Arterial and Mixed Venous Kinetics of Desflurane and Sevoflurane, Administered Simultaneously, at Three Different Global Ventilation to Perfusion Ratios in Piglets with Normal Lungs.
Previous studies have established the role of various tissue compartments in the kinetics of inhaled anesthetic uptake and elimination. The role of normal lungs in inhaled anesthetic kinetics is less understood. In juvenile pigs with normal lungs, the authors measured desflurane and sevoflurane washin and washout kinetics at three different ratios of alveolar minute ventilation to cardiac output value. The main hypothesis was that the ventilation/perfusion ratio (VA/Q) of normal lungs influences the kinetics of inhaled anesthetics. Seven healthy pigs were anesthetized with intravenous anesthetics and mechanically ventilated. Each animal was studied under three different VA/Q conditions: normal, low, and high. For each VA/Q condition, desflurane and sevoflurane were administered at a constant, subanesthetic inspired partial pressure (0.15 volume% for sevoflurane and 0.5 volume% for desflurane) for 45 min. Pulmonary arterial and systemic arterial blood samples were collected at eight time points during uptake, and then at these same times during elimination, for measurement of desflurane and sevoflurane partial pressures. The authors also assessed the effect of VA/Q on paired differences in arterial and mixed venous partial pressures. For desflurane washin, the scaled arterial partial pressure differences between 5 and 0 min were 0.70 ± 0.10, 0.93 ± 0.08, and 0.82 ± 0.07 for the low, normal, and high VA/Q conditions (means, 95% CI). Equivalent measurements for sevoflurane were 0.55 ± 0.06, 0.77 ± 0.04, and 0.75 ± 0.08. For desflurane washout, the scaled arterial partial pressure differences between 0 and 5 min were 0.76 ± 0.04, 0.88 ± 0.02, and 0.92 ± 0.01 for the low, normal, and high VA/Q conditions. Equivalent measurements for sevoflurane were 0.79 ± 0.05, 0.85 ± 0.03, and 0.90 ± 0.03. Kinetics of inhaled anesthetic washin and washout are substantially altered by changes in the global VA/Q ratio for normal lungs.


Heat shock protein 70 fused to or complexed with hantavirus nucleocapsid protein significantly enhances specific humoral and cellular immune responses in C57BL/6 mice.
Heat shock proteins (HSPs) are known to act as an effective molecular adjuvant to enhance the induction of antigen peptide-specific cellular immunity, when coupled with the antigen or peptide. Hantaan virus (HTNV) nucleocapsid protein (NP) is relatively conserved among hantaviruses and highly immunogenic in both animals and humans. To analyze the influence of HSP70 on NP vaccine potency, and evaluate the possibility of developing a novel effective vaccine against hantaviruses, we constructed prokaryotic expression plasmids, and expressed three recombinant proteins, namely, HTNV NP, HSP70 and HSP70-NP fusion protein. As an alternative to fusion protein, we also generated HSP70 and HTNV NP complexes (HSP70+NP) in vitro. C57BL/6 mice were immunized with those recombinant proteins, the humoral and cellular responses elicited against NP were measured by ELISA, fluorescence flow cytometry, cytotoxicity assays, and IFN-gamma ELISPOT assay. We found that immunization of mice with HSP70-NP fusion protein, or HSP70+NP complexes elicited significantly higher NP-specific antibody titers, frequencies of IFN-gamma-producing cells and cytotoxic T lymphocyte (CTL) activities in vivo than conventional HTNV NP vaccination. Antibody isotype analysis showed that the antibody response was characterized by a higher HTNV NP-specific titer of IgG2a than IgG1 antibodies, resulting in a significant higher IgG2a/IgG1 ratio. By comparison, HSP70-NP fusion protein is significantly superior to HSP70+NP complexes in enhancement of NP antigenicity. These results indicated that HSP70, when fused to or complexed with HTNV NP, greatly enhance NP vaccine potency by preferential induction of a predominant Th1 immune response in a NP-specific, HSP70-dependent manner.


Undernutrition and its association with socio-demographic, anemia and intestinal parasitic infection among pregnant women attending antenatal care at the University of Gondar Hospital, Northwest Ethiopia.
Under nutrition is a worldwide public health problem affecting the well-being of millions of pregnant women in the developing world. Only limited research has been conducted on the prevalence and determinants of maternal nutritional status in Ethiopia. Particularly, data on the nutritional status of pregnant women are lacking. The aim of this study was to assess the prevalence and determinants of undernutrition among pregnant women attending antenatal care at the University of Gondar Hospital, Northwest Ethiopia. An institution based cross-sectional study was conducted in January and February 2016. Randomly selected 409 pregnant women were included in the study. Nutritional status was estimated using mid-upper-arm circumference. Data on potential determinants of undernutrition were gathered using a structured questionnaire. The blood sample was collected to analyze hemoglobin. The stool sample was collected to identify intestinal parasitic infections. Statistical analysis was done using logistic regression. P-value < 0.05 at 95% confidence interval was considered as statistically significant. The prevalence of undernutrition among pregnant women was 16.2% (95% CI: 12.4-20.1%). Using a logistic regression model, factors significantly associated with the undernutrition were living in rural areas (AOR = 2.26), low educational status [no formal education (AOR = 2.91), primary education (AOR = 2.69)], history of too many births (AOR = 2.55), anemia (AOR = 2.01), and intestinal parasitic infection (AOR = 2.73). The study findings provide evidence for the public health significance of under nutrition among pregnant women in the study area. The problem must be combated through rural livelihood promotion, socioeconomic empowerment of women, sustained nutrition education and expansion of family-planning services in the area.


Relationship Among Radiological Measurements of Anterior Mediastinal Fat and Outcomes of Lung Transplantation in Fibrotic Patients.
Lung transplantation (LT) for pulmonary fibrosis is related to higher mortality than other transplant indications. We aim to assess whether the amount of anterior mediastinal fat (AMF) was associated to early and long-term outcomes in fibrotic patients undergoing LT. Retrospective analysis of 92 consecutive single lung transplants (SLT) for pulmonary fibrosis over a 10-year period. AMF dimensions were measured on preoperative CT-scan: anteroposterior axis (AP), transverse axis (T), and height (H). AMF volumes (V) were calculated by the formula: AP×T×H×3.14/6. According to the radiological AMF dimensions, patients were distributed into two groups: low-AMF (V<20cm3) and high-AMF (V>20cm3), and early and long-term outcomes were compared by univariable and multivariable analyses. There were 92 SLT: 73M/19F, 53±11 [14-68] years old. 30-Day mortality (low-AMF vs. high-AMF): 5 (5.4%) vs. 15 (16.3%), p=0.014. Patients developing primary graft dysfunction within 72h post-transplant, and those dying within 30 days post-transplant presented higher AMF volumes: 21.1±19.8 vs. 43.3±24.7cm3 (p=0.03) and 24.4±24.2 vs. 56.9±63.6cm3 (p<0.01) respectively. Overall survival (low-AMF vs. high-AMF) (1, 3, and 5 years): 85%, 81%, 78% vs. 55%, 40%, 33% (p<0.001). Factors predicting 30-day mortality were: BMI (HR=0.77, p=0.011), AMF volume (HR=1.04, p=0.018), CPB (HR=1.42, p=0.002), ischaemic time (HR=1.01, p=0.009). Factors predicting survival were: AMF volume (HR=1.02, p<0.001), CPB (HR=3.17, p=0.003), ischaemic time (HR=1.01, p=0.001). Preoperative radiological assessment of mediastinal fat dimensions and volumes may be a useful tool to identify fibrotic patients at higher risk of mortality after single lung transplantation.


Increased prostaglandin formation in rat brain following systemic application of kainic acid.
The arachidonic acid (AA) metabolites prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2 alpha) and thromboxane B2 (TXB2) were measured in the dorsal hippocampus, amygdala/pyriform cortex and parietal cortex of the rat brain following the application of kainic acid (KA, s.c. 10 mg/kg). The first significant increases in the prostanoids were seen 10 min following the KA injection, at this time the first behavioral change 'staring' was observed. In the hippocampus the highest concentrations of the PGs were reached 30 min after the injection of the neurotoxin. At this time frequent wet dog shakes (WDS) and rare focal convulsions effecting head and extremities occurred. In the amygdala/pyriform cortex and parietal cortex the maximal prostanoid formation was seen after 120 min. At this time tonic clonic seizures were registered. In contrast to other seizure models, where PGD2 was the predominant prostanoid formed, PGF2 alpha was the major AA-metabolite found in KA-treated animals. From the time-course of the seizure-related behavior and the increased prostanoid synthesis we conclude that the initiation of the prostanoid synthesis was triggered by the increased neuronal activity rather than by cell damage.


Pneumomediastinum, pneumopericardium, and pneumoperitoneum caused by peridiverticulitis of the colon: report of a case.
A 50-year-old woman with breast carcinoma metastases in the left supraclavicular region was treated because of free air in the mediastinum, around the heart and vascular pedicle, below the diaphragmatic dome, and subcutaneous neck and supraclavicular emphysema, without radiologic signs of pneumothorax. Diverticulosis of the colon and an occult perforation of the diverticulum in the retroperitoneal region of the colon were diagnosed. The patient was treated by segmental resection of the colon with anastomosis, drainage of the abdominal cavity, and antibiotics. To our knowledge, this is the only report in the literature about pneumopericardium caused by peridiverticulitis of the colon.


Activity of cefditoren against beta-lactamase-positive and -negative Haemophilus influenzae and Moraxella catarrhalis.
Cefditoren is a novel broad-spectrum oral cephalosporin. To determine the influence of beta-lactamase production on cefditoren activity, 1,170 H. influenzae and 641 M. catarrhalis isolated during 2000 were tested by NCCLS broth microdilution methodology (M7-A5, 2000). Against H. influenzae the potency of cefditoren (MIC(90,) 0.015 microg/mL) was similar to that of ceftriaxone (MIC(90,) < or = 0.015 microg/mL) and levofloxacin (MIC(90,) 0.015 microg/mL), and its MIC distribution was unaffected by beta-lactamase production. In comparison, the beta-lactamase status of M. catarrhalis affected the potency of all beta-lactams tested, including cefditoren, as well as trimethoprim-sulfamethoxazole. However, regardless of the presence of beta-lactamase, cefditoren demonstrated potent activity, as concentrations of 0.5 and 1 microg/mL inhibited 93.1 and 100% of M. catarrhalis isolates, respectively. We conclude that cefditoren is highly active in vitro against beta-lactamase-positive H. influenzae and M. catarrhalis.


