The canine kallikrein-related peptidases 9 and 10: structural characterization and expression in mammary cancer.
Human kallikrein-related peptidases are serine proteases, with diverse, yet poorly defined, roles in carcinogenesis. Recently, we have suggested that the dog may represent a suitable animal model for studying kallikrein (KLK) functions in cancer. The initial objective of the present study was to investigate KLK10 expression in cancerous and noncancerous canine mammary tissues. Our results revealed that the in silico predicted canine KLK10 mRNA sequence (GenBank accession No. XM_541467) is not accurate. Specifically, the predicted mRNA harbors a 183-bp segment, which constitutes part of (CANFA)KLK10 intron I, and a 756-bp sequence that corresponds to the nonpreviously characterized (CANFA)KLK9 coding region. In this report we experimentally determined the coding regions of canine KLK9 and KLK10, which were shown to exhibit high homology to their human counterparts and possess all KLK-defining features. For (CANFA)KLK9, other than the classical form of the gene, three more alternatively spliced variants bearing exon 3 skipping and/or intron I retention were identified. The classical form and variant 1 of KLK9, as well as KLK10, were found to be widely expressed among all tissues examined. Lower positivity rates were detected for KLK9 variants 2 and 3. None of these transcripts, however, showed any preferential or differential expression between tumor and normal tissues. Interestingly, (CANFA)KLK9 and (CANFA)KLK10 were concurrently expressed in almost all tissue samples; this suggests a possible participation of these serine proteases in a common proteolytic cascade. Overall, this is the first study that experimentally characterizes canine KLK9 and KLK10 and demonstrates their expression in normal and malignant tissues.


Associations between psychosis endophenotypes across brain functional, structural, and cognitive domains.
A range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related. This multi-centre study includes 8754 participants: 2212 people with a psychotic disorder, 1487 unaffected relatives of probands, and 5055 healthy controls. We investigated cognition [digit span (N = 3127), block design (N = 5491), and the Rey Auditory Verbal Learning Test (N = 3543)], electrophysiology [P300 amplitude and latency (N = 1102)], and neuroanatomy [lateral ventricular volume (N = 1721)]. We used linear regression to assess the interrelationships between endophenotypes. The P300 amplitude and latency were not associated (regression coef. -0.06, 95% CI -0.12 to 0.01, p = 0.060), and P300 amplitude was positively associated with block design (coef. 0.19, 95% CI 0.10-0.28, p 0.38). All the cognitive endophenotypes were associated with each other in the expected directions (all p < 0.001). Lastly, the relationships between pairs of endophenotypes were consistent in all three participant groups, differing for some of the cognitive pairings only in the strengths of the relationships. The P300 amplitude and latency are independent endophenotypes; the former indexing spatial visualisation and working memory, and the latter is hypothesised to index basic processing speed. Individuals with psychotic illnesses, their unaffected relatives, and healthy controls all show similar patterns of associations between endophenotypes, endorsing the theory of a continuum of psychosis liability across the population.


Analysis of the plasma elimination kinetics and conformational stabilities of native, proteinase-complexed, and reactive site cleaved serpins: comparison of alpha 1-proteinase inhibitor, alpha 1-antichymotrypsin, antithrombin III, alpha 2-antiplasmin, angiotensinogen, and ovalbumin.
Proteinase inhibitors of the serpin superfamily may exist in one of three distinct conformations: the native form, a fully active protein with the reactive site loop intact; the proteolytically modified form in which inhibitory capacity is abolished; and the proteinase-complexed form, a stable equimolar complex between the inhibitor and a target proteinase. Here, the specificity and kinetics of the plasma elimination of different serpin conformations are compared. Proteinase-complexed serpins were rapidly cleared from the circulation. However, the native and modified forms were not cleared rapidly, indicating that the receptor-mediated pathways which recognize the complexes fail to recognize the native and modified forms. This result suggests that significant structural differences exist between modified and proteinase-complexed serpins. The structural differences were probed by using transverse urea gradient gel electrophoresis, a technique that allows comparisons of the conformational stabilities of proteins. With the exception of the noninhibitory serpins ovalbumin and angiotensinogen, the modified and proteinase-complexed serpins were both stabilized thermodynamically compared to the native forms. In addition, the proteinase component of the serpin-proteinase complex was usually thermodynamically stabilized. These data are used to compare the conformations of serpin-proteinase complexes with those of native and modified serpins; they are discussed in terms of a model whereby serpins inhibit proteinases in a manner similar to that described for other types of protein inhibitors of serine proteinases.


Postactivation Performance Enhancement of Amateur Boxers' Punch Force and Neuromuscular Performance Following 2 Upper-Body Conditioning Activities.
The purpose of this study was to assess the efficacy of upper-body punch-specific isometric (ISO) and elastic resistance (ER) conditioning activities (CAs) on the punch force and neuromuscular performance of amateur boxers. Ten male senior elite amateur boxers (19.7 [1.2]| y; height 180.9 [7.0] cm; mass 78.7 [9.6] kg) visited the laboratory on 4 separate occasions. Initially, the participants performed baseline physical tests comprising bench-press 1-repetition maximum and countermovement jumps. On the other 3 occasions, the boxers performed maximal punches against a vertically mounted force plate and maximal countermovement jumps prior to and following an ISO or ER CA, as well as a control trial. No interactions between CA × time were found in all performance variables. As observed by mean changes, effect sizes, and signal:noise ratio, both the ISO and ER, but not the control trial, consistently produced small to moderate, worthwhile increases in punch force and rate of force development, with the greatest increases in performance typically observed in the ISO trial. No meaningful improvements were observed in countermovement jump performance in all trials, indicative of a localized postactivation performance enhancement effect. In conclusion, the ISO and ER CAs may be implemented in an amateur boxers' warm-up to acutely enhance punch-force variables, although the ISO punch appears to be the superior CA to improve punch-specific performance. The CAs used in the present study may also be relevant to other combat sports inclusive of a striking element.


The Contrast of Color: Why the Black Community Continues to Suffer Health Disparities.
The evidence of racial health disparities is profound. Much attention has been given to the disparity in maternal morbidity and mortality experienced by Black mothers. The disparity in Black lives lost from coronavirus disease 2019 (COVID-19) has further highlighted the disparity in health outcomes for Black people. Although COVID-19 is a new disease, the reason for the health disparity is the same as in maternal morbidity and mortality: implicit bias and structural racism. Implicit bias among health care professionals leads to disparities in how health care is delivered. Generations of structural racism perpetuated through racial residential segregation, economic suppression, and health care inequality have normalized the poorer health outcomes for Black Americans. It is easy to dismiss these issues as someone else's problem, because health care professionals often fail to acknowledge the effect of implicit bias in their own practices. We all need to be highly critical of our own practices and look introspectively for implicit bias to find the cure. Health care organizations must invest time and resources into investigating the structural racism that exists within our own walls.


Serologic microbial associated markers can predict Crohn's disease behaviour years before disease diagnosis.
Patients with Crohn's disease (CD) have serologic responses to various microbial antigens. Serologic markers are associated with aggressive forms of disease and can be detected before onset of symptoms. Their utility in pre-clinical disease or prediction of complicated disease course before diagnosis is unclear. To evaluate the pattern of serologic anti-microbial antibodies long prior to diagnosis and the subsequent risk of complicated Crohn's disease at diagnosis. Sera from 100 US military personnel with Crohn's disease were obtained from the Department of Defense Serum Repository. For each patient, four samples were obtained at different time points before and around diagnosis, and were tested for 6 microbiota-directed antibodies (ASCA-IgA, ASCA-IgG, anti-OmpC, anti-CBir1, anti-A4-Fla2 and anti-FlaX). Associations between the presence and accumulation of Crohn's disease anti-microbial antibodies before diagnosis and with the later development of complications were evaluated. Overall, 65 patients were positive for at least one Crohn's disease associated anti-microbial antibody in the earliest available sample, at a median of 6 years before Crohn's disease diagnosis (interquartile range, 5.6-8.2). The number of positive anti-microbial antibodies increased up to the time of Crohn's disease diagnosis. Complicated disease developed around the time of diagnosis in 24 patients. The proportion of positive antimicrobial antibodies before diagnosis was higher in patients with complicated vs. noncomplicated Crohn's disease. There was an inverse relationship between the time to first complication and the magnitude of serologic response before diagnosis. The presence and accumulation of circulating anti-microbial antibodies years before Crohn's disease diagnosis was associated with complicated Crohn's disease at or shortly after diagnosis.


Modeling human hematopoietic and cardiovascular diseases in zebrafish.
Zebrafish have emerged as a useful vertebrate model system in which unbiased large-scale screens have revealed hundreds of mutations affecting vertebrate development. Many zebrafish mutants closely resemble known human disorders, thus providing intriguing prospects for uncovering the genetic basis of human diseases and for the development of pharmacologic agents that inhibit or correct the progression of developmental disorders. The rapid pace of advances in genomic sequencing and map construction, in addition to morpholino targeting and transgenic techniques, have facilitated the identification and analysis of genes associated with zebrafish mutants, thus promoting the development of zebrafish as a model for human disorders. This review aims to illustrate how the zebrafish has been used to identify unknown genes, to assign function to known genes, and to delineate genetic pathways, all contributing valuable leads toward understanding human pathophysiology.


Transforming growth factor-beta1 modulates the expression of vascular endothelial growth factor by osteoblasts.
Angiogenesis is essential to both normal and pathological bone physiology. Vascular endothelial growth factor (VEGF) has been implicated in angiogenesis, whereas transforming growth factor-beta1 (TGF-beta1) modulates bone differentiation, matrix formation, and cytokine expression. The purpose of this study was to investigate the relationship between TGF-beta1 and VEGF expression in osteoblasts and osteoblast-like cells. Northern blot analysis revealed an early peak of VEGF mRNA (6-fold at 3 h) in fetal rat calvarial cells and MC3T3-E1 osteoblast-like cells after stimulation with TGF-beta1 (2.5 ng/ml). The stability of VEGF mRNA in MC3T3-E1 cells was not increased after TGF-beta1 treatment. Actinomycin D inhibited the TGF-beta1-induced peak in VEGF mRNA, whereas cycloheximide did not. Blockade of TGF-beta1 signal transduction via a dominant-negative receptor II adenovirus significantly decreased TGF-beta1 induction of VEGF mRNA. Additionally, TGF-beta1 induced a dose-dependent increase in VEGF protein expression by MC3T3-E1 cells (P < 0.01). Dexamethasone similarly inhibited VEGF protein expression. Both TGF-beta1 mRNA and VEGF mRNA were concurrently present in rat membranous bone, and both followed similar patterns of expression during rat mandibular fracture healing (mRNA and protein). In summary, TGF-beta1-induced VEGF expression by osteoblasts and osteoblast-like cells is a dose-dependent event that may be intimately related to bone development and fracture healing.


