Effect of a new beta-blocker, nipradilol, on cardiac function and neurohumoral factors in idiopathic dilated cardiomyopathy.
This study investigated the therapeutic efficacy of a new beta-blocker, nipradilol, a non-selective agent with vasodilating activity, for the treatment of idiopathic dilated cardiomyopathy (DCM). The New York Heart Association functional class improved in the nipradilol group (n = 9, p < 0.01), but not in the control group who received conventional therapy (n = 9). The observation period was 19 +/- 7 months in the nipradilol group, and 20 +/- 9 months in the control group. Before therapy there was no difference in heart rate between the 2 groups (76 +/- 12 vs 79 +/- 15 beats/min). The end-diastolic and end-systolic left ventricular dimensions decreased in the nipradilol group (p < 0.05), but not in the control group. Radionuclide ventriculography revealed that the left ventricular ejection fraction increased in the nipradilol group (27 +/- 8 to 41 +/- 18%, p < 0.05), but not in the control group (27 +/- 11 to 27 +/- 8%). Plasma norepinephrine tended to be lowered, although not significantly, whereas plasma alpha atrial natriuretic peptide significantly decreased after the therapy (p < 0.01) in the treatment group. Lymphocyte beta-adrenoceptors were up-regulated in the nipradilol group (p < 0.05). None of these parameters changed during the observation period in the control group. Thus, nipradilol improved symptoms and cardiac function with a favorable effect on neurohumoral factors in patients with DCM.


Adolescent and caregiver experiences with epilepsy.
Epilepsy during adolescence can impede the development of psychosocial independence and typical biological maturational processes. We examined in parallel the experiences and perceptions of adolescent patients with epilepsy and their caregivers. Specifically, we focused on frequency and type of seizures, comorbid conditions, adherence to therapies, productivity, clinical and quality of life consequences of seizures, estimated use and content of seizure emergency plans, and the patient-physician relationship. Two cross-sectional online surveys were conducted among 153 adolescent patients with epilepsy and their respective caregivers. A total of 35% of adolescents indicated that they had been nonadherent to antiepileptic medications in the prior month. Adolescents scored significantly lower compared with their peers on quality-of-life measures. Adolescents and caregivers reported similarly on nearly all domains. An adolescent-centered epilepsy management program may help alleviate concerns and also help the adolescent independently manage their epilepsy as they transition into adulthood.


Exosomal Long Non-Coding RNA: Interaction Between Cancer Cells and Non-Cancer Cells.
Exosomes are small membranous vesicles released by many kinds of cells, and are indispensable in cell-to-cell communication by delivering functional biological components both locally and systemically. Long non-coding RNAs (lncRNAs) are long transcripts over 200 nucleotides that exhibit no or limited protein-coding potentials. LncRNAs are dramatic gene expression regulators, and can be selectively sorted into exosomes. Exosomal lncRNAs derived from cancer cells and stromal cells can mediate the generation of pre-metastatic niches (PMNs) and thus promote the progression of cancer. In this review, we summarized the fundamental biology and characteristics of exosomal lncRNAs. Besides, we provided an overview of current research on functions of exosomal lncRNAs between cancer cells and non-cancer cells. A deep understanding of exosomal lncRNAs' role in cancer will be facilitated to find important implications for cancer development and treatment.


Influence of heparin coating of coronary stents and ex vivo efficacy of different doses of acetylsalicylic acid and ticlopidine in a pulsed floating model of recirculating human plasma.
Acute occlusion of stented coronary vessels still occurs in up to 3%. Activated platelets have been found to play a major role in the pathogenesis of these complications. We therefore analyzed the efficacy of a heparin coating of coronary stents and investigated the ex vivo efficacy of different antiplatelet drugs. Each of seven healthy volunteers was treated with each of the following medications for 7 days: ASA 100 mg/day, ASA 300 mg/day, ticlopidine 250 mg/day, and ticlopidine 500 mg/day. Three standardized in vitro silicon tubing models, one of them containing an uncoated stent, one a heparin-coated stent, and one without a stent (control) were filled with PRP and circulation was started. TOS in systems with heparin-coated stents was 2.4-times longer compared to systems with uncoated stents (P<0.001), and 1.5-times longer compared to the control (P<0.01). The increase of CD62p expression within the first 5 min was 2.5-times higher in systems with uncoated stents and 1.7-times higher in the control than in systems with heparin-coated stents (P<0.05). Aggregometry revealed significant medication- and dose-dependent inhibition of platelet aggregability for all medications. Heparin-coating of coronary stents reduces their thrombogenicity significantly. ASA and ticlopidine effectively reduce platelet activation ex vivo. The used in vitro system facilitates a reproducible method to estimate the thrombogenicity of coronary stents prior to in vivo trials.


Overexpression of a glycine-rich protein gene in Lablab purpureus improves abiotic stress tolerance.
Glycine-rich protein (GRP) is involved in the response to abiotic and biotic stresses in plants. A novel GRP gene in Lablab purpureus has been identified. The cDNA of LpGRP was obtained from an SSH library constructed with root tissues of L. purpureus MEIDOU 2012 by waterholding for 10 days. The function of LpGRP was also evaluated in Arabidopsis. The cDNA of LpGRP has 555 bp and encodes a 184-amino acid protein. LpGRP was induced by drought and improved tolerance to abiotic stress. In LpGRP overexpressing Arabidopsis, the tolerance of transgenic seedlings to drought and salt was improved, and transgenic seeds showed insensitivity to both ABA and NaCl. The insensitivity to ABA indicated that there was crosstalk between LpGRP and ABA-responsive genes. These results indicated that LpGRP is a drought-responsive gene that can increase the drought and salt tolerance of Arabidopsis seedlings overexpressing LpGRP.


Normal colposcopy following abnormal Pap smear evoking LGSIL: a follow-up study.
The aim of this study was to determine the optimal treatment policy in women presenting with an abnormal Pap smear showing low-grade squamous intraepithelial lesion (LGSIL), who additionally had normal colposcopic findings. We prospectively studied 160 women with LGSIL and normal colposcopy, and divided them into two groups. Group A, consisting of 54 women, was followed-up for a mean period of 42 months and had a new control smear 12 months after the initial one. Group B, consisting of 106 women, was followed-up for a mean period of 44 months and had two consecutive control smears (6 and 12 months after the initial), and a new colposcopy, depending on the findings. At the end of the first year, the lesion persisted in 37% and 39% of the patients in groups A and B, respectively. At the end of the study, regression or persistence of the LGSIL was revealed in 63% and 61% of the women in groups A and B, respectively. Aggravation of the lesions occurred after 16.5 and 15 months, respectively, in groups A and B. Our findings suggest that women with LGSIL and normal colposcopy do not need further therapeutic measures during the first year after the initial smear.


Concepts and profitability of biogas production from landscape management grass.
Landscape management grass is generally harvested late, resulting in unfavorable composition for many utilization purposes. This study explores various technical concepts of biogas production and their economic viability. The Lower Oder Valley National Park is taken here as an example. This National Park in North-East Germany comprises large grassland areas with conservation-related restrictions on management. The concepts of biogas production and use considered are: (1) decentralized digestion and use of biogas at five autonomous combined heat and power (CHP) units, (2) decentralized digestion and delivery of the biogas to a centralized CHP unit, (3) decentralized digestion, upgrading of the biogas and feeding into the natural gas grid, and (4) one central biogas plant with centralized CHP unit. Annual costs and revenues of biogas production were calculated for each alternative. Biogas production from landscape management grass meets the conservational demands of late cutting periods and under certain circumstances shows a profit.


[A Meta analysis of family risk factors for attention deficit hyperactivity disorder].
To investigate the risk factors for attention deficit hyperactivity disorder (ADHD) and to provide a basis for future prevention and treatment of this disease. Following a systematic search for case-control studies on the risk factors for ADHD in China between 2000 and 2014, relevant family risk factors were extracted accordingly. The quality of selected studies was evaluated according to the NOS scale. A Meta analysis on the selected studies was conducted using Stata 12.0 software. A total of 16 studies were selected, involving 2 167 children with ADHD and 2 148 normal controls. Results of Meta analysis showed that good parenting (OR=0.32, 95% CI: 0.26-0.40), nuclear family (OR=0.56, 95% CI: 0.41-0.76), high education level of father (OR=0.56, 95% CI: 0.41-0.76), high education level of mother (OR=0.65, 95% CI: 0.47-0.89), and extroversion of mother (OR=0.33, 95% CI: 0.18-0.61) are favorable factors for ADHD. Poor parental relationship (OR=1.90, 95% CI: 1.17-3.06) and family history of ADHD (OR=5.86, 95% CI: 3.67-9.35) are risk factors for ADHD. Good parenting, nuclear family, high education level of parents, and mother with extroversion are protective factors for ADHD, whereas poor parental relationship and family history of ADHD are associated with an increased risk for ADHD.


Anisotropic diffusion and correlation analysis.
A method of statistical analysis of the correlation between two given scale invariant sequences is proposed. The relation between the fractal dimension of a two-dimensional random walk, generated with jumps derived from the signals, and the scaling exponents of the sequences is investigated, and a well-defined relation is found in the case of statistically independent signals. The method of analysis, whose performance is described for the case of an intermittent map, might represent a new tool for the study of the correlation between coupled complex systems.


The occurrence of the rat lungworm, Angiostrongylus cantonensis, in nonindigenous snails in the Gulf of Mexico region of the United States.
Nonindigenous apple snails, Pomacea maculata (formerly Pomacea insularum), are currently spreading rapidly through the southeastern United States. This mollusk serves as an intermediate host of the rat lungworm parasite (Angiostrongylus cantonensis), which can cause eosinophilic meningitis in humans who consume infected mollusks. A PCR-based detection assay was used to test nonindigenous apple snails for the rat lungworm parasite in Louisiana, Texas, Mississippi, and Florida. Only apple snails obtained from the New Orleans, Louisiana, area tested positive for the parasite. These results provide the first evidence that Angiostrongylus cantonensis does occur in nonindigenous apple snails in the southeastern United States. Additionally, Angiostrongylus cantonensis was identified in the terrestrial species Achatina fulica in Miami, Florida, indicating that rat lungworm is now established in Florida as well as Louisiana. Although the study suggests that the rat lungworm is not widespread in the Gulf States region, the infected snail population could still pose a risk to human health and facilitate the spread of the parasite to new areas.