Influence of the antimitotic naphthoquinone on the cleavage of the eggs of the mollusc,Mytilus edulis L.
1. A brief account is given of the cleavage ofMytilus edulis L.2.Naphthoquinone in concentrations above 1∶ million produces cytolysis of the newly fertilised eggs. It causes some blockage of cleavage at the single cell stage in concentrations down to 1∶40 M. The main area of its antimitotic activity is in the range between 1∶ M and 1∶6 M. Resistance to the substance increases as cleavage proceeds. 3. Some abnormalities of cleavage are found at all antimitotic concentrations. The types of abnormality are described. They do not appear to fit easily into the hypothesis of Huber (1947) that the effect of this substance is to enhance the contraction and inhibit the expansion of the cell cortex.


Culprit factors for the failure of well-conducted warfarin therapy to prevent ischemic events in patients with atrial fibrillation: the role of homocysteine.
In patients with atrial fibrillation (AF), oral anticoagulant therapy (OAT) is effective in reducing stroke and embolism. However, despite OAT, ischemic events do occur in some patients. Studies specifically addressing the identification of risk factors for ischemic events during well-conducted OAT are not available. In this study, we prospectively investigated the role of classic risk factors and homocysteine levels in the occurrence of ischemic complications in 364 AF patients on OAT. The quality of anticoagulation levels and the occurrence of bleeding and thrombotic events were recorded. During follow-up (859 patient years) 21 patients had ischemic complications (rate 2.4 x 100 patient-years). Homocysteine plasma levels were higher in these patients than in patients without ischemic complications during OAT (P<0.01), whereas no difference was observed in relation to the quality of OAT. The presence of a history of previous ischemic events, hypertension, and homocysteine plasma levels over the 90th percentile were all associated with an increased risk of ischemic events during OAT (odds ratio [OR]=7, 4.5, and 4.7, respectively). The coexistence of these risk factors markedly increased the risk (OR=13.1; 95% CI, 3.7 to 45.7; P=0.001). In conclusion, our results indicate that AF patients with multiple risk factors may not be sufficiently protected by OAT, even when this is well conducted.


Long Non-Coding RNAs as Potential Regulators of EMT-Related Transcription Factors in Colorectal Cancer-A Systematic Review and Bioinformatics Analysis.
Epithelial-mesenchymal transition (EMT) plays a pivotal role in carcinogenesis, influencing cancer progression, metastases, stemness, immune evasion, metabolic reprogramming and therapeutic resistance. EMT in most carcinomas, including colorectal carcinoma (CRC), is only partial, and can be evidenced by identification of the underlying molecular drivers and their regulatory molecules. During EMT, cellular reprogramming is orchestrated by core EMT transcription factors (EMT-TFs), namely ZEB1/2, TWIST1/2, SNAI1 (SNAIL) and SNAI2 (SLUG). While microRNAs have been clearly defined as regulators of EMT, the role of long non-coding RNAs (lncRNAs) in EMT is poorly defined and controversial. Determining the role of lncRNAs in EMT remains a challenge, because they are involved in a number of cellular pathways and are operating through various mechanisms. Adding to the complexity, some lncRNAs have controversial functions across different tumor types, acting as EMT promotors in some tumors and as EMT suppressors in others. The aim of this review is to summarize the role of lncRNAs involved in the regulation of EMT-TFs in human CRC. Additional candidate lncRNAs were identified through a bioinformatics analysis.


[The formation of a new medical discipline: psychiatry in Austria in the 19th century].
The first psychiatric chairs and university departments of psychiatry in Austria were founded in Vienna and Graz in 1870: hence they celebrate their 150th anniversary this year 2020. These foundations represent a peak in the development of psychiatry as a scientific medical discipline. It is the aim of this paper to sketch that step by step development in its connection with the development of care institutions of the time and with reference to important personalities in the field. Vienna-as the metropole of the state and the most prominent place in the field-is taken as an example. One can distinguish four developmental periods: (1) The establishment of care institutions (asylums), at first without an own medical staff and unqualified male and female keepers (late 18th century up to early 19th). (2) The growing independance of these institutions-in Vienna the 'Tower of Fools'-and the emergence of 'alienists' who began to reflect on their activities and to share their experiences on academic grounds and the publication of a first Austrian textbook (1st half of 19th century). (3) From the 1850s on several alienists habilitated, partly with special emphasis on forensic psychology or cerebral anatomy and physiology, and developed a systematic academic teaching, again with a new 'modern' textbook, in some connection with a new care institution, and the foundation of a scientific association of psychiatry and forensic psychology in 1868. (4) An early activity of that association was to call for the institution of a chair and a university department of psychiatry within the asylum, both realised in 1870.


The cerebrovascular permeability to protein after bicuculline and amphetamine administration in spontaneously hypertensive rats. Evidence for increased resistance of pressure-induced blood-brain barrier dysfunction.
Hemodynamic and morphometric studies on spontaneously hypertensive rats (SHR) have suggested that the lumen to wall ratio of the resistance vessels is decreased due to hypertrophy of the media. As the tension in the vessel wall increases with the pressure and the radius and decreases with the vessel wall thickness, such vessels would be expected to withstand higher pressure than vessels of normotensive rats (NR) unless local wall defects were present. Bicuculline-induced epileptic activity and amphetamine intoxication, two conditions with cerebral vasodilatation and high blood pressure, give rise to extensive protein leakage in the brain of NR. Consistent with the hypothesis presented above, less protein leakage occurred in brains of SHR than in brains of NR after amphetamine and bicuculline administration.


Magnesium deficiency: pathogenesis, prevalence, and clinical implications.
Hypomagnesemia is probably the most underdiagnosed electrolyte deficiency in current medical practice. Patients with cardiovascular disease who are at greatest risk for the development of magnesium deficiency are those treated with diuretics or digitalis. Both potassium and magnesium deficiencies are associated with increased ventricular ectopy and may increase the risk of sudden unexpected death. Refractory potassium repletion can be caused by concomitant magnesium depletion, and can be corrected with magnesium supplementation. Routine serum magnesium determination is recommended whenever the testing of electrolyte levels is required, especially in patients taking diuretic drugs or digitalis. Because hypomagnesemia is not necessarily present in a magnesium-deficient state, it is recommended that both potassium and magnesium be repleted in patients with hypokalemia. Potassium-/magnesium-sparing diuretics may be helpful in the prevention of these electrolyte deficiencies.


Multiple-stable anisotropic magnetoresistance memory in antiferromagnetic MnTe.
Commercial magnetic memories rely on the bistability of ordered spins in ferromagnetic materials. Recently, experimental bistable memories have been realized using fully compensated antiferromagnetic metals. Here we demonstrate a multiple-stable memory device in epitaxial MnTe, an antiferromagnetic counterpart of common II-VI semiconductors. Favourable micromagnetic characteristics of MnTe allow us to demonstrate a smoothly varying zero-field antiferromagnetic anisotropic magnetoresistance (AMR) with a harmonic angular dependence on the writing magnetic field angle, analogous to ferromagnets. The continuously varying AMR provides means for the electrical read-out of multiple-stable antiferromagnetic memory states, which we set by heat-assisted magneto-recording and by changing the writing field direction. The multiple stability in our memory is ascribed to different distributions of domains with the Néel vector aligned along one of the three magnetic easy axes. The robustness against strong magnetic field perturbations combined with the multiple stability of the magnetic memory states are unique properties of antiferromagnets.


Silane modification of TiO2 nanoparticles and usage in acrylic film for effective photocatalytic degradation of methylene blue under visible light.
To fabricate a photocatalytic acrylic paint, TiO2 nanoparticles were surface modified by a bi-functional amino silane (i.e. bis-3-(aminopropyltriethoxysilane)) at different concentrations and applied at 1, 3 and 5 wt% to an acrylic latex. It was found that the surface modification of nano TiO2 enhanced its specific surface area about 42%. The tensile properties of the pristine and nanocomposite acrylic films were assessed. The photocatalytic degradation of aqueous solution and stain of methylene blue (MB) were evaluated (under solar, visible, and UV illuminations) by nanoparticles and nanocomposites, respectively. Results showed that incorporating 3 wt% of the pure and modified nano TiO2 to arylic film caused 62 and 144% increment in the tensile strength. The modified nanoparticles showed higher MB degradation contents under UV, visible and solar irradiation (82, 70, 48%, respectively). The addition of pure and modified nanoparticles to the acrylic film caused decrement in the water contact angle from 84 to 70 and 46°, respectively. It also caused considerable enhancement in the glass transition temperature (Tg) of acrylic film compared to the pristine and pure nanocomposite films (i.e. about 17 and 9 °C, respectively). Furthermore, it was found that the modified nanocomposite caused more color change of MB stain (65%).


Nutrient analysis of Exchange Lists for Meal Planning. II. Nutrient density food profiles.
Nutrietn density profiles, generated for the individual subgroups within the revised Exchange Lists for Meal Planning, are presented. The authors suggest that the profiles would be useful for educational purposes.


Assessing professional identity formation (PIF) amongst medical students in Oncology and Palliative Medicine postings: a SEBA guided scoping review.
Introduction to a multi-professional team who are working and caring for the dying, and facing complex moral and ethical dilemmas during Oncology and Palliative Medicine postings influence a medical student's professional identity formation (PIF). However, limited appreciation of PIF, inadequate assessments and insufficient support jeopardise this opportunity to shape how medical students think, feel and act as future physicians. To address this gap, a systematic scoping review (SSR) of PIF assessment methods is proposed. A Systematic Evidence-based Approach (SEBA) guided SSR of assessments of PIF in medical schools published between 1st January 2000 and 31st December 2021 in PubMed, Embase, ERIC and Scopus databases was carried out. Included articles were concurrently content and thematically analysed using SEBA's Split Approach and the themes and categories identified were combined using SEBA's Jigsaw Perspective. The review hinged on the following questions: "what is known about the assessment of professional identity formation amongst medical students?", "what are the theories and principles guiding the assessment of professional identity formation amongst medical students?", "what factors influence PIF in medical students?", "what are the tools used to assess PIF in medical students?", and "what considerations impact the implementation of PIF assessment tools amongst medical students?". Two thousand four hundred thirty six abstracts were reviewed, 602 full-text articles were evaluated, and 88 articles were included. The 3 domains identified were 1) theories, 2) assessment, and 3) implementation in assessing PIF. Differing attention to the different aspects of the PIF process impairs evaluations, jeopardise timely and appropriate support of medical students and hinder effective implementation of PIF assessments. The Krishna-Pisupati model combines current theories and concepts of PIF to provide a more holistic perspective of the PIF process. Under the aegis of this model, Palliative Care and Oncology postings are envisaged as Communities of Practice influencing self-concepts of personhood and identity and shaping how medical students see their roles and responsibilities as future physicians. These insights allow the forwarding of nine recommendations to improve assessments of PIF and shape the design of a PIF-specific tool that can direct timely and personalized support of medical students.


