Bioartificial liver treatment prolongs survival and lowers intracranial pressure in pigs with fulminant hepatic failure.

Intracranial hypertension leading to brainstem coning is a major cause of death in fulminant hepatic failure (FHF). We have developed a bioartificial liver (BAL) utilizing plasma perfusion through a bioreactor loaded with porcine hepatocytes and a column with activated charcoal. In a Phase I clinical trial, we observed a decrease in intracranial pressure (ICP) in FHF patients. However, these patients received BAL therapy together with other measures. We therefore examined whether BAL therapy alone could prevent development of intracranial hypertension in pigs with surgically induced FHF. Pigs (40-60 kg) underwent end-to-side portacaval shunt, transection of all hepatic ligaments, and placement of slings around the hepatic artery and bile duct. After 3 days, the slings were tightened to induce liver necrosis. After 4 h, Group 1 pigs (n = 6) underwent a 6 h treatment with the BAL utilizing 10 billion cryopreserved pig hepatocytes and a charcoal column, Group 2 pigs (n = 6) with the BAL containing charcoal but no cells, and Group 3 pigs (n = 6) with the BAL containing neither cells nor charcoal. Group 1 pigs maintained a normal ICP during BAL treatment and for 14 h afterward and because of this effect they survived longer than Groups 2 and 3 animals. In contrast, Groups 2 and 3 pigs showed an early (6-8 h) rise in ICP.

The isolation and function of porcine islets from market weight pigs.

The efficacy of clinical islet transplantation has been demonstrated with autografts, and although islet allografts have established insulin independence in a small number of IDDM patients, the treatment is confounded by the necessity of immunosuppression. the lack of donor tissue, and recurring islet immunogenicity. These limitations underscore a need to develop therapies to serve the large population of diabetic patients. Porcine islet xenotransplantation, together with a successful immune intervention strategy, may provide the necessary clinical alternative. However, a major obstacle in evaluating this approach has been the difficulty of obtaining adequate volumes of functional islet tissue from pigs. Donors of market weight are preferable to retired breeders due to their abundance, lower animal and husbandry costs. and are more suitable to meet regulatory guidelines for donor tissue for xenotransplantation. We describe a simple isolation procedure that following purification yields a mean of 350,000 IE, corresponding to 179 units of insulin and 1.8 mg of DNA with an islet purity and viability in excess of 85% (n = 317 isolations). In both short- and long-term cell cultures, porcine islets demonstrated glucose-responsive insulin secretion. However, this secretion is density dependent, which may have significant consequences in the development of immunoisolation technologies to support porcine islet xenotransplantation. Following implantation into diabetic nude mice, porcine islets remained functional in excess of 1 year. Implantation of a bioartificial pancreas containing porcine islets into pancreatectomized dogs provided significant clinical benefit with an improved diabetic condition. Finally, secretagogue-induced insulin release was demonstrated in vitro from these devices after removal from immunocompetent recipients. Immunohistochemical staining identified well-granulated islets following long-term implantation in both the rodent and canine models. This study demonstrates the ability to isolate porcine islets in clinically relevant numbers from market animals, which survive and remain functional for prolonged periods of time in an immune-deficient or immunoprotected environment.

Percutaneous placement of an intercostal central venous catheter for chronic hyperalimentation guided by transhepatic venography.

BACKGROUND AND METHODS: Increased utilization of central venous catheters for hyperalimentation has caused a rise in the incidence of central venous complications including occlusions and stenoses. When this occurs, the continued use of these catheters becomes more difficult. We describe a technique for catheter placement in a patient requiring access for total parenteral nutrition who had extensive central venous occlusion involving both internal jugular veins, both subclavian veins, and the infrorenal inferior vena cava (IVC). RESULTS: A percutaneous transhepatic venous catheter had been placed in a patient with inferior vena caval, subclavian, and internal jugular venous occlusions. The Hickman catheter functioned well until the patient developed fungal sepsis and a large fibrin sheath around the catheter tip creating the need for a new access site. Placement of an intercostal venous catheter was performed using transhepatic venography to map patent collateral veins and microcatheters to access an intercostal route for Hickman placement. CONCLUSIONS: Patients who require long-term central venous access often develop stenotic and occlusive complications in the central venous circulation. Individualized, unique and innovative routes to the central venous circulation must often be utilized to maintain venous access in these patients. Transhepatic venous mapping and microcatheter techniques aid in the finding of alternative sites in these patients with difficult access problems.

