Changes in C-reactive protein predict insulin sensitivity in severely obese individuals after weight loss surgery

The production of inflammatory mediators by abdominal adipose tissue may link obesity and insulin resistance. We determined the influence of systemic levels of interleukin-6 and C-reactive protein on insulin sensitivity after weight loss via Roux-en-Y gastric bypass surgery. Severely obese individuals (n 5 15) were evaluated at baseline and at 6 months after surgery. Insulin sensitivity was determined by frequently sampled intravenous glucose tolerance testing at the same time points. Visceral and subcutaneous adipose tissue volumes were quantified by computed tomography. Interleukin-6 and C-reactive protein were measured by enzyme-linked immunoassay in plasma and in adipose tissue biopsies. Correlation analysis was used to determine associations between insulin sensitivity and other outcome variables. Significance was set at P < 0.05. Plasma interleukin-6 concentrations were significantly correlated to the IL-6 content of subcutaneous adipose tissue (r = 0.71). At 6 months postsurgery, subcutaneous and visceral adipose tissue volumes were significantly reduced (34.7% and 44.1%, respectively) and insulin sensitivity had improved by 160.9%. Significant longitudinal correlations were found between insulin sensitivity and plasma C-reactive protein (r = 20.61), but not plasma interleukin-6 at 6 months. These findings offer insights that link obesity and insulin resistance via the activity of inflammatory mediators. Presented at the Forty-Sixth Annual Meeting of The Society for Surgery of the Alimentary Tract, Chicago, Illinois, May 14–18, 2005 (oral presentation). Supported by National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases 1R03 DK067167-01A1 (N.G.), the Emory University Research Committee Grant (N.G.), and the National Institutes of Health/National Center for Research Resources General Clinical Research Center Grant M01 RR00039 (N.G., E.L.).     

The Role of TGF‐β in the Association Between Primary Graft Dysfunction and Bronchiolitis Obliterans Syndrome

Primary graft dysfunction (PGD) is a possible risk factor for bronchiolitis obliterans syndrome (BOS) following lung transplantation; however, the mechanism for any such association is poorly understood. Based on the association of TGF‐β with acute and chronic inflammatory disorders, we hypothesized that it might play a role in the continuum between PGD and BOS. Thus, the association between PGD and BOS was assessed in a single‐center cohort of lung transplant recipients. Bronchoalveolar lavage fluid concentrations of TGF‐β and procollagen collected within 24 h of transplantation were compared across the spectrum of PGD, and incorporated into Cox models of BOS. Immunohistochemistry localized expression of TGF‐β and its receptor in early lung biopsies posttransplant. We found an association between PGD and BOS in both bilateral and single lung recipients with a hazard ratio of 3.07 (95% CI 1.76–5.38) for the most severe form of PGD. TGF‐β and procollagen concentrations were elevated during PGD (p < 0.01), and associated with increased rates of BOS. Expression of TGF‐β and its receptor localized to allograft infiltrating mononuclear and stromal cells, and the airway epithelium. These findings validate the association between PGD and the subsequent development of BOS, and suggest that this association may be mediated by receptor/TGF‐β biology.     

Increasing the number of biopsy cores improves the concordance of biopsy Gleason score to prostatectomy Gleason score

OBJECTIVE: To evaluate taking more biopsy cores for predicting the radical prostatectomy (RP) Gleason score compared with the biopsy Gleason score, as although random sextant biopsies are the standard for a tissue diagnosis of prostate cancer, and taking more biopsies increases the detection rate, it is uncertain whether taking more cores improves the prediction of the RP Gleason score. PATIENTS AND METHODS: We analysed retrospectively 404 patients from three centres (Seattle 162, Washington 107 and Chicago 135) who had RP for prostate cancer. Six, eight or 10 biopsies were taken based on the physician's preference and the patient's characteristics. RESULTS: Before RP, 158 (39%) patients had six, 65 (16%) had eight and 181 (45%) had 10 biopsy cores taken. The accuracy of the Gleason sum of the three groups was 65/158 (41%), 26/65 (40%) and 104/181 (57.5%), respectively (P < 0.004, 10-core vs six-core). However, when comparing the Gleason score separately (i.e. 4 + 3 is not equal to 3 + 4), the accuracy of the three groups was 48/158 (30%), 20/65 (31%), and 95/181 (52.5%), respectively (P < 0.001, 10-core vs six core). CONCLUSIONS: Taking more biopsy cores improves the accuracy of the biopsy Gleason score in predicting the final Gleason score at RP; the predictive accuracy of the final Gleason score may be increased from 41% to 58% by increasing the number of biopsies from six to 10.     

Femoral neck trabecular microstructure in ovariectomized ewes treated with calcitonin: MRI microscopic evaluation.

