Left ventricular assist device implantation combined with hemiarch replacement for severe aortic atherosclerosis.
Implantation of the left ventricular assist device (LVAD) has emerged as a widely employed therapeutic approach for specifically chosen individuals suffering from severe heart failure. Stroke is a well-known complication of LVAD implantation. Concomitant aortic surgeries in patients requiring LVAD implantation to avoid outflow graft anastomosis to a severe atherosclerotic aorta are unknown. We illustrate a successful LVAD implantation with hemiarch replacement for severe aortic atherosclerosis to decrease the risk of postoperative stroke. A 72-year-old male patient with advanced heart failure has chosen to undergo LVAD treatment. Preoperative examinations detected severe atherosclerosis in the ascending aorta. It was determined that clamping the ascending aorta and directly connecting the outflow graft could increase the risk of stroke after surgery. Therefore, it was decided to replace the diseased ascending aorta entirely. The HeartMate 3 was implanted under cardiopulmonary bypass (CPB) using right axillary artery cannulation. And moderate hypothermia and bilateral antegrade cerebral perfusion were utilized to perform hemiarch replacement. Subsequently, the outflow graft was connected to an artificial ascending aortic graft. The patient did not exhibit any specific complications, such as neurological abnormalities, after the surgery. Based on our observations, it appears that LVAD implantation combined with aortic replacement could be a viable option for specific patients, particularly those who have a perioperative stroke risk due to aortic atherosclerosis.


Assessing Australia's future solar power ramps with climate projections.
Increasing levels of photovoltaic (PV) penetration to the electricity grid brings challenges to both design and operation of the grid due to its vulnerability to climate change. A crucial aspect of PV operation is power ramps leading to variability and instability in the grid. With notable large-scale PV deployment planned, including the world's largest planned solar energy infrastructure in Powell Creek Australia, characterising future ramps is crucial for ensuring stable power generation to support large-scale economic development. Using CORDEX-Australasia projections under RCP8.5 and RCP4.5 emission scenarios, future solar ramps across Australia have been characterised up to 2100. Results predict a reduction in ramp magnitude across Australia, with changes in frequency and period length varying with the location. This work highlights the importance of considering future changes in climate when designing large-scale solar farms to ensure the incorporation of frequency control devices and storage plans for a reliable power supply.


Evaluation of the physiochemical and aromatic qualities of pickled Chinese pepper (Paojiao) and their influence on consumer acceptability by using targeted and untargeted multivariate approaches.
Paojiao, which is traditionally pickled Chinese chili peppers (Capsicum frutescens Linn.), possesses unique flavors. This study was conducted to investigate the flavor, mouthfeel, and consumer acceptability of Paojiao. The quality of six homemade and two industrial Paojiao samples were evaluated by integrating untargeted (to fingerprint volatile fraction) and targeted (to analyze free amino acids or FAAs, capsaicinoids, and texture) approaches. Furthermore, multivariate data analysis (MVDA) was applied to identify the quality characteristics that drive the consumer acceptability for Paojiao. As for the targeted quality, hardness (1.30-10.52 N) and capsaicin (2.22-3.84 mg/g) varied with different samples. The main taste-active FAAs in Paojiao were detected. A total of 127 volatiles were observed, and esters were the major components. Based on sensory analysis, the homemade samples received higher acceptability than the industrial samples. MVDA demonstrated that some key volatiles, taste-active FAAs, and chewiness were the discriminant quality attributes affecting consumer acceptability.


Gracilis muscle transposition for complex fistula and persistent nonhealing sinus in perianal Crohn's disease.
Complex fistulas and persistent perineal sinuses as a result of perianal Crohn's disease remain a major therapeutic challenge. A muscle transposition may promote wound healing by filling the perineal cavity and increasing tissue oxygenation. We aimed to evaluate the outcomes of the treatment at our institution over 8 years. A retrospective review was performed for patients who underwent gracilis muscle transposition for complex perianal Crohn's disease between 1999 and 2007. Data collected included patients' demographic data, previous treatments (medical and surgical), and outcome of the operation. A structured telephone interview was conducted to evaluate medium- to long-term outcomes of the treatment. Eighteen patients (8 men and 10 women, median age 33 years, range 17-59 years) underwent a gracilis muscle transposition between 1999 and 2007. Fourteen patients had a complex fistula, and 4 patients had a persistent nonhealing perineal sinus. Gracilis muscle transposition healed the perineum of 11 patients (61%) at a median follow-up of 10 months (range 1-88 months). The success rate for complex fistulas was 64% and that for persistent nonhealing perineal sinuses was 50%. Eight graft site infections and delayed healing were noted. There were no donor-site problems or major complication. Healing was maintained in 8 of 9 patients who were available for medium- to long-term follow-up (median 64 months, range 23-123 months), with high patient satisfaction. Gracilis transposition is a viable option as a treatment for complex perianal Crohn's disease. Efficacy was maintained in nearly 90% of patients in the medium to long term.


Immune aging - A mechanism in autoimmune disease.
Evidence is emerging that the process of immune aging is a mechanism leading to autoimmunity. Over lifetime, the immune system adapts to profound changes in hematopoiesis and lymphogenesis, and progressively restructures in face of an ever-expanding exposome. Older adults fail to generate adequate immune responses against microbial infections and tumors, but accumulate aged T cells, B cells and myeloid cells. Age-associated B cells are highly efficient in autoantibody production. T-cell aging promotes the accrual of end-differentiated effector T cells with potent cytotoxic and pro-inflammatory abilities and myeloid cell aging supports a low grade, sterile and chronic inflammatory state (inflammaging). In pre-disposed individuals, immune aging can lead to frank autoimmune disease, manifesting with chronic inflammation and irreversible tissue damage. Emerging data support the concept that autoimmunity results from aging-induced failure of fundamental cellular processes in immune effector cells: genomic instability, loss of mitochondrial fitness, failing proteostasis, dwindling lysosomal degradation and inefficient autophagy. Here, we have reviewed the evidence that malfunctional mitochondria, disabled lysosomes and stressed endoplasmic reticula induce pathogenic T cells and macrophages that drive two autoimmune diseases, rheumatoid arthritis (RA) and giant cell arteritis (GCA). Recognizing immune aging as a risk factor for autoimmunity will open new avenues of immunomodulatory therapy, including the repair of malfunctioning mitochondria and lysosomes.


Wide-area transepithelial sampling in adjunct to forceps biopsy increases the absolute detection rates of Barrett's oesophagus and oesophageal dysplasia: a meta-analysis and systematic review.
Wide-area transepithelial sampling (WATS) is a new technique that uses an abrasive brush to obtain samples from a larger surface area of the oesophagus. Studies have shown promising results that WATS in adjunct to forceps biopsy (FB) increases the detection rate of Barrett's oesophagus (BE) as well as oesophageal dysplasia (ED). We conducted a systematic review and meta-analysis to compare the detection rates of BE and ED between FB and WATS in adjunct to FB. A Literature search was done using electronic databases, including PubMed, Embase, Scopus, Cochrane and CINAHL from inception to 26 April 2020. A meta-analysis comparing detection rates of WATS in adjunct to FB versus FB using the random-effects model was done using RevMan V.5.3. Pooled data from 20 392 endoscopies across 11 studies showed an absolute increase in detection of 16% (95% CI 0.10% to 0.22%, p<0.00001). A relative increase of 1.62 was seen in detection rates of BE (95% CI 1.28 to 2.05, p<0.0001) when WATS was used with FB with the number needed to test (NNT) of 6.1 patients. For ED, a 2% absolute increase (95% CI 0.01 to 0.03, p=0.001) in additional diagnostic yield from WATS. A relative increase of 2.05 was seen in the detection rate of ED (95% CI 1.42 to 2.98, p=0.0001) yielding an NNT of 50 patients. Our study shows that WATS, as an adjunct to FB, improves both the absolute detection rate and relative detection rate of both BE and ED as compared to FB alone.


The effect of prednisolone trimethylacetate on the pathogenicity of Dermatophilus congolensis to white mice.
Albino mice were successfully infected intravenously, subcutaneously, intraperitoneally and on the intact and scarified skin with Dermatophilus congolensis. Various gross lesions were observed. Large subcutaneous nodules were produced in mice that were injected subcutaneously. Lesions involving the internal organs were obtained in mice that had been injected intravenously and intraperitoneally in addition to microabsessation and scab formation on the tails of those that were injected intravenously. The application of D. congolensis on scarified skin resulted in scab formation covering the whole area while its application on non-scarified skin produced isolated lesions. The organism was isolated in pure culture from exudate, pus and scab material obtained from lesions. Severe histopathological changes were noted in sections prepared from the lesions. Premedication of mice with prednisolone trimethylacetate increased the severity of the experimentally induced lesions.


Identification of two core genes in glioblastomas with different isocitrate dehydrogenase mutation status.
Glioblastoma (GBM) is one of the most common malignancies of the central nervous system, and the Isocitrate Dehydrogenase (IDH) mutation status of GBM has been recognized as a critical prognostic indicator. However, the molecular mechanism underlying the GBM with different IDH mutation status is still not unclear. In this study, a total of 353 DEGs including 207 up-regulated and 146 down-regulated were screened from multiple GBM data sets. Moreover, the biological processes and pathways enriched by DEGs were mainly associated with tumor progression, especially invasion and migration. Then, eight hub genes, including SDC4, SERPINE1, TNC, THBS1, COL1A1, CXCL8, TIMP1 and VEGFA, were selected from a PPI network. Finally, core genes, SERPINE1 and TIMP1, were identified from hub genes by survival analysis and sample validation. Overall, in this study, we revealed underlying molecular mechanisms in GBMs with different IDH mutation status and identified core genes that could be potential markers and targets for diagnosis and treatment of GBMs.


Genoprotective effects of lignin isolated from oil palm black liquor waste.
Black liquor waste (BLW), a major by-product of palm oil extraction process contains lignin as one of the constituents. Lignin isolated from BLW was evaluated for antioxidant and genoprotective properties and was compared with the commercial lignin for overall efficacy. Antioxidant compounds (phenolics and tannins) and antioxidant activities (phosphomolybdenum assay, ABTS(+) and FRAP assays) of lignin isolated from BLW were compared with commercial lignin. Bone marrow micronucleus (MN) test was employed for evaluating the dose-yield protective effect against cyclophosphamide (CP, 50mg/kg b.w.) induced genotoxicity in mouse. Results revealed isolated lignin to exhibit rich antioxidant activities. A decrease in MN frequency and recovery of P/N ratio (P: polychromatic erythrocytes, N: normochromatic erhythocytes) indicated protective effects of lignin against cyclophosphamide induced genotoxicity and cytotoxicity. The efficacy of BLW-derived lignin as an antioxidant and genoprotective agent was comparable to commercial lignin. Results on lignin isolated from BLW are envisaged to find potential applications in food and/or pharmaceutical industries.


