The effects of short-term manipulation of thyroid hormone status coinciding with primary wool follicle development on fleece characteristics in Merino sheep.

Thyroidectomy surgery performed late in gestation results in perturbations in wool follicle development in foetal sheep, showing the importance of thyroid hormones for wool follicle development. The aim of this study was to determine the influence of transient manipulation of thyroid hormone status at a time corresponding with foetal primary wool follicle initiation. Pregnant Merino ewes (n = 12 per treatment) were treated daily between gestational days 55 and 64 with control (vehicle), exogenous thyroxine (T4) or propylthiouracil (PTU), an inhibitor of T4 synthesis, and conversion to the active form of the thyroid hormone (triiodothyronine). There were no significant differences in birth weight, gestational lengths and birth coat scores of the resultant lambs. The total primary and secondary follicle densities were significantly lower in lambs exposed to exogenous T4 compared with other treatments (P < 0.05). However, the T4 group displayed a higher proportion of mature secondary follicles (reflected by increased mature secondary follicle densities and mature secondary/primary follicle ratios) than the other treatment groups (P < 0.05). The skin morphology of the lambs differed 12 months later, with the T4 group having significantly higher total follicle densities compared with the PTU group, largely attributed to increased mature and total secondary follicle densities. However, this increase in wool follicle densities did not translate to differences in the fleece yields and weight, fibre diameter, staple lengths or any other fibre parameters. This study showed that transient manipulation of thyroid hormone status during foetal primary follicle initiation does have long-term consequences on the morphology of wool follicles, in particular the maturity of secondary wool follicles.

Wool fibre crimp is determined by mitotic asymmetry and position of final keratinisation and not ortho- and para-cortical cell segmentation.

Crimp, a distinguishing feature of sheep fibres, significantly affects wool value, processing and final fabric attributes. Several explanations for fibre bending have been proposed. Most concentrate on relative differences in the physicochemical properties of the cortical cells, which comprise the bulk of the fibre. However, the associations between cortical properties and fibre crimp are not consistent and may not reflect the underlying causation of fibre curvature (FC). We have formulated a mechanistic model in which fibre shape is dictated primarily by the degree of asymmetry in cell supply from the follicle bulb, and the point at which keratinisation is completed within the follicle. If this hypothesis is correct, one would anticipate that most variations in fibre crimp would be accounted for by quantitative differences in both the degree of mitotic asymmetry in follicle bulbs and the distance from the bulb to the point at which keratinisation is completed. To test this hypothesis, we took skin biopsies from Merino sheep from sites producing wool differing widely in fibre crimp frequency and FC. Mitotic asymmetry in follicle bulbs was measured using a DNA-labelling technique and the site of final keratinisation was defined by picric acid staining of the fibre. The proportion of para- to ortho-cortical cell area was determined in the cross-sections of fibres within biopsy samples. Mitotic asymmetry in the follicle bulb accounted for 0.64 (P < 0.0001) of the total variance in objectively measured FC, while the point of final keratinisation of the fibre accounted for an additional 0.05 (P < 0.05) of the variance. There was no association between ortho- to para-cortical cell ratio and FC. FC was positively associated with a subjective follicle curvature score (P < 0.01). We conclude that fibre crimp is caused predominantly by asymmetric cell division in follicles that are highly curved. Differential pressures exerted by the subsequent asymmetric cell supply and cell hardening in the lower follicle cause fibre bending. The extent of bending is then modulated by the point at which keratinisation is completed; later hardening means the fibre remains pliable for longer, thereby reducing the pressure differential and reducing fibre bending. This means that even highly asymmetric follicles may produce a straight fibre if keratinisation is sufficiently delayed, as is the case in deficiencies of zinc and copper, or when keratinisation is perturbed by transgenesis. The model presented here can account for the many variations in fibre shape found in mammals.

The role of activins and follistatins in skin and hair follicle development and function.

