with unexplained respiratory disease identified a large number of reads mapping to a previously uncharacterized porcine polyomavirus. Sus scrofa polyomavirus 2 was most closely related to betapolyomaviruses frequently detected in mammalian respiratory samples.


Interplay of mycolic acids, antimycobacterial compounds and pulmonary surfactant membrane: a biophysical approach to disease.
This work focuses on the interaction of mycolic acids (MAs) and two antimycobacterial compounds (Rifabutin and N'-acetyl-Rifabutin) at the pulmonary membrane level to convey a biophysical perspective of their role in disease. For this purpose, accurate biophysical techniques (Langmuir isotherms, Brewster angle microscopy, and polarization-modulation infrared reflection spectroscopy) and lipid model systems were used to mimic biomembranes: MAs mimic bacterial lipids of the Mycobacterium tuberculosis (MTb) membrane, whereas Curosurf® was used as the human pulmonary surfactant (PS) membrane model. The results obtained show that high quantities of MAs are responsible for significant changes on PS biophysical properties. At the dynamic inspiratory surface tension, high amounts of MAs decrease the order of the lipid monolayer, which appears to be a concentration dependent effect. These results suggest that the amount of MAs might play a critical role in the initial access of the bacteria to their targets. Both molecules also interact with the PS monolayer at the dynamic inspiratory surface. However, in the presence of higher amounts of MAs, both compounds improve the phospholipid packing and, therefore, the order of the lipid surfactant monolayer. In summary, this work discloses the putative protective effects of antimycobacterial compounds against the MAs induced biophysical impairment of PS lipid monolayers. These protective effects are most of the times overlooked, but can constitute an additional therapeutic value in the treatment of pulmonary tuberculosis (Tb) and may provide significant insights for the design of new and more efficient anti-Tb drugs based on their behavior as membrane ordering agents.


Improvement of the CRISPR-Cas9 mediated gene disruption and large DNA fragment deletion based on a chimeric promoter in Acremonium chrysogenum.
Acremonium chrysogenum has been employed in the industrial production of cephalosporin C (CPC). However, there are still some impediments to understanding the regulation of CPC biosynthesis and improving strains due to the difficulty of genetic manipulation in A. chrysogenum, especially in the CPC high-producing strain C10. Here, an improved CRISPR-Cas9 system was constructed based on an U6/tRNA chimeric promoter. Using this system, high efficiency for single gene disruption was achieved in C10. In addition, double loci were simultaneously targeted when supplying with the homology-directed repair templates (donor DNAs). Based on this system, large DNA fragments up to 31.5 kb for the yellow compound sorbicillinoid biosynthesis were successfully deleted with high efficiency. Furthermore, CPC production was significantly enhanced when the sorbicillinoid biosynthetic genes were knocked out. This study provides a powerful tool for gene editing and strain improvement in A. chrysogenum.


DFT study of adsorbing SO2, NO2, and NH3 gases based on pristine and carbon-doped Al24N24 nanocages.
The adsorption of SO2, NO2, and NH3 toxic gases on Al24N24 and Al24N23C nanocages was investigated by using density functional theory (DFT) calculations. The adsorption energies, frontier orbitals, charge transfer using natural bonding orbital (NBO) analysis, dipole moment, the partial density of states (PDOS), thermodynamic relationships, non-covalent interaction (NCI), and quantum theory of atoms in molecules (QTAIM) were considered. The results reveal that carbon-doped Al24N24 nanocage increases the adsorption energies for SO2 and NO2 gases while decreasing the adsorption energy of NH3 gas. The ΔG for all configurations were negative except the configurations A1 and G2 confirming the weak adsorption of these two complexes. In conclusion, Al24N24 and Al24N23C nanocages are in general promising adsorbents for the removal of SO2, NO2, and NH3 toxic gases. The Al24N24 and Al24N23C nanocages are ideal electronic materials.


