Parallel signatures of sequence evolution among hearing genes in echolocating mammals: an emerging model of genetic convergence.

Recent findings of sequence convergence in the Prestin gene among some bats and cetaceans suggest that parallel adaptations for high-frequency hearing have taken place during the evolution of echolocation. To determine if this gene is an exception, or instead similar processes have occurred in other hearing genes, we have examined Tmc1 and Pjvk, both of which are associated with non-syndromic hearing loss in mammals. These genes were amplified and sequenced from a number of mammalian species, including echolocating and non-echolocating bats and whales, and were analysed together with published sequences. Sections of both genes showed phylogenetic signals that conflicted with accepted species relationships, with coding regions uniting laryngeal echolocating bats in a monophyletic clade. Bayesian estimates of posterior probabilities of convergent and divergent substitutions provided more direct evidence of sequence convergence between the two groups of laryngeal echolocating bats as well as between echolocating bats and dolphins. We found strong evidence of positive selection acting on some echolocating bat species and echolocating cetaceans, contrasting with purifying selection on non-echolocating bats. Signatures of sequence convergence and molecular adaptation in two additional hearing genes suggest that the acquisition of high-frequency hearing has involved multiple loci.

Outbreeding increases offspring survival in wild greater horseshoe bats (Rhinolophus ferrumequinum).

The factors influencing the survival of greater horseshoe bat (Rhinolophus ferrumequinum) offspring born over seven years at a maternity colony in south-west Britain were studied. The effects of a range of phenotypic and maternal variables were analysed using a historical data set. In addition, the influence of two genetic measures on mortality, individual heterozygosity and a new measure of outbreeding, termed mean d(2), was assessed. Logistic regressions were undertaken with survival modelled as a binary response variable. Survival to two life stages was studied for each variable and all models were developed for both sexes separately and together. Only one variable, mean d(2), was significantly associated with survival. Male offspring with high mean d(2) scores were more likely to survive to their first and second summers. The influence of mean d(2) was not due to a single locus under selection but a wider multilocus effect and probably represents heterosis as opposed to solely inbreeding depression. Therefore, the extent to which an individual is outbred may determine survival more than widely used phenotypic characteristics such as size and mass. Mean d(2) may reflect immunocompetence, which influences mortality. Protection of mating sites in order to facilitate gene flow and, therefore, outbreeding may help to promote population stability and growth.

Genetic variation and population structure in the endangered greater horseshoe bat Rhinolophus ferrumequinum.

Following a dramatic decline last century, the British population of the endangered greater horseshoe bat Rhinolophus ferrumequinum is highly fragmented. To examine the consequences of fragmentation and limited dispersal on patterns of genetic structure and variation, we used microsatellite markers to screen bats from around 50% of the known maternity colonies in Britain, and two areas from continental Europe. Analyses revealed that Welsh and English colonies were genetically isolated. This, and lower variability in Britain than north France, may result from either genetic drift, or the species' colonization history. Gene flow among most neighbouring colonies was not generally restricted, with one exception. These findings have important implications for the ongoing conservation management of this species.

Parentage, reproductive success and breeding behaviour in the greater horseshoe bat (Rhinolophus ferrumequinum).

Female greater horseshoe bats form maternity colonies each summer in order to give birth and raise young. During the mating period, females visit males occupying territorial sites, copulation takes place and sperm are stored until ovulation occurs, normally in April. Using microsatellite markers and a likelihood method of parentage analysis, we studied breeding behaviour and male reproductive success over a five-year period in a population of bats in south-west Britain. Paternity was assigned with 80% confidence to 44% of young born in five successive cohorts. While a small annual skew in male reproductive success was detected, the variance increased over five years due to the repeated success of a few individuals. Mating was polygynous, although some females gave birth to offspring sired by the same male in separate years. Such repeated partnerships probably result from fidelity for either mating sites or individuals or from sperm competition. Females mated with males born both within and outside their own natal colony; however, relatedness between parents was no less than the average recorded for male female pairs. Gene flow between colonies is likely to be primarily mediated by both female and male dispersal during the mating period rather than more permanent movements.

Hemodynamic and clinical comparison of the Hancock modified orifice and standard orifice bioprostheses in the aortic position.

