Factors influencing patients with stage 5 chronic kidney disease to opt for conservative management: a practitioner research study.
This study explored decision-making experiences of patients with stage 5 chronic kidney disease when opting for conservative management of their renal failure. Dialysis is an invasive treatment, and for some older patients, there is an associated treatment burden of dialysis-related symptoms. An alternative choice is conservative management, but little is known about those who make this decision and how they are supported through the process. Qualitative practitioner research study. Data were generated from nine patients' naturally occurring clinic consultations with a renal clinical nurse specialist between May 2010 - July 2010. Interviews were transcribed verbatim and findings fed back at three multi-disciplinary meetings to check for relevance and resonance. Common themes were identified and codes applied. Patients reported age and having to travel three times a week to hospital for dialysis as reasons not to opt for treatment. Others felt well without dialysis not wanting to upset the 'status quo' or to burden loved ones. Most felt equipped to make the decision following explanation and discussion with the clinical nurse specialist in the renal clinic. Patients opting for conservative management give numerous reasons for this including old age, travel limitations, feeling well without dialysis and not wanting to be a burden, but appear content with their decision. One-to-one discussions with the clinical nurse specialist appear helpful during the decision-making process presenting an opportunity for advancing nursing roles in the chronic kidney disease service. Understanding patients' reasons for refusing dialysis assists in supporting until death. There is an opportunity for developing nursing practice to meet the multi-faceted needs of this group.


Imported chikungunya fever in Madrid.
Chikungunya Fever is a mosquito-transmitted viral disease that causes fever, rash and musculoskeletal complaints. The latest may persist for several months, or even years or developed a relapsing course, that deserve an adequate treatment. Due to the large outbreak declared in the Caribbean in 2013, imported cases of Chikungunya as well as the risk of autochthonous transmission in case of available vectors have increased in non-endemic countries, like Spain. We described four cases of Chikungunya treated in our clinic.


Seasonal variations in nitrate content, total nitrogen, and nitrate reductase activities of macrophytes from a chalk stream in Upper Bavaria.
11 macrophytic species from a groundwater influenced chalk stream in Upper Bavaria were investigated during a period of one year in order to determine differences in the endogenous nitrate content, in total nitrogen content and in nitrate reductase activity (NRA). Nitrate concentrations of different plants taken from the same site of the river varied by a factor of approximately 103. A maximum of 1,958 μmol NO 3- g-1 dry w. could be measured in the petioles of Nasturtium officinale, which accounts for 12% of plant dry w. Very high values were also found in Callitriche obtusangula and Veronica angallis-aquatica. In comparison to the ambient water, mean accumulation rates of up to 131 could be found. In Fontinalis antipyretica, the plant poorest in nitrate, the ratio was only 1.24:1. Elodea canadensis belonged to a group of plants having very low nitrate concentrations. Since NRA was very low too, it is assumed that nitrogen nutrition of this species depends rather on ammonia than on nitrate. With a few exceptions nitrate content of different plant organs varied markedly. In general they were lowest in leaves and highest in shoot axes. Appreciable amounts of nitrate were also found in the roots of plants. No correlation could be found between endogenous nitrate content and NRA. In contrast to endogenous nitrate content and NRA, total nitrogen concentrations of the plants did not differ significantly.


Analysis of DNA double strand breakage and repair using orthogonal field alternation gel electrophoresis.
Orthogonal field alternation gel electrophoresis (OFAGE) allows separation of DNA molecules in the size range of 200 kb to 3000 kb. These sizes encompass the chromosome sizes of the genome of Saccharomyces cerevisiae. Using this technique, we have found that yeast cells exposed to X-rays generate a smear of DNA fragments corresponding to the products of random, independent double strand breaks, and that the bands corresponding to unbroken chromosomes decrease in intensity in direct proportion to chromosome size. If exposed wild type cells are permitted time to repair (5 h at 30 degrees C on YEPD), the fragments partially disappear and the chromosome bands reappear, although at less than normal intensity. In certain radiation-sensitive mutants (rad51, rad52 and rad54), the fragment smear appears following X-ray exposure but no repair of broken chromosomes occurs. In fact, loss of the fragments occurs; this could appear as partial repair using other procedures.


An encapsulated oncoytic neoplasm of follicular origin of thyroid, expressing neuroendocrine markers. A case report and literature review.
A case is reported of an oncocytic tumor of the thyroid expressing simultaneously follicular and neuroendocrine markers, but not calcitonin. The data reported in the literature and the possible relationships of these lesions with the calcintonin-negative medullary carcinomas were examined.


Orthography-phonology consistency in English: Theory- and data-driven measures and their impact on auditory vs. visual word recognition.
Research on orthographic consistency in English words has selectively identified different sub-syllabic units in isolation (grapheme, onset, vowel, coda, rime), yet there is no comprehensive assessment of how these measures affect word identification when taken together. To study which aspects of consistency are more psychologically relevant, we investigated their independent and composite effects on human reading behavior using large-scale databases. Study 1 found effects on adults' naming responses of both feedforward consistency (orthography to phonology) and feedback consistency (phonology to orthography). Study 2 found feedback but no feedforward consistency effects on visual and auditory lexical decision tasks, with the best predictor being a composite measure of consistency across grapheme, rime, OVC, and word-initial letter-phoneme. In Study 3, we explicitly modeled the reading process with forward and backward flow in a bidirectionally connected neural network. The model captured latent dimensions of quasi-regular mapping that explain additional variance in human reading and spelling behavior, compared to the established measures. Together, the results suggest interactive activation between phonological and orthographic word representations. They also validate the role of computational analyses of language to better understand how print maps to sound, and what properties of natural language affect reading complexity.


Distinct EGFR Mutation Pattern in Patients With Non-Small Cell Lung Cancer in Xuanwei Region of China: A Systematic Review and Meta-Analysis.
In the Xuanwei region of China, lung cancer incidence and mortality are among the highest in China, attributed to severe air pollution generated by combustion of smoky coal. No study has yet comprehensively evaluated the prevalence of epidermal growth factor receptor (EGFR) mutation characteristics in patients with non-small cell lung cancer (NSCLC) in Xuanwei. This meta-analysis was designed to analyze the EGFR mutation pattern in NSCLC patients in Xuanwei region of Yunnan Province in China. Electronic databases were comprehensively searched and relevant literatures were retrieved. The odds ratio (OR) for EGFR mutations between Xuanwei region and non-Xuanwei region was calculated, and the absolute incidence of EGFR mutations in Xuanwei was pooled by mutation subtype. Seven studies involving 1,355 patients with NSCLC from Yunnan Province (442 in Xuanwei and 913 in other regions) were included. The EGFR mutation rate ranged between 30.19% and 55.56%. Higher uncommon EGFR mutations (OR: 5.69, 95%CI: 2.23-14.49, P<0.001) and lower common EGFR mutations (OR: 0.18, 95%CI: 0.07-0.45, P<0.001) were found in Xuanwei region, compared with non-Xuanwei region. Specifically, the uncommon EGFR mutation rate was 59.50% and common EGFR mutation rate was 40.50% in Xuanwei. The mutation incidence of exon 18 G719X (OR: 3.21, 95%CI: 1.48-6.97, P=0.003), exon 20 S768I (OR: 6.44; 95%CI: 2.66-15.60; P<0.001), and exon 18 G719X + 20 S768I (OR: 6.55; 95%CI: 1.92-22.33; P=0.003) in Xuanwei were significantly higher, while the frequency of 19 deletion (OR: 0.28, 95%CI: 0.11-0.77, P<0.001) and 21 L858R mutation (OR: 0.51, 95%CI: 0.31-0.84, P=0.007) were lower. The results highlight the distinct EGFR mutation spectrum of NSCLC patients in Xuanwei region compared with other regions, with higher uncommon mutations but lower common mutations. The distinct Xuanwei featured genetic variations provide a unique model to further study carcinogenesis of lung cancer.


Hydroxyl substituted benzoic acid/cinnamic acid derivatives: Tyrosinase inhibitory kinetics, anti-melanogenic activity and molecular docking studies.
The inhibition of tyrosinase is an established strategy for treating hyperpigmentation. Our previous findings demonstrated that cinnamic acid and benzoic acid scaffolds can be effective tyrosinase inhibitors with low toxicity. The hydroxyl substituted benzoic and cinnamic acid moieties of these precursors were incorporated into new chemotypes that displayed in vitro inhibitory effect against mushroom tyrosinase. The most active compound, (2-(3-methoxyphenoxy)-2-oxoethyl (E)-3-(4-hydroxyphenyl) acrylate) 6c, inhibited tyrosinase with an IC50 of 5.7 µM, while (2-(3-methoxyphenoxy)-2-oxoethyl 2, 4-dihydroxybenzoate) 4d had an IC50 of 23.8 µM. In comparison, the positive control, kojic acid showed tyrosinase inhibition with an IC50 = 16.7 µM. Analysis of enzyme kinetics revealed that 6c and 4d displayed noncompetitive reversible inhibition of the second tyrosinase enzymatic reaction with Ki values of 11 µM and 130 µM respectively. In silico docking studies with mushroom tyrosinase (PDB ID 2Y9X) predicted possible binding modes in the catalytic site for these active compounds. The phenolic para-hydroxy group of the most active compound 6c is predicted to interact with the catalytic site Cu++ ion. The methoxy part of this compound is predicted to form a hydrogen bond with Arg 268. Compound 6c had no observable toxic effects on cell morphology or cell viability at the highest tested concentration of 91.4 µM. When dosed at 91.4 µM onto B16F10 melanoma cells in vitro6c showed anti-melanogenic effects equivalent to kojic acid at 880 µM. 6c displayed no PAINS (pan-assay interference compounds) alerts. Our results show that compound 6c is a more potent tyrosinase inhibitor than kojic acid and is a candidate for further development. Our exposition of the details of the interactions between 6c and the catalytic pocket of tyrosinase provides a basis for rational design of additional potent inhibitors of tyrosinase, built on the cinnamic acid scaffold.


