Corylin Attenuates CCl4-Induced Liver Fibrosis in Mice by Regulating the GAS6/AXL Signaling Pathway in Hepatic Stellate Cells.
Liver fibrosis is reversible when treated in its early stages and when liver inflammatory factors are inhibited. Limited studies have investigated the therapeutic effects of corylin, a flavonoid extracted from Psoralea corylifolia L. (Fabaceae), on liver fibrosis. Therefore, we evaluated the anti-inflammatory activity of corylin and investigated its efficacy and mechanism of action in ameliorating liver fibrosis. Corylin significantly inhibited inflammatory responses by inhibiting the activation of mitogen-activated protein kinase signaling pathways and the expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha in human THP-1 and mouse RAW264.7 macrophages. Furthermore, corylin inhibited the expression of growth arrest-specific gene 6 in human hepatic stellate cells (HSCs) and the activation of the downstream phosphoinositide 3-kinase/protein kinase B pathway. This inhibited the activation of HSCs and the expression of extracellular matrix proteins, including α-smooth muscle actin and type I collagen. Additionally, corylin induced caspase 9 and caspase 3 activation, which promoted apoptosis in HSCs. Moreover, in vivo experiments confirmed the regulatory effects of corylin on these proteins, and corylin alleviated the symptoms of carbon tetrachloride-induced liver fibrosis in mice. These findings revealed that corylin has anti-inflammatory activity and inhibits HSC activation; thus, it presents as a potential adjuvant in the treatment of liver fibrosis.


Conservative treatment of patellofemoral subluxation.
As pointed out in the preface of this book, patellofemoral subluxation is probably the most common knee problem seen in many orthopedists' offices today. Whereas the other authors have emphasized the anatomy and diagnosis, this article should serve as a dry but basic instruction on the exercise program that has been used in our clinic. We have had a success rate with this program of approximately 80 per cent. Certainly not all of the 20 per cent that fail require surgery. The classic exercises are quadricep sets, straight leg raises, hip abductors, hip adductors, hip flexors, and hamstring stretches, which have endured the test of time. The prevention of flexion extension activity, such as running the stadium stairs in order to strengthen the quadriceps of the patient with patellofemoral subluxation should be emphasized. Complications of conservative treatment, such as low back pain, iliopsoas tendinitis, and muscle soreness and the treatment of these is described. Finally, the importance of stretching the hamstring muscles is a cornerstone in the treatment of patellofemoral problems. Likewise, a tight IT band can put abnormal stress on the lateral aspect of the patella. In this article I have tried to point out our approach to conservative treatment of patellofemoral subluxation.


Clinical differences among mild cognitive impairment subtypes in Parkinson's disease.
Mild cognitive impairment is increasingly recognized as a construct in Parkinson's disease (PD) and occurs in about 25% of nondemented PD patients. Although executive dysfunction is the most frequent type of cognitive deficit in PD, the cognitive phenotype of PD mild cognitive impairment (PD-MCI) is broad. PD-MCI subtypes are represented by amnestic and nonamnestic domain impairment as well as single- and multiple-domain impairment. However, it is unclear whether patients with different PD-MCI subtypes also differ in other clinical characteristics in addition to cognitive profile. We studied 128 PD-MCI subjects at our Movement Disorders center, comparing clinical, motor, and behavioral characteristics across the PD-MCI subtypes. We found varying proportions of impairment subtypes: nonamnestic single domain, 47.7%; amnestic multiple domain, 24.2%; amnestic single domain, 18.8%; and nonamnestic multiple domain, 9.5%. Attentional/executive functioning and visuospatial abilities were the most frequently impaired domains. PD-MCI subtypes differed in their motor features, with nonamnestic multiple-domain PD-MCI subjects showing particularly pronounced problems with postural instability and gait. Differences among PD-MCI subtypes in age, PD duration, medication use, mood or behavioral disturbances, and vascular disease were not significant. Thus, in addition to differing cognitive profiles, PD-MCI subtypes differed in motor phenotype and severity but not in mood, behavioral, or vascular comorbidities. Greater postural instability and gait disturbances in the nonamnestic multiple-domain subtype emphasize shared nondopaminergic neural substrates of gait and cognition in PD. Furthermore, increased burden of cognitive dysfunction, rather than type of cognitive deficit, may be associated with greater motor impairment in PD-MCI.


Beyond Roe: Implications for End-of-Life Decision-Making During Pregnancy.
The end of Roe v. Wade has significant implications for the autonomy of pregnant patients at the end of life. At least thirty states restrict the choice to withhold/withdraw life-sustaining treatments from pregnant patients without decisional capacity, invalidating prior advance directives and prohibiting others from choosing these options for the patient. Many restrictions are based on the Roe framework, applying after "viability" or similar considerations of fetal development or prospect for live birth. Scholars have also relied on the abortion framework, arguing that the restrictions impose an undue burden. The end of Roe will free states from having to craft limited restrictions designed to work around prior abortion jurisprudence. Similarly, advocates will no longer be able to draw support from the abortion framework, forcing them to rely instead on cases supporting rights to autonomy/bodily integrity in medical decision-making.


'Nobody likes damaged goods': the experience of adult visible acne.
While mild to severe acne is a common problem in the teenage years, many adults also suffer from the condition. Although there is an appreciable body of dermatological literature on this issue, the psychosocial concomitants of severe, visible adult acne are little elaborated. The aim of this research is to detail the salient experiences of adults with severe visible acne, and to set out the implications of these experiences. A phenomenological qualitative approach was adopted to elicit detailed accounts of the impact of visible acne upon the lives of a small sample of sufferers. 11 adults suffering from severe visible acne took part in semi-structured interviews via e-mail, over an extended period of time. Transcripts of these interviews served as the data for an interpretative phenomenological analysis. Five themes emerged, detailing different aspects of respondents' personal and social lives in the context of their acne. These were: powerlessness and the variable nature of acne; comparisons, self-image and identity; the experience of general social interaction; relationships with family and friends; and gender, sexuality, and romantic relationships. These themes allowed a deeper understanding of issues reported in previous quantitative research in the area, as well as revealing findings that had not been previously reported in relation to the experience of adult acne and its impact upon personal and social relationships. With an acknowledgement of these experiences, personal and professional acquaintances have the potential to improve their interpersonal relationship with the person concerned, and encourage positive changes in their psychological health and social interaction.


An extension of biorelevant fed-state dissolution tests to clinical pharmacokinetics - A study on gastrointestinal factors influencing rivaroxaban exposure and efficacy in atrial fibrillation patients.
A direct oral anticoagulant rivaroxaban fails to prevent stroke and systemic embolism in one-to-several percent of patients with nonvalvular atrial fibrillation (NVAF), but the reasons are unknown. The study used semi-mechanistic in vitro-in vivo prediction (IVIVP) modeling to explore the reasons for ineffective thrombosis prevention in NVAF patients. Steady-state drug concentrations in plasma were measured at 0 h (Ctrough), 3 h (C3h), and 12 h post-dosing in thirty-four patients treated with 20 mg rivaroxaban daily. The clinical data were compared against "virtual twins" generated with a novel IVIVP model that combined drug dissolution modeling, mechanistic description of gastric drug transit, and population pharmacokinetics defining the variability of drug disposition. The nonresponders had significantly lower C3h and Ctrough than the responders (p < 0.001) and the covariates included in the population pharmacokinetic submodel did not fully explain this difference. Simulations involving varied gastrointestinal parameters in the "virtual twins" revealed that lower small intestinal effective permeability (Peff), rather than a slower stomach emptying rate, could explain low rivaroxaban exposure in the nonresponders. IVIVP modeling was effectively used for exploring pharmacotherapy failure. Low Peff, found as a major determinant of ineffective rivaroxaban treatment, encourages further research to find (pato)physiological factors influencing suboptimal absorption.


Long-Term Follow-Up of the E1199 Phase III Trial Evaluating the Role of Taxane and Schedule in Operable Breast Cancer.
To determine long-term outcomes in a clinical trial evaluating the role of taxane type and schedule in operable breast cancer and evaluate the impact of obesity and black race on outcome. A total of 4,954 eligible women with stage II to III breast cancer treated with four cycles of doxorubicin plus cyclophosphamide were randomly assigned to receive paclitaxel or docetaxel every 3 weeks for four doses or weekly for 12 doses using a 2 × 2 factorial design. The primary end point was disease-free survival (DFS). Results are expressed as hazard ratios (HRs) from Cox proportional hazards models. All P values are two sided. When compared with the standard every-3-week paclitaxel arm, after a median follow-up of 12.1 years, DFS significantly improved and overall survival (OS) marginally improved only for the weekly paclitaxel (HR, 0.84; P = .011 and HR, 0.87; P = .09, respectively) and every-3-week docetaxel arms (HR, 0.79; P = .001 and HR, 0.86; P = .054, respectively). Weekly paclitaxel improved DFS and OS (HR, 0.69; P = .010 and HR, 0.69; P = .019, respectively) in triple-negative breast cancer. For hormone receptor-positive, human epidermal growth factor receptor 2-nonoverexpressing disease, no experimental arm improved OS, and black race and obesity were associated with increased risk of breast cancer recurrence and death. Improved outcomes initially observed for weekly paclitaxel were qualitatively similar but quantitatively less pronounced with longer follow-up, although exploratory analysis suggested substantial benefit in triple-negative disease. Further research is required to understand why obesity and race influence clinical outcome in hormone receptor-positive disease.


A psychometric evaluation of the 16-item PHQ-ADS concomitant anxiety and depression scale in the UK biobank using item response theory.
The Patient Health Questionnaire Anxiety and Depression Scale (PHQ-ADS) provides a reliable and valid measure of concomitant depression and anxiety. However, research on its psychometric efficiency and optimal scale length using item-response theory (IRT) has not been reported. This study aimed to optimize the length of the PHQ-ADS scale without losing information by discarding items that were a poor fit to the IRT model. The UK Biobank is a large cohort study designed to investigate risk factors for a broad range of disease. PHQ-ADS data were available from n = 152,826 participants (age = 55.87 years; SD = 7.73; 56.4 % female), 30.4 % of the entire UK Biobank sample. Psychometric properties of the PHQ-ADS were investigated using a 2-parameter IRT and Mokken analysis. Item statistics included discrimination, difficulty and Loevinger H coefficients of monotonicity. In the entire 16-item scale, item discrimination ranged from 1.40 to 4.22, with the item 'worrying' showing the highest level of discrimination and the item 'sleep disturbance' showing the lowest. Mokken analysis showed that the 16-item PHQ-ADS scale could be reduced to a 7-item scale without loss of test information. The reduced scale comprised mainly items measuring cognitive-affective symptoms of anxiety/depression, whereas items measuring somatic symptoms were discarded. The revised scale showed high discrimination and scalability. Findings are limited by the use of cross-sectional data that only included the baseline online questionnaire, but not other waves. IRT is a useful technique for scale reductions which serve the clinical and epidemiological need to optimize screening questionnaires to reduce redundancy and maximize information. A reduced-item 7-item PHQ-ADS scale reduces the response burden on participants in epidemiological research settings, without loss of information.


