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.

Low-Frequency Spike-Field Coherence Is a Fingerprint of Periodicity Coding in the Auditory Cortex.

The extraction of temporal information from sensory input streams is of paramount importance in the auditory system. In this study, amplitude-modulated sounds were used as stimuli to drive auditory cortex (AC) neurons of the bat species Carollia perspicillata, to assess the interactions between cortical spikes and local-field potentials (LFPs) for the processing of temporal acoustic cues. We observed that neurons in the AC capable of eliciting synchronized spiking to periodic acoustic envelopes were significantly more coherent to theta- and alpha-band LFPs than their non-synchronized counterparts. These differences occurred independently of the modulation rate tested and could not be explained by power or phase modulations of the field potentials. We argue that the coupling between neuronal spiking and the phase of low-frequency LFPs might be important for orchestrating the coding of temporal acoustic structures in the AC.

Processing of temporally patterned sounds in the auditory cortex of Seba's short-tailed bat,Carollia perspicillata.

This article presents a characterization of cortical responses to artificial and natural temporally patterned sounds in the bat species Carollia perspicillata, a species that produces vocalizations at rates above 50 Hz. Multi-unit activity was recorded in three different experiments. In the first experiment, amplitude-modulated (AM) pure tones were used as stimuli to drive auditory cortex (AC) units. AC units of both ketamine-anesthetized and awake bats could lock their spikes to every cycle of the stimulus modulation envelope, but only if the modulation frequency was below 22 Hz. In the second experiment, two identical communication syllables were presented at variable intervals. Suppressed responses to the lagging syllable were observed, unless the second syllable followed the first one with a delay of at least 80 ms (i.e., 12.5 Hz repetition rate). In the third experiment, natural distress vocalization sequences were used as stimuli to drive AC units. Distress sequences produced by C. perspicillata contain bouts of syllables repeated at intervals of ~60 ms (16 Hz). Within each bout, syllables are repeated at intervals as short as 14 ms (~71 Hz). Cortical units could follow the slow temporal modulation flow produced by the occurrence of multisyllabic bouts, but not the fast acoustic flow created by rapid syllable repetition within the bouts. Taken together, our results indicate that even in fast vocalizing animals, such as bats, cortical neurons can only track the temporal structure of acoustic streams modulated at frequencies lower than 22 Hz.

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.

Are there gender differences in outcomes after the Cox-Maze procedure for atrial fibrillation?

OBJECTIVE: Atrial fibrillation (AF) management suggests that women do not tolerate medication rhythm control strategies as well as men do; however, AF percutaneous catheter ablation has been found to be favorable. The study purpose was to compare the sex-based outcomes for patients who undergo the Cox-Maze procedure for AF. METHODS: Data were collected through our AF surgical ablation registry. Rhythm was verified by electrocardiogram and 24-hour holter at 6 and 12 months. General health-related quality of life (Short-Form 12) and specific AF symptom burden (Atrial Fibrillation Symptom Checklist: Frequency and Severity, version 3) were obtained at baseline and 12 months. RESULTS: Since 2005, a total of 540 patients have undergone a Cox-Maze procedure (34% were women). The women presented with higher operative risk [additive European System for Cardiac Operative Risk Evaluation (EuroSCORE), 6.71 ± 2.61 vs 5.25 ± 2.80, t = 5.85, P < 0.001], higher rates of congestive heart failure (49% vs 32%, P < 0.001), and more concomitant mitral valve procedures (32% vs 19%, P = 0.001). Perioperative outcomes were similar. Return to sinus rhythm off antiarrhythmics were not different at 6 and 12 months (78% vs 75%, P = 0.53, and 81% vs 80%, P = 1.00, respectively). Cumulative 2-year survival (93.9% for the men and 89.3% for the women) was not different for all-cause mortality (hazard ratio, 1.47; confidence interval, 0.68-3.21; P = 0.33) and cardiac-related mortality [women: 10/14 (71%) vs men 7/11 (64%), P = 1.00]. Health-related quality of life showed significant improvement; AF symptoms significantly decreased across the sexes. CONCLUSIONS: Outcomes after the Cox-Maze procedure are similar across sex. Atrial fibrillation surgical ablation should be considered a treatment option for women-it is safe and effective, improves general health-related quality of life, and reduces AF symptom burden.

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.

Development of a novel proteomic approach for mitochondrial proteomics from cardiac tissue from patients with atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting approximately 2.2 million Americans. Because several studies have suggested that changes in mitochondrial function and morphology may contribute to AF, we developed a novel proteomic workflow focused on the identification of differentially expressed mitochondrial proteins in AF patients. Right human atrial tissue was collected from 20 patients, 10 with and 10 without AF, and the tissue was subjected to hydrostatic pressure cycling-based lysis followed by label-free mass spectrometric (MS) analysis of mitochondrial enriched isolates. Approximately 5% of the 700 proteins identified by MS analysis were differentially expressed between the AF and non-AF samples. We chose four differentially abundant proteins for further verification using reverse phase protein microarray analysis based on their known importance in energy production and regulatory association with atrial ion channels: four and a half LIM, destrin, heat shock protein 2, and chaperonin-containing TCP1. These initial study results provide evidence that a workflow to identify AF-related proteins that combines a powerful upfront tissue cell lysis with high resolution MS for discovery and protein array technology for verification may be an effective strategy for discovering candidate markers in highly fibrous tissue samples.

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.

Anger experiences among hepatitis C patients: relationship to depressive symptoms and health-related quality of life.

