Sex-Based Differences in Revascularization and 30-Day Readmission After ST-Segment-Elevation Myocardial Infarction in the United States.

BACKGROUND: Cardiovascular disease is the leading cause of death for women in the United States. Revascularization is considered the standard of care for treatment of ST-segment elevation myocardial infarction (STEMI) and is known to reduce readmission. However there is a paucity of data that examines the sex-dependent impact of revascularization on readmission. We aimed to investigate sex differences in revascularization rates, 30-day readmission rates, and primary cause of readmissions following STEMIs. METHODS: STEMI hospitalizations were selected in the Nationwide Readmissions Database from 2010 to 2014. Revascularization rates, 30-day readmission rates, and primary cause of readmission were examined. Interaction between sex and revascularization was assessed. Multivariable regression analysis was performed to identify predictors of 30-day readmission and revascularization for both sexes. RESULTS: 219,944 women and 489,605 men were admitted with STEMIs. Women were more likely to be older, and have more comorbidities. Women were less likely to undergo revascularization by percutaneous coronary intervention (adjusted odds ratio [OR]: 0.68; 95% confidence interval [CI]: 0.66-0.70) or coronary artery bypass graft surgery (adjusted OR 0.40; CI 0.39-0.44). Women had higher 30-day readmission rates (15.7% vs. 10.8%, p < 0.001; OR 1.20, CI 1.17-1.23), and revascularization in women was not associated with a decreased likelihood of 30-day readmission. The primary cardiac cause of readmission in women was heart failure. CONCLUSION: Compared to men, women with STEMIs had lower rates of revascularization and higher rates of 30-day readmission. When revascularized, women were still more likely to be readmitted as compared to non-revascularized women.

Metabolic biomarkers, body condition, uterine inflammation and response to superovulation in lactating Holstein cows.

The objective was to determine associations between response to superovulation and body condition, subclinical endometritis and circulating metabolic biomarkers [adiponectin, leptin, insulin, IGF1, tumor necrosis factor (TNF) α, interleukin (IL) 1ß, IL6, and urea] in lactating dairy cows. Ten multiparous lactating Holstein cows in each body condition score (1-5; 1 emaciated; 5 obese) category (BCSC) 2.00 to < 2.50 (BCSC1), 2.50 to < 3.00 (BCSC2), 3.00 to <3.50 (BCSC3), 3.50 to <4.00 (BCSC4) and 4.00 to 5.00 (BCSC5) groups (total n = 50) were randomly selected and superovulated, timed artificially inseminated with frozen-thawed semen from three sires and embryos collected (n = 50 collections). At embryo collection, blood samples and embryo recovery fluid were collected for determination of metabolic markers and presence of subclinical endometritis (lavage technique; > 6% PMN). In total, 379 embryos were collected (average of 7.6 embryos per superovulation). Mean numbers of total ova and embryos was greater for cows in BCSC2, BCSC3 and BCSC4 groups compared with cows in BCSC1 and BCSC5 groups (P < 0.01). Total number of transferrable embryos were greater for cows in BCSC 2 and BCSC3 groups compared with cows in BCSC1, BCSC4 and BCSC5 groups (P < 0.01). Mean number of total ova and embryos and of transferrable embryos was higher for cows with 0 or 1-6% PMN compared to cows with >6% PMN (P < 0.01). In addition, there was a quadratic association between blood urea nitrogen concentrations and % transferrable embryos (r2 = 0.85; P < 0.05) and between BCS and % transferrable embryos (r2 = 0.73; P < 0.05). Circulating adiponectin, leptin, insulin, IGF1 and TNFα were greater in cows with moderate to good body condition compared to thin or obese cows (P < 0.05). Circulating adiponectin, leptin, IGF1 and insulin were greater in normal cows (≤6% PMNs), whereas, TNFα and IL1ß and IL6 were greater in cows with subclinical endometritis (P < 0.05). In conclusion, BCS and subclinical endometrial inflammation were associated with superovulatory response and embryo quality. Further, circulating metabolic biomarkers were associated with superovulatory response and embryo quality, likely due to donor's metabolic status and uterine environment. Optimizing superovulatory responses and embryo quality in lactating dairy cows requires management of nutrition and uterine health.

