Impact of Prosigna test on adjuvant treatment decision in lymph node-negative early breast cancer-a prospective national multicentre study (EMIT-1).

BACKGROUND: EMIT-1 is a national, observational, single-arm trial designed to assess the value of the Prosigna, Prediction Analysis of Microarray using the 50 gene classifier (PAM50)/Risk of Recurrence (ROR), test as a routine diagnostic tool, examining its impact on adjuvant treatment decisions, clinical outcomes, side-effects and cost-effectiveness. Here we present the impact on treatment decisions. PATIENTS AND METHODS: Patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative pT1-pT2 lymph node-negative early breast cancer (EBC) were included. The Prosigna test and standard histopathology assessments were carried out. Clinicians' treatment decisions were recorded before (pre-Prosigna) and after (post-Prosigna) the Prosigna test results were disclosed. RESULTS: Of 2217 patients included, 2178 had conclusive Prosigna results. The pre-Prosigna treatment decisions were: no systemic treatment (NT) in 27% of patients, endocrine treatment alone (ET) in 38% and chemotherapy (CT) followed by ET (CT + ET) in 35%. Post-Prosigna treatment decisions were 25% NT, 51% ET and 24% CT + ET, respectively. Adjuvant treatment changed in 28% of patients, including 21% change in CT use. Among patients assigned to CT + ET pre-Prosigna, 45% were de-escalated to ET post-Prosigna. Of patients assigned to ET, 12% were escalated to CT + ET and 8% were de-escalated to NT; of those assigned to NT, 18% were escalated to ET/CT + ET. CT was more frequently recommended for patients aged ≤50 years. In the subgroup with pT1c-pT2 G2 and intermediate Ki67 (0.5-1.5× local laboratory median Ki67 score), the pre-Prosigna CT treatment decision varied widely across hospitals (3%-51%). Post-Prosigna, the variability of CT use was markedly reduced (8%-24%). The correlation between Ki67 and ROR score within this subgroup was poor (r = 0.25-0.39). The median ROR score increased by increasing histological grade, but the ROR score ranges were wide (for G1 0-79, G2 0-90, G3 16-94). CONCLUSION: The Prosigna test result changed adjuvant treatment decisions in all EBC clinical risk groups, markedly decreased the CT use for patients categorized as higher clinical risk pre-Prosigna and reduced treatment decision discrepancies between hospitals.

Attendance in a national screening program for diabetic retinopathy: a population-based study of 205,970 patients.

AIMS: A nationwide diabetic retinopathy (DR) screening program has been established in Denmark since 2013. We aimed to perform an evaluation of adherence to DR screenings and to examine whether non-adherence was correlated to DR progression. METHODS: The population consisted of a register-based cohort, who participated in the screening program from 2013 to 2018. We analyzed age, gender, marital status, DR level (International Clinical DR severity scale, none, mild-, moderate-, severe non-proliferative DR (NPDR) and proliferative DR (PDR)), comorbidities and socioeconomic factors. The attendance pattern of patients was grouped as either timely (no delays > 33%), delayed (delays > 33%) or one-time attendance (unexplained). RESULTS: We included 205,970 patients with 591,136 screenings. Rates of timely, delayed and one-time attendance were 53.0%, 35.5% and 11.5%, respectively. DR level at baseline was associated with delays (mild-, moderate-, severe NPDR and PDR) and one-time attendance (moderate-, severe NPDR and PDR) with relative risk ratios (RRR) of 1.68, 2.27, 3.14, 2.44 and 1.18, 2.07, 1.26, respectively (P < 0.05). Delays at previous screenings were associated with progression to severe NPDR or PDR (hazard ratio (HR) 2.27, 6.25 and 12.84 for 1, 2 and 3+ delays, respectively). Any given delay doubled the risk of progression (HR 2.28). CONCLUSIONS: In a national cohort of 205,970 patients, almost half of the patients attended DR screening later than scheduled or dropped out after first screening episode. This was, in particular, true for patients with any levels of DR at baseline. DR progression in patients with delayed attendance, increased with the number of missed appointments.

Sociodemographic characteristics associated with a higher wish to complain about health care.

