Dental pulp stem cells (DPSCs) are particularly promising for tissue engineering (TE) due to the ease of their isolation procedure, great expansion potential and capability to differentiate towards ...several cell types of the mesodermal, ectodermal and endodermal lineages. Although several studies hint that DPSCs exhibit potential for cartilage tissue formation, the chondrogenic potential of DPSCs has only been marginally explored. Thus, the aim of the present study was to closely investigate the chondrogenic differentiation capacity of DPSCs for TE applications. More specifically, the potential of DPSCs for engineering hyaline and fibrous cartilage was determined. DPSCs obtained from 7 human molars were expanded and chondrogenically differentiated in a 3D pellet culture model. After 21 d of differentiation with chondrogenic stimuli, DPSCs displayed glycosaminoglycan, aggrecan and limited collagen type II deposition. Cells presented an elongated morphology and produced a collagen-rich extracellular matrix, with a predominance of collagen type I in most of the samples, a characteristic of fibrous cartilage tissue. Variations in the administration periods of several chondro-inductive growth factors, including transforming growth factor beta 3, bone morphogenetic protein-2, -6, -7 and insulin-like growth factor-1, did not increase glycosaminoglycan or collagen type II deposition, typical markers of hyaline cartilage tissue. Furthermore, DPSCs could not be stimulated to go into hypertrophic chondrogenesis. These results indicated that under a large variety of chondro-inductive culture conditions, DPSCs could form fibrocartilaginous tissues but not hyaline cartilage. Thus, DPSCs represent a valuable cell source for the regeneration of fibrocartilage in joints.
The effect of classic breast cancer risk factors on hormone receptor-defined breast cancer is not fully clarified. We explored
these associations in a Swedish population-based study. Postmenopausal ...women ages 50 to 74 years, diagnosed with invasive
breast cancer during 1993 to 1995, were compared with 3,065 age frequency-matched controls. We identified 332 estrogen receptor
(ER − ) and progesterone receptor (PR − ) negative, 286 ER + PR − , 71 ER − PR + , 1,165 ER + PR + , and 789 tumors with unknown receptor status. Unconditional logistic regression was used to calculate odds ratios (OR) and
95% confidence intervals (95% CI). Women ages ≥30 years, compared with those ages 20 to 24 years at first birth, were at an
increased risk of ER + PR + tumors (OR, 1.5; 95% CI, 1.2-1.8) but not ER − PR − tumors (OR, 1.1; 95% CI, 0.8-1.6). Women who gained ≥30 kg in weight during adulthood had an ∼3-fold increased relative risk
of ER + PR + tumors (OR, 2.7; 95% CI, 1.9-3.8), but no risk increase of ER − PR − tumors (OR, 1.0; 95% CI, 0.5-2.1), compared with women who gained <10 kg. Compared with never users, women who used menopausal
estrogen-progestin therapy for at least 5 years were at increased risk of ER + PR + tumors (OR, 3.0; 95% CI, 2.1-4.1) but not ER − PR − tumors (OR, 1.3; 95% CI, 0.7-2.5). In conclusion, other risk factors were similarly related to breast cancer regardless of
receptor status, but high age at first birth, substantial weight gain in adult age, and use of menopausal estrogen-progestin
therapy were more strongly related to receptor-positive breast cancer than receptor-negative breast cancer. (Cancer Epidemiol
Biomarkers Prev 2006;15(12):2482–8)
CYP2D6 bioactivates codeine and tramadol, with intermediate and poor metabolizers (IMs and PMs) expected to have impaired analgesia. This pragmatic proof-of-concept trial tested the effects of ...CYP2D6-guided opioid prescribing on pain control.
Participants with chronic pain (94% on an opioid) from seven clinics were enrolled into CYP2D6-guided (n = 235) or usual care (n = 135) arms using a cluster design. CYP2D6 phenotypes were assigned based on genotype and CYP2D6 inhibitor use, with recommendations for opioid prescribing made in the CYP2D6-guided arm. Pain was assessed at baseline and 3 months using PROMIS
measures.
On stepwise multiple linear regression, the primary outcome of composite pain intensity (composite of current pain and worst and average pain in the past week) among IM/PMs initially prescribed tramadol/codeine (n = 45) had greater improvement in the CYP2D6-guided versus usual care arm (-1.01 ± 1.59 vs. -0.40 ± 1.20; adj P = 0.016); 24% of CYP2D6-guided versus 0% of usual care participants reported ≥30% (clinically meaningful) reduction in the composite outcome. In contrast, among normal metabolizers prescribed tramadol or codeine at baseline, there was no difference in the change in composite pain intensity at 3 months between CYP2D6-guided (-0.61 ± 1.39) and usual care (-0.54 ± 1.69) groups (adj P = 0.540).
These data support the potential benefits of CYP2D6-guided pain management.
TRAIL is a tumor necrosis factor-related ligand that induces apoptosis upon binding to its death domain-containing receptors, DR4 and DR5. Two additional TRAIL receptors, TRID/DcR1 and DcR2, lack ...functional death domains and function as decoy receptors for TRAIL. We have identified a fifth TRAIL receptor, namely osteoprotegerin (OPG), a secreted tumor necrosis factor receptor homologue that inhibits osteoclastogenesis and increases bone density in vivo. OPG-Fc binds TRAIL with an affinity of 3.0 nm, which is slightly weaker than the interaction of TRID-Fc or DR5-Fc with TRAIL. OPG inhibits TRAIL-induced apoptosis of Jurkat cells. Conversely, TRAIL blocks the anti-osteoclastogenic activity of OPG. These data suggest potential cross-regulatory mechanisms by OPG and TRAIL.
