Differential effects of jump versus running exercise on trabecular bone architecture and strength in rats.
This study compared differences in trabecular bone architecture and strength caused by jump and running exercises in rats. Ten-week-old male Wistar rats (n=45) were randomly assigned to three body weight-matched groups: a sedentary control group (CON, n=15); a treadmill running group (RUN, n=15); and a jump exercise group (JUM, n=15). Treadmill running was performed at 25 m/min without inclination, 1 h/day, 5 days/week for 8 weeks. The jump exercise protocol comprised 10 jumps/day, 5 days/week for 8 weeks, with a jump height of 40 cm. We used microcomputed tomography to assess microarchitecture, mineralization density, and fracture load as predicted by finite element analysis (FEA) at the distal femoral metaphysis. Both jump and running exercises produced significantly higher trabecular bone mass, thickness, number, and fracture load compared to the sedentary control group. The jump and running exercises, however, showed different results in terms of the structural characteristics of trabecular bone. Jump exercises enhanced trabecular bone mass by thickening the trabeculae, while running exercises did so by increasing the trabecular number. FEA-estimated fracture load did not differ significantly between the exercise groups. This study elucidated the differential effects of jump and running exercise on trabecular bone architecture in rats. The different structural changes in the trabecular bone, however, had no significant impact on trabecular bone strength.


[Dynamics of typhoid-paratyphoid infection morbidity in Chimkent Province].
The study of the time course of typhoid-paratyphoid infections in the Chimkent region for the period of 1944-1979 has revealed the periodicity of their rises (falls) repeating every 2-4 years. Since 1964 the tendency towards the decrease of morbidity has been observed. The annual rate of this decrease is 4.9%. Periodic changes in the annual level of typhoid-paratyphoid infections do not depend on the temperature of the air and the seasonal number of winged flies. There is a pronounced direct correlation between the annual morbidity level and the frequency of summer precipitations, this correlation being more pronounced during the first 2 summer months.


In vivo hemodynamic and electrocardiographic changes following Crataegus aronia syn. Azarolus L administration to normotensive Wistar rats.
To evaluate the effects of the whole plant aqueous extract of Crataegus aronia (C. aronia) syn. Azarolus (L) on the hemodynamic and electrocardiographic intervals in albino rats. This study was carried out in 2 stages at the Research Laboratory, Physiology Department, Medical College of King Khalid University, Abha, Kingdom of Saudi Arabia between February and June 2012. First, the effects of C. aronia syn. Azarolus (L) on the hemodynamics and electrocardiograph in 54 Wistar male rats were assessed, then the mechanisms underlying the hemodynamic and electrocardiographic changes observed in the first stage were evaluated in 48 rats of the same species. The C. aronia administered at escalating doses (0.05-20 microgram/kg) produced a dose-time-dependent decrease in heart rate (HR) and mean arterial pressure (MAP). Higher doses (15 and 20 microgram/kg) produced the most significant reduction in both HR and MAP, and induced sinus node suppression and progressive atrio-ventricular blockade. The underlying mechanism of the induced bradyarrhythmia appeared to be due to the direct stimulation of the muscarinic receptor M2 and possible blockade of beta-receptors, while the hypotension was caused by enhanced nitric oxide release. No significant alterations in the electrocardiogram (ECG) components were observed. The administration of the C. aronia syn. Azarolus extract induced bradyarrhythmia and hypotension, without alteration in the ECG components.


Adjuvant chemotherapy following chemoradiotherapy as primary treatment for locally advanced cervical cancer versus chemoradiotherapy alone (OUTBACK): an international, open-label, randomised, phase 3 trial.
Standard treatment for locally advanced cervical cancer is chemoradiotherapy, but many patients relapse and die of metastatic disease. We aimed to determine the effects on survival of adjuvant chemotherapy after chemoradiotherapy. The OUTBACK trial was a multicentre, open-label, randomised, phase 3 trial done in 157 hospitals in Australia, China, Canada, New Zealand, Saudi Arabia, Singapore, and the USA. Eligible participants were aged 18 year or older with histologically confirmed squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma of the cervix (FIGO 2008 stage IB1 disease with nodal involvement, or stage IB2, II, IIIB, or IVA disease), Eastern Cooperative Oncology Group performance status 0-2, and adequate bone marrow and organ function. Participants were randomly assigned centrally (1:1) using a minimisation approach and stratified by pelvic or common iliac nodal involvement, requirement for extended-field radiotherapy, FIGO 2008 stage, age, and site to receive standard cisplatin-based chemoradiotherapy (40 mg/m2 cisplatin intravenously once-a-week for 5 weeks, during radiotherapy with 45·0-50·4 Gy external beam radiotherapy delivered in fractions of 1·8 Gy to the whole pelvis plus brachytherapy; chemoradiotherapy only group) or standard cisplatin-based chemoradiotherapy followed by adjuvant chemotherapy with four cycles of carboplatin (area under the receiver operator curve 5) and paclitaxel (155 mg/m2) given intravenously on day 1 of a 21 day cycle (adjuvant chemotherapy group). The primary endpoint was overall survival at 5 years, analysed in the intention-to-treat population (ie, all eligible patients who were randomly assigned). Safety was assessed in all patients in the chemoradiotherapy only group who started chemoradiotherapy and all patients in the adjuvant chemotherapy group who received at least one dose of adjuvant chemotherapy. The OUTBACK trial is registered with ClinicalTrials.gov, NCT01414608, and the Australia New Zealand Clinical Trial Registry, ACTRN12610000732088. Between April 15, 2011, and June 26, 2017, 926 patients were enrolled and randomly assigned to the chemoradiotherapy only group (n=461) or the adjuvant chemotherapy group (n=465), of whom 919 were eligible (456 in the chemoradiotherapy only group and 463 in the adjuvant chemotherapy group; median age 46 years [IQR 37 to 55]; 663 [72%] were White, 121 [13%] were Black or African American, 53 [6%] were Asian, 24 [3%] were Aboriginal or Pacific islander, and 57 [6%] were other races) and included in the analysis. As of data cutoff (April 12, 2021), median follow-up was 60 months (IQR 45 to 65). 5-year overall survival was 72% (95% CI 67 to 76) in the adjuvant chemotherapy group (105 deaths) and 71% (66 to 75) in the chemoradiotherapy only group (116 deaths; difference 1% [95% CI -6 to 7]; hazard ratio 0·90 [95% CI 0·70 to 1·17]; p=0·81). In the safety population, the most common clinically significant grade 3-4 adverse events were decreased neutrophils (71 [20%] in the adjuvant chemotherapy group vs 34 [8%] in the chemoradiotherapy only group), and anaemia (66 [18%] vs 34 [8%]). Serious adverse events occurred in 107 (30%) in the adjuvant chemotherapy group versus 98 (22%) in the chemoradiotherapy only group, most commonly due to infectious complications. There were no treatment-related deaths. Adjuvant carboplatin and paclitaxel chemotherapy given after standard cisplatin-based chemoradiotherapy for unselected locally advanced cervical cancer increased short-term toxicity and did not improve overall survival; therefore, it should not be given in this setting. National Health and Medical Research Council and National Cancer Institute.


Natural history and therapy of 66 patients with mixed cryoglobulinemia.
Cryoglobulinemia, a relatively uncommon disorder, is classified into types I, II, and III, with type II consisting of a monoclonal immunoglobulin possessing activity toward a polyclonal component. Many disease associations and therapies have been described but clinical trials are few, and the natural history, causes, therapy, and pathways of cryoglobulinemia require further investigation. Here, we describe the symptoms, comorbidities, treatments, and response of 66 patients with type II cryoglobulinemia by examining the records of all patients evaluated at Mayo Clinic, Rochester, Minnesota, between 3/2/1994 and 11/27/2000, using our prospective dysproteinemia database. Symptoms varied greatly among patients and during the disease course. Most common were purpura (55% of patients), renal disease (26%), edema (24%), neuropathy (18%), and arthralgia (21%). Renal disease required the most aggressive intervention. Laboratory findings did not correlate with disease manifestations or severity. Only age was a significant predictor of mortality. Ten patients had cryoglobulinemia without an identified comorbidity. Thirty-three patients had viral hepatitis alone, 6 had a lymphoproliferative disorder alone, and 5 had a rheumatologic disease alone. Ten patients had a combination of disorders, such that hepatitis C was identified in a total of 40 patients, lymphoproliferative disorders in 16, and rheumatologic disease in 8. Twenty-two different treatments were administered. Corticosteroids were the most common treatment, followed by interferon with or without ribavirin. Type II cryoglobulinemia is a nonfatal disease most frequently associated with hepatitis C. Treatment is generally directed at the underlying condition. Not all patients require treatment, and many can be followed and treated symptomatically.


Representing Uncertainty in Graph Edges: An Evaluation of Paired Visual Variables.
When visualizing data with uncertainty, a common approach is to treat uncertainty as an additional dimension and encode it using a visual variable. The effectiveness of this approach depends on how the visual variables chosen for representing uncertainty and other attributes interact to influence the user's perception of each variable. We report a user study on the perception of graph edge attributes when uncertainty associated with each edge and the main edge attribute are visualized simultaneously using two separate visual variables. The study covers four visual variables that are commonly used for visualizing uncertainty on line graphical primitives: lightness, grain, fuzziness, and transparency. We select width, hue, and saturation for visualizing the main edge attribute and hypothesize that we can observe interference between the visual variable chosen to encode the main edge attribute and that to encode uncertainty, as suggested by the concept of dimensional integrality. Grouping the seven visual variables as color-based, focus-based, or geometry-based, we further hypothesize that the degree of interference is affected by the groups to which the two visual variables belong. We consider two further factors in the study: discriminability level for each visual variable as a factor intrinsic to the visual variables and graph-task type (visual search versus comparison) as a factor extrinsic to the visual variables. Our results show that the effectiveness of a visual variable in depicting uncertainty is strongly mediated by all the factors examined here. Focus-based visual variables (fuzziness, grain, and transparency) are robust to the choice of visual variables for encoding the main edge attribute, though fuzziness has stronger negative impact on the perception of width and transparency has stronger negative impact on the perception of hue than the other uncertainty visual variables. We found that interference between hue and lightness is much greater than that between saturation and lightness, though all three are color-based visual variables. We also found a compound relationship between discriminability level and the degree of dimensional integrality. We discuss the generalizability and limitation of the results and conclude with design considerations for visualizing graph uncertainty derived from these results, including recommended choices of visual variables when the relative importance of data attributes and graph tasks is known.


