Secondary analysis of Radiation Therapy Oncology Group study (RTOG) 9310: an intergroup phase II combined modality treatment of primary central nervous system lymphoma.
To determine whether a lower dose of hyperfractionated whole brain radiation reduces central nervous system morbidity without compromising survival for primary CNS lymphoma (PCNSL) patients receiving combined modality treatment. One hundred and two patients received a course of pre-radiation chemotherapy, followed by whole brain radiation, followed by cytosine-arabinoside. Initial radiation dose was 45 Gy/25 fractions (RT) then the study was amended to reduce this dose for complete responders to induction chemotherapy to 36 Gy/30 fractions/3 weeks (HFX). Eighty-two patients received radiotherapy and were evaluable for toxicity analysis (66 RT patients and 16 HFX patients). MMSE scores and survival for the 40 patients who received radiotherapy after complete response to chemotherapy (27 RT and 13 HFX) were compared. There were no notable differences in pre-treatment patient characteristics between the RT and HFX groups. Neurotoxicity: By 4 years, there were 8/82 (10%) grade 5 neurotoxicities which included 2/16 (13%) grade 5 encephalopathies and 0/27 in the RT group of complete responders to chemotherapy. Survival: There was no statistically significant difference in overall or progression-free survival (PFS) between the chemotherapy-complete responders who received RT and HFX. Cognitive function testing: MMSE scores improved at 8 months across both treatment groups. Analysis of the area under the MMSE curve at 8 months showed no statistically significant difference between RT and HFX groups (P=0.81). Leukoencephalopathy occurred later in the HFX group than in the RT patients. Although the HFX schedule represented a 25% reduction in biologically effective tumor dose in comparison, PFS and overall survival were not significantly affected. The HFX regimen delayed but did not eliminate severe neurotoxicity from chemoradiation in PCNSL patients.


Genetic analysis of chromatin remodeling using budding yeast as a model.
Novel discoveries result from genetic analyses of transcription and chromatin remodeling because these methods identify activities in an unbiased manner. By describing our genetic approaches to identify regulators of PHO5 transcription and chromatin remodeling, we hope to encourage others to apply similar strategies to their genes of interest.


The presence of oleate stabilized ZnO nanoparticles (NPs) and reduced the toxicity of aged NPs to Caco-2 and HepG2 cells.
The presence of food components may alter the colloidal aspects and toxicity of nanoparticles (NPs). In this study, the toxicity of ZnO NPs to Caco-2 and HepG2 cells was assessed, with the emphasis on the interactions between ZnO NPs and oleate (OA). The presence of OA increased UV-Vis spectra and hydrodynamic sizes, decreased Zeta potential, and markedly reduced the release of Zn ions from the dissolution of ZnO NPs, which combined indicated that OA could coat ZnO NPs and stabilize ZnO NPs. Exposure to ZnO NPs significantly induced cytotoxicity to Caco-2 and HepG2 cells, associated with increased intracellular Zn ions but not superoxide. When OA was added to the freshly prepared ZnO NP suspensions, the cytotoxicity, intracellular Zn ions and superoxide induced by ZnO NPs were not significantly affected. However, when ZnO NPs were aged for 24 h with the presence of OA, the cytotoxicity of ZnO NPs to Caco-2 and HepG2 cells was significantly reduced, associated with a reduction of intracellular Zn ions. The results from this study suggested that the presence of OA could increase colloidal stability of ZnO NPs and consequently reduce the toxicity of ZnO NPs after aging associated with reduced accumulation of intracellular Zn ions.


Long-term outcome after treatment of pulmonary atresia with ventricular septal defect: nationwide study of 109 patients born in 1970-2007.
Treatment of pulmonary atresia with ventricular septal defect (PA + VSD) has evolved during recent decades, but it still remains challenging. This study evaluated 41-year experience of outcome, survival and treatment of PA + VSD patients. Patient records and angiograms of 109 patients with PA + VSD born in Finland between 1970 and 2007, and treated at the Children's Hospital, Helsinki University Central Hospital, were retrospectively analysed in this nationwide study. Of the 109 patients, 66 (61%) had simple PA + VSD without major aortopulmonary collateral arteries (MAPCAs). Although we observed no difference in overall survival between those with or without MAPCAs, the patients without MAPCAs had better probability to achieve repair (64 vs 28%, P < 0.0003). Only 3 patients were treated by compassionate care. Overall survival was affected by the size of true central pulmonary arteries on the first angiogram (P = 0.001) and whether repair was achieved (P < 0.0001). After successful repair, the survival rate was 93% at 1 year, 91% from the second year, and functional capacity as assessed by New York Heart Association (NYHA) I-II remained in 85% of patients alive at the end of follow-up. Palliated patients at 1, 5, 10 and 20 years of age had Kaplan-Meier estimated survival rates of 55, 42, 34 and 20%, respectively. Patients who underwent repair attempts but were left palliated with right ventricle (RV)-pulmonary artery connection and septal fenestration had better survival than the rest of the palliated patients (P = 0.001). Further, the McGoon index improved after implementation of a systemic-pulmonary artery shunt in the overall PA + VSD population (P < 0.0001). These findings show that achievement of repair and initial size of true central pulmonary arteries affect survival of patients with PA + VSD. Although the overall survival of patients with MAPCAs showed no difference compared with simple PA + VSD patients, they had a higher risk of remaining palliated. However, palliative surgery may have a role in treatment of PA + VSD because the size of pulmonary arteries increased after placement of systemic-pulmonary artery shunt. In addition, subtotal repair by a RV-pulmonary artery connection and septal fenestration improved survival over extracardiac palliation.


Syndemic conditions and quality of life in the PISCIS Cohort of people living with HIV in Catalonia and the Balearic Islands: a cross sectional study.
People living with HIV (PLWH) face structural and psychosocial factors that affect health-related quality of life (HRQoL). We aimed to evaluate how syndemic conditions affected HRQoL in PLWH. A cross-sectional survey was conducted among 861 PLWH, to determine whether syndemic conditions (monthly income; sexual satisfaction; depressive symptoms; social role satisfaction; social isolation; cognitive function; nicotine dependence; perception of stigma) have an effect on HRQoL. A linear regression model and measures of Additive Interaction (AI) were used to determine the effects of syndemic conditions on HRQoL, controlling for other risk factors. Overall, the most frequently observed were stigma perception (56.9%), poor cognitive function (50.6%) and the perception of social isolation (51.6%). The presence of depressive symptoms was the risk factor most associated with worse Physical Health (PH) (B 3.93, 2.71-5.15) and Mental Health (MH) (B 5.08, 3.81-6.34) in linear regression model. Specifically, an interaction was observed between poor cognitive function and poor satisfaction with social role on worse PH and MH (AI 2.08, 0.14-4.02; AI 2.69, 0.15-5.22, respectively); and low income and perception of stigma (AI 2.98, 0.26-5.71), low income and perception of social isolation (AI 2.79, 0.27-5.32), and low income and poor satisfaction with social role (AI 3.45, 0.99-5.91) on MH. These findings provide evidence that syndemic factors impact HRQoL. HIV prevention programs should screen and address co-occurring health problems to improve patient-centered health care and outcomes.


Propofol Anesthesia Increases Long-range Frontoparietal Corticocortical Interaction in the Oculomotor Circuit in Macaque Monkeys.
A decrease in frontoparietal functional connectivity has been demonstrated with multiple anesthetic agents, and this decrease has been proposed as a final common functional pathway to produce anesthesia.Two alternative measures of long-range cortical interaction are coherence and phase-amplitude coupling. Although phase-amplitude coupling within frontal cortex changes with propofol administration, the effects of propofol on phase-amplitude coupling between different cortical areas have not previously been reported. Using a previously published monkey electrocorticography data set, it was found that propofol induced coherent slow oscillations in visual and oculomotor networks made up of cortical areas with strong anatomic projections.Frontal eye field within-area phase-amplitude coupling increased.Contrary to expectations from previous functional connectivity studies, interareal phase-amplitude coupling also increased with propofol. Frontoparietal functional connectivity decreases with multiple anesthetics using electrophysiology and functional imaging. This decrease has been proposed as a final common functional pathway to produce anesthesia. Two alternative measures of long-range cortical interaction are coherence and phase-amplitude coupling. Although phase-amplitude coupling within frontal cortex changes with propofol administration, the effects of propofol on phase-amplitude coupling between different cortical areas have not previously been reported. Based on phase-amplitude coupling observed within frontal lobe during the anesthetized period, it was hypothesized that between-lead phase-amplitude coupling analysis should decrease between frontal and parietal leads during propofol anesthesia. A published monkey electrocorticography data set (N = 2 animals) was used to test for interactions in the cortical oculomotor circuit, which is robustly interconnected in primates, and in the visual system during propofol anesthesia using coherence and interarea phase-amplitude coupling. Propofol induces coherent slow oscillations in visual and oculomotor networks made up of cortical areas with strong anatomic projections. Frontal eye field within-area phase-amplitude coupling increases with a time course consistent with a bolus response to intravenous propofol (modulation index increase of 12.6-fold). Contrary to the hypothesis, interareal phase-amplitude coupling also increases with propofol, with the largest increase in phase-amplitude coupling in frontal eye field low-frequency phase modulating lateral intraparietal area β-power (27-fold increase) and visual area 2 low-frequency phase altering visual area 1 β-power (19-fold increase). Propofol anesthesia induces coherent oscillations and increases certain frontoparietal interactions in oculomotor cortices. Frontal eye field and lateral intraparietal area show increased coherence and phase-amplitude coupling. Visual areas 2 and 1, which have similar anatomic projection patterns, show similar increases in phase-amplitude coupling, suggesting higher order feedback increases in influence during propofol anesthesia relative to wakefulness. This suggests that functional connectivity between frontal and parietal areas is not uniformly decreased by anesthetics.


Enhancer-origin interaction in plasmid R6K involves a DNA loop mediated by initiator protein.
Initiation of DNA replication from ori beta of plasmid R6K requires the presence of the ori gamma sequence in cis. We demonstrate that binding of initiator protein to the seven strong, tandem binding sites in gamma increases binding of the protein at the very weak binding site present in ori beta by cooperativity at a distance. The gamma-beta interaction via the initiator results in a DNA loop, as revealed by the novel technique of cyclization enhancement and as confirmed by exonuclease III protection, electron microscopy, and chemical footprinting. The protein-mediated gamma-beta interaction in vitro suggests that the cooperative interaction of gamma-bound protein with the beta sequence by DNA looping is an early step in the initiation of DNA replication at the beta origin of R6K.