Cognitive subtypes of probable Alzheimer's disease robustly identified in four cohorts.
Patients with Alzheimer's disease (AD) show heterogeneity in profile of cognitive impairment. We aimed to identify cognitive subtypes in four large AD cohorts using a data-driven clustering approach. We included probable AD dementia patients from the Amsterdam Dementia Cohort (n = 496), Alzheimer's Disease Neuroimaging Initiative (n = 376), German Dementia Competence Network (n = 521), and University of California, San Francisco (n = 589). Neuropsychological data were clustered using nonnegative matrix factorization. We explored clinical and neurobiological characteristics of identified clusters. In each cohort, a two-clusters solution best fitted the data (cophenetic correlation >0.9): one cluster was memory-impaired and the other relatively memory spared. Pooled analyses showed that the memory-spared clusters (29%-52% of patients) were younger, more often apolipoprotein E (APOE) ɛ4 negative, and had more severe posterior atrophy compared with the memory-impaired clusters (all P < .05). We could identify two robust cognitive clusters in four independent large cohorts with distinct clinical characteristics.


Soluble proteins of guinea pig seminal vesicle lumen: purification and partial characterization.
Luminal contents of guinea pig seminal vesicle were extracted with 0.154 M NaCl and the soluble protein fraction was studied by DEAE-cellulose and Sephadex G-100 column chromatography; anionic, cationic, and SDS-polyarcylamide disc gel electrophoresis; isoelectric focusing; molecular weight determinations by SDS-polyacrylamide disc gel electrophoresis; analysis for neutral carbohydrate; sucrose density-gradient centrifugation for determination of sedimentation coefficients; and amino acid analyses. Four protein fractions (referred to as proteins 1, 2, 3, and 4 in order to elution) were obtained by DEAE-cellulose column chromatography. Proteins 1, 2, and 4 gave single major bands in multiple disc gel electrophoretic systems. Protein 3 gave one major band and one minor component believed to be a fragment of a primary vesicular protein. Protein 1 is very basic and probably represents the clotting protein of guinea pig semen. The three nonclotting proteins could not be detected in serum and are probably intrinsic to seminal vesicle epithelium. All four proteins were found in animals weighing 700 g or more; only two of the three nonclotting proteins were found in more than half of the younger animals. This makes it even more likely that one or more of the nonclotting proteinc could serve as a useful gene marker in studies of androgen mechanisms.


Enrichment of rat hepatic organelles by vitamin E administered subcutaneously.
Novel modes of administering antioxidants to improve delivery to targeted tissues or cells may be advantageous in preventing oxidant-induced pathologies. Vitamin E (alpha-tocopherol) has been shown to be protective in several models of liver injury. The objectives of this study were: (1) to determine if subcutaneously (s.q.) administered emulsified vitamin E enriched liver and hepatic subcellular fractions with the antioxidant and (2) to carry out a time-dependent analysis of serum and tissue vitamin E in rats receiving daily s.q. vitamin E. In the first experiment rats injected daily s.q. with emulsified vitamin E for 9 d increased serum, total liver, liver mitochondria, and liver microsomes by 8-, 16-, 30-, and 29-fold, respectively, compared with placebo injections. Similar enrichment was observed after intramuscular injections. In the second experiment, daily doses of s.q. vitamin E increased liver concentrations 40-fold by 9 d, which decreased to 22-fold by 18 d, whereas serum adjusted vitamin E levels maximized with a 24-fold increase by day 3 and plateaued thereafter. In conclusion, s.q. administration of emulsified vitamin E to rats resulted in substantially elevated serum and liver concentrations of alpha-tocopherol compared with levels achievable by dietary supplementation. The s.q. route of administration is a potentially effective parenteral mode of delivery of vitamin E for conditions in which hepatic oxidative stress is present.


