CD34-related coexpression of MDR1 and BCRP indicates a clinically resistant phenotype in patients with acute myeloid leukemia (AML) of older age

Clinical resistance to chemotherapy in acute myeloid leukemia (AML) is associated with the expression of the multidrug resistance (MDR) proteins P-glycoprotein, encoded by the MDR1/ABCB1 gene, multidrug resistant-related protein (MRP/ABCC1), the lung resistance-related protein (LRP), or major vault protein (MVP), and the breast cancer resistance protein (BCRP/ABCG2). The clinical value of MDR1, MRP1, LRP/MVP, and BCRP messenger RNA (mRNA) expression was prospectively studied in 154 newly diagnosed AML patients ≥60 years who were treated in a multicenter, randomized phase 3 trial. Expression of MDR1 and BCRP showed a negative whereas MRP1 and LRP showed a positive correlation with high white blood cell count (respectively, p < 0.05, p < 0.001, p < 0.001 and p < 0.001). Higher BCRP mRNA was associated with secondary AML (p < 0.05). MDR1 and BCRP mRNA were highly significantly associated (p < 0.001), as were MRP1 and LRP mRNA (p < 0.001) expression. Univariate regression analyses revealed that CD34 expression, increasing MDR1 mRNA as well as MDR1/BCRP coexpression, were associated with a lower complete response (CR) rate and with worse event-free survival and overall survival. When adjusted for other prognostic actors, only CD34-related MDR1/BCRP coexpression remained significantly associated with a lower CR rate (p = 0.03), thereby identifying a clinically resistant subgroup of elderly AML patients

Development and internal validation of a multivariable prediction model for biochemical failure after whole-gland salvage iodine-125 prostate brachytherapy for recurrent prostate cancer

BACKGROUND: Localized recurrent prostate cancer after primary radiotherapy can be curatively treated using salvage iodine-125 ((125)I) brachytherapy. Selection is hampered by a lack of predictive factors for cancer control. This study aims to develop and internally validate a prognostic model for biochemical failure (BF) after salvage (125)I brachytherapy. METHODS AND MATERIALS: Whole-gland salvage (125)I brachytherapy patients were treated between 1993 and 2010 in two radiotherapy centers in the Netherlands. Multivariable Cox regression was performed to assess the predictive value of clinical parameters related to BF (Phoenix-definition [prostate-specific antigen [PSA]-nadir + 2.0 ng/mL]). Missing data were handled by multiple imputation. The model's discriminatory ability was assessed with Harrell's C-statistic. Internal validation was performed using bootstrap resampling (2000 data sets). Goodness-of-fit was evaluated with calibration plots. All analyses were performed using the recently published TRIPOD (Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis) statement. RESULTS: After median followup of 74 months (range 5-138), 43 of a total 62 patients developed BF. In multivariable analysis, disease-free survival interval (DFSI) after primary therapy and pre-salvage prostate-specific antigen doubling time (PSADT) were predictors of BF: corrected hazard ratio (HR) 0.99 (95% confidence interval 0.97-0.999; p = 0.04) and 0.94 (95% confidence interval 0.89-0.99; p = 0.03), both for a 1-month increase (optimism-adjusted C-statistic 0.70). Calibration was accurate up to 36 months. Of patients with PSADT >30 months and DFSI >60 months, 36-month biochemical disease-free survival was >75%. Every 12-month increase in DFSI will allow 3-month decrease in PSADT while maintaining the same biochemical recurrence-free rates. CONCLUSIONS: We have presented results from a cohort of patients undergoing salvage (125)I-brachytherapy. Our data show that better selection of patients is possible with the DFSI and PSADT

Genetic Covariance Structure of Reading, Intelligence and Memory in Children

This study investigates the genetic relationship among reading performance, IQ, verbal and visuospatial working memory (WM) and short-term memory (STM) in a sample of 112, 9-year-old twin pairs and their older siblings. The relationship between reading performance and the other traits was explained by a common genetic factor for reading performance, IQ, WM and STM and a genetic factor that only influenced reading performance and verbal memory. Genetic variation explained 83% of the variation in reading performance; most of this genetic variance was explained by variation in IQ and memory performance. We hypothesize, based on these results, that children with reading problems possibly can be divided into three groups: (1) children low in IQ and with reading problems; (2) children with average IQ but a STM deficit and with reading problems; (3) children with low IQ and STM deficits; this group may experience more reading problems than the other two

Brain endothelial miR-146a negatively modulates T-cell adhesion through repressing multiple targets to inhibit NF-κB activation.

Pro-inflammatory cytokine-induced activation of nuclear factor, NF-κB has an important role in leukocyte adhesion to, and subsequent migration across, brain endothelial cells (BECs), which is crucial for the development of neuroinflammatory disorders such as multiple sclerosis (MS). In contrast, microRNA-146a (miR-146a) has emerged as an anti-inflammatory molecule by inhibiting NF-κB activity in various cell types, but its effect in BECs during neuroinflammation remains to be evaluated. Here, we show that miR-146a was upregulated in microvessels of MS-active lesions and the spinal cord of mice with experimental autoimmune encephalomyelitis. In vitro, TNFα and IFNγ treatment of human cerebral microvascular endothelial cells (hCMEC/D3) led to upregulation of miR-146a. Brain endothelial overexpression of miR-146a diminished, whereas knockdown of miR-146a augmented cytokine-stimulated adhesion of T cells to hCMEC/D3 cells, nuclear translocation of NF-κB, and expression of adhesion molecules in hCMEC/D3 cells. Furthermore, brain endothelial miR-146a modulates NF-κB activity upon cytokine activation through targeting two novel signaling transducers, RhoA and nuclear factor of activated T cells 5, as well as molecules previously identified, IL-1 receptor-associated kinase 1, and TNF receptor-associated factor 6. We propose brain endothelial miR-146a as an endogenous NF-κB inhibitor in BECs associated with decreased leukocyte adhesion during neuroinflammation