Understanding the acceptability of a computer decision support system in pediatric primary care.
Individual users' attitudes and opinions help predict successful adoption of health information technology (HIT) into practice; however, little is known about pediatric users' acceptance of HIT for medical decision-making at the point of care. We wished to examine the attitudes and opinions of pediatric users' toward the Child Health Improvement through Computer Automation (CHICA) system, a computer decision support system linked to an electronic health record in four community pediatric clinics. Surveys were administered in 2011 and 2012 to all users to measure CHICA's acceptability and users' satisfaction with it. Free text comments were analyzed for themes to understand areas of potential technical refinement. 70 participants completed the survey in 2011 (100% response rate) and 64 of 66 (97% response rate) in 2012. Initially, satisfaction with CHICA was mixed. In general, users felt the system held promise; however various critiques reflected difficulties understanding integrated technical aspects of how CHICA worked, as well as concern with the format and wording on generated forms for families and users. In the subsequent year, users' ratings reflected improved satisfaction and acceptance. Comments also reflected a deeper understanding of the system's logic, often accompanied by suggestions on potential refinements to make CHICA more useful at the point of care. Pediatric users appreciate the system's automation and enhancements that allow relevant and meaningful clinical data to be accessible at point of care. Understanding users' acceptability and satisfaction is critical for ongoing refinement of HIT to ensure successful adoption into practice.


[Meniscal injuries in the aged patient].
The author analyses clinical and radiographic aspects of 46 patients with meniscal injuries, with age over 60 years, and submitted to arthroscopic procedures for treatment. The relations of the clinical and arthroscopic findings with the surgical results were evaluated. The night pain complain, joint swelling, the knee flexion deformity were the most frequent clinical findings. The fact of being female, having injuries of lateral meniscus, narrowing of the joint space at the X-ray were bad prognosis signs. The medial femural condile osteonecrosis was the main cause of bad result in patients with medial meniscus injuries.


Effect of CD4+ T cell count on treatment-emergent adverse events among patients with and without HIV receiving immunotherapy for advanced cancer.
The Food and Drug Administration recommends that people living with HIV (PWH) with a CD4+ T cell count (CD4) ≥350 cells/µL may be eligible for any cancer clinical trial, but there is reluctance to enter patients with lower CD4 counts into cancer studies, including immune checkpoint inhibitor (ICI) studies. Patients with relapsed or refractory cancers may have low CD4 due to prior cancer therapies, irrespective of HIV status. It is unclear how baseline CD4 prior to ICI impacts the proportion of treatment-emergent adverse events (TEAE) and whether it differs by HIV status in ICI treated patients. We conducted a pilot retrospective cohort study of participants eligible for ICI for advanced cancers from three phase 1/2 trials in the USA and Spain. We determined whether baseline CD4 counts differed by HIV status and whether the effect of CD4 counts on incidence of TEAE was modified by HIV status using a multivariable logistic regression model. Of 122 participants, 66 (54%) were PWH who received either pembrolizumab or durvalumab and 56 (46%) were HIV-negative who received bintrafusp alfa. Median CD4 at baseline was 320 cells/µL (IQR 210-495) among PWH and 356 cells/µL (IQR 260-470) among HIV-negative participants (p=0.5). Grade 3 or worse TEAE were recorded among 7/66 (11%) PWH compared with 7/56 (13%) among HIV-negative participants. When adjusted for prior therapies, age, sex, and race, the effect of baseline CD4 on incidence of TEAE was not modified by HIV status for any TEAE (interaction term p=0.7), or any grade ≥3 TEAE (interaction term p=0.1). There was no significant difference in baseline CD4 or the proportions of any TEAE and grade ≥3 TEAE by HIV status. CD4 count thresholds for cancer clinical trials should be carefully reviewed to avoid unnecessarily excluding patients with HIV and cancer.


Cinacalcet for Treatment of Chronic Kidney Disease-Mineral and Bone Disorder: A Meta-Analysis of Randomized Controlled Trials.
Cinacalcet could decrease serum calcium, phosphate, and parathyroid hormone (PTH) in previous meta-analyses. However, the effect of cinacalcet on the new biomarkers such as fibroblast growth factor-23 (FGF-23), bone markers, and vascular calcification are still unestablished. We conducted a meta-analysis to examine the effects of cinacalcet on all laboratory and clinical spectrums of chronic kidney disease-mineral bone disorders (CKD-MBD). A systematic literature search was conducted in MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, and Clinical Trials.gov to identify randomized controlled trials (RCTs) comparing the effect of cinacalcet relative to standard treatment on CKD-MBD surrogate markers and clinical outcomes. Random-effect models were used to compute the weighted mean difference for continuous variables and the risk ratio for binary variables. Twenty-four RCTs (10,031 dialysis patients) were identified. Besides lowering effects on calcium, phosphate, and PTH, cinacalcet significantly reduced bone resorptive marker (tartrate-resistant acid phosphatase 5b) but unaltered bone formation markers (bone alkaline phosphatase and osteocalcin). Cinacalcet also resulted in significant higher risk of hypocalcemia, nausea, vomiting, and diarrhea. Cinacalcet significantly lowered serum FGF-23 level, although unaltered all-cause mortalities. Use of cinacalcet in dialysis patients improves several CKD-MBD-related surrogate markers. However, the benefit on all-cause mortalities was not demonstrated.


Simultaneous Visualization of Parental and Progeny Viruses by a Capsid-Specific HaloTag Labeling Strategy.
Real-time, long-term, single-particle tracking (SPT) provides us an opportunity to explore the fate of individual viruses toward understanding the mechanisms underlying virus infection, which in turn could lead to the development of therapeutics against viral diseases. However, the research focusing on the virus assembly and egress by SPT remains a challenge because established labeling strategies could neither specifically label progeny viruses nor make them distinguishable from the parental viruses. Herein, we have established a temporally controllable capsid-specific HaloTag labeling strategy based on reverse genetic technology. VP26, the smallest pseudorabies virus (PrV) capsid protein, was fused with HaloTag protein and labeled with the HaloTag ligand during virus replication. The labeled replication-competent recombinant PrV harvested from medium can be applied directly in SPT experiments without further modification. Thus, virus infectivity, which is critical for the visualization and analysis of viral motion, is retained to the largest extent. Moreover, progeny viruses can be distinguished from parental viruses using diverse HaloTag ligands. Consequently, the entire course of virus infection and replication can be visualized continuously, including virus attachment and capsid entry, transportation of capsids to the nucleus along microtubules, docking of capsids on the nucleus, endonuclear assembly of progeny capsids, and the egress of progeny viruses. In combination with SPT, the established strategy represents a versatile means to reveal the mechanisms and dynamic global picture of the life cycle of a virus.


Women's experiences with isotretinoin risk reduction counseling.
Isotretinoin, an effective anti-acne therapy, is a known teratogen that is strictly regulated through the iPLEDGE program. However, since this program has not significantly reduced rates of pregnancies exposed to isotretinoin, new strategies for reducing rates of isotretinoin-exposed pregnancies are needed. To explore women's experiences with counseling about isotretinoin risk reduction. Structured interviews were conducted between January and September 2012. Two independent coders performed content analysis using a grounded theory approach. The study participants were 16 women who had used isotretinoin to treat severe skin disease and who were recruited from a single urban community via flyers displayed on college campuses, at dermatology clinics, and at student health facilities. Perceptions of isotretinoin-associated risks and understanding of ways teratogenic risks can be avoided. Participants clearly understood that isotretinoin is teratogenic but had less understanding of contraceptive methods that effectively prevent pregnancy. Most described the counseling they received as anxiety provoking. Few were counseled about highly effective reversible contraceptives such as the subdermal implant or intrauterine contraception; most counseling focused on oral contraceptives. Women cited multiple influences on their contraceptive choices, including friends, family, physicians, the internet, and other media; however, some expressed concerns about the accuracy of these sources of information. For many, iPLEDGE was their first introduction to contraception. When presented with evidence-based information on the relative effectiveness of available contraceptives, participants expressed surprise that this was not part of the iPLEDGE materials. Since few clinicians provide women information on highly effective (ie, intrauterine or subdermal) contraceptives, the iPLEDGE program increases anxiety about isotretinoin more than it helps women feel protected from the teratogenic risks of isotretinoin.


Recent advances in computer-aided drug design as applied to anti-influenza drug discovery.
Influenza is a seasonal and serious health threat, and the recent outbreak of H7N9 following the pandemic spread of H1N1 in 2009 has served to emphasize the importance of anti-influenza drug discovery. Zanamivir (Relenza™) and oseltamivir (Tamiflu(®)) are two antiviral drugs currently recommended by the CDC for treating influenza. Both are examples of the successful application of structure-based drug design strategies. These strategies have combined computer- based approaches, such as docking- and pharmacophore-based virtual screening with X-ray crystallographic structural analyses. Docking is a routinely used computational method to identify potential hits from large compound libraries. This method has evolved from simple rigid docking approaches to flexible docking methods to handle receptor flexibility and to enhance hit rates in virtual screening. Virtual screening approaches can employ both ligand-based and structurebased pharmacophore models depending on the available information. The exponential growth in computing power has increasingly facilitated the application of computer-aided methods in drug discovery, and they now play significant roles in the search for novel therapeutics. An overview of these computational tools is presented in this review, and recent advances and challenges will be discussed. The focus of the review will be anti-influenza drug discovery and how advances in our understanding of viral biology have led to the discovery of novel influenza protein targets. Also discussed will be strategies to circumvent the problem of resistance emerging from rapid mutations that has seriously compromised the efficacy of current anti-influenza therapies.


