Experimental and Computational Considerations in the Study of RNA-Binding Protein-RNA Interactions.
After an RNA is transcribed, it undergoes a variety of processing steps that can change the encoded protein sequence (through alternative splicing and RNA editing), regulate the stability of the RNA, and control subcellular localization, timing, and rate of translation. The recent explosion in genomics techniques has enabled transcriptome-wide profiling of RNA processing in an unbiased manner. However, it has also brought with it both experimental challenges in developing improved methods to probe distinct processing steps, as well as computational challenges in data storage, processing, and analysis tools to enable large-scale interpretation in the genomics era. In this chapter we review experimental techniques and challenges in profiling various aspects of RNA processing, as well as recent efforts to develop analyses integrating multiple data sources and techniques to infer RNA regulatory networks.


Glucocorticoid receptor binding to calf thymus DNA. 1. Identification and characterization of a macromolecular factor involved in receptor-steroid complex binding to DNA.
Activation of receptor-steroid complexes to a form with high affinity for DNA is a poorly understood process involving multiple components in addition to the holoreceptor. Employing rat HTC cells as the source of glucocorticoid receptor, we show that maximal receptor binding to calf thymus DNA is mediated by a previously unknown small molecular weight factor. This factor can be removed from cytosolic preparations of receptor by gel filtration chromatography. Salt extraction of crude nuclear pellets afforded much larger amounts of a similar DNA-binding activity factor. The cytoplasmic factor and the more abundant nuclear factor were identical on the basis of their similar physical properties. The factor was precipitable in the crude state with (NH4)2SO4 and stable to heat as well as freezing and thawing. Chromatography on DNA-cellulose revealed that the factor itself did not bind to DNA. The factor could be filtered through a Centricon C-3 microconcentrator (molecular weight cutoff approximately 3000) but was excluded from Sephadex G-10 columns. These parameters enable us to determine an apparent molecular weight of 700-3000 for this factor. The presence of large amounts of this factor in nuclei accounts for the previously unexplained observation that, following size exclusion chromatography, more activated complexes bind to nuclei than to DNA. These data indicate that some, but not all, of the activated complexes require factor to be able to bind to DNA. The predominantly nuclear localization of this factor, coupled with its ability to increase DNA binding, attests to the biological relevance of this factor in the whole cell action of receptor-glucocorticoid complexes.


National operative case log growth charts in otolaryngology-head and neck surgery training.
To report national standard case log growth curves for operative procedures in otolaryngology and to describe a method by which program directors can chart surgical case numbers over resident training to longitudinally assess sufficiency of cases and parity between residents. Data visualization and analysis. American Council for Graduate Medical Education (ACGME) national case log data for otolaryngology residency. National data set; no individual subjects. National statistical case log reports for otolaryngology were obtained from the ACGME for each postgraduate year (PGY) level in 2009, 2010, and 2011. Estimated means and standard deviations were calculated. The mean and increments of standard deviation were graphed against time to create case log growth charts, similar to pediatric growth charts. Case log growth charts were made for each ACGME Otolaryngology Residency Review Committee key indicator procedure. Progress of an individual resident or of a cohort of residents may be graphed against this growth chart background over their training time. National operative case log growth charts allow residents and program directors to graphically assess progress in obtaining a sufficient variety and number of operative procedures over time throughout training. This can provide early identification when residents begin to fall below the growth curve during training.


Influence of tumor size on oncological outcomes of pathological T3aN0M0 renal cell carcinoma treated by radical nephrectomy.
To evaluate the prognostic significance of tumor size in pathological T3aN0M0 renal cell carcinoma (RCC) treated by radical nephrectomy. Patients who underwent radical nephrectomy for sporadic RCC with pathological T3aN0M0 RCC at our institution between January 2006 and June 2015 were identified. The entire cohort was divided into two groups according to the cutoff of tumor size obtained from receiver operating characteristic (ROC) curve. Clinicopathological variables were retrospectively collected and compared. Kaplan-Meier analysis and multivariate Cox regression were conducted to evaluate the effect of tumor size on survival outcomes. 163 pT3aN0M0 RCC patients were included with a median follow-up period of 31 months. The optimal cutoff for tumor size was 7 cm according to the ROC curve. 90 cases (55.2%) presented tumors which measured 7 cm or less, and 73 cases (44.8%) showed tumor size greater than 7 cm. Patients with larger tumors tended to exhibit higher rates of symptoms and higher Fuhrman grades; they also indicated more necrosis features, and were more likely to invade the collecting system and renal vein. Compared with patients who exhibited tumor size of≤7 cm, those with tumor size>7 cm were associated with shorter estimated five-year cancer-specific survival (CSS, 46.6% versus 75.0%, P = 0.003) and five-year recurrence-free survival (RFS, 35.6% versus 62.7%, P = 0.011). Multivariate Cox analysis revealed that tumor size was retained as an independent factor for CSS (HR = 2.506, 95% CI 1.169-5.373, P = 0.018). The tumor size significantly affected the survival outcomes of pT3aN0M0 RCC treated by radical nephrectomy, and a cutoff size of 7 cm can help enhance the prognostic discrimination. Thus, the tumor size may be considered in the future TNM classification of stage pT3a.


Cognitive Effects of ThinkRx Cognitive Rehabilitation Training for Eleven Soldiers with Brain Injury: A Retrospective Chart Review.
Cognitive rehabilitation training is a promising technique for remediating the cognitive deficits associated with brain injury. Extant research is dominated by computer-based interventions with varied results. Results from clinician-delivered cognitive rehabilitation are notably lacking in the literature. The current study examined the cognitive outcomes following ThinkRx, a clinician-delivered cognitive rehabilitation training program for soldiers recovering from traumatic brain injury and acquired brain injury. In a retrospective chart review, we examined cognitive outcomes of 11 cases who had completed an average of 80 h of ThinkRx cognitive rehabilitation training delivered by clinicians and supplemented with digital training exercises. Outcome measures included scores from six cognitive skill batteries on the Woodcock Johnson - III Tests of Cognitive Abilities. Participants achieved gains in all cognitive skills tested and achieved statistically significant changes in long-term memory, processing speed, auditory processing, and fluid reasoning with very large effect sizes. Clinically significant changes in multiple cognitive skills were also noted across cases. Results of the study suggest that ThinkRx clinician-delivered cognitive training supplemented with digital exercises may be a viable method for targeting the cognitive deficits associated with brain injury.


Cost and cost-effectiveness in a randomized trial of long-acting risperidone for schizophrenia.
The effect of long-acting injectable (LAI) risperidone on health care costs was determined in a multisite clinical trial. Veterans Health Administration patients with unstable schizophrenia or schizoaffective disorder established by the Structured Clinical Interview for DSM-IV (N = 369) were randomized between 2006 and 2009 to long-acting risperidone or physician's choice of oral antipsychotic. Health care utilization and cost were tracked in administrative data. Medication administered by the trial was recorded on case report forms. Medication cost was based on unit costs to the US Medicaid program. Economic outcomes were assessed with the Quality of Well-Being instrument. Participants randomized to LAI risperidone (n = 187) incurred $14,916 per quarter in total health care costs, which was not significantly different from the $13,980 cost incurred by the control group (P = .732) (n = 182). The LAI group incurred $3,028 per quarter in medication cost, significantly more than the $1,913 incurred by the control group (P = .003). Hospitalization costs were $7,088 in the experimental group and $6,891 in the control group (P = .943); outpatient costs were $11,888 in the experimental group and $12,067 in the control group (P = .639). LAI risperidone did not result in better outcomes as evaluated by a measure of schizophrenia symptoms or an assessment of health related quality of life and incurred more adverse events. Patients with unstable schizophrenia were randomized in a practical trial of LAI risperidone. This antipsychotic significantly increased medication costs but did not reduce hospital or total health care cost or improve outcomes and was thus not cost-effective. ClinicalTrials.gov identifier: NCT00132314.


Learning stable, regularised latent models of neural population dynamics.
Ongoing advances in experimental technique are making commonplace simultaneous recordings of the activity of tens to hundreds of cortical neurons at high temporal resolution. Latent population models, including Gaussian-process factor analysis and hidden linear dynamical system (LDS) models, have proven effective at capturing the statistical structure of such data sets. They can be estimated efficiently, yield useful visualisations of population activity, and are also integral building-blocks of decoding algorithms for brain-machine interfaces (BMI). One practical challenge, particularly to LDS models, is that when parameters are learned using realistic volumes of data the resulting models often fail to reflect the true temporal continuity of the dynamics; and indeed may describe a biologically-implausible unstable population dynamic that is, it may predict neural activity that grows without bound. We propose a method for learning LDS models based on expectation maximisation that constrains parameters to yield stable systems and at the same time promotes capture of temporal structure by appropriate regularisation. We show that when only little training data is available our method yields LDS parameter estimates which provide a substantially better statistical description of the data than alternatives, whilst guaranteeing stable dynamics. We demonstrate our methods using both synthetic data and extracellular multi-electrode recordings from motor cortex.


Folate conjugase activity in the plasma and tumors of breast-cancer patients.
The activity of folate conjugase (pteroylpolyglutamate hydrolase, EC 184.108.40.206) was measured in plasma from normal subjects and patients with breast cancer using pteroylglutamyl-gamma-glutamyl-gamma-(U14C) glutamate as the substrate. Conjugase assays also were performed on samples of breast-tumor tissue, normal breast, and fibroadenoma. When assayed at pH 4.5 and 7.4, mean plasma conjugase activity was significantly (p less than 0.05) elevated in a group of patients with anatomically proven metastatic disease (n = 21) when compared with control subjects (n = 12) and a group of patients (n = 13) with no clinical evidence of disease after mastectomies. Mean plasma conjugase activity assayed at pH 4.5 also was significantly higher in the metastatic disease group when compared with breast cancer patients before mastectomy (n = 9) and fibroadenoma patients before biopsy (n = 3). The specific activity of tissue conjugase assayed at pH 4.5 was significantly higher (p less than or equal to 0.05) in infiltrating ductal carcinoma than in normal adjacent breast tissue according to the Wilcoxon test for paired samples (n = 10).


