A genome-wide analysis of the response to inhaled ß2-agonists in chronic obstructive pulmonary disease.

Short-acting ß2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified. We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African-American and four white populations. BDR was defined as the quantitative spirometric response to inhaled ß2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1 (P=2.02 × 10(-7)) and KCNJ2 (P=1.79 × 10(-7)) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1 × 10(-9)). A nominal association with CDH13 was identified in a gene-based analysis in all subjects. We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1 and KCNJ2). SNPs in CDH13 were significantly associated with BDR in African Americans.The Pharmacogenomics Journal advance online publication, 27 October 2015; doi:10.1038/tpj.2015.65.

The effect of cyclosporine administration on the cellular distribution and content of cyclophilin.

Cyclophilin (CYP), an intracellular protein sharing amino acid sequence identity with the enzyme peptidyl-prolyl cis-trans isomerase has become the leading candidate for the receptor responsible for cyclosporine biological effects. Avid binding of CYP to cyclosporine and immunosuppressive cyclosporine metabolites has been demonstrated, while nonimmunosuppressive cyclosporine metabolites have tended not to bind to cyclophilin. A previous immunohistochemical analysis documented that CYP localized principally to the cytoplasmic cellular compartment, but nuclear staining was observed among some cells. This study was undertaken to more precisely define the ultrastructural distribution of CYP, and to determine whether CYP cellular content was affected by CsA therapy. Untreated Wistar rats or those receiving 7 days of CsA (15 mg/kg/day, i.p.) were anesthetized, perfusion-fixed in situ, and sacrificed. Analyses of lymph node, spleen, thymus, kidney, liver, heart, brain, and ileum used an affinity purified, rabbit anticyclophilin IgG. Transmission electron microscopy was performed after staining with anti-CYP using a horseradish peroxidase/biotin/avidin technique. Quantitative immunofluorescence was measured by confocal microscopy using anti-CYP, with a biotin/avidin/phycoerythrin technique. Cyclophilin localized to the cytoplasmic compartment--however, association with mitochondria endoplasmic reticulum, Golgi, and with the nuclear membrane among lymphocytes, as well as cells from kidney, liver and ileum--was documented. Cyclophilin was not identified within the nucleus proper. Tissues obtained from animals receiving CsA exhibited a generalized increase in CYP content compared with tissues from untreated controls, suggesting the possibility that CsA may exert a regulatory influence upon CYP gene activation. Collectively, the data were consistent with the hypothesis that CYP exerts a central role in cellular metabolism, and that CsA-mediated biologic effects result from the CsA/CYP interaction.

Corrected transposition. Another approach for repair of associated intracardiac malformations.

A variety of surgical approaches have been used for repair of cardiac lesions associated with corrected transposition of the great vessels. These techniques have met with variable success and generally high surgical mortality rates. In an effort to simplify the surgical approach to repair of ventricular septal defect and replacement of left atrioventricular valve in a 4-year-old youngster, we chose to correct the defects through a left posterolateral thoracotomy and through the left atrium utilizing profound hypothermia and circulatory arrest. Ease of intracardiac assessment and repair and postoperative results to date have been most gratifying.

Reduced survival in women after valve surgery for aortic regurgitation: effect of aortic enlargement and late aortic rupture.

OBJECTIVE: We sought to investigate the relationship of female sex, aortic pathology, and left ventricular function to outcome after an operation for aortic regurgitation. METHODS: One hundred nine women underwent aortic valve replacement (n = 92) or repair (n = 17) for pure aortic regurgitation between 1985 and 1996. Mean follow-up was 5.7 +/- 2.6 years. New York Heart Association functional class III-IV symptoms were present in 70 patients, whereas left ventricular function was normal in 60 patients. Ascending aortic diameter in 97% exceeded the 90th percentile for a size-matched healthy population. A concomitant aortic operation was performed by means of root replacement in 31 patients and by means of interposition graft in 28 patients. Of 50 patients undergoing isolated valve procedures, 19 had aortas of 4.0 cm or larger. RESULTS: At 5 and 10 years, survival was 78% and 44%, respectively. Fatal aortic rupture occurred in 13 patients, and 2 others underwent emergency operations for impending aortic rupture, for a total of 15 late aortic events. Freedom from aortic events was 87% and 76% at 5 and 10 years, respectively. Risk factors for aortic events were older age (P =.07) and increasing ascending aortic diameter indexed to body surface area (P =.03) in women who had not undergone replacement of the ascending aorta. Rupture location was at the ascending aorta in 71% without ascending replacement and the descending aorta in 62% with ascending grafts. CONCLUSION: In women, late survival after an operation for aortic regurgitation is importantly decreased by coexisting aortic pathology with subsequent aortic rupture. Aortic replacement at the time of a valve operation should be considered on the basis of indexed aortic size.