OBJECTIVES: Previous research has shown that patients who are older, less educated, or have lower income are less likely to lodge complaints about health care. This variation may reflect less wish to complain or inequitable access to complaint channels or remedies. We aimed to investigate associations between sociodemographic characteristics and health users' wish to complain. STUDY DESIGN: This was a randomized case vignette survey among 6756 Danish men aged 45-70 years (30% response rate). METHODS: Assuming they received the care in vignettes about prostate cancer (prostate-specific antigen) testing, participants rated their wish to complain on a 5-point Likert scale. Information on sociodemographic characteristics was obtained through self-reports and municipality-level information from national registries. RESULTS: Lower education was associated with an increased wish to complain (mean Likert difference 0.44 [95% CI 0.36-0.51]; P < .001). The wish to complain was higher among unemployed men (difference 0.16 [95% CI 0.04-0.28]; P < .011) and those with a chronic illness (difference 0.06 [95% CI 0.02-0.10]; P < .004). Given the same healthcare scenarios, there was no difference in wish to complain among health users who were retired, living rurally, or from lower income groups. CONCLUSIONS: Health users who are less educated, lower income, elderly, or from rural or minority communities appear to be as likely, or more likely, to wish to complain about health care as others. Yet, younger, well-educated, and higher income citizens are overrepresented in actual complaint statistics. The finding suggests persisting inequalities in the suitability or accessibility of complaint processes for some groups of patients.

Routine postoperative CT to detect anastomotic leakage after low anterior resection for rectal cancer has a low sensitivity and specificity and a poor interobserver agreement.

AIM: To compare the accuracy and interobserver variation of routine computed tomography (CT) on postoperative day 6-8 to detect anastomotic leakage (AL) verified by re-operation and/or endoscopy. A secondary objective was to identify the predictive values of different CT findings as an indicator for AL. MATERIAL AND METHODS: The material for this study originates from two previous prospective multicentre studies including 277 patients who were scheduled for routine abdominal CT postoperative day 6-8. Inclusion criteria for the present study were routine CT without contrast medium followed by CT with rectal contrast medium. Two independent senior radiologists blinded to the clinical outcome reviewed the CT examinations for specific findings according to a predefined scheme. RESULTS: A total of 52 patients fulfilled the inclusion criteria. AL occurred in 14 patients of which nine were clinical and five subclinical. The two radiologists diagnosed AL at unenhanced CT with sensitivities of 71.4% and 50%, respectively, and of 57.1% and 35.7% with rectal contrast medium. The corresponding specificities were 55.3% and 81.6%, and 94.7% and 92.1%. Peri-anastomotic free air and contrast medium leakage had the highest odds ratios for AL. CONCLUSION: The diagnostic sensitivity and specificity of routine postoperative CT to detect AL after low anterior resection for rectal cancer is low and with considerable interobserver variation.

Study protocol for OptimalTTF-2: enhancing Tumor Treating Fields with skull remodeling surgery for first recurrence glioblastoma: a phase 2, multi-center, randomized, prospective, interventional trial.

BACKGROUND: OptimalTTF-2 is a randomized, comparative, multi-center, investigator-initiated, interventional study aiming to test skull remodeling surgery in combination with Tumor Treating Fields therapy (TTFields) and best physicians choice medical oncological therapy for first recurrence in glioblastoma patients. OptimalTTF-2 is a phase 2 trial initiated in November 2020. Skull remodeling surgery consists of five burrholes, each 15 mm in diameter, directly over the tumor resection cavity. Preclinical research indicates that this procedure enhances the effect of Tumor Treating Fields considerably. We recently concluded a phase 1 safety/feasibility trial that indicated improved overall survival and no additional toxicity. This phase 2 trial aims to validate the efficacy of the proposed intervention. METHODS: The trial is designed as a comparative, 1:1 randomized, minimax two-stage phase 2 with an expected 70 patients to a maximum sample size of 84 patients. After 12-months follow-up of the first 52 patients, an interim futility analysis will be performed. The two trial arms will consist of either a) TTFields therapy combined with best physicians choice oncological treatment (control arm) or b) skull remodeling surgery, TTFields therapy and best practice oncology (interventional arm). Major eligibility criteria include age ≥ 18 years, 1st recurrence of supratentorial glioblastoma, Karnofsky performance score ≥ 70, focal tumor, and lack of significant co-morbidity. Study design aims to detect a 20% increase in overall survival after 12 months (OS12), assuming OS12 = 40% in the control group and OS12 = 60% in the intervention group. Secondary endpoints include hazard rate ratio of overall survival and progression-free survival, objective tumor response rate, quality of life, KPS, steroid dose, and toxicity. Toxicity, objective tumor response rate, and QoL will be assessed every 3rd month. Endpoint data will be collected at the end of the trial, including the occurrence of suspected unexpected serious adverse reactions (SUSARs), unacceptable serious adverse events (SAEs), withdrawal of consent, or loss-to-follow-up. DISCUSSION: New treatment modalities are highly needed for first recurrence glioblastoma. Our proposed treatment modality of skull remodeling surgery, Tumor Treating Fields, and best practice medical oncological therapy may increase overall survival significantly. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT0422399 , registered 13. January 2020.

