Genome-wide association analysis identifies genetic variations in subjects with myalgic encephalomyelitis/chronic fatigue syndrome.

Myalgic encephalomyelitis, also known as chronic fatigue syndrome or ME/CFS, is a multifactorial and debilitating disease that has an impact on over 4 million people in the United States alone. The pathogenesis of ME/CFS remains largely unknown; however, a genetic predisposition has been suggested. In the present study, we used a DNA single-nucleotide polymorphism (SNP) chip representing over 906,600 known SNPs to analyze DNA from ME/CFS subjects and healthy controls. To the best of our knowledge, this study represents the most comprehensive genome-wide association study (GWAS) of an ME/CFS cohort conducted to date. Here 442 SNPs were identified as candidates for association with ME/CFS (adjusted P-value<0.05). Whereas the majority of these SNPs are represented in non-coding regions of the genome, 12 SNPs were identified in the coding region of their respective gene. Among these, two candidate SNPs resulted in missense substitutions, one in a pattern recognition receptor and the other in an uncharacterized coiled-coil domain-containing protein. We also identified five SNPs that cluster in the non-coding regions of T-cell receptor loci. Further examination of these polymorphisms may help identify contributing factors to the pathophysiology of ME/CFS, as well as categorize potential targets for medical intervention strategies.

Transgenic swine lungs expressing human CD59 are protected from injury in a pig-to-human model of xenotransplantation.

BACKGROUND: Pulmonary xenotransplantation is currently limited by hyperacute rejection mediated in part by xenoreactive natural antibody and complement. Transgenic swine organs that express the human complement regulatory protein CD59 have demonstrated improved survival in models of pig-to-primate xenotransplantation. OBJECTIVE: The purpose of this study was to evaluate transgenic swine lungs that express the human complement regulatory protein CD59 in a model of pig-to-human xenotransplantation. METHODS: Transgenic swine lungs (n = 5, experimental group) and outbred swine lungs (n = 6, control group) were perfused with fresh, whole human blood through a centrifugal pump on an ex vivo circuit. Functional data were collected throughout perfusion. Immunoglobulin and complement studies were performed on perfusate samples, and both histologic and immunofluorescent analyses were performed on tissue sections. RESULTS: Mean lung survival for the experimental group was increased when compared with controls, 240 +/- 0 minutes versus 35.3 +/- 14.5 minutes, respectively, with a P value of less than.01. A decreased rise in pulmonary vascular resistance at 15 minutes was observed in the experimental group (343 +/- 87 mm Hg. L(-1). min(-1), in contrast to the control group (1579 +/- 722 mm Hg. L(-1). min(-1); P <.01). Pulmonary compliance at 15 minutes was improved for the experimental group versus control group (9.31 +/- 1.41 mL. cm(-2) H(2)O and 4.11 +/- 2.84 mL. cm(-2) H(2)O, respectively; P <.01). SC5b-9 generation in the plasma perfusate was delayed for the experimental group versus the control group. Immunofluorescent examination of tissue sections demonstrated equivalent deposition of immunoglobulin G, immunoglobulin M, C1q, and C3 in both groups, with reduced deposition of C9 in the experimental group. CONCLUSIONS: Transgenic swine pulmonary xenografts that express the human complement regulatory protein CD59 demonstrated improved function and survival in an ex vivo model of pig-to-human xenotransplantation.

Temporary ECMO support following lung and heart-lung transplantation.

7 days) failure. Seven (78%) patients in the early group were weaned off ECMO and 5 (56%) survived to hospital discharge. In the late group, none of the patients could be weaned off ECMO, yielding 100% mortality. ECMO support instituted for pulmonary graft failure that occurred within 24 hours of transplantation may improve patient survival.

Assessment of university students' coping strategies and reasons for driving in high-risk drinking-driving situations.

A total of 116 students (87 women; 29 men) enrolled at a large, public Midwestern university in the United States were recruited to complete a set of demographic questionnaires and drinking-driving episode surveys. The latter surveys assessed participants' reported motivations for driving or not driving during four recent drinking episodes. Content analyses were used to develop lists of commonly reported reasons for not driving (e.g. found alternate transportation), reasons for driving after drinking (e.g. perceived need to go to destination), potential alternatives to driving after drinking (e.g. walking to destination), and strategies used to avoid detection or arrest by police (e.g. driving more slowly, using back roads or side streets). Participants made both situational and self-coping attributions to explain why they did not, on occasion, drive after drinking. These results may be used as a foundation for prevention and education programs that are designed to: (a) encourage use of coping strategies and alternatives to driving while disputing peer-generated justifications for driving after drinking, and (b) challenge the value of potentially unsafe strategies for avoiding detection and arrest when driving under the influence.

