Variability among nonsteroidal antiinflammatory drugs in risk of upper gastrointestinal bleeding

Objective

Traditional nonsteroidal antiinflammatory drugs (NSAIDs) increase the risk of upper gastrointestinal (GI) bleeding/perforation, but the magnitude of this effect for coxibs in the general population and the degree of variability between individual NSAIDs is still under debate. This study was undertaken to assess the risk of upper GI bleeding/perforation among users of individual NSAIDs and to analyze the correlation between this risk and the degree of inhibition of whole blood cyclooxygenase 1 (COX‐1) and COX‐2 in vitro.

Methods

We conducted a systematic review of observational studies on NSAIDs and upper GI bleeding/perforation published between 2000 and 2008. We calculated pooled relative risk (RR) estimates of upper GI bleeding/perforation for individual NSAIDs. Additionally, we verified whether the degree of inhibition of whole blood COX‐1 and COX‐2 in vitro by average circulating concentrations predicted the RR of upper GI bleeding/perforation.

Results

The RR of upper GI bleeding/perforation was 4.50 (95% confidence interval [95% CI] 3.82–5.31) for traditional NSAIDs and 1.88 (95% CI 0.96–3.71) for coxibs. RRs lower than that for NSAIDs overall were observed for ibuprofen (2.69 [95% CI 2.17–3.33]), rofecoxib (2.12 [95% CI 1.59–2.84]), aceclofenac (1.44 [95% CI 0.65–3.2]), and celecoxib (1.42 [95% CI 0.85–2.37]), while higher RRs were observed for ketorolac (14.54 [95% CI 5.87–36.04]) and piroxicam (9.94 [95% CI 5.99–16.50). Estimated RRs were 5.63 (95% CI 3.83–8.28) for naproxen, 5.57 (95% CI 3.94–7.87) for ketoprofen, 5.40 (95% CI 4.16–7.00) for indomethacin, 4.15 (95% CI 2.59–6.64) for meloxicam, and 3.98 (95% CI 3.36–4.72) for diclofenac. The degree of inhibition of whole blood COX‐1 did not significantly correlate with RR of upper GI bleeding/perforation associated with individual NSAIDs (r² = 0.34, P = 0.058), but a profound and coincident inhibition (>80%) of both COX isozymes was associated with higher risk. NSAIDs with a long plasma half‐life and with a slow‐release formulation were associated with a greater risk than NSAIDs with a short half‐life.

Conclusion

The results of our analysis demonstrate that risk of upper GI bleeding/perforation varies between individual NSAIDs at the doses commonly used in the general population. Drugs that have a long half‐life or slow‐release formulation and/or are associated with profound and coincident inhibition of both COX isozymes are associated with a greater risk of upper GI bleeding/perforation.

     

Effects of transforming growth factor-beta1 and tumour necrosis factor-alpha on cultured fibroblasts from skin fibroma as modulated by toremifene

To determine how toremifene, an anti-oestrogen triphenylethylene derivate, reduces tumour mass, we investigated its modulation of TGF-beta1 and TNF-alpha in fibroma fibroblasts. Normal and fibroma fibroblasts, isolated from patients affected by Gardner's syndrome without or with fibroma manifestation, were cultured in vitro. Secretion of GAG, collagen and TGF-beta1 was increased in fibroma fibroblasts compared to healthy cells. The increase in TGF-beta1 secretion into the medium was associated with a parallel increase in TGF-beta1 gene expression and receptor number. Receptor cross-linking studies using radiolabelled TGF-beta1 revealed more receptors, particularly types I and II, in fibroma fibroblasts than in normal cells. Normal and fibroma fibroblasts did not synthesise TNF-alpha, but they had TNF-alpha membrane receptors, as shown by TNF-alpha assay. TNF-alpha secreted by human monocytes, which may be present in the peritumoral area, increased cell proliferation and GAG accumulation and was, in turn, enhanced by TGF-beta1 treatment. Both growth factors increased angiogenesis, as shown by the CAM assay. Toremifene reduced TGF-beta1 secretion by fibroma fibroblasts and TNF-alpha secretion by monocytes, thus downregulating cell proliferation, ECM macromolecule accumulation and angiogenic progression. We hypothesise that increased TGF-beta1 gene expression and TGF-beta1 secretion in fibroma fibroblasts as well as the subsequent rise in TNF-alpha production by monocytes may facilitate fibroma growth and that toremifene inhibits autocrine and paracrine growth factor production.     

Caveolin-1 expression is variably displayed in astroglial-derived tumors and absent in oligodendrogliomas: concrete premises for a new reliable diagnostic marker in gliomas

