Managing junctional haemorrhage in the combat environment.

Tactical combat casualty care and the application of extremity tourniquets have saved lives in combat. In the modern combat environment junctional injuries are common and difficult to treat. Recently, junctional tourniquets have emerged as a potential solution to this problem. Junctional tourniquets can be used as an adjunct to persistent haemorrhage despite application of conventional tourniquets or in the persistently hypotensive casualty. Surgeons must have an approach to receiving patients with junctional tourniquets in place in the operating room. The algorithms presented allow for an evidence-based and command-driven implantation of junctional tourniquets as part of tactical combat casualty care.

The future of resuscitative endovascular balloon occlusion in combat operations.

Damage control resuscitation and early thoracotomy have been used to increase survival after severe injury in combat. There has been a renewed interest in resuscitative endovascular balloon occlusion of the aorta (REBOA) in both civilian and military medical practices. REBOA may result in visceral and limb ischaemia that could be harmful if use of REBOA is premature or prolonged. The purpose of this paper is to align our experience of combat injuries with the known capability of REBOA to suggest an implementation strategy for the use of REBOA in combat care. It may replace the resuscitative effect of thoracotomy; can provide haemostasis of non-compressible torso injuries such as the junctional and pelvic haemorrhage caused by improvised explosive devices. However, prehospital use of REBOA must be in the context of an overall surgical plan and should be restricted to deployment in the distal aorta. Although REBOA is technically easier than a thoracotomy, it requires operator training and skill to add to the beneficial effect of damage control resuscitation and surgery.

Treatment of rectal war wounds.

Treatment strategies for penetrating rectal injuries (PRI) in civilian settings are still not uniformly agreed, in part since high-energy transfer PRI, such as is frequently seen in military settings, are not taken into account. Here, we describe three cases of PRI, treated in a deployed combat environment, and outline the management strategies successfully employed. We also discuss the literature regarding PRI management. Where there is a major soft tissue component, repetitive debridement and vacuum therapy is useful. A loop or end colostomy should be used, depending on the degree of damage to the anal sphincter complex.

Scarpa's fascia and clinical signs: the role of the membranous superficial fascia in the eponymous clinical signs of retroperitoneal catastrophe.

INTRODUCTION: The membranous superficial fascia (MSF) was described early in the 19th century, as was its role in the clinical sign of urethral disruption. Clinical signs of haemorrhage or leakage of pancreatic and biliary fluid into the retroperitoneum, which were described throughout the 20th century, all relied on circumscribed discolouration of the skin of the torso. The objective of this study was to relate the anatomy of the MSF to clinical signs of retroperitoneal catastrophe. METHODS: The MSF was dissected in the torso of seven embalmed cadavers to note its extent and its attachments. The attachments of the MSF were mapped to the areas of skin discolouration that are described in the clinical signs. RESULTS: The well known extent of the MSF in the inguinal region, its continuation into the perineum and its attachment to the fascia lata of the thigh were confirmed with our method of dissection. Dissection was continued superiorly, demonstrating continuation of the MSF over the entire torso with loose fibrous attachment of the MSF to the deep fascia. The MSF is firmly adherent to the midline of the abdomen except for the umbilicus, to a horizontal line below the clavicles and laterally in the abdomen to form pockets. The lines of firm adhesion correspond with the borders of the discoloured areas described in the clinical signs. CONCLUSIONS: Circumscription of discolouration seen in the eponymous clinical signs of retroperitoneal catastrophe is explained by confinement of coloured retroperitoneal fluid by the MSF and its deep attachments.

Absence of the genicular arterial anastomosis as generally depicted in textbooks.