Age-related disturbance of memory and CREB phosphorylation in CA1 area of hippocampus of rats.
In the early process of long-term memory formation, cyclic AMP response element-binding protein (CREB), a transcription factor on which multiple signal transduction pathways converge, has been implicated. We examined whether the age difference in the performance of contextual fear conditioning (CFC) is associated with a change in activation of CREB in the hippocampus which is an important neural structure for long-term memory. The activation of CREB in the hippocampus in young (15 weeks old) and old (120 weeks old) male rats was determined immunohistochemically with an antibody that specifically recognizes the phosphorylated form of CREB (pCREB). Young rats exhibited better performance than old rats with respect to the freezing time in CFC. Phosphorylation of CREB as revealed by the ratio of the pCREB-immunoreactive cell number to the CREB-immunoreactive cell number was increased in the CA1 region, but not in other hippocampal regions following training for CFC. The close relationship between behavioral performance and CREB phosphorylation in the CA1 region suggests that hippocampal CREB is involved in age-related decline of learning and memory.


Seven days treatment with the angiotensin II type 2 receptor agonist C21 in hospitalized COVID-19 patients; a placebo-controlled randomised multi-centre double-blind phase 2 trial.
COVID-19 morbidity and mortality remains high and the need for safe and effective drugs continues despite vaccines. Double-blind, placebo-controlled, multi-centre, randomised, parallel group phase 2 trial to evaluate safety and efficacy of oral angiotensin II type 2 receptor agonist C21 in hospitalized patients with COVID-19 and CRP ≥ 50-150 mg/L conducted at eight sites in India (NCT04452435). Patients were randomly assigned 100 mg C21 bid or placebo for 7 days in addition to standard of care. Primary endpoint: reduction in CRP. The study period was 21 July to 13 October 2020. 106 patients were randomised and included in the analysis (51 C21, 55 placebo). There was no significant group difference in reduction of CRP, 81% and 78% in the C21 and placebo groups, respectively, with a treatment effect ratio of 0.85 [90% CI 0.57, 1.26]. In a secondary analysis in patients requiring supplemental oxygen at randomisation, CRP was reduced in the C21 group compared to placebo. At the end of the 7-day treatment, 37 (72.5%) and 30 (54.5%) of the patients did not require supplemental oxygen in the C21 and placebo group, respectively (OR 2.20 [90% CI 1.12, 4.41]). A post hoc analysis showed that at day 14, the proportion of patients not requiring supplemental oxygen was 98% and 80% in the C21 group compared to placebo (OR 12.5 [90% CI 2.9, 126]). Fewer patients required mechanical ventilation (one C21 patient; four placebo patients), and C21 was associated with a numerical reduction in the mortality rate (one vs three in the C21 and placebo group, respectively). Treatment with C21 was safe and well tolerated. Among hospitalised patients with COVID-19 receiving C21 for 7 days there was no reduction in CRP compared to placebo. However, a post-hoc analysis indicated a marked reduction of requirement for oxygen at day 14. The day 14 results from this study justify further evaluation in a Phase 3 study and such a trial is currently underway. Vicore Pharma AB and LifeArc, UK.


Time-dependent loss of mitochondrial function precedes progressive histologic cartilage degeneration in a rabbit meniscal destabilization model.
The goals of this work were to characterize progression of osteoarthritic cartilage degeneration in a rabbit medial meniscus destabilization (MMD) model and then to use the model to identify pre-histologic disruptions in chondrocyte metabolism under chronically elevated joint contact stresses in vivo. To characterize PTOA progression, 24 rabbits received either MMD or sham surgery. Limb loading was analyzed preoperatively and at regular postoperative intervals using a Tekscan pressure-sensitive walkway. Animals were euthanized 8 (n = 8 MMD; n = 8 sham) or 26 weeks (n = 8 MMD) postoperatively for histological cartilage evaluation by an objective, semi-automated Mankin scoring routine. To examine pre-histologic pathology, MMD was performed on an additional 20 rabbits, euthanized 1 (n = 9) or 4 weeks (n = 10) postoperatively. Chondrocytes were harvested fresh for measurement of mitochondrial function, an intracellular indicator of pathology after mechanical injury. Both MMD and sham surgery caused slight decreases in limb loading which returned to preoperative levels after 2 weeks. Histologically apparent cartilage damage progressed from 8 to 26 weeks after MMD. Changes in chondrocyte respiration were variable at 1 week, but by 4 weeks postoperatively chondrocyte mitochondrial function was significantly reduced. Many human injuries that lead to PTOA are relatively mild, and the cell-level mechanisms leading to disease remain unclear. We have documented PTOA progression in an animal model of subtle joint injury under continued use, and demonstrated that this model provides a realistic environment for investigation of multi-stage cellular pathology that develops prior to overt tissue degeneration and which could be targeted for disease modifying treatments. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:590-599, 2017.


Antihypertensive effects of Korean wild simulated ginseng (Sanyangsam) extracts in spontaneously hypertensive rats.
Ginseng possesses a wide spectrum of medicinal effects and has widely been used in traditional medicine for thousands of years. In this study, the antihypertensive effect of Korean wild simulated ginseng in spontaneously hypertensive rats was investigated. Three groups of hypertensive rats-a group without wild simulated ginseng treatment; another group treated with 100 mg of wild simulated ginseng extract/kg of body weight; and the other group treated with 200 mg of wild simulated ginseng extract/kg of body weight were tested over 8 weeks. The two wild simulated ginseng-treated groups showed significantly (p < 0.05) reduced systolic blood pressure at 4 and 6 weeks of wild simulated ginseng treatment. However, the wild simulated ginseng treatment did not adversely affect the food intake, serum electrolytes, osmolality, heart weight, heart rate, and the cross-section of the aorta as well as enzyme activities. The results suggested that Korean wild simulated ginseng is effectively used for reducing high systolic blood pressure in hypertensive patients without causing adverse health effects.


Quantification of mitral and tricuspid regurgitation by the proximal flow convergence method using two-dimensional colour Doppler and colour Doppler M-mode: influence of the mechanism of regurgitation.
In patients with mitral (n=77: organic=49, functional=28) and tricuspid regurgitation (n=55: functional=54) quantified by angiography, the temporal variation of the proximal flow convergence region throughout systole was assessed by colour Doppler M-Mode, and peak and mean radius of the proximal isovelocity surface area for 28 cm/s blood flow velocity were measured. Additionally, the peak radius derived from two-dimensional colour Doppler was obtained. About 50% of the patients with mitral and tricuspid regurgitation showed a typical temporal variation of the flow convergence region related to the mechanism of regurgitation. The different proximal isovelocity surface area radii were similarly correlated to the angiographic grade in mitral and tricuspid regurgitation (rank correlation coefficients 0.55-0.89) and they differentiated mild to moderate (grade < or =II) from severe (grade > or =III) mitral and tricuspid regurgitation with comparable accuracy (82-96%). However, moderate mitral regurgitation due to leaflet prolapse in two patients was correctly classified by the mean M-mode radius and overestimated by both peak radii. Only half of the patients showed a typical variation of the flow convergence region related to the mechanism of regurgitation. The different proximal isovelocity surface area radii were suitable to quantify mitral and tricuspid regurgitation in most patients. However, in mitral regurgitation due to leaflet prolapse the use of the mean M-mode radius may avoid overestimation.


Is there progression of endolymphatic hydrops in Ménière's disease? Longitudinal magnetic resonance study.
Endolymphatic hydrops (EH) is universal in Ménière´s disease (MD). Given its chronic course, with variable interval before complete clinical picture is installed, it seems relevant to understand the progression of vestibular EH and hemato-perilymphatic barrier disruption in patients with MD and monosymptomatic presentations. 239 consecutive patients were referred to us with suspected hydropic ear disease. 50 individuals accepted to participate in this study-final longitudinal sample included 24 patients (7 D1, 7 D2, 10 D3). Control group included ten patients. At recruitment, a clinical and MRI re-evaluation was done (3T, intravenous technique) (MR2) and 2 years after MRI was repeated (MR3). Previous MRI (MRI1) were retrospectively evaluated. Patients were classified as definite (D1), possible (D2) and atypical (D3-monosymptomatic) MD. Control group included non-typical symptoms (C2/C3) and 6 asymptomatic (C1). Vestibular endolymphatic ratio (vER) and grading, presence/absence of cochlear EH, asymmetry of cochlear perilymphatic enhancement, and rate of progression of vER were assessed by two independent neuroradiologists and compared between patient and control groups (index ear). EH was universal and pronounced in D1 and remained stable. vER progression was more variable and higher in some D3 patients (index ear worse) and in D2 (non-index), although this observation was not statistically significant. Considering that many probable and monosymptomatic presentations progress years later into definite MD and given the bilateral tendency of the disease, these findings may indicate that there is an initial accelerated worsening of EH in initial stages of the disease. These data should be confirmed with controlled and larger sample studies.


Selective alpha-1a adrenergic receptor antagonists. Effects of pharmacophore regio- and stereochemistry on potency and selectivity.
The anti-anxiety agent ipsapirone has been shown to have modest affinity for alpha-1 receptors. We disclose the discovery of potent alpha-1a receptor subtype selective antagonists based on the ipsapirone structure which possess selectivity versus the 5-HT receptors tested. These antagonists were obtained by tethering a saccharin ring to 4-phenyl-3-carboxyethyl piperidines. The design principles which led to this structural motif are discussed. The synthesis of key analogs, their SAR, as well as results of selected in vitro and in vivo studies are described.


Efficient lipase purification using reverse micellar extraction.
Reverse micellar extraction (RME) of enzyme provides an attractive option for conventional method with the potential to achieve purification and concentration in a single step with high yield. This study presents a methodology for optimization of RME with Pseudomonas lipase as model system. Fold-purification, percent recovery and extraction time were the objective functions while the type and concentration of surfactant, contact time, pH, ionic strength, and the ratio of organic to aqueous phase were the decision variables. Under optimized conditions, the AOT (Aerosol OT (bis 2-ethylhexyl) sodium sulfosuccinate)-isooctane system gave a 15-fold purification, 80% recovery and 2.5-fold concentration of the Pseudomonas lipase with process time of 45 min.