Mobility of the First Ray in Patients With or Without Hallux Valgus Deformity: Systematic Review and Meta-Analysis.
The hypermobility theory of the first ray is the reason for the popularization of procedures such as the modified Lapidus procedure involving arthrodesis of the first tarsal-metatarsal joint for correction of hallux valgus deformity. Although many studies have involved motion of the first ray in hallux valgus patients, the presence and clinical significance of hypermobility in the first ray remains controversial. We performed a systematic review and meta-analysis to evaluate the difference in the first ray range of motion between patients with or without hallux valgus deformity. The databases used for the present review included Ovid EMBASE, Ovid MEDLINE, CINAHL, and the Cochrane Database. We searched for comparative studies that had evaluated the motion of the first ray in patients with or without hallux valgus. After screening for inclusion and exclusion criteria, we identified 3 studies that were relevant to our study question. All 3 studies showed more first ray motion in the hallux valgus group. Our quantitative synthesis showed a mean difference in the range of motion of the first ray of 3.62 mm (95% confidence interval 2.26 to 4.98) between those with and without hallux valgus deformity. Thus, we found statistically significantly increased first ray motion in patients with hallux valgus deformity compared with those without hallux valgus deformity. However, the clinical significance of this small amount of increased sagittal plane motion as a response to or a cause of hallux valgus remains unanswered.


Sialic acid metabolism's dual function in Haemophilus influenzae.
Many bacterial commensals and pathogens use the sialic acids as carbon and nitrogen sources. In Escherichia coli, the breakdown of these sugars is catalysed by gene products of the nan (Nacylneuraminate) operon; other microorganisms may use a similar catabolic strategy. Despite the known ligand and antirecognition functions of the sialic acids, the contribution of their catabolism to infection or host colonization has never been directly investigated. We addressed these questions with Haemophilus influenzae type b, which metabolizes relatively few carbohydrates, using the infant-rat infection model. The predicted H. influenzae homologue (HI0142) of the E. coli sialic acid aldolase structural gene, nanA, was subcloned and mutagenized by insertion of a kanamycin resistance cassette. Phenotypic investigation of the resulting H. influenzae aldolase mutants showed that: (i) HI0142 is essential for sialic acid degradation; (ii) the products of the open reading frames (ORFs) flanking HI0142 (HI0140, 41, 44 and 45) are likely to have the same functions as those of their counterparts in E. coli; (iii) sialylation of the lipooligosaccharide (LOS) epitope recognized by monoclonal antibody 3F11 is dependent on an environmental source of sialic acid; (iv) a nanA mutant hypersialylates its LOS sialyl acceptor, corresponding to an apparent increased fitness of the mutant in the infant-rat model; and (v) expression of the LOS sialyl acceptor is altered in cells grown without exogenous sialic acid, indicating the direct or indirect effect of sialic acid metabolism on LOS antigenicity. Taken together the data show the dual role of sialic acid catabolism in nutrition and cell surface modulation.


The impact of standardized care pathway on reporting time for invasive melanoma - results from one pathology department in Sweden.
Background: Standardized care pathway (SCP) was introduced by the Swedish health authorities to eliminate unwanted delay in the diagnostics of cancer patients; for melanoma, SCP started in 2016. The aim of this study was to investigate the impact of SCP on reporting time for invasive melanomas.Materials and methods: Information on reporting time was collected on all samples handled according to the SCP and on all invasive melanomas diagnosed in 2016-2018 at the Department of Clinical Pathology, Akademiska University Hospital, Uppsala, Sweden.Results: During the study period, 205 samples were handled according to the SCP, resulting in 53 cases (26%) diagnosed with invasive melanomas. A total of 301 invasive melanomas from 286 patients were diagnosed during the study period; 67 (22%) were submitted as SCP, 36 (12%) as a general priority case, and 198 (66%) as non-priority. The reporting time for the SCP cases was 8 days, for general priority cases 6 days, and for non-priority cases it was 24 days. The reporting time increased from 18 to 31 days for the non-priority cases and from 15 to 25 days for all cases with invasive melanomas during the study period.Conclusion: This study demonstrates prolonged reporting times for invasive melanomas since the implementation of SCP. This is probably caused by the crowd-out effect of the SCP samples, limited personnel resources, and inaccuracy of the clinical diagnosis. SCP might therefore be a suboptimal method to shorten reporting times for invasive melanomas.


A new technique to improve cup inclination accuracy in primary total hip arthroplasty.
Accurate inclination and anteversion of the acetabular component is paramount to achieve a stable total hip arthroplasty, prevent prosthetic dislocation and minimize long- term wear. We present and evaluate a simple new technique to improve consistency in cup inclination during primary total hip arthroplasty, based on information available from the preoperative plan. The technique consists of assessing the distance and relationship between the inferomedial border of the acetabular cup and the inferomedial margin of the teardrop, with the use of a measuring probe. This simple surgical gesture improved consistency in cup inclination during total hip arthroplasty.;


Safety and tolerability of medicinal parasite ova (Trichuris suis) in healthy Japanese volunteers: A randomized, double-blind, placebo-controlled trial.
Trichuris suis ova (TSO), with the potential to modulate the human immune system, have been tested for therapeutic application in autoimmune and allergic diseases such as inflammatory bowel disease (IBD). Previous clinical studies were limited to European and American participants, whereas Asian populations have not been well documented. In this study, a clinical trial was conducted to examine the safety and tolerability of TSO administration among a healthy Japanese population. The study was a randomized, double-blind, placebo-controlled trial held at Jikei University Hospital, Tokyo. Twelve volunteers were stratified into three groups receiving different doses of TSO (TSO 1000, 2500, and 7500) and another into the control group. These cases were limited to healthy Japanese men aged over 20 years old. Single doses of medicinal TSO or placebo were given to three participants of each group. All participants were followed up to 56 days after ingestion. During the follow-up period, clinical practitioners checked each participant at the clinic at 7, 14, 28, and 56 days post-ingestion (dpi). Clinical symptoms were evaluated using questionnaire-based self-reporting, which participants filled at every visit. Blood samples were drawn at 7, 14, 28, and 56 dpi. Fecal samples were collected at 28 and 56 dpi. During the study period, twelve healthy Japanese male volunteers were enrolled. All participants completed the follow-up period. No severe adverse events were observed during the study period in all groups. Three participants in the TSO 1000, 2500, and 7500 groups had mild to moderate abdominal symptoms, diarrhea, bloating, and appetite loss during the observation period. One participant in the placebo group presented with mild diarrhea. Microscopic examination identified no parasite ova in any fecal samples. Blood sample examination indicated elevated eosinophil count in several cases, especially in the groups with the higher dose of TSO. No extra-abdominal symptoms were present in all cases. Healthy Japanese people tolerated all doses of TSO without any severe adverse events. On the other hand, mild to moderate abdominal symptoms were observed in several participants. This study suggested that the medicinal use of TSO in Japan is relatively safe, and close follow-up is recommended for sustainable usage.


A Retrospective Study on the Epidemiological and Clinical Features of Emergency Patients with Large or Massive Consumption of Caffeinated Supplements or Energy Drinks in Japan.
Objective We conducted a retrospective study on the epidemiological and clinical features of patients with acute caffeine poisoning in Japan. Methods Letters requesting participation were sent to 264 emergency departments of hospitals, and questionnaires were mailed to those that agreed to participate. Patients Participants were patients transported to emergency departments of hospitals between April 2011 and March 2016 after consuming large or massive amounts of caffeinated supplements and/or energy drinks (caffeine dose ≥1.0 g). Results We surveyed 101 patients from 38 emergency departments. Since April 2013, the number of patients has markedly increased. Of these young patients (median age, 25 years), 53 were men, and 97 had consumed caffeine in tablet form. Estimated caffeine doses (n=93) ranged from 1.2 to 82.6 g (median, 7.2 g). Serum caffeine levels on admission (n=17) ranged from 2.0 to 530.0 μg/mL (median level, 106.0 μg/mL). Common abnormal vital signs and laboratory data on admission included tachypnea, tachycardia, depressed consciousness, hypercreatinekinasemia, hyperglycemia, hypokalemia, hypophosphatemia, and hyperlactatemia. Common signs and symptoms in the clinical course included nausea, vomiting, excitement/agitation, and sinus tachycardia. Seven patients (6.9%) who had consumed ≥6.0 g of caffeine, or whose serum caffeine levels on admission were ≥200 μg/mL, developed cardiac arrest. Ninety-seven patients (96.0%) recovered completely, but 3 patients (3.0%) died. Conclusion The present analysis of data from more than 100 emergency patients revealed clinical features of moderate to fatal caffeine poisoning. We recommend highlighting the toxicity risks associated with ingesting highly caffeinated tablets.


A single treatment with IL-4 via retrovirally transduced lymphocytes partially protects against diabetes in BioBreeding (BB) rats.
Type 1 diabetes mellitus is a T cell mediated autoimmune disease with no known methods of prevention. The BioBreeding rat is used as an animal model for the study of human Type 1 diabetes. In spite of a severe lymphopenia, these animals develop spontaneous diabetes at the age of 10-12 weeks. To examine whether anti-inflammatory gene therapy could be used to prevent autoimmune diabetes in the BioBreeding rat. A retroviral DNA vector, MSCVneo.IL-4, carrying the DNA sequence encoding the rat interleukin-4, was designed to transfer interleukin-4 to BioBreeding rats. Spleen cells of prediabetic animals were activated and transduced in vitro with replication-defective retroviruses expressing the MSCVneo.IL-4 vector. These lymphocytes were subsequently administered intraperitoneally to 3-4 week old prediabetic BioBreeding rats. Control animals were reconstituted with spleen cells transduced with MSCVneo vector. The neo gene marker was detectable by RT-PCR in rat spleen cells of up to 6 to 12 months after treatment. Fifty percent (6 out of 12) of the animals treated were protected from autoimmune disease development. Our results suggest that the BioBreeding rat can be used as a useful model to develop gene therapy regimens for diabetes. These studies provide further support for the hypothesis that interleukin-4 based gene therapy may have potential clinical value for preventing autoimmune diabetes in humans.


Ferromagnetism in doped excitonic insulators
The theory of doped excitonic insulators is reinvestigated in light of recent experiments on hexaborides. For the appropriate valley-degenerate X3,X'3 band structure, "intravalley" condensation is energetically favored. Ferromagnetism occurs upon doping due to the quenching of kinetic energy at the otherwise direct first-order excitonic insulator-metal transition. The phase diagram includes states of spatially inhomogeneous density and magnetization at low temperatures.