The effect of the community midwifery model on maternal and newborn health service utilization and outcomes in Busia County of Kenya: a quasi-experimental study.
Poor women in hard-to-reach areas are least likely to receive healthcare and thus carry the burden of maternal and perinatal mortality from complications of childbirth. This study evaluated the effect of an enhanced community midwifery model on skilled attendance during pregnancy/childbirth as well as on maternal and perinatal outcomes against the backdrop of protracted healthcare workers' strikes in rural Kenya. The study used a quasi-experimental (one-group pretest-posttest) design. The study spanned three time periods: December 2016-February 2017 when doctors were on strike (P1), March-May 2017 when no healthcare providers were on strike (P2), and June-October 2017 when nurses/midwives were on strike (P3), which was also the period when the project enhanced the capacity of community midwives (CMs) to provide services at the community level. Analysis entailed comparison of frequencies/means of maternal and newborn health service utilization data across the three periods. The monthly average number of clients obtaining services from CMs across the three time periods was: first antenatal care (ANC) (P1-1.8, P2-2.3, P3-9.9), fourth ANC (P1-1.4, P2-1.0, P3-7.1), skilled birth (P1-1.5, P2-1.7, P3-13.1) and the differences in means were statistically significant (p < 0.05). Over the period, the monthly average number of clients obtaining services from health facilities was: first ANC (P1-55.7, P2-70.8, P3-4.0), fourth ANC (P1-29.6, P2-38.1, P3-1.2) and skilled birth (P1-63.1, P2-87.4, P3-5.6), p < 0.05. There were no statistically significant differences in the average number of clients obtaining services from CMs or health facilities between P1 and P2 (p > 0.05). There was, however, a statistically significant increase in the average number of clients obtaining services from CMs in P3 accompanied by a statistically significant decline in the average number of clients obtaining services from health facilities (p < 0.05). First ANC increased by 68%, fourth ANC by 75%, skilled births by 68%, and postnatal care by 33% in P3 (p < 0.0001). There was a non-significant decline in macerated stillbirths and neonatal deaths in P3. The findings underscore the importance of integrating community-level health service providers (CMs and health volunteers) into the primary health care system to complement service delivery according to their level of expertise, especially in low-resource settings.


Ca2+ entry in CHO cells, after Ca2+ stores depletion, is mediated by arachidonic acid.
Transfected Chinese hamster ovary cells expressing the rat neurotensin receptor (CHO-NTR cells) were used to study the 'Ca2+ stores depletion-Ca2+ entry' coupling which follows stimulation with neurotensin and liberation of inositol 1,4,5-trisphosphate. This coupling could be dissociated in time: the stores were emptied by stimulation with neurotensin in the absence of extracellular Ca2+; thereafter, readmission of extracellular Ca2+ produced a transient entry of Ca2+ that was progressively restored in the endoplasmic reticulum. We showed previously that the rise of [Ca2+]i during Ca2+ stores depletion controls the subsequent entry of Ca2+ and that unknown protein kinases and phosphatases may also be involved in this coupling. Here we show that: 1. W-7 (25 microM), KN-62 (10 microM) and a myristoylated autocamtide-2 related inhibitory peptide (20 microM), three inhibitors of the calcium-calmodulin-dependent protein kinase II (CaM kinase II) inhibit the entry of Ca2+ induced by emptying the stores of Ca2+ with neurotensin and thapsigargin. 2. Ca2+ stores depletion-Ca2+ entry coupling is also greatly diminished by 10 microM ONO-RS-082, an inhibitor of the phospholipase A2 (PLA2). 3. Arachidonic acid (5-100 microM) produces an entry of Ca2+; the same result is obtained by use of 5, 8, 11, 14-eicosatetraynoic acid, a non-metabolizable analog of arachidonic acid. 4. NTR-CHO cells are labeled with [3H] arachidonic acid for 24 h (progressively incorporated in membrane phospholipids). Upon neurotensin (1 nM) and thapsigargin (1 microM) stimulation, these cells produce a release of arachidonic acid which lasts for as long as the stores are empty and stops when they are reloaded with Ca2+. This production of arachidonic acid is significantly diminished by suppressing the [Ca2+]i transient during stores depletion (with cell permeant EGTA), by the PLA2 inhibitor ONO-RS-082 (10 microM) and by the CaM kinase II inhibitor KN-62 (10 microM). 5. The rise of [Ca2+]i by itself (induced by flash photolysis of nitrophenyl-EGTA), i.e. without depletion of the stores, is not sufficient to trigger an entry of Ca2+. 6. The reloading process of Ca2+ into the endoplasmic reticulum is inhibited by 10 microM chelerythrine, 100 nM GF 109203X, two inhibitors of protein kinases C (PKC) or by their downregulation by a prolonged treatment of the cells with 1 microM phorbol-12, 13-dibutyrate. We therefore suggest the involvement of CaM kinase II and PLA2 in the 'Ca2+ stores depletion-Ca2+ entry' coupling in these transfected CHO cells.


Tobramycin Serum Concentrations After Aerosol and Oral Administration in Cystic Fibrosis.
We sought to describe tobramycin absorption after aerosol administration to cystic fibrosis (CF) subjects. Serum tobramycin concentrations were determined by modification of the radioimmuno-assay (RIA) technique, lowering the limit of detection from 1.0 &mgr;g ml(minus sign1) to 0.05 &mgr;g ml(minus sign1). In 37 studies, after aerosol delivery of 666 plus minus 195 mg to the airway of 24 patients, in which 222 samples were assayed, only 1 serum sample contained tobramycin at a concentration greater than 1.0 &mgr;g ml(minus sign1). Twenty-six of the 37 studies permitted estimation of pharmacokinetic parameters of tobramycin. The serum clearance of tobramycin following aerosol adminstration is 39.13 plus minus 0.393 L h(minus sign1) (mean plus minus standard error of the mean), with an elimination half-life of 3.072 plus minus 0.194 h. The half-life was significantly longer than that found after intravenous adminstration. The elimination rate constant (K(e)) was calculated to be 0.234 plus minus 0.002 h(minus sign1). Estimated total-body clearance in which systemic absorption was determined from sputum and urinary recovery of tobramycin was 0.094 plus minus 0.002 1 hr(minus sign1) kg(minus sign1). We also studied tobramycin absorption in six CF subjects after ingestion of a 80-mg m(minus sign2) dose, to gain insight into the tobramycin levels observed after swallowing an aerosol. Four out of the six subjects had measurable serum tobramycin concentration after ingestion. The serum concentration-time curve mirrored what was seen after aerosol administration. We concluded that tobramycin has poor systemic absorption in CF subjects after aerosol administration. Tobramycin in serum after aerosol administration is in part due to the gastrointestinal absorption of swallowed drug, as well as absorption from lower respiratory tract.


Effect of bone sialoprotein and collagen coating on cell attachment to TICER and pure titanium implant surfaces.
To improve integration between implants and biological tissues, this study compared bone sialoprotein (BSP) as a surface-coating material against the major organic and inorganic components of bone, collagen type I and hydroxyapatite (TICER). The expression of osteocalcin, osteonectin and transforming growth factor ss was evaluated using immunohistochemical staining procedures. The distribution patterns of osteoblasts on the surface of pure titanium with a smooth machined surface and a rough surface (TICER) were determined by image processing using confocal laser scanning microscopy. The results compared to uncoated control materials showed that, at all times investigated, the number of cells on the surface of the TICER and pure titanium samples differed significantly (P<0.1), demonstrating the superiority of TICER over pure titanium in this respect. For pure titanium implants, collagen-precoated surfaces were not beneficial for the attachment of bone-derived cells with the exception of day 3 in vitro (P<0.01). BSP-precoated implant surfaces displayed non-significantly higher numbers of settled cells. BSP-precoated implant surfaces were beneficial for osteoinduction as revealed by osteocalcin and osteonectin expression. BSP precoating of the rough TICER implant surface enhanced the osteoinductive effect much more than did collagen precoating. These results contribute to the consideration of at least two distinct pathways of osseointegration.


Transition of Femtosecond-Filament-Solid Interactions from Single to Multiple Filament Regime.
High-peak-power fs-laser filaments offer unique characteristics attractive to remote sensing via techniques such as remote laser-induced breakdown spectroscopy (R-LIBS). The dynamics of several ablation mechanisms following the interaction between a filament and a solid determines the emission strength and reproducibility of target plasma, which is of relevance for R-LIBS applications. We investigate the space- and time-resolved dynamics of ionic and atomic emission from copper as well as the surrounding atmosphere in order to understand limitations of fs-filament-ablation for standoff energy delivery. Furthermore, we probe the shock front produced from filament-target interaction using time-resolved shadowgraphy and infer laser-material coupling efficiencies for both single and multiple filament regimes through analysis of shock expansion with the Sedov model for point detonation. The results provide insight into plasma structure for the range of peak powers up to 30 times the critical power for filamentation P cr . Despite the stochastic nucleation of multiple filaments at peak-powers greater than 16 P cr , emission of ionic and neutral species increases with pump beam intensity, and short-lived nitrogen emission originating from the ambient is consistently observed. Ultimately, results suggest favorable scaling of emission intensity from target species on the laser pump energy, furthering the prospects for use of filament-solid interactions for remote sensing.


Schema therapy for patients with borderline personality disorder and comorbid alcohol dependence: A multiple-baseline case series design study.
This study tested the effectiveness of schema therapy (ST) for borderline personality disorder (BPD) and comorbid alcohol dependence (AD). Twenty patients participated in a case series study with multiple baselines. The baseline phase consisted of treatment as usual. It was followed by a case conceptualization phase, an experiential techniques phase and a behavioural change phase. Patients showed a significant decrease in BPD and AD symptoms; change was mainly accomplished in the experiential techniques phase, with medium to large effect sizes. Three months after termination of therapy, 68% of the patients had remitted from BPD, and the number of drinking days decreased clearly. This study shows that, although treatment is challenging in this group of patients, meaningful change can be obtained in patients with BPD and AD using ST.