Feasibility study of combined dynamic imaging and lymphaticovenous anastomosis surgery for breast cancer-related lymphoedema.

BACKGROUND: Breast cancer-related lymphoedema (BCRL) presents a significant healthcare burden and adversely affects quality of life of breast cancer survivors. A prospective feasibility study was performed on lymphaticovenous anastomosis (LVA) for the treatment of BCRL. METHODS: Patients with BCRL underwent near-infrared spectroscopy with indocyanine green lymphatic mapping to identify suitable lymphatic channels for LVA. End-to-end anastomoses to subdermal venules were performed and patients recommenced compression garment therapy (CGT) after surgery. Volumetric assessment of the affected limb was performed at regular intervals using infrared perometry to calculate the excess volume reduction. RESULTS: Over a 24-month interval, 27 patients with BCRL underwent LVA. The mean duration of lymphoedema was 3·5 (range 0·5-18) years, and the mean number of LVAs performed was 3 (range 2-5). Twenty-four of the 27 patients completed 12-month follow-up. Patients exhibited three patterns of volumetric response following LVA: sustained response (16 patients), transient response (5) or no response (6). Sustained responders showed an excess volume reduction of -33·2 per cent at 12 months, and this correlated positively with the number of LVAs performed (r = -0·56, P = 0·034). Overall, ten patients were able to downgrade CGT after surgery, and two patients were CGT-free at 12 months. CONCLUSION: LVA resulted in a sustained volume reduction in selected patients and may offset the burden of CGT. Further work is required to identify biomarkers that predict a favourable response to LVA surgery.

An atypical presentation of ACAD9 deficiency: Diagnosis by whole exome sequencing broadens the phenotypic spectrum and alters treatment approach.

Acyl-CoA dehydrogenase 9 (ACAD9), linked to chromosome 3q21.3, is one of a family of multimeric mitochondrial flavoenzymes that catalyze the degradation of fatty acyl-CoA from the carnitine shuttle via ß-oxidation (He et al. 2007). ACAD9, specifically, is implicated in the processing of palmitoyl-CoA and long-chain unsaturated substrates, but unlike other acyl-CoA dehydrogenases (ACADs), it has a significant role in mitochondrial complex I assembly (Nouws et al. 2010 & 2014). Mutations in this enzyme typically cause mitochondrial complex I deficiency, as well as a mild defect in long chain fatty acid metabolism (Haack et al. 2010, Kirby et al. 2004, Mcfarland et al. 2003, Nouws et al. 2010 & 2014). The clinical phenotype of ACAD9 deficiency and the associated mitochondrial complex I deficiency reflect this unique duality, and symptoms are variable in severity and onset. Patients classically present with cardiac dysfunction due to hypertrophic cardiomyopathy. Other common features include Leigh syndrome, macrocephaly, and liver disease (Robinson et al. 1998). We report the case of an 11-month old girl presenting with microcephaly, dystonia, and lactic acidosis, concerning for a mitochondrial disorder, but atypical for ACAD9 deficiency. Muscle biopsy showed mitochondrial proliferation, but normal mitochondrial complex I activity. The diagnosis of ACAD9 deficiency was not initially considered, due both to these findings and to her atypical presentation. Biochemical assay for ACAD9 deficiency is not clinically available. Family trio-based whole exome sequencing (WES) identified 2 compound heterozygous mutations in the ACAD9 gene. This discovery led to optimized treatment of her mitochondrial dysfunction, and supplementation with riboflavin, resulting in clinical improvement. There have been fewer than 25 reported cases of ACAD9 deficiency in the literature to date. We review these and compare them to the unique features of our patient. ACAD9 deficiency should be considered in the differential diagnosis of patients with lactic acidosis, seizures, and other symptoms of mitochondrial disease, including those with normal mitochondrial enzyme activities. This case demonstrates the utility of WES, in conjunction with biochemical testing, for the appropriate diagnosis and treatment of disorders of energy metabolism.

The Association between the History of HIV Diagnosis and Oral Health.