Onset and duration of rocuronium-induced neuromuscular blockade in patients with Duchenne muscular dystrophy.
In patients with Duchenne muscular dystrophy (DMD) the response to nondepolarizing muscle relaxants is scarcely documented and conflicting. The current study was conducted to determine the time to peak effect and the time for complete spontaneous recovery after a single dose of 0.6 mg/kg of rocuronium in patients with DMD. Twenty-four patients (12 with DMD, 12 controls, aged 10-16 yr) were studied. All patients were anesthetized with propofol and fentanyl/remifentanil. Neuromuscular transmission was monitored by acceleromyography. After induction all patients received a single dose of 0.6 mg/kg of rocuronium. The complete time course of onset and spontaneous recovery were recorded Significant (P < 0.01) increase in the onset times to 95% neuromuscular block was observed in DMD patients (median, 203 s; range, 90-420 s) compared with controls (median, 90 s; range, 60-195 s). The time between rocuronium administration and recovery of first twitch of the train-of-four to 90% was significantly (P < 0.01) prolonged in DMD compared with controls (median, 132 min; range, 61-209 min versus 39 min; 22-55 min). The recovery index was also significantly prolonged in the DMD group compared with controls (median, 28 min, range, 15-70 min versus 8 min; 3-14 min). The most striking and surprising result of this study is the delayed onset of blockade in DMD after a standard dose of rocuronium. This effect should be kept in mind in situations when a rapid airway protection is necessary in DMD patients. The documented very long recovery from rocuronium-induced block emphasizes the need for careful assessment of neuromuscular function in DMD patients.


Molecular characterization of Asian maize inbred lines by multiple laboratories.
This study focuses on the standardization of techniques across laboratories to enable multiple datasets to be compared and combined in order to obtain reliable and robust wide-scale patterns of diversity. A set of protocols using a core collection of simple sequence repeat (SSR) markers, reference lines and standard alleles, plus a common system of allele nomenclature, was adopted in the study of maize genetic diversity in a network of laboratories in Asia. Pair-wise allele comparisons of the reference lines, done to assess the general agreement between datasets from four laboratories, showed error rates (raw) ranging from 5.8% to 9.7%, which were reduced to less than 8% after adjustments of correctable errors, and further reduced to less than 6% after the exclusion of all markers with greater than 10% individual error rates. Overall, 45% of the total mismatches were due to frameshift errors, 39% to wrong allele size, 15% to failed amplification and 1% to "extra" alleles. Higher genetic similarity values of the reference lines were achieved using fewer markers with data of higher quality rather than with more markers of questionable quality. Cluster analysis of the merged datasets showed the lines from southern China to be highly diverse, falling into six of the seven clusters observed and all well represented by tester lines. The lines from Indonesia fell into five of six groups, with two main groups represented by tester lines. The CIMMYT lines developed for the Asian region showed a relatively narrow genetic base, falling in two out of seven and in three out of six clusters in China and Indonesia, respectively. In contrast to the case in southern China where 95% of the lines clustered separately from the CIMMYT lines, lines in the Indonesian breeding program show a closer relationship with the CIMMYT lines, reflecting a long history of germplasm exchange.


An atlas of chromatin accessibility in the adult human brain.
Most common genetic risk variants associated with neuropsychiatric disease are noncoding and are thought to exert their effects by disrupting the function of cis regulatory elements (CREs), including promoters and enhancers. Within each cell, chromatin is arranged in specific patterns to expose the repertoire of CREs required for optimal spatiotemporal regulation of gene expression. To further understand the complex mechanisms that modulate transcription in the brain, we used frozen postmortem samples to generate the largest human brain and cell-type-specific open chromatin data set to date. Using the Assay for Transposase Accessible Chromatin followed by sequencing (ATAC-seq), we created maps of chromatin accessibility in two cell types (neurons and non-neurons) across 14 distinct brain regions of five individuals. Chromatin structure varies markedly by cell type, with neuronal chromatin displaying higher regional variability than that of non-neurons. Among our findings is an open chromatin region (OCR) specific to neurons of the striatum. When placed in the mouse, a human sequence derived from this OCR recapitulates the cell type and regional expression pattern predicted by our ATAC-seq experiments. Furthermore, differentially accessible chromatin overlaps with the genetic architecture of neuropsychiatric traits and identifies differences in molecular pathways and biological functions. By leveraging transcription factor binding analysis, we identify protein-coding and long noncoding RNAs (lncRNAs) with cell-type and brain region specificity. Our data provide a valuable resource to the research community and we provide this human brain chromatin accessibility atlas as an online database "Brain Open Chromatin Atlas (BOCA)" to facilitate interpretation.


Sequence and diversity of bovine T-cell receptor beta-chain genes.
The nucleotide sequences of 38 T-cell receptor (Tcr) beta-chain cDNA clones which were isolated from a cDNA library (2 x 10(6) plaques) constructed from bovine peripheral blood lymphocytes were determined. Of 38 cDNA clones, 22 were rearranged and contained the functional variable (V) gene segments. These clones were tentatively divided into nine Tcrb-V gene families which correspond to the human Tcrb-V family. Among them, a Tcrb-V12 gene segment was isolated from 9 out of 22 clones, suggesting that this Tcrb-V family was expressed in the bovine peripheral blood lymphocytes. Two different constant (C) gene segments were found, and both C regions were composed of 178 amino residues. The amino acid sequences of bovine Tcrb-C regions are approximately 80%-82%, 78%, and 78% similar to those from human, mouse, and rabbit, respectively. To estimate Tcrb-V-associated restriction fragment length polymorphisms (RFLPs), Southern blot analysis was performed using liver DNAs from four bovine breeds, Holstein, Angus, Hereford, and Japanese Black. However, no significant difference was observed among genomic DNAs of Tcrb-V loci from these four breeds.


Polymorphisms in estrogen related genes may modify the protective effect of isoflavones against prostate cancer risk in Japanese men.
Soy isoflavones and estrogen related genes may play a major role in the etiology of prostate cancer. This study examined whether the genetic polymorphisms of estrogen receptors (ESR-alpha and ESR-beta) and cytochrome P450 19A1 (CYP19A1) modified the protective effect of isoflavones against prostate cancer. One hundred and eighty cases and 177 controls were selected from three geographic areas of Japan. The odds ratio for more than or equal to 60 versus less than 60 mg/day of the intake of isoflavones was 0.63 (95% confidence interval=0.41-0.96). The TTTA long repeat was significantly associated with an increased risk (odds ratio=1.76, 95% confidence interval=1.15-5.70). The interaction between the polymorphisms and the intake of isoflavones on prostate cancer risk was analyzed by the multifactor dimensionality reduction method. The combination of the TTTA long repeats and the minor alleles of rs10046 in CYP19A1 and rs2077647 in ESR-alpha was a high risk for prostate cancer despite greater than or equal to 60 mg isoflavones/day. The combination of the TTTA short repeat and those homozygous for the major allele of rs10046 in CYP19A1 was low risk despite less than 60 mg isoflavones/day. In conclusion, the findings of this case-control study suggest that the protective effect of isoflavones may differ between the genotypes of estrogen related genes.


Locomotion behavior testing as a complementary tool in Collembola avoidance assays with neurotoxic insecticides.
This study aimed (1) to assess the ability of collembolans Folsomia candida to avoid soils contaminated with three seed dressing insecticides imidacloprid, clothianidin, and fipronil; (2) to assess the effects of the insecticides on collembolans' locomotion behavior; (3) to check if changes in the locomotion behavior would explain the avoidance/preference responses; and (4) to evaluate the possibility to use locomotion behavior as toxicity biomarker of the tested insecticides. Avoidance and locomotion behavior assays with collembolans F. candida were performed with commercial seed dressing formulations of three insecticides (imidacloprid, clothianidin, and fipronil). Results showed no avoidance behavior at any concentration, while a "preference" was observed with increasing concentrations of the three tested insecticides. Significant reductions in the locomotion of exposed collembolans were observed at ≥ 1 mg kg-1 for imidacloprid (18-38%) and fipronil (29-58%) and ≥ 4 mg kg-1 for clothianidin (10-47%). At the higher insecticide concentrations, the collembolans had their trajectories restricted to smaller areas, with a tendency for circular movements. Our results confirm that the "preference" for contaminated soils with neurotoxic substances is likely due to locomotion inhibition impairing the ability of organisms to escape. This effect highlights that only avoidance assays may be not sufficient to assure the safety of some substances and confirm the potential of locomotion behavior as a sensitive toxicity biomarker for neurotoxic insecticides.


"They were only joking": efforts to decrease LGBTQ bullying and harassment in seattle public schools.
Seattle Public Schools has implemented policies and programs to increase safety, family involvement, and student achievement for lesbian, gay, bisexual, transgender, and questioning (LGBTQ) youth. This case study examines students' perceptions of bullying and harassment in the school environment, and teacher intervention when these problems arise in the presence of strong district policies and programs aimed at reducing LGBTQ bullying and harassment in schools. We surveyed students in Gay-Straight Alliance (GSA) groups at 13 secondary schools (N = 107). We also conducted focus groups with GSA students and students not involved in the GSAs in 7 of 13 schools (N = 16 groups, including 154 students). GSA students who were lesbian, gay, bisexual, or questioning (LGBQ) were significantly more likely than straight students to experience several types of harassment. On the basis of student report, the 2 most common intervention strategies by teachers for verbal harassment included stopping the harassment and explaining why it is wrong; teachers intervened in physical harassment by trying to stop the harassment. Students provided input on how to strengthen teacher interventions, including the need for more consistency in responding and following up. Students also noted a need for more focus on educating those who harass, rather than just asking them to stop. Seattle Public Schools has made great strides in creating safe and welcoming schools for LGBTQ students, but still have to work further toward reaching this goal. Data from students on how they experience their school environment can help identify areas for improvement.