Grouping in object recognition: the role of a Gestalt law in letter identification.
The Gestalt psychologists reported a set of laws describing how vision groups elements to recognize objects. The Gestalt laws "prescribe for us what we are to recognize 'as one thing'" (Kohler, 1920). Were they right? Does object recognition involve grouping? Tests of the laws of grouping have been favourable, but mostly assessed only detection, not identification, of the compound object. The grouping of elements seen in the detection experiments with lattices and "snakes in the grass" is compelling, but falls far short of the vivid everyday experience of recognizing a familiar, meaningful, named thing, which mediates the ordinary identification of an object. Thus, after nearly a century, there is hardly any evidence that grouping plays a role in ordinary object recognition. To assess grouping in object recognition, we made letters out of grating patches and measured threshold contrast for identifying these letters in visual noise as a function of perturbation of grating orientation, phase, and offset. We define a new measure, "wiggle", to characterize the degree to which these various perturbations violate the Gestalt law of good continuation. We find that efficiency for letter identification is inversely proportional to wiggle and is wholly determined by wiggle, independent of how the wiggle was produced. Thus the effects of three different kinds of shape perturbation on letter identifiability are predicted by a single measure of goodness of continuation. This shows that letter identification obeys the Gestalt law of good continuation and may be the first confirmation of the original Gestalt claim that object recognition involves grouping.


Heterogeneity of smooth endoplasmic reticulum from rat liver studied by two-phase partitioning.
Smooth microsomal membranes, prepared from rat liver by sucrose-density-gradient centrifugation, were subfractionated by counter-current distribution in an aqueous two-phase system consisting of poly(ethylene glycol) and Dextran T500. A comparison of the distribution curves of marker enzymes, together with theoretically calculated curves, indicated the presence of at least five membrane subfractions, differing in the ratios of the marker enzymes. Glucose-6-phosphatase and arylesterase distributed in one manner, and NADPH-cytochrome c reductase and NADH-ferricyanide reductase in another. Evidence for further heterogeneities in the distribution of marker enzymes in smooth microsomes was obtained by analysing the membrane domain structure using a recently described method [Albertsson (1988) Q. Rev. Biophys. 21, 61-98]. Phenobarbital treatment did not influence the behaviour of the marker enzymes.


Microfabrication-derived DDS: From batch to individual production.
As a result of recent advances in microfabrication technology (MFT), microparticles including microcapsules and microspheres can be prepared individually and the disadvantages of the conventional microparticles produced by batch production, i.e. (i) low loading efficiency, (ii) large size variation, and (iii) initial burst release, have been remedied. In addition, all conventional microparticles have the same structure, a spherical shape, so they have only one function, sustained release. Threelayer microcapsules (TLMCs) have been designed to address these issues. TLMCs consist of a surface layer, a drug carrying layer, and a basement layer. TLMCs have sustained release as well as adhesiveness and targeting functions. TLMCs are prepared using ink-jet printer nozzle technology. The obtained TLMCs are used for the oral delivery of peptide/protein drugs and long-term sustained-release injection preparation. In addition, self-dissolving micropiles (SDMPs) can be individually produced by MFT as a percutaneous preparation. MFT allows biopharmaceutical drugs like insulin, erythropoietin, and growth hormone to be absorbed through the skin. Thus, advances in MFT have accelerated the development of pharmaceutical technology.


Antibiotics-induced depletion of mice microbiota induces changes in host serotonin biosynthesis and intestinal motility.
The gastrointestinal motility is affected by gut microbiota and the relationship between them has become a hot topic. However, mechanisms of microbiota in regulating motility have not been well defined. We thus investigated the effect of microbiota depletion by antibiotics on gastrointestinal motility, colonic serotonin levels, and bile acids metabolism. After 4 weeks with antibiotics treatments, gastrointestinal and colon transit, defecation frequency, water content, and other fecal parameters were measured and analyzed in both wild-type and antibiotics-treated mice, respectively. Contractility of smooth muscle, serotonin levels, and bile acids levels in wild-type and antibiotics-treated mice were also analyzed. After antibiotics treatment, the richness and diversity of intestinal microbiota decreased significantly, and the fecal of mice had less output (P < 0.01), more water content (P < 0.01), and longer pellet length (P < 0.01). Antibiotics treatment in mice also resulted in delayed gastrointestinal and colonic motility (P < 0.05), and inhibition of phasic contractions of longitudinal muscle from isolated proximal colon (P < 0.01). In antibiotics-treated mice, serotonin, tryptophan hydroxylase 1, and secondary bile acids levels were decreased. Gut microbiota play an important role in the regulation of intestinal bile acids and serotonin metabolism, which could probably contribute to the association between gut microbiota and gastrointestinal motility as intermediates.


[Nuclear magnetic resonance tomographic staging of tumors of the oral cavity, oro- and hypopharynx and the larynx. A comparison with computed tomography and sonography].
Thirty-six patients with tumours of the mouth, the oropharynx and hypopharynx and the larynx were examined by nuclear resonance tomography. The results were compared with the clinical findings of inspection and palpation and with CT and sonography, with respect to T and N classification. In seven patients the classification could be confirmed at operation. NMR provides very good anatomical detail and marked contrast between tumour and the surrounding tissues, particularly on T2 weighted images. NMR showed the best correlation with the clinical findings as regards the T classification and was the most accurate method, as confirmed by surgery. It is superior to CT and sonography for diseases in the oropharynx and hypopharynx. For the examination of the cervical lymphatics, sonography remains the recommended method.


Adrenal hemorrhage in patients with primary antiphospholipid syndrome: imaging findings.
The primary antiphospholipid syndrome consists of recurrent thromboses, early stroke, recurrent fetal loss, and livedo reticularis in patients with antiphospholipid antibodies and without systemic lupus erythematosus. The purpose of this study was to analyze the imaging findings in patients who had this syndrome as well as adrenal hemorrhage. The medical records and reports of radiologic examinations of 228 patients with elevated titers of lupus anticoagulant or anticardiolipin antibodies from January 1992 to April 1994 were examined for indications of adrenal hemorrhage. Four patients (two men and two women 38-78 years old) were identified as having adrenal hemorrhage. The abdominal CT and MR imaging findings for three patients and autopsy data for the fourth patient were analyzed. Adrenal hemorrhage was seen in all three patients who underwent abdominal CT and in one patient who underwent MR imaging. Adrenal hemorrhage was bilateral in three patients. Extension of hemorrhage into the perinephric space was present in two patients. Associated clinical findings probably attributable to the presence of antiphospholipid antibodies included amaurosis fugax (two patients), deep venous thrombosis (three patients), and transient ischemic attacks or stroke (two patients). Antiphospholipid antibodies appear to be a risk factor for adrenal hemorrhage. The presence of these antibodies should be suspected in patients who have adrenal hemorrhage as well as recurrent thromboses and early stroke.


Proteomic investigation of phosphorylation sites in poly(ADP-ribose) polymerase-1 and poly(ADP-ribose) glycohydrolase.
Phosphorylation is a very common post-translational modification event known to modulate a wide range of biological responses. Beyond the regulation of protein activity, the interrelation of phosphorylation with other post-translational mechanisms is responsible for the control of diverse signaling pathways. Several observations suggest that phosphorylation of poly(ADP-ribose) polymerase-1 (PARP-1) regulates its activity. There is also accumulating evidence to suggest the establishment of phosphorylation-dependent assembly of PARP-1-associated multiprotein complexes. Although it is relatively straightforward to demonstrate phosphorylation of a defined target, identification of the actual amino acids involved still represents a technical challenge for many laboratories. With the use of a combination of bioinformatics-based predictions tools for generic and kinase-specific phosphorylation sites, in vitro phosphorylation assays and mass spectrometry analysis, we investigated the phosphorylation profile of PARP-1 and poly(ADP-ribose) glycohydrolase (PARG), two major enzymes responsible for poly(ADP-ribose) turnover. Mass spectrometry analysis revealed the phosphorylation of several serine/threonine residues within important regulatory domains and motifs of both enzymes. With the use of in vivo microirradiation-induced DNA damage, we show that altered phosphorylation at specific sites can modify the dynamics of assembly and disassembly of PARP-1 at sites of DNA damage. By documenting and annotating a collection of known and newly identified phosphorylation sites, this targeted proteomics study significantly advances our understanding of the roles of phosphorylation in the regulation of PARP-1 and PARG.


Pharmacological and biological evidence for differing mechanisms of doxorubicin resistance in two human tumor cell lines.
The cellular pharmacology of doxorubicin resistance (DOXR) has most commonly been associated with decreased drug uptake, enhanced drug efflux, cross-resistance to multiple anticancer agents, and the overproduction of a Mr 170,000 cell surface glycoprotein (termed P-glycoprotein). In this study, the pharmacological and genetic characteristics of two newly derived human DOXR sublines were examined. These DOXR sublines were established following continuously increasing DOX exposure until a 222-fold resistant fibrosarcoma subline (HT1080/DR4) and a 285-fold resistant colon adenocarcinoma subline (LoVo/DR5) were developed. However, three major lines of evidence suggest that despite the similar selection strategy, the mechanism of DOXR differs significantly between these two cell lines. First, Western blotting using the C219 antibody specific to P-glycoprotein revealed the overexpression of the Mr 170,000 cell surface glycoprotein in LoVo DOXR cells but not in HT1080 DOXR cells. Second, LoVo DOXR cells are cross-resistant to vincristine, actinomycin D, colchicine, etoposide, and gramicidin D, but not to 1-beta-D-arabinofuranosylcytosine. In contrast, HT1080 DOXR cells display cross-resistance to vincristine, actinomycin D, vinblastine, and etoposide; however, they are not cross-resistant to gramicidin D, and show an increased (approximately 18-fold) cross-resistance to 1-beta-D-arabinofuranosylcytosine. Third, intracellular DOX accumulation (as measured by [14C]DOX at 1-h and high-performance liquid chromatography analysis) was decreased approximately 2.7-fold in LoVo DOXR cells and approximately 2.0-fold in HT1080/DR4 cells. However, while net accumulation studies in the presence of 5 micrograms/ml verapamil reversed DOXR to parental values in LoVo colon adenocarcinoma cells, it only minimally decreased DOX resistance (12.6%) in HT1080/DR4 cells. Efflux patterns of [14C]DOX were similar for the DOXR sublines with an approximately 50% decrease in DOX retention after 1 h when compared to their respective parental cell lines. Our results suggest that DOXR in LoVo/DR5 cells may result from overexpression of P-glycoprotein. In contrast, DOXR in HT1080/DR4 appears to be non-P-glycoprotein mediated and may be related to an alternative mechanism capable of altering drug efflux or differential drug binding.


