Showing papers by "Heidelberg University published in 1998"

Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells.

Abstract: Melanoma is the main cause of death in patients with skin cancer1. Cytotoxic T lymphocytes (CTLs) attack melanoma cells in an HLA-restricted and tumor antigen-specific manner. Several melanoma-associated tumor antigens have been identified2. These antigens are suitable candidates for a vaccination therapy of melanoma. Dendritic cells (DCs) are antigen-presenting cells (APCs) specialized for the induction of a primary T-cell response3. Mouse studies have demonstrated the potent capacity of DCs to induce antitu-mor immunity4–11. In the present clinical pilot study, DCs were generated in the presence of granulocyte/macrophage-colony stimulating factor (GM-CSF) and interleukin 4 (IL-4) and were pulsed with tumor lysate or a cocktail of peptides known to be recognized by CTLs, depending on the patient's HLA haplotype. Keyhole limpet hemocyanin (KLH) was added as a CD4 helper antigen and immunological tracer molecule. Sixteen patients with advanced melanoma were immunized on an outpatient basis. Vaccination was well tolerated. No physical sign of autoimmunity was detected in any of the patients. DC vaccination induced de-layed-type hypersensitivity (DTH) reactivity toward KLH in all patients, as well as a positive DTH reaction to peptide-pulsed DCs in 11 patients. Recruitment of peptide-specific CTLs to the DTH challenge site was also demonstrated. Therefore, antigen-specific immunity was induced during DC vaccination. Objective responses were evident in 5 out of 16 evaluated patients (two complete responses, three partial responses) with regression of metastases in various organs (skin, soft tissue, lung, pancreas) and one additional minor response. These data indicate that vaccination with autologous DCs generated from peripheral blood is a safe and promising approach in the treatment of metastatic melanoma. Further studies are necessary to demonstrate clinical effectiveness and impact on the survival of melanoma patients.

Molecular Conformation in Oligo(ethylene glycol)-Terminated Self-Assembled Monolayers on Gold and Silver Surfaces Determines Their Ability To Resist Protein Adsorption

Abstract: We report data from infrared absorption (FTIR) and X-ray photoelectron spectroscopies that correlate the molecular conformation of oligo(ethylene glycol) (OEG)-terminated self-assembled alkanethiolate monolayers (SAMs) with the ability of these films to resist protein adsorption. We studied three different SAMs of alkanethiolates on both evaporated Au and Ag surfaces. The SAMs were formed from substituted 1-undecanethiols with either a hydroxyl-terminated hexa(ethylene glycol) (EG6-OH) or a methoxy-terminated tri(ethylene glycol) (EG3-OMe) end group, or a substituted 1-tridecanethiol chain with a methoxy-terminated tri(ethylene glycol) end group and a −CH2OCH3 side chain at the C-12 atom (EG[3,1]-OMe). The infrared data of EG6-OH-terminated SAMs on both Au and Ag surfaces reveal the presence of a crystalline helical OEG phase, coexisting with amorphous OEG moieties; the EG[3,1]-OMe-terminated alkanethiolates on Au and Ag show a lower absolute coverage and greater disorder than the two other compounds. The...

Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase.

Abstract: Peutz-Jeghers (PJ) syndrome is an autosomal-dominant disorder characterized by melanocytic macules of the lips, multiple gastrointestinal hamartomatous polyps and an increased risk for various neoplasms, including gastrointestinal cancer. The PJ gene was recently mapped to chromosome 19p13.3 by linkage analysis, with the highest lod score at marker D19S886. In a distance of 190 kb proximal to D19S886, we identified and characterized a novel human gene encoding the serine threonine kinase STK11. In a three-generation PJ family, we found an STK11 allele with a deletion of exons 4 and 5 and an inversion of exons 6 and 7 segregating with the disease. Sequence analysis of STK11 exons in four unrelated PJ patients has identified three nonsense and one acceptor splice site mutations. All five germline mutations are predicted to disrupt the function of the kinase domain. We conclude that germline mutations in STK11, probably in conjunction with acquired genetic defects of the second allele in somatic cells, cause the manifestations of PJ syndrome.