Investigations of the signalling between epithelial and mesenchymal compartments of skin during hair follicle initiation in utero and hair cycling have revealed the importance of the TGFbeta superfamily in ectodermal organogenesis and morphogenesis. In particular the activins, their receptors and binding proteins such as follistatin, have been shown to be important regulators of cell proliferation, differentiation and apoptosis in hair follicle initiation, hair cycling, normal skin homeostasis and wound healing. Transgenic mice lacking various components of the activin signalling pathways display varying ectodermal pathologies including altered pelage hair follicle initiation. This review summarises the activin signal transduction pathways and the interactions between activins and other TGFbeta signalling systems during hair follicle formation, hair growth cycling, skin function and wound healing.

Physicochemical properties of hull-less barley fibre-rich fractions varying in particle size and their potential as functional ingredients in two-layer flat bread.

The performance of barley fibre-rich fractions (FRF), as high dietary fibre ingredients, in two-layer flat bread was investigated. In addition, the effects of particle size reduction by pin milling on functional properties of FRF were studied. FRF enriched in non-starch polysaccharides (ß-glucans and arabinoxylans) were obtained by roller milling of hull-less barley. Pin milling (PM) of FRF significantly reduced their particle size, slightly increased the solubility of ß-glucans and arabinoxylans, and increased the viscosity of water slurries containing FRF. The addition of 20% of barley FRF to wheat flour significantly increased dough water absorption and weakened the dough properties, as indicated by farinograph mixing curves, but the FRF-enriched doughs exhibited good handling characteristics at the dividing and sheeting stages. The appearance, diameter, layer separation, crumb, and aroma of the FRF-enriched flat breads were comparable to that of the control. The PM of FRF did not significantly affect the dough handling or the quality characteristics of flat breads. The addition of 20% of barley FRF to wheat flour flat bread provided substantial health benefits by significantly increasing the total and soluble dietary fibre contents and by decreasing starch digestibility.

Novel technique to repair type A acute aortic dissection in patients with a left ventricular assist device.

Acute type A aortic dissection is an uncommon complication with left ventricular assist device insertion, but is often fatal even if successfully repaired with conventional techniques including aortic valve repair. Residual aortic insufficiency is common because this valve is now subjected to systolic pressure. We present a novel technique for the repair of type A acute aortic dissection in patients with a left ventricular assist device with no chance of residual aortic insufficiency.

Increased prevalence of autoimmune phenomena and greater risk for alloreactivity in female heart transplant recipients.

BACKGROUND: The influence of sex on alloreactivity and graft outcome after heart transplantation was evaluated. METHODS AND RESULTS: A retrospective review of 520 consecutive recipients of a primary cardiac allograft between 1992 and 2000 at a single center was performed. The influence of sex on alloreactivity, acute rejection, transplant-related coronary artery disease, and survival was determined. Statistical methods included logistic regression analysis and Kaplan-Meier actuarial survival analysis. Female recipients had an increased prevalence before transplant of idiopathic cardiomyopathy, antinuclear antibodies, and HLA-B8, DR3 haplotypes. After transplant, female sex predicted shorter duration to a first rejection, higher cumulative rejection frequency, and earlier posttransplant production of anti-HLA antibodies. Female recipients had higher early mortality rates (<6 months) that were due to infection. Fatal infections correlated with 2-fold higher cyclosporine levels in female recipients. However, the incidence of transplant-related coronary artery disease developing beyond 1 year after transplant was lower in female than in male recipients. CONCLUSIONS: Females undergoing cardiac transplantation are more likely to manifest features of an underlying autoimmune state. This may predispose to a higher posttransplant risk of allograft rejection and requirement for increased immunosuppression. Earlier diagnosis and management of alloreactivity in female recipients before development of acute rejection and the use of more focused and less globally immunosuppressive agents during established rejections may have a significant effect on the clinical outcome of female cardiac allograft recipients.

Long-term outcomes after cardiac transplantation: an experience based on different eras of immunosuppressive therapy.