How do "selfies" impact adolescents' well-being and body confidence? A narrative review.
Social media use has grown rapidly in recent years, with one of the most popular activities for young people being the taking, sharing, and browsing of digital self-photos, known as selfies. However, research has only recently begun to investigate selfies, and little is known about selfie practices in adolescents, or the associations between these practices and well-being and body confidence. This paper aimed to address this gap and conduct a narrative review of selfie practices and the relationships with well-being and body confidence in adolescents. No studies were found reporting on selfie practices and these relationships among children. However, taking selfies appears to be common practice among adolescents, although posting selfies online is less frequent. The studies reviewed indicate that certain aspects of selfie behaviors may be more problematic than others. Specifically, viewing selfies online appears to have a negative impact on adolescents' well-being and body confidence, at least in the short term in experimental contexts. Moreover, seeking and placing importance on feedback from others may also be a harmful aspect of selfie practices. Finally, consistent with research examining social media, social comparison has been identified in this emerging body of research as a potential mechanism which links selfie engagement to well-being and body confidence. To further advance understanding of the correlates and effects of selfie practices, research with children and with boys, and research focused on a wider range of indicators of well-being, is needed. Most importantly, prospective research is required to examine the directionality of links between selfie practices and well-being and body confidence.


Increased angiogenesis and lymphangiogenesis in inflammatory versus noninflammatory breast cancer by real-time reverse transcriptase-PCR gene expression quantification.
Inflammatory breast cancer is a distinct and aggressive form of locally advanced breast cancer with unique clinical and pathological features. Recently, histologic evidence of intense angiogenesis was found in inflammatory breast cancer specimens. The aim of this study was to confirm the angiogenic phenotype of inflammatory breast cancer and to investigate its potential to induce lymphangiogenesis. Real-time quantitative reverse transcriptase-PCR was used to measure levels of mRNA of tumor angiogenesis and lymphangiogenesis-related factors [vascular endothelial growth factor (VEGF)-A, VEGF-C, VEGF-D, Flt-1, KDR, Flt-4, Ang-1, Ang-2, Tie-1, Tie-2, cyclooxygenase-2, fibroblast growth factor-2 (FGF-2), Egr-1, Prox-1, and LYVE-1] in tumor specimens of 16 inflammatory breast cancer and 20 noninflammatory breast cancer patients. Tissue microarray technology and immunohistochemistry were used to study differential protein expression of some of the angiogenic factors in inflammatory breast cancer and noninflammatory breast cancer. Active lymphangiogenesis was further assessed by measuring lymphatic endothelial cell proliferation. Inflammatory breast cancer specimens had significantly higher mRNA expression levels than noninflammatory breast cancer specimens of the following genes: KDR (P = 0.033), Ang-1, (P = 0.0001), Tie-1 (P = 0.001), Tie-2 (P = 0.001), FGF-2 (P = 0.002), VEGF-C (P = 0.001), VEGF-D (P = 0.012), Flt-4 (P = 0.001), Prox-1 (P = 0.005), and LYVE-1 (P = 0.013). High mRNA levels of FGF-2 and cyclooxygenase-2 corresponded to increased protein expression by immunohistochemistry. Inflammatory breast cancer specimens contained significantly higher fractions of proliferating lymphatic endothelial cells than noninflammatory breast cancer specimens (P = 0.033). Using real-time quantitative reverse transcriptase-PCR and immunohistochemistry, we confirmed the intense angiogenic activity in inflammatory breast cancer and demonstrated the presence of active lymphangiogenesis in inflammatory breast cancer. This may help explain the high metastatic potential of inflammatory breast cancer by lymphatic and hematogenous route. Both pathways are potential targets for the treatment of inflammatory breast cancer.


Differential expression of steroid 5alpha-reductase isozymes and association with disease severity and angiogenic genes predict their biological role in prostate cancer.
The biological role of steroid 5alpha-reductase isozymes (encoded by the SRD5A1 and SRD5A2 genes) and angiogenic factors that play important roles in the pathogenesis and vascularization of prostate cancer (PC) is poorly understood. The sub-cellular expression of these isozymes and vascular endothelial growth factor (VEGF) in PC tissue microarrays (n=62) was examined using immunohistochemistry. The effect of SRD5A inhibition on the angiogenesis pathway genes in PC was also examined in prostate cell lines, LNCaP, PC3, and RWPE-1, by treating them with the SRD5A inhibitors finasteride and dutasteride, followed by western blot, quantitative PCR, and ELISA chip array techniques. In PC tissues, nuclear SRD5A1 expression was strongly associated with higher cancer Gleason scores (P=0.02), higher cancer stage (P=0.01), and higher serum prostate specific antigen (PSA) levels (P=0.01), whereas nuclear SRD5A2 expression was correlated with VEGF expression (P=0.01). Prostate tumor cell viability was significantly reduced in dutasteride-treated PC3 and RWPE-1 cells compared with finasteride-treated groups. Expression of the angiogenesis pathway genes transforming growth factor beta 1 (TGFB1), endothelin (EDN1), TGFalpha (TGFA), and VEGFR1 was upregulated in LNCaP cells, and at least 7 out of 21 genes were upregulated in PC3 cells treated with finasteride (25 muM). Our findings suggest that SRD5A1 expression predominates in advanced PC, and that inhibition of SRD5A1 and SRD5A2 together was more effective in reducing cell numbers than inhibition of SRD5A2 alone. However, these inhibitors did not show any significant difference in prostate cell angiogenic response. Interestingly, some angiogenic genes remained activated after treatment, possibly due to the duration of treatment and tumor resistance to inhibitors.


Cortical FMRI activation to sequences of tones alternating in frequency: relationship to perceived rate and streaming.
Human listeners were functionally imaged while reporting their perception of sequences of alternating-frequency tone bursts separated by 0, 1/8, 1, or 20 semitones. Our goal was to determine whether functional magnetic resonance imaging (fMRI) activation of auditory cortex changes with frequency separation in a manner predictable from the perceived rate of the stimulus. At the null and small separations, the tones were generally heard as a single stream with a perceived rate equal to the physical tone presentation rate. fMRI activation in auditory cortex was appreciably phasic, showing prominent peaks at the sequence onset and offset. At larger-frequency separations, the higher- and lower-frequency tones perceptually separated into two streams, each with a rate equal to half the overall tone presentation rate. Under those conditions, fMRI activation in auditory cortex was more sustained throughout the sequence duration and was larger in magnitude and extent. Phasic to sustained changes in fMRI activation with changes in frequency separation and perceived rate are comparable to, and consistent with, those produced by changes in the physical rate of a sequence and are far greater than the effects produced by changing other physical stimulus variables, such as sound level or bandwidth. We suggest that the neural activity underlying the changes in fMRI activation with frequency separation contribute to the coding of the co-occurring changes in perceived rate and perceptual organization of the sound sequences into auditory streams.


Allogeneic hematopoietic cell transplantation for chemotherapy-unresponsive mantle cell lymphoma: a cohort analysis from the center for international blood and marrow transplant research.
Patients with chemorefractory mantle cell lymphoma (MCL) have a poor prognosis. We used the Center for International Blood and Marrow Transplant Research database to study the outcome of 202 patients with refractory MCL who underwent allogeneic hematopoietic cell transplantation (allo-HCT) using either myeloablative (MA) or reduced-intensity/nonmyeloablative conditioning (RIC/NST), during 1998-2010. We analyzed nonrelapse mortality (NRM), progression/relapse, progression-free survival (PFS), and overall survival (OS). Seventy-four patients (median age, 54 years) received MA, and 128 patients (median age, 59 years) received RIC/NST. Median follow-up after allo-HCT was 35 months in the MA group and 43 months in the RIC/NST group. At 3 years post-transplantation, no significant between-group differences were seen in terms of NRM (47% in MA versus 43% in RIC/NST; P = .68), relapse/progression (33% versus 32%; P = .89), PFS (20% versus 25%; P = .53), or OS (25% versus 30%; P = .45). Multivariate analysis also revealed no significant between-group differences in NRM, relapse, PFS, or OS; however, receipt of a bone marrow or T cell-depleted allograft was associated with an increased risk of NRM and inferior PFS and OS. Our data suggest that despite a refractory disease state, approximately 25% of patients with MCL can attain durable remission after allo-HCT, and conditioning regimen intensity does not influence outcome of allo-HCT.


Predictors of relapse: interaction of drinking-related locus of control and reasons for drinking.
Pretreatment scores from the drinking-related locus of control scale (DRIE) and reasons for drinking were investigated as predictors of drinking relapse over a nine-month follow-up in a sample of 232 male alcoholics. A significant relationship was found between reasons for drinking and the probability of relapse, with the lowest relapse rates occurring among patients who identified interpersonal conflicts or positive emotional states as the most important reasons for their pretreatment drinking. Results of a reasons for drinking by relapse status ANOVA on DRIE scores revealed no significant main effects. There was, however, a significant interaction. Among patients who attributed their drinking to negative emotional states, those who either relapsed or were lost to follow-up had significantly more external DRIE scores. Among patients who identified negative physical states (i.e., craving) as their primary reason for drinking, relapse or attrition was associated with significantly more internal DRIE scores. Results support assessment of these cognitive social learning constructs for differential treatment planning with patients at increased risk of relapse.


A 4D CT digital phantom of an individual human brain for perfusion analysis.
Brain perfusion is of key importance to assess brain function. Modern CT scanners can acquire perfusion maps of the cerebral parenchyma in vivo at submillimeter resolution. These perfusion maps give insights into the hemodynamics of the cerebral parenchyma and are critical for example for treatment decisions in acute stroke. However, the relations between acquisition parameters, tissue attenuation curves, and perfusion values are still poorly understood and cannot be unraveled by studies involving humans because of ethical concerns. We present a 4D CT digital phantom specific for an individual human brain to analyze these relations in a bottom-up fashion. Validation of the signal and noise components was based on 1,000 phantom simulations of 20 patient imaging data. This framework was applied to quantitatively assess the relation between radiation dose and perfusion values, and to quantify the signal-to-noise ratios of penumbra regions with decreasing sizes in white and gray matter. This is the first 4D CT digital phantom that enables to address clinical questions without having to expose the patient to additional radiation dose.


