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Biomedical subjects

R F Klein

Publications and source records attributed to R F Klein.

At least 37 records · Page 2Linked to original sources
PubMed1993

Regulation of osteoblastic gene expression by lead.

Although it is well recognized that lead accumulates in bone, skeletal tissue is considered primarily a sequestering compartment and not a site of toxic action for lead. However, exposure to lead is associated with impaired skeletal growth in children and reductions in indices of bone formation in laboratory animals. Osteoblastic ROS 17/2.8 cells were used in an effort to better understand the consequences of lead exposure on skeletal homeostasis. Studies on confluent cultures of ROS 17/2.8 cells revealed that lead (2-200 microM) had no effect on cell number or DNA and protein synthesis. However, alkaline phosphatase activity was reduced by lead in a dose- and time-dependent manner. Reductions in steady state alkaline phosphatase mRNA levels paralleled the lead-induced inhibition of enzyme activity. Moreover, lead exposure resulted in similar dose-dependent reductions in steady state type 1 procollagen and bone Gla protein mRNA levels. The effect of lead on osteoblastic gene expression in ROS 17/2.8 cultures, however, was selective in nature, as similar lead exposures resulted in no alterations in beta-actin or glyceraldehyde-3-phosphate dehydrogenase mRNA levels. These data demonstrate that lead, in the absence of over toxicity, specifically restricts the expression of certain aspects of the differentiated osteoblast phenotype. Such alterations in osteoblast function may contribute to the skeletal abnormalities observed in settings of lead intoxication.

Alkaline Phosphatase↗
PubMed1991

Pertussis toxin inhibits hormonal stimulation of bone resorption in fetal rat limb bones.

The cellular basis for hormonal control of bone resorption is poorly understood. As the identifiable receptors for bone resorbing agents such as parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] are located on osteoblasts rather than osteoclasts, the nature of cellular signaling is obscure. Here it is reported that exposure of fetal rat limb bones to pertussis toxin, a bacterial protein that inhibits certain GTP binding proteins (G-proteins) involved in signal transduction, markedly inhibits bone resorption elicited by PTH, 1,25(OH)2D3 and prostaglandin E2. Pertussis toxin does not block the inhibition of alkaline phosphatase activity by PTH or 1,25(OH)2D3, and it potentiates the cyclic AMP response to PTH. These data support the existence of a pertussis toxin-sensitive G-protein that participates in regulation of bone resorption. The putative G-protein is apparently not involved in the initial transduction of hormonal signals, but it may be part of a final common pathway through which the osteoclast is activated by agents with widely divergent initial actions.

Animals↗
PubMed1989

Increased serum levels of a parathyroid hormone-like protein in malignancy-associated hypercalcemia.

STUDY OBJECTIVE: To measure the serum levels of a newly described parathyroid hormone-like protein (PLP) which was isolated from malignant tumors associated with hypercalcemia, and determine whether PLP is a humoral factor in malignancy-associated hypercalcemia. DESIGN: A cross-sectional study of serum levels of PLP using a newly developed radioimmunoassay. SETTING: A university-affiliated Veterans Administration hospital in San Francisco, California, a University hospital in Hong Kong, and a private hospital in Danville, Pennsylvania. PATIENTS: Patients with hypercalcemia (calcium greater than 2.65 mmol/L) and a diagnosis of malignancy were studied. Control groups included normocalcemic patients with malignancy, patients with hyperparathyroidism, and normal subjects. MEASUREMENTS AND MAIN RESULTS: Serum immunoreactive PLP (iPLP) levels in normal subjects were less than 2.5 pmol eq/L (10 pg/mL), and 68% of subjects had undetectable levels. The serum concentration of iPLP was normal in 15 of 16 hypercalcemic patients with hyperparathyroidism. Serum iPLP was increased (greater than 2.5 pmol eq/L) in 36 of 65 (55%) patients with malignancy-associated hypercalcemia, with a mean value of 6.1 +/- 0.9 pmol eq/L (24 pg/mL). In a subgroup of patients with solid tumors serum iPLP was increased in 30 (71%) of 42 hypercalcemic patients, with a mean value of 6.5 +/- 0.9 pmol eq/L. Serum iPLP was elevated in only 3 of 23 normocalcemic patients with cancer. In patients with solid malignancies (n = 59), levels of iPLP were positively correlated with the total serum calcium (r = 0.43, P less than 0.01). CONCLUSION: The data indicate a relation between the serum concentration of iPLP and the presence of hypercalcemia in solid malignancies. The results support a role for PLP as a humoral mediator of hypercalcemia in most patients with solid tumors. Measurement of iPLP should be useful in the differential diagnosis of hypercalcemia.