Bioprosthetic aortic valve replacement in patients with a small aortic root has been associated with postoperative transvalvular gradients. A modified orifice Hancock xenograft bioprosthesis has been developed and is purported to increase significantly the effective orifice area (as evaluated by in vitro testing) compared to the standard orifice Hancock bioprosthesis. To assess the in vivo differences, we compared 481 patients with standard orifice prostheses with 156 patients with modified orifice prostheses. Postoperative catheterization was performed in 24 patients with modified orifice (valve diameters 19 to 25 mm) with 14 with standard orifice valves (valve diameters 21 to 25 mm). Actuarial rates of survival, valve failure, endocarditis, and thromboembolism did not differ significantly between the two subgroups. Peak aortic valve gradients on the whole were less in the modified orifice subgroup than in the standard origice subgroup (12 +/- 1 torr versus 20 +/- 6 torr [mean +/- SEM]), but the difference was not statistically significant (p greather than 0.05). The calculated in vivo aortic valve areas were slightly, but insignificantly, greater in the modified orifice subgroup than in the standard orifice subgroup (p greater than 0.05). These in vivo data partially corroborate the in vitro findings of increased effective orifice area and internal-to-external diameter ratio for the modified orifice bioprosthesis. The hemodynamic differences between the two valve types are small, however, and the putative clinical advantages inherent in the use of the modified orifice bioprosthesis remain to be completely defined.

Concomitant resection of ascending aortic aneurysm and replacement of the aortic valve: operative and long-term results with "conventional" techniques in ninety patients.

We reviewed a consecutive series of 90 patients undergoing concomitant resection of ascending aortic anerysm and aortic valve replacement (AVR) utilizing noncomposite "conventional" techniques in order to assess the early and late results, to define limitations of this operative approach, and thereby to clarify the indications for composite reconstruction of the aortic root. Mean age was 55 years. Twenty percent had Marfan's syndrome, and 13% had aortic dissections. The cause of the aneurysm was dissection in 13% of cases, syphilis in 11%, atherosclerosis in 9%, and degeneration (with or without cystic medionecrosis) in 67%. Follow-up averaged 3.8 years and extended to 11.5 years maximum. AVR and complete excision of the aneurysm (preserving small tongues of aortic wall circumscribing the coronary artery ostia) coupled with tubular graft replacement of the ascending aorta were performed. Nineteen percent of patients required individual technical modifications relating to the coronary arteries. Operative mortality rate was 13%, with the majority of deaths being due to cardiac causes. Contemporary (1975 to 1978) operative mortality rate was 4.3%. Seven percent required re-exploration for hemorrhage and 2.4% had perioperative myocardial infarctions. Late functional results were generally good (average N.Y.H.A. Class 1.4). Late thromboembolism, angina, myocardial infarction, and congestive heart failure occurred at linearized rates of 3.4% per patient-year, 4.9% per patient-year, 1.1% per patient-year, and 5.2% per patient-year, respectively. No prosthetic valve endocarditis, graft infection, or recurrent aneurysms of the aortic root were observed. Late reoperation was necessary in eight patients (3% per patient-year), but reoperation for disease confined to the ascending aorta accounted for only three of these cases (1.1% per patient-year). Overall actuarial survival rates were 67% +/- 5% at 5 years and 50% +/- 9% at 10 years; survival rates for the 78 operative survivors were 77% +/- 5% and 57% +/- 10% at the same time intervals, respectively. Only one late death could be attributed to complications arising in the reconstructed aortic root. These results confirm that such simple, noncomposite techniques are safe, portend minimal risk of late complications and the attendant necessity for reoperation, and provide satisfactory long-term survival. We believe that composite techniques should be primarily reserved for selected cases of advanced necrotizing prosthetic or natural endocarditis.

Aortic and mitral prosthetic valve reoperations: early and late results.