Diagnostic utility of anti-cyclic citrullinated peptide and anti-modified citrullinated vimentin antibodies in rheumatoid arthritis.
Several autoantibodies found in RA are directed to epitopes in citrullinated proteins. One of them is anti modified citrullinated vimentin (Anti-MCV). We tested the value a newly developed ELISA for the detection of antibodies against a genetically modified citrullinated vimentin (anti-MCV) in comparison with an anti-CCP based ELISA system for the diagnosis of RA. Thirty-five patients with RA (mean age; 42.6 +/- 10.87 years, mean disease duration; 9.37 +/- 3.98 years) were enrolled in this study. Twenty -five ankylosing spondylitis (mean age; 35.88 +/- 6.64 years, mean disease duration; 10.25 +/- 4.61 years), and 19 healthy subjects (mean age; 40.26 +/- 5.11 years) served as controls. Anti-CCP antibodies and Anti-MCV antibodies were measured using ELISA. In all RA patients, mean anti- CCP level was 69.07 +/- 90.43 U/ml and anti-MCV level was 665.77 +/- 1040.19 U/ml. In patients with AS, the mean anti-CCP level was 10.7 +/- 5.22 U/ml and anti-MCV level was 40.54 +/- 20.15 U/ml. In healthy controls, the mean anti-CCP level was 11.11 +/- 7.65 U/ml, anti-MCV level was 23.12 +/- 12.04 U/ml. In patients with active RA, the mean serum anti-CCP level was 100.54 +/- 98.07 U/ml and anti-MCV level was 998.74 +/- 1154.93 U/ml. In patients with inactive RA, the mean serum anti-CCP level was 8.77 +/- 1.55 U/ml and anti-MCV level was 27.59 +/- 23.10 U/ml. According to these results; In patients with RA, the mean serum anti-MCV and anti-CCP levels were significantly high compared to patients with AS and healthy controls (p=0.002, p=0.001, p=0.002, p=0.001 respectively). The mean serum anti-MCV and anti- CCP levels were significantly higher in active patients with RA than in inactive patients with RA patients (p=0.001 and p=0.001 respectively). In inactive patients with RA, the mean serum anti-MCV and anti-CCP levels were similar in patients with AS and patients (p=0.484, p=0.308, p=0.09 and p=0.222 respectively). The mean serum anti-MCV levels were correlated with DAS 28 (r=0.531, p=0.001), VAS score (r=0.332, p=0.01), ESR (r=0.458, p=0.001), serum CRP levels (r=0.568, p=0.01), serum RF levels (r=0.529, p=0.001), swollen joints number (r=0.525, p=0.001) and tender joints number (r=0.638, p=0.001). As a result; measurement of serum anti-MCV levels is useful for diagnosis of RA and combined use of anti-MCV and RF may be more useful prognostic factor than either method alone, RF and anti-CCP.


Immunologic classification of lymphoma and lymphoid leukemia.
Important insights into lymphocyte differentiation and the cellular origins of lymphoma and lymphoid leukemia have been gained through the use of monoclonal antibodies that define cell surface antigens and molecular probes that identify immunoglobulin and T cell receptor genes. Results of these studies have been combined with markers such as surface membrane and cytoplasmic immunoglobulin on B lymphocytes, sheep erythrocyte receptors on T lymphocytes, and cytochemical stains. Utilising all of the above markers, it is now clear that acute lymphoblastic leukemia (ALL) is heterogeneous. Furthermore, monoclonal antibodies that identify B cells such as the anti-B1 and anti-B4 antibodies in combination with studies of immunoglobulin gene rearrangement have demonstrated that virtually all cases of non-T-ALL involve B lymphocytes. At least six distinct subgroups of non-T-ALL can now be identified. T-ALL is subdivided by the anti-Leu-9, anti-Leu-1, and additional antibodies that separate T lymphocyte subsets into three primary subgroups. Monoclonal antibodies are also useful in the subclassification of non-Hodgkin's lymphoma, and certain distinct markers can be correlated with morphologic classification.


Specialist care of heart failure improves appropriate pharmacotherapy at the expense of greater polypharmacy and drug-interactions.
There is growing concern at the nature and extent of polypharmacy in heart failure (HF), which may be associated with increased drug interactions, adverse drug effects and a poor understanding of and compliance with therapy. This study evaluates polypharmacy in a relatively unselected community heart failure population following emergency admission and determines the impact of an in-hospital, specialist heart failure care programme on appropriate pharmacotherapy, polypharmacy and drug interactions. We analysed the medication profiles of 91 consecutive patients with an emergency admission for HF to our institution on admission and discharge. The numbers of inappropriate medicines, inappropriate dosages and omitted medicines according to guidelines were recorded. Medication profiles were analysed for potential drug-drug, drug-liver and drug-kidney interactions using standard criteria. In the study population, average age 71.1+/-10.4 years, 65.9% were male, 68.1% had left ventricular systolic dysfunction and the average ejection fraction on transfer to the specialist HF service was 38+/-13%. A total of 66 inappropriate medicines, 107 omitted medicines and 37 inappropriate dosage regimens were identified in the cohort on admission. These figures had dropped to 31, 33 and 19, respectively, on discharge, with per patient averages decreasing significantly (all P<0.0001). However, polypharmacy and potential drug interactions increased by 33% and 62%, respectively, from admission to discharge (P<0.0001) as did drug-kidney interactions and drug-liver interactions. Only ischemic aetiology and hypercholesterolaemia predicted polypharmacy in this cohort on discharge, whereas age, sex, renal function and heart failure type did not. Specialist care of heart failure following emergency admission results in more appropriate pharmacotherapy of heart failure. However, increased polypharmacy and drug-interactions are an inevitable consequence independent of age, sex and renal function. We advocate a practice of systematic evaluation of polypharmacy in all heart failure patients to identify potential problems and modify therapy where appropriate.


Larvicidal and ovicidal properties of leaf and seed extracts of Delonix elata (L.) Gamble (family: Fabaceae) against malaria (Anopheles stephensi Liston) and dengue (Aedes aegypti Linn.) (Diptera: Culicidae) vector mosquitoes.
Mosquito-borne diseases with an economic impact create loss in commercial and labor outputs, particularly in countries with tropical and subtropical climates. Mosquito control is facing a threat because of the emergence of resistance to synthetic insecticides. Extracts from plants may be alternative sources of mosquito control agents because they constitute a rich source of bioactive compounds that are biodegradable into nontoxic products and potentially suitable for use to control mosquitoes. Insecticides of botanical origin may serve as suitable alternative biocontrol techniques in the future. In view of the recently increased interest in developing plant origin insecticides as an alternative to chemical insecticide, this study was undertaken to assess the larvicidal and ovicidal potential of the crude hexane, benzene, chloroform, ethyl acetate, and methanol solvent extracts from the medicinal plant Delonix elata against the medically important mosquito vectors, Anopheles stephensi and Aedes aegypti (Diptera: Culicidae). The larval mortality was observed after 24 h of exposure. All extracts showed moderate larvicidal effects; however, the highest larval mortality was found in methanol extract of leaf of D. elata against the larvae of A. stephensi and A. aegypti with the LC(50) and LC(90) values being 93.59 and 111.83, and 163.69 and 202.77 ppm, respectively. Compared to leaf extracts, seeds have low potency against two mosquitoes with the LC(50) and LC(90) values being 115.28 and 139.04, and 225.07 and 273.03 ppm, respectively. The mean percent hatchability of the eggs was observed after 48 h post-treatment. The percent hatchability was inversely proportional to the concentration of extract and directly proportional to the eggs. All the five solvent extracts showed moderate ovicidal activity; however, the methanol extract showed the highest ovicidal activity. One hundred percent mortality was observed at 300 ppm for leaf methanol extract and 500 ppm for seed methanol extract of D. elata against A. stephensi and A. aegypti, respectively. These results suggest that the leaf and seed extracts have the potential to be used as an ideal ecofriendly approach for the control of mosquitoes. This is the first report on the mosquito larvicidal and ovicidal activities of the reported D. elata plant.


Intracoronary retrieval of the dehisced radiopaque ring of a guiding catheter: an unusual complication of coronary angioplasty.
The guiding catheter used in coronary intervention may be damaged or some parts could be dehisced during the procedure, producing adverse effects in the vascular tree. So much so that immediate surgery is usually indicated. We report a case with a dehisced radiopaque ring of the catheter during the procedure. It was retrieved percutaneously without thoracotomy.


Assessment of ventricular tachyarrhythmia in patients with hypertrophic cardiomyopathy with machine learning-based texture analysis of late gadolinium enhancement cardiac MRI.
To assess the diagnostic value of machine learning-based texture feature analysis of late gadolinium enhancement images on cardiac magnetic resonance imaging (MRI) for assessing the presence of ventricular tachyarrhythmia (VT) in patients with hypertrophic cardiomyopathy. This retrospective study included 64 patients with hypertrophic cardiomyopathy who underwent cardiac MRI and 24-hour Holter monitoring within 1 year before cardiac MRI. There were 42 men and 22 women with a mean age of 48.13±13.06 (SD) years (range: 20-70 years). Quantitative textural features were extracted via manually placed regions of interest in areas with high and intermediate signal intensity on late gadolinium-chelate enhanced images. Feature selection and dimension reduction were performed. The diagnostic performances of machine learning classifiers including support vector machines, Naive Bayes, k-nearest-neighbors, and random forest for predicting the presence of VT were assessed using the results of 24-hour Holter monitoring as the reference test. All machine learning models were assessed with and without the application of the synthetic minority over-sampling technique (SMOTE). Of the 64 patients with hypertrophic cardiomyopathy, 21/64 (32.8%) had VT. Of eight machine learning models investigated, k-nearest-neighbors with SMOTE exhibited the best diagnostic accuracy for the presence or absence of VT. k-nearest-neighbors with SMOTE correctly identified 40/42 (95.2%) VT-positive patients and 40/43 (93.0%) VT-negative patients, yielding 95.2% sensitivity (95% CI: 82.5%-99.1%), 93.0% specificity (95% CI: 79.8%-98.1%) and 94.1% accuracy (95% CI: 88.8%-98%). Machine learning-based texture analysis of late gadolinium-chelate enhancement-positive areas is a promising tool for the classification of hypertrophic cardiomyopathy patients with and without VT.


