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Background: Conventional immunosuppression for heart transplantation is associated with various adverse effects. Tacrolimus monotherapy (TM) is an alternative strategy that minimizes exposure to additional immunosuppressants., Methods: We retrospectively reviewed clinical data for all adult transplant recipients between January 1, 1996 and May 1, 2004. Clinical outcomes were analyzed according to immunosuppressive regimen., Results: A total of 167 heart transplants were performed at our center. Eight patients died before receiving calcineurin inhibitors and were excluded from analysis. The mean follow-up for the 159 surviving patients was 1,520 +/- 78 days. Ninety of 124 patients initially treated with tacrolimus and corticosteroids were weaned to TM without the use of an anti-proliferative agent (Group A), resulting in an overall success rate of 75% at an average of 271 +/- 18 days after transplant. The remaining 69 recipients were treated with other tacrolimus- or cyclosporine-based regimens (Group B). Survival was significantly greater in Group A. The prevalence of high-grade rejection within the first year and incidence of cardiac allograft vasculopathy were similar between groups. Ten patients (11%) in Group A required recommencement of combination immunosuppression at an average of 768 +/- 772 days., Conclusions: TM is achievable in the majority of cardiac transplant recipients. Patients who tolerated reduced immunosuppression enjoyed greater survival than those treated with other regimens, without additional high-grade rejection or vasculopathy. These promising results remain to be confirmed in a prospective trial.

Heart failure is a deadly disease. Every year, tens of thousands of patients die from this condition, many of them suddenly. Efforts aimed at reducing mortality centered initially on antagonizing the neurohormonal system, which is maladaptively upregulated in response to myocardial failure. Antagonists of the renin-angiotensin-aldosterone and adrenergic nervous systems have reduced the rates of cardiovascular mortality and sudden cardiac death. Antiarrhythmic drug therapy has not fared as well. Consequently, efforts to reduce the risk of sudden death have focused on the use of implantable cardioverter-defibrillators (ICDs). How best to identify patients who will benefit from this invasive and expensive therapy has yet to be clearly determined. In this review, we discuss the effectiveness of ICDs in primary and secondary prevention of sudden death in heart failure patients, and examine the impact that the use of ICDs has had on clinical decision making.

Our aim was to determine the effect of left ventricular assist device (LVAD) implantation on bypass graft patency and to measure myocardial oxygen consumption (MVO2) and blood flow during LVAD support. Five patients who underwent coronary artery bypass grafting and required LVAD implantation for post-cardiotomy cardiogenic shock had coronary angiography during device support to assess graft patency. Positron emission tomography measurements were made in a separate cohort of LVAD patients with dilated cardiomyopathy to assess the effects of LVAD support on MVO2 and myocardial blood flow. In this small series, LVAD unloading led to a high rate of premature graft occlusion in post-cardiotomy cardiogenic shock patients supported with a device; whereas, positron emission tomography measurements showed significantly reduced MVO2 and myocardial flood flow in dilated cardiomyopathy patients supported with an LVAD, compared with healthy subjects. Reduced myocardial blood flow may be implicated in the premature graft failure observed in post-cardiotomy cardiogenic shock patients and may negatively impact the potential for myocardial recovery and device weaning in this population.

Background: Percutaneous coronary intervention (PCI) to palliate cardiac allograft vasculopathy (CAV) has been associated with high restenosis rates, possibly related to increased inflammation associated with this disease. Whether markers of immunologic rejection are associated with restenosis in this population is unknown. The goal of the study was to determine the predictors of restenosis after PCI for CAV., Methods: Records were reviewed retrospectively from a single, high-volume cardiac transplant center. Clinical, angiographic, and immunologic data were collected on all patients postorthotopic heart transplantation (OHT) that had subsequent PCI. Restenosis was defined as greater than 50% stenosis at the previous intervention site., Results: PCI was successfully performed on 62 de novo lesions in 40 patients an average of 6.8+/-3.9 years after OHT. Angiographic follow-up data was available for 79%, with an average follow-up of 1.54+/-1.22 years. The 1-year restenosis rate was 49% (64% for balloon percutaneous transluminal coronary angioplasty and 33% for coronary stenting [P=0.09 for difference]). The frequency of immunoglobulin (Ig)G antibody to major histocompatibility complex (MHC) class I antigen was highly associated with risk of restenosis (hazard ratio [HR] 11.33, P=0.01). Greater stenosis severity and smaller target vessel diameter were also predictors of restenosis as in the nontransplant population., Conclusions: The findings suggest that in patients postPCI for CAV, humoral allo-immunity may contribute to restenosis and that IgG antibodies to MHC class I antigen may help predict the risk of restenosis after PCI in this population.