New triggers and non-motor findings in a family with rapid-onset dystonia-parkinsonism.
A woman from Italy presented with dystonic leg symptoms at the age of 59. Rapid-onset dystonia-parkinsonism (RDP) was not suspected until 3 affected children (2 male, 1 female) with presentations consistent with the disorder were recognized. The mother and four of her children (3 with and 1 without dystonia) were evaluated with an extensive battery including standardized history questionnaire and rating scales. In addition, all four children had cognitive testing and three of the four children had psychiatric interviews. In this family, a T613M mutation in the ATP1A3 gene was confirmed, the most common mutation present in patients with RDP. The proband's limb dystonia was atypical of RDP, symptoms of the others affected included dysarthria, asymmetric limb dystonia, and dysphagia more consistent with RDP. The two sons developed dystonia-parkinsonism in adolescence after consuming large amounts of alcohol. All 3 of those with psychiatric interviews reached diagnosable thresholds for mood disorder (bipolar or dysthymia) and some form of anxiety disorder. The phenotype and age of onset is broader than previously reported in RDP, suggesting that it could be under-reported. Prior to this study, neuropsychologic symptoms associated with RDP were under-appreciated. Those patients who are at risk or suspected of having RDP should be cautioned to avoid excessive alcohol intake. Further study is needed to assess if the cognitive and psychiatric features are part of a broader RDP phenotype and this may have implications for future research into genetic susceptibility for psychiatric disease.


Duplex scanning and plaque histology in cerebral ischaemia.
Twenty-seven patients undergoing carotid endarterectomy (21 M, 6 F), with a mean age of 62 years, were studied by carotid ultrasound imaging, angiography, and histological examination of endarterectomy specimens, including Perl's stain to detect haemorrhage more than a week old. Haemorrhage into a plaque was seen histologically in 21 patients (78%), compared with 19 (70%) diagnosed preoperatively as echolucent heterogeneous plaques on ultrasound imaging. The remainder were echogenic homogeneous, fibrous plaques. In only one case was the nature of the plaque diagnosed by contrast arteriography. Excised endarterectomy specimens were inspected independently of the ultrasound assessment to determine whether the site of haemorrhage communicated with the base of an atherosclerotic ulcer. Communicating haemorrhages were present in 9 of 11 with episodic symptoms and non-communicating haemorrhages in 7 of 10 patients with a single cerebrovascular event. Perl's stain showed recent haemorrhage in 7 of 11 patients with multiple symptoms, and old haemorrhage in 9 of 10 patients with a single event. These findings suggest that ultrasonically heterogeneous communicating carotid plaques are symptomatically more active than homogeneous non-communicating plaques.


IL-25 induces airway remodeling in asthma by orchestrating the phenotypic changes of epithelial cell and fibrocyte.
Previous studies have shown that IL-25 levels are increased in patients with asthma with fixed airflow limitation (FAL). However, the mechanism by which IL-25 contributes to airway remodeling and FAL remains unclear. Here, we hypothesized that IL-25 facilitates pro-fibrotic phenotypic changes in bronchial epithelial cells (BECs) and circulating fibrocytes (CFs), orchestrates pathological crosstalk from BECs to CFs, and thereby contributes to airway remodeling and FAL. Fibrocytes from asthmatic patients with FAL and chronic asthma murine models were detected using flow cytometry, multiplex staining and multispectral imaging analysis. The effect of IL-25 on BECs and CFs and on the crosstalk between BECs and CFs was determined using cell culture and co-culture systems. We found that asthmatic patients with FAL had higher numbers of IL-25 receptor (i.e., IL-17RB)+-CFs, which were negatively correlated with forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC). The number of airway IL-17RB+-fibrocytes was significantly increased in ovalbumin (OVA)- and IL-25-induced asthmatic mice versus the control subjects. BECs stimulated with IL-25 exhibited an epithelial-mesenchymal transition (EMT)-like phenotypic changes. CFs stimulated with IL-25 produced high levels of extracellular matrix (ECM) proteins and connective tissue growth factors (CTGF). These profibrotic effects of IL-25 were partially blocked by the PI3K-AKT inhibitor LY294002. In the cell co-culture system, OVA-challenged BECs facilitated the migration and expression of ECM proteins and CTGF in CFs, which were markedly blocked using an anti-IL-17RB antibody. These results suggest that IL-25 may serve as a potential therapeutic target for asthmatic patients with FAL.


Conventional and conservative management of placenta accreta is two ends of a single continuum: A report of three cases and literature review.
Placenta accreta (PA) is a critical condition that represents a significant source of morbidity and mortality observed in women with multiple prior cesarean sections. Precise prenatal identification of affected pregnancies permits optimal obstetric management. Antenatal diagnosis leads to less blood loss and a requirement for blood transfusion than women diagnose during cesarean section.


Differential selection of growth rate-related traits in wild barley, Hordeum spontaneum, in contrasting greenhouse nutrient environments.
Across-species comparisons show that inherent variation in relative growth rate (RGR) and its underlying traits are correlated with habitat productivity. In this study, we test the hypothesis that growth rate-related traits confer differential selective effects in contrasting nutrient environments. We specifically test whether high RGR is targeted by selection in nutrient-rich environments whereas low values of traits that underlie RGR [specific leaf area (SLA), leaf mass fraction and leaf area ratio (LAR)] confer a direct fitness advantage in nutrient-poor environments, resulting in selection of low RGR as a correlated response. We measured RGR, its underlying component traits, and estimated fitness in a range of wild barley (Hordeum spontaneum) accessions grown under high and low nutrient conditions. Selection on component traits differed between the two environments, while total selection of RGR was not significant. Using multiple regression and path analysis to estimate direct fitness effects, a selective advantage of high LAR and SLA was demonstrated only under nutrient-rich conditions. While supporting the view that observed associations between habitat richness and some RGR-component traits reflect adaptation to differing nutrient regimes, our data suggest that direct selection targets component traits rather than RGR itself.


Hyperdynamic myocardial response to beta-adrenergic stimulation in patients with chest pain and normal coronary arteries.
The goal of this study was to test the hypothesis that an abnormal response to beta-adrenergic stimulation may play a role in the pathophysiology of chest pain in patients with normal coronary arteries. The mechanism of angina-like (AL) chest pain in patients with angiographically normal coronary arteries remains controversial. Fifty-eight patients with AL pain and a normal coronary angiogram underwent dobutamine echocardiography (DE) to evaluate regional wall motion and intraventricular flow velocities (IFV). Control patients consisted of 22 matched patients free of angina and coronary artery disease. Abnormal IFV were defined as dagger-shaped Doppler spectrum > or =3 m/s. Dobutamine-induced regional wall motion abnormalities did not develop in any of the patients. An IFV > or = 3 m/s was found in 28 patients (48%) with AL pain but in only 4 (18%) control patients (p < 0.05). In the subgroup of patients with AL pain and IFV > or =3 m/s, plasma renin concentration (PRC) was higher as compared with those with IFV <3 m/s (18 +/- 17 pg/ml vs. 9 +/- 6 pg/ml, p < 0.05). There were no differences in plasma ADR, NADR, or angiotensin-converting enzyme levels. Fourteen patients with angina and IFV > or =3 underwent control DE and blood sampling after 6 weeks treatment with 10 mg of bisoprolol. In these patients, a decrease in IFV (from 3.4 +/- 0.35 m/s to 2.46 +/- 0.64 m/s, p < 0.001) and a decrease in angina score (from 5.4 +/- 1.5 to 0.6 +/- 1.4, p < 0.001) were observed at follow-up. The present data suggest that an exaggerated myocardial response to beta-adrenergic stimulation plays a role in the mechanisms of chest pain in some patients with normal coronary arteries.


Protective effect of anticholinergic drugs and psyllium in a nosocomial outbreak of Norwalk gastroenteritis.
An outbreak of Norwalk agent gastroenteritis occurred in a chronic-care hospital in Tennessee in April 1981. Fifty-five per cent of the elderly psychiatric patients and 61 per cent of the nursing employees on one floor became ill. Infection was most likely to have spread from patient-to-patient by nursing employees. Certain chronic medications seemed to protect patients from symptomatic infection. Anticholinergic drugs appeared to mask the symptoms of this disease; psyllium ('Metamucil') may have prevented infection in some patients. We suggest that prospective studies be undertaken to confirm the possible value of psyllium in averting infection with Norwalk agent.


Endoscopic management of pancreaticopleural fistula after recurrent acute pancreatitis.
Pancreaticopleural fistula is an extremely rare complication of pancreatitis. We present a case of pancreaticopleural fistula in a patient with recurrent acute pancreatitis who presented with right-sided symptomatic pleural effusion. Pancreatic sphincterotomy and pancreatic duct stenting led to resolution of pleural effusion and withdrawal of the chest tube within 3 weeks.


Antibacterial and membrane damaging activity of Livistona chinensis fruit extract.
Livistona chinensis is used in traditional Chinese medicine as an anticancer agent. Experimental studies have shown the antiproliferative and antiangiogenic properties of extracts of L. chinensis fruits and seeds. In the present study, qualitative phytochemical composition of L. chinensis fruits was investigated. We hypothesized that the presence of high concentration of phenolic compounds with astringent properties may result in bacterial cell death. Hence, antibacterial activity of an aqueous extract of L. chinensis fruits was investigated against Staphylococcus aureus. The antibacterial activity was attributed to DNA, enzyme and protein denaturing properties of the phenolic compounds present in the extract. The extract also resulted in increased membrane permeability. The antibacterial, DNA and enzyme denaturing and membrane damaging activity was limited to an acid-precipitable fraction of the extract and these effects were abrogated in presence of proteins. The membrane damaging activity of phenolic compounds was also observed in leucocytes. In conclusion, this study reported the antibacterial activity of the fruits of L. chinensis due to their high content of phenolic compounds.


Preliminary evaluation of LATEX/T. b. gambiense and alternative versions of CATT/T. b. gambiense for the serodiagnosis of human african trypanosomiasis of a population at risk in Côte d'Ivoire: considerations for mass-screening.
A study was conducted to compare classical card agglutination test for trypanosomiasis (CATT)/T. b. gambiense with CATT-EDTA and LATEX/T. b. gambiense as alternative field tests for serodiagnosis of Human African Trypanosomiasis. The tests were performed on freshly collected blood in an endemic and a low prevalence area in Côte d'Ivoire. Diagnostic performance of each test was assessed using Quantitative Buffy Coat as the parasitological reference and immune trypanolysis as the serological reference test. According to the parasitological data, CATT-EDTA on 10 microl and LATEX/T. b. gambiense on blood diluted 1:4, detecting all confirmed cases with good specificity (respectively 94.6% and 98.1%) yielded better results than the classical CATT did (one false negative and 92.5% specific). However, when immune trypanolysis data and feasibility are taken into account, the classical CATT remains the test of choice for mass screening under the given field conditions.


