Ring sequestrum: radiographic characteristics of skeletal fixation pin- tract osteomyelitis

Major pin-tract infections are a potentially dangerous complication associated with the use of skeletal transfixation pins. The presence of a characteristic radiographic finding, the ring sequestrum, is virtually diagnostic of this abnormality. The clinical and radiographic findings in seven patients treated for this complication are presented. Thermal necrosis without infection presents as a zone of sclerosis around the tract. A narrow, radiolucent halo may surround the dense bone. When a narrow ring sequestrum is surrounded by a radiolucent halo, there is associated infection.     

Warfarin potentiation with bezafibrate

Two cases are described in which lack of awareness of the potentiation of bezafibrate on warfarin was of clinical importance.     

The effect of soluble complement receptor type 1 on acute humoral xenograft rejection in hDAF-transgenic pig-to-primate life-supporting kidney xenografts

BACKGROUND: In pig-to-nonhuman primate solid organ xenotransplantation using organs from donors transgenic for human decay-accelerating factor (hDAF), the main type of rejection is antibody-mediated (acute humoral xenograft rejection, AHXR). This occurs despite the complement-regulatory function of the transgene, neutralization of natural antibodies to Galalpha1-3Gal (Gal) using soluble glycoconjugates, and chronic immunosuppression. As complement components play a major role in graft destruction after antibody binding, we evaluated the efficacy of chronic complement inhibition by soluble complement receptor type 1 (TP10). METHODS: Life-supporting hDAF-transgenic kidney transplantation was performed in cynomolgus monkeys, using cyclophosphamide induction, and maintenance immunosuppression with cyclosporin A, mycophenolate sodium, and tapering steroids. Rejection was treated with bolus steroid injections: if not successful animals were terminated. Three groups were studied: in group 1 (n=4) GAS914 (a soluble glycoconjugate comprising Gal on a poly-L-lysine backbone) was added before and after transplantation; group 2 (n=2) received GAS914 as in group 1 and in addition TP10 before and after transplantation; in group 3 (n=4) GAS914 was only given before transplantation and TP10 as in group 2. Monitoring included the regular assessment of anti-porcine antibodies, complement activity (soluble C5b-9), therapeutic drug monitoring, and graft histology. Results: Survival in group 1 was 6, 12, 31 and 37 days, respectively, and in all four cases graft histology showed AHXR. The two animals in groups 2 survived 3 and 15 days, respectively, and similarly showed AHXR in graft histology. In group 3 two animals showed AHXR (10 and 37 days survival, respectively), and two others did not show AHXR (20 and 32 days survival, respectively). The diagnosis AHXR included the deposition of complement activation products in the graft, which were present at lower intensity in animals treated with TP10. In all animals GAS914 effectively neutralized circulating anti-Gal antibody. Antibodies were detectable in the circulation of all animals using porcine erythrocytes in a hemolytic assay, although at lower levels than before transplantation. Soluble C5b-9 was not detectable in the circulation of animals receiving TP10, and circulating TP10 concentrations in these animals were in a presumed pharmacologically active range. CONCLUSIONS: The inclusion of TP10 in the immunosuppressive protocol does not clearly lead to improved xenograft survival. Despite effective neutralization of anti-Gal antibodies and effective inhibition of systemic complement activity, AHXR was apparent in four of six animals under chronic TP10 treatment, including deposits of complement activation products in the graft. Apparently, effective systemic complement inhibition by TP10 in combination with local complement regulation by the hDAF transgene product does not necessarily result in effective inhibition of complement activation at locations in the xenograft upon binding of anti-porcine antibodies to the grafted endothelium.     

Depletion of anti-Gal antibodies by the intravenous infusion of Gal type 2 and 6 glycoconjugates in baboons

Abstract: Background: Natural anti‐Gal antibodies (NAb) to Gal epitopes play a key role in the rejection of pig cells or organs transplanted into primates. We have investigated the effect on NAb return after extracorporeal immunoadsorption (EIA) of the continuous intravenous (i.v.) infusion of (i) bovine serum albumin conjugated to Gal type 6 oligosaccharides (BSA‐Gal) or (ii) a poly l ‐lysine backbone conjugated to Gal type 2 or 6 oligosaccharides (PLL‐Gal). Methods: Porcine mobilized peripheral blood progenitor cells (PBPC) obtained by leukapheresis from MHC‐inbred miniature swine (n = 9) were infused intravenously (i.v.) into baboons: Group 1 baboons (n = 4) received whole body and thymic irradiation, splenectomy, antithymocyte globulin, cobra venom factor, cyclosporine, mycophenolate mofetil, anti‐CD154mAb, porcine hematopoietic growth factors, and EIA before transplantation of high doses (2 to 4 × 10¹⁰ cells/kg) of PBPC; Group 2 baboons (n = 3) received the Group 1 regimen plus a continuous i.v. infusion of BSA‐Gal for up to 30 days; Group 3 baboons (n = 5) received the Group 1 regimen plus a continuous i.v. infusion of PLL‐Gal type 2 (n = 2) or both PLL‐Gal types 2 and 6 (n = 3) for up to 30 days. Results: Group 1: NAb returned to pre‐PBPC levels within 20–30 days, but there was no induction of antibody to Gal or non‐Gal determinants; Group 2: NAb was undetectable or at very low level during BSA‐Gal therapy. In one baboon, however, IgG to Gal type 2, but not to type 6, returned during BSA‐Gal therapy; Group 3: NAb was undetectable or at very low level during PLL‐Gal therapy. In two baboons that received PLL‐Gal type 2, NAb to Gal type 6, but not to type 2, returned during PLL‐Gal treatment. Two of five baboons, however, developed systemic infection. Four of five baboons died within 14 days; autopsy revealed focal hemorrhagic injury to their hearts, lungs, and small intestines, with histologic abnormalities that varied between animals from hemorrhage and/or thrombosis in some organs (heart, lungs, or intestine) to signs of infections (bacteria in intestine, cytomegalovirus in liver). Conclusions: (i) BSA‐Gal and PLL‐Gal therapy maintained depletion of NAb. (ii) Some heterogeneity in specificity of NAb was identified, indicating that the infusion of a combination of Gal type 2 and 6 glycoconjugates may be required. (iii) The addition of PLL‐Gal to the immunosuppressive regimen was associated with a high incidence of morbidity and mortality without a clear histopathologic entity underlying the cause of death.     