Caveolins are basic constituents of flask-shaped cell membrane microdomains (caveolae), which are involved in many cell functions, including signalling, trafficking, and cellular growth control. The distribution of caveolae within the normal brain and in brain tumors is controversial. In the present study, we describe the expression of caveolin-1 (cav-1) in 64 brain tumors of different grade, of either astroglial or oligodendroglial origin. All studied astrocitomas of any grade (from II to IV) were cav-1 positive, displaying staining patterns and intensity specifically associated to the different tumor grades. In all glioblastomas and gliosarcomas, cav-1 staining was extremely intense, typically localized at the cell membrane and recognized a variable percentage of cells, including the majority of spindle cells and palisade-oriented perinecrotic cells. In anaplastic astrocytomas, a less intense membrane staining or a cytoplasmic dotlike immunoreactivity were present, the latter being almost the exclusive pattern observed in diffuse astrocitomas grade II. In contrast to astroglial tumors, the striking totality of grade II oligodendrogliomas and the large majority of grade III were lacking cav-1 expression. Interestingly, a cav-1 distribution overlapping the pattern described in tissues was observed also in primary cell cultures of human glioblastomas and astrocytomas, and also in one established glioblastoma cell line (U251 MG), analyzed by means of confocal microscopy and flow cytometry. In conclusion, among astroglial tumors cav-1 expression varies in distribution, pattern, and intensity specifically according to tumor types and grades. The association between tumor progression and a more structured membranous pattern of cav-1 expression could suggest the hypothesis of a neoplastic shift towards a mesenchymal phenotype, whose behavioral and biologic significance worth further studies. Finally, the lack of cav-1 immunoreactivity in oligodendrogliomas suggests its concrete application as a useful diagnostic marker.     

Effectiveness of a cluster-randomized controlled trial community-based lifestyle intervention program to control prehypertension and/or prediabetes in Thailand

International Journal of Diabetes in Developing Countries - Lifestyle intervention is recommended as the primary management for prehypertension and prediabetes. The aim of the study was to examine...     

Osmotic water permeability of the apical membrane of proximal straight tubular (PST) cells

Osmotic steps, C, were produced across the apical cell membrane of isolated rabbit PST by perfusing their lumens with double barreled micropipettes at a rate of 0.5–0.8 nl/s. C=15–46 mOsmolar were induced with mannitol. Changes in luminal diameter were recorded as a function of time with a TV camera and an integrator-processor system with space and time resolutions of 0.03 m and 0.0167 s (3). The tubules were bathed with oil. Outer tubule diameter was time invariant. P _os ^ca , the apical cell osmotic permeability was therefore calculated from cell volume changes with time in units of 10^–4 cm³/cm². s. Osmolar. P _os ^ca was independent of C. The mean is 22.8±1.3 (n=55). With a basolateral permeability of 50.4 (3,12), the transcellular permeability is 14 (same units) smaller than the transepithelial values available. This leads to the conclusion that a significant paracellular water osmotic permeability must exist.     

Ligasure versus Ultracision® in thyroid surgery: a prospective randomized study

PURPOSE: New hemostatic technologies (NT) are often employed in thyroid surgery in the effort to reduce operating time and complications. The aim of this study is to compare three different hemostatic techniques. METHODS: This is a prospective randomized study. There were 150 patients, aged 56 +/- 14 years, randomized for total thyroidectomy with conventional technique (CT), Ligasure vessel sealing system (LI) or Harmonic Scalpel (HS) at the university surgical department. One hundred thirty-five patients had benign diseases; 15 had malignancies. RESULTS: Mean postoperative hospital stay was 2.6 days. Mean operation time was 113 +/- 31 min; in HS patients, it was significantly shorter (p < 0.001). Morbidity was 43.3%; mortality was nil. Morbidity was significantly different between CT and NT groups (p = 0.0002); HS and LI groups had a higher morbidity (p = 0.0001 and p = 0.02, respectively). Mean postoperative calcemia was 1.12 +/- 0.1 mmol/l with a significant difference between groups; NT patients had a significantly lower calcemia (p < 0.05). There was no difference in recurrent laryngeal nerve palsies and in intraoperative blood losses (p = ns). CONCLUSIONS: According to our experience, the only real advantage of new hemostatic technologies was a shorter operation time with HS.     

Surfactant phosphatidylcholine metabolism in neonates with meconium aspiration syndrome

OBJECTIVE: Because meconium directly inhibits surfactant function, we sought to determine the effect of meconium on endogenous surfactant synthesis and clearance. STUDY DESIGN: We studied surfactant phosphatidylcholine kinetics with the use of stable isotopes in 11 newborn infants with meconium aspiration syndrome (MAS) who required extracorporeal membrane oxygenation (ECMO). For comparison we studied 6 neonates with persistent pulmonary hypertension (PPHN) on ECMO and 10 term neonates ventilated for non-pulmonary indications and not on ECMO. All patients received a 24-hour [U- 13C]glucose infusion as precursor for the palmitic acid in surfactant phosphatidylcholine. RESULTS: In the meconium group, the maximal 13C-incorporation in phosphatidylcholine (PC) was half of that in controls (0.09 +/- 0.01 vs 0.18 +/- 0.03 atom percent excess [APE], P = .027). There was a trend toward lower surfactant synthesis in the MAS group (3.3 +/- 0.7%/day) and PPHN group (2.6 +/- 0.3%/day) compared with controls 8.0 +/- 2.4%/day, P = .058). Significantly lower PC concentrations in tracheal aspirates were found in the MAS group (4.4 +/- 2.6 mg/mL) and PPHN group (3.6 +/- 2.0 mg/mL) compared with controls (12.8 +/- 2.6 mg/mL, P = .01). Endogenously synthesized surfactant had a similar half-life in all groups, ranging from 63 to 98 hours. CONCLUSION: We conclude that surfactant synthesis is disturbed and that surfactant PC concentrations are low in infants with MAS on ECMO.