Multimodality Treatment of Gastric Lymphoma.
Gastric lymphoma is rare, accounting for 3% of gastric neoplasms and 10% of lymphomas. Treatment should be stratified based on histologic type, stage, Helicobacter pylori infection, and t(11;18) translocation status. Surgery is no longer a mainstay for treatment and should be reserved for rare situations such as perforation, fistula formation, and severe bleeding. Multimodal treatment, including H pylori eradication, radiation therapy, chemotherapy, and immunotherapy, should be provided as appropriate and can result in excellent outcomes.


Angiotensin II infusion induces site-specific intra-laminar hemorrhage in macrophage colony-stimulating factor-deficient mice.
Angiotensin II (AngII) infusion promotes macrophage infiltration into the aortic wall resulting in several forms of vascular pathology. To determine the causal role of macrophages in these vascular diseases, we used osteopetrotic (op) male mice in which a natural mutation ablates production of M-CSF and results in severe depletion of monocytes. AngII infusion into apoE-/- mice resulted in increased atherosclerosis that was attenuated in op mice. AngII infusion in op mice unexpectedly produced grossly discernable thickening of the proximal thoracic aorta characterized by intra-mural hematoma. This pathology was also observed in apoE+/+ x op male mice, and therefore, independent of hyper-lipidemia. No perceptible structural properties of aortas from op mice could be discerned prior to AngII infusion. Regional effects in the contractile response to phenylephrine were noted in aortic rings with enhanced responsivity in the upper thoracic aortas of op mice compared to those from +/+ mice. No differences in contractile response were noted in aortic rings from the lower thorax. In conclusion, deficiency of M-CSF attenuated AngII-induced atherosclerosis but led to an unanticipated pathology of intra-laminar hemorrhage in the upper aortic regions.


Fibrosis of two: Epithelial cell-fibroblast interactions in pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is characterized by the progressive and ultimately fatal accumulation of fibroblasts and extracellular matrix in the lung that distorts its architecture and compromises its function. IPF is now thought to result from wound-healing processes that, although initiated to protect the host from injurious environmental stimuli, lead to pathological fibrosis due to these processes becoming aberrant or over-exuberant. Although the environmental stimuli that trigger IPF remain to be identified, recent evidence suggests that they initially injure the alveolar epithelium. Repetitive cycles of epithelial injury and resultant alveolar epithelial cell death provoke the migration, proliferation, activation and myofibroblast differentiation of fibroblasts, causing the accumulation of these cells and the extracellular matrix that they synthesize. In turn, these activated fibroblasts induce further alveolar epithelial cell injury and death, thereby creating a vicious cycle of pro-fibrotic epithelial cell-fibroblast interactions. Though other cell types certainly make important contributions, we focus here on the "pas de deux" (steps of two), or perhaps more appropriate to IPF pathogenesis, the "folie à deux" (madness of two) of epithelial cells and fibroblasts that drives the progression of pulmonary fibrosis. We describe the signaling molecules that mediate the interactions of these cell types in their "fibrosis of two", including transforming growth factor-β, connective tissue growth factor, sonic hedgehog, prostaglandin E2, angiotensin II and reactive oxygen species. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.


Impact of human herpesvirus-6 on the frequency and severity of recurrent hepatitis C virus hepatitis in liver transplant recipients.
A role of tumor necrosis factor-alpha (TNF-alpha) In the immunopathogenesis of hepatitis C virus (HCV) infection has been proposed. The novel herpes virus, human herpes virus-6 (HHV-6), is amongst the most potent inducers of cytokines, including TNF-alpha. The impact of HHV-6 viremia on the progression of recurrent HCV hepatitis was assessed in 51 HCV-positive liver transplant recipients. The frequency of recurrent HCV hepatitis did not differ between patients with HCV viremia (47.6%, 10/21) as compared with those without HCV viremia (46.7%, 14/30, p = 0.9). However, the patients with HHV-6 viremia had a significantly higher fibrosis score upon HCV recurrence than those without HHV-6 viremia (mean 1.5 vs. 0.3, p = 0.01). An association between cytomegalovirus (CMV) viremia and HCV recurrence was not documented; 50% (15/30) of the patients with CMV viremia and 42.8% (9/21) of those without CMV viremia had recurrent HCV hepatitis (p > 0.5). Receipt of ganciclovir (administered upon the detection of CMV viremia) was associated with lower total Knodell score (mean 5.2 vs. 6.9, p = 0.05) and a trend towards lower fibrosis score (mean 0.44 vs. 1.00, p = 0.12) in patients with recurrent HCV hepatitis. Thus, HHV-6 viremia in HCV-positive liver transplant recipients identified a subgroup of patients at increased risk for early fibrosis upon HCV recurrence.


Laccase as an efficacious approach to remove anticancer drugs: A study of doxorubicin degradation, kinetic parameters, and toxicity assessment.
The degradation of an anticancer drug by laccase was investigated for the first time, bringing a new approach to treat these hazardous substances through the direct enzymatic application. Degradations of doxorubicin by laccase were performed in different enzymatic concentrations, pH values and temperatures through kinetic studies. The highest enzymatic degradation of doxorubicin was achieved at pH 7 and 30 ºC, which resembles effluent characteristics from wastewater treatment plants. Assays were carried out in different doxorubicin concentrations to comprehend the enzymatic kinetics of degradation. Michaelis-Menten kinetic parameters obtained were maximum velocity obtained (Vmax) of 702.8 µgDOX h-1 L-1 and Michaelis-Menten constant (KM) of 4.05 µM, which showed a good affinity for the substrate. The toxicity was evaluated against L-929 cell line, and the degraded doxorubicin solution did not show a reduction in cell viability in the concentration of 250 µg L-1. In contrast, the doxorubicin shows a reduction of 27% in cell viability. Furthermore, in the highest tested concentration (1000 µg L-1), enzymatic degradation reduced in up 41.4% the toxicity of doxorubicin, which indicates laccase degrades doxorubicin to non-toxic compounds. In conclusion, this study provides a new application to laccase since the results showed great potential to remove anticancer drugs from effluents.


[Inheritance in erythropoietic protoporphyria].
Erythropoietic protoporphyria (EPP) is an inherited disorder of heme biosynthesis that results from an accumulation of protoporphyrin IX in erythroid cells, plasma, skin and liver. EPP leads to acute photosensitivity and, in about 2% of patients, liver disease. EPP is a complex syndrome in which two genes are independently involved: FECH and ALAS2. More than 96% of unrelated EPP patients have ferrochelatase (FECH) deficiency (MIM 177000). Four percent of them present with autosomal recessive inheritance with two mutated FECH alleles. In dominant cases (95%) the inheritance of a common hypomorphic IVS3-48C FECH allele trans to a deleterious FECH mutation reduces FECH activity below a critical threshold. The frequency of the IVS3-48C allele differs widely from the Japanese (45%), to Black West Africans (<1%) populations. These differences in the frequency of this single common SNP account for the prevalence of overt EPP in different countries and for the absence of EPP in Black Africans. The phylogenic origin of the IVS3-48C haplotypes strongly suggests that the IVS3-48C allele arose from a single recent mutational event that occurred 60 Kyears ago. Acquired somatic mutation of FECH secondary to myeloid disease may also exceptionally cause EPP (<1%). Finally, about 4% of unrelated EPP patients have X-linked dominant protoporphyria (XLDPP) (MIM 300752) caused by gain-of-function mutations in the ALAS2 gene leading to an increased erythroid heme biosynthesis and subsequently an accumulation of protoporphyrin without any FECH deficiency.


N-Heterocyclic carbene-palladium catalysts for the direct arylation of pyrrole derivatives with aryl chlorides.
New Pd-NHC complexes have been synthesized and employed for palladium-catalyzed direct arylation of pyrrole derivatives by using electron-deficient aryl chlorides as coupling partners. The desired coupling products were obtained in moderate to good yields by using 1 mol % of these air-stable palladium complexes. This is an advantage compared to the procedures employing air-sensitive phosphines, which have been previously shown to promote the coupling of aryl chlorides with heteroarenes.


Evaluating the association between socioeconomic position and cardiometabolic risk markers in young adulthood by different life course models.
Cardiometabolic health in adulthood is associated with socioeconomic position (SEP) in childhood. Although this has been studied by previous research several questions need to be addressed. E.g. knowledge about the association with timing, extent of the exposure as well as lifestyle and adult SEP, is essential to address the increasing social gradient in cardiometabolic diseases. This study included a sub-sample (N = 264, 50% women, age 28-30) from an ongoing cohort study. We used a combination of national registers, longitudinal questionnaire data and clinical data. We examined the association between childhood SEP and cardiometabolic risk, measured by a score of multiple risk markers in young adulthood. SEP-indicators included mother's educational level and household income. The association was evaluated by four different life course models; the latent effects model, the pathway model, the cumulative model and the social mobility model. We found an inverse association between mother's educational level and cardiometabolic risk. The association was statistically significant evaluated by the pathway and cumulative life course models, however statistically insignificant evaluated by the latent effects model. No specific association with social mobility was observed. However, high adult educational level seems to have a protecting impact on the association. No association was found between household income and cardiometabolic risk in any of the applied life course models. Low childhood SEP, represented by mother's educational level but not household income, is associated with increased cardiometabolic risk in young adulthood. The accumulation of exposure, lifestyle and adult educational attainment are important for the association. In contrast, intergenerational social mobility does not seem to have a specific impact on the association and we find no evidence for a particular timing in childhood.


Changes in corneal curvature during accommodation in chicks.
Evidence is presented for an active corneal component of accommodation in chicks. Using anesthetized chicks, consistent increases in corneal curvature were observed during accommodation produced either by electrical stimulation of the Edinger-Westphal nucleus or by topical application of 0.4% nicotine sulfate to the cornea. Electrical stimulation produced a mean accommodative amplitude of 9.2 diopters (D) and a change in corneal power of 3.9 D whereas nicotine treatment elicited 15.1 D of accommodation and 6.1 D of change in corneal power. The change in corneal power increased proportionately with accommodative amplitude up to about 10 D of total accommodation where the corneal power change appeared to level off at approximately 6 D. This limit to corneal curvature change implies that it plays a proportionately greater role in the lower range of accommodation.


Is there a role for the glycemic index in coronary heart disease prevention or treatment?
The clinical application of the glycemic index (GI) to the prevention and treatment of chronic diseases is controversial. No evidence exists for the implementation of low-GI diets for a reduction in coronary heart disease (CHD) mortality, events, or morbidity. Observational studies report conflicting evidence on the role of low-GI diets in CHD and risk factors for CHD. Randomized clinical trials report a small reduction in total cholesterol (-6.6 mg/dL) from low-GI diets compared with high-GI diets, but no reduction in other risk factors, such as low-density lipoprotein or high-density lipoprotein cholesterol, triglycerides, fasting glucose, insulin, or body weight. Currently, the research suggests a minimal role for the implementation of low-GI diets in the prevention or treatment of CHD.


