Progressive Multifocal Leukoencephalopathy Following Combined Rituximab-Based Immune-Chemotherapy for Post-transplant Lymphoproliferative Disorder in a Renal Transplant Recipient: A Case Report.

BACKGROUND: Transplant recipients are at risk of developing progressive multifocal leukoencephalopathy (PML), an opportunistic infection due to reactivation of JC virus. Post-transplant lymphoproliferative disorders (PTLDs) represent a common malignancy in this population, and antiCD20-therapy has become an established component of its treatment. CASE PRESENTATION: We describe the first case of a renal allograft transplant recipient with PTLD who received rituximab-based immune-chemotherapy and developed PML shortly thereafter. Despite early suspicion and diagnosis, the disease ran a relentlessly progressive course, and the patient succumbed to his illness shortly thereafter. CONCLUSION: PML should be strongly suspected whenever unusual neurologic symptoms appear in the context of immunosuppression. Clinicians and patients should be aware of the potential for PML after rituximab therapy.

2'-(R)-Fluorinated mC, hmC, fC and caC triphosphates are substrates for DNA polymerases and TET-enzymes.

A deeper investigation of the chemistry that occurs on the newly discovered epigenetic DNA bases 5-hydroxymethyl-(hmdC), 5-formyl-(fdC), and 5-carboxy-deoxycytidine (cadC) requires chemical tool compounds, which are able to dissect the different potential reaction pathways in cells. Here we report that the 2'-(R)-fluorinated derivatives F-hmdC, F-fdC, and F-cadC, which are resistant to removal by base excision repair, are good substrates for DNA polymerases and TET enzymes. This result shows that the fluorinated compounds are ideal tool substances to investigate potential C-C-bond cleaving reactions in the context of active demethylation.

Differences in the intrinsic immunogenicity and allergenicity of Bet v 1 and related food allergens revealed by site-directed mutagenesis.

BACKGROUND: Birch pollen allergies are frequently associated with adverse reactions to various fruits, nuts, or vegetables, described as pollen-food syndrome (PFS) and caused by cross-reactive IgE antibodies primarily directed against Bet v 1. Specific immunotherapy (SIT) represents an effective treatment for inhalant allergies; however, successful birch pollen SIT does not correlate well with the amelioration of concomitant food allergies. METHODS: As vaccine candidates, apple Mal d 1 as well as hazelnut Cor a 1 derivatives were designed by in silico backbone analyses of the respective allergens. The proteins were produced by site-directed mutagenesis as fold variants of their parental allergens. Because Mal d 1 and Cor a 1 form cysteine-mediated aggregates, nonaggregative cysteine to serine mutants were also generated. The proteins were characterized physicochemically, immunologically, and in in vivo models with or without adjuvant. RESULTS: The structurally modified proteins showed significantly decreased IgE binding capacity. Notably, both in vivo models revealed reduced immunogenicity of the hypoallergenic fold variants. When formulated with alum, the monomeric cysteine mutants induced a similar immune response as the aggregated parental allergens, which is in contrast with data published on Bet v 1. CONCLUSION: These findings lead to the suggestion that the Bet v 1 structure has unique intrinsic properties, which could account for its high allergenicity. Obviously, these characteristics are not entirely shared with its food homologues from apple and hazelnut. Thus, it is important to tackle pollen-related food allergies from different angles for the generation of effective vaccine candidates to treat birch PFS.

Effects of unconjugated bilirubin on chromosomal damage in individuals with Gilbert's syndrome measured with the micronucleus cytome assay.