Barretts's esophagus: does an antireflux procedure reduce the need for endoscopic surveillance?

Barrett's esophagus, a premalignant condition associated with chronic gastroesophageal reflux, carries an approximate 40-fold increase in the incidence of adenocarcinoma. Between 1975 and 1994, 113 patients with Barrett's esophagus underwent antireflux procedures at the Mayo Clinic. The antireflux procedure was performed more than 3 months after the diagnosis of Barrett's disease in 39 patients (34.5%) and during the initial preoperative evaluation in 74 (65.5%). Uncut Collis-Nissen fundoplication was performed in 69 patients (61.1%), Nissen fundoplication was performed in 16 (14.2%), cut Collis-Nissen fundoplication was performed in 12 (10.6%), Belsey repair was performed in nine (8.0%), Collis-Belsey repair was performed in six (5.3%), and Nissen fundoplication with an anterior gastropexy was performed in one (0.9%). There was one operative death (0.9% mortality). Morbidity occurred in 41 patients (36.3%), including cardiac arrhythmia in eight (7.0%), pneumonia in six (5.3%), empyema in five (4.4%), hemorrhage in four (3.6%), myocardial infarction in two (1.8%), and wound dehiscence, wound infection, perforated duodenal ulcer, and postoperative leak in one each (0.9%). Median follow-up for the 112 survivors of operation was 6.5 years (range 4 months to 18.2 years). Excellent or good alleviation of symptoms was obtained in 92 patients (82.2%). Ninety-nine patients (88.4%) are currently alive and 13 (11.6%) have died. Three patients (2.7%) subsequently had adenocarcinoma of the esophagus after the antireflux procedure at 13, 25, and 39 months; two of these died of cancer. The incidence of esophageal carcinoma in this select group of patients was one in 273.8 patient-years of follow-up. We conclude that although antireflux procedures in patients with Barrett's esophagus result in long-term control of reflux symptoms, the possibility of esophageal cancer still exists. Endoscopic surveillance should therefore be recommended.

Benign biliary strictures: repair and outcome with a contemporary approach.

BACKGROUND: The Hepp-Couinaud technique is an innovative approach for repair of proximal biliary strictures. We have used this method selectively for bile duct reconstruction since 1982. Our aim was to analyze our experience with the surgical repair of benign biliary strictures in the decade since the Hepp-Couinaud technique has become an integral component of our surgical management strategy. METHODS: Seventy-two patients undergoing surgical repair of benign biliary stricture between 1983 and 1992 were reviewed retrospectively. A grading system on clinical symptoms, results of liver function studies, and need for reintervention was used to assess outcome. RESULTS: For the 27 patients with noniatrogenic strictures, followed up a mean of 3.9 years, excellent or good results (grade A or B) were obtained in 88.9%. For the 45 patients with iatrogenic strictures, followed up a mean of 4.6 years, 86.7% were categorized as grade A or B. The cumulative probability of anastomotic failure was significantly less for the 21 patients in whom the Hepp-Couinaud method was used when compared with the 24 patients in whom it was not (p = 0.032). Outcome was not influenced by age, time delay from injury to reconstruction, preoperative stenting, the number of previous repairs, or the duration of postoperative stenting. CONCLUSIONS: Surgical reconstruction affords excellent or good results for the vast majority of patients with benign biliary strictures. For proximal iatrogenic strictures superior anastomotic durability is achieved with the Hepp-Couinaud technique.

Preoperative highly selective catheter localization of occult small-intestinal hemorrhage with methylene blue dye.

In patients with occult lower gastrointestinal bleeding, locating of the source of the hemorrhage can be quite difficult. While multiple diagnostic tests may confirm a small bowel source of bleeding, precise localization allowing a directed, conservative surgical resection may be problematic. We describe three patients each of whom presented with hemorrhage from the small intestine. The preoperative use of highly selective angiographic catheter placement combined with intraoperative methylene blue dye injection allowed us to precisely locate the source of hemorrhage and to resect a conservative length of small intestine. This technique has been successful in the three patients herein, and we believe that it should be included in the options available to the surgeon.

