Diabetic patients on renal replacement therapy.
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Diabetic Nephropathies↗
Biomedical subjects
G Stein
Publications and source records attributed to G Stein.
Ciliated cells in peritoneal dialysis fluid.
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Adult↗
The problem of cytomegalovirus (CMV) prophylaxis in high-risk renal transplant recipients.
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Antibodies, Viral↗
Sequence-specific DNA binding activities of nuclear matrix proteins of mammalian lens epithelial cells.
This study examines matrix and nonmatrix nuclear proteins of the rabbit lens epithelial cells. The nuclear matrix proteins were isolated by modified Penman technique, which requires presence of detergents and nucleases, whereas nonmatrix nuclear proteins were obtained by high salt extraction. The data from these experiments revealed presence of DNA binding activities for SP-1 and OCT-1 proteins in both matrix and non-matrix compartments of rabbit lens epithelial cells. Comparison of the relative abundance of SP-1 and OCT-1 binding activities in nuclear matrix and nonmatrix fractions suggest the distribution between these two compartments is cell type specific and possibly related to the control of cell growth.
Animals↗
Selective expression of fos- and jun-related genes during osteoblast proliferation and differentiation.
Developmental studies of oncogene expression and transgenic animal studies implicate c-fos and other fos and jun family members in the regulation of bone tissue formation. Therefore, to initiate experimental examination of the hypothesis that expression of fos- and jun-related genes is functionally coupled to modulation of gene expression which supports bone development, we determined levels of expression of the principle fos and jun family members during progressive differentiation of normal rat calvaria-derived osteoblasts within two contexts. First, cellular mRNA levels were quantitated under conditions where expression of serum-induced early response genes had returned to basal levels. Our findings demonstrate high levels of c-fos, c-jun, and jun B mRNA transcripts during the proliferative period of osteoblast development, while expression of fra-1 and fra-2 is enhanced during the differentiation period. jun D is constitutively expressed during the time course exhibiting only a 30% decline in levels postproliferatively, and fos B mRNA is undetectable by Northern blot analyses. Late in the developmental sequence, apoptosis is evident. At this time, fra-1 expression is completely downregulated, while c-fos, fra-2, c-jun, jun B, and jun D show a dramatic enhancement in expression. Second, we addressed differential expression of fos and jun family members in relation to serum responsiveness as a function of stages of phenotypic development. Proliferating cells exhibit a prolonged induction of fos and jun family members in response to serum. While in differentiated cells, which are refractory to growth stimulus even when exposed to fresh serum every 2 days, a spike in fos and jun expression is observed. Thus, our data demonstrate significant differences in basal and serum responsiveness of fos and jun family members over the course of osteoblast differentiation. These findings are consistent with multiple lines of evidence linking activity of these early response genes to regulation of cell growth and development of the bone tissue phenotype.
Animals↗
No association of converting enzyme insertion/deletion polymorphism with immunoglobulin A glomerulonephritis.
It has been recently reported that in type 1 diabetes the insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme gene is associated with the presence of diabetic nephropathy. Tissue angiotensin I-converting enzyme is determined by I/D polymorphism, and it has been speculated that in diabetes differences of local angiotensin II availability determine the risk of renal disease. Since angiotensin II is thought to play an important role in the evolution of renal disease in general, we tested whether genotype distribution of the I/D polymorphism is also different in patients with immunoglobulin A-glomerulonephritis (IgA-GN). Furthermore we compared IgA-GN patients with (1) stable renal function or (2) terminal renal failure to investigate a potential role of the I/D polymorphism in the renal prognosis. We examined 122 patients with biopsy-confirmed IgA-GN who had stable renal function and 82 dialysis-dependent or transplanted patients with biopsy-confirmed IgA-GN. Furthermore, in 134 healthy individuals used as controls we analyzed the DNA for normal distribution of genotypes and allele frequencies. The polymorphic region was amplified using polymerase chain reaction with specific primers. Alleles were detected on 2% agarose gels. Genotype distributions and allele frequencies were not significantly different between controls and patients with IgA-GN and stable renal function. Furthermore, no significant difference in genotype distribution was detected between patients with IgA-GN and stable renal function compared with patients with IgA-GN and end-stage renal failure, although a trend for a higher frequency of DD-homozygotes was noted in the latter group (P = 0.07).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Low-dose calcitriol prevents the rise in 1,84-iPTH without affecting serum calcium and phosphate in patients with moderate renal failure (prospective placebo-controlled multicentre trial).