Comparison of guanidine hydrochloride (GdnHCl) and urea denaturation on inactivation and unfolding of human placental cystatin (HPC).
The activity and conformational change of human placental cystatin (HPC), a low molecular weight thiol proteinase inhibitor (12,500) has been investigated in presence of guanidine hydrochloride (GdnHCl) and urea. The denaturation of HPC was followed by activity measurements, fluorescence spectroscopy and Circular Dichroism (CD) studies. Increasing the denaturant concentration significantly enhanced the inactivation and unfolding of HPC. The enzyme was 50% inactivated at 1.5 M GdnHCl or 3 M urea. Up to 1.5 M GdnHCl concentration there was quenching of fluorescence intensity compared to native form however at 2 M concentration intensity increased and emission maxima had 5 nm red shift with complete unfolding in 4-6 M range. The mid point of transition was in the region of 1.5-2 M. In case of urea denaturation, the fluorescence intensity increased gradually with increase in the concentration of denaturant. The protein unfolded completely in 6-8 M concentration of urea with a mid-point of transition at 3 M. CD spectroscopy shows that the ellipticity of HPC has increased compared to that of native up to 1.5 M GdnHCl and then there is gradual decrease in ellipticity from 2 to 5 M concentration. At 6 M GdnHCl the protein had random coil conformation. For urea the ellipticity decreases with increase in concentration showing a sigmoidal shaped transition curve with little change up to 1 M urea. The protein greatly loses its structure at 6 M urea and at 8 M it is a random coil. The urea induced denaturation follows two-state rule in which Native-->Denatured state transition occurs in a single step whereas in case of GdnHCl, intermediates or non-native states are observed at lower concentrations of denaturant. These intermediate states are possibly due to stabilizing properties of guanidine cation (Gdn+) at lower concentrations, whereas at higher concentrations it acts as a classical denaturant.


Antibiotic-associated pseudomembranous colitis in children.
Antibiotic-associated colitis is a rare complication of antimicrobial therapy in children. Ampicillin, penicillin, and clindamycin are the drugs most frequently reported to cause pseudomembranous colitis in pediatric patients. This diagnosis should be suspected in any child with significant diarrhea during or after a course of antimicrobial therapy, especially if the diarrhea persists after the drug has been discontinued. The diagnosis is established by proctoscopic findings of typical plaques of pseudomembranes. Most cases resolve promptly when the implicated antibiotic is stopped; however, the disease can be fulminant, progressing to toxic megacolon, peritonitis, and shock. Therapy of patients who have persistent diarrhea after the offending antibiotic has been discontinued should include oral vancomycin. Close fluid management is crucial for survival.


Isolation and characterization of the human mismatch repair gene hMSH2 promoter region.
Hereditary nonpolyposis colorectal cancer (HN-PCC) is one of man's commonest hereditary diseases. Several studies have identified four responsible genes that are involved in a process known as DNA mismatch repair; hMSH2 is the most important of these four genes. In addition to mutational analysis of these genes, investigations of transcriptional regulatory mechanisms are important. Therefore, our purpose has been to isolate the hMSH2 promoter region. Using direct sequencing of P1 recombinant DNA we have characterized 1100 bp of the hMSH2 promoter.


Interoceptive inference: From computational neuroscience to clinic.
The central and autonomic nervous systems can be defined by their anatomical, functional and neurochemical characteristics, but neither functions in isolation. For example, fundamental components of autonomically mediated homeostatic processes are afferent interoceptive signals reporting the internal state of the body and efferent signals acting on interoceptive feedback assimilated by the brain. Recent predictive coding (interoceptive inference) models formulate interoception in terms of embodied predictive processes that support emotion and selfhood. We propose interoception may serve as a way to investigate holistic nervous system function and dysfunction in disorders of brain, body and behaviour. We appeal to predictive coding and (active) interoceptive inference, to describe the homeostatic functions of the central and autonomic nervous systems. We do so by (i) reviewing the active inference formulation of interoceptive and autonomic function, (ii) survey clinical applications of this formulation and (iii) describe how it offers an integrative approach to human physiology; particularly, interactions between the central and peripheral nervous systems in health and disease.