Genetic clonal mapping of in situ and invasive ductal carcinoma indicates the field cancerization phenomenon in the breast.
Nearly 80% of well-differentiated in situ duct carcinomas (g1 DCIS) have been shown to be multicentric (multilobar) lesions, while most in situ poorly differentiated duct carcinomas (g3 DCIS) were unifocal (unilobar) lesions. Here we present a clonality study of 15 cases of DCIS, all showing multiple foci. Twelve of these cases were associated with an invasive duct carcinoma. Fifteen cases of female breast cancer patients all showing multiple DCIS foci (5 g1 DCIS, 5 g2 DCIS, 5 g3 DCIS) were randomly selected and histologically studied using large histological sections. Care was taken to laser-microdissect DCIS foci that were most distantly located from one another in the same large section, and pertinent cells were genetically studied. Invasive duct carcinoma and ipsilateral lymph node metastases and/or contralateral lesions, whenever present, were additionally microdissected. DNA of neoplastic cells was purified, and the mtDNA D-loop region was sequenced. Genetic distance of different foci from the same case was visualized by phylogenetic analyses using the neighbor-joining method. Patients ranged in age from 36 to 87 years (mean 65.1). All 9 cases of widely spread DCIS were not clonal. Four of 6 cases that showed multiple adjacent foci were clonally related on mtDNA analysis. In the present series, 11/15 DCIS appeared as multiple synchronous primary breast tumors, genetically not related to one another. The present data enhance the view that breast can also show the field cancerization phenomenon, paralleling what has already been proposed in other organs.


[Daptomycin in the context of antimicrobial resistance in Gram-positive bacteria].
Infection by antimicrobial-resistant Gram-positive bacteria (GPB) is highly prevalent, especially in the hospital setting. The increase in the use of glycopeptides has a microbiological cost: vancomycin-resistant strains (scarce), strains with intermediate sensitivity, heteroresistant and glycopeptide-tolerant strains and glycopeptide-sensitive strains but with a higher minimal inhibitory concentration require a higher dose of vancomycin, increasing toxicity. Because of its pharmacodynamics profile, linezolide has allowed more effective treatment of localized GPB infections in areas with complex spread and in ischemic tissues with little cost in terms of the selection of resistant strains. Similarly, because of its broad spectrum, tigecycline can be used to treat complex mixed infections caused by resistant pathogens. However, because linezolide and tigecycline are bacteriostatic agents, their use in the initial management of bacteremia, endocarditis and infection in immunocompromised hosts is limited. Because daptomycin has potent early bactericidal activity and has not been affected by heteroresistance or tolerance, this drug is an effective alternative against these severe GPB infections.


Sulindac inhibits bumetanide-induced sodium and water excretion.
In an open-label pilot study, we investigated the effect of sulindac on bumetanide-induced diuresis. Nine healthy volunteers were placed on diets with a standard sodium and potassium content. Each volunteer received 1 mg bumetanide orally, and blood and urine samples were collected during an 8-hour period. Urinary losses were replaced isovolumetrically with intravenous normal saline solution. Creatinine clearance and sodium and potassium excretion were compared with and without sulindac pretreatment (200 mg administered orally b.i.d. for 5 days). Sulindac pretreatment resulted in a 22% decrease in the mean cumulative sodium excretion after 3 hours (p less than 0.05) and a 21% decrease in the mean urine flow rate after 2 hours (p less than 0.05). The results suggest that sulindac has an effect on the kidney similar to that of other nonsteroidal agents.


Replication of the five-dimensional structure of positive psychotic experiences in young adulthood.
Previous work has examined the structure of subclinical positive psychotic experiences. The current study, using confirmatory factor analysis in a general population sample of young adult females, replicated a five-dimensional model, which showed excellent model fit. The results suggest stability of the five-dimensional model across adolescent and young adult life.


First report of a gallbladder hemangioma coexisting with gallstones: a case report and literature review of a rare finding.
Gallbladder hemangioma is an exceptionally rare entity, with only ten cases reported in literature hitherto. The here described case is the first report of a gallbladder hemangioma coexisting with gallstones. A 76-year-old male was hospitalized following repeated episodes of epigastric pain. Patient's medical history included primary hypertension, type 2 diabetes mellitus, dyslipidemia, obesity and hyperuricemia. Physical examination revealed marked pain in the right hypochondriac region, and laboratory workup was notable for mildly elevated glycemia (125 mg/dL) and pancreatic amylase (60 IU/L). Abdominal ultrasound showed multiple gallstones, a thickened gallbladder wall and mild edema of the perivisceral adipose tissue as well as a hepatic angioma. During surgery, an incidental subserosal nodule of about 1 cm was detected within the gallbladder fundus. After surgery, the clinical course was uneventful and the patient was discharged. Histopathological examination of the subserosal nodule showed multiple dilated vascular channels within a sclerosing matrix, a finding consistent with a cavernous hemangioma. Diffuse chronic cholecystitis was also present. Gallbladder hemangiomas represent a rare, likely underdiagnosed condition which can be undetected during the preoperative workup.


An automated extraction approach for isolation of 24 polyaromatic hydrocarbons (PAHs) from various marine matrixes.
An efficient and selective analytical method for determination and quantification of 24 various polyaromatic hydrocarbons (PAHs) in blue mussel (Mytilus edulis), salmon fillet (Salmo salar), fish oil and fish feed has been developed. The samples were extracted by means of accelerated solvent extraction (ASE) technique followed by a purification step with gel permeation chromatography (GPC). Identification and quantification were performed by using GC/MS. The novel combination of silica and alumina in the extraction step furnishes highly purified analytes for the most of the 24 PAHs investigated, and thus a fast and selective analytical method is developed. A small limitation with the method concerns the quantification of acenaphthene (Ace), fluorene (Fl), pyrene (Py) and benzo[a]anthracene (BaA), as the found values for these compounds do not match the certified values (SRM 2977, mussel tissue). Chrysene (Chr) and triphenylene (Tph) give unresolved peaks. The limits of detection (LOD) and limits of quantification (LOQ) found for benzo[a]pyrene (BaP) were 1.7 and 0.44 pg/g (LOD), and 5.8 and 1.5 pg/g (LOQ) for salmon fillet and blue mussel, respectively. This is in a very good accordance with respect to the European Community legislation for official control of BaP levels in foodstuff. The method may be used for qualitative identification of petroleum compounds in marine matrixes.


Geometric Perfusion Deficits: A Novel OCT Angiography Biomarker for Diabetic Retinopathy Based on Oxygen Diffusion.
To develop geometric perfusion deficits (GPD), an optical coherence tomography angiography (OCTA) biomarker based on oxygen diffusion, and to evaluate its utility in a pilot study of healthy subjects and patients with diabetic retinopathy (DR). Retrospective cross-sectional study. Commercial spectral-domain optical coherence tomography angiography (OCTA) instruments were used to acquire repeated 3 × 3-mm2 and 6 × 6-mm2 motion-corrected macular OCTA volumes. En face OCTA images corresponding to the superficial capillary plexus (SCP), deep capillary plexus (DCP), and full retinal projections were obtained using automatic segmentation. For each projection, the GPD percentage and the vessel density percentage, the control metric, were computed, and their values were compared between the normal and DR eyes. The repeated OCTA acquisitions were used to assess the test-retest repeatability of the GPD and vessel density percentages. Repeated OCTA scans of 15 normal eyes and 12 DR eyes were obtained. For all en face projections, GPD percentages were significantly higher in DR eyes than in normal eyes; vessel density percentages were significantly lower in all but 1 projection (DCP). Large GPD areas were used to identify focal perfusion deficits. Test-retest analysis showed that the GPD percentage had superior repeatability than the vessel density percentage in most cases. A strong negative correlation between the GPD percentage and the vessel density percentage was also found. Geometric perfusion deficits, an OCTA biomarker based on oxygen diffusion, provides a quantitative metric of macular microvascular remodeling with a strong physiological underpinning. The GPD percentage may serve as a useful biomarker for detecting and monitoring DR.


The Impact of Discharge Against Medical Advice on Readmission After Opioid Use Disorder-Associated Infective Endocarditis: a National Cohort Study.
Hospitalizations for infective endocarditis (IE) associated with opioid use disorder (O-IE) have increased in the USA and have been linked to high rates of discharge against medical advice (DAMA). DAMA represents a truncation of care for a severe infection, yet patient outcomes after DAMA are unknown. This study aimed to assess readmissions following O-IE and quantify the impact of DAMA on outcomes. A retrospective study of a nationally representative dataset of persons' inpatient discharges in the USA in 2016 PARTICIPANTS: A total of 6018 weighted persons were discharged for O-IE, stratified by DAMA vs. other discharge statuses. Of these, 1331 (22%) were DAMA. The primary outcome of interest was 30-day readmission rates, stratified by discharge type. We also examined the total number of hospitalizations during the year and estimated the effect of DAMA on readmission. Compared with non-DAMA, those experiencing DAMA were more commonly female, resided in metropolitan areas, lower income, and uninsured. Crude 30-day readmission following DAMA was 50%, compared with 21% for other discharge types. DAMA was strongly associated with readmission in an adjusted logistic regression model (OR 3.72, CI 3.02-4.60). Persons experiencing DAMA more commonly had ≥2 more hospitalizations during the period (31% vs. 18%, p<0.01), and were less frequently readmitted at the same hospital (49% vs 64%, p<0.01). DAMA occurs in nearly a quarter of patients hospitalized for O-IE and is strongly associated with short-term readmission. Interventions to address the root causes of premature discharges will enhance O-IE care, reduce hospitalizations and improve outcomes.


Gingival lesions as a first symptom of pemphigus vulgaris in pregnancy.
The erosive gingival lesions associated with vesiculobullous diseases can be an important early clinical manifestation of serious diseases such as pemphigus vulgaris (PV). PV is a vesiculobullous disease of the skin and mucosa which tends to be chronic and which normally affects people of 40-60 years of age. Its incidence varies from 0.5 to 3.2 cases per 100,000 per year. Mucosal lesions are located mainly in the oral and pharyngeal mucosa, although conjunctiva, larynx, nasal mucosa, vulva, vagina, cervix, and ano-rectal mucosa may also be involved. It is a serious mucocutaneous disease of an autoimmune nature, whose appearance during pregnancy is extremely rare.


