ADAM19 cleaves the PTH receptor and associates with brachydactyly type E.

Brachydactyly type E (BDE), shortened metacarpals, metatarsals, cone-shaped epiphyses, and short stature commonly occurs as a sole phenotype. Parathyroid hormone-like protein (PTHrP) has been shown to be responsible in all forms to date, either directly or indirectly. We used linkage and then whole genome sequencing in a small pedigree, to elucidate BDE and identified a truncated disintegrin-and-metalloproteinase-19 (ADAM19) allele in all affected family members, but not in nonaffected persons. Since we had shown earlier that the extracellular domain of the parathyroid hormone receptor (PTHR1) is subject to an unidentified metalloproteinase cleavage, we tested the hypothesis that ADAM19 is a sheddase for PTHR1. WT ADAM19 cleaved PTHR1, while mutated ADAM-19 did not. We mapped the cleavage site that we verified with mass spectrometry between amino acids 64-65. ADAM-19 cleavage increased Gq and decreased Gs activation. Moreover, perturbed PTHR1 cleavage by ADAM19 increased ß-arrestin2 recruitment, while cAMP accumulation was not altered. We suggest that ADAM19 serves as a regulatory element for PTHR1 and could be responsible for BDE. This sheddase may affect other PTHrP or PTH-related functions.

Systemic inflammatory response during cardiac surgery: a pilot study.

OBJECTIVE: There is a growing body of evidence indicating that perioperative fluid management during cardiac surgery influences patient care and outcome. The choice of fluid therapy and the degree of systemic inflammatory response triggered during surgery control the effects of tissue edema formation and end-organ function. As such, "goal-directed" fluid resuscitation protocols that measure colloid osmotic pressure (COP) may promote improvements in patient morbidity and mortality. METHODS: Thirty patients scheduled for primary coronary artery bypass grafting were prospectively randomized for perioperative fluid treatment under COP guidance [albumin (ALB), n = 17] or conventional fluid protocols without COP support (control, n = 13). Whole-blood samples were drawn at four different time intervals including (A) anesthesia induction, (B) 10 minutes after the initiation of cardiopulmonary bypass, (C) at the completion of sternal skin approximation, and (D) 3 hours after admission to the cardiac intensive care unit. Interleukin 6 (IL-6) and IL-8 were measured by immunometric, enzyme-linked immunosorbent assays as well as C-reactive protein. Colloid osmotic pressure values were measured using a colloid osmometer. RESULTS: As compared with conventional fluid protocols, the patients treated in the intervention (ALB) group received significantly less total perioperative fluid [7893.6 (1874.5) vs 10,754.8 (2403.9), P = 0.001], and this relationship remained after controlling for age, sex, and The Society of Thoracic Surgeons risk score (ß = -0.5, t = -3.1, P = 0.005). Colloid osmotic pressure values were significantly higher in the ALB group at time point D after surgery (P = 0.03). There were no significant differences in IL-6, IL-8, and C-reactive protein values between the groups at any of the time blood draw intervals. Perioperative outcomes were evaluated by treatment group. For both groups, the incidence of perioperative morbidity was low and did not differ by treatment group. CONCLUSIONS: The use of COP-guided fluid resuscitation was associated with a significant reduction in perioperative fluid demand. However, patients prescribed to COP-guided fluid therapy did not experience a reduction in whole-body inflammation or improved surgical outcome as compared with conventional fluid management techniques.

Health-related quality of life after coronary artery bypass grafting surgery and the role of gender.