Examining the upper urinary tract in patients with hematuria-time to revise the CT urography protocol?
Three-phase CT urography (CTU) is the gold standard for evaluating the upper urinary tract in patients with hematuria. We aimed to evaluate the accuracy of CTU for detecting upper urothelial cell carcinomas (UCC) in patients with hematuria and negative cystoscopy. Secondly, we aimed to determine the tumor visibility on each CTU phase. This retrospective study included all patients with hematuria referred to CTU after a negative cystoscopy during 2016 and 2017. The original CTU reports were dichotomized as negative or positive. All patient charts were reviewed after a minimum of 18-month follow-up in order to register missed cancers. The results of biopsies and clinical follow-up were used as the reference standard. Two reviewers retrospectively evaluated the tumor visibility of each CT sequence in all true-positive CTUs. We included 376 patients with hematuria who underwent CTU after a negative cystoscopy. Macroscopic and microscopic hematuria occurred in 87% (327) and 13% (49), respectively. The incidence of upper urothelial cell carcinoma was 1.9% (7), and the sensitivity of CTU was 100% (95% CI, 59-100), specificity was 99% (95% CI, 98-100), positive predictive value was 88% (95% CI, 47-99), and negative predictive value was 100% (95% CI, 99-100). The accuracy was 99% (95% CI, 90-100). All UCCs were visible on the nephrographic phase for both reviewers. CTU is highly accurate for detecting upper UCCs. All cases were seen on the nephrographic phase. This suggests that the CTU protocol can be simplified. • CT urography is highly accurate for detecting upper urothelial cell carcinomas. • All cancers were seen on the nephrographic phase. • All cancers were detected in patients with macroscopic hematuria.


Prediction of the antidepressant response to total sleep deprivation of depressed patients: longitudinal versus single day assessment of diurnal mood variation.
The relationship between diurnal variation of mood and the clinical response to total sleep deprivation (TSD) was investigated in 43 depressed patients. The question asked was whether the propensity to produce diurnal variations of mood or the actual mood course on the day before TSD determines the clinical response to TSD. Patients rated their mood three times daily during an experimental period of 56 days. The frequency as well as the amplitude of daily mood changes were assessed during this period. For each patient six TSDs were scheduled: two after days with a positive mood course, two after a negative mood course, and two after days without a diurnal change of mood. This strategy allowed comparisons of TSD responses within patients. Moreover, longitudinally and retrospectively assessed diurnal variation were compared with each other. It was found that patients vary largely in the occurrence of diurnal variations of mood. The propensity to produce diurnal variations either in terms of frequency or amplitude was positively correlated with the response to TSD. Within patients no differences were found in responses to TSDs applied after days with diurnal variations (positive or negative) or without diurnal variations. A second aim was to get more insight into the mechanism relating diurnal variations of mood and the TSD response. Therefore, the interrelatedness of various measures of diurnal variations, such as amplitudes and frequencies of positive or negative diurnal mood changes, was studied, as well as the relationships of these variables with TSD responses. On the basis of the strong interrelatedness it is suggested that they all reflect the same underlying mechanism, to be symbolized by an oscillator, producing positive daily fluctuations of mood.


The effect of age at surgery and compensatory articulation on speech outcome in submucous cleft palate patients treated with double-opposing Z-plasty: A 10-year experience.
Submucous cleft palate is a congenital deformity that may present as velopharyngeal insufficiency. The degree of anatomical abnormality varies widely among patients and does not predict severity of symptom. We present our 10-year experience treating submucous cleft palate patients with double opposing z-plasty and explore the effect of age at surgery and compensatory articulation on speech. Preoperative assessment included intraoral examination, nasoendoscopy, and perceptual speech evaluation. Age, gap size, and severity of hypernasality were assessed to determine the timing and type of surgery. A retrospective study of 74 submucous cleft palate patients undergoing double-opposing z-plasty from 2005 to 2016 by a single surgeon (Baek RM) was conducted. Double opposing z-plasty was modified to fully release all abnormal insertions of the levator veli palatini muscle. Postoperative velopharyngeal function was measured and statistical analyses were performed. The ages of patients at surgery ranged from 11 months to 19 years. Postoperatively 87 percent of the patients achieved velopharyngeal competency and 13 percent had remaining mild hypernasality. Age was a significant factor in predicting speech outcome, and patients receiving surgery prior to the age of 5.5 years had a higher normalization rate. Compensatory articulation did not have an impact on postoperative hypernasality. There were no cases of postoperative hyponasality or airway problems. Satisfactory speech outcome was achieved with the authors' protocol and modification of the double-opposing z-plasty. A comprehensive assessment of patient age, intraoral findings, severity of hypernasality, and gap size, is necessary for proper treatment of submucous cleft palate patients.


Practice models used by pharmacists in rural Minnesota to obtain Medicare reimbursement.
(1) Define "incident-to" rules for Medicare reimbursement; (2) Describe how pharmacists can meet incident-to rules; (3) Provide examples of models of practice in rural areas that could be useful for meeting incident-to rules; and (4) Develop a strategy for creating a pharmacy practice model that could meet Medicare reimbursement rules in rural areas. A survey of participants from the Pharmacy Rural Education, Practice and Policy Institute and the College of Pharmacy, University of Minnesota. Community, hospital, and clinic practice sites in rural Minnesota. Four distinct models of practice have evolved that meet the incident-to rules of Medicare for reimbursement. Travel, proximity to physicians, and employment are the major determinants of the models described. Pharmacists in rural areas have demonstrated the ability to satisfy the incident-to rules for Medicare reimbursement. Collaborative agreements with physicians must include specific employment, practice, and supervisory relationships in order to satisfy these rules.


Muscle fatigue in acute respiratory failure.
Fatigue of the respiratory muscles is now well documented but still remains a process that cannot be assessed easily. Several methods are available to detect fatigue; they represent windows allowing different viewpoints on the same phenomenon. The definition and determinants of respiratory muscle fatigue and some of the methods used to detect it are reviewed. On the basis of the available evidence provided by each of these methods, the role played by muscle fatigue in acute respiratory failure (ARF) is discussed.


Non-prescribed pharmaceutical stimulants use among adolescents: A way to self-care or peer success?
the use of pharmaceutical stimulants without a medical prescription (PSWMP) among adolescents is considered an established public health issue. The present study aimed to investigate the potential links between different patterns of non-medical use of pharmaceutical stimulants, psycho-social factors, and other risky behaviours (e.g. psychoactive substance use). For this purpose, data from a sample of 14,685 adolescents aged 15-19 participating in the ESPAD®Italia 2019 study were analysed by conducting descriptive analyses and multinomial logistic regressions. The findings highlight the key role of psycho-social factors and engagement in other risky behaviours in either reducing or promoting the risk of PSWMP use. Particularly, being satisfied with peer relationships and with oneself is significantly associated with lower use of PSWMP. Conversely, the consumption of other psychoactive substances (both legal and illegal) and engagement in other risky behaviours (e.g., gambling and cyberbullying) may increase this phenomenon. Considering their representativeness, the results of the present study could be used as groundwork for the development of effective and targeted prevention programs and interventions.


Heart Failure and Exercise: A Narrative Review of the Role of Self-Efficacy.
Chronic heart failure (CHF) is a common, debilitating condition associated with significant health and economic burden. CHF management is multidisciplinary, however, achieving better health relies on a collaborative effort and patient engagement in self-care. Despite the importance of self-care in CHF, many patients have poor adherence to their medical and lifestyle regimens, in particular with regards to engaging in physical exercise. The patient's confidence in their ability, otherwise known as self-efficacy, is an important determinant of CHF health outcomes, most likely due to its effect on the uptake of CHF self-care activities especially exercise initiation and maintenance. Self-efficacy is responsive to experience such as exercise training, however the critical components of exercise interventions to improve self-efficacy have yet to be determined. This narrative review provides an overview of the role of self-efficacy in exercise adherence in CHF.


Preparation and photocatalytic properties of Fe3+-doped Ag@TiO2 core-shell nanoparticles.
Ag@TiO2 core-shell-type nanophotocatalysts have been prepared using a simple and convenient method. The products were characterized by TEM, XRD, and UV-vis spectra. To make the catalysts achieve the highest photocatalytic activity under UV light illumination, the Ag content of Ag@TiO2 was optimized. The results showed that Ag@TiO2-doped Fe3+ extend their absorption into the visible region. Among the Fe3+-doped samples, Ag@Fe-TiO2 with low Ag content showed higher photocatalytic activity under visible light illumination. An excessive added amount of Ag would reduce Fe3+ to Fe2+ and make them difficult to be incorporated into the lattice of titania. From the experiments, we found that Fe3+ ions could stabilize the Ag@TiO2 colloid by holding back the aggregation of the core-shell nanoparticles.


Myocardial deformation after radiotherapy: a layer-specific and territorial longitudinal strain analysis in a cohort of left-sided breast cancer patients (BACCARAT study).
Radiotherapy for breast cancer (BC) and its resulting cardiac exposure are associated with subclinical left ventricular dysfunction characterized by early decrease of global longitudinal strain (LS) measurement based on 2D speckle-tracking echocardiography. Recent software allows multi-layer and segmental analysis of strain, which may be of interest to quantify and locate the impact of cardiac exposure on myocardial function and potentially increase the early detection of radiation-induced cardiotoxicity. The aim of the study was to evaluate whether decrease in LS 6 months after radiotherapy is layer-specific and if it varies according to the left ventricular regional level and the coronary arterial territories. LS was measured at baseline before radiotherapy and 6 months post-radiotherapy. The LS was obtained for each myocardial layer (endocardial, mid-myocardial, epicardial), left ventricular regional level (basal, mid, apical) and coronary artery territory (left anterior descending artery (LAD), circumflex artery, right coronary artery). The study included 64 left-sided BC patients. Mean age was 58 years, mean doses to the heart, the left ventricle and the LAD were respectively 3.0, 6.7 and 16.4 Gy. The absolute decrease of LS was significant for the three layers (endocardial: - 20.0 ± 3.2% to - 18.8 ± 3.8%; mid-myocardial: - 16.0 ± 2.7% to - 15.0 ± 3.1%; epicardial: - 12.3 ± 2.5% to - 11.4 ± 2.8%, all p = 0.02), but only the relative decrease of LS in the endocardial layer was close to be significant (- 4.7%, p = 0.05). More precisely, the LS of the endocardial layer was significantly decreased for the most exposed parts of the left ventricle corresponding to the apical level (- 26.3 ± 6.0% vs. -24.2 ± 7.1%, p = 0.03) and LAD territory (- 22.8 ± 4.0% vs. -21.4 ± 4.8%, p = 0.03). Six months post-radiotherapy, LS decreased predominantly in the endocardial layer of the most exposed part of the left ventricle. For precise evaluation of radiotherapy-induced cardiotoxicity and early left ventricular dysfunction, the endocardial layer-based LS might be the most sensitive parameter. ClinicalTrials.gov: NCT02605512 , Registered 6 November 2015 - Retrospectively registered.