Methods for analyzing anisotropic flow in relativistic nuclear collisions

Abstract: The strategy and techniques for analyzing anisotropic flow (directed, elliptic, etc.) in relativistic nuclear collisions are presented. The emphasis is on the use of the Fourier expansion of azimuthal distributions. We present formulas relevant for this approach, and in particular, show how the event multiplicity enters into the event plane resolution. We also discuss the role of nonflow correlations and a method for introducing flow into a simulation.

On the validity of the Beck Depression Inventory. A review.

Abstract: The present review discusses validity aspects of the Beck Depression Inventory (BDI) on the basis of meta-analyses of studies on the psychometric properties. Shortcomings of the BDI are its high item difficulty, lack of representative norms, and thus doubtful objectivity of interpretation, controversial factorial validity, instability of scores over short time intervals (over the course of 1 day), and poor discriminant validity against anxiety. Advantages of the inventory are its high internal consistency, high content validity, validity in differentiating between depressed and nondepressed subjects, sensitivity to change, and international propagation. The present paper outlines agreements and contradictions between the various studies on the BDI and discusses the potential factors (composition of the subject sample, statistical procedures, point in time of measurement) accounting for the variance in their results.

Axonal swellings and degeneration in mice lacking the major proteolipid of myelin

Abstract: Glial cells produce myelin and contribute to axonal morphology in the nervous system. Two myelin membrane proteolipids, PLP and DM20, were shown to be essential for the integrity of myelinated axons. In the absence of PLP-DM20, mice assembled compact myelin sheaths but subsequently developed widespread axonal swellings and degeneration, associated predominantly with small-caliber nerve fibers. Similar swellings were absent in dysmyelinated shiverer mice, which lack myelin basic protein (MBP), but recurred in MBP*PLP double mutants. Thus, fiber degeneration, which was probably secondary to impaired axonal transport, could indicate that myelinated axons require local oligodendroglial support.

Association of a human G-protein β3 subunit variant with hypertension

Abstract: Hypertension is a common disorder of multifactorial origin that constitutes a major risk factor for cardiovascular events such as stroke and myocardial infarction. Previous studies demonstrated an enhanced signal transduction via pertussis toxin-sensitive G proteins in lymphoblasts and fibroblasts from selected patients with essential hypertension. We have detected a novel polymorphism (C825T) in exon 10 of the gene encoding the beta3 subunit of heterotrimeric G proteins (GNB3). The T allele is associated with the occurrence of a splice variant, GNB3-s (encoding G beta3-s), in which the nucleotides 498-620 of exon 9 are deleted. This in-frame deletion causes the loss of 41 amino acids and one WD repeat domain of the G beta subunit. By western-blot analysis, G beta3-s appears to be predominantly expressed in cells from individuals carrying the T allele. Significant enhancement of stimulated GTPgammaS binding to Sf9 insect cells expressing G beta3-s together with G alpha(i)2 and G gamma5 indicates that this splice variant is biologically active. Genotype analysis of 427 normotensive and 426 hypertensive subjects suggests a significant association of the T allele with essential hypertension.

Reduction in New Metastases in Breast Cancer with Adjuvant Clodronate Treatment

Abstract: Background Bisphosphonates are effective against the increased bone resorption caused by certain diseases because they inhibit the activity of osteoclasts. In patients who have breast cancer and metastatic bone disease, the bisphosphonate clodronate (clodronic acid) reduces the frequency of skeletal complications. Experiments in animals and preliminary clinical observations indicate that early clodronate therapy reduces the incidence of new bony metastases in breast cancer. We investigated the effects of clodronate on the incidence and extent of new metastases in patients with breast cancer. Methods Between 1990 and 1995, 302 patients with primary breast cancer and tumor cells in the bone marrow (the presence of which is a risk factor for the development of distant metastases) were randomly assigned to receive clodronate at a dose of 1600 mg per day orally for two years (157 patients) or standard follow-up (145 patients). The median length of observation was 36 months. All patients in both groups received...