Picky eaters: selective autophagy in plant cells.
Autophagy, a fundamental cellular process, plays a vital role in maintaining cellular homeostasis by degrading damaged or unnecessary components. While selective autophagy has been extensively studied in animal cells, its significance in plant cells has only recently gained attention. In this review, we delve into the intriguing realm selective autophagy in plants, with specific focus on its involvement in nutrient recycling, organelle turnover, and stress response. Moreover, recent studies have unveiled the interesting interplay between selective autophagy and epigenetic mechanisms in plants, elucidating the significance of epigenetic regulation in modulating autophagy-related gene expression and finely tuning the selective autophagy process in plants. By synthesizing existing knowledge, this review highlights the emerging field of selective autophagy in plant cells, emphasizing its pivotal role in maintaining nutrient homeostasis, facilitating cellular adaptation, and shedding light on the epigenetic regulation that governs these processes. Our comprehensive study provides the way for a deeper understanding of the dynamic control of cellular responses to nutrient availability and stress conditions, opening new avenues for future research in this field of autophagy in plant physiology.


Drug interactions with antisecretory agents.
Antisecretory agents may affect the absorption, metabolism, and renal excretion of other drugs. Inhibition of gastric acid secretion may decrease the gastrointestinal absorption of drugs such as ketoconazole that dissolve poorly in the absence of adequate acid. With anti-secretory agents, the drug interaction mechanism most likely to result in adverse effects is the inhibition of hepatic oxidative drug metabolism, primarily a problem with cimetidine. Omeprazole also appears to inhibit the hepatic metabolism of some drugs, but available evidence indicates that it interacts with fewer drugs than cimetidine and the magnitude of the inhibition is lower. Cimetidine decreases the renal clearance of procainamide and its active metabolite, N-acetylprocainamide, probably through interference with active renal tubular secretion. In therapeutic doses, other H2-receptor antagonists probably have minimal effects on renal procainamide elimination.


Psychometric properties of the empathy questionnaire for children and adolescents in a sample of Tanzanian adolescents.
Construct definitions of empathy have sought to distinguish between different domains of empathetic capacity that are related to psychological distress or wellbeing. This study aims to validate the psychometric properties of the Empathy Questionnaire for Children and Adolescents (EmQue-CA) and to test for measurement invariance by gender in a sample of 579 very young adolescents (270 boys and 309 girls) ages 9-12 from Tanzania. Exploratory and confirmatory factor analysis were completed to assess the factor analytic structure of the EmQue-CA, indicating a three-factor model fit these data well. Concurrent validity was demonstrated through strong significant correlations with prosocial behavior and generosity measures. Convergent validity indicated the behavioral subdimension of empathy, intent to comfort, was significantly and negatively associated with externalizing behaviors. Measurement invariance by gender was not supported for these data due to configural invariance in covariance between cognitive empathy and intent to comfort latent constructs. These findings confirm the EmQue-CA is an important measure of three dimensions of empathy; affective empathy, cognitive empathy, and behavioral empathy (intent to comfort) in a sample of Tanzanian adolescents.


mtCLIC/CLIC4, an organellular chloride channel protein, is increased by DNA damage and participates in the apoptotic response to p53.
mtCLIC/CLIC4 (referred to here as mtCLIC) is a p53- and tumor necrosis factor alpha-regulated cytoplasmic and mitochondrial protein that belongs to the CLIC family of intracellular chloride channels. mtCLIC associates with the inner mitochondrial membrane. Dual regulation of mtCLIC by two stress response pathways suggested that this chloride channel protein might contribute to the cellular response to cytotoxic stimuli. DNA damage or overexpression of p53 upregulates mtCLIC and induces apoptosis. Overexpression of mtCLIC by transient transfection reduces mitochondrial membrane potential, releases cytochrome c into the cytoplasm, activates caspases, and induces apoptosis. mtCLIC is additive with Bax in inducing apoptosis without a physical association of the two proteins. Antisense mtCLIC prevents the increase in mtCLIC levels and reduces apoptosis induced by p53 but not apoptosis induced by Bax, suggesting that the two proapoptotic proteins function through independent pathways. Our studies indicate that mtCLIC, like Bax, Noxa, p53AIP1, and PUMA, participates in a stress-induced death pathway converging on mitochondria and should be considered a target for cancer therapy through genetic or pharmacologic approaches.


A Computerized Lifestyle Application to Promote Multiple Health Behaviors at the Workplace: Testing Its Behavioral and Psychological Effects.
Preventive health behaviors, such as regular physical activity and healthy nutrition, are recommended to maintain employability and to facilitate the health of employees. Theory-based workplace health promotion needs to include psychological constructs and consider the motivational readiness (so-called stages of change) of employees. According to the stages, people can be grouped as nonintenders (not motivated to change and not performing the goal behavior), intenders (decided to adopt the goal behavior but not started yet), or actors (performing the goal behavior already). The tailoring to these stages can be done computer based and should make workplace health promotion more effective. It was tested whether a parsimonious computer-based health promotion program implemented at the workplace was effective in terms of lifestyle changes and psychological outcomes as well as body weight. We hypothesized that the stage-matched intervention would outperform the one-size-fits-all active control condition (standard care intervention). In a randomized controlled trial, a total of 1269 employees were recruited by a trained research assistant at their workplace during a routine medical examination. After excluding noneligible employees, 560 completed Time 1 (T1), and 384 also completed Time 2 (T2), achieving a retention rate of 68.6%. Two fully automated computer-based treatments were adopted: (1) an active control condition with information about benefits of exercise and healthy nutrition (n=52), or (2) a stage-matched multiple-behavior intervention that provided different psychological treatments to 9 subgroups, addressing stages of change (nonintenders, intenders, and actors per behavior; n=332). Baseline assessments (T1) on behavior, psychological constructs, and body weight were repeated after 4 weeks (T2). The stage-matched intervention outperformed the active control condition for lifestyle changes containing physical activity and nutrition (χ(2) 1=3.5; P=.04, for N=384) as well as psychological variables (physical activity intention, P=.04; nutrition intention, P=.03; nutrition planning, P=.02; and general social support to live healthily, P=.01). When predicting a healthy lifestyle at follow-up, baseline lifestyle (odds ratio, OR, 2.25, 95% CI 1.73-2.92; P<.01) and the intervention (OR 1.96, 95% CI 1.00-3.82; P=.05) were found to be significant predictors. Physical activity planning mediated the effect of the intervention on the adoption of an overall healthy lifestyle (consisting of activity and nutrition, R(2) adj=.08; P<.01), indicating that if the stage-matched intervention increased planning, the adoption of a healthy lifestyle was more likely. Matching an intervention to the motivational readiness of employees can make a health promotion program effective. Employees' motivation, planning, social support, and lifestyle can be supported by a stage-matched intervention that focuses on both physical activity and healthy nutrition. Occupational settings provide a potential to implement parsimonious computer-based health promotion programs and to facilitate multiple behavior change.


Spermatogenesis-preventing substance in Japanese eel.
Under fresh-water cultivation conditions, spermatogenesis in the Japanese eel is arrested at an immature stage before initiation of spermatogonial proliferation. A single injection of human chorionic gonadotropin can, however, induce complete spermatogenesis, which suggests that spermatogenesis-preventing substances may be present in eel testis. To determine whether such substances exist, we have applied a subtractive hybridisation method to identify genes whose expression is suppressed after human chorionic gonadotropin treatment in vivo. We found one previously unidentified cDNA clone that was downregulated by human chorionic gonadotropin, and named it 'eel spermatogenesis related substances 21' (eSRS21). A homology search showed that eSRS21 shares amino acid sequence similarity with mammalian and chicken Müllerian-inhibiting substance. eSRS21 was expressed in Sertoli cells of immature testes, but disappeared after human chorionic gonadotropin injection. Expression of eSRS21 mRNA was also suppressed in vitro by 11-ketotestosterone, a spermatogenesis-inducing steroid in eel. To examine the function of eSRS21 in spermatogenesis, recombinant eSRS21 produced by a CHO cell expression system was added to a testicular organ culture system. Spermtogonial proliferation induced by 11-ketotestosterone in vitro was suppressed by recombinant eSRS21. Furthermore, addition of a specific anti-eSRS21 antibody induced spermatogonial proliferation in a germ cell/somatic cell co-culture system. We conclude that eSRS21 prevents the initiation of spermatogenesis and, therefore, suppression of eSRS21 expression is necessary to initiate spermatogenesis. In other words, eSRS21 is a spermatogenesis-preventing substance.


Seed coat microsculpturing is related to genomic components in wild Brassica juncea and Sinapis arvensis.
It has been reported that wild Brassica and related species are widely distributed across Xinjiang, China, and there has been an argument for species identification. Seed coat microsculpturing (SCM) is known to be an excellent character for taxonomic and evolutionary studies. By identifying collections from Xinjiang, China, and combining SCM pattern, flow cytometry, and genome-specific DNA markers as well as sexual compatibility with known species, this study aimed to detect potential relationships between SCM and genomic types in wild Brassica and related species. Three wild collections were found to be tetraploid with a SCM reticulate pattern similar to B. juncea, and containing A and B genome-specific loci, indicating relatively high sexual compatibility with B. juncea. The others were diploid, carrying S-genome-specific DNA markers, and having relatively high sexual compatibility with Sinapis arvensis. Moreover, their SCM was in a rugose pattern similar to that of S. arvensis. It was suggested that SCM, as a morphological characteristic, can reflect genomic type, and be used to distinguish B-genome species such as B. juncea from the related S. arvensis. The relationship between SCM and genomic type can support taxonomic studies of the wild Brassica species and related species.


[Contributions to the strain-specific virulence of Cryptococcus neoformans. Animal experiments with two C. neoformans-strains isolated from bird manure. Preliminary report (author's transl)].
The results briefly presented here highlight some of the observations met with during the course of a study aimed at finding out differential pathogenic behavior of the two strains of Cryptococcus neoformans i.e. W71/A117 and W2/A94 with special reference to cryptococcoma formation. Both strains were isolated from bird excreta but differed in their gross and microscopic morphology. Groups of male albino mice NMRI were separately inoculated, intramuscularly, with a comparable dose of the two strains. All the 50 animals challenged with W71/A117 developed macroscopically distinct cryptococcoma of variable size, and fatally progressive disease, involving most of the internal organs, namely, brain, heart, lung, liver, spleen and kidneys. On the contrary, only 34 of the 50 mice infected with the strain W2/A94 showed cryptococcoma formation at the site of inoculation, which were comparatively much smaller in size and gradually diminished. None of the animals, observed over a period of 93 days, died, and showed any sign of metastasis. In another series of experiment, only one instance of mortality was observed in a group of 80 mice inoculated intraperitoneally with about 2 X 10(7) viable cells of this strain. However, the fungus could be recovered, in a majority of cases, only from the brain of animals sacrificed after one month, though most of them showed no sign of sickness. The number of mice yielding positive cultures gradually decreased, and after 87 days the fungus could not be isolated from any organ. The high morbidity and mortality in mice caused by strains W71/A117 was significantly lowered when the animals were infected intramuscularly 3 months ago with the strain W2/A94. After an observation period of 61 days, 91% of the double infected animals were still alive in comparison to 23% survival among the animals challenged with the strain W71/A117 only.