Bone Neoplasms↗
PubMed1989

The effect of interleukin-1 alpha and tumor necrosis factor alpha on the secretion of human chorionic gonadotropin by JAR human choriocarcinoma cells.

The regulation of human chorionic gonadotropin (hCG) secretion by placental trophoblasts is incompletely understood. A recent study reports that Interleukin-1 beta (IL-1 beta) stimulates hCG production in vitro by human, first trimester, placental trophoblasts, but not by a human choriocarcinoma cell line. Human decidua has been shown to produce IL-1 alpha and beta, and Tumor Necrosis Factor alpha (TNF alpha). The precise role(s) of these proteins in pregnancy is unknown. In the present study, hCG production by human choriocarcinoma cells (JAR) was evaluated in the presence of recombinant human IL-1 alpha (rHIL-1 alpha) and rHTNF alpha. hCG production was increased by rHIL-1 alpha in a dose-dependent manner, and heat-inactivation of this cytokine abolished the effect. Equimolar quantities of rHTNF alpha failed to influence hCG production or cell viability. IL-1 may be important in the regulation of hCG production by human trophoblasts, and therefore may play a physiologic role in pregnancy. Furthermore, TNF does not appear to participate in the regulation of the production of this hormone by human choriocarcinoma cells. This is the first demonstration of a divergence of activity of these two cytokines in the reproductive process.

Choriocarcinoma↗
PubMed1988

Effects of tobacco glycoprotein (TGP) on the immune system. II. TGP stimulates the proliferation of human T cells and the differentiation of human B cells into Ig secreting cells.

We have been studying the effects of tobacco glycoprotein (TGP), a polyphenol-rich glycoprotein isolated from cured tobacco leaves, on the immune system. We have shown previously that mice immunized with TGP produce preferentially antibodies of the IgE isotype and that TGP is a T cell-independent B cell mitogen for mice, which stimulates B cell proliferation and B cell differentiation into Ig-secreting cells. We report herein that TGP stimulates a significant increase in [3H]TdR incorporation by human PBL and by human cord blood lymphocytes. The magnitude of the proliferative response of PBL to TGP does not correlate with the donor's titer of IgE antibodies to TGP, as assayed by a wheal and flare response after an i.d. injection of TGP, neither does it correlate with the donor's smoking history. [3H]TdR uptake is not observed before day 5 of culture, and the response peaks between days 5 and 10 of culture. Analysis of the cellular basis for the proliferative response suggests that T cells are proliferating. Two-parameter analysis by flow cytometry shows that CD3+, CD4+, and CD8+ cells are in the S + G2 + M phases, but not Ig-bearing cells or monocytes. A significant increase in HLA-DR (Ia)-bearing cells is observed on cells in all of the cell cycle phases. This increase coincides with cells entering the S phase. No increase is observed in the expression of the IL-2-R as assayed by the anti-Tac antibody. TGP also stimulates human PBL to differentiate and to produce Ig of the IgM, IgG, and IgA isotypes, without stimulating a detectable B cell proliferative response. The proliferative response of PBL is clearly due to TGP and not to contamination with LPS, because by the limulus amebocyte assay the TGP preparation contains less than 2% LPS, which could not account for the stimulation observed.

Adult↗
PubMed1988

Forskolin mimics the effects of calcitonin but not parathyroid hormone on bone resorption in vitro.