Radiation pneumonitis as a function of mean lung dose: An analysis of pooled data of 540 patients

Abstract: Purpose: To determine the relation between the incidence of radiation pneumonitis and the three-dimensional dose distribution in the lung. Methods and Materials: In five institutions, the incidence of radiation pneumonitis was evaluated in 540 patients. The patients were divided into two groups: a Lung group, consisting of 399 patients with lung cancer and 1 esophagus cancer patient and a Lymph./Breast group with 78 patients treated for malignant lymphoma, 59 for breast cancer, and 3 for other tumor types. The dose per fraction varied between 1.0 and 2.7 Gy and the prescribed total dose between 20 and 92 Gy. Three-dimensional dose calculations were performed with tissue density inhomogeneity correction. The physical dose distribution was converted into the biologically equivalent dose distribution given in fractions of 2 Gy, the normalized total dose (NTD) distribution, by using the linear quadratic model with an α/β ratio of 2.5 and 3.0 Gy. Dose–volume histograms (DVHs) were calculated considering both lungs as one organ and from these DVHs the mean (biological) lung dose, NTD mean , was obtained. Radiation pneumonitis was scored as a complication when the pneumonitis grade was grade 2 (steroids needed for medical treatment) or higher. For statistical analysis the conventional normal tissue complication probability (NTCP) model of Lyman (with n = 1) was applied along with an institutional-dependent offset parameter to account for systematic differences in scoring patients at different institutions. Results: The mean lung dose, NTD mean , ranged from 0 to 34 Gy and 73 of the 540 patients experienced pneumonitis, grade 2 or higher. In all centers, an increasing pneumonitis rate was observed with increasing NTD mean . The data were fitted to the Lyman model with NTD 50 = 31.8 Gy and m = 0.43, assuming that for all patients the same parameter values could be used. However, in the low dose range at an NTD mean between 4 and 16 Gy, the observed pneumonitis incidence in the Lung group (10%) was significantly ( p = 0.02) higher than in the Lymph./Breast group (1.4%). Moreover, between the Lung groups of different institutions, also significant ( p = 0.04) differences were present: for centers 2, 3, and 4, the pneumonitis incidence was about 13%, whereas for center 5 only 3%. Explicitly accounting for these differences by adding center-dependent offset values for the Lung group, improved the data fit significantly ( p −5 ) with NTD 50 = 30.5 ± 1.4 Gy and m = 0.30 ± 0.02 (± 1 SE) for all patients, and an offset of 0–11% for the Lung group, depending on the center. Conclusions: The mean lung dose, NTD mean , is relatively easy to calculate, and is a useful predictor of the risk of radiation pneumonitis. The observed dose–effect relation between the NTD mean and the incidence of radiation pneumonitis, based on a large clinical data set, might be of value in dose-escalating studies for lung cancer. The validity of the obtained dose–effect relation will have to be tested in future studies, regarding the influence of confounding factors and dose distributions different from the ones in this study.

Fgf8 is mutated in zebrafish acerebellar (ace) mutants and is required for maintenance of midbrain-hindbrain boundary development and somitogenesis

Abstract: We describe the isolation of zebrafish Fgf8 and its expression during gastrulation, somitogenesis, fin bud and early brain development. By demonstrating genetic linkage and by analysing the structure of the Fgf8 gene, we show that acerebellar is a zebrafish Fgf8 mutation that may inactivate Fgf8 function. Homozygous acerebellar embryos lack a cerebellum and the midbrain-hindbrain boundary organizer. Fgf8 function is required to maintain, but not initiate, expression of Pax2.1 and other marker genes in this area. We show that Fgf8 and Pax2.1 are activated in adjacent domains that only later become overlapping, and activation of Fgf8 occurs normally in no isthmus embryos that are mutant for Pax2.1. These findings suggest that multiple signaling pathways are independently activated in the midbrain-hindbrain boundary primordium during gastrulation, and that Fgf8 functions later during somitogenesis to polarize the midbrain. Fgf8 is also expressed in a dorsoventral gradient during gastrulation and ectopically expressed Fgf8 can dorsalize embryos. Nevertheless, acerebellar mutants show only mild dorsoventral patterning defects. Also, in spite of the prominent role suggested for Fgf8 in limb development, the pectoral fins are largely unaffected in the mutants. Fgf8 is therefore required in development of several important signaling centers in the zebrafish embryo, but may be redundant or dispensable for others.

Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease

Abstract: The search for the causes of neurodegenerative disorders is a major theme in brain research. Acquired disturbances of several aspects of cellular metabolism appear pathologically important in sporadic Alzheimer's disease (SDAT). Among these brain glucose utilisation is reduced in the early stages of the disease and the regulatory enzymes important for glucose metabolism are reduced. In the brain, insulin, insulin-like growth factors and their receptors regulate glucose metabolism and promote neuronal growth. To detect changes in the functional activity of the brain insulin neuromodulatory system of SDAT patients, we determined the concentrations of insulin and c-peptide as well as insulin receptor binding and IGF-I receptor binding in several regions of postmortem brain cortex during aging and Alzheimer's disease. Additionally, we performed immunohistochemical staining with antibodies against insulin in neocortical brain areas in SDAT and controls. We show for the first time that insulin and c-peptide concentration in the brain are correlated and decrease with aging, as do brain insulin receptor densities. Weak insulin-immunoreactivity could be demonstrated histochemically in pyramidal neurons of controls, whereas in SDAT a stronger insulin-immunoreactivity was found. On a biochemical level, insulin and c-peptide levels were reduced compared to middle-aged controls, but were unchanged compared to age-matched controls. Brain insulin receptor densities in SDAT were decreased compared to middle-aged controls, but increased in comparison to age-matched controls. IGF-I receptor densities were unchanged in aging and in SDAT. Tyrosine kinase activity, a signal transduction mechanism common to both receptor systems, was reduced in SDAT in comparison to middle-aged and age-matched control groups. These data are consistent with a neurotrophic role of insulin in the human brain and a disturbance of insulin signal transduction in SDAT brain and favor the hypothesis that insulin dependent functions may be of pathogenetic relevance in sporadic SDAT.

Early Hemicraniectomy in Patients With Complete Middle Cerebral Artery Infarction

Abstract: Background and Purpose—Malignant, space-occupying supratentorial ischemic stroke is characterized by a mortality rate of up to 80%. Several reports indicate a beneficial effect of hemicraniectomy in this situation. However, whether and when decompressive surgery is indicated in these patients is still a matter of debate. Methods—In an open, prospective trial we performed hemicraniectomy in 63 patients with acute complete middle cerebral artery infarction. Initial clinical presentation was assessed by the Scandinavian Stroke Scale (SSS) and the Glasgow Coma Scale (GCS). All survivors were reexamined 3 months after surgical decompression, with the clinical evaluation graded according to the Rankin Scale (RS) and Barthel Index (BI). We analyzed the influence of early decompressive surgery ( 24 hours after first reversible signs of herniation) on mortality, functional outcome, and the length of t...

Moderate Hypothermia in the Treatment of Patients With Severe Middle Cerebral Artery Infarction

Abstract: Background and Purpose—Animal research and clinical studies in head trauma patients suggest that moderate hypothermia may improve outcome by attenuating the deleterious metabolic processes in neuronal injury. Clinical studies on moderate hypothermia in the treatment of acute ischemic stroke patients are still lacking. Methods—Moderate hypothermia was induced in 25 patients with severe ischemic stroke in the middle cerebral artery (MCA) territory for therapy of postischemic brain edema. Hypothermia was induced within 14±7 hours after stroke onset and achieved by external cooling with cooling blankets, cold infusions, and cold washing. Patients were kept at 33°C body-core temperature for 48 to 72 hours, and intracranial pressure (ICP), cerebral perfusion pressure, and brain temperature were monitored continuously. Outcome at 4 weeks and 3 months after the stroke was analyzed with the Scandinavian Stroke Scale (SSS) and Barthel index. The side effects of induced moderate hypothermia were analyzed. Results—Fo...

