Outcomes at 3 years of a prospective pilot study of Campath-1H and sirolimus immunosuppression for renal transplantation

Campath-1H (alemtuzumab) induction was used for renal transplantation in combination with sirolimus as immunosuppression. We previously reported a high (28%) rate of early rejection with this regimen, and now report 3-year outcomes. Twenty-nine patients were recipients of either deceased donor or non-HLA (Human Leukocyte Antigen) identical living donor primary renal allografts. Clinical parameters including infection, malignancy, kidney function, and kidney histology were followed prospectively for 3 years. Three-year cumulative graft and patient survival were 96% and 100%, respectively. Twenty patients were maintained on steroid-free immunosuppressive regimens, and 15 patients were maintained on monotherapy for immunosuppression (12 on sirolimus). No serious infectious complications were observed and two patients developed basal cell skin cancer. The 3-year results of our initial pilot study demonstrate good graft (96%) and patient (100%) outcomes. Campath-1H induction has yielded a high proportion of patients maintained on immunosuppressive monotherapy (57%) without serious infectious- and no malignancy-related complications. The reported regimen yielded novel insights into both Campath-1H and sirolimus therapy in renal transplantation. Because of the higher incidence of early rejection, we recommend a modified strategy of immunosuppression including a brief course of a calcineurin inhibitor.     

Dissociation of Depletional Induction and Posttransplant Lymphoproliferative Disease in Kidney Recipients Treated With Alemtuzumab

Transplant patients are at the risk for posttransplant lymphoproliferative disease (PTLD), a virally-driven malignancy. Induction with the depleting antibody preparations Thymoglobulin and OKT3 is associated with PTLD suggesting that the T-cell depletion increases PTLD risk. We therefore studied 59 560 kidney recipients from the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) database for a relationship between induction agent use and PTLD. Two agents with comparable T-cell depletional effects, alemtuzumab and Thymoglobulin, were compared to nondepletional induction agents or no induction. The overall incidence of PTLD was 0.46% and differed significantly by induction strategy (p < 0.01): without induction (0.43%), basiliximab (0.38%), daclizumab (0.33%), Thymoglobulin (0.67%) and alemtuzumab (0.37%). Thymoglobulin was associated with significantly increased PTLD risk (p = 0.0025), but alemtuzumab (p = 0.74), basiliximab (p = 0.33) and daclizumab, which trended toward a protective effect (p = 0.06), were not. Alemtuzumab and Thymoglobulin treated patients did not differ in any established parameter affecting PTLD risk although alemtuzumab is known to have a more pronounced B-cell depleting effect. Interestingly, maintenance therapy with an mTOR inhibitor was strongly associated with PTLD (0.71%, p < 0.0001). Thus, depletional induction is not an independent risk factor for PTLD. Rather, maintenance drug selection or perhaps the balance between B- and T-cell depletion may be more relevant determinants of PTLD risk.     

Endoscopically controlled erbium:YAG goniopuncture versus trabeculectomy: effect on intraocular pressure in combination with cataract surgery

PURPOSE:. To compare the efficacy of endoscopic erbium:YAG laser goniopuncture in glaucoma treatment to trabeculectomy, both methods as adjuncts to cataract surgery. METHODS:. Fifty-nine eyes of 59 glaucoma patients with coexistent cataract were treated by phacoemulsification and endoscopic Er:YAG goniopuncture in a combined fashion. The primary study endpoints were intraocular pressure (IOP), number of antiglaucomatous drugs, postoperative complications, hospitalisation time and visual acuity at 1 year after surgery. To date, 24 eyes have finished the 1-year follow-up. This prospective treatment arm was compared to a retrospective inclusion-matched control group treated by trabeculectomy and cataract surgery in a single procedure. RESULTS:. In the laser-treated group, the mean IOP dropped by 30% from 23.4+/-3.7 mmHg to 16.3+/-6 mmHg ( P<0.0001) after 12 months. Without reoperation, treatment was successful in 71% of these eyes. In the control group, the IOP decreased by 33.5% from 22.7+/-3.3 mmHg to 15.1+/-3.8 mmHg ( P<0.0001). The success rate without reoperation was 46%. The number of antiglaucomatous drugs needed decreased from 1.48+/-0.95 to 0.48+/-0.7 ( P<0.0001) in the laser-treated group and from 2.0+/-0.9 to 0.39+/-0.6 ( P<0.0001) in the control group. Postoperative complications were found more frequently in the control group ( P<0.0001). Hospitalisation was shorter in the laser group ( P<0.0001). Postoperative visual acuity was lower in the control group ( P=0.004). CONCLUSION:. Combined Er:YAG goniopuncture and cataract surgery lowers the IOP to an extent comparable to combined trabeculectomy and cataract surgery. Due to fewer postoperative complications, Er:YAG goniopuncture seems to be superior to standard fistulation surgery as the primary approach within the first year.     

Selective degeneration of CA1 pyramidal cells by chronic application of bismuth

The heavy metal bismuth induces a new type of selective neuronal degeneration that shares some common aspects with that seen following hypoxia and ischemia. Continuous application of 3 μm bismuth to organotypic cultures of rat hippocampus resulted after 2–3 weeks in selective degeneration of CA1 pyramidal cells, while CA3 pyramidal cells, dentate granule cells, and subicular neurons were resistant. With 10 μm MK-801, a noncompetitive NMDA-antagonist, during the entire culturing period failed to prevent neuronal degeneration induced by 3 μm bismuth. GABA-immunoreactive interneurons were also affected by bismuth, but were generally less sensitive than CA1 pyramidal cells. Acute application of up to 100 μm bismuth did not change the electrophysiological properties of CA1 pyramidal cells. © 1994 Wiley-Liss, Inc.     

