Increase in substance P precursor mRNA in noninflamed small-bowel sections in patients with Crohn's disease

BACKGROUND: Neuropeptides, such as substance P (SP), are mediators of neurogenic inflammation and play an important role in inflammatory disorders. To further investigate the role of the SP pathway in inflammatory bowel disease (IBD), we analyzed the following in normal intestinal tissue specimens and in tissue specimens from patients with Crohn's disease (CD) and ulcerative colitis (UC): neurokinin receptor-1 (NK-1R); its isoforms (NK-1R-L and NK-1R-S); its ligand SP, encoded by preprotachykinin-A (PPT-A); and the SP-degradation enzyme, neutral endopeptidase (NEP). METHODS: Real-time quantitative reverse transcription-polymerase chain reaction was used to simultaneously determine the expression of NK-1R-L, NK-1R-S, and PPT-A. Protein levels of NK-1R and NEP were determined by immunoblot analysis. RESULTS: In noninflamed small-bowel tissue samples of CD patients, PPT-A mRNA expression was significantly increased, whereas there was no difference between inflamed or noninflamed UC and normal intestinal tissue samples. Examining subgroups of diverse intestinal segments from CD and UC samples with various levels of inflammation revealed no differences in NK-1R-L and NK-1R-S mRNA expression, whereas there was a tendency toward overall lower NK-1R-S mRNA copy numbers. Immunoblot analysis showed upregulation of NK-1R protein levels in cases of IBD, with more pronounced enhancement in cases of CD than in UC. For NEP, there were no differences in protein levels in normal, CD, and UC intestinal tissues. COMMENTS: These observations suggest a contribution of SP and its receptor, NK-1R, in the local inflammatory reaction in IBD and particularly in ileal CD. Moreover, significant upregulation of PPT-A mRNA in the noninflamed ileum of these patients suggests an influence of inflamed intestines on their healthy counterparts.

Intermediate results of health related quality of life after vertical banded gastroplasty

OBJECTIVES: The purpose of this study is to evaluate (a) health-related quality of life (HRQL) after vertical banded gastroplasty (VBG) (Mason) and (b) predictors of HRQL. SUBJECTS: Eighty-two consecutive patients were assessed preoperatively and then after 6, 12 and 24 months. Patients filled out questionnaires for subjective appraisal of HRQL (physical well-being, mood, physical performance, perceived health, social support and coping/adjustment). RESULTS: The greatest improvement in weight and HRQL was seen within 6 months of surgery. Twenty-four months after VBG weight reduction (P<0.05), perceived health (P<0.05), physical well-being (P<0.05), physical performance (P<0.05), mood (P<0.05), coping/adjustment (P<0.05) continued to be better than before surgery. Preoperative binge eating was the most important predictor of HRQL. CONCLUSION: Two years after VBG weight loss and a significant improvement of HRQL can be found. HRQL and weight loss are not associated in terms of outcome, indicating that weight loss alone may not be enough to improve HRQL.

Inhibition of mTOR in combination with doxorubicin in an experimental model of hepatocellular carcinoma

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is resistant to chemotherapy. We reported that sirolimus, an mTOR inhibitor, has antiangiogenic properties in HCC. Since antiangiogenic therapy may enhance chemotherapy effects, we tested the antitumorigenic properties of sirolimus combined with doxorubicin in experimental HCC. METHODS: Morris Hepatoma (MH) cells were implanted into livers of syngeneic rats. Animals were assigned to sirolimus, pegylated liposomal doxorubicin, both combined or control groups. Tumoral growth was followed by MRI. Antiangiogenic effects were assessed by CD31 immunostaining and capillary tube formation assays. Cell proliferation was monitored in vitro by thymidine incorporation. Expression of p21 and phosphorylated MAPKAP kinase-2 was quantified by immunoblotting. RESULTS: Animals treated with the combination developed smaller tumors with decreased tumor microvessel density compared to animals that received monotherapies. In vitro, inhibition of mTOR further impaired capillary formation in the presence of doxorubicin. Doxorubicin reduced endothelial cell proliferation; inhibition of mTOR accentuated this effect. Doxorubicin stimulated p21 expression and the phosphorylation of MAPKAP kinase-2 in endothelial cells. Addition of mTOR inhibitor down-regulated p21, but did not decrease MAPKAP kinase-2 phosphorylation. CONCLUSIONS: Sirolimus has additive antitumoral and antiangiogenic effects when administered with doxorubicin. These findings offer a rationale for combining mTOR inhibitors with chemotherapy in HCC treatment.