Microlens performance limits in sub-2mum pixel CMOS image sensors.
CMOS image sensors with smaller pixels are expected to enable digital imaging systems with better resolution. When pixel size scales below 2 mum, however, diffraction affects the optical performance of the pixel and its microlens, in particular. We present a first-principles electromagnetic analysis of microlens behavior during the lateral scaling of CMOS image sensor pixels. We establish for a three-metal-layer pixel that diffraction prevents the microlens from acting as a focusing element when pixels become smaller than 1.4 microm. This severely degrades performance for on and off-axis pixels in red, green and blue color channels. We predict that one-metal-layer or backside-illuminated pixels are required to extend the functionality of microlenses beyond the 1.4 microm pixel node.


Ion channels in gastrointestinal smooth muscle and interstitial cells of Cajal.
A requirement for normal gastrointestinal motility is the tight regulation of ion channels expressed in interstitial cells of Cajal and smooth muscle. Interstitial cells of Cajal generate the slow wave and amplify neuronal signals; smooth muscle functions as the final effector organ. Recent advances in our understanding of the expression and mechano-regulation of these different subtypes of ion channels have allowed the development of hypotheses on how ion channels transduce a variety of inputs into electrical signals that directly or indirectly regulate gastrointestinal motor activity.


Immunogenicity and reactogenicity of alternative schedules of HPV vaccine in Vietnam: a cluster randomized noninferiority trial.
Human papillomavirus (HPV) vaccine programs may decrease the morbidity and mortality due to cervical cancer seen among women in low-resource countries. However, the 3-dose schedule over a 6-month period is a potential barrier to vaccine introduction in such settings. To determine the immunogenicity and reactogenicity of different dosing schedules of quadrivalent HPV vaccine in adolescent girls in Vietnam. Open-label, cluster randomized, noninferiority study (conducted between October 2007 and January 2010) assessing 4 schedules of an HPV vaccine delivered in 21 schools to 903 adolescent girls (aged 11-13 years at enrollment) living in northwestern Vietnam. Intramuscular injection of 3 doses of quadrivalent HPV vaccine delivered on a standard dosing schedule (at 0, 2, and 6 months) and 3 alternative dosing schedules (at 0, 3, and 9 months; at 0, 6, and 12 months; or at 0, 12, and 24 months). Serum anti-HPV geometric mean titers (GMT) measured 1 month after the third dose of the HPV vaccine was administered; GMT was determined by type-specific competitive immunoassay. Noninferiority of each alternative vaccination dosing schedule was achieved if the lower bound of the multiplicity-adjusted confidence interval (CI) of the type-specific GMT ratio for HPV-16 and HPV-18 was greater than 0.5 (primary outcome). Safety outcomes were immediate reactions, local reactions, fever within 7 days after each dose, and serious adverse events up to 30 days following the last dose. In the intention-to-treat analysis, 809 girls who received at least 1 HPV vaccine dose had valid serum measurements 1 month after the third dose. After the third dose, the GMTs for those in the standard schedule group who received doses at 0, 2, and 6 months were 5808.0 (95% CI, 4961.4-6799.0) for HPV-16 and 1729.9 (95% CI, 1504.0-1989.7) for HPV-18; 5368.5 (95% CI, 4632.4-6221.5) and 1502.3 (95% CI, 1302.1-1733.2), respectively, for those whose received doses at 0, 3, and 9 months; 5716.4 (95% CI, 4876.7-6700.6) and 1581.5 (95% CI, 1363.4-1834.6), respectively, for those who received doses at 0, 6, and 12 months; and 3692.5 (95% CI, 3145.3-4334.9) and 1335.7 (95% CI, 1191.6-1497.3), respectively, for those who received doses at 0, 12, and 24 months. Noninferiority criteria were met for the alternative schedule groups that received doses at 0, 3, and 9 months (HPV-16 GMT ratio: 0.92 [95% CI, 0.71-1.20]; HPV-18 GMT ratio: 0.87 [95% CI, 0.68-1.11]) and at 0, 6, and 12 months (HPV-16 GMT ratio: 0.98 [95% CI, 0.75-1.29]; HPV-18 GMT ratio: 0.91 [95% CI, 0.71-1.17]). Prespecified noninferiority criteria were not met for the alternative schedule group that received doses at 0, 12, and 24 months (HPV-16 GMT ratio: 0.64 [95% CI, 0.48-0.84]; HPV-18 GMT ratio: 0.77 [95% CI, 0.62-0.96]). Pain at the injection site was the most common adverse event. Among adolescent girls in Vietnam, administration of the HPV vaccine on standard and alternative schedules was immunogenic and well tolerated. The use of 2 alternative dosing schedules (at 0, 3, and 9 months and at 0, 6, and 12 months) compared with a standard schedule (at 0, 2, and 6 months) did not result in inferior antibody concentrations. clinicaltrials.gov Identifier: NCT00524745.


Cadaveric fascia lata sling: analysis of five recent adverse outcomes.
To report a series of adverse outcomes of urethral sling procedures that used allograft fascia lata and to review the literature regarding the use of this material in genitourinary reconstruction. Five neurologically normal patients presented to our center between August 1999 and October 1999 with complaints of recurrent incontinence or voiding dysfunction after undergoing urethral sling procedures at outside institutions that used fascia lata allografts. All patients underwent a thorough evaluation, including history and physical examination, voiding cystourethrography, and urodynamic studies. Sections of fascia were removed for histology in 2 patients at the time of operation. Three patients were diagnosed with de novo bladder outlet obstruction, 1 with recurrent urethral hypermobility, and 1 with intrinsic sphincteric deficiency. Histology of cadaveric fascia demonstrated collagen with almost complete absence of cellularity. There was no evidence of capillary or fibroblast ingrowth. All patients underwent reoperation and have had clinical improvement with short-term follow-up. Although distressing, the present series of adverse outcomes may simply reflect an overall increase in the number of sling procedures being performed nationally. Although decreased operative time and morbidity have been attributed to the use of fascia lata in urethral sling procedures, it is essential to ensure that long-term safety and efficacy will not be jeopardized before accepting it as a new standard of care.


Toxoplasmal and toxocaral infections: a clinical investigation into their relationship.
An investigation was carried out to determine whether a relationship existed between infections with Toxoplasma gondii and Toxocara canis. Antibodies were sought by the toxoplasma dye test and the toxocara skin sensitivity test. Sixty-seven patients were examined in the United Kingdom; 38 had positive toxoplasma dye tests, two of these being toxocara-positive; and 29 had negative dye tests, six of them being toxocara-positive. From the total of eight toxocarapositive patients antibodies to toxoplasma were detected in two, an incidence no greater than that expected for a normal population.Sera from 60 toxocara-positive African patients were examined; 20 possessed antibodies to Toxoplasma. Analysis according to age group or geographical location indicated that this incidence was no greater than that expected for patients without evidence of toxocaral infection.This study therefore showed no causal or clinically important relationship between toxoplasmal and toxocaral infections.


Antibiotic therapy for Klebsiella pneumoniae bacteremia: implications of production of extended-spectrum beta-lactamases.
The prevalence of extended-spectrum beta -lactamase (ESBL) production by Klebsiella pneumonia approaches 50% in some countries, with particularly high rates in eastern Europe and Latin America. No randomized trials have ever been performed on treatment of bacteremia due to ESBL-producing organisms; existing data comes only from retrospective, single-institution studies. In a prospective study of 455 consecutive episodes of Klebsiella pneumoniae bacteremia in 12 hospitals in 7 countries, 85 episodes were due to an ESBL-producing organism. Failure to use an antibiotic active against ESBL-producing K. pneumoniae was associated with extremely high mortality. Use of a carbapenem (primarily imipenem) was associated with a significantly lower 14-day mortality than was use of other antibiotics active in vitro. Multivariate analysis including other predictors of mortality showed that use of a carbapenem during the 5-day period after onset of bacteremia due to an ESBL-producing organism was independently associated with lower mortality. Antibiotic choice is particularly important in seriously ill patients with infections due to ESBL-producing K. pneumoniae.


Sexual dimorphism in the age changes of the pituitary lactotrophs in rats.
It is known that aging is associated with alterations in hypothalamic and pituitary functions. In the present study, we have undertaken a quantitative immunohistochemical assessment of the lactotroph cell population as well as prolactin (PRL) secretion, in male and female rats of different ages. Pituitaries from young (3 months), old (20 months) and senescent (29 months) male and female Sprague-Dawley rats were processed for the immunohistochemical detection of lactotrophs. Serum PRL was measured by a homologous RIA. Additionally, the in vitro PRL secretory activity was estimated by perifusion of pituitary cells from senescent animals. Analysis of morphometric parameters revealed age-related changes of PRL cell population in animals of both sexes. The cell density (CD), surface density (SD) and volume density (VD) decreased with age in both male and female rats. However, CD as well as SD appeared to have increased in females when compared to males, either in young or old animals, while VD was higher only in old females. The pituitaries of senescent females displayed chromophobic microadenomas on a background of diffuse PRL cell hyperplasia. Prolactin serum levels showed a marked increase with age in females, but only a modest elevation in males. In senescent females, PRL production per cell was reduced. We conclude that in rats, there exists a clear sexual dimorphism in the age-related changes of pituitary PRL cells.


Practice environments and their associations with nurse-reported outcomes in Belgian hospitals: development and preliminary validation of a Dutch adaptation of the Revised Nursing Work Index.
To study the relationship between nurse work environment, job outcomes and nurse-assessed quality of care in the Belgian context. Work environment characteristics are important for attracting and retaining professional nurses in hospitals. The Revised Nursing Work Index (NWI-R) was originally designed to describe the professional nurse work environment in U.S. Magnet Hospitals and subsequently has been extensively used in research internationally. The NWI-R was translated into Dutch to measure the nurse work environment in 155 nurses across 13 units in three Belgian hospitals. Factor analysis was used to identify a set of coherent subscales. The relationship between work environments and job outcomes and nurse-assessed quality of care was investigated using logistic and linear regression analyses. Three reliable, consistent and meaningful subscales of the NWI-R were identified: nurse-physician relations, nurse management at the unit level and hospital management and organizational support. All three subscales had significant associations with several outcome variables. Nurse-physician relations had a significant positive association with nurse job satisfaction, intention to stay the hospital, the nurse-assessed unit level quality of care and personal accomplishment. Nurse management at the unit level had a significant positive association with the nurse job satisfaction, nurse-assessed quality of care on the unit and in the hospital, and personal accomplishment. Hospital management and organizational support had a significant positive association with the nurse-assessed quality of care in the hospital and personal accomplishment. Higher ratings of nurse-physician relations and nurse management at the unit level had significant negative associations with both the Maslach Burnout Inventory emotional exhaustion and depersonalization dimensions, whereas hospital management and organizational support was inversely associated only with depersonalization scores. A Dutch version of the NWI-R questionnaire produced comparable subscales to those found by many other researchers internationally. The resulting measures of the professional practice environment in Belgian hospitals showed expected relationships with nurse self-reports of job outcomes and perceptions of hospital quality.