Acute monocytic leukemia in children. Response to VP-16-213 as a single agent.
Three patients were studied: two infants with acute monocytic leukemia who failed to respond to the initial combination therapy of daunorubicin with cytosine arabinoside, and an adolescent with relapsed acute monocytic leukemia. They were intensively treated with epipodophyllotoxin (VP-16-213) alone and subsequently had complete remission. One patient showed apparently dose-dependent cytotoxic effect. All three patients have maintained complete remission for 6, 7, and 11 months, respectively. Toxicities, including myelosuppression, alopecia, nausea, vomiting, and renal dysfunction, were well tolerated. Intensive treatment with VP-16-213 alone was thus found to have a potent therapeutic effect on acute monocytic leukemia in children. VP-16-213 deserves a further assessment in the therapeutic protocol for patients with childhood acute monocytic leukemia.


A phase I study of talazoparib (BMN 673) combined with carboplatin and paclitaxel in patients with advanced solid tumors (NCI9782).
Inhibitors of poly(ADP-ribose) polymerase (PARP) proteins potentiate antitumor activity of platinum chemotherapy. This study sought to determine the safety and tolerability of PARP inhibitor talazoparib with carboplatin and paclitaxel. We conducted a phase I study of talazoparib with carboplatin AUC5-6 and paclitaxel 80 mg/m2 days 1, 8, 15 of 21-day cycles in patients with advanced solid tumors. Patients enrolled using a 3 + 3 design in two cohorts with talazoparib for 7 (schedule A) or 3 days (schedule B). After induction with 4-6 cycles of triplet therapy, patients received one of three maintenance options: (a) continuation of triplet (b) carboplatin/talazoparib, or (c) talazoparib monotherapy. Forty-three patients were treated. The MTD for both schedules was talazoparib 250mcg daily. The main toxicity was myelosuppression including grade 3/4 hematologic treatment-related adverse events (TRAEs). Dose modification occurred in 87% and 100% of patients for schedules A and B, respectively. Discontinuation due to TRAEs was 13% in schedule A and 10% in B. Ten out of 22 evaluable patients in schedule A and 5/16 patients in schedule B had a complete or partial response. Twelve out of 43 patients received ≥6 cycles of talazoparib after induction, with a 13-month median duration of maintenance. We have established the recommended phase II dose of Talazoparib at 250mcg on a 3- or 7-day schedule with carboplatin AUC6 and paclitaxel 80 mg/m2 on days 1, 8, 15 of 21-day cycles. This regimen is associated with significant myelosuppression, and in addition to maximizing supportive care, modification of the chemotherapy component would be a consideration for further development of this combination with the schedules investigated in this study.


Autophagic degradation of MVBs in LSECs promotes Aldosterone induced-HSCs activation.
The important role of extracellular vesicles (EVs) in liver fibrosis has been confirmed. However, EVs derived from liver sinusoidal endothelial cells (LSECs) in the activation of hepatic stellate cells (HSCs) and liver fibrosis is still unclear. Our previous work demonstrated that Aldosterone (Aldo) may have the potential to regulate EVs from LSECs via autophagy pathway. Thus, we aim to investigate the role of Aldo in the regulation of EVs derived from LSECs. Using an Aldo-continuous pumping rat model, we observed that Aldo-induced liver fibrosis and capillarization of LSECs. In vitro, transmission electron microscopy (TEM) revealed that stimulation of Aldo led to the upregulation of autophagy and degradation of multivesicular bodies (MVBs) in LSECs. Mechanistically, Aldo upregulated ATP6V0A2, which promoted lysosomal acidification and subsequent autophagy in LSECs. Inhibiting autophagy with si-ATG5 adeno-associated virus (AAV) in LSECs effectively mitigated Aldo-induced liver fibrosis in rats. RNA sequencing and nanoparticle tracking (NTA) analyses of EVs derived from LSECs indicated that Aldo result in a decrease in both the quantity and quality of EVs. We also observed a reduction in the protective miRNA-342-5P in EVs derived from Aldo-treated LSECs, which may play a critical role in HSCs activation. Target knockdown of EV secretion with si-RAB27a AAV in LSECs led to the development of liver fibrosis and HSC activation in rats. Aldo-induced Autophagic degradation of MVBs in LSECs promotes a decrease in the quantity and quality of EVs derived from LSECs, resulting in the activation of HSCs and liver fibrosis under hyperaldosteronism. Modulating the autophagy level of LSECs and their EV secretion may represent a promising therapeutic approach for treating liver fibrosis. In a physiological state, LSECs transmit inhibitory signals to HSCs via the secretion of EVs that are rich in miR-342-5p. However, in pathological conditions, the elevated levels of serum aldosterone induce capillarization and excessive autophagy in LSECs. This autophagy leads to the degradation of MVBs in LSECs, resulting in a reduction of the number of EVs and miR-342-5p content within EVs. This reduction ultimately leads to a diminished inhibitory signal transmitted to HSCs, thereby activating HSCs and promoting the development of liver fibrosis.


Application of CRISPR/Cas9 technologies combined with iPSCs in the study and treatment of retinal degenerative diseases.
Retinal degeneration diseases, such as age-related macular degeneration and retinitis pigmentosa, affect millions of people worldwide and are major causes of irreversible blindness. Effective treatments for retinal degeneration, including drug therapy, gene augmentation or transplantation approaches, have been widely investigated. Nevertheless, more research should be dedicated to therapeutic methods to improve future clinical treatments. Recently, with the rapid development of genome-editing technology, gene therapy has become a potentially effective treatment for retinal degeneration diseases. A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system has been developed as a powerful genome-editing tool in ophthalmic studies. The CRISPR/Cas9 system has been widely applied in basic research to develop animal models and gene therapies in vivo. With the ability to self-renew and the potential to differentiate into different types of cells, induced pluripotent stem cells (iPSCs) have already been used as a promising tool for understanding disease pathophysiology and evaluating the effect of drug and gene therapeutics. iPSCs are also a cell source for autologous transplantation. In this review, we compared genome-editing strategies and highlighted the advantages and concerns of the CRISPR/Cas9 system. Moreover, the latest progress and applications of the CRISPR/Cas9 system and its combination with iPSCs for the treatment of retinal degenerative diseases are summarized.


Patients' and next of kin's expectations and experiences of a mobile integrated care model with a home health care physician - a qualitative thematic study.
The organizational principle of remaining at home has offset care from the hospital to the home of the older person where care from formal and informal caregivers is needed. Globally, formal care is often organized to handle singular and sporadic health problems, leading to the need for several health care providers. The need for an integrated care model was therefore recognized by health care authorities in one county in Sweden, who created a cross-organisational integrated care model to meet these challenges. The Mobile integrated care model with a home health care physician (MICM) is a collaboration between regional and municipal health care. Descriptions of patients' and next of kin's experiences of integrated care is however lacking, motivating exploration. A qualitative thematic study. Data collection was done before the patients met the MICM physician, and again six months later. The participants expected a sense of relief when admitted to MICM, and hoped for shared responsibility, building a personal contact and continuity but experienced lack of information about what MICM was. At the follow-up interview, participants described having an easier daily life. The increased access to the health care personnel (HCP) allowed participants to let go of responsibility, and created a sense of safety through the personalised contact and continuity. However, some felt ignored and that the personnel teamed up against the patient. The MICM structure was experienced as hierarchical, which influenced the possibility to participate. However, the home visits opened up the possibility for shared decision making. Participants had an expectation of receiving safe and coherent health care, to share responsibility, personal contact and continuity. After six months, the participants expressed that MICM had provided an easier daily life. The direct access to HCP reduced their responsibility and they had created a personalised contact with the HCP and that the individual HCP mattered to them, which could be perceived as in line with the goals in the shift to local health care. The MICM was experienced as a hierarchic structure with impact on participation, indicating that all dimensions of person-centred care were not fulfilled.


Seasonal variations in colonization dynamics of periphytic protozoa in coastal waters of the Yellow Sea, northern China.
The colonization features of periphytic protozoa have proved to be a useful tool for indicating water quality status in aquatic ecosystems. In order to reveal the seasonal variations in colonization dynamics of the protozoa, a 1-year baseline survey was carried out in coastal waters of the Yellow Sea, northern China. Using glass slides as artificial substrates, a total of 240 slides were collected at a depth of 1 m in four seasons after colonization periods of 3, 7, 10, 14, 21, and 28 days. A total of 122 ciliate species were identified with 21 dominant species. The colonization dynamics of the protozoa were well fitted to the MacArthur-Wilson and logistic models in all four seasons (P < 0.05). However, the equilibrium species numbers (Seq), colonization rates (G), and the time to 90% Seq (T90%) represented a clear seasonal variability: (1) more or less similar levels in spring and autumn (Seq = 29/23; G = 0.301/0.296; T90%=7.650/7.779); (2) with a significant difference in summer and winter (Seq = 32/121; G = 0.708/0.005; T90% = 3.252/479.705). Multivariate approaches demonstrated that the exposure time for the species composition and community structure of the protozoa to an equilibrium period were 10-14 days in spring and autumn, but less and more time periods were needed in summer and winter, respectively. Based on the results, we suggest that the colonization dynamics of periphytic protozoa were different within four seasons, and an optimal sampling strategy for monitoring surveys should be modified during different seasons in marine ecosystems.


Toward a sustainable environment: nexus between geothermal energy growth and land use change in EU economies.
There are many advantages of geothermal energy as an environmentally friendly resource; however, there are quite a several challenges that need to be overcome to completely harness sustainable and renewable energy that is also natural. The primary aim of this study is to examine what influence geothermal energy will have on land use changes among the considered 27 states in the European Union from the time being 1990 to 2021. The study adopts the auto-regressive distributed lag (ARDL); the findings show that geothermal energy growth could be leveraged to achieve remarkable growth in land use change among the 13 European developing economies than among the 14 EU developed economies. On the other hand, results from analysis further show that a remarkable decrease in land use change could be better attained among the 14 EU developed economies that among the 13 EU developing economies as a result of institutional quality. Furthermore, the result suggests that through economic growth, there could be a remarkable increase in land use change among the 14 EU developed economies than among the 13 EU developing economies. It was further revealed by the study that the level of land use change among the 27 EU nations could be remarkably increased, boosting the level of geothermal energy production that will assist in attaining the aims behind the 2030 energy union. This will eventually help in curbing the incidence of climate change and pollution in the environment; the projected calculations are observed to be valid, as confirmed through the chosen three estimators for this research. The chosen estimators are the pooled mean group, mean group, and dynamic fixed effect. The regulations and governors in 27 European Union countries should give priority to using geothermal in their renewable energy mix to reduce the incidence of changes in land structures. Also, an increased level of efficiency and effectiveness should be made to the generation of geothermal energy by state actors and investors to prompt sustainability and attainability with no further depreciation in agricultural and forest natural states.