INTRODUCTION: Textbook representations of the genicular arterial anastomosis show a large direct communication between the descending branch of the lateral circumflex femoral artery (DBLCFA) and a genicular branch of the popliteal artery but this is not compatible with clinical experience. The aim of this study was to determine whether the arterial anastomosis at the knee is sufficient, in the event of traumatic disruption of the superficial femoral artery, to infuse protective agents or to place a stent to restore flow to the lower leg. METHODS: Dissection of ten cadaveric lower limbs was performed to photograph the arterial anatomy from the inguinal ligament to the tibial tubercle. Anastomosis with branches of the popliteal artery was classified as: 'direct communication', 'approaching communication' or 'no evident communication'. RESULTS: A constant descending artery in the lateral thigh (LDAT) was found to have five types of origin: Type 1 (2/10 limbs) involved the lateral circumflex femoral branch of the femoral artery, Type 2 (3/10 limbs) the lateral circumflex femoral branch of the profunda femoris artery, Type 3 (1/10 limbs) the femoral artery, Type 4 (3/10 limbs) the superficial femoral artery and Type 5 (2/10 limbs) the profunda femoris artery. In one limb, there were two descending arteries (Types 4 and 5). Collateral circulation at the knee was also variable: direct communicating vessels (3/10 limbs); approaching vessels with possible communication via capillaries (5/10 limbs); no evident communication (2/10 limbs). Communicating vessels, if present, are too small to provide immediate collateral circulation. CONCLUSIONS: Modern representations of the genicular arterial anastomosis are inaccurate, derived commonly from an idealised image that first appeared Gray's Anatomy in 1910. The afferent vessel is not the DBLCFA. The majority of subjects have the potential to recruit collateral circulation via the LDAT following gradual obstruction to normal arterial flow, which may be important if the LDAT is removed for bypass or flap surgery. A direct communication is rarely present and is never as robust as generally depicted in textbooks.

Management of devastating ocular trauma--experience of maxillofacial surgeons deployed to a forward field hospital.

Combat-related eye injuries continue to increase in frequency and are generally secondary to Improvised Explosive Devices. Many ocular injuries are potentially preventable by the wearing of ballistic eye protection. The management of penetrating eye trauma is normally outside the routine practice of maxillofacial surgeons in the UK. The aim of this paper is to describe the surgical techniques used in the modern management of devastating ocular trauma including selected case examples managed by British military maxillofacial surgeons deployed to Afghanistan.

Recombinant activated factor VII in the treatment of non-haemophilia patients: physician under-reporting of thromboembolic adverse events.

The objective of this study was to determine if clinically important thromboembolic adverse events (TAEs) because of recombinant activated factor VII (rFVIIa) administration are being under-reported. rFVIIa is a potent haemostatic agent with a short half-life of 2.6 h that is increasingly used in 'off-label' situations. Retrospective review of 94 patients who received rFVIIa during 1 January 2003 to 30 June 2007 was carried out at a tertiary care centre. Sixty-nine patients, 32 females and 37 males, mean age 55 years (18-84 years), satisfied study criteria of off-label usage. This was a high-risk population with 33 (48%) deaths. A mean dose of 8.2 mg (2.4-19.2 mg) was administered in two average divided doses. Thirty-six potential TAEs were identified in 29 patients, and of these, 12 patients had TAEs deemed to be rFVIIa related and were identified on average 8.8 days after exposure to rFVIIa. Forty-eight (70%) physician questionnaires were completed; however, no TAEs were reported in these questionnaires or on chart review. Potential clinically significant TAEs are being under-reported by treating physicians. Until further evidence, we suggest the urgent need to develop consensus recommendations for utilization and required follow up to monitor the safety of rFVIIa and that at a minimum, all use of rFVIIa should be regulated through a gate-keeping mechanism that ensures adherence to these policies. Furthermore, prospective registries and trials are necessary to evaluate the efficacy and safety of rFVIIa in off-label settings.

Cholecystectomy deferral in patients with endoscopic sphincterotomy.