Oxidative stress in the thyroid gland: from harmlessness to hazard depending on the iodine content.
In basal conditions, thyroid epithelial cells produce moderate amounts of reactive oxygen species (ROS) that are physiologically required for thyroid hormone synthesis. They are not necessarily toxic because they are continuously detoxified either in the process of hormone synthesis or by endogenous antioxidant systems. Using a rat model of goiter formation and iodine-induced involution, we found that compared with control thyroids, the oxidative stress, assessed by the detection of 4-hydroxynonenal, was strongly enhanced both in hyperplastic and involuting glands. The level of antioxidant defenses (glutathione peroxidases and peroxiredoxins) was also up-regulated in both groups, although somewhat less in the latter. Of note, increased oxidative stress came along with an inflammatory reaction, but only in involuting glands, suggesting that although antioxidant systems can adequately buffer a heavy load of ROS in goiter, it is not necessarily the case in involuting glands. The effects of 15-deoxy-Delta(12,14)-prostaglandin J2 (15dPGJ2), an endogenous ligand of peroxisome proliferated-activated receptor gamma (PPARgamma) with antiinflammatory properties, were then investigated in involuting glands. This drug strongly reduced both 4-hydroxynonenal staining and the inflammatory reaction, indicating that it can block iodine-induced cytotoxicity. When experiments were carried out with the PPARgamma antagonist, bisphenol A diglycidyl ether, 15dPGJ2-induced effects remained unchanged, suggesting that these effects were not mediated by PPARgamma. In conclusion, thyroid epithelial cells are well adapted to endogenously produced ROS in basal and goitrous conditions. In iodine-induced goiter involution, the increased oxidative stress is accompanied by inflammation that can be blocked by 15dPGJ2 through PPARgamma-independent protective effects.


[Dutch drug registration: greater openness is urgently desired].
The centralized European registration of drugs is characterized by relative openness, like the publication of public assessment reports. In our country the registration authorities should also be more focused on the users and become more accountable for their decisions. Then, in their daily practice, the prescriber and pharmacist can make better use of the available expertise.


Does music reduce anxiety and discomfort during flexible sigmoidoscopy? A systematic review and meta-analysis.
To investigate the role of music in reducing anxiety and discomfort during flexible sigmoidoscopy. A systematic review of all comparative studies up to November 2016, without language restriction that were identified from MEDLINE and the Cochrane Controlled Trials Register (1960-2016), and EMBASE (1991-2016). Further searches were performed using the bibliographies of articles and abstracts from major conferences such as the ESCP, NCRI, ASGBI and ASCRS. MeSH and text word terms used included "sigmoidoscopy", "music" and "endoscopy" and "anxiety". All comparative studies reporting on the effect of music on anxiety or pain during flexible sigmoidoscopy, in adults, were included. Outcome data was extracted by 2 authors independently using outcome measures defined a priori. Quality assessment was performed. A total of 4 articles published between 1994 and 2010, fulfilled the selection criteria. Data were extracted and analysed using OpenMetaAnalyst. Patients who listened to music during their flexible sigmoidoscopy had less anxiety compared to control groups [Random effects; SMD: 0.851 (0.467, 1.235), S.E = 0.196, P < 0.001]. There was no statistically significant heterogeneity (Q = 0.085, df = 1, P = 0.77, I2 = 0). Patients who listened to music during their flexible sigmoidoscopy had less pain compared to those who did not, but this difference did not reach statistical significance [Random effects; SMD: 0.345 (-0.014, 0.705), S.E = 0.183, P = 0.06]. Patients who listened to music during their flexible sigmoidoscopy felt it was a useful intervention, compared to those who did not (P < 0.001). There was no statistically significant heterogeneity (P = 0.528, I2 = 0). Music appeared to benefit patients undergoing flexible sigmoidoscopies in relation to anxiety and was deemed a helpful intervention. Pain may also be reduced however further investigation is required to ascertain this.


Errors and adverse outcomes on a surgical service: what is the role of residents?
The extensive changeover in residents that occurs every July in university-affiliated hospitals has been postulated to result in impaired delivery of patient care as new house staff are less experienced and unfamiliar with hospital-specific systems (the "July phenomenon"). To assess the impact of this process on patient safety, we examined the incidence and sources of medical error and adverse outcomes on a pediatric general surgery service during the final month of an academic year and the first month of the subsequent academic year. All admissions to two pediatric surgeons during June and July 2002 were prospectively followed. The attending surgeon, a surgical fellow, and a medical student reviewed in-patient care daily. Errors committed by doctors, nurses, and allied health workers were identified through daily patient encounters, nursing rounds, medical rounds, and chart audit. Adverse outcomes were evaluated based on type and contributing factors, including involvement of residents. To correct for variations in patient volume, the incidence of errors and adverse outcomes were expressed as a percentage of total patient days. The error rate was 46/643 patient days (7.1%) in June, and 58/776 patient days (7.5%) in July (P = 0.9). Resident error accounted for 52.2% of errors in June and 39.7% of errors in July (P = 0.28). There was no significant difference in the adverse outcome rates (5% versus 6.7%, P = 0.21) or incidence of error-related adverse outcomes (10.8% versus 22.4%, P = 0.2) between June and July. Most errors were made by the on-call resident. Resident changeover at the completion of an academic year did not result in an increased number of medical errors or adverse outcomes, indicating that effective systems are in place to prevent the "July phenomenon."


Dorsal root entry zone lesions for the treatment of post-herpetic neuralgia.
Post-herpetic pain was treated in 12 patients using dorsal root entry zone ( DREZ ) lesions. All patients had failed to receive adequate pain relief from conservative therapy consisting of transcutaneous nerve stimulation, carbamazepine, and/or amitriptyline. Dorsal root entry zone lesions were made to include the involved dermatomes plus one-half of the dermatomes above and below the painful areas. Eight patients reported good pain relief with follow-up periods ranging from 6 to 21 months. A ninth patient obtained satisfactory pain relief, but the superior 1 cm of the original painful area was not included in the distribution of the DREZ lesions. Patients whose lesions were performed using a thermally controlled lesion probe suffered no significant postoperative neurological deficit. Dorsal root entry zone lesions appeared to be a satisfactory treatment for post-herpetic neuralgia in patients who have failed to respond to more conservative modes of therapy.


Glomerular hyperfiltration and blood viscosity in type I (insulin-dependent) diabetic subjects.
To investigate whether the increased glomerular filtration rate (GFR) in short-term diabetic patients is related to increased blood- or plasma viscosities, GFR [( 51Cr] EDTA-clearance), whole blood- and plasma viscosities were simultaneously determined in 16 insulin-dependent diabetic subjects, aged 11 to 34 years (duration of disease 0.1 to 8 years) and compared to the results in healthy subjects. Mean standard GFR +/- SD (that is, GFR corrected to body surface area of 1.73 m2) was significantly higher in the diabetics than in 16 age- and sex matched controls (142 +/- 26 ml/min vs. 123 +/- 18 ml/min, P less than 0.02). Blood viscosities at different shear rates and the plasma viscosity were not significantly different in the two groupes , although the plasma fibrinogen level was significantly elevated in the diabetics (376 +/- 60 mg%, vs. 289 +/- 37 mg%, P less than 0.001). No correlation was found between GFR and the viscosity measurements. The results of the present study do not support the suggestion that the increased GFR in short-term diabetics is related to changes in blood viscosity.


Cadmium Accumulation Involves Synthesis of Glutathione and Phytochelatins, and Activation of CDPK, CaMK, CBLPK, and MAPK Signaling Pathways in Ulva compressa.
In order to analyze the effect of cadmium in Ulva compressa (Chlorophyta), the alga was cultivated with 10, 25, and 50 μM of cadmium for 7 days, and the level of intracellular cadmium was determined. Intracellular cadmium showed an increase on day 1, no change until day 5, and an increase on day 7. Then, the alga was cultivated with 10 μM for 7 days, and the level of hydrogen peroxide, superoxide anions, and lipoperoxides; activities of antioxidant enzymes ascorbate peroxidase (AP), dehydroascorbate reductase (DHAR), and glutathione reductase (GR); the level of glutathione (GSH) and ascorbate (ASC); and the level of phytochelatins (PCs) and transcripts encoding metallothioneins (UcMTs) levels were determined. The level of hydrogen peroxide increased at 2 and 12 h, superoxide anions on day 1, and lipoperoxides on days 3 to 5. The activities of AP and GR were increased, but not the DHAR activity. The level of GSH increased on day 1, decreased on day 3, and increased again on day 5, whereas ASC slightly increased on days 3 and 7, and activities of enzymes involved in GSH and ASC synthesis were increased on days 3 to 7. The level of PC2 and PC4 decreased on day 3 but increased again on day 5. The level of transcripts encoding UcMT1 and UcMT2 increased on days 3 to 5, mainly that of UcMT2. Thus, cadmium accumulation induced an oxidative stress condition that was mitigated by the activation of antioxidant enzymes and synthesis of GSH and ASC. Then, the alga cultivated with inhibitors of calcium-dependent protein kinases (CDPKs), calmodulin-dependent protein kinases (CaMKs), calcineurin B-like protein kinases (CBLPKs), and MAPKs and 10 μM of cadmium for 5 days showed a decrease in intracellular cadmium and in the level of GSH and PCs, with the four inhibitors, and in the level of transcripts encoding UcMTs, with two inhibitors. Thus, CDPKs, CaMK, CBLPKS, and MAPKs are involved in cadmium accumulation and GSH and PC synthesis, and GSH and PCs and/or UcMTs may participate in cadmium accumulation.