Unmet oral care needs are high among people living with human immunodeficiency virus (HIV)/AIDS (PLWH). Oral health care is of increasing importance as life expectancy is being prolonged extensively among PLWH. The benefit of oral health care in relation to time since HIV diagnosis has not previously been assessed. A retrospective multivariable analysis of the Special Project of National Significance Oral Health Initiative observational cohort study ( N = 2,178) was performed to estimate the odds ratios (ORs) of oral health outcomes comparing historically diagnosed subjects (>1 y since HIV diagnosis) to newly diagnosed subjects (≤1 y since HIV diagnosis). ORs were adjusted for age, study site, language, income, last dental care visit, and dental insurance. Historically diagnosed subjects were more likely to report oral problems than newly HIV-diagnosed subjects (OR, 2.10). Historically diagnosed subjects were more likely to require oral surgery (OR, 1.52), restorative treatment (OR, 1.35), endodontic treatment (OR, 1.63), and more than 10 oral clinic visits over the 24-mo study period (OR, 2.02). The crude cumulative 2-y risk of requiring prosthetic (risk difference [RD], 0.21) and endodontic (RD, 0.11) treatment was higher among historically than newly diagnosed subjects, despite no significance postadjustment. Furthermore, poor oral health outcomes were exacerbated among non-highly active antiretroviral therapy users. Summarizing, the authors found that historically diagnosed subjects were more likely to report oral problems and require dental procedures compared with newly diagnosed subjects, suggesting that oral health among PLWH declines over time since HIV diagnosis. Hence, newly diagnosed PLWH may benefit from the implementation of early oral interventions.

Impact of periodontal intervention on local inflammation, periodontitis, and HIV outcomes.

OBJECTIVE: The aim of this study was to determine active periodontal disease status in HIV and to determine the impact of periodontal disease resolution on HIV status. METHODS: In this longitudinal cohort study, 73 HIV-positive subjects received comprehensive dental care. AAP, CDC/AAP, and BGI case definitions determined periodontal classification. Likelihood and frequency of moderate/severe periodontal disease were assessed based on demographic variables. The influence of periodontal intervention was assessed at baseline, 12, and 24 months. IL-6 was measured in a subset of subjects. RESULTS: Of the periodontal classifications, BGI demonstrated the highest percentage category improvement with the intervention (>50%). Moderate/severe periodontitis was positively associated with HIV regardless of race, smoking status, gender, income level, and age, and was associated with increased IL-6. At baseline, the majority of subjects had severe periodontal disease regardless of ART status. Subjects with suppressed viral load at baseline demonstrated a significant improvement in BGI classification (P = 0.026), increased CD4 counts (P = 0.027), and decreased IL-6 levels (P = 0.03). CONCLUSIONS: Periodontal inflammation was prevalent regardless of ART status. In virologically suppressed subjects, the intervention decreased periodontitis with a concomitant IL-6 decrease and CD4 increase. These findings suggest a relationship between periodontal inflammation, oral microbial translocation, and HIV status.

The role of galectin-3 and galectin-3-binding protein in venous thrombosis.

Galectin-3-binding protein (gal3bp) and its receptor/ligand, galectin-3 (gal3), are secreted proteins that initiate signaling cascades in several diseases, and recent human proteomic data suggest they may play a role in venous thrombosis (VT). We hypothesized that gal3bp and gal3 may promote VT. Using a mouse stasis model of VT, we found that gal3bp and gal3 were localized on vein wall, red blood cells, platelets, and microparticles, whereas leukocytes expressed gal3 only. Gal3 was dramatically increased during early VT and gal3bp:gal3 colocalized in the leukocyte/endothelial cell interface, where leukocytes were partially attached to the vein wall. Thrombus size correlated with elevated gal3 and interleukin-6 (IL-6) vein wall levels. Recombinant gal3 promoted VT and increased vein wall IL-6 mRNA. Although recombinant gal3 restored the VT size in gal3(-/-) mice, it had no effect on IL6(-/-) mice, suggesting that gal3:gal3bp promotes VT through IL-6. Moreover, significantly fewer activated neutrophils were present in the gal3(-/-) vein walls. In a group of human patients, elevated circulating gal3bp correlated with acute VT. In conclusion, gal3bp:gal3 play a critical role in VT, likely via IL-6 and PMN-mediated thrombotic mechanisms, and may be a potential biomarker in human VT.