BACKGROUND: Constantly changing practices in heart transplantation have improved posttransplant survival in patients with end-stage heart disease. The objective of this study was to evaluate long-term outcomes in different eras of immunosuppressive therapy after cardiac transplantation at a single center during a two-decade period. METHODS: A retrospective review of 1,086 consecutive cardiac allograft recipients who underwent transplantation between 1977 to 1999 was performed. Patients were divided into four eras based on type of immunosuppressive therapy: era 1 = steroids, azathioprine (n = 26, February 1977 to March 1983), era II = steroids, cyclosporine (n = 43, April 1983 to April 1985), era III = cyclosporine, steroids, azathioprine (n = 752, April 1985 to December 1995), era IV = cyclosporine, steroids, mycophenolate mofetil (n = 315, January 1996 to October 1999). RESULTS: The actuarial survival of the entire cohort of 1,086 patients undergoing cardiac transplantation was 79%, 66%, and 49% at 1, 5, and 10 years, respectively. There were significant trends in recipient age and gender distribution among the four eras with increasing proportion of older age (> 60 years) and female recipients in eras III and IV (p = 0.001 and 0.02). Early mortality and long-term survival improved significantly over all eras (p < 0.001). Rejection as a cause of death decreased over time (era I, 24%; era II, 21%; era III, 15%; era IV, 9%; p = 0.02), whereas the contribution of transplant coronary artery disease as a cause of death remained unchanged. CONCLUSIONS: Cardiac transplantation provides satisfactory long-term survival for patients with end-stage heart failure. The improving outcomes in survival correlate with improved immunosuppressive therapy in each era. Although the reasons for improvement in survival over time are multifactorial, we believe that changes in immunosuppressive therapy have had a major impact on survival as evidenced by the decreasing number of deaths due to rejection.

Pretransplant cachexia and morbid obesity are predictors of increased mortality after heart transplantation.

BACKGROUND: Extremes in body weight are a relative contraindication to cardiac transplantation. METHODS: We retrospectively reviewed 474 consecutive adult patients (377 male, 97 female, mean age 50.3+/-12.2 years), who received 444 primary and 30 heart retransplants between January of 1992 and January of 1999. Of these, 68 cachectic (body mass index [BMI]<20 kg/m2), 113 overweight (BMI=>27-30 kg/m2), and 55 morbidly obese (BMI>30 kg/m2) patients were compared with 238 normal-weight recipients (BMI=20-27 kg/m2). We evaluated the influence of pretransplant BMI on morbidity and mortality after cardiac transplantation. Kaplan-Meier survival distribution and Cox proportional hazards model were used for statistical analyses. RESULTS: Morbidly obese as well as cachectic recipients demonstrated nearly twice the 5-year mortality of normal-weight or overweight recipients (53% vs. 27%, respectively, P=0.001). An increase in mortality was seen at 30 days for morbidly obese and cachectic recipients (12.7% and 17.7%, respectively) versus a 30-day mortality rate of 7.6% in normal-weight recipients. Morbidly obese recipients experienced a shorter time to high-grade acute rejection (P=0.004) as well as an increased annual high-grade rejection frequency when compared with normal-weight recipients (P=0.001). By multivariable analysis, the incidence of transplant-related coronary artery disease (TCAD) was not increased in morbidly obese patients but cachectic patients had a significantly lower incidence of TCAD (P=0.05). Cachectic patients receiving oversized donor hearts had a significantly higher postoperative mortality (P=0.02). CONCLUSIONS: The risks of cardiac transplantation are increased in both morbidly obese and cachectic patients compared with normal-weight recipients. However, the results of cardiac transplantation in overweight patients is comparable to that in normal-weight patients. Recipient size should be kept in mind while selecting patients and the use of oversized donors in cachectic recipients should be avoided.

Surgical management of valvular disease in patients requiring left ventricular assist device support.

BACKGROUND: Success with long-term implantable left ventricular assist devices (LVAD) has led to increased use in patients previously thought to be unsuitable for mechanical circulatory assistance. Patients with preexisting or newly diagnosed valvular disease have been traditionally excluded from device placement. The purpose of this study was to review our experience with LVAD support in patients with valvular disease and to develop a management algorithm for these difficult patients. METHODS: We reviewed the clinical records of 199 consecutive patients who received the ThermoCardiosystems, Inc, HeartMate Pneumatic or Vented Electric LVAD. There were 18 patients (9%) who required surgical management of native or prosthetic valvular disease during LVAD implantation. RESULTS: Suture or patch closure of the aortic valve was performed in 6 patients, aortic valve plication and repair in 1 patient, mitral valve repair in 4 patients, and tricuspid valve annuloplasty in 5 patients. Two patients with mechanical mitral valve prostheses were treated with postoperative warfarin anticoagulation. Fifteen of the 18 patients with valvular pathology survived the immediate postoperative period (17% mortality). Eleven patients have either undergone transplantation or continue to be supported with an LVAD (61%). Operative mortality in LVAD patients without concomitant valve repair was 18% (n = 33) with a late mortality of 7% (n = 13). Seven of these late deaths occurred in patients who received a device as destination therapy. In the remaining 6 patients, the cause of death was sepsis (n = 2), multisystem organ failure (n = 2), driveline rupture (n = 1), and massive gastrointestinal bleed (n = 1). CONCLUSIONS: Preexisting native or prosthetic valve pathology does not increase the immediate perioperative risk of LVAD insertion; however, these patients continue to pose a challenge for postoperative management while awaiting transplantation.