Residential parenting services: An integrative literature review of characteristics, service usage and parent and staff perspectives.
The primary aim of the review was to provide an overall assessment of residential parenting services in Australia, by describing the characteristics of infants and parents using residential parenting services, their prior service use and reasons for admission, referral pathways for access and parenting and infant outcomes. The secondary aims were to explore parent and staff perception of the programmes. An integrative literature review. A systematic and comprehensive search of health and social sciences databases was conducted for studies related to residential parenting services (published between 1st January 1990-31st December 2019). Six hundred and eleven peer-reviewed papers were identified, after which 301 duplicates were removed and an additional 256 papers excluded after titles/abstracts were read. Of the remaining 54 abstracts/papers, a further 14 were omitted as not relevant. Forty papers were independently reviewed by four authors. ENTREQ and MOOSE checklists were applied. Thirty studies were quantitative, nine were qualitative, and one was mixed methods. All studies originated from in Australia. Women and babies admitted to residential parenting services were found more likely to be: older, Australian born, from higher socio-economic groups, and first-time mothers, and having labour and birth interventions and a history of mental health disorders. The babies were more likely to be twins, male and admitted with sleep disorders and dysregulated behaviour. Studies reporting postintervention outcomes demonstrated improvements to maternal mental health, breastfeeding, parenting confidence and sleep quality, and infant sleeping and behaviour.


[Study on enriching total flavonoids from folium chrysanthemi with polyamide and macroporous resin].
To study the technology of enriching total flavonoids from Folium Chrysanthemi with polyamide and macroporous resin. By using the content of flavonoids as index, firstly absorbed with polyamide and removed impurity with purified water. Then added polyamide to macroporous resin column, eluted with ethanol and determined the flavonoids content. Total flavonoids could be effectively purified by the polyamide and macroporous resin. Best technological conditions were as follows: resin of type X-5 was better, and elution agent was 70% ethanol, the ratio of extract amount (mL) and polyamide quantity (g) was 1. 5: 1, ratio of resin (g) - extract (mL) was 4: 3, ratio of diameter and height was 1: 20, the volume of collected eluent was 2BV. The purity of total flavonoids reached to 87.48%. The technology is stable and can be viewed as a way to study and develop the resources of Folium Chrysanthemi.


Defensins.
Defensins are a family of small cationic, antibiotic peptides that contain six cysteines in disulfide linkage. The peptides are abundant in phagocytes and small intestinal mucosa of humans and other mammals and in the hemolymph of insects. They contribute to host defense against microbes and may participate in tissue inflammation and endocrine regulation during infection. Bioengineered defensins are potentially useful as prophylactic and therapeutic agents in infections.


Engipore acts on human bone marrow stem cells.
Porous HA scaffolds are promising materials for tissue engineering because they offer a tridimensional support and serve as template for cell proliferation and at last tissue formation. Engipore provide a natural 3D scaffold with organic fibrous material in bone. However, how this material alters osteoblast activity to promote bone formation is poorly understood. To study how Engipore can induce osteoblast differentiation in mesenchymal stem cells, the expression levels of bone related genes and mesenchymal stem cells marker were analyzed. Engipore causes a significant induction of osteoblast transcriptional factors like SP7 and RUNX2 and of the bone-related gene osteocalcin (BGLAP). The expression of CD105 was not significantly changed in stem cells treated with Engipore with respect to untreated cells, while SSP1 (osteopontin) was significantly down expressed thus reducing osteoclast activity. The obtained results can be relevant to better understand the molecular mechanism of bone regeneration.


Expression of three different mutations in the arginine vasopressin gene suggests genotype-phenotype correlation in familial neurohypophyseal diabetes insipidus kindreds.
The autosomal dominant form of familial neurohypophyseal diabetes insipidus (adFNDI) is a rare disease characterized by a severe and progressive deficiency of AVP secondary to mutations in the gene encoding the AVP precursor. Whereas a number of studies have investigated the pathogenetic mechanisms behind the disease only few studies have included detailed clinical characterization of the affected patients, thereby making genotype-phenotype correlations difficult. The aims of the present study were to investigate the cellular effects of three different adFNDI mutations (A19T, L81P and C110X) by heterologous expression in a neurogenic cell line and to correlate these findings to the corresponding clinical phenotype as determined by extensive clinical tests. The clinical studies showed a later age of onset in the family carrying the A19T mutation (3.4 years, range 2-9 years) compared with families with the L81P and C110X mutations [0.75 year, range 0.5-1 year and 1.0 year (n = 1), respectively]. No other differences could be demonstrated in the clinical phenotype between families. Expression studies showed that each of the three mutant genes caused significant reduction of the amount of immunoreactive AVP in the cell culture medium and severe impairment of the intracellular trafficking and processing of the AVP prohormone, supporting the disease causing nature of all three mutations. However, the A19T mutation was associated with some capacity for processing and trafficking consistent with the clinical observations. Immunoflourescence studies provided evidence of reticular accumulation of protein within the ER in the A19T and C110X mutants but a unique accumulation of much larger aggregates in the L81P, which were localized both within and immediately outside the ER. The study suggests a genotype-phenotype correlation with regard to age of onset of diabetes insipidus symptoms and provides support by expression studies.


Differential Associations of Religious Involvement with the Mental Health of Asian-American Subgroups: A Cultural Perspective.
In the USA, Asian-Americans (AA) constitute the fastest growing ethnic minority group, in which heterogeneous religious patterns and acculturation experiences can impose significant impacts on their mental health. Using national data, the present study examined the contributions of religious involvement and social support to self-rated mental health (SRMH) of Chinese, Vietnamese, and Filipinos. Findings demonstrated cross-group variations, with Filipinos reporting the highest levels of SRMH, acculturation, and discrimination. However, religious involvement was associated with better SRMH in the least religious Chinese subgroup but not in the most religious Filipino subgroup. Social support predicted SRMH for both Chinese and Vietnamese subgroups. The differential religious patterns in the more acculturated generations between the two AA subgroups suggest religious assimilation as part of their acculturation in the context of divergent immigration experiences.


Up-regulation of nuclear receptor coactivator amplified in breast cancer-1 in papillary thyroid carcinoma correlates with lymph node metastasis.
Nuclear receptor coactivator amplified in breast cancer-1 (AIB1), a new oncogenic coactivator, is commonly overexpressed and amplified in variety of human cancers. However, the expression of AIB1 in papillary thyroid carcinoma (PTC), the major histologic type of thyroid cancer, and its clinical significance are still unclear. AIB1 expression in PTC was examined by immunohistochemistry using tissue microarrays comprised of 90 primary PTC, 46 matched lymph node, and 20 normal thyroid tissue specimens in this study. In the normal thyroid specimens, AIB1 expression was either absent or at low levels. In contrast, AIB1 overexpression was detected in 50 of 83 (60.2 %) primary PTC specimens. Up-regulated AIB1 was evident in 39 of 46 (73.5 %) matched lymph nodes. Overexpression of AIB1 was observed more frequently in PTCs with lymph node metastasis [N1a/N1b, 39/46 (73.5 %)] versus PTCs without lymph node metastasis [N0, 14/34 (41.2 %)]. Furthermore, high-level AIB1 expression was only observed in the lymph node-positive specimens. Moreover, we found no correlation between AIB1 expression and ER expression in PTC tissues. Our findings suggest that overexpression of AIB1 may be a biomarker for tumorigenesis and progression of PTC and may play an important role in its acquisition of a metastatic phenotype.


The Importance of Weight Change Experiences for Performance of Diabetes Self-Care: A Patient-Centered Approach to Evaluating Clinical Outcomes in Type 2 Diabetes.
The aim of this study was to examine the influence of weight change experiences over time on motivation to perform diabetes self-care behaviors using data from a study of canagliflozin (an agent that inhibits sodium glucose co-transporter 2) versus glimepiride in dual therapy with metformin and background diet/exercise. Weight and motivation for performing healthy behaviors were collected at baseline and over time. The motivation questionnaire enabled categorization into two groups: those performing or not performing health behaviors. Four distinct patterns of weight change were determined: losing weight, gaining weight, and two patterns for fluctuating weight. The relationships between these patterns and motivation for weight loss, following a diet, and exercise were examined using logistic regression models. Of 1182 subjects, more than half were already performing behaviors to lose weight, diet, and exercise at baseline. Among those who were not, 52% (246/474) started taking action to lose weight after baseline, 54% (241/448) started following a diet, and 42% (232/556) started exercising. Weight change patterns were significantly related to performance of healthy behaviors at follow-up (week 36). Compared to the weight gain pattern, those who experienced a continuous weight loss pattern from baseline to week 36 were 2.2 (95% confidence interval 1.49, 3.37) times more likely to perform the healthy behaviors. Baseline behavior and confidence were also predictive of performing healthy behaviors. The current work highlights the importance of weight change patterns for performance of diabetes self-care. Tracking weight patterns over time, assessing confidence for performance of healthy behaviors, and being aware of the relationship between weight changes and diabetes self-care behaviors are viable, concrete ways to practice patient-centered care. Janssen Global Services, LLC.


A chemical defense deters cannibalism in migratory locusts.
Many animals engage in cannibalism to supplement their diets. Among dense populations of migratory locusts, cannibalism is prevalent. We show that under crowded conditions, locusts produce an anticannibalistic pheromone called phenylacetonitrile. Both the degree of cannibalism and the production of phenylacetonitrile are density dependent and covary. We identified the olfactory receptor that detects phenylacetonitrile and used genome editing to make this receptor nonfunctional, thereby abolishing the negative behavioral response. We also inactivated the gene underlying phenylacetonitrile production and show that locusts that lack this compound lose its protection and are more frequently exposed to intraspecific predation. Thus, we reveal an anticannibalistic feature built on a specifically produced odor. The system is very likely to be of major importance in locust population ecology, and our results might therefore provide opportunities in locust management.


