Molecular Biomarker of Drug Resistance Developed From Patient-Derived Organoids Predicts Survival of Colorectal Cancer Patients.
The drug 5-fluorouracil (5-Fu) is the critical composition of colorectal cancer (CRC) treatments. Prognostic and predictive molecular biomarkers for CRC patients (CRCpts) treated with 5-Fu-based chemotherapy can provide assistance for tailoring treatment approach. Here, we established a molecular biomarker of 5-Fu resistance derived from colorectal cancer organoids (CRCOs) for predicting the survival of CRCpts. Forty-one CRCO cultures were generated from 50 CRC tumor tissues after surgery (82%). The following experiments revealed a great diversity in drug sensitivity for 10 μM 5-Fu treatment tested by using organoid size change. Fourteen cases (34.1%) were 5-Fu sensitive and the other 27 (65.9%) were resistant. Then, differentially expressed genes (DEGs) associated with 5-Fu resistance were outputted by transcriptome sequencing. In particular, DEGs were generated in two comparison groups: 1) 5-Fu sensitive and resistant untreated CRCOs; 2) CRCOs before 5-Fu treatment and surviving CRCOs after 5-Fu treatment. Some molecules and most of the pathways that have been reported to be involved in 5-Fu resistance were identified in the current research. By using DEGs correlated with 5-Fu resistance and survival of CRCpts, the gene signature and drug-resistant score model (DRSM) containing five molecules were established in The Cancer Genome Atlas (TCGA)-CRC cohort by least absolute shrinkage and selection operator (LASSO) regression analysis and 5-fold cross-validation. Multivariate analysis revealed that drug-resistant score (DRS) was an independent prognostic factor for overall survival (OS) in CRCpts in TCGA-CRC cohort (P < 0.001). Further validation results from four Gene Expression Omnibus (GEO) cohorts elucidated that the DRSM based on five genes related to 5-Fu chemosensitivity and developed from patient-derived organoids can predict survival of CRCpts. Meanwhile, our model could predict the survival of CRCpts in different subgroups. Besides, the difference of molecular pathways, tumor mutational burden (TMB), immune response-related pathways, immune score, stromal score, and immune cell proportion were dissected between DRS-high and DRS-low patients in TCGA-CRC cohort.


Facile synthesis and enhanced microwave absorption properties of novel hierarchical heterostructures based on a Ni microsphere-CuO nano-rice core-shell composite.
A novel hierarchical heterostructure of Ni microspheres-CuO nano-rices was fabricated using a simple two-step process. The CuO rices were densely deposited on the surfaces of Ni microspheres. The phase purity, morphology, and structure of composite heterostructures are characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), energy dispersive X-ray spectroscopy (EDS), and transmission electron microscopy (TEM). Different structured Ni-CuO composite heterostructures are also investigated by adjusting the volume ratio of the reactants. The core-shell rice-like CuO-coated Ni exhibits better antioxidation capability than pure Ni due to the presence of the barrier effect of the CuO shell, which is revealed by the thermogravimetric analysis (TGA). In comparison with pristine Ni microspheres and CuO nanoflakes, the Ni-CuO composites exhibit excellent microwave absorption properties. Moreover, the amount of CuO plays a vital role in the microwave attenuation of Ni-CuO composites. The Ni-CuO heterostructures prepared at 0.017 M Cu(2+) exhibit the best electromagnetic wave absorption capabilities. A minimum reflection loss reaches -62.2 dB (>99.9999% microwave absorption) at 13.8 GHz with the thickness of only 1.7 mm. The effective absorption (below -10 dB) bandwidth can be tuned between 6.4 GHz and 18.0 GHz by tuning the absorber thickness of 1.3-3.0 mm. Thus, the Ni-CuO composite possesses a fascinating microwave absorption performance as a novel absorbing material with strong absorption, wide-band gap and thin thickness.


Observation of nuclear fusion driven by a pyroelectric crystal.
While progress in fusion research continues with magnetic and inertial confinement, alternative approaches--such as Coulomb explosions of deuterium clusters and ultrafast laser-plasma interactions--also provide insight into basic processes and technological applications. However, attempts to produce fusion in a room temperature solid-state setting, including 'cold' fusion and 'bubble' fusion, have met with deep scepticism. Here we report that gently heating a pyroelectric crystal in a deuterated atmosphere can generate fusion under desktop conditions. The electrostatic field of the crystal is used to generate and accelerate a deuteron beam (> 100 keV and >4 nA), which, upon striking a deuterated target, produces a neutron flux over 400 times the background level. The presence of neutrons from the reaction D + D --> 3He (820 keV) + n (2.45 MeV) within the target is confirmed by pulse shape analysis and proton recoil spectroscopy. As further evidence for this fusion reaction, we use a novel time-of-flight technique to demonstrate the delayed coincidence between the outgoing alpha-particle and the neutron. Although the reported fusion is not useful in the power-producing sense, we anticipate that the system will find application as a simple palm-sized neutron generator.


[Luminescent characteristics of the functional state of sarcoma 45 cells].
Various functional states of cells of sarcoma 45 in the course of its growth and regression were studied by photometry and spectral analysis using acridine orange. Fluorescent spectral analysis proved to be the most reliable procedure for quantitative evaluation of tumor cell function using the alpha-coefficient.


Carboxyhemoglobinemia in a pediatric cardiopulmonary bypass patient derived from a contaminated unit of allogenic blood.
A 4.3 kg, three-month-old patient, diagnosed with a perimembranous ventricular septal defect, presented for cardiac surgery. Upon initiation of cardiopulmonary bypass (CPB), the patient developed carboxyhemoglobinemia (11.1%). Potential sources for the unexpected acquired carboxyhemoglobinemia were sought quickly. Testing of residual blood from the unit of packed red blood cells (PRBCs) used to prime the CPB circuit revealed a carboxyhemoglobin (COHb) of 15.1 %. A decrease in cerebral oximetry (rSO(2)) on CPB was initially felt to be a result of the elevated COHb levels. When ventilation of the oxygenator with 100% oxygen (O(2)) failed to decrease COHb levels, a partial exchange transfusion was performed with reduction in COHb to 7.1%. The operation was completed successfully and the patient's COHb levels returned to normal within 75 minutes. Post case analysis of events and data collected during the case revealed a broader differential for explaining the compromised patient's O(2) delivery than the transient acquired carboxyhemoglobinemia. A partial obstruction of the superior vena cava could have triggered the drop in rSO(2) on CPB. Follow-up of the donor blood confirmed the donor had previously undiagnosed carboxyhemoglobinemia as a result of chronic carbon monoxide exposure from a faulty vehicle exhaust system.


Autonomic regulation of postprandial plasma somatostatin, gastrin, and insulin.
To evaluate the neural regulation of postprandial somatostatin release we studied the effect of blockade of (a) alpha-adrenergic and beta-adrenergic and (b) cholinergic receptors on the plasma somatostatin, gastrin and insulin responses to a standard meal in two groups of five fasting healthy male volunteers. Thymoxamine (0.1 mg/kg iv over two minutes then 10 mg/hour for two hours) and propranolol (0.15 mg/kg iv over two minutes, then 0.75 mg/kg/hour for two hours) were started just before eating while atropine (0.04 mg/kg/im) was given at 15 minutes on completion of the meal. There was a prompt and sustained rise in plasma somatostatin after a control meal in all experiments. This rise was arrested by atropine but not altered by either thymoxamine or propranolol. The plasma gastrin response to a meal was moderately enhanced by thymoxamine and markedly enhanced by atropine. Postprandial insulin release was not affected by alpha- or beta-adrenergic blockade but was abolished by atropine. The effect of atropine on the postprandial plasma somatostatin rise might have been mediated through reduction in gastric acidity or delay in gastric emptying. Hence we gave five fasting male volunteers and intraduodenal infusion of fat emulsion (25 calories in 30 minutes) on two occasions both alone and after atropine. Plasma somatostatin rose during the fat infusion alone and this rise was abolished by atropine. These data suggest that (a) cholinergic but not adrenergic mechanisms are important modulators of plasma somatostatin release after orally ingested and intraduodenally infused nutrients (b) atropine abolishes plasma somatostatin release independently of its effects on gastric acidity and motility and (c) are consistent with the hypothesis that atropine potentiates postprandial gastrin release through reduction of somatostatin mediated inhibition.


Left aortic arch with right-sided descending aorta associated with sudden neonatal death: a case report.
We present the case of a 26-day-old female in whom left aortic arch with right-sided descending aorta occurred. The previously healthy newborn baby was found dead on her bed. This anomaly is very uncommon and its clinical presentation as sudden death is also exceptional with only a few cases having been reported in the literature. The pathological findings and embryological origins of this malformation, so-called 'circumflex aorta' are discussed. The pertinent literature is reviewed.


The advantages of problem-based curricula.
Problem-based curricula provide a learning environment in which competence is fostered not primarily by teaching to impart knowledge, but through encouraging an inquisitive style of learning. Preliminary discussion in small groups, contextual learning, integration of knowledge and an emphasis on patient problems, have several cognitive effects on student learning. These effects are increased retention of knowledge, enhancement of integration of basic science concepts into clinical problems, the development of self-directed learning skills, and the enhancement of students' intrinsic interest in the subject matter. In this paper a number of studies will be reviewed that provide empirical evidence for these premises.