BACKGROUND: Cholecystectomy is not required in up to 64% of patients who adopt a wait-and-see policy after endoscopic clearance of common bile duct stones. Although reports of retrospective cohort series have shown a higher mortality among patients who defer cholecystectomy, it is not known if this is due to the patients' premorbid health status or due to the deferral of cholecystectomy. Randomised clinical trials of prophylactic cholecystectomy versus wait-and-see have not had sufficient power to demonstrate differences in survival. OBJECTIVES: To evaluate the beneficial and harmful effects of cholecystectomy deferral (wait-and-see) versus elective (prophylactic) cholecystectomy in patients who have had an endoscopic biliary sphincterotomy. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Controlled Trials Register (CENTRAL) in The Cochrane Library, MEDLINE (1966 to 2007), EMBASE (1980 to 2007), and Science Citation Index Expanded without language restrictions until April 2007. SELECTION CRITERIA: Randomised clinical trials comparing patients whose gallbladder was left in-situ after endoscopic sphincterotomy (wait-and-see group) versus patients who had cholecystectomy with either endoscopic sphincterotomy or common bile duct exploration (prophylactic cholecystectomy group), irrespective of blinding, language, or publication status. DATA COLLECTION AND ANALYSIS: We assessed the impact of a wait-and-see policy on mortality. Secondary outcomes assessed were the incidence of biliary pain, cholangitis, pancreatitis, need for cholangiography, need for cholecystectomy, and the rate of difficult cholecystectomy. We pooled data using relative risk with fixed-effect and random-effects models. MAIN RESULTS: We included 5 randomised trials with 662 participants out of 93 publications identified through the literature searches. The number of deaths was 47 in the wait-and-see group (334 patients) compared to 26 in the prophylactic cholecystectomy group (328 patients) for a 78% increased risk of mortality (RR 1.78, 95% CI 1.15 to 2.75, P = 0.010). The survival benefit of prophylactic cholecystectomy was independent of trial design, inclusion of high risk patients or inclusion of any one of the five trials. Patients in the wait-and-see group had higher rates of recurrent biliary pain (RR 14.56, 95% CI 4.95 to 42.78, P < 00001), jaundice or cholangitis (RR 2.53, 95% CI 1.09 to 5.87, P = 0.03), and of repeat ERCP or other forms of cholangiography (RR 2.36, 95% CI 1.29 to 4.32, P = 0.005). Cholecystectomy was eventually performed in 35% (115 patients) of the wait-and-see group. AUTHORS' CONCLUSIONS: Prophylactic cholecystectomy should be offered to patients whose gallbladders remain in-situ after endoscopic sphincterotomy and common bile duct clearance.

Intracerebral co-transplantation of liposomal tacrolimus improves xenograft survival and reduces graft rejection in the hemiparkinsonian rat.

Immunosuppression remains a key issue in neural transplantation. Systemic administration of cyclosporin-A is currently widely used but has many severe adverse side effects. Newer immunosuppressive agents, such as tacrolimus (TAC) and rapamycin (RAPA), have been investigated for their neuroprotective properties on dopaminergic neurons. These drugs have been formulated into liposomal preparations [liposomal tacrolimus (LTAC) and liposomal rapamycin (LRAPA)] which retain these neuroprotective properties. Due to the slower release of the drugs from the liposomes, we hypothesized that co-transplantation of either LTAC or LRAPA within a xenogeneic cell suspension would increase cell survival and decrease graft rejection in the hemiparkinsonian rat, and that a combination of the two drugs may have a synergistic effect. 6-hydroxydopamine-lesioned rats were divided to four groups which received intra-striatal transplants of the following: 1) a cell suspension containing 400,000 fetal mouse ventral mesencephalic cells; 2) the cell suspension containing 0.63 microM LRAPA; 3) the cell suspension containing a dose of 2.0 microM LTAC; 4) the cell suspension containing 2.0 microM LTAC and 0.63 microM LRAPA. Functional recovery was assessed by amphetamine-induced rotational behavior. Animals were killed at 4 days or 6 weeks post-transplantation, and immunohistochemistry was performed to look at the expression of tyrosine hydroxylase and major histocompatibility complex classes I and II. Only the group receiving LTAC had a decrease in rotational behavior. This observation correlated well with significantly more surviving tyrosine hydroxylase immunoreactive cells compared with the other groups and significantly lower levels of immunorejection as assessed by major histocompatibility complex class I and II staining. This study has shown the feasibility of using local immunosuppression in xenotransplantation. These findings may be useful in optimizing immunosuppression in experimental neural transplantation in the laboratory and its translation into the clinical setting.