Guideline for diagnosis and treatment of subacromial pain syndrome

Treatment of "subacromial impingement syndrome" of the shoulder has changed drastically in the past decade. The anatomical explanation as "impingement" of the rotator cuff is not sufficient to cover the pathology. "Subacromial pain syndrome", SAPS, describes the condition better. A working group formed from a number of Dutch specialist societies, joined by the Dutch Orthopedic Association, has produced a guideline based on the available scientific evidence. This resulted in a new outlook for the treatment of subacromial pain syndrome. The important conclusions and advice from this work are as follows: (1) The diagnosis SAPS can only be made using a combination of clinical tests. (2) SAPS should preferably be treated non-operatively. (3) Acute pain should be treated with analgetics if necessary. (4) Subacromial injection with corticosteroids is indicated for persistent or recurrent symptoms. (5) Diagnostic imaging is useful after 6 weeks of symptoms. Ultrasound examination is the recommended imaging, to exclude a rotator cuff rupture. (6) Occupational interventions are useful when complaints persist for longer than 6 weeks. (7) Exercise therapy should be specific and should be of low intensity and high frequency, combining eccentric training, attention to relaxation and posture, and treatment of myofascial trigger points (including stretching of the muscles) may be considered. (8) Strict immobilization and mobilization techniques are not recommended. (9) Tendinosis calcarea can be treated by shockwave (ESWT) or needling under ultrasound guidance (barbotage). (10) Rehabilitation in a specialized unit can be considered in chronic, treatment resistant SAPS, with pain perpetuating behavior. (11) There is no convincing evidence that surgical treatment for SAPS is more effective than conservature management. (12) There is no indication for the surgical treatment of asymptomatic rotator cuff tears

The functioning of the Cuban home hospitalization programme: a descriptive analysis

BACKGROUND: Over the last decades hospital at home (HaH) programmes have been set up in many, mainly European, countries. The Cuban HaH programme is not hospital driven, but the responsibility of the first line health services, and family doctors play a pivotal role. METHODS: We analyse the structure and functioning of the Cuban programme. In this descriptive study, information was prospectively collected on HaH patients admitted between July 1st 2001 and June 30th 2002. RESULTS: Admission rates varied between areas from 0.014 to 0.035 per person per year (ppy). The < 1 y and 1-4 y age groups had the highest admission rates. In one area the follow-up of pregnancy problems led to high 15-24 y and 25-49 y female admission rates (0,070 and 0,058 respectively). Respiratory affections were the most frequent reason for admission (32,6%), followed by early hospital discharge (16,0%) and gynaeco-obstetrical problems (10.8%). The median length of stay varied from 5 to 7 days between regions and from 5 days (early discharge) to 7 days (gynaeco-obstetrical problems) in function of the reason for admission. On average an HaH episode entailed 1.4 and 1.6 contacts per patient-day with the family doctor and nurse respectively. CONCLUSION: Difference in admission criteria in function of geography, distance to the hospital, transport facilities, and staff factors, as well as differences in hospital policy on early discharge explain the observed variability. The programme plays an important role in the integrated approach to quality care in the Cuban health system, but could benefit from more uniform admission criteria

Hidden attractors in fundamental problems and engineering models

Recently a concept of self-excited and hidden attractors was suggested: an attractor is called a self-excited attractor if its basin of attraction overlaps with neighborhood of an equilibrium, otherwise it is called a hidden attractor. For example, hidden attractors are attractors in systems with no equilibria or with only one stable equilibrium (a special case of multistability and coexistence of attractors). While coexisting self-excited attractors can be found using the standard computational procedure, there is no standard way of predicting the existence or coexistence of hidden attractors in a system. In this plenary survey lecture the concept of self-excited and hidden attractors is discussed, and various corresponding examples of self-excited and hidden attractors are considered

Prognostic Factors in 77 Curative Chest Wall Resections for Isolated Breast Cancer Recurrence

Background: Full-thickness chest wall resection (CWR) is the preferred treatment for breast cancer (BC) patients with extensive isolated locoregional recurrence. It remains a challenge to select patients that will benefit most from this treatment. The aim of this study was to define prognostic factors in patients who undergo CWR with curative intent. Methods: BC patients who underwent a CWR with curative intent for recurrence of disease between 1986 and 2006 were included in this retrospective study. Twenty-two factors were studied in a univariate analyses, and multivariate stepwise Cox regression analyses was performed. Results: Seventy-seven patients were included in this study. The 5-year overall survival was 25%. There was one postoperative death. Univariate analyses showed that three prognostic factors were significantly correlated with OS and disease-free survival: (1) interval between primary treatment and CWR (P = .02 and .004, respectively), (2) chemotherapy for recurrence (P = .05 and .05, respectively), and (3) resection specimen smaller than 150 cm2(P = .03 and .009, respectively). An interval lasting >10 years between primary treatment and CWR remained statistically significantly correlated with better overall survival and disease-free survival after multivariate analyses. Conclusions: CWR is a safe treatment in patients who have isolated extensive BC recurrence. The best survival outcome was seen in patients after a disease-free interval of >10 years. Existing data show that adjuvant radiotherapy and adjuvant hormone therapy for estrogen-positive tumors improves overall survival. Neoadjuvant chemotherapy may be considered in individual patients