TGF-beta promotes the establishment of renal cell carcinoma bone metastasis.

Bone metastases develop in approximately 30% of patients with RCC, and the mechanisms responsible for this phenomenon are unknown. We found that TGF-beta1 stimulation of RCC bone metastasis cells promotes tumor growth and bone destruction possibly by stimulating paracrine interactions between tumor cells and the bone. INTRODUCTION: Bone metastasis is a frequent complication and causes marked morbidity in patients with renal cell carcinoma (RCC). Surprisingly, the specific mechanisms of RCC interaction with bone have been scarcely studied despite the inability to prevent or effectively treat bone metastasis. Bone is a reservoir for various growth factors including the pleiotropic cytokine TGF-beta1. TGF-beta1 has been shown to have tumor-supportive effects on advanced cancers and evidence suggests its involvement in promoting the development of breast cancer bone metastasis. Here, we studied the potential role of TGF-beta1 in the growth of RCC bone metastasis (RBM). MATERIALS AND METHODS: To inhibit TGF-beta1 signaling, RBM cells stably expressing a dominant-negative (DN) TGF-betaRII cDNA were generated. The in vivo effect of TGF-beta1 on RBM tumor growth and osteolysis was determined by histological and radiographic analysis, respectively, of athymic nude mice after intratibial injection of parental, empty vector, or DN RBM cells. The in vitro effect of TGF-beta1 on RBM cell growth was determined after TGF-beta1 treatment by MTT assay. RESULTS: TGF-beta1 and the TGF-beta receptors I and II (TGF-betaRI/II) were consistently expressed in both RBM tissues and cell lines. Inhibition of TGF-beta1 signaling in RBM cells significantly reduced tumor establishment and osteolysis observed in vivo after injection into the murine tibia, although no effect on tumor establishment was observed after injection of RBM cells subcutaneously or into the renal subcapsule. Treatment of five RBM cell lines with TGF-beta1 in vitro either had no effect (2/5) or resulted in a significant inhibition (3/5) of cell growth, suggesting that TGF-beta1 may promote RBM tumor growth indirectly in vivo. CONCLUSIONS: TGF-beta1 stimulation of RBM cells plays a role in promoting tumor growth and subsequent osteolysis in vivo, likely through the initiation of tumor-promoting paracrine interactions between tumor cells and the bone microenvironment. These data suggest that inhibition of TGF-beta1 signaling may be useful in the treatment of RBM.     

Changes in pulmonary function test and cardio-pulmonary exercise capacity in COPD patients after lobar pulmonary resection.

OBJECTIVE: Pulmonary Function Tests (PFT) and Cardio-Pulmonary Exercise Testing (C-PET) are useful to evaluate operability in functionally compromised patients. Although modifications of PFT and C-PET after lung surgery have been widely explored, little information exists as to modifications of exercise capacity in COPD patients undergoing lung resection. We prospectively analyzed the changes in PFT and C-PET in patients with COPD after a pulmonary lobar resection. METHODS: From January 2003 to March 2004 all patients scheduled for lung resection were considered for participation in the study protocol. Those patients with a preoperative diagnosis of COPD on PFT were explored through a C-PET. Only patients who had undergone a lobar pulmonary resection were subsequently considered; these patients had a new complete cardio-respiratory evaluation 3 months after surgery. The pre- and postoperative values compared were those of FEV1, TLC, DLCO, VO2max, and VE/VCO2. Data are expressed as mean +/- standard deviation (SD). Statistic evaluation was made using the Wilcoxon test. RESULTS: During this period 11 patients completed the study protocol. Ten patients underwent surgery for NSCLC and one for a pulmonary aspergilloma. Nine lobectomies and two bilobectomies were performed. In the study population, the preoperative mean value of FEV1 resulted as being 53% (SD+/-20) of the predicted mean value, that of TLC 120% (SD+/-35) and that of DLCO 65% (SD+/-27). The preoperative mean value of VO2max resulted as being 17.8 ml/Kg/min (SD+/-3.25) and mean VE/VCO2 resulted as being 35.7 (SD+/-4). Three months after surgery the measured mean value of FEV1 was 53% (SD+/-18), that of TLC was 99% (SD+/-24) and that of DLCO 52% (SD+/-18). The mean value of VO2max resulted as being 14.1 ml/Kg/min (SD+/-3.04) and that of VE/VCO2 was 42.5 (SD+/-12.8). Statistical analysis of PFT values showed that FEV1 and DLCO were not significantly modified (P > 0.05); in contrast, TLC had significantly decreased (P = 0.008). VO2max had significantly decreased (P = 0.004) and VE/VCO2 had significantly increased (P = 0.018). CONCLUSIONS: Three months after a lobar pulmonary resection, patients with COPD were found to have a significant decrease in exercise tolerance. PFT alone can underestimate the postoperative loss of exercise capacity through exercise.     