Evoked potential monitoring during posterior fossa aneurysm surgery: a comparison of two modalities.
The purpose of this study was to compare and assess the ability of two different evoked potential (EP) modalities, median nerve somatosensory evoked potentials (SSEP) and brainstem auditory evoked potentials (BAEP) in monitoring for cerebral ischaemia and in predicting neurological outcome during posterior fossa aneurysm surgery. During 70 procedures, patients were monitored with both SSEP and BAEP. Temporary occlusion of an artery was used in 52 patients and permanent occlusion in 21 patients. A change was defined as a greater than 50% decrease in amplitude and/or an increase in latency greater than 1 msec of the N20 (cortical waveform) for SSEP monitoring and of the fifth peak for BAEP monitoring. Neurological assessment of the patient was performed immediately on emergence, after 24 hr and at the time of discharge. In total, 14 patients had an SSEP change which predicted a neurological deficit in eight patients (57%). Ten patients had a change in BAEP; six had a neurological deficit (60%). Five patients had a change in both, two had a deficit (40%). The incidence of false negative results (a neurological deficit but no EP change) for both modalities was 20% (SSEP 47%, BAEP 60%). The incidence of false positive results (an EP change but no deficit) was 13% overall (SSEP 11%, BAEP 7%). All patients who had a permanent EP change developed a neurological deficit. We did not find a difference in the ability of SSEP compared with BAEP in predicting neurological deficits but, using both modalities, the incidence of false negative results was decreased.(ABSTRACT TRUNCATED AT 250 WORDS)


In vitro cytotoxicity assay to evaluate the toxicity of an electrophilic reactive metabolite using glutathione-depleted rat primary cultured hepatocytes.
Glutathione plays an important role as not only a scavenger of reactive oxygen species but also in the conjugation or detoxification of electrophilic reactive metabolites, which has been thought to be one of the causes for idiosyncratic drug toxicity (IDT). Therefore, toxic responses to the reactive metabolites have been expected to be expressed more strongly in a glutathione-depleted condition. In the present study, we attempted to establish an in vitro cytotoxicity assay method to evaluate the toxicity of the reactive metabolite using rat primary cultured hepatocytes with cellular glutathione depletion by l-buthionine-S,R-sulfoximine. Also, we investigated whether the IDT risk is predictable by comparing the cytotoxic sensitivity between glutathione-depleted hepatocytes and untreated hepatocytes. Consequently, 10 drugs of 42 approved drugs, which were classified into 4 IDT categories (Withdrawn, Black box warning, Warning, and Safe), demonstrated higher cytotoxic sensitivity in the glutathione-depleted hepatocytes. Furthermore, a correlation was observed between the incidence of drugs with higher cytotoxic sensitivity in the glutathione-depleted hepatocytes and the IDT risk. The incidence was 50% in the Withdrawn category, 38% in the Black box warning category, 22% in the Warning category, and 8% in the Safe category. These results suggest that the IDT risk of some drugs may be predicted by comparing the cytotoxic sensitivity between them. Additionally, this method may be useful as a screening in the early stage of drug development where leads/candidates are optimized.


Peroneal tendon injuries: an evaluation of 49 tears in 41 patients.
Forty-one patients sustaining 49 tears of the peroneal tendons were evaluated prospectively a minimum of 1 year after surgical treatment. Preoperative and postoperative function and activity were assessed by using the American Orthopedic Foot and Ankle (AOFAS) score. Mean age at the time of surgery was 44.0 +/- 11.7 years. Mean follow-up after the index surgery was 35.5 +/- 22.2 months. There were 17 women and 24 men. One woman had bilateral surgery 1 year apart. There were a total of 18 tears of the peroneus longus tendon; 11 of these were isolated, whereas 7 had a combined tear with peroneus brevis. There 31 peroneus brevis tears; 24 of these were isolated and 7 were combined. Using 3-way analysis of variance, there were no significant differences in return to activity or postoperative AOFAS scores among those with a longus, brevis, or combined tear. The mean return to activity for peroneus longus, peroneus brevis, and combined tears were 3.2, 3.6, and 3.7 months, respectively. The mean postoperative AOFAS scores were 90.6, 90.8, and 84.3 respectively. The mean preoperative AOFAS score was 52.0 +/- 16.8. The mean postoperative score was 89.7 +/- 10.3 (P <.00001). Using this scoring system, there were 24 excellent, 12 good, 4 fair, and 2 poor scores. Three patients underwent additional surgery. Fourteen of 16 athletes returned to full sporting level. The average return to activity for the entire group was 3.49 +/- 1.15 months.


Implementation of a top-down noise control strategy for a liquefied natural gas peak-shaving facility.
There have been many previous noise-related studies on liquefied natural gas (LNG) facilities in the United States; however, noise control of these facilities using a top-down approach has not been explored in detail. Most studies have demonstrated noise compliance to applicable standards by focusing on a combination of treatments and specifications, with less consideration on control technology feasibility, ranking, and cost-effectiveness. The Federal Energy Regulatory Commission (FERC) prohibits natural gas facilities from emitting day-night noise levels in excess of 55 dB(A) (equivalent to 24-hr continuous level of 49 dB(A)) at nearby receivers. A case study was conducted to evaluate a top-down approach to reduce noise at a typical LNG peak-shaving facility under normal operating conditions, accounting for technical feasibility, control effectiveness, and cost implications. A modeling approach (International Organization for Standardization standard ISO 9613-2) was used to predict and evaluate the facility's noise reduction potential. The study found that the strategy could achieve feasible and environmentally effective reductions up to 11 dB(A) at 500 m from the facility by first identifying source groups with highest-emitting sources and then targeting major noise source contributors per group. This approach is cost-effective because the FERC noise goals can still be achieved by avoiding unnecessary control costs associated with lower-ranked sources. The study identified the following four source groups as the highest noise emitters: (1) liquefaction and instrument air, (2) boil-off gas (BOG) compression, (3) glycol water system (air coolers), and (4) pretreatment. Of all the treatments evaluated, installation of enhanced silencers for gas turbine (GT) package-as well as construction of an acoustical building for the BOG compressors and drivers-resulted in the greatest noise reduction at nearby receivers. The study notes that incremental treatment costs presented in this paper are approximate estimates that may vary depending on factors such as facility size and region. Implications: This study assessed potential noise reductions associated with implementing a top-down noise control strategy on a typical LNG peak-shaving facility. The study determined the top-down noise control strategy could achieve feasible and environmentally effective reductions up to 11 decibels at receivers within 500 m from the facility's center. As LNG suppliers need to support potential supply disruptions, some regions of the US, including New England and Gulf Coast with projected increase in LNG exports and growing needs from power sector, may find information in this study useful with regard to evaluating and prioritizing noise reduction potential of their LNG peak-shaving facilities.


A novel full symmetric diarylethene-based ratiometric fluorescent sensor for lysine and the application for a logic circuit.
A novel diarylethene-based ratiometric fluorescent sensor with full symmetric structure, 1o, was designed and synthesized successfully. 1o could identify lysine (Lys) with high selectivity and sensitivity and the fluorescence emission peak was red shifted 85 nm upon addition of Lys, which could realize ratio recognition. It exhibited excellent anti-interference performance in the presence of various amino acids in CH3 CN/H2 O (7/3, v/v) solution. Moreover, the limit of detection of 1o to Lys could reach 0.019 μM based on a good linear range of 0-40 μM. In addition, the fluorescence emission intensity of 1o could be turned off/on by ultraviolet/visible light due to the special structure of diarylethene. A logic circuit was designed with three inputs. The ratiometric fluorescent sensor 1o could be as a new tool and provide a new method for detection of Lys.


A critical cytoprotective role of endogenous adrenomedullin in acute myocardial infarction.
Exogenous administration or transfection of adrenomedullin (AM) affords protection against ischaemia-reperfusion injury. Here we have examined the role of endogenous AM in regulating the development of myocardial infarction. Wild type (WT) and AM(+/-) mice underwent 30 min regional myocardial ischaemia and 120 min reperfusion. In AM(+/-) hearts, tetrazolium-determined infarct size was greater than in WT controls (27.9 +/- 2.0 vs. 17.7 +/- 2.4%, P < 0.01) and mortality rate was increased (35% vs. 14%, P < 0.05). Treatment with exogenous recombinant AM (200 ng/kg) prior to coronary occlusion rescued the ischaemia-reperfusion intolerant phenotype of AM(+/-) mice and further limited infarct development in WT mice. Administration of recombinant AM was associated with augmented phosphorylation of Akt and eNOS in early reperfusion suggesting a role for AM in regulating this survival pathway. These studies provide the first evidence that expression of AM is a critical factor regulating myocardial tolerance to ischaemia-reperfusion injury.


Comparative impact of 2 botulinum toxin injection techniques for elbow flexor hypertonia.
To compare 2 techniques of botulinum toxin injection for elbow flexor hypertonia. Parallel-group, randomized, controlled trial with blinded outcome assessment. Laboratory, tertiary rehabilitation hospital. Adults (N=31) with acquired brain injury (21 with traumatic brain injury, 8 with stroke, 2 with hypoxic encephalopathy) provided 36 sets of elbow flexors with Ashworth Scale scores equal to 3. Botulinum toxin type A (BTX-A) was injected with a motor point or a multisite injection technique after obtaining 2 baseline evaluations of the main outcome measures. Motor point technique involved decremental electric stimulation with delivery of 60U of BTX-A (Botox) in 2.4mL or 30U BTX-A in 1.2mL of preservative-free saline at single biceps and brachioradialis motor points, respectively. Distributed injection was performed using electromyographic feedback. Fifteen units in 0.6mL were delivered to each of 4 biceps sites and 2 brachioradialis sites. Total dose (90U) and total injection volume (3.6mL) were identical across groups. Only sites and injection techniques varied. The brachialis was not injected in either group. Ashworth Scale, Tardieu catch angle, and root mean square surface electromyographic activity of the biceps, brachialis, and brachioradialis. Postintervention testing at 3 weeks showed no significant differences between groups (P range, .31-.82 across 3 outcome measures). However, within each group, significant treatment effects were observed on all outcome measures (all P<.01). For the uninjected brachialis muscle, electromyographic reduction was greater for the distributed group. In 31 adults with acquired brain injury, single motor point and multisite distributed injections of low-dose, high-volume BTX-A had similar impact. Findings suggest that low-dose, high-volume strategies may have a potential role in reducing drug cost and helping clinicians stay within accepted limits for total body dose in patients with upper motoneuron syndrome requiring many injections.


[The importance of steroid receptors for the prognosis and hormone treatment of breast cancer patients: a retrospective study in Southeastern Netherlands].
To assess the effect of oestrogen (ER) and progesterone (PgR) receptors on the prognosis of patients with operable breast cancer and the decision to treat these patients with adjuvant tamoxifen. Retrospective. Eight community hospitals in the Southeast Netherlands. Using the registry of the Comprehensive Cancer Centre South, 2862 breast cancer patients were identified with stage I, II or IIIA tumours, treated during the period 1984-1992. ER and PgR status were known for 2393 (84%) and 1761 (62%) patients respectively. From 1991, over 80% of the postmenopausal, lymph node positive patients had received tamoxifen, irrespective of the steroid receptor status. Of all lymph node negative patients fewer than 3% received adjuvant systemic treatment. Among the lymph node negative patients the steroid receptor status was not a significant predictor of survival. Among the lymph node positive patients whose tumours were both ER-negative and PgR-negative, a 2.8-fold increased risk of death was found during the first four years after primary treatment. The risk of death was not increased if only the ER or only the PgR status was negative. This study shows that ER and PgR receptors are significant prognostic factors for survival in breast cancer patients with involved axillary lymph nodes. The prognostic effect appeared to be restricted to the first four years after primary treatment. Selection of patients for endocrine treatment should be based on the steroid receptor status, considering the importance of the steroid receptors for predicting the response to endocrine treatment.