Cyclosporin versus tacrolimus for liver transplanted patients.

BACKGROUND: Most liver transplant recipients receive either cyclosporin or tacrolimus to prevent rejection. Both drugs inhibit calcineurin phosphatase which is thought to be the mechanism of their anti-rejection effect and principle toxicities. The drugs have different pharmacokinetic profiles and potencies. Several randomised clinical trials have compared cyclosporin and tacrolimus in liver transplant recipients, but it remains unclear which is superior. OBJECTIVES: To evaluate the beneficial and harmful effects of immunosuppression with cyclosporin versus tacrolimus for liver transplanted patients. SEARCH STRATEGY: The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded, and conference proceedings were searched (August 2005) to identify relevant randomised clinical trials. Our search included scanning of reference lists in relevant articles and correspondence with investigators and pharmaceutical companies. SELECTION CRITERIA: All randomised clinical trials where tacrolimus was compared with cyclosporin for the initial treatment of first-time liver transplant recipients. We included randomised trials irrespective of blinding, language, and publication status. DATA COLLECTION AND ANALYSIS: The primary outcome measure was all-cause mortality. Data were synthesised (fixed-effect model) and results expressed as relative risk (RR), values less than 1.0 favouring tacrolimus, with 95% confidence intervals (CI). Two authors assessed trials for eligibility, quality, and extracted data independently. MAIN RESULTS: We included 16 randomised trials. The number of deaths was 254 in the tacrolimus group (1899 patients) and 302 in the cyclosporin group (1914 patients). At one year, mortality (RR 0.85, 95% CI 0.73 to 0.99) and graft loss (RR 0.73, 95% CI 0.61 to 0.86) were significantly reduced in tacrolimus-treated recipients. Tacrolimus reduced the number of recipients with acute rejection (RR 0.81, 95% CI 0.75 to 0.88), and steroid-resistant rejection (RR 0.54, 95% CI 0.47 to 0.74) in the first year. Differences were not seen with respect to lymphoproliferative disorder or de-novo dialysis rates, but more de-novo insulin-requiring diabetes mellitus (RR 1.38, 95% CI 1.01 to 1.86) occurred in the tacrolimus group. More patients were withdrawn from cyclosporin therapy than from tacrolimus (RR 0.57, 95% CI 0.49 to 0.66). AUTHORS' CONCLUSIONS: Tacrolimus is superior to cyclosporin in improving survival (patient and graft) and preventing acute rejection after liver transplantation, but it increases the risk of post-transplant diabetes. Treating 100 recipients with tacrolimus instead of cyclosporin would avoid acute rejection and steroid-resistant rejection in nine and seven patients, respectively, and graft loss and death in five and two patients, respectively, but four additional patients would develop diabetes after liver transplantation.

Cyclosporin versus tacrolimus as primary immunosuppressant after liver transplantation: a meta-analysis.