Thyroid hormone- and estrogen receptor interactions with natural ligands and endocrine disruptors in the cerebellum.
Although the effects of phytoestrogens on brain function is widely unknown, they are often regarded as "natural" and thus as harmless. However, the effects of phytoestrogens or environmental pollutants on brain function is underestimated. Estrogen (17beta-estradiol, E2) and thyroid hormones (THs) play pivotal roles in brain development. In the mature brain, these hormones regulate metabolism on cellular and organismal levels. Thus, E2 and THs do not only regulate the energy metabolism of the entire organism, but simultaneously also regulate important homeostatic parameters of neurons and glia in the CNS. It is, therefore, obvious that the mechanisms through which these hormones exert their effects are pleiotropic and include both intra- and intercellular actions. These hormonal mechanisms are versatile, and the experimental investigation of simultaneous hormone-induced mechanisms is technically challenging. In addition, the normal physiological settings of metabolic parameters depend on a plethora of interactions of the steroid hormones. In this review, we discuss conceptual and experimental aspects of the gonadal and thyroid hormones as they relate to in vitro models of the cerebellum.


[Cerebral malaria with renal insufficiency in a 5 months pregnant woman. The use of prostaglandines for delivery (author's transl)].
Report of a typical case of cerebral malaria with coma during 3 days, pneumopathy and renal insufficiency with failure of concentration. The delivery of a dead foetus has been started by prostaglandines.


Langerhans cell histiocytosis located in the spheno-orbital bone and the pons: illustrative case.
This is a case of aggressive Langerhans cell histiocytosis (LCH) with an atypical intracranial location. In this report, the authors present the diagnosis and treatment of a 12-year-old male patient diagnosed with LCH. The patient was admitted to the emergency department with left-sided facial palsy, and a solid lesion with mass effect in the pons was found. A biopsy was performed via suboccipital craniotomy, and the diagnosis was LCH. A chemotherapy regimen was started since the LCH sample was the resistant type. The patient showed improvement in his neurological deficit following treatment. This rare localized and aggressive case's diagnosis process and treatment choices may apply to future cases.


Effects of inorganic ions on autotrophic denitrification by Thiobacillus denitrificans and on heterotrophic denitrification by an enrichment culture.
Salinity of nitrate-laden wastewaters, such as those produced by metal industries, tanneries, and wet flue gas cleaning systems may affect their treatment by denitrification. Salt inhibition of denitrification has been reported, while impacts of individual ions remain poorly understood whilst being relevant for wastewaters where often the concentration of a single ion rather than the salts varies. The aim of this study was to determine the inhibition by inorganic ions (Na+, Cl-, SO42- and K+) commonly present in saline wastewaters on denitrification and reveal its potential for the treatment of such waste streams, like those produced by NOx-SOx removal scrubbers. The inhibitory effects were investigated for both heterotrophic (enrichment culture) and autotrophic (T. denitrificans) denitrification in batch assays, by using NaCl, Na2SO4, KCl and K2SO4 salts at increasing concentrations. The half inhibition concentrations (IC50) of Na+ (as NaCl), Na+ (as Na2SO4) and Cl- (as KCl) were: 4.3 ± 0.3, 7.9 ± 0.5 and 5.2 ± 0.3 g/L for heterotrophic, and 1-2.5, 2.5-5 and 4.1 ± 0.3 g/L for autotrophic denitrification, respectively. Heterotrophic denitrification was completely inhibited at 20 g/L Na+ (as NaCl), 30 g/L Na+ (as Na2SO4) and 30 g/L Cl- (as KCl), while autotrophic at 8 g/L Na+ (as NaCl), 10 g/L Na+ (as Na2SO4) and 15 g/L Cl- (as KCl). In both cases, Cl- addition had the most important role in decreasing denitrification rate, while Na+ at 1 g/L stimulated autotrophic denitrification but rapidly inhibited the rate at higher concentrations. Nitrite reduction was less inhibited by the ions than nitrate reduction and both the osmotic pressure and the toxicity of the single ions played key roles in the overall inhibition of denitrification. Eventually, both autotrophic and heterotrophic denitrification showed potential for the treatment of a saline wastewater from a NOx-SO2 removal scrubber from a pulp mill.


Nitrotyrosine, dityrosine, and nitrotryptophan formation from metmyoglobin, hydrogen peroxide, and nitrite.
The biological relevance of tyrosine nitration is a subject of much interest, because extensive evidence supports formation of 3-nitrotyrosine in vivo under a variety of different pathological conditions. Several reagents are likely to be responsible for nitration in vivo, among others peroxynitrite and nitrite in the presence of H(2)O(2)/peroxidases. In this work we show that also metmyoglobin and methemoglobin can nitrate free tyrosine in the presence of nitrite and H(2)O(2). The results of these studies are simulated rather well by using a scheme that comprehends all the possible reactions that can take place in the system. Thus, a good understanding of the factors that determine the yields is achieved. Finally, we demonstrate that the system metMb/H(2)O(2)/NO(2)(-) can also lead to the nitration of tryptophan and produces, in particular, 6-, 4-, and 5-nitrotryptophan.


A green extraction design for enhancing flavonoid compounds from Ixora javanica flowers using a deep eutectic solvent.
In this study, an environmentally friendly extraction method for flavonoid compound from Ixora javanica, as a new raw material candidate for herbal medicine and cosmetics, was developed. The objectives of the present work were to provide recommendations for the optimal extraction conditions and to investigate the effects of any extraction parameters on flavonoid yields from the I. javanica flower. The extraction process was performed using deep eutectic solvent (DES) (choline chloride and propylene glycol at molar ratio of 1 : 1) and the ultrasound-assisted extraction method. Both single-factor and response surface analyses using three-level and three-factor Box Behnken designs were conducted to obtain the optimum flavonoid concentrations. The results showed that the optimum extraction conditions for total flavonoids featured an extraction time of 40 min, 25% water content in DES and a solid-to-liquid ratio of 1 : 25 g ml-1. An extract obtained under optimum extraction conditions showed higher total flavonoid yields than an ethanolic extract which was used for comparison. Scanning electron microscope images demonstrated that both of the solvents also showed different effects on the outer surface of the I. javanica flower during the extraction process. In summary, our work succeeded in determining the optimum conditions for total flavonoids in the I. javanica flower using a green extraction method.


Automated mass spectrometry imaging with a matrix-assisted laser desorption ionization time-of-flight instrument.
The automated use of a matrix-assisted laser desorption ionization (MALDI) mass spectrometer (MS) is described for image analysis of samples through implementation of new software for instrument control, data acquisition, and data analysis. The software permits automated acquisition of MS MALDI spectra to form an ordered data array and contains display features to provide images at one or more mass-to-charge ratio values. The technique can be used to scan tissue samples, blotted samples, gels, or other sample surfaces where the image analysis of that sample is required. The program achieves a time of typically 1 s per image point, permitting an analysis made up of large numbers of points with high spatial resolution up to 850 dpi. The features of the software are demonstrated in this paper with samples of printed images, where visible images can be compared to those obtained by mass spectrometry. Quantitative aspects are introduced by analyzing a series of sample spots containing different amounts of several proteins.


Spontaneous bilateral rupture of the extensor mechanism of the knee in two patients on chronic ambulatory peritoneal dialysis.
Two cases of patients on Chronic Ambulatory Peritoneal Dialysis (CAPD) who suffered bilateral, spontaneous rupture of the extensor mechanism of the knee are presented. In neither case was the diagnosis readily apparent. Both patients did well with standard surgical treatment. A review of the literature and consideration of the mechanism of tendon rupture is presented.


Theoretical Reproductive Outcomes of the Sexual Conflict in Humans.
This paper presents an updated mathematical model of the evolutionary dynamics of the sexual conflict ("battle of the sexes") and its simulated reproductive outcomes. The authors highlight a whole range of life-history traits unique to our species, such as prolonged childhood, growth in parental care, etc. Based on these biosocial premises, the sexual conflict between men and women shifts into the mathematical realm of the "Prisoner's Dilemma" game. The evolutionarily stable strategy of mutual rejection of parenthood would be dominant with this PD strategy in both parents; oscillation dynamics predicted in previous models would not be expected. Despite fatal theoretical prediction of the PD evolutionary game, the newish genetic data of the EPP rates in the historical populations reveals prevalence of cooperation between both sexes, predominantly utilizing the monogamous form of sexuality. Presumably, this sexual norm could have potentially ensured reproductive success in the societies in the past.


Synchronous pulmonary carcinoid tumour and non-Hodgkin's lymphoma: report of two cases.
Two cases of synchronous pulmonary carcinoid tumour and non-Hodgkin's lymphoma are described.


Sorafenib Plus Ixabepilone as First-Line Treatment of Metastatic HER2-Negative Breast Cancer: A Sarah Cannon Research Institute Phase I/II Trial.
The purposes of the present phase I/II trial were (1) to define tolerable doses of ixabepilone and sorafenib when used in combination and (2) to evaluate the efficacy and toxicity of this combination in the treatment of patients with human epidermal growth factor receptor-negative metastatic breast cancer (MBC). The eligible patients had human epidermal growth factor receptor-negative MBC and had not received previous chemotherapy in the metastatic setting. All patients received ixabepilone intravenously on day 1 of each 21-day treatment cycle; sorafenib was administered orally twice daily. Patients in phase II received the maximum doses identified in phase I. The patients were reevaluated after the completion of 3 treatment cycles; treatment continued until disease progression or intolerable toxicity. A total of 67 patients were required in phase II to demonstrate increased median progression-free survival from 4.2 to 6.2 months (90% power, α = 0.05). Ten patients entered the phase I portion; the maximum tolerated doses were ixabepilone 32 mg/m(2) and sorafenib 400 mg orally twice daily. A total of 76 patients were treated at the phase II dose. The median progression-free survival was 4.8 months (95% confidence interval, 3.5-6.3 months). The overall response rate was 37%. The regimen was difficult to tolerate for many patients; 20 patients discontinued because of toxicity, and dose reductions were frequent. The common toxicities included neutropenia, fatigue, rash, and neuropathy. The combination of ixabepilone and sorafenib was poorly tolerated as first-line treatment of patients with MBC. The activity of the combination was similar to the activity previously reported with single-agent ixabepilone or taxanes. Further development of this combination is not recommended.


Does 5 + 5 Equal Better Radiation Treatment Plans in Head and Neck Cancers?
Accurate contouring in head and neck cancer (HNC) is critical. International consensus guidelines recommend the 5 + 5 mm rule for expansions around the primary tumor, wherein high- and low-dose clinical target volumes (CTV-P1 and CTV-P2, respectively) are created using successive 5 mm expansions on the gross tumor volume. To our knowledge, the necessity of a low-dose CTV-P2 has never been assessed; therefore, we evaluated the dosimetric impact of adding a CTV-P2 expansion using the 5 + 5 mm rule compared with contouring with a high-dose CTV-P1 alone. A retrospective study of clinically delivered (chemo)radiation therapy treatment plans for HNC was conducted. All patients were treated with 70 Gy in 35 fractions using volumetric modulated arc therapy in a single phase. CTV-P2 was retrospectively contoured per guidelines as a 5 mm expansion on CTV-P1 from the clinical plan, carving off specified barriers to spread. We used a 5 mm planning target volume (PTV) expansion. Our primary outcome was whether 95% of the volume of the PTV for the CTV-P2 contour (ie, PTV-P2) received at least 56 Gy. To assess dose falloff, the coverage of a PTV ring structure was created by subtracting PTV-P1 from PTV-P2. Twenty-seven patients from 4 HNC subsites (base of tongue, tonsil, hypopharynx, and supraglottic larynx) were included. In all 108 treatment plans, at least 95% of the PTV-P2 structure received at least 56 Gy. The minimum volume of the PTV-P2 structure receiving at least 56 Gy was 97.4%. Eight of 108 treatment plans had borderline coverage of the PTV ring substructure alone. Adding a CTV-P2 structure using the 5 + 5 mm rule had no dosimetric impact, adds contouring time, adds treatment planning complexity, and could potentially introduce errors. The 5 + 5 mm rule may have value in other settings, such as when smaller PTV margins are used, and warrants further evaluation with prospective or randomized studies.