OBJECTIVE: Heart disease is the leading cause of death for women. Previous studies suggest that women undergoing coronary artery bypass (CABG) surgery present with a higher severity of disease and that this may be an indicator of delays in treatment preceding diagnosis thus presenting challenges for recovery. The aim of this study was to examine gender differences in CABG morbidity and reported health-related quality of life (HRQL) at baseline and six months post-surgery. It was hypothesized that female gender would be an independent predictor for lower HRQL at six months following CABG surgery. METHODS: Four hundred and ninety-six (n=496) adult patients who underwent a first-time, isolated CABG procedure with baseline and 6-month follow-up were included. Stepwise multivariate regressions were conducted to evaluate the factors predictive of 6-month HRQL scores. RESULTS: Females had more preoperative co-morbidities and scored significantly lower on HRQL compared to males at both baseline (p values<0.01) and six months (p values<0.01) on all ten domains. Gender was a significant predictor of 6-month HRQL in regression models for 8 out of 10 HRQL domains including Physical Component Summary score (B=-2.54, p=0.02). CONCLUSIONS: Female patients were at higher risk as reflected by their perioperative risk factors and baseline HRQL. These findings may reflect a delayed referral for surgery. Results indicated that female gender predicts lower HRQL 6-months post-CABG surgery, which can have an impact on recovery and outcomes. Efforts should be made to identify and treat female patients earlier to improve post-surgical outcomes.

Impact of body mass index on clinical outcome and health-related quality of life following open heart surgery.

The effect of increased body mass index (BMI) on survival following open heart surgery is unclear. We explored the relationship between BMI, survival following elective open heart surgery, and health-related quality of life. Our results suggest that increased BMI need not be a deterrent for undergoing open heart surgery. Patients with increased BMI can expect similar complication rates, significant gains in health-related quality of life at 1 year, and comparable intermediate survival.

Survival and quality of life following elective open-heart surgery.

Eight hundred thirty-six patients who had open-heart surgery were available for analysis of health-related quality of life (HRQL) data and survival at the 1-year follow-up. Elective open-heart surgery patients with decreasing HRQL at 1 year following surgery may experience a survival disadvantage in comparison with those patients experiencing positive gains. Clinical care should extend beyond the immediate postoperative period.

The association between early outcome, health-related quality of life, and survival following elective open-heart surgery.

We investigated the impact of perioperative complications on patients' health-related quality of life (HRQL) and intermediate-term survival after cardiac surgery. Improved results for cardiac surgery are well demonstrated in low rates of operative mortality and morbidity. However, the association between perioperative morbid events, HRQL at 1 year, and survival is unclear. We performed a prospective study among 836 elective cardiac surgery patients to assess the impact of perioperative outcomes on survival and HRQL at 1 year. Health-related quality of life was generated using the 20-item short-form questionnaire. Kaplan-Meier and life-table estimates were used to examine the relationship of HRQL at 1-year and intermediate-term survival. All HRQL domains were statistically improved at 1 year, with the highest gains in general health perception (+19.4%) and the least gains in social (+5.1%) and mental (+5.1%) domains. Patients experiencing 1 or more perioperative complication or increased length of stay reported similar HRQL scores as patients with no complications. Patients with negative changes in social (94.5% vs 99.2%, P < .001) and general health perception (99.4% vs 95.5%, P < .001) domains showed a reduced survival compared with patients with positive HRQL gains at 2 to 5 years after surgery. Perioperative complications had minimal or no effect on HRQL at 1 year after cardiac surgery.

Comparative methodologies of regulatory T cell depletion in a murine melanoma model.

There has been recent interest in the depletion of regulatory T cells (Tregs) as part of a multi-faceted approach to the immunotherapy of melanoma patients. This is in part due recent findings that convincingly show that Tregs are an integral part of regulating and even suppressing an immune response to growing tumor cells. We therefore compared three methods of Treg depletion and/or elimination, utilizing low dose cyclophosphamide (CY), a specific antibody directed against the IL-2 receptor found on Tregs (PC61) and the use of denileukin diftitox (DD), which is a fusion protein designed to have a direct cytocidal action on cells which express the IL-2 receptor. We show that CY administration resulted in the highest reduction in Tregs among the three reagents. However, the reduction in Tregs with CY was also associated with the concomitant reduction of CD8(+) T cells and a lack of tumor antigen priming. Utilization of DD resulted in a >50% Treg cell reduction without parallel cytocidal effects upon other T cell subsets but did not enhance anti-tumor immunity against B16 melanoma. Lastly, the PC61 showed a moderate reduction of Tregs that lasted longer than the other reagents, without a reduction in the total number of CD8(+) T cells. Furthermore, PC61 treatment did not abrogate tumor antigen-specific immunity elicited by dendritic cells (DC). We therefore conclude that PC61 administration was the most effective method of reducing Tregs in a murine melanoma model in addition to providing evidence of a synergistic effect when combined with DC-based immunotherapy.