A new off-pump technique for thoratec right ventricular assist device insertion.

The need for right ventricular support as an adjunct to left ventricular assistance is uncommon. When required, the insertion of a right ventricular assist device may be complicated by preexisting hepatic dysfunction, coagulation abnormalities, and renal failure, all of which are exacerbated by cardiopulmonary bypass. We report a technique for insertion of a right ventricular assist device without the need for cardiopulmonary bypass.

Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function.

Left ventricular remodeling is a major cause of progressive heart failure and death after myocardial infarction. Although neoangiogenesis within the infarcted tissue is an integral component of the remodeling process, the capillary network is unable to support the greater demands of the hypertrophied myocardium, resulting in progressive loss of viable tissue, infarct extension and fibrous replacement. Here we show that bone marrow from adult humans contains endothelial precursors with phenotypic and functional characteristics of embryonic hemangioblasts, and that these can be used to directly induce new blood vessel formation in the infarct-bed (vasculogenesis) and proliferation of preexisting vasculature (angiogenesis) after experimental myocardial infarction. The neoangiogenesis resulted in decreased apoptosis of hypertrophied myocytes in the peri-infarct region, long-term salvage and survival of viable myocardium, reduction in collagen deposition and sustained improvement in cardiac function. The use of cytokine-mobilized autologous human bone-marrow-derived angioblasts for revascularization of infarcted myocardium (alone or in conjunction with currently used therapies) has the potential to significantly reduce morbidity and mortality associated with left ventricular remodeling.

Factors affecting long-term survival (>10 years) after cardiac transplantation in the cyclosporine era.

OBJECTIVES: The aim of this study was to determine long-term survival (>10 years) after cardiac transplantation in the cyclosporine era and identify risk factors influencing long-term survival. BACKGROUND: Despite the availability of newer modalities for heart failure, cardiac transplantation remains the treatment of choice for end-stage heart disease. METHODS: Between 1983 and 1988, 195 patients underwent heart transplantation at a single center for the treatment of end-stage heart disease. Multivariable logistic regression analysis of pretransplant risk factors affecting long-term survival after cardiac transplantation included various recipient and donor demographic, immunologic and peritransplant variables. RESULTS: Among the group of 195 cardiac transplant recipients, actuarial survival was 72%, 58% and 39% at 1, 5 and 10 years respectively. In the 65 patients who survived >10 years, mean cardiac index was 2.91/m2 and mean ejection fraction was 58%. Transplant-related coronary artery disease (TRCAD) was detected in only 14 of the 65 patients (22%). By multivariable analysis, the only risk factor found to adversely affect long-term survival was a pretransplant diagnosis of ischemic cardiomyopathy (p = 0.04). CONCLUSIONS: Long-term survivors maintain normal hemodynamic function of their allografts with a low prevalence of TRCAD. It is possible that similar risk factors that lead to coronary artery disease in native vessels continue to operate in the post-transplant period, thereby contributing to adverse outcomes after cardiac transplantation. Aggressive preventive and therapeutic measures are essential to limit the risk factors for development of coronary atherosclerosis and enable long-term survival after cardiac transplantation.

Transaortic repair of mitral regurgitation.