Selection and validation of reference genes for qPCR in the human dermatophyte Trichophyton rubrum exposed to different carbon sources which promote adhesion-inducing conditions.
The present study aimed to identify reference genes for qPCR analysis of T. rubrum growth in culture media which promote adhesion-inducing conditions to the host tissue. We investigated the suitability of six candidate reference genes: β-act, β-tub, ef1-α, gapdh, sdha and rpl2 in reference strain of Trichophyton rubrum in response to different environmental stimuli. The stability of these genes was determined by NormFinder, geNorm and BestKeeper software. Our data obtained from the three algorithms revealed that mRNA expression levels of two candidate reference genes, ef1-α and β-tub, remained the most stable in response to different carbon sources, while different sample sets had their own most stable reference genes, highlighting the importance of the choice of internal controls in qPCR experiments. We then checked the stability of ef1-α and β-tub reference genes expression in different T. rubrum strains, suggesting that these two genes are reliable for normalisation of qPCR. Finally, we validated the suitability of selected reference genes as internal controls for target gene (SUB3) using the 2-ΔΔCt method. The best result indicating an increase of SUB3 transcript of T. rubrum was found when the two the most stable reference (ef1-α and β-tub ) genes were used, as revealed by all three algorithms. We recommend the use of ef1-α and β-tub as reference genes for qPCR analysis of target gene expression in T. rubrum exposed to different carbon sources which promote adhesion-inducing conditions.


Structure of apolipoprotein A-I in three homogeneous, reconstituted high density lipoprotein particles.
To elucidate further the conformation of human apolipoprotein A-I (apoA-I) in lipid-bound states and its effect on the reaction with lecithin cholesterol acyltransferase (LCAT), we prepared reconstituted HDL (rHDL) particles from a reaction mixture containing dipalmitoylphosphatidylcholine/cholesterol/apoA-I in the molar ratios of 150:7.5:1. The particles were separated by gel filtration into three classes of highly homogeneous and reproducible discs with diameters of 97, 136, and 186 A, containing 2, 3, and 4 molecules of apoA-I/disc, respectively, and increasing proportions of phospholipid and cholesterol. These three classes of particles were then investigated by a variety of fluorescence techniques, to probe the average environment and mobility of the tryptophan (Trp) residues in the structure of apoA-I. We found small, gradual changes in the fluorescence parameters with changes in the size of the rHDL, consistent with a shift of Trp residues to a more hydrophobic and more rigid environment, as well as an increased resistance of apoA-I to denaturation by guanidine hydrochloride in the larger particles. In contrast, circular dichroism measurements and binding studies with seven monoclonal antibodies indicated a similar alpha-helical structure (73%) for apoA-I in all the particles, and similar exposure of apoA-I epitopes in the COOH-terminal two-thirds of the apolipoprotein. Thus the structure of apoA-I is comparable for the three classes of particles and is consistent with the presence of eight alpha-helical segments per apoA-I in contact with the lipid. In addition, we obtained the apparent kinetic parameters for the reaction of the rHDL particles with lecithin cholesterol acyltransferase. The apparent Km values were similar but the apparent Vmax decreased almost 8-fold, going from the 97- to the 186-A particles; therefore, the decreasing reactivity for the larger particles can be attributed mainly to differences in the catalytic rate constant. The rate limiting step is probably affected by local structural differences in the apoA-I, or by the interfacial properties of the lipid.


An audit of clinical service examining the uptake of genetic testing by at-risk family members.
The aim of this study was to investigate the uptake of genetic testing by at-risk family members for four genetic conditions: chromosomal translocations, fragile X syndrome, Huntington disease, and spinal muscular atrophy. A clinical audit was undertaken using genetics files from Genetic Health Services Victoria. Data were extracted from the files regarding the number of at-risk family members and the proportion tested. Information was also collected about whether discussion of at-risk family members and family communication during the genetic consultation was recorded. The proportion of at-risk family members who had genetic testing ranged from 11% to 18%. First-degree family members were most frequently tested and the proportion of testing decreased by degree of relatedness to the proband. Smaller families were significantly more likely to have genetic testing for all conditions except Huntington disease. Female at-risk family members were significantly more likely to have testing for fragile X syndrome. The majority of at-risk family members do not have genetic testing. Family communication is likely to influence the uptake of genetic testing by at-risk family members and therefore it is important that families are supported while communicating to ensure that at-risk family members are able to make informed decisions about genetic testing.


Iranians' Self-Report Knowledge and Practice about Arbitrary Use of Antibiotics.
Scientific studies revealed a high prevalence rate of self-medication among Iranians, nevertheless there are few studies exploring the factors affecting on. This study was conducted to detect the knowledge and behaviour of individuals who take antibiotics arbitrarily. The research population included all Iranian men and women between 20 and 60 years. The sample size based on previous studies and after applying the correction factor 1.6. Total of 950 subjects were involved in this cross-sectional study. Face and content validity (qualitative) tool was confirmed by expert faculty members. It was estimated based on Cronbach's alpha reliability 0.73. After coding, all data were entered into SPSS and analyzed. The mean and SD of knowledge was 4.58±0.65. Sore throat (80%) and runny nose (70%) were the most common causes of antibiotic consumption in the participants. The most common reason for antibiotic use was its availability. More than 68% of participants said they never read the brochure of antibiotics. More than 51% of them were unable to understand the content of the brochure. There was a positive relation between participants' knowledge and performance. More than 60% of them had a history of dosage change. Results of present study revealed that the study population did not possess the requisite knowledge about the appropriate behaviour in the use of antibiotics. It is recommended to do some educational program in order to improve their knowledge and behaviour. Further studies with larger sample in this regard are recommended.


N-(4-azido-2-nitrophenyl)-2-aminoethylsulfonate (NAP-taurine) as a photoaffinity probe for identifying membrane components containing the modifier site of the human red blood cell anion exchange system.
Exposure of cells to intense light with the photoactivatable reagent, N-(4-azido-2-nitrophenyl)-2-aminoethylsulfonate (NAP-taurine), present in the external medium results in irreversible inhibition of chloride or sulfate exchange. This irreversible inhibition seems to result from covalent reaction with the same sites to which NAP-taurine binds reversibly in the dark. As shown in the preceding paper, high chloride concentrations decrease the reversible inhibition by NAP-taurine in the dark, in a manner suggesting that NAP-taurine and chloride compete for the modifier site of the anion transport system. In a similar fashion, high chloride concentrations in the medium during exposure to light cause a decrease in both the irreversible binding of NAP-taurine to the membrane and the inhibition of chloride exchange. Most of the chloride-sensitive irreversibly bound NAP-taurine is found in the 95,000 dalton polypeptide known as band 3 and, after pronase treatment of intact cells, in the 65,000 dalton fragment of this protein produced by proteolytic cleavage. After chymotrypsin treatment of ghosts, the NAP-taurine is localized in the 17,000 dalton transmembrane portion of this fragment. Although the possible involvement of minor labeled proteins cannot be rigorously excluded, the modifier site labeled by external NAP-taurine appears, therefore, to be located in the same portion of the 95,000 dalton polypeptide as is the transport site.


Effects of physiological manipulations on locus coeruleus neuronal activity in freely moving cats. II. Cardiovascular challenge.
Several cardiovascular manipulations were examined for their effects on single-unit activity of locus coeruleus noradrenergic (LC-NE) neurons in unanesthetized, unrestrained cats: hydralazine (1 mg/kg, i.v.) was administered to present a tonic hypotensive stimulus, and to activate preferentially the neural component of the sympathoadrenal system; hemorrhage was used to decrease blood volume and to activate both the neural and hormonal components of the sympathoadrenal system; intravenous infusion of isotonic saline was used to increase blood volume. LC-NE neurons were activated by hydralazine, in parallel with the sympathetic response (indicated by elevated heart rate and plasma NE). LC-NE unit activity was decreased following a volume load. However, contrary to previous findings in anesthetized animals, hemorrhage had no effect on LC-NE unit activity, but did activate both components of the sympathetic response. It is concluded that: (1) cardiovascular stimuli can influence the activity of LC-NE neurons, though they show less sensitivity to such stimuli than do primary regulatory mechanisms; (2) the response of LC-NE neurons to physiological stimuli can occur independent of changes in behavioral state; (3) these neurons do not appear to play a specific role in cardiovascular regulation, but may respond to physiological challenges in general; (4) finally, in agreement with previous studies, our data show that LC-NE neurons are generally co-activated with the sympathetic nervous system, but also that the two can be dissociated (e.g. hemorrhage).


Treatment of newly diagnosed advanced stage Hodgkin lymphoma.
ABVD continues to be the standard of care for patients with advanced stage Hodgkin Lymphoma (HL) although escalated BEACOPP has improved survival in one randomized controlled trial (RCT). More intensive regimens have higher rates of acute and late toxicities and this poses significant issues for patients. Consolidation strategies such as radiation or autologous stem cell transplantation (ASCT) have not demonstrated an improvement in overall survival in RCTs. Novel technology and therapeutics are leading us to investigate new questions. Interim FDG-PET scanning is now being tested in prospective studies. Small, typically retrospective trials suggest that interim PET scans are independent markers of outcome and current trials are piloting the use of PET-adapted therapy. Targeted therapeutics have been evaluated in the relapsed and refractory setting and now show promising single agent activity. Agents including brentuximab vedotin (a conjugated anti-CD30 monoclonal antibody) and the histone deacetylase inhibitor panabinostat have reported encouraging single agent activity and a large study of brentuximab vedotin maintenance post ASCT is underway. Combination and maintenance trials are planned or ongoing in the primary treatment setting that will hopefully improve on the treatment standards of the past decade. This review will discuss the current standard of care in advanced stage HL, summarize some of the current data regarding interim FDG-PET scans and will conclude with some issues related to the development of new agents that are likely to be involved in the future standard of therapy.