Impaired fecundity as a marker of health and survival: a Danish twin cohort study.

STUDY QUESTION: Is fecundity, measured as self-reported time to first pregnancy (TTP), a marker for subsequent health and survival? SUMMARY ANSWER: Long TTP was a marker for increased mortality among women and higher hospitalization rates for both women and men. WHAT IS KNOWN ALREADY: Poor semen quality has been linked to increased mortality and morbidity from a wide range of diseases. Associations among fecundity, health and survival among women are still uncertain and studies on actual measures of fecundity and health outcomes are rare. STUDY DESIGN, SIZE, DURATION: We performed a prospective cohort study of 7825 women and 6279 men, aged 18 and above with measures on first TTP, who participated in one of the Danish nation-wide twin surveys in 1994 (twins born 1953-1976) and 1998 (twins born 1931-1952). They were followed-up for mortality and hospital admissions from the interview until 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Twins were identified in the Danish Twin Registry and linked to Danish registers. TTP was restricted to the first pregnancy as a categorical outcome with cut-off points at 2, 10 and 18 months. We analysed the association between TTP and survival using a Cox proportional hazards model estimating hazards ratios (HRs) with 95% confidence intervals (CIs). Fine-Gray survival models were used to estimate sub-hazard ratios for specific causes of death allowing for competing risks. Using negative binomial regression, we estimated incidence rate ratios (IRRs) with 95% CIs for all-cause and cause-specific hospitalizations. All analyses were stratified by sex and adjusted for age at interview, birth cohorts, age at first attempt to become pregnant, smoking, years in school and BMI. MAIN RESULTS AND THE ROLE OF CHANCE: In the total study population, 49.9% of women and 52.7% of men reported a TTP of less than 2 months, 30.8% of women and 29.6% of men reported a TTP of 2-9 months, 6.6% of women and 5.7% of men reported a TTP of 10-17 months, and 13.3% of women and 12.0% of men reported a TTP of 18 months or more. Among 1305 deaths, we found a higher mortality for women (HR = 1.46; 95% CI 1.15, 1.87) with a TTP of ≥18 months relative to those with a TTP of <2 months, while the highest mortality was indicated for men with a TTP of 10-17 months (HR = 1.31; 95% CI 0.98, 1.74). Among 53 799 hospitalizations, we found an increased hospitalization rate among women (HR = 1.21; 95% CI 1.0-1.41) and men (HR = 1.16; 95% CI 1.00-1.35) with a TTP of ≥18 months, and for men with a TTP of 2-9 months (HR = 1.14; 95% CI 1.01-1.30). A dose-response relationship was found for women regarding both mortality (P = 0.022) and hospitalizations (P = 0.018). Impaired fecundity was associated with a wide range of diseases and some causes of death, indicating a multi-factorial causal influence on fecundity, especially among women. LIMITATIONS, REASONS FOR CAUTION: A major limitation was that fecundity depends on both partners, which was not considered in this study. Moreover, we could not obtain information on a number of potential confounders. WIDER IMPLICATIONS OF THE FINDINGS: Fecundity seems positively correlated with overall health and may be a universal marker of future health and survival. These results add knowledge to the limited findings showing that reduced fecundity in women and poor semen quality in men may reflect worse health and a shorter life, particularly among women. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by NIH grant HD096468 (M.L.E., T.K.J. and R.L.J.). The authors declare that they have no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Use of antiosteoporotic medication in the Danish ROSE population-based screening study.