Suppression of male rhesus testicular function and sexual behavior by a gonadotropin-releasing-hormone agonist.
Castrated rhesus monkeys tested in pair tests in small areas mate up to 6 yr after castration, though there is high individual variability (22,23). The generalizability of these findings to social groups in larger areas is unknown. The sexual behavior of 4 adult rhesus males tested singly with a group of 9 intact adult females was examined during short-term, counterbalanced, gonadotropin-releasing-hormone(GnRH)-agonist-induced testicular suppression and control treatment. GnRH-agonist treatment suppressed testosterone to less than 0.6 ng/ml within 16 days. Ten days later (e.g., after 26 days of GnRH-agonist treatment) males were observed for 7 days. The frequency of hiptouches, mounts, intromissons and ejaculations were significantly reduced by testicular suppression. This behavioral reduction was more marked than previously reported in pair-tested castrates during a similar time-period, suggesting testicular suppression more profoundly affects behavior in multifemale groups in larger areas. Males differed in the extent that testicular suppression reduced their sexual behavior. Male ejaculations were completely unaffected in one male and completely eliminated in another. Sexual behavior was reduced less in males with high control levels of testosterone and behavior. Behavioral suppression was unrelated to differences in female behavior and appeared to result from reduced male sexual responsiveness or motivation.


Multiple infections, kin selection and the evolutionary epidemiology of parasite traits.
The coinfection of a host by several parasite strains is known to affect selective pressures on parasite strategies of host exploitation. I present a general model of coinfections that ties together kin selection models of virulence evolution and epidemiological models of multiple infections. I derive an analytical expression for the invasion fitness of a rare mutant in a population with an arbitrary distribution of the multiplicity of infection (MOI) across hosts. When a single mutation affects parasite strategies in all MOI classes, I show that the evolutionarily stable level of virulence depends on a demographic average of within-host relatedness across all host classes. This generalization of previous kin selection results requires that within-host parasite densities do not vary between hosts. When host exploitation strategies are allowed to vary across classes, I show that the strategy of host exploitation in a focal MOI class depends on the relative magnitudes of parasite reproductive values in the focal class and in the next. Thus, in contrast to previous findings, lower within-host relatedness in competitive parasite interactions can potentially correspond to either higher or lower levels of virulence.


Traditional Chinese medicine treatment in sinusitis after radiotherapy for nasopharyngeal carcinoma: a systematic review and network meta-analysis.
Radiation sinusitis after radiotherapy for nasopharyngeal carcinoma occupies a large proportion and affects the subsequent therapeutic process as well as diagnosis, which can be improved by traditional Chinese medicine treatments. Based on the relevant clinical randomized controlled trials (RCTs) from eight databases, a network meta-analysis (NMA) in a frequentist framework was constructed after study selection, data extraction, and quality evaluation of the included studies. The outcomes included total effect, the Lund Kennedy score of nasal endoscopy and the Lund Mackay score of sinus CT. For total effect, the order of probability for the effect is: external herbal medicine + herbal medicine orally > nasal saline + herbal medicine orally > herbal medicine orally > external herbal medicine > external herbal medicine + nasal saline > nasal saline + western medicine orally > none > nasal saline. For the Lund Kennedy score, the order of probability for the effect is: nasal saline + herbal medicine orally > herbal medicine orally > external herbal medicine > none > nasal saline. For Lund Mackay score, the order of probability for the effect is: herbal medicine orally > nasal saline + western medicine orally > nasal saline + herbal medicine orally > nasal saline > external herbal medicine. Herbal medicine taken orally and through nasal cavities combined with nasal saline has a better clinical effect than a single intervention for total effect and Lund Kennedy score. As the classification of this research is relatively macro and the sample size is insufficient, further higher-quality studies are needed to verify the conclusion. PROSPERO ID: CRD42022384113, 2022-12-25.


Epinephrine-induced changes in the distribution of lymphocyte subsets in peripheral blood of humans.
We have previously demonstrated that mitogen responsiveness of mononuclear cells (MNC) from peripheral blood is reduced after a single injection of epinephrine to human subjects. The purpose of the present study was to characterize the relative distributions of MNC subsets after epinephrine administration using monoclonal antibodies and conventional cell markers. The absolute number of circulating MNC increased 64% within 30 min after injection of epinephrine, and returned to baseline by 2 hr. Analysis of MNC subsets revealed that there were no changes in the relative percentages of total T lymphocytes [T3+ cells, or neuraminidase-treated sheep red blood cell rosettes (EN-rosettes)], B lymphocytes (B1+, or cells with surface-bound immunoglobulin), or monocytes (by morphologic criteria) after epinephrine administration. The percentage of inducer T cells (T4+) declined at 30 and 60 min postinjection. Overall, the percentage of suppressor/cytotoxic T cells (T8+) did not change after injection of epinephrine; however, analysis of individual subjects revealed opposing responses of this subset. The T4:T8 ratio was 2.19 before injection, declined to 1.56 at 60 min, then increased to 3.10 2 hr postinjection. The percentage of natural killer/killer cells (HNK-1+) increased from a baseline of 15.5% before epinephrine injection to 29.6% at 30 min postinjection, then declined to 11.4% at 2 hr. Therefore, the administration of physiologic doses of epinephrine results in changes in the relative proportions of lymphocyte subsets in peripheral blood, in addition to reduced mitogen responsiveness as reported previously.


Differential expression of interferon-γ and chemokine genes distinguishes Rasmussen encephalitis from cortical dysplasia and provides evidence for an early Th1 immune response.
Rasmussen encephalitis (RE) is a rare complex inflammatory disease, primarily seen in young children, that is characterized by severe partial seizures and brain atrophy. Surgery is currently the only effective treatment option. To identify genes specifically associated with the immunopathology in RE, RNA transcripts of genes involved in inflammation and autoimmunity were measured in brain tissue from RE surgeries and compared with those in surgical specimens of cortical dysplasia (CD), a major cause of intractable pediatric epilepsy. Quantitative polymerase chain reactions measured the relative expression of 84 genes related to inflammation and autoimmunity in 12 RE specimens and in the reference group of 12 CD surgical specimens. Data were analyzed by consensus clustering using the entire dataset, and by pairwise comparison of gene expression levels between the RE and CD cohorts using the Harrell-Davis distribution-free quantile estimator method. Consensus clustering identified six RE cases that were clearly distinguished from the CD cases and from other RE cases. Pairwise comparison showed that seven mRNAs encoding interferon-γ, CCL5, CCL22, CCL23, CXCL9, CXCL10, and Fas ligand were higher in the RE specimens compared with the CD specimens, whereas the mRNA encoding hypoxanthine-guanine phosphoribosyltransferase was reduced. Interferon-γ, CXCL5, CXCL9 and CXCL10 mRNA levels negatively correlated with time from seizure onset to surgery (P <0.05), whereas CCL23 and Fas ligand transcript levels positively correlated with the degree of tissue destruction and inflammation, respectively (P <0.05), as determined from magnetic resonance imaging (MRI) T2 and FLAIR images. Accumulation of CD4+ lymphocytes in leptomeninges and perivascular spaces was a prominent feature in RE specimens resected within a year of seizure onset. Active disease is characterized by a Th1 immune response that appears to involve both CD8+ and CD4+ T cells. Our findings suggest therapeutic intervention targeting specific chemokine/chemokine receptors may be useful in early stage RE.


Apoptosis as pathogenic mechanism of infection with vesicular stomatitis virus. Evidence in primary bovine fibroblast cultures.
To determine whether fibroblasts from Blanco Orejinegro cattle, exhibit any level of resistance to infection against vesicular stomatitis virus (VSV) serotypes Indiana (VSV-I) or New Jersey (VSV-NJ), 30 fibroblast cultures were phenotyped to evaluate their resistance/susceptibility. Thirty three % of Blanco Orejinegro fibroblast cultures were classified as very resistant, 50% as resistant, and 17% as susceptible to VSV-I infection, whereas 20% were classified as very resistant, 50% as resistant and 30% as susceptible to VSV-NJ infection. Therefore, there appears to be a large variation in phenotypic polymorphism among the fibroblasts to infection by VSV. To elucidate the mechanisms responsible for this diversity, we searched for a possible relationship between resistance/susceptibility and production of factors with antiviral activity; however fibroblasts did not secrete factors with antiviral activity. We examined also whether apoptosis where induced by infection and its correlation with the polymorphism of resistance/susceptibility to VSV. Using morphological analyses, hypoploidy measurements, and level of phosphatidyl serine expression, high levels of apoptosis were measured in VSV infected fibroblasts. However, no correlation exists between apoptosis and the category of resistance/susceptibility to infection, indicating that apoptosis is a pathogenic mechanism of VSV.


Septic arthritis of the distal interphalangeal joint in 12 horses.
The medical records of 12 horses with septic arthritis of a distal interphalangeal joint were reviewed to determine clinical features and response to treatment. Sepsis was caused by trauma or an injection that resulted in an open or contaminated distal interphalangeal joint. All horses were severely lame. Treatment included broad-spectrum parenterally administered antimicrobial drugs (ten horses), percutaneous through-and-through joint lavage (eight horses), indwelling drains (three horses), immobilization of the limb in a cast (three horses), intraarticular injection of sodium hyaluronate (one horse), intraarticular injection of antimicrobial drugs (five horses), curettage of the distal phalanx (one horse), and cancellous bone grafting to promote fusion (one horse). Five horses were euthanatized. Ankylosis of the affected joint developed in five horses, four of which are pasture sound. Two horses treated medically are sound although one underwent subsequent palmar digital neurectomy for treatment of navicular syndrome.


Phosphorus removal from UASB reactor effluent by reactive media filtration.
The phosphorus (P) and BOD7 removal performance of an upflow packed bed reactor (PBR) filled with two reactive filter media was studied over 50 weeks. The lower one-fifth of the reactor was filled with calcium-silicate-hydrate (Sorbulite®) and the upper four-fifth with calcium-silicate (Polonite®). A laboratory-scale upflow anaerobic sludge bed reactor (UASB) delivered wastewater to the PBR. A model was developed to describe the gradient in P concentration change in the reactor, based on reaction kinetics. The reaction terms were assumed to follow the Langmuir isotherm, based on the results obtained in a batch test. First, a comparison was made between experimental and simulated results. The capability of the model to forecast P removal capacity was then tested for three hypothetical cases: (i) reactor filled with Sorbulite and Polonite, (ii) reactor filled with only Sorbulite, and (iii) reactor filled with only Polonite. Finally, a sensitivity analysis was performed for the main parameters in the model. The average removal of P and BOD7 from the UASB effluent was 98% and 90%, respectively. The starting pH of the dual-medium effluent was 12.2 and decreased gradually over time to 11.1. The simulation both overestimated and underestimated mean measured P removal but was within the range of maximum and minimum measured values. The hypothetical cases revealed that most P was removed by Polonite due to calcium phosphate precipitation. The removal capacity of the two filter materials and their layer height in the reactor were the most sensitive parameters in the simulation.