Circulating unconjugated bilirubin (UCB) has been reported to protect against lung and colorectal cancer. The present study aimed to explore, for the first time, whether mildly elevated circulating UCB, as found in Gilbert`s syndrome (GS), is associated with changes of DNA damage. A random 76 individuals, matched for age and gender, were recruited from the general population and allocated into the GS group (UCB ≥ 17.1 µM; n = 38) or control group (UCB <17.1 µM; n = 38). Chromosomal and cytological changes were determined in lymphocytes and buccal cells using the cytokinesis-block micronucleus cytome assay (CBMN) and buccal micronucleus cytome assay (BMcyt). No significant differences were found between GS subjects and the control group in the CBMN and BMcyt determined endpoints. Subsequently, when age dependency of effects were analysed, lower formation of buccal micronucleated cells (by 73.3%) and buccal nuclear buds (by 70.9%) in the GS subgroup ≥ 30 years were found, compared to the GS subgroup <30 years. These findings suggest DNA protection in epithelial tissue of older individuals with GS.

Basis of the gabamimetic profile of ethanol.

This article summarizes the proceedings of a symposium held at the 2005 Research Society on Alcoholism meeting. The initial presentation by Dr. Wallner provided evidence that selected GABA(A) receptors containing the delta subunit display sensitivity to low intoxicating ethanol concentrations and this sensitivity is further increased by a mutation in the cerebellar alpha6 subunit, found in alcohol-hypersensitive rats. Dr. Mameli reported that ethanol affects gamma-aminobutyric acid (GABA) function by affecting neural circuits that influence GABA release. Dr. Parsons presented data from electrophysiological and microdialysis investigations that ethanol is capable of releasing GABA from presynaptic terminals. Dr. Morrow demonstrated that systemic ethanol increases neuroactive steroids in brain, the absence of which alters various functional responses to ethanol. Dr. Criswell presented evidence that the ability of ethanol to increase GABA was apparent in some, but not all, brain regions indicative of regional specificity. Further, Dr. Criswell demonstrated that neurosteroids alone and when synthesized locally by ethanol act postsynaptically to enhance the effect of GABA released by ethanol in a region specific manner. Collectively, this series of reports support the GABAmimetic profile of acutely administered ethanol being dependent on several specific mechanisms distinct from a direct effect on the major synaptic isoforms of GABA(A) receptors.

Hormonal profile and fertility in patients with Anderson-Fabry disease.

Anderson-Fabry disease is a glycosphingolipid storage disorder with an X-linked recessive inheritance. The alpha-galactosidase A deficiency leads to a progressive accumulation of globotriaosylceramide in the endothelium and tissue cells of various organs. The kidney, heart and brain are predominantly affected. Reports on endocrine function and fertility rates in patients with Anderson-Fabry disease are sparse. In the present study, we assessed ovarian, testicular and adrenal function in a cohort of patients with Anderson-Fabry disease. Plasma follicle-stimulating hormone, luteinizing hormone, prolactin, estradiol, testosterone, sex hormone-binding globulin, somatotropin, insulin-like growth factor-I and serum cortisol were measured in 13 patients (six female and seven male), currently observed in an outpatient clinic. The profile revealed an undisturbed hormonal function and a normal fertility rate in both male and female Anderson-Fabry patients when compared with the corresponding Austrian population.

Granulocyte function in patients with L-ferritin iron-responsive element (IRE) 39C-->T-positive hereditary hyperferritinaemia-cataract syndrome.

BACKGROUND: Hereditary hyperferritinaemia-cataract syndrome (HHCS) is an autosomal dominant trait associated with mutations in the iron responsive element (IRE) of the ferritin light-chain (L-ferritin) gene. Patients typically show elevated serum ferritin concentrations without iron overload and a bilateral cataract. Hyperferritinaemia can be associated with granulocyte dysfunction in patients with thalassemia beta and in haemodialysis patients. The effect of increased L-ferritin levels on granulocyte function in patients with HHCS is unknown. MATERIAL AND METHODS: We examined glucose uptake, oxidative burst, chemotaxis, phagocytosis, apoptosis and intracellular calcium concentrations in polymorphonuclear leucocytes (PMNLs) of five affected members of a family with HHCS and in five healthy individuals matched for age and gender. RESULTS: Mutation testing revealed a 39C-->T transition in IRE in all five patients with HHCS. Serum ferritin levels of patients ranged between 907 and 2030 microg L(-1), respectively. In comparison with healthy individuals, PMNLs of patients with HHCS showed a significant increase in PMA-mediated stimulation of the oxidative burst, as well as a significantly higher stimulation of glucose uptake but no difference with respect to chemotaxis, phagocytosis, apoptosis and intracellular calcium concentrations. CONCLUSION: In summary, our study suggests that hyperferritinaemia in patients with IRE 39C-->T-positive HHCS is associated with activation of PMNLs but not with disturbance of fundamental PMNL function.