Utilization of surgery in trimodality-eligible patients with locally advanced esophageal adenocarcinoma in a nonprotocol setting.
Trimodality therapy with neoadjuvant chemoradiation followed by surgery significantly improves the survival of locally advanced (clinical stage IIA-III) esophageal cancer patients compared to treatment with surgery alone. This has resulted in an increased use of neoadjuvant therapy in recent years, yet little is known regarding how this increase has impacted the utilization of surgery in the treatment of locally advanced disease. Although previous reports of experimental protocols suggest that 90-95% of patients complete trimodality therapy including a surgical resection, trimodality therapy completion among adenocarcinoma patients eligible for curative resection has not been evaluated in a nonprotocol setting. We sought to (i) assess the completion of trimodality therapy among locally advanced esophageal adenocarcinoma patients; (ii) characterize the reasons for avoiding surgery; and (iii) identify factors associated with failure to complete trimodality therapy. We identified 296 patients with locally advanced esophageal adenocarcinoma eligible for trimodality therapy at our institution. All patients were evaluated in a multidisciplinary setting and considered eligible for curative resection after initial staging and physiologic assessment. Multivariable logistic regression was used to identify factors associated with failure to complete trimodality therapy. Of 296 trimodality-eligible patients, 33% (97/296) did not complete trimodality therapy. Reasons for not undergoing surgery included patient choice (27.8%, 27/97), distant progression of disease during chemoradiation (23.7%, 23/97), and physician preference for surveillance (23.7%, 23/97). In addition, 17.5% (17/97) of patients had physical deterioration in performance status, and treatment-related deaths occurred in 7.2% (7/97) prior to surgery. In the total study population (n = 296), multivariable logistic regression identified older age (≥70 years: odds ratio [OR] = 6.611, 95% confidence interval [CI]: 2.900-15.071), pretreatment standard uptake value (6.8-10.1: OR = 2.393, 95% CI: 1.050-5.455; ≥15.8: OR = 3.623, 95% CI: 1.604-8.186), and a radiation dose of 50.4 Gy (OR = 5.312, 95% CI: 2.365-11.929) as being significantly associated with failure to complete trimodality therapy. Among the subgroup of patients that successfully completed chemoradiation (n = 266), older patients (≥70 years: OR = 9.606, 95% CI: 3.637-25.372), those with a comorbidity score of 2 or higher (OR = 4.059, 95% CI: 1.257-13.103), and those that received a radiation dose of 50.4 Gy (OR = 4.878, 95% CI: 1.974-12.054) were at a significantly higher risk of not completing trimodality therapy. Trimodality therapy completion among patients with locally advanced esophageal adenocarcinoma in a nonprotocol setting is considerably lower than what has previously been reported in clinical trials. Our findings suggest that a selective approach to surgery is commonly utilized in clinical practice. Trimodality-eligible patients that are older and have a higher comorbidity score are at risk for not completing trimodality therapy.


[Incidence of celiac disease in patients with chronic diarrhea].
To study prevalence of celiac disease (CD) among patients with chronic diarrhea (ChD). Serum levels of IgA-antibodies to gliadin, endomysium, reticulin and tissue transglutaminase were examined in 206 patients with CD. Biopsies were obtained from a distal portion of the duodenum or a proximal portion of the jejunum. CD was diagnosed in 35 (16.9%) of 206 patients with ChD. The disease was typical in 5 (2.4%) patients and was latent in 30 (14.5%) patients. Antibodies to gliadin, endomysium, reticulin and tissues transglutaminase in diagnostically significant titers were detected in the serum of all the examinees with CD. Formation of the antitissue antibodies occurred because of destructive-dystrophic alterations of the connective tissue of the lamina propria mucosae pointing to the autoimmune nature of a pathological process in celiac disease. To diagnose CD in ChD patients, it is necessary to supplement standard examination with duodenobiopsy, tests for antibodies to gliadin, tissue transglutaminase and to tissue structures--endomysium and reticulin.


Behavioral effects of long-term neuroleptic treatment in Cebus monkeys.
Tardive dyskinesia (TD) occurs in predisposed individuals receiving neuroleptic treatment, but prior to the onset of symptoms it is not possible to predict who is at risk for this disorder. If the time course for evolving symptoms, perhaps mediated through dopamine hypersensitivity, could be identified, treatment interventions could be initiated. Eight male Cebus monkeys (15-18 years old) were tested with the dopamine agonists apomorphine, d-amphetamine, bromocriptine, and pergolide before, during, and after 3 months of treatment with haloperidol 0.25 mg/kg daily PO. This treatment cycle was repeated four times. Apomorphine and amphetamine produced moderate buccolinguo-masticatory (BLM) signs. Bromocriptine and pergolide produced very few BLMs. Initially haloperidol suppressed dopamine agonist-induced BLMs, but tolerance to the effect developed and was replaced by a potentiation of apomorphine-induced BLMs. Markedly increased apomorphine- and amphetamine-induced BLMs were seen following the first 3 months of haloperidol medication (behavioral hypersensitivity), but this gradually decreased to near-baseline levels, even with re-exposure to neuroleptics in the four treatment cycles. Bromocriptine and pergolide produced no signs of BLM behavioral hypersensitivity. These findings suggest that long-term neuroleptic treatment in nonhuman primates induces dynamic compensatory CNS changes, which may not fully explain the pathogenesis of TD on the basis of dopamine hypersensitivity.


1,4-phenylenebis(methylene)selenocyanate, but not selenomethionine, inhibits androgen receptor and Akt signaling in human prostate cancer cells.
The lack of treatment for worried-well patients with high-grade prostatic intraepithelial neoplasia combined with issues of recurrence and hormone resistance in prostate cancer survivors remains a major public health obstacle. The long latency of prostate cancer development provides an opportunity to intervene with agents of known mechanisms at various stages of disease progression. A number of signaling cascades have been shown to play important roles in prostate cancer development and progression, including the androgen receptor (AR) and phosphatidylinositol 3-kinase/Akt signaling pathways. Crosstalk between these two pathways is also thought to contribute to progression and hormone-refractory prostate disease. Our initial investigations show that the naturally occurring organoselenium compound selenomethionine (SM) and the synthetic 1,4-phenylenebis(methylene)selenocyanate (p-XSC) can inhibit human prostate cancer cell viability; however, in contrast to SM, p-XSC is active at physiologically relevant doses. In the current investigation, we show that p-XSC, but not an equivalent dose of SM, alters molecular targets and induces apoptosis in androgen-responsive LNCaP and androgen-independent LNCaP C4-2 human prostate cancer cells. p-XSC effectively inhibits AR expression and transcriptional activity in both cell lines. p-XSC also decreases Akt phosphorylation as well as Akt-specific phosphorylation of the AR. Inhibition of Akt, however, does not fully attenuate p-XSC-mediated downregulation of AR activity, suggesting that inhibition of AR signaling by p-XSC does not occur solely through alterations in the phosphatidylinositol 3-kinase/Akt survival pathway. Our data suggest that p-XSC inhibits multiple signaling pathways in prostate cancer, likely accounting for the downstream effects on proliferation and apoptosis.


Carbonate inhibits the crystallization of aluminum hydroxide in bauxite.
Although the role of anions such as nitrate, chloride, and sulfate in inhibiting the crystallization of aluminum hydroxide in soils and geological deposits is generally accepted, the dramatic effect of the carbonate ion in maintaining aluminum hydroxide gel in the amorphous form has been overlooked by most earth scientists. Examination of bauxite occurrences suggests that the inhibiting effect of carbonate is quite apparent in the smaller grain size of gibbsite in karstic bauxite deposits as compared to that in lateritic bauxite. Scarbröite, a crystalline aluminum hydroxy carbonate, has been observed in rare instances. It is suggested that the highly reactive carbonate-containing aluminum hydroxide gels used as pharmaceutical antacids are amorphous or poorly crystalline forms of scarbröite. The effect of the sulfate anion is also apparent in certain bauxite deposits where dissolution of gibbsite by sulfuric acid has resulted from the oxidation of pyrite, with subsequent reprecipitation of gibbsite.


Repeat Targeted Prostate Biopsy under Guidance of Multiparametric MRI-Correlated Real-Time Contrast-Enhanced Ultrasound for Patients with Previous Negative Biopsy and Elevated Prostate-Specific Antigen: A Prospective Study.
To prospectively determine whether multi-parametric MRI (mpMRI) - contrast-enhanced ultrasound (CEUS) correlated, imaging-guided target biopsy (TB) method could improve the detection of prostate cancer in re-biopsy setting of patients with prior negative biopsy. From 2012 to 2014, a total of 42 Korean men with a negative result from previous systematic biopsy (SB) and elevated prostate-specific antigen underwent 3T mpMRI and real-time CEUS guided TB. Target lesions were determined by fusion of mpMRI and CEUS. Subsequently, 12-core SB was performed by a different radiologist. We compared core-based cancer detection rates (CaDR) using the generalized linear mixed model (GLIMMIX) for each biopsy method. Core-based CaDR was higher in TB (17.92%, 38 of 212 cores) than in SB (6.15%, 31 of 504 cores) (p < 0.0001; GLIMMIX). In the cancer-positive TB cores, CaDR with suspicious lesions by mpMRI was higher than that by CEUS (86.8% vs. 60.5%, p= 0.02; paired t-test) and concordant rate between mpMRI and CEUS was significantly different with discordant rate (48% vs. 52%, p=0.04; McNemar's test). The mpMRI-CEUS correlated TB technique for the repeat prostate biopsy of patients with prior negative biopsy can improve CaDR based on the number of cores taken.


Protein engineering of toluene-o-xylene monooxygenase from Pseudomonas stutzeri OX1 for enhanced chlorinated ethene degradation and o-xylene oxidation.
Toluene-o-xylene monooxygenase (ToMO) from Pseudomonas stutzeri OX1 has been shown to degrade all chlorinated ethenes individually and as mixtures. Here, DNA shuffling of the alpha hydroxylase fragment of ToMO (TouA) and saturation mutagenesis of the TouA active site residues I100, Q141, T201, F205, and E214 were used to enhance the degradation of chlorinated aliphatics. The ToMO mutants were identified using a chloride ion screen and then were further examined by gas chromatography. Escherichia coli TG1/pBS(Kan)ToMO expressing TouA saturation mutagenesis variant I100Q was identified that has 2.8-fold better trichloroethylene (TCE) degradation activity (apparent Vmax of 1.77 nmol min-1 mg-1 protein-1 vs 0.63 nmol min-1 mg-1 protein-1). Another variant, E214G/D312N/M399V, has 2.5-fold better cis-1,2-dichloroethylene (cis-DCE) degradation activity (apparent Vmax of 8.4 nmol min-1 mg-1 protein-1 vs 3.3 nmol min-1 mg-1 protein-1). Additionally, the hydroxylation regiospecificity of o-xylene and naphthalene were altered significantly for ToMO variants A107T/E214A, T201G, and T201S. Variant T201S produced 2.0-fold more 2,3-dimethylphenol (2,3-DMP) from o-xylene than the wild-type ToMO, whereas variant A107T/E214A had 6.0-fold altered regiospecificity for 2,3-DMP formation. Variant A107T/E214A also produced 3.0-fold more 2-naphthol from naphthalene than the wild-type ToMO, whereas the regiospecificity of variant T201S was altered to synthesize 3.0-fold less 2-naphthol, so that it made almost exclusively 1-naphthol (96%). Variant T201G was more regiospecific than variants A107T/E214A and T201S and produced 100% 3,4-DMP from o-xylene and >99% 1-naphthol from naphthalene. Hence, ToMO activity was enhanced for the degradation of TCE and cis-DCE and for the regiospecific hydroxylation of o-xylene and naphthalene through DNA shuffling and saturation mutagenesis.