Effect of forced deflation maneuvers upon measurements of respiratory mechanics in ventilated infants.
To determine the effect of forced deflation maneuvers on respiratory mechanics and to assess the reproducibility of such measurements in intubated infants with lung disease. Prospective study in the pediatric intensive care unit of a university children's hospital. Ten clinically stable infants requiring mechanically assisted ventilation for acute pulmonary disease, mean age 5.9 months (1-18), mean weight 5.8 kg (3.2-13). Two sets of measurements of compliance (Crs) and resistance (Rrs) were obtained at 20-min intervals both before and after +40/-40 cmH(2)O forced deflation maneuvers. Forced deflation measurements were repeated at the end of the study. . Forced deflation caused a significant increase in Crs from 0.53+/-0.09 and 0.58+/-0.11 ml/cmH(2)O/kg to 0.71+/-0.11 and 0.68+/-0.11 ml/cmH(2)O/kg. Rrs measurements did not differ. The low coefficients of variation for repeated measures of the baseline measurements (Crs 4.2+/-0.5%, Rrs 7.1+/-0.8%, for forced vital capacity 8.6+/-2.5%, maximum expiratory flows at 25% vital capacity 16.0%+/-3.3%) confirmed the good reproducibility during stable conditions. Inflation and deflation maneuvers affect subsequent measurements of respiratory system compliance but not measurements of maximum expiratory flow-volume relationships in intubated infants, probably through recruitment of lung volume. Careful interpretation and planning of the sequence of infant pulmonary function testing is necessary to reassure that changes are not related to short-term alterations in volume history.


Influence of boron- and barium-containing modifiers on the structure of low-chromium cast iron.
The paper presents the results of studying the effect of modifying low-chromium hypoeutectic cast iron (chromium content about 1%) with boron- and barium-containing additives on its structure and hardness. The modification was carried out with carbothermicferroboron (0.08% of weight of the liquid metal); ferrosilicobarium (0.05% of weight of liquid metal); complex boron barium ferroalloy (0.14% by weight of liquid metal). The microstructure and properties were compared with a sample of unmodified cast iron of the same composition. The Thixomet Pro software was used as the main method of the quantitative analysis of the microstructure that allows quantitative metallographic analyzing with high accuracy and repeatability. The analysis of the results obtained shows a positive effect of modification on changes in the microstructure. In all the experimental samples, grinding and more uniform distribution of carbides, as well as transformation of the carbides morphology from dendritic to compact granular form, take place. Pearlite colonies in the modified cast iron are characterized by a higher degree of dispersion than in the reference sample. Such changes in the structure lead to increasing the hardness of the prototypes.


Face and emotion recognition in MCDD versus PDD-NOS.
Previous studies indicate that Multiple Complex Developmental Disorder (MCDD) children differ from PDD-NOS and autistic children on a symptom level and on psychophysiological functioning. Children with MCDD (n = 21) and PDD-NOS (n = 62) were compared on two facets of social-cognitive functioning: identification of neutral faces and facial expressions. Few significant group differences emerged. Children with PDD-NOS demonstrated a more attention-demanding strategy of face processing, and processed neutral faces more similarly to complex patterns whereas children with MCDD showed an advantage for face recognition compared to complex patterns. Results further suggested that any disadvantage in face recognition was related more to the autistic features of the PDD-NOS group rather than characteristics specific to MCDD. No significant group differences emerged for identifying facial expressions.


Osteoporosis risk assessment and treatment intervention after hip or shoulder fracture. A comparison of two centres in the United Kingdom.
This study compares the investigation of and treatment for osteoporosis in two groups of fracture patients at two orthopaedic centres in the UK. One centre had a formal fracture liaison service (FLS) responsible for screening fracture patients for osteoporosis. The other centre relied upon individual clinicians to initiate investigation or treatment for osteoporosis in patients following fracture. Patients who had been treated in either centre for a proximal humeral or hip fracture during a 6-month period were followed up 6 months later to identify how many had received screening or treatment for osteoporosis. Information was retrieved from a prospectively compiled database or by postal questionnaire. The study revealed that in the centre with an FLS 85% of patients with a proximal humeral fracture and 20% with a hip fracture had been offered a dual-energy X-ray absorptiometry (DEXA) scan. Approximately 50% and 85%, respectively, were receiving treatment for osteoporosis 6 months following their fracture. This compared with DEXA being offered to only 6% and 9.7% of humeral and hip fracture patients, respectively, and 20% (hip) and 27% (proximal humerus) receiving osteoporosis treatment in the other centre. The presence of an FLS resulted in a considerably higher proportion of patients receiving investigation and treatment for osteoporosis following a hip or proximal humeral fracture.


New breakpoints in both the H4 and RET genes create a variant of PTC-1 in a post-Chernobyl papillary thyroid carcinoma.
Two main types of RET/PTC oncogene, named RET/PTC-1 and 3, occur in papillary thyroid carcinomas especially in those from Belarus children after the Chernobyl nuclear accident. Several variants of RET/PTC-3 have also been found, having different break points with respect to the classical RET/PTC-3. To our knowledge, no variant of RET/PTC-1 has been described up to now. We found a post-Chernobyl papillary thyroid carcinoma with an RET/PTC-1 rearrangement characterized by a transcript longer than expected. Sequence analysis of the PCR product obtained after RT-PCR revealed new fusion points between H4 and RET genes. The genomic sequence showed new breakpoints in both H4 intronic and in RET exonic regions. The RET gene breakpoint occurred within exon 11, at variance with the classical form of RET/PTC-1, in which it is in intron 11. As a consequence of this new fusion point, the transcript included 132 nucleotides of exon 11, coding for 44 amino acids of RET protein. Regarding the H4 gene, the classical breakpoint is in the first intron and the cDNA contains a fragment of 339 nucleotides. In our case the cDNA had a longer fragment of H4 involving a total of 1266 nucleotides. Sequencing of genomic DNA revealed a rearrangement breakpoint at position 886 of a new H4 intron located downstream of the 1266 coding region. Furthermore, as a consequence of the activation of a cryptic splicing site, 132 nucleotides of this intron were spliced between the H4 and RET genes. Sequence analysis of the new chimera showed that the original frames of H4 and RET were joint with the intronic sequence without disruption of the open reading frame (ORF). Moreover, the genomic DNA of this case showed transforming activity in the DNA-mediated transfection assay using NIH-3T3 cells. In conclusion, we describe here the first variant of RET/PTC-1 oncogene, which we have termed 'long'-PTC-1, characterized by new breakpoints of both genes involved in the rearrangement and having transforming activity. Similar to previously reported PTC-3 variants, long-PTC-1 has been found in a post-Chernobyl papillary thyroid carcinoma confirming that RET/PTC rearrangements other than the classical forms (RET/PTC-1 and -3) are specifically associated with radiation-induced papillary thyroid cancer.


Comparison of microbial tests for the detection of heavy metal genotoxicity.
Heavy metal genotoxicity was evaluated by using different microbial tests. Four genotoxicity assays were employed: the Ames test, the E. coli WP2 test, the Mutatox test detecting mutagenicity, and the SOS assay with E. coli-detecting enzyme induction. All the metals tested (cadmium, chromium, copper, mercury, nickel, and zinc) were detected as genotoxic by the Mutatox and the SOS tests. The Ames test and the E. coli WP2 assay only detected chromium as genotoxic, causing a mutagenic effect. The sensitivity to metals of all the assays used was maintained when they were dissolved in sewage, although there was a slight increase in the sensitivity thresholds.


Reliability of confocal corneal microscopy for measurement of dendritic cell density in suspected small fiber neuropathy.
Dendritic cells (DCs) and their contacts with corneal nerves are described in animal models of nerve damage. Dendritic cell density (DCD) is a potential marker of immune activity in suspected small-fiber neuropathy (SFN). Here, we aim to evaluate the intra- and inter-rater reliability of DCD measurements in suspected SFN. This retrospective study collected DCD from confocal microscopy images from the corneal sub-basal epithelium of the eye from 48 patients (mean age 49.6 ± 12.1 y, 61% female). Two examiners, each blinded to the other's examinations and measurements, assessed DCD to evaluate inter-rater reliability. For intra-rater reliability, the first examiner performed a second measurement after 14 days. DCs were classified into two cell morphological subtypes: mature and immature. Test-retest reliability for total DCD showed excellent agreement, with an intraclass correlation coefficient of 0.96 and inter-rater reliability intraclass correlation coefficient of 0.77. The immature cell subtype showed excellent intra-rater reliability but lower inter-rater reliability. We found that DCD measurements in the corneal sub-basal epithelium are sufficiently reliable for consideration in clinical studies of patients with suspected SFN.


Eco-friendly cubic-ZnS coupled Cu7S4 spines on chitosan matrix: Unravelling defect-engineered nanoplatform for the photodegradation of p-chlorophenol.
Novel ZnS-Cu7S4 nanohybrid supported on chitosan matrix, as an ideal photocatalyst, was fabricated by the sonochemical method wherein high-resolution transmission electron microscopy (HRTEM) and X-ray powder diffraction (XRD) analysis confirmed the co-existence of both ZnS and Cu7S4; presence of vacancy sites in ZnS was verified by electron paramagnetic resonance (EPR) analysis and their introduction could promote two-photon excitation facilitated visible light response and charge transport/separation. The type II interface is formed in the ZnS-Cu7S4/Chitosan heterojunction owing to interstitial states that promote charge separation. The ZnS-Cu7S4/Chitosan was used for the photodegradation of a pharmaceutical pollutant, p-chlorophenol (PCP); over 98.8% of PCP photodegradation was achieved under visible-light irradiation where the ensued ·O2- and ·OH serve a key role in the photodegradation of PCP. In vitro cytotoxicity studies substantiated that the ZnS-Cu7S4/Chitosan is nontoxic to the ecosystem and human beings and endowed with promising photodegradation properties and accessibility via an environmentally friendly design, bodes well for its potential remediation applications.