Diagnostic accuracy of angiography-based vessel fractional flow reserve after chronic coronary total occlusion recanalization.
Angiography-based vessel fractional flow reserve (vFFR) demonstrated a strong correlation with invasive fractional flow reserve (FFR) in both a pre- and post-percutaneous coronary intervention (PCI) setting. However, the role of vFFR and its correlation with post-PCI FFR in chronic coronary occlusions (CTO) has not been evaluated yet. We sought to investigate the diagnostic performance of post-PCI vFFR with post-PCI FFR as a reference in patients undergoing successful CTO PCI. Between March 2016 and April 2020, a total of 80 patients from the FFR-SEARCH (prospective registry) and FFR REACT (randomized controlled trial) studies underwent successful CTO recanalization with post-PCI FFR measurements. A total of 50 patients (median age 66 (interquartile range [IQR]: 56-74) years, 76% were male) were eligible for the analysis. Median post-PCI FFR was 0.89 (IQR: 0.84-0.94), while median post-PCI vFFR was 0.91 (IQR: 0.85-0.94) (p 0.10). Suboptimal physiological results, defined as FFR and vFFR <0.90, were identified in 26 (52%) and in 21 (42%) patients, respectively. A strong correlation (r = 0.82) was found between vFFR and FFR with a mean bias of 0.013 ± 0.051. Receiver-operating characteristics curve analysis revealed an excellent accuracy of vFFR in predicting FFR <0.90 (area under the curve: 0.97; 95% confidence interval: 0.93-1.00). Post-PCI vFFR shows a good correlation with post-PCI FFR and a high diagnostic accuracy for post-PCI FFR ≤0.90 in patients undergoing successful PCI of a CTO lesion.


Purification of foamy viral particles.
Foamy viruses are non-pathogenic retroviruses and represent a tool for vector development. For gene therapy applications and for analyses of viral protein composition infectious particles need to be purified, which has been difficult for foamy viruses in the past. Here, we describe a novel, simple, and fast purification method for prototype foamy viruses with high purity using size exclusion and affinity chromatography. More than 99,9% of the contaminating proteins were removed. The purified viruses were used to determine the amount of the incorporated Pol protein relative to Gag. The determined Gag to Pol PR-RT ratio of 30:1 confirmed previous studies suggesting FV virions encapsidate fewer number of Pol molecules than orthoretroviruses.


The Repeatability and Reproducibility of a New Minimally Invasive Method for Orbital Pressure Measurement.
Evaluation of orbital pressure is crucial for monitoring various orbital disorders. However, there is currently no reliable technique to accurately measure direct orbital pressure (DOP). This study aimed to establish a new method for the DOP as well as to verify its repeatability and reproducibility in rabbits. The study included 30 normal eyes from fifteen 3-month-old New Zealand white rabbits. After administering inhalation anesthesia, intraocular pressure (IOP) was determined by tonometry (Tonopen). For DOP manometry, a TSD104 pressure transducer was inserted between the disposable injection needle and the syringe, and the output results were displayed on a computer. Two observers independently participated in the experiment to verify its repeatability and reproducibility. The mean IOP of rabbits was significantly higher than the DOP in normal rabbits (11.67 ± 1.08 mm Hg versus 4.91 ± 0.86 mm Hg, P < 0.001). No significant interocular difference was detected for both IOP and DOP ( P > 0.05). A high correlation was found for intraobserver measurements of both IOP (intraclass correlation coefficient = 0.87, P < 0.001) and DOP (intraclass correlation coefficient = 0.89, P < 0.001). A high agreement was also presented for the interobserver reproducibility for the measurements of IOP [Pearson correlation coefficient ( R ) = 0.86, P < 0.001] and DOP ( R = 0.87, P < 0.001). Direct orbital pressure was positively correlated with IOP in both observers ( R 1 = 0.66, R 2 = 0.62, P < 0.001). The Bland-Altman plots revealed that 5.0% (3/60) of the IOP and DOP measurement points were outside of the 95% limits of agreement, respectively. The TSD104 pressure transducer-based manometry may serve as a reliable device for the measurement of DOP, providing real-time measuring results with acceptable reproducibility and repeatability.


Oncocytic Renal Neoplasms on Resections and Core Biopsies: Our Approach to This Challenging Differential Diagnosis.
Distinguishing oncocytomas from their malignant mimics is very challenging. This review highlights our approach to classifying low-grade oncocytic tumors on both resections and biopsies. We also discuss how we use immunohistochemical stains in this challenging differential diagnosis.


Implementing change: evaluating the Accelerated Chest pain Risk Evaluation (ACRE) project.
To evaluate hospital length of stay (LOS) and admission rates before and after implementation of an evidence-based, accelerated diagnostic protocol (ADP) for patients presenting to emergency departments (EDs) with chest pain. Quasi-experimental design, with interrupted time series analysis for the period October 2013 - November 2015. Setting, participants: Adults presenting with chest pain to EDs of 16 public hospitals in Queensland. Implementation of the ADP by structured clinical re-design. Primary outcome: hospital LOS. ED LOS, hospital admission rate, proportion of patients identified as being at low risk of an acute coronary syndrome (ACS). Outcomes were recorded for 30 769 patients presenting before and 23 699 presenting after implementation of the ADP. Following implementation, 21.3% of patients were identified by the ADP as being at low risk for an ACS. Following implementation of the ADP, mean hospital LOS fell from 57.7 to 47.3 hours (rate ratio [RR], 0.82; 95% CI, 0.74-0.91) and mean ED LOS for all patients presenting with chest pain fell from 292 to 256 minutes (RR, 0.80; 95% CI, 0.72-0.89). The hospital admission rate fell from 68.3% (95% CI, 59.3-78.5%) to 54.9% (95% CI, 44.7-67.6%; P < 0.01). The estimated release in financial capacity amounted to $2.3 million as the result of reduced ED LOS and $11.2 million through fewer hospital admissions. Implementing an evidence-based ADP for assessing patients with chest pain was feasible across a range of hospital types, and achieved a substantial release of health service capacity through reductions in hospital admissions and ED LOS.


Quantification and localisation of angiotensin II receptors and angiotensin converting enzyme in the developing rat heart.
The aim was to determine the quantification and localisation of angiotensin II receptors and angiotensin converting enzyme (ACE) in the developing rat heart. Quantitative autoradiography was used to determine the density of [125I]Sar1-angiotensin II binding to angiotensin II receptors and the density of [125I]351A binding to ACE. Angiotensin II receptors were first detected in the myocardium on embryonic day 14, and reached a maximum density within the first postnatal week. During the perinatal period, the density of angiotensin II receptors was twofold higher in atrial than in ventricular myocardium [27(SEM 7) v 11(1) fmol.mg-1 protein]. By adulthood, however, the density of angiotensin II receptors did not differ between atria and ventricles. A high density of angiotensin II receptors was first detected in the cardiac vasculature on embryonic day 19, with binding density decreasing during development. During the embryonic and early postnatal periods, most of the binding in the cardiac vasculature was to AT2 receptors. ACE was first detected in the myocardium on the day of birth, with the density of binding to ACE increasing during development. On postnatal day 56, the density of binding to ACE was fourfold higher in atrial than in ventricular myocardium [99(22) v 22(4) fmol.mg-1 protein]. A moderate density of binding to ACE was first detected in the cardiac vasculature and heart valves on embryonic day 19, with binding density increasing during development. By adulthood, the density of binding to ACE was 10- to 25-fold higher in the cardiac vasculature and heart valves than in the myocardium. The density of angiotensin II receptors and the density of binding to ACE are developmentally regulated in the heart. Both AT1 and AT2 receptors were present in the rat heart by late gestation and could, therefore, mediate the effects of angiotensin II on early cardiac growth and development.


Supernatants from cultured human epidermal keratinocytes stimulate angiogenesis.
Conditioned media from three different strains of human epidermal keratinocytes in culture were assayed on the chorioallantoic membrane of the chick embryo. Vascular responses were examined 4 days later stereo-microscopically and compared with controls--unconditioned medium and medium incubated with 3T3 cells. Specimens were also collected after 1, 2, 3 and 4 days for serial histological examination. Media from all three strains of keratinocytes stimulated statistically significant vascular growth relative to controls. Leukocytic infiltration was not demonstrated histologically at any time. In addition, quantitation of ectodermal epithelial hyperplasia in experimental groups did not reveal any significant difference when compared with controls. These results have demonstrated that epidermis may directly encourage vascular growth in the absence of significant inflammation.


HLA histocompatibility antigens in open-angle glaucoma.
HLA-typing of 125 patients with open-angle glaucoma (glaucoma simplex) showed no statistically significant deviations from a control series of 1197 blood donors. Some earlier, but mutually inconsistent, reports contradict this result. In evaluating investigations of this kind care must be taken to avoid statistical pitfalls.


General Principles for the Safe Performance, Training, and Adoption of Ablation Techniques for Benign Thyroid Nodules: An American Thyroid Association Statement.
Background: The primary goal of this interdisciplinary consensus statement is to provide a framework for the safe adoption and implementation of ablation technologies for benign thyroid nodules. Summary: This consensus statement is organized around three key themes: (1) safety of ablation techniques and their implementation, (2) optimal skillset criteria for proceduralists performing ablative procedures, and (3) defining expectations of success for this treatment option given its unique risks and benefits. Ablation safety considerations in pre-procedural, peri-procedural, and post-procedural settings are discussed, including clinical factors related to patient selection and counseling, anesthetic and technical considerations to optimize patient safety, peri-procedural risk mitigation strategies, post-procedural complication management, and safe follow-up practices. Prior training, knowledge, and steps that should be considered by any physician who desires to incorporate thyroid nodule ablation into their practice are defined and discussed. Examples of successful clinical practice implementation models of this emerging technology are provided. Conclusions: Thyroid ablative procedures provide valid alternative treatment strategies to conventional surgical management for a subset of patients with symptomatic benign thyroid nodules. Careful patient and nodule selection are critical to the success of these procedures as is extensive pre-procedural patient counseling. Although these emerging technologies hold great promise, they are not without risk and require the development of a unique skillset and environment for optimal, safe performance and consistent outcomes.


FDG-PET Patterns Predict Amyloid Deposition and Clinical Profile in Corticobasal Syndrome.
Corticobasal syndrome (CBS) is an atypical parkinsonian syndrome related to multiple underlying pathologies. To investigate if individual brain [18 F]fluorodeoxyglucose-positron emission tomography (FDG-PET) patterns could distinguish CBS due to Alzheimer's disease (AD) from other pathologies based on [11 C]Pittsburgh Compound-B (PIB)-PET. Forty-five patients with probable CBS were prospectively evaluated regarding cognitive and movement disorders profile. They underwent FDG-PET and were distributed into groups: likely related to AD (CBS FDG-AD) or likely non-AD (CBS FDG-nonAD) pathology. Thirty patients underwent PIB-PET on a hybrid PET-magnetic resonance imaging equipment to assess their amyloid status. FDG and PIB-PET images were classified individually based on visual and semi-quantitative analysis, blinded to each other. Quantitative group analyses were also performed. CBS FDG-AD group demonstrated worse cognitive performances, mostly concerning attention, memory, visuospatial domains, and displayed more myoclonus and hallucinations. The non-AD metabolic group presented more often limb dystonia, ocular motor dysfunction, motor perseveration, and dysarthria. All patients classified as CBS FDG-AD tested positive at PIB-PET compared to 3 of 20 in the non-AD group. The individual FDG-PET classification demonstrated 76.92% of sensitivity, 100% of specificity and positive predictive value and 88.5% of balanced accuracy to detect positive PIB-PET scans. Individuals with positive and negative PIB-PET showed hypometabolism in posterior temporoparietal areas and in thalamus and brainstem, respectively, mainly contralateral to most affected side, disclosing possible metabolic signatures of CBS variants. FDG-PET was useful to predict AD and non-AD CBS variants depicting their specific degeneration patterns, different clinical features, and brain amyloid deposition. © 2020 International Parkinson and Movement Disorder Society.