In vivo intrarater and interrater precision of measuring apparent bone mineral density in vertebral subregions using supine lateral dual-energy x-ray absorptiometry.
Analysis of apparent bone mineral density (BMD) in the lumbar spine is commonly based on anteroposterior (AP) scanning using dual-energy X-ray absorptiometry (DXA). Although not widely used, clinically important information can also be derived from lateral scanning. Vertebral bone density, and therefore strength, can may vary in different subregions of the vertebral body. Therefore, subregional BMD measurements might be informative about fracture risk. However, the intrarater and interrater precision of in vivo subregional BMD assessments from lateral DXA remains unknown. Ten normal, young (mean: 24 yr) and 10 older (mean: 63 yr) individuals with low BMD were scanned on one occasion using an AP/lateral sequence. Each lateral scan was reanalyzed six times at L2 by three raters to determine the intrarater and interrater precision in selecting seven regions of interest (subregions). Precision was expressed using percentage coefficients of variation (% CV) and intraclass correlation coefficients (ICC). Intrarater precision ranged from ICC(1,1) 0.971 to 0.996 (% CV: 0.50-3.68) for the young cohort and ICC(1,1) 0.934 to 0.993 (% CV: 1.46-5.30) for the older cohort. Interrater precision ranged from ICC(2,1) 0.804 to 0.915 (% CV: 1.11-2.35) for the young cohort and ICC(2,1) 0.912 to 0.984 (% CV: 1.85-4.32) for the older cohort. Scanning a subgroup of participants twice with repositioning was used to assess short-term in vivo precision. At L2, short-term in vivo precision ranged from ICC(1,1) 0.867 to 0.962 (% CV: 3.38-9.61), at L3 from ICC(1,1) 0.961 to 0.988 (% CV: 2.02-5.57) and using an L2/L3 combination from ICC(1,1) 0.942 to 0.980 (% CV: 2.04-4.61). This study demonstrated moderate to high precision for subregional analysis of apparent BMD in the lumbar spine using lateral DXA in vivo.


Enhanced removal of radioactive iodine anions from wastewater using modified bentonite: Experimental and theoretical study.
Efficient and cost-effective removal of radioactive iodine anions from contaminated water has become a crucial task and a great challenge for waste treatment and environmental remediation. Herein, we present hexadecylpyridinium chloride monohydrate modified bentonite (HDPy-bent) for the efficient and selective removal of iodine anions (I- and IO3-) from contaminated water. Batch experiments showed that HDPy-bent could remove more than 95% of I- and IO3- within 10 min, and had maximum I- and IO3- adsorption capacities of 80.0 and 50.2 mg/g, respectively. Competitive experiments indicated that HDPy-bent exhibited excellent I- and IO3- selectivity in the excessive presence of common concomitant anions including PO43-, SO42-, HCO3-, NO3-, Cl- (maximum mole ratio of anions vs iodine anions was ∼50,000). An anion exchange mechanism was proposed for the selective adsorption of iodine anions. Optimal adsorption structure of HDPy+/I- (IO3-) at atomic level and driving forces of the I- (IO3-) adsorption were calculated by density functional theory (DFT) simulations. Moreover, the good durability and reusability of the HDPy-bent has been demonstrated with 5 adsorption-desorption cycles. Dynamic column experiment also demonstrated that HDPy-bent exhibited excellent removal and fractional recovery capabilities towards I- and IO3- from simulated groundwater and environmental water samples. In conclusion, this work presents a promising adsorbent material for the decontamination of radioactive iodine anions from wastewater on a large scale.


Discordant fetal platelet counts in a twin gestation complicated by idiopathic thrombocytopenic purpura.
The twin gestation in a patient with idiopathic thrombocytopenic purpura presents a unique problem if vaginal delivery is being considered. Scalp platelet sampling to exclude fetal thrombocytopenia only allows assessment of the presenting fetus. A case is described in which cordocentesis revealed discordant platelet counts in dizygotic twin fetuses.


Change of isozyme pattern during activation of a transforming gene product: its relation to other biochemical markers of cellular transformation and differentiation.
Isozyme patterns of leucine aminotransferase were studied in connection with glucose transport and DNA synthesis during the activation and deactivation of the transforming gene product in rat kidney cells transformed by one Rous sarcoma virus mutant (which has a temperature-sensitive lesion in its transforming gene. On temperature shift-down of confluent transformed cells grown at 40 degrees C in the presence of fresh serum, isozyme III of leucine aminotransferase appeared in 12--20 h, with increasing amounts from 24 to 48 h. Upon temperature shift-up, isozyme I became the predominant form in these cells within 4 days, the major change occurring within the first 24 h. The rate of protein turnover was similar to the rate of loss of isozymes I and III during temperature shift-down and shift-up, respectively. A stimulation of incorporation of [3H]thymidine into DNA was observed within 8--12 h after temperature shift-down of the transformed cells. For the maintenance of stimulated DNA synthesis for at least 16 h, continued exposure to the permissive temperature is not necessary. Stimulation of glucose transport occurred prior to the stimulation of [3H]thymidine incorporation. The isozymes of leucine aminotransferase also changed during the in vitro differentiation of Yaffee L6A cells in such a way that isozyme I represented the major part of this enzyme in the fused myotube, and isozyme III was more predominant in the less differentiated state (mononucleated cells).


Was a Change to a Urologist Owned Pathology Laboratory Associated with a Change in Prostate Biopsy Use?
We assessed the impact of self-referral to urologist owned pathology facilities on prostate biopsy practice patterns, clinical decision making and pathology service use. We reviewed a transrectal ultrasound guided prostate biopsy database during 2 periods, including 1) August 5, 2008 to April 10, 2010 (613 days) when pathology samples were sent to an independent service laboratory, and 2) June 11, 2010 to February 13, 2012 (613 days) when samples were assessed at a urologist owned pathology laboratory. We also examined data on 3 additional preceding equal length periods before urologist ownership to determine baseline biopsy rates. Billing databases were used to identify the number of new patient visits for increased prostate specific antigen and/or abnormal digital rectal examination. The Student t-test, and Wilcoxon rank sum and chi-square tests were used for statistical comparisons. All biopsies were obtained using a standard transrectal ultrasound guided prostate biopsy protocol. The biopsy rate in patients with increased or abnormal digital rectal examination was 39% during the urologist owned pathology laboratory era, and 35%, 40%, 35% and 40% during the 4 preceding independent service laboratory periods of equal length. There was no statistically significant difference in patient age, rate of abnormal digital rectal examination or indications for repeat transrectal ultrasound guided prostate biopsy among the periods. The prostate cancer detection rate was 45% in the independent service laboratory era and 46% in the urologist owned pathology laboratory era. Self-referral of transrectal ultrasound guided prostate biopsy specimens to urologist owned pathology facilities was not associated with a significant variation in the biopsy rate, the repeat biopsy rate, indications triggering repeat biopsy or the cancer detection rate.


Protease and phospholipase inhibition protect Veneza zonata (Hemiptera Coreidae) against septicemia caused by parasite trypanosomatid 563DT.
Veneza zonata (Hemiptera Coreidae) is an insect which causes losses in several crops, and it is also an important vector of lower trypanosomatids. V. zonata specimens were collected on rural properties in Londrina, state of Paraná, Southern Brazil. Inoculation of Leptomonas 563DT into V. zonata hemocoel caused insect death within approximately 24 h, with large bacterial proliferation into their hemocoels. Some bacteria which were found in the digestive tract of those insects, such as Escherichia coli, Providencia rettgeri, and Kluyveria ascorbata, were also found in their hemolymph, which suggests that trypanosomatid crossing into hemocoel caused mechanical lesions in the digestive tract that allowed intestinal bacteria to infect the hemolymph, thereby leading to lethal septicemia. In this study we analysed proteolytic activities from the 563DT Leptomonas strain, which is pathogenic for V. zonata, aiming at evaluating the potential use of this Leptomonas strain for the biocontrol of the insect. The proteolytic action was evaluated on cells and on culture supernatants of trypanosomatids. We also evaluated the gelatinolytic activities, the action over natural and synthetic substrates for aminopeptidases, and the action of protease inhibitors during all trypanosomatid growth stages. A significant reduction in the number of insect deaths was observed when Leptomonas 563DT were incubated with inhibitors of proteases and phospholipases before being inoculated into the insects, which suggests that those enzymes are involved in the pathogenic mechanism.


Alveolar lymphocytosis in patients with chronic uveitis: relationship to sarcoidosis.
Bronchoalveolar lavage (BAL) is frequently performed in patients with suspected ocular sarcoidosis. This study describes the immunogenetical, immunological, radiological, and functional features of a subclinical alveolar lymphocytosis unrelated to sarcoidosis in patients with chronic uveitis. Two hundred and ten patients with chronic uveitis of unknown origin, who underwent fiber-optic bronchoscopy with BAL as part of a prospective protocol over a three-year period, were evaluable for retrospective analysis. Sixty-five patients had alveolar lymphocytosis: Sarcoidosis was diagnosed in 13 (6%) patients, whereas alveolar lymphocytosis was considered unrelated to sarcoidosis in 52 (25%). Alveolar lymphocytosis unrelated to sarcoidosis was not associated with radiologically detectable interstitial lung disease or pulmonary function impairment. CD4/CD8 lymphocyte ratio was 3.7 +/- 3.0. Total cell count, total lymphocyte, and CD4 lymphocyte percentage were significantly lower when compared with sarcoidosis-related alveolitis (129,000 +/- 80,000 vs. 218,000 +/- 117,000, p <0.05; 33.1% +/- 13.2 vs. 39.7% +/- 13.2, p <0.05; and 54.3% +/- 18.2 vs. 65.4% +/- 10.1, p <0.05, respectively). Patients with alveolar lymphocytosis unrelated to sarcoidosis were older (47.8 +/- 17.7 years vs. 42.7 +/- 14.2 years, p <0.05) and more likely to carry the HLA-B51 allele (19.7% vs. 7.1%, p <0.01) than patients with chronic uveitis without alveolar lymphocytosis. They did not appear to be at risk of developing clinically apparent interstitial lung disease on followup. We conclude that alveolar lymphocytosis is frequently observed in patients with chronic uveitis. It is generally unrelated to sarcoidosis and may then be associated with a distinctive immunogenetic phenotype.


Development of a SERS-based lateral flow immunoassay for rapid and ultra-sensitive detection of anti-SARS-CoV-2 IgM/IgG in clinical samples.
The accurate and rapid screening of serum antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the key to control the spread of 2019 coronavirus disease (COVID-19). In this study, we reported a surface-enhanced Raman scattering-based lateral flow immunoassay (SERS-LFIA) for the simultaneous detection of anti-SARS-CoV-2 IgM/IgG with high sensitivity. Novel SERS tags labeled with dual layers of Raman dye were fabricated by coating a complete Ag shell on SiO2 core (SiO2@Ag) and exhibited excellent SERS signals, good monodispersity, and high stability. Anti-human IgM and IgG were immobilized onto the two test lines of the strip to capture the formed SiO2@Ag-spike (S) protein-anti-SARS-CoV-2 IgM/IgG immunocomplexes. The SERS signal intensities of the IgM and IgG test zones were easily recorded by a portable Raman instrument and used for the high-sensitivity analysis of target IgM and IgG. The limit of detection of SERS-LFIA was 800 times higher than that of standard Au nanoparticle-based LFIA for target IgM and IgG. The SERS-LFIA biosensor was tested on 19 positive serum samples from COVID-19 patients and 49 negative serum samples from healthy people to demonstrate the clinical feasibility of our proposed assay. The results revealed that the proposed method exhibited high accuracy and specificity for patients with SARS-CoV-2 infection.