Fludarabine, cyclophosphamide, antithymocyte globulin, with or without low dose total body irradiation, for alternative donor transplants, in acquired severe aplastic anemia: a retrospective study from the EBMT-SAA Working Party.
We analyzed the outcome of 100 patients with acquired severe aplastic anemia undergoing an alternative donor transplant, after immune suppressive therapy had failed. As a conditioning regimen, patients received either a combination of fludarabine, cyclophosphamide, and antithymocyte globulin (n=52, median age 13 years) or this combination with the addition of low dose (2 Gy) total body irradiation (n=48, median age 27 years). With a median follow-up of 1665 and 765 days, the actuarial 5-year survival was 73% for the group that received fludarabine, cyclophosphamide, and antithymocyte globulin and 79% for the group given the conditioning regimen including total body irradiation. Acute graft-versus-host disease grade III-IV was seen in 18% and 7% of the groups, respectively. Graft failure was seen in 17 patients with an overall cumulative incidence of 17% in patients receiving conditioning with or without total body irradiation: 9 of these 17 patients survive in the long-term. The most significant predictor of survival was the interval between diagnosis and transplantation, with 5-year survival rates of 87% and 55% for patients grafted within 2 years of diagnosis and more than 2 years after diagnosis, respectively (P=0.0004). Major causes of death were graft failure (n=7), post-transplant-lymphoproliferative-disease (n=4) and graft-versus-host disease (n=4). This study confirms positive results of alternative donor transplants in patients with severe aplastic anemia, the best outcomes being achieved in patients grafted within 2 years of diagnosis. Prevention of rejection and Epstein-Barr virus reactivation may further improve these results.


[Continuous fiberoptic monitoring of oxygen saturation in cerebral veins in severe craniocerebral trauma--experiences and results].
Monitoring of jugular-venous O2-saturation (SjO2) enables the assessment of cerebral oxygen supply and the rapid detection of cerebral desaturation in patients with severe head injury. Furthermore, it may help to optimize circulation, ventilation, and intracranial hypertension therapy in these patients. This study was performed to evaluate the reliability of SjO2-monitoring as well as to measure cerebral O2-extraction and the frequency of episodes of cerebral desaturation after traumatic brain injury. In 16 patients with severe head injury (GCS 3-8), SjO2 (fibreoptic system), arterial blood pressure, and intracranial pressure were continuously recorded after admission of the patients to the intensive care unit. Fluctuations of SjO2 (> 10% within 30 min), which were not included by therapeutic measures, were classified by off-line analysis as irregular-isolated or irregular-combined, if accompanied by similar fluctuations of ICP and arterial blood pressure. Recordings which were unreliable due to technical reasons, mainly because of wall adherence of the tip of the fibreoptic catheter, were evaluated separately. Episodes of cerebral desaturations (SjO2 < 50%) were assessed with regard to their frequency, duration (5-10/> 10 min) and underlying mechanisms. Cerebral O2-extraction was calculated as the difference between arterial and cerebrovenous O2-saturation and averaged for each day after trauma. Mean time of measurement for each patient was 194 hrs, a total of 3106 hrs were recorded. The correlation coefficient between in-vivo and in-vitro measured SjO2 was r = 0.62 (n = 367, p < 0.001). Reliable and artifact-free measurements of SjO2 were obtained only during 58.3% of all hours. Irregular-isolated fluctuations of the SjO2 occurred in 22.2% of the hours, and technical problems in 14.5%. Erroneous readings due to irregular-combined fluctuations of the jugular-venous O2-saturation were detected in 5.0% of the time periods. A total number of 66 episodes of cerebral desaturation (SjO2 < 50%) were found in all 16 patients, 41 of them had a duration of more than 10 minutes. Cerebral hypoxia was attributed to low cerebral perfusion pressure in 35% and hypocapnia in 17%. Global cerebral O2-extraction was significantly elevated at the day of injury compared to days 1-5 after trauma (37.4% vs. 28.9%-31.9%, p < 0.05). Monitoring of SjO2 in severe head injury provides an estimate of cerebral oxygen supply and may improve the assessment of therapeutic measures in these patients. The high incidence of erroneous readings of the SjO2 is a major drawback of this method. Initially after trauma, a high extraction of oxygen was found, followed by a marked decrease in the subsequent days, presumably reflecting an early, decreased cerebral blood flow and a hyperaemic flow pattern thereafter. Continuous measurements of SjO2 may contribute to advanced, organ-specific cerebral monitoring in severe craniocerebral trauma. The reliability of data, however, should be considerably improved for common clinical use.


Determination of 14 polycyclic aromatic hydrocarbons in mainstream smoke from U.S. brand and non-U.S. brand cigarettes.
Tobacco smoke contains thousands of chemical compounds, including many carcinogenic polycyclic aromatic hydrocarbons (PAHs). To determine the concentration ranges of PAHs in tobacco smoke and to understand what factors alter their levels, we quantitatively measured 14 PAHs in mainstream smoke from a transnational U.S. brand (Marlboro) and from locally popular brand cigarettes from 14 countries. We used standardized machine smoking conditions (35-mL puff volume, 60-s puff interval, and 2-s puff duration), extraction of total particulate matter from the Cambridge filters, and gas chromatography/mass spectrometry detection. Deliveries of total PAHs in mainstream smoke of local brands were statistically significantly higher (p < 0.01) than Marlboros in seven countries. In four countries, Marlboro cigarettes had mainstream smoke total PAH levels that were statistically significantly higher (p < 0.01) than local brands. In the remaining three countries, the differences in PAH levels were not statistically significant. Under standard machine smoking conditions, PAH levels were negatively correlated with cigarette filter ventilation levels. We found that several local brands containing primarily flue-cured tobacco filler had relatively high mainstream smoke PAH deliveries, in agreement with findings by previous researchers that flue-cured tobacco typically delivers more PAHs than other tobacco types. We also observed that PAHs were inversely correlated with total carcinogenic tobacco-specific nitrosamines and nitrate content, but these correlations were not statistically significant at the 95% confidence interval. The findings suggest that tobacco blend and nitrate levels may influence PAH deliveries, but other factors may confound this relation.


Learning sung lyrics aids retention in normal ageing and Alzheimer's disease.
Previous studies have suggested that presenting to-be-memorised lyrics in a singing mode, instead of a speaking mode, may facilitate learning and retention in normal adults. In this study, seven healthy older adults and eight participants with mild Alzheimer's disease (AD) learned and memorised lyrics that were either sung or spoken. We measured the percentage of words recalled from these lyrics immediately and after 10 minutes. Moreover, in AD participants, we tested the effect of successive learning episodes for one spoken and one sung excerpt, as well as long-term retention after a four week delay. Sung conditions did not influence lyrics recall in immediate recall but increased delayed recall for both groups. In AD, learning slopes for sung and spoken lyrics did not show a significant difference across successive learning episodes. However, sung lyrics showed a slight advantage over spoken ones after a four week delay. These results suggest that singing may increase the load of initial learning but improve long-term retention of newly acquired verbal information. We further propose some recommendations on how to maximise these effects and make them relevant for therapeutic applications.


Imaging in Tubercular Choroiditis: Current Concepts.
Ocular tuberculosis has protean clinical manifestations. Because of its varied clinical presentation, multimodal imaging is very important to characterize the disease activity, presence of inflammation, determining therapeutic response, and detection of complications. Narrative review. In this review, various imaging modalities employed in the management of ocular tuberculosis including fluorescein angiography (FA), indocyanine green angiography (ICGA), optical coherence tomography (OCT), and optical coherence tomography angiography (OCTA) have been reviewed. Not only do these imaging tools complement each other in providing a comprehensive assessment of the pathology, they also help in gaining valuable insights regarding the evolution of the disease. Fundus imaging plays a vital role in the diagnosis and management of patients with posterior uveitis due to tuberculosis. Fundus imaging may have a useful role in defining clinical endpoints for ocular tuberculosis in the future.


[Knowledge and application of the HAS recommendations concerning the diagnosis of undernutrition in people aged 70 and above: an international online survey among members of the "Société Française de Gériatrie et de Gérontologie"].
To assess the knowledge and the use in clinical practice of the "French National Authority for Health" (HAS) 2021 recommendations on the diagnosis of malnutrition in older adults aged 70 years and above. An online survey was developed by the working Group on Geriatrics and Nutrition (GEGN) of the "Société Française de Gériatrie et de Gérontologie (SFGG)" and conducted among members of the SFGG. A self-administered questionnaire composed of 21 closed questions was used. A total of 132 (10.2 %) members of the SFGG responded to the survey. The respondents were aged 43.4 ± 9.94 years old and 97 (73.5 %) were women. Almost half of them were medical doctors (n = 53 ; 40.2 %). Of the respondents, 81 % had already heard of the HAS 2021 recommendations. This percentage is higher for doctors (96 %) than for other professions (74 %). French respondents were more likely to have heard of these -recommendations (84 %) than respondents from other countries (42.9 %). However, only 41.6 % of the respondents believe they know these recommendations in detail. On a visual analogue scale from 0 (never) to 100 (always), respondents use these recommendations in their professional practice at 76.8 ± 20.2 %. However, on a scale from 0 (never difficult) to 100 (always difficult), some barriers to their use in clinical practice were highlighted. These mainly concerned the measurement of muscle mass (84.4 ± 17.2 %) and muscle strength (79.5 ± 19.9 %) in patients. Although the majority of respondents use the HAS 2021 recommendations in their professional practice, they often have difficulties in measuring muscle strength and muscle mass of their patients. The assessment of sarcopenia still needs to be implemented in clinical routine. Until then, better communication about simple alternatives that do not require special equipment is needed.


Inducibility of Ia antigen on astrocytes by murine coronavirus JHM is rat strain dependent.
Inducibility of Ia molecules on cultivated astrocytes by JHM virus correlates with demyelinating disease susceptibility of animals from which these astrocytes are derived. On the contrary, class I induction of both astrocytes and oligodendrocytes occurs as a consequence of normal cultivation procedures in both susceptible and resistant strains. Increased expression of class I antigens on rat astrocytes and oligodendrocytes is not related to JHM viral infection as it is in the mouse. These data indicate that strain differences in Ia inducibility, rather than inducibility of class I antigens, by JHM virus may explain higher levels of T cell-mediated damage to myelin during infection in susceptible rat strains compared with resistant strains.