Development of a droplet digital PCR method for detection of Streptococcus agalactiae.
Streptococcus agalactiae (GBS) is the causative pathogen of puerperal sepsis in pregnant women and pneumonia, sepsis and meningitis in infants. Infection of GBS is responsible for the increased morbidity in pregnant women and the elderly, and bring challenges to clinical diagnosis and treatment. However, culture-based approaches to detect S.agalactiae is time-consuming with limited sensitivity. Besides, real-time quantitative PCR demands expensive instruments with tedious steps. Thus, we aim to establish a new detection method for more accurate and rapid detection of S.agalactiae. The ddPCR primer targeted the CpsE gene showed better amplified efficiency in the reaction. The limit of detection for GBS DNA with ddPCR was able to reach 5 pg/μL. Moreover, no positive amplified signals could be detected in the reactions which served 11 non-GBS strains DNA as templates. Furthermore, the coefficient of variation of this method was 4.5%, indicating excellent repeatability of ddPCR assay. In our study, ddPCR was performed as a rapid detection of S.agalactiae with high sensitivity and specificity. This technique can promote the accuracy of the diagnosis of GBS infection and provide a scientific basis for clinical treatment.


Cancer-associated fibroblasts impact the clinical outcome and treatment response in colorectal cancer via immune system modulation: a comprehensive genome-wide analysis.
Cancer-associated fibroblasts (CAFs) in the tumour microenvironment are associated with poor prognosis and chemoresistance in multiple solid tumours. However, there is a lack of universal measures of CAFs in colorectal cancer (CRC). The aim of this study was to assess the utility of a fibroblast-related gene signature (FRGS) for predicting patient outcomes and reveal its relevant mechanism. The GSE39582 dataset, which includes 316 CRC patients who did not receive adjuvant chemotherapy was used as a discovery cohort to identify the prognostic fibroblast-related genes (FRGs). A total of 1352 CRC patients were divided into one training cohort (GSE39582, n = 461) and two validation cohorts (TCGA, n = 338; meta-validation, n = 553) for the construction of the FRGS and the verification of its prognostic value in stage II/III CRC patients. Functional annotation and analysis were performed to explore the underlying mechanism. The ability of the FRGS to predict immunotherapy response was further tested in a clear cell renal cell carcinoma (ccRCC) cohort. An 11-gene signature that had prognostic value for stage II/III CRC patients in both validation cohorts was developed (TCGA cohort: HR = 1.90, 95% CI 1.16-3.12, P < 0.01; meta-validation cohort: HR = 1.95, 95% CI 1.39-2.73, P < 0.001). A high level of CAFs was correlated with worse prognosis in CRC patients who did not receive adjuvant chemotherapy (HR = 3.63, 95% CI 2.24-5.88, P < 0.001). Importantly, patients in the low-risk group were found to be benefit from chemotherapy (P < 0.01), but not in the high CAF group (P > 0.05). Similar results were found in the TCGA cohort. Integrated with clinical characteristics, the FRGS was confirmed to be an independent prognostic factor in the multivariate analysis after adjustment for tumour TNM stage (GSE39582 cohort: HR = 3.19, 95% CI 1.88-5.41, P < 0.001; TCGA cohort: HR = 5.00, 95% CI 1.58-15.85, P = 0.007; meta-validation cohort: HR = 2.99, 95% CI 1.44-6.21, P = 0.003). Furthermore, the enrichment analysis found that the antitumour immune response was suppressed and the infiltration of CD4 T cells and M1 macrophages was depressed in the high CAF group. The FRGS was also found to have value in predicting for immunotherapy response in the ccRCC cohort. The 11-gene FRGS had independent prognostic value for CRC patients, as well as utility in the prediction of benefit from chemotherapy. CAFs in the tumour microenvironment might have an impact on the prognosis of CRC patients via inhibiting immune response.


Sacrococcygeal teratoma: A population-based study of incidence and prenatal prognostic factors.
Sacrococcygeal teratoma (SCT) is a rare congenital tumor associated with high rates of perinatal mortality and morbidity. This study evaluated the incidence, prenatal detection rate, and early predictors of a complicated outcome following diagnosis of SCT. We retrospectively identified all fetuses and newborns diagnosed with SCT in southern Sweden from 2000 to 2013. Prenatal sonograms, charts, and pathology reports were reviewed and analyzed. Each case of SCT was defined as complicated or uncomplicated based on the postnatal outcome. All cases with a fatal outcome or that required cardiac resuscitation during birth or surgery were classified as complicated. The overall incidence of SCT was 1:13,982 (19 children in a cohort of 265,658 live births). A prenatal diagnosis was made in 74% of cases, there were no stillbirths or intrauterine deaths, and the overall mortality rate was 11%. Four cases of SCT (21%) were classified as complicated, and these cases had a significantly larger tumor size at gestational week 20 (P=0.048), had a significantly higher tumor growth rate (P=0.003), and were more often associated with polyhydramnios (P=0.01), and mainly solid/mixed morphology (P=0.001). The incidence of SCT in southern Sweden was higher than those reported in most previous studies; however, the associated mortality rate was relatively low. Fetuses with large tumors, rapidly growing tumors, and polyhydramnios were more likely to experience a complicated outcome during the postnatal period.


Management of locally advanced HPV-related oropharyngeal squamous cell carcinoma: where are we?
HPV-related (HPV+) oropharyngeal cancer (OPC) has a better prognosis compared to HPV unrelated (HPV-) OPC. This review summarizes and discusses several of the controversies regarding the management of HPV+ OPC, including the mechanism of its treatment sensitivity, modern surgical techniques, chemotherapy regimens, and treatment de-intensification protocols. We also discuss and reconsider potential adverse prognostic factors such as tumor EGFR expression, tumor hypoxia, and patient smoking history, as well as the significance of retropharyngeal adenopathy. Finally, we discuss elective nodal treatment of uninvolved lymph node stations. While this review does not exhaust all controversies related to the management of HPV+ OPC, it aims to highlight some of the most clinically relevant ones.


Abol-Enein pouch modification after radical cystectomy in bladder rhabdomyosarcoma in 5 years old child during COVID-19 pandemic: A case report.
To discuss the consideration of performing radical cystectomy for rhabdomyosarcoma in children during the COVID-19 pandemic in the urology department of Adam Malik Hospital, Medan. Rhabdomyosarcoma is a rare malignancy that develops from primitive mesenchymal stem cells. The gold standard for the treatment of rhabdomyosarcoma is radical cystectomy. However, during the COVID-19 pandemic, radical cystectomy becomes a concern due to the risk of virus transmission. This article reported a patient who underwent radical cystectomy during the COVID-19 pandemic. A five-year-old female child was admitted to the hospital with chief complaints of bloody urine 1 month before admission. A month before hospital admission, the patient had pain during urination and was treated with radical cystectomy with Abol-Enein pouch modification. After the surgery, the patient was able to urinate without any disturbance. Hematuria was not found. There was no complaint related to stricture of the ureter after the surgery. In our center, radical cystectomy could be performed in child with bladder rhabdomyosarcoma during COVID-19 pandemic. The procedure is considered a high priority therapy in most regions during COVID-19 pandemic. Abol-Enein technique after radical cystectomy resulted in improvement of symptom with no reported complication in our case.


Circular Migration and Precarity: Perspectives from Rural Bihar.
Migration and mobilities are vastly underestimated in India. In particular, circular migration remains poorly captured as circular migrants move back and forth between source and destination regions. Based on survey data from rural Bihar, an important source region of migration in India, this paper finds that a vast majority of migrants work and live in precarity in predominantly urban and prosperous destinations across India. However, those at the lowest rungs of the social and economic ladder in source regions-the scheduled castes and scheduled tribes, other backward classes I and the labouring class-are the worst off at destination; they are part of the most precarious shorter-term migration streams, earn the lowest incomes, have the poorest conditions of work, and live in the harshest circumstances. The paper shows that social and economic hierarchies, and in turn, precarity in source region is reproduced at destination, and, thus, there is little evidence that spatial mobility is associated with social mobility. Focusing on migrants' location, work, employment, income, housing, and access to basic services at destination, the paper foregrounds migrant precarity and adds to a small body of empirical literature that is significant in understanding the spatial and structural elements of circular migration in India and in turn, the migration crisis that emerged as a result of the economic shock of the COVID 19 pandemic.


Percutaneous Vertebroplasty Versus Conservative Treatment and Rehabilitation in Women with Vertebral Fractures due to Osteoporosis: A Prospective Comparative Study.
Percutaneous vertebroplasty is commonly used in the management of osteoporosis-related vertebral fractures, although there is controversy on its superiority over conservative treatment. Here we compare pain and function in women with vertebral osteoporotic fractures who underwent percutaneous vertebroplasty versus conservative treatment with a protocolized rehabilitation program. A longitudinal and comparative prospective study was conducted. Women ≥ 60 years of age with a diagnosis of osteoporosis who had at least one vertebral thoracic or lumbar compression fracture were included and divided into two groups, conservative treatment or vertebroplasty. The Visual Analogue Scale (VAS) and Oswestry Disability Index (ODI) were used to assess pain and function, respectively, as the outcome measures. We included 31 patients, 13 (42%) treated with percutaneous vertebroplasty and 18 (58%) with conservative treatment. Baseline clinical characteristics, bone densitometry and fracture data were similar in both groups. At baseline, VAS was 73.1 ± 28.36 in the vertebroplasty group and 68.6 ± 36.1 mm in the conservative treatment group (p = 0.632); at three months it was 33.11 ± 10.1 vs. 42 ± 22.21 mm (p = 0.111); and at 12 months, 32.3 ± 11.21 vs. 36.1 ± 12.36 mm (p = 0.821). The ODI at baseline was 83% in the vertebroplasty group vs. 85% for conservative management (p = 0.34); at three months, 36 vs. 39% (p = 0.36); and at 12 months, 29.38 vs. 28.33% (p = 0.66). Treatment with percutaneous vertebroplasty had no advantages over conservative treatment for pain and function in this group of women ≥ 60 years of age with osteoporosis.