Lifestyle and health factors associated with progressing and remitting trajectories of untreated lower urinary tract symptoms among elderly men.

BACKGROUND: Knowledge of factors associated with the course of lower urinary tract symptoms (LUTS) before treatment is needed to inform preventive interventions. In a prospective study of elderly men untreated for LUTS, we identified factors associated with symptom progression and remission. METHODS: In community-dwelling US men aged ≥65 years, the American Urological Association Symptom Index (AUA-SI) was repeated four times, once at baseline (2000-2002) and then every 2 years thereafter. Analyses included 1740 men with all four AUA-SI assessments, who remained free from diagnosed prostate cancer, and who reported no treatment for LUTS or BPH during follow-up that averaged 6.9 (±0.4) years. LUTS change was determined with group-based trajectory modelingof the repeated AUA-SI measures. Multivariable logistic regression was then used to determine the baseline factors associated with progressing compared with stable trajectories, and with remitting compared with progressing trajectories. Lifestyle, body mass index (BMI) (kg/m(2)), mobility, mental health (Short-Form 12), medical history and prescription medications were considered for selection. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for variables in each model. RESULTS: We identified 10 AUA-SI trajectories: 4 stable (1277 men, 73%), three progressing (345 men, 20%), two remitting (98 men, 6%) and one mixed (20 men, 1%). Men in progressing compared with stable trajectories were more likely to have mobility limitations (OR=2.0, 95% CI: 1.0-3.8), poor mental health (OR=1.9, 95% CI: 1.1-3.4), BMI≥25.0 kg m(-2) (OR=1.7, 95% CI: 1.0-2.8), hypertension (OR=1.5, 95% CI: 1.0-2.4) and back pain (OR=1.5, 95% CI: 1.0-2.4). Men in remitting compared with progressing trajectories more often used central nervous system medications (OR=2.3, 95% CI: 1.1-4.9) and less often had a history of problem drinking (OR=0.4, 95% CI: 0.2-0.9). CONCLUSIONS: Several non-urological lifestyle and health factors were independently associated with risk of LUTS progression in older men.

Gliosarcoma metastatic to the leptomeninges and dura.

We describe a rare case of a patient with left frontotemporal gliosarcoma, which metastasized through the cerebrospinal fluid (CSF) to the leptomeninges and pachymeninges. Pathologically confirmed, magnetic resonance imaging-visible leptomeningeal spread of gliosarcoma via the CSF has not been previously reported.

[Principles of revascularization in treatment of giant intracranial aneurysms].

During recent decades extra-intracranial and intra-intracranial bypasses have deserved high interest among neurosurgeon, especially in management of giant cerebral aneurysms. Development of microsurgery and neuroanesthesiological techniques, advances in neuroradiology and neurophysiology prerequisite improvement of revascularization surgery. Evolution of competitive endovascular methods pushes the surgeons to improve microneurosurgical technique of revascularization and elaboration of new approaches to management of intracranial aneurysms. In this review we discuss principles of surgery of cerebrovascular bypasses in management of giant aneurysms applied in our clinic.

Facial augmentation with core fat graft: a preliminary report.

BACKGROUND: Facial rejuvenation with autologous fat has the advantage of replacing or augmenting tissue with like tissue. The results of injected fat are unpredictable because of cellular trauma and other factors. Excised whole or en bloc fat grafting has been shown experimentally to have a greater percentage of adipocyte survival when compared with blunt cannula delivery techniques. En bloc grafting, however, requires an incision for the harvesting and placement of the fat graft with visible scars. A novel, less traumatic cylinder core fat harvest and delivery technique for facial augmentation with minimal incisional access is reported here. METHODS: Twenty-six facial augmentation procedures were performed involving the malar area, buccal area, lips, nasolabial folds, and mental region. Fat transfer volume ranged between 1 and 4 cc per site. In this report, 16 patients' results were documented 6 to 16 months postoperatively (mean follow-up time, 9.5 months) with a postoperative questionnaire and photographs. RESULTS: Social recovery for patients was short, with a recovery time of 2 to 20 days (mean, 10.91 days). There were no procedure-related complications at the fat harvest or recipient graft sites. The need for overcorrection was minimal. Graft maintenance during the average follow-up at 9.5 months appeared excellent and without appreciable volume loss. The mean patient satisfaction score was 7.64 +/- 2.97 on a scale of 0 to 10. CONCLUSIONS: The authors' preliminary results have demonstrated that this technique is effective and highly predictable. The surgical time was short, and patient recovery time has been significantly reduced compared with recovery time after other fat injection techniques.