Surgical instrumentation for the in vivo determination of lumbar spinal segment stiffness and viscoelasticity

The definition of spinal instability is still controversial. For this reason, it is essential to better understand the difference in biomechanical behaviour between healthy and degenerated human spinal segments in vivo. A novel computer-assisted instrument was developed with the objective to characterize the biomechanical parameters of the spinal segment. Investigation of the viscoelastic properties as well as the dynamic spinal stiffness was performed during a minimally invasive procedure (microdiscectomy) on five patients. Measurements were performed intraoperatively and the protocol consisted of a dynamic part, where spinal stiffness was computed, and a static part, where force relaxation of the segment under constant elongation was studied. The repeatability of the measurement procedure was demonstrated with five replicated tests. The spinal segment tissues were found to have viscoelastic properties. Preliminary tests confirmed a decrease in stiffness after decompression surgery. Patients with non-relaxed muscles showed higher stiffness and relaxation rate compared to patients with relaxed muscles, which can be explained by the contraction and relaxation reflex of muscles under fast and then static elongation. The results show the usefulness of the biomechanical characterization of the human lumbar spinal segment to improve the understanding of the contribution of individual anatomical structures to spinal stability.

Factorization and N3LLp+NNLO predictions for the Higgs cross section with a jet veto

We have recently derived a factorization formula for the Higgs-boson production cross section in the presence of a jet veto, which allows for a systematic resummation of large Sudakov logarithms of the form αn s lnm(pveto T /mH), along with the large virtual corrections known to affect also the total cross section. Here we determine the ingredients entering this formula at two-loop accuracy. Specifically, we compute the dependence on the jet-radius parameter R, which is encoded in the two-loop coefficient of the collinear anomaly, by means of a direct, fully analytic calculation in the framework of soft-collinear effective theory. We confirm the result obtained by Banfi et al. from a related calculation in QCD, and demonstrate that factorization-breaking, soft-collinear mixing effects do not arise at leading power in pveto T /mH, even for R = O(1). In addition, we extract the two-loop collinear beam functions numerically. We present detailed numerical predictions for the jet-veto cross section with partial next-to-next-to-next-to-leading logarithmic accuracy, matched to the next-to-next-to-leading order cross section in fixed-order perturbation theory. The only missing ingredients at this level of accuracy are the three-loop anomaly coefficient and the four-loop cusp anomalous dimension, whose numerical effects we estimate to be small.

Higgs-boson production at small transverse momentum

Using methods from effective field theory, we have recently developed a novel, systematic framework for the calculation of the cross sections for electroweak gauge-boson production at small and very small transverse momentum q T , in which large logarithms of the scale ratio m V /q T are resummed to all orders. This formalism is applied to the production of Higgs bosons in gluon fusion at the LHC. The production cross section receives logarithmically enhanced corrections from two sources: the running of the hard matching coefficient and the collinear factorization anomaly. The anomaly leads to the dynamical generation of a non-perturbative scale q∗~mHe−const/αs(mH)≈8 GeV, which protects the process from receiving large long-distance hadronic contributions. We present numerical predictions for the transverse-momentum spectrum of Higgs bosons produced at the LHC, finding that it is quite insensitive to hadronic effects.

Early changes in biochemical markers of bone formation during teriparatide therapy correlate with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis

Summary Changes of the bone formation marker PINP correlated positively with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis (GIO) who received 18-month treatment with teriparatide, but not with risedronate. These results support the use of PINP as a surrogate marker of bone strength in GIO patients treated with teriparatide. Introduction To investigate the correlations between biochemical markers of bone turnover and vertebral strength estimated by finite element analysis (FEA) in men with GIO. Methods A total of 92 men with GIO were included in an 18-month, randomized, open-label trial of teriparatide (20 μg/day, n = 45) and risedronate (35 mg/week, n = 47). High-resolution quantitative computed tomography images of the 12th thoracic vertebra obtained at baseline, 6 and 18 months were converted into digital nonlinear FE models and subjected to anterior bending, axial compression and torsion. Stiffness and strength were computed for each model and loading mode. Serum biochemical markers of bone formation (amino-terminal-propeptide of type I collagen [PINP]) and bone resorption (type I collagen cross-linked C-telopeptide degradation fragments [CTx]) were measured at baseline, 3 months, 6 months and 18 months. A mixed-model of repeated measures analysed changes from baseline and between-group differences. Spearman correlations assessed the relationship between changes from baseline of bone markers with FEA variables. Results PINP and CTx levels increased in the teriparatide group and decreased in the risedronate group. FEA-derived parameters increased in both groups, but were significantly higher at 18 months in the teriparatide group. Significant positive correlations were found between changes from baseline of PINP at 3, 6 and 18 months with changes in FE strength in the teriparatide-treated group, but not in the risedronate group. Conclusions Positive correlations between changes in a biochemical marker of bone formation and improvement of biomechanical properties support the use of PINP as a surrogate marker of bone strength in teriparatide-treated GIO patients.