Background: Displaced talar neck fractures are relatively rare injuries with potentially serious long-term morbidity. Expedient treatment has long been held as a treatment principle. The purpose of this study was to assess the current state of practice of treating displaced talar neck fractures by recognized orthopaedic trauma experts working at level 1 trauma centers., Methods: A group of expert orthopaedic trauma surgeons were surveyed to determine what they considered "the maximal acceptable time delay from injury to the operating room representing the minimal standard of care at a level 1 trauma center for a displaced talar neck fracture?" Each survey recipient had been selected as a moderator at a national orthopaedic trauma meeting during the past 5 years. Eighty-nine of 109 (82%) responded to the survey., Results: For a displaced talar neck fracture, 60% of respondents stated that treatment after 8 hours is acceptable, with 46% percent of respondents stating that treatment at or after 24 hours is acceptable., Conclusion: These results indicate that most expert orthopedic trauma surgeons do not believe that an immediate operation is necessary to adequately treat a displaced talar neck fracture.

Background: Rating scales that are valid, reliable, and responsive communicate the severity of a functional problem, facilitate the accurate study of treatment modalities, and provide a common language for those involved in research. The purpose of this study was to determine which outcome rating scales are currently used in the foot and ankle literature and to identify rating scales with proven reliability, validity, and responsiveness., Method: A meta-analysis of the foot and ankle literature from 1990 to 2001 was done. All referenced rating scales were reviewed to determine if any had proven to be reliable, valid, or responsive., Results: Forty-nine different rating scales were identified. The most frequently referenced scales were the subscales of the American Orthopaedic Foot and Ankle Society (AOFAS). No rating scale was identified that demonstrated reliability, validity, and responsiveness in patients with a variety of foot and ankle conditions., Conclusions: The development of a reliable, valid, and responsive rating scale would have value not only in assessing patient outcomes but also in reporting the results of clinical studies in foot and ankle surgery.

Background: Cardiac transplantation vasculopathy is the leading cause of late death in heart transplantation recipients. Rapamycin is an immunosuppressant drug with potent antiproliferative and antimigratory effects. We investigated whether rapamycin could prevent progression of graft vasculopathy in 46 patients (age, 54+/-10 years; 4.3+/-2.3 years after transplantation) with severe disease., Methods and Results: At annual cardiac catheterization, patients were randomly assigned to treatment with rapamycin (n=22) versus continued current immunosuppression (n=24). Clinical characteristics including recipient age and sex, underlying cause of congestive heart failure, donor age and sex, and ischemic time were recorded. Cardiac catheterization was graded with the use of a semiquantitative scale and repeated annually. Clinically significant adverse events were defined as death, need for angioplasty or bypass surgery, myocardial infarction, and a >25% worsening of the catheterization score. These events were monitored as primary study end points. Anti-HLA class I and II antibody production and lymphocyte growth assays were measured with each biopsy. Patients selected for rapamycin had azathioprine or mycophenolate mofetil discontinued and were given rapamycin. Outcomes were compared by means of log-rank analysis. There were no significant differences in baseline characteristics. Duration of follow-up was comparable (rapamycin, 689+/-261; control, 630+/-207 days; NS). In the rapamycin group, 3 patients reached primary end points versus 14 patients in the control group (P<0.001). There was no difference in baseline or subsequent anti-HLA class I or II antibody production., Conclusions: In this patient cohort with cardiac vasculopathy, treatment with rapamycin slowed disease progression probably by its antiproliferative and antimigratory effects.