CD8+ T cell-mediated control of distant tumours following local photodynamic therapy is independent of CD4+ T cells and dependent on natural killer cells.

Cancer survival rates decrease in the presence of disseminated disease. However, there are few therapies that are effective at eliminating the primary tumour while providing control of distant stage disease. Photodynamic therapy (PDT) is an FDA-approved modality that rapidly eliminates local tumours, resulting in cure of early disease and palliation of advanced disease. Numerous pre-clinical studies have shown that local PDT treatment of tumours enhances anti-tumour immunity. We hypothesised that enhancement of a systemic anti-tumour immune response might control the growth of tumours present outside the treatment field. To test this hypothesis we delivered PDT to subcutaneous (s.c.) tumours of mice bearing both s.c. and lung tumours and monitored the growth of the untreated lung tumours. Our results demonstrate that PDT of murine tumours provided durable inhibition of the growth of untreated lung tumours. The inhibition of the growth of tumours outside the treatment field was tumour-specific and dependent on the presence of CD8(+) T cells. This inhibition was accompanied by an increase in splenic anti-tumour cytolytic activity and by an increase in CD8(+) T cell infiltration into untreated tumours. Local PDT treatment led to enhanced anti-tumour immune memory that was evident 40 days after tumour treatment and was independent of CD4(+) T cells. CD8(+) T cell control of the growth of lung tumours present outside the treatment field following PDT was dependent upon the presence of natural killer (NK) cells. These results suggest that local PDT treatment of tumours lead to induction of an anti-tumour immune response capable of controlling the growth of tumours outside the treatment field and indicate that this modality has potential in the treatment of distant stage disease.

Follicular anatomy of the anterior temporal hairline and implications for rhytidectomy.

BACKGROUND: Incisions made perpendicular to the hair follicles during anterior frontal hairline brow lifts or forehead shortening procedures help produce an inconspicuous forehead scar. The success of this "hidden" incision relies on the anteriorly directed frontal hairline follicles and their growth vector. The authors hypothesized that a similar incision could be made perpendicular to the hair follicles in the temple region during rhytidectomy. A well-designed anterior hairline beveled incision over the temple would allow for improved leverage during soft-tissue repositioning and a concealed hairline incision in the temple region. METHODS: Anterior temporal hairline strips 4 cm in length at the level of the lateral canthus were excised from 16 fresh cadavers. Hairline follicles (n = 227) were assessed for direction and angle of growth after appropriate tissue preparation and staining (hematoxylin and eosin). The hair follicle angle was analyzed microscopically as it approached the epidermis. RESULTS: The anterior temporal hairline follicles were oriented at a mean angle with the epidermis of 16 +/- 3 degrees anteriorly and inferiorly. CONCLUSIONS: The anterior temporal hairline follicles of the scalp are oriented anteriorly and inferiorly with the epidermis, providing the surgical rational for using a beveled hairline incision angled 30 to 45 degrees to the external skin surface to undercut the distal flap. This incision is perpendicular to and transects the temporal hair follicles during rhytidectomy, permitting hair growth through and anterior to the scar. This modified anterior temporal hairline incision reduces visibility of the scar at the hairline for patients in whom scar show and hairstyle versatility are important concerns.

Electrically stimulated rectus abdominis muscle flap to achieve enterostomal continence: development of a functional canine model.