Apolipoprotein A-I mimetic peptides: potential role in atherosclerosis management.
Atherothrombotic vascular disease continues to be a leading cause of morbidity and mortality in much of the world. Although a healthy lifestyle and low-density lipoprotein cholesterol lowering significantly reduce cardiovascular morbidity and mortality, substantial number of adverse vasoocclusive events continue to occur. These realities have brought attention to additional therapies that could further reduce cardiovascular events. High-density lipoprotein (HDL)/apolipoprotein A-I (apo A-I)-based therapies are a potential therapeutic strategy against atherothrombotic vascular disease because of the known inverse relationship between HDL cholesterol and coronary heart disease, favorable and pleotrophic biologic effects of HDL/apo A-I, results of preclinical experimental studies, and emerging proof of concept in clinical studies. A variety of HDL/apo A-I-based therapies are currently under investigation, including synthetic peptides that mimic the function of HDL. Such apo A-I mimetic peptides are the focus of this review.


[Inhibition of secondary increase of intraocular pressure following cyclokryocoagulation (author's transl)].
Prostaglandin mediated transient increase in intraocular pressure following cryokoagulation of the ciliary body in rabbits was completely inhibited by preoperative administration of Aspisol (D, L-Lysin-mono-(acetylsalicylat)). To avoid additional increase in intraocular pressure in patients chosen for cyclocryotherapy, pretreatment with Aspisol could prove to be effective.


Developmental and androgenic regulation of chromatin regulators EZH2 and ANCCA/ATAD2 in the prostate Via MLL histone methylase complex.
Chromatin regulators ANCCA and EZH2 are overexpressed in prostate cancer and play crucial roles in androgen-stimulated and castration-refractory prostate tumor growth and survival. However, how their expression is regulated in the tumors and whether they play a role in prostate development remains unclear. Prostate tissue from different developmental stages of mouse and human were examined by IHC, qRT-PCR and Western for expression of ANCCA, EZH2, and Ki-67. Animals were castrated and T-implanted for the expression response in normal prostate and tumors. siRNA knockdown and ChIP were performed for the mechanism of ANCCA regulation of EZH2. In contrast to their very low level expression in adult prostate, ANCCA and EZH2 are strongly expressed in the epithelium and mesenchyme of mouse and human UGS. Their expression becomes more restricted to epithelial cells during later development and displays a second peak during puberty, which correlates with the proliferative status of the epithelium. Importantly, their expression in normal prostate and tumors is strongly suppressed by castration and markedly induced by testosterone replacement. While androgen suppresses EZH2 in CRPC cells, in LNCaP cells, physiological concentrations of androgen stimulate expression of PRC2 genes (EZH2, SUZ12, and EED), which is mediated by androgen-induced ANCCA and involves E2F and histone H3K4me3 methylase MLL1 complex. EZH2 and ANCCA are androgen regulated and strongly expressed in early prostate morphogenesis and during puberty, suggesting their important role in prostate development. Regulation of EZH2 by ANCCA emphasizes bromodomain protein ANCCA as a potential therapeutic target against prostate cancer.


Increased interstitial fluid in periventricular and deep white matter hyperintensities in patients with suspected idiopathic normal pressure hydrocephalus.
Periventricular white matter changes are common in patients with idiopathic normal pressure hydrocephalus (iNPH) and considered to represent focally elevated interstitial fluid. We compared diffusion measures in periventricular hyperintensities in patients with imaging features of iNPH to patients without. The hypothesis is that periventricular hyperintensities in patients with presumed iNPH show higher water content than in patients without imaging features of iNPH. 21 patients with iNPH Radscale 7-12 ("high probability of iNPH") and 10 patients with iNPH Radscale 2-4 ("low probability of iNPH") were examined with a neurodegeneration imaging protocol including a diffusion microstructure imaging sequence. Periventricular hyperintensities and deep white matter hyperintensities were segmented and diffusion measures were compared. In patients with imaging features of iNPH, the free water content in periventricular hyperintensities was significantly higher compared to the control group (p = 0.005). This effect was also detectable in deep white matter hyperintensities (p = 0.024). Total brain volumes and total gray or white matter volumes did not differ between the groups. Periventricular cap free water fraction was highly discriminative regarding patients with presumed iNPH and controls with an ROC AUC of 0.933. Quantitative diffusion microstructure imaging shows elevated water content in periventricular hyperintensities in patients with imaging features of iNPH, which could be the imaging correlate for pathologic fluid accumulation and may be used as an imaging biomarker in the future.