Dynamics of the hysteretic voltage-induced torsional strain in tantalum trisulfide.
We have studied how the hysteretic voltage-induced torsional strain, associated with charge-density-wave (CDW) depinning, in orthorhombic tantalum trisulfide depends on square-wave and triangle-wave voltages of different frequencies and amplitudes. The strains are measured by placing the sample, with a wire glued to the center as a transducer, in a radio frequency cavity and measuring the modulated response of the cavity. From the triangle waves, we map out the time dependence of the hysteresis loops, and find that the hysteresis loops broaden for waves with periods less than 30 s. The square-wave response shows that the dynamic responses to positive and negative voltages can be quite different. The overall frequency dependence is relaxational, but with multiple relaxation times which typically decrease with increasing voltage. The detailed dynamic response is very sample dependent, suggesting that it depends in detail on interactions of the CDW with sample defects.


Clinical physiology: a successful academic and clinical discipline is threatened in Sweden.
Clinical physiologists in Sweden are physicians (the majority with a PhD degree) with thorough training in system physiology and pathophysiology. They investigate patients in a functional approach and are engaged in basic and applied physiology teaching and research. In 1954, clinical physiology was founded as an independent academic and clinical discipline by the Swedish government to ensure "contact between routine clinical work and the scientific progression." Up until 2008, clinical physiology was an independent clinical discipline but was then made a subdiscipline to radiology, a fundamentally different discipline. Individuals wishing to become clinical physiologists are required to be trained and certified as European radiologists, after which training and certification as clinical physiologists may be pursued. This means that radiologists without training in clinical physiology have become gatekeepers for future clinical physiologists. Unfortunately, this development takes place at a time when research and education in preclinical integrative physiology have diminished in favor of other organizational levels, such as cellular and molecular biology. The responsibilities for education and research in integrative human physiology have therefore mainly been transferred to clinical physiologists. Clinical physiology has been a successful independent clinical discipline in Sweden for the past 55 years and could serve as a model for other countries. Unless clinical physiologists regain control over their own discipline, systems physiology as a knowledge base and resource for patient care, education, and research will be severely impaired.


Natural history of cognitive deficits and their relationship to MRI T2-hyperintensities in NF1.
Cognitive impairment is the most common complication of neurofibromatosis type 1 (NF1) in childhood. Current research suggests a strong relationship between cognitive deficits and brain T2-hyperintensities. The majority of these lesions disappear as the child ages. Cross-sectional data suggest that there also are improvements in intellect. To determine the natural history of cognitive functioning and MRI T2-hyperintensities from childhood into adulthood, and whether changes in MRI T2-hyperintensities over time are predictive of changes in cognitive functioning. The authors conducted a prospective longitudinal study of a cohort of 32 patients with NF1 and 11 unaffected sibling controls. All patients underwent neuropsychological assessments and 27 children underwent MRI examinations. The patients were then reassessed after an 8-year period. and There was no improvement in cognitive ability as the children with NF1 developed into adulthood compared with controls. Despite significant decreases in the number, size, and intensity of the T2-hyperintensities over the 8-year period, these changes were not associated with changes in cognitive ability. T2-hyperintensities in the cortex or subcortical or deep white matter are more frequent with age and these lesions are likely to have a different pathology than basal ganglia lesions. The best predictor of cognitive dysfunction in adulthood was the presence of T2-hyperintensities in childhood, rather than current lesion status. There is a limited time window (<18 years) in which the presence of T2-hyperintensities can be used as biologic markers of cognitive dysfunction.


Barriers and Facilitators Associated With App-Based Treatment for Female Urinary Incontinence: Mixed Methods Evaluation.
App-based treatment for urinary incontinence is a proven effective and cost-effective alternative to care as usual, but successful implementation requires that we identify and address the barriers and facilitators associated with app use. The goal of the research was to explore the factors influencing app-based treatment for urinary incontinence and identify which barriers or facilitators are associated with treatment success or failure. We used a sequential explanatory mixed methods design to connect the results of a randomized controlled trial with data from semistructured interviews. This previous RCT had shown the noninferiority of app-based treatment compared with care as usual for urinary incontinence over 4 months. Participants who reported success or failure with app-based treatment, as measured by the change in International Consultation on Incontinence Modular Questionnaire Urinary Incontinence Short Form symptom score, were selected for telephone interview by purposive sampling (n=17). This study reports mainly on the qualitative component of our mixed methods study. Qualitative analyses were conducted in two ways. First, we analyzed the qualitative data of all interviewed participants and discussed the relationships between the main themes. Second, the experiences between the success (n=9) and failure group (n=8) were compared and contrasted to explore factors that were positively or negatively associated with the quantitative effect of app-based treatment. These factors were then interpreted as barriers to and facilitators of successful app-based treatment. Four interrelated themes were identified as affecting the app based treatment effect: adherence, personal factors, app factors, and awareness. Qualitative analyses of the relationships between the themes showed that adherence-related factors directly influenced treatment effect in both a positive and negative matter. In turn, adherence was also positively and negatively influenced by the other 3 themes. Additionally, awareness was positively influenced by the treatment effect. Within these themes, several factors were identified that acted as barriers (eg, unrealistic expectation of time investment and interfering personal circumstances), facilitators (eg, strict integration of exercises and prior pelvic floor muscle therapy), or both (eg, personality traits and increased awareness of symptoms). This study shows that the effect of app-based treatment for urinary incontinence is mainly influenced by adherence, which in turn is affected by personal factors, app-based factors, and awareness. The identified factors could function as both facilitators and barriers depending on the user and interaction with other themes. Insight into these facilitators and barriers could lead to improved implementation and increased treatment effectiveness by targeting women most likely to benefit and through further development of the app. RR2-10.1002/nau.23507.


Depression in opioid users varies with substance use status.
The relation of substance use status to depressed mood during careers of 173 opioid users was estimated using the Zung Self-Rating Depression Scale. The data suggested a progression in severity of depression from those abstinent or using occasionally, who were least depressed, through intermediate substance use states, to those dependent on illicit opioids, who were most depressed. One hundred five subjects completed the Scale in two interviews separated by a mean of 4.5 years. Change in substance use status from not dependent at first interview to dependent at second interview was associated with increased depression.


The prevalence of antibodies against B. burgdorferi, an indicator for Lyme borreliosis in dogs? A comparison of serological tests.
Five serological tests for the detection of IgM and IgG antibodies to Borrelia burgdorferi, the causative microorganism of Lyme borreliosis (LB), were compared in 1177 sera from Dutch dogs: 401 healthy working hunting dogs, 100 healthy city pet dogs, 629 city dogs suspected of having LB with various clinical symptoms, and 47 hunting dogs with intermittent lameness. The results of the in-house species-independent enzyme immunoassay (i.e. an EIA which can be used to test serum samples from different animal species) showed a strong agreement (kappa: 0.78-0.81) with those of an experimental and a commercially available EIA (Genzyme Virotech, Rüsselsheim, Germany) for the detection of canine IgG antibodies to B. burgdorferi. Furthermore, the sensitivity of the in-house EIAs for the detection of antibodies to B. burgdorferi was independent of the antigenic heterogeneity, as demonstrated by the results of sera from dogs suspected of LB with various clinical symptoms: lameness (n = 60), and neurological (n = 60) and skin disorders (n = 52). Because of its high sensitivity for IgM antibodies, the indirect assay (Diagast, Pessac, France) proved to be an interesting tool for the detection of an acute Lyme infection in dogs. However, in this study a positive serological result could not be linked to any clinical symptom that has been related to LB in dogs. Results showed no difference in seroprevalence between dogs considered at high or at low risk of a B. burgdorferi infection. It was concluded that LB is an uncommon disease in the Dutch dog population despite the fact that many of Dutch dogs are infected with B. burgdorferi. Because of this low prevalence, the use of any immunoassay to support the clinical diagnosis of LB in dogs might be of limited value. Nevertheless, the species-independent EIA could be valuable in seroepidemiological studies when sera of several different animal species need to be tested.


Cytotoxicity and cell-proliferation induced by the nephrocarcinogen hydroquinone and its nephrotoxic metabolite 2,3,5-(tris-glutathion-S-yl)hydroquinone.
Hydroquinone, an intermediate used in the chemical industry and a metabolite of benzene, is a nephrocarcinogen in the 2-year National Toxicology Program bioassay in male Fischer 344 rats. Current evidence suggests that certain chemicals may induce carcinogenesis by a mechanism involving cytotoxicity, followed by sustained regenerative hyperplasia and ultimately tumor formation. Glutathione (GSH) conjugates of a variety of hydroquinones are potent nephrotoxicants, and we now report on the effect of hydroquinone and 2,3,5-(tris-glutathion-S-yl)hydroquinone, on site-selective cytotoxicity and cell proliferation in rat kidney. Male Fischer 344 rats (160-200 g) were treated with hydroquinone (1.8 mmol/kg or 4.5 mmol/kg, p.o.) or 2,3,5-(tris-glutathion-S-yl)hydroquinone (7.5 micromol/kg; 1.2-1.5 micromol/rat, i.v.), and blood urea nitrogen (BUN), urinary gamma-glutamyl transpeptidase (gamma-GT), alkaline phosphatase (ALP), glutathione-S-transferase (GST) and glucose were measured as indices of nephrotoxicity. Hydroquinone (1.8 mmol/kg, p.o.) is nephrotoxic in some rats, but not others, but cell proliferation (BrDU incorporation) in proximal tubular cells of the S3M region correlates with the degree of toxicity in individual rats. At 4.5 mmol/kg, hydroquinone causes significant increases in the urinary excretion of gamma-GT, ALP and GST. Pretreatment of rats with acivicin prevents hydroquinone-mediated nephrotoxicity, indicating that toxicity is dependent on the formation of metabolites that require processing by gamma-GT. Consistent with this view, 2,3,5-(tris-glutathion-S-yl)hydroquinone, a metabolite of hydroquinone, causes increases in BUN, urinary gamma-GT and ALP, all of which are maximal 12 h after administration of 2,3,5-(tris-glutathion-S-yl)hydroquinone. In contrast, the maximal excretion of GST and glucose occurs after 24 h. By 72 h, BUN and glucose concentrations return to control levels, while gamma-GT, ALP and GST remain slightly elevated. Examination of kidney slices by light microscopy revealed the presence of tubular necrosis in the S3M segment of the proximal tubule, extending into the medullary rays. Cell proliferation rates in this region were 2.4, 6.9, 15.3 and 14.3% after 12, 24, 48 and 72 h, respectively, compared to 0.8-2.4% in vehicle controls. Together with the metabolic data, the results indicate a role for hydroquinone-thioether metabolites in hydroquinone toxicity and carcinogenicity.


