Graft-implanted, enzyme responsive, tacrolimus-eluting hydrogel enables long-term survival of orthotopic porcine limb vascularized composite allografts: A proof of concept study.

BACKGROUND: Currently, patients receiving vascularized composite allotransplantation (VCA) grafts must take long-term systemic immunosuppressive therapy to prevent immunologic rejection. The morbidity and mortality associated with these medications is the single greatest barrier to more patients being able to receive these life-enhancing transplants. In contrast to solid organs, VCA, exemplified by hand or face transplants, allow visual diagnosis of clinical acute rejection (AR), directed biopsy and targeted graft therapies. Local immunosuppression in VCA could reduce systemic drug exposure and limit adverse effects. This proof of concept study evaluated, in a large animal forelimb VCA model, the efficacy and tolerability of a novel graft-implanted enzyme-responsive, tacrolimus (TAC)-eluting hydrogel platform, in achieving long-term graft survival. METHODS: Orthotopic forelimb VCA were performed in single haplotype mismatched mini-swine. Controls (n = 2) received no treatment. Two groups received TAC hydrogel: high dose (n = 4, 91 mg TAC) and low dose (n = 4, 49 mg TAC). The goal was to find a dose that was tolerable and resulted in long-term graft survival. Limbs were evaluated for clinical and histopathological signs of AR. TAC levels were measured in serial blood and skin tissue samples. Tolerability of the dose was evaluated by monitoring animal feeding behavior and weight. RESULTS: Control limbs underwent Banff Grade IV AR by post-operative day six. Low dose TAC hydrogel treatment resulted in long-term graft survival time to onset of Grade IV AR ranging from 56 days to 93 days. High dose TAC hydrogel also resulted in long-term graft survival (24 to 42 days), but was not well tolerated. CONCLUSION: Graft-implanted TAC-loaded hydrogel delays the onset of Grade IV AR of mismatched porcine forelimb VCA grafts, resulting in long term graft survival and demonstrates dose-dependent tolerability.

Composite Graft Pretreatment With Hydrogen Sulfide Delays the Onset of Acute Rejection.

INTRODUCTION: Vascularized composite allotransplantation can reconstruct devastating tissue loss by replacing like-with-like tissues, most commonly in the form of hand or face transplantation. Unresolved technical and ethical challenges have meant that such transplants remain experimental treatments. The most significant barrier to expansion of this field is the requirement for systemic immunosuppression, its toxicity and effect on longevity.Hydrogen sulfide (H2S) has been shown experimentally to ameliorate the ischemia reperfusion injury associated with composite tissue autotransplantation, which has been linked to acute rejection in solid organ transplantation. In this protocol, a large-animal model was used to evaluate the effect of H2S on acute rejection after composite tissue allotransplantation. MATERIALS AND METHODS: A musculocutaneous flap model in SLA-mismatched swine was used to evaluate acute rejection of allotransplants in 2 groups: control animals (n = 8) and a treatment group in which the allografts were pretreated with hydrogen sulfide (n = 8). Neither group was treated with systemic immunosuppression. Acute rejection was graded clinically and histopathologically by an independent, blinded pathologist. Data were analyzed by t tests with correction for multiple comparisons by the Holm-Sídák method. RESULTS: Clinically, H2S-treated tissue composites showed a delay in the onset of rejection that was statistically significant from postoperative day 6. Histopathologically, this difference between groups was also apparent, although evidence of a difference in groups disappeared beyond day 10. CONCLUSIONS: Targeted hydrogen sulfide treatment of vascularized composite allografts immediately before transplantation can delay acute rejection. This may, in turn, reduce or obviate the requirement for systemic immunosuppression.

A diagnostic evolution: surgical experience with popliteal artery entrapment syndrome at a military tertiary referral center.

BACKGROUND: Popliteal artery entrapment syndrome (PAES) is an increasingly encountered disorder that typically presents as claudication in young and active individuals. However, despite the increased recognition, accurate preoperative diagnosis can be difficult. The objective of this study was to describe the surgical assessment and outcomes of patients treated for PAES. METHODS: Retrospective case series of all patients managed surgically for a diagnosis of PAES at the San Antonio Military Medical Center from 2005 to 2013. RESULTS: Over 8 years, PAES was surgically treated in 25 consecutive limbs of 15 patients (mean age, 35; range, 21-49) in a military tertiary medical center. Type III was the most common variant (n = 13, 52%), followed by type VI (n = 7, 28%). Most patients presented with class I or II ischemia (88%), with anterolateral symptoms (56%), and were referred by orthopedics (66%). Diagnostic work-up included stress ankle-brachial indices, magnetic resonance imaging (MRI) and provocative angiography. Sixty-three percent of limbs with negative MRI demonstrated findings consistent with either type III or V PAES. Tendon release was used in those with types III and V, whereas liberal myectomy was used in those with types I, II, or VI. Two patients required revascularization. At a median follow-up of 126 days (range, 25 days-7 years), 83% of patients with type III demonstrated partial resolution of symptoms. Only 27% of patients without an identifiable muscle slip had clinical improvement. CONCLUSIONS: Despite modern imaging, open surgical exploration remains the definitive diagnostic modality for PAES. Patients with a muscular or tendinous slip identified intraoperatively have the best clinical outcomes. Those with no identifiable muscle slip (functional entrapment) are less likely to demonstrate clinical improvement. Further evaluation on outcomes in the management in PAES is warranted.