Use of antiosteoporotic medication in the population-based, risk-stratified osteoporosis strategy evaluation (ROSE) screening study, comparing the use of FRAX followed by DXA with usual care, was examined. Screening increased the overall use of medication. Being recommended treatment by the hospital and higher age increased the likelihood of starting medication, but, nevertheless, a large percentage opted not to start treatment. INTRODUCTION: The aim of the study was to examine the impact on medication prescription, adherence, and persistence of osteoporotic medicine in the randomized population-based ROSE screening study for osteoporosis. METHODS: The Danish ROSE study included a population-based random sample of women aged 65-81 years randomized to either a two-step screening program consisting of FRAX followed by DXA for high-risk participants or opportunistic screening for osteoporosis (usual care). This sub-study on the intention-to-treat population examined the impact of the screening program on antiosteoporotic medication redemption rates, adherence, and persistence using Danish registers. RESULTS: A total of 30,719 of 34,229 women were treatment-naïve. Significantly more participants in the screening group started on antiosteoporotic medication, but no differences in adherence and persistence rates were found. Higher age was associated with a higher likelihood of starting medication. A low Charlson comorbidity score (= 1) was associated with higher treatment initiation but lower adherence and persistence of antiosteoporotic treatment. A total of 31.7% of participants advised to initiate treatment did not follow the advice. CONCLUSIONS: Screening for osteoporosis using FRAX followed by DXA increased the overall use of antiosteoporotic medication in the screening group without differences in adherence and persistence rates. A large percentage of participants advised to initiate treatment did nevertheless fail to do so.

Religiousness and Diseases in Europe: Findings from SHARE.

Recent research in religiousness and health suggests that epidemiological forces can have opposed effects. Here we examine two forms of religiousness and their association with disease. We performed a cross-sectional study of 23,864 people aged 50+ included in wave 1 (2004-2005) of the Survey of Health, Ageing and Retirement in Europe and a longitudinal study including people from wave 1, who were followed up during 11 years. Results suggested that taking part in a religious organization was associated with lower odds of heart attack (OR 0.74, 95% CI 0.60, 0.90), stroke (OR 0.68, 95% CI 0.50, 0.95), and diabetes (OR 0.72, 95% CI 0.58, 0.90) and longitudinally associated with lower odds of cancer (OR 0.78, 95% CI 0.60, 1.00). Conversely, praying was longitudinally associated with higher odds of heart attack (OR 1.27, 95% CI 1.10, 1.48) and high cholesterol (OR 1.12, 95% CI 1.00, 1.26). The most religious people had lower odds of stroke, diabetes, and cancer than other respondents, and in the longitudinal model, people who only prayed had higher odds of heart attack than non-religious people. Our findings lend support to the hypothesis that restful religiousness (praying, taking part in a religious organization, and being religiously educated) was associated with lower odds of some diseases, whereas little evidence was present that crisis religiousness (praying only) was associated with higher odds of disease.

Effectiveness of a two-step population-based osteoporosis screening program using FRAX: the randomized Risk-stratified Osteoporosis Strategy Evaluation (ROSE) study.

The Risk-stratified Osteoporosis Strategy Evaluation (ROSE) study investigated the effectiveness of a two-step screening program for osteoporosis in women. We found no overall reduction in fractures from systematic screening compared to the current case-finding strategy. The group of moderate- to high-risk women, who accepted the invitation to DXA, seemed to benefit from the program. INTRODUCTION: The purpose of the ROSE study was to investigate the effectiveness of a two-step population-based osteoporosis screening program using the Fracture Risk Assessment Tool (FRAX) derived from a self-administered questionnaire to select women for DXA scan. After the scanning, standard osteoporosis management according to Danish national guidelines was followed. METHODS: Participants were randomized to either screening or control group, and randomization was stratified according to age and area of residence. Inclusion took place from February 2010 to November 2011. Participants received a self-administered questionnaire, and women in the screening group with a FRAX score ≥ 15% (major osteoporotic fractures) were invited to a DXA scan. Primary outcome was incident clinical fractures. Intention-to-treat analysis and two per-protocol analyses were performed. RESULTS: A total of 3416 fractures were observed during a median follow-up of 5 years. No significant differences were found in the intention-to-treat analyses with 34,229 women included aged 65-80 years. The per-protocol analyses showed a risk reduction in the group that underwent DXA scanning compared to women in the control group with a FRAX ≥ 15%, in regard to major osteoporotic fractures, hip fractures, and all fractures. The risk reduction was most pronounced for hip fractures (adjusted SHR 0.741, p = 0.007). CONCLUSIONS: Compared to an office-based case-finding strategy, the two-step systematic screening strategy had no overall effect on fracture incidence. The two-step strategy seemed, however, to be beneficial in the group of women who were identified by FRAX as moderate- or high-risk patients and complied with DXA.