Physical Inactivity, Sedentary Behavior and Quality of Life in the Chilean Population: ENCAVI Results, 2015-2016.
Regular physical activity (PA) is indicated to be one of the main healthy habits that allow populations to achieve a good quality of life (QoL); however, levels of physical inactivity (PI) and sedentary behavior (SB) have risen worldwide, with negative health effects. The aim of this study is to analyze PI and SB levels, as well as their association with QoL in the Chilean population. A secondary analysis was performed based on the database from the 2015-2016 National Quality of Life Survey (ENCAVI) in Chile, using the modules for sociodemographic characteristics, health, and PA. Contingency tables and logistic regressions were conducted to determine the association between PI (low-intensity PA, LIPA; low-moderate PA, LMPA), SB (P75), and QoL adjusted for sociodemographic variables. Approximately 84%, 83%, and 47% of the participants presented LIPA, LMPA, and moderate-high SB, respectively. Participants that presented high PI and SB had lower QoL scores than those who were more active (p < 0.05). We observe that, in people with PI (LIPA), there is a higher risk of a low QoL regarding mental and physical components (OR 1.941; OR 1.189, p < 0.001) among females (OR 1.473; OR 1.513, p < 0.001) and those of a low educational level (OR 2.170; OR 1.410 p < 0.001). People with PI (LMPA) increased their risk for a low QoL in regard to mental and physical components (OR 1.750; OR 1.458, p < 0.001) among females (OR 1.528; OR 1.507, p < 0.001) and those of a low educational level (OR 2.195; OR 1.402 p < 0.001). We observe that people with SB (P75) increased their risk of a low QoL concerning physical and mental components (OR 1.475; OR 1.257, p < 0.001) for those of the female gender (OR 1.615; OR 1.563, p < 0.001) and a low educational level (OR 2.248; OR 1.423 p < 0.001). High levels of PI in both intensities and SB impact QoL in the Chilean population. It is crucial to generate public policies for more PA, especially for females and those of lower educational levels.


Oxygen glucose deprivation switches the transport of tPA across the blood-brain barrier from an LRP-dependent to an increased LRP-independent process.
Despite uncontroversial benefit from its thrombolytic activity, the documented neurotoxic effect of tissue plasminogen activator (tPA) raises an important issue: the current emergency stroke treatment might not be optimum if exogenous tPA can enter the brain and thus add to the deleterious effects of endogenous tPA within the cerebral parenchyma. Here, we aimed at determining whether vascular tPA crosses the blood-brain barrier (BBB) during cerebral ischemia, and if so, by which mechanism. First, BBB permeability was assessed in vivo by measuring Evans Blue extravasation following intravenous injection at 0 or 3 hours after middle cerebral artery electrocoagulation in mice. Second, the passage of vascular tPA was investigated in an in vitro model of BBB, subjected or not to oxygen and glucose deprivation (OGD). We first demonstrated that after focal permanent ischemia in mice, the BBB remains impermeable to Evans Blue in the early phase (relative to the therapeutic window of tPA), whereas at later time points massive Evans Blue extravasation occurs. Then, the passage of tPA during these 2 phases, was investigated in vitro and we show that in control conditions, tPA crosses the intact BBB by a low-density lipoprotein (LDL) receptor-related protein (LRP)-dependent transcytosis, whereas OGD leads to an exacerbation of tPA passage, which switches to a LRP-independent process. We evidence 2 different mechanisms through which vascular tPA can reach the brain parenchyma, depending on the state of the BBB. As discussed, these data show the importance of taking the side effects of blood-derived tPA into account and offer a basis to improve the current thrombolytic strategy.


The larval attachment organ of the bowfin Amia ocellicauda Richardson, 1836 (Amiiformes: Amiidae) and its phylogenetic significance.
Larval attachment organs (LAOs) are unicellular or multicellular organs that enable the larvae of many actinopterygian fishes to adhere to a substrate before yolk-sac absorption and the free-swimming stage. Bowfins (Amiiformes) exhibit a sizable LAO on the snout, which was first described in the late 19th and early 20th centuries. In this study, we document the LAO of Amia ocellicauda (Richardson, 1836) using a combination of scanning electron microscopy (SEM) and light microscopy, and histochemistry. We examined material representing three stages with SEM ranging in size from 5.8 to 11.2 mm in notochord length and one stage histochemically. We compare the LAO of A. ocellicauda to that of the lepisosteid Atractosteus tropicus Gill, 1863 and show that although the LAOs of A. ocellicauda and A. tropicus are both super-organs, the two differ in the ultrastructure of the entire organ. A. ocellicauda possesses two distinct lobes, with the organs arranged on the periphery with none in the middle, whereas A. tropicus also possesses two lobes, but with the organs scattered evenly across the super-organ. The individual organs of A. ocellicauda possess adhesive cells set deep to support cells with the adhesive substance released through a pore, whereas A. tropicus possesses both support cells and adhesive cells sitting at a similar level, with the adhesive substance released directly onto the surface of the organ. We additionally provide a table summarizing vertebrate genera in which attachment organs have been documented and discuss the implications of our study for hypotheses of the homology of attachment organs in the Holostei.


A comparison of two types of explicitly correlated Gaussian functions for non-Born-Oppenheimer molecular calculations using a model potential.
A new functional form of the explicitly correlated Gaussian-type functions (later called Gaussians or ECGs) for performing non-Born-Oppenheimer (BO) calculations of molecular systems with an arbitrary number of nuclei is presented. In these functions, the exponential part explicitly depends on all interparticle distances and the preexponential part depends only on the distances between the nuclei. The new Gaussians are called sin/cos-Gaussians and their preexponential part is a product of sin and/or cos factors. The effectiveness of the new Gaussians in describing non-BO pure vibrational states is investigated by comparing them with r(m)-Gaussians containing preexponential multipliers in the form of non-negative powers of internuclear distances (the internuclear distance in the diatomic case). The testing is performed for a diatomic system with the nuclei interacting through a Morse potential. It shows that the new sin/cos-Gaussian basis set is capable of providing equally accurate results as obtained with the r(m)-Gaussians. However, especially for lower vibrational states, more sin/cos-Gaussians are needed to reach a similar accuracy level as obtained with the r(m)-Gaussians. Implementation of the sin/cos-Gaussians in non-BO calculations of diatomic and, in particular, of triatomic systems, which will follow, will provide further assessment of the efficiency of the new functions.


The curvature changes induced by grafted polymers in microemulsions.
The results on Winsor phases, droplet and bicontinous microemulsions phases with polymer-grafted lipids studied by Small Angle Neutron Scattering (SANS) are reported below, together with the contrast variation techniques used to characterize the average curvature in the system. We have clearly shown that polymer-grafted lipids change the interaction between microemulsion droplets --it need not be just repulsive but could also be attractive. They induce structural changes or bring about complete phase changes as observed visually in the Winsor phases when added in sufficient amounts. In the bicontinous microemulsion phases, the polymer-grafted lipids decrease the persistence length, hence the bending rigidity, increase the apparent average thickness of the film, and cause a complex deformation of the film which brings about a negative curvature change at a semi-local scale. Contrary to the naive prediction that the polymer-grafted lipids should increase membrane rigidity our experiments show a decrease. This is a subtle effect caused by perhaps an indirect coupling between film curvature and concentration fluctuations.


Effect of retinoic acid-induced transglutaminase on cell growth in regenerating liver.
Transglutaminase 2 (TG2) is implicated in the inhibitory regulation of the hepatocyte growth in vitro. In vivo, however, the role of TG2 in liver regeneration after partial hepatectomy (PH) is almost unknown. A dramatic increase of TG2 expression and activation is induced by retinoic acid (RA). Here we show the effect of the RA-induced overexpression of TG2 on liver regeneration after PH. Regenerating rat liver was prepared by 70% PH. RA was intraperitoneally injected immediately after PH. TG2 activity was determined by incorporation of 14C-putrescine into dimethylcasein. Cell cycle was evaluated for incorporation of BrdU into hepatocytes and detected by a flow cytometric analysis. The treatment of RA greatly increased TG2 activity at 1 day after PH. At that time, DNA synthesis was significantly reduced by the treatment of RA. The recovery of liver weight after PH was significantly delayed by the treatment of RA. These results suggested that TG2 was involved in growth capacity in regenerating rat liver after PH.


Comparative tumorigenicity of 1-nitropyrene, 1-nitrosopyrene, and 1-aminopyrene administered by gavage to Sprague-Dawley rats.
The carcinogenic activities of 1-nitropyrene, a mutagenic component of diesel exhaust, and its reduced derivatives 1-nitrosopyrene and 1-aminopyrene were evaluated in male and female Sprague-Dawley rats. Within 24 h of birth, groups of 22-36 rats were treated by gavage with trioctanoin or the appropriate compound in trioctanoin once weekly for 16 weeks. The approximate total doses per rat were as follows: 1-nitropyrene, high dose (800 mumol); 1-nitropyrene, low dose (320 mumol); 1-nitrosopyrene (320 mumol); 1-aminopyrene (320 mumol). The experiment was terminated after 94 weeks. The main site of tumor induction was the mammary glands of female rats. Percentages of incidences of mammary adenocarcinomas in female rats were as follows: 1-nitropyrene, high dose (63%); 1-nitropyrene, low dose (42%); 1-nitrosopyrene (19%); 1-aminopyrene (4%) trioctanoin (3%). These incidences were significantly greater than those of controls for the female rats treated with either 1-nitropyrene or 1-nitrosopyrene. Low and generally insignificant incidences of tumors of a variety of other sites were also observed in rats treated with 1-nitropyrene. The induction of mammary tumors by 1-nitropyrene confirms the results of a previous study (Hirose et al., Cancer Res., 44: 1158-1162, 1984). The present results also demonstrate that, under the conditions of this bioassay, 1-nitropyrene was significantly more carcinogenic than either 1-nitrosopyrene or 1-aminopyrene.