Hypoplasia of the Posterior Leaflet as a Rare Cause of Congenital Mitral Insufficiency

A bstract A rare case of congenital mitral insufficiency characterized by the hypoplasia of the posterior leaflet is reported. At operation, the mitral valve was successfully repaired by a ring annuloplasty, which created a satisfactory surface of coaptation between the anterior leaflet and the bulky posterior muscular structure. The presence of this posterior muscular structure represents a developmental arrest at the stage of conversion from muscular chordae and leaflets to thin connective structures.     

NMR Investigation of the Futile Cycling of Ethanol in Chronic Alcoholic Rats

Weight gain efficiency differences previously reported between alcohol-fed rats and their controls were investigated. Additionally, the futile cycling of ethanol proposed to explain such differences was studied by NMR spectroscopy. Male Sprague-Dawley rats were fed a nutritionally adequate diet containing 36% of the calories as alcohol, and their paired controls were fed an isocaloric diet for 1 f weeks to establish conditions of chronic alcohol feeding. Normalized metabolic efficiencies varied significantly during the initial 2-week period (6.86 ± 0.51 vs. 2.83 ± 0.18 g/kcal × 10⁻²) for control and alcohol-fed groups, respectively, and to a lesser extent over the entire feeding period (6.41 ± 0.78 vs. 4.60 ± 0.27 g/kcal × 10⁻²) for control and alcohol-fed groups, respectively. Alcohol-induced weight gain inefficiency in metabolism has previously been studied and explained by a variety of different biochemical and physiological mechanisms. One possible pathway of energy wastage may occur due to ethanol futile cycling from ethanol to acetaldehyde through the microsomal ethanol oxidation system pathway, and simultaneously from acetaldehyde to ethanol via the ADH pathway. This futile cycle represents a net loss of 6 ATP/cycle, corresponding to the loss of two reducing equivalents (NADH and NADPH). 1H NMR spectroscopy was used to test for this cycling in blood extracts after administration of 1,1-²H₂ ethanol. No futile cycling was detected either during the initial 2 weeks of feeding or after the entire feeding period.     

Molecular basis of essential fructosuria: molecular cloning and mutational analysis of human ketohexokinase (fructokinase)

Essential fructosuria is one of the oldest known inborn errorsof metabolism. It is a benign condition which is believed toresult from deficiency of hepatic fructokinase (ketohexokinase,KHK, E.C.2.7.1.3). This enzyme catalyses the first step of metabolismof dietary fructose, conversion of fructose to fructose-1-phosphate.Despite the early recognition of this disorder, the primarystructure of human KHK and the molecular basis of essentialfructosuria have not been previously defined. In this report,the isolation and sequencing of full-length cDNA clones encodinghuman ketohexokinase are described. Alternative mRNA speciesand alternative KHK isozymes are produced by alternative polyadenylationand splicing of the KHK gene. The KHK proteins show a high levelof sequence conservation relative to rat KHK. Direct evidencethat mutation of the KHK structural gene is the cause of essentialfructosuria was also obtained. In a well-characterized family,in which three of eight siblings have fructosurla, all affectedindividuals are compound heterozygotes for two mutations Gly40Argand Ala43Thr. Both mutations result from G     

Granulocyte Colony-stimulating Factor Supports Liver Regeneration in a Small-for-size Liver Remnant Mouse Model

Experimental partial hepatectomy of more than 80% of the liver weight bears an increased mortality in rodents, due to impaired hepatic regeneration in small-for-size liver remnants. Granulocyte colony-stimulating factor (G-CSF) promotes progenitor cell expansion and mobilization and also has immunomodulatory properties. The aim of this study was to determine the effect of systemically administered G-CSF on liver regeneration and animal survival in a small-for-size liver remnant mouse model. Mice were preconditioned daily for 5 days with subcutaneous injections of 5 μg G-CSF or aqua ad injectabile. Subsequently, 83% partial hepatectomy was performed by resecting the median, the left, the caudate, and the right inferior hepatic lobes in all animals. Daily sham or G-CSF injection was continued. Survival was significantly better in G-CSF-treated animals (P < 0.0001). At 36 and 48 h after microsurgical hepatic resection, markers of hepatic proliferation (Ki67, BrdU) were elevated in G-CSF-treated mice compared to sham injected control animals (P < 0.0001) and dry liver weight was increased (P < 0.05). G-CSF conditioning might prove to be useful in patients with small-for-size liver remnants after extended hepatic resections due to primary or secondary liver tumors or in the setting of split liver transplantation. Presented at the Forty-seventh Annual Meeting of The Society for Surgery of the Alimentary Tract, Los Angeles, CA, May 14–19, 2006 (poster presentation).     

Phenotypic variability of a distinct deletion in McLeod syndrome

The X‐linked McLeod neuroacanthocytosis syndrome strongly resembles Huntington's disease and has been reported in various countries world‐wide. Herein, we report two Chilean brothers with predominant psychiatric features at disease onset including schizophrenia‐like psychosis and obsessive compulsive disorder. Molecular genetic analysis revealed a small deletion in the XK gene (938‐942delCTCTA), which has been already described in a North American patient of Anglo‐Saxon descent and a Japanese family, presenting with seizures, muscle atrophy or chorea yet absence of psychiatric features. These findings argue against a founder effect and indicate a profound phenotypic variability associated with the 938‐942delCTCTA deletion. Our report supports the inclusion of McLeod syndrome in the differential diagnosis of Huntington's disease as well as acute psychosis in male subjects. © 2007 Movement Disorder Society