Acute nicotine induces anxiety and disrupts temporal pattern organization of rat exploratory behavior in hole-board: a potential role for the lateral habenula.
Nicotine is one of the most addictive drugs of abuse. Tobacco smoking is a major cause of many health problems, and is the first preventable cause of death worldwide. Several findings show that nicotine exerts significant aversive as well as the well-known rewarding motivational effects. Less certain is the anatomical substrate that mediates or enables nicotine aversion. Here, we show that acute nicotine induces anxiogenic-like effects in rats at the doses investigated (0.1, 0.5, and 1.0 mg/kg, i.p.), as measured by the hole-board apparatus and manifested in behaviors such as decreased rearing and head-dipping and increased grooming. No changes in locomotor behavior were observed at any of the nicotine doses given. T-pattern analysis of the behavioral outcomes revealed a drastic reduction and disruption of complex behavioral patterns induced by all three nicotine doses, with the maximum effect for 1 mg/kg. Lesion of the lateral habenula (LHb) induced hyperlocomotion and, strikingly, reversed the nicotine-induced anxiety obtained at 1 mg/kg to an anxiolytic-like effect, as shown by T-pattern analysis. We suggest that the LHb is critically involved in emotional behavior states and in nicotine-induced anxiety, most likely through modulation of monoaminergic nuclei.


Characteristics of high-risk HPV infection in women with vaginal intraepithelial neoplasia in Beijing, China.
We evaluated the characteristics of high-risk human papillomavirus (Hr-HPV) infection in different grades of vaginal intraepithelial neoplasia (VaIN). 7469 participants were involved in this study, of which 601 were diagnosed with VaIN, including single vaginal intraepithelial neoplasia (s-VaIN, n = 369) and VaIN+CIN (n = 232), 3414 with single cervical intraepithelial neoplasia (s-CIN), 3446 with cervicitis or vaginitis and 8 with vaginal cancer. We got those results. First, the most popular HPV genotypes in VaIN were HPV16, 52, 58, 51, and 56. Second, our study showed that higher parity and older age were risk factors for VaIN3 (p < 0.005). Third, the median Hr-HPV load of VaIN+CIN (725) was higher than that of s-CIN (258) (p = 0.027), and the median Hr-HPV load increased with the grade of VaIN. In addition, the risk of VaIN3 was higher in women with single HPV16 infections (p = 0.01), but those with multiple HPV16 infections faced a higher risk of s-VaIN (p = 0.003) or VaIN+CIN (p = 0.01). Our results suggested that women with higher gravidity and parity, higher Hr-HPV load, multiple HPV16 infections, and perimenopause or menopause status faced a higher risk for VaIN, while those with higher parity, single HPV16 infections, and menopause status are more prone to VaIN3.


Protective effects of vitamin B12, ginseng saponin, and folic acid against murine fetal deformities caused by hyperthermia.
To investigate the protective effects of vitamin B(12), ginseng saponin, and folic acid on mouse embryos subjected to high heat. Mice were used for the experiment. After exposure of pregnant mice to high heat, the rates of teratism, stillbirth, and fetal absorption were markedly lower in mice treated with ginseng saponin and folic acid following heat exposure than in untreated mice. There were no significant differences in these rates when comparing mice treated with vitamin B(12) with the untreated mice. Ginseng saponin and folic acid can lessen injuries to murine embryos caused by high heat, while vitamin B(12) has little protective effect against high temperature except for promoting overall embryonic growth.


[Formation of the ductal and vascular components of the rabbit kidney countercurrent system].
Series of graphic and plastic reconstructed models, injections of vessels with successive clearing, injections with successive reconstruction and other methods have been performed and applied to study certain peculiarities of anlage and formation, as well as topographic-anatomical interconnections in the canalicular and vascular components in the rabbit counterflow system during prenatal ontogenesis. It has been stated that the conoid fasciculus of the tubular formations (collecting tube, descending and ascending parts of the nephron loop, vessels) is the structural unit in the osmoregulating nephric apparatus; the collecting tube occupies the central position, and loops of three nephrons belonging to the same generations and having connections with the tube are situated, in a definite order, around it.


Real time monitoring of propofol blood concentration in ponies anaesthetized with propofol and ketamine.
This study examined the pharmacokinetics of propofol by infusion in ponies using an analyser for the rapid measurement of propofol concentrations. The analyser (Pelorus 1000; Sphere Medical Ltd., Cambridge, UK) has a measurement cycle of approximately five minutes. Ten Welsh-cross ponies (weighing 135-300 kg) undergoing minor procedures were studied after premedication with acepromazine 0.03 mg/kg and detomidine 0.015 mg/kg. Anaesthesia was induced with ketamine 2 mg/kg and diazepam 0.03 mg/kg, and maintained with an infusion of propofol at an initial rate of 0.16 mg/kg/min for the first thirty minutes, after a bolus of 0.3 mg/kg; and ketamine by infusion (20-40 μg/kg/min). Blood samples (<2 mL) were collected prior to, during and after the infusion, and on assuming standing position. Anaesthesia was uneventful; with the duration of infusion 31-89 min. Blood propofol concentrations during the infusion ranged between 1.52 and 7.65 μg/mL; pseudo-steady state concentrations 3.64-6.78 μg/mL, and concentrations on assuming standing position 0.75-1.40 μg/mL. Propofol clearance and volume of distribution were 31.4 (SD 6.1) mL/min/kg and 220.7 (132.0) mL/kg, respectively. The propofol analyser allows titration of propofol to a given concentration; and may be useful for anaesthesia in animals where kinetics are unknown; in disease states; and where intercurrent therapies affect propofol disposition.


Cortical excitability and the shape of the haemodynamic response.
Individual differences in the temporal dynamics of the haemodynamic response can reflect cortical excitation and can reveal underlying cortical physiology. Here, we show differences in the shape of the haemodynamic response that are dependent on stimulus parameters. Two sets of visual stimuli were used varying in parameters that are known to manipulate the haemodynamic response in the visual cortex. We measured the oxyhaemoglobin response using near infrared spectroscopy. The first set of stimuli comprised chromatic square-wave gratings that varied with respect to the separation in the CIE UCS chromaticities of the alternating bars. The gratings with large separations in chromaticity evoked an oxyhaemoglobin response with greater amplitude, consistent with greater activation of the visual cortex. The second set of stimuli comprised horizontal achromatic gratings that (1) were static, (2) drifted at a constant velocity towards fixation, or (3) reversed direction every half spatial cycle to create a vertical vibrating motion. Although the three types of grating had a similar effect on the amplitude of the oxyhaemoglobin response, the moving gratings (2 and 3) evoked a steeper decrease in oxyhaemoglobin concentration after stimulus-offset. The steeper slope appears to reflect the post-stimulus undershoot and the slope may provide a correlate of cortical excitability when the amplitude of the haemodynamic response has saturated.


Patch size drives colonization by aquatic insects, with minor priority effects of a cohabitant.
Patch size is one of the most important factors affecting the distribution and abundance of species, and recent research has shown that patch size is an important niche dimension affecting community structure in aquatic insects. Building on this result, we examined the impact of patch size in conjunction with presence of larval anurans on colonization by aquatic insects. Hyla chrysoscelis (Cope's gray treefrog) larvae are abundant and early colonists in fishless lentic habitats, and these larvae can fill multiple ecological roles. By establishing larvae in mesocosms prior to colonization, we were able to assess whether H. chrysoscelis larvae have priority effects on aquatic insect assemblages. We conducted a series of three experiments in naturally colonized experimental landscapes to test whether (1) H. chrysoscelis larval density affects insect colonization, (2) variation in patch size affects insect colonization, and (3) the presence and larval density of H. chrysoscelis shift colonization of insects between patches of different size. Larval density independently had almost no effect on colonization, while patch size had species-specific effects consistent with prior work. When larvae and patch size were tested in conjunction, patch size had numerous, often strong, species-specific effects on colonization; larval density had effects largely limited to the assemblages of colonizing beetles and water bugs, with few effects on individual species. Higher larval densities in large mesocosms shifted some insect colonization to smaller patches, resulting in higher beta diversity among small patches in proximity to high density large mesocosms. This indicates establishing H. chrysoscelis larvae prior to insect colonization can likely create priority effects that slightly shape insect communities. Our results support the importance of patch size in studying species abundances and distributions and also indicate that colonization order plays an important role in determining the communities found within habitat patches.


Comparative pharmacokinetic study of high-dose etoposide and etoposide phosphate in patients with lymphoid malignancy receiving autologous stem cell transplantation.
The pharmacokinetics of two etoposide (E) formulations were evaluated in patients with refractory hematologic malignancies receiving high-dose conditioning with autologous stem cell transplantation. Patients were randomized to either E at 800 mg/m(2) (containing polysorbate 80 and polyethylene glycol) or etoposide phosphate (EP) at 910 mg/m(2) on days -7 and -5, prior to melphalan, 80 mg/m(2) on day -5. On day -3, EP was repeated. Plasma E was analyzed after each formulation on days -7 and -5 to compare intrapatient pharmacokinetics. In total, 10 patients were treated: four each with multiple myeloma or Hodgkin's disease and two with non-Hodgkin's lymphoma. Mucositis was the major toxicity with seven patients. EP first produced grade 3 mucositis. There was no procedure-related mortality and eight patients remained alive 1 year post-transplant. Cumulative etoposide exposure (AUC) was slightly greater with EP (P=0.056). Conversely, the volume of distribution was slightly, 33%, larger (P=0.052) and clearance was increased with the E infusion (P=0.14). As none of the differences reached statistical significance, both E formulations appear to be pharmacokinetically equivalent in the high-dose transplant setting. The combination of high-dose EP with melphalan is an active preparative regimen prior to ABMT for hematologic malignancies.