Mitral valve injury after blunt chest trauma.

Isolated mitral valve injury after blunt chest trauma is a very rare event. This disruption, causing sudden and severe mitral regurgitation, will rapidly lead to congestive heart failure and death unless operatively corrected. A high index of suspicion coupled with appropriate diagnostic tests will provide the diagnosis and allow operative correction. We report a patient who survived this injury and review all previous reports of blunt traumatic disruption of the mitral valve.

Purely internal thoracic artery grafts: outcomes.

BACKGROUND: Most of our patients with coronary artery disease have undergone bypass exclusively with purely internal thoracic artery grafts (PITA). Our goal has been to lengthen the time a patient benefits from coronary bypass operations. The present report describes an 8.5-year study of outcomes including mortality and the need for reintervention in patients who have undergone bypass with PITA. METHODS: We studied 897 patients who underwent PITA with a total of 3,784 internal thoracic artery (ITA) grafts (4.2 grafts per patient). Connecting ITA to ITA along with sequential anastomosis made the procedure possible. RESULTS: Early mortality for the group was 2.3%. Freedom from death was 86% and freedom from reintervention was 94% at 5 years after the operation. CONCLUSIONS: The acceptable early and late mortality and the 94% freedom from reintervention as long as 8.5 years after operation in this group of patients inspire us to continue choosing PITA for patients with three-vessel coronary artery disease.

Use of the anterior mitral leaflet to reinforce the posterior mitral annulus after debridement of calcium.

In mitral valve surgery, preservation of continuity between the papillary muscles, chordae, and annulus is associated with preservation of left ventricular function and reduced risk of postoperative left ventricular rupture. However, at mitral valve replacement, extensive annulus and leaflet calcification can necessitate resection of the posterior mitral leaflet. We describe a technique in which the anterior mitral leaflet and its subvalvular apparatus are used to reinforce the posterior mitral annulus after extensive debridement of calcium along the same annulus.

Carcinoid heart disease and carcinoid syndrome: successful surgical treatment.

Tumor debulking can greatly improve quality of life for patients with malignant carcinoid syndrome, but hepatic cytoreduction is confounded by carcinoid heart disease, which can cause postsinusoidal portal hypertension, thereby increasing the risk of death from hemorrhage during hepatic resection. We describe a patient with metastatic carcinoid syndrome and carcinoid heart disease who had repair of his carcinoid heart disease and, after improvement of right-sided heart function, had successful hepatic debulking of carcinoid metastases.

Hemodynamic performance of small aortic valve bioprostheses: is there a difference?

BACKGROUND: There is the potential for left ventricular outflow obstruction when small aortic valve bioprostheses are employed in normal-sized or large adults. It has been hoped that bovine pericardial valves would improve hemodynamic performance in the smaller tissue valve sizes. METHODS: To determine in vivo hemodynamic performance of heterograft aortic valve prostheses, we analyzed echocardiographic data from patients receiving 21- or 23-mm Carpentier-Edwards pericardial, Medtronic Intact, and Carpentier-Edwards porcine bioprostheses. In addition, data from 19-mm Carpentier-Edwards pericardial valves were included for comparison of hemodynamic performance between valve sizes. Doppler echocardiography was performed in 151 patients within 2 weeks of operation. Left ventricular outflow gradient was derived from continuous Doppler measurements of flow velocity, and effective orifice area was calculated by the continuity equation. RESULTS: There were statistically significant differences in hemodynamic performance of different sized prostheses for each valve type (effective orifice area, p < 0.01; valvular gradient, p < 0.03). There were, however, no significant differences in effective orifice area or mean gradient for different valve types within each size category. CONCLUSIONS: The in vivo hemodynamic performance of these three different aortic valve heterograft bioprostheses is similar. Patient-prosthesis mismatch with heterograft prostheses, as demonstrated by the indexed effective orifice area can be avoided by appropriate sizing and use of annular enlarging techniques when necessary.

Pulmonary resection for metastatic breast cancer.