BACKGROUND: Higher doses of calcitriol are effective in lowering markedly elevated 1,84 PTH levels of patients with renal secondary hyperparathyroidism. It has not been established, however, whether prophylactic administration of low doses of calcitriol prevents an increase of 1,84 PTH without causing side-effects, i.e. hypercalcaemia, hypercalciuria, or hyperphosphataemia. STUDY DESIGN: We carried out a placebo-controlled, double-blind prospective multicentre trial over 12 months in 45 patients with mild to moderate renal failure. Criteria for inclusion were S-creatinine 1.4 mg/dl and 1,84 PTH > 6 pmol/l (normal 6). Calcitriol 0.125 microgram/day per os was compared with placebo. The patients received calcium carbonate per os if serum P exceeded 1.7 mmol/l. RESULTS: Baseline 1,84 iPTH concentrations were not significantly different, i.e. 14.0 pmol/l (6.7-63.3) on placebo vs 16.2 (6.85-82.0) on calcitriol. Intention to treat analysis revealed a significant difference of final 1,84 iPTH, i.e. 27.8 (4.2-68.5) on placebo vs 18.2 (4.45-75.5) on calcitriol. On post-hoc analysis the difference was even more pronounced at S-creatinine concentrations above 3 mg/dl. S-calcium, S-phosphate, and urinary excretion of calcium did not change significantly on either placebo or on calcitriol. There were no episodes of hypercalcaemia or hyperphosphataemia. There was no significant difference of final S-creatinine or change in S-creatinine between placebo and calcitriol. One patient on calcitriol and two on placebo progressed to terminal renal failure. Bone alkaline phosphatase as a non-invasive index of bone metabolism was not decreased to subnormal levels. CONCLUSION: The results document that a therapeutic window exists in patients with moderate renal failure and elevated of 1,84 iPTH, where low-dose calcitriol (0.125 microgram/day) prevents the increase in 1,84 iPTH without causing side-effects. This observation suggests that the parathyroid is more sensitive to calcitriol than intestine and bone.
Adult↗
Replication of an osteopetrosis-inducing avian leukosis virus in fibroblasts, osteoblasts, and osteopetrotic bone.
Avian leukosis virus (ALV)-induced osteopetrosis is caused by the abnormal growth and differentiation of osteoblasts. To evaluate the role of infection in osteopetrosis induction, the replication of an osteopetrosis-inducing virus (Br21) has been compared in osteopetrotic bone, calvarial-derived osteoblasts, and chick embryo fibroblasts. Much higher levels of infection occurred in diseased bone than in the cultures. Severe cases of osteopetrosis contained 10 times more viral DNA, 30 times more mature capsid protein, 5 to 10 times more Gag precursor protein, and 2 to 3 times more Env protein than the infected cultures. Virus replication in the cultured osteoblasts was similar to that in fibroblasts except for a distinctive asymmetric localization of Gag proteins. In osteopetrotic chickens, bones became atypically enlarged and sera contained elevated levels of osteoblast differentiation markers (alkaline phosphatase and osteocalcin). In cultures, infections did not affect the growth or differentiation of osteoblasts. Thus, the infected cultures lacked aspects of the bone environment that support both the high levels of infection and the aberrant function of osteoblasts characteristic of ALV-induced osteopetrosis.
Animals↗
[ACE inhibitors in kidney diseases--only another antihypertensive agent?].
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Angiotensin-Converting Enzyme Inhibitors↗
[Kidney function in hypertensive patients with chronic renal failure treated with the dual eliminated ACE-inhibitor spirapril].