Parathyroid hormone (PTH) and calcitonin stimulate bone adenylate cyclase activity and increase bone cAMP content, but PTH enhances and calcitonin inhibits bone resorption. This study examined the effects of forskolin, a non-hormonal activator of adenylate cyclase, on bone resorption and cAMP accumulation in 19-day fetal rat limb bones. Forskolin (10(-9) to 10(-5) M) stimulated bone cAMP generation in a concentration-dependent manner. However, in contrast to bPTH(1-34), which also stimulated cAMP accumulation, forskolin did not stimulate bone resorption. Moreover, forskolin did not augment the bone-resorbing activity of PTH even though it potentiated PTH stimulation of bone cAMP levels. Rather, high doses of forskolin (10(-6) to 10(-5) M) exhibited a calcitonin-like effect to inhibit PTH-mediated bone resorption. These results support a second-messenger function of cAMP for the inhibitory effects of calcitonin, but not for the stimulatory effects of PTH on bone resorption.

Adenylyl Cyclases↗
PubMed1988

Vitamin D metabolites and bioactive parathyroid hormone levels during Spacelab 2.

The purpose of this study was to determine whether plasma levels of the vitamin D hormone and parathyroid hormone (PTH), two potent activators of bone remodeling sites, were altered in four astronauts during the 8-day (d) Spacelab 2 mission (SL2). Increased circulating levels of either hormone could change calcium homeostasis and bone cell activity and, thus, contribute to bone loss in crewmembers in space. The vitamin D hormone was elevated in all astronauts at the end of the first inflight day but returned to normal by the seventh day. Biologically active PTH tended to be normal throughout the mission. Both hormones were within the normal range by the end of the 8-d flight of this SL2 crew. Plasma levels of 25OHD, 24,25(OH)2D, calcium, phosphorus, and albumin were essentially normal during the mission.

24,25-Dihydroxyvitamin D 3↗
PubMed1987

Effect of age on circulating immunoreactive and bioactive parathyroid hormone levels in women.

Although levels of serum immunoreactive parathyroid hormone (iPTH) increase with age in women, this could be caused by retention of non-biologically active PTH fragments by the aging kidney. In 102 normal women, aged 30 to 89 yr, serum iPTH increased with age by 58% (r = 0.33, p less than 0.001) with antiserum GP-1M (which has midmolecule specificity) and 43% (r = 0.32, p less than 0.001) with antiserum CH-12M (which may have whole molecule specificity); urinary cAMP/GFR excretion increased by 29% (r = 0.22, p less than 0.05). The results of these assays were validated by comparison with serum levels of biologically active PTH (BioPTH) in immunoextracts of serum followed by renal adenylate cyclase assay in a selected subgroup of 25 of the women. Serum BioPTH correlated with serum iPTH assessed by antiserum GP-1M (r = 0.48, p less than 0.05) and antiserum CH-12M (r = 0.48, p less than 0.05) but not with urinary cAMP. The data are consistent with an increase of parathyroid function with aging: clearly, we do not find decreased parathyroid function as would be expected if age-related bone loss was not mediated, in part, by PTH.

Adult↗
PubMed1987

Parathyroid hormonelike protein from human renal carcinoma cells. Structural and functional homology with parathyroid hormone.

A variety of solid tumors secrete proteins that are immunochemically distinct from parathyroid hormone (PTH) but activate PTH-responsive adenylate cyclase. Such PTH-like proteins have been proposed as mediators of the hypercalcemia and hypophosphatemia frequently associated with malignancies. We purified to apparent homogeneity a PTH-like protein with a molecular weight of 6,000, that is produced by human renal carcinoma cells. The amino-terminal sequence of the PTH-like protein and that of human PTH were found to display at least five identities in the first 13 positions. The purified protein bound to PTH receptors, activated adenylate cyclase in renal plasma membranes, and stimulated cAMP formation in rat osteosarcoma cells. The PTH-like protein reproduced two additional effects of PTH, stimulation of bone resorption in fetal rat limb bone cultures and inhibition of phosphate uptake in cultured opossum kidney cells. These properties are consistent with a role for PTH-like proteins as mediators of the syndrome of malignancy-associated hypercalcemia.

Carcinoma, Renal Cell↗
PubMed1987

Parathyroid hormone-like adenylate cyclase-stimulating activity from a human carcinoma is associated with bone-resorbing activity.