Troponin I is released in bloodstream of patients with acute myocardial infarction not in free form but as complex.
Fourteen monoclonal antibodies (mAbs) against human cardiac troponin I (cTnI) were generated by commonly used experimental techniques. All these antibodies, as well as antibody 414 (HyTest), were specific for human cTnI. Fifteen antibodies thus obtained were tested in a sandwich cTnI immunofluorescence assay (altogether 196 combinations). Ten pairs giving the highest sensitivity were selected for further investigation. The effect of TnI-TnC complex formation on antibody interaction with antigen was analyzed. The formation of TnI-TnC complex results in a significant decrease of the interaction of mAbs with TnI for seven of 10 analyzed pairs of antibodies. Using two pairs of cTnI-specific mAbs, one that recognized only free cTnI but not cTnI complexed with cTnC, and another that could be used for measurement of total cTnI (free cTnI and cTnI in complex with cTnC), we demonstrated that the main part of cTnI in serum collected from acute myocardial infarction patients is presented in the complex from. We concluded that effective and reliable immunological detection of TnI is possible only when antibodies used for assay development recognize both free TnI and TnI complexed with other troponin components.


Quantitative Shedding of Multiple Genotypes of Cryptosporidium and Giardia by Deer Mice (Peromyscus maniculatus) in a Major Agricultural Region on the California Central Coast.
Deer mice (Peromyscus maniculatus) are abundant and widely distributed rodents in North America that occupy diverse habitats, including agricultural landscapes. Giardia and Cryptosporidium are common parasites in wildlife including deer mice, which may play a role in on-farm contamination of produce. An important step in assessing the risk of produce contamination by Cryptosporidium and Giardia shed by deer mice is to determine the prevalence, levels, and genotypes of (oo)cysts in mouse feces. A total of 63 (30.3%) and 53 (25.5%) of 208 deer mice trapped on 12 farms on the California Central Coast were positive for Cryptosporidium and Giardia, respectively. Of these mice, 41 (19.7%) contained both parasites. The odds of Cryptosporidium shedding were 2.5 to 5 times higher for mice trapped in autumn than for mice trapped in summer or spring. Female mice had a higher prevalence and two- to threefold higher levels of Cryptosporidium and Giardia compared with male mice. Female adults and female juveniles had the highest rates of contamination of the environment with Cryptosporidium and Giardia, respectively. We estimated that 20 infected deer mice inhabiting 1 ha of a typical leafy green produce farm in the study region could shed approximately 5.3 × 108 Cryptosporidium and 10.5 × 108 Giardia, respectively, per day into the environment. The small-subunit rRNA gene loci from a subset of protozoan isolates were sequenced and compared with existing sequences in GenBank. Multiple genotypes of Cryptosporidium and Giardia were found, and BLAST analyses suggest that Giardia and the majority of Cryptosporidium genotypes in deer mice circulate within various rodent populations, but some Cryptosporidium isolates possess zoonotic potential.


Male gonadal dysfunction in Hodgkin's disease. A prospective study.
Forty-seven men (median age, 31.5 years) were studied prospectively to assess the effect of Hodgkin's disease and subsequent chemotherapy on gonadal function. Before therapy, 16 (43%) of 37 men were functionally subfertile, as assessed by impotence (four of 37) and "inadequate" sperm counts (12 of 37). Histological abnormalities were noted in eight of nine pretreatment testicular biopsy specimens. Additionally, changes were noted in blood hormone levels and libido. After completion of only two cycles of chemotherapy, 14 of 14 men became persistently azoospermic, with blood follicle-stimulating hormone levels four to five times normal. Posttreatment testicular biopsy specimens confirmed germ cell aplasia. During therapy 17 (81%) of 21 men had mild or no libido; irritability in 16 (84%) of 19 and violence in four (18%) of 22 caused additional family distress. While it is clear that cytotoxic therapy induces infertility, these data further indicate that a proportion of men have gonadal dysfunction prior to treatment.


Effects of air pollution on adverse birth outcomes and pregnancy complications in the U.S. state of Kansas (2000-2015).
Neonatal mortality and morbidity are often caused by preterm birth and lower birth weight. Gestational diabetes mellitus (GDM) and gestational hypertension (GH) are the most prevalent maternal medical complications during pregnancy. However, evidence on effects of air pollution on adverse birth outcomes and pregnancy complications is mixed. Singleton live births conceived between January 1st, 2000, and December 31st, 2015, and reached at least 27 weeks of pregnancy in Kansas were included in the study. Trimester-specific and total pregnancy exposures to nitrogen dioxide (NO2), particulate matter with an aerodynamic diameter less than 2.5 μm (PM2.5), and ozone (O3) were estimated using spatiotemporal ensemble models and assigned to maternal residential census tracts. Logistic regression, discrete-time survival, and linear models were applied to assess the associations. After adjustment for demographics and socio-economic status (SES) factors, we found increases in the second and third trimesters and total pregnancy O3 exposures were significantly linked to preterm birth. Exposure to the second and third trimesters O3 was significantly associated with lower birth weight, and exposure to NO2 during the first trimester was linked to an increased risk of GDM. O3 exposures in the first trimester were connected to an elevated risk of GH. We didn't observe consistent associations between adverse pregnancy and birth outcomes with PM2.5 exposure. Our findings indicate there is a positive link between increased O3 exposure during pregnancy and a higher risk of preterm birth, GH, and decreased birth weight. Our work supports limiting population exposure to air pollution, which may lower the likelihood of adverse birth and pregnancy outcomes.


Renal transplant in a patient with augmentation cystoplasty.
A 20 years old girl, had undergone surgery for meningocele six weeks after birth, suffered from neurogenic bladder dysfunction. She underwent an augmentation ileocystoplasty and was trained to perform clean intermittent self catheterization (CISC). After two years she developed renal failure secondary to recurrent urinary tract infections and she was started on chronic hemodialysis. On account of repeated line sepsis, a live related donor renal transplant was performed. About three months after renal transplantation she reported in emergency with an episode of graft rejection secondary to severe infection and later on complicated by leakage of urine from the renal pelvis of the allograft into the peritoneal cavity suggestive of a rent. A percutaneous nephrostomy of the allograft was performed which facilitated healing of the rent in the renal pelvis. The nephrostomy was withdrawn and patient started voiding through urethral catheter and gradually returned to CISC.


Dedicated multi-detector CT of the esophagus: spectrum of diseases.
Multi-detector computed tomography (CT) offers new opportunities in the imaging of the gastrointestinal tract. Its ability to cover a large volume in a very short scan time, and in a single breath hold with thin collimation and isotropic voxels, allows the imaging of the entire esophagus with high-quality multiplanar reformation and 3D reconstruction. Proper distention of the esophagus and stomach (by oral administration of effervescent granules and water) and optimally timed administration of intravenous contrast material are required to detect and characterize disease. In contrast to endoscopy and double-contrast studies of the upper GI tract, CT provides information about both the esophageal wall and the extramural extent of disease. Preoperative staging of esophageal carcinoma appears to be the main indication for MDCT. In addition, MDCT allows detection of other esophageal malignancies, such as lymphoma and benign esophageal tumors, such as leiomyma. A diagnosis of rupture or fistula of the esophagus can be firmly established using MDCT. Furthermore, miscellaneous esophageal conditions, such as achalasia, esophagitis, diverticula, and varices, are incidental findings and can also be visualized with hydro-multi-detector CT. Multi-detector CT is a valuable tool for the evaluation of esophageal wall disease and serves as an adjunct to endoscopy.


Effects and applications of surfactants on the release, removal, fate, and transport of microplastics in aquatic ecosystem: a review.
Microplastics (MPs) and surfactants (STs) are emerging pollutants in the environment. While many studies have focused on the interactions of STs with MPs, there has not been a comprehensive review focusing on the effect of STs on MPs in aquatic ecosystems. This review summarizes methods for removal of MPs from wastewater (e.g., filtration, flotation, coagulation/flocculation, adsorption, and oxidation-reduction) and the interactions and effects of STs with MPs (adsorption, co-adsorption, desorption, and toxicity). STs can modify MPs surface properties and influence their removal using different wastewater treatments, as well as the adsorption-desorption of both organic and inorganic chemicals. The concentration of STs is a crucial factor that impacts the removal or adsorption of pollutants onto MPs. At low concentrations, STs tend to facilitate MPs removal by flotation and enhance the adsorption of pollutants onto MPs. High ST concentrations, mainly above the critical micelle concentrations, cause MPs to become dispersed and difficult to remove from water while also reducing the adsorption of pollutants by MPs. Excess STs form emulsions with the pollutants, leading to electrostatic repulsion between MPs/STs and the pollutant/STs. As for the toxicity of MPs, the addition of STs to MPs shows complicated results, with some cases showing an increase in toxicity, some showing a decrease, and some showing no effect.


The Kinetochore Receptor for the Cohesin Loading Complex.
The ring-shaped cohesin complex brings together distant DNA domains to maintain, express, and segregate the genome. Establishing specific chromosomal linkages depends on cohesin recruitment to defined loci. One such locus is the budding yeast centromere, which is a paradigm for targeted cohesin loading. The kinetochore, a multiprotein complex that connects centromeres to microtubules, drives the recruitment of high levels of cohesin to link sister chromatids together. We have exploited this system to determine the mechanism of specific cohesin recruitment. We show that phosphorylation of the Ctf19 kinetochore protein by a conserved kinase, DDK, provides a binding site for the Scc2/4 cohesin loading complex, thereby directing cohesin loading to centromeres. A similar mechanism targets cohesin to chromosomes in vertebrates. These findings represent a complete molecular description of targeted cohesin loading, a phenomenon with wide-ranging importance in chromosome segregation and, in multicellular organisms, transcription regulation.


Dermatofibrosarcoma protuberans, version 1.2014.
Dermatofibrosarcoma protuberans (DFSP) is an uncommon soft tissue tumor characterized by a relatively high risk of local recurrence and low risk of metastasis. The NCCN Guidelines for DFSP provide multidisciplinary recommendations on the management of patients with this rare disease. These NCCN Guidelines Insights highlight the addition of the Principles of Pathology section, which provides recommendations on the pathologic assessment of DFSP. Because DFSP can mimic other lesions, immunohistochemical studies are often required to establish diagnosis. Cytogenetic testing for the characteristic translocation t(17;22)(q22;q13) can also be valuable in the differential diagnosis of DFSP with other histologically similar tumors.