Ovariectomy induces deterioration of the trabecular structure in the femoral neck of ewes, as depicted by MR microscopic imaging. This structural deterioration is prevented by salmon calcitonin treatment. INTRODUCTION: This study evaluated the trabecular (Tb) microarchitecture of an ovariectomy (OVX)-induced osteoporotic model in ewes and determined the effects of salmon calcitonin (sCT), an osteoclast inhibitor, on the Tb structure. This is the first report of OVX-induced changes in the Tb structure in the femoral neck in the ewes and effect of sCT on the microarchitecture. MATERIALS AND METHODS: Ewes (5-8 years old, n = 28) were equally allocated into sham (Sham), OVX injected with vehicle, or OVX injected with sCT at 50 or 100 IU, three injections per week. They were killed 6 months after OVX. The femoral neck was examined with an MR imager at 9.4 T in axial, coronal, and sagittal planes. An internal calibration procedure as a means of standardizing image analysis was used to adjust the segmentation threshold. Data from all three planes were averaged. RESULTS AND CONCLUSIONS: Compared with Sham, OVX induced significant changes (p < 0.0125) in the MRI-derived femoral neck Tb structure: Tb bone volume fraction (BV/TV), -18%; Tb number, -20%; Tb separation, +23%; number of free ends, +28%; number of nodes, -39%; number of Tb branches, -23%; mean length of Tb branches, -19%. Compared with OVX, treatment of sCT at 100 IU significantly improved all the Tb structural parameters to the Sham level (p < 0.0001 approximately p = 0.0281), whereas 50 IU significantly increased the Tb number and the mean length of the Tb branches. BV/TV explained 74% of the variation of compressive stress of the trabecular cylinder cores of the femoral neck. Combining all structural parameters in a multivariate regression analysis significantly improved the explanation to 84%, and adding BMD further improved the predictive ability of the model to 92%. We conclude that OVX induces deterioration of the MRI-derived Tb microstructure in the femoral neck of ewes. sCT treatment prevents OVX-induced changes. The femoral neck microarchitecture significantly correlates with its biomechanical properties. Combining microstructural parameters with BMD further improves the prediction of bone biomechanical properties. The effects of sCT on OVX ewes may help explain reduced fracture risk in postmenopausal osteoporotic women treated with sCT.     

Patient-centered Applications: Use of Information Technology to Promote Disease Management and Wellness. A White Paper by the AMIA Knowledge in Motion Working Group

Advances in information technology (IT) enable a fundamental redesign of health care processes based on the use and integration of electronic communication at all levels. New communication technologies can support a transition from institution centric to patient-centric applications. This white paper defines key principles and challenges for designers, policy makers, and evaluators of patient-centered technologies for disease management and prevention. It reviews current and emerging trends; highlights challenges related to design, evaluation, reimbursement and usability; and reaches conclusions for next steps that will advance the domain.     

Role for interleukin-1 (IL-1) in benzene-induced hematotoxicity: inhibition of conversion of pre-IL-1 alpha to mature cytokine in murine macrophages by hydroquinone and prevention of benzene-induced hematotoxicity in mice by IL-1 alpha

Chronic exposure of humans to benzene (BZ), a myelotoxin, causes aplastic anemia and acute leukemia. The stromal macrophage that produces interleukin-1 (IL-1), a cytokine essential for hematopoiesis, is a target of BZ's toxicity. Monocyte dysfunction and decreased IL-1 production have been shown to be involved in aplastic anemia in humans. Hydroquinone (HQ), a toxic bone marrow (BM) metabolite of BZ, causes time- and concentration-dependent inhibition of processing of the 34-Kd pre-interleukin-1 alpha (IL-1 alpha) to the 17-Kd mature cytokine in murine P388D1 macrophages and BM stromal macrophages, as measured by Western immunoblots of cell lysate proteins using a polyclonal rabbit antimurine IL-1 alpha antibody. HQ over a 10-fold concentration range had no effect on the lipopolysaccharide (LPS)-induced production of pre- IL-1 alpha precursor or on cell viability or DNA and protein synthesis. Stromal macrophages obtained from the femoral BM of C57Bl/6 mice exposed to BZ (600 or 800 mg/kg body weight) for 2 days were incapable of processing the 34-Kd pre-IL-1 alpha to the mature 17-Kd cytokine when stimulated in culture with LPS. Stromal macrophages from mice coadministered BZ and indomethacin, a prostaglandin H synthase (PHS) inhibitor that has been shown to prevent BZ-induced myelotoxic and genotoxic effects in mice when coadministered with benzene were able to convert the pre-IL-1 alpha to mature cytokine. Administration of recombinant murine IL-1 alpha (rMuIL-1 alpha) to mice before a dose of BZ that causes severe depression of BM cellularity completely prevents BM depression, most probably by bypassing the inability of the stromal macrophage in BZ-treated animals to process pre-IL-1 alpha to the mature cytokine.     