Homocysteine-Lowering Therapy and Early Progression of Transplant Vasculopathy: A Prospective, Randomized, IVUS-Based Study

Although observational studies suggest that hyperhomocysteinemia may be a risk factor for coronary allograft vasculopathy (CAV), prospective data on homocysteine-lowering interventions and CAV development are lacking. We, therefore, randomized 44 de novo heart transplant (HT) recipients to 15 mg/day of 5-methyl-tetrahydrofolate (n=22), or standard therapy (control group, n=22) to investigate the effect of homocysteine lowering on the change in coronary intimal hyperplasia during the first 12 months after transplant, as detected by intra-vascular ultrasound (IVUS). Although 12 months after HT, homocysteinemia was lower in folate-treated patients (p<0.001), coronary intimal area increased similarly in the two groups (p>0.4). Conversely, hypercholesterolemia and cytomegalovirus infection were both associated with increased intimal hyperplasia (p<0.04), independently from folate intake. Sub-group analysis revealed that folate therapy reduced intimal hyperplasia in patients with hyperhomocysteinemia before randomization (n=19; p=0.02), but increased intimal hyperplasia in patients with normal homocysteine plasma concentrations (p=0.02). This bimodal effect of folate therapy persisted significantly after adjusting for cytomegalovirus infection and hypercholesterolemia. Despite effective in prevent hyperhomocysteinemia after heart transplantation, folate therapy does not seem to affect early CAV onset. However, sub-group analysis suggests that folate therapy may delay CAV development only in patients with baseline hyperhomocysteinemia, while may favor CAV progression in recipients with normal baseline homocysteinemia.     

Retrospective review of the preoperative biliary and gastrointestinal evaluation for gastric bypass surgery

BACKGROUND: The purpose of this study was to analyze the frequency and results of preoperative biliary and gastrointestinal (GI) evaluation of patients undergoing Roux-en-Y gastric bypass (RYGB). METHODS: Retrospective review of the preoperative evaluation of 144 consecutive RYGB patients. RESULTS: Cholecystectomy had already been performed in 43 (30%) patients; 22% of those patients with an intact gallbladder had cholelithiasis. Ten patients (7%) had an upper GI x-ray (UGI), and 94 patients (65%) had an esophagogastroduodenoscopy (EGD). Abnormalities were found in 40% of the UGIs and 84% of the EGDs. A total of 96 patients (67%) were tested for Helicobacter pylori; 11% were positive. Twenty-one patients (15%) underwent preoperative colonoscopy; 48% were abnormal, but most of the abnormalities were not clinically significant. Three patients had barium enema x-ray, which was normal in all cases. CONCLUSIONS: The preoperative biliary and GI evaluation of bariatric surgery patients should include a routine ultrasound of the gallbladder. Routine preoperative EGD will detect a significant number of abnormalities that should be treated, but should rarely alter the bariatric surgical procedure or result in denial of bariatric surgery. Many abnormalities will be asymptomatic. Patients should be routinely screened for H. pylori and, if positive, treated before bariatric surgery. Lower GI evaluation should be performed selectively based on the patient's symptoms, physical findings, and guidelines for colorectal cancer and polyp screening.     