Novel contributions to the molecular and morphological diversity of freshwater monothalamid foraminifera: Description of six new species.
Non-marine monothalamous foraminifera are common in freshwater and soil habitats. They comprise a poorly-known group lacking sufficient information about diversity, morphology, reproduction, distribution and ecology. Based on an integrative morphological and molecular approach we describe a new family, a new genus and six new species of freshwater monothalamids from different localities in the Netherlands and France. We establish Astroperula as a new genus of organic walled freshwater foraminifera that contains two species, Astroperula dumacki and Astroperula parvipila. Furthermore, two new agglutinated freshwater monothalamids are described and illustrated, Limnogromia leanneae and Lacogromia pawlowskii, one new organic walled, Velamentofex dujardini, and a new naked monothalamid, Haplomyxa retiforma. Additional information is provided about a special form of cell division in Claparedellus lachmannii and L. leanneae, and feeding behavior in cultures of V. dujardini. Morphological observations are added for an unidentified Limnogromia sampled from the Netherlands and two types of Lacogromia sampled from an alpine region in the French Pyrenees and a karst sinkhole in Bosnia and Herzegovina. The present study provides additional insight into the ecology, diversity and occurrence of freshwater monothalamids and emphasizes the fact that a combination of morphological and molecular methods is necessary to clearly distinguish species in this group.


Phosphorylation of tyrosine residues in the kinase domain and juxtamembrane region regulates the biological and catalytic activities of Eph receptors.
Members of the Eph family of receptor tyrosine kinases exhibit a striking degree of amino acid homology, particularly notable in the kinase and membrane-proximal regions. A mutagenesis approach was taken to address the functions of specific conserved tyrosine residues within these catalytic and juxtamembrane domains. Ligand stimulation of wild-type EphB2 in neuronal NG108-15 cells resulted in an upregulation of catalytic activity and an increase in cellular tyrosine phosphorylation, accompanied by a retraction of neuritic processes. Tyrosine-to-phenylalanine substitutions within the conserved juxtamembrane motif abolished these responses. The mechanistic basis for these observations was examined using the highly related EphA4 receptor in a continuous coupled kinase assay. Tandem mass spectrometry experiments confirmed autophosphorylation of the two juxtamembrane tyrosine residues and also identified a tyrosine within the kinase domain activation segment as a phosphorylation site. Kinetic analysis revealed a decreased affinity for peptide substrate upon substitution of activation segment or juxtamembrane tyrosines. Together, our data suggest that the catalytic and therefore biological activities of Eph receptors are controlled by a two-component inhibitory mechanism, which is released by phosphorylation of the juxtamembrane and activation segment tyrosine residues.


Evaluation of frozen section in parotid gland surgery.
One hundred eight patients underwent primary parotid gland resections at Stanford University Medical Center between 1977 and 1980. Sixty-nine percent of the patients received intraoperative frozen-section diagnosis. Of these, 81% were benign and 19% were malignant. Four patients who received frozen-section diagnosis benefited by further surgery during the initial procedure. Two of four patients who did not receive frozen-section diagnosis could have benefited by further surgery. False-negative results (a malignant tumor called benign on frozen-section diagnosis) occurred in 5%. False-positive results (a benign lesion called malignant on frozen-section diagnosis) did not occur and no unnecessary surgery was performed.


[Possibilities for using sonography in sports injuries of the shoulder joint].
Sonography is a useful tool for the examination of the shoulder joint. Concomitant cartilaginous and soft tissue lesions (Hill-Sachs, effusion, cuff-tears) can be visualized. Subacromial pathology can be differentiated. The type of instability in the unstable shoulder can be documented. The ultrasound investigation is of diagnostic value for the unstable shoulder as well as for the impingement shoulder in athletes. Therefore it may be helpful for planning the adequate treatment and also for the follow up of the patients.


How, for whom, and in what contexts will artificial intelligence be adopted in pathology? A realist interview study.
There is increasing interest in using artificial intelligence (AI) in pathology to improve accuracy and efficiency. Studies of clinicians' perceptions of AI have found only moderate acceptability, suggesting further research is needed regarding integration into clinical practice. This study aimed to explore stakeholders' theories concerning how and in what contexts AI is likely to become integrated into pathology. A literature review provided tentative theories that were revised through a realist interview study with 20 pathologists and 5 pathology trainees. Questions sought to elicit whether, and in what ways, the tentative theories fitted with interviewees' perceptions and experiences. Analysis focused on identifying the contextual factors that may support or constrain uptake of AI in pathology. Interviews highlighted the importance of trust in AI, with interviewees emphasizing evaluation and the opportunity for pathologists to become familiar with AI as means for establishing trust. Interviewees expressed a desire to be involved in design and implementation of AI tools, to ensure such tools address pressing needs, but needs vary by subspecialty. Workflow integration is desired but whether AI tools should work automatically will vary according to the task and the context. It must not be assumed that AI tools that provide benefit in one subspecialty will provide benefit in others. Pathologists should be involved in the decision to introduce AI, with opportunity to assess strengths and weaknesses. Further research is needed concerning the evidence required to satisfy pathologists regarding the benefits of AI.


Kinetic differences at low temperatures between R and T state carbon monoxide-carp hemoglobin.
We use the low-temperature recombination kinetics of carbon monoxide with carp hemoglobin to determine that the R and T states of hemoglobin exhibit different low-temperature geminate recombination kinetics. The peak of the fitted Gaussian activation energy spectrum is at 1.5 kcal/mol for R state and 1.8 kcal/mol for T state. The distribution in activation energies is fit well by the Agmon-Hopfield linear strain model. The T state is fit with a stronger elastic constant than R, and has a larger displacement of the protein conformation coordinate than does the R state, indicating that the T state does have a significantly greater rigidity and also stores more strain energy in its conformational states than does R hemoglobin. The pre-exponential in the activation energy spectrum is only a factor of two greater in the R than the T state and the low-temperature activation energy spectrum does not correctly predict the difference in the on rates for R and T states at 300 degrees K, indicating that processes removed from the binding site are important in cooperativity.


Temporal lobe epilepsy, sleep and arousal: stereo-EEG findings.
By means of combined surface and depth EEG recordings (32 channels) and split-screen video-monitoring (infra red light), complete all-night sleep studies were carried out in drug-resistant epileptics suffering from complex partial seizures. These data were supplemented by (1) all-night sleep recordings from three patients who had chronically implanted electrodes in the periaqueductal grey matter because of severe pain problems, and (2) incomplete sleep recordings (day-time or only partial night) from other drug-resistant epileptics, who underwent chronic stereo-electroencephalographic (SEEG) examination in view of the surgical therapy. The following questions of importance were studied and the results were compared between different patient groups. 1. Relationship between overt clinical seizures or subclinical seizure discharges and the time course of night sleep. 2. Topic behavior of the epileptogenic area and different propagation phenomena of interictal spikes and ictal seizure discharges in different sleep stages. 3. Influence of arousal on the average spike incidence of any location with special attention to the different (slow and fast) components of the K-complex and their association with spiky elements, thus testing the hypothesis that the K-complex might serve as a vehicle for the seizure discharge. 4. Incidence and time-relationship of seizure discharges with clinical overt awakenings.


Planar nonlinear metasurface optics and their applications.
Metasurfaces are artificial two-dimensional (2D) planar surfaces that consist of subwavelength 'meta-atoms' (i.e. metallic or dielectric nanostructures). They are known for their capability to achieve better and more efficient light control in comparison to their traditional optical counterparts. Abrupt and sharp changes in the electromagnetic properties can be induced by the metasurfaces rather than the conventional gradual accumulation that requires greater propagation distances. Based on this feature, planar optical components like mirrors, lenses, waveplates, isolators and even holograms with ultrasmall thicknesses have been developed. Most of the current metasurface studies have focused on tailoring the linear optical effects for applications such as cloaking, lens imaging and 3D holography. Recently, the use of metasurfaces to enhance nonlinear optical effects has attracted significant attention from the research community. Benefiting from the resulting efficient nonlinear optical processes, the fabrication of integrated all-optical nano-devices with peculiar functionalities including broadband frequency conversions and ultrafast optical switching will become achievable. Plasmonic excitation is one of the most effective approaches to increase nonlinear optical responses due to its induced strong local electromagnetic field enhancement. For instance, continuous phase control on the effective nonlinear polarizability of plasmonic metasurfaces has been demonstrated through spin-rotation light coupling. The phase of the nonlinear polarization can be continuously tuned by spatially changing the meta-atoms' orientations during second and third harmonic generation processes, while the nonlinear metasurfaces also exhibit homogeneous linear properties. In addition, an ultrahigh second-order nonlinear susceptibility of up to 104 pm V-1 has recently been reported by coupling the plasmonic modes of patterned metallic arrays with intersubband transition of multi-quantum-well layered substrate. In order to develop ultra-planar nonlinear plasmonic metasurfaces, 2D materials such as graphene and transition metal dichalcogenides (TMDCs) have been extensively studied based on their unique nonlinear optical properties. The third-order nonlinear coefficient of graphene is five times that of gold substrate, while TMDC materials also exhibit a strong second-order magnetic susceptibility. In this review, we first focus on the main principles of planar nonlinear plasmonics based on metasurfaces and 2D nonlinear materials. The advantages and challenges of incorporating 2D nonlinear materials into metasurfaces are discussed, followed by their potential applications including orbital angular momentum manipulating and quantum optics.


Cytomegalovirus as a cause of cecal ulcer with massive hemorrhage in a renal transplant recipient.
Although cytomegalovirus disease following renal transplantation occurs frequently, ulcerative lesions of the gastrointestinal tract are not common. This report describes a patient with a single large cecal ulcer, with cytomegalovirus inclusion bodies located in the ulcer bed. The patient presented with massive rectal bleeding necessitating a right hemicolectomy. No other manifestations of systemic cytomegalovirus disease were present in this patient.


Tc17 cells are capable of mediating immunity to vaccinia virus by acquisition of a cytotoxic phenotype.
CD8 T cells can acquire cytokine-secreting phenotypes paralleling cytokine production from Th cells. IL-17-secreting CD8 T cells, termed Tc17 cells, were shown to promote inflammation and mediate immunity to influenza. However, most reports observed a lack of cytotoxic activity by Tc17 cells. In this study, we explored the anti-viral activity of Tc17 cells using a vaccinia virus (VV) infection model. Tc17 cells expanded during VV infection, and TCR transgenic Tc17 cells were capable of clearing recombinant VV infection. In vivo, adoptively transferred Tc17 cells lost the IL-17-secreting phenotype, even in the absence of stimulation, but they did not acquire IFN-gamma-secreting potential unless stimulated with a virus-encoded Ag. However, examination of cells following infection demonstrated that these cells acquired cytotoxic potential in vivo, even in the absence of IFN-gamma. Cytotoxic potential correlated with Fasl expression, and the cytotoxic activity of postinfection Tc17 cells was partially blocked by the addition of anti-FasL. Thus, Tc17 cells mediate VV clearance through expression of specific molecules associated with cytotoxicity but independent of an acquired Tc1 phenotype.