A systematic review of randomized clinical trials (RCT) was undertaken to evaluate the beneficial and harmful effects of immunosuppression with cyclosporin versus tacrolimus for liver transplanted patients. MEDLINE, EMBASE, Cochrane Central and Hepato-Biliary Group Controlled Trials Registers were searched. Using fixed and random effects model, relative risk (RR), values <1 favoring tacrolimus, with 95% confidence intervals (CI) were calculated. Of 717 potentially relevant references, 16 RCTs were eligible for inclusion. Mortality and graft loss at 1 year were significantly reduced in tacrolimus-treated recipients (Death: RR 0.85, 95% CI 0.73-0.99; graft loss: RR 0.73, 95% CI 0.61-0.86). Tacrolimus reduced the number of recipients with acute rejection (RR 0.81, 95% CI 0.75-0.88) and steroid-resistant rejection (RR 0.54, 95% CI 0.47-0.74) in the first year. Lymphoproliferative disorder or dialysis rates were not different but more de novo diabetes (RR 1.38, 95% CI 1.01-1.86) occurred with tacrolimus. More patients stopped cyclosporin than tacrolimus (RR 0.57, 95% CI 0.49-0.66). Treating 100 recipients with tacrolimus instead of cyclosporin would avoid rejection and steroid-resistant rejection in nine and seven patients respectively, graft loss and death in five and two patients respectively, but four additional patients would develop diabetes after liver transplantation.

Catastrophic microangiopathy induced by high-titre factor VIII inhibitors after liver transplantation for haemophilia A with cirrhosis.

Liver transplantation may induce immune tolerance to factor VIII inhibitors but de novo development of inhibitors after transplantation may cause intractable haemorrhage. We report a patient with mild haemophilia A and high-titre FVIII inhibitors who received an orthotopic liver transplantation for complications of hepatitis C virus cirrhosis. Recombinant activated FVII was used in addition to routine haemostatic agents. Conventional immunosuppression was supplemented with antithymocyte globulin and cyclophosphamide. FVIII inhibitors disappeared from the circulation with liver transplantation but they were found to have bound to the graft endothelium, which became activated and induced catastrophic microangiopathy. A subsequent anamnestic response resulted in FVIII inhibitor titres of 1000 Bethesda Units. Uncontrollable haemorrhage persisted until the recipient's death. In patients with high-titre FVIII inhibitors resilient desensitization is required before liver transplantation.

Long-term follow-up of pediatric en bloc renal transplantation.

We reviewed the outcomes of pediatric en bloc renal transplantation at two Canadian centers in the cyclosporine era. Between 1984 and 2002, 16 patients received pediatric en bloc renal transplants. Mean recipient age and weight were 45 +/- 17 years and 72.2 +/- 14.4 kg, respectively. En bloc kidneys were procured from donors aged 2.1 +/- 0.8 years (range, 0.7 to 4.0), weighing an average of 14.3 +/- 2.0 kg (range, 12 to 17). All en bloc kidneys were successfully transplanted without thrombosis. All patients received calcineurin inhibitors and corticosteroids. Only three patients received antibody-based induction therapy. Rejection episodes occurring in seven grafts were all successfully treated. Mean follow-up was 3.7 years (range 0.4 to 15.0). Mean serum creatinine values at 3 months and 1 and 3 years were 138.8 +/- 54.5 micromol/L, 118.6 +/- 38.1 micromol/L, and 95.1 +/- 24.4 micromol/L, respectively. The mean creatinine value of five patients with at least 5 years follow-up was 96.8 +/- 12.3 micromol/L. Three-year graft and patient survival rates were 94%. Two deaths with functioning grafts occurred secondary to cardiac and infectious etiologies. None of the grafts were lost independent of death. We conclude that en bloc transplantation has excellent short- and long-term results. Improving graft function after 3 years represented by reduced serum creatinine suggests that these kidneys have excellent renal reserve and growth potential.

Mesh hood fascial closure in renal allograft compartment syndrome.