Rheological characteristics of faecal sludge from VIP latrines and implications on pit emptying.
This work aims at characterizing the rheological properties of faecal sludge from Ventilated Improved Pit (VIP) latrines and their implication on pit emptying. Faecal sludge was sampled from 3 pit latrines located in the eThekwini Municipality (Durban, South Africa). Samples were taken at different positions within the pit. For each of the samples, measurements in the rheometer in triplicates were performed in order to determine their rheological properties, and their moisture and ash content were measured also in triplicates. Experiments in the rheometer were performed for samples for which its moisture content was modified. In order to better understand the influence of water addition into the pit. During pit emptying, calculations were carried out from the experimental data, based in the criteria set in the Omni-Ingestor initiative, carried out by the Bill & Melinda Gates Foundation. Faecal sludge exhibited a shear thinning behaviour, i.e. a decrease in viscosity with increasing shear rate, and presented a yield stress comprised between 500 to 1000 Pa. This needs to be surpassed in order to overcome the elastic resistance of the sludge to flow. Similar viscosities were found for the samples from the different pits, irrespective of the position within the pit, except for the sample from the bottom of one of the pits for which it was not possible to induce a flow. This sample had a considerably lower moisture content (67% wet basis) compared to the other samples (around 80% wet basis), probably due to a higher biodegradation as it was the most aged sludge in the pit. According to the experimental results and calculations, the pumping requirements during pit emptying will decrease drastically by increasing the moisture content of the sludge. The addition of water into the pit would then facilitate the pit emptying operation by reducing the head and power required for pumping. However, this practice would require employing considerable amounts of water and handling higher volumes of sludge, which would lead to longer pit emptying times and increase the difficulty of the operation. For example, increasing the moisture content of the sludge from 75 to 90% will reduce the head and power of the pump by a factor 100, but will triplicate the amount of water in the sludge and, consequently, the time for pit emptying. Therefore, a compromise has to be made between increasing the pumping feasibility and adding water to the pit.


Comparison of the effects of amino-terminal synthetic parathyroid hormone-related peptide (PTHrP) of malignancy and parathyroid hormone on resorption of cultured fetal rat long bones.
We have compared the effects of of various synthetic amino-terminal forms of human parathyroid hormone-related peptide (PTHrP) of malignancy with synthetic parathyroid hormone (PTH) on the resorptive responses of fetal rat long bones in organ culture. PTH and PTHrP increased 45Ca release at concentrations of 0.1-25 nM. PTHrP (1-40) and bovine PTH (1-34) were more potent than human PTH (1-34) and PTHrP (1-34). However, the slopes of the dose-response curves and the maximal resorptive effects were similar. There was a marked decrease in the potency of amino-terminal PTHrP peptides as the length was decreased. PTHrP (1-29) and PTHrP (1-25) were inactive at 120 nM. Further comparison of bPTH (1-34) and PTHrP (1-34) showed that both could induce bone resorption after a brief (6 hours) exposure and that the response to PTHrP (1-34) was qualitatively similar to that of bPTH (1-34) with respect to enhancement by ACTH and inhibition by calcitonin and glucocorticoids. Hydroxyurea and indomethacin did not block the resorptive response to either agonist. Cyclic AMP production in response to PTHrP (1-34) and (1-40) was similar to that for bPTH (1-34) in ROS 17/2.8 cells. The cyclic AMP (cAMP) response was much smaller in fetal rat long bones and calvariae, and bPTH was more potent than PTHrP. These studies confirm that PTHrP is quantitatively similar in its effects on bone resorption to PTH and are consistent with the two agents acting on the same receptor.


Recurrent injection site reactions to vaccines: Two clinical patterns of presentation.
After administration of injectable vaccines, skin manifestations are common and they usually disappear in a few hours or days. We describe a case series of recurrent injection site reactions in 8 children undergoing vaccines of the regional immunization schedule, which required specialized evaluation and advice for subsequent vaccinations. Two clinical patterns of reactions were observed. Four children manifested recurrent wheal and erythema with pruritus at vaccine injection site for up to 7 months; the remaining children showed an itching plaque or nodule at injection site, that lasted several months after vaccination with exacerbations of pruritus and erythema. Hypersensitivity to aluminium salts was demonstrated in the second group. The flare-up manifestations, related to Meningococcal B vaccine in 5 reactions, were triggered by concurrent viral infections in two patients. Communication of risks and diagnostic testing, when appropriate, resulted important to reassure parents of children and favour adequate completion of vaccination.


Slow replenishment of carnitine deficiency after cessation of long-term treatment with pivaloyl-containing antibiotics.
Long-term treatment with pivampicillin and pivmecillinam for 6-24 months in five adults and one child reduced the total serum carnitine concentration to 3.7-14 mumol/l (reference value: 25-66 mumol/l). Muscle carnitine was reduced to 0.3-0.7 mumol/g wet weight (reference value: 3-5 mumol/g) in two cases. All patients had muscle symptoms with weakness, asthenia and pains. One showed signs of carnitine depletion in the liver with increased secretion of dicarboxylic acids (C6, C8, C10) in urine and limited ketone body formation during prolonged fasting. Serum carnitine increased slowly after cessation of therapy and reached normal concentrations after 6-12 months. All symptoms caused by carnitine depletion disappeared. This was achieved on a normal diet without carnitine supplementation.


[Digital transformation for more equitable and sustainable public health in the age of digital interdependenceTransformação digital para uma saúde pública mais equitativa e sustentável na era da interdependência digital].
This article describes eight guiding principles for the digital transformation of the health sector and identifies their relationship with the COVID-19 pandemic, as well as highlighting their importance to countries undergoing digital transformation processes. In the Region of the Americas, among other gaps, 30% of people do not have access to the Internet, which is why it is mandatory to develop policies and actions to deliver public health interventions equitably and sustainably to ensure that no one is left behind. The eight principles focus on the four areas of a sustainable health system - human, social, economic and environmental - and highlight the broader possibilities using digital technology to impact the sustainability of health systems.


T lymphocyte sensitization to HBcAg and T cell-mediated unresponsiveness to HBsAg in hepatitis B virus-related chronic liver disease.
Using a newly developed indirect T lymphocyte migration inhibition test, cell-mediated immunity to HBsAg and HBcAg was directly and simultaneously examined in a total of 21 patients with HBsAg-positive chronic liver disease (CLD), and in seven subjects whose sera contained anti-HBs (2 previous acute hepatitis B; 4 hepatitis B vaccine recipients and 1 chronic active hepatitis). T cell sensitization to HBcAg was invariably detected in the HBsAg-positive CLD patients tested (12/12), whereas T cell sensitization to HBsAg was not present in any of the patients (0/21). In contrast, T cell sensitization to HBsAg was present in all anti-HBs-positive subjects. These results support the hypothesis that the cellular immune response to HBcAg, rather than to HBsAg, is implicated in the pathogenesis of HBsAg-positive CLD. Moreover, the observation that the addition of T cells from patients with HBsAg-positive CLD to T cells from anti-HBs positive subjects in a ratio of 1 to 9 reversed their sensitization to HBsAg, suggests that a hyperactivity of HBsAg-specific suppressor T cell population may be responsible for persistent HBs antigenemia.


Bortezomib-based Chemotherapy for Multiple Myeloma Patients Without Comorbid Cardiovascular Disease Shows No Cardiotoxicity.
Proteasome inhibitors used in the treatment of multiple myeloma act primarily through the disruption of intrinsic cellular protein quality maintenance, resulting in proteotoxic stress, cellular dysfunction, and, ultimately, cell death. We assessed whether evidence has shown off-target myocardial dysfunction related to the administration of bortezomib-based chemotherapy for multiple myeloma. Patients aged 18 to 70 years who were free of significant cardiovascular disease were included. They underwent evaluations before and after each dose of bortezomib to assess for clinical, subclinical, and transient cardiotoxicity using echocardiography and serum biomarker measurement. Cardiac magnetic resonance imaging was performed at 3 separately defined intervals. The primary modality for determining subclinical myocardial dysfunction was echocardiographic assessment of the global longitudinal strain (GLS). Eleven patients (7 men) with an average age of 55 years were included. No evidence of cumulative myocardial dysfunction was found using echocardiographic markers, primarily GLS (average change in absolute GLS, -1.17; P = .064). Additionally, no echocardiographic evidence of transient cardiotoxicity was found. The left ventricular ejection fraction (LVEF) also did not show any significant changes (ΔLVEF, -2.17%; P = .15). Magnetic resonance imaging confirmed no changes in structure or function (ΔLVEF, -2.6%; P = .54) and extracellular volume fraction (Δ = 2%; P = .46). The serum biomarker levels also did not change significantly over time. We did not observe cardiotoxicity from bortezomib-based chemotherapy despite very intensive evaluation with multiple modalities. Neither cumulative nor transient alterations were found in our metrics, suggesting that bortezomib is safe from a cardiovascular standpoint for patients free of cardiovascular disease.


Inhibiting ALK2/ALK3 Signaling to Differentiate and Chemo-Sensitize Medulloblastoma.
Medulloblastoma (MB) is a malignant pediatric brain tumor, and it represents the leading cause of death related to cancer in childhood. New perspectives for therapeutic development have emerged with the identification of cancer stem cells (CSCs) displaying tumor initiating capability and chemoresistance. However, the mechanisms responsible for CSCs maintenance are poorly understood. The lack of a universal marker signature represents the main constraints to identify and isolate CSCs within the tumor. To identify signaling pathways promoting CSC maintenance in MB, we combined tumorsphere assays with targeted neurogenesis PCR pathway arrays. We showed a consistent induction of signaling pathways regulating pluripotency of CSCs in all the screened MB cells. BMP4 signaling was consistently enriched in all tumorsphere(s) independently of their specific stem-cell marker profile. The octamer-binding transcription factor 4 (OCT4), an important regulator of embryonic pluripotency, enhanced CSC maintenance in MBs by inducing the BMP4 signaling pathway. Consistently, inhibition of BMP4 signaling with LDN-193189 reduced stem-cell traits and promoted cell differentiation. Our work suggests that interfering with the BMP4 signaling pathway impaired the maintenance of the CSC pool by promoting cell differentiation. Hence, differentiation therapy might represent an innovative therapeutic to improve the current standard of care in MB patients.