Non-participation in systematic screening for osteoporosis-the ROSE trial.

Population-based screening for osteoporosis is still controversial and has not been implemented. Non-participation in systematic screening was evaluated in 34,229 women age 65-81 years. Although participation rate was high, non-participation was associated with comorbidity, aging other risk factors for fractures, and markers of low social status, e.g., low income, pension, and living alone. A range of strategies is needed to increase participation, including development of targeted information and further research to better understand the barriers and enablers in screening for osteoporosis. INTRODUCTION: Participation is crucial to the success of a screening program. The objective of this study was to analyze non-participation in Risk-stratified Osteoporosis Strategy Evaluation, a two-step population-based screening program for osteoporosis. METHODS: Thirty-four thousand two hundred twenty-nine women aged 65 to 81 years were randomly selected from the background population and randomized to either a screening group (intervention) or a control group. All women received a self-administered questionnaire designed to allow calculation of future risk of fracture based on FRAX. In the intervention group, women with an estimated high risk of future fracture were invited to DXA scanning. Information on individual socioeconomic status and comorbidity was obtained from national registers. RESULTS: A completed questionnaire was returned by 20,905 (61%) women. Non-completion was associated with older age, living alone, lower education, lower income, and higher comorbidity. In the intervention group, ticking "not interested in DXA" in the questionnaire was associated with older age, living alone, and low self-perceived fracture risk. Women with previous fracture or history of parental hip fracture were more likely to accept screening by DXA. Dropping out when offered DXA, was associated with older age, current smoking, higher alcohol consumption, and physical impairment. CONCLUSIONS: Barriers to population-based screening for osteoporosis appear to be both psychosocial and physical in nature. Women who decline are older, have lower self-perceived fracture risk, and more often live alone compared to women who accept the program. Dropping out after primary acceptance is associated not only with aging and physical impairment but also with current smoking and alcohol consumption. Measures to increase program participation could include targeted information and reducing physical barriers for attending screening procedures.

A comparison of patients' and physicians' assessments of disease activity using the Swedish version of the Systemic Lupus Activity Questionnaire.

OBJECTIVES: We compared patients' assessments of systemic lupus erythematosus (SLE) disease activity by a Swedish version of the Systemic Lupus Activity Questionnaire (SLAQ) with physicians' assessments by the Systemic Lupus Activity Measure (SLAM) and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). We also explored the performance of the SLAQ in patients with short (< 1 year) versus long (≥ 1 year) disease duration. METHOD: Patients filled out the SLAQ before physicians' assessments. Correlations between SLAQ total, subscales (Symptom score, Flares, Patients global) and SLAM and SLEDAI-2K, as well as between the corresponding items in SLAQ and SLAM, were evaluated using Spearman's ρ. Comparisons between patients with different disease durations were performed with Mann-Whitney U or chi-squared tests. RESULTS: We included 203 patients (79% women), with a median age of 45 years [interquartile range (IQR) 33-57 years] and disease duration of 5 years (IQR 0-14 years). Correlations between physicians' SLAM without laboratory items (SLAM-nolab) and patients' assessments were: SLAQ total, ρ = 0.685, Symptom score, ρ = 0.651, Flares, ρ = 0.547, and Patients global, ρ = 0.600. Of the symptom items, fatigue (ρ = 0.640), seizures (ρ = 0.635), and headache (ρ = 0.604) correlated most closely. Neurology/stroke syndrome, skin, and lymphadenopathy correlated less well (ρ < 0.24). Patients' and physicians' assessments were notably more discordant for patients with short disease durations. CONCLUSION: We confirm that the SLAQ can be used to monitor disease activity. However, the discrepancy between patients' and physicians' assessments was greater for patients with short versus long disease duration. We encourage further use of the SLAQ, but would like to develop a shorter version which would be valuable in modern, partly web-based, clinical care.