Autosomal Recessive Retinitis Pigmentosa and Cone-rod Dystrophy Caused by Splice Site Mutations in the Stargardt's Disease Gene ABCR

Abstract: Ophthalmological and molecular genetic studies were performed in a consanguineous family with individuals showing either retinitis pigmentosa (RP) or cone-rod dystrophy (CRD). Assuming pseudodominant (recessive) inheritance of allelic defects, linkage analysis positioned the causal gene at 1p21-p13 (lod score 4.22), a genomic segment known to harbor the ABCR gene involved in Stargardt's disease (STGD) and age-related macular degeneration (AMD). We completed the exon-intron structure of the ABCR gene and detected a severe homozygous 5[prime] splice site mutation, IVS30+1G->T, in the four RP patients. The five CRD patients in this family are compound heterozygotes for the IVS30+1G->T mutation and a 5[prime] splice site mutation in intron 40 (IVS40+5G->A). Both splice site mutations were found heterozygously in two unrelated STGD patients, but not in 100 control individuals. In these patients the second mutation was either a missense mutation or unknown. Since thus far no STGD patients have been reported to carry two ABCR null alleles and taking into account that the RP phenotype is more severe than the STGD phenotype, we hypothesize that the intron 30 splice site mutation represents a true null allele. Since the intron 30 mutation is found heterozygously in the CRD patients, the IVS40+5G->A mutation probably renders the exon 40 5[prime] splice site partially functional. These results show that mutations in the ABCR gene not only result in STGD and AMD, but can also cause autosomal recessive RP and CRD. Since the heterozygote frequency for ABCR mutations is estimated at 0.02, mutations in ABCR might be an important cause of autosomal recessive and sporadic forms of RP and CRD.

AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept

Abstract: Objective: This is the first part of a bipartite review that summarizes the rising knowledge on the molecular mechanisms underlying the action of advanced glycation endproducts (AGEs) and their contribution to diabetic complications and vascular disease. While the first part presented here focusses on AGE formation, the second part will describe the AGE-protein/receptor interactions and their role in mediating AGE-dependent intracellular signalling. Results: Nonenzymatic glycation, in which reducing sugars are covalently attached to free amino groups and ultimately form AGEs, has been found to occur during normal aging and at accelerated rate in diabetes mellitus. Oxidation, accompanying glycation in vivo, further supports chemical modifications. AGE formation and protein crosslinking are irreversible processes that alter the structural and functional properties of proteins, lipid components and nucleic acids. AGE modifications do not only change the physicochemical properties of the afflicted molecules, but also induce cellular signalling, activation of transcription factors and subsequent gene expression in vitro and in vivo. Conclusions: AGEs elicit a wide range of cell-mediated responses that might contribute to the pathogenesis of diabetic complications, vascular and renal disease and Alzheimer's disease. Substances that inhibit AGE formation, reduce oxidative stress or destroy already formed crosslinks may limit the progression of disease and may offer new tools for therapeutic interventions in the therapy of AGEs mediated disease.

Mixing and Decay Constants of Pseudoscalar Mesons

Abstract: We propose a new eta-eta' mixing scheme where we start from the quark flavor basis and assume that the decay constants in that basis follow the pattern of particle state mixing. On exploiting the divergences of the axial vector currents - which embody the axial vector anomaly - all basic parameters are fixed to first order of flavor symmetry breaking. That approach naturally leads to a mass matrix, quadratic in the masses, with specified elements. We also test our mixing scheme against experiment and determine corrections to the first order values of the basic parameters from phenomenology. Finally, we generalize the mixing scheme to include the eta(c). Again the divergences of the axial vector currents fix the mass matrix and, hence, mixing angles and the charm content of the eta and eta'.

Importin beta, transportin, RanBP5 and RanBP7 mediate nuclear import of ribosomal proteins in mammalian cells.

Abstract: The assembly of eukaryotic ribosomal subunits takes place in the nucleolus and requires nuclear import of ribosomal proteins. We have studied this import in a mammalian system and found that the classical nuclear import pathway using the importin α/β heterodimer apparently plays only a minor role. Instead, at least four importin β‐like transport receptors, namely importin β itself, transportin, RanBP5 and RanBP7, directly bind and import ribosomal proteins. We found that the ribosomal proteins L23a, S7 and L5 can each be imported alternatively by any of the four receptors. We have studied rpL23a in detail and identified a very basic region to which each of the four import receptors bind avidly. This domain might be considered as an archetypal import signal that evolved before import receptors diverged in evolution. The presence of distinct binding sites for rpL23a and the M9 import signal in transportin, and for rpL23a and importin α in importin β might explain how a single receptor can recognize very different import signals.

Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats

Abstract: Drastic abnormalities have been demonstrated to occur in cerebral glucose and energy metabolism in sporadic Alzheimer's disease, pointing to a primary disturbance in neuronal insulin and insulin receptor signal transduction and contributing to the causation of dementia. The compound streptozotocin (STZ) is known to inhibit insulin receptor function. The study was designed to investigate whether intracerebroventricularly (icv) applied STZ would inhibit neuronal insulin receptor function and would induce changes in both behavior and neuronal energy metabolism. Adult rats with icv-injected STZ developed long-term and progressive deficits in learning, memory, and cognitive behavior, indicated by decreases in working and reference memory in the holeboard task and the passive avoidance paradigm, along with a permanent and ongoing cerebral energy deficit. This animal model may be appropriate for investigations related to sporadic Alzheimer's dementia.

Reduced Pulmonary Function in Patients with Spinal Osteoporotic Fractures

Abstract: Vertebral deformation in spinal osteoporosis results in spinal and thoracic deformation, causing pain, disability and an overall decrease in quality of life. We sought to determine whether thoracic spinal deformation may lead to impaired pulmonary function. We studied expiratory relaxed vital capacity (VC) and forced expiratory volume in 1 s (FEV1) in 34 patients with spinal osteoporotic fractures and 51 patients with chronic low back pain (CLBP) due to reasons other than osteoporosis. Measurements of pulmonary function tests were calculated as a percentage of the normal range adjusting for age, sex, and height using the equations for normal values of the EKGS (Europaische Gesellschaft fur Kohle und Stahl). Severity of osteoporosis was determined by calculation of the spine deformity index (SDI-total and SDI-anterior) on lateral radiographs of the spine and clinical measures of body stature (height reduction, distance from lowest ribs to iliac crest and distance from the occiput to the wall). Patients with osteoporosis had a lower vital capacity (%VC of the reference value) than patients with CLBP. The differences were more prominent (p<0.05) when the previous body height, at age 25 years, was used as reference for calculation of VC (mean ± SD: 93.6%± 15.3% in patients with osteoporosis v 105.6%± 15.1% in patients with CLBP). FEV1 was significantly (p<0.05) lower in patients with osteoporosis when previous body height was considered, in comparison with patients with CLBP (mean ± SD: 85.0%± 14.2% in patients with osteoporosis v 92.4%± 13.6% in patients with CLBP). In patients with osteoporosis VC (standardized on previous body height) was significantly negatively correlated with SDI-anterior (r=–0.4, p<0.03). Furthermore, VC standardized on previous body height showed a weak but significant negative correlation with some clinical measures of osteoporosis (height reduction vs %VC: r=–0.34, p<0.05; distance from the lowest ribs to iliac crest vs %VC: r= 0.35, p<0.04). In conclusion, we found that pulmonary function is significantly diminished in patients with spinal osteoporotic fractures as compared with CLBP patients without evidence of manifest osteoporosis. Reduction of pulmonary function is correlated significantly with clinical and radiological measures of severity of spinal deformation due to osteoporotic fractures.

NTF2 mediates nuclear import of Ran

Abstract: Importin beta family transport receptors shuttle between the nucleus and the cytoplasm and mediate transport of macromolecules through nuclear pore complexes (NPCs). The interactions between these receptors and their cargoes are regulated by binding RanGTP; all receptors probably exit the nucleus complexed with RanGTP, and so should deplete RanGTP continuously from the nucleus. We describe here the development of an in vitro system to study how nuclear Ran is replenished. Nuclear import of Ran does not rely on simple diffusion as Ran's small size would permit, but instead is stimulated by soluble transport factors. This facilitated import is specific for cytoplasmic RanGDP and employs nuclear transport factor 2 (NTF2) as the actual carrier. NTF2 binds RanGDP initially to NPCs and probably also mediates translocation of the NTF2-RanGDP complex to the nuclear side of the NPCs. A direct NTF2-RanGDP interaction is crucial for this process, since point mutations that disturb the RanGDP-NTF2 interaction also interfere with Ran import. The subsequent nuclear accumulation of Ran also requires GTP, but not GTP hydrolysis. The release of Ran from NTF2 into the nucleus, and thus the directionality of Ran import, probably involves nucleotide exchange to generate RanGTP, for which NTF2 has no detectable affinity, followed by binding of the RanGTP to an importin beta family transport receptor.