BACKGROUND: Dynamic myoplasty has many clinical applications and has proven to be a versatile surgical procedure with great promise. This procedure has been used to achieve fecal/urinary continence, as in the dynamic graciloplasty, and to augment cardiac ventricular function, as is commonly seen with dynamic latissimus cardiomyoplasty. In the present study, the authors describe a functional innovative island flap sphincter created from the rectus abdominis muscle in a large-animal model to provide stomal continence for future clinical studies. METHODS: The caudal region of the rectus abdominis muscle in eight mongrel canines (23 to 25 kg) was investigated through anatomical dissections during which the location of the neurovascular pedicles and the intersegmental muscle dimensions between the muscle inscriptions were noted. The rectus abdominis muscle was used to create functional dynamic stomal sphincters that were trained with subcutaneously implanted pulse stimulators. RESULTS: The neurovascular pedicles were consistently found in similar locations along the posterior medial aspect of the caudal portion of the canine's rectus abdominis muscle. The vertical height of the deep inferior epigastric pedicle and caudal intercostal nerve muscular mean entry points were 6.75 +/- 1.89 cm and 7.44 +/- 0.86 cm, respectively. The mean caudal intersegmental muscle length of the rectus abdominis muscle used to create the sphincter was 9.69 +/- 1.81 cm. CONCLUSIONS: The canine rectus abdominis muscle has reliable anatomical locations where the neurovascular pedicle may be found. This canine muscle may be used to create a continent island flap stomal sphincter. This large-animal sphincter model is versatile, durable, and easy to manipulate, with minimal morbidity to the animal.

Investigation of risk acceptance in hand transplantation.

PURPOSE: Twenty-four hands have been transplanted in 18 individuals and clinicians continue to debate whether the risks justify the benefits in these procedures. To assess quantitatively the risks versus benefits in hand transplantation we used a validated instrument (Louisville Instrument for Transplantation) to measure the degree of risk individuals are willing to accept to receive different types of transplantation procedures. METHODS: The Louisville Instrument for Transplantation contains 237 standardized questions that incorporate modified standard gamble and time trade-off outcome measures and questions that assess body image perception, depression, self-esteem, optimism, socially desirable responding, and demographics. Respondents were questioned on the extent to which they would trade off specific numbers of life-years or sustain other costs in exchange for receiving 7 different transplantation procedures. For this study we questioned 227 individuals in 4 study populations with differing life experiences: healthy individuals, organ transplant recipients, upper-extremity amputee patients, and lower-extremity amputee patients. RESULTS: All populations questioned perceived risk similarly despite their differing life experiences and would accept differing degrees of risk for the different transplantation procedures. Organ transplant recipients were the most risk-tolerant group whereas upper-extremity amputee patients were the most risk adverse, even when considering a single hand transplant. All groups that were questioned would accept a higher degree of risk to receive a double versus a single hand transplant. CONCLUSIONS: By questioning individuals who have experienced directly the risks of immunosuppression and those who could benefit from hand transplantation, this study presents an empiric basis for assessing risk versus benefit in this procedure.

Massive lower gastrointestinal bleeding after rejection of pancreatic transplants.

BACKGROUND: This article highlights two cases of massive lower gastrointestinal bleeding in patients on dialysis after rejection of kidney-pancreas transplants. Patient 1 was a 34-year-old female with 27 years of type I diabetes, who had a kidney-pancreas transplant in 1996, which was complicated by rejection of the kidney and pancreas in 2000 and 2002, respectively. Later in 2002, she presented in shock after experiencing cramping abdominal pain and passage of large bloody stools. Patient 2 was a 38-year-old male with 26 years of type I diabetes, who had a pancreas-kidney transplant in 1998, which was complicated by rejection of the kidney and pancreas in early 2003. He presented in late 2003 with a single episode of coffee-ground emesis and two episodes of brisk hematochezia. INVESTIGATION: Arterial angiography. DIAGNOSIS: Pseudoaneurysm and small-bowel fistula from the arterial supply to the transplanted pancreas. MANAGEMENT: Angiographic embolization of the aneurysmal vessel and fistula achieved hemostasis. Patient 1 did not have her transplanted organ surgically removed and suffered a recurrent massive lower gastrointestinal bleed that proved fatal. In Patient 2, subsequent surgery and removal of the rejected pancreas was performed and the patient continues to do well.