Adjuvant treatment of refractory lung transplant rejection with extracorporeal photopheresis.

BACKGROUND: Extracorporeal photopheresis is an immunomodulatory technique in which a patient's leukocytes are exposed to ultraviolet-A light after pretreatment with 8-methoxypsoralen (methoxsalen). There have been few reports describing the use of extracorporeal photopheresis in lung transplant recipients. METHODS: We reviewed our experience using extracorporeal photopheresis in 8 lung transplant recipients since 1992. All 8 patients had progressively decreasing graft function and 7 were in bronchiolitis obliterans syndrome grade 3 before the initiation of photopheresis. One patient had undergone a second transplant operation for obliterative bronchiolitis. Two patients had a pretransplantation diagnosis of chronic obstructive pulmonary disease, 1 alpha1-antitrypsin deficiency, 1 cystic fibrosis, 1 bronchiectasis, 1 idiopathic pulmonary fibrosis, and 2 primary pulmonary hypertension. Before refractory rejection developed, all patients had been treated with 3-drug immunosuppression and anti-T-cell therapy. The median time from transplantation to the start of extracorporeal photopheresis was 16.5 months and the median number of treatments was 6. RESULTS: The condition of 5 of 8 patients subjectively improved after extracorporeal photopheresis therapy. In these 5 patients photopheresis was associated with stabilization of the forced expiratory volume in 1 second. In 2 patients there was histologic reversal of rejection after photopheresis. With a median follow-up of 36 months, 7 patients are alive and well. Three patients required retransplantation at a median of 21 months after completion of the treatments. Four patients have remained in stable condition after photopheresis. There were no complications related to extracorporeal photopheresis. CONCLUSION: We believe that this treatment is a safe option for patients with refractory lung allograft rejection when increased immunosuppression is contraindicated or ineffective.

Management of recurrent ventricular tachycardia with ventricular assist device placement.

Life-threatening, recurrent ventricular tachycardia developed in a 54-year-old heart transplant candidate with ischemic cardiomyopathy. The episodes of ventricular tachycardia were refractory to aggressive medical management and implantable cardiac defibrillator placement. A Heartmate left ventricular assist device was implanted, in combination with isolated right coronary artery bypass grafting, which abolished any further episode of ventricular tachycardia. The patient successfully underwent cardiac transplantation 79 days later.

Randomized study to evaluate the relation between oral isosorbide dinitrate dosing interval and the development of early tolerance to its effect on left ventricular filling pressure in patients with chronic heart failure.

BACKGROUND: Early development of nitrate tolerance has been shown in patients with chronic congestive heart failure (CHF) receiving continuous nitroglycerin therapy. The influence of dosing interval of oral isosorbide dinitrate (ISDN), the nitrate preparation most widely used for the treatment of CHF, has not been investigated. METHODS AND RESULTS: We performed a prospective, randomized study to evaluate the effect of various regimens of oral ISDN on the development of early tolerance to its effect on left ventricular filling pressure in patients with moderate to severe CHF. Forty-four responders (20% or greater reduction in mean pulmonary artery wedge pressure lasting 1 hour or longer) were divided into four groups of 11 patients each, and randomized to receive their effective ISDN dose (40-120 mg) Q 4 hours, Q 6 hours, Q 8 hours, or t.i.d. (drug given at 0, 6, 12, and 24 hours allowing 12 hours of ISDN washout interval between the third and fourth doses). All groups demonstrated a significant and comparable reduction in LV filling pressure following administration of the first ISDN dose. Early attenuation of hemodynamic response was demonstrated with frequent dosing (Q 4 hours and Q 6 hours) ISDN. Tolerance was with a Q 8-hour regimen as demonstrated by preserved hemodynamic response to each dose. The effect of each dose, however, was short-term, with return of pulmonary artery wedge pressure to baseline level at 2 to 4 hours, resulting in an intermittent effect totaling no longer than 12 hours of the 30-hour study period. The use of a t.i.d. regimen resulted in marked attenuation of response after the third dose with complete restoration of nitrate effect following a 12-hour washout period between the third and fourth doses. ISDN plasma concentration was measured in five patients in each of the Q 4- and Q 8-hour groups. In the Q 4-hour group, plasma levels were significantly higher after administration of the last dose than after the first dose (area under the curve, 242 +/- 216 versus 123 +/- 130 ng/ml, p less than 0.05), and trough levels before administration of the second and the fifth dose (15 +/- 17 and 27 +/- 27 ng/ml, respectively) were both markedly higher than the baseline value of 2 +/- 4 ng/ml. CONCLUSIONS: Our data demonstrate the development of tolerance and early attenuation of effect on left ventricular filling pressure with frequent oral dosing (Q 4 and Q 6 hours) with ISDN in patients with chronic CHF, which may be related to persistently elevated trough blood levels of ISDN. The development of tolerance can be reversed after a washout period of 12 hours and can be prevented with a Q 8-hour administration. These regimens, however, are limited by an inconsistent effect. Although long-term implications of these findings need further evaluation, the present study demonstrates the difficulty of maintaining a persistent ISDN-mediated reduction in left ventricular filling pressure in patients with chronic, moderate to severe CHF. These results suggest the need to use intermittent ISDN therapy allowing a daily nitrate washout interval and the rationale for combined vasodilator therapy in patients with CHF.