Accuracy of indirect bonding trays - a measurement algorithm.
To present an image-processing measurement algorithm to evaluate the transfer accuracy of indirect bonding (IDB) trays, exemplified by a CAD/CAM-based IDB tray integrated into a digital orthodontic workflow. Plaster casts of 24 patients with full dentition and different malocclusions were scanned with an intraoral scanner (Trios; 3Shape, Copenhagen, Denmark) to obtain digital models, which served for the virtual placement of orthodontic brackets in simulation software (OnyxCeph; Image Instruments, Chemnitz, Germany). The resulting STL files were sent to a dental laboratory (CA Digital; Hilden, Germany) for the production of INDIVIDUA IDB trays. These trays were used to transfer the brackets to the respective plaster casts. Finally, a second scan was performed to record the actual bracket positions. The transfer accuracy was then analyzed by a measurement algorithm scripted to automation, which calculated the deviations of the planned and real bracket positions with a local best-fit alignment, resulting in three linear and three angular measurements for each bracket. In total, 622 brackets and tubes were transferred successfully. The presented algorithm analyzed the transfer accuracy and demonstrated that the linear measurements were 98.3% within the range of the American Board of Orthodontics standard. The angular measurements were 86.7% within this range when the INDIVIDUA IDB tray was used. Scripted measurement algorithms facilitated the evaluation of present and future materials and designs for IDB trays to obtain an efficient solution for orthodontic practice. The INDIVIDUA IDB tray is a digital alternative to conventional IDB trays (Int J Comput Dent 2022;25(3):295-302; doi: 10.3290/j.ijcd.b2599775).


Azelastine reduces histamine-induced swelling of nasal mucosa.
In a monocentric placebo-controlled double-blind study with two-period cross-over the anti-obstructive effect of azelastine nasal spray was evaluated. Nasal provocation with histamine or specific allergen respectively was performed before the pollen season in 28 patients with a history of seasonal allergic rhinitis. Efficacy was documented by rhinomanometry, acoustic rhinometry, rhinoscopy and symptom score. Acoustic rhinometry showed a statistically significant lesser decrease in nasal cavity volume in favour of azelastine after histamine provocation (p < 0.05). Reduction in nasal flow as determined by rhinomanometry confirmed this tendency (p < 0.1) after allergen provocation. The analysis of the patients' symptom scores clearly indicated the superior efficacy of azelastine as compared to placebo, especially for nasal obstruction after provocation with both histamine (p = 0.005) and allergen (p < 0.02).


Effects of Angiotensin-Neprilysin Inhibition in Canines with Experimentally Induced Cardiorenal Syndrome.
Sacubitril/valsartan (Sac/Val), a combined angiotensin-II receptor blocker (Val) and neprilysin inhibitor (Sac) in a 1:1 molar ratio, was shown to decrease the risk of cardiovascular death or heart failure (HF) hospitalization in patients with HF and reduced left ventricular (LV) ejection fraction. This study examined the effects of Sac/Val on LV structure, function, and bioenergetics, and on biomarkers of kidney injury and kidney function in dogs with experimental cardiorenal syndrome. Fourteen dogs with cardiorenal syndrome (coronary microembolization-induced HF and renal dysfunction) were randomized to 3 months Sac/Val therapy (100 mg once daily, n = 7) or no therapy (control, n = 7). LV ejection fraction and troponin-I, as well as biomarkers of kidney injury/function including serum creatinine and urinary kidney injury molecule-1 were measured before and at end of therapy and the change (treatment effect change) calculated. Mitochondrial function measures, including the maximum rate of adenosine triphosphate synthesis, were measured in isolated cardiomyocytes at end of therapy. In Sac/Val dogs, the change in ejection fraction increased compared with controls, 6.9 ± 1.4 vs 0.7 ± 0.6%, P < .002, whereas change in troponin I decreased, -0.16 ± 0.03 vs -0.03 ± 0.02 ng/mL, P < .001. Urinary change in kidney injury molecule 1 decreased in Sac/Val-treated dogs compared with controls, -17.2 ± 7.9 vs 7.7 ± 3.0 mg/mL, P < .007, whereas the change in serum creatinine was not significantly different. Treatment with Sac/Val increased adenosine triphosphate synthesis compared with controls, 3240 ± 121 vs 986 ± 84 RLU/µg protein, P < .05. In dogs with cardiorenal syndrome, Sac/Val improves LV systolic function, improves mitochondrial function and decreases biomarkers of heart and kidney injury. The results offer mechanistic insights into the benefits of Sac/Val in HF with compromised renal function.


Low antioxidant concentrations impact on multiple signalling pathways in Arabidopsis thaliana partly through NPR1.
Production of reactive oxygen species (ROS) is linked to signalling in both developmental and stress responses. The level of ROS is controlled by both production and removal through various scavengers including ascorbic acid and glutathione. Here, the role of low ascorbic acid or glutathione concentrations was investigated on ozone-induced cell death, defence signalling, and developmental responses. Low ascorbic acid concentrations in vtc1 activated expression of salicylic acid (SA)-regulated genes, a response found to be dependent on the redox-regulated transcriptional co-regulator NPR1. In contrast, low glutathione concentrations in cad2 or pad2 reduced expression of SA-regulated genes. Testing different responses to jasmonic acid (JA) revealed the presence of at least two separate JA signalling pathways. Treatment of the vtc1 mutant with JA led to hyper-induction of MONODEHYDROASCORBATE REDUCTASE3, indicating that low ascorbic acid concentrations prime the response to JA. Furthermore, NPR1 was found to be a positive regulator of JA-induced expression of MDHAR3 and TAT3. The vtc1 and npr1 mutants were sensitive to glucose inhibition of seed germination; an opposite response was found in cad2 and pad2. Overall, low ascorbic acid concentrations mostly led to opposite phenotypes to low glutathione concentrations, and both antioxidants interacted with SA and JA signalling pathways.


EUK-8, a synthetic superoxide dismutase and catalase mimetic, ameliorates acute lung injury in endotoxemic swine.
Reactive oxygen metabolites are believed to be important mediators of sepsis- or lipopolysaccharide (LPS)-induced adult respiratory distress syndrome. EUK-8 is a novel, synthetic, low-molecular-weight salen-manganese complex that exhibits both superoxide dismutase and catalase activities in vitro. We hypothesized that treatment with EUK-8 would ameliorate pulmonary dysfunction in a porcine model of LPS-induced adult respiratory distress syndrome. At T = -18 h, pigs received an intravenous priming dose of LPS (20 micrograms/kg). Anesthetized ventilated swine were randomized to receive 1) no further treatment (n = 5); 2) LPS (250 micrograms/kg from T = 0 to 60 min, n = 6); 3) LPS and a low dose of EUK-8 (10-mg/kg bolus at T = -15 min and 1 mg/kg.h from T = 0 to 240 min, n = 6) or 4) LPS and a higher dose of EUK-8 (10-mg/kg bolus and 3 mg/kg.h, n = 6). Treatment with EUK-8, particularly at the higher dose, significantly attenuated many of the features of LPS-induced acute lung injury, including arterial hypoxemia, pulmonary hypertension, decreased dynamic pulmonary compliance and pulmonary edema. LPS caused an increase in lung tissue malondialdehyde content that was abrogated in both EUK-8-treated groups. EUK-8 treatment had no effect on circulating plasma levels of tumor necrosis factor-alpha, thromboxane B2 or 6-keto-prostaglandin F1 alpha. We conclude that EUK-8 prevents many of the manifestations of LPS-induced adult respiratory distress syndrome in pigs by detoxifying reactive oxygen metabolites without affecting the release of other important proinflammatory mediators.


Combating Biofilm by Targeting Its Formation and Dispersal Using Gallic Acid against Single and Multispecies Bacteria Causing Dental Plaque.
Exploring biological agents to control biofilm is a vital alternative in combating pathogenic bacteria that cause dental plaque. This study was focused on antimicrobial, biofilm formation and biofilm dispersal efficacy of Gallic acid (GA) against bacteria, including Proteus spp., Escherichia coli, Pseudomonas spp., Salmonella spp., Streptococcus mutans, and Staphylococcus aureus and multispecies bacteria. Biofilm was qualitatively and quantitatively assessed by crystal violet assay, florescence microscopy (bacterial biomass (µm2), surface coverage (%)) and extracellular polymeric substances (EPS). It was exhibited that GA (1-200 mg/L) can reduce bacterial growth. However, higher concentrations (100-200 mg/L) markedly reduced (86%) bacterial growth and biofilm formation (85.5%), while GA did not exhibit any substantial dispersal effects on pre-formed biofilm. Further, GA (20-200 mg/L) exhibited 93.43% biomass reduction and 88.6% (p < 0.05) EPS (polysaccharide) reduction. Microscopic images were processed with BioImageL software. It was revealed that biomass surface coverage was reduced to 2% at 200 mg/L of GA and that 13,612 (µm2) biomass was present for control, while it was reduced to 894 (µm2) at 200 mg/L of GA. Thus, this data suggest that GA have antimicrobial and biofilm control potential against single and multispecies bacteria causing dental plaque.


Changes in the Body Size of Carabid Beetles Along Elevational Gradients: A Multispecies Study of Between- and Within-Population Variation.
Geographic variation in body size has fascinated biologists since the 19th century as it can provide insight into the evolution of the body size of various organisms. In this study, we investigated body size variation in eight carabid species/subspecies (Coleoptera: Carabidae) along elevational gradients in six Central European mountain ranges. First, we examined elevational variation in body size and whether female and male body sizes differed in their responses to elevation. Second, we examined intrapopulation variation in body size along an elevational gradient, and we compared the degrees of intrapopulation variation between males and females. The investigated species either followed a converse Bergmann's cline (Carabus auronitens auronitens Fabricius 1792; Carabus linnei Panzer 1810; Pterostichus melanarius (Illiger, 1798); Pterostichus pilosus (Host, 1789)) or their size was unaffected by elevation (Carabus auronitens escheri Palliardi, 1825; Carabus sylvestris sylvestris Panzer, 1796; Carabus sylvestris transsylvanicus Dejean, 1826; Pterostichus burmeisteri Heer, 1838). Females were the larger sex in all the investigated species, but the degree of sexual size dimorphism differed between species. In general, the degree of sexual size dimorphism showed no change with elevation. The degree of intrapopulation variation in body size slightly increased with elevation in C. sylvestris sylvestris and P. pilosus. Overall, the intrapopulation variation in body size significantly differed among the investigated carabid species. The existing literature on intrapopulation variation in the body size of insects is limited, but further investigation of this issue could provide a better understanding of the mechanisms that generate geographical clines.


The Xenopus YB3 protein binds the B box element of the class III promoter.
We have isolated a Xenopus cDNA encoding the YB3 protein which binds specifically to the B box promoter element of class III genes. Northern analysis shows YB3 is expressed in a variety of adult tissues. Fractionation of oocyte S150 extracts demonstrates YB3 is present in phosphocellulose fraction IIIC, as well as in the fraction isolated by B box DNA affinity chromatography. Silver staining indicates that YB3, or a protein of the same mobility in SDS gels, is the most abundant component in either fraction.