Bone quality and healing in a swine vascularized bone allotransplantation model using cyclosporine-based immunosuppression therapy.

Although vascularized bone and joint allotransplantation is a promising new treatment option for reconstructing large bone defects, the need for immunosuppressive agents to prevent rejection in these procedures poses a major problem. This problem stems from the fact that several of these agents can cause harmful side effects, such as alterations in bone quality and healing. Therefore, the purpose of this study was to determine what effect the commonly used immunosuppressant regimen cyclosporine A-based combination therapy has on bone quality and healing. In 10 pigs, vascularized bone allografts with skin and muscle components (osteomyocutaneous free flaps) were transplanted from size-matched donor animals. Recipient animals received oral cyclosporine A/mycophenolate mofetil/prednisone therapy for 90 days. Bone quality was studied before and after transplantation by measuring the bone's acoustic velocity and density and calculating the bone's elastic coefficient. Bone healing was assessed using radiographic analysis. Four animals were lost as a result of graft rejection or immunosuppression-related complications before the 90-day endpoint of the study. Although bone specimens taken from the six animals that completed the 90-day protocol had histological signs of rejection, they all seemed to have normal bone healing. Posttransplant bone density values were significantly decreased (p < 0.05) (1544.7 +/- 47.5 kg/m3) as compared with pretransplant values (1722.7 +/- 44.1 kg/m3). Results of the acoustic velocity and elastic coefficients measurements showed a significant decrease (p < 0.05) in posttransplant values (from 3503.0 +/- 165.1 meters/sec to 2963.0 +/- 54.6 meters/sec and from 21.6 +/- 2.2 GPa to 13.6 +/- 0.5 GPa, respectively), indicating diminished bone quality. The findings indicate that cyclosporine A/mycophenolate mofetil/prednisone combination therapy is ineffective in preventing bone rejection, that it decreases bone quality, and that it is associated with systemic toxicity, suggesting that this immunosuppressive regimen at the doses used in this study is not ideal for vascularized bone allotransplantation procedures.

Composite tissue allotransplantation in chimeric hosts: part I. Prevention of graft-versus-host disease.

BACKGROUND: Mixed allogeneic chimerism (MAC) has been shown to induce tolerance to composite tissue allografts (CTA). However, transplantation of unmanipulated donor-specific limbs results in severe graft-versus-host disease (GVHD). This suggests that nontolerant mature donor-derived cells in the CTA may affect the stability of chimerism, potentially resulting in GVHD. The aim of this study was to develop an approach to study and prevent GVHD in a mixed chimeric-rat hind-limb transplantation model. METHODS: [ACI-->WF] chimeras received a limb from Wistar Furth (WF) (syngeneic), Fisher (third-party), or ACI (irradiated [1,050 cGy] or nonirradiated) rats. In vitro tolerance was assessed using mixed lymphocyte reactivity (MLR) assays at the time the animals were killed. RESULTS: [ACI-->WF] chimeras with greater than 85% chimerism exhibited rejection-free survival of donor-specific hind limbs. However, 100% of these animals developed lethal GVHD 22.4+/-2.8 days after limb transplantation. [ACI-->WF] chimeras that underwent transplantation with irradiated ACI or syngeneic WF limbs showed no signs of rejection or GVHD at 5 months. Nonchimeric and third-party controls rejected limbs within 10 days. CONCLUSIONS: Conditioning of the host WF rats with 950 cGy of irradiation (sublethal, myeloablative) led to high levels of MAC without GVHD. The mature T-cell content of nonirradiated donor (ACI) limbs was sufficient to induce lethal GVHD in 100% of tolerant mixed chimeric [ACI-->WF] hosts. Irradiation of donor limbs before transplantation resulted in long-term donor-specific tolerance and prevented GVHD. These data demonstrate that (1) established chimeras could be susceptible to GVHD caused by immunocompetent donor cells transferred with the hind limb, and (2) inactivating these cells with irradiation prevents GVHD and destabilization of chimerism, and permits rejection-free graft acceptance.