The nature of voluntary action.
This paper extends the microgenetic theory of action to the problem of volition and the nature of free will and responsibility. Volition is interpreted as an elaboration of the action structure without causal or agentive status in relation to the action. The implications of this approach for philosophy of mind are explored.


On absorbed dose in narrow 60Co gamma-ray beams and dosimetry of the gamma knife.
Using separate analytical functions describing primary dose, P0(dm,r), collimator scatter, Sc(r), and phantom scatter, TAR(d,r), an expression for absorbed dose in narrow 60Co gamma-ray beams is developed and each function is quantified: D(d,r) = P0(dm,r) Sc(r) TAR(d,r). The absorbed dose is calculated in beams as narrow as 0.2 cm in radius. Analytical and experimental results are compared using measured dose data for the Gamma Knife. Close agreement with experimental data is observed.


The relationship between cortisol reactivity and emotional brain function is differently moderated by childhood trauma, in bipolar disorder, schizophrenia and healthy individuals.
Childhood trauma is a risk factor for psychotic and mood disorders that is associated with abnormal hypothalamic-pituitary-adrenal (HPA) axis function in response to stress and abnormal social brain function. Here, we aimed to determine whether childhood trauma exposure would differently moderate associations between cortisol reactivity and social brain function, among cases with schizophrenia (SZ), bipolar disorder (BD) and in healthy individuals (HC). Forty cases with SZ, 35 with BD and 34 HCs underwent functional magnetic resonance imaging while performing an emotional face-matching task. Participants completed the Childhood Trauma Questionnaire and cortisol reactivity (i.e. the slope indexing the within-subject difference between pre- and post-imaging salivary cortisol levels) was determined. The severity of childhood trauma moderated the relationship between cortisol reactivity and brain activation in the bilateral temporo-parieto-insular junctions, right middle cingulum, right pre/postcentral gyri, left cerebellum and right lingual gyrus, differently depending on the clinical group. When exposed to high levels of trauma, the cortisol slope was negatively associated with activation in these regions in HC, while the cortisol slope was positively associated with activation in these regions in SZ cases. Similarly, there were differences between the groups in how trauma severity moderated the relationship between cortisol reactivity and functional connectivity between the amygdala and dorsolateral prefrontal cortex. In addition to reflecting typical associations between cortisol reactivity and emotional brain function when not exposed to childhood trauma, these findings provide new evidence that trauma exposure disrupts these relationships in both healthy individuals and in cases with SZ or BD.


Characterization of an Abc1 kinase family gene OsABC1-2 conferring enhanced tolerance to dark-induced stress in rice.
Leaf senescence is a complex and highly organized process resulting in numerous changes of gene expression and metabolic procedures. However, the exact mechanisms underlying these changes are not well understood. In this study, we reported a rice (Oryza sativa) T-DNA insertion mutant impaired in an Abc1 kinase family gene with a dwarf and pale-green phenotype. The mutant showed reduced pigment content and photosynthetic efficiency and increased superoxide dismutase activity in leaves. The mutated gene, designated OsABC1-2, is expressed primarily in green tissues and/or organs and encodes a protein localized in chloroplast envelope. Expression of the gene was drastically suppressed by dark treatment. Overexpression of the gene in rice enhanced tolerance to prolonged dark-induced stress. Phylogenetic analysis revealed that the plant Abc1 proteins could be divided into three subgroups and OsAbc1-2 resides in a subgroup with potential chloroplast origin. Our results suggest that divergence has occurred among plant Abc1 family and chloroplast Abc1 kinases play potential roles in regulating dark-induced senescence of plants.


Pathology in the era of "Personalized Medicine": The need to learn how to integrate multivariate immunohistochemical and "omics" data with clinicopathologic information in a clinically relevant way".
"Personalized medicine" has been proposed as a new paradigm for patient care that, based on the integration of genomics and other "omics" data with clinical and other multidisciplinary information, promises early disease detection, improved outcomes and reduced side effects to therapies. Pathologists have become important participants in this new approach as the guardians of tissues and experts in the performance of molecular and other laboratory tests. Large amounts of new laboratory data in multiple neoplasms and other entities are being reported but there has been limited discussion about how best to evaluate the clinical significance of this information and how to integrate it into currently available diagnostic and therapeutic modalities. This article introduces a variety of epistemological problems presented by the "personalized medicine" paradigm and briefly discusses various topics that will be evaluated in further detail in future articles of this new series on Evidence-Based Pathology.


Description of lesions in cattle in a natural outbreak of Babesia bovis infection in Brazil.
This paper describes the pathologic features of a natural infection by Babesia bovis (B. argentina) in Brazil. Microscopic examination of cerebrum, midbrain, cerebellum, liver, kidney, heart and spleen of five fatal cases revealed variable degrees of congestion, particularly in the brain, liver and kidney. The packing of erythrocytes, the majority of which were parasitized, was most marked in the capillaries of brain, kidney and less in liver. Lymphocytic glomerulonephritis was observed. Variable degrees of fatty degeneration were noted in the liver, distention of hepatic canaliculi and biliary retention was marked. A strong activation of the mononuclear phagocytic system was evident in all the subjects studied.


The effect of preoperative statin therapy on cardiovascular outcomes in patients undergoing infrainguinal vascular surgery.
Patients undergoing vascular surgery are at increased risk for perioperative cardiovascular (CV) complications. Our goal was to determine the effect of preoperative statin therapy on perioperative cardiac and vascular outcomes, and long-term survival in patients undergoing infrainguinal vascular bypass surgery. We retrospectively reviewed consecutive infrainguinal vascular bypass surgeries on 446 patients performed between 1995-2001 at the University of Chicago Medical Center. Information was collected on preoperative statin and beta-blocker use, baseline characteristics, perioperative cardiac and major vascular complications, and length of stay (LOS). Long-term survival was assessed using the Social Security Death Index (SSDI). Thirty day perioperative complications included all-cause mortality (2.5%), CV mortality (1.8%), myocardial infarction (MI) (4.7%), stroke (1.1%), and major peripheral vascular complications (12.8%), and the composite of cardiac and vascular complications [combined CV complications] (17.9%). Statin therapy was associated with fewer combined CV complications (6.9% vs 20.1%, p=0.008), and a shorter LOS (6.4 vs 9.7 days, p=0.007). On multivariate logistic regression analysis, adjusting for significant baseline characteristics including beta-blocker use, statin therapy was independently associated fewer combined CV complications (odds ratio (OR) 0.36, 95% confidence interval (CI) 0.14-0.93, p=0.035) and a shorter LOS (OR 1.49, 95% CI 1.14-1.95, p=0.003). In a mean follow up period of 5.5 years, 215 deaths (48%) occurred. Statin therapy was independently associated with improved long-term survival (OR 0.52, 95% CI 0.32-0.84, p<0.004), after adjusting for significant baseline characteristics. Preoperative statin therapy is associated with fewer combined perioperative cardiac and major vascular complications, a shorter length of stay, and improved long-term survival in patients undergoing infrainguinal vascular bypass surgery.


Data processing pipeline for serial femtosecond crystallography at SACLA.
A data processing pipeline for serial femtosecond crystallography at SACLA was developed, based on Cheetah [Barty et al. (2014). J. Appl. Cryst.47, 1118-1131] and CrystFEL [White et al. (2016). J. Appl. Cryst.49, 680-689]. The original programs were adapted for data acquisition through the SACLA API, thread and inter-node parallelization, and efficient image handling. The pipeline consists of two stages: The first, online stage can analyse all images in real time, with a latency of less than a few seconds, to provide feedback on hit rate and detector saturation. The second, offline stage converts hit images into HDF5 files and runs CrystFEL for indexing and integration. The size of the filtered compressed output is comparable to that of a synchrotron data set. The pipeline enables real-time feedback and rapid structure solution during beamtime.


Influence of pentavalent dopant addition to polarization and bioactivity of hydroxyapatite.
Influence of pentavalent tantalum doping in bulk hydroxyapatite (HAp) ceramics has been investigated for polarizability and bioactivity. Phase analysis from X-ray diffraction measurement indicates that increasing dopant concentration decreased the amount of HAp phase and increased β-TCP and/or α-TCP phases during sintering at 1250 °C in a muffle furnace. Results from thermally stimulated depolarization current (TSDC) measurements showed that doping hindered charge storage ability in HAp ceramics, and doped samples stored fewer charge compared to pure HAp. However, doping enhanced wettability of HAp samples, which was improved further due to polarization. In vitro human osteoblast cell-material interaction study revealed an increase in bioactivity due to dopant addition and polarization compared to pure HAp. This increase in bioactivity was attributed to the increase in wettability due to surface charge and dopant addition.


Management of adrenal incidentaloma: the role of adrenalectomy may be underestimated.
To demonstrate clinical characteristics of adrenal incidentaloma in South China and explore its comprehensive management. The clinical data of patients with adrenal neoplasm from Jan 1998 to Dec 2012 were retrospectively analysed. Patients with suspicion of adrenal abnormalities or those in whom adrenal abnormalities were detected in the staging procedures of other cancers were excluded. Most patients with adrenal incidentaloma chose to have adrenalectomy, and some chose surveillance. The relationships between clinical features were analysed with a chi-square test and rank sum test. In total, 634 patients with adrenal incidentaloma were studied. Their age ranged from 17 to 85 years old with a median age of 50 years. Of 478 cases with pathological results, adenoma was the most common tumour (233/478), with 84 cases of pheochromocytoma and 36 cases of adrenocortical carcinoma were 84 and 36. When the tumour size was ≤4 cm, >95 % were benign; when the tumour size was >6 cm, 33 % were malignant. For patients with a tumour size ≤4 cm, 249/376 cases had an adrenalectomy performed. Due to anxiety over a potential malignant transformation and enlargement, most patients (>80 %) under surveillance preferred to undergo adrenalectomy. Pheochromocytoma and adrenocortical carcinoma were not rare tumours of adrenal incidentaloma, and 4 cm is a good size cutoff to use in the diagnosis of an adrenal incidentaloma. Other than surveillance, laparoscopic adrenalectomy may become the method of choice for management of small adrenal incidentaloma.


Transcription factor complexes.
Considerable progress has been made during the past year on structural studies of the eukaryotic and bacterial transcription factors that control RNA polymerase function via the formation of multiprotein complexes on promoter DNA. Recently determined structures include negative cofactor 2 recognizing a preformed TATA-box-binding protein-DNA binary complex, a dimer of BmrR bound to both DNA and tetra-phenylphosphonium, DNA-bound complexes of SarA and FadR, leukemia-associated AML1-CBFbeta-DNA ternary complexes and a SAP1-SRF-DNA ternary complex.