Renal allograft compartment syndrome (RACS) is an underreported and poorly described surgical complication of renal transplantation. It occurs when a tight fascial closure compresses the graft in its limited retroperitoneal space. Without early recognition and reexploration, graft loss is inevitable. We describe a technique using a polypropylene mesh fascial closure (MHFC) to prevent and treat RACS. MHFC was performed primarily to prevent RACS and secondarily to treat this complication. Between April 2001 and October 2002, 16 patients undergoing 17 renal transplants underwent MHFC. Mean recipient body weight was 17% less than the mean donor weight. Mean follow-up was 9 months. Mean serum creatinine after primary MHFC was 148.4 micromol/L. Three of four patients with RACS regained function following secondary MHFC and had a mean serum creatinine of 155.3 micromol/L. Wound complications were seen in 5 (31%) with no wound or mesh infections and one patient was diagnosed with a lymphocele. We conclude that MHFC can be safely performed after kidney transplantation to prevent or treat RACS.

Transplantation in Canada: report of the Canadian Organ Replacement Register.

The solid organ transplant rate in Canada grew from 49.5 per million population (PMP) in 1993 to 56.8 PMP in 2002, with a peak rate of 61.0 in 2000. Most of this increase was seen in living donor kidney, liver, and lung transplants where combined rates rose twofold, from 124.9 per 1000 transplants to 243.5. Despite this, the rate of organ transplantation in the United States was 150% that of Canada in 2002. As of December 31, 2002, there were 3,956 patients waiting for an organ transplant in Canada, an 84% increase in the total number of patients on the waiting list as of December 31, 1993, 10 years ago. Cadaveric organ donation did not change over this period. An international comparison of cadaveric organ donation rates for 2001 place Canada (13.5 PMP) well below Spain (32.5 PMP) and the United States (22.6 PMP) but above Australia (9.3 PMP). As a result the annual gap between transplants performed and the waiting list has grown from 927 in 1992 to 2230 in 2001, representing an annual increase of 8.3%.

Liver transplantation for primary sclerosing cholangitis.

UNLABELLED: Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease that progresses to end-stage liver disease. This report is a retrospective analysis of a Canadian centre experience with liver transplantation (LT) for PSC. Of 1107 LTs performed between 1984 and 2002, 132 were performed on 111 patients with PSC. Patient survival at 1, 3, 5, and 10 years was 84.5%, 84.5%, 83.4%, and 68.9%, respectively. Graft survival at 1, 3, 5, and 10 years was 80.8%, 79.8%, 72.7%, and 55.3%. These were not significantly different from overall patient survival (P =.91) or graft survival (P =.28) in non-PSC patients transplanted over the same time period. Early mortality was predominantly related to primary nonfunction and multi-organ failure; late mortality was predominantly related to malignancy. No patient with known cholangiocarcinoma (CCA) underwent LT, but three patients had an incidental CCA noted on explant pathology. All three died of widespread metastatic disease (10.8, 38.0, and 39.8 months after LT). Nineteen patients lost their primary grafts requiring retransplantation, and two of these patients required a third transplant. Recurrent PSC was detected in six patients and suspected in another six. Four patients have been retransplanted for recurrent PSC. Chronic rejection was detected in nine patients. Eight have required retransplantation. The incidence of biliary complications was 16.2%. CONCLUSIONS: LT is effective therapy for PSC. Patient and graft survival is comparable to that seen in patients transplanted for indications other than PSC, but long-term graft survival may be lower. Recurrent PSC and chronic rejection are the major determinants of graft loss.

Survival after liver transplantation for hepatocellular carcinoma.

BACKGROUND: Selection criteria for patients with hepatocellular carcinoma (HCC) suitable for liver transplantation (LT) include tumor size and number and vascular invasion. There has been a recent trend to expand the transplant criteria for HCC. We reviewed our experience to determine survival following LT based on tumor characteristics. METHODS: A retrospective analysis was performed on 72 patients with HCC who underwent LT between 1985 and July 2002. The Milan criteria were applied for LT candidacy for HCCs that were deemed unresectable from anatomical considerations and/or the severity of underlying cirrhosis. Patients were divided into four groups: group 1: patients with known HCC who satisfied the selection criteria (n = 22); group 2: patients with known HCC that exceeded the criteria (n = 17); group 3: patients with incidental HCC found at pathological examination of the explant (n = 33); group 4: contemporary LT recipients without HCC (n = 935). RESULTS: In the known HCC group, the interval between listing as status 2 and transplantation was 72.2 +/- 133.6 days (median 23 days). Three-year patient survival was 80.2% in group 1, 35.8% in group 2, 63.2% in group 3, and 81.5% in group 4. In group 2 patients, the tumors were significantly larger, had more nodules, and were more often bilobar. In group 3, five (15%) exceeded the criteria mainly because of tumor size and four patients died within 3 years post-LT (three from tumor recurrence). CONCLUSION: Liver transplantation for HCC yields acceptable survival in early-stage tumors, particularly if transplanted soon after listing. Long-term survival was inferior in patients with multiple tumors and tumors that were greater than 5 cm in diameter.