BACKGROUND: In the operative management of mitral regurgitation (MR) associated with aortic valve disease, a transaortic approach combining the bowtie mitral valve repair with replacement of the aortic valve appears to offer a less invasive and technically simple, expeditious alternative to conventional left atriotomy and Carpentier style repair. METHODS: Between February 1997 and December 1999, four patients underwent a bowtie repair of the mitral valve via the aortic root with concomitant aortic valve replacement. The diagnosis of MR was established and followed postoperatively by echocardiogram. The operative technique involved a transaortic annular approach to the mitral valve with a single edge-to-edge suture approximating the prolapsing posterior mitral leaflet to a normal segment of the anterior leaflet. RESULTS: There were no operative mortalities. Mean cross-clamp time for both valve procedures was 104 +/- 24 min and cardiopulmonary bypass was 155 +/- 31. Mean postoperative cardiac output was 5 +/- 1 L/min. Semiquantitative estimation of mitral regurgitation by doppler improved from a mean of 3.2 +/- 0.5 preoperatively to a mean of 0.25 +/- 0.5 (p = 0.0052) postoperatively, while ejection fraction (EF) remained stable (48 +/- 9% preoperatively and 49 +/- 9% prior to discharge). One patient with rheumatic mitral pathology had a mild increased mitral gradient which did not resolve with takedown of the bowtie repair. Mitral stenosis was not evident in any of the other patients. CONCLUSIONS: Our initial experience with the combined transaortic bowtie repair and aortic valve replacement has demonstrated that this approach is very quick, feasible, effective, and technically simple with gratifying midterm results.

Infections during left ventricular assist device support do not affect posttransplant outcomes.

BACKGROUND: Although infections acquired during ventricular assist device support may increase the risk of infection and have an impact on transplant survival, their true posttransplant consequences remain to be determined. This study evaluates the impact of an outpatient program, newer devices, and an updated infection management protocol on infection-related patient outcomes after transplant. METHODS AND RESULTS: Eighty-six patients received a left ventricular assist device (LVAD) between June 1996 and June 1999. Fifty patients transplanted during the same period, without prior device support, were used as controls; they were matched to transplanted LVAD recipients by age, sex, diagnosis, and transplant date. The nature of and actuarial freedom from peritransplant and posttransplant infections were compared at 6 months after transplant; actuarial patient survival was compared at 3 years. Infection was defined as leukocytosis or leukopenia, with a positive culture requiring either medical or surgical intervention. Forty-four patients (51%) were successfully discharged home on LVAD support, and 61 (71%) were transplanted. A high incidence of infection during device support did not have an impact on pretransplant or posttransplant mortality, posttransplant infectious rate, or overall patient survival. Active infections at transplant also did not significantly influence 6-month mortality. In comparison, LVAD recipients had a lower freedom from infection than did controls (P:<0.05); however, 3-year survival did not differ: 79% and 87% for the LVAD and control groups, respectively. CONCLUSIONS: Although LVADs increase the risk of infection in the early posttransplant period, this appears not to have an impact on transplantability or patient survival and likely reflects effective infection control in both inpatient and outpatient settings.

Recurrent remodeling after ventricular assistance: is long-term myocardial recovery attainable?

BACKGROUND: Long-term left ventricular assist devices (LVAD) have been used both as a bridge to heart transplantation and to recovery of native myocardial function. Despite much evidence for reversal of some of the structural and functional changes present in the failing heart during LVAD support, clinical evidence for sustained myocardial recovery is scant. We describe 2 patients in whom myocardial recovery during LVAD support led to device explanation only to have heart failure recur. This necessitated a second LVAD implantation, a process that we have termed recurrent remodeling. METHODS: The medical records of 2 patients with cardiomyopathy supported with HeartMate LVADs (Thermo Cardiosystems, Inc, Woburn, MA) were retrospectively reviewed. RESULTS: One patient was supported with an LVAD for 2 months, at which time the LVAD was explanted. Progressive deterioration of cardiac function followed, requiring a second LVAD 19 months after LVAD explanation. After 2 months of further LVAD support, a second episode of apparent myocardial recovery was observed during a period of device malfunction. The other patient was supported with an LVAD for 12 months, at which time the LVAD was explanted. The patient experienced progressive hemodynamic deterioration and required a second LVAD 6 months after LVAD explantation. Heart transplantations of both patients were successful. CONCLUSIONS: Our understanding of myocardial recovery in the setting of hemodynamic unloading with LVAD support has not yet progressed to the point where we are able to accurately predict successful long-term LVAD explantation. The evolution of reliable predictors of sustainable myocardial recovery will help to avoid further cases of recurrent remodeling requiring repeat LVAD implantation.