Heritability of Caffeine Metabolism: Environmental Effects Masking Genetic Effects on CYP1A2 Activity but Not on NAT2.

Heritability of caffeine pharmacokinetics and cytochrome P450 1A2 (CYP1A2) activity is controversial. Here, we analyzed the pharmacokinetics of caffeine, an in vivo probe drug for CYP1A2 and arylamine N-acetyltransferase 2 (NAT2) activity, in monozygotic (MZ) and dizygotic (DZ) twins. In the entire group, common and unique environmental effects explained most variation in caffeine area under the curve (AUC). Apparently, smoking and hormonal contraceptives masked the genetic effects on CYP1A2 activity. However, when excluding smokers and users of hormonal contraceptives, 89% of caffeine AUC variation was due to genetic effects and, even in the entire group, 8% of caffeine AUC variation could be explained by a CYP1A1/1A2 promotor polymorphism (rs2470893). In contrast, nearly all of the variations (99%) of NAT2 activity were explained by genetic effects. This study illustrates two very different situations in pharmacogenetics from an almost exclusively genetic determination of NAT2 activity with no environmental modulation to only moderate genetic effects on CYP1A2 activity with strong environmental modulation.

Advances in the treatment of portal hypertension in cirrhosis.

Non-selective beta-blockers and handling of esophageal varices has been key elements in the treatment of portal hypertension in recent decades. Liver vein catheterization has been essential in diagnosis and monitoring of portal hypertension, but ongoing needs for noninvasive tools has led to research in areas of both biomarkers, and transient elastography, which displays promising results in discerning clinically significant portal hypertension. Novel research into the areas of hepatic stellate cell function and the dynamic components of portal hypertension has revealed promising areas of treatment modalities, targeting intestinal decontamination, angiogenesis, inflammation and oxidative stress. Future studies may reveal if these initiatives lead to developments of new drugs for treatment of portal hypertension.

Heritability of metoprolol and torsemide pharmacokinetics.

Genetic variation in the pharmacokinetics of metoprolol and torsemide due to polymorphisms in CYP2D6, CYP2C9, and OATP1B1 has been extensively studied. However, it is still unknown how much of the variation in pharmacokinetics of these two clinically important drugs in total is due to genetic factors. Metoprolol and torsemide were intravenously administered to 44 monozygotic and 14 dizygotic twin pairs. Metoprolol area under the curve (AUC) varied 4.7-fold and torsemide AUC 3.5-fold. A very high fraction of AUC variations, 91% of metoprolol and 86% of torsemide, were found to be due to additive genetic effects. However, known genetic variants of CYP2D6, -2C9, and OATP1B1 explained only 39%, 2%, and 39% of that variation, respectively. Comparable results for genetically explained variation in pharmacokinetics and pharmacodynamics have been found for other substrates of these enzymes earlier. These findings indicate that a substantial fraction of the heritable variability in the pharmacokinetics of metoprolol and torsemide remains to be elucidated.

TNFAIP3 and IL12B gene polymorphisms associated with psoriasis vulgaris in an Egyptian cohort.