Recombinant expression, purification, and characterization of polyphenol oxidase 2 (VvPPO2) from "Shine Muscat" (Vitis labruscana Bailey × Vitis vinifera L.).
Polyphenol oxidases (PPOs) catalyze browning reactions in various plant organs, therefore controlling the reactions is important for the food industry. PPOs have been assumed to be involved in skin browning of white grape cultivars; however, the molecular mechanism underlying PPO-mediated browning process remains elusive. We have recently identified a new PPO gene named VvPPO2 from "Shine Muscat" (Vitis labruscana Bailey × V. vinifera L.), and have shown that the gene is transcribed at a higher level than the previously identified VvPPO1 in browning, physiologically disordered berry skins at the maturation stage. In this study, we expressed VvPPO2 in Escherichia coli and, using the purified preparation, revealed unique physicochemical characteristics of the enzyme. Our study opens up a way to not only understand the berry skin browning process but also to elucidate the enzymatic maturation process of grape PPOs.


New Approach to the Study of Particle-Surface Adhesion Using Atomic Force Microscopy.
The colloidal probe technique is commonly employed to determine the adhesion force between a particle and a solid surface. Characterization of the adhesion of a particle across a surface can be as important, if not more so, as the determination of an average value for the adhesion. Unfortunately, the measurement of the variation in adhesion can be difficult at best. A new approach for studying particle-surface adhesion based on the force-volume technique is presented. Upon combining the force-volume technique with a colloidal probe, not only is it possible to determine the average adhesion force, but an image of the spatial variation of the adhesion can also be obtained. This method is envisioned to have great potential for examining and analyzing the adhesion behavior in complex natural and technological systems. Copyright 2000 Academic Press.


Rationale, objectives, and interpretation of randomized controlled trials.
A randomized controlled trial (RCT) is the most definitive tool for evaluation of the effectiveness of an intervention and can establish a cause-and-effect relationship between an intervention and an improved disease outcome. However, the undertaking of an RCT does not guarantee valid results, and the findings of RCTs of the same intervention are often discrepant. While many reported trials are of high quality, a significant number have deficiencies in design, conduct, analysis, or interpretation of results. Medical practitioners must become familiar with the methodology of RCTs in order to assess the validity of the reported findings and the relevance of the results to their own patients. Trialists must report sufficient information about the methods used so that readers can judge for themselves if the trial worked as planned.


The Dual Androgen Receptor and Glucocorticoid Receptor Antagonist CB-03-10 as Potential Treatment for Tumors that have Acquired GR-mediated Resistance to AR Blockade.
CB-03-10 (cortexolone 17α-valerate-21-propionate) is a synthetic steroidal compound derived from cortexolone (11-deoxycortisone), an intermediate in cortisol biosynthesis. Characterization of the activity of CB-03-10 and its main related compound CB-03-05 (cortexolone 17α-valerate) included in vitro binding to the androgen and glucocorticoid receptors (AR and GR), antagonism of AR and GR transcriptional activities, and screening for antitumor activity across a selected panel of human prostate and in triple-negative breast cancer cell lines. CB-03-10 cytotoxic activity in these cancer cell lines was in the low micromolar range and was primarily associated with induction of the apoptotic cascade via activation of caspases. The compound's potential for antitumor activity was verified in a murine xenograft model utilizing the AR-positive LNCaP prostate cancer cell line as well as in an orthotopic model utilizing AR-negative/GR-positive MDA-MB-231 breast cancer cell line. Orally administered CB-03-10 inhibited prostate tumor growth and orthotopically implanted breast tumor growth in these mice and maintained body weight, as compared with vehicle-treated mice. On the basis of AR/GR binding affinities, antagonism of androgen and glucocorticoid-dependent transcriptional activities, and AR/GR mRNA and protein expression, the mechanism of tumor growth suppression is related to AR and GR antagonist activities. Importantly, these compounds lack biologically relevant AR/GR agonist activities. Overall, these preclinical findings support the selection of CB-03-10 for further development as an anticancer agent in cases where resistance to AR-targeted therapy or chemotherapy, via upregulation of GR activity, continues to limit the efficacy and duration of clinical benefit with these interventions.


More slices, less truth: effects of different test-set design strategies for magnetic resonance image classification.
To assess the effects of different test-set design strategies for magnetic resonance (MR) image classification using deep learning. Error rates in 10 experimental settings were assessed. The performance of pretrained models and data augmentation were examined as possible contributing factors. Error rates in experimental settings using MR images of different patients for training and test sets were ten times higher than those in experimental settings using MR images of the same patients (four disease groups with whole-chest images, 46.80% vs 2.06%; four disease groups without whole-chest images, 49.09% vs 1.29%; sex classification with whole-chest images, 16.02% vs 0.96%; and sex classification without whole-chest images, 23.56% vs 0.30%). Error rates were higher when data augmentation was applied to settings that used MR images of different patients for training and test sets. When deep learning is applied to MR image classification, training and test sets should consist of MR images of different patients. Models built on training and test sets consisting of images of the same patients yield optimistic error rates and lead to wrong conclusions. MR images of neighboring slices are so similar that they cause data leakage effect.


Caspofungin Treatment of Aspergillus fumigatus Results in ChsG-Dependent Upregulation of Chitin Synthesis and the Formation of Chitin-Rich Microcolonies.
Treatment of Aspergillus fumigatus with echinocandins such as caspofungin inhibits the synthesis of cell wall β-1,3-glucan, which triggers a compensatory stimulation of chitin synthesis. Activation of chitin synthesis can occur in response to sub-MICs of caspofungin and to CaCl2 and calcofluor white (CFW), agonists of the protein kinase C (PKC), and Ca(2+)-calcineurin signaling pathways. A. fumigatus mutants with the chs gene (encoding chitin synthase) deleted (ΔAfchs) were tested for their response to these agonists to determine the chitin synthase enzymes that were required for the compensatory upregulation of chitin synthesis. Only the ΔAfchsG mutant was hypersensitive to caspofungin, and all other ΔAfchs mutants tested remained capable of increasing their chitin content in response to treatment with CaCl2 and CFW and caspofungin. The resulting increase in cell wall chitin content correlated with reduced susceptibility to caspofungin in the wild type and all ΔAfchs mutants tested, with the exception of the ΔAfchsG mutant, which remained sensitive to caspofungin. In vitro exposure to the chitin synthase inhibitor, nikkomycin Z, along with caspofungin demonstrated synergistic efficacy that was again AfChsG dependent. Dynamic imaging using microfluidic perfusion chambers demonstrated that treatment with sub-MIC caspofungin resulted initially in hyphal tip lysis. However, thickened hyphae emerged that formed aberrant microcolonies in the continued presence of caspofungin. In addition, intrahyphal hyphae were formed in response to echinocandin treatment. These in vitro data demonstrate that A. fumigatus has the potential to survive echinocandin treatment in vivo by AfChsG-dependent upregulation of chitin synthesis. Chitin-rich cells may, therefore, persist in human tissues and act as the focus for breakthrough infections.


A reassessment of the relationship between international reference preparations for human and rabbit thromboplastins.
Two established international reference preparations (IRP) for thromboplastins, i.e. RBT/90 (rabbit, plain) and rTF/95 (recombinant human, plain) have been calibrated against each other in a 7-centre exercise performed in 2000. The purpose of the study was to compare the calibration results with those of the original calibration study performed in 1995. The international sensitivity index (ISI) for rTF/95 was calculated relative to the ISI for RBT/90. The mean ISI for rTF/95 was 0.961 (between-lab SD 0.028) which was 2% greater than the historical value determined in 1995. There is no indication that the two IRP have deteriorated, but further monitoring of the calibration relationship is recommended.


Relationship Between the Altered Expression and Epigenetics of GSTM3 and Age-Related Cataract.
Glutathione S-Transferase Mu 3 (GSTM3) protects the lens from oxidative stress that contributes to age-related cataract (ARC) formation. We examined the expression and epigenetics of GSTM3 in lens epithelial cells (LECs) and lens cortex of ARC, and investigated the potential role of molecular changes in ARC pathogenesis. This study included 120 ARCs and 40 controls. Expression of GSTM3, DNA methylation, and histone modification were assessed by quantificational real-time PCR, Western blot, bisulfite-sequencing PCR, pyrosequencing, and chromatin immunoprecipitation assay. Human lens epithelial (HLE) cell lines, SRA01/04 and HLEB3, were served as an in vitro model to observe the relationship between epigenetic status and GSTM3 expression. Potential transcription factors binding to GSTM3 promoter were detected by electrophoretic mobility shift assay. Expression of GSTM3 decreased in ARC lens tissues compared to that in the controls, which correlated with the hypermethylation of GSTM3 promoter. Lower level of GSTM3 was detected in HLEB3 than in SRA01/04, while HLEB3 displayed hypermethylation of GSTM3 and SRA01/04 did not. Compared to SRA01/04, HLEB3 displayed lower acetylated H3 and higher trimethylated H3K9 levels. After treatment with DNA methyltransferase inhibitor or histone deacetylase inhibitor, HLEB3 had an increased GSTM3 expression. Methylation of GSTM3 promoter abrogated the potential transcription factor binding. The GSTM3 expression declined in hydrogen peroxide-treated HLE cell lines. Expression of GSTM3 might be regulated by epigenetic changes in lens tissue. Hypermethylation in GSTM3 promoter and altered histone modification might have a role in the ARC formation. The results provided a potential strategy of ARC management by manipulating epigenetic changes.


[Implantation of a mutant of Escherichia coli requiring diaminopimelic acid in the digestive tract of gnotobiotic mice].
A DAP- auxotroph mutant of Escherichia coli DP50 requiring DAP and thymidine for growth was used as the receptor strain in genetic engineering. It failed to be implanted in axenic mice. However, when an inoculum containing more than 10(7) bacteria/ml was used, the DAP+ reverse mutant devoid of requirement for DAP became implanted. When axenic mice were previously associated with Clostridium difficile containing DAP in the cell wall, the strain DAP- became implanted even when the inoculum was too small to permit implantation in axenic mice. Conversely, C. butyricum and C. perenne, whose cell walls also contain DAP, did not allow the establishment of a DAP- mutant. In animals associated with complex human flora without enterobacteria, neither of the 2 DAP- and DAP+ mutants became implanted.