Current role of digitalis therapy in patients with congestive heart failure.

Digitalis has been used in the treatment of chronic congestive heart failure for 215 years. In this article, numerous clinical studies and trials that have evaluated the efficacy of digitalis in the treatment of patients with congestive heart failure are reviewed. The data indicate that digitalis is a valuable therapeutic agent for relieving symptoms and improving exercise performance and left ventricular function in patients with congestive heart failure. Comparison of the various advantages and disadvantages of digitalis with alternative therapies in patients with congestive heart failure shows an important continuing role for digitalis therapy.

Risk stratification in survivors of acute myocardial infarction: routine cardiac catheterization and angiography is a reasonable approach in most patients.

Noninvasive risk assessment in survivors of AMI can effectively subdivide patients into groups with differing risk profiles after hospital discharge, but some patients at risk for late death or recurrent AMI may be incorrectly identified; data from cardiac catheterization and angiography provide complementary and generally more powerful prognostic information. Many patients may derive particular benefit from early cardiac catheterization and angiography, including: (1) patients with AMI complicated by recurrent myocardial ischemia, congestive heart failure, and/or complex ventricular arrhythmias; (2) patients with abnormal or inconclusive results of noninvasive testing or those patients unable to perform an exercise test; (3) patients with abnormal left ventricular global systolic function and those with increased left ventricular end-systolic volume; (4) "young" patients (younger than 50 years of age?); (5) older patients (older than 65 to 70 years of age?); (6) patients with non-Q wave AMI; and (7) patients who are receiving thrombolytic therapy. Performance of early cardiac catheterization and angiography in virtually all survivors of AMI, with selective use of appropriate noninvasive tests, may provide a more efficacious means of risk assessment after AMI; if all tests are performed judiciously, the cost of such an approach need not be excessive. A combination of invasive and selected noninvasive tests probably provides optimal information. The risks to the routine performance of diagnostic cardiac catheterization and angiography in all survivors of AMI are: (1) adequate care and attention may not be paid to proper performance of the procedure(s) and to detailed and proper analyses of the data; (2) the need for additional noninvasive testing in selected patients may be ignored; and most importantly, (3) premature or unnecessary revascularization procedures may be performed subsequently. For optimal patient care, the clinician must obtain all necessary data, avoid unnecessary and repetitive tests, know the accuracy of individual tests at his or her own facility, interpret all data in proper context, and then counsel patients objectively about available management strategies. With this approach, all patients who might appropriately benefit from coronary artery revascularization will be correctly identified, and patients who are truly at very low risk (minimal residual coronary artery disease and preserved left ventricular function particularly if associated with a patent infarct-related artery) may be similarly identified and managed appropriately with elimination of unnecessary additional testing and pharmacologic therapy. Finally, whatever approach to risk stratification one chooses for an individual patient, the importance of and the need to correct and/or ameliorate risk factors for coronary artery disease must be recognized and undertaken.

Coronary arteriography in the anginal syndromes.

Coronary arteriography maintains a major role in the management of patients with stable and unstable anginal syndromes, in the establishment of diagnosis and prognosis, and in guiding the choice of therapeutic alternatives. Included in this article are discussions of assessment of coronary artery disease, and coronary arteriography in patients with stable and unstable angina pectoris.

Preliminary experience with 5 and 6 French diagnostic catheters as guiding catheters for coronary angioplasty.