Botulinum toxin type A therapy for palmar and digital hyperhidrosis.

OBJECTIVE: We evaluated the efficacy of subepidermal injections of botulinum toxin type A on recalcitrant palmar and digital hyperhidrosis. METHODS: Twenty patients with recalcitrant palmar and digital hyperhidrosis were treated with subepidermal injections of botulinum toxin. Nineteen patients completed the 12-month study. Injections were performed in 3 stages. The total dose of toxin for each hand, which included the palm, thenar eminence, and digits, was 165 units. Patients were followed up on a monthly basis. RESULTS: Botulinum toxin significantly reduced sweat production in the treated areas. Anhidrosis lasted 9 months in 3 patients, 8 months in 3 patients, 7 months in 8 patients, 6 months in 3 patients, 5 months in 1 patient, and 4 months in 1 patient. Reduced sweating of the palm and digits continued in all patients for the 12-month evaluation period, with the greatest reduction of sweating in the nondominant hand. Mild weakness of the thumb occurred in 4 patients at a mean duration of 3 weeks, with the greatest duration being 6 weeks. CONCLUSION: Botulinum toxin provides a safe and efficacious alternative in the treatment of recalcitrant palmar and digital hyperhidrosis.

Functional recovery of porcine hepatocytes after hypothermic or cryogenic preservation for liver support systems.

The provision of an immediate supply of isolated porcine hepatocytes for artificial liver support requires preservation techniques that will allow maintenance of cell viability and detoxification functions. By means of a simple and cost-effective cryopreservation system, porcine hepatocytes can be available for both local and distant medical treatment facilities. Additionally, cryopreservation provides an adequate period for quality control testing to be completed prior to use of any specific cell lot. We are reporting a dual approach, namely the preservation of porcine hepatocytes, at 4 degrees C and at -196 degrees C in liquid nitrogen (LN2). Using a combination of cryoprotectant agents with Chee's modified Eagle's culture media (CEM), collagenase isolated hepatocytes stored at 4 degrees C for 24 h maintained 80% of the initial diazepam metabolism measured in freshly isolated cells and nearly 100% of initial function was preserved in hepatocytes stored up to 6 mo at -196 degrees C. University of Wisconsin solution (UW) was also tested and while adequate for 4 degrees C storage, it certainly did not match the performance of the CEM formulations for preservation of metabolic function of cells stored in liquid nitrogen. Based on our results of viability and detoxification function the combination of CEM with DMSO, polyethylene glycol and serum provided optimal protection for LN2 frozen cells. Other findings in these studies underlined the importance of the gradual introduction of DMSO in the prefreezing process, the period of osmotic equilibration, and the rapid postthaw withdrawal of this agent to minimize cytotoxic effects at these critical stages. Our freezing methodology provides the foundation for further technological developments in the cryopreservation of the large numbers of cells (billions) that are necessary for extracorporeal liver assist devices.

Tinea incognito and "over-the-counter" potent topical steroids.

The term tinea incognito has been used to describe a dermatophyte infection modified by corticosteroid treatment. Lesions are often atypical appearing and the diagnosis is frequently delayed or missed. This difficulty is often exacerbated by the random misuse of potent dermatologic preparations that can alter the initial presentation to the dermatologist. Recently, we have encountered an increasing number of patients who have obtained potent superpotent topical steroids "over the counter" to self-treat various dermatoses. We report two such cases of tinea incognito that were exacerbated and altered clinically by the use of such preparations.

Transient cutaneous vesicles in a teenager: the final piece to a puzzle.

Cicatricial pemphigoid is a chronic blistering disease that predominantly affects the mucous membranes. It has a peak occurrence in the seventh decade. Pediatric cicatricial pemphigoid is a rare entity, with fewer than 20 cases reported. We report an 18-year-old man who was recently diagnosed with cicatricial pemphigoid after six years of diagnostic uncertainty.

Porcine islets for xenotransplantation.

Long-term function of isolated porcine islets was investigated in diabetic nude mice. Seven of eight mice that received transplants of porcine islets remained normoglycemic for 1 year with progressive weight gain. Circulating porcine C-peptide was detected throughout the study period. Intravenous glucose tolerance tests showed a rapid glucose clearance rate. Together with our recent finding that porcine islets contained within an immunoexclusion device achieved glycemic control in a totally pancreatectomized dog, these results clearly demonstrate that isolated porcine islets are capable of functioning for prolonged periods in xenogeneic hosts and are suitable for long-term use in an immunoexclusion device in a discordant host.