Understanding the Therapeutic Potential of Ascorbic Acid in the Battle to Overcome Cancer.
Cancer, a fatal disease, is also one of the main causes of death worldwide. Despite various developments to prevent and treat cancer, the side effects of anticancer drugs remain a major concern. Ascorbic acid is an essential vitamin required by our bodies for normal physiological function and also has antioxidant and anticancer activity. Although the body cannot synthesize ascorbic acid, it is abundant in nature through foods and other natural sources and also exists as a nutritional food supplement. In anticancer drug development, ascorbic acid has played an important role by inhibiting the development of cancer through various mechanisms, including scavenging reactive oxygen species (ROS), selectively producing ROS and encouraging their cytotoxicity against tumour cells, preventing glucose metabolism, serving as an epigenetic regulator, and regulating the expression of HIF in tumour cells. Several ascorbic acid analogues have been produced to date for their anticancer and antioxidant activity. The current review summarizes the mechanisms behind ascorbic acid's antitumor activity, presents a compilation of its derivatives and their biological activity as anticancer agents, and discusses delivery systems such as liposomes, nanoparticles against cancer, and patents on ascorbic acid as anticancer agents.


Dendritic cells, loaded with recombinant bacteria expressing tumor antigens, induce a protective tumor-specific response.
Dendritic cells (DCs) are considered the most potent antigen-presenting cells and probably the only ones able to prime naive T cells. Indeed, DCs are distributed in tissues that interface the external environment, where they act as sentinels for incoming bacteria, viruses, and fungi. We have previously analyzed the capacity of DCs to interact with bacteria, and we have shown that bacteria can act as "Trojan horses," delivering heterologous proteins to DCs in a processed form that allows extremely efficient loading of both MHC class I and class II molecules. In this study, we have optimized the usage of recombinant bacteria as an antigen delivery system for DCs, with the aim to develop a new DC vaccination strategy in antitumor immunity. We have focused on a low immunogenic antigen, the tyrosinase-related protein-2 (Trp-2), a self-antigen expressed in mouse and human melanoma for which induction of antitumor immunity has proven to be very ineffective. We have given mice injections of either Trp-2/recombinant bacteria-loaded DCs or with bacteria alone engineered to express the Trp-2 melanoma antigen. We have shown that only DCs loaded with recombinant bacteria, but not with wild-type bacteria, were able to induce Trp-2-specific CTLs and immunity against the B16 tumor. Immunity was obtained in experiments of tumor vaccination as well as in experiments of tumor therapy. When therapy with bacteria-loaded DCs was performed in B16 tumor-bearing mice, 60% of the treated mice were tumor free 2 months after the initial tumor growth.


Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study.
Ofatumumab, the human CD20 monoclonal antibody that binds a distinct epitope from rituximab, has demonstrated clinical benefit as monotherapy for patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab (FA-ref) and patients refractory to fludarabine with bulky (> 5 cm) lymph nodes (BF-ref). To potentially gain insight into outcomes in patients previously treated with or refractory to rituximab, we performed an ad hoc retrospective analysis in the final 96 FA-ref and 111 BF-ref patients. There were 117 patients previously treated with rituximab (98 rituximab-refractory); 89 patients were rituximab-naive. For rituximab-treated, rituximab-refractory, and rituximab-naive patients, overall response rate was 43%, 44%, and 53%; median progression-free survival was 5.3, 5.5, and 5.6 months; and median overall survival was 15.5, 15.5, and 20.2 months. There were no significant differences in ofatumumab-related infusion reactions, or hematologic or infectious adverse events between subgroups. In summary, ofatumumab monotherapy was effective and well tolerated in patients with fludarabine-refractory chronic lymphocytic leukemia, including in patients with previous rituximab exposure. This trial was registered at www.clinicaltrials.gov as #NCT00349349.


Production of outer surface protein A by Borrelia burgdorferi during transmission from infected mammals to feeding ticks is insufficient to trigger OspA seroconversion.
The Lyme disease spirochete, Borrelia burgdorferi, produces two outer surface lipoproteins, OspA and OspB, that are essential for colonization of tick vectors. Both proteins are highly expressed during transmission from infected mammals to feeding ticks and during colonization of tick midguts, but are repressed when bacteria are transmitted from ticks to mammals. Humans and other infected mammals generally do not produce antibodies against either protein, although some Lyme disease patients do seroconvert and produce antibodies against OspA for unknown reasons. We hypothesized that, if such patients had been fed upon by additional ticks, bacteria moving from the patients' bodies to the feeding ticks would have produced OspA and OspB proteins, which then led to immune system recognition and antibody production. This hypothesis was tested by analyzing immune responses of infected mice following feedings by additional Ixodes scapularis ticks. However, results of the present studies demonstrate that expression of OspA and OspB by B. burgdorferi during transmission from infected mammals to feeding ticks does not trigger seroconversion.


Bruceantin targets HSP90 to overcome resistance to hormone therapy in castration-resistant prostate cancer.
Rationale: Aberrant androgen receptor (AR) signaling via full-length AR (AR-FL) and constitutively active AR variant 7 (AR-V7) plays a key role in the development of castration-resistant prostate cancer (CRPC) and resistance to hormone therapies. Simultaneous targeting of AR-FL and AR-V7 may be a promising strategy to overcome resistance to hormone therapy. This study aimed to identify novel drug candidates co-targeting AR-FL and AR-V7 activities and elucidate their molecular mechanism of anti-CRPC activities. Methods: Using a CRPC cell-based reporter assay system, we screened a small library of antimalarial agents to explore the possibility of repositioning them for CRPC treatment and identified bruceantin (BCT) as a potent anti-CRPC drug candidate. A series of cell-based, molecular, biochemical, and in vivo approaches were performed to evaluate the therapeutic potential and molecular mechanism of BCT in CRPC. These approaches include reporter gene assays, cell proliferation, RNA-seq, qRT-PCR, mouse xenografts, co-immunoprecipitation, GST pull-down, immobilized BCT pull-down, molecular modeling, and bioinformatic analyses. Results: We identified BCT as a highly potent inhibitor co-targeting AR-FL and AR-V7 activity. BCT inhibits the transcriptional activity of AR-FL/AR-V7 and downregulates their target genes in CRPC cells. In addition, BCT efficiently suppresses tumor growth and metastasis of CRPC cells. Mechanistically, BCT disrupts the interaction of HSP90 with AR-FL/AR-V7 by directly binding to HSP90 and inhibits HSP90 chaperone function, leading to degradation of AR-FL/AR-V7 through the ubiquitin-proteasome system. Clinically, HSP90 expression is upregulated and correlated with AR/AR-V7 levels in CRPC. Conclusion: Our findings suggest that BCT could serve as a promising therapeutic candidate against CRPC and highlight the potential benefit of targeting AR-FL/AR-V7-HSP90 axis to overcome resistance caused by aberrant AR-FL/AR-V7 signaling.


[Efforts to Reduce the Risk of Febrile Neutropenia and to Increase the Response Rate to Docetaxel and Ramucirumab Therapy in Patients with Non-Small Cell Lung Cancer].
Docetaxel(DTX)plus ramucirumab(RAM)therapy is recommended as second-line or later treatment by the Japanese lung cancer guideline. However, febrile neutropenia(FN)is a frequent complication with this therapy. Efforts for reducing FN risk are essential. We administered pegfilgrastim, a durable granulocyte colony-stimulating factor, as primary prophylaxis for FN to all patients. We also reduced the dose of DTX according to its toxicity. Moreover, we used RAM monotherapy. Herein, we report the results of these efforts regarding DTX plus RAM therapy. We retrospectively reviewed the therapeutic results and occurrence of various adverse effects in 11 patients who started receiving DTX plus RAM therapy in our department between August 2016 and December 2017. Median number of DTX plus RAM cycles was 8(1-25). The following best effects were noted: 2(18%)patients, complete response: 5(45%), partial response: 2(18%), stable disease: and 2(18%), nonevaluable. No patient showed progressive disease. The overall response rate was 63.6%, and the disease control rate was 81.8%. Median progression-free survival was 127 days, and the 1-year progression-free survival rate was 27.3%. The median overall survival duration was not reached, and the 1-year overall survival rate was 53.0%. Adverse effects higher than Grade 3 occurred in 2 cases. FN was not observed. By using pegfilgrastim as primary prophylaxis, we could suppress FN onset in patients; furthermore, we observed better overall response and disease control rates than those observed in clinical trials.


Effects of Dietary Phytoestrogens on Hormones throughout a Human Lifespan: A Review.
Dietary phytoestrogens are bioactive compounds with estrogenic activity. With the growing popularity of plant-based diets, the intake of phytoestrogen-rich legumes (especially soy) and legume-derived foods has increased. Evidence from preclinical studies suggests these compounds may have an effect on hormones and health, although the results of human trials are unclear. The effects of dietary phytoestrogens depend on the exposure (phytoestrogen type, matrix, concentration, and bioavailability), ethnicity, hormone levels (related to age, sex, and physiological condition), and health status of the consumer. In this review, we have summarized the results of human studies on dietary phytoestrogens with the aim of assessing the possible hormone-dependent outcomes and health effects of their consumption throughout a lifespan, focusing on pregnancy, childhood, adulthood, and the premenopausal and postmenopausal stages. In pregnant women, an improvement of insulin metabolism has been reported in only one study. Sex hormone alterations have been found in the late stages of childhood, and goitrogenic effects in children with hypothyroidism. In premenopausal and postmenopausal women, the reported impacts on hormones are inconsistent, although beneficial goitrogenic effects and improved glycemic control and cardiovascular risk markers have been described in postmenopausal individuals. In adult men, different authors report goitrogenic effects and a reduction of insulin in non-alcoholic fatty liver patients. Further carefully designed studies are warranted to better elucidate the impact of phytoestrogen consumption on the endocrine system at different life stages.


Hepatic cirrhosis: a clinico-pathological review of 520 cases.
A clinico-pathological review of 520 patients with hepatic cirrhosis coming to necropsy at the Western Infirmary, Glasgow over the period 1900-69 is reported. There has been an overall increase in incidence of cirrhosis since the 1940s, and this has been largely due to a rise in female incidence. A similar trend in the period 1940-71 has been confirmed at a national level in data abstracted from the Annual Reports of the Registrar General for Scotland. The mean age at death has risen for both sexes. Aetiologically, the cirrhosis was alcoholic in 18.5%, posticteric in 10.4%, cryptogenic in 61.9%, and haemochromatosis was diagnosed in 7.5%. Primary malignant tumours of liver supervened in 12.3%. The causes of death and the morphological patterns of the cirrhosis are reviewed.