With the reduction in profile of balloon dilation catheters, until recently, it has been the internal dimensions and performance of the guiding catheter that has mandated the use of 7, 8 or 9 French (F) systems for the performance of percutaneous transluminal coronary angioplasty (PTCA). A new 5F catheter design (Sherwood Medical Co., St. Louis, MO) provided a large inner lumen (0.4") permitting use of 0.20-0.22" fixed-wire PTCA balloon catheters with good coronary visualization. Potential advantages include reduced coronary artery ostial trauma and catheter induced damping and enhanced patient comfort. We report our initial experience in 14 patients undergoing PTCA with a 5 and 6F guide/fixed-wire system. Mean age was 63 +/- 10 (43-78 years). PTCA indications: Cardiogenic shock (1), post-myocardial infarction angina pectoris (2), grade III angina (5) and unstable angina pectoris (6). Vessel attempted: Left anterior descending (3), circumflex (4), obtuse marginal (2), diagonal (1), right coronary artery (3), and internal thoracic artery (1). Twelve patients had femoral approach; two brachial approach. The USCI Probe (USCI Division, Billerica, MA) was used in 8 lesions and SCIMED ACE (SCIMED Life Systems, Maplegrove, MN) catheter in 7 lesions. Successful 5 or 6F guide/fixed-wire dilations reduced the stenosis (77 +/- 14 to 37 +/- 30%) and were successfully performed in 79% (11/14). One 5F patient required 8F guiding catheter and was dilated with 2.0 fixed-wire balloon. A second failed 5F PTCA could not be dilated with any larger conventional system. A third total occlusion could not be crossed with a guidewire or fixed wire balloon. No patient had a complication.(ABSTRACT TRUNCATED AT 250 WORDS)

Day to day reproducibility of electrically inducible ventricular arrhythmias in survivors of acute myocardial infarction.

Day to day reproducibility of the response to programmed ventricular stimulation has not been evaluated in survivors of acute myocardial infarction. Programmed ventricular stimulation was performed prospectively on 2 consecutive days in 56 patients on an average of 12 +/- 5 days (range 7 to 29) after an acute myocardial infarction. No patient had a history of documented or suspected sustained ventricular tachycardia or fibrillation occurring greater than 48 h after infarction. During initial programmed ventricular stimulation, 21 patients had induction of sustained ventricular tachycardia or fibrillation (Group I), and 35 patients had induction of either nonsustained ventricular tachycardia or no ventricular tachycardia (Group II). Repeat programmed ventricular stimulation in Group I patients induced sustained ventricular tachycardia or fibrillation in 16 of 21 patients (reproducibility 76%); the maximal induced response in the other 5 patients was nonsustained ventricular tachycardia in 2 patients and fewer than six repetitive ventricular responses in 3 patients. The day to day reproducibility was significantly higher for inducible sustained ventricular tachycardia of cycle length greater than or equal to 240 ms compared with rapid sustained ventricular tachycardia of cycle length less than 240 ms (100% versus 44%, p less than 0.009) or ventricular fibrillation (100% versus 43%, p less than 0.009). Repeat programmed ventricular stimulation in Group II patients did not induce sustained ventricular arrhythmias in 31 of 35 patients (reproducibility 89%). Thus, in survivors of acute myocardial infarction, inducible slow sustained ventricular tachycardia was a highly reproducible finding, whereas inducibility of rapid sustained ventricular tachycardia and ventricular fibrillation showed a significant day to day variability.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of acute hemodynamic decompensation on electrical inducibility of ventricular arrhythmias in patients with dilated cardiomyopathy and complex nonsustained ventricular arrhythmias.

In patients with dilated cardiomyopathy, hemodynamic decompensation has been postulated to increase vulnerability to reentrant ventricular arrhythmias. To test this hypothesis, we performed programmed ventricular stimulation with three extrastimuli on nine patients with dilated cardiomyopathy and asymptomatic complex ventricular arrhythmias during a period of acute hemodynamic decompensation; programmed ventricular stimulation was then repeated following hemodynamic improvement with nitroprusside. These patients did not have a history of documented or suspected sustained ventricular tachycardia or fibrillation. The mean left ventricular ejection fraction was 0.21 +/- 0.04 (range 0.15 to 0.26). In the baseline state, mean right atrial pressure was 8 +/- 4 mm Hg, pulmonary artery wedge pressure was 20 +/- 3 mm Hg, and cardiac index was 3.2 +/- 0.5 L/min/m2. Following acute hemodynamic decompensation, mean right atrial pressure increased to 16 +/- 5 mm Hg and pulmonary artery wedge pressure to 33 +/- 8 mm Hg; cardiac index decreased to 2.1 +/- 0.5 L/min/m2. In this decompensated state, programmed ventricular stimulation failed to induce sustained or nonsustained ventricular arrhythmias in any patient. Following nitroprusside administration (mean dose 1.5 +/- 1.1 micrograms/kg/min), there were significant decreases in mean right atrial pressure (11 +/- 3 mm Hg) and pulmonary artery wedge pressure (16 +/- 3 mm Hg), and a significant increase in cardiac index (3.1 +/- 1.1 L/min/m2) (p less than 0.05 for all values versus the decompensated state). In the improved hemodynamic state, programmed ventricular stimulation induced nonsustained ventricular tachycardia (six beats) in only one patient, and sustained arrhythmias in none.(ABSTRACT TRUNCATED AT 250 WORDS)