Effect of rosuvastatin compared with other statins on lipid levels and National Cholesterol Education Program goal attainment for low-density lipoprotein cholesterol in a usual care setting.
To compare, in a usual care setting, the effects of rosuvastatin and other 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) on lipid levels and on goal attainment of low-density lipoprotein cholesterol (LDL) levels from the National Cholesterol Education Program (NCEP) third report of the Adult Treatment Panel (ATP III). Retrospective, longitudinal, cohort study. Managed care medical and pharmacy claims and laboratory database. A total of 8251 patients starting treatment with rosuvastatin, atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin from August 1, 2003-September 30, 2004, excluding those who received dyslipidemic therapy in the previous 12 months. Patients with at least one pretreatment and posttreatment lipid level were followed until their initial statin was changed or they reached the end of benefit eligibility or the study period. Percent changes in lipid levels were calculated, and adjusted changes in LDL and goal attainment were evaluated by regression techniques. Absolute and percent reductions in LDL, triglyceride, and total cholesterol levels were significantly greater with rosuvastatin than with other statins (all p<0.05 except for triglyceride reduction vs atorvastatin). After adjustment for age, sex, and baseline LDL, percent LDL reductions still were significantly greater with rosuvastatin than with other statins (p<0.05). Changes in high-density lipoprotein cholesterol were not significant. Goal attainment was higher with rosuvastatin than with other statins after adjustment for age, sex, baseline LDL, risk status, dose, and duration of therapy (p<0.05). Dose-stratified analysis showed that LDL goal attainment was significantly higher with rosuvastatin 10 mg than with atorvastatin 10 or 20 mg. Rosuvastatin was more effective than other statins in reducing LDL, triglyceride (except vs atorvastatin), and total cholesterol levels. Significantly more patients taking rosuvastatin than patients taking other statins attained their LDL goals.


Starclose SE® hemostasis after 6F direct antegrade superficial femoral artery access distal to the femoral head for peripheral endovascular procedures in obese patients.
Direct superficial femoral artery (SFA) antegrade puncture is a valid alternative to common femoral artery (CFA) access for peripheral vascular interventions. Data investigating vascular closure device (VCD) hemostasis of distant SFA 6F access are limited. We aimed to investigate the safety and effectiveness of the Starclose SE® VCD for hemostasis, following direct 6F antegrade SFA access distal to the femoral head. This prospective, single-center study included patients who were not suitable for CFA puncture and were scheduled to undergo peripheral endovascular interventions using direct antegrade SFA 6F access, at least 2 cm below the inferior edge of femoral head. Hemostasis was obtained with the Starclose SE® VCD (Abbott Laboratories). Primary endpoints were successful hemostasis rate and periprocedural (30-day) major complication rate. Secondary endpoint was the rate of minor complications. Clinical and Doppler ultrasound follow-up was performed at discharge and at one month. Between September 2014 and August 2015, a total of 30 patients (21 male; 70.0%) with a mean body mass index of 41.2 kg/m2 were enrolled. Mean age was 72±9 years (range, 67-88 years). Most patients suffered from critical limb ischemia (87.1%) and diabetes (61.3%). Calcifications were present in eight cases (26.6%). Reason for direct SFA puncture was obesity (100%). Successful hemostasis was achieved in 100% of the cases. No major complications were noted after one-month follow-up. Minor complications included two <5 cm hematomas (6.6%) not necessitating treatment. In this prospective study, Starclose SE® VCD was safe and effective for hemostasis of antegrade direct SFA puncture. Uncomplicated hemostasis was achieved even in cases of puncturing 2 to 7 cm below the inferior edge of the femoral head.


Longitudinal monitoring of sex steroid hormones in excrement of spectacled eiders (Somateria fischeri).
From the 1970s to the 1990s, the breeding population of spectacled eiders (Somateria fischeri) in western Alaska declined by 96%, which led to the listing of this species as threatened under the Endangered Species Act in 1993. Since then, the population has stabilized, but has not recovered to pre-decline numbers. While little is known about reproductive endocrinology in spectacled eiders, in other avian species, estrogen and testosterone are known to initiate and modulate various reproductive processes including yolk protein synthesis, reproductive behaviors and secondary sex characteristics. Measurement of the metabolites of estrogen and testosterone (EM and TM, respectively) in excrement reflect circulating hormone concentrations and provide a non-invasive method to monitor reproductive physiology. We measured concentrations of excreted EM in captive females and TM in males to (1) determine the efficacy of commercially available radioimmunoassay kits to detect EM and TM, (2) describe annual profiles of EM and TM concentrations, and (3) define the reproductive season of captive spectacled eiders using endocrine status. Excrement samples were collected from captive female and male spectacled eiders three times per week throughout 1 year. Female EM and male TM levels were quantified using radioimmunoassay. Mean female EM profile exhibited values exceeding the threshold for "peak" values (EM>193.3 ng/g) from mid-February to early July, and again in September. Additionally, the highest average concentrations of EM were seen in March, May and September. Elevated TM concentrations occurred in mid March, mid May and late June. These data suggest that levels of excreted sex steroids reflect patterns predicted by breeding landmarks in the annual cycle and will assist in field monitoring and captive breeding programs for spectacled eiders.


A straightforward method of analysis for direct quantum dynamics: application to the photochemistry of a model cyanine.
We present a new way of analyzing direct quantum dynamics simulations based on a Mulliken-type population analysis. This provides a straightforward interpretation of the wavepacket in much the same way as semiclassical trajectories are usually analyzed. The result can be seen as a coupled set of quantum trajectories. We apply this to the study of the photochemistry of a 12-atom model cyanine to explore possibilities for intelligent optimal control. The work presented here builds on previous semiclassical dynamics simulations [ Hunt , P. A. ; Robb , M. A. J. Am. Chem. Soc. 2005 , 127 , 5720 ]. Those calculations suggested that, by controlling the distribution of momentum components in the initial wavepacket, it should be possible to drive the system to a specific region of the conical intersection seam and ultimately control the product distribution. This was confirmed experimentally by optimal control methods [ Dietzek , B. ; Bruggemann , B. ; Pascher , T. ; Yartsev , A. J. Am. Chem. Soc. 2007 , 129 , 13014 ]. This paper aims to demonstrate this in a quantum dynamics context and give further insight into the conditions required for control. Our results show that directly addressing the trans-cis torsional modes is not efficient. Instead, one needs to decrease the momentum in the skeletal deformation coordinates to prompt radiationless decay near the minimum conical intersection at large twist angles.


Expert stakeholders' perspectives on a Data-to-Care strategy for improving care among HIV-positive individuals incarcerated in jails.
Data-to-Care (D2C) uses surveillance data (e.g., laboratory, Medicaid billing) to identify out-of-care HIV-positive persons to re-link them to care. Most US states are implementing D2C, yet few studies have explored stakeholders' perspectives on D2C, and none have addressed these perspectives in the context of D2C in jail. This article reports findings from qualitative, semi-structured interviews conducted with expert stakeholders regarding their perspectives on the ethical challenges of utilizing D2C to understand and improve continuity of care among individuals incarcerated in jails. Participants included 47 professionals with expertise in ethics and privacy, public health and HIV care, the criminal justice system, and community advocacy. While participants expressed a great deal of support for extending D2C to jails, they also identified many possible risks. Stakeholders discussed many issues specific to D2C in jails, such as heightened stigma in the jail setting, the need for training of jail staff and additional non-medical community-based resources, and the high priority of this vulnerable population. Many experts suggested that the actual likelihood of benefits and harms would depend on contextual details. Implementation of D2C in jails may require novel strategies to minimize risk of disclosing out-of-care patients' HIV status.


Evaluation of Toluene Adsorption Performance of Mortar Adhesives Using Porous Carbon Material as Adsorbent.
Porous carbon materials are advantageous in adsorbing pollutants due to their wide range of specific surface areas, pore diameter, and pore volume. Among the porous carbon materials in the current study, expanded graphite, xGnP, xGnP C-300, xGnP C-500, and xGnP C-750 were prepared as adsorbent materials. Brunauer-Emmett-Teller (BET) analysis was conducted to select the adsorbent material through the analysis of the specific surface area, pore size, and pore volume of the prepared porous carbon materials. Morphological analysis using SEM was also performed. The xGnP C-500 as adsorbent material was applied to a mortar adhesive that is widely used in the installation of interior building materials. The toluene adsorption performances of the specimens were evaluated using 20 L small chamber. Furthermore, the performance of the mortar adhesive, as indicated by the shear bond strength, length change rate, and water retention rate, was analyzed according to the required test method specified in the Korean standards. It was confirmed that for the mortar adhesives prepared using the xGnP C-500 as adsorbent material, the toluene adsorption performance was excellent and satisfied the required physical properties.


Metabolomic study of eyeball rupture and patients with cataracts in aqueous humor.
The purpose of the present study was to identify metabolic biomarkers and study the metabolic changes in relation to cataracts and eyeball rupture in human aqueous humor. This case-control study included 3 patients with traumatic ocular rupture treated by surgery as the control group, 10 patients with severe cataracts as the severe cataracts group and 10 patients with mild cataracts as the mild cataracts group. The present study used liquid chromatography-mass spectrometry to analyze the metabolomics of aqueous humor samples. Databases including the Kyoto Encyclopedia of Genes and Genomes and MetaboAnalyst were used to find potential pathways for metabolites. Aqueous humor metabolic spectrum can competently distinguish patients with different degrees of cataracts from the control group. A total of 34 metabolites were identified as potential biomarkers that could distinguish patients with different degrees of cataracts; 36 metabolites were identified as potential biomarkers that could distinguish patients with severe cataracts from the control group; 34 metabolites were identified as potential biomarkers that could distinguish patients with mild cataracts from controls. In pathway analysis, glycerolphospholipid metabolism was highly affected, which meant that these metabolic markers serve an important role in the regulation of this pathway. The present study identified valuable metabolic biomarkers and pathways, which is helpful for an improved understanding of the pathogenesis of cataracts. This discovery has transformation value for the development of new treatment methods for cataracts.


