Miracle-dz/UniFAR-FTUs huggingface dataset:
Remodelling of human osteoarthritic cartilage by FGF‐2, alone or combined with Sox9 via rAAV gene transfer

Compensating for the loss of extracellular cartilage matrix, as well as counteracting the alterations of the chondrocyte phenotype in osteoarthritis are of key importance to develop effective therapeutic strategies against this disorder. In the present study, we analysed the benefits of applying a potent gene combination to remodel human osteoarthritic (OA) cartilage. We employed the promising recombinant adeno‐associated virus (rAAV) vector to deliver the mitogenic fibroblast growth factor 2 (FGF‐2) factor, alone or simultaneously with the transcription factor Sox9 as a key activator of matrix synthesis, to human normal and OA articular chondrocytes. We evaluated the effects of single (FGF‐2) or combined (FGF‐2/SOX9) transgene expression upon the regenerative activities of chondrocytes in three‐dimensional cultures in vitro and in cartilage explants in situ. Single overexpression of FGF‐2 enhanced the survival and proliferation of both normal and OA chondrocytes, without stimulating the matrix synthetic processes in the increased pools of cells. The mitogenic properties of FGF‐2 were maintained when SOX9 was co‐overexpressed and concomitant with an increase in the production of proteoglycans and type‐II collagen, suggesting that the transcription factor was capable of counterbalancing the effects of FGF‐2 on matrix accumulation. Also important, expression of type‐X collagen, a marker of hypertrophy strongly decreased following treatment by the candidate vectors. Most remarkably, the levels of activities achieved in co‐treated human OA cartilage were similar to or higher than those observed in normal cartilage. The present findings show that combined expression of candidate factors in OA cartilage can re‐establish key features of normal cartilage and prevent the pathological shift of metabolic homeostasis. These data provide further motivation to develop coupled gene transfer approaches via rAAV for the treatment of human OA.
EORTC trial 11001: distribution of two 10B‐compounds in patients with squamous cell carcinoma of head and neck, a translational research/phase 1 trial

Boron neutron capture therapy (BNCT) provides highly targeted delivery of radiation through the limited spatial distribution of its effects. This translational research/phase I clinical trial investigates whether BNCT might be developed as a treatment option for squamous cell carcinoma of head and neck (SCCHN) relying upon preferential uptake of the two compounds, sodium mercaptoundecahydro‐closo‐dodecaborate (BSH) or L‐para‐boronophenylalanine (BPA) in the tumour. Before planned tumour resection, three patients received BSH and three patients received BPA. The 10B‐concentration in tissues and blood was measured with prompt gamma ray spectroscopy. Adverse effects from compounds did not occur. After BPA infusion the 10B‐concentration ratio of tumour/blood was 4.0 ± 1.7. 10B‐concentration ratios of tumour/normal tissue were 1.3 ± 0.5 for skin, 2.1 ± 1.2 for muscle and 1.4 ± 0.01 for mucosa. After BSH infusion the 10B‐concentration ratio of tumour/blood was 1.2 ± 0.4. 10B‐concentration ratios of tumour/normal tissue were 3.6 ± 0.6 for muscle, 2.5 ± 1.0 for lymph nodes, 1.4 ± 0.5 for skin and 1.0 ± 0.3 for mucosa. BPA and BSH deliver 10B to SCCHN to an extent that might allow effective BNCT treatment. Mucosa and skin are the most relevant organs at risk.
Lectin‐based glycoproteomics to explore and analyze hepatocellular carcinoma‐related glycoprotein markers