Human challenge trials in vaccine development: Strasbourg, September 29 - October 1, 2014.
An international workshop to discuss the role of Human Challenge Trials (HCT) in vaccine development was held in Strasbourg, France from 29 September to 1 October 2015. In addition to scientific presentations, several panel discussions focused on key questions and proposed recommendations, including the acknowledgement that HCT have proven to be useful tools to explore vaccine targets, identify immune correlates of protection, and evaluate clinical efficacy, and when appropriate they should be continued and encouraged. In some cases, a HCT may be the only feasible way to move forward with development of an investigational product. HCT must be strongly scientifically justified, because the need for a given investigational objective must be always balanced against the risks a HCT may pose, understanding that an infectious organism will be given to the study participants. It should be noted that numerous HCT have been successfully performed, safely and ethically, to the benefit of vaccine development and public health. This workshop report highlights the scientific presentations, discussions by the panelists and attendees, and twenty recommendations that emerged as considerations for future development of international guidance on the role of HCT in vaccine development and licensure.


The impact of integrating emotion focused components into psychological therapy: A randomized controlled trial.
This paper presents a randomized controlled trial on assimilative integration, which is aimed at integrating elements from other orientations within one approach to enrich its conceptual and practical repertoire. Elements from Emotion-Focused Therapy (EFT) were integrated into a form of cognitive behavior therapy: Psychological Therapy (PT). In one treatment condition, EFT was added to PT (+EFT) with the intent to enhance therapists' working with emotions. In the other condition, concepts and interventions based on the socialpsychological self-regulation approach were added to PT (+SR). Our assumption was that the +EFT would lead to greater and deeper change, particularly in the follow-up assessments. Patients (n = 104) with anxiety, depression, or adjustment disorders were randomized to the two conditions and treated by 38 therapists who self-selected between the conditions. Primary outcome was symptom severity at 12-month follow-up; secondary outcomes included several measures such as interpersonal problems and quality of life. Variables were assessed at baseline, after 8 and 16 sessions, at posttreatment, and at 6- and 12-month follow-up. Contrary to our hypothesis, no significant between-group effects were found. The findings first suggest the difficulty of topping an already very effective approach to psychotherapy. Alternative interpretations were that the EFT training, while corresponding to regular practice in AI, was not sufficient to make a difference in outcome, or that while profiting from the enhancement of abilities for working with emotions, this was outbalanced by negative effects of difficulties related to the implementation of the new elements.


Audit of laparoscopic surgery for colon cancer in Morocco: A report of the results of a prospective multicentre cohort study.
Little data is available about colon laparoscopic surgery in low mid-income countries. The aim of this study was to audit the status and results of laparoscopic colon cancer surgery in Morocco. This was a prospective study performed at 4 academic departments in Morocco between January 1, 2018, and March 31, 2020. All adult patients who underwent elective right or left colonic resection for colon adenocarcinoma were included. The main outcomes were the rate of laparoscopic surgery (LS) and the comparison of its short-term outcomes with open surgery (OS). Among 121 patients included, 52 (43%) underwent laparoscopic resection (0-49.3%). Five surgeons (29%) performed at least one laparoscopic resection. There were more left colectomies in the laparoscopic group (71.2% vs. 39.1%. p = 0.0004), and more extended resections (23.1% vs. 40.6%. p = 0.043) and T4 stage (19% vs. 37.5%. p = 0.037) in the open group. There were no differences in 90-days overall and serious complications. OS patients had significantly more harvested lymph nodes (14 vs. 18. P = 0.007) and higher median surgical margins (6 cm vs. 9 cm. P = 0.003) than LS patients. LS for colon cancer in Morocco is performed by few surgeons, who apply strict patient selection for laparoscopic cases. It was associated with lower quality resections compared to open surgery. There are still many challenges requiring more focus on training, certification, centralization and standardisation of care across the nation.


Pharmaceutical Applications of Electrospraying.
The electrohydrodynamic atomization technique, or simply called electrospraying, has been extensively studied for biomedical as well as for pharmaceutical applications over the past years. The simplicity, flexibility, and efficiency of producing particles at the microscale or nanoscale, with tailored size, shape, morphology, and microstructure, make electrospraying to become one of the most promising and well-practiced approaches to be applied in many biomedical and pharmaceutical fields, from improving the bioavailability of poorly aqueous soluble drugs, preparing targeted drug delivery systems, and controllable drug release systems to delivering sensitive therapeutic agents such as protein-based drugs or even living cells. Nevertheless, some issues still remain with respect to low throughput as well as the complex interplay between a great number of processing and formulation factors. A comprehensive understanding of these fundamental aspects is essential for the successful application of electrospraying for the production of particulate formulations with desired properties.


Correction: Youth friendly sexual and reproductive health service utilization among high and preparatory school students in Debre Tabor town, Northwest Ethiopia: A cross sectional study.
[This corrects the article DOI: 10.1371/journal.pone.0240033.].


The role of exercise in the prevention and treatment of wasting in acquired immune deficiency syndrome.
Involuntary weight loss with lean tissue depletion is a serious and AIDS-defining complication of HIV infection. This article explores definitions of AIDS wasting syndrome (AWS), its etiology, methods of assessing body composition, and pharmacological treatments. Recent research literature on the role of exercise in the prevention and treatment of AWS is reviewed. Included are studies of the safety of exercise, the effects of exercise on the immune system, and the effects of exercise on weight gain and body composition as well as studies of exercise in combination with medications and other interventions. Implications for clinical practice are discussed.


Clinical research of peri-implant diseases--quality of reporting, case definitions and methods to study incidence, prevalence and risk factors of peri-implant diseases.
To review the quality of reporting and the methodology of clinical research on the incidence, prevalence and risk factors of peri-implant diseases. A MEDLINE search was conducted for cross-sectional, case-control and prospective longitudinal studies reporting on peri-implant diseases. To evaluate the quality of reporting of the selected studies the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) checklist was utilized. The search provided 306 titles and abstracts, out of which 40 were selected for full-text analysis. Finally, 16 studies were included out of which five assessed prevalence and only two the incidence of peri-implant diseases. 13 articles studied risk indicators for peri-implant diseases. None of the scrutinized articles adhered fully to the STROBE criteria. The large majority of articles did not (i) clearly state the applied study design, (ii) describe any effort to address potential sources of bias, (iii) explain how missing data were addressed, (iv) perform any kind of sensitivity analysis, (v) indicate the number of participants with missing data for each variable of interest. Collectively, the findings of this review indicate a need for improved reporting of epidemiological studies on peri-implant diseases.


Amide proton spin-lattice relaxation in polypeptides. A field-dependence study of the proton and nitrogen dipolar interactions in alumichrome.
The proton nuclear magnetic resonance (NMR) spin-lattice relaxation of all six amides of deferriferrichrome and of various alumichromes dissolved in hexadeutero-dimethylsulfoxide have been investigated at 100, 220, and 360 MHz. We find that, depending on the type of residue (glycyl or ornithyl), the amide proton relaxation rates are rather uniform in the metal-free cyclohexapeptide. In contrast, the (1)H spinlattice relaxation times (T(1)'s) are distinct in the Al(3+)-coordination derivative. Similar patterns are observed in a number of isomorphic alumichrome homologues that differ in single-site residue substitutions, indicating that the spin-lattice relaxation rate is mainly determined by dipole-dipole interactions within a rigid molecular framework rather than by the specific primary structures. Analysis of the data in terms of (1)H-(1)H distances (r) calculated from X-ray coordinates yields a satisfactory linear fit between T(1) (-1) and Sigmar(-6) at the three magnetic fields. Considering the very sensitive r-dependence of T(1), the agreement gives confidence, at a quantitative level, both on the fitness of the crystallographic model to represent the alumichromes' solution conformation and on the validity of assuming isotropic rotational motion for the globular metallopeptides. An extra contribution to the amide proton T(1) (-1) is proposed to mainly originate from the (1)H-(14)N dipolar interaction: this was supported by comparison with measurements on an (15)N-enriched peptide. The nitrogen dipolar contribution to the peptide proton relaxation is discussed in the context of {(1)H}-(1)H nuclear Overhauser enhancement (NOE) studies because, especially at high fields, it can be dominant in determining the amide proton relaxation rates and hence result in a decreased effectiveness for the (1)H-(1)H dipolar mechanism to cause NOE's. From the slope and intersect values of T(1) (-1) vs. Sigmar(-6) linear plots, a number of independent estimates of tau(r), the rotational correlation time, were derived. These and the field-dependence of the T(1)'s yield a best estimate <tau(r)> approximately 0.37 ns, in good agreement with 0.38 ns [unk] <tau(r)> [unk] 0.41 ns, previously determined from (13)C and (15)N spin-lattice relaxation data.


QRS Duration After Pulmonary Valve Replacement in Adults with Repaired Tetralogy of Fallot: Association with Ventricular Arrhythmia and Correlation with Right Ventricular Size.
The aim of this study is to analyze the relationship between QRS duration after pulmonary valve replacement (PVR) and ventricular arrhythmias (VA) in patients with repaired tetralogy of Fallot (ToF). ToF patients may face complications such as heart failure and VA after primary repair, often mitigated by PVR. Prior studies have shown a decrease in QRS duration and right ventricular (RV) size following PVR. It remains unclear whether a lack of QRS duration reduction identifies patients at risk of VA. We retrospectively identified adult patients with repaired ToF who underwent surgical or transcatheter PVR. EKG data (pre-PVR, 30 days to 1-year post-PVR, and closest to CMR) was collected. The primary endpoint was sustained ventricular tachycardia (VT), ICD shock for sustained VT, or inducible VT on EP study. 85 patients were included (median follow-up 3.6 years; median age 34 years; 51% females). The primary outcome was noted in 8 patients. Mean QRS duration decreased by 5 ms following PVR (p = 0.0001). Increased age at PVR, QRS ≥ 180 ms post-PVR, no reduction in QRS after PVR, and a history of VT were associated with higher risk of the primary endpoint. The change in QRS was linearly correlated with the change in RVEDVi (R = 0.66). Adults with repaired ToF experience a reduction in QRS duration post-PVR that correlates with the change of the RV size. Patients with QRS ≥ 180 ms post-PVR, no reduction in QRS, increased age at repair, and a history of VT are at risk for recurrent VT and warrant closer monitoring/ICD consideration.