Prognostic factors obtained from long-term follow-up of pituitary adenomas and other sellar tumors.
Pituitary adenomas do not have a single factor of aggressive behavior or recurrence. The objective of this study was to determine factors influencing the prognosis in pituitary adenomas. 243 patients who were operated between January 2000 and June 2012 were included in this retrospective study. Demographic data, age at diagnosis, date of diagnosis, date of operation, type of operation, post-operative medications, pre- and postoperative hormone levels, and MRI findings were evaluated in each patient. The rate of total resection of sellar tumors was less than 50% in our patient population. The prognosis was better in cases with total resection. Tumor size was a poor prognostic factor in sellar tumors. Female sex was a poor prognostic factor in acromegaly and male sex in prolactinoma. The prognosis was worse in patients with cavernous sinus invasion. In acromegaly, pre-operative level of 850 ng/ml for IGF-1 was noted as a possible prognostic cut-off value. Long-term follow-up results of our study suggest that factors common to all sellar tumors including tumor type, tumor size, total resection, and cavernous sinus invasion and tumor type-specific factors including sex and hormone levels play important roles in the prognosis.


The fibronectin-binding MSCRAMM FnbpA of Staphylococcus aureus is a bifunctional protein that also binds to fibrinogen.
Staphylococcus aureus is an important pathogen capable of causing a wide spectrum of diseases in humans and animals. This bacterium expresses a variety of virulence factors that participate in the process of infection. These include MSCRAMMs (microbial surface components recognizing adhesive matrix molecules) that mediate the adherence of the bacteria to host extracellular matrix components, such as collagen, fibronectin (Fn), and fibrinogen (Fg). Two Fn-binding MSCRAMMs, FnbpA and FnbpB, have been previously identified. The Fn binding activity has been localized to the approximately 40-amino acid residue D repeats in the C-terminal part of these proteins. However, no biological activity has yet been attributed to the N-terminal A regions of these proteins. These regions exhibit substantial amino acid sequence identity to the A regions of other staphylococcal MSCRAMMs, including ClfA, ClfB, and SdrG (Fbe), all of which bind Fg. This raises the question of whether the Fn-binding MSCRAMMs can also bind specifically to Fg. In this report, we show that a recombinant form of the A region of FnbpA does specifically recognize Fg. We localize the binding site in Fg for recombinant FnbpA to the gamma-chain, in particular to the C-terminal residues of this polypeptide, the site also recognized by ClfA. In addition, we demonstrate that recombinant FnbpA can compete with ClfA for binding to both immobilized and soluble Fg. By the use of surface plasmon resonance spectroscopy and fluorescence polarization, we determine the dissociation equilibrium constant for the interaction of recombinant FnbpA with intact immobilized Fg and with a synthetic C-terminal gamma-chain peptide, respectively. Finally, by overexpressing FnbpA in a mutant strain of S. aureus that lacks the expression of both ClfA and ClfB, we show that native FnbpA can mediate the interaction of S. aureus with soluble Fg.


High throughput cellular localization of specific plant mRNAs by liquid-phase in situ reverse transcription-polymerase chain reaction of tissue sections.
Advances in high throughput DNA sequencing and bioinformatic gene discovery far outpace our ability to analyze gene function, necessitating development of more efficient means to examine expression at the cellular level. Here we present a polymerase chain reaction-based method to detect mRNA species in situ in which essentially all of the steps are carried out in liquid phase in a 96-well microtiter tray and only the final signal detection is performed on a microscope slide. We demonstrate the sensitivity of the method by the cellular localization of mRNA for the Tkn2 transcription factor in a wide variety of plant tissues, and its selectivity in discriminating a single gene family member by the in situ localization of rbcs3 transcripts. Furthermore, we demonstrate the utility of the in-well in situ method in detecting FDL and IFL1 transcripts in Arabidopsis sections, thus establishing the method as a tool to determine spatial expression pattern of sequences obtained from genomic sequencing projects. Being amenable to robotic processing, in-well in situ reverse transcription-polymerase chain reaction permits a great enhancement in the number of tissue samples that can be processed. Consequently, this method may become a powerful tool for functional genomics studies, permitting the cellular site of transcription of large numbers of sequences obtained from databases to be rapidly established.


Cellular mechanisms of aneurysm occlusion after treatment with a flow diverter.
To characterize the progression of healing across aneurysm necks following treatment with a flow diverter in a rabbit aneurysm model. With institutional animal care and use committee approval, saccular aneurysms were created in 20 rabbits and treated with flow diverters. On days 1, 3, and 7 and weeks 4 and 8 after implantation, the aneurysm and the device-implanted vessel were harvested. En face staining of the gross specimen was performed for endothelial cells, endothelial progenitor cells, smooth muscle cells, and inflammatory cells. The parent artery segments covered by the flow diverters were completely devoid of endothelial cells at 1 and 3 days but had completely reendothelialized by 7 days. At all time points, the struts along the patent portions of the aneurysm necks harbored scattered tissue islands composed exclusively of inflammatory cells. At 4 and 8 weeks, all samples contiguous with the tissue along the parent arteries had translucent tissue present along the occluded segments of the aneurysm neck. The vast majority of endothelial cells were contiguous with the parent artery and had smooth muscle cells underlying them. Endothelial progenitor cells were not observed along the neck of any aneurysm. Aneurysm closure was noted only when complete or nearly complete endothelialization over the device struts was present. The initial event following flow diversion treatment is adherence of clusters of inflammatory cells across the aneurysm neck. Endothelialization is relatively delayed and derived exclusively from cells in the adjacent parent artery.


Distribution of electrotonic synapses on identified lamprey neurons: a comparison of a model prediction with an electron microscopic analysis.
1. Intracellular recordings of the monosynaptic excitatory postsynaptic potential (EPSP) were made from an identified giant interneuron in the lamprey spinal cord following stimulation of a single identified presynaptic giant axon. The EPSP had both electrotonic and chemical components. 2. The giant interneuron and sometimes the giant axon were labeled with horseradish peroxidase (HRP). Using combined light and electron microscopy (EM), gap junctions formed by the axon on the HRP-labeled dendritic trees of seven interneurons were identified and their position marked on dendritic diagrams made from tracings of the cells. 3. The total number of gap junctions on a giant interneuron varied from a minimum of 9 to a maximum of 23. The number of gap junctions on a branch of a dendritic tree varied from 1 to 9. For all seven neurons the closest gap junction was located approximately 65 microns from the soma and the furthest 280 microns from the soma. 4. When gap junction position was plotted as a function of electrotonic distance from the soma, the variability in their distribution decreased significantly. Synaptic location was found to be on the average about 0.5 space constants from the soma, and this value compared favorably with that determined from an analysis of half-width and rise time of the electrotonic synaptic potential for these neurons. 5. These results suggest that the presynaptic axon tends to make, on the average, synaptic contact at the same electrical distance from the soma.


Ifosfamide and actinomycin-D, added in the induction phase to vincristine, cyclophosphamide and doxorubicin, improve histologic response and prognosis in patients with non metastatic Ewing's sarcoma of the extremity.
The role of ifosfamide as first-line chemotherapy treatment of non metastatic Ewing's sarcoma of the extremity is still under discussion. The purpose of this paper is to report the results achieved in a neoadjuvant protocol (REN-3) in which ifosfamide, added to the conventional VACA regimen, was employed since the induction phase. Induction chemotherapy consisted of vincristine, cyclophosphamide, doxorubicin, actinomycin-D and ifosfamide. After local treatment, patients received the drugs used in the induction phase and etoposide. Between November 1991 and November 1994, 61 patients with non metastatic Ewing's sarcoma of the extremity were treated. Forty-nine patients underwent surgery and 73.5% of them had a good histologic response. At a median follow-up of 60 months (range 32-76), 48 patients (79%) remained continuously disease-free. The 5-year event-free and overall survival were 77% and 87%, respectively. These results were significantly better both in terms of histologic response or event-free and overall survival than those obtained in 58 patients with non metastatic Ewing's sarcoma of the extremity treated in a previous protocol (REN-2) in which the same drugs were used, but ifosfamide was employed only in the maintenance phase. The present study suggests the importance of early use of ifosfamide in the treatment of patients with non metastatic Ewing's sarcoma of the extremity.


Airway remodeling measured by multidetector CT is increased in severe asthma and correlates with pathology.
To prospectively apply an automated, quantitative three-dimensional approach to imaging and airway analysis to assess airway remodeling in asthma patients. Using quantitative software (Pulmonary Workstation, version 0.139; VIDA Diagnostics; Iowa City, IA) that enables quantitative airway segment measurements of low-dose, thin-section (0.625 to 1.25 mm), multidetector-row CT (MDCT) scans, we compared airway wall thickness (WT) and wall area (WA) in 123 subjects participating in a prospective multicenter cohort study, the National Institutes of Health Severe Asthma Research Program (patients with severe asthma, n = 63; patients with mild-to-moderate asthma, n = 35); and healthy subjects, n = 25). A subset of these subjects underwent fiberoptic bronchoscopy and endobronchial biopsies (n = 32). WT and WA measurements were corrected for total airway diameter and area: WT and WA, respectively. Subjects with severe asthma had a significantly greater WT% than patients with mild-to-moderate asthma and healthy subjects (17.2 +/- 1.5 vs 16.5 +/- 1.6 [p = 0.014] and 16.3 +/- 1.2 [p = 0.031], respectively) and a greater WA percentage (WA%) compared to patients with mild-to-moderate asthma and healthy subjects (56.6 +/- 2.9 vs 54.7 +/- 3.3 [p = 0.005] and 54.6 +/- 2.4 [p = 0.003], respectively). Both WT% and WA% were inversely correlated with baseline FEV(1) percent predicted (r = -0.39, p < 0.0001 and r = -0.40, p < 0.0001, respectively) and positively correlated with response to a bronchodilator (r = 0.28, p = 0.002 and r = 0.35, p < 0.0001, respectively). The airway epithelial thickness measure on the biopsy sample correlated with WT% (r = 0.47; p = 0.007) and WA% (r = 0.52; p = 0.003). In the same individual, there is considerable regional heterogeneity in airway WT. Patients with severe asthma have thicker airway walls as measured on MDCT scan than do patients with mild asthma or healthy subjects, which correlates with pathologic measures of remodeling and the degree of airflow obstruction. MDCT scanning may be a useful technique for assessing airway remodeling in asthma patients, but overlap among the groups limits the diagnostic value in individual subjects.