Subfraction analysis of circulating lipoproteins in a patient with Tangier disease due to a novel ABCA1 mutation.
Tangier disease, characterized by low or absent high-density lipoprotein (HDL), is a rare hereditary lipid storage disorder associated with frequent, but not obligatory, severe premature atherosclerosis due to disturbed reverse cholesterol transport from tissues. The reasons for the heterogeneity in atherogenicity in certain dyslipidemias have not been fully elucidated. Here, using high-performance liquid chromatography with a gel filtration column (HPLC-GFC), we have studied the lipoprotein profile of a 17-year old male patient with Tangier disease who to date has not developed manifest coronary atherosclerosis. The patient was shown to be homozygous for a novel mutation (Leu1097Pro) in the central cytoplasmic region of ATP-binding cassette transporter A1 (ABCA1). Serum total and HDL-cholesterol levels were 59mg/dl and 2mg/dl, respectively. Lipoprotein electrophoretic analyses on agarose and polyacrylamide gels showed the presence of massively abnormal lipoproteins. Further analysis by HPLC-GFC identified significant amounts of lipoproteins in low-density lipoprotein (LDL) subfractions. The lipoprotein particles found in the peak subfraction were smaller than normal LDL, were rich in triglycerides, but poor in cholesterol and phospholipids. These findings in an adolescent Tangier patient suggest that patients in whom these triglyceride-rich, cholesterol- and phospholipid-poor LDL-type particles accumulate over time, would experience an increased propensity for developing atherosclerosis.


Peri-administration of clonidine or MK801 delays but does not prevent the development of mechanical hyperalgesia in a model of mononeuropathy in the rat.
Following loose ligation of the sciatic nerve, rats develop a persistent hyperalgesia which mimics some of the features of traumatic neuropathy seen in man. Previously, we have shown that administration of MK801 or clonidine prior to and 30 min following loose ligation of the sciatic nerve prevented the development of hyperalgesia up to 30 days following surgery. In the current study, we have extended our observation and examined the effect of administration of clonidine (1 mg/kg, s.c.) or MK801 (0.3 mg/kg, s.c.) 30 min prior to and 6 h following loose ligation of the sciatic nerve on the development of hyperalgesia assessed at 9 time points between 16 and 150 days after loose ligation. We have found that compared with saline treatment, the degree of hyperalgesia apparent in animals receiving MK801 was significantly reduced when tested 16, 28, or 42 days after surgery. No significant difference between the 2 treatment groups was detected at any other time points during the study. Similarly, when compared with saline treated controls, the degree of hyperalgesia measured in animals following peri-administration of clonidine was significantly less when measured 16 and 28 days after surgery, but did not differ significantly at any of the time points tested between 42 and 150 days following surgery. Our results indicate that peri-administration of MK801 or clonidine significantly delay, but do not prevent, the onset of neuropathic hyperalgesia.


Trends in Obesity Prevalence among US Older Adults in the Last Two Years of Life, 1998-2018.
The prevalence of obesity has grown in the US over the decades. The temporal trends of body mass index categories in the last two years of life are poorly understood. To describe the trends in body mass categories in the last two years of life over the past two decades controlling for other demographic changes. We performed a cross-sectional study of prospectively collected survey data from the nationally representative Health and Retirement Study (HRS) among decedents who died between 1998 and 2018. We categorized BMI into five categories and calculated the proportion of decedents with each BMI category during each four epochs (1998-2003, 2004-2008, 2009-2013, 2014-2018). We examined trends in regression models with survey wave groupings modeled as an orthogonal polynomial and adjusted for factors commonly associated with BMI: sex, age, race, ethnicity, education, and tobacco use. The analytic cohort included 14,797 decedents. From 1998-2003 to 2014-2018 time periods, those categorized as having mild-to-moderate obesity in the last two years of life increased from 12.4% to 14.8% (linear trend P < 0.001), a 19% increase. Severe obesity increased from 1.9% to 4.3%, a 126% increase (linear trend P < 0.001). Underweight decreased from 9.9% to 5.9%, a 40% decrease (linear trend P < 0.001), adjusted for demographic factors. Adjusted quadratic temporal trends for BMI category were nonsignificant, except for in mild-to-moderate obesity. Severe obesity has increased greatly while underweight has decreased. As obesity increases in the final years of life, it is critical to assess how the existing and future palliative services and end of life care system address body size and weight.


Robotically assisted percutaneous coronary intervention: benefits to the patient and the cardiologist.
Robotic percutaneous interventional systems represent the future of interventional cardiology. Robotic technology significantly reduces operator exposure to ionizing radiation, and improves ergonomics in the cardiac catheterization laboratory, thereby preventing orthopedic injuries. It may enable more accurate stent implantation and reduce the incidence of contrast-induced nephropathy. Robotics has the potential of converting the current 'high-risk' catheterization laboratory into a safe, physician- and patient-friendly environment.


Chromosome assignment of monoclonal antibody-defined determinants on human leukemic cells.
Hybrids formed between human acute lymphoblastic leukemia (ALL) cells and mouse myeloma have been used to determine the chromosomal location of genes required for the expression of several monoclonal antibody (mAb)-defined cell surface antigens on ALL cells. Cloned hybrids were tested for antibody binding, immunoprecipitation of the relevant protein, chromosome isoenzyme markers and karyotype. Two antigens of those studies could be definitively mapped, OKT10/p45 to chromosome 4 and BA-2/p24 to chromosome 12. mAb BA-2 reacts with the same protein as another mAb designated 609-29 (anti-teratocarcinoma). Reactivity with the latter mAb has been previously shown to segregate with chromosome 12.


The Step approach to Message Design and Testing (SatMDT): A conceptual framework to guide the development and evaluation of persuasive health messages.
This paper provides an important and timely overview of a conceptual framework designed to assist with the development of message content, as well as the evaluation, of persuasive health messages. While an earlier version of this framework was presented in a prior publication by the authors in 2009, important refinements to the framework have seen it evolve in recent years, warranting the need for an updated review. This paper outlines the Step approach to Message Design and Testing (or SatMDT) in accordance with the theoretical evidence which underpins, as well as empirical evidence which demonstrates the relevance and feasibility of, each of the framework's steps. The development and testing of the framework have thus far been based exclusively within the road safety advertising context; however, the view expressed herein is that the framework may have broader appeal and application to the health persuasion context.


Tannase production by solid state fermentation of cashew apple bagasse.
The ability of Aspergillus oryzae for the production of tannase by solid state fermentation was investigated using cashew apple bagasse (CAB) as substrate. The effect of initial water content was studied and maximum enzyme production was obtained when 60 mL of water was added to 100.0 g of CAB. The fungal strain was able to grow on CAB without any supplementation but a low enzyme activity was obtained, 0.576 U/g of dry substrate (g(ds)). Optimization of process parameters such as supplementation with tannic acid, phosphorous, and different organic and inorganic nitrogen sources was studied. The addition of tannic acid affected the enzyme production and maximum tannase activity (2.40 U/g(ds)) was obtained with 2.5% (w/w) supplementation. Supplementation with ammonium nitrate, peptone, and yeast extract exerted no influence on tannase production. Ammonium sulphate improved the enzyme production in 3.75-fold compared with control. Based on the experimental results, CAB is a promising substrate for solid state fermentation, enabling A. oryzae growth and the production of tannase, with a maximum activity of 3.42 U/g(ds) and enzyme productivity of 128.5x10(-3) U x g(ds)(-1) x h(-1).


A recombinant baculovirus-expressed S glycoprotein vaccine elicits high titers of SARS-associated coronavirus (SARS-CoV) neutralizing antibodies in mice.
A recombinant SARS-CoV spike (S) glycoprotein vaccine produced in insect cells in a pre-clinical development stage is described. A truncated version of S glycoprotein, containing only the ecto-domain, as well as a His-tagged full-length version were cloned and expressed in a serum-free insect cell line, ExpresSF+. The proteins, purified to apparent homogeneity by liquid column chromatography, were formulated without adjuvant at 3, 9, 27, and 50 microg per dose in phosphate saline and used to immunize mice. Both antigens in each formulation elicited a strong immune response after two or three vaccinations with the antigen. Neutralizing antibody titers correlated closely with standard ELISA reactivity against the S glycoprotein. The truncated S protein was also formulated with an adjuvant, aluminum hydroxide, at 1 microg per dose (+/-adjuvant), and 5 microg per dose (+/-adjuvant). Significantly enhanced immune responses, manifested by higher titers of serum ELISA and viral neutralizing antibodies, were achieved in adjuvanted groups with fewer doses and lower concentration of S glycoprotein. These findings indicate that the ecto-domain of SARS-CoV S glycoprotein vaccine, with or without adjuvant, is immunogenic and induces high titers of virus neutralizing antibodies to levels similar to those achieved with the full S glycoprotein vaccine.


Mapping the co-benefits of climate change action to issues of public concern in the UK: a narrative review.
To avoid a 1·5°C rise in global temperatures above preindustrial levels, the next phase of reductions in greenhouse gas emissions will need to be comparatively rapid. Linking the co-benefits of climate action to wider issues that the public are concerned about can help decision makers to prioritise decarbonisation options that increase the chance of public support for such changes, while ensuring that a just transition is delivered. We identified key issues of concern to the UK public by use of Ipsos MORI public opinion data from 2007 to 2020 and used these data to guide a narrative review of academic and grey literature on the co-benefits of climate change action for the UK. Correspondence with civil servants, third sector organisations, and relevant academics allowed us to identify omissions and to ensure policy relevance of the recommendations. This evidence-based Review of the various co-benefits of climate change action for the UK identifies four main areas: health and the National Health Service; security; economy and unemployment; and poverty, housing, and inequality. Associated trade-offs are also discussed. City-level and regional-level governments are particularly well placed to incorporate co-benefits into their decision making because it is at this scale that co-benefits most clearly manifest, and where interventions can have the most immediate effects.


Acute colonic diverticulitis.
Colonic diverticulosis is truly a disease of the 20th century. A direct correlation is thought to exist between the incidence of diverticular disease and the amount of dietary fiber. Acute colonic diverticulitis occurs in approximately 25 per cent of the patients with diverticula, and 20 per cent of the patients with diverticulitis will ultimately require surgical intervention. Because of the often virulent nature of the disease in younger patients and the prevalence in the geriatric population, an aggressive approach is advocated. Primary resection of the involved segment of colon is advocated in all cases requiring operation. A primary anastomosis can be constructed in stage I and some cases of stage II disease. This results in lower morbidity and mortality rates as well as fewer days of hospitalization and disability. Newer techniques such as diagnostic CT scanning, percutaneous drainage of diverticular abscess, and greater application of surgical stapling devices have done much to improve the ultimate outcome of colonic diverticulitis.