A total of 232 valvular reoperations (123 mitral valve reoperations [RMVR] and 109 aortic valve reoperations [RAVR] were performed in 194 patients with previously implanted prosthetic valves. Early mortality was 10% (12/123) for the RMVR subgroup and 14% (15/109) for the RAVR subgroup (P = NS). Late mortality was 16% (18/111) for the RMVR subgroup and 25% (23/94) for the RAVR subgroup (P = NS). Patients with prosthetic endocarditis or prosthetic stenosis constituted higher-risk subpopulations. Principal determinants of both operative mortality and late attrition were preoperative cardiac functional status and the nature of the pathology mandating valve replacement. Early prosthetic valve replacement is advocated to correct hemodynamic abnormalities before advanced ventricular decompensation ensues, especially when prosthetic valvular endocarditis or prosthetic stenosis exists.

Operative treatment of aortic dissections. Experience with 125 patients over a sixteen-year period.

An unselected, consecutive cohort of 125 patients underwent operative repair of acute and chronic aortic dissections with tubular graft interposition over a 16 year span. The absence of remote geographical referral biases and the unselected nature of this series provided a patient population that was representative of the disease process (as assessed heretofore only from autopsy series). Furthermore, this enabled high-risk subsets to be defined by retrospective analysis. Patients were classified according to whether the ascending aorta was involved (type A with involvement, type B without), irrespective of the site of intimal tear, and according to age of the dissection: Fifty-three patients had acute type A (Ac-A), 29 had chronic type A (Ch-A), 20 had acute type B (Ac-B), and 23 had chronic type B (Ch-B) dissections. Fourteen percent (17/125) of the dissections had ruptured. Concomitant aortic valve replacement (AVR) was performed in 11% (6/53) for Ac-A cases and 38% (11/29) of the Ch-A cases. A total of 391 patient-years of follow-up was analyzed; follow-up averaged 4.5 years and extended to 13.7 years. Over-all operative mortality rate was 34% (18/53) for Ac-A, 14% (4/29) for Ch-A, 45% (9/20) for Ac-B, and 22% (5/23) for Ch-B; during the most recent 5 year interval these figures were lower: 27%, 8%, 20%, and 20%, respectively, N = 50. Multiple preoperative variables were found to correlate significantly with both operative death and long-term survival. Operative survivors generally experienced satisfactory functional benefit. Late attrition averaged 8% per year; 61% of all late deaths were related to cardiac or cerebral causes. Over-all actuarial survival (+/- SEM) for the entire cohort was 54% +/- 5% at 5 years and 26% +/- 7% at 10 years; for the 89 patients surviving operation, these figures were 76% +/- 5% and 37% +/- 10%, respectively. No significant differences in long-term survival were evident between the different subgroups. Whether the primary intimal tear had been resected or concomitant AVR had been performed had no statistically significant bearing on operative mortality, functional result, necessity for late reoperation, or late attrition. The long-term "natural" history of surgically treated patients with aortic dissections, as defined in this study, should facilitate comparison with other treatment modalities. Results of the present analysis support immediate operative intervention for patients with Ac-A dissections and probably for those with Ac-B dissections. Additionally, surgical treatment of patients with symptomatic or enlarging Ch-A and Ch-B dissections provides satisfactory rehabilitation and long-term survival. Finally, we re-emphasize our recommendation for simplified classification of aortic dissections, based solely upon the presence or absence of ascending aortic involvement. Pathophysiology and expected biologic behavior pivot on this feature, and appropriate clinical strategy can thereby be defined.

Late right heart reconstruction following repair of tetralogy of Fallot.

Twenty-two symptomatic patients underwent a total of 28 reoperative procedures after initial surgical repair of tetralogy of Fallot. Sixteen of the patients were considered to have unfavorable anatomy of the right ventricular outflow tract (RVOT) or pulmonary artery at the time of initial repair. Pulmonary or tricuspid valve replacement, or replacement of both valves, utilizing a xenograft bioprosthesis was performed in 1 of the 22 initial repairs, 7 of the 22 first reoperations, and 5 of the 6 second reoperations. Ultimately, 14 patients received transannular RVOT patches. The interval between the first and second reoperations for 6 patients who required 2 late reconstructive procedures was 5.8 years. No operative deaths occurred. There were 2 late deaths (1 sudden and 1 due to aspiration). Actuarial survival probability (+/- standard error of the mean) 16 years after initial repair was 72 +/- 21%. Eighteen of the 20 current survivors in the present series are completely asymptomatic without physical restrictions; the other 2 are considered to be in New York Heart Association Functional Class II. No xenograft bioprosthetic dysfunction has occurred to date, but cumulative valve follow-up is limited (13 patient-years). In selected patients, earlier pulmonary or tricuspid valve replacement or replacement of both of these valves can provide some degree of protection against recurrent deterioration.