Photoperiodic diapause in Drosophila melanogaster involves a block to the juvenile hormone regulation of ovarian maturation.
Females of Drosophila melanogaster held under short-day photoperiods at a moderately low temperature (12 degrees) enter a state of ovarian diapause in which yolk deposition in the oocytes is suspended (D. S. Saunders, V. C. Henrich, and L. I. Gilbert, Proc. Natl. Acad. Sci. USA 86, 3748-3752, 1989). An enzyme-linked immunosorbent assay (ELISA) using polyclonal antibodies raised against D. melanogaster yolk polypeptides (YPs) showed that diapausing flies synthesize and accumulate YPs in the hemolymph, but very little in the ovary. Nondiapausing females at the same temperature but at long days, and short-day flies in which diapause was broken by an upshift in temperature or topical application of juvenile hormone (JH), showed enhanced titers of YPs in the ovaries, suggesting stimulating uptake. Determinations of juvenile hormone bisepoxide (JHB3) and JH III synthesis in vitro by single excised corpora allata showed that glands from nondiapausing flies or corpora allata from flies in which diapause had been broken synthesized JH at a rate about four times higher than glands from diapausing flies. Corpora allata incubated in medium supplemented with farnesoic acid showed an increase in the rate of JH synthesis, but the increase was relatively greater with corpora allata from nondiapausing flies. Glands from diapausing flies presented the appearance of newly emerged or "immature" glands. Ovarian diapause is terminated at 12 degrees LD 10:14 in 7 days following topical application of either JH III or JHB3 at a concentration of about 0.5 micrograms per fly, diapause termination being expressed by an increased rate of vitellogenesis and by an increase in the number of fully developed eggs per vitellogenic female. It is concluded that the short-day-elicited diapause in D. melanogaster results from a "block" to the JH-stimulated uptake of yolk proteins from the hemolymph, caused by a reduced rate of JH synthesis by the corpus allatum. Photoperiodic regulation of the corpus allatum may be mediated via the brain.


Seasonal and diurnal patterns of non-structural carbohydrates in source and sink tissues in field maize.
Carbohydrate partitioning and utilization is a key determinant of growth rate and of yield in plants and crops. There are few studies on crops in field conditions. In Arabidopsis, starch accumulation in leaves is a negative indicator of growth rate. Here, we wished to establish if starch accumulation in leaves could potentially be a marker for growth rate and yield in crops such as maize. We characterized daily patterns of non-structural carbohydrate (NSC) at different growth stages over two seasons for maize hybrids in the field. In 27 commercial hybrids, we found a significant negative relationship between residual starch in leaves and plant growth, but not with final yield and biomass. We then focused on three typical hybrids and established a method for calculation of C turnover in photosynthetic leaves that took into account photosynthesis, leaf area and NSC accumulation. The ratios of stored NSC decreased from approximately 15% to less than 4% with ongoing ontogeny changes from V7 to 28 days after pollination. The proportion rather than absolute amount of carbon partitioned to starch in leaves at all stages of development related well with yield and biomass accumulation. It is proposed that screening plants at an early vegetative growth stage such as V7 for partitioning into storage may provide a prospective method for maize hybrid selection. Our study provides the basis for further validation as a screening tool for yield.


Supporting the Evaluation and Implementation of Musculoskeletal Models of Care: A Globally Informed Framework for Judging Readiness and Success.
To develop a globally informed framework to evaluate readiness for implementation and success after implementation of musculoskeletal models of care (MOCs). Three phases were undertaken: 1) a qualitative study with 27 Australian subject matter experts (SMEs) to develop a draft framework; 2) an eDelphi study with an international panel of 93 SMEs across 30 nations to evaluate face validity, and refine and establish consensus on the framework components; and 3) translation of the framework into a user-focused resource and evaluation of its acceptability with the eDelphi panel. A comprehensive evaluation framework was developed for judging the readiness and success of musculoskeletal MOCs. The framework consists of 9 domains, with each domain containing a number of themes underpinned by detailed elements. In the first Delphi round, scores of "partly agree" or "completely agree" with the draft framework ranged 96.7%-100%. In the second round, "essential" scores ranged 58.6%-98.9%, resulting in 14 of 34 themes being classified as essential. SMEs strongly agreed or agreed that the final framework was useful (98.8%), usable (95.1%), credible (100%) and appealing (93.9%). Overall, 96.3% strongly supported or supported the final structure of the framework as it was presented, while 100%, 96.3%, and 100% strongly supported or supported the content within the readiness, initiating implementation, and success streams, respectively. An empirically derived framework to evaluate the readiness and success of musculoskeletal MOCs was strongly supported by an international panel of SMEs. The framework provides an important internationally applicable benchmark for the development, implementation, and evaluation of musculoskeletal MOCs.


Chemotherapy impairs skeletal muscle mitochondrial homeostasis in early breast cancer patients.
Chemotherapy is extensively used to treat breast cancer and is associated with skeletal muscle deconditioning, which is known to reduce patients' quality of life, treatment efficiency, and overall survival. To date, skeletal muscle mitochondrial alterations represent a major aspect explored in breast cancer patients; nevertheless, the cellular mechanisms remain relatively unknown. This study was dedicated to investigating overall skeletal muscle mitochondrial homeostasis in early breast cancer patients undergoing chemotherapy, including mitochondrial quantity, function, and dynamics. Women undergoing (neo)adjuvant anthracycline-cyclophosphamide and taxane-based chemotherapy participated in this study (56 ± 12 years). Two muscle biopsies were collected from the vastus lateralis muscle before the first and after the last chemotherapy administration. Mitochondrial respiratory capacity, reactive oxygen species production, and western blotting analyses were performed. Among the 11 patients, we found a decrease in key markers of mitochondrial quantity, reaching -52.0% for citrate synthase protein levels (P = 0.02) and -38.2% for VDAC protein levels (P = 0.04). This mitochondrial content loss is likely explained by reduced mitochondrial biogenesis, as evidenced by a decrease in PGC-1α1 protein levels (-29.5%; P = 0.04). Mitochondrial dynamics were altered, as documented by a decrease in MFN2 protein expression (-33.4%; P = 0.01), a key marker of mitochondrial outer membrane fusion. Mitochondrial fission is a prerequisite for mitophagy activation, and no variation was found in either key markers of mitochondrial fission (Fis1 and DRP1) or mitophagy (Parkin, PINK1, and Mul1). Two contradictory hypotheses arise from these results: defective mitophagy, which probably increases the number of damaged and fragmented mitochondria, or a relative increase in mitophagy through elevated mitophagic potential (Parkin/VDAC ratio; +176.4%; P < 0.02). Despite no change in mitochondrial respiratory capacity and COX IV protein levels, we found an elevation in H2 O2 production (P < 0.05 for all substrate additions) without change in antioxidant enzymes. We investigated the apoptosis pathway and found an increase in the protein expression of the apoptosis initiation marker Bax (+72.0%; P = 0.04), without variation in the anti-apoptotic protein Bcl-2. This study demonstrated major mitochondrial alterations subsequent to chemotherapy in early breast cancer patients: (i) a striking reduction in mitochondrial biogenesis, (ii) altered mitochondrial dynamics and potential mitophagy defects, (iii) exacerbated H2 O2 production, and (iv) increased initiation of apoptosis. All of these alterations likely explain, at least in part, the high prevalence of skeletal muscle and cardiorespiratory deconditioning classically observed in breast cancer patients.


Acute cocaine effects on stereotype and defense: an ethoexperimental approach.
Cocaine administration to laboratory animals may produce locomotor hyperactivity and stereotypies that include sniffing and rearing, in addition to anxiety-like effects. A time-sampling study of the effects of 3, 10 or 30 mg/kg cocaine (i.p.) over time following injection indicated early enhancement of locomotion and crouching, with the latter most increased in low- and intermediate-dose cocaine groups, with increased rearing and standing during the second hour of the test period. Additional analyses at 30-60 min post-injection suggested qualitative changes in rearing, with high dose animals showing more, but shorter, rears, and a higher frequency of sniffing. The high dose cocaine enhancement of sniffing was strongly associated with rear and stand behaviors, but also occurred while the animal was crouching. This pattern of changes, with initial crouching/freezing and locomotion (flight?), followed by rearing, standing, and sniffing behaviors similar to those seen in risk assessment suggests that cocaine, particularly at high doses, may elicit defense. An additional study using only saline or the high (30 mg/kg) dose indicated that cocaine produced more sniffing regardless of the direction from which the air stream entered the test cage (i.e. top or bottom). However, cocaine animals oriented their sniffing behaviors toward the incoming air, with reliably more sniffs up in cages with the air stream entering from the top, and more sniffs down, when the air stream entered through a wire mesh cage bottom. Controls showed the same pattern, but their sniff orientation differences were not reliable. These results indicate that the sniffing that follows acute high dose cocaine administration is appropriately oriented toward relevant environmental stimuli, a factor disconsonant with the interpretation of sniffing as a stereotypical behavior, but one that is in agreement with the view that it may reflect a risk assessment component of the defense pattern.


Daycase hernia surgery: a missed training opportunity.
Traditionally uncomplicated elective hernia operations were performed by surgical trainees; allowing them to develop key competencies and skills transferable to emergency hernia surgery. Daycase surgical units (DCU) are increasingly accommodating operations that traditionally contributed to operating lists in general elective theatres. We aim to assess whether DCU could help improve training in hernia surgery. Operative Room Information System (ORMIS) data was collected retrospectively to identify hernia operations performed at a large NHS hospital between January 2007 and 2012. Data collected included operating surgeon(s), procedure performed and procedure time (PT). Hospital coding records were used to collect data related to patient length of stay (LOS), complications, readmissions and deaths within 30 days of procedure. 4668 hernia operations were performed; 3063 in DCU. 91.5% (n = 2803) were open and 8.5% (n = 260) laparoscopic repairs. Trainees assisted in 24.6% (n = 752) and led 7.8% (n = 238) of cases. Overall, the mean PT for consultant led open hernia operations was 37.44 min (95% CI 36.75-38.12) and 43.07 min (95% CI 40.99-45.16) for trainees (p < 0.05). Subgroup analysis of all hernia operations performed showed no significant difference in PT between consultants and trainees when performing open bilateral inguinal, femoral, epigastric, incisional and laparoscopic hernia operations. There were no differences in LOS, readmissions and death rates within 30 days of the operation. DCU are an underutilised opportunity for trainees to acquire experience of hernia operations. When given the opportunity to lead hernia operations in DCU, trainees have similar PT and complication rates to consultants in many instances. Trainees should be encouraged to assist and lead hernia cases in DCU under adequate supervision to ensure appropriate competency is achieved and high standards are maintained.