Tapping the potential in resistance.
Resistance is energy and effort focused on noncompliance with a new direction for a group or organization. It results in significant costs to an organization including lost opportunity from delayed or truncated implementation, managers who are distracted and under stress, loss of high-performing talent, lost clients, and reduced client service. Managers overextend themselves when they take on the responsibility to overcome or bypass resistance to create the compliance. Resistance also is within each person and has significant cost to the individuals who resist as they experience stress and various losses: confidence, alternatives, performance, status, position, and relationships. The fear and uncertainty related to a future that is unclear and related to whether a successful transition can happen, becomes the underpinning of thinking and activity while resistance exists. Both the managers promoting compliance and the individuals resisting are expending energy, which can be diverted to uncovering potential for the future.


Simple synthesized Pt/GNs/TiO2 with good mass activity and stability for methanol oxidation.
Pt/GNs/TiO2 (GNs, graphene nanosheets) catalyst was synthesized by a simple two-step method, including a rapid solution plasma technique to obtained Pt nanoparticles with a size of 2-5 nm and followed by an ultrasonic mixing of the Pt, GNs and TiO2 nanoparticles. After coupling with TiO2 nanoparticles, the Pt/GNs/TiO2 catalyst exhibited a promoting catalytic activity towards methanol oxidation, which was superior to the Pt/GNs catalyst. The mass activity of the Pt/GNs/TiO2 catalyst was 3464 mA mgPt-1, which was 3.5 and 3.4 times higher than those of the Pt/GNs and the commercial Pt/C, respectively. And the Pt/GNs/TiO2 showed a strongly negative shift onset potential of methanol oxidation. The results of long-term cyclic voltammetry and CO-stripping tests showed an improved CO tolerance of the Pt/GNs/TiO2. Moreover, the mass activity of the Pt/GNs/TiO2 was further enhanced under light irradiation, with the mass activity of 4715 mA mgPt-1, which was 1.4 times higher than that of in dark. This work provides new opportunities for exploiting efficient visible photo-assisted electro-catalytic methanol oxidation.


C-fiber axon reflex flare size correlates with epidermal nerve fiber density in human skin biopsies.
The size of the neurogenic axon reflex flare (ARFS) has been proposed to serve as a non-invasive measure of C-fiber neuropathies. This idea is based on the observation that ARFS is often reduced in patients with small-fiber neuropathies. In this study, we compared ARFS and electrically evoked axon reflex sweating with intraepidermal nerve fiber density (IENF) in patients with peripheral neuropathy in order to validate these methods against an objective standard method of diagnosing small-fiber neuropathy. ARFS was significantly correlated with IENF, while axon reflex sweating was not correlated to IENF. We conclude that measurement of ARFS is a potential objective non-invasive diagnostic tool for analysis of C-fiber function in patients with small-fiber neuropathies.


Individual and contextual predictors of young Ukrainian adults' subjective well-being during the Russian-Ukrainian war.
The Russian invasion of Ukraine is accompanied by horrific losses among civilians. This study investigates various individual (hope, optimism, resilience, post-traumatic growth, and coping strategies) and contextual predictors (experience of life under occupation, actively hostile home environment, and frequent moves) of subjective well-being among the youth living in Ukraine. A total sample of 593 students from several universities participated in the study using surveys that contained questions about sociodemographic characteristics, life satisfaction, hope, optimism, personal post-traumatic growth, resilience, and coping strategies. Data were analyzed using JAMOVI software. The level of dissatisfaction with their own lives was 34.7%; most of the respondents had a higher incidence of minimal/mild hopelessness (88.7%) and high/moderate level of optimism (60.9%). The majority of participants had moderate and high levels of post-traumatic growth (51.9% and 6.7%, respectively) and resilience (46.0% and 14.5%, respectively). Optimism, hope, resilience, post-traumatic growth, using emotional support, and life in occupation predicted life satisfaction among the study sample.


Topical κ-opioid receptor agonist asimadoline improves dermatitis in a canine model of atopic dermatitis.
This prospective, 4-week, placebo-controlled, cross-over study aimed to investigate the efficacy of 1% topical κ-opioid agonist, asimadoline, in a model of canine atopic dermatitis (AD). Fourteen beagles were challenged with house dust mites every 3-4 days for a total of 9 challenges. Severity of dermatitis was assessed, and pruritus was monitored using GoPro HERO cameras. Pruritus scoring was evaluated at 10 time periods; baseline, 4 h post allergen challenge and the last day of the study on Day 28. Scoring was done blindly by personnel using BORIS software. A global subjective score was also given using a visual analogue scale (VAS). A 4-week washout period occurred and dogs were crossed-over, the study was repeated, and the results were analysed using combined data. Gel was applied once daily on inguinal area (0.6 ml/dog). ANOVA showed significant effect of time (p < 0.0001) and group (p = 0.0001) on dermatitis scores. Overall, no statistically significant effect on pruritus was found due to a crossing of scores on Day 17. Overtime the placebo scores increased while the active ingredient showed decrease after first 3 weeks. It is concluded that this approach is promising in dogs with AD and longer studies with more frequent application may be beneficial.


Implementation strategy for complete pathogen reduction technology treated apheresis platelet inventory.
Bacterial contamination in platelets remain a major public health concern, which prompted the US Food and Drug Administration guidance for bacterial contamination mitigation. Pathogen reduction technology (PRT) is one mitigation strategy that has shown success in Europe over the last decade. Therefore, our center sought to transition from a dual system of bacterial culturing (BacT) and PRT to full PRT. A 1 month pilot study was conducted to simulate 100% PRT conditions. Our center also collected baseline data on key platelet production metrics in the 4 months prior to 100% PRT and compared it to the 4 months post-implementation. The pilot study showed no statistical differences in split rate, proportion of low-yield products, or proportion of single, double, and triple collections. The only observed difference was an 11 min increase in the average duration of double collections. Our baseline versus post-implementation monitoring showed no difference in split rate, discard rate, percentage of low-yield units, and average yield of low yield units. Statistical differences were detected in the proportion of single, double, and triple collections, as well as the average yield of full dose products. Roughly 20% of our inventory consisted of low-yield products. With suitable mitigation strategies, transitioning to a full PRT inventory may result in higher net margins while not adversely affecting overall platelet production. A pilot study is a good way to project potential effects of switching from a dual BacT and PRT inventory to full PRT, and can be adopted by other centers aiming to make the transition.


Neutrino mass and mixing with discrete symmetry.
This is a review paper about neutrino mass and mixing and flavour model building strategies based on discrete family symmetry. After a pedagogical introduction and overview of the whole of neutrino physics, we focus on the PMNS mixing matrix and the latest global fits following the Daya Bay and RENO experiments which measure the reactor angle. We then describe the simple bimaximal, tri-bimaximal and golden ratio patterns of lepton mixing and the deviations required for a non-zero reactor angle, with solar or atmospheric mixing sum rules resulting from charged lepton corrections or residual trimaximal mixing. The different types of see-saw mechanism are then reviewed as well as the sequential dominance mechanism. We then give a mini-review of finite group theory, which may be used as a discrete family symmetry broken by flavons either completely, or with different subgroups preserved in the neutrino and charged lepton sectors. These two approaches are then reviewed in detail in separate chapters including mechanisms for flavon vacuum alignment and different model building strategies that have been proposed to generate the reactor angle. We then briefly review grand unified theories (GUTs) and how they may be combined with discrete family symmetry to describe all quark and lepton masses and mixing. Finally, we discuss three model examples which combine an SU(5) GUT with the discrete family symmetries A₄, S₄ and Δ(96).


[Effect of reagent batch on activated partial thromboplastin time in canine plasma and use of the ratio system for standardization].
In order to test the variability of the results of the activated partial thromboplastin time (APTT) in different reagent batches, 40 samples (20 from healthy dogs, 15 from patients with prolonged APTT as a result of different congenital or acquired haemostasis disorders, 5 from healthy dogs after in vitro addition of heparin) were used to compare 6 different lot Nos. of two commercial APTT-reagents (Pathromtin, PTT Reagent). Although the Friedman test showed a reagent batch dependency (p < 0.0001) for both reagents, only minor quantitative differences were observed with a variation coefficient of 2.7% (Pathromtin) and 2.4% (PTT Reagent), respectively. A second experiment was based on 105 samples measured with two batches of a third reagent (APTT-FS) with remarkable differences of results. Convergence of the results was achieved by converting into ratio values (quotient measurement value/control). However, statistical comparison still showed a significant difference. The study shows the good reproducibility of the APTT measured with different batches of the reagents Pathromtin and PTT Reagent in canine plasma, indicating that standardization is unnecessary. A standardization based on the ratio system can be used for reagents with a low batch consistency, requiring a high-quality control.


Microbial bio-production of a recombinant stimuli-responsive biosurfactant.
Biosurfactants have been the subject of recent interest as sustainable alternatives to petroleum-derived compounds in areas ranging from soil remediation to personal and health care. The production of naturally occurring biosurfactants depends on the presence of complex feed sources during microbial growth and requires multicomponent enzymes for synthesis within the cells. Conversely, designed peptide surfactants can be produced recombinantly in microbial systems, enabling the generation of improved variants by simple genetic manipulation. However, inefficient downstream processing is still an obstacle for the biological production of small peptides. We present the production of the peptide biosurfactant GAM1 in recombinant E. coli. Expression was performed in fusion to maltose binding protein using chemically defined minimal medium, followed by a single-step affinity capture and enzymatic cleavage using tobacco etch virus protease. Different approaches to the isolation of peptide after cleavage were investigated, with special emphasis on rapid and simple procedures. Solvent-, acid-, and heat-mediated precipitation of impurities were successfully applied as alternatives to post-cleavage chromatographic peptide purification, and gave peptide purities exceeding 90%. Acid precipitation was the method of choice, due to its simplicity and the high purification factor and recovery rate achieved here. The functionality of the bio-produced peptide was tested to ensure that the resulting peptide biosurfactant was both surface active and able to be triggered to switch between foam-stabilizing and foam-destabilizing states.


Multiple maps and activity-dependent representational plasticity in the anterior Wulst of the adult barn owl (Tyto alba).
In the present study we addressed the issue of somatosensory representation and plasticity in a nonmammalian species, the barn owl. Multiunit mapping techniques were used to examine the representation of the specialized receptor surface of the claw in the anterior Wulst. We found dual somatotopic mirror image representations of the skin surface of the contralateral claw. In addition, we examined both representations 2 weeks after denervation of the distal skin surface of a single digit. In both representations, the denervated digital representation became responsive to stimulation of the adjacent, mutually functional, digit. The mutability and multiple representations indicates that the Wulst provides the owl with sensory processing capabilities analogous to those in mammals.