Social role functioning by adolescents with psychiatric disorders.
To identify aspects of social role functioning that are impaired in adolescents with specific psychiatric disorders in order to improve the psychiatric taxonomy and clinical knowledge base. Adolescents in four urban public schools were screened for mental health problems. Structured psychiatric interviews (National Institute of Mental Health Diagnostic Interview Schedule for Children Version 2.2) with 288 adolescents and their mothers were used to identify youths with psychiatric disorders, and 10 aspects of social role functioning were assessed. Aspects of social role functioning that discriminated between youths with and without psychiatric disorders and between those with emotional disorders and those with disruptive disorders were identified for boys and for girls. Boys with any type of disorder and all youths with disruptive disorders had significant, consistent impairment in academic performance and several other areas of functioning. Youths with emotional disorders, especially girls, demonstrated impairment in social activity participation and peer acceptance, but girls with disorders were not as consistently different from those without as were the boys with emotional disorders. Role functioning differs in important ways between youths with and without psychiatric disorders and between girls and boys with disorders. The results underscore the importance of investigating observable aspects of role behavior in order to improve the timely detection and effective management of psychiatric disorders in youth.


Immunocytochemistry of neuron specific enolase (NSE) in the rat brain after single and repeated epileptic seizures.
The aim of this study was to investigate neuron-specific enolase (NSE) immunoreactivity of the different brain regions after pentylenetetrazol (PTZ)- induced epileptic seizures in rats. Light microscopic examinations provided evidences for changes of neuronal activity after single and repeated seizures. The number of NSE (+) cells was well correlated with Nissl staining. The results suggest that NSE immunoreactivity may be a valuable marker for determination of the number of metabolically active neurons in different brain regions after single and repeated experimental seizures.


Detection of attractors of large Boolean networks via exhaustive enumeration of appropriate subspaces of the state space.
Boolean models are increasingly used to study biological signaling networks. In a Boolean network, nodes represent biological entities such as genes, proteins or protein complexes, and edges indicate activating or inhibiting influences of one node towards another. Depending on the input of activators or inhibitors, Boolean networks categorize nodes as either active or inactive. The formalism is appealing because for many biological relationships, we lack quantitative information about binding constants or kinetic parameters and can only rely on a qualitative description of the type "A activates (or inhibits) B". A central aim of Boolean network analysis is the determination of attractors (steady states and/or cycles). This problem is known to be computationally complex, its most important parameter being the number of network nodes. Various algorithms tackle it with considerable success. In this paper we present an algorithm, which extends the size of analyzable networks thanks to simple and intuitive arguments. We present lnet, a software package which, in fully asynchronous updating mode and without any network reduction, detects the fixed states of Boolean networks with up to 150 nodes and a good part of any present cycles for networks with up to half the above number of nodes. The algorithm goes through a complete enumeration of the states of appropriately selected subspaces of the entire network state space. The size of these relevant subspaces is small compared to the full network state space, allowing the analysis of large networks. The subspaces scanned for the analyses of cycles are larger, reducing the size of accessible networks. Importantly, inherent in cycle detection is a classification scheme based on the number of non-frozen nodes of the cycle member states, with cycles characterized by fewer non-frozen nodes being easier to detect. It is further argued that these detectable cycles are also the biologically more important ones. Furthermore, lnet also provides standard Boolean analysis features such as node loop detection. lnet is a software package that facilitates the analysis of large Boolean networks. Its intuitive approach helps to better understand the network in question.


[Study of intestinal irrigation of colostomy patients: previous note].
The author relates the problems of colostomy patient during the rehabilitation, intestinal control, adequate equipment and skin care. She refers to the control of intestinal habit with colostomy irrigation and relates comparative studies that demonstrated the efficiency and superiority of this method in relation to natural evacuation. She proposes an experimental sistematized study with adaptable and cheap equipment which will not interfere in the therapeutic effect of colostomy and will be used in hospital, ambulatory and at home. The data of this study is being collected in the Proctology Ambulatorial Service of a General Hospital.


The cost of Pancreatoduodenectomy - An analysis of clinical determinants.
Health care spending is increasing the world over. Determining preventable or correctable factors may offer us valuable insights into developing strategies aimed at reducing costs and improving patient care. The aim of this study was to conduct an exploratory analysis of clinical factors influencing costs of Pancreatoduodenectomy (PD). The financial and clinical records of 173 consecutive patients who underwent PD at a tertiary care referral centre, between January 2013 and June 2015 were analysed. Complications, by themselves, did not increase costs associated with PD unless they resulted in an increase in the duration of stay more than 11 days. Intraoperative blood transfusion (p-.098) and performance of an end-to-side PJ (p-.043) were independent factors significantly affecting costs. Synchronous venous resections significantly increased costs (p-.006) without affecting duration of stay. Advancing age, hypertension, neurological and respiratory disorders, preoperative endoscopic retrograde cholangiopancreatography (ERCP), performance of a feeding jejunostomy, and surgical complications eg PPH, POPF and DGE significantly increased the duration of stay sufficient enough to influence costs of PD. It is not the merely the development, but severity of complications that significantly increase the cost of PD by increasing hospital stay. Strategies aimed at reducing intraoperative blood transfusion requirement as well as minimising the development of POPF can help reduce costs. Synchronous venous resections significantly increase costs independent of hospital stay. This study identified nine factors that may be included in the development of a preoperative nomogram that could be used in preoperative financial counselling of patients undergoing PD.


[Isoenzyme composition of cathepsin D from bovine hypothalamus].
The isoenzyme composition of cathepsin D from bovine hypothalamus was studied by isoelectric focusing. It was found that the soluble fraction of hypothalamic proteins contains five peaks of endopeptidase activity at pH 3.2. The properties studied allowed to identify these peaks of endopeptidase activity as isoenzyme forms of cathepsin D.


Diagnosis and augmentation therapy for alpha-1 antitrypsin deficiency: current knowledge and future potential.
The underdiagnosis of alpha-1 antitrypsin (AAT) deficiency (AATD) has been recognized for many years, yet little progress has been made in treatment of the disease. In this review, we summarize the AATD disease process as well as its diagnosis and treatment by AAT augmentation therapy. AATD is a rare autosomal disease that primarily affects the lungs and liver. AATD is associated with an increased susceptibility to developing pulmonary emphysema. The specific pharmacological treatment for AATD is intravenous administration of exogenous AAT. Augmentation therapy with AAT increases serum and pulmonary epithelial AAT levels, restores anti-elastase capacity, and decreases inflammatory mediators in the lung. Augmentation therapy reduces the loss of lung density over time, thus slowing progression of the disease. The effects of augmentation therapy on outcomes, such as frequency/duration of flare-ups, quality of life, lung function decline and mortality, are assessed. Wider testing for AATD, potentially through primary care physicians, could result in earlier treatment and better outcomes for individuals with AATD-induced lung respiratory disease.


Optical Trapping of Gold Nanoparticles in Air.
Most progress on optical nanoparticle control has been in liquids, while optical control in air has proven more challenging. By utilizing an air chamber designed to have a minimum of turbulence and a single laser beam with a minimum of aberration, we trapped individual 200 to 80 nm gold nanoparticles in air and quantified the corresponding trapping strengths. These results pave the way for construction of metallic nanostructures in air away from surfaces.


Genetic divergence and phylogeographic relationships among european perch (Perca fluviatilis) populations reflect glacial refugia and postglacial colonization.
We used the widely distributed freshwater fish, perch (Perca fluviatilis), to investigate the postglacial colonization routes of freshwater fishes in Europe. Genetic variability within and among drainages was assessed using mitochondrial DNA (mtDNA) D-loop sequencing and RAPD markers from 55 populations all over Europe as well as one Siberian population. High level of structuring for both markers was observed among drainages and regions, while little differentiation was seen within drainages and regions. Phylogeographic relationships among European perch were determined from the distribution of 35 mtDNA haplotypes detected in the samples. In addition to a distinct southern European group, which includes a Greek and a southern Danubian population, three major groups of perch are observed: the western European drainages, the eastern European drainages including the Siberian population, and Norwegian populations from northern Norway, and western side of Oslofjord. Our data suggest that present perch populations in western and northern Europe were colonized from three main refugia, located in southeastern, northeastern and western Europe. In support of this, nested cladistic analysis of mtDNA clade and nested clade distances suggested historical range expansion as the main factor determining geographical distribution of haplotypes. The Baltic Sea has been colonized from all three refugia, and northeastern Europe harbours descendants from both eastern European refugia. In the upper part of the Danube lineages from the western European and the southern European refugia meet. The southern European refugium probably did not contribute to the recolonization of other western and northern European drainages after the last glaciation. However, phylogenetic analyses suggest that the southern European mtDNA lineage is the most ancient, and therefore likely to be the founder of all present perch lineages. The colonization routes used by perch probably also apply to other freshwater species with similar distribution patterns.


Gamma-tocotrienol promotes TRAIL-induced apoptosis through reactive oxygen species/extracellular signal-regulated kinase/p53-mediated upregulation of death receptors.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor superfamily, is in clinical trials for cancer therapy, but its anticancer potential is limited by the development of resistance. We investigated the ability of tocotrienol (T3), an unsaturated vitamin E present in palm oil, rice bran, barley, oats, and wheat germ, to sensitize tumor cells to TRAIL. Results from esterase staining, colony formation, caspase activation, and sub-G(1) cell cycle arrest revealed that gamma-T3 can sensitize human colon cancer cells to TRAIL. When examined for the mechanism, we found that gamma-T3 significantly downregulated the expression of antiapoptotic proteins (c-IAP2 and Bcl-xL). We also found that gamma-T3, but not tocopherol, induced the expression of the TRAIL receptors death receptor (DR)-4 and DR5. This induction was not cell type specific, as upregulation was also found in pancreatic, kidney, and leukemic cells. Upregulation of DRs by gamma-T3 required the production of reactive oxygen species (ROS), and sequestering of ROS abolished both upregulation of the receptors and potentiation of TRAIL-induced apoptosis. Induction of DRs by gamma-T3 also required activation of extracellular signal-regulated kinase 1 (ERK1), as silencing of ERK1 by specific siRNA abrogated the upregulation of TRAIL receptors. Further, induction of DRs by gamma-T3 required the expression of p53 and Bax, as no induction of the receptors was found in colon cancer cells with deletion of these genes. Overall, our results show that gamma-T3 sensitizes tumor cells to TRAIL by upregulating DRs through the ROS/ERK/p53 pathway and by downregulating cell survival proteins.