PATIENTS AND METHOD: Spirapril is a recent ACE inhibitor with a both renal and hepatic elimination pathway. In order to determine its tolerability, primarily the impact on renal function, Spirapril was tested in a single-blind trial with a 2-week placebo run-in phase and a 4-week active treatment period. Forty-nine patients (34 males and 15 females) with varying degrees of renal impairment were included. Their pretreatment diastolic blood pressure (DBP) ranged from 95 to 115 mm Hg. Spirapril was administered in oral doses of 6 mg once daily. RESULTS: Forty-four patients completed the study. Four patients dropped out due to side effects, 1 patient was withdrawn from the study due to lack of antihypertensive efficacy. 48% of the completers with renal failure achieved a normalized diastolic blood pressure (DBP < or = 90 mm Hg) or a reduction in DBP of > or = 10 mm Hg; the corresponding figure for patients with normal renal function was 31%. Renal function was assessed in the beginning and at the end of the active Spirapril treatment period using Tc-99m-DTPA-clearance (representing glomerular filtration rate), J-131-hippuran-clearance (representing renal plasma flow) and creatinine clearance. Particularly in patients with renal impairment, Spirapril did not deteriorate renal function as given by these parameters. Regression analysis revealed a linear correlation between total plasma clearance of the active metabolite Spiraprilate and creatinine clearance. There was no evidence for drug accumulation. CONCLUSION: In patients with renal impairment the pharmacokinetic results indicate a non-renal elimination of the drug. Spirapril 6 mg once daily is concluded to be a well tolerated antihypertensive therapy for patients with mild to moderate hypertension and varying degrees of chronic renal failure.
Administration, Oral↗
DNase I hypersensitive sites in promoter elements associated with basal and vitamin D dependent transcription of the bone-specific osteocalcin gene.
Nuclease hypersensitive sites were mapped in the proximal promoter of the osteocalcin gene, which is expressed only in bone cells exhibiting the mature osteoblast phenotype. Nuclei from proliferating and confluent rat osteosarcoma (ROS) 17/2.8 cells were subjected to DNase I digestion, and hypersensitivity was assayed by the indirect end-labeling method, using osteocalcin gene probes. Hypersensitive sites were detected in two promoter domains: -590 to -390, which spans the vitamin D responsive element, and -170 to -70, which spans the TATA box and the CCAAT-containing OC box domain. Together, these elements regulate basal and vitamin D enhanced osteocalcin gene transcription. We observed a parallel relationship between the intensity of bands representing the hypersensitive sites and the extent to which the osteocalcin gene is transcribed. Both in confluent cultures and in response to vitamin D, when osteocalcin transcription was upregulated, the hypersensitive bands were significantly intensified. Additionally, the bands were decreased under conditions that downregulate osteocalcin gene transcription. A functional relationship between the presence of hypersensitive sites and osteocalcin gene transcription is further supported by the absence of hypersensitivity in nonosseous cells that do not express osteocalcin, although these proliferating cells exhibited hypersensitivity in a cell cycle regulated histone gene promoter. Our results suggest the involvement of chromatin structure in transcriptional responsiveness of the osteocalcin gene to physiologic modulation.
Animals↗
Interferon alpha selectively affects expression of the human myeloid cell nuclear differentiation antigen in late stage cells in the monocytic but not the granulocytic lineage.
The human myeloid cell nuclear differentiation antigen (MNDA) is expressed constitutively in cells of the myeloid lineage, appearing in myeloblast cells in some cases of acute myeloid leukemia and consistently being detected in promyelocyte stage cells as well as in all later stage cells including peripheral blood monocytes and granulocytes. The human myeloid leukemia cell lines, HL-60, U937, and THP-1, express similar levels of immunochemically detectable MNDA. Although, the level of MNDA mRNA in primary monocytes is very low it was up-regulated at 6 h following the addition of interferon alpha. The effect of interferon alpha on the MNDA mRNA is also observed in the cell lines HL-60, U937, and THP-1. The MNDA mRNA level in primary granulocytes was unaffected by addition of interferon alpha and other agents including interferon gamma, endotoxin, poly (I).poly (C), and FMLP. The MNDA mRNA level in the myeloid cell lines was also unaffected by the latter four agents. Induction of differentiation in the myeloid cell lines with phorbol ester induces monocyte differentiation which was accompanied by a decrease in MNDA mRNA level. This reduced level of mRNA could then be elevated with subsequent interferon alpha treatment. The effects of phorbol ester on MNDA mRNA appeared to be associated with induced differentiation since inhibiting cell proliferation did not alter the level of MNDA mRNA and cell cycle variation in MNDA mRNA levels were not observed. The ability of interferon alpha to up-regulate MNDA mRNA in phorbol ester treated myeloid cell lines is consistent with the observations made in primary monocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
Antigens, Differentiation, Myelomonocytic↗
Expression of cell growth and bone phenotypic genes during the cell cycle of normal diploid osteoblasts and osteosarcoma cells.