Inhibitory effects of substrate and product on the carvone biotransformation activity of Rhodococcus erythropolis.
The aqueous substrate and product toxicity thresholds in the microbial biotransformation of (-)-trans-carveol to the fragrance/flavor compound (R)-(-)-carvone by Rhodococcus erythropolis were determined. Above aqueous phase concentrations of approx. 500 mg carveol/l and 200-600 mg carvone/l, the biotransformation activity of the biocatalyst was inhibited. This biotransformation was undertaken in a single aqueous phase 3 l [corrected] reactor in which a total of 5 ml carveol (mixture of isomers) was added before the biotransformation rate decreased significantly. The carvone volumetric productivity was 31 mg/lh. Although the growth of the organism post-exposure was not affected, dramatic morphological changes in response to the accumulation of the inhibitory substrate and product were observed.


Dynamic lung aeration and strain with positive end-expiratory pressure individualized to maximal compliance versus ARDSNet low-stretch strategy: a study in a surfactant depletion model of lung injury.
Positive end-expiratory pressure (PEEP) individualized to a maximal respiratory system compliance directly implies minimal driving pressures with potential outcome benefits, yet, raises concerns on static and dynamic overinflation, strain and cyclic recruitment. Detailed accurate assessment and understanding of these has been hampered by methodological limitations. We aimed to investigate the effects of a maximal compliance-guided PEEP strategy on dynamic lung aeration, strain and tidal recruitment using current four-dimensional computed tomography (CT) techniques and analytical methods of tissue deformation in a surfactant depletion experimental model of acute respiratory distress syndrome (ARDS). ARDS was induced by saline lung lavage in anesthetized and mechanically ventilated healthy sheep (n = 6). Animals were ventilated in a random sequence with: (1) ARDSNet low-stretch protocol; (2) maximal compliance PEEP strategy. Lung aeration, strain and tidal recruitment were acquired with whole-lung respiratory-gated high-resolution CT and quantified using registration-based techniques. Relative to the ARDSNet low-stretch protocol, the maximal compliance PEEP strategy resulted in: (1) improved dynamic whole-lung aeration at end-expiration (0.456 ± 0.064 vs. 0.377 ± 0.101, P = 0.019) and end-inspiration (0.514 ± 0.079 vs. 0.446 ± 0.083, P = 0.012) with reduced non-aerated and increased normally-aerated lung mass without associated hyperinflation; (2) decreased aeration heterogeneity at end-expiration (coefficient of variation: 0.498 ± 0.078 vs. 0.711 ± 0.207, P = 0.025) and end-inspiration (0.419 ± 0.135 vs. 0.580 ± 0.108, P = 0.014) with higher aeration in dorsal regions; (3) tidal aeration with larger inspiratory increases in normally-aerated and decreases in poorly-aerated areas, and negligible in hyperinflated lung (Aeration × Strategy: P = 0.026); (4) reduced tidal strains in lung regions with normal-aeration (Aeration × Strategy: P = 0.047) and improved regional distributions with lower tidal strains in middle and ventral lung (Region-of-interest [ROI] × Strategy: P < 0.001); and (5) less tidal recruitment in middle and dorsal lung (ROI × Strategy: P = 0.044) directly related to whole-lung tidal strain (r = 0.751, P = 0.007). In well-recruitable ARDS models, a maximal compliance PEEP strategy improved end-expiratory/inspiratory whole-lung aeration and its homogeneity without overinflation. It further reduced dynamic strain in middle-ventral regions and tidal recruitment in middle-dorsal areas. These findings suggest the maximal compliance strategy minimizing whole-lung dynamically quantified mechanisms of ventilator-induced lung injury with less cyclic recruitment and no additional overinflation in large heterogeneously expanded and recruitable lungs.


Fast prediction of pulsed nonlinear acoustic fields from clinically relevant sources using time-averaged wave envelope approach: comparison of numerical simulations and experimental results.
The primary goal of this work was to verify experimentally the applicability of the recently introduced time-averaged wave envelope (TAWE) method [J. Wójcik, A. Nowicki, P.A. Lewin, P.E. Bloomfield, T. Kujawska, L. Filipczyński, Wave envelopes method for description of nonlinear acoustic wave propagation, Ultrasonics 44 (2006) 310-329.] as a tool for fast prediction of four dimensional (4D) pulsed nonlinear pressure fields from arbitrarily shaped acoustic sources in attenuating media. The experiments were performed in water at the fundamental frequency of 2.8 MHz for spherically focused (focal length F=80 mm) square (20 x 20 mm) and rectangular (10 x 25mm) sources similar to those used in the design of 1D linear arrays operating with ultrasonic imaging systems. The experimental results obtained with 10-cycle tone bursts at three different excitation levels corresponding to linear, moderately nonlinear and highly nonlinear propagation conditions (0.045, 0.225 and 0.45 MPa on-source pressure amplitude, respectively) were compared with those yielded using the TAWE approach [J. Wójcik, A. Nowicki, P.A. Lewin, P.E. Bloomfield, T. Kujawska, L. Filipczyński, Wave envelopes method for description of nonlinear acoustic wave propagation, Ultrasonics 44 (2006) 310-329.]. The comparison of the experimental results and numerical simulations has shown that the TAWE approach is well suited to predict (to within+/-1 dB) both the spatial-temporal and spatial-spectral pressure variations in the pulsed nonlinear acoustic beams. The obtained results indicated that implementation of the TAWE approach enabled shortening of computation time in comparison with the time needed for prediction of the full 4D pulsed nonlinear acoustic fields using a conventional (Fourier-series) approach [P.T. Christopher, K.J. Parker, New approaches to nonlinear diffractive field propagation, J. Acoust. Soc. Am. 90 (1) (1991) 488-499.]. The reduction in computation time depends on several parameters, including the source geometry, dimensions, fundamental resonance frequency, excitation level as well as the strength of the medium nonlinearity. For the non-axisymmetric focused transducers mentioned above and excited by a tone burst corresponding to moderately nonlinear and highly nonlinear conditions the execution time of computations was 3 and 12h, respectively, when using a 1.5 GHz clock frequency, 32-bit processor PC laptop with 2 GB RAM memory, only. Such prediction of the full 4D pulsed field is not possible when using conventional, Fourier-series scheme as it would require increasing the RAM memory by at least 2 orders of magnitude.


3-deazaneplanocin A, a histone methyltransferase inhibitor, improved the chemoresistance induced under hypoxia in melanoma cells.
One of common characteristics of solid tumors is low O2 level, so-called hypoxia, which plays a critical role in chemoresistance. Epigenetic mechanism such as DNA methylation and histone modification is involved in cancer development and progression. There is ample evidence that epigenetic drugs reversed acquired chemoresistance in cancer cells under normal O2 level, normoxia. However, it remains unknown whether epigenetic drugs improve acquired chemoresistance under hypoxia. The aim of our study was to investigate whether epigenetic drugs can improve the chemoresistance induced under hypoxia in cancer cells. In murine melanoma B16-BL6 (B16) cells, the culture under hypoxia, 1%O2 caused the elevated expression of hypoxia-inducible factor-1α (HIF-1α) and its target genes. The chemoresistance to 7-ethyl-10-hydroxycamptothecin (SN-38, the active metabolite of irinotecan) was also acquired under hypoxia in B16 cells. In addition, as epigenetic mechanisms, the protein expression of the enhancer of zeste homolog 2 (EZH2), histone methyltransferase and its target histone H3 trimethylation at lysine 27 (H3K27Me3) level increased under hypoxia. The induction of H3K27Me3 under hypoxia was suppressed by EZH2 siRNA and 3-deazaneplanocin A (DZNep), an EZH2 inhibitor. Furthermore, both EZH2 siRNA and DZNep significantly reduced the cell viability after SN-38 treatment and improved the chemoresistance to SN-38 under hypoxia. These results indicated that the chemoresistance to SN-38 under hypoxia would arise from epigenetic mechanism, H3K27Me3 elevation due to EZH2 induction. In conclusion, a histone methyltransferase EZH2 inhibitor, DZNep was capable of tackling acquired chemoresistance via the suppression of histone methylation induced under hypoxic tumor microenvironment.


Body mass index as independent predictor of overall survival in patients with advanced renal cell carcinoma at start of systemic treatment-Analyses from the German clinical RCC-Registry.
A high body mass index (BMI) is associated with an increased risk for developing renal cell carcinoma (RCC), a higher complication rate after surgery, and a postoperative decline in renal function after nephrectomy. In contrast, a high preoperative BMI has been associated with increased survival in patients with localized RCC. We examined the prognostic impact of the BMI in patients treated for metastatic RCC (mRCC) in daily routine practice in Germany. The ongoing prospective, multicenter German clinical cohort study on mRCC (RCC-Registry) has recruited patients from more than 110 oncology/urology outpatient centers and hospitals at initiation of systemic first-line treatment. Data on patients' demographics, treatment, and outcome in routine practice, so called "real world data", have been collected. For this analysis, 606 patients were stratified into a low (BMI < 24), medium (24 < BMI < 28), and high (BMI > 28) BMI group. The influence of the BMI on the overall survival (OS) was analyzed using a multivariate Cox proportional hazards model. Median OS was 24.5 (95% confidence interval [CI], 19.3-28.5), 17.9 (95% CI, 15.3-20.8) and 10.9 (95% CI, 7.3-13.4) months in the high, medium, and low BMI patient group, respectively. A significant correlation of BMI with OS, independent of other factors, was found (low vs. high BMI: hazard ratio (HR): 1.94, 95% CI, 1.48-2.54; medium vs. high BMI: HR: 1.40, 95% CI, 1.10-1.78). Memorial Sloan Kettering Cancer Center risk factors were independently correlated with shorter OS. Our analysis showed a significant and independent correlation of a high BMI with longer OS in a prospective German cohort of mRCC routine patients starting first-line systemic treatment.