More and more new diagnostic biomarkers of hepatocellular carcinoma (HCC) have been found in association with advances in the standardization of 2‐DE coupled with MS analysis. However, the diagnosis of HCC is still detected in the late stages of the disease, when treatment options are limited and prognosis is poor. The glycosylation of proteins is known to change in tumor cells during the development of HCC as the result of alterations in the levels of glycosyltransferases, such as increased fucosylation of Golgi Protein 73 and α‐fetoprotein. These structural changes can influence the function or physiochemical properties of a protein, resulting in abnormal cancer cell behavior. Therefore, identification of HCC‐related glycoprotein markers and analysis of glycan structural alterations might assist in the early detection of HCC. Here, we summarize lectin‐based glycoproteomic strategies for the discovery of relevant biomarkers of HCC. The carbohydrate‐binding specificities of different lectins offer a biological affinity approach that complements existing MS capabilities. These strategies involve the enrichment of glycoproteins or glycopeptides by lectins, followed by releasing carbohydrates with peptide‐N‐glycosidase F or reductive β‐elimination. The obtained glycopeptides are then identified by automated MS/MS and structural analysis of glycans is performed through modern methods such as quadrupole IT‐TOF, MALDI‐TOF/TOF and lectin microarray. These strategies will lead to faster and more clinically adaptable tests with greater sensitivity and specificity.
CONTRIBUTION OF HISTOCYTOCHEMISTRY TO THE UROLOGICAL FIELD

polyclonal antibodies (5, 29) and then monoclonal antibodies (33). Tumor markers for testicular tumors such as human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) were also evaluated with regard to the correlations of the serum level and tumor tissue expression (15). Then antibodies for prostate specific antigen (PSA) and androgen receptors were also investigated in the prostatic lesion (1, 14) . At the same time, the group A, B and H blood type isoantigens were discussed in association with their expressions by malignant tumors of the urothelium, especially bladder tumors (11). The loss of these isoantigens was considered to be related to the invasive potential of the tumor (7, 8). The T-antigen was also evaluated in bladder tumors (12). Monoclonal antibodies for blood type isoantigens were developed in the mid-1.980
A psychosocial comparison of 35- and 55-year-old men and women in sweden and estonia: The swestonia cardiovascular risk factor study

During the past decade, the incidence ofcoronary heart disease (CHD) has declined in the United States and in Western Europe, but has increased in Eastern Europe and in many non-European countries. This study is a baseline comparison of psychosocial factors in a random sample of 35-year-old and 55-year-old men and women from Tartu, Estonia and Sollentuna, Sweden, who will be followed longitudinally to investigate CHD risk. One hundred men and women from each country in each age group were invited by letter to participate in a study of risk factors for CHD. Complete data were available for 279 Estonians and 272 Swedes. All participants were given the same physical examination and answered the same self-report questionnaires concerning demographics, lifestyle, and psychosocial factors. In general, Swedish men and women in both age groups rated their quality of life higher than Estonians. Self-reported health and depressive symptoms, both of which have predicted CHD risk, were also worse in Estonians than in Swedes. The psychosocial differences found here, together with the lack of major differences in traditional risk factors, reflect the results found in other East-West comparisons. Implications for CHD risk are discussed.
INSULIN‐LIKE GROWTH FACTOR‐I RECEPTOR AS A CANDIDATE FOR A NOVEL MOLECULAR TARGET IN GASTROINTESTINAL CANCERS

Abnormal activation of growth factor receptors and their signal pathways are required for neoplastic transformation and tumor progression. The concept of targeting specific tumorigenic receptors has been validated by successful clinical application of multiple new drugs, such as those acting against HER2/neu, epidermal growth factor receptor 1, and c‐Kit. In this review, we focus on the next promising therapeutic molecular target of insulin‐like growth factor (IGF)‐I receptor (IGF‐Ir). The IGF/IGF‐Ir system is an important modifier of cancer cell proliferation, survival, growth, and treatment sensitivity in a number of neoplastic diseases, including human gastrointestinal carcinomas. Preclinical studies demonstrated that downregulation of IGF‐Ir signals reversed the neoplastic phenotype and sensitized cells to antitumor treatments. We summarize a variety of ways to disrupt IGF‐Ir function. Then, we introduce our strategy of adenoviruses expressing dominant negative of IGF‐Ir (IGF‐Ir/dn) against gastrointestinal cancers, including stomach, colon, and pancreas. IGF‐Ir/dn suppresses tumorigenicity both in vitro and in vivo and increases stressor‐induced apoptosis. IGF‐Ir/dn expression upregulates chemotherapy‐induced apoptosis and these combination therapies with chemotherapy are very effective against tumors in mice. Some drugs blocking IGF‐Ir function are now entering clinical trial, thus IGF‐Ir might be a candidate for a therapeutic target in several gastrointestinal malignancies.
Analysis of a data-fusion system for continuous vital sign monitoring in an emergency department