Alterations in a cross-hemispheric circuit associates with novelty discrimination deficits in mouse models of neurodegeneration.
A major pathological hallmark of neurodegenerative diseases, including Alzheimer's, is a significant reduction in the white matter connecting the two cerebral hemispheres, as well as in the correlated activity between anatomically corresponding bilateral brain areas. However, the underlying circuit mechanisms and the cognitive relevance of cross-hemispheric (CH) communication remain poorly understood. Here, we show that novelty discrimination behavior activates CH neurons and enhances homotopic synchronized neural oscillations in the visual cortex. CH neurons provide excitatory drive required for synchronous neural oscillations between hemispheres, and unilateral inhibition of the CH circuit is sufficient to impair synchronous oscillations and novelty discrimination behavior. In the 5XFAD and Tau P301S mouse models, CH communication is altered, and novelty discrimination is impaired. These data reveal a hitherto uncharacterized CH circuit in the visual cortex, establishing a causal link between this circuit and novelty discrimination behavior and highlighting its impairment in mouse models of neurodegeneration.


Teaching medical error disclosure to physicians-in-training: a scoping review.
This scoping review identified published studies of error disclosure curricula targeting physicians-in-training (residents or medical students). In 2011, the authors searched electronic databases (e.g., MEDLINE, EMBASE, ERIC) for eligible studies published between 1960 and July 2011. From the studies that met their inclusion criteria, they extracted and summarized key aspects of each curriculum (e.g., level of learner, program discipline) and educational features (e.g., curriculum design, teaching and assessment methods, and learner outcomes). The authors identified 21 studies that met their inclusion criteria. These studies described 19 error disclosure curricula, which were either a stand-alone educational activity, part of a larger curriculum in patient safety or communication skills, or part of simulation training. Most curricula consisted of a brief, single encounter, combining didactic lectures or small-group discussions with role-play. Fourteen studies described learners' self-reported improvements in knowledge, skills, and attitudes. Five studies used a structured assessment and reported that learners' error disclosure skills improved after completing the curriculum; however, these studies were limited by their small to medium sample size and lack of assessment of skills retention. Attempts to assess the change in learners' error disclosure behavior in the clinical context were limited. Studies of existing error disclosure curricula demonstrate improvements in learners' knowledge, skills, and attitudes. A greater emphasis is needed on the more rigorous assessment of skills acquisition and behavior change to determine whether formal training leads to long-term effects on learner outcomes that translate into real-world clinical practice.


Predicting the survival of patients with pancreatic neuroendocrine neoplasms using deep learning: A study based on Surveillance, Epidemiology, and End Results database.
The study aims to evaluate the performance of three advanced machine learning algorithms and a traditional Cox proportional hazard (CoxPH) model in predicting the overall survival (OS) of patients with pancreatic neuroendocrine neoplasms (PNENs). The clinicopathological dataset obtained from the Surveillance, Epidemiology, and End Results database was randomly assigned to the training set and testing set at a ratio of 7:3. The concordance index (C-index) and integrated Brier score (IBS) were used to compare the predictive performance of the models. The accuracy of the model in predicting the 5-year and 10-year survival rates was compared using the receiver operating characteristic curve, decision curve analysis (DCA) and calibration curve. This study included 3239 patients with PNENs in total. The DeepSurv model had the highest C-index of 0.7882 in the testing set and training set and the lowest IBS of 0.1278 in the testing set compared with the CoxPH, neural multitask logistic and random survival forest models (C-index = 0.7501, 0.7616, and 0.7612, respectively; IBS = 0.1397, 0.1418, and 0.1432, respectively). Moreover, the DeepSurv model had the highest accuracy in predicting 5- and 10-year OS rates (area under the curve: 0.87 and 0.90). DCA showed that the DeepSurv model had high potential for clinical decisions in 5- and 10-year OS models. Finally, we developed an online application based on the DeepSurv model for clinical use (https://whuh-ml-neuroendocrinetumor-app-predict-oyw5km.streamlit.app/). All four models analyzed above can predict the prognosis of PNENs well, among which the DeepSurv model has the best prediction performance.


Altered T and B lymphocytes in multitransfused patients of thalassemia major.
T and B lymphocytes were estimated in 25 patients with Thalassemia major to evaluate their immune status. The percentage of T cells was significantly reduced (p < 0.001) while that of B cells was significantly raised (p < 0.001) in patients of thalassemia major as compared to age and sex matched controls.


Use of the glucose oxidase/peroxidase method for glucose assay leads to overestimation of the inhibition of gluconeogenesis by aminopyrine.
4-Aminoantipyrine strongly inhibits glucose determination by the glucose oxidase/peroxidase/dianisidine assay but does not interfere in the assay using glucose-6-phosphate dehydrogenase, hexokinase and ATP. As a result, the inhibition of gluconeogenesis by aminopyrine reported to be 50-90% (Bánhegyi, G., Mandl, J., Antoni, F. and Garzó, T. (1987) Biochim. Biophys. Acta 927, 406-416) is strongly overestimated and amounts to only 10-30%.


Reproducibility and relation to specific and non-specific anti-tumor resistance of the tumor "sneaking through" phenomenon.
The reproducibility and immunological specificity of the tumor "sneaking through" phenomenon and enhancement of tumor growth were studied in syngeneic and random-bred Syrian hamsters by means of a quantitative modification of the transplantation test. After primary challenge the phenomenon was neither observed in normal animals nor in animals effectively immunized against tumor. However, it was regularly observed in some "immune" animals after secondary challenge. In primary challenge of animals "sneaking through" phenomenon was most often observed in animals pretreated with large doses of heat-inactivated tumor cells. This characteristic could not be transferred with serum of pretreated animals. In contrast to specific tumor immunity, the "sneaking through" pbenomenon appeared to be immunologically non-specific. This was observed in cross-transplantation tests with tumor cells bearing different TSTAs. Thus, TSTA is not an inducer and apparently not a target for a response leading to enhancement of tumor growth in pretreated hamsters. Experiments demonstrating enhanced tumor growth in pretreated animals at the same time demonstrate two other possibly more essential findings: (1) normal animals are naturally resistant to transplantation of 1 to about 1 x 10(3) (or more) tumor cells; and (2) this resistance can be totally abrogated by the pretreatment of normal animals with tumor cell preparations. The preliminary data demonstrate that abrogation of natural anti-tumor resistance in adult hamsters subsequently inoculated with SV40 leads to rapid development of primary tumors in such animals. The development of specific anti-tumor immune response in animals treated with inactivated tumor cell preparations was also studied. Significant non-specific inhibition of sponse in Syrian hamsters treated with inactivated syngeneic tumor cells was observed. The data obtained are considered to demonstrate two anti-tumor defense systems in the animal, i.e., non-specific natural resistance and specific anti-tumor immunity. The first seems to be responsible for elimination of low numbers of tumor cells in the normal organism and also to be esseitial for effective induction and functioning of the specific anti-tumor immunity.


Epstein-Barr virus-infected B lymphoblastoid cell lines: dynamics of interferon and 2'5'-oligoadenylate synthetase activity.
Levels of 2'-5'-oligoadenylate synthetase (2'-5'OAS) activity measured in cell-free extracts of 23 Epstein-Barr virus transformed beta lymphoblastoid cell lines (LCL) were measured. Enzyme activity was low during stationary or log phase growth, and rapidly rose to peak values during log phase. Peak levels of 2'-5'OAS activity were characteristic for each LCL, and were significantly higher (P less than 0.05) in lines derived from patients with infectious mononucleosis (IM) than in lines from healthy individuals. Peak 2'-5'OAS activity correlated with maximal titers of endogenous human interferon-alpha (HuIFN-alpha); (r = 0.80). Enzyme activity levels could be increased by treating LCLs with exogenous HuIFN-alpha, or decreased by neutralization of endogenous interferon with antibody to HuIFN-alpha. 2'-5'OAS activity always peaked during log-phase growth, even in cultures depleted of interferon by antibody and in cultures which did not produce interferon. Thus, although peak levels of 2'-5'OAS activity in a given LCL correlated with maximal interferon titers, the growth phase associated variations in enzyme activity were independent of interferon. We conclude that regulation of constitutive levels of 2'-5'OAS in LCLs is partially independent of interferon.


Difference in anxiety and sensitization of the acoustic startle response between the two inbred mouse strains BALB/cAN and DBA/2N.
The inbred mouse strain BALB has been proposed to be an animal model for pathological anxiety. BALB exhibits a stronger acoustic startle response (ASR) than the 'less emotional' inbred strain DBA. Four experiments were conducted to determine whether this strong ASR is due to a higher anxiety level and/or to greater sensitization in BALB than in DBA, with the following results: (1) The ASR to the very first startle stimulus was found to be much stronger in BALB than in DBA, and freezing behavior evoked by startle stimuli was more pronounced in BALB than in DBA. These findings indicate a higher level of anxiety in this strain. (2) ASR amplitudes of BALB initially rose much higher during consecutive startle stimuli and remained at a high level much longer than in DBA. Thereafter, ASR amplitude dropped more slowly and to a lesser degree than in DBA. Startle amplitudes decreased similarly in both strains (strong exponential decrease) only when a low sound pressure level (SPL) was used which elicited approximately the same low ASR in both strains. These results can only be explained by increased sensitization in BALB. (3) The slope of the i/o-function, which represents the relation between sensory input and motor output, was steeper in BALB than in DBA. As it has been shown recently, sensitization increases the slope of the startle i/o-function indicating increased sensitization in BALB. It is discussed, however, whether anxiety also contributes to this effect. (4) Footshocks increased the ASR much less in BALB than in DBA, again showing increased sensitization in BALB. Both a higher level of anxiety and greater sensitization therefore determined the greater strength of the ASR in BALB than in DBA.


Immunotoxins containing ricin A or B chains with modified carbohydrate residues act synergistically in killing neoplastic B cells in vitro.
Partially deglycosylated (dg) ricin A and B chains were coupled to rabbit anti-human Ig (IT-dg-A) and goat anti-rabbit Ig (IT-dg-B), respectively. The deglycosylation was accomplished by treating intact ricin (before separation into its constituent chains) with a mixture of sodium metaperiodate and sodium cyanoborohydride. The two immunotoxins (ITs) acted synergistically in vitro to kill Daudi cells, albeit to a four-to-eight-fold lesser degree than ITs prepared with native A and B chains.