Subcutaneous immunization with heat shock protein-65 reduces atherosclerosis in Apoe⁻/⁻ mice.
To modulate atherosclerosis by combining subcutaneous immunization with heat shock protein 65 (hsp65) in alum adjuvant and anti-CD45RB monoclonal antibodies (mAb). 8 week old Apoe⁻/⁻ mice on normal chow were treated for 12 weeks: group A received hsp65-alum immunization combined with anti-CD45RB mAb, group B hsp65-alum immunization combined with isotype control antibody, and group C mock vaccine combined with isotype control antibody. Unexpectedly, atherosclerotic lesions in the aortic root were significantly reduced in both hsp65-alum immunization groups (A and B) compared with the control group (C). Significantly elevated antibody titers against hsp65 were detected in both groups along with a significant increase in MHC class II expression on B cells. Body weight, total cholesterol and triglyceride levels were not different between groups. Treatment with anti-CD45RB antibody mediated a shift on CD4⁺ T cells from the CD45RB(high) to CD45RB(low) isoform with a relative increase in CD4⁺Foxp3⁺ regulatory T cells (Treg) in an overall reduced T cell pool. Furthermore, anti-CD45RB treatment mediated a transient reduction of peripheral leukocytes and increased IFN-γ and IL-17A plasma levels. Subcutaneous immunization with hsp65-alum protects Apoe⁻/⁻ mice against progression of early atherosclerosis. Administration of anti-CD45RB antibody provided no incremental benefit to the athero-protective effects of hsp65-alum treatment alone.


Efficient generalized matrix approximations for biomarker discovery and visualization in gene expression data.
In most real-life gene expression data sets, there are often multiple sample classes with ordinals, which are categorized into the normal or diseased type. The traditional feature or attribute selection methods consider multiple classes equally without paying attention to the up/down regulation across the normal and diseased types of classes, while the specific gene selection methods particularly consider the differential expressions across the normal and diseased, but ignore the existence of multiple classes. In this paper, for improving the biomarker discovery, we propose to make the best use of these two aspects: the differential expressions (that can be viewed as the domain knowledge of gene expression data) and the multiple classes (that can be viewed as a kind of data set characteristic). Therefore, we simultaneously take into account these two aspects by employing the 1-rank generalized matrix approximations (GMA). Our results show that the consideration of both aspects can not only improve the accuracy of classifying the samples, but also provide a visualization method to effectively analyze the gene expression data on both genes and samples. Based on the GMA mechanism, we further propose an algorithm for obtaining the compact biomarker by reducing the redundancy.


H7 Hemagglutinin nanoparticles retain immunogenicity after >3 months of 25°C storage.
Vaccine distribution infrastructure remains inadequate in many parts of the world, and it is estimated that up to 40-50% of all vaccine doses are wasted in certain countries. Vaccines that can maintain viability outside of the cold chain would decrease vaccine wastage and increase immunization rates in regions of the world with underdeveloped vaccine distribution infrastructure. We examined the potential of crosslinked protein nanoparticles, made from trimerized influenza hemagglutinin (3HA), to maintain immunogenicity after cold-chain-independent storage. We found that the nanoparticles could be stored for 112 days at room temperature without any loss in hemagglutinating activity or immunogenicity, and that nanoparticles could be stored at 37°C for 2 weeks without any loss in hemagglutinating activity. As vaccine development moves towards the use of recombinant subunit antigens, our results demonstrate the potential of crosslinked antigen nanoparticles as an immunogenic vehicle for bringing effective vaccines to underdeveloped regions outside of the cold chain.


Cytomegalovirus antivirals and development of improved animal models.
Cytomegalovirus (CMV) is a ubiquitous pathogen that establishes a lifelong asymptomatic infection in healthy individuals. Infection of immunesuppressed individuals causes serious illness. Transplant and AIDS patients are highly susceptible to CMV leading to life-threatening end-organ disease. Another vulnerable population is the developing fetus in utero, where congenital infection can result in surviving newborns with long-term developmental problems. There is no vaccine licensed for CMV and current antivirals suffer from complications associated with prolonged treatment. These include drug toxicity and emergence of resistant strains. There is an obvious need for new antivirals. Candidate intervention strategies are tested in controlled preclinical animal models but species specificity of human CMV precludes the direct study of the virus in an animal model. This review explores the current status of CMV antivirals and development of new drugs. This includes the use of animal models and the development of new improved models such as humanized animal CMV and bioluminescent imaging of virus in animals in real time. Various new CMV antivirals are in development, some with greater spectrum of activity against other viruses. Although the greatest need is in the setting of transplant patients, there remains an unmet need for a safe antiviral strategy against congenital CMV. This is especially important as an effective CMV vaccine remains an elusive goal. In this regard, greater emphasis should be placed on suitable preclinical animal models and greater collaboration between industry and academia.


Thermogenesis in obese women: effect of fructose vs. glucose added to a meal.
To assess the effect of a fructose meal on resting energy expenditure (EE), indirect calorimetry was used in 23 women (10 lean and 13 obese) for 30 min before and 6 h after the ingestion of a mixed meal containing 20% protein, 33% fat, and either 75 g glucose or 75 g fructose as carbohydrate source (47%). Expressed as a percentage of the energy content of the meal, the thermogenic response to the fructose meal was significantly greater (10.2 +/- 0.5%) than that of the glucose meal (8.4 +/- 0.4%, P less than 0.01). This difference was still apparent when the lean and obese women were considered separately. The mean respiratory quotient during the 6-h postprandial period was significantly greater (P less than 0.01) for the fructose (0.85 +/- 0.01) than for the glucose meal (0.83 +/- 0.01) in the combined subjects. In addition, cumulative carbohydrate oxidation was significantly greater after the fructose than after the glucose meal (51.1 +/- 2.3 vs. 40.9 +/- 2.0 g/6 h, respectively, P less than 0.01). Only small changes were observed in postprandial plasma levels of glucose and insulin after the fructose meal, but the plasma levels of lactate increased more with fructose than with the glucose meal. These results suggest that there might be some advantages (higher thermogenesis and carbohydrate oxidations) in using fructose as part of the carbohydrate source in diet of people with obesity and/or insulin resistance.


Structure-Activity Relationship Study of Heterocyclic Phenylethenyl and Pyridinylethenyl Derivatives as Tau-Imaging Agents That Selectively Detect Neurofibrillary Tangles in Alzheimer's Disease Brains.
In order to explore novel tau-imaging agents that can selectively detect neurofibrillary tangles in Alzheimer's disease (AD) brains, we designed and synthesized a series of heterocyclic phenylethenyl and (3-pyridinyl)ethenyl derivatives with or without a dimethyl amino group. In in vitro autoradiography using AD brain sections, all radioiodinated ligands with a dimethyl amino group bound to Aβ deposits in the sections. In contrast, the ligands without a dimethyl amino group showed different patterns of radioactivity accumulation in the sections depending on the kind of heterocycle contained in their molecules. Particularly, a phenylethenyl benzimidazole derivative ([(125)I]64) showed marked radioactivity accumulation in the temporal lobe which corresponded with the distribution of tau deposits. [(125)I]64 also showed the most favorable pharmacokinetics in normal mouse brains (3.69 and 0.06% ID/g at 2 and 60 min postinjection, respectively) among all ligands in this study. Taken together, these results suggest that [(123)I]64 may be a new candidate tau-imaging agent.


Ventricular arrhythmias during treatment with alteplase (recombinant tissue plasminogen activator) in suspected acute myocardial infarction.
Continuous electrocardiography during the first 24 hours of a stay in a coronary care unit was used to record ventricular arrhythmias during treatment with alteplase (recombinant tissue plasminogen activator) or placebo. Recordings were made on 378 of the 436 patients admitted to a double blind trial of alteplase or placebo in one participating centre of the Anglo-Scandinavian study of early thrombosis (ASSET), patients being selected according to the availability of recorders. Of these, 309 (158 given alteplase and 151 placebo) had greater than 5 hours of analysable data. Most of the arrhythmias were recorded in patients with an in hospital diagnosis of myocardial infarction. Ventricular couplets and ventricular tachycardia were significantly more common in the patients treated with alteplase. Further, in patients with myocardial infarction who had ventricular extrasystoles, couplets, or ventricular tachycardia type a, the number of hours in which each arrhythmia was recorded was significantly higher in the alteplase group. The various ventricular arrhythmias in the alteplase group tended to cluster in the first 4-12 hours of the recordings. During the first 24 hours admission there were four episodes of ventricular fibrillation in the alteplase group and five in the placebo group of taped patients. By one month there had been 18 deaths in these 309 patients (alteplase four, placebo 14). These bore no relation to any recorded arrhythmia. Clinical records for the patients with no or minimal tape data yielded six further episodes of ventricular fibrillation during the first 24 hours (three in the alteplase group and three in the placebo group). Of the total 436 patients, 10 of the 218 patients in the alteplase group had died by one month compared with 22 of the 218 patients treated with placebo. The use of alteplase increases the incident of non-life threatening ventricular arrhythmias. These results, however suggest that arrhythmia after thrombolysis in the pre-hospital phase may be less of a problem than it is perceived to be.


Network Oncology (NO)--a clinical cancer register for health services research and the evaluation of integrative therapeutic interventions in anthroposophic medicine.
Concepts of integrative oncology (IO), as have been offered by anthroposophic medicine (AM) for decades, are gaining increasing interest and acceptance. Central aspects are multimodal therapeutic interventions, health-related quality of live, and patients' preference as well as therapeutic relationship and clinical outcome. Despite its broad application, IO lacks evaluation in clinical practice and complementary therapies are not monitored by any cancer registries. To close this gap we established 'Network Oncology' (NO), a conjoint registry of German outpatient AM practitioners and AM hospitals. In this paper we present the project and a first data overview and compare it to epidemiological registers and current literature. NO has collected 10,405 cancer patients' records in 6 years. Compared to epidemiological registers our data show minor differences in disease entity distribution, age, and gender. There is an overproportional amount of young breast cancer patients in NO institutions indicating a demand for integrative therapies in this group. There is no difference between the UICC (Union for International Cancer Control) stages at first diagnosis and at admission to a NO facility. According to our data conventional therapies were less frequently administered after admission to a NO facility. Nevertheless, one third of the patients received their first conventional therapy in a NO facility. 80% of the patients received mistletoe preparations and 63% had nonpharmacotherapeutic, complementary interventions. Integrative oncological approaches attract a great number of patients visiting AM institutions. The NO provides an infrastructure to evaluate integrative interventions in AM, allows comparison to other clinical registers, and thus can contribute to health service research in this field.