Shikonin Prolongs Allograft Survival via Induction of CD4+FoxP3+ Regulatory T Cells.
A transplanted organ is usually rejected without any major immunosuppressive treatment because of vigorous alloimmune responsiveness. However, continuous global immunosuppression may cause severe side effects, including nephrotoxicity, tumors, and infections. Therefore, it is necessary to seek novel immunosuppressive agents, especially natural ingredients that may provide sufficient efficacy in immunosuppression with minimal side effects. Shikonin is a bioactive naphthoquinone pigment, an ingredient originally extracted from the root of Lithospermum erythrorhizon. Previous studies have shown that shikonin regulates immunity and exerts anti-inflammatory effects. In particular, it can ameliorate arthritis in animal models. However, it is unclear whether shikonin inhibits alloimmunity or allograft rejection. In this study and for the first time, we demonstrated that shikonin significantly prolonged the survival of skin allografts in wild-type mice. Shikonin increased the frequencies of CD4+Foxp3+ regulatory T cells (Tregs) post-transplantation and induced CD4+Foxp3+ Tregs in vitro as well. Importantly, depleting the Tregs abrogated the extension of skin allograft survival induced by shikonin. It also decreased the frequencies of CD8+CD44highCD62Llow effector T cells and CD11c+CD80+/CD11c+CD86+ mature DCs after transplantation. Moreover, we found that shikonin inhibited the proliferation of T cells in vitro and suppressed their mTOR signaling. It also reduced the gene expression of pro-inflammatory cytokines, including IFNγ, IL-6, TNFα, and IL-17A, while increasing the gene expression of anti-inflammatory mediators IL-10, TGF-β1, and indoleamine-2, 3-dioxygenase (IDO) in skin allografts. Further, shikonin downregulated IDO protein expression in skin allografts and DCs in vitro. Taken together, shikonin inhibits allograft rejection via upregulating CD4+Foxp3+ Tregs. Thus, shikonin is a novel immunosuppressant that could be potentially used in clinical transplantation.


Regulation of TRPV5 and TRPV6 by associated proteins.
The epithelial Ca2+ channels TRPV5 and TRPV6 are the most Ca2+-selective members of the TRP channel superfamily. These channels are the prime target for hormonal control of the active Ca2+ flux from the urine space or intestinal lumen to the blood compartment. Insight into their regulation is, therefore, pivotal in our understanding of the (patho)physiology of Ca2+ homeostasis. The recent elucidation of TRPV5/6-associated proteins has provided new insight into the molecular mechanisms underlying the regulation of these channels. In this review, we describe the various means of TRPV5/6 regulation, the role of channel-associated proteins herein, and the relationship between both processes.


Cutaneous Hypersensitivity Dermatoses in the Feline Patient: A Review of Allergic Skin Disease in Cats.
Feline allergic skin disease presents a unique set of challenges to the veterinary practitioner. Although there is some similarity to what is seen in the allergic canine patient, cutaneous hypersensitivity dermatoses in cats can manifest with strikingly different clinical signs, treatment options and outcomes, and secondary complications/disease entities. Additionally, less is known about the pathogenesis of feline allergic skin diseases, particularly "feline atopic syndrome" when compared to dogs or people. This article aims to review what is currently known in regards to allergic skin disease in the feline patient, with focus on non-flea, non-food hypersensitivity dermatitis.


Guidelines for gynecological cancer-an audit of current network documents in England and Wales.
The objective of this study was to assess the adequacy of network cancer guidelines paying particular attention to referral criteria, referral routes, tumor diagnosis, staging, and suggested management and care pathways for ovarian and endometrial cancer. Guidelines from 15 regions in England and Wales were analyzed quantitatively and qualitatively as a prospective audit of predefined data items and subsequently agreed management recommendations. Details of unit and center clinicians were included in a minority of documents (2 to 5/15). Multidisciplinary team membership was not usually offered (6/15). Among the least reported data items were histopathology minimum dataset for endometrial cancer and an algorithm for management or summary and clinical symptoms and signs for both cancers. Among the most reported data items were hysteroscopy and ultrasound scanning for endometrial cancer and CA125 and chemotherapy for ovarian cancer. Qualitative analysis revealed differing criteria for the use of endometrial biopsy and radiotherapy in endometrial cancer, for lymphadenectomy and management of recurrent disease in ovarian cancer, and for referral pathways and the use of computed tomography/magnetic resonance (MR) scanning in the assessment of either disease. This study concludes that consideration should be given to the development of national guidelines or templates to ensure consistency of management for gynecological malignancy in England and Wales.


Crew and patient safety in ambulances: results of a personnel survey and experimental side impact crash test.
Ambulance drivers often travel under stressful conditions at high speed while using vehicles with poor high-speed maneuverability. The occupant safety of ambulance vehicles has not yet been addressed by the automotive safety paradigm; particularly for the rear patient compartment. This study had two objectives: (1) to assess by survey the French Emergency Medical Services (EMS) to determine the layout of the vehicle most often used and the EMS personnel's behavior during transport; and (2) to conduct a crash test to analyze the injuries which may affect EMS personnel and patients in the rear patient compartment. Firstly, a survey was distributed to the 50 largest metropolitan French EMS programs. Secondly, a crash test was performed with a Mobile Intensive Care Unit (MICU) in conditions closest to reality. Forty-nine of the 50 biggest metropolitan French EMS programs responded to the survey. This represents 108 French MICUs. During the last three years, 12 of 49 EMS programs (24%) identified at least one accident with an MICU, and six of these 12 (50%) suffered at least one death in those accidents. A crash test using a typical French EMS MICU showed that after impact of a collision, the ambulance was moved more than five meters with major consequences for all passengers. A study-approved human cadaver placed in the position of a potential patient was partially thrown from the stretcher with a head impact. The accelerometric reaction of the anthropomorphic manikin head was measured at 48G. The crash test demonstrated a lack of safety for EMS personnel and patients in the rear compartment. It would be preferable if each piece of medical equipment were provided with a quick release system resistant to three-dimensional 10G forces. The kinetic changes undergone by the "patient" substitute on the stretcher would probably have an effect of causing injury pathology. This study highlights the need for more research and development in this area.


The relationship between stressful life events and school-related performances of type A and type B adolescents.
Previous research indicates that an individual's style of coping with stress and the nature of stressful events combine to mediate responses to stress. The present study investigated the responses of Type A and Type B high school students to controllable and uncontrollable stressful life events. Specifically, the associations between life stress and gradepoint average, extracurricular activity, sports involvement, days absent, and delinquent behavior were examined. The results revealed a negative relationship between life stress and school-related performance that was more pronounced for Type B than for Type A adolescents. These findings are discussed in terms of different coping mechanisms used by Type A's and B's when encountering environmental stress.


[Combined modality treatment of locally advanced oral and oropharyngeal cancer following primary radiotherapy with and without taxol radiosenzitization]
AIM: To determine the effect of radiosensitization with Taxol and multimodality treatments on the survival of advanced oral and oropharyngeal cancer. Patients, methods: 56 patients with St. III-IV oral or oropharyngeal cancer were treated with external beam radiotherapy; 26 of them were sensitized by low-dose paxlitaxel and 30 were irradiated traditionally. The median follow up was 23 months (17-36). Endpoints of the study were: response to radiotherapy, progression-free and overall survival and the results of surgery and chemotherapy following radiation. RESULTS: 73.3% (41/56) of treatments resulted in CR or PR with median 10 months (0-33) progression-free and 14 months (4-33) overall survival. There was no significant difference between the radiosensitized and traditional radiotherapy group (p=0.6). The survival was significantly influenced by the stage of tumor and the response to primary radiotherapy. Seven (38.9%) of 16 patients treated also by either surgery or chemotherapy for recurrent or residual disease are free of cancer, 6 (35%) alive with tumor and 5 (26.1%) died with median survivals of 21, 20.5 and 18 months, respectively. Those treated only with radiotherapy with or without sensitization are free of cancer in 31.6%, alive with cancer 5.3%, died 63.2%. CONCLUSION: There were significant correlation between tumor stage, response to radiotherapy and combined modality treatment, and surival. The radiosensitizing effect of Taxol was not obvious so far, it may be apparent in the future by analyzing the long term survival data.


Regulation by Dietary Carbohydrates of Intermediary Metabolism in Liver and Muscle of Two Isogenic Lines of Rainbow Trout.
Rainbow trout (Oncorhynchus mykiss) is recognized as a typical "glucose-intolerant" fish, and the limits of dietary carbohydrate utilization have been investigated for many years. In this study, the objective was to test the molecular effects of dietary carbohydrates on intermediary metabolism in two major metabolic tissues, liver and muscle. Another objective was also to study if the response to carbohydrate intake depended on the genetic background. We fed two isogenic lines of rainbow trout (named A22h and N38h) with high carbohydrate diet (carbohydrate, 22.9%) or low carbohydrate diet (carbohydrate, 3.6%) for 12 weeks. Carbohydrates were associated with higher feed utilization owned by the well-known protein-sparing effect, with better fish growth performance. However, atypical regulation of glycolysis and gluconeogenesis in liver and absence of hk and glut4 induction in muscle, were also observed. Regarding the effects of carbohydrates on other metabolism, we observed an increased, at a molecular level, of hepatic cholesterol biosynthesis, fatty acid oxidation and mitochondrial energy metabolism. Genetic variability (revealed by the differences between the two isogenic lines) was observed for some metabolic genes especially for those involved in the EPA and DHA biosynthetic capacity. Finally, our study demonstrates that dietary carbohydrate not only affect glucose metabolism but also strongly impact the lipid and energy metabolism in liver and muscle of trout.


Educating patients about warfarin therapy using information technology: A survey on healthcare professionals' perspectives.
To explore healthcare professionals' views about the benefits and challenges of using information technology (IT) resources for educating patients about their warfarin therapy. A cross-sectional survey of both community and hospital-based healthcare professionals (e.g., doctors, pharmacists and nurses) involved using a purpose-designed questionnaire. The questionnaires were distributed using a multi-modal approach to maximise response rates. Of the total 300 questionnaires distributed, 109 completed surveys were received (43.3% response rate). Over half (53.2%) of the healthcare participants were aged between 40-59 years, the majority (59.5%) of whom were female. Fifty nine (54.1%) participants reported having had no access to warfarin-specific IT-based patient education resources, and a further 19 (38.0%) of the participants who had IT-access reported that they never used such resources. According to the healthcare participants, the main challenges associated with educating their patients about warfarin therapy included: patient-related factors, such as older age, language barriers, cognitive impairments and/or ethnic backgrounds or healthcare professional factors, such as time constraints. The healthcare professionals reported that there were several aspects about warfarin therapy which they found difficult to educate their patients about which is why they identified computers and interactive touch screen kiosks as preferred IT devices to deliver warfarin education resources in general practices, hospital-based clinics and community pharmacies. At the same time, the healthcare professionals also identified a number of facilitators (e.g., to reinforce warfarin education, to offer reliable and easily comprehensible information) and barriers (e.g., time and costs of using IT resources, difficulty in operating the resources) that could impact on the effective implementation of these devices in educating patients about their warfarin therapy. The findings of the study suggest that there is a need for improving healthcare professionals' use of, and access to IT-based warfarin education resources for patients. The study findings also suggest addressing the concerns raised by the healthcare professionals when implementing such IT resources successfully to help educate patients about their warfarin therapy.