Sequence comparisons have implied the presence of genes encoding enzymes of the mevalonate pathway for isopentenyl diphosphate biosynthesis in the gram-positive pathogen Staphylococcus aureus. In ...this study we showed through genetic disruption experiments that mvaA, which encodes a putative class II 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, is essential for in vitro growth of S. aureus. Supplementation of media with mevalonate permitted isolation of an auxotrophic mvaA null mutant that was attenuated for virulence in a murine hematogenous pyelonephritis infection model. The mvaA gene was cloned from S. aureus DNA and expressed with an N-terminal His tag in Escherichia coli. The encoded protein was affinity purified to apparent homogeneity and was shown to be a class II HMG-CoA reductase, the first class II eubacterial biosynthetic enzyme isolated. Unlike most other HMG-CoA reductases, the S. aureus enzyme exhibits dual coenzyme specificity for NADP(H) and NAD(H), but NADP(H) was the preferred coenzyme. Kinetic parameters were determined for all substrates for all four catalyzed reactions using either NADP(H) or NAD(H). In all instances optimal activity using NAD(H) occurred at a pH one to two units more acidic than that using NADP(H). pH profiles suggested that His378 and Lys263, the apparent cognates of the active-site histidine and lysine of Pseudomonas mevalonii HMG-CoA reductase, function in catalysis and that the general catalytic mechanism is valid for the S. aureus enzyme. Fluvastatin inhibited competitively with HMG-CoA, with a K(i) of 320 microM, over 10(4) higher than that for a class I HMG-CoA reductase. Bacterial class II HMG-CoA reductases thus are potential targets for antibacterial agents directed against multidrug-resistant gram-positive cocci.
Systemic lupus erythematosus (SLE) predominantly affects women, but previous studies suggest that men with SLE present a more severe disease phenotype. In this study, we investigated a large and ...well-characterized patient group with the aim of identifying sex differences in disease manifestations, with a special focus on renal involvement.
We studied a Swedish multi-center SLE cohort including 1226 patients (1060 women and 166 men) with a mean follow-up time of 15.8 ± 13.4 years. Demographic data, disease manifestations including ACR criteria, serology and renal histopathology were investigated. Renal outcome and mortality were analyzed in subcohorts.
Female SLE patients presented more often with malar rash (p < 0.0001), photosensitivity (p < 0.0001), oral ulcers (p = 0.01), and arthritis (p = 0.007). Male patients on the other hand presented more often with serositis (p = 0.0003), renal disorder (p < 0.0001), and immunologic disorder (p = 0.04) by the ACR definitions. With regard to renal involvement, women were diagnosed with nephritis at an earlier age (p = 0.006), while men with SLE had an overall higher risk for progression into end-stage renal disease (ESRD) with a hazard ratio (HR) of 5.1 (95% CI, 2.1-12.5). The mortality rate among men with SLE and nephritis compared with women was HR 1.7 (95% CI, 0.8-3.8).
SLE shows significant sex-specific features, whereby men are affected by a more severe disease with regard to both renal and extra-renal manifestations. Additionally, men are at a higher risk of developing ESRD which may require an increased awareness and monitoring in clinical practice.
Background
Emergency abdominal surgery carries a considerable risk of death and postoperative complications. Early detection and timely management of complications may reduce mortality. The aim was ...to evaluate the effect and feasibility of intermediate care compared with standard ward care in patients who had emergency abdominal surgery.
Methods
This was a randomized clinical trial carried out in seven Danish hospitals. Eligible for inclusion were patients with an Acute Physiology And Chronic Health Evaluation (APACHE) II score of at least 10 who were ready to be transferred to the surgical ward within 24 h of emergency abdominal surgery. Participants were randomized to either intermediate care or standard surgical ward care after surgery. The primary outcome was 30‐day mortality.
Results
In total, 286 patients were included in the modified intention‐to‐treat analysis. The trial was terminated after the interim analysis owing to slow recruitment and a lower than expected mortality rate. Eleven (7·6 per cent) of 144 patients assigned to intermediate care and 12 (8·5 per cent) of 142 patients assigned to ward care died within 30 days of surgery (odds ratio 0·91, 95 per cent c.i. 0·38 to 2·16; P = 0·828). Thirty (20·8 per cent) of 144 patients assigned to intermediate care and 37 (26·1 per cent) of 142 assigned to ward care died within the total observation period (hazard ratio 0·78, 95 per cent c.i. 0·48 to 1·26; P = 0·310).
Conclusion
Postoperative intermediate care had no statistically significant effect on 30‐day mortality after emergency abdominal surgery, nor any effect on secondary outcomes. The trial was stopped prematurely owing to slow recruitment and a much lower than expected mortality rate among the enrolled patients. Registration number: NCT01209663 (http://www.clinicaltrials.gov).
Trial closed early, no effect on mortality
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