Hepatitis risk in cardiac surgery patients receiving factor IX concentrates.

Experience with the clinical use and hepatitis risks of factor IX concentrate (Proplex) in cardiac surgical patients is presented in this report. Seventy-five patients received the concentrate for severe intraoperative or postoperative hemorrhage and 75 patients constituted matched controls. The incidence of probable type B viral hepatitis in patients receiving factor IX concentrate was 13.8 percent (four of 29) versus zero percent (zero of 29) in control patients (difference not significant). However, there was a greater incidence (p less than 0.05) of anti-HBs in patients receiving factor IX concentrate as compared to control subjects. No hepatitis-associated deaths or major morbidity were noted in these patients. It is confirmed that factor IX concentrate carries an associated significant risk of hepatitis. However, its use is justified in certain severe, acquired coagulopathies in which conventional platelet and fresh-frozen plasma therapy is inadequate.

Impact of simultaneous myocardial revascularization on operative risk, functional result, and survival following mitral valve replacement.

A cohort of 282 patients who underwent mitral valve replacement with a xenograft bioprosthesis was strictly segregated according to etiology of mitral dysfunction and analyzed regarding the impact of arteriographic coronary artery disease (CAD) and concomitant coronary artery bypass grafting (CABG) on operative risk, functional result, and survival. CAD was present in 21% of the 122 patients with predominant mitral stenosis (MS) and 59% of the 155 patients with mitral regurgitation (MR); moreover, discordance between the presence of angina and anatomic CAD was found in 27% (33 of 122) of the MS subgroup and 36% (56 of 155) of the MR subgroup. Etiology of the valvular dysfunction was rheumatic in 148 patients, myxomatous degeneration in 83, and ischemic in 32. Within these subgroups, 41 patients (27%), 40 patients (48%), and 32 patients (100%), respectively, had CAD. Of those patients with CAD, 85% of the rheumatic subgroup, 90% of the degenerative subgroup, and 81% of the ischemic subgroup underwent concomitant CABG at the time of valve replacement. Within each subgroup no statistically significant (P greater than 0.05) differences in operative mortality rate, perioperative myocardial infarction rate, incidence of late angina or late infarction, or late actuarial survival were evident when compared on the basis of CAD, and/or CABG, with one exception. The exception was the 10% incidence of perioperative myocardial infarction in the rheumatic subgrohp with coronary disease versus 2% in the rheumatic subgroup without coronary disease (P = 0.05). Within the time constraints of this study (mean follow-up = 2.3 years; maximum follow-up = 5.9 years), these results support simultaneous MVR and CABG when hemodynamically appreciable CAD is found. Moreover, the overall 43% incidence of arteriographic CAD warrants routine coronary angiography in most adults undergoing preoperative catheterization for mitral valvular disease.

Myocardial damage in combined valvular and coronary bypass surgery.

The incidence of perioperative myocardial infarction (MI) and acute ischemic injury was determined in 44 patients having aortic valve replacement plus aortocoronary vein grafts (AVR + CABG) and in 22 patients having mitral valve repair or replacement plus aortocoronary vein grafts (MVR + CABG). These data were correlated with aortic cross-clamp time, fibrillation time, presence of left ventricular hypertrophy, and, in selected cases, left ventricular biopsy. Perioperative MI occurred in 21% (9/44) of the AVR + CABG patients and 5% (1/22) of MVR + CABG patients. In contrast, the MI rate for isolated valve replacement was 7% (15/213), and for isolated CABG 14% (16/112). In the AVR + CABG group, 100% (5/5) of patients with combined cross-clamp and fibrillation times greater than 120 minutes suffered MI. These results indicate that patients with combined AVR + CABG are subject to substantially greater risk of perioperative myocardial damage than the other groups. Excessive aortic cross-clamp times and fibrillation plus aortic cross-clamp times should be avoided in AVR + CABG patients.