Abstract temporal diagnosis in medical domains.
Most current model-based diagnosis formalisms and algorithms are defined only for static systems, which is often inadequate for medical reasoning. In this paper we describe a model-based framework plus algorithms for diagnosing time-dependent systems where we can define qualitative temporal scenarios. Complex temporal behavior is described within a logical framework extended by qualitative temporal constraints. Abstract observations aggregate from observations at time points to assumptions over time intervals. These concepts provide a very natural representation and make diagnosis independent of the number of actual observations and the temporal resolution. The concept of abstract temporal diagnosis captures in a natural way the kind of indefinite temporal knowledge which is frequently available in medical diagnoses. We use viral hepatitis B (including a set of real hepatitis B data) to illustrate and evaluate our framework. The comparison of our results with the results of HEPAXPERT-I is promising. The diagnosis computed in our system is often more precise than the diagnosis in HEPAXPERT-I and we detect inconsistent data sequences which cannot be detected in the latter system.


Identification of Unique Transcriptomic Signatures and Hub Genes Through RNA Sequencing and Integrated WGCNA and PPI Network Analysis in Nonerosive Reflux Disease.
Transcriptomic studies on gastroesophageal reflux disease are scarce, and gene expression signatures in nonerosive reflux disease (NERD) remain elusive. The aim of the study was to identify gene expression profiles and potential hub genes in NERD. We performed RNA sequencing on biopsy samples from nine consecutive patients with NERD and six healthy controls. Differentially expressed genes (DEGs) were analysed with the DESeq2 R package. A DEG-based protein-protein interaction (PPI) network was constructed to filter hub genes using Cytoscape. Weighted gene coexpression network analysis (WGCNA) was conducted to identify the coexpression relationships of all modules and explore the relationship between gene sets and clinical traits. In total, 1195 DEGs were identified, including 649 upregulated and 546 downregulated genes involved in regulating the inflammatory response and epithelial cell differentiation. Overlap of the PPI and WGCNA networks identified five shared genes, namely, THY1, BMP2, LOX, KDR and MMP9, as candidate hub genes in NERD. Quantitative PCR analysis of the expression of these five genes confirmed the sequencing results. Receiver operating characteristic analyses indicated that these hub genes had diagnostic potential for NERD patients. Gene set enrichment analysis confirmed that each hub gene was closely associated with the pathophysiological processes of NERD. In addition, a regulatory network comprising 42 transcription factors (TFs), 28 miRNAs and 5 hub genes was established. The five core genes may be promising biomarkers of NERD. The TF/miRNA/hub gene network can improve the understanding of the molecular mechanisms underlying disease progression.


University efforts to address confidentiality issues for STI services.
Objective: This study assessed university policies for addressing confidentiality issues for students seeking STI services. Participants: Universities with sponsored health insurance plans (SHIP) and/or wellness centers were selected from a university health services survey in 2017. Methods: STI service coverage and polices for addressing confidentiality issues related to explanation of benefit (EOB) forms were stratified by institution type (4-year versus 2-year) and minority serving institution (MSI) status. Rao-Scott chi-square tests were used to assess for differences in STI service coverage and polices. Results: More non-MSIs (61.6%) had SHIPs compared to MSIs (40.0%, p < .001). Only 40.8% of health centers had a policy for addressing EOB-related confidently issues. Of those, the most reported policy was that students could pay out-of-pocket to avoid generating an EOB (36.2%). Conclusions: Reducing confidentiality barriers are important for STI prevention in students. Universities may consider establishing policies for addressing EOB-related confidentiality concerns.


Development and evaluation of swine vesicular disease isotype-specific antibody ELISAs based on recombinant virus-like particles.
Swine vesicular disease (SVD) is a contagious viral disease of pigs. The clinical signs of SVD are indistinguishable from other vesicular diseases, such as senecavirus A infection (SVA) and foot-and-mouth disease (FMD). Rapid and accurate diagnostic tests of SVD are considered essential in countries free of vesicular diseases. Competitive ELISA (cELISA) is the serological test used routinely. However, although cELISA is the standard test for SVD antibody testing, this test produces a small number of false-positive results, which caused problems in international trade. The current project developed a SVD isotype antibody ELISA using recombinant SVD virus-like particles (VLP) and an SVD-specific monoclonal antibody (mAb) to reduce the percentage of false positives. The diagnostic specificities of SVD-VLP isotype ELISAs were 98.7% and 99.6% for IgM and IgG. The SVD isotype ELISAs were SVD-specific, without cross-reactivity to other vesicular diseases. A panel of 16 SVD-positive reference sera was evaluated using the SVD-VLP isotype ELISAs. All sera were correctly identified as positive by the two combined SVD-VLP isotype ELISAs. Comparison of the test results showed a high level of correlation between the SVDV antigen isotype ELISAs and SVD-VLP isotype ELISAs. 303 sera from animals lacking clinical signs and history of SVDV exposure were identified positive using SVD cELISA. These samples were examined using SVD-VLP isotype ELISAs. Of the 303 serum samples, five were positive for IgM, and five of 303 were positive for IgG. Comparable to virus neutralization test results, SVD isotype ELISAs significantly reduced the false-positive samples. Based on above test results, the combined use of cELISA and isotype ELISAs can reduce the number of false-positive samples and the use of time-consuming virus neutralization tests, with benefit for international trade in swine and related products.


Microvascular endothelial cell shape and size in situ.
To estimate total cleft length per unit surface area, previous studies assumed that endothelial cell clefts were oriented randomly with respect to the axis of the microvessel (Bundgaard and Frøkjaer-Jensen, Microvasc. Res. 23, 1-30, 1982). In the present study, silver precipitation along the intercellular clefts of capillary endothelium ("silver lines") in the frog mesentery allowed observation of cleft orientation as well as estimation of cell shape, cell area (CA), and cleft length per unit area (CL). In all vessels, the endothelial cells were highly elongated polygons, usually hexagonal, which were oriented along the vessel axis. The clefts were highly oriented with a preferred orientation which was parallel to the vessel axis. Clefts exhibited very little local meandering, with a contour length only 7% greater than endpoint-to-endpoint length. Therefore, the assumption of random cleft orientation was not valid, and its use yielded an overestimate of CL. New estimates of CL were 0.16, 0.12, and 0.12 microns-1 for arterial, true, and venous capillaries, respectively. Cell lengths (mean +/- SD, n) were 135 microns (+/- 28, 79) in arterial capillaries, 98 microns (+/- 28, 19) in true capillaries, and 139 microns (+/- 20, 21) in venous capillaries.


Esophageal reflux hypersensitivity: Non-GERD or still GERD?
The most recent iteration of the classifications for functional esophageal disorders, Rome IV, proposed relevant modifications of the previous definitions for Rome III. They specifically considered increased esophageal acid exposure as the marker of gastroesophageal reflux disease (GERD), including the remaining part of non-erosive reflux disease patients with normal acid in the group with functional alterations, considering both reflux hypersensitivity and functional heartburn. However, recent pathophysiological and therapeutic data suggest the need for a return to including reflux hypersensitivity in the GERD spectrum. Indeed, physiologic alterations in esophageal mucosal integrity and chemical clearance, the presence of microscopic esophagitis, and strict symptom-reflux association support the concept that reflux hypersensitivity pertains to GERD. Surgical anti-reflux therapy has resulted in positive outcomes, even in the long term, in patients with reflux hypersensitivity and not in those with functional heartburn. Moreover, clinical trials using neuromodulators have been scarce and provided conflicting results. As a result, the real progress of the Rome IV classifications is in dispute. This article aims to summarize the most recent knowledge of non-erosive reflux disease and reflux hypersensitivity to discuss the utility of Rome IV criteria in the identification and management of functional esophageal disorders.


Early esophageal cancer.
Early esophageal cancer (EEC) accounted for only seven (4.7%) of 148 cases of esophageal cancer diagnosed at the authors' hospital between 1977 and 1984. Two patients with EEC had squamous cell carcinoma and five had adenocarcinoma arising in Barrett's mucosa. All seven patients had associated clinical findings, including low-grade gastrointestinal bleeding (three cases), odynophagia (one case), and chronic reflux symptoms due to underlying reflux esophagitis and Barrett esophagus (three cases). Since Barrett esophagus is a premalignant condition, the high proportion of adenocarcinomas in this series presumably reflects the more frequent radiologic evaluation of symptomatic patients with Barrett esophagus. On esophagography, four patients had 3-4.5-cm polypoid intraluminal masses that could not be distinguished radiographically from advanced esophageal carcinoma. In the other three patients, esophagrams revealed secondary achalasia, irregular flattening of the esophageal wall, and diffuse nodularity of the mucosa. The authors conclude that "early" esophageal cancers are not necessarily small cancers, since they may undergo considerable intraluminal or intramural growth and still be classified histologically as EEC. Radiologists should be aware of these findings, since EEC has an excellent prognosis with a 5-year survival approaching 90%.


Inhibition of Fatty Acid-Binding Protein 4 Attenuated Kidney Fibrosis by Mediating Macrophage-to-Myofibroblast Transition.
The macrophage-to-myofibroblast transition (MMT) process is an important pathway that contributing to renal interstitial fibrosis (RIF). Fatty acid-binding protein 4 (FABP4) deteriorated RIF via promoting inflammation in obstructive nephropathy. However, the clinical significance of FABP4 in fibrotic kidney disease remains to be determined and little is known of the FABP4 signaling in MMT. Biopsy specimens of chronic kidney disease patients and kidneys subjected to unilateral ureteral obstruction (UUO) of FABP4-deficient mice or FABP4 inhibitor-treated mice were collected for the investigation of FABP4 mediating MMT of RIF. We conducted kidney RNA-seq transcriptomes and TGF-β1-induced bone marrow-derived macrophage (BMDM) assays to determine the mechanisms of FABP4. We found that FABP4 expression correlated with RIF in biopsy specimens and the injured kidneys of UUO mice where FABP4 was co-expressed with MMT cells. In UUO mice, FABP4 deficiency and a highly selective FABP4 inhibitor BMS309403 treatment both suppressed RIF. FABP4 ablation also attenuated the UUO-induced number of MMT cells and serum amyloid A1 (Saa1) expression. The siRNA-mediated Saa1 knockdown decreased the number of MMT cells in vitro. In conclusion, FABP4 is an important factor contributing to RIF by mediating MMT, and genetic/pharmacological inhibition of FABP4 provides a novel approach for the treatment of kidney fibrosis.