Lysines K117 and K147 play conserved roles in Ras activation from Drosophila to mammals.
Ras signaling plays an important role in growth, proliferation, and developmental patterning. Maintaining appropriate levels of Ras signaling is important to establish patterning in development and to prevent diseases such as cancer in mature organisms. The Ras protein is represented by Ras85D in Drosophila and by HRas, NRas, and KRas in mammals. In the past dozen years, multiple reports have characterized both inhibitory and activating ubiquitination events regulating Ras proteins. Inhibitory Ras ubiquitination mediated by Rabex-5 or Lztr1 is highly conserved between flies and mammals. Activating ubiquitination events at K117 and K147 have been reported in mammalian HRas, NRas, and KRas, but it is unclear if these activating roles of K117 and K147 are conserved in flies. Addressing a potential conserved role for these lysines in Drosophila Ras activation requires phenotypes strong enough to assess suppression. Therefore, we utilized oncogenic Ras, RasG12V, which biases Ras to the GTP-loaded active conformation. We created double mutants RasG12V,K117R and RasG12V,K147R and triple mutant RasG12V,K117R,K147R to prevent lysine-specific post-translational modification of K117, K147, or both, respectively. We compared their phenotypes to RasG12V in the wing to reveal the roles of these lysines. Although RasG12V,K147R did not show compelling or quantifiable differences from RasG12V, RasG12V,K117R showed visible and quantifiable suppression compared to RasG12V, and triple mutant RasG12V,K117R,K147R showed dramatic suppression compared to RasG12V and increased suppression compared to RasG12V,K117R. These data are consistent with highly conserved roles for K117 and K147 in Ras activation from flies to mammals.


[System design of small intellectualized ultrasound hyperthermia instrument in the LabVIEW environment].
Small-scale intellectualized medical instrument has attracted great attention in the field of biomedical engineering, and LabVIEW (Laboratory Virtual Instrument Engineering Workbench) provides a convenient environment for this application due to its inherent advantages. The principle and system structure of the hyperthermia instrument are presented. Type T thermocouples are employed as thermotransducers, whose amplifier consists of two stages, providing built-in ice point compensation and thus improving work stability over temperature. Control signals produced by specially designed circuit drive the programmable counter/timer 8254 chip to generate PWM (Pulse width modulation) wave, which is used as ultrasound radiation energy control signal. Subroutine design topics such as inner-tissue real time feedback temperature control algorithm, water temperature control in the ultrasound applicator are also described. In the cancer tissue temperature control subroutine, the authors exert new improvments to PID (Proportional Integral Differential) algorithm according to the specific demands of the system and achieve strict temperature control to the target tissue region. The system design and PID algorithm improvement have experimentally proved to be reliable and excellent, meeting the requirements of the hyperthermia system.


Heavy menstrual bleeding in women with inherited bleeding disorders.
Heavy menstrual bleeding (HMB) is the commonest bleeding symptom among women with inherited bleeding disorders (IBD). Since HMB starts at the very onset of menarche and continues throughout the reproductive life, the health related quality of life of these women is affected and they are at an increased risk of developing iron-deficiency anemia. Because of the entrenched stigma and taboos, women and girls are often reluctant to discuss the problem of HMB within their families and do not seek medical advice. Increased awareness and multidisciplinary management approach for the management of these women are essential in ensuring an optimal outcome. It is important to take a careful history and undertake a thorough gynecological assessment to exclude other underlying/concomitant causes of HMB. Iron supplementation is essential. Strategies for decreasing menstrual blood flow are similar to those used for HMB in general with the addition of desmopressin and replacement therapy and the exclusion of non-steroidal anti-inflammatory drugs. Tranexamic acid and/or hormonal intervention are usually recommended as first-line therapy. Treatment choice should be individualized taking into account whether the woman wishes to preserve her fertility, if she requires contraception, the type of IBD, the severity of bleeding, and her social and religious background as well as acceptability and availability of the treatment options.


Sexual behaviors during antiretroviral therapy among HIV-infected patients, Thailand.
An increasing trend in sexual risk behavior has occurred in the era of antiretroviral therapy (ART) in Thailand. This study was conducted to identify sexual risk behavior and examine relationships between unprotected sex and CD4 levels among HIV-infected patients receiving ART in the National Antiretroviral Program. A cross-sectional survey was conducted in 460 HIV-infected patients age 18-49 years who visited the out-patient clinic of Bamrasnaradura Infectious Diseases Institute in February 2006 by using a standardized self-administered questionnaire. The results show that 60.4% of participants were men. The median most recent CD4 cell count during the prior 6 months was 261 cells/mm3. Twenty-three percent of the participants who had no sexual activity after they knew their HIV positive status started having sex again after receiving ART with a 12-week median duration period from starting ART to having first sex. There was a significant difference between the number of those having sexual activity before and after starting ART (p-value=0.013). Fifty-six percent of participants had sex during the previous 6 months. Of these, 26.5% had sex with commercial partners and 28.4% with non-regular partners. Inconsistent condom use, with commercial partners or non-regular partners, in females (35.3-36.8%) was higher than in males (7.8-11.1%). Participants with a known HIV-negative regular partner were 0.25 times more likely to have unprotected sex than those with a known HIV-positive regular partner (adjusted OR, 0.25; 95%CI, 0.09-0.73). No association between unprotected sex and CD4 levels was found. The findings support the need for reinforcing risk reduction programs among HIV-infected persons, particularly couple counseling, and promoting awareness of risk of acquirring sexually transmitted infections and drug-resistant strains of HIV.


Monte Carlo simulations of out-of-field skin dose due to spiralling contaminant electrons in a perpendicular magnetic field.
The purpose of this study was to evaluate the potential skin dose toxicity contribution of spiralling contaminant electrons (SCE) generated in the air in an MR-linac with a 0.35 or 1.5 T magnetic field using the EGSnrc Monte Carlo (MC) code. Comparisons to experimental results at 1.5 T are also performed. An Elekta generated phase space file for the Unity MR-linac is used in conjunction with the EGSnrc enhanced electric and magnetic field transport macros to simulate surface dose profiles and depth-dose curves in panels located 5 cm away from the beam edge and positioned either parallel or perpendicular to the magnetic field. Electrons generated in the air will spiral along the magnetic field lines, and though surface doses within the field will be reduced, the electrons can contribute to out-of-field surface doses. Surface dose profiles showed good agreement with experimental findings and the maximum simulated doses at surfaces perpendicular to the magnetic field were 3.77 ± 0.01% and 3.55 ± 0.01% for 1.5 and 0.35 T. These results are expressed as a percentage of the maximum dose to water delivered by the photon beam. The surface dose variations in the out-of-field region converge to the 0 T doses within the first 0.5 cm of material. An asymmetry in the dose distribution in surfaces positioned on either side of the photon beam and aligned parallel to the magnetic field is determined to be due to the magnetic field directing electrons deeper into, or localizing them to the surface of, the measurement panel. These results confirm the SCE dose contribution in surfaces perpendicular to the magnetic field and show these doses to be of the order of a few percentage of the maximum dose to water of the beam. Good agreement in the dose profiles is seen in comparisons between the MC simulations and experimental work. The effect is apparent in 0.35 and 1.5 T magnetic fields and dissipates within the first few millimeters of material. It should be noted that only SCEs from beam anteriorly incident on the patient will influence the patient surface dose, and the use of beams incident over different angles will reduce the dose to any particular patient surface.


Design and synthesis of some acridine-piperazine hybrids for the improvement of cognitive dysfunction.
A novel series of hybrid molecules (5a-5m) was designed, synthesized and evaluated as multifunctional cholinesterase (ChE) inhibitors against cognitive dysfunction. Heterocyclic moieties acridine and piperazine were conjugated with suitable linkers in a single scaffold, and the structures of the target compounds were confirmed by IR, 1 H NMR, 13 C NMR, and LC-MS analysis. The pharmacological activity of synthesized compounds was evaluated using behavioral models of amnesia viz. step-down passive avoidance and elevated plus maze at a dose 0.5 mg/kg as compared to standard rivastigmine. In vitro acetylcholinesterase (AChE) inhibition studies using brain homogenate of mice as the enzyme source revealed that most of the compounds exhibited a significant ability to inhibit the enzyme cholinesterase with compound 5c being the most potent (IC50 0.33 μm). Biochemical estimation of oxidative stress markers viz. plasma nitrite, thiobarbituric acid reactive substances, catalase, superoxide dismutase, and glutathione has been carried out using the respective assays to see the effect of the synthesized compounds on the scopolamine-induced oxidative damage. The molecular docking studies indicated the binding mode of the compounds to the catalytic site, peripheral site, and mid-gorge of AChE simultaneously. The calculated absorption, distribution, metabolism and excretion properties ensured the drug-likeness of the target compounds. The synthesized compounds were found to be potential cognitive enhancers, which were able to interfere with the scopolamine-induced oxidative stress also.


Notch signaling mediates the age-associated decrease in adhesion of germline stem cells to the niche.
Stem cells have an innate ability to occupy their stem cell niche, which in turn, is optimized to house stem cells. Organ aging is associated with reduced stem cell occupancy in the niche, but the mechanisms involved are poorly understood. Here, we report that Notch signaling is increased with age in Drosophila female germline stem cells (GSCs), and this results in their removal from the niche. Clonal analysis revealed that GSCs with low levels of Notch signaling exhibit increased adhesiveness to the niche, thereby out-competing their neighbors with higher levels of Notch; adhesiveness is altered through regulation of E-cadherin expression. Experimental enhancement of Notch signaling in GSCs hastens their age-dependent loss from the niche, and such loss is at least partially mediated by Sex lethal. However, disruption of Notch signaling in GSCs does not delay GSC loss during aging, and nor does it affect BMP signaling, which promotes self-renewal of GSCs. Finally, we show that in contrast to GSCs, Notch activation in the niche (which maintains niche integrity, and thus mediates GSC retention) is reduced with age, indicating that Notch signaling regulates GSC niche occupancy both intrinsically and extrinsically. Our findings expose a novel role of Notch signaling in controlling GSC-niche adhesion in response to aging, and are also of relevance to metastatic cancer cells, in which Notch signaling suppresses cell adhesion.