We found previously that a human renal carcinoma cell line derived from a hypercalcemic patient induces humoral hypercalcemia when grown as allografts in the nude mouse and secretes a protein that activates adenylate cyclase via the PTH receptor. The purpose of this study was to examine the conditioned medium of this cell line for bone-resorbing activity in vitro. Processed conditioned medium produced dose-dependent stimulation of bone resorption in cultured fetal rat limb bone explants. Two PTH antagonists were used to assess the PTH receptor dependence of this bone-resorbing activity. Neither [8Nle,18Nle,34Tyr]bovine (b) PTH-(3-34) amide nor [34Tyr]bPTH-(7-34)amide inhibited bone resorption or limb bone cAMP accumulation induced by either processed conditioned medium or equivalent concentrations of bPTH-(1-34). As an alternate means to assess whether this tumor-derived PTH-like protein had intrinsic bone-resorbing activity, the latter was measured during partial purification of PTH-like adenylate cyclase-stimulating activity (ACSA) from conditioned medium by consecutive gel filtration and reverse phase HPLC. The bone-resorbing activity in conditioned medium could not be resolved from PTH-like ACSA by these two separation techniques, indicating that the activities may be intrinsic to the same protein. These results are consistent with the view that a tumor-derived protein with PTH-like ACSA and bone-resorbing activity may be responsible for hypercalcemia in vivo.

Adenocarcinoma↗
PubMed1986

A trial of amitriptyline and fluphenazine in the treatment of painful diabetic neuropathy.

We conducted a double-blind, placebo-controlled, crossover study of the effectiveness of amitriptyline and fluphenazine in alleviating the pain of diabetic peripheral neuropathy in six diabetic patients. Pain was evaluated by the patients with a graphic rating scale. A placebo response was found, but no additional effect of amitriptyline and fluphenazine was seen. Although the statistical power of this study was low, these data, when combined with a reevaluation of previous trials of amitriptyline and fluphenazine in the treatment of painful diabetic neuropathy, indicate that there is no justification for the use of these agents in the treatment of painful neuropathy outside of large, controlled clinical trials. Depression as a possible cause of this condition should not go unnoted or untreated.

Adult↗
PubMed1986

Immune complex glomerulopathy in a child with food hypersensitivity.

This report describes the occurrence of immune complex glomerulonephritis in a patient with eosinophilic gastroenteritis and food hypersensitivity. A coincident allergen injection may have been a contributing factor in the sudden development of the nephrotic syndrome. Markedly elevated levels of circulating immune complexes (greater than 6400 mg/dl) were found containing kappa-casein and bovine serum albumin (BSA), the latter predominating. Markedly elevated serum BSA hemagglutinating titers were also present (1:40,960). Cross-reacting precipitating antibodies to BSA, beef, and pork were demonstrated, but not to flounder or ovalbumin. Renal biopsy revealed immune complex glomerulonephritis with BSA, immunoglobulins M and G and complement deposited focally in the glomerular basement membrane. With strict dietary limitation of identified causative antigens and prednisone therapy, CIC levels decreased to 16,000 micrograms/dl and serum BSA antibody hemagglutinating titer fell 32-fold over a period of 15 months. There was prompt symptomatic relief and amelioration of signs of nephritis. The patient was able to consume a diet normal in protein and caloric content, and statural catch-up growth occurred. Recognition of food antigens to which the patient was hypersensitive provided a rationale for the relief of the gastrointestinal disturbance, growth stunting, and renal disease.

Adolescent↗
PubMed1986

Reimplantation in infection. Elution of gentamicin from cement and beads.