The authors examined anger among hepatitis C (HCV) patients and its relationship to health-related quality of life (HRQL) and depression. Eighty-seven HCV patients who received pegylated interferon-alpha(2b) and ribavirin were included. Patients' mean age was 48 years; 42% were women, and 60% were white. Patients experienced moderate anger while undergoing HCV treatment. Angry feelings increased during treatment in some domains, specifically, Control Over Anger and Angry Reaction. Greater anger was associated with more depression and poorer HRQL. Findings point to the importance for physicians to screen for a wide range of neuropsychiatric side effects of interferon, including anger.

Depression, anemia and health-related quality of life in chronic hepatitis C.

BACKGROUND/AIMS: Hepatitis C (HCV) infected patients have significant health-related quality of life (HRQL) impairment which worsens during anti-viral therapy. Our aim was to examine the association of HRQL with treatment-induced depression and anemia. METHODS: Two hundred and seventy-one HCV patients who received pegylated interferon alfa 2b and ribavirin were included. Data on HRQL, depressive symptoms, laboratory values and socio-demographic characteristics were collected. RESULTS: Mean age was 47.1+/-6.5, 69% were male, and 73% were White. HCV patients' HRQL declined during anti-viral therapy but returned to or exceeded baseline levels within 24 weeks of completion. Anemia and depression were both associated with HRQL impairment. The effects of depression on HRQL were strong; once depression scores were included other factors were no longer significant. Patients' depressive symptoms tended to increase during the initial half of treatment regimen. Those with higher body mass index (BMI), cirrhosis, and women reported more HRQL impairments. HRQL scales were generally not associated with alcohol abuse, age, race, ALT and HCV RNA levels. CONCLUSIONS: Anti-viral therapy for HCV is associated with diminished HRQL. Although anemia and depression were associated with this impairment, depression was the most consistent predictor. Future studies are needed to see whether proactive management of these side effects can improve patients' HRQL and the efficacy of antiviral therapy for hepatitis C.

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.

Pegylated interferon alpha-2b, ribavirin and amantadine for chronic hepatitis C.

In an attempt to improve the efficacy of antiviral therapy for chronic hepatitis C, a three-drug combination of pegylated interferon alpha-2b, ribavirin, and amantadine has been suggested. Despite the initial enthusiasm, the role of amantadine in the treatment of chronic hepatitis C remains controversial. In a multi-center, open-label clinical trial, the potential efficacy and safety of this triple combination regimen were assessed. In this open-label pilot study, two separate patient populations with chronic hepatitis C and viremia were enrolled: treatment-naive and those who had failed a previous course of treatment. Patients were started on pegylated interferon alpha-2b at a dose of 1.5 microg/kg weekly with ribavirin, 1000-1200 mg/day, and amantadine, 200 mg/day, for 4 weeks, followed by pegylated interferon alpha-2b, 0.5 microg/kg weekly, ribavirin, 1000-1200 mg/day, and amantadine, 200 mg/day, for another 20 weeks. Patients with undetectable HCV RNA at week 24 continued this regimen for a total of 48 weeks and were followed for another 24 weeks. Patients with undetectable virus (<50 IU/mL) after 24 weeks of follow-up were considered to have SVR. Health-related quality of life and safety data were also collected. Sixty-nine treatment-naive and 99 nonresponder patients with chronic hepatitis C were enrolled in the study. Of all patients enrolled, 74% were male, aged 47.27+/-5.76 years; their body mass index (BMI) was 28.87+/-5.05 kg/m2, 79.4% were white, 85% had HCV genotypes 1 and 4, and 36% had cirrhosis. Their baseline HCV RNA was 689,242+/-698,030 IU/mL, with a baseline ALT of 107.25+/-79.08. Of the entire cohort, 35 (21%) discontinued early due to side effects or loss to follow-up. Significant anemia (hemoglobin, < 10 g/dL) occurred in 11% (19/168), while severe anemia (hemoglobin, <8.5 g/dL) occurred in 0.6% (1/168). In the treatment-naive group, sustained virologic response (SVR) was 34.3%, versus 19.4% for the group who had previously failed to respond to a course of treatment (P = 0.01). For both groups combined, virologic response after 24 weeks of therapy was 40.5%, with an end-of-treatment virologic response of 35.7% and a SVR of 26.2%. Patients with genotypes 1 and 4 had lower response rates than those with genotypes 2 and 3 (SVR, 21 vs. 46%; P = 0.001). Patients with advanced fibrosis (Metavir stages 3 and 4) tended to have lower response rates than those with minimal or mild fibrosis (Metavir stages 0-2) (SVR, 10 vs. 30%; P = 0.08). African-American patients with HCV had lower response rates than Caucasians or other ethnic groups (SVR, 4 vs. 29 vs. 20%; P = 0.04). Age, gender, and BMI did not affect SVR. The addition of amantadine to pegylated interferon alpha-2b and ribavirin does not seem to increase the efficicacy of this regimen.

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.

The impact of liver disease on health-related quality of life: a review of the literature.

Quality of life as an outcome variable has become an important measure in clinical research. Making a transition from a "biomedical model" of health to one that incorporates the social aspects of disease, clinicians and researchers dealing with chronic illness now incorporate quality-of-life measures into clinical practice and research. Chronic liver disease has shown a significant impact on the well-being of patients and contributes to the significant morbidity associated with these conditions. In this article, we review the recent research that has examined the impact of chronic liver disease on health-related quality of life.