A neuronal beta subunit (KCNMB4) makes the large conductance, voltage- and Ca2+-activated K+ channel resistant to charybdotoxin and iberiotoxin.

Large conductance voltage and Ca(2+)-activated K(+) (MaxiK) channels couple intracellular Ca(2+) with cellular excitability. They are composed of a pore-forming alpha subunit and modulatory beta subunits. The pore blockers charybdotoxin (CTx) and iberiotoxin (IbTx), at nanomolar concentrations, have been invaluable in unraveling MaxiK channel physiological role in vertebrates. However in mammalian brain, CTx-insensitive MaxiK channels have been described [Reinhart, P. H., Chung, S. & Levitan, I. B. (1989) Neuron 2, 1031-1041], but their molecular basis is unknown. Here we report a human MaxiK channel beta-subunit (beta4), highly expressed in brain, which renders the MaxiK channel alpha-subunit resistant to nanomolar concentrations of CTx and IbTx. The resistance of MaxiK channel to toxin block, a phenotype conferred by the beta4 extracellular loop, results from a dramatic ( approximately 1,000 fold) slowdown of the toxin association. However once bound, the toxin block is apparently irreversible. Thus, unusually high toxin concentrations and long exposure times are necessary to determine the role of "CTx/IbTx-insensitive" MaxiK channels formed by alpha + beta4 subunits.

[Angioleiomyoma of the gallbladder: a rare cause of hemobilia in a patient on dialysis]. / Angioleiomyom der Gallenblase. Seltene Ursache einer Hämobilie bei einem Dialysepatienten.

HISTORY AND FINDINGS: Acute colicky upper abdominal pain occurred in a 47-year-old man on renal dialysis who also had chronic recurrent pancreatitis. On physical examination he was noted to be slightly jaundiced and he had slight pain when the liver edge was palpated. A few days later melaena developed and the haemoglobin concentration fell from normal levels to 6.9 g/dl. INVESTIGATIONS: Serology gave no evidence of acute pancreatitis, but biochemical tests indicated cholestasis. Ultrasonography revealed widening of the intra- and extrahepatic biliary tract. Endoscopic retrograde cholecystopancreatography demonstrated bleeding from the biliary tract (haemobilia) as the source of the bleeding. Selective angiography of the coeliac trunk showed extravasation in the region of the gallbladder. TREATMENT AND COURSE: As a vascular anomaly in the gallbladder was suspected, a cholecystectomy was performed. The surgical specimen revealed an angioleiomyoma of the gallbladder. The postoperative course was without complications and there was no further haemobilia. CONCLUSIONS: Haemobilia is a relatively rare cause of upper gastrointestinal bleeding. It is usually due to trauma (accidental or iatrogenic) to the liver or the biliary tract. Rarely, as in this case, it can be caused by a benign mesenchymal neoplasm. Clotting disorder in uraemia or intermittent heparin administration for dialysis may in this patient have contributed to the bleeding.

Angiotensin-converting enzyme gene polymorphism determines the antiproteinuric and systemic hemodynamic effect of enalapril in patients with proteinuric renal disease. Austrian Study Group of the Effects of Enalapril Treatment in Proteinuric Renal Disease.