DNA damage-induced cell-cycle arrest of hematopoietic cells is overridden by activation of the PI-3 kinase/Akt signaling pathway

Exposure of hematopoietic cells to DNA-damaging agents induces cell-cycle arrest at G1 and G2/M checkpoints. Previously, it was shown that DNA damage-induced growth arrest of hematopoietic cells can be overridden by treatment with cytokine growth factors, such as erythropoietin (EPO) or interleukin-3 (IL-3). Here, the cytokine-activated signaling pathways required to override G1 and G2/M checkpoints induced by gamma-irradiation (gamma-IR) are characterized. Using factor-dependent myeloid cells stably expressing EPO receptor (EPO-R) mutants, it is shown that removal of a minimal domain required for PI-3K signaling abrogated the ability of EPO to override gamma-IR-induced cell-cycle arrest. Similarly, the ability of cytokines to override gamma-IR-induced arrest was abolished by an inhibitor of PI-3K (LY294002) or by overexpression of dominant-negative Akt. Moreover, the ability of EPO to override these checkpoints in cells expressing defective EPO-R mutants could be restored by overexpression of a constitutively active Akt. Thus, activation of a PI-3K/Akt signaling pathway is required for cytokine-dependent suppression of DNA-damage induced checkpoints. Together, these findings suggest a novel role for PI-3K/Akt pathways in the modulation of growth arrest responses to DNA damage in hematopoietic cells. (Blood. 2001;98:834-841)     

Distribution of cardioplegic solution infused antegradely and retrogradely in normal canine hearts

The adequacy of retrograde delivery of cardioplegic solution to the right ventricle and interventricular septum is controversial. To address this issue quantitatively, we infused blood cardioplegic solution labeled with radioactive microspheres (15 microns diameter) into the coronary sinus (n = 8 dogs) at a pressure of 51 +/- 1 mm Hg (mean +/- standard error of the mean) to be compared with the same quantity of labeled cardioplegic solution (20 ml/kg) delivered through the aorta (n = 6 dogs) at 97 +/- 7 mm Hg. Both methods of delivery produced cardiac arrest, but retrograde infusion required a significantly longer time to complete the infusion (6.2 +/- 0.8 minutes versus 1.5 +/- 0.1 minutes, p less than 0.01). Greater than 99% of the microspheres passing through the vasculature of the left ventricle were trapped in the left ventricular myocardium with antegrade infusion, and the distribution of the cardioplegic solution was uniform. Antegrade delivery (cardioplegic flow x infusion time) averaged approximately 3.0 to 4.0 ml/gm, except at the apex, where delivery averaged approximately 2.0 ml/gm. With retrograde infusion, 93% of the microspheres perfusing the left ventricle were trapped and delivery of the cardioplegic solution was not uniform. In the anterolateral free wall, delivery of cardioplegic solution averaged between 1.5 and 2.9 ml/gm (p less than 0.001 compared with antegrade) and only 0.6 to 0.8 ml/gm in the posteroseptal region of the basal left ventricle (p less than 0.001 compared with the antegrade group and anterolateral samples of the retrograde group). In the middle portion of the right ventricle, antegrade trapping of microspheres was 99% and delivery of cardioplegic solution averaged approximately 2.0 ml/gm. With retrograde delivery, only 16.5% (range 11.8% to 26.0%) of the microspheres passing through the right ventricular vasculature were trapped in the right ventricular myocardium, which indicates that substantial shunting had occurred. Corrected for the high shunt fraction, retrograde delivery of cardioplegic solution to the middle portion of the right ventricle averaged only 0.5 ml/gm (p less than 0.01). Retrograde delivery to the atrial septum and right atrium was also low. Because retrograde delivery of cardioplegic solution was markedly nonuniform, we conclude that inadequate cardioplegic delivery to the middle portion of the right ventricle and posteroseptal portion of the left ventricle could result with cardioplegic infusion through the coronary sinus.     

Independent home versus supervised rehabilitation following arthroscopic knee surgery--a prospective randomized trial

This prospective study compared 30 patients randomly assigned to either a home exercise program or supervised outpatient physical therapy following arthroscopic partial medial meniscectomy. Their knee functions were assessed at 2, 4, and 8 weeks postoperatively using isokinetic analysis and subjective questionnaires. At each evaluation, the home exercise group performed as well or better than the supervised physical therapy group. There were no statistically significant differences between the two groups. At 4 weeks postoperation, the mean percent deficit in torque (strength) between the affected and unaffected limbs was 22.1% in the supervised rehabilitation group and 22.0% in the home exercise. The percent deficit in terms of endurance was 7.7% in the supervised group and 3.6% in the home group. Similar results were noted with regard to the patients' subjective evaluations of their knee function and ability to resume work and recreational activities. We conclude that a well-planned, unsupervised home exercise knee rehabilitation program can produce equally good postoperative recovery as compared to a supervised outpatient physical therapy regimen in properly selected patients following arthroscopic partial meniscectomy of the knee.