A prospective study was performed to evaluate the arthroplasty fluid, serum, and urine antibiotic levels in 38 patients implanted with gentamicin-impregnated cement and in 18 patients with gentamicin-impregnated beads. Radioimmune assays were performed on arthroplasty fluid, serum, and urine samples at various times after surgery. On day 1, high arthroplasty fluid levels of gentamicin were eluted from bead-implanted patients (mean, 36.9 micrograms/ml; range, 19.6-69.5) and cement-implanted patients (mean, 14.9 micrograms/ml; range, 2.7-38.9) with very low serum and urine levels. The arthroplasty levels of gentamicin obtained in bead-implanted patients on day 1 were 17 times higher, and in cement-implanted patients, seven times higher, than those obtained with intravenous administration of gentamicin. The serum and urine levels were approximately ten to 20 times less in patients with gentamicin-impregnated cement or beads compared to those levels obtained after intravenous administration. These very low systemic levels should preclude nephrotoxic and ototoxic effects. No toxic effects were observed in these patients. Bioactivity of gentamicin in the specimens was confirmed. Staphylococci were exquisitely sensitive, while Streptococci were moderately resistant to gentamicin. Both gentamicin-impregnated beads and cement appear safe and provide substantial local in vivo antibacterial activity.

Bone Cements↗
PubMed1985

Lupus pregnancy. II. Unusual pattern of hypocomplementemia and thrombocytopenia in the pregnant patient.

To explore the causes of complications in pregnant women with systemic lupus erythematosus (SLE), we prospectively evaluated 34 pregnancies in 28 SLE patients, and 2 additional pregnancies in patients with lupus anticoagulant and positive antinuclear antibody, but no other manifestations of SLE. Nineteen pregnancies (55%) were complicated by marked proteinuria, thrombocytopenia, and/or lupus anticoagulant. Hypocomplementemia occurred in 18 pregnancies (52%). Neither thrombocytopenia-anticoagulant nor proteinuria was accompanied by an increase in antibody to double-stranded DNA or by clinical signs of active SLE. Antibody to Ro antigen did not predict fetal death. Both thrombocytopenia and proteinuria appeared abruptly during pregnancy and disappeared quickly after delivery. Fetal death was the result in 7 of 9 (77%) pregnancies in patients with anticoagulant, 6 of 10 (60%) in patients with thrombocytopenia, 6 of 18 (33%) in patients with hypocomplementemia, and 3 of 11 (27%) in patients with proteinuria. Twenty of 29 (68%) children were identified as male. The pathogenesis of hypocomplementemia was evaluated by a new assay, C1s-C1 inhibitor complex, which is thought to measure rate of complement activation by the classical pathway. Most pregnant patients with low CH50 levels and proteinuria had normal levels of C1s-C1 inhibitor complex, whereas nonpregnant patients with equivalent proteinuria and hypocomplementemia had high levels, as did pregnant patients with hypocomplementemia who did not have SLE. Pregnant and nonpregnant hypocomplementemic patients with proteinuria had similar levels of C3 and C4. In pregnant patients with SLE, C1s-C1 inhibitor complex was independent of CH50; in nonpregnant patients a linear relationship between C1s-C1 inhibitor complex and CH50 was seen.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Antinuclear↗
PubMed1985

High performance liquid chromatography used to distinguish the autoimmune hypoglycemia syndrome from factitious hypoglycemia.

Recurrent episodes of spontaneous hypoglycemia developed in a 30-yr-old woman who had received a brief course of insulin therapy 10 yr previously. She denied surreptitious insulin administration, and the autoimmune hypoglycemia syndrome was considered. Her insulin levels could not be reliably measured because of the presence of circulating antiinsulin antibodies, which interfere with standard RIA techniques. Reverse phase high performance liquid chromatographic analysis of serum obtained during a hypoglycemic episode revealed a mixture of beef and pork insulins but no human insulin, firmly establishing the diagnosis of factitious hypoglycemia. This case illustrates the value of reverse phase high performance liquid chromatography in characterizing patients in whom the autoimmune hypoglycemia syndrome is suspected.

Adult↗
PubMed1984

Acute psychosis in a 45-year-old man with bipolar disorder and primary Epstein-Barr virus infection: a case report.

A 45-year-old physician with bipolar disorder presented with an acute organic psychosis, fever, and hematologic and serologic findings of a primary Epstein-Barr virus infection. Pathogenesis was complicated by the history of discontinued lithium therapy prior to the psychosis. The patient recovered completely. Literature concerning psychosis and infectious mononucleosis is reviewed.

Acute Disease↗