Indications of Potassium Titanyl Phosphate Laser Therapy for Slow-Flow Vascular Malformations in Oral Region.
Indications for laser therapy for slow-flow vascular malformations in the oral and maxillofacial regions have not been clearly documented. The authors aimed to estimate the frequency of resolution of slow-flow vascular malformations and to identify risk and prognostic factors associated with resolution in potassium titanyl phosphate (KTP) laser treatment. This study was designed as a prospective cohort study. Patients who had diagnosed slow-flow vascular malformations were continuously assigned to receive KTP laser therapy. All patients had intralesional laser photocoagulation performed under local anesthesia. Administered power of the KTP laser was fixed at 2 watts throughout the procedure in all patients. The primary endpoint was to understand the frequency of resolution of slow-flow vascular malformations in KTP laser treatment. Secondary endpoints were: treatment outcomes based on lesion size; treatment outcomes based on location; treatment outcomes based on total energy in joules; types of complications. Treatment outcomes were judged by a clinical assessment as well as reduction in lesion size on magnetic resonance imaging. Data were obtained from 26 patients (9 men, 17 women) with 38 lesions. The average lesion size was 13.5 ± 7.7 mm. Treatment outcomes based on lesion size showed that cure and regression were obtained in lesions less than 30 mm in size. However, lesions larger than 30 mm showed no response. Lesions in the tongue and lips showed higher cure rates than in other areas. Treatment outcomes based on administered total energy in joules showed that 68% of lesions were treated and responded well at less than 400 joules. Complication rate was relatively high in the buccal mucosal lesions. Immediate postoperative complications such as necrosis were more common in high-energy administration than in low-energy administration. Our results indicated that KTP laser therapy was effective for slow-flow vascular malformations less than 30 mm in size without significant side effects.


Distribution of endo-beta-N-acetylglucosaminidase amongst enterococci.
Enterococci are becoming increasingly important nosocomial pathogens, a fact mainly attributed to their antimicrobial resistance profiles. However, the enzymic activities required for these organisms to proliferate in vivo have received little attention. Enterococcus faecalis has been shown previously to produce an endo-beta-N-acetylglucosaminidase activity which cleaves high mannose-type glycans in glycoproteins between the N-acetylglucosamine residues of the pentasaccharide core. This study investigated the distribution of this endoglycosidase activity amongst the other enterococcal species. Ribonuclease B, a high mannose-type glycoprotein, was used as a substrate and endoglycosidase activity was demonstrated by a combination of matrix-assisted laser desorption ionisation time-of-flight mass spectrometry and high pH anion-exchange chromatography. Endo-beta-N-acetylglucosaminidase activity was present in 10 of the 18 enterococcal species isolated from both human and animal sources, including all E. faecalis strains. The most notable exception was the lack of this activity in all E. faecium isolates tested. All enterococcal species possessing endoglycosidase activity utilised the liberated glycans to support bacterial growth.


Recombinant soybean protein beta-conglycinin alpha'-subunit expression and induced hypersensitivity reaction in rats.
The major storage protein in soybean seed is beta-conglycinin and this protein has been identified as being responsible for food-allergic reactions in several species. However, the mechanism through which beta-conglycinin induces an allergic reaction has not yet been elucidated. In addition, assessing the antigenic activity of beta-conglycinin by studying the activity of a subunit has rarely been conducted. Therefore, the objective of the present study was to characterize the antigenic specificity of the beta-conglycinin alpha'-subunit. We established an Escherichia coli expression system to obtain beta-conglycinin alpha'-subunit. The fusion proteins were then used in a rat model to induce a hypersensitive reaction. Immunoblotting, IgE and IgG1 level, histamine release, and passive cutaneous anaphylaxis reactions and intestinal histology were tested to assess the allergenic activity of the beta-conglycinin alpha'-subunit. Pure beta-conglycinin alpha'-subunit was obtained by expression in E. coli. The recombinant proteins were shown to have the same biological activity as the natural beta-conglycinin alpha'-subunit using immunoblotting analysis. Both the IgE and IgG1 level in serum and the histamine concentration in the intestine were increased while passive cutaneous anaphylactic reactions were induced in Brown Norway rats by intragastric gavage with the alpha'-subunit. Histamine release of mast cells was also elevated in vitro. Our results indicate that the beta-conglycinin alpha'-subunit possesses an intrinsic immune-stimulating capacity and that it can induce an allergic reaction. Moreover, this study showed that beta-conglycinin alpha'-subunit-induced anaphylaxis is IgE mediated, and mast cell degranulation and histamine release are associated with anaphylactic symptoms.


Myelin-forming cell-specific cadherin-19 is a marker for minimally infiltrative glioblastoma stem-like cells.
Glioblastoma stem-like cells (GSCs) exhibit stem-like properties, are highly efficient at forming tumor xenografts, and are resistant to many current therapies. Current molecular identifiers of GSCs are scarce and controversial. The authors describe differential cell-surface gene expression profiling to identify GSC-specific markers. Independent human GSC lines were isolated and maintained in standard neural stem cell (NSC) media and were validated for self-renewal, multipotent differentiation, and tumor initiation properties. Candidate upregulated GSCspecific plasma membrane markers were identified through differential Affymetrix U133 Plus 2.0 Array gene expression profiling of GSCs, human NSCs (hNSCs), normal brain tissue, and primary/recurrent glioblastoma multiforme samples. Results were validated by using comparative quantitative reverse transcription polymerase chain reaction and Western blot analysis of GSCs, hNSCs, normal human astrocytes, U87 glioma cell line, and patient-matched serum-cultured glioblastoma multiforme samples. A candidate GSC-specific signature of 19 upregulated known and novel plasma membrane-associated genes was identified. Preferential upregulation of these plasma membrane-linked genes was validated by quantitative polymerase chain reaction. Cadherin-19 (CDH19) protein expression was enhanced in minimally infiltrative GSC lines. Gene expression profiling of GSCs has shown CDH19 to be an exciting new target for drug development and study of GBM tumorigenesis.


Cervical Screening Reminders for Aboriginal and Torres Strait Islander Women in Primary Care-Randomised Controlled Trial of Letter vs. Phone/SMS Reminders.
(1) Background: Aboriginal women have a higher mortality from cervical cancer, yet cervical screening rates are lower than for other Australian women. (2) Methods: A randomised controlled trial of reminder letter vs. phone call/SMS for routine cervical screening testing in an Aboriginal Community Controlled Health Organisation in NSW. (3) Results: 256 women aged between 25 and 74 who were due for cervical screening were randomised to receive a reminder letter (and up to two further letters for non-responders) or a phone call (followed by up to two SMS) to attend the screening. A total of 15 women (12.5%) attended for cervical screening test within 3 months following a letter, and 24 women (17.6%) after a phone call/SMS reminder; this difference was not significant (p = 0.252). Time spent on sending letters vs. phone calls/SMS was similar; the cost was lowest for SMS. (4) Conclusion: Response to reminders was lower than expected. While there was no significant difference in effectiveness in letter vs. phone call/SMS for cervical screening recalls, reminder systems, including opportunistic reminders, can play a role in encouraging women to participate in screening programs in conjunction with national screening registers. The choice of reminder type should be left to service and consumer preference.


Defining Learning Outcomes as a Prerequisite of Implementing a Longitudinal and Transdisciplinary Curriculum with Regard to Digital Competencies at Hannover Medical School.
Worldwide educational programs face the challenge how to define and integrate digital competencies in medical education. This article describes the implementation of learning outcomes with respect to digital competencies in the compulsory curriculum at Hannover Medical School (MHH). An interdisciplinary MHH project group was constituted consisting of physicians and experts in medical informatics and in curriculum development. Over the course of 7 work sessions the group compared different international and national frameworks dealing with digital competencies for physicians. By a consensus driven approach the working group drew up a collection of learning outcomes which were regarded relevant to be incorporated in the curriculum at MHH. The analysis of different frameworks indicated that data literacy is a central domain within all viewed preexisting catalogs. During the course of the project group analysis, 57 learning outcomes with respect to digital competencies were identified as necessary to be integrated in the compulsory curriculum. They were divided in 5 main categories: "handling of medical data," "the digital infrastructure of the health system," "scope of application: usage in patient care and in the field of preventive medicine," "medico-legal and ethical basics," and "transformation processes in medicine due to digitalization." The MHH project group concluded that medical students should be taught digital competencies that enable an understanding of underlying functional principles of digital systems rather than their correct utilization. The presented project indicates that a close interdisciplinary collaboration of physicians and medical informaticians can be a promising approach to incorporate digital competencies in the undergraduate medical curriculum.


[Increasing the scar strength after preventive skin irradiation with low-intensity laser].
In the experiment on 218 white rats, it was established that preliminary influencing upon the site of a future incision with the infrared laser radiation in constant regime within the range of from 1 to 150 mW (dosage of radiation per 1 field of 0.06-9.3 J/cm2) facilitated pronounced stimulation of the processes of collagen formation and significant increase in strength of a forming scar. In increasing the power of radiation, the reparative processes in a wound are slowed and disturbed; in power of 250 mW, a wound heals by second intention, in average, after (32.6 +/- 3.2) days.


Detection and characterization of the fibroblast growth factor-related oncoprotein INT-2.
Products of the fibroblast growth factor-related proto-oncogene int-2 have been detected by using a monoclonal antibody and polyclonal antisera raised against synthetic peptides predicted from the DNA sequence. COS-1 monkey cells transfected with int-2 DNA linked to the simian virus 40 early promoter contained at least four int-2-specific proteins, presumably representing modified forms of the expected 27-kilodalton primary translation product. The level of expression was increased approximately six- to eightfold by mutation of sequences around the presumed initiation codon, negating their capacity to encode a short oligopeptide in the +1 reading frame. Both tunicamycin inhibition and in vitro translation experiments indicated that some of the modifications correspond to asparagine-linked glycosylation, for which the sequence predicts a single site. In line with the similarities between INT-2 and other fibroblast growth factors, the in vitro translation products functioned as weak mitogens for mammary epithelial cells.