Pharmacy Fill Patterns in Young Urban Children with Persistent Asthma

Background. Medication adherence impacts healthcare utilization. Pharmacy records are useful to establish fill patterns. Objective. Use pharmacy records to establish medication patterns fill patterns for comparison to healthcare utilization. Methods. Pharmacy records of 175 children with persistent asthma were collected and compared to healthcare utilization. Results. Majority of subjects had significant healthcare utilization, low numbers of rescue medications, and poor controller medication fill rates. Those with more rescue medications had more healthcare utilization and more controller medications. Conclusions. Pharmacy fill patterns demonstrate few rescue and/or controller medication fills. Those with more rescue medications reported increased healthcare utilization despite controller medications.     

Effects of heart rate on phasic Y-graft blood flow and flow reserve in patients with complete arterial myocardial revascularizaton: an intravascular Doppler catheter study.

OBJECTIVE: It is not well established whether the blood flow of arterial composite Y-grafts can efficiently respond to the flow demand of the coronary system early postoperatively. The aim of this study was to evaluate if soon after the operation, arterial composite Y-grafts can increase blood flow in response to an increase in myocardial oxygen consumption (MVO2). METHODS: Twenty-seven patients who received complete arterial myocardial revascularization using the left internal thoracic artery (LITA) and the radial artery (RA) as composite Y-graft gave their consent to a pre-discharge coronary angiography and intravascular flow velocity measurements using a Doppler guide wire. Flow measurements were performed in the LITA main stem, the distal LITA and the RA, both at rest and during atrial pacing at the 85% of the patient age-predicted maximum. The heart rate-systolic blood pressure product was considered as an indirect index of MVO2. Hyperemic flow was determined after injection of adenosine. The flow reserve (FR) was defined as the ratio of blood flow during maximal hyperemia (Qmax) to baseline flow (Qbasal). RESULTS: Atrial pacing increased MVO2 significantly (P<0.000). None of the patients developed ischemic S-T segment modifications or complained of chest pain. Q(basal) increased significantly in the LITA main stem (P=0.001), distal LITA (P=0.041) and RA (P=0.004) while Qmax did not change significantly. As a consequence, the FR decreased in the LITA main stem (P=0.002), distal LITA (P<0.000) and RA (P<0.000) but was not completely exhausted. CONCLUSIONS: Soon after the operation, arterial composite Y-grafts can significantly increase blood flow in response to conditions of increased MVO2, keeping normal the myocardial O2 supply-to-demand ratio.     

Aversion to risk and guilt

Much research has shown that cognitive processes are largely guided by individuals' states of mind (Mancini & Gangemi, 2002a, in press; Smeets, de Jong, & Mayer, 2000). In this paper, we specifically consider a state of mind characterized by guilt for having acted irresponsibly. This state is currently considered the breeding ground for the obsessive–compulsive disorder (Rachman, 2002; Salkovskis & Forrester, 2002). Our aim is to examine the impact of this state of mind on decision under risk. We hypothesize that individuals' choices (risk seeking/risk aversion) depend on how they evaluate themselves, as guilty or as victims of a wrong, and thus on moral values. People who evaluate them‐selves as guilty are expected to show a risk‐averse preference. People who evaluate themselves as victims are expected to show a risk‐seeking preference. In two different experiments, we demonstrated that non‐clinical participants' aversion to risky choices and preference for risky choices vary as a function of their moral role (guilty/victim). As predicted, in both the experiments, participants experienced intolerance for risk, making more riskless choices, in the context of guilt. Thus, aversion to risk‐taking is actually affected by a mental state of guilt. Copyright © 2004 John Wiley & Sons, Ltd.     

Correlation of serum metalloproteinase levels with lung cancer metastasis and response to therapy.

Cancer cells elaborate metalloproteinases which may play a role in invasion and metastasis. The serum level of the M(r) 72,000 type IV collagenase (MMP-2) was measured in 87 lung cancer patients. Stage IV cancer levels were significantly elevated (P less than 0.0001) compared to normal sera. A significant difference (P less than 0.01) was found between enzyme levels in the presence versus the absence of distant metastasis. For 29 patients treated with combination chemotherapy, a positive relationship was noted between response failure and elevated enzyme levels. Serum metalloproteinase levels may provide information relevant to prognosis as well as treatment decisions.