Analysis of the second heart sound using continuous wavelet transform.
This paper is concerned with a synthesis study of Continuous Wavelet Transform (CWT) in analysing the second heart sound of the phonocardiogram (PCG). The second heart sound S2 consists of two major components (A2 and P2) with a time delay between them which is very important for a diagnosis. It is shown that CWT provides enough features of these components of time, frequency and time delay to aid diagnosis.


To Die, to Sleep - to Sleep, Perchance to Dream…Without Hypertension: Dreams of the Visionary Christian Guilleminault Revisited.
Javaheri S, Gay PC. To die, to sleep - to sleep, perchance to dream…without hypertension: dreams of the visionary Christian Guilleminault revisited. J Clin Sleep Med. 2019;15(9):1189-1190.


Percutaneous vertebroplasty: a bone cement procedure for spinal pain relief.
Percutaneous vertebroplasty (PV), a procedure where bone cement is injected into a partially collapsed vertebral body, is used to relieve pain and provide mechanical stability in cases of osteoporosis or tumour infiltration. PV provided rapid pain relief and increased mobility in most patients according to the results from 15 uncontrolled studies in 882 persons where over 1,500 vertebrae were treated. Serious complications from bone cement leaks and adjacent vertebral fractures were rare. Despite the increasing use of PV there are no controlled prospective studies on safety and efficacy with long-term follow-up. Physician and supply costs range from C $300 -600 per vertebra treated. This figure excludes hospital or investigational costs.


ConCysFind: a pipeline tool to predict conserved amino acids of protein sequences across the plant kingdom.
Post-translational modifications (PTM) of amino acid (AA) side chains in peptides control protein structure and functionality. PTMs depend on the specific AA characteristics. The reactivity of cysteine thiol-based PTMs are unique among all proteinaceous AA. This pipeline aims to ease the identification of conserved AA of polypeptides or protein families based on the phylogenetic occurrence in the plant kingdom. The tool is customizable to include any species. The degree of AA conservation is taken as indicator for structural and functional significance, especially for PTM-based regulation. Further, this pipeline tool gives insight into the evolution of these potentially regulatory important peptides. The web-based or stand-alone pipeline tool Conserved Cysteine Finder (ConCysFind) was developed to identify conserved AA such as cysteine, tryptophan, serine, threonine, tyrosin and methionine. ConCysFind evaluates multiple alignments considering the proteome of 21 plant species. This exemplar study focused on Cys as evolutionarily conserved target for multiple redox PTM. Phylogenetic trees and tables with the compressed results of the scoring algorithm are generated for each Cys in the query polypeptide. Analysis of 33 translation elongation and release factors alongside of known redox proteins from Arabidopsis thaliana for conserved Cys residues confirmed the suitability of the tool for identifying conserved and functional PTM sites. Exemplarily, the redox sensitivity of cysteines in the eukaryotic release factor 1-1 (eRF1-1) was experimentally validated. ConCysFind is a valuable tool for prediction of new potential protein PTM targets in a broad spectrum of species, based on conserved AA throughout the plant kingdom. The identified targets were successfully verified through protein biochemical assays. The pipeline is universally applicable to other phylogenetic branches by customization of the database.


Efficacy of Lantigen B in the prevention of bacterial respiratory infections.
Respiratory tract infections are among the most common diseases both in adults and children. This multicentre study, was carried out in 212 patients (118 adults with chronic respiratory diseases and 94 children with recurrent respiratory infections) at six Italian study centres. It was performed to establish the efficacy of Lantigen B for the prevention of bacterial complications and/or reduction of associated symptoms. Lantigen B is an oral product based on bacterial lysates of six different inactivated strains commonly involved in respiratory tract infections. The results of prophylactic treatment with Lantigen B in the population investigated were as follows: - the mean incidence of recurrence in the pediatric patients over the 6-month observation period of the study was 1.643 in the placebo group and 1.211 in the Lantigen B group (a relative reduction of 35.7%); - the mean incidence of recurrence in the adult patients over the 6-month observation period of the study was 0.73 in the placebo group and 0.56 in the Lantigen B group (a relative reduction of 30.4%). The improvement in other important parameters, such as the number of days with a high temperature, cough, and catarrh in the children and objective clinical findings at the lymph nodes of the neck, chest, and pharyngotonsillar region in the adults, provides further evidence of the efficacy of Lantigen B. This study demonstrates Lantigen B's effectiveness in the prevention of bacterial complications and suggests that it can be used in patients who are particularly at risk of infection (children, the elderly, diabetics, and immunocompromised patients) or those in whom an infection might aggravate a clinical picture that is already inherently complicated (diabetics again, but also patients with heart, kidney, or liver disease).


Seroprevalence of IgG antibodies against measles in health care workers of the Strakonice Hospital.
Due to mandatory vaccination introduced in the Czech Republic since 1969, only few measles cases were reported annually until recently. However, a rapid increase of cases has been recorded in last two years. In contrast to the pre-vaccination era, in recent measles outbreaks, many cases have been reported among vaccinated adults. Health care workers (HCWs) are particularly at high risk of contact with measles. Therefore, to minimize transmission in health care settings, many hospitals evaluate measles immune status of their HCWs and offer free vaccination to those with too low anti-measles antibody levels. The aim of this study was to evaluate the seroprevalence of IgG antibodies against measles in all HCWs of the Strakonice Hospital. Anti-measles IgG serum levels were measured using quantitative ELISA. Almost all HCWs born before 1969, when the mandatory vaccination started, showed high levels of IgG antibodies (93.5%). Contrarily, among previously vaccinated individuals, only 64.8% were seropositive. A high percentage of seronegative or borderline samples was observed even in the age groups who were previously vaccinated with two doses. In total, 25.4% of all HCWs of the Strakonice Hospital had too low anti-measles IgG levels, and most of them were immunized with one dose of MMR vaccine. Prioritized vaccination substantially decreased the number of staff at higher risk of measles acquisition and, at the same time, of those who would need to be quarantined after exposure.


An Inhibitor of Thyroid Hormone Synthesis Protects Tail Skin Grafts Transplanted to Syngenic Adult Frogs.
Tail regression in amphibian tadpoles during metamorphosis is one of the most dynamic morphological changes in animal development and is induced by thyroid hormone (TH). It has been proposed that tail resorption is driven by immunological rejection in Xenopus laevis, based on experimental evidence showing that larval skin grafts become atrophic on syngenic recipient adult frogs. This led to the hypothesis that tail regression is induced by an immunological rejection against larval skin-specific antigens called Ouro proteins. However, our group has demonstrated that ouro-knockout tadpoles undergo normal metamorphosis, including tail resorption in Xenopus tropicalis, which indicates that the expression of ouro genes is not necessary for tail regression. In the present study, we showed that an inhibitor of TH synthesis promotes the survival of larval tail skin grafts on syngenic adult Xenopus tropicalis frogs. The levels of endogenous THs in adult frogs were also comparable to those in metamorphosing tadpoles of Xenopus laevis with a regressing tail, and TH induced the regression of tadpole tail tips of Xenopus tropicalis in organ culture. Taken together, these results strongly suggest that endogenous THs in the recipient adult frog induce the degeneration of syngenic tail skin grafts.


Metabolic acidosis status and mortality in patients on the end stage of renal disease.
Uncorrected metabolic acidosis leads to higher death risk in dialysis patients. We observed the relationship between metabolic acidosis status and mortality rate in patients on renal replacement therapy during a median follow up time of 60 months. We studied 76 patients on an on-line hemodiafiltration. The dialysis adequacy was defined by Kt/V for urea. The Framingham risk score (FRS) points were used to determine the 10-year risk for coronary heart disease. We examined the impact of high or low serum bicarbonate concentrations on mortality rate and on 10-year risk for coronary heart disease via the Kaplan-Meier method. Cox's model was used to evaluate a combination of prognostic variables, such as dialysis adequacy defined by Kt/V for urea, age and serum bicarbonate concentrations. We divided the enrolled patients in three groups according to serum bicarbonate concentrations (< 20 mmol/L, 20-22 mmol/L and > 22 mmol/L). Kaplan-Meier survival curve for the impact of serum bicarbonate concentrations on overall mortality was found significant (log-rank = 7.8, P = 0.02). The prevalence of serum bicarbonate less or more than 20 mmol/L on high FRS (> 20%) by Kaplan-Meier curve was also found significant (log-rank = 4.9, P = 0.02). Cox's model revealed the significant predictive effect of serum bicarbonate on overall mortality (P = 0.006, OR = 1.5, 95% CI = 1.12-1.98) in combination to Kt/V for urea and age. Uncorrected severe metabolic acidosis, defined by serum bicarbonate concentrations less than 20 mmol/L, is associated with a 10-year risk for coronary heart disease more than 20% and high overall mortality in patients on renal replacement therapy.


Vascular surgical site infection: risk factors and preventive measures.
Surgical site infection (SSI) after arterial intervention is a common nosocomial vascular complication and an important cause of postoperative morbidity. Its prevention requires the vascular surgeon and the health care team to be cognizant of its epidemiology and patient-specific risk factors to apply effective measures to reduce the incidence. The majority of vascular SSIs are caused by Gram-positive bacteria with methicillin-resistant Staphylococcus aureus (MRSA) now a prevalent pathogen that is involved in more than one-third of cases. Nasal carriage of methicillin-sensitive S. aureus or MRSA strains, recent hospitalization, a failed arterial reconstruction, and the presence of a groin incision are major risk factors for developing a vascular SSI. Overall, the SSI rate after arterial intervention is higher than predicted by the Centers for Disease Control and Prevention's National Nosocomial Infections Surveillance Risk Category System, and ranges from 1% to 2% after open or endovascular aortic interventions, to as high as 10% to 20% after lower-limb bypass grafting procedures. Application of perioperative measures to reduce S. aureus nasal and skin colonization in conjunction with appropriate, bactericidal antibiotic prophylaxis, meticulous wound closure, and postoperative care to optimize patient host defense regulation mechanisms (eg, temperature, oxygenation, and blood sugar) can minimize SSI occurrence.