Difference in pathway of Escherichia coli outer membrane permeation between penicillins and cephalosporins.
The differences in the outer membrane permeation between two major subgroups of beta-lactam antibiotics were studied. The permeation of cephalosporins was closely related to porin channels in the outer membrane. In contrast, the outer membrane permeation of penicillins did not decrease in porin-deficient mutants and, in Rd-type mutants, their permeability became proportional to the hydrophobicity of the molecules. The activation enthalpy of the penicillin permeation was significantly larger than that of cephalosporins. These observations indicate that penicillins can use the hydrophobic region for the major route of outer membrane passage whereas the cephalosporin permeation is restricted to the pathway via the porin pore.


Geographic variation in the effects of temperature on life-history traits in the large milkweed bug Oncopeltus fasciatus.
Complete sets of life-history data (sufficient to construct life-tables and calculate intrinsic rates of increase) were collected at each of three constant temperatures for descendants of two tropical populations of the Large Milkweed Bug, Oncopeltus fasciatus. Although the two populations occur only about 60 km apart, they experience quite different thermal regimes, with little variation in mean monthly temperature at either site. In addition to the pronounced effect of ambient temperature on life-history traits, significant population-by-temperature interactions were observed for six of the eight traits examined. The data and the recent history of the species' distribution are consistent with the hypothesis that natural selection in the cool habitat has favored improved survival and increased reproduction at cool temperatures, with some trade-offs with respect to performance at higher (but ecologically relevant) temperatures.


Tunneling through a tilted tight-binding band.
In the single-band approximation, an explicit expression of the exponential factor, that governs tunneling through a thin crystal subjected to a constant electric field, is derived. The basic features of Wannier-Stark, Airy, and intermediate type of quantization, as they are displayed in the transmission spectrum and hence in tunneling current, are thus described analytically.


Identification of androgen receptor antagonists: In vitro investigation and classification methodology for flavonoid.
A tremendous gap exists between the number of potential endocrine disrupting chemicals (EDCs) possibly in the environment and the limitation of traditional regulatory testing. In this study, the anti-androgenic potencies of 21 flavonoids were analyzed in vitro, and another 32 flavonoids from the literature were selected as additional chemicals. Molecular dynamic simulations were employed to obtain four different separation approaches based on the different behaviors of ligands and receptors during the process of interaction. Specifically, ligand-receptor complex which highlighted the discriminating features of ligand escape or retention via "mousetrap" mechanism, hydrogen bonds formed during simulation times, ligand stability and the stability of the helix-12 of the receptor were investigated. Together, a methodology was generated that 87.5% of flavonoids could be discriminated as active versus inactive antagonists, and over 90% inactive antagonists could be filtered out before QSAR study. This methodology could be used as a "proof of concept" to identify inactive anti-androgenic flavonoids, as well could be beneficial for rapid risk assessment and regulation of multiple new chemicals for androgenicity.


Questionnaire survey of detrimental fur animal epidemic necrotic pyoderma in Finland.
In 2007, a previously unrecorded disease, fur animal epidemic necrotic pyoderma (FENP), was detected in farmed mink (Neovision vision), foxes (Vulpes lagopus) and Finnraccoons (Nyctereutes procyonoides) in Finland. Symptoms included severe pyoderma with increased mortality, causing both animal welfare problems and economic losses. In 2011, an epidemiologic questionnaire was mailed to all members of the Finnish Fur Breeders' Association to assess the occurrence of FENP from 2009 through the first 6 months of 2011. The aim was to describe the geographical distribution and detailed clinical signs of FENP, as well as sources of infection and potential risk factors for the disease. A total of 239 farmers (25%) returned the questionnaire. Clinical signs of FENP were observed in 40% (95% CI 34-46%) of the study farms. In addition, the survey clarified the specific clinical signs for different animal species. The presence of disease was associated with the importation of mink, especially from Denmark (OR 9.3, 95% CI 2.6-33.0). The transmission route between Finnish farms was associated with fur animal purchases. Some risk factors such as the farm type were also indicated. As such, FENP was detected more commonly on farms with more than one species of fur animal in comparison to farms with, for example, only foxes (OR 4.6, 95% CI 2.4-8.6), and the incidence was higher on farms with over 750 breeder mink compared to smaller farms (OR 3.8, 95% CI 1.6-9.0). Contact between fur animals and birds and other wildlife increased the risk of FENP on farms. Responses also indicated that blocking the entry of wildlife to the animal premises protected against FENP. FENP was most likely introduced to Finland by imported mink and spread further within the country via domestically purchased fur animals. Some potential risk factors, such as the type and size of the farm and contact with wildlife, contributed to the spread of FENP. Escape-proof shelter buildings block the entry of wildlife, thus protecting fur animals against FENP.


Recurrence of benign phonotraumatic vocal fold lesions after microlaryngoscopy.
To determine recurrence rates for benign phonotraumatic vocal fold lesions after microlaryngoscopic surgery. Retrospective review. Records of adults who underwent microlaryngoscopy between 2006 and 2017 for vocal fold cysts, midfold masses, polyps, pseudocysts, sulcus vocalis (Ford type 3), and varices were reviewed for demographics, medical history, treatment, and lesion recurrence. Patients operated for nonphonotraumatic lesions (e.g., granuloma, keratosis/leukoplakia, papilloma) were excluded. Stroboscopic examinations were re-reviewed to confirm diagnosis and outcome. Five hundred ten adults (223 male:287 female; mean age 40.3 ± 14.9 years) were included. Overall, 62 of 510 (12.2%) recurred (median time to recurrence: 70.0 months). Of these, 44 (71.0%) recurred to the same lesion type and 49 (79.0%) to the same side. Recurrence rates by initial lesion type were as follows: cysts, two of 92 (2.2%); midfold masses, four of 18 (22.2%); polyps, 25 of 235 (10.6%); pseudocysts, 30 of 145 (20.7%); sulcus vocalis, one of 18 (5.6%); and varices, zero of two (0%) (χ 2 = 28.7, degrees of freedom [df] = 5, P < 0.001). No significant difference in recurrence existed between males (21 of 223, 9.4%) and females (41 of 287, 14.3%). However, young adults (17 of 86, 19.8%) had significantly higher recurrence rates compared to middle-aged (12 of 155, 7.7%) and older adults (3/60, 5.0%) (χ 2 = 9.5, df = 3, P = 0.023). Of 62 recurrences, 18 were re-operated and four re-recurred. Benign phonotraumatic vocal fold lesions recur at variable rates. This variation suggests pathophysiologic differences between categories that may not be entirely explained by behavioral factors. 4 Laryngoscope, 130: 1989-1995, 2020.


Mechanisms of clinical tachycardias.
Animal data suggest that cardiac arrhythmias can result from a variety of mechanisms. In clinical settings, arrhythmias that are easily initiated and terminated with programmed electrical stimulation are often designated as reentry tachycardias. However, proof of reentry is contingent upon demonstration of the entire circuit; this relation has been proposed for arrhythmias associated with large circuits, such as those seen in the Wolff-Parkinson-White syndrome. Reentry has also been proposed as the mechanism responsible for a variety of other tachycardias, including bundle branch and atrioventricular nodal reentry tachycardia, permanent junctional reentrant tachycardia, reentry tachycardia associated with nodoventricular Mahaim fibers and inducible atrial and ventricular tachycardia. Documentation of triggered rhythms as the mechanism responsible for clinical arrhythmias has been even more difficult. Examples of arrhythmias resulting from triggered activity may include those associated with digitalis toxicity arising from the atria, the atrioventricular junction or the ventricles. Clinical arrhythmias due to triggered activity in the absence of digitalis have also been described. Cardiac arrhythmias that cannot be induced by electrical stimulation are presumably due to normal or abnormal automaticity. Examples of normal automaticity in the human heart are sinus rhythm and junctional and idioventricular escape rhythms. Tachycardias by abnormal automaticity have seldom been investigated for the purpose of documenting the mechanism and therefore the limited data available make it difficult to draw any final conclusions.


Budd-Chiari syndrome in children: report of 22 cases.
Clinical, radiologic, and histologic features in 22 children with Budd-Chiari syndrome are reported. Three children had acute refractory ascites; all the others had hepatomegaly, which was detected either fortuitously or because of abdominal pain or distention. Results of liver function tests were normal or only moderately abnormal. In most cases a combination of ultrasonography and needle liver biopsy pointed to the diagnosis of Budd-Chiari syndrome, which was confirmed by angiography. Eighteen children underwent surgery involving various techniques, depending on the degree of patency of the inferior vena cava. Five children died postoperatively. Histologic studies of the liver, carried out in 12 of the surviving children, showed disappearance or regression of centrilobular hemorrhagic infiltration. Half of the surviving surgical patients are now free of complications after a follow-up of 7 months to 7 years; the others have either secondary thrombosis of the inferior vena cava or stenosis of the shunt or have experienced late pulmonary complications. Our results suggest that (1) Budd-Chiari syndrome must be considered a possible diagnosis in children with firm hepatomegaly and normal or near normal liver function, (2) surgery provides good results in many instances, and (3) the possibility of late complications requires careful follow-up.


Pivotal clinical trials with patient-reported outcome measures in premarket approval applications for high-risk medical devices from 2005 to 2018: Review, examples, and regulatory considerations.
Patient-reported outcome (PRO) measures are key to reflecting the patient experience and patient perspective when developing new medical devices. The PRO measures used in pivotal clinical trials for investigational medical devices are miscellaneous and diversified. This article analyzes and presents the trend and distribution of the use of PRO measures in the pivotal clinical trials for high-risk medical devices regulated and approved by the United States Food and Drug Administration (FDA) from 2005 to 2018 through Premarket Approval (PMA). As clinical endpoints in pivotal clinical trials, the use of PRO measures in FDA-approved PMA applications for high-risk Class III medical devices significantly increased from September 2005 to December 2018. The percentage of PRO use peaked at the years 2014 and 2015 and remains high till 2018. The most used PRO measure among these PMAs was the 36-Item Short Form Survey quality-of-life questionnaire. Three examples are further elaborated in this article to show how the pivotal clinical trials are designed and analyzed with PRO measures as their clinical endpoints for FDA-regulated high-risk medical devices. The article also reiterates regulatory perspectives and considerations from the FDA. The regulatory perspectives and considerations provided by the FDA on evaluating PRO instruments and design and analysis of pivotal clinical trials with PRO measures should be closely followed in the development process of new medical devices.


[ECG changes in psychiatric patients under long-term therapy with psychopharmacological drugs (author's transl)].
1726 psychiatric patients, aged 40-69, under permanent hospitalization were examined electrocardiographically. There were few pronounced indications of a relationship between pathological ECG findings and drugs. ECG changes, mainly T-flattening, were rarest among patients treated exclusively with non-tricyclic drugs, and most often among those patients who received tricyclic and non-tricyclic compounds simultaneously. These disturbances appeared more often among women.