Energetics of thrombin-thrombomodulin interaction.
Temperature and salt dependence studies of thrombin interaction with thrombomodulin, with and without chondroitin sulfate, and two fragments containing the EGF-like domains 4-5 and 4-5-6 reveal the energetic signatures and the mechanism of recognition of this physiologically important cofactor. Binding of thrombomodulin is affected drastically by the particular salt present in solution and is positively linked to Na+ binding to thrombin and the conversion of the enzyme from the slow to the fast form, but is opposed by Cl- binding to the fibrinogen recognition site and especially to the heparin binding site. Binding of thrombomodulin has an unusually large salt dependence (gamma(salt) = -4.8) contributed mostly by the polyelectrolyte-like nature of the chondroitin sulfate moiety that binds to the heparin binding site and increases the affinity of the cofactor by almost 10-fold. On the other hand, the chondroitin sulfate has no effect on the deltaCp of binding, which is determined predominantly by contacts made by the EGF-like domains 5 and 6 with the fibrinogen recognition site. The modest heat capacity change (-0.2 kcal mol(-1) K(-1)) observed when thrombomodulin binds to the fast form suggests a rigid-body association of the cofactor with the enzyme. In the slow form, however, the heat capacity change is significantly more pronounced (-0.5 kcal mol(-1) K(-1)) and signals the presence of a conformational transition of the enzyme linked to binding of the cofactor that mimics the slow-->fast conversion. These results demonstrate that recognition of thrombomodulin by thrombin is steered electrostatically by the highly charged regions of the fibrinogen recognition site and the heparin binding site, to which the chondroitin sulfate moiety binds and enhances the affinity of the interaction. The recognition event also involves conformational changes of the enzyme in the slow form mediated by binding of the EGF-like domains 5-6 to the fibrinogen recognition site. Consistent with this model, binding of thrombomodulin to the fast form has only a small effect on the hydrolysis of nine chromogenic substrates carrying substitutions at P1, P2, and P3 aimed at probing the environment of the specificity sites S1, S2, and S3 of the enzyme. Binding to the slow form, on the other hand, enhances the specificity toward all substrates up to 15-fold. For substrates carrying a Gly at P2, binding of thrombomodulin changes the relative specificity of the slow and fast forms and makes the slow form more specific. Interestingly, these effects are not specific of thrombomodulin and depend solely on binding to the fibrinogen recognition site of the enzyme. In fact, they are also observed with the hirudin C-terminal fragment 55-65. The characterization of the mechanism of thrombin-thrombomodulin interaction and the effects of the cofactor on the hydrolysis of chromogenic substrates probing the interior of the catalytic pocket bear on the thrombomodulin-induced enhancement of protein C cleavage by thrombin. We propose that this enhancement is due predominantly to an effect of thrombomodulin on the bound protein C in the ternary complex. Therefore, thrombomodulin would carry out its physiological function by making protein C a better substrate for thrombin, rather than making thrombin a better enzyme for protein C.


Tumor necrosis factor induces apoptosis in hepatoma cells by increasing Ca(2+) release from the endoplasmic reticulum and suppressing Bcl-2 expression.
Tumor necrosis factor (TNF) plays an import role in the control of apoptosis. The most well known apoptotic pathway regulated by TNF involves the TNFR1-associated death domain protein, Fas-associated death domain protein, and caspase-8. This study examines the mechanism of TNF-induced apoptosis in FaO rat hepatoma cells. TNF treatment significantly increased the percentage of apoptotic cells. TNF did not activate caspase-8 but activated caspase-3, -10, and -12. The effect of TNF on the expression of different members of the Bcl-2 family in these cells was studied. We observed no detectable changes in the steady-state levels of Bcl-X(L), Bax, and Bid, although TNF suppresses Bcl-2 expression. Dantrolene suppressed the inhibitory effect of TNF on Bcl-2 expression. TNF induced release of Ca(2+) from the endoplasmic reticulum (ER) that was blocked by dantrolene. Importantly, the expression of Bcl-2 blocked TNF-induced apoptosis and decreased TNF-induced Ca(2+) release. These results suggest that TNF induces apoptosis by a mechanism that involves increasing Ca(2+) release from the ER and suppression of Bcl-2 expression.


Intestinovesical fistula in a patient with chronic lymphocytic leukemia: case report and literature review.
A case of intestinovesical fistula secondary to leukemic infiltration is described. The patient was known to have chronic lymphocytic leukemia and had been receiving chemotherapy fo ten months. She presented complaining of nausea, vomiting and vague abdominal pain. She initially denied genitourinary tract symptoms, although admitting urinalysis revealed pyuria, hematuria and bacteriuria. Urine cultures repeatedly grew E. coli despite broad spectrum antibiotic therapy. She eventually developed fecalant material in her urine and pneumaturia. Cystoscopy revealed a fistulous tract. At surgery an ileovesical fistula was found and histopathology showed lymphocytic leukemic infiltration. Intestinovesical fistulas are uncommon. Congenital, traumatic, inflammatory and solid neoplastic etiologies are well established in the literature. No previous cases have been attributed to hematologic malignancies. Since higher remission rates and longer periods of remission are being achieved with chemotherapy, and since fistula symptomatology may present quite subtly, awareness of this association may expedite diagnosis.


The art of being healthy: a qualitative study to develop a thematic framework for understanding the relationship between health and the arts.
In recent years the health-arts nexus has received increasing attention; however, the relationship is not well understood and the extent of possible positive, negative and unintended outcomes is unknown. Guided by the biopsychosocial model of health and theories of social epidemiology, the aim of this study was to develop a framework pertaining to the relationship between arts engagement and population health that included outcomes, confounders and effect modifiers. A health-arts framework is of value to researchers seeking to build the evidence base; health professionals interested in understanding the health-arts relationship, especially those who use social prescribing for health promotion or to complement treatments; in teaching medical, nursing and health-science students about arts outcomes, as well as artists and health professionals in the development of policy and programmes. A qualitative study was conducted. Semistructured interviews were analysed thematically. Western Australia. 33 Western Australian adults (18+ years). Participants were randomly selected from a pool of general population nominees who engaged in the arts for enjoyment, entertainment or as a hobby (response rate=100%). A thematic analysis was conducted using QSR-NVivo10. The resulting framework contained seven outcome themes and 63 subthemes. Three themes specifically related to health, that is, mental, social and physical health, while economic, knowledge, art and identity outcomes were classified as health determinants. Within each theme, positive, negative and unintended outcomes (subthemes) were identified and categorised as relating to the individual and/or to the community. A list of confounding and/or effect modifying factors, related to both the arts and health, was identified. Given the increasing pressure on health resources, the arts have the potential to assist in the promotion of health and healing. This framework expands on current knowledge, further defines the health-arts relationship and is a step towards the conceptualisation of a causal health-arts model.


Chronic myeloproliferative disorders.
The Philadelphia chromosome-negative chronic myeloproliferative disorders (CMPD), polycythemia vera (PV), essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (IMF), have overlapping clinical features but exhibit different natural histories and different therapeutic requirements. Phenotypic mimicry amongst these disorders and between them and nonclonal hematopoietic disorders, lack of clonal diagnostic markers, lack of understanding of their molecular basis and paucity of controlled, prospective therapeutic trials have made the diagnosis and management of PV, ET and IMF difficult. In Section I, Dr. Jerry Spivak introduces current clinical controversies involving the CMPD, in particular the diagnostic challenges. Two new molecular assays may prove useful in the diagnosis and classification of CMPD. In 2000, the overexpression in PV granulocytes of the mRNA for the neutrophil antigen NBI/CD177, a member of the uPAR/Ly6/CD59 family of plasma membrane proteins, was documented. Overexpression of PRV-1 mRNA appeared to be specific for PV since it was not observed in secondary erythrocytosis. At this time, it appears that overexpression of granulocyte PRV-1 in the presence of an elevated red cell mass supports a diagnosis of PV; absence of PRV-1 expression, however, should not be grounds for excluding PV as a diagnostic possibility. Impaired expression of Mpl, the receptor for thrombopoietin, in platelets and megakaryocytes has been first described in PV, but it has also been observed in some patients with ET and IMF. The biologic basis appears to be either alternative splicing of Mpl mRNA or a single nucleotide polymorphism, both of which involve Mpl exon 2 and both of which lead to impaired posttranslational glycosylation and a dominant negative effect on normal Mpl expression. To date, no Mpl DNA structural abnormality or mutation has been identified in PV, ET or IMF. In Section II, Dr. Tiziano Barbui reviews the best clinical evidence for treatment strategy design in PV and ET. Current recommendations for cytoreductive therapy in PV are still largely similar to those at the end of the PVSG era. Phlebotomy to reduce the red cell mass and keep it at a safe level (hematocrit < 45%) remains the cornerstone of treatment. Venesection is an effective and safe therapy and previous concerns about potential side effects, including severe iron deficiency and an increased tendency to thrombosis or myelofibrosis, were erroneous. Many patients require no other therapy for many years. For others, however, poor compliance to phlebotomy or progressive myeloproliferation, as indicated by increasing splenomegaly or very high leukocyte or platelet counts, may call for the introduction of cytoreductive drugs. In ET, the therapeutic trade-off between reducing thrombotic events and increasing the risk of leukemia with the use of cytoreductive drugs should be approached by patient risk stratification. Thrombotic deaths seem very rare in low-risk ET subjects and there are no data indicating that fatalities can be prevented by starting cytoreductive drugs early. Therefore, withholding chemotherapy might be justifiable in young, asymptomatic ET patients with a platelet count below 1500000/mm(3) and with no additional risk factors for thrombosis. If cardiovascular risk factors together with ET are identified (smoking, obesity, hypertension, hyperlipidemia) it is wise to consider platelet-lowering agents on an individual basis. In Section III, Dr. Gianni Tognoni discusses the role of aspirin therapy in PV based on the recently completed European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) Study, a multi-country, multicenter project aimed at describing the natural history of PV as well as the efficacy of low-dose aspirin. Aspirin treatment lowered the risk of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke (relative risk 0.41 [95% CI 0.15-1.15], P =.0912). Total and cardiovascular mortality were also reduced by 46% and 59%, respectively. Major bleedings were slightly increased nonsignificnsignificantly by aspirin (relative risk 1.62, 95% CI 0.27-9.71). In Section IV, Dr. Giovanni Barosi reviews our current understanding of the pathophysiology of IMF and, in particular, the contributions of anomalous megakaryocyte proliferation, neoangiogenesis and abnormal CD34(+) stem cell trafficking to disease pathogenesis. The role of newer therapies, such as low-conditioning stem cell transplantation and thalidomide, is discussed in the context of a general treatment strategy for IMF. The results of a Phase II trial of low-dose thalidomide as a single agent in 63 patients with myelofibrosis with meloid metaplasia (MMM) using a dose-escalation design and an overall low dose of the drug (The European Collaboration on MMM) will be presented. Considering only patients who completed 4 weeks of treatment, 31% had a response: this was mostly due to a beneficial effect of thalidomide on patients with transfusion dependent anemia, 39% of whom abolished transfusions, patients with moderate to severe thrombocytopenia, 28% of whom increased their platelet count by more than 50 x 10(9)/L, and patients with the largest splenomegalies, 42% of whom reduced spleen size of more than 2 cm.