Angiotensin-converting enzyme (ACE) inhibitors are known to reduce blood pressure and proteinuria in a variety of different glomerular diseases. Nonetheless, a marked interindividual difference in the efficacy of these agents exists. The activity of the ACE and therefore of the renin-angiotensin-aldosterone system (RAAS) has been shown to be under genetic influence. Patients with a deletion genotype at the intron 16 of the ACE gene have been shown to exhibit higher activity of plasmatic ACE when compared to patients with the insertion genotype. We therefore studied prospectively the hemodynamic and antiproteinuric effect of a 6-month therapy with enalapril in patients with biopsy-proven proteinuric glomerular diseases and the DD (n = 10) and ID/II (n = 26) genotype. Although patients with the DD genotype received a slightly higher dose of enalapril, blood pressure and proteinuria did not change significantly. However, both were significantly reduced in the II/ID group after 10 weeks and 6 months of therapy. Creatinine clearance decreased steadily in DD patients. In II/ID patients, creatinine clearance was reduced significantly after 10 weeks of therapy but increased again thereafter and the value at 6 months was again comparable to the one obtained in the DD patients. We conclude from our study that the ACE genotype influences the blood pressure-lowering and antiproteinuric effect of enalapril in patients with proteinuric glomerular disease.

[Complications of diagnostic and interventional colonoscopy]. / Komplikationen der diagnostischen und interventionellen Koloskopie.

The Wels General Hospital is a large teaching hospital where all endoscopies are performed by the staff of the First Department of Internal Medicine. The reports of 10,000 colonoscopies between January 1st, 1986 and February 15th, 1994 were scrutinized by the authors, 15 complications of diagnostic and therapeutic colonoscopies were identified. There were seven perforations and one ileus associated with diagnostic colonoscopy (8989 patients) and five bleeding episodes and two perforations after polypectomy (1609 polyps removed; 1011 patients). Four bleeding episodes after polypectomy were controlled endoscopically with circumlesional injection of adrenaline. One patient required emergency surgical treatment. All perforations were treated surgically. Two elderly patients with multimorbidity died after perforation and emergency surgery (peritonitis and pulmonary embolism being the respective causes of death). The frequency of perforation was 0.09% (9 of 10,000), the mortality rate was 0.02% (2 of 10,000), and the bleeding rate after polypectomy was 0.05% (5 of 10,000). The frequency of complications in relation to the experience of the physicians revealed that five of seven perforations associated with diagnostic colonoscopy occurred in the hands of less experienced endoscopists (doctors in training with less than 400 completed endoscopies). Life-threatening complications related to the performance of flexible fiberoptic colonoscopies are rare, especially during diagnostic procedures. As reported in the literature, our results show that the risks are greatest with relatively inexperienced physicians but are not entirely avoidable even with the most experienced endoscopists.

[Spontaneous regression of a small cell bronchial carcinoma]. / Spontanregression eines kleinzelligen Bronchuskarzinoms.

A circular focus of 1 cm diameter was discovered by chance on a thoracic x-ray of a female patient of 66 years of age suffering from chronic interstitial nephritis due to analgesics. Bronchoscopic suction revealed histologically a small-cell carcinoma of the lung but there was no indication of formation of metastases. The patient refused any tumor-specific treatment. In the further course of the disease the focus showed up radiologically for seven months and was then no longer visible throughout the following 14 months. The patient finally died subsequent to an extensive posterior myocardial infarction. Postmortem examination excluded the presence of a primary tumor of the lung or metastases. Our case suggests the rare occurrence of a spontaneous regression of a small-cell bronchial carcinoma. Although spontaneous regression of malignant diseases is ascribed to immunological factors, such regression can also occur if the immunological system is impaired, as had been the case in this particular patient with chronic renal insufficiency.

Tn polyagglutinability occurring in a patient with B cell lymphoma.

A case of polymorphic immunocytoma (B cell lymphoma) coinciding with expression of Tn antigen on a population of erythrocytes is presented. Tn activation was found incidentally by screening blood samples of patients suffering from hematologic malignancies with a Tn specific lectin from Salvia sclarea. So far, Tn activation has been reported only in apparently healthy subjects or in subjects suffering from or developing myeloid leukemia.