Liking More Means Doing More: Dispositional Attitudes Predict Patterns of General Action.
Dispositional attitudes are an individual difference in the tendency to form positive versus negative attitudes. As positive (negative) attitudes promote active (inactive) responses to stimuli, we predicted that dispositional attitudes would be positively correlated with patterns of general action. In Study 1, participants reported all activities they engaged in during a 1-week period using a structured time use survey. Dispositional attitudes were positively correlated with the number of unique behaviors participants engaged in and with the total number of behaviors reported for the entire week. Study 2 replicated Study 1 using a free response time use survey. Overall, the results demonstrated that dispositional attitudes predict general action, such that the tendency to form positive (negative) attitudes predicts the tendency to engage in many (few) behaviors in daily life. This pattern occurred for both low effort and high effort behaviors. Implications for understanding activity patterns are discussed.


The role of postpartum weight retention in obesity among women: a review of the evidence.
Young, adult women appear to be at increased risk for substantial weight gain. Pregnancy has frequently been cited as a contributor to overweight in women. This article reviews the literature examining the role of pregnancy in the development of overweight. Average postpartum weight retention ranges from 0.5 to 3 kg; however, postpartum weight retention appears to be highly variable among women, with some women retaining as much as 17.7 kg. Excessive postpartum weight retention seems to be especially prevalent among minority women. Factors such as prepregnancy weight and excessive gestational weight gain have the strongest support as risk factors for postpartum weight retention and could guide targeted intervention efforts. However, there are few controlled studies of behavioral interventions to prevent substantial pregnancy-related weight gain or postpartum weight retention. Weight loss methods successful in promoting weight control in other populations would likely also be effective with pregnant or postpartum women, although modifications for the needs of mothers may be required. Particular attention to the needs of minority mothers is warranted given the likelihood of greater weight retention in this group.


Specificity, degeneracy, and molecular mimicry in antigen recognition by HLA-Class II restricted T cell receptors: implications for clinical medicine.
Abstract In humans, increased susceptibility to specific autoimmune diseases is closely associated with specific HLA-class II alleles. CD4(+) T cells that recognize short self-peptides in the context of HLA-class II molecules via their T cell receptor (TCR) are considered to mediate the central role of pathogenesis in autoimmunity. Although both self- and nonself-peptides are presented on HLA-class II molecules under physiological conditions, several mechanisms exist to avoid the T cell response to the self-peptide/HLA-class II complex. One of the mechanisms that account for the breakdown in immune tolerance is cross-recognition by TCR between a pathogen-derived antigen and a host antigen (molecular mimicry theory). Epidemiological studies have indicated that a number of autoimmune diseases are developed or exacerbated after infections. Therefore, elucidating the recognition nature of HLA-class II restricted TCR in detail is necessary in order to understand disease processes. A large body of evidence indicates that T cell recognition is highly degenerate, and many different peptides can activate an individual T cell. Degeneracy of TCR recognition also can appear in various physiological outcomes, ranging from full activation to strong antagonism. Here, we review the clinical implications of our findings on T cell recognition, as well as a new direction of future applications for analyses in molecular mimicry. We also describe the latest developments in methods of mapping TCR epitopes for CD4(+) T cells using a peptide epitope expression library generated in the class II-associated invariant chain peptide substituted invariant chain gene format.


[Study of the degradation reaction of paranitrosodimethylaniline by a C-nitrosoreductase of yeast].
We have purified, by a three step procedure, a yeast C-nitrosoreductase and studied its action on p-nitroso-N,N-dimethylaniline. Microcalorimetric measurements performed on the microcalorimeter LKB "batch", have been given the number of protons exchanged during the reaction : four protons are involved. Two are given by NADH and the others are supplied by the buffer. We could observe two steps in the catalytic mechanism. The enthalpy change of the first one is greater than that of the second. Spectrophotometric and polarographic experiments corroborate this results : two enzymatic steps could be demonstrated. The reduction of p-nitroso-N,N-dimethylaniline is characterized by a peak with a half wave potential at -0,31 V (in M Tris-HCl, pH 8,30). While the amplitude of this one decreases, a second wave appears at -1,03 V.


A double mesogen based on linked p-terphenyl units.
The structure of bis(4,4"-decyloxy-p-terphenyl-2'-ylmethyl) carbonate, C(79)H(110)O(7), (I), has been determined at 123 K. It is a new type of twin mesogen. No two adjacent aromatic rings are coplanar and the four decyloxy side chains are maximally extended. Molecules of the compound are packed along the crystallographic a axis. The molecular arrangement is a precursor of a smectic A phase.


Biofilm assembly becomes crystal clear - filamentous bacteriophage organize the Pseudomonas aeruginosa biofilm matrix into a liquid crystal.
Pseudomonas aeruginosa is an opportunistic bacterial pathogen associated with many types of chronic infection. At sites of chronic infection, such as the airways of people with cystic fibrosis (CF), P. aeruginosa forms biofilm-like aggregates. These are clusters of bacterial cells encased in a polymer-rich matrix that shields bacteria from environmental stresses and antibiotic treatment. When P. aeruginosa forms a biofilm, large amounts of filamentous Pf bacteriophage (phage) are produced. Unlike most phage that typically lyse and kill their bacterial hosts, filamentous phage of the genus Inovirus, which includes Pf phage, often do not, and instead are continuously extruded from the bacteria. Here, we discuss the implications of the accumulation of filamentous Pf phage in the biofilm matrix, where they interact with matrix polymers to organize the biofilm into a highly ordered liquid crystal. This structural configuration promotes bacterial adhesion, desiccation survival, and antibiotic tolerance - all features typically associated with biofilms. We propose that Pf phage make structural contributions to P. aeruginosa biofilms and that this constitutes a novel form of symbiosis between bacteria and bacteriophage.


Endovenous ablation of the saphenous vein.
The introduction of the minimally invasive, endovenous thermal techniques of superficial reflux ablation have revolutionized the treatment of varicose veins in the last 8 years. The ease of performance even in an office setting, reduced discomfort, and quicker return to normal activity have resulted in universally superior patient acceptance and have made these endovenous procedures the mainstay of present treatment of varicose veins. With encouraging early and mid-term results, future developments in this field must mandate standardization of technical aspects, follow-up imaging, and reporting. The significance of reflux in the great saphenous vein stump, of reflux-free recanalization of a segment of the vein, and their potential for causing recurrent varicose veins remains unknown. The incidence of groin neovascularization and its significance needs to be determined. Ultrasound-guided foam sclerotherapy is also emerging as a competitor to other endovenous techniques and is particularly useful in superficial and tortuous veins not ideally suited for endovenous thermal ablation, as well as recanalized segments of ablated veins.


Comparative effectiveness of single and dual rapid diagnostic tests for syphilis and HIV in antenatal care services in Colombia.
To assess the effectiveness of a dual rapid test compared to a single rapid test for syphilis and HIV screening. A cluster-randomized open-label clinical trial was performed in 12 public antenatal care (ANC) centers in the cities of Bogotá and Cali, Colombia. Pregnant women who were over 14 years of age at their first antenatal visit and who had not been previously tested for HIV and syphilis during the current pregnancy were included. Pregnant women were randomized to single HIV and single syphilis rapid diagnostic tests (Arm A) or to dual HIV and syphilis rapid diagnostic tests (Arm B). The four main outcomes measured were: (1) acceptability of the test, (2) uptake in testing, (3) treatment on the same day (that is, timely treatment), and (4) treatment at any time for positive rapid test cases. Bivariate and multivariate analyses were calculated to adjust for the clustering effect and the period. A total of 1 048 patients were analyzed in Arm A, and 1 166 in Arm B. Acceptability of the rapid tests was 99.8% in Arm A and 99.6% in Arm B. The prevalence of positive rapid tests was 2.21% for syphilis and 0.36% for HIV. Timely treatment was provided to 20 of 29 patients (69%) in Arm A and 16 of 20 patients (80%) in Arm B (relative risk (RR), 1.10; 95% confidence interval (CI): (1.00 -1.20). Treatment at any time was given to 24 of 29 patients (83%) in Arm A and to 20 of 20 (100%) in Arm B (RR, 1.11; 95% CI: 1.01-1.22). There were no differences in patient acceptability, testing and timely treatment between dual rapid tests and single rapid tests for HIV and syphilis screening in the ANC centers. Same-day treatment depends also on the interpretation of and confidence in the results by the health providers.


Improving Diagnosis Through Digital Pathology: Proof-of-Concept Implementation Using Smart Contracts and Decentralized File Storage.
Recent advancements in digital pathology resulting from advances in imaging and digitization have increased the convenience and usability of pathology for disease diagnosis, especially in oncology, urology, and gastroenteric diagnosis. However, despite the possibilities to include low-cost diagnosis and viable telemedicine, digital pathology is not yet accessible owing to expensive storage, data security requirements, and network bandwidth limitations to transfer high-resolution images and associated data. The increase in storage, transmission, and security complexity concerning data collection and diagnosis makes it even more challenging to use artificial intelligence algorithms for machine-assisted disease diagnosis. We designed and prototyped a digital pathology system that uses blockchain-based smart contracts using the nonfungible token (NFT) standard and the Interplanetary File System for data storage. Our design remediates shortcomings in the existing digital pathology systems infrastructure, which is centralized. The proposed design is extendable to other fields of medicine that require high-fidelity image and data storage. Our solution is implemented in data systems that can improve access quality of care and reduce the cost of access to specialized pathological diagnosis, reducing cycle times for diagnosis. The main objectives of this study are to highlight the issues in digital pathology and suggest that a software architecture-based blockchain and the Interplanetary File System create a low-cost data storage and transmission technology. We used the design science research method consisting of 6 stages to inform our design overall. We innovated over existing public-private designs for blockchains but using a 2-layered approach that separates actual file storage from metadata and data persistence. Here, we identified key challenges to adopting digital pathology, including challenges concerning long-term storage and the transmission of information. Next, using accepted frameworks in NFT-based intelligent contracts and recent innovations in distributed secure storage, we proposed a decentralized, secure, and privacy-preserving digital pathology system. Our design and prototype implementation using Solidity, web3.js, Ethereum, and node.js helped us address several challenges facing digital pathology. We demonstrated how our solution, which combines NFT smart contract standard with persistent decentralized file storage, solves most of the challenges of digital pathology and sets the stage for reducing costs and improving patient care and speed of diagnosis. We identified technical limitations that increase costs and reduce the mass adoption of digital pathology. We presented several design innovations using NFT decentralized storage standards to prototype a system. We also presented the implementation details of a unique security architecture for a digital pathology system. We illustrated how this design can overcome privacy, security, network-based storage, and data transmission limitations. We illustrated how improving these factors sets the stage for improving data quality and standardized application of machine learning and artificial intelligence to such data.