[Intrathoracic compressions of the respiratory tract due to a double aortic arch in children].
Overall, twenty-eight children with intrathoracic airway compressions (IAC) caused by double aortic arch (DAA), who ranged 1.5 months to eleven years old, were kept under medical surveillance. The following respiratory symptoms were found to dominate the clinical picture in the above pediatric patient population: stridor, dyspnea, bouts of asphyxia, orthopnea, with secondary bronchopulmonary complications having been disclosed in all. The diagnosis of IAC and its complications in DAA was based on findings from thoracic roentgenography, esophagography, digital subtraction angiography, and tracheobronchoscopy. This pathology surgical correction indications were unquestionable. The policy has been worked out of treating DAA-associated IAK through surgery, with particular regard to the anatomical variants of the defect under question and its complications.


Laparoscopic wedge resection for gastrointestinal stromal tumour of the duodenum.
We report the case of a 40-year-old male patient who presented with melaena and acute anaemia. Endoscopic ultrasound examination revealed a lesion with a central depression measuring 2.5 cm, arising from the lateral wall of the second portion of the duodenum. Because of this rare location, a very invasive procedure (duodenopancreatectomy) might have been required for tumour resection. We avoided this operation and implemented an alternative solution. A laparoscopic wedge resection of the duodenal tumour was successfully completed. Operating time was 200 min and blood loss 50 ml. The patient was discharged on postoperative day 3, after an uneventful postoperative recovery. Histopathologically, the tumour was diagnosed as a low-risk gastrointestinal stromal tumour. Despite the fact that laparoscopic surgery requires more complex technique than open surgery and the acquisition of advanced laparoscopic skills depending on prior laparoscopic experience, laparoscopic wedge resection should be considered as a valid treatment for duodenal stromal tumour.


Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure.
Studies of the mode of action of the bisphosphonate alendronate showed that 1 d after the injection of 0.4 mg/kg [3H]alendronate to newborn rats, 72% of the osteoclastic surface, 2% of the bone forming, and 13% of all other surfaces were densely labeled. Silver grains were seen above the osteoclasts and no other cells. 6 d later the label was 600-1,000 microns away from the epiphyseal plate and buried inside the bone, indicating normal growth and matrix deposition on top of alendronate-containing bone. Osteoclasts from adult animals, infused with parathyroid hormone-related peptide (1-34) and treated with 0.4 mg/kg alendronate subcutaneously for 2 d, all lacked ruffled border but not clear zone. In vitro alendronate bound to bone particles with a Kd of approximately 1 mM and a capacity of 100 nmol/mg at pH 7. At pH 3.5 binding was reduced by 50%. Alendronate inhibited bone resorption by isolated chicken or rat osteoclasts when the amount on the bone surface was around 1.3 x 10(-3) fmol/microns 2, which would produce a concentration of 0.1-1 mM in the resorption space if 50% were released. At these concentrations membrane leakiness to calcium was observed. These findings suggest that alendronate binds to resorption surfaces, is locally released during acidification, the rise in concentration stops resorption and membrane ruffling, without destroying the osteoclasts.


Modernizing Clinical Trial Eligibility Criteria: Recommendations of the American Society of Clinical Oncology-Friends of Cancer Research HIV Working Group.
Purpose People with HIV are living longer as a result of effective antiretroviral therapy. Cancer has become a leading cause of morbidity and mortality in this patient population. However, studies of novel cancer therapeutics have historically excluded patients with HIV. Critical review of eligibility criteria related to HIV is required to accelerate development of and access to effective therapeutics for HIV-infected patients with cancer and make studies more generalizable to this patient population. Methods From January through April 2016, the HIV Working Group conducted a series of teleconferences; a review of 46 New Drug Applications from registration studies of unique agents studied in adults with cancer that led to the initial US Food and Drug Administration approval of that agent from 2011 to 2015; and a review of HIV-related eligibility criteria from National Cancer Institute-sponsored studies. Results were discussed and refined at a multistakeholder workshop held May 12, 2016. The HIV Working Group developed recommendations for eligibility criteria that focus on pharmacologic and immunologic considerations in this patient population and that balance patient safety, access to appropriate investigational agents, and study integrity. Results Exclusion of patients with HIV remains common in most studies of novel cancer agents. Models for HIV-related eligibility criteria in National Cancer Institute-sponsored studies are instructive. HIV infection itself should no longer be an exclusion criterion for most studies. Eligibility criteria related to HIV infection that address concurrent antiretroviral therapy and immune status should be designed in a manner that is appropriate for a given cancer. Conclusion Expanding clinical trial eligibility to be more inclusive of patients with HIV is justified in most cases and may accelerate the development of effective therapies in this area of unmet clinical need.


Age related acute effects of microcystin-LR on Daphnia magna biotransformation and oxidative stress.
As a result of eutrophication among other factors, bloom forming species of cyanobacteria frequently thrive and dominate communities in freshwater ecosystems. Cyanobacteria are considered as a nuisance and hazardous due to the production of toxins. The most potent and studied cyanobacterial toxins are the microcystins, especially the variant microcystin-LR (MC-LR). Daphnia magna plays a central role in freshwater pelagic food webs and its populations are negatively affected by cyanobacteria due to nutritional inadequacy, feeding interference and toxic effects on growth and reproduction. Biotransformation and antioxidant enzymes, amongst others enable D. magna capacity to cope with MC-LR up to a certain concentration. Aim of our study was to investigate the age related acute effects of MC-LR on D. magna biotransformation and antioxidant enzymes (glutathione S-transferase, GST and catalase, CAT), subsequent lipid peroxidation and furthermore to lactate and the enzyme lactate dehydrogenase (LDH). D. magna neonates (<3 days old) and young adults (7 days old), were exposed to increasing concentrations of MC-LR (up to 100 μg/L) for 24 and 48 h. D. magna sGST activities at both ages, but more pronounced in adults, increased at low MC-LR concentrations followed by decreased activities at the higher ones suggesting diminished ability to biotransform the cyanotoxin. Oxidative protection was more efficient in neonates, where CAT was elevated strongly and contributed to buffer oxidative stress, evidenced by the constant TBARS concentrations. LDH was negatively affected by MC-LR exposure leading to constant and low concentrations of lactate. As this enzyme is involved in the production of rapidly required energy, the findings suggest an energetic impairment due to MC-LR.


Key Role of Obesity in Genitourinary Tumors with Emphasis on Urothelial and Prostate Cancers.
Background: In human populations, a certain amount of data correlate obesity/body mass index (BMI) with urothelial cancer (UC) and prostate cancer (PCa) occurrence, however this is not fully elucidated at all stages of disease. In an attempt to shed light on uncertain areas in such field, in the present review we illustrate the main molecular mechanisms linking obesity and cancer, focusing on the correlation between obesity and tumor risk, disease progression and response to chemo- and immunotherapy in patients with UC and the predictive/prognostic role of obesity in PCa patients treated with the currently available therapeutic approaches. Methods: We did a large-scale literature search on existing scientific websites focusing on keywords "obesity", "body mass index (BMI)", "urothelial cancer", "prostate cancer", "docetaxel", "cabazitaxel", "abiraterone acetate", "enzalutamide", and "radium223". Results: Many adipocytes-induced molecules support tumor proliferation through activation of various cellular pathways. The available evidence in the postoperative setting do the role of BMI in oncological outcomes prediction still not completely clear. Likewise, in metastatic UC patients controversial results link the role of obesity/BMI with clinical outcomes of tumor response to chemotherapy. Adipose stromal cells recruitment, induced by PCa cells, from white adipose tissue to the tumor sites inducing cell invasiveness was associated with poor survival. Conflicting data, although more oriented towards a better survival outcome, resulted in obese patients treated with docetaxel. In PCa cell-lines a certain cabazitaxel chemo resistance adipose stromal cells (ASC)-mediated was demonstrated. In metastatic castration-resistant PCa patients with high BMI (>25 kg/m2) receiving abiraterone acetate there were significant worse survival outcomes, while in enzalutamide patients BMI did not affect survival outcome. In radium 223 patients higher BMI significantly correlated with favorable overall survival. Conclusions: The main focus of this review was to understand the interplay between obesity/BMI and UC/PCa. Several pathogenic cellular pathways exploring the issue are discussed, opening the way to challenging tailored treatments on the basis of BMI. Improving the knowledge of molecular connections between obesity and UC and PCa could favor the development of new therapies likely reducing chemo- and immunotherapy drug resistance.


Hyperglycemia Suppresses Age-Related Increases in Corneal Peripheral Sensory Nerves in Wistar Bon Kobori (WBN/Kob) Rats.
Nerve fiber density in the cornea is an alternative marker for diabetic peripheral neuropathy combined with intraepidermal nerve fiber density (IENFD). Recent studies investigated corneal nerves using rodent models of diabetes. Male Wistar Bon Kobori (WBN/Kob) rats spontaneously develop long-lasting diabetes and human-like diabetic peripheral neuropathy with vascular lesions. This study investigated corneal nerve fiber density and IENFD in diabetic male WBN/Kob rats as morphological markers of diabetic peripheral neuropathy. Male WBN/Kob rats exhibit abnormal glucose tolerance and diabetes at approximately 30 weeks of age, which progresses until approximately 90 weeks of age. Male WBN/Kob rats aged 36 and 90 weeks were therefore used for histological investigations and compared with age-matched nondiabetic female rats. Terminal epithelial nerve density and subbasal nerve plexus density in the central cornea were significantly greater in nondiabetic female rats aged 90 weeks when compared with nondiabetic female rats aged 36 weeks. However, terminal epithelial nerve density and subbasal nerve plexus density did not increase with age in diabetic male WBN/Kob rats, instead lowering by up to 40%, relative to measurements in nondiabetic female rats aged 90 weeks. However, this difference was not statistically significant. IENFD was significantly lower in diabetic male rats aged 90 weeks than in male rats aged 36 weeks, but did not differ between diabetic male rats and nondiabetic female rats aged 90 weeks. In WBN/Kob rats, hyperglycemia suppresses an age-related increase in peripheral sensory corneal nerve density; therefore, corneal sensory nerves may be important morphological markers of diabetic peripheral sensory neuropathy.