[Cytogenetic effects of chloroquine in a culture of human lymphocytes].
Chloroquine added to human lymphocyte culture at the G1 stage had no influcence on the chromosome aberration level in the concentration of 15 mug/ml and suppressed the mitotic activity of the cells almost completely in the concentration of 60 and 100 mug/ml. At the G2 stage chloroquine in the concentration of 15 mug/ml had no cytogenetic effect and in the concentration of 100 mug/ml -- it increased the number of chromosome aberrations significantly.


Factors Generating Glucose Degradation Products In Sterile Glucose Solutions For Infusion: Statistical Relevance Determination Of Their Impacts.
Sterilising glucose solutions by heat promotes the generation of a large number of glucose degradation products (GDPs). It has been shown that high levels of GDPs may result in Advanced Glycation End products that have an impact on cellular homeostasis and health in general. If data is available for peritoneal dialysis solutions, little has been published for glucose infusion fluids. It is essential to identify the parameters causing the formation of GDPs and so limit the risk of exposing patients to them. After quantifying both 5-hydroxymethyl-2-furfural, considered as an important indicator of degradation, and 2-furaldehyde, an ultimate GDP of one degradation pathway, in marketed solutions, the aim of this work is to build a model integrating all the parameters involved in the formation rates of these two GDPs: supplier, glucose amount, container material, oxygen permeability coefficient and time-lapse since manufacture. Our results show a good logarithmic relationship between GDP formation rates and time-lapse since manufacture for both GDPs. The amount of GDPs in the glucose solutions for infusion depends on the initial glucose amount, the polymer of the container, the time elapsed since manufacturing and the supplier.


Biocompatibility of resin-modified filling materials.
Increasing numbers of resin-based dental restorations have been placed over the past decade. During this same period, the public interest in the local and especially systemic adverse effects caused by dental materials has increased significantly. It has been found that each resin-based material releases several components into the oral environment. In particular, the comonomer, triethyleneglycol di-methacrylate (TEGDMA), and the 'hydrophilic' monomer, 2-hydroxy-ethyl-methacrylate (HEMA), are leached out from various composite resins and 'adhesive' materials (e.g., resin-modified glass-ionomer cements [GICs] and dentin adhesives) in considerable amounts during the first 24 hours after polymerization. Numerous unbound resin components may leach into saliva during the initial phase after polymerization, and later, due to degradation or erosion of the resinous restoration. Those substances may be systemically distributed and could potentially cause adverse systemic effects in patients. In addition, absorption of organic substances from unpolymerized material, through unprotected skin, due to manual contact may pose a special risk for dental personnel. This is borne out by the increasing numbers of dental nurses, technicians, and dentists who present with allergic reactions to one or more resin components, like HEMA, glutaraldehyde, ethyleneglycol di-methacrylate (EGDMA), and dibenzoyl peroxide (DPO). However, it must be emphasized that, except for conventional composite resins, data reported on the release of substances from resin-based materials are scarce. There is very little reliable information with respect to the biological interactions between resin components and various tissues. Those interactions may be either protective, like absorption to dentin, or detrimental, e.g., inflammatory reactions of soft tissues. Microbial effects have also been observed which may contribute indirectly to caries and irritation of the pulp. Therefore, it is critical, both for our patients and for the profession, that the biological effects of resin-based filling materials be clarified in the near future.


Age dependency of the effects of dietary sodium restriction on blood pressure in spontaneously hypertensive rats.
Spontaneously hypertensive rats (SHR) were placed on sodium restricted diets (9 and 17 mumol/g) or on a regular sodium diet (101 mumol/g) at 2, 7 and 10 weeks of age, and continued until 16 weeks of age. Sodium restriction initiated at 2 weeks prevented (9 mumol/g) or attenuated (17 mumol/g) the development of hypertension, and severely retarded growth. When sodium restriction was started at 7 weeks, these effects were not so pronounced. Starting at 10 weeks, sodium restriction no longer affected blood pressure, although growth rate was still reduced. These results indicate that there is a period early in life in SHR during which hypertension development critically depends on a minimum amount of sodium intake.


Induction of the ATP-dependent proteolytic system in guinea pig reticulocyte lysates by triiodothyronine.
The mechanism involved in the decreased numbers of several trans-membrane proteins such as sodium pump sites, sodium-lithium countertransport, sodium potassium cotransport proteins, proteins mediating the passive efflux of sodium and insulin receptors in erythrocytes from patients with hyperthyroidism is not known. The ATP-dependent proteolytic system which is involved in the loss of trans-membrane proteins during the maturation of the reticulocyte may be involved in the accelerated loss of these membrane proteins. Therefore, the effect of thyroid hormones on the ATP-dependent proteolytic activity of reticulocyte lysates was examined in this study. Reticulocytosis was induced in 14 guinea pigs by phenylhydrazine hydrochloride injections for 5 consecutive days followed by 2 days of rest. T3 (10 micrograms/100 g body weight) was injected into 7 animals on day 4 and day 6. Reticulocyte-rich blood was withdrawn on day 8. Oxygen consumption determined 24 hours after injection of T3 was 25% higher (p less than 0.01) and T3 treated animals had a 2.5 fold higher (p less than 0.01) weight loss than control animals. The ATP-dependent proteolytic activity measured in reticulocyte lysates using 125I labelled lysozyme was 3.6 fold higher in the T3 than in the control group of guinea pigs (p less than 0.01). We conclude that thyroid hormones induce the ATP-dependent proteolytic activity of reticulocyte lysates which may be responsible for the reduced number of several trans-membrane proteins found in erythrocytes from patients with hyperthyroidism.


Thermal balloon ablation versus endometrial resection for the treatment of abnormal uterine bleeding.
This study compares the clinical efficacy and safety of a thermal uterine balloon system with hysteroscopic endometrial resection in the treatment of dysfunctional uterine bleeding. In all, 147 women were treated by two experienced gynaecological surgeons: one performed 73 thermal balloon ablations and the other 74 endometrial resections between November 1994 and April 1998. The inclusion criteria were similar in both groups. The operative time was reduced significantly with the uterine balloon technique. There were no intra-operative complications in either group and postoperative morbidities were minimal and not statistically different. Multivariate analysis noted two prognostic factors associated with failures: retroverted uterus with thermal balloon ablation and age under 43 years with endometrial resection. The overall success rate did not differ significantly between the two groups 83.0 +/- 5% for balloon ablation and 76.3 +/- 6% for endometrial resection. Uterine balloon ablation appears to be as efficacious as endometrial resection. The former is much easier to perform, making the technique readily reproducible, especially by those with limited expertise in hysteroscopic surgery, and thus more widely applicable and safer.


Subcutaneous sarcoidosis without systemic involvement.
Subcutaneous sarcoidosis is a rare variant of cutaneous sarcoidosis, which typically presents as single or multiple, indurated, ill-defined plaques, typically on the upper extremities. Granulomas consisting of macrophages with multinucleated giant cells and sparse lymphocytic inflammation are confined to the subcutaneous tissue, rather than to their usual location within the dermis in typical lesions of cutaneous sarcoidosis. An association between subcutaneous sarcoidosis and systemic involvement has been reported, although response to treatment and prognosis remain good. We report a case of a middle-aged woman with subcutaneous sarcoidosis, with negative work-up for systemic involvement of sarcoidosis. Interestingly, family history was significant for a son who died from complications of pulmonary sarcoidosis. The patient was successfully treated with a tapering course of oral prednisone in combination with hydroxychloroquine.


BRCA1/2 Reversion Mutations in Patients Treated with Poly ADP-Ribose Polymerase (PARP) Inhibitors or Platinum Agents.
Background: Reversion mutations in BRCA1/2, resulting in restoration of the open reading frame, have been identified as a mechanism of resistance to platinum-based chemotherapy or PARP inhibition. We sought to explore the incidence of BRCA1/2 reversion mutations in different tumor types. Methods: We retrospectively analyzed molecular profiling results from primary and/or metastatic tumor samples submitted by multiple institutions. The samples underwent DNA and RNA sequencing at a CLIA/CAP-certified clinical lab. Reversion mutations were called only in patients whose available clinical records showed the use of PARP inhibitors or platinum agents prior to tumor profiling. Results: Reversion mutations were identified in 75 of 247,926 samples profiled across all tumor types. Among patients carrying pathogenic or likely pathogenic BRCA1/2 mutations, reversion mutations in BRCA1/2 genes were seen in ovarian cancer (OC) (30/3424), breast cancer (BC) (27/1460), endometrial cancer (4/564), pancreatic cancer (2/340), cholangiocarcinoma (2/178), prostate cancer (5/461), cervical cancer (1/117), cancer of unknown primary (1/244), bladder cancer (1/300), malignant pleural mesothelioma (1/10), and a neuroendocrine tumor of the prostate. We identified 22 reversion mutations in BRCA1 and 8 in BRCA2 in OC. In BC, we detected 6 reversion mutations in BRCA1 and 21 in BRCA2. We compared molecular profile results of 14 high-grade serous ovarian cancers (HGSOC) with reversion mutations against 87 control HGSOC with pathogenic BRCA1/2 mutations without reversion mutations. Tumors with reversion mutations trended to have had lower ER expression (25% vs. 64%, p = 0.024, q = 0.82) and higher KDM6A mutation rate (15% vs. 0, p = 0.016, q = 0.82). Conclusions: We present one of the largest datasets reporting reversion mutations in BRCA1/2 genes across various tumor types. These reversion mutations were rare; this may be because some patients may not have had repeat profiling post-treatment. Repeat tumor profiling at times of treatment resistance can help inform therapy selection in the refractory disease setting.


The skin microbiome: Associations between altered microbial communities and disease.
A single square centimetre of the human skin can contain up to one billion microorganisms. These diverse communities of bacteria, fungi, mites and viruses can provide protection against disease, but can also exacerbate skin lesions, promote disease and delay wound healing. This review addresses the current knowledge surrounding the healthy skin microbiome and examines how different alterations to the skin microbial communities can contribute to disease. Current methodologies are considered, changes in microbial diversity and colonisation by specific microorganisms are discussed in the context of atopic dermatitis, psoriasis, acne vulgaris and chronic wounds. The recent impact of modern Westernised lifestyles on the human skin microbiome is also examined, as well as the potential benefits and pitfalls of novel therapeutic strategies. Further analysis of the human skin microbiome, and its interactions with the host immune system and other commensal microorganisms, will undoubtedly elucidate molecular mechanisms for disease and reveal gateways for novel therapeutic treatment strategies.