Objective The aim of the study was to evaluate the ability of a data-fusion patient status index (PSI) to detect patient deterioration in the emergency department (ED) in comparison with track-and-trigger (T&T). Materials and methods A single-centre observational cohort study was conducted in a medium-sized teaching hospital ED. Vital sign data and any documented T&T scores (paper T&T) were collected from adults attending the resuscitation room, majors or observation ward. For each set of vital signs, we retrospectively calculated T&T (eT&T). PSI was calculated retrospectively from the continuous vital sign data using a statistical model of normality. Clinical notes were examined to identify ‘escalation’ events, and the numbers of these escalations identified by paper T&T, eT&T and PSI were retrospectively calculated. Results Data from 472 patient episodes were examined. A total of 20 patients had PSI data at the time of an escalation related to vital sign abnormalities that occurred during their ED stay (vs. on arrival). Only four patient events were detected at the time by paper T&T. In all, 17 were detected retrospectively by eT&T and 15 by PSI. PSI had a calculated false-alert rate of 1.13 alerts/bed-day. Conclusion Electronic data capture offers opportunities for increased detection of deteriorating patients in a busy clinical environment compared with paper charts. Sample size in this study is insufficient to determine which electronic method (eT&T or PSI) offers superior detection of the need for escalation.
Cost-effectiveness of combination daclatasvir-sofosbuvir for treatment of genotype 3 chronic hepatitis C infection in the United States

Abstract Background: A phase III trial evaluated the efficacy and safety of Daklinza (daclatasvir or DCV) in combination with sofosbuvir (SOF) for treatment of genotype (GT) 3 hepatitis C virus (HCV) patients. Aim: This study evaluated the cost-effectiveness of DCV + SOF vs SOF in combination with ribavirin (RBV) over a 20-year time horizon from the perspective of a United States (US) payer. Methods: A published Markov model was adapted to reflect US demographic characteristics, treatment patterns, costs of drug acquisition, monitoring, disease and adverse event management, and mortality risks. Clinical inputs came from the ALLY-3 and VALENCE trials. The primary outcome was the incremental cost-utility ratio. Life-years, incidence of complications, number of patients achieving sustained virological response (SVR), and the total cost per SVR were secondary outcomes. Costs (2014 USD) and quality-adjusted life years (QALYs) were discounted at 3% per year. Deterministic, probabilistic, and scenario sensitivity analyses were conducted. Results: DCV + SOF was associated with lower costs and better effectiveness than SOF + RBV in the base case and in almost all scenarios (i.e. treatment-experienced, non-cirrhotic, time horizons of 5, 10, and 80 years). DCV + SOF was less costly, but also slightly less effective than SOF + RBV in the cirrhotic and treatment-naïve population scenarios. Results were sensitive to variations in the probability of achieving SVR for both treatment arms. DCV + SOF costs less than $50,000 per QALY gained in 79% of all probabilistic iterations compared with SOF + RBV. Conclusion: DCV + SOF is a dominant option compared with SOF + RBV in the US for the overall GT 3 HCV patient population.
Post‐stroke fatigue and return to work: a 2‐year follow‐up

Andersen G, Christensen D, Kirkevold M, Johnsen SP. Post‐stroke fatigue and return to work: a 2‐year follow‐up. Acta Neurol Scand: 2012: 125: 248–253. © 2011 John Wiley & Sons A/S.
Development of a health economic model to evaluate the potential benefits of optimal serum potassium management in patients with heart failure