BACKGROUND: Psoriasis vulgaris is a common chronic inflammatory skin disease. Development of early onset psoriasis is, to some extent, genetically determined and a strong association with the major histocompatibility complex HLA-Cw6 has been demonstrated. The use of genome-wide association studies has highlighted novel genes associated with the development of psoriasis as IL12B, IL23R, TNFAIP3 and IL13 for instance. The majority of these studies were performed on cohorts of European descent. OBJECTIVE: To determine whether inter-ethnic differences exist in the genetic susceptibility to psoriasis, we genotyped single-nucleotide polymorphism variations in the vicinity of candidate genes in 132 Egyptian patients and 175 healthy controls. METHODS: Blood samples of patients and controls were screened for nucleotide polymorphisms in four candidate genes by TaqMan single-nucleotide polymorphisms Genotyping Assays. RESULTS: We found a significant association between psoriasis and the single-nucleotide polymorphism rs610604, within the TNFAIP3 gene. The TNFAIP3 gene is involved in the TNF-α signalling cascade (P-value: 0.004952), a key step in the pathogenesis of psoriasis. Although there was no significant association found between rs610604 (IL12B) and rs11209026 (IL23R) in this population, the interaction of these two genes showed a significant association with psoriasis (P-value: 0.025). Moreover, when selecting the patients with early disease onset (less than 30 years), we also found that the association of IL12B and psoriasis was highly significant (P-value 1.14 × 10(-12)). No association between rs20541 (IL13) and psoriasis was observed in our Egyptian cohort. CONCLUSION: Replicating the association of single-nucleotide polymorphisms in the TNFAIP3, IL12B and IL23R genes with psoriasis vulgaris, in subjects from different ethnic backgrounds, underlines their importance in the pathogenesis of the disease. In contrast, the lack of any association between rs20541 (IL13) and psoriasis in our Egyptian cohort suggests the existence of important inter-ethnic genetic differences in psoriasis susceptibility.

[Porencephaly in a female Greater Swiss Mountain Dog]. / Porenzephalie bei einer Großen Schweizer Sennenhündin.

A 15-month-old female Greater Swiss Mountain Dog was presented after an epileptic episode. In addition, the owner had noticed a recent marked change in the animal's behaviour. Because of the progressive nature of the neurological signs, a magnetic resonance imaging scan of the brain was performed and porencephaly in the parietal lobe of the right hemisphere was diagnosed. The dog was euthanized and submitted for pathology. Because of the histopathological findings and the history of a craniocerebral injury whilst a puppy, a traumatic genesis of this rare cystic lesion is discussed.

Artificial extracellular matrices of collagen and sulphated hyaluronan enhance the differentiation of human mesenchymal stem cells in the presence of dexamethasone.

In this study we investigated the potential of artificial extracellular matrix (aECM) coatings containing collagen II and two types of glycosaminoglycan (GAGs) with different degrees of sulphation to promote human bone formation in biomedical applications. To this end their impact on growth and osteogenic differentiation of human mesenchymal stem cells (hMSCs) was assessed. The cell proliferation was found to be significantly retarded in the first 14 days of culture on surfaces coated with collagen II and GAGs (coll-II/GAG) as compared to tissue culture polystyrol (TCPS) and those coated with collagen II. At later time points it only tended to be retarded on coll-II/sHya3.1. Heat-inactivation of the serum significantly reduced cell numbers on collagen II and coll-II/sHya3.1. Alkaline phosphatase (ALP) activity and calcium deposition, on the other hand, were higher for coatings containing sHya3.1 and were not significantly changed by heat-inactivation of the serum. Expression levels of the bone matrix proteins bone sialoprotein (BSP-II) and osteopontin (OP) were also increased on aECM coatings as compared to TCPS, which further validated the differentiation of hMSCs towards the osteogenic lineage. These observations reveal that aECM coatings, in particular those containing sHya3.1, are suitable to promote the osteogenic differentiation of hMSCs.

Sulfated hyaluronan/collagen I matrices enhance the osteogenic differentiation of human mesenchymal stromal cells in vitro even in the absence of dexamethasone.

Glycosaminoglycans (GAG) are multifunctional components of the extracellular matrix (ECM) involved in different steps of the regulation of cellular differentiation. In this study artificial extracellular matrices (aECM) consisting of collagen (Col) I and different GAG derivatives were used as a substrate for human mesenchymal stromal cells (hMSC) to study osteogenic differentiation in vitro. hMSC were cultured on aECM containing col and hyaluronan sulfates (HyaS) with increasing degrees of sulfation (DS(S)) and were compared with aECM containing col and the natural GAG hyaluronan or chondroitin 4-sulfate. hMSC were analyzed for osteogenic differentiation markers such as calcium phosphate deposition, tissue non-specific alkaline phosphatase (TNAP) and expression of runt-related transcription factor 2 (runx2), osteocalcin (ocn) and bone sialoprotein II (bspII). Compared with aECM containing Col and natural GAG all Col/HyaS-containing aECM induced an increase in calcium phosphate deposition, TNAP activity and tnap expression. These effects were also seen in the absence of dexamethasone (an established osteogenic supplement). The expression of runx2 and ocn was not altered and the expression of bspII was diminished on the col/HyaS-containing aECM. The impact of the Col/HyaS-containing aECM on hMSC differentiation was independent of the DS(S) of the HyaS derivatives, indicating the importance of the primary (C-6) hydroxyl group of N-acetylglucosamine. These results suggest that Col/HyaS-containing aECM are able to stimulate hMSC to undergo osteogenic differentiation even in the absence of dexamethasone, which makes these matrices an interesting tool for hMSC-based tissue engineering applications and biomaterial functionalizations to enhance bone formation.