Early development of the zebrafish pronephros and analysis of mutations affecting pronephric function

Abstract: The zebrafish pronephric kidney provides a simplified model of nephron development and epithelial cell differentiation which is amenable to genetic analysis. The pronephros consists of two nephrons with fused glomeruli and paired pronephric tubules and ducts. Nephron formation occurs after the differentiation of the pronephric duct with both the glomeruli and tubules being derived from a nephron primordium. Fluorescent dextran injection experiments demonstrate that vascularization of the zebrafish pronephros and the onset of glomerular filtration occurs between 40 and 48 hpf. We isolated fifteen recessive mutations that affect development of the pronephros. All have visible cysts in place of the pronephric tubule at 2-2.5 days of development. Mutants were grouped in three classes: (1) a group of twelve mutants with defects in body axis curvature and manifesting the most rapid and severe cyst formation involving the glomerulus, tubule and duct, (2) the fleer mutation with distended glomerular capillary loops and cystic tubules, and (3) the mutation pao pao tang with a normal glomerulus and cysts limited to the pronephric tubules. double bubble was analyzed as a representative of mutations that perturb the entire length of the pronephros and body axis curvature. Cyst formation begins in the glomerulus at 40 hpf at the time when glomerular filtration is established suggesting a defect associated with the onset of pronephric function. Basolateral membrane protein targeting in the pronephric duct epithelial cells is also severely affected, suggesting a failure in terminal epithelial cell differentiation and alterations in electrolyte transport. These studies reveal the similarity of normal pronephric development to kidney organogenesis in all vertebrates and allow for a genetic dissection of genes needed to establish the earliest renal function.

The Nephrotic Syndrome

Abstract: The nephrotic syndrome is defined by a urinary protein level exceeding 3.5 g per 1.73 m2 of body-surface area per day. At the turn of the century, clinicians distinguished a nephritic syndrome of inflammatory origin and a nephrotic syndrome of presumed degenerative origin. Today these concepts are outmoded, but the term “nephrotic syndrome” is clinically useful and has persisted, because heavy proteinuria, irrespective of its origin, is associated with a spectrum of clinically important sequelae, particularly sodium retention, hyperlipoproteinemia, and thromboembolic and infectious complications. The definition given above is arbitrary, however, and special significance should not be given to the . . .

Impact of renal cadaveric transplantation on survival in end-stage renal failure: evidence for reduced mortality risk compared with hemodialysis during long-term follow-up.

Abstract: Despite a superior quality of life and a favorable cost effectiveness, it has not been well established thus far whether renal cadaveric transplantation contributes to superior survival probability of end-stage renal disease patients in Europe, because the mortality rate on dialysis is lower compared with the United States. This analysis was undertaken to compare the mortality of wait-listed patients and transplant recipients during long-term follow-up, including the possibility of a retransplant in a single-center study. The study cohort included 309 consecutive patients, ages 17 to 72 yr, being registered on the waiting list of the Renal Transplantation Center of Mannheim since the initiation of the transplantation program on June 3, 1989. Follow-up was terminated on September 30, 1997, with a mean of 4.15 yr. A total of 144 renal cadaveric transplants (four retransplants) was performed during the follow-up period. A Cox regression model considering the time-dependent exposure to the different therapy modalities was applied for statistical analysis. Patients being removed from the waiting list or coming back to dialysis after transplantation were censored at time of withdrawal or graft failure. Transplantation resulted in a lower hazard ratio, which was 0.36 (95% confidence interval, 0.15 to 0.87) when the hazard of the wait-listed group was taken as 1.00. The underlying incidence rate of death was 0.026 per patient-year (0.032 on dialysis versus 0.016 with functioning graft). Performing the evaluation on an intention-to-treat basis without censoring the lower risk of the transplanted group was still pronounced according to a hazard ratio of 0.44 (95% confidence interval, 0.22 to 0.89). Thus, patients receiving a renal cadaveric transplantation have a substantial survival advantage over corresponding end-stage renal disease patients on the waiting list even in the setting of a single transplantation center where mortality on regular dialysis therapy was comparatively low.