Desmoplastic fibroblastoma presenting as a parotid tumour: a case report and review of the literature.
Desmoplastic fibroblastomas (DFs) are rare fibrous soft tissue tumours that usually arise in subcutaneous tissue or skeletal muscle in a variety of anatomical sites. These lesions most frequently present as painless, slow-growing mobile masses. A case of DF is described in a 47-year-old man who presented with a painless right parotid mass of 2 months duration. At surgery, the lesion was attached to the tail of the right parotid gland. Histopathological examination demonstrated a fibrous lesion comprising spindled and stellate shaped fibroblasts with focal myxoid stromal change. The features were consistent with a DF. This report documents a rare parotid lesion which may mimic other more common parotid gland neoplasms.


High-performance liquid chromatographic separation of noreximide and norendimide in bulk material, tablets and animal feed.
Noreximide, a sedative, is generally contaminated to some extent with its endo-isomer, norendimide, which produces excitation. A high-performance liquid chromatographic assay was developed to separate and quantitate these compounds on a 5-microns Ultrasphere ODS column with methanol-water (20:30) as mobile phase and detection at 254 nm. Assay of mixtures of these compounds in bulk material and tablets utilized isoniazide as internal standard. Peak area ratios were linear (r = 0.9999) over 1.4-66.2 micrograms of injected noreximide and 0.2-8.4 micrograms of injected norendimide. Overall percent recovery from simulated tablets containing noreximide alone was 99.6 +/- 0.8% (S.D., n = 3). Overall percent recoveries (+/- S.D.) from tablets containing a mixture of these compounds were 98.9 +/- 0.5% and 102.3 +/- 1.1% for noreximide and norendimide, respectively (n = 3). Noreximide in animal feed for long-term pharmacological studies was isolated by ether extraction and after work up, subjected to the same procedure, except that theophylline was the internal standard. Peak area ratios were linear over 0.2-19.3 micrograms of injected noreximide (r = 0.9999). Overall percent recoveries (+/- S.D., n = 3) of noreximide from spiked animal feed were 97.4 +/- 1.4% and 99.0 +/- 0.5% at the 500- and 5000-ppm levels, respectively. Limits of detection at the 95% confidence level (0.01 a.u.f.s., 20-microliters sample volume injected) were 1.67 microgram/ml and 2.56 micrograms/ml of noreximide and norendimide, respectively, in the final test solution.


Nickel-Catalyzed Regioselective Cross-Dehydrogenative Coupling of Inactive C(sp(3))-H Bonds with Indole Derivatives.
A nickel-catalyzed regiosepecific C2- versus C3-oxidative cross-coupling reaction of indoles with 1,4-dioxane and other inactive C(sp(3))-H bonds is described. The divergent synthesis of C(sp(3))-C(sp(2)) bonds was achieved in satisfactory yields with di-tert-butyl peroxide (DTBP) as the oxidant, which provides an efficient strategy for the selective construction of cyclic ethers containing heteroaromatic core structures.


Therapy of extragonadal germ-cell tumors.
Sixteen patients with primary extragonadal germ-cell tumors were treated at the Department of Chemotherapy, Finsen Institute, Copenhagen from 1976 to 1982. Twelve patients received a combination of cis-diamminedichloroplatinum (cisplatin), vinblastine and bleomycin (PVB). Eight patients had a complete remission and 5 had a partial response. Eighty-six percent of the patients achieving complete remission remain free of disease after a median follow-up of 42 months. The best results with PVB were obtained in teratocarcinomas and embryonal carcinomas, while more effective chemotherapy regimens are needed for the treatment of choriocarcinomas and endodermal sinus tumours.


Antibodies against polypeptides of purified Epstein-Barr virus in sera from patients with connective tissue diseases.
Antibodies to Epstein-Barr virus (EBV) were investigated in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD) by immunoblotting using purified virus. Compared with sera from Epstein-Barr virus seropositive healthy individuals who served as control, sera from patients less frequently recognized several polypeptides. In particular, a 100 kDa envelope polypeptide was recognized by 92% of healthy subjects and only 11% of patients (P less than 0.001). On the other hand, 62% of the patient sera had antibodies to the 42 kDa envelope polypeptide, whereas these antibodies were only present in 4% of the sera from the control subjects (P less than 0.001). These results could reflect either perturbations of the immune response associated with connective tissue disorders or a possible pathogenic role of EBV.


Twelve weeks of treadmill exercise does not alter age-dependent chronic kidney disease in the Fisher 344 male rat.
The ageing kidney exhibits slowly developing chronic kidney disease (CKD) and is associated with nitric oxide (NO) deficiency and increased oxidative stress. The impact of exercise on the ageing kidney is not well understood. Here, we determined whether 12 weeks of treadmill exercise can influence age-dependent CKD in old (22-24 months) Fisher 344 (F344) male rats by comparing sedentary (SED) and exercise (EX) trained rats; young (3 months) rats were also studied. In addition to renal structure and function, we assessed protein levels of various isoforms of the NO synthases (NOS) and superoxide dismutase (SOD) enzymes as well as markers of oxidative stress, in kidney cortex and medulla. Renal function as determined by plasma creatinine, proteinuria, and glomerular structural injury worsened with age and was unaffected by exercise. Ageing also increased the protein abundance of neuronal NOSβ and p22phox while decreasing extracellular (EC) and copper/zinc (CuZn) SOD, in kidney cortex and medulla. H(2)O(2) content and nitrotyrosine abundance also increased in the kidney with age. None of these age-related changes were altered with exercise. However, exercise did increase renal cortical endothelial (e)NOS and EC SOD in young rats. Data indicate that exercise-induced increases in eNOS and EC SOD seen in young rats are lost with age. We conclude that chronic exercise is ineffective in reversing age-dependent CKD in the male F344 rat.


Influences of L-Arginine In Ovo Feeding on the Hatchability, Growth Performance, Antioxidant Capacity, and Meat Quality of Slow-Growing Chickens.
The aim of this study was to evaluate the effects of in ovo feeding (IOF) of L-arginine (Arg) on the hatchability, growth performance, antioxidant capacity, and meat quality of slow-growing chickens. A total of 480 eggs were randomly divided into a non-injected control group (NC group) and a 1% Arg-injected group (Arg group). On day 18 of incubation, 0.5 mL of Arg solution was injected into the embryonic amnion in the Arg group. Upon hatching, 160 mixed-sex chickens were randomly assigned to two groups, with four replicates per group. This experiment lasted for 63 days. The results showed that the hatchability, growth performance, carcass traits, and meat quality were not significantly different (p > 0.05) between the two groups. However, the malondialdehyde (MDA) content was lower (p < 0.05), and the glutathione (GSH) level was higher (p < 0.05) on day of hatching in the Arg group. The total antioxidant capacity (T-AOC) activity was increased (p < 0.05) on day 21 post-hatch in the Arg group compared to that in the NC group. In conclusion, IOF of Arg increased the antioxidant capacity of the breast muscle in the starter period, which may have a positive effect on health status of slow-growing chickens post-hatch.


Modeling data from titration, amide H/D exchange, and mass spectrometry to obtain protein-ligand binding constants.
We recently reported a new method for quantification of protein-ligand interaction by mass spectrometry, titration and H/D exchange (PLIMSTEX) for determining the binding stoichiometry and affinity of a wide range of protein-ligand interactions. Here we describe the method for analyzing the PLIMSTEX titration curves and evaluate the effect of various models on the precision and accuracy for determining binding constants using H/D exchange and a titration. The titration data were fitted using a 1:n protein:ligand sequential binding model, where n is the number of binding sites for the same ligand. An ordinary differential equation was used for the first time in calculating the free ligand concentration from the total ligand concentration. A nonlinear least squares regression method was applied to minimize the error between the calculated and the experimentally measured deuterium shift by varying the unknown parameters. A resampling method and second-order statistics were used to evaluate the uncertainties of the fitting parameters. The interaction of intestinal fatty-acid-binding protein (IFABP) with a fatty-acid carboxylate and that of calmodulin with Ca(2+) are used as two tests. The modeling process described here not only is a new tool for analyzing H/D exchange data acquired by ESI-MS, but also possesses novel aspects in modeling experimental titration data to determine the affinity of ligand binding.


Transepithelial crosslinking retreatment of progressive corneal ectasia unresponsive to classic crosslinking.
A 41-year-old man presented 10 years after uneventful laser in situ keratomileusis (LASIK) with symptomatic post-LASIK ectasia. He had treatment with the classic Dresden epithelium-off technique and presented 4 years later with progression of the ectasia. He was subsequently retreated with conductive keratoplasty (CK) followed by a new proprietary epithelium-on corneal collagen crosslinking (CXL) procedure using a proprietary transepithelial riboflavin formulation and delivery system on the following day. One year after retreatment, the patient noted stable vision in the treated eye with a corrected distance visual acuity (CDVA) of 20/60+. Thus, epithelium-on CXL, if performed with appropriate formulations and delivery technology as well as careful attention to appropriate riboflavin loading of the stroma, can stabilize an ectatic cornea. In addition, when performed prior to CXL, CK can induce a significant, lasting improvement in corneal shape and CDVA. This technique merits further study.


Underestimating isolated bilateral hygroma as non-accidental head injury with dramatic consequences: a case presentation.
Abusive head injury (AHI) in infancy is associated with significantly worse outcomes compared to accidental traumatic brain injury. The decision-making of the diagnosis of AHI is challenging especially if the clinical signs are not presenting as a multifactorial pattern. We present a case of isolated bilateral hygroma in which this differential diagnosis of AHI was evaluated but primarily not seen as such leading subsequently to extensive secondary AHI with fatal brain injury. The case of an 8-week-old infant with apparently isolated bilateral hygroma without any external signs of abuse and no retinal hemorrhages was interpreted in causative correlation to the perinatal complex course of delivery. At a second readmission of the case, severe brain injury with bilateral cortical hypoxia, subarachnoid and subdural hemorrhages, and skull and extremity fractures led to severe disability of the affected infant. Any early suspicion of AHI with at least one factor possibly being associated with abusive trauma should be discussed in multidisciplinary team conferences to find the best strategy to protect the child. Beside clinical factors, social factors within the family household may additionally be evaluated to determine stress-related risk for traumatic child abuse. In general, prevention programs will be essential in future perspective.