Objectives: To determine the preventive benefit of "medical oophorectomy" and transdermal estradiol in women with migraine., Background: Epidemiological studies have demonstrated that declines in serum estrogen levels occurring during normal menstrual cycles can trigger headache in women with migraine. Prior to this study, no randomized controlled trials have evaluated whether minimizing these hormonal changes pharmacologically can prevent headache., Methods: Twenty-one women with regular menstrual cycles and a diagnosis of migraine headache were enrolled. After a 2.5-month placebo run-in phase, all patients received a subcutaneous goserelin implant (a gonadotropin-releasing hormone agonist) to induce a medical oophorectomy. One month later, while continuing goserelin, participants were randomized to receive a transdermal patch containing 100 microg of estradiol-17beta (gonadotropin-releasing hormone agonist/estradiol group, n = 9) or a placebo patch (gonadotropin-releasing hormone agonist/placebo group, n = 12) during a 2-month treatment phase. The primary outcome measure was the headache index, which was defined as the mean of pain severity ratings (0 to 10 scale) recorded three times per day by daily diary. Secondary outcome measures included headache disability, headache severity, headache frequency, and the percentage of headaches with a pain severity rating of 7 or greater., Results: The headache index was significantly lower during the treatment period in the gonadotropin-releasing hormone agonist/estradiol group than in the gonadotropin-releasing hormone agonist/placebo group (P =.025). Similar improvements were observed in the gonadotropin-releasing hormone agonist/estradiol group for all secondary outcome measures with the exception of headache frequency, which was unchanged between the groups. Within the gonadotropin-releasing hormone agonist/estradiol group, there was a 33.7% reduction (95% confidence interval, -64.4 to -3.0) in the headache index during the treatment phase when compared with the placebo run-in phase; no difference was seen between those phases within the gonadotropin-releasing hormone agonist/placebo group., Conclusions: Minimization of hormonal fluctuations with gonadotropin-releasing hormone agonist therapy alone is inadequate to prevent headache in women who are premenopausal with migraine. The addition of transdermal estradiol to existing gonadotropin-releasing hormone agonist therapy provides a modest preventive benefit.

While current human exposure to 4-aminobiphenyl (4-ABP) is mainly through inhalation, historically, occupational exposure occurred most often through the skin. 4-ABP targets the urinary bladder in humans, dogs, and rats and the liver and urinary bladder in mice. This study examines the time course of DNA adduct levels in mouse target tissues, liver and urinary bladder, and nontarget tissues, lung and skin, after repeated dermal exposure to subcarcinogenic doses of 4-ABP. It was found that, in female mice dermally treated with 50 nmol of 4-ABP twice weekly for 21 weeks, DNA adduct levels measured by 32P-postlabeling increased over time in target and nontarget tissues, but the greatest rate of accumulation occurred in urinary bladder. At 21 weeks liver, urinary bladder, and skin reached their highest median adduct levels of 55, 82, and 58, respectively. Median adduct levels in lung reached a maximum of 3.2 at 3 weeks of exposure. An adduct which had similar chromatographic properties to a standard previously identified as N-(deoxyguanosin-8-yl)-4-aminobiphenyl was the primary adduct detected in all tissues. There were significant correlations in adduct levels between liver and urinary bladder and liver and skin, but not between skin and urinary bladder. These data suggest that urinary bladder adducts are the result of hepatic and not dermal activation. However, adducts were detected at relatively high levels in skin but not in lung, suggesting that skin may have the metabolic capacity to activate 4-ABP when it is applied topically.