Obesity-related differential gene expression in the visceral adipose tissue.

BACKGROUND: This study investigates the expression patterns in human adipose tissue, and identifies genes that may be involved in the abnormal energy homeostasis. METHODS: Subjects were prospectively recruited from morbidly obese patients undergoing bariatric surgery and from non-obese organ donors. Extensive clinical data and visceral fat specimens were obtained from each subject at the time of surgery. A group of 50 obese patients and 9 non-obese controls were selected for further study. Two custom two-color cDNA microarrays were produced with 40,173 human individual cDNA clones. Microarray experiments were performed for each sample, and a selected group of gene expression values were confirmed with real-time RT-PCR. RESULTS: A comparison of gene expression profiles from obese and non-obese patients identified 1,208 genes with statistically significant differential expression between the 2 groups. Most prominent among these genes are multiple glycolysis enzyme encoding genes; others are involved in oxysterol biosynthesis and signaling, or are ATP-binding transporters and solute carriers. CONCLUSION: Differential gene expression in the adipose tissue of morbidly obese patients includes genes related to lipid and glucose metabolism, membrane transport, and genes promoting the cell cycle. These findings are a first step toward clarifying the molecular pathogenesis of obesity and identifying potential targets for therapeutic intervention.

Obesity and non-alcoholic fatty liver disease in chronic hepatitis C.

BACKGROUND: Superimposed non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) may affect HCV-related fibrosis. We performed a study to determine the relationship between NAFLD and chronic hepatitis C. METHODS: One hundred and twenty patients with chronic hepatitis C and available liver biopsies were included. Baseline liver biopsies were read by 1 hepatopathologist using Metavir, as well as a fatty liver pathology protocol. Patients' baseline clinical, demographic, and virologic data were associated with the extent of steatosis (>33% vs. < or =33%), the type of fatty liver (no steatosis vs. steatosis only vs. NASH), and the stage of fibrosis seen on the liver biopsy. RESULTS: Seventy percent of patients were men and 80% were white. The mean age was 47.48+/-5.70 years, mean BMI was 29.01 +/-5.01 kg/m, and mean waist to hip ratio (W/H) was 0.90+/-0.08. Patients with higher grade of steatosis had higher BMI (32.83+/-6.26 vs. 28.49+/-4.62, P = 0.034), more likely to have genotype 3 (21.4% vs. 5.7%, P = 0.037) and advanced fibrosis (92.9% vs. 62.3%, P = 0.033) than those with lower grade of steatosis. Of these, only HCV-genotype 3 remained independently associated with higher grade of steatosis. When patients with superimposed NASH (n = 22) were compared with those with only steatosis (n = 49) and those without steatosis (n = 49), patients with superimposed NASH had more evidence of obesity (BMI: 30.64+/-5.23 vs. 29.90+/-5.35 vs. 27.33+/-4.07, P = 0.008; W/H: 0.97+/-0.06 vs. 0.91+/-0.08 vs. 0.87+/-0.07, P < 0.001), more commonly infected with HCV genotype 3 (14% vs. 12% vs. 0%, P = 0.036) and had more advanced fibrosis (95.5% vs. 75.5% vs. 42.9%, P < 0.001). Race, gender, and age did not affect extent of steatosis or presence of superimposed NASH. CONCLUSION: In conclusion, markers of obesity (BMI and W/H) and HCV genotype 3 are associated with the extent of steatosis and type of fatty liver. Higher grade of steatosis and presence of superimposed NASH are both associated with advanced hepatic fibrosis.