Effects of folate supplementation on recurrence and metabolic status of cervical intraepithelial neoplasia grade 2/3 in overweight and obese women: a randomized double-blind placebo-controlled trial.
Inconsistent evidence showed that folate supplementation may be associated with reduced risk of cancer due to improved metabolic profiles and reduced markers of oxidative stress and inflammation. The aim of this investigation was to quantify the effects of folate supplementation on the recurrence and other metabolic factors of women with cervical intraepithelial neoplasia grade 2/3 (CIN2/3). This randomized, double-blind, placebo-controlled clinical trial was performed among 60 overweight/obese women with CIN2/3. Definitive CIN2/3 confirmation was done via biopsy, pathological diagnosis, as well as colposcopy. Participants were randomly assigned to the intervention group to take 5 mg/day folate supplements or placebo group (n = 30 in each group) for 12 weeks. The results of the current study showed a non-significant decrease in recurrence of CIN2/3 in the folate group in comparison with the placebo group (3.3% vs. 16.7%, P = 0.08). Compared with the placebo, folate supplementation significantly decreased plasma homocysteine (Hcy) levels (P < 0.001), serum insulin values (in the crude model) (P = 0.01), and homeostasis model assessment of insulin resistance (P = 0.01). Also, folate supplementation resulted in a significant improvement in the quantitative insulin sensitivity check index (P = 0.002) and total antioxidant capacity (P = 0.04) and a significant reduction in high-sensitivity C-reactive protein (P = 0.015) in comparison with the placebo group. In conclusion, folate supplementation for 12 weeks among overweight/obese women with CIN2/3 showed a non-significant decrease in its recurrence and had beneficial effects on insulin sensitivity, inflammation, and oxidative stress markers.


Incidental findings in computed tomographic angiography for planning percutaneous aortic valve replacement: advanced age, increased cancer prevalence?
Increased age is linked with a higher cancer risk according to model calculations. Patients with severe atherosclerotic aortic stenosis are of old age, therefore, a high incidence of malignancies should be found. To evaluate the prevalence of clinically significant and potentially malignant incidental findings at computed tomographic angiography (CTA) performed in patients with severe aortic stenosis being assessed as to their suitability for transcatheter aortic valve replacement (TAVR). Between August 2008 and April 2010, CTA of the thoraco-abdominal aorta and the pelvic arterial vessels was performed in 131 patients. There were 62 women (47%) and 69 men (53%); the mean age was 81.6 years (range, 64-91 years). Incidental findings were recorded and categorized as potentially malignant, clinically significant, and clinically insignificant. Clinically significant findings were defined as those requiring immediate therapy, intervention or imaging, or follow-up examination. Of the 131 study patients, 31 (23.7%) presented significant extravascular incidental findings, 19 (14.5%) in the thorax, and 12 (9.2%) in the abdomen. Five lesions (3.8%) were considered potentially malignant, three of them (2.3%) were new and highly suspicious for malignancies (two renal cell carcinomas and one hepatocellular carcinoma). In two patients (1.5%) mediastinal lymphadenopathy was found (recurrent malignant lymphoma und new metastases from known bladder cancer). The prevalence of highly suspicious malignant incidental findings in patients undergoing TAVR is 3.8% with an average age of 81.6 years which is not high compared to prevalence in the literature dealing with patients aged <70 years.


Three-Finger Toxin Diversification in the Venoms of Cat-Eye Snakes (Colubridae: Boiga).
The Asian genus Boiga (Colubridae) is among the better studied non-front-fanged snake lineages, because their bites have minor, but noticeable, effects on humans. Furthermore, B. irregularis has gained worldwide notoriety for successfully invading Guam and other nearby islands with drastic impacts on the local bird populations. One of the factors thought to allow B. irregularis to become such a noxious pest is irditoxin, a dimeric neurotoxin composed of two three-finger toxins (3FTx) joined by a covalent bond between two newly evolved cysteines. Irditoxin is highly toxic to diapsid (birds and reptiles) prey, but roughly 1000 × less potent to synapsids (mammals). Venom plays an important role in the ecology of all species of Boiga, but it remains unknown if any species besides B. irregularis produce irditoxin-like dimeric toxins. In this study, we use transcriptomic analyses of venom glands from five species [B. cynodon, B. dendrophila dendrophila, B. d. gemmicincta, B. irregularis (Brisbane population), B. irregularis (Sulawesi population), B. nigriceps, B. trigonata] and proteomic analyses of B. d. dendrophila and a representative of the sister genus Toxicodryas blandingii to investigate the evolutionary history of 3FTx within Boiga and its close relative. We found that 92.5% of Boiga 3FTx belong to a single clade which we refer to as denmotoxin-like because of the close relation between these toxins and the monomeric denmotoxin according to phylogenetic, sequence clustering, and protein similarity network analyses. We show for the first time that species beyond B. irregularis secrete 3FTx with additional cysteines in the same position as both the A and B subunits of irditoxin. Transcripts with the characteristic mutations are found in B. d. dendrophila, B. d. gemmicincta, B. irregularis (Brisbane population), B. irregularis (Sulawesi population), and B. nigriceps. These results are confirmed by proteomic analyses that show direct evidence of dimerization within the venom of B. d. dendrophila, but not T. blandingii. Our results also suggest the possibility of novel dimeric toxins in other genera such as Telescopus and Trimorphodon. All together, this suggests that the origin of these peculiar 3FTx is far earlier than was appreciated and their evolutionary history has been complex.


Intravascular hemolysis in the late course of aortic valve.
The degree of intravascular hemolysis was evaluated in 315 patients in the late course of aortic valve replacement. Starr-Edwards aortic ball valves of series 2300 caused significantly more hemolysis than did those of series 1200, as estimated from the serum lactate dehydrogenase levels. Smaller valves of series 2300 caused a higher degree of hemolysis than did the larger ones. Aortic disc valves induced a more moderate red cell destruction than did the ball valves, the Lillehei-Kaster significantly more than the Bjørk-Shiley prostheses. Crushing of red cells is thought to be a more important cause of hemolysis than shearing forces in turbulent blood. Hemolytic anemia represented a problem only in some patients with Starr-Edwards valve type 2300, although iron substitution was necessary also in some with other prostheses, since the hemoglobin-binding capacity of haptoglobin was exceeded in several patients. Valvular or paravalvular leakage was associated with stronger hemolysis in some patients, and should be suspected whenever the rate of red cell destruction increases. Longstanding intravascular hemolysis did not seriously affect renal function.


Developing a protocol for normothermic ex-situ limb perfusion.
Ischemia time represents a significant limitation for successful extremity transplantation because of the rapid deterioration of ischemic muscle. Normothermic ex-situ preservation is an emergent method to prolong the organ viability following procurement, by replicating the physiologic conditions. The aim of this study was to develop an ex-situ normothermic limb perfusion system to preserve the viability and function of porcine limbs for 12 hours following procurement. A total of 18 swine limbs were perfused. Thirteen limbs were used to develop the perfusion protocol. Five limbs were perfused according to the optimized protocol. These limbs were perfused at 39°C for twelve hours using an oxygenated colloid solution containing red blood cells. Glucose and electrolytes were kept within physiologic range by partial perfusate exchange. Limb specific perfusion quality was assessed by muscle contractility upon electrical nerve stimulation, compartment pressure, creatine kinase (CK) and myoglobin concentrations, tissue oxygen saturation (near infrared spectroscopy), indocyanine green angiography, and infrared radiation by thermographic imaging. The last five limbs reached the 12 hours' perfusion target maintaining normal compartment pressure (16.4 ± 8.20 mmHg), minimal weight increase (0.54 ± 7.35%), and mean muscle temperature of 33.6 ± 1.67°C. Myoglobin and CK concentrations were 875 ± 291.4 ng/mL, and 53344 ± 14850.34 U/L, respectively, at the end of perfusion. Muscle contraction was present in all limbs until cessation of perfusion. Differences in uniformity and quality of distal perfusion were identified with thermography and angiography imaging at 12 hours of perfusion. Ex-situ normothermic limb perfusion preserves swine limb physiology and function for at least 12 hours.


Prediction of Renal Allograft Acute Rejection Using a Novel Non-Invasive Model Based on Acoustic Radiation Force Impulse.
Point shear wave elastography based on acoustic radiation force impulse is a novel technology used to quantify tissue stiffness by measuring shear wave speed. A total of 115 kidney transplantation recipients were consecutively enrolled in this prospective study. The patients were subdivided into two groups using 1 mo post-transplantation as the cutoff time for determining the development of acute rejection (AR). Shear wave speed was significantly higher in the AR group than in the non-AR group. We created a model called SEV, comprising shear wave speed, estimated glomerular filtration rate and kidney volume change, that could successfully discriminate patients with or without AR. The area under the receiver operating characteristic curve of SEV was 0.89, which was higher than values for other variables; it was even better in patients within 1 mo post-transplantation (0.954), but was lower than the estimated glomerular filtration rate in patients after 1 mo post-transplantation. Therefore, the SEV model may predict AR after renal transplantation with a high degree of accuracy, and it may be more useful in the early post-operative stage after renal transplantation.


In situ forming implants - an attractive formulation principle for parenteral depot formulations.
In the area of parenteral controlled release formulations, in situ forming implants (ISFI) are attractive alternatives to preformed implants and microparticles. ISFI avoid the use of large needles or microsurgery and they can be manufactured in simple steps with a low requirement of equipment and processes. They are injected as low viscous solutions and transform in the body to a gel or solid depot. Different triggers can be used to stimulate this transformation: (1) in situ cross-linking, (2) in situ solidifying organogels, and (3) in situ phase separation. The review discusses the principles and the pros and cons of each strategy. It also gives examples of clinically used products or systems which are currently in clinical trials. Although the principle of ISFI is so attractive, key issues remain to be solved. They include (i) variability of the implant shape and structure, (ii) avoidance of burst release during implant formation, and (iii) toxicity issues. Unfortunately, until now our knowledge concerning the detailed processes of the implant formation is still very limited. This is due to the fact that the processes of implant formation and degradation, drug release and tissue response are complex, heterogeneous, interconnected and not easy to follow, especially in vivo. Despite this statement, many efforts are made in industry and academia to improve current approaches. New materials and approaches enter the preclinical and clinical phases and one can be sure, that ISFI will gain further clinical importance within the next years.