Outcome Measurement for Distal Radius Fractures.
Distal radius fractures (DRFs) are among the most common upper extremity injuries. Multiple medical conditions now are evaluated by standardized outcome sets that enable comparability. Recent international working groups have provided consensus statements for outcomes measurement after DRFs. These statements emphasized the growing importance of patient-reported outcome measures as well as traditional measures, including pain assessment, radiographic alignment, performance, and assessment of complications. A standardized instrument and timeline for measuring outcomes following DRFs offers clinicians, researchers, and health care economists a powerful tool. This article reviews the current evidence and provides recommendations for a DRF standardized outcome set.


Utility of the fractional flow reserve in the evaluation of angiographically moderate in-stent restenosis.
The evaluation of in-stent restenosis (ISR) is usually based on angiographic quantification. This evaluation is sometimes difficult and it has not an accurate clinical correlation. Fractional flow reserve (FFR) measured by intracoronary pressure wire has demonstrated its value in determining the functional repercussion of coronary stenosis. The aim of this study was to evaluate the relation between quantitative angiography-FFR in borderline in-stent restenotic lesions and the accuracy of FFR in deciding the treatment of ISR. Quantitative angiographic values of 65 lesions in 62 patients with angiographically moderate ISR are compared with the FFR value obtained by pressure wire. An FFR value<0.75 was considered significant. Patients with non-revascularized ISR (FFR > or = 0.75) were clinically followed during a year. An FFR value > or = 0.75 was obtained in 41 lesions (63%), 21 of them with stenosis > or = 50%. The co-efficient of correlation between parameters of quantitative angiography and FFR value was <0.5. No events related to the non-treated lesions were observed. A poor correlation between angiographic quantification and FFR of moderate ISR was found. Conservative management of moderate 40-70% in-stent restenotic lesions with FFR value > or = 0.75 is safe avoiding unnecessary revascularizations based solely on the angiography.


Dose measurements nearby low energy electronic brachytherapy sources using radiochromic film.
We investigate the effect of the GafChromic™ film EBT3 model absorbed dose energy response when used for dose measurements around low-energy photon sources. Monte Carlo based correction procedure in synergy with appropriate calibration curves was shown to provide more accurate absorbed dose (either relative or absolute). An assessment was made of possible dose errors that might be encountered if such energy dependent response is ignored. We measured PDDs in water from a Xoft 50 kVp source using EBT3 film, and compared to PDD measurements acquired with a PTW-TN34013 parallel-plate ionization chamber. For the x-ray source, we simulated spectra using the EGSnrc (BEAMnrc) Monte Carlo code, and calculated Half Value Layer (HVL) at different distances from the source in water. Measurement strips of EBT3 film were positioned at distances of 2-6 cm from the Xoft source in a water phantom using a custom-made holder and irradiated simultaneously. Our results show that film calibration curves obtained at beam qualities near the effective energy of the Xoft 50 kVp source in water lead to variation in absorbed dose energy dependence of the response of around 5%. However, if the calibration curve was established in an MV beam quality, the error in absorbed dose could be as large as 20%. Accurate dose measurements using radiochromic films at low photon energies require that the radiochromic film dosimetry system be calibrated at appropriate corresponding low energies, as large absorbed dose errors are expected when film calibration is performed in MV beam qualities.


Case Report: Short-Term Application of Topical Imiquimod Is Practical for Chromoblastomycosis.
Chromoblastomycosis is a chronic cutaneous fungal infection caused by dematiaceous fungi. It is a therapeutic challenge because of the lack of specific treatments. We describe a refractory case of chromoblastomycosis in which the lesion did not respond to initial treatment, but then use of topical imiquimod cured the lesion successfully.