Optimizing the size of the area surveyed for monitoring a Eurasian lynx (Lynx lynx) population in the Swiss Alps by means of photographic capture-recapture

We studied the influence of surveyed area size on density estimates by means of camera-trapping in a low-density felid population (1-2 individuals/100 km(2) ). We applied non-spatial capture-recapture (CR) and spatial CR (SCR) models for Eurasian lynx during winter 2005/2006 in the northwestern Swiss Alps by sampling an area divided into 5 nested plots ranging from 65 to 760 km(2) . CR model density estimates (95% CI) for models M0 and Mh decreased from 2.61 (1.55-3.68) and 3.6 (1.62-5.57) independent lynx/100 km(2) , respectively, in the smallest to 1.20 (1.04-1.35) and 1.26 (0.89-1.63) independent lynx/100 km(2) , respectively, in the largest area surveyed. SCR model density estimates also decreased with increasing sampling area but not significantly. High individual range overlaps in relatively small areas (the edge effect) is the most plausible reason for this positive bias in the CR models. Our results confirm that SCR models are much more robust to changes in trap array size than CR models, thus avoiding overestimation of density in smaller areas. However, when a study is concerned with monitoring population changes, large spatial efforts (area surveyed ≥760 km(2) ) are required to obtain reliable and precise density estimates with these population densities and recapture rates.

Comparative effects of Teriparatide and Risedronate in glucocorticoid‐induced osteoporosis in men: 18‐month results of the EuroGIOPs trial

Data on treatment of glucocorticoid-induced osteoporosis (GIO) in men are scarce. We performed a randomized, open-label trial in men who have taken glucocorticoids (GC) for ≥3 months, and had an areal bone mineral density (aBMD) T-score ≤ –1.5 standard deviations. Subjects received 20 μg/d teriparatide (n = 45) or 35 mg/week risedronate (n = 47) for 18 months. Primary objective was to compare lumbar spine (L1–L3) BMD measured by quantitative computed tomography (QCT). Secondary outcomes included BMD and microstructure measured by high-resolution QCT (HRQCT) at the 12th thoracic vertebra, biomechanical effects for axial compression, anterior bending, and axial torsion evaluated by finite element (FE) analysis from HRQCT data, aBMD by dual X-ray absorptiometry, biochemical markers, and safety. Computed tomography scans were performed at 0, 6, and 18 months. A mixed model repeated measures analysis was performed to compare changes from baseline between groups. Mean age was 56.3 years. Median GC dose and duration were 8.8 mg/d and 6.4 years, respectively; 39.1% of subjects had a prevalent fracture, and 32.6% received prior bisphosphonate treatment. At 18 months, trabecular BMD had significantly increased for both treatments, with significantly greater increases with teriparatide (16.3% versus 3.8%; p = 0.004). HRQCT trabecular and cortical variables significantly increased for both treatments with significantly larger improvements for teriparatide for integral and trabecular BMD and bone surface to volume ratio (BS/BV) as a microstructural measure. Vertebral strength increases at 18 months were significant in both groups (teriparatide: 26.0% to 34.0%; risedronate: 4.2% to 6.7%), with significantly higher increases in the teriparatide group for all loading modes (0.005 < p < 0.015). Adverse events were similar between groups. None of the patients on teriparatide but five (10.6%) on risedronate developed new clinical fractures (p = 0.056). In conclusion, in this 18-month trial in men with GIO, teriparatide showed larger improvements in spinal BMD, microstructure, and FE-derived strength than risedronate.