Subcritical water extraction of polysaccharides from Gastrodiae Rhizoma: optimization, characterization and in vitro hepatoprotective activity.
Subcritical water extraction (SWE) is an efficient and eco-friendly technology that rapidly extracts valuable compounds from natural materials. In this study, response surface methodology (RSM) was utilized to determine the optimal extraction conditions for Gastrodiae Rhizoma using SWE (GRP-S). The optimum conditions were found to be 161 °C extraction temperature, 41 min extraction time, and a solid-to-liquid ratio of 1.55 mg/mL. Under these optimal conditions, the experimental yield of GRP-S was 66.32% ± 0.10% (n = 3), demonstrating a significant increase compared to hot water reflux extraction (HWE) in the extraction yield of polysaccharides. Characterization studies employing SEM, FT-IR, and HPAEC-PAD confirmed the differences between GRP-S and GRP-H (GRP obtained by HWE). Furthermore, both GRP-S and GRP-H exhibited a significant ability to protect HepG2 cells from ethanol-induced damage, with GRP-S showcasing a superior effect. The widespread adoption of SWE technology can lead to high GRP content in extracts and promote the green and sustainable development of natural products extraction processes.


In vitro effects of antiprotozoan drugs and immune serum on Pneumocystis carinii.
The in vitro survival of Pneumocystis carinii isolated from the lungs of rats with glucocorticoid-induced pneumocystosis has been evaluated by quantitation of uptake of vital dyes by the organisms after exposure to a variety of drugs, immune serum, and medium enriched with macrophage lysosomal enzyme. On the basis of these tests, it appears that pentamidine and chloroquine are directly lethal to the organisms, but that suramin, trimethoprim, and sulfamethoxazole are not. Neither immune serum supplemented with complement and lysozyme nor the supernatant of phagocytosing macrophages appeared to affect the viability of the organisms. Inhibitors of glucose uptake and metabolism appeared to kill Pneumocystis, but neither cycloheximide nor iododeoxyuridine was effective.


Differences in the sensitisation to ragweed pollen and occurrence of late summer allergic symptoms between native and immigrant workers of the nuclear power plant of Hungary.
Regular medical screening including allergic symptoms of workers of the Nuclear Power Plant in Paks, Hungary, offered a unique opportunity to study the influence of the environmental factors on the development of allergy. The city Paks has been one the areas of the country most heavily exposed to ragweed pollen allergens. The occurrence and extent of sensitisation assessed by skin prick test to common allergens and prevalence of seasonal and perennial allergic symptoms were compared among 880 workers (695 immigrants, 185 natives) with self-reported allergic symptoms. The percentage of sensitised people against common allergens (ragweed, grass, D. pteronyssinus) was almost the same in the natives and immigrants. When, however, the strength of sensitivity to ragweed was determined by quantitative skin prick test and specific IgE determination, significantly (P<0.0001) more immigrants (69%) than native workers (20%) exhibited high sensitivity to ragweed and the titres of specific IgE antibodies was also significantly (p < 0.0001) higher in the former group. Similar differences were found in the occurrence and type of allergic symptoms. Seasonal symptoms alone occurred in 69% and 38% of the immigrant and native workers (p < 0.0001). This difference was mostly due to those with late summer symptoms characteristic to ragweed allergy. These symptoms occurred in 57% of the immigrant workers, much more frequently (p < 0.0001) than in the natives (18%). Our findings indicate that the length of exposure to an inhalant allergen does affect the extent of sensitisation to ragweed allergen and markedly influences the clinical symptoms that develop in the ragweed allergic patients upon allergen exposure. It can be assumed that the natives who have been living with ragweed pollen for a long time (that is were exposed to natural immunotherapy), developed a natural tolerance to it.


Transcontinental communication and quantitative digital histopathology via the Internet; with special reference to prostate neoplasia.
To describe practical experiences in the sharing of very large digital data bases of histopathological imagery via the Internet, by investigators working in Europe, North America, and South America. Experiences derived from medium power (sampling density 2.4 pixels/microm) and high power (6 pixels/microm) imagery of prostatic tissues, skin shave biopsies, breast lesions, endometrial sections, and colonic lesions. Most of the data included in this paper were from prostate. In particular, 1168 histological images of normal prostate, high grade prostatic intraepithelial neoplasia (PIN), and prostate cancer (PCa) were recorded, archived in an image format developed at the Optical Sciences Center (OSC), University of Arizona, and transmitted to Ancona, Italy, as JPEG (joint photographic experts group) files. Images were downloaded for review using the Internet application FTP (file transfer protocol). The images were then sent from Ancona to other laboratories for additional histopathological review and quantitative analyses. They were viewed using Adobe Photoshop, Paint Shop Pro, and Imaging for Windows. For karyometric analysis full resolution imagery was used, whereas histometric analyses were carried out on JPEG imagery also. The three applications of the telecommunication system were remote histopathological assessment, remote data acquisition, and selection of material. Typical data volumes for each project ranged from 120 megabytes to one gigabyte, and transmission times were usually less than one hour. There were only negligible transmission errors, and no problem in efficient communication, although real time communication was an exception, because of the time zone differences. As far as the remote histopathological assessment of the prostate was concerned, agreement between the pathologist's electronic diagnosis and the diagnostic label applied to the images by the recording scientist was present in 96.6% of instances. When these images were forwarded to two pathologists, the level of concordance with the reviewing pathologist who originally downloaded the files from Tucson was as high as 97.2% and 98.0%. Initial results of studies made by researchers belonging to our group but located in others laboratories showed the feasibility of making quantitative analysis on the same images. These experiences show that diagnostic teleconsultation and quantitative image analyses via the Internet are not only feasible, but practical, and allow a close collaboration between researchers widely separated by geographical distance and analytical resources.


The CD8-derived chemokine XCL1/lymphotactin is a conformation-dependent, broad-spectrum inhibitor of HIV-1.
CD8+ T cells play a key role in the in vivo control of HIV-1 replication via their cytolytic activity as well as their ability to secrete non-lytic soluble suppressive factors. Although the chemokines that naturally bind CCR5 (CCL3/MIP-1α, CCL4/MIP- 1β, CCL5/RANTES) are major components of the CD8-derived anti-HIV activity, evidence indicates the existence of additional, still undefined, CD8-derived HIV-suppressive factors. Here, we report the characterization of a novel anti-HIV chemokine, XCL1/lymphotactin, a member of the C-chemokine family that is produced primarily by activated CD8+ T cells and behaves as a metamorphic protein, interconverting between two structurally distinct conformations (classic and alternative). We found that XCL1 inhibits a broad spectrum of HIV-1 isolates, irrespective of their coreceptor-usage phenotype. Experiments with stabilized variants of XCL1 demonstrated that HIV-1 inhibition requires access to the alternative, all-β conformation, which interacts with proteoglycans but does not bind/activate the specific XCR1 receptor, while the classic XCL1 conformation is inactive. HIV-1 inhibition by XCL1 was shown to occur at an early stage of infection, via blockade of viral attachment and entry into host cells. Analogous to the recently described anti-HIV effect of the CXC chemokine CXCL4/PF4, XCL1-mediated inhibition is associated with direct interaction of the chemokine with the HIV-1 envelope. These results may open new perspectives for understanding the mechanisms of HIV-1 control and reveal new molecular targets for the design of effective therapeutic and preventive strategies against HIV-1.


Assessing the Economic Importance of Dasineura oxycoccana (Diptera: Cecidomyiidae) in Northern Highbush Blueberries.
Infestation by blueberry gall midge, Dasineura oxycoccana Johnson, is common in northern highbush blueberries, but its effects on crop productivity are unknown. We examined whether infestation by blueberry gall midge reduces flower bud production when compared with uninfested shoots, and how infestation at different times affects the crop response. From the fall of 2009 to the spring of 2011, the number of flower buds on infested and uninfested shoots of blueberry bushes was counted and compared. Despite causing branching of vegetative growth, there was no significant effect of infestation on flower bud production. During the summer of 2010, damaged shoots were marked throughout the growing season in June, July, or August. The number of flower buds set per shoot declined with later infestation dates, and shoots damaged in August had significantly fewer buds than those damaged in June and July. We discuss the implications of these findings for management of blueberry gall midge in northern highbush blueberry.


Structure and microwave characteristics of Co/TiO2 nanocomposites prepared by ball milling.
Co/TiO2 nanocomposites were fabricated via direct ball milling. The structure and microwave characteristics of the Co/TiO2 nanocomposites were investigated. The results show that the hcp and fcc Co phases coexist in the nanocomposites for a long milling duration. The accumulation of the stacking faults in Co and the increase of the Co/TiO2 interfaces were detected by nuclear magnetic resonance. The measured relative complex permittivity of the ComTiO2 nanocomposite-paraffin wax mixture indicates that a high electrical resistivity and a dielectric loss exist in the Co/TiO2 nanocomposites. The dielectric loss mainly results from the polarisation of the metal/insulator interfaces. The imaginary part of the relative complex permeability of the mixture exhibits a broad resonance peak at 5.1 GHz which originates from the natural resonance in Co. The broadening of the resonance peak can be attributed to the fluctuating magnetocrystalline anisotropy at the stacking faults and interfaces regions. The calculated reflection loss curves show that the minimal reflection loss value of the Co/TiO2 nanocomposite-paraffin wax mixture can reach -32 dB at 4.0 GHz with a 3 mm sample thickness. The improved microwave absorption properties may result from the high electrical resistivity, dielectric loss and natural resonance.