The purpose of this study was to evaluate the intercorrelation between three genetic assays in 112 subjects. The group was pooled from two originally separate but homogeneous subgroups of 56 persons each. Procedures included assays for hprt mutant frequencies, micronuclei in human lymphocytes, and mutations at the glycophorin A (gpa) loci. We found no statistically significant or biologically important intercorrelations among the three biomarkers. We did, however, observe significant correlations between log(e) hprt mutant frequency and cloning efficiency (inverse correlation for these 2 variables), age and log(e) hprt mutant frequency, an inverse relationship between cloning efficiency and age, and an important differential sex effect favoring a greater micronuclei frequency in females than males. No significant correlations between the covariates of interest and glycophorin A variant frequencies NN or NO were observed. Using multivariable linear regression, age was found to account for the majority of the variability in hprt mutant frequency (greater than sex and/or smoking); for micronuclei data, only sex contributed a statistically significant and biologically important proportion to the total variation. We conclude that despite observing no significant intercorrelations between the three assays performed simultaneously from the same individuals in a large population database, a significant correlation between age and hprt mutant frequency and an inverse association between cloning efficiency and hprt do exist; furthermore, we verified the strong differential sex-specific effect on micronucleus frequencies.

The objective of this study was to examine if individuals living near a uranium processing site have greater mutagenic damage, as measured by three mutagenicity assays, compared with subjects unexposed to any nuclear facilities. The design was a cross-sectional exploratory analysis of 112 subjects; 56 volunteer residents were from within a 5-mile radius of the Fernald Uranium Processing site and 56 'control' subjects were from a geographically separate area unexposed to any known uranium emissions. The groups were constrained to be similar in age and sex composition. The main outcome measures were three human somatic gene mutation assays consisting of the HPRT T-lymphocyte cloning assay to measure 6-thioguanine resistant lymphocytes; the glycophorin A assay to detect the loss of expression of the M or N allele; and the micronucleus assay as a marker of chromosomal damage. The results showed no statistically significant or quantitatively important differences between groups for all three mutagenicity assays; only the unselected cloning efficiency was statistically significantly different between groups (0.42 +/- 0.16 for the Fernald versus 0.35 +/- 0.12 for the comparison groups). In both groups, age was significantly related to HPRT mutant frequency, with a 1.25% rate of increase in mutant frequencies for each 1-year gain of age in the Fernald group and a 1.12% rate of increase in mutant frequencies for each 1-year gain of age in the comparison group. For the micronucleus data, females had a greater mean micronucleus frequency than males. In addition, smokers had an increased mean ln (natural logarithm) HPRT mutant frequency (3.06 +/- 0.14 for current smokers compared with a mean of 2.72 +/- 0.05 for non-current (i.e. never plus former) smokers). Our results are consistent with the previously reported association between sex type and micronucleus frequency, the known relationship between age and T-lymphocyte cloning efficiency and age and HPRT mutant frequency, and verify the wide inter-subject variability for the latter. Finally, we conclude that at a population level, the relationships between current cigarette use and HPRT mutant frequency, and sex type and micronucleus frequency, are stronger than is the association between geographic proximity to a uranium processing site and mutagenic abnormalities.

Preoperative assessment of posttraumatic flexion contracture of the elbow includes plain radiographs and tomograms, which are difficult to obtain in the coronal plane due to the contracture. We conducted this study to determine the usefulness of MR imaging in the work-up of these patients. Twelve patients with flexion contracture of the elbow were studied. In addition to standard spin-echo sequences, a sagittally acquired spoiled gradient-recalled echo 3D data set of the flexed elbow was obtained and reformatted coronally using a curved plane of reconstruction. The MR findings were compared to the plain films, tomograms and surgical results. MRI allowed identification of loose bodies that were sometimes poorly visualized, or not seen, on plain films, and demonstrated degenerative changes equally as well as tomograms. MR showed soft tissue abnormalities including capsular and collateral ligament thickening. Curvilinear reconstructions were helpful in the assessment of collateral ligaments in patients with severe contractures. We conclude that MR is useful in the evaluation of elbow flexion contractures, particularly in assessing soft tissue causes.

A hyperventilation clinic was established specifically to deal with patients referred from the accident and emergency department with the hyperventilation syndrome. This was run by a staff nurse, who counselled the patients and taught abdominal breathing techniques and relaxation. In 30 patients so managed, 63% said their symptoms were much better or had completely gone and in only 6% was there no improvement; 43% had previously had more than one attendance at the A&E department, but following treatment only 2 patients represented during 5 months of follow up. The use of a nurse counsellor seems to be a simple and effective approach to managing these patients and considerably reduces both casualty and outpatient physician time.