Mechanism of stent failure in a patient with fibromuscular dysplasia following renal artery stenting.

Endovascular techniques used in the management of renal artery stenosis (RAS) have unique complications, to include stent facture, thrombosis, aneurysm formation, migration, and in-stent restenosis. Described here is an unusual complication of renal artery obstruction and recurrent hypertension without progressive loss of renal function, secondary to intermittent arterial kinking with respiratory and cardiac motion in a patient with fibromuscular dysplasia. This mechanical complication has implication not only in successful endovascular treatment of RAS, but raises questions regarding the alterations in dynamic motion with the cardio-respiratory cycle in stented visceral arteries in other vascular pathologies requiring renal artery stenting (i.e., juxtarenal or pararenal aortic aneurysms).

Effect of biomass open burning on particulate matter and polycyclic aromatic hydrocarbon concentration levels and PAH dry deposition in ambient air.

The objectives of the present study were to investigate particulate matter (PM) and polycyclic aromatic hydrocarbon (PAH) concentrations in ambient air during rice straw open burning and non-open burning periods. In the ambient air of a rice field, the mean PM concentration during and after an open burning event were 1828 and 102 µg m⁻³, respectively, which demonstrates that during a rice field open burning event, the PM concentration in the ambient air of rice field is over 17 times higher than that of the non-open burning period. During an open burning event, the mean total PAH and total toxic equivalence (BaP(eq)) concentrations in the ambient air of a rice field were 7206 ng m⁻³ and 10.3 ng m⁻³, respectively, whereas after the open burning event, they were 376 ng m⁻³ and 1.50 ng m⁻³, respectively. Open burning thus increases total PAH and total BaP(eq) concentrations by 19-fold and 6.8-fold, respectively. During a rice straw open burning event, in the ambient air of a rice field, the mean dry deposition fluxes of total PAHs and total BaP(eq) were 1222 µg m⁻² day⁻¹ and 4.80 µg m⁻² day⁻¹, respectively, which are approximately 60- and 3-fold higher than those during the non-open burning period, respectively. During the non-open burning period, particle-bound PAHs contributed 79.2-84.2% of total dry deposition fluxes (gas + particle) of total PAHs. However, an open burning event increases the contribution to total PAH dry deposition by particle-bound PAHs by up to 85.9-95.5%. The results show that due to the increased amount of PM in the ambient air resulting from rice straw open burning, particle-bound PAHs contributed more to dry deposition fluxes of total PAHs than they do during non-open burning periods. The results show that biomass (rice straw) open burning is an important PAH emission source that significantly increases both PM and PAH concentration levels and PAH dry deposition in ambient air.

Contributions of dry and wet depositions of polychlorinated dibenzo-p-dioxins and dibenzofurans to a contaminated site resulting from a penetachlorophenol manufacturing process.

The soils at a factory for manufacturing pentachlorophenol were heavily contaminated by polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs). In order to verify the contributions of dry and wet deposition of PCDD/Fs from the ambient air, the concentration of PCDD/Fs in ambient air and soil were measured, the partition of particle- and gas-phases of atmospheric PCDD/Fs was calculated, and the annual fluxes of total dry and wet PCDD/F depositions were modeled. Average atmospheric PCDD/F concentration was 1.24 ng Nm(-3) (or 0.0397 ng I-TEQ Nm(-3)). Moreover, over 92.8% of total PCDD/Fs were in the particle phase, and the dominant species were high chlorinated congeners. The total PCDD/F fluxes of dry and wet deposition were 119.5 ng m(-2) year(-1) (1.34 ng I-TEQ m(-2) year(-1)) and 82.0 ng m(-2) year(-1) (1.07 ng I-TEQ m(-2) year(-1)), respectively. By scenario simulation, the total fluxes of dry and wet PCDD/F depositions were 87.1 and 68.6 ng I-TEQ, respectively. However, the estimated PCDD/F contents in the contaminated soil were 839.9 µ g I-TEQ. Hence, the contributions of total depositions of atmospheric PCDD/F were only 0.02%. The results indicated that the major sources of PCDD/F for the contaminated soil could be attributed to the pentachlorophenol manufacturing process.

Partition of polychlorinated dibenzo-p-dioxins and dibenzofurans distribution in water in both suspended solid and dissolved phases.

The contents of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) were measured in soil and water impacted by a chemical factory (chloralkali and pentachlorophenol) and both the PCDD/F contents in soil (14.4 mu g I-TEQ kg(-1)) and water (11.97 pg I-TEQ L(-1)) were heavily contaminated. Additionally, the PCDD/F distributions in the aquatic environment (suspended solid and dissolved phases) were investigated by performing a water tank experiment with 30 g of soil and 20 L of water. Moreover, the effects of PCDD/F distributions in water were estimated base on three soil sizes (26, 180 and 250 mu m). Analytical results indicated that the PCDD/F content in the suspended solid and dissolved phases was 2.19 mu g I-TEQ kg(-1) and 2.34 pg I-TEQ L(-1), respectively, or 85.11% and 14.89%, respectively. The PCDD/F distribution in the suspended solid phase was dominant, while its distribution was independent of soil size. Additionally, placing soil with a high PCDD/F content in water increased the PCDD/F content in suspended solid phase. Moreover, the equation developed in this study can accurately predict the PCDD/F partition between the suspended solid and dissolved phases.