Genome-Wide Transposon Screen of a Pseudomonas syringae mexB Mutant Reveals the Substrates of Efflux Transporters.
Bacteria express numerous efflux transporters that confer resistance to diverse toxicants present in their environment. Due to a high level of functional redundancy of these transporters, it is difficult to identify those that are of most importance in conferring resistance to specific compounds. The resistance-nodulation-division (RND) protein family is one such example of redundant transporters that are widespread among Gram-negative bacteria. Within this family, the MexAB-OprM protein complex is highly expressed and conserved among Pseudomonas species. We exposed barcoded transposon mutant libraries in isogenic wild-type and ΔmexB backgrounds in P. syringae B728a to diverse toxic compounds in vitro to identify mutants with increased susceptibility to these compounds. Mutants with mutations in genes encoding both known and novel redundant transporters but with partially overlapping substrate specificities were observed in a ΔmexB background. Psyr_0228, an uncharacterized member of the major facilitator superfamily of transporters, preferentially contributes to tolerance of acridine orange and acriflavine. Another transporter located in the inner membrane, Psyr_0541, contributes to tolerance of acriflavine and berberine. The presence of multiple redundant, genomically encoded efflux transporters appears to enable bacterial strains to tolerate a diversity of environmental toxins. This genome-wide screen performed in a hypersusceptible mutant strain revealed numerous transporters that would otherwise be dispensable under these conditions. Bacterial strains such as P. syringae that likely encounter diverse toxins in their environment, such as in association with many different plant species, probably benefit from possessing multiple redundant transporters that enable versatility with respect to toleration of novel toxicants.IMPORTANCE Bacteria use protein pumps to remove toxic compounds from the cell interior, enabling survival in diverse environments. These protein pumps can be highly redundant, making their targeted examination difficult. In this study, we exposed mutant populations of Pseudomonas syringae to diverse toxicants to identify pumps that contributed to survival in those conditions. In parallel, we examined pump redundancy by testing mutants of a population lacking the primary efflux transporter responsible for toxin tolerance. We identified partial substrate overlap for redundant transporters, as well as several pumps that appeared more substrate specific. For bacteria that are found in diverse environments, having multiple, partially redundant efflux pumps likely allows flexibility in habitat colonization.


In vitro activity of TR-700, the active ingredient of the antibacterial prodrug TR-701, a novel oxazolidinone antibacterial agent.
TR-701 is the prodrug of the microbiologically active molecule TR-700, a novel orally and intravenously administered oxazolidinone antibacterial agent. The in vitro activity of TR-700 was evaluated against 1,063 bacterial clinical isolates including staphylococci, enterococci, streptococci, Moraxella catarrhalis, Haemophilus influenzae, and a variety of anaerobic bacterial species. The test strains were recent (2005 to 2008) clinical isolates from diverse U.S. (80%) and non-U.S. (20%) sites. MIC assays were conducted using reference broth microdilution and agar dilution methods with the principal comparators linezolid and vancomycin. TR-700 was four- to eightfold more potent than linezolid against staphylococci and generally fourfold more potent against enterococci and streptococci. TR-700 was less active against M. catarrhalis and H. influenzae but was twofold more active than linezolid. Against anaerobic species, the activity of TR-700 was equivalent to or up to fourfold higher than that of linezolid. These results indicate that TR-700 is a promising new oxazolidinone antibacterial agent with greater in vitro potency than linezolid against clinically important gram-positive bacteria.


Nitidine Chloride Is a Potential Alternative Therapy for Glioma Through Inducing Endoplasmic Reticulum Stress and Alleviating Epithelial-Mesenchymal Transition.
Background: Malignant glioma is a lethal brain tumor that is highly resistant to standard therapy. Our research aims to explore the suppressive effects of nitidine chloride (NC) on gliomas and the mechanisms involved, showing that it is a potential agent for integrative therapy of gliomas. Methods: After glioma cells were treated with NC, several experiments were performed to evaluate NC's antitumor effects. CCK-8 assay was used to detect viability. Transwell and 3-dimensional spheroid invasion assays were used to evaluate motility of glioma in vitro, and the sphere-formation assay showed NC's influence on glioma stem cells. Apoptosis and intracellular reactive oxygen species were measured by means of flow cytometry. Subcellular structures were observed through transmission electron microscopy. Western blot analysis reflected expression of endoplasmic reticulum (ER) stress and epithelial-mesenchymal transition (EMT) marker proteins. An orthotopic xenograft model was established to investigate the tumor suppressive effects in vivo. Results: Nitidine chloride inhibited glioma cell migration and invasion in vitro, downregulated the EMT proteins, and suppressed sphere formation of glioma stem cells. Furthermore, NC induced persistent ER stress that contributed to apoptosis and reactive oxygen species production. The xenograft model showed that NC effectively restricted glioma growth and invasion in vivo. Furthermore, we confirmed the signaling pathways that ER stress downregulates C/EBPβ and slug, as well as inhibition of the AKT/GSK3β/β-catenin axis caused by NC, in U-87 MG. Conclusion: We demonstrated that NC inhibits gliomas in vitro and in vivo by activating ER stress and downregulating EMT, which provides a basis for glioma therapy.


What is adenine doing in photolyase?
The short answer to the title question is that it acts as an electrostatic bouncer that shoves the charge flow from flavin toward the DNA lesion that photolyase repairs. This explanation is provided by an explicit time-dependent quantum mechanical approach, which is used to investigate the electron transfer process that triggers the repair mechanism. The transfer occurs from the flavin photolyase cofactor to the cyclobutane ring of DNA, previously formed by light-induced cycloaddition of adjacent pyrimidine bases. The electron wave function dynamics accurately accounts for the previously proposed mechanism of transfer via the terminal methyl group of the flavin moiety present in the catalytic electron-donor cofactor, FADH(-), which also contains adenine. This latter moiety, which has often been assumed to be present mainly for structural reasons, instantaneously modifies the interaction between acceptor and donor by a variation of the electrostatic interactions so that the presence of its local atomic charges is necessary to trigger the transfer. In principle, knowledge of the details of the electron transfer dynamics and of the important role of polarization effects can be exploited to improve the efficiency of the repair mechanism in artificial systems.


The value of repeat kidney biopsy in quiescent Argentinian lupus nephritis patients.
The duration of maintenance therapy after induction therapy for lupus nephritis has not been rigorously established. A common practice is to maintain immunosuppression for 1-2 years after complete remission, and longer for partial remission. The present work addresses whether a repeat kidney biopsy might be informative in deciding who should continue immunosuppression after complete or partial remission. The practice in a large Buenos Aires nephrology unit is to repeat a kidney biopsy before finalizing the decision to withdraw or continue immunosuppression. This work reports on a cohort of 25 Hispanic patients that had two or more kidney biopsies, the last occurring after at least 24 months of clinically quiescent disease. Despite normalization of serum creatinine and reduction of proteinuria to <500 mg/d, 30% of patients still had significant activity at the last biopsy. Conversely, 60% of patients with ongoing proteinuria (500-1000 mg/d), or stable but abnormal serum creatinine, had no activity by biopsy. Univariate association analyses demonstrated that improvement in the activity index (AI) of the last biopsy was associated with choice of induction therapy (cyclophosphamide or mycophenolate), improvement in serum creatinine over the first six months of treatment, and improvement in complement component C4. By multivariate regression analyses, two AI prediction models emerged. Cyclophosphamide plus change in serum creatinine or cyclophosphamide plus change in C4 accounted for 50% of the improvement in AI. These data suggest that a repeat biopsy may be useful in making the decision to withdraw or continue maintenance immunosuppression.


Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia.
Natural killer (NK) cells are an emerging cellular immunotherapy for patients with acute myeloid leukemia (AML); however, the best approach to maximize NK cell antileukemia potential is unclear. Cytokine-induced memory-like NK cells differentiate after a brief preactivation with interleukin-12 (IL-12), IL-15, and IL-18 and exhibit enhanced responses to cytokine or activating receptor restimulation for weeks to months after preactivation. We hypothesized that memory-like NK cells exhibit enhanced antileukemia functionality. We demonstrated that human memory-like NK cells have enhanced interferon-γ production and cytotoxicity against leukemia cell lines or primary human AML blasts in vitro. Using mass cytometry, we found that memory-like NK cell functional responses were triggered against primary AML blasts, regardless of killer cell immunoglobulin-like receptor (KIR) to KIR-ligand interactions. In addition, multidimensional analyses identified distinct phenotypes of control and memory-like NK cells from the same individuals. Human memory-like NK cells xenografted into mice substantially reduced AML burden in vivo and improved overall survival. In the context of a first-in-human phase 1 clinical trial, adoptively transferred memory-like NK cells proliferated and expanded in AML patients and demonstrated robust responses against leukemia targets. Clinical responses were observed in five of nine evaluable patients, including four complete remissions. Thus, harnessing cytokine-induced memory-like NK cell responses represents a promising translational immunotherapy approach for patients with AML.


In Situ Analysis of a Silver Nanoparticle-Precipitating Shewanella Biofilm by Surface Enhanced Confocal Raman Microscopy.
Shewanella oneidensis MR-1 is an electroactive bacterium, capable of reducing extracellular insoluble electron acceptors, making it important for both nutrient cycling in nature and microbial electrochemical technologies, such as microbial fuel cells and microbial electrosynthesis. When allowed to anaerobically colonize an Ag/AgCl solid interface, S. oneidensis has precipitated silver nanoparticles (AgNp), thus providing the means for a surface enhanced confocal Raman microscopy (SECRaM) investigation of its biofilm. The result is the in-situ chemical mapping of the biofilm as it developed over time, where the distribution of cytochromes, reduced and oxidized flavins, polysaccharides and phosphate in the undisturbed biofilm is monitored. Utilizing AgNp bio-produced by the bacteria colonizing the Ag/AgCl interface, we could perform SECRaM while avoiding the use of a patterned or roughened support or the introduction of noble metal salts and reducing agents. This new method will allow a spatially and temporally resolved chemical investigation not only of Shewanella biofilms at an insoluble electron acceptor, but also of other noble metal nanoparticle-precipitating bacteria in laboratory cultures or in complex microbial communities in their natural habitats.