Cervical neoplasia and human papilloma virus infection in prostitutes.
To evaluate the prevalence and incidence of PAP smears indicating cervical dysplasia as well as human papillomavirus (HPV) infection in prostitutes. Prevalence and incidence study of cervical dysplasia and HPV infection in prostitutes. For detection and typing of HPV-DNA In Situ Hybridisation (ISH) was performed in tissue samples with CIN gained by colposcopically directed punch biopsies. Second Department of Obstetrics and Gynecology, University of Vienna Medical School and STD Clinic of the Public Health Office, Vienna. Registered prostitutes attending the STD Clinic of the Public Health Office and a control group. 978 prostitutes and 5493 women with unknown cytological anamnesis were compared. Frequency of positive PAP smears was significantly higher in prostitutes (6.13% versus 1.43%). To determine the pick-up rate of cervical dysplasia during one year after negative cytology we compared 722 prostitutes and 3162 controls. Prostitutes showed a significant higher dysplasia pick-up rate (3.05% to 1.07%) compared with controls. HPV detection rate in prostitutes was similar to that in the control group. The distribution of HPV types revealed a higher frequency of "high risk" HPV 16/18 and 31/33 in prostitutes. The results demonstrate a higher incidence and prevalence of cervical dysplasia in prostitutes and therefore suggest regular cervical PAP smear screening in registered prostitutes twice a year.


F-actin reorganization by V-ATPase inhibition in prostate cancer.
The vacuolar ATPase (V-ATPase) proton pump sustains cellular pH homeostasis, and its inhibition triggers numerous stress responses. However, the cellular mechanisms involved remain largely elusive in cancer cells. We studied V-ATPase in the prostate cancer (PCa) cell line PC-3, which has characteristics of highly metastatic PCa. V-ATPase inhibitors impaired endo-lysosomal pH, vesicle trafficking, migration, and invasion. V-ATPase accrual in the Golgi and recycling endosomes suggests that traffic of internalized membrane vesicles back to the plasma membrane was particularly impaired. Directed movement provoked co-localization of V-ATPase containing vesicles with F-actin near the leading edge of migrating cells. V-ATPase inhibition prompted prominent F-actin cytoskeleton reorganization. Filopodial projections were reduced, which related to reduced migration velocity. F-actin formed novel cytoplasmic rings. F-actin rings increased with extended exposure to sublethal concentrations of V-ATPase inhibitors, from 24 to 48 h, as the amount of alkalinized endo-lysosomal vesicles increased. Studies with chloroquine indicated that F-actin rings formation was pH-dependent. We hypothesize that these novel F-actin rings assemble to overcome widespread traffic defects caused by V-ATPase inhibition, similar to F-actin rings on the surface of exocytic organelles.


The inhibition of inwardly rectifying K+ channels by memantine in macrophages and microglial cells.
Memantine (MEM) can block N-methyl-D-aspartate receptors non-competitively and is recognized to exert anti-inflammatory action. Whether MEM and other related compounds produce any effects on K(+) currents in macrophages and in microglial cells is largely unknown. In this study, we investigated the effects of MEM and other related compounds on inwardly rectifying K(+) current (IK(IR)) in RAW 264.7 macrophages and in BV2 microglial cells. Patch-clamp recordings under whole-cell, cell-attached or inside-out configuration were performed in standard patch-clamp technique. MEM suppressed the IK(IR) amplitude in a concentration-dependent manner with an IC50 value of 12 µM. This agent significantly slowed the inactivation time rate of IK(IR) evoked with membrane hyperpolarization. In cells dialyzed spermine (10 µM), MEM-mediated inhibition of IK(IR) no longer existed. MEM-suppressed activity is associated with a decrease in the slow component of mean open time and an increase in mean closed time, despite no detectable change in single-channel conductance of inwardly rectifying K(+) (Kir) channels. Under current-clamp conditions, the addition of MEM resulted in membrane depolarization of RAW 264.7 cells. Similarly, in BV2 microglial cells, addition of MEM suppressed IK(IR) as well as depolarized the membrane. However, neither C6 astrocytic cells nor Jurkat T-lymphoces were noted to display IK(IR). The block by MEM of Kir2.1 channels is thus one of the important mechanisms underlying its actions on the functional activities of either macrophages or microglial cells, if similar findings occur in vivo.


Cognitive Impairment in Individuals With Spinal Cord Injury: Findings of a Systematic Review With Robust Variance and Network Meta-analyses.
Estimates of the prevalence (10-60%) of cognitive impairment in individuals with spinal cord injury (SCI) are too broad and which domains of cognition are most affected is unclear. We performed a meta-analysis to investigate impairments across domains of cognitive functioning to provide a nuanced picture of research conducted to date into cognitive impairment following SCI. Results of peer reviewed studies published in English between 1980 and 2021 comparing ≥20 participants with SCI to able-bodied controls were synthesized using meta-analysis. The primary outcomes were neurocognitive test scores categorized into five cognitive domains as listed in the Diagnostic and Statistical Manual of Mental Disorders: Complex Attention, Executive Functioning, Learning and Memory, Language, and Perceptual Motor Function. Two researchers independently assessed and verified extracted data to comply with meta-analytic reporting guidelines. Robust variance estimation (RVE) meta-analysis was conducted to determine an overall pooled effect size across all cognitive domains using data extracted from studies. Using network meta-analysis, we synthesised eligible studies and made comparisons with the five domains of cognitive functioning serving as the outcomes and SCI as the condition. Of 4,783 potential studies, 13 met final inclusion criteria. Studies met 6 of 8 quality assessment criteria generally. Results suggested that adults with SCI have reduced cognitive functioning (effect size:-0.84; 95%CI: -1.24, -0.44, p < .001) compared to able-bodied individuals, with deficits mostly in attention (g= -0.64; 95%CI: -0.92, -0.38) and executive functioning (g= -0.61, 95%CI: -0.89, -0.04). Publication bias and high heterogeneity (I2:86%) qualify these findings and highlight the need to improve research methods in this area. Adults with SCI appear more likely than adults who are able-bodied to display cognitive impairments mostly in areas of attention and executive functioning. Research practices must become consistent to reduce heterogeneity so that the validity and reliability of the results of future studies into cognitive impairment following SCI improves.


Accuracy and usefulness of a clinical prediction rule and D-dimer testing in excluding deep vein thrombosis in cancer patients.
Deep vein thrombosis (DVT) can be safely and reliably excluded in patients with a low clinical probability and a negative D-dimer result but the accuracy and utility of such a strategy is less certain in cancer patients. We sought to compare the performance of the Wells pretest probability (PTP) model and D-dimer testing between patients with and without cancer and to examine the utility of the two PTP model classification schemes (low/moderate/high versus unlikely/likely) in excluding DVT in patients with cancer. Pooled analysis of databases from three prospective diagnostic studies evaluating consecutive outpatients with suspected DVT. A total of 2696 patients were evaluated. DVT was diagnosed in 403 (15%) patients overall and in 83 of 200 (41.5%) cancer patients. The PTP distribution and the prevalence of DVT in each PTP category were significantly different between patients with and without cancer, regardless of the classification used (p<0.01). In patients with cancer, the negative predictive values of a low or unlikely PTP score in combination with a negative D-dimer result were 100% (95% CI 69.8%-100%) and 100% (95% CI 82.8%-96.6%), respectively. However, the specificities ranged from 46.2% (95%CI 27.1%-66.3%) to 57.1% (95%CI 41.1%-71.9%). Further testing was required in 94% of cancer patients using the low/moderate/high PTP classification and in 88% using the unlikely/likely stratification. As in patients without cancer, the combination of a low or unlikely PTP with a negative D-dimer result can exclude DVT in patients with cancer. However, this strategy has limited utility because very few cancer patients present with this combination.


Keratinocyte cytokines.
It is now clear that keratinocytes produce a wide range of cytokines that can be regarded as important mediators of intercellular communication. A major emphasis has been placed on IL-1 because of its relationships with other cytokines and other differentiated tissues. Dysregulation of IL-1, IL-1 receptor, and inhibitory factors for IL-1 may cause imbalance of skin biology, leading to perpetuation of immune and inflammatory events. Interaction of IL-1 with other cytokines in vivo is also important in the understanding of the pathophysiology of skin diseases. More fundamental questions regarding the homeostatic significance of IL-1 in keratinocytes still remain to be answered.


The antibody response to HPV proteins and the genomic state of HPVs in patients with cervical cancer.
Human papillomavirus (HPV) DNAs are often found to be integrated into the human genome in high-grade cervical intraepithelial neoplasia (CIN) as well as in invasive cervical cancers. Investigation of the relationship between the genomic status of specific HPV genes and their antibody responses to the virus-like particles (VLPs) of HPV-16 L1/L2 proteins and the in vitro translated HPV-16 E6 and E7 proteins may help to illustrate the mechanism of HPV-related cervical carcinogenesis and host immune response. Cervical cancer tissues obtained from 39 patients were studied to evaluate the physical status of HPV genes by Southern blotting, DNA-PCR, and RT-PCR of E2. The antibody response against the HPV-16 L1/L2 VLPs of serum specimens were tested by ELISA and the antibody response against the HPV-16 E6 and E7 proteins were tested by radioimmunoprecipitation assay (RIPA), respectively. Integrated forms of HPV-16 DNA were found in 23 of the 38 patients (60.5%). The HPV-16 positive cervical cancer patients showed a significantly higher prevalence rate (39.5%; 15/38) of antibodies to HPV-16 L1/L2 VLPs than that of the control group (8.7%; 2/28) (P < 0.05). Antibodies to HPV-16 L1/L2 VLPs were more commonly detectable in cervical cancer patients having the episomal form of HPV-16 DNA (pure episomal and mixed forms) (60%; 9/15) than in those who had only the integrated forms of HPV-16 DNA (26.1%; 6/23) (P < 0.05). Antibodies to E6 and E7 proteins were positive in 36.8% (14/38) and 50% (19/38) of the patients with HPV-16 positive cervical cancer, respectively. These were significantly higher than the positive rates for the control group (8.3% and 2.8%) (P < 0.05). The differences between sero-reactivities to E6 and E7 proteins in the patients with episomal forms of HPV-16 DNA and those with integrated forms of HPV-16 DNA were not statistically significant (P > 0.05). Integrated forms of HPV-16 DNA were prevalent in most patients with cervical cancer in Korea. Antibodies to HPV-16 L1/L2 VLPs, in vitro translated HPV-16 E6 and E7 proteins, appeared in a significantly larger proportion of the HPV-associated cervical cancer patients than in the controls. Antibodies to HPV-16 L1/L2 VLPs were more often detected in cervical cancer patients having the episomal form of HPV-16 DNA than in those having only integrated forms of HPV-16 DNA. Antibody responses to HPV-16 E6 and E7 proteins were not influenced by the different viral states.