Cimetidine therapy for recalcitrant warts in adults.

BACKGROUND: Common warts, or verrucae vulgaris, occur most often in children. However, many adults are plagued by this ubiquitous viral infection. Various modalities have been used to treat warts, but none is uniformly effective or directly antiviral. A recent study showed cimetidine to be effective in the treatment of multiple warts in children. Anecdotal reports have suggested that the administration of high doses of cimetidine, through various proposed immunomodulating mechanisms, can improve recalcitrant warts in adults. There have been no data published to date supporting these claims. OBSERVATIONS: An open-label study was conducted to determine the safety and efficacy of high-dose cimetidine in 20 adult patients with recalcitrant warts. Of the 18 patients who completed the study, 16 patients (84%) had either dramatic clinical improvement or complete resolution of their wart lesions after 3 months of cimetidine therapy without any adverse effects. No patient demonstrated disease progression while receiving the medication and complete responders remained free of lesions at 1-year follow-up. CONCLUSIONS: This study further confirms that high-dose cimetidine therapy appears to be beneficial and safe in the treatment of recalcitrant warts in adults. Further placebo-controlled studies are needed to determine its true efficacy.

Quality of care: issue or oversight in health care reform?

BACKGROUND: Health care reform is not dead but merely on hiatus. The vehicle for the reform is managed care, in particular health maintenance organizations (HMOs). HMOs employ primary care physicians as gatekeepers to act as regulators and points of entry into the health care system. It is through these gatekeepers that most dermatologic care is rendered. OBJECTIVE: Our purpose was to assess (1) the level of dermatology training of family practice physicians compared with dermatologists and (2) the impact on the delivery of quality dermatology services. METHODS: a national study of university residency programs was undertaken. Twenty color Kodachromes of typical cutaneous diseases were analyzed by the two physician groups. A questionnaire was used to evaluate the average formal dermatology training received, the number of primary dermatology patients examined by family practitioners, the correct response rates to the questions, and the dermatologic procedures performed by family practitioners. A total of 723 family practice physicians and 443 dermatologists responded. RESULTS: Our results indicate that, in comparison to dermatologists, primary care physicians significantly are deficient in their ability to recognize common and serious dermatoses. CONCLUSION: this study provides data emphasizing the need for reevaluation of the dermatology curriculum in medical schools and family practice residencies. Most important, it suggests that direct access to dermatologists provides better quality of care to members of HMOs and hence indirectly is most cost effective for the provision of dermatology services.

Treatment of diabetes by xenogeneic islets without immunosuppression. Use of a vascularized bioartificial pancreas.

Tight glycemic control by intensive insulin therapy effectively delays the onset and slows the progression of diabetic complications but is associated with frequent dose adjustments and a high incidence of hypoglycemia. Successful pancreas transplantation corrects abnormal glucose metabolism but subjects patients to morbidity and mortality associated with chronic immunosuppression. A vascularized artificial pancreas device containing pancreatic islets is designed to provide glycemic control without immunosuppression. We report here that devices seeded with porcine islets implanted into pancreatectomized severely diabetic dogs maintained a marked improvement in glycemic control with reduced exogenous insulin requirements for up to 9 months with improved glucose tolerance and a reduction in glycosylated hemoglobin levels. No immunosuppression was used. Thus, use of a vascularized artificial pancreas containing xenogeneic porcine islets could be an alternative to intensive insulin therapy and pancreatic transplantation in treating diabetic patients before the development of severe diabetic complications.

Early treatment of diabetes with porcine islets in a bioartificial pancreas.

Successful pancreas transplantation is an effective therapy for insulin-dependent diabetes mellitus (IDDM) but subjects patients to morbidity and mortality associated with chronic immunosuppression. Bioartificial pancreas devices containing pancreatic islets provide glycemic control without immunosuppression by physically separating the islet grafts from immune lymphocytes and immunoglobulins. Because immunosuppression is not required, the bioartificial pancreas may offer early treatment of IDDM prior to the development of debilitating diabetic complications. Use of xenogeneic islets (i.e., porcine islets) in the device also provides a solution to the limited availability of human donor organs. This report provides a brief summary of our experience with vascularized bioartificial pancreas devices containing xenogeneic porcine islets used for treatment of experimental diabetes in dogs and describes our plans for a clinical phase I/II trial of the vascularized bioartificial pancreas in patients with IDDM.