Abstract Aims: Patients with heart failure are at increased risk of hyperkalemia, particularly when treated with renin-angiotensin-aldosterone system inhibitor (RAASi) agents. This study developed a model to quantify the potential health and economic value associated with sustained potassium management and optimal RAASi therapy in heart failure patients. Materials and methods: A patient-level, fixed-time increment stochastic simulation model was designed to characterize the progression of heart failure through New York Heart Association functional classes, and predict associations between serum potassium levels, RAASi use, and consequent long-term outcomes. Following internal and external validation exercises, model analyses sought to quantify the health and economic benefits of optimizing both serum potassium levels and RAASi therapy in heart failure patients. Analyses were conducted using a UK payer perspective, independent of costs and utilities related to pharmacological potassium management. Results: Validation against multiple datasets demonstrated the predictive capability of the model. Compared to those who discontinued RAASi to manage serum potassium, patients with normokalemia and ongoing RAASi therapy benefited from longer life expectancy (+1.38 years), per-patient quality-adjusted life year gains (+0.53 QALYs), cost savings (£110), and associated net monetary benefit (£10,679 at £20,000 per QALY gained) over a lifetime horizon. The predicted value of sustained potassium management and ongoing RAASi treatment was largely driven by reduced mortality and hospitalization risks associated with optimal RAASi therapy. Limitations: Several modeling assumptions were made to account for a current paucity of published literature; however, ongoing refinement and validation of the model will ensure its continued accuracy as the clinical landscape of hyperkalemia evolves. Conclusions: Predictions generated by this novel modeling approach highlight the value of sustained potassium management to avoid hyperkalemia, enable RAASi therapy, and improve long-term health economic outcomes in patients with heart failure.
Retinal Degeneration in Mice Lacking the γ Subunit of the Rod cGMP Phosphodiesterase

The retinal cyclic guanosine 3′,5′-monophosphate (cGMP) phosphodiesterase (PDE) is a key regulator of phototransduction in the vertebrate visual system. PDE consists of a catalytic core of α and β subunits associated with two inhibitory γ subunits. A gene-targeting approach was used to disrupt the mouse PDEγ gene. This mutation resulted in a rapid retinal degeneration resembling human retinitis pigmentosa. In homozygous mutant mice, reduced rather than increased PDE activity was apparent; the PDEαβ dimer was formed but lacked hydrolytic activity. Thus, the inhibitory γ subunit appears to be necessary for integrity of the photoreceptors and expression of PDE activity in vivo.
Plain abdomen radiographs: the right view?

Background Plain abdomen radiographs (PAR) have limited use in the setting of the emergency department. We conducted this study to look at the appropriateness of requests and its utilization in our emergency department. Methodology We conducted a retrospective analysis of scanned emergency department notes between the period of December 2005 and February 2006 (3 months). Those cases with PAR requested by an emergency department doctor were recruited in this study. The documented history, examination, and provisional diagnosis in the case notes were reviewed to look at the appropriateness of the indications for requests. Results Only 67% (50 of 75) of the requests were appropriate according to the Royal College of Radiologists guidelines with bowel obstruction/paralytic ileus, renal colic and foreign body ingestion being the common presentations. Thirty three percent (25 of 75) (95% confidence interval: 24–45) of the requests were inappropriate and could have been avoided by referring to the aforementioned guidelines. Conclusion We recommend implementing strict local protocols and guidelines for requesting PAR to reduce inappropriate requests. We also recommend staff education and awareness programs for reducing the over-utilizing of PAR.
Can an 18-point clock-drawing scoring system predict dementia in elderly individuals with mild cognitive impairment?

The purpose of this study was to develop a clock-drawing scoring system better suited to detecting possible early markers of dementia in individuals with mild cognitive impairment (MCI). We modified the scoring system of Freedman et al. (1994), in which the major components are integrity of the circle, placement and size of the hands, and placement and sequence of the numbers. We rescored the clock-drawing test using a novel 18-point scoring system, which emphasizes hand elements—number of hands, direction indicated, and size differences. We retrospectively assessed 123 individuals (ages 58–88 years) selected from the Memory Clinic at the Jewish General Hospital in Montreal. These consisted of 21 normal elderly individuals (NORM group), 41 participants with mild cognitive impairment who did not develop dementia on follow-up visits (MCI-NP), 41 participants with mild cognitive impairment who became demented after a 48-month follow-up (MCI-D), and 20 participants diagnosed with Alzheimer's disease (AD). On the 18-point system, the MCI-NP and the MCI-D did not show any difference on overall total score (p = .166), However, using Pearson chi-squares to examine the within-categories effects comparing the mildly cognitively impaired groups (MCI-NP and MCI-D), there were three significant hand items that appear to be possible early markers of progression to dementia. The clock has two hands (p = .043), hour hand is towards correct number (p = .023), and size difference of the hands is respected (p = .004), all showed significant differences between progressors and nonprogressors. The 18-point clock-drawing scoring system may have advantages in better indicating MCI individuals more likely to progress to dementia.
A Danish national cohort study on neonatal outcome in singleton pregnancies with placenta previa