Serum free culture for the expansion and study of type 2 innate lymphoid cells.
Type 2 innate lymphoid cells (ILC2s) were discovered approximately ten years ago and their clinical relevance is gaining greater importance. However, their successful isolation from mammalian tissues and in vitro culture and expansion continues to pose challenges. This is partly due to their scarcity compared to other leukocyte populations, but also because our current knowledge of ILC2 biology is incomplete. This study is focused on ST2+ IL-25Rlo lung resident ILC2s and demonstrate for the first time a methodology allowing mouse type 2 innate lymphoid cells to be cultured, and their numbers expanded in serum-free medium supplemented with Interleukins IL-33, IL-2, IL-7 and TSLP. The procedures described methods to isolate ILC2s and support their growth for up to a week while maintaining their phenotype. During this time, they significantly expand from low to high cell concentrations. Furthermore, for the first time, sub-cultures of primary ILC2 purifications in larger 24- and 6-well plates were undertaken in order to compare their growth in other media. In culture, ILC2s had doubling times of 21 h, a growth rate of 0.032 h-1 and could be sub-cultured in early or late phases of exponential growth. These studies form the basis for expanding ILC2 populations that will facilitate the study and potential applications of these rare cells under defined, serum-free conditions.


Risk and protective factors distinguishing profiles of adolescent peer and dating violence perpetration.
Violence profiles were created on the basis of whether adolescents used violence against both peers and dates, against dates but not peers, against peers but not dates, or against neither peers nor dates. We determined (1) whether risk and protective factors from five domains (individual attributes and behaviors, the peer, family, school, and neighborhood contexts), based primarily on social learning and social control theories, were associated with violence profiles, (2) whether factors distinguishing profiles varied by gender, and (3) which of the domains was most important in distinguishing profiles. Data are from adolescents in grades 8 through 10 from schools in three nonmetropolitan Counties (n = 2,907). Adolescents who used violence against both peers and dates used more of each type of violence compared with those who used only one type of violence. They also had more maladaptive risk and protective scores than adolescents perpetrating only peer violence or neither type of violence, although they had few differences from those perpetrating only dating violence. Most social learning theory risk factors and social control theory protective factors distinguished the profiles as did psychological attributes and substance use. Factors distinguishing profile membership were generally the same for boys and girls, although some associations were stronger for boys than for girls. The model fit statistics suggest that the individual attributes and behaviors and the peer context models fit the data the best. Suggestions for developing theoretically based interventions for preventing both peer and dating violence are presented.


Integrated biorefinery development using winery waste streams for the production of bacterial cellulose, succinic acid and value-added fractions.
An integrated biorefinery has been developed using winery wastes (grape pomace-GP, stalks-GS, wine lees-WL). Bacterial cellulose was produced from GP extracted free sugars. Grape-seed oil and polyphenols were extracted from GP. Experimental design was employed to optimize lignin removal (50.8%) from mixtures of remaining GP solids and GS via NaOH (1.19% w/v) treatment at 70°C for 30 min. Delignification liquid contained condensed tannins with 76% Stiasny number. Enzymatic hydrolysis produced a sugar-rich hydrolysate (40.2 g/L sugars). Ethanol, antioxidants, tartaric acid and nutrient-rich hydrolysate were produced from WL. The crude hydrolysates were used in fed-batch Actinobacillus succinogenes cultures for 37.2 g/L succinic acid production. The biorefinery produces 42.65 g bacterial cellulose, 24.3 g oil, 40.3 g phenolic-rich extract with 1.41 Antioxidant Activity Index, 80.2 g ethanol, 624.8 g crude tannin extract, 20.03 g tartaric acid and 157.8 g succinic acid from 1 kg of each waste stream.


Design, synthesis and evaluation of anti-CD38 antibody drug conjugate based on Daratumumab and maytansinoid.
Daratumumab, an FDA approved antibody drug, displays specific targeting ability to abnormal white blood cells overexpressing CD38 and provides efficacious therapy for multiple myeloma. Here, in order to achieve enhanced remission of multiple myeloma, we designed Dara-DM4, antibody drug conjugates (ADCs) by conjugating Daratumumab and DM4 via a disulfide linker. Dara-DM4 showed significantly higher cellular uptake and inhibitory efficacy on MM1S cells that overexpressing CD38 with an IC50 of 0.88 µg/mL post 72 hr treatment. These results support a promising ADCs strategy for multiple myeloma treatment.