An injury-responsive mmp14b enhancer is required for heart regeneration.
Mammals have limited capacity for heart regeneration, whereas zebrafish have extraordinary regeneration abilities. During zebrafish heart regeneration, endothelial cells promote cardiomyocyte cell cycle reentry and myocardial repair, but the mechanisms responsible for promoting an injury microenvironment conducive to regeneration remain incompletely defined. Here, we identify the matrix metalloproteinase Mmp14b as an essential regulator of heart regeneration. We identify a TEAD-dependent mmp14b endothelial enhancer induced by heart injury in zebrafish and mice, and we show that the enhancer is required for regeneration, supporting a role for Hippo signaling upstream of mmp14b. Last, we show that MMP-14 function in mice is important for the accumulation of Agrin, an essential regulator of neonatal mouse heart regeneration. These findings reveal mechanisms for extracellular matrix remodeling that promote heart regeneration.


How do distracting events influence children's arithmetic performance?
To understand how distraction influences children's arithmetic performance, we examined effects of irrelevant sounds on children's performance while they solve arithmetic problems. Third and fifth graders were asked to verify true/false, one-digit addition problems (e.g., 9 + 4 = 12. True? False?) under silence and sound conditions. The sounds began when the problems started to appear on the screen (Experiment 1; N = 76) or slightly after (Experiment 2; N = 92) and continued until participants responded. The results showed that (a) children solved arithmetic problems more quickly in the sound condition than in the silence condition when the sounds started with problem display (phasic arousal effects); (b) children were slower on the arithmetic problem verification task when the sounds was played slightly after the problems started to appear on the screen (distraction effects); (c) phasic arousal effects were found only in third graders, whereas distraction effects were found in both grades, although their magnitudes were smaller in fifth graders; (d) distraction effects increased with increasing latencies in third graders but did not change across the entire latency distribution in fifth graders; and (e) distraction effects on current trials were smaller after sound trials than after silence trials in both age groups (sequential modulations of distraction effects). These findings have important implications for furthering our understanding of effects of irrelevant sounds on arithmetic performance as well as cognitive processes involved in children's arithmetic.


Effect of yogic package on rheumatoid arthritis.
This study aimed at studying the effect of yogic package (YP) with some selected pranayama, cleansing practices and meditation on pain intensity, inflammation, stiffness, pulse rate (PR), blood pressure (BP), lymphocyte count (LC), C-reactive protein (CRP) and serum uric acid (UA) level among subjects of rheumatoid arthritis (RA). Randomized control group design was employed to generate pre and post data on participants and controls. Repealed Measure ANOVAs with Bonferroni adjustment were applied to check significant overall difference among pre and post means of participants and controls by using PASW (SPSS Inc. 18th Version). Observed result favored statistically significant positive effect of YP on selected RA parameters and symptoms under study at P<0.05, 0.01 and 0.001 respectively that showed remarkable improvement in RA severity after 40-day practice of YP. It concluded that YP is a significant means to reduce intensity of RA.


Regulation of chondrocyte gene expression.
Extracellular influences known to affect the regulation of chondrocyte biosynthetic and catabolic activity have been shown to include soluble factors, extracellular matrix and mechanical stress. A balance of these numerous extracellular influences is required for normal function of articular cartilage. It is likely that OA is the result of an imbalance of regulatory influences, ultimately resulting in deleterious changes in gene expression, altered extracellular matrix (ECM) and tissue degeneration. Molecular signaling via soluble mediators has been shown to be crucial to cartilage homeostasis. A number of vitamins, hormones, growth/differentiation factors and cytokines have been implicated in chondrocyte differentiation and cartilage metabolism. During normal maintenance, as well as in aging and pathology, these soluble factors can significantly influence the physical properties and the function of cartilage. Chondrocytes, like cells in other tissues, exist within an information-rich extracellular environment consisting of ECM molecules, a milieu which interacts with and modulates the activity of growth factors, hormones and ECM remodeling enzymes. Cell surface matrix receptors, including a family of proteins known as integrins, connect structural information in the ECM to a complex cellular response mechanism in the cell's interior. Integrins on cell surfaces detect and transduce signals in a cooperative manner with other adhesion receptor classes and/or growth factor receptors. The effects of mechanical stress upon a number of chondrocyte biological parameters has been examined in several laboratories. Other investigations have addressed the mechanism by which mechanical force affects biochemical and biosynthetic processes in chondrocytes, in particular synthesis of aggrecan, a major component of the cartilage ECM. Each of these extracellular influences upon chondrocyte metabolism may affect regulation of chondrocyte ECM biosynthesis at many levels, including mRNA transcription, RNA splicing, nuclear transport, protein translation, post-translational modification, intracellular vesicular transport, and protein secretion. Transcriptional regulation of some of the major protein and proteoglycan components of the cartilage ECM has been examined in a number of species, and promoters have been characterized for aggrecan, link protein and collagen type II genes. There is evidence that gene expression may be altered in OA cartilage, providing clues as to which subsets of genes expressed in chondrocytes may be considered relevant to OA pathophysiology.


[Operation of the Department of Adult Psychotherapy at the Institute of Behaviour Research & Therapy in Athens].
The article presents the demographics of the total number of people (n=515) who were administered Cognitive Behavior Psychotherapy from October 2005 until July 2009 as well as the demographics of those who completed therapy (n=180), along with the diagnoses and the course of their treatment based on the scores of psychometric assessments. Demographic variables include: sex, age, course of treatment, professional and marital status, educational level, number of sessions, previous visits to mental health professionals and possible medication uptake. The course of treatment was assessed by scores on: Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), Symptom Checklist-90-Revised (SCL-90R) and Personality Diagnostic Questionnaire (PDQ-4) that were completed at the beginning, in the middle and at the end of treatment. According to data analysis, 180 people completed treatment at the Institute of Behaviour Research and Therapy, of whom 133 were women and 47 men. The profile of these individuals showed that they were highly educated, employed, with an average of 33 (SD=9.2) years of age and with previous visits to mental health professionals. The average number of sessions was 34 (SD=15). Anxiety (n=76, 42.22%) and Mood Disorders (n=52, 28.9%) were the most frequent Axis I diagnoses. In relation to Axis II diagnoses, 22.22% of the sample was diagnosed with Avoidant Personality Disorder (n=40) and 16,11% with Obsessive-Compulsive Personality Disorder (n=29) with or without comorbidity with an Axis I Disorder according to DSM IV-TR. Means of the scores of psychometric measurements showed a statistically significant reduction in reported symptoms after the completion of treatment. In particular, there was a statistically significant reduction with a large effect size: (1) t(143)=12.02, p<0.0005, eta squared statistic (0.50) for BAI, (2) t(142)=17.93, p<0.0005, eta squared statistic (0.69) for BDI, (3) t(133)=15.77, p<0.0005, eta squared statistic (0.65) for SCL-90-R, and (4) t(56)=7.59, p<0.0005, eta squared statistic (0.50) for PDQ-4. In conclusion, Department of Adult Psychotherapy is a unit that has been thoroughly designed, operates according to a strict protocol and provides community members with the opportunity to receive effective Cognitive Behaviour Psychotherapy with a high quality of provided services.


Comparison of Unsatisfactory Samples from Conventional Smear versus Liquid-Based Cytology in Uterine Cervical Cancer Screening Test.
Cervical cytology for uterine cervical cancer screening has transitioned from conventional smear (CS) to liquid-based cytology (LBC), which has many advantages. The aim of this study was to compare the proportion of unsatisfactory specimens from CS versus LBC at multiple institutions including general hospitals and commercial laboratories. Each participating institution provided a minimum of 500 Papanicolaou (Pap) test results for analysis. Pap tests were classified according to the participating institution (commercial laboratory or general hospital) and the processing method (CS, ThinPrep, SurePath, or CellPrep). The causes of unsatisfactory results were classified as technical problems, scant cellularity, or complete obscuring factors. A total of 38,956 Pap test results from eight general hospitals and three commercial laboratories were analyzed. The mean unsatisfactory rate of LBC was significantly lower than that of CS (1.26% and 3.31%, p = .018). In the LBC method, samples from general hospitals had lower unsatisfactory rates than those from commercial laboratories (0.65% vs 2.89%, p = .006). The reasons for unsatisfactory results were heterogeneous in CS. On the other hand, 66.2% of unsatisfactory results in LBC were due to the scant cellularity. Unsatisfactory rate of cervical cancer screening test results varies according to the institution and the processing method. LBC has a significantly lower unsatisfactory rate than CS.


[Effect of intracellular injections of cyclic adenosine monophosphate on the electrical characteristics of identified edible snail neurons].
Electrical activity of silent RPa3, LPa2, LPa3, LPa8, LP11 neurons and spontaneously active RPa1 neuron was investigated as affected by iontophoretic intracellular cAMP injection. It is shown that in all cases the cAMP injection caused depolarization of the membrane; cAMP injection into the neuron when its membrane potential is clamped at the resting potential level evoked the appearance of transmembrane current (cAMP-current). External theophylline (1 mM/1) increased the amplitude and duration of vAMP-current approximately by 50%. It is concluded that variation in the cAMP concentration inside the neuron may alter the ionic permeability of its membrane, thus changing its electrical activity.


Current Perspective on Retinal Migraine.
Retinal migraine was first formally described in 1882. Various terms such as "ocular migraine" and "ophthalmic migraine" have since been used interchangeably in the literature. The lack of a consistent consensus-based definition has led to controversy and potential confusion for clinicians and patients. Retinal migraine as defined by the International Classification of Headache Disorders (ICHD) has been found to be rare. The latest ICHD defined retinal migraine as 'repeated attacks of monocular visual disturbance, including scintillation, scotoma or blindness, associated with migraine headache', which are fully reversible. Retinal migraine should be considered a diagnosis of exclusion, which requires other causes of transient monocular visual loss to be excluded. The aim of this narrative review is to summarize the literature on retinal migraine, including: epidemiology and risk factors; proposed aetiology; clinical presentation; and management strategies. It is potentially a misnomer as its proposed aetiology is different from our current understanding of the mechanism of migraine.