Objective. To describe the incidence of placenta previa and to assess neonatal morbidity and mortality in pregnancies with placenta previa after adjustment for previous cesarean section, smoking, multiparity, maternal age and in vitro fertilization. Design. National cohort study. Setting. Danish national IVF‐, birth‐ and patient registers. Population. All pregnancies in Denmark from 1978–2006 and a subpopulation of all singleton pregnancies during the years 2001–2006 with placenta previa (n=1721) compared to pregnancies without this diagnosis. Methods. Incidence rates and multivariate analysis. Main outcome measures. Gestational age, birthweight, Apgar score after five minutes, stillbirth, neonatal mortality and admittance to neonatal intensive care unit. Results. The incidence of placenta previa in Denmark was 0.54% in 2006. Neonates born after pregnancies with placenta previa had a higher risk of being born at a gestational age below 37 weeks (OR 8.6; 95%CI 7.5–9.9), having an Apgar score of ≤7 at five minutes (OR 2.7; 95%CI 2.0–3.7), being transferred to a neonatal intensive care unit (OR 4.3; 95%CI 3.8–4.9) and for stillbirth and neonatal mortality combined (OR 1.8; 95%CI 1.1–3.0), compared with neonates born in pregnancies without placenta previa. No increased risk of being small‐for‐gestational age was found (OR 1.0; 95%CI 1.0–1.2). Conclusion. When adjusting for confounders, neonates born after pregnancies with placenta previa had a significantly higher risk of being born preterm, having a low Apgar score, being transferred to neonatal intensive care, and death.
Maternal age and elective cesarean section in a low‐risk population

Objective. To examine the association between maternal age and elective cesarean section in primiparous and para one women in a low‐risk population. Design. Population‐based registry study. Setting. Norway. Population. The source population was all mothers giving birth to their first or second child from 1 January 1999 to 31 December 2006. The final study population comprised 229 370 primiparous and para one low‐risk mothers. Methods. Data were extracted from the Medical Birth Registry of Norway. We constructed a low‐risk population by excluding pregnancies with medical conditions associated with elective cesarean section and maternal age. The association between maternal age and elective cesarean was analysed by relative‐risk models. Main outcome measures. Elective cesarean section. Results. In this low‐risk population, the proportion of cesarean section was 9%, and 27% of these were elective. Cesarean delivery increased substantially with increasing maternal age, especially elective cesarean section. In primipara, elective cesarean section increased from 0.6 to 7.5% of all deliveries, corresponding to a relative risk of 11.7 (95% confidence interval 8.9–15.4) in women ≥40 years relative to 20–24 years. When comparing women ≥40 years with those aged below 25 years, the relative risk in para one without previous cesarean section was 4.5 (95% confidence interval 3.5–5.8; the proportion increasing from 1.4 to 6.2%), while in para one with previous cesarean section it was 2.9 (95% confidence interval 2.4–3.6; the proportion increasing from 17.5 to 51.5%). Conclusions. We found a close association between maternal age and elective cesarean section in a low‐risk population.
A palmtop‐sized microfluidic cell culture system driven by a miniaturized infusion pump

A palmtop‐sized microfluidic cell culture system is presented. The system consists of a microfluidic device and a miniaturized infusion pump that possesses a reservoir of culture medium, an electrical control circuit, and an internal battery. The footprint of the system was downsized to 87 × 57 mm, which is, to the best of our knowledge, the smallest integrated cell culture system. Immortalized human microvascular endothelial cells (HMEC‐1) and human umbilical vein endothelial cells (HUVEC) were cultured in the system. HMEC‐1 in the system proliferated at the same speed as cells in a microchannel perfused by a syringe pump and cells in a culture flask. HUVEC in the system oriented along the direction of the fluid flow. Claudin‐5, a tight junction protein, was localized along the peripheries of the HUVEC. We expect that the present system is applicable to various cell types as a stand‐alone and easy‐to‐use system for microfluidic bioanalysis.