Liposomal tacrolimus lotion as a novel topical agent for treatment of immune-mediated skin disorders: experimental studies in a murine model.

BACKGROUND: Systemic but not topical tacrolimus (TAC) is effective against psoriasis. Mechanical methods that enhance skin penetration by TAC increase its topical antipsoriatic effect. Liposomal delivery of TAC would increase its penetration of skin, allow for slow release and diminish its toxicity. OBJECTIVES: To test a liposomal TAC (LTAC) formulation in a murine model. METHODS: Drug penetration was assessed using radiolabelled LTAC, and the effect of TAC and LTAC on Balb/c skin graft survival and on ovalbumin-induced delayed-type hypersensitivity reactions was tested in C57BL/6 mice. RESULTS: Radiotracer studies showed that topical application of LTAC achieved nine times the concentration of TAC at a target site than did systemic administration of TAC. Combination of systemic and topical LTAC significantly increased mean +/- SD skin graft survival (14.8 +/- 1.5 days) compared with systemic TAC (8.0 +/- 0.7 days) and control mice (8.4 +/- 1.2 days). LTAC was more effective systemically than TAC in the prevention of delayed-type hypersensitivity reactions. Topical LTAC also prevented this response. CONCLUSIONS: Topical LTAC was effective in this model of immune-mediated skin disease. Because LTAC achieves higher skin concentrations than systemic TAC it may be an effective delivery system for TAC in the treatment of psoriasis.

Liposomal tacrolimus administered systemically and within the donor cell suspension improves xenograft survival in hemiparkinsonian rats.

The most widely used immunosuppressant in neural transplantation is cyclosporine- A (CsA). However, CsA has significant toxic effects when administered systemically. Tacrolimus (FK506), is a more potent immunosuppressant than CsA and can be prepared in lipid micelles (LTAC). This liposomal preparation allows for the administration of tacrolimus to the site of transplantation, possibly reducing the systemic side effects of immunosuppression. In this study we investigated the ability of LTAC to promote graft survival in hemiparkinsonian rats implanted with fetal mouse xenografts when LTAC is administered systemically to the host, when added to the donor cell suspension, or in combination. Rats with unilateral 6-hydroxydopamine lesions were transplanted with 800,000 fetal mouse ventral mesencephalic (VM) cells and were randomly divided into four groups. Group 1 was not immunosuppressed; Group 2 received daily systemic injections of LTAC; Group 3 received LTAC within the cell suspensions of mouse VM cells; and Group 4 received LTAC in the cell suspensions along with daily systemic administration of LTAC. Transplanted rats were assessed for rotational behavior 3 and 6 weeks posttransplantation. Cell survival was assessed using tyrosine hydroxylase (TH) immunohistochemistry. A significant reduction in rotational scores was observed only in the group of animals receiving the combination of LTAC-treated donor cells and systemic LTAC administration. This functional improvement correlated with a significantly greater survival of TH-immunoreactive cells in this group of animals. The other groups had poor cell survival and no significant functional improvement. We conclude that a combination of systemic immunosuppression and treatment of the cell suspension with LTAC may be a superior strategy to optimize xenograft survival. This strategy may have important implications for clinical neural transplantation.