Peptide-urea interaction

The excess enthalpies of the ternary aqueous solutions containing urea and the glycyl-glycine, glycyl-L-alanine, L-alanyl-L-alanine and sarcosyl-sarcosine diketopiperazines respectively have been determined. A weak but favourable enthalpic contribution to the interaction between these solutes is found. The difference between “strong” and “weak” interactions in aqueous solutions of non-electrolytes is stressed and the role of water in the weak, non-specific interactions, is discussed. The consequence of the weakness of the urea-peptide interactions on the binding of urea to the proteins is also briefly discussed.     

Pancreatic Pseudocyst as a Cause of Gastrointestinal Bleeding and Hemobilia

A case of hemobilia from a pancreatic pseudocyst which developed after cholecystostomy and aspiration of the pseudocyst, intended to relieve biliary obstruction, is discussed. These previously reported cases are briefly reviewed.     

Population Pharmacokinetic Modeling of Tribendimidine Metabolites in Opisthorchis viverrini-Infected Adults

There is a pressing need for alternative treatments against the liver fluke Opisthorchis viverrini. Oral tribendimidine is a promising candidate, but its population pharmacokinetic properties are unknown. Two phase IIa trials were conducted in Laos in O. viverrini-infected adults receiving single oral doses of 25 to 600 mg tribendimidine administered as different formulations in each study (study 1 used 200-mg tablets, and study 2 used 50-mg tablets). Venous whole blood, plasma, and capillary dried blood spots were sampled frequently from 68 adults, and concentrations of the tribendimidine metabolites dADT (deacetylated amidantel) and adADT (acetylated dADT) were measured. Population pharmacokinetics were assessed by using nonlinear mixed-effects modeling. The relationship between drug exposure and cure (assessed at 21 days posttreatment) was evaluated by using univariable logistic regression. A six-transit compartment absorption model with a one-disposition compartment for each metabolite described the data well. Compared to the 50-mg formulation (study 2), the 200-mg formulation (study 1) had a 40.1% higher mean transit absorption time, a 113% higher dADT volume of distribution, and a 364% higher adADT volume of distribution. Each 10-year increase in age was associated with a 12.7% lower dADT clearance and a 21.2% lower adADT clearance. The highest cure rates (≥55%) were observed with doses of ≥100 mg. Higher dADT, but not adADT, peak concentrations and exposures were associated with cure (P = 0.004 and 0.003, respectively). For the first time, population pharmacokinetics of tribendimidine have been described. Known differences in the 200-mg versus 50-mg formulations were captured by covariate modeling. Further studies are needed to validate the structural model and confirm covariate relationships. (This study has been registered with the ISRCTN Registry under no. ISRCTN96948551.)     

Disposition of Mefloquine and Enpiroline Is Highly Influenced by a Chronic Schistosoma mansoni Infection

Chronic Schistosoma mansoni infections lead to severe tissue destruction of the gut wall and liver and can influence drug disposition. This study aimed to investigate the impact of a chronic S. mansoni infection on the pharmacokinetic (PK) parameters of two promising antischistosomal lead candidates (mefloquine and enpiroline) in mice. Studies were conducted in two different mouse cohorts (S. mansoni-infected and uninfected mice) for both drugs. Plasma samples were collected at various time points after oral treatment (200 mg/kg of body weight) with study drugs. A high-performance liquid chromatography (HPLC) method was validated to analyze enpiroline and mefloquine in plasma. Livers and intestines were collected from infected animals to determine the onset of action, hepatic shift, and worm burden reduction. Following mefloquine administration, hepatic shifting and significant worm burden reductions (79.2%) were observed after 72 h. At 1 week posttreatment with enpiroline, the majority of worms had migrated to the liver and significant worm burden reductions were observed (93.1%). The HPLC method was selective, accurate (87.8 to 111.4%), and precise (<10%) for the analysis of both drugs in plasma samples. The PK profiles revealed increased values for half-life (t_1/2) and area under the concentration-time curve (AUC) for both drugs in infected animals compared to the t_1/2 and AUC values in uninfected animals. Considerable changes were observed for mefloquine, with a 5-fold increase of t_1/2 (182.7 h versus 33.6 h) and 2-fold increase of AUC (1,116,517.8 ng · h/ml versus 522,409.1 ng · h/ml). S. mansoni infections in mice influence the PK profiles of enpiroline and mefloquine, leading to delayed clearance. Our data confirm that drug disposition should be carefully studied in schistosomiasis patients.