High Output Chylous Fistula Post First Rib Resection.
We present a patient who developed high output chyle leak post left first-rib resection for neurogenic thoracic outlet syndrome. The persistent high output chylorrhea was refractory to 3 surgical reexplorations attempting to ligate leaking branches, bed rest, nonfat diet, parenteral nutrition, octreotide administration, and vacuum-assisted closure (VAC) therapy. In addition, she developed hypovolemia, hyponatremia, and hypoalbuminemia. Control of the chylous fistula was achieved by reattaching the sternocleidomastoid muscle laterally to protect the phrenic nerve and brachial plexus in order to redirect chyle to the medial portion of the neck incision site. This was supported by the application of fibrin sealants in combination with VAC therapy. The patient was discharged after a 27-day hospital stay with complete resolution of her chylous fistula prior to discharge.


On the cholinergic component of action of meptazinol.
The effects of meptazinol, morphine and fentanyl on the indirect twitch contractions, the contractions produced by periarterial nerve stimulation, by field stimulation and by applied acetylcholine (ACh) were studied in rat isolated diaphragm and ileum respectively. Meptazinol (1-200 microM) increased the amplitudes of the indirect twitch tension in a dose-dependent manner. High concentrations of meptazinol (370 microM) reduced the twitch tension without the initial stimulation. The mean EC50 value of meptazinol-induced increase in twitch tension was 50 +/- 4.2 microM (n = 6). Morphine (2.9-290 microM) and fentanyl (2.9-290 microM) always reduced the amplitude of the twitch tension without initial stimulation. In the rat ileum, low concentrations of meptazinol (3.7-37 microM) increased the contractions produced by periarterial nerve stimulation, elicited at 10 or 20 Hz, in the presence of adrenergic blocking drugs, by 30%. Naloxone (1 microM) only partially reduced these contractions (by 25%), whereas atropine (1 microM) reduced these responses by 70%. Meptazinol (3.7 microM) increased the amplitude of the spontaneous contractions (by 50-100%) and sometimes this was accompanied by repetitive firing in the muscle. The twitch tension, in response to electrical field stimulation, was also increased by meptazinol (by 40-50%). At low concentrations, meptazinol produced no significant antagonism of applied ACh contracture, whereas at high concentrations, meptazinol (370 microM), morphine (29 microM) and fentanyl (29 microM) reduced the ACh response and shifted, to the right, the concentration-response curve, morphine being the most effective agent. Dose-ratios (test/control) of 100:4:2, with morphine, fentanyl and meptazinol, were obtained. Compared to meptazinol (relative potency = 1), morphine was 60 times as potent as meptazinol. Furthermore, the relative potency of meptazinol did not significantly change in the presence of naloxone, whereas those of morphine and fentanyl were changed significantly (by a factor of 10 and 2 respectively). These results showed that meptazinol, in low concentrations, may facilitate neuromuscular transmission, possibly via an increase in transmitter release. At high concentrations, meptazinol, like morphine and fentanyl, reduced the sensitivity of the post-junctional membrane to ACh. Furthermore, the blocking effect of meptazinol was only partially reduced by naloxone, and completely abolished by atropine in combination with naloxone. The latter effect may indicate a cholinergic mechanism in the action of meptazinol and that this may, in part, contribute to the analgesic effect of meptazinol.


A comparative field study of radiolabeled and enzyme-conjugated synthetic DNA probes for the diagnosis of falciparum malaria.
Synthetic, 21-base, DNA probes to the genome of Plasmodium falciparum were either 32P-labeled or enzyme-conjugated for comparative field studies. The sensitivity of both probes was compared with microscopy in the examination of blood samples from 97 Thai villagers, 47 Thai Rangers, and 19 malaria-free Bangkok residents. The probes were also used to monitor the therapeutic response of 18 of the Rangers during 7 days of treatment. The probes proved highly specific. Both probes had lower limits of detection of about 100 parasites per microliter blood. Thus, the low parasite densities in partially immune villagers from an endemic area were often missed, while higher parasite densities in the nonimmune Rangers were usually detected. As monitors of response to treatment, the probes paralleled microscopy in identifying reversion from positive to negative parasitemia. The enzymelabeled DNA probe as shown to perform similarly to the radiolabeled probe in populations with different malarial immune status and during curative treatment.


Cellular localization of apelin and its receptor in the anterior pituitary: evidence for a direct stimulatory action of apelin on ACTH release.
Apelin is a bioactive peptide recently identified as the endogenous ligand of the human orphan G protein-coupled receptor APJ. The presence of apelin-immunoreactive nerve fibers, together with the detection of apelin receptor mRNA in the parvocellular part of the paraventricular nucleus and the stimulatory action of apelin on corticotropin-releasing hormone release, indicate that apelin modulates adrenocorticotropin (ACTH) release via an indirect action on the hypothalamus. However, a direct action of apelin in the anterior pituitary cannot be excluded. Here, we provided evidence for the existence of an apelinergic system within the adult male rat pituitary gland. Double immunofluorescence staining indicated that apelin is highly coexpressed in the anterior pituitary, mainly in corticotrophs (96.5 +/- 0.3%) and to a much lower extent in somatotropes (3.2 +/- 0.2%). Using in situ hybridization combined with immunohistochemistry, a high expression of apelin receptor mRNA was also found in corticotrophs, suggesting a local interaction between apelin and ACTH. In an ex vivo perifusion system of anterior pituitaries, apelin 17 (K17F, 10(-6) M) significantly increased basal ACTH release by 41%, whereas apelin 10 (R10F, 10(-6) M), an inactive apelin fragment, was ineffective. In addition, K17F but not R10F induced a dose-dependent increase in K(+)-evoked ACTH release, with maximal increase being observed for a 10(-6) M concentration. Taken together, these data outline the potential role of apelin as an autocrine/paracrine-acting peptide on ACTH release and provide morphological and neuroendocrine basis for further studies that explore the physiological role of apelin in the regulation of anterior pituitary functions.


Gastric Glomus Tumors: The Roles of Endoscopic Ultrasound and Shared Decision-Making.
Gastric glomus tumors (GGTs) are mesenchymal neoplasms with indolent behavior that originate from the subepithelial layers of the stomach and represent up to 1% of all gastric tumors. GGT is detected incidentally during esophagogastroduodenoscopy (EGD) in a proportion of patients. Endoscopic ultrasound (EUS) evaluation of GGT is essential to establish the diagnosis and to differentiate it from gastrointestinal stromal tumors or gastric neuroendocrine tumors. An 80-year-old man who presented for abdominal discomfort was incidentally found to have a gastric antral nodule on EGD. Endoscopic biopsy demonstrated moderately erythematous gastric antral mucosa and a 1.5 cm subepithelial lesion along the greater curvature. An EUS revealed a subepithelial 1.6 cm × 1.3 cm isoechoic, homogenous lesion with small calcifications. Immunohistochemical staining of the fine needle biopsy specimen of the nodule was positive for neoplastic cells, smooth muscle actin, vimentin, patchy muscle-specific actin, and synaptophysin. There were no atypical cytologic features. These findings were consistent with GGT. The patient was not deemed to be a candidate for surgical resection due to advanced age and resolution of his symptoms. A shared decision was made to pursue regular surveillance. EUS is essential for evaluation of GGT. Currently, there are no guideline recommendations for surveillance of GGT detected on routine EGD in asymptomatic individuals. A definitive surgical treatment with partial gastrectomy was favored in previously published literature. For asymptomatic patients with GGT or those with resolution of symptoms, careful surveillance with serial abdominal imaging and EUS may be a reasonable option, especially in older patients with poor surgical candidacy.


Control of the AtMAP65-1 interaction with microtubules through the cell cycle.
Cell division depends on the fine control of both microtubule dynamics and microtubule organisation. The microtubule bundling protein MAP65 is a ;midzone MAP' essential for the integrity of the anaphase spindle and cell division. Arabidopsis thaliana MAP65-1 (AtMAP65-1) binds and bundles microtubules by forming 25 nm cross-bridges. Moreover, as AtMAP65-1 bundles microtubules in interphase, anaphase and telophase but does not bind microtubules in prophase or metaphase, its activity through the cell cycle must be under tight control. Here we show that AtMAP65-1 is hyperphosphorylated during prometaphase and metaphase and that CDK and MAPK are involved in this phosphorylation. This phosphorylation inhibits AtMAP65-1 activity. Expression of non-phosphorylatable AtMAP65-1 has a negative effect on mitotic progression resulting in excessive accumulation of microtubules in the metaphase spindle midzone causing a delay in mitosis. We conclude that normal metaphase spindle organisation and the transition to anaphase is dependent on inactivation of AtMAP65-1.


Effect of tiger nut-derived products in gluten-free batter and bread.
Tiger nut is a tuber used to produce tiger nut milk that yields a high quantity of solid waste, which can be dried and used as fiber source. The objective of this paper was to evaluate the quality of gluten-free bread formulated with different tiger nut-derived products in order to substitute soya flour (which is an allergen ingredient) and, at the same time, increase the use of tiger nut-derived products. Four gluten-free formulations based on corn starch and containing tiger nut milk, tiger nut milk by-product, tiger nut flour, or soya flour (as reference formulation) were studied. Tiger nut milk increased G' of gluten-free batter and rendered breads with the softest crumb (502.46 g ± 102.05), the highest loaf-specific volume (3.35 cm(3)/g ± 0.25), and it was mostly preferred by consumers (61.02%). Breads elaborated with tiger nut flour had similar characteristics than soya flour breads (except in color and crumb structure). The addition of tiger nut milk by-product resulted in a hard (1047.64 g ± 145.74) and dark (L(*) = 70.02 ± 3.38) crumb bread, which was the least preferred by consumers. Results showed that tiger nut is a promising ingredient to formulate gluten-free baked products.


The relationship between surgical factors and margin status after breast-conservation surgery for early stage breast cancer.
The study's aim was to identify technical factors that are predictive of negative margins after breast-conserving surgery (BCS). This was a retrospective, cohort study of patients who underwent BCS for early-stage cancer from 2000 to 2002. Pathological and specific surgical factors were compared with margin status. Univariate and multivariate regression analyses were performed. Four hundred eighty-nine cases were reviewed. The positive margin rate after the initial surgery was 26%. In univariate analysis, lobular histology, size, grade, multifocality, and the presence of EIC and LVI were associated with positive margins (P < .05). The absence of cavity margin dissection and specimen orientation labeling, the absence of a confirmed diagnosis, and smaller volumes of excision were also associated with positive margins (P < .05). In multivariate analysis, confirmed diagnosis, small tumor size, ductal histology, absence of LVI and multifocality, palpability, cavity margin dissection, and larger volumes of excision were predictors of negative margins. This study shows that specific surgical factors are predictive of margin status. Both tumor and technical factors should be considered when planning BCS.