Determination of moisture content of single-wall carbon nanotubes.
Several techniques were evaluated for the establishment of reliable water/moisture content of single-wall carbon nanotubes. Karl Fischer titration (KF) provides a direct measure of the water content and was used for benchmarking against results obtained by conventional oven drying, desiccation over anhydrous magnesium perchlorate as well as by thermogravimetry and prompt gamma-ray activation analysis. Agreement amongst results was satisfactory with the exception of thermogravimetry, although care must be taken with oven drying as it is possible to register mass gain after an initial moisture loss if prolonged drying time or elevated temperatures (120 °C) are used. Thermogravimetric data were precise but a bias was evident that could be accounted for by considering the non-selective loss of mass as volatile carbonaceous components. Simple drying over anhydrous magnesium perchlorate for a minimum period of 8-10 days is recommended if KF is not available for this measurement.


Corneal decompensation in Chandler's syndrome. A scanning and transmission electron microscopic study.
A corneal button obtained from a 58-year-old woman with Chandler's syndrome was studied by light and electron microscopy. Clinically, the patient had mild unilateral glaucoma, slight changes in the iris, endothelial dystrophy, and corneal edema that was increasingly sensitive to intraocular pressure. Corneal pathology included loss of large numbers of endothelial cells with consequent exposure of Descemet's membrane. Endothelial cells demonstrated irregular shape, partial loss of tight junctions, and increased numbers of cytoplasmic filaments. Some endothelial cells appeared metaplastic or perhaps were replaced by cells from some source other than the cornea. Proliferation of cells was not apparent. A thin layer of acellular tissue, containing long-spacing collagen and 15-nm-wide fibrils, was interposed between normal Descemet's membrane and the endothelium. These observations suggest a basis for the corneal edema that distinguishes Chandler's syndrome from other forms of essential iris atrophy.


Goose-neck snare-assisted transcatheter ASD closure: A safety procedure for large and complex ASDs.
To report on a new technique that increases the safety of percutaneous atrial septal defect (ASD) closure using a goose-neck snare system. ASD transcatheter closure is a widespread procedure. However, in some cases, ASDs may be large and with soft rims. In these situation, a potential risk exists for device malposition or embolization. When transesophageal echocardiography (TEE) evaluation and balloon sizing showed large defects with floppy rims the chosen Amplatzer device was implanted in a standard way. In large defects with floppy rims, before release a 5-mm goose-neck snare with its 4 Fr catheter was placed across the delivery cable and fixed to catch the screwing mechanism of implanted Amplatzer device. The delivery cable was unscrewed and the device reached its final position without any tension. If the position was considered satisfactory the device was released from the goose-neck snare. Thirteen patients had a snare-assisted ASD transcatheter closure. Median device size was 24 mm (range 14-38 mm). Retrieval or repositioning of the device using the goose-neck snare was performed in four cases: in three patients, because of device malposition after delivery cable release and in one patient, because of unsuitability of closure of a second significant defect. Furthermore, in two subjects with multiple ASDs, a second fenestration looked quite significant with the device still attached to the delivery cable while it appeared smaller after release. Snare-assisted Amplatzer ASD device placement is a new method for ASD percutaneous closure and adds safety to the procedure.


Emotional attentional capture in children with conduct problems: the role of callous-unemotional traits.
Appropriate reactivity to emotional facial expressions, even if these are seen whilst we are engaged in another activity, is critical for successful social interaction. Children with conduct problems (CP) and high levels of callous-unemotional (CU) traits are characterized by blunted reactivity to other people's emotions, while children with CP and low levels of CU traits can over-react to perceived emotional threat. No study to date has compared children with CP and high vs. low levels of CU traits to typically developing (TD) children or each other, using a task that assesses attentional capture by irrelevant emotional faces. All participants performed an attentional capture task in which they were asked to judge the orientation of a single male face that was displayed simultaneously with two female faces. Three types of trials were presented, trials with all neutral faces, trials with an emotional distractor face and trials with an emotional target face. Fifteen boys with CP and high levels of CU traits, 17 boys with CP and low levels of CU traits and 17 age and ability matched TD boys were included in the final study sample. Compared to TD children and children with low levels of CU traits, children with CP and high levels of CU traits showed reduced attentional capture by irrelevant emotional faces. This study is the first to demonstrate a different pattern in emotional attentional capture in children with CP depending on their level of CU traits.


Quantitative 68Ga-DOTATATE PET/CT Parameters for the Prediction of Therapy Response in Patients with Progressive Metastatic Neuroendocrine Tumors Treated with 177Lu-DOTATATE.
The aim of this study was to determine whether quantitative PET parameters on baseline 68Ga-DOTATATE PET/CT and interim PET (iPET) performed before the second cycle of therapy are predictive of the therapy response and progression-free survival (PFS). Methods: Ninety-one patients with well-differentiated neuroendocrine tumors (mean Ki-67 index, 8.3%) underwent 68Ga-DOTATATE PET/CT to determine suitability for peptide receptor radionuclide therapy as part of a prospective multicenter study. The mean follow-up was 12.2 mo. Of the 91 patients, 36 had iPET. The tumor metrics evaluated were marker lesion-based measures (mean SUVmax and ratio of the mean lesion SUVmax to the SUVmax in the liver or the SUVmax in the spleen), segmented 68Ga-DOTATATE tumor volumes (DTTVs), SUVmax and SUVmean obtained with the liver and spleen as thresholds, and heterogeneity parameters (coefficient of variation, kurtosis, and skewness). The Wilcoxon rank sum test was used for the association between continuous variables and the therapy response, as determined by the clinical response. Univariable and multivariable Cox proportional hazards models were used for the association with PFS. Results: There were 71 responders and 20 nonresponders. When marker lesions were used, higher mean SUVmax and ratio of the mean lesion SUVmax to the SUVmax in the liver were predictors of the therapy response (P = 0.018 and 0.024, respectively). For DTTV parameters, higher SUVmax and SUVmean obtained with the liver as a threshold and lower kurtosis were predictors of a favorable response (P = 0.025, 0.0055, and 0.031, respectively). The latter also correlated with a longer PFS. The iPET DTTV SUVmean obtained with the liver as a threshold and the ratio of mean SUVmax obtained from target lesions at iPET to baseline PET correlated with the therapy response (P = 0.024 and 0.048, respectively) but not PFS. From the multivariable analysis with adjustment for age, primary site, and Ki-67 index, the mean SUVmax (P = 0.019), ratio of the mean lesion SUVmax to the SUVmax in the liver (P = 0.018), ratio of the mean lesion SUVmax to the SUVmax in the spleen (P = 0.041), DTTV SUVmean obtained with the liver (P = 0.0052), and skewness (P = 0.048) remained significant predictors of PFS. Conclusion: The degree of somatostatin receptor expression and tumor heterogeneity, as represented by several metrics in our analysis, were predictive of the therapy response or PFS. Changes in these parameters after the first cycle of peptide receptor radionuclide therapy did not correlate with clinical outcomes.


Phase I study of the gamma secretase inhibitor PF-03084014 in combination with docetaxel in patients with advanced triple-negative breast cancer.
The NOTCH signaling pathway may be involved in the survival of stem cell-like tumor-initiating cells and contribute to tumor growth. In this phase Ib, open-label, multicenter study (NCT01876251), we evaluated PF-03084014, a selective gamma-secretase inhibitor in patients with advanced triple-negative breast cancer. The dose-finding part was based on a 2×3 matrix design using the modified toxicity probability interval method. Oral PF-03084014 was administered twice daily continuously in combination with intravenous docetaxel given on day 1 of each 21-day cycle. Primary endpoint was first-cycle dose-limiting toxicity (DLT) for the dose-finding part and 6-month progression-free survival (PFS) for the expansion cohort treated at the maximum tolerated dose (MTD). Secondary endpoints included safety, objective response, and pharmacokinetics of the combination. The MTD was estimated to be PF-03084014 100 mg twice daily / docetaxel 75 mg/m2. At this dose level, combination treatment was generally well tolerated (one DLT, grade 3 diarrhea, among eight DLT-evaluable patients). The most common all-grade, treatment-related adverse events reported in all patients (N = 29) were neutropenia (90%), fatigue (79%), nausea (72%), leukopenia (69%), diarrhea (59%), alopecia (55%), anemia (55%), and vomiting (48%). No effect was observed on the pharmacokinetics of docetaxel when administered in combination with PF-03084014. Four (16%) of 25 response-evaluable patients achieved a confirmed partial response; nine (36%) patients had stable disease, including five patients with unconfirmed partial response. In the expansion cohort, median PFS was 4.1 (95% CI 1.3-8.1) months (6-month PFS rate 17.1% [95% CI 0.8-52.6%]).


Effect of Ni2+, Co2+, Zn2+, Fe2+, Cd2+, Hg2+, Cu2+ and VO-3 on coronary vascular resistance in the isolated perfused rat heart.
The coronary vascular effect of various divalent cations and of sodium-metavanadate was compared in isolated perfused rat hearts. Their order of activity was as follows (the concentrations (microM) evoking a half-maximum increase of coronary resistance are indicated (in parentheses): Ni2+ (0.03) greater than Co2+ (0.1) greater than Hg2+ (0.16) greater than VO-3 (0.2) greater than Cu2+ (15) greater than Zn (50). Iron (Fe2+) and cadmium (Cd2+) were ineffective. The order of coronary vasoconstrictor potency of these metal ions differs from the order of their other physico-chemical properties indicating that their coronary action cannot be explained as being singly a consequence of ion-membrane interaction. In contrast to Ni2+, the effect of Hg2+ was totally inhibited by phenoxybenzamine (10(-5)M) indicating that coronary vasoconstriction induced by mercury ions is mediated by alpha-receptors. Coronary vasoconstriction induced by sodium-meta-vanadate was resistant to verapamil while removal of external Ca2+ potentiated its effect. These data suggest that in contrast to Ni2+ and Hg2+, vanadate increases coronary resistance by mobilizing intracellular Ca2+ in vascular smooth muscle cells.


A near-fatal consequence of chiropractor massage: massive stroke from carotid arterial dissection and bilateral vertebral arterial oedema.
A 35-year-old Chinese man with no risk factors for stroke presented with a 2-day history of expressive dysphasia and a 1-day history of right-sided weakness. The presentation was preceded by multiple sessions of neck, shoulder girdle and upper back massage for pain relief in the prior 2 weeks. CT of the brain demonstrated an acute left middle cerebral artery infarct and left internal carotid artery dissection. MRI cerebral angiogram confirmed left carotid arterial dissection and intimal oedema of bilateral vertebral arteries. In the absence of other vascular comorbidities and risk factors, massage-induced internal carotid arterial dissection will most likely precipitate the near-fatal cerebrovascular event. The differential diagnosis of stroke in a younger population was consequently reviewed and discussed.