An active fixation quadripolar left ventricular lead for cardiac resynchronization therapy with reduced postoperative complication rates.
The rate of left ventricular (LV) lead displacement after cardiac resynchronization therapy (CRT) remains high despite improvements in lead technology. In 2017, a novel quadripolar lead with active fixation technology became available in the UK. This was a retrospective, observational study analyzing device complications in 476 consecutive patients undergoing successful first-time implantation of a CRT device at a tertiary center from 2017 to 2020. Both active (n = 135) and passive fixation (n = 341) quadripolar leads had similar success rates for implantation (99.3% vs. 98.8%, p = 1.00), although the pacing threshold (0.89 [0.60-1.25] vs. 1.00 [0.70-1.60] V, p = .01) and lead impedance (632 [552-794] vs. 730 [636-862] Ohms, p < .0001) were significantly lower for the active fixation lead. Patients receiving an active fixation lead had a reduced incidence of lead displacement at 6 months (0.74% vs. 4.69%, p = .036). There was no significant difference in the rate of right atrial (RA) and right ventricular (RV) lead displacement between the two groups (RA: 1.48% vs. 1.17%, p = .68; RV: 2.22% vs. 1.76%, p = .72). Reprogramming the LV lead after displacement was unsuccessful in most cases (successful reprogramming: Active fix = 0/1, Passive fix = 1/16) therefore nearly all patients required a repeat procedure. As a result, the rate of intervention within 6 months for lead displacement was significantly lower when patients were implanted with the active fixation lead (0.74% vs. 4.40%, p = .049). The novel active fixation lead in our study has a lower incidence of lead displacement and re-intervention compared to conventional quadripolar leads for CRT.


Arsenate (As V) in water: quantitative sensitivity relationships among biomarker, ecotoxicity and genotoxicity endpoints.
It is useful to test ecotoxicity and genotoxicity endpoints in the environmental impact assessment. Here, we compare and discuss ecotoxicity and genotoxicity effects in organisms in response to exposure to arsenate (As V) in solution. Eco(geno)toxicity responses in Aliivibrio fischeri, Lytechinus variegatus, Daphnia magna, Skeletonema costatum and Vicia faba were analyzed by assessing different endpoints: biomass growth, peroxidase activity, mitotic index, micronucleus frequency, and lethality in accordance with the international protocols. Quantitative sensitivity relationships (QSR) between these endpoints were established in order to rank endpoint sensitivity. The results for the QSR values based on the lowest observed effect concentration (LOEC) ratios varied from 2 (for ratio of root peroxidase activity to leaf peroxidase activity) to 2286 (for ratio of higher plant biomass growth to root peroxidase activity). The QSR values allowed the following sensitivity ranking to be established: higher plant enzymatic activity>daphnids≈echinoderms>bacteria≈algae>higher plant biomass growth. The LOEC values for the mitotic index and micronucleus frequency (LOEC=0.25mgAsL(-1)) were similar to the lowest LOEC values observed in aquatic organisms. This approach to the QSR of different endpoints could form the basis for monitoring and predicting early effects of pollutants before they give rise to significant changes in natural community structures.


Bridging annuloplasty for left atrioventricular valve of partial atrioventricular septal defect.
Residual left atrioventricular valve regurgitation after conventional repair technique for partial atrioventricular septal defect most commonly occurs in the central position. We describe here the technique for bridging annuloplasty on the opposing anterior and posterior annuli of the atrioventricular valve in selected patients with short leaflets.


Angiogenesis in normal tissue adjacent to colon cancer.
Angiogenesis in malignant neoplasms, as measured by microvessel density, has been shown to correlate with survival or stage in some studies of breast, gastric, and colorectal cancer. We hypothesized that aggressive cancers promote angiogenesis in normal tissue adjacent to the invading neoplasm. To test this hypothesis, 36 specimens of colon adenocarcinoma curatively resected between 1986 and 1990 were sectioned and stained for factor VIII-related antigen, vascular endothelial growth factor (VEGF), and interleukin-8 (IL-8). Microvessel density was measured within the colon cancer and in adjacent, histologically normal tissue. Clinical/pathological variables were examined using multivariate analysis and Student t-test. Microvessel density was higher in the neoplasms (26.0+/-1.66/ 0.25 mm2) than in the surrounding normal tissue (22.3+/-1.88/0.25 mm2) (P=0.03). The difference was primarily due to smaller neoplasms (T1 and T2) which had vessel counts of 10.6+/-0.74/0.25 mm2 in the adjacent normal tissue compared to vessel counts of 18.9+/-3.02/0.25 mm2 within these tumors (P=0.02). T3 and T4 neoplasms had equivalent amounts of angiogenesis within the lesion (26.9+/-1.81/0.25 mm2) and in the histologically normal margin (24.2+/-1.98/0.25 mm2) (P=0.12). VEGF was present in the tumor microenvironment in 100% and IL-8 in 45% of specimens stained for these angiogenic cytokines. Microvessel density did not correlate with 5-year survival. Our data suggest that colon cancers that invade through the muscularis propria may have a greater ability to induce angiogenesis in adjacent normal tissue.


Spontaneous formation of tumorigenic hybrids between breast cancer and multipotent stromal cells is a source of tumor heterogeneity.
Breast cancer progression involves cancer cell heterogeneity, with generation of invasive/metastatic breast cancer cells within populations of nonmetastatic cells of the primary tumor. Sequential genetic mutations, epithelial-to-mesenchymal transition, interaction with local stroma, and formation of hybrids between cancer cells and normal bone marrow-derived cells have been advocated as tumor progression mechanisms. We report herein the spontaneous in vitro formation of heterotypic hybrids between human bone marrow-derived multipotent stromal cells (MSCs) and two different breast carcinoma cell lines, MDA-MB-231 (MDA) and MA11. Hybrids showed predominantly mesenchymal morphological characteristics, mixed gene expression profiles, and increased DNA ploidy. Both MA11 and MDA hybrids were tumorigenic in immunodeficient mice, and some MDA hybrids had an increased metastatic capacity. Both in culture and as xenografts, hybrids underwent DNA ploidy reduction and morphological reversal to breast carcinoma-like morphological characteristics, while maintaining a mixed breast cancer-mesenchymal expression profile. Analysis of coding single-nucleotide polymorphisms by RNA sequencing revealed genetic contributions from both parental partners to hybrid tumors and metastasis. Because MSCs migrate and localize to breast carcinoma, our findings indicate that formation of MSC-breast cancer cell hybrids is a potential mechanism of the generation of invasive/metastatic breast cancer cells. Our findings reconcile the fusion theory of cancer progression with the common observation that breast cancer metastases are generally aneuploid, but not tetraploid, and are histopathologically similar to the primary neoplasm.


Success Rate of Transcranial Doppler Scanning of Cerebral Arteries at Different Transtemporal Windows in Healthy Elderly Individuals.
This study measured the rates of success in applying transcranial Doppler (TCD) scanning at the middle, posterior and anterior temporal windows (MTW, PTW and ATW) in the elderly. A hand-held 1.6-MHz pulsed-wave TCD transducer was used to search for cerebral arteries at MTW, PTW and ATW locations. Physical attributes of the head, including head circumference and the distance between tragi on both sides ("tragus-to-tragus arc length"), were also measured to explore the associations with successful rates. Among 396 healthy elderly participants (aged 62.6 ± 6.0 y, 140 men), 81.1% (n = 321; 127 men) had one or more temporal windows penetrable by TCD ultrasound (n = 286 [72.2%] at MTW, n = 195 [49.2%] at PTW and n = 106 [26.8%] at ATW). Regression analysis revealed that successful scanning increased significantly in male participants at three window locations. Younger age significantly increased successful scanning at the MTW and ATW. Smaller tragus-to-tragus arc length increased successful scanning at the MTW, but unsuccessful scanning at the ATW. Our findings support using MTW as the first location when positioning the TCD transducer for the scanning of cerebral arteries in the elderly population. When performing TCD scanning on two temporal windows, we propose choosing the MTW and PTW.


Binding to nucleophosmin determines the localization of human and chicken ARF but not its impact on p53.
The ARF tumour suppressor gene encodes a small highly basic protein whose known functions are largely determined by the amino acids encoded within the first exon. In mammals, the protein incorporates additional residues specified by an alternative reading frame in the second exon of INK4a, but this arrangement does not apply to the chicken homologue. In exploring the intracellular localization of chicken p7(ARF), we found that while the FLAG- and HA-tagged versions localize in the nucleolus, in line with mammalian ARF, the GFP-tagged version is excluded from the nucleolus. Here we show that irrespective of the source or composition of the ARF fusion proteins, versions that accumulate in the nucleolus share the ability to bind to nucleophosmin (NPM). Depletion of NPM with siRNA results in the re-location and destabilization of nucleolar forms of ARF but has little effect on the location or stability of a nucleoplasmic form of ARF. Importantly, knockdown of endogenous NPM does not impair the ability of ARF to bind to MDM2 and stabilize p53. These findings support the view that nucleolar localization determines the stability of ARF but not its primary function.


Autonomic correlates of defense responses, including tonic immobility (TI).
Animal models of autonomic correlates of defense behavior range from fish to mammals. There is however no study reporting heart and respiratory rate, blood pressure and body temperature simultaneously recorded in the same animal in association to different forms of immobility in response to threat: freezing, restraint-sustained immobility and tonic immobility (TI). In a prey/ predator context freezing behavior is associated with bradycardia and no change in blood pressure but in other conditions (e.g., extreme stressful stimuli) may be associated with tachycardia and hypertension. Restraint-sustained immobility does not affect blood pressure but may reduce heart rate according to the type of stimulus and mechanical pressure. Blood pressure and heart rate oscillate during TI induction and adjust at basal levels during TI, sometimes gradually decreasing below basal levels. In conclusion, in all these passive defense responses, the immobility is not due to a blood pressure collapse.


Blood parameters as indicators of upper airway obstruction in children with adenoid or adenotonsillar hypertrophy.
Adenotonsillar hypertrophy (ATH) is the most common cause of obstructive sleep apnea in children. This study aimed to evaluate the blood parameters of children with ATH who underwent surgery. The study included a review of the medical records of 130 children who underwent adenoidectomy or adenotonsillectomy with a diagnosis of adenoid hypertrophy and/or chronic tonsillitis. Patients were classified into 3 groups: group 1 (n=69) underwent adenoidectomy, group 2 (n=61) underwent adenotonsillectomy, and group 3 consisted of 82 healthy children. White blood cell count, platelet count, hemoglobin levels, mean platelet volume, and platelet distribution width values were the primary outcome measures. Mean platelet volume, platelet distribution width and hemoglobin values decreased in the groups that underwent surgery. Whereas the decrease in group 1 was insignificant, it was significant in group 2. White blood cell count values increased in both group 1 (adenoidectomy) and group 2 (adenotonsillectomy), but the increase in group 2 was significant. No significant difference in platelet count was detected before versus after the operation. Upper airway obstruction caused by ATH remarkably changes the blood parameters related to chronic hypoxia. Significant improvement can be achieved after adenotonsillectomy rather than adenoidectomy alone.


An attempt to separate xiphopagus twins sharing a common heart, liver, and duodenum.
An attempt was made to separate 7-wk-old conjoined twins. It proved unsuccessful because of extensive cardiac malformations in the shared heart. Details of operation and postmortem findings are described.