Impact of current management practices on early and late death in more than 500 consecutive cardiac transplant recipients.

OBJECTIVE: To study risk factors for early and late death after heart transplantation in the current era. SUMMARY BACKGROUND DATA: The current cardiac transplant population differs from earlier periods in that an increasing number of sicker patients, such as those with ventricular assist device (LVAD) support, prior cardiac allotransplantation, and pulmonary hypertension, are undergoing transplantation. In addition, sensitized patients constitute a greater proportion of the transplanted population. Emphasis has been placed on therapies to prevent early graft loss, such as the use of nitric oxide and improved immunosuppression, in addition to newer therapies. METHODS: Five hundred thirty-six patients undergoing heart transplantation between 1993 and 1999 at a single center were evaluated (464 adults and 72 children; 109 had received prior LVAD support and 24 underwent retransplantation). The mean patient age at transplantation was 44.9 years. Logistic regression and Cox proportional hazard models were used to evaluate the following risk factors on survival: donor and recipient demographics, ischemic time, LVAD, retransplantation, pretransplant pulmonary vascular resistance, and immunologic variables (ABO, HLA matching, and pretransplant anti-HLA antibodies). RESULTS: The rate of early death (less than 30 days) was 8.5% in adults and 8.8% in children. The actuarial survival rate of the 536 patients was 83%, 77%, and 71% at 1, 3, and 5 years, respectively, by Kaplan Meier analysis. Risk factors adversely affecting survival included the year of transplant, donor age, and donor-recipient gender mismatching. Neither early nor late death was influenced by elevated pulmonary vascular resistance, sensitization, prior LVAD support, or prior cardiac allotransplantation. CONCLUSIONS: Previously identified risk factors did not adversely affect short- or long-term survival of heart transplant recipients in the current era. The steady improvement in survival during this period argues that advances in transplantation have offset the increasing acuity of transplant recipients.

Cardiac transplantation and other therapeutic options in the treatment of end-stage heart disease.

This article focuses on the surgical treatment of heart failure. It reviews the advances and limitations of heart transplantation and gives a broad overview of emerging technologies in the treatment of end-stage heart disease.

Implantable left ventricular assist devices can successfully bridge adolescent patients to transplant.

BACKGROUND: Left ventricular assist devices (LVAD) have been used successfully as a life-sustaining bridge to transplantation in adults with end-stage heart failure. Long-term implantable cardiac assist devices for smaller adolescent patients are not yet available in the United States. METHODS: This study reviews the experience with patients less than 21 years old that received HeartMate LVADs (TCI) at our institution. Twelve patients were implanted with 13 LVADs. The patients ranged in age from 11 to 20 years (mean 16 years). Body surface area ranged from 1.4 to 2.2 m2 (mean 1.8 m2). Patients were selected for LVAD placement based on eligibility for heart transplant and evidence of end-organ dysfunction. Device placement in small patients was facilitated with prosthetic graft abdominal wall closure. No patient received systemic anticoagulation. RESULTS: The duration of LVAD support ranged from 0 to 397 days (mean 123 days). Seven of the 8 patients eligible for discharge from the hospital with a vented-electric LVAD were supported at home while awaiting transplantation. Outcomes of LVAD support were: LVAD explantation in 2 cases (15%), expiration with LVAD in place in 3 cases (23%), and successful transplantation in 8 cases (62%). Complications included 4 patients with systemic infection, 3 re-operations for hemorrhage, 1 embolic event, and 1 intraoperative air embolus that proved fatal. One explanted patient required a subsequent LVAD and the other expired 4 months after explantation. Six of the 8 transplanted patients are alive and well with follow-up ranging from 8 to 43 months. CONCLUSIONS: Adolescent patients with heart failure can be successfully supported on a long-term basis to heart transplantation with the HeartMate LVAD. The wearable device allows for discharge home while awaiting transplantation. Device explantation without subsequent transplantation can be unpredictable. The incidence of thromboembolism remains low despite the absence of systemic anticoagulation. The technique of prosthetic graft closure of the abdominal wall facilitates the use of this device in smaller patients.