Automatic remote monitoring of implantable cardioverter-defibrillator lead and generator performance: the Lumos-T Safely RedUceS RouTine Office Device Follow-Up (TRUST) trial.
Monitoring performance of implantable cardioverter-defibrillator (ICD) generators and leads is important. Methods available are with in-person evaluations or by automatic remote home monitoring (HM). These were prospectively evaluated and compared in the TRUST trial. The HM technology tested performed daily self-checks and databasing with rapid event notifications for out-of-range (including asymptomatic) conditions. Patients (n=1339) were randomly assigned after ICD implant 2:1 to HM or to conventional groups. Both groups underwent scheduled checks every 3 months and were followed for 15 months. In HM, in-person office visits were scheduled at 3 and 15 months. At 6, 9, and 12 months, HM only was used with subsequent office visits if necessary. Between these time points, ICDs triggered event notifications for system integrity problems. Patients randomly assigned to conventional follow-up were evaluated with office visits only. HM and conventional patients were similar (age, 63.3±12.8 versus 64.0±12.1 years; 72.0% versus 73.1% male; New York Heart Association II class, 55.9% versus 60.4%; left ventricular ejection fraction, 29.0±10.7% versus 28.5±9.8%; coronary artery disease, 64.8% versus 71.7%; primary prevention, 72.2% versus 73.8%; DDD devices, 57.8% versus 56.6%). Four patients crossed over from conventional to HM because of advisories. Scheduled checks were more successfully accomplished in HM (92.7% versus 89.2% in conventional, P<0.001). Sixty-two device-related events (53 in HM versus 9 in conventional) were observed in 46 patients (40 [4.4%] in HM versus 6 [1.39%] in conventional, P=0.004). Forty-seven percent were asymptomatic. HM detected generator and lead problems earlier (HM versus conventional: median, 1 versus 5 days; P=0.05). A total of 20 device problems (eg, lead fracture, elective replacement indicators) requiring surgical revision (0.012 per patient-year) were found, 15 in HM and 5 in the conventional groups. Other events were managed nonsurgically (eg, reprogramming, initiation of antiarrhythmics). ICD lead and generator malfunction was infrequent and often asymptomatic. Only a minority of detected events required surgical intervention. Automatic HM enhanced discovery, permitted prompt detection, and facilitated management decisions. Longitudinal parameter trending, with component function evaluated daily by remote monitoring, may enable long-term performance assessment. URL: http://clinicaltrials.gov. Unique identifier: NCT00336284.


Evaluation of inductively heated ferromagnetic alloy implants for therapeutic interstitial hyperthermia.
Ferromagnetic alloys heated by magnetic induction have been investigated as interstitial hyperthermia delivery implants for over a decade, utilizing low Curie temperatures to provide thermal self-regulation. The minimally invasive method is attractive for fractionated thermal treatment of tumors which are not easily heated by focused microwave or ultrasound techniques. Past analyses of ferromagnetic seeds by other authors depict poor experimental correlation with theoretical heating predictions. Improvements in computer hardware and commercially available finite element analysis software have simplified the analysis of inductively heated thermal seeds considerably. This manuscript examines end effects of finite length implants and nonlinear magnetic material properties to account for previous inconsistencies. Two alloys, Ni-28 wt% Cu (NiCu) and Pd-6.15 wt% Co (PdCo), were used for comparison of theoretical and experimental calorimetric results. Length to diameter (L/d) ratios of over 20 for cylindrical seeds are necessary for minimization of end effects. Magnetic properties tested for alloys of NiCu and PdCo illustrate considerable nonlinearity of these materials in field strength ranges used for induction heating. Field strength dependent magnetic permeabilities and calorimetric data illustrate that more detailed material information must be included to accurately estimate induction power loss for these implants.


Programmed cell death during animal development.
The formation of the hand during embryogenesis, the peeling of sunburned skin and the tremor associated with Parkinson's disease all result from a common process: cell death. Cell death occurs throughout the life span of the organism and represents the ultimate differentiative decision made by cells. Insight into the process of cell death will not only contribute to our understanding of basic developmental issues, but will also facilitate the development of therapeutic interventions that could alter the course of disease. Since all cells have the genetic machinery required to commit suicide, the ability to initiate it in a lineage-specific, non-inflammatory manner would allow for the irradication of specific cancers. Alternatively, inhibition of cell death pathways could rescue valuable but condemned cells, such as HIV infected CD4+ T cells or dopaminergic neurons in Parkinson's disease. The goal of this chapter is to provide both an overview of the basic principles that govern the cellular and molecular mechanisms mediating cell death, as well as serve as a reference of known examples of PCD and the genes that mediate this process.


Extensor Pollicis Brevis Transosseous Tenodesis Technique for Treatment of Acquired Metacarpophalangeal Hyperextension Deformity of the Thumb: A Preliminary Report.
Hyperextension deformity of the metacarpophalangeal joint of the thumb causes pain and loss of function. Although many treatments have been proposed, none of them are universally accepted as ideal. The authors report a study of 12 symptomatic hyperextension deformities of the thumb metacarpophalangeal joint in 10 patients who underwent surgical correction. The purpose of this study was to describe a new technique of tenodesis of the thumb metacarpophalangeal joint using the extensor pollicis brevis tendon. The technique consists of extensor pollicis brevis tenotomy at the wrist and tendon transfer through two bone tunnels to the palmar aspect of the metacarpophalangeal joint before metacarpal fixation with a flexor tenodesis effect. Correction of hyperextension and range of motion were assessed. Functional changes were evaluated by Quick Disabilities of the Arm, Shoulder, and Hand score, pain visual analogue scale, Kapandji opposition scheme, and pinch strength. The Wilcoxon test was used for statistical analysis. Mean preoperative and postoperative metacarpophalangeal joint hyperextension deformities were +50.83 ± 5.57 degrees and -17.91 ± 7.82 degrees, respectively. Thumb opposition improved by one point on Kapandji's scheme. Mean perceived pain decreased from 7.66 to 1.16. On average, the Quick Disabilities of the Arm, Shoulder, and Hand score was reduced by 34.4 points and pinch strength increased by 50.42 percent. The authors found that extensor pollicis brevis transosseous tenodesis is a safe and minimally invasive method for successfully correcting the functionality and cosmetic appearance of metacarpophalangeal joint hyperextension deformities in posttraumatic and trapeziometacarpal osteoarthritis cases. The patients retained functional active flexion, even in deformities greater than 40 degrees. Therapeutic, IV.


CD8 T cell-mediated rejection of intestinal allografts is resistant to inhibition of the CD40/CD154 costimulatory pathway.
Disruption of the CD40/CD154 pathway inhibits rejection in numerous models. The importance of this pathway on intestinal allograft rejection was examined in this study. Intestinal grafts from B6C3F1 mice transplanted into C57BL/6 recipients were assessed histologically for rejection. The monoclonal antibody to CD154, MR1, failed to inhibit rejection in wild-type mice. Similarly, CD154-/- recipient mice rejected intestinal allografts. MR1 did inhibit early rejection in CD8-/- mice, but had no effect in CD4-/- recipients. All MR1-treated CD8-/- recipients eventually developed rejection. No benefit was observed when blockade of the CD40/CD154 pathway by MR1 was combined with blockade of the CD28/B7 pathway by mCTLA4Ig. These data suggest that CD4+ T cells mediating intestinal allograft rejection may be more dependent upon the CD40/CD154 pathway than CD8+ T cells. This finding highlights the importance of identifying agents that suppress CD8+ T cell-mediated rejection.


The clinical utility of automated breast volume scanner: a pilot study of 139 cases.
The aim of this study is to evaluate the clinical utility of automated breast volume scanner (ABVS) for detecting and diagnosing the breast lesions. From December 2010 to January 2012, bilateral whole breast examinations were performed with ABVS for 139 women. Based on the Breast Imaging Reporting and Data System (BI-RADS) categories, the breast lesions were evaluated on coronal multiplanar reconstruction images using the ABVS workstation. Then, the imaging results were compared with those on conventional handheld ultrasound (HHUS) images. Histological diagnoses were performed on BI-RADS category 4 and 5 lesions. A total of 453 lesions were detected by ABVS. On the HHUS, 33 new lesions were detected but 69 lesions were not detected. BI-RADS category 2 and 3 matched to those on ABVS at 73.5% (61/83) and 85.4% (276/323). In 47 lesions of BI-RADS category 4 or 5, there was an exact match to those on ABVS. In addition, 47 lesions were classified as BI-RADS category 4 and 5, for which an ultrasound-guided core needle biopsy was performed. The malignant lesions of BI-RADS category 4 and 5 showed the following: 2/27 (7.4%) in 4A, 4/5 (80%) in 4B, 2/2 (100%) in 4C, and 13/13 (100%) in 5. The ABVS showed 21 true positives and a positive predictive value of 44.7% (21/47). There was considerable agreement in the assessment of the breast lesions by ABVS and HHUS. The ABVS had advantages of high diagnostic accuracy, examiner-independence, multislice visualization of the whole breast and less time-consuming. Our results indicate that ABVS might be a useful modality in diagnosing breast lesions.


OATP1B3 is expressed in pancreatic β-islet cells and enhances the insulinotropic effect of the sulfonylurea derivative glibenclamide.
Organic anion transporting polypeptide OATP1B3 is a membrane-bound drug transporter that facilitates cellular entry of a variety of substrates. Most of the previous studies focused on its hepatic expression and function in hepatic drug elimination. In this study, we report expression of OATP1B3 in human pancreatic tissue, with the abundance of the transporter localized in the islets of Langerhans. Transport studies using OATP1B3-overexpressing MDCKII cells revealed significant inhibition of the cellular uptake of the known substrate cholecystokinin-8 in the presence of the insulinotropic antidiabetes compounds tolbutamide, glibenclamide, glimepiride, and nateglinide and identified glibenclamide as a novel substrate of OATP1B3. Sulfonylurea derivatives exert their insulinotropic effect by binding to the SUR1 subunit of the KATP channels inducing insulin secretion in β-cells. Here, we show that transient overexpression of human OATP1B3 in a murine β-cell line (MIN6)-which exhibits glucose and glibenclamide-sensitive insulin secretion-significantly enhances the insulinotropic effect of glibenclamide without affecting glucose-stimulated insulin secretion. Taken together, our data provide evidence that the drug transporter OATP1B3 functions as a determinant of the insulinotropic effect of glibenclamide on the tissue level. Changes in transport activity based on drug-drug interactions or genetic variability may therefore influence glibenclamide efficacy.


Diffuse leptomeningeal hyperintensity on fluid-attenuated inversion recovery MR images in neurocutaneous melanosis.
Neurocutaneous melanosis (NCM) is a rare neuroectodermal dysplasia characterized by large or multiple cutaneous congenital pigmented nevi and benign or malignant melanocytic tumors of the leptomeninges. Although the MR manifestations of this disease have been reported in a small series of cases, the usefulness of fluid-attenuated inversion recovery (FLAIR) MR findings has not been documented. We present a case of NCM that showed diffuse leptomeningeal hyperintensity on FLAIR images. This FLAIR finding may be a clue to the detection of leptomeningeal abnormalities in NCM.