Establishing regulatory mechanisms that mediate proliferation of osteoblasts while restricting expression of genes associated with mature bone cell phenotypic properties to post-proliferative cells is fundamental to understanding skeletal development. To gain insight into relationships between growth control and the developmental expression of genes during osteoblast differentiation, we have examined expression of three classes of genes during the cell cycle of normal diploid rat calvarial-derived osteoblasts and rat osteosarcoma cells (ROS 17/2.8): cell cycle and growth-related genes (e.g., histone), genes that encode major structural proteins (e.g., actin and vimentin), and genes related to the biosynthesis, organization, and mineralization of the bone extracellular matrix (e.g., alkaline phosphatase, collagen I, osteocalcin, and osteopontin). In normal diploid osteoblasts as well as in osteosarcoma cells we found that histone genes, required for cell progression, are selectively expressed during S phase. All other genes studied were constitutively expressed both at the transcriptional and posttranscriptional levels. Alkaline phosphatase, an integral membrane protein in both osteoblasts and osteosarcoma cells, exhibited only minimal changes in activity during the osteoblast and osteosarcoma cell cycles. Our findings clearly indicate that despite the loss of normal proliferation-differentiation interrelationships in osteosarcoma cells, cell cycle regulation or constitutive expression of growth and phenotypic genes is maintained.
Actins↗
Non-lectin component in a fermented extract from Viscum album L. grown on pines induces proliferation of lymphocytes from healthy and allergic individuals in vitro.
Mistletoe preparations have been shown to express immunomodulatory properties. In order to evaluate the stimulatory potency of different mistletoe extracts, peripheral blood mononuclear cells (PBMC) from healthy and allergic/atopic individuals were exposed to aqueous or fermented extracts derived from Viscum album L. grown on apple trees (Mali-extracts) or on pines (Pini-extracts). None of them had received any mistletoe treatment. Iscador Pini was the only extract which strongly induced proliferation of PBMC in contrast to the other five preparations. On testing these extracts by Western blotting with anti-mistletoe lectin-1 (ML-1) antibody positive sera from mistletoe-treated patients, it became evident that Iscador Pini was almost devoid of lectins. The stimulatory potency of Iscador Pini for PBMC from three different groups was examined: PBMC from 35 normal controls (Group I), 23 patients with drug-induced adverse effects (Group II) and 16 individuals with allergic manifestations (Group III). Cells were exposed in 7-day cultures to the extract at concentrations between 1 and 10,000 micrograms/ml. PBMC from 63% of Group III individuals showed strong stimulation (SI varying from 6 to 97) in contrast to only 9% from Group I and 22% from Group II individuals. Anti-ML-1 antibodies were detected in 5% and anti-IP antibodies in 11% of subjects in the three groups. They were either of the IgA or IgM type but not of the IgG type. Our findings strongly imply that a non-lectin associated antigen from Iscador Pini is able to activate PBMC from healthy and allergic/atopic individuals, thereby demonstrating sensitization to probably highly conserved plant antigens.
Adult↗
The structure of human S-phase chromosome fibres.