Regulation of Gramicidin Channel Function Solely by Changes in Lipid Intrinsic Curvature.
Membrane protein function is regulated by the lipid bilayer composition. In many cases the changes in function correlate with changes in the lipid intrinsic curvature (c 0), and c 0 is considered a determinant of protein function. Yet, water-soluble amphiphiles that cause either negative or positive changes in curvature have similar effects on membrane protein function, showing that changes in lipid bilayer properties other than c 0 are important-and may be dominant. To further investigate the mechanisms underlying the bilayer regulation of protein function, we examined how maneuvers that alter phospholipid head groups effective "size"-and thereby c 0-alter gramicidin (gA) channel function. Using dioleoylphospholipids and planar bilayers, we varied the head groups' physical volume and the electrostatic repulsion among head groups (and thus their effective size). When 1,2-dioleyol-sn-glycero-3-phosphocholine (DOPC), was replaced by 1,2-dioleyol-sn-glycero-3-phosphoethanolamine (DOPE) with a smaller head group (causing a more negative c 0), the channel lifetime (τ) is decreased. When the pH of the solution bathing a 1,2-dioleyol-sn-glycero-3-phosphoserine (DOPS) bilayer is decreased from 7 to 3 (causing decreased head group repulsion and a more negative c 0), τ is decreased. When some DOPS head groups are replaced by zwitterionic head groups, τ is similarly decreased. These effects do not depend on the sign of the change in surface charge. In DOPE:DOPC (3:1) bilayers, pH changes from 5→9 to 5→0 (both increasing head group electrostatic repulsion, thereby causing a less negative c 0) both increase τ. Nor do the effects depend on the use of planar, hydrocarbon-containing bilayers, as similar changes were observed in hydrocarbon-free lipid vesicles. Altering the interactions among phospholipid head groups may alter also other bilayer properties such as thickness or elastic moduli. Such changes could be excluded using capacitance measurements and single channel measurements on gA channels of different lengths. We conclude that changes gA channel function caused by changes in head group effective size can be predicted from the expected changes in c 0.


Weighted likelihood method for grouped survival data in case-cohort studies with application to HIV vaccine trials.
Grouped failure time data arise often in HIV studies. In a recent preventive HIV vaccine efficacy trial, immune responses generated by the vaccine were measured from a case-cohort sample of vaccine recipients, who were subsequently evaluated for the study endpoint of HIV infection at prespecified follow-up visits. Gilbert et al. (2005, Journal of Infectious Diseases 191, 666-677) and Forthal et al. (2007, Journal of Immunology 178, 6596-6603) analyzed the association between the immune responses and HIV incidence with a Cox proportional hazards model, treating the HIV infection diagnosis time as a right-censored random variable. The data, however, are of the form of grouped failure time data with case-cohort covariate sampling, and we propose an inverse selection probability-weighted likelihood method for fitting the Cox model to these data. The method allows covariates to be time dependent, and uses multiple imputation to accommodate covariate data that are missing at random. We establish asymptotic properties of the proposed estimators, and present simulation results showing their good finite sample performance. We apply the method to the HIV vaccine trial data, showing that higher antibody levels are associated with a lower hazard of HIV infection.


Lacrimal Gland Hamartoma (Formerly Termed Dacryoadenoma).
Since the original description of "dacryadenoma" by Jakobiec and associates, the data on this unusual epibulbar lacrimal gland lesion remain sparse. The aim of this study was to characterize clinically, morphologically, and immunohistochemically this isolated epibulbar lacrimal gland lesion. Retrospective observational case series. Institutional pathology records between 2000 and 2019 were searched for all cases of isolated epibulbar lacrimal gland lesions. Tissue from 3 normal lacrimal glands and 1 complex choristoma were included for comparative analysis. Clinical, histopathologic, and immunohistochemical findings were recorded. Four patients with isolated epibulbar lacrimal gland lesions, 2 male and 2 female, with a median age of 18 years (range, 12-57) were identified. All patients presented with recent onset of unilateral pink-to-orange, well-circumscribed subepithelial juxtaforniceal (3/4, 75%), or nasal (1/4, 25%) bulbar conjunctival nodules, which were asymptomatic (3/4, 75%) or associated with foreign body sensation (1/4, 25%). When compared with the normal lacrimal gland and complex choristoma, all isolated epibulbar lacrimal gland lesions were composed predominantly of variably dilated, branching tubular structures with pseudo-apocrine snouts, and either totally absent (2/2, 50%) or rare (2/2, 50%) ducts and rare acinar zymogen granules (3/4, 75%). Our study confirms that a subset of isolated epibulbar lacrimal gland lesions differs morphologically and immunohistochemically from normal lacrimal gland tissue and the lacrimal gland in a complex choristoma. These differences range from subtle to overt, suggesting that isolated epibulbar lacrimal gland lesions may have originated from precursor cellular elements indigenous to the conjunctiva (hamartia) and grew into disorganized lacrimal gland tissue.


The Drosophila nuclear factor DREF positively regulates the expression of the mitochondrial transcription termination factor DmTTF.
The DREF [DRE (DNA replication-related element)-binding factor], which regulates the transcription of a group of cell proliferation-related genes in Drosophila, also controls the expression of three genes involved in mtDNA (mitochondrial DNA) replication and maintenance. In the present study, by in silico analysis, we have identified DREs in the promoter region of a gene participating in mtDNA transcription, the DmTTF (Drosophila mitochondrial transcription termination factor). Transient transfection assays in Drosophila S2 cells, with mutated versions of DmTTF promoter region, showed that DREs control DmTTF transcription; moreover, gel-shift and ChIP (chromatin immunoprecipitation) assays demonstrated that the analysed DRE sites interact with DREF in vitro and in vivo. Accordingly, DREF knock-down in S2 cells by RNAi (RNA interference) induced a considerable decrease in DmTTF mRNA level. These results clearly demonstrate that DREF positively controls DmTTF expression. On the other hand, mtRNApol (mitochondrial RNA polymerase) lacks DREs in its promoter and is not regulated in vivo by DREF. In situ RNA hybridization studies showed that DmTTF was transcribed almost ubiquitously throughout all stages of Drosophila embryogenesis, whereas mtRNApol was efficiently transcribed from stages 11-12. Territories where transcription occurred mostly were the gut and Malpighi tubes for DmTTF, and the gut, mesoderm, pharyngeal muscle and Malpighi tubes for mtRNApol. The partial overlapping in the temporal and spatial mRNA expression patterns confirms that transcription of the two genes is differentially regulated during embryogenesis and suggests that DmTTF might play multiple roles in the mtDNA transcription process, for which different levels of the protein with respect to mtRNApol are required.


A discrete population of mononuclear phagocytes detected by monoclonal antibody.
Rat monoclonal antibody raised against cultured mouse bone marrow was used to detect an antigenic determinant on a discrete population of mouse mononuclear phagocytes by indirect immunofluorescence. The antigen was expressed on adherent, late-cultured bone marrow macrophages and chronic inflammatory peritoneal macrophages elicited by the injection of thioglycolate broth. Binding of the antibody to resident peritoneal or alveolar macrophages, blood monocytes, or freshly explanted bone marrow cells was not detected. Less than 10% of acute inflammatory mononuclear phagocytes expressed the antigen. The antibody did not bind detectably to lymphocytes, granulocytes, erythrocytes, fibroblasts, or the cells of several murine tumor lines. Results suggesting binding to mast cells were equivocal. The antigen was species, but not strain, specific. It was concluded that maturation, at least, was required for expression of the antigen. Results suggested that additional influences were also involved.


In vitro and in vivo evaluation of organometallic gold(I) derivatives as anticancer agents.
Alkyne gold(I) derivatives with the water soluble phosphanes PTA (1,3,5-triaza-7-phosphaadamantane) and DAPTA (3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane) were described and their anticancer potential against the colon cancer cell line Caco-2 (PD7 and TC7 clones) was studied. Strong antiproliferative effects are found, for all the new complexes, to be even more pronounced than for the reference drug cisplatin, and similar to auranofin. The interaction of these derivatives with bovine serum albumin (BSA) was studied by fluorescence spectroscopy. The types of quenching and binding constants were determined by a fluorescence quenching method. Moderate values of the binding constants are calculated for the tested derivatives indicating that these complexes can be stored and carried easily by this protein in the body. The study of the thermodynamic parameters in the case of [Au(C[triple bond, length as m-dash]CCH2Spyridine)(PTA)] points out to the presence of van der Waals interactions or hydrogen bonding between the metallic complex and the protein. In addition, the complex [Au(C[triple bond, length as m-dash]CCH2Spyridine)(PTA)] has shown inhibition in colon cancer proliferation of HTC-116-luc2 cell lines via the apoptotic pathway and S-phase arrest of the cell cycle. Intraperitoneal injection of this derivative in athymic nude mice inoculated with HTC-116-luc2 cells prolonged their survival and displayed moderate inhibition of the tumour growth with no subsequent organ (kidney and liver) damage after treatment.


Requirement for a fluid host cell membrane in injection of coliphage T5 DNA.
Injection of T5 first-step-transfer DNA was prevented at 29 degrees C, after adsorption to an unsaturated fatty acid mutant grown on elaidate (phase transition at 35 degrees C). Local anesthetics, which increase membrane fluidity, did not inhibit injection above transition temperature and could even reverse the inhibition observed at 29 degrees C on elaidate cells.


A novel circ_0099999/miR-330-5p/FSCN1 ceRNA crosstalk in pancreatic cancer.
Pancreatic cancer is a lethal malignancy in both sexes throughout the world. Circular RNAs (circRNAs) have been implicated in the development of pancreatic cancer by operating as competing endogenous RNAs (ceRNAs). Here, we explored circ_0099999-mediated ceRNA activity in regulating pancreatic tumorigenesis. Ribonuclease R (RNase R) and subcellular localization assays were utilized to characterize circ_0099999. The levels of circ_0099999, microRNA (miR)-330-5p, and fascin actin-bundling protein 1 (FSCN1) were gauged by quantitative real-time PCR (qRT-PCR) and western blot. Cell proliferation, colony formation, apoptosis, migration, and invasion were evaluated by the Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, and transwell assays, respectively. The levels of glucose consumption and lactate production were determined using the assay kits. A direct relationship between miR-330-5p and circ_0099999 or FSCN1 was validated by dual-luciferase reporter assay. Tumour xenograft assays were used to analyse the role of circ_0099999 in vivo. Circ_0099999 was highly up-regulated in pancreatic cancer tissues and cells. Knockdown of circ_0099999 impeded cell proliferation, migration, invasion, glycolysis, and promoted apoptosis in vitro, as well as diminished tumour growth in vivo. Circ_0099999 targeted miR-330-5p, and miR-330-5p was a downstream mediator of circ_0099999 function. FSCN1 was a direct and functional target of miR-330-5p. Furthermore, circ_0099999 operated as a ceRNA for miR-330-5p to modulate FSCN1 expression. Our findings established a novel causal mechanism, circ_0099999/miR-330-5p/FSCN1 ceRNA crosstalk, in regulating pancreatic carcinogenesis and provided that inhibition of circ_0099999 might have therapeutic benefits in pancreatic cancer.