Diagnostic and prognostic signatures from the small non-coding RNA transcriptome in prostate cancer.

Prostate cancer (PCa) is the most frequent male malignancy and the second most common cause of cancer-related death in Western countries. Current clinical and pathological methods are limited in the prediction of postoperative outcome. It is becoming increasingly evident that small non-coding RNA (ncRNA) species are associated with the development and progression of this malignancy. To assess the diversity and abundance of small ncRNAs in PCa, we analyzed the composition of the entire small transcriptome by Illumina/Solexa deep sequencing. We further analyzed the microRNA (miRNA) expression signatures of 102 fresh-frozen patient samples during PCa progression by miRNA microarrays. Both platforms were cross-validated by quantitative reverse transcriptase-PCR. Besides the altered expression of several miRNAs, our deep sequencing analyses revealed strong differential expression of small nucleolar RNAs (snoRNAs) and transfer RNAs (tRNAs). From microarray analysis, we derived a miRNA diagnostic classifier that accurately distinguishes normal from cancer samples. Furthermore, we were able to construct a PCa prognostic predictor that independently forecasts postoperative outcome. Importantly, the majority of miRNAs included in the predictor also exhibit high sequence counts and concordant differential expression in Illumina PCa samples, supported by quantitative reverse transcriptase-PCR. Our findings provide miRNA expression signatures that may serve as an accurate tool for the diagnosis and prognosis of PCa.

[Lameness and osteoarthritis development following Tibial Plateau Leveling Osteotomy (TPLO) and potential prognostic predictors. A long-term retrospective study]. / Lahmheits- und Osteoarthroseentwicklung nach Tibial Plateau Leveling Osteotomy (TPLO) und potenzielle prognostische Einflussfaktoren. Eine retrospektive Langzeitstudie.

OBJECTIVE: Evaluation of lameness and osteoarthritis (OA) progression following Tibial Plateau Leveling Osteotomy (TPLO) in dogs with naturally-occurring rupture of the cranial cruciate ligament (CCL) and investigation of factors with potential influence on long-term outcome. MATERIAL AND METHODS: In a retrospective clinical study medical records of 119 client-owned dogs (135 operated stifle joints) and corresponding client-questionnaires were reviewed, collecting data on radiologic and surgery results, course of surgery and complications. In a check-up, orthopaedic examination and stifle radiographs were performed to assess status quo of OA, lameness, and progression of OA. RESULTS: 58 dogs (66 stifle joints) could be examined clinically and radiologically, whereas 61 dogs (69 stifle joints) were re-checked by client-questionnaire only. Up to 6.8 years after TPLO surgery, in 90.4% of all cases lameness results were judged "excellent" (n=84) or "good" (n=38). In the long term, there was a moderate but significant progression of OA following TPLO surgery. Patients with totally ruptured CCL were significantly more likely to have meniscal injury than dogs with partially ruptured CCL. Dogs with partial meniscectomy had a significantly higher rate of "excellent" long-term clinical results and less frequently showed progression of OA compared to those having the meniscus released or left untouched. The overall complication rate was 22.2% (n=30), with the type of complication having no influence on the long-term clinical outcome. CONCLUSIONS AND CLINICAL RELEVANCE: Regarding lameness, the long-term outcome following TPLO is very satisfying. Early surgical treatment of CCL rupture using TPLO can help to decrease the likelihood of OA progression. Partial medial meniscectomy may help to avoid repeated surgery due to subsequent meniscal injury without having a negative impact on long-term functional outcome or the progression of OA in the affected joint. Neither long-term clinical results, especially regarding lameness, nor OA were impaired by previous surgery prior to TPLO or the occurrence of complications associated with TPLO surgery.