Recent in situ hybridization studies suggested that within the range of 0.1-1.0 Mb, human interphase chromosomes follow a random walk model (i.e. they behave as flexible polymers without major constraints). However, chromosome structure may differ in the G1, S, and G2 phases, and phase-specific constraints may be masked if the chromosome analysis does not discriminate between the phases. Therefore, using confocal microscopy, we examined the structure of S-phase chromosomes labelled with 5-iododeoxyuridine after prolonged treatment with 5-fluorodeoxyuridine. In the S-phase, labelled 0.32 mu chromosome fibres mostly appear as semi-circles with an average diameter of 0.83 +/- 0.03 mu. These semi-circles are joined together to form different 3D structures, and two semicircles frequently adopt s- or omega-like conformations involving about 2.5 mu of the chromosome contour length (L). Morphometric analysis of the S-phase fibres suggests that our data fit both the random flexible polymer model and also a model in which two constrained semi-circles are attached to each other by a flexible joint, thus eliminating constraints at long distances (L more than 2 mu).
Breast Neoplasms↗
Symptoms and rate of temperature change in febrile outpatients.
Although patient comfort is a frequent rationale for antipyretic therapy, there have been few systematic studies of relationships between temperature and comfort. In this study, adult outpatients with febrile illnesses were asked to complete a symptom diary at multiple time points at which temperature was recorded. Temperature readings showed modest correlation (0.316) with scores of "feeling better or worse" and moderate correlation (0.586) with aggregate symptom scores. Rate of temperature change showed low levels of correlation (< 0.25) with both measurements. Direction of temperature change was not significantly associated with overall subjective score of "feeling better or worse" although aggregate symptom scores were slightly higher with rising than falling temperature. These findings suggest that temperature is a partial determinant of morbidity in minor febrile illnesses but contribution of temperature change to well being may be small. Further study is needed to determine the appropriate priority of temperature reduction in symptomatic therapy.
Adult↗
Glutathione status, lipid peroxidation and kidney function in streptozotocin diabetic rats.
In adult female rats diabetic nephropathy was induced by i.v. administration of streptozotocin (6 mg/100 g b.w.). The animals survive for 3 weeks when very low daily doses of insulin (0.3 IU/animal) are administered. High blood urea concentrations and distinct proteinuria indicate the impairment of kidney function in streptozotocin diabetic rats. Streptozotocin induces mild polyuria and increased renal excretion of potassium; there is also an increase in renal excretion of administered p-aminohippurate. Three weeks after administration of streptozotocin the formation of lipid peroxides is increased in the kidney. At this time glutathione content (GSH, GSSG) is unchanged in liver and kidney of streptozotocin diabetic rats. Impairment of kidney function in streptozotocin diabetic rats can be prevented by daily supplementation with sufficient doses of insulin (about 3 IU/animal).
Animals↗
Parathyroid-responsive modifications in the nuclear matrix of ROS 17/2.8 rat osteosarcoma cells.
PTH is a mediator of skeletal development and remodeling that influences gene expression in osteoblastic cells. It is well established that PTH modulates the activity of membrane-associated second messenger signal transduction pathways. In these studies we have addressed the potential contribution of components of cell structure to the integration of PTH-related regulatory signals that influence the expression of bone cell genes. Chronic treatment of ROS 17/2.8 rat osteosarcoma cells with PTH is accompanied by changes in gene expression that are at least in part transcriptionally controlled. To explore the involvement of nuclear architecture in PTH-responsive modifications in gene expression, we investigated changes in the nuclear matrix after PTH treatment. Consistent with a role for the nuclear matrix in determining spatial organization and topology of chromatin as well as in the localization and targeting of transcription factors, we observed PTH-associated changes in a 200-kilodalton nuclear matrix protein in response to PTH. A significant down-regulation of synthesis was observed when nuclear matrix proteins were resolved electrophoretically in two-dimensional gels. This protein was restricted to the nuclear matrix and was not detected in the chromatin or cytoskeletal cellular fractions. These alterations in nuclear matrix proteins that occur after PTH treatment in osteosarcoma cells were phenotype related. They did not occur in UMR-106 POL or H4 hepatoma cells. Our findings support a role for the nuclear matrix in transducing PTH-mediated regulatory signals to facilitate the extent to which genes in osteoblasts are transcribed.
Animals↗