[The primary cruciate ligament suture--is the method outdated? Results in follow-up of 58 patients].
In the present study 58 out of 105 patients, who had been operated on for anterior cruciate ligament rupture from 1980-1992 by the same experienced surgeon, were followed up clinically and by X-ray examination. Most of them were sports accidents, above all skiing and soccer. In 11 patients an isolated rupture of the anterior cruciate ligament was found, the remaining 47 had sustained additional injuries (mainly the medial collateral ligament and the medial meniscus). In 52 cases the operation was performed with primary repair of the anterior cruciate ligament. For chronic instability 4 patients (7%) had to be treated with secondary anterior cruciate ligament reconstruction. In the follow-up study 60% of all patients achieved a Lysholm-score of 95-100 points, 19% of 84-94 points. The remaining 21% achieved less than 84 points. In the side to side comparison the Lachman Test was equal or showed a slightly diminished stability of the operated knee in 91% of 54 patients without secondary reconstruction. The anterior stability with 90 degrees flexed knee in neutral position was within a similar scope, the anterior medial stability was a little worse. In 48% of all patients we found radiological signs of osteoarthritis (stage II and III according to the classification of Jäger and Wirth).


[Endocrinology of climacteric and postmenopause].
Climacterium is the transition from a cyclical ovarian function with ovulation to primarily irregularities and ultimately cessation of follicular maturation with its cyclical production of estrogens and progestins. The reason is the decline in follicle count and the decreasing sensitivity of follicles to pituitary gonadotropins. In this transition a phase of elevated androgen action is found in early menopause ultimately in late menopause the ovarian androgen production decreases while the androgen production through the adrenal glands is maintained and especially prohormones which are metabolished peripherally to active androgens and estrogens are produced. In the late menopause also the adrenal androgen production is decreased. This deficiency of estrogens results in processes of deprivation and degeneration which also are dependent on the decreasing growth hormone action according to decreased production and secretion.


In-source collision-induced dissociation (IS-CID): Applications, issues and structure elucidation with single-stage mass analyzers.
A discussion of the definition, advantages, and issues with the formation of ions in the transition region between an electrospray ionization (ESI) source and the ion optics of a mass analyzer is presented. The various types of ions formed in the so-called in-source collision-induced dissociation (IS-CID) process are illustrated. Applications of IS-CID with single-stage mass analyzers, such as structure elucidation and quantitation, are demonstrated. The discussion is illustrated by examples of the in-source fragmentation of ginkgolides, which are marker compounds found only in Ginkgo biloba. Supercritical fluid chromatography (SFC) with non-aqueous eluents was used to achieve a fast resolution of the ginkgolides without the hydrolysis reactions possible with aqueous high-performance liquid chromatography (HPLC) eluents. In-source ion generation occurs at relatively high pressures (ca. 1-3 torr) compared to the low pressure normally observed in collision chambers of tandem mass spectrometry (MS/MS). As a result, the fragmentation process is complex and often generates ions other than the fragments observed with classic CID or the same ions at different intensities. The objective of the current tutorial is to illustrate the conditions under which single-stage, quadrupole or time-of-flight mass analyzers with electrospray or in-air (direct analysis in real time; DART) ionization can be used for quantitation and structure elucidation in a manner similar to that observed with MS/MS. While the low m/z (≤ [M±H]± ) ions formed in-source often duplicate the ions observed in MS/MS systems, it is the focus of this discussion to illustrate the utility of in-source generated fragment ions that may not be observed or observed at different intensities than in the collision cells of MS/MS instruments.


Spitz nevus of the tongue with pseudoepitheliomatous hyperplasia: report of three cases of a pseudomalignant condition.
Three cases of Spitz nevus of the tongue associated with pseudoepitheliomatous hyperplasia are reported: two occurring in children and one in an adult. The location at an unusual site and the complex pattern resulting from the intimate admixture of the neoplastic melanocytic component and the hyperplastic keratinocytic component led in each case to consider diagnoses such as malignant melanoma and invasive squamous cell carcinoma. Staining for S-100 protein and keratin was useful to identify and separate the two components. Spitz nevus of the tongue carries some intriguing similarities with granular cell tumor, suggesting a possible histogenetic and pathogenetic relationship.


Potential use of chymotrypsin-like proteasomal activity as a biomarker for prostate cancer.
Although it is the most widely used biomarker for prostate cancer, the use of prostate specific antigen (PSA) is controversial due to its limitations in specificity and sensitivity. The proteasome is a complex associated with cell proliferation and apoptosis, and the abnormity of these processes may lead to tumor occurrence. Previous studies have reported that proteasomal activity is associated with cancer progression and can be used in risk stratification. The purpose of the present study was thus to investigate the feasibility of proteasome activity as a biomarker for prostate cancer. Proteasome activity in vitro and in vivo was detected, along with the expression of the substrate proteins NF-κB inhibitor-α (IκB-α), Bcl-2-associated X (Bax) and p27. Chymotrypsin-like proteasomal activity was elevated by 70% in vitro and 23% in vivo, and the expression levels of the proteasome substrate proteins IκB-α, Bax and p27 were decreased in prostate cancer cells and prostate tumor xenografts compared with normal mouse prostate tissue. In conclusion, proteasomal chymotrypsin-like activity maybe a potential biomarker for prostate cancer, and may be suitable to supplement PSA in clinical application for prostate cancer diagnosis.


Lack of circulating immune complexes in inflammatory bowel disease.
Multi-organ involvement and especially extraintestinal manifestations have suggested an immune complex-mediated pathogenesis of ulcerative colitis and Crohn's disease. Using various techniques controversial data have been reported on the incidence and levels of circulating immune complexes and their correlation to clinical presentation. Sera of 131 patients with inflammatory bowel disease (78 Crohn's disease, 53 ulcerative colitis) representing a wide spectrum of disease activity, treatment and presence or absence of extraintestinal manifestations were tested for circulating immune complexes using Raji cell indirect immunofluorescence assay, Raji cell radioimmunoassay, C1q solid phase assay and polyethylene glycol precipitation coupled with measurements of optical density and subsequent immunoelectrophoresis or radial immunodiffusion. Circulating immune complexes in low concentrations were observed in a small number of patients with inflammatory bowel disease, the frequency and concentrations being slightly higher in patients with Crohn's disease than in those with ulcerative colitis. No association of concentrations of circulating immune complexes with disease activity or presence of extraintestinal manifestations could be demonstrated. These data do not support the claim for a major role of circulating immune complexes in the pathogenesis of inflammatory bowel disease.


[Factors influencing olfactory dysfunction in patients with chronic rhinosinusitis].
To evaluate the relative factors influencing olfactory dysfunction in patients with chronic rhinosinusitis (CRS). Visual analogue scale (VAS) was applied to measure the severity of olfactory dysfunction of 270 patients with CRS. Patients were divided into two groups, one was that the quality of life (QOL) of patients was affected by olfactory dysfunction (VAS > 5), the other was that without QOL affected by olfactory dysfunction (VAS ≤ 5). The association between age, gender, nasal polyps, allergic rhinitis, smoking history, early nasal surgery history and other clinical factors, and serum total IgE level, peripheral blood eosinophil count, peripheral blood mononuclear cell count and olfactory dysfunction was analyzed. The number of patients with nasal polyps, allergic rhinitis, previous nasal surgeries, the level of serum total IgE, and the severity of edema were significantly increased in patients with impaired QOL associated with olfactory dysfunction (P < 0.05). Sex distribution, age, smoking history, deviation of nasal septum, eosinophil and mononuclear cell count did no statistically differ between the groups with and without impaired QOL associated with olfactory dysfunctions (P > 0.05). Serum total IgE increased (OR = 1.003, P < 0.01) and severe edema (OR = 2.483, P < 0.01) were the risk factors for the impairment of olfactory function, more notably for edema; whereas previous nasal surgeries was a protective factor (OR = 0.408, P < 0.01). Sever edema and increased serum total IgE are risk factors, whereas previous nasal surgeries history is a protective factor for the olfactory dysfunction.


Temporal lobe asymmetry and dyslexia: an in vivo study using MRI.
Three measures of the right and left temporal lobes were taken with magnetic resonance imaging (MRI) in groups of dyslexics (N = 17), retarded readers (N = 6), and normal controls (N = 12). The most pronounced differences among the groups were found with measures on coronal slices of the cross sectional area of the temporal cortex with subcortical white matter--in particular lateral to insula. While most of the normal and the retarded readers (13 of 18) had left asymmetry (left area larger than right), most of the dyslexics (14 of 17) had symmetry or right asymmetry. The degree of left asymmetry, (L-R)/[0.5(L + R)], was found to correlate with both reading skills and skills in phonemic analysis of spoken language. These results were also found when differences in non-verbal IQ were accounted for. The implications for definitions of dyslexia, for psycholinguistic research on dyslexia, and for remedial teaching are discussed.


Psychometric evaluation of the Persian version of the European Health Literacy Instrument (P-HLS-EU-Q47).
Health literacy is one of the most critical determinants of health for effectively improving health services and reducing health inequalities. The importance of accurate measurement cannot be overstated. The European 47-item Health Literacy Questionnaire (HLS-EU-Q47) can provide precise measurements of health literacy. Therefore, this study aimed to evaluate the psychometric properties of the European Health Literacy Instrument in Iranian society (HLS-PV-Q47) for its Persian version. This cross-sectional study was conducted using a convenient sampling of 560 people referred to comprehensive healthcare centers. The construct validity was assessed by exploratory (280 people) and confirmatory factor (with 280 people). The internal consistency was calculated using Cronbach's alpha coefficients. Based on the exploratory factor analysis, three factors of healthcare, disease prevention, and health promotion explained 48.9% of the total variance of health literacy. Cronbach's alpha was 0.96 for the whole instrument. The Persian version of the European Health Literacy Instrument (P-HLS-EU-Q47) had good validity and reliability, which can be used in future studies due to its good psychometric properties.