Between 1982 and 1992, 60 consecutive female patients underwent pulmonary resection for metastatic breast carcinoma. Median age was 58 years (range, 21 to 81 years). The median tumor-free interval after primary breast cancer operation was 2.2 years (range, 7 days to 20.6 years). Thirty-one patients (51.6%) had solitary pulmonary metastases. Forty patients (66.7%) had complete pulmonary resection, which consisted of wedge excision in 33, lobectomy in 6, and pneumonectomy in 1. The remaining 20 patients had incomplete resection, which consisted of wedge excision in all. Altogether, 8 patients (13.3%) had development of postoperative complications, which included pneumothorax, prolonged air leak, pulmonary embolism, retained secretions requiring bronchoscopy, atrial fibrillation, and chest tube site infection. There was one operative death (1.7%). Follow-up was complete in all patients and ranged from 23 days to 10.7 years (median, 3.5 years). Recurrence developed in 32 of the 39 survivors (82.1%) who had complete resection. Median disease-free interval after lung resection was 1.6 years (range, 23 days to 9.3 years). Overall 5-year survival was 37.8% (95% confidence interval, 25.1% to 50.5%). The 40 patients who had complete resection had a 5-year survival of 35.6% (95% confidence interval, 20.4% to 50.8%) as compared with 42.1% (95% confidence interval, 19.0% to 65.3%) for the 20 patients with incomplete resection (p = not significant). Although pulmonary resection is safe, we could not demonstrate improved survival after complete pulmonary resection of metastatic breast carcinoma in this highly selected group of patients.

Genetic association of cyclic AMP signaling genes with bipolar disorder.

The genetic basis for bipolar disorder (BPD) is complex with the involvement of multiple genes. As it is well established that cyclic adenosine monophosphate (cAMP) signaling regulates behavior, we tested variants in 29 genes that encode components of this signaling pathway for associations with BPD type I (BPD I) and BPD type II (BPD II). A total of 1172 individuals with BPD I, 516 individuals with BPD II and 1728 controls were analyzed. Single SNP (single-nucleotide polymorphism), haplotype and SNP × SNP interactions were examined for association with BPD. Several statistically significant single-SNP associations were observed between BPD I and variants in the PDE10A gene and between BPD II and variants in the DISC1 and GNAS genes. Haplotype analysis supported the conclusion that variation in these genes is associated with BPD. We followed-up PDE10A's association with BPD I by sequencing a 23-kb region in 30 subjects homozygous for seven minor allele risk SNPs and discovered eight additional rare variants (minor allele frequency < 1%). These single-nucleotide variants were genotyped in 999 BPD cases and 801 controls. We obtained a significant association for these variants in the combined sample using multiple methods for rare variant analysis. After using newly developed methods to account for potential bias from sequencing BPD cases only, the results remained significant. In addition, SNP × SNP interaction studies suggested that variants in several cAMP signaling pathway genes interact to increase the risk of BPD. This report is among the first to use multiple rare variant analysis methods following common tagSNPs associations with BPD.

An economic model of general practice.

The public perceives that doctors earn too much, while general practitioners complain that their income is dwindling . In the absence of reliable data on doctors' incomes, it is impossible to determine whether medical fees are set appropriately, and what effects Medicare might have on general practice. An economic model of practice, using estimates of income and expenditure derived from specified assumptions, was constructed. Then, the effects of changes in various parameters of the model were examined in turn to show how economic forces are likely to affect the behaviour of doctors. It is shown that a general practitioner working at a moderate rate during a normal working week will earn a low income under current schedule fees. Some implications of these findings for practitioners, fee setting, and the public are explored.

Potential role of modifier genes influencing transforming growth factor-beta1 levels in the development of vascular defects in endoglin heterozygous mice with hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder because of mutations in the genes coding for endoglin (HHT1) or ALK-1 (HHT2). The disease is associated with haploinsufficiency and a murine model was obtained by engineering mice that express a single Endoglin allele. Of a total of 171 mice that were observed for 1 year, 50 developed clinical signs of HHT. Disease prevalence was high in 129/Ola strain (72%), intermediate in the intercrosses (36%), and low in C57BL/6 backcrosses (7%). Most mice first presented with an ear telangiectasia and/or recurrent external hemorrhage. One-third of mice with HHT showed severe vascular abnormalities such as dilated vessels, hemorrhages, liver and lung congestion, and/or brain and heart ischemia. Disease sequelae included stroke, hydrocephalus, fatal hemorrhage, and congestive heart failure. Thus the murine model reproduces the multiorgan manifestations of the human disease. Levels of circulating latent transforming growth factor (TGF)-beta1 were significantly lower in the 129/Ola than in the C57BL/6 strain. Intercrosses and 129/Ola mice expressing reduced endoglin also showed lower plasma TGF-beta1 levels than control. These data suggest that modifier genes involved in the regulation of TGF-beta1 expression act in combination with a single functional copy of endoglin in the development of HHT.