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Biomedical subjects

J Silver

Publications and source records attributed to J Silver.

At least 127 records · Page 7Linked to original sources
PubMed1996

New insights into the regulation of parathyroid hormone synthesis and secretion in chronic renal failure.

The main factors which regulate parathyroid hormone (PTH) production are calcium, phosphate, vitamin D and the sex steroids, estrogens and progestagins. Hypocalcaemia leads to increased PTH secretion in seconds and minutes, gene expression in hours and parathyroid cell number in weeks and months. Hypercalcaemia leads to a decrease in PTH secretion by its action on the parathyroid cell calcium receptor and no decrease in PTH mRNA concentrations. There is now convincing evidence that phosphate regulates the parathyroids independent of its effect on serum calcium and 1,25-dihydroxyvitamin D3. (1,25(OH)2D3). In vivo in rats hypophosphataemia markedly decreases PTH mRNA and serum PTH independent of its effect on serum calcium and 1,25(OH)2D3. Clinical studies also indicate that phosphate regulates the parathyroids independent of its effect on serum calcium and 1,25(OH)2D3 1,25(OH)2D3 itself has a marked effect on the parathyroids where it decreases PTH gene transcription by a direct action. Parathyroid cell proliferation is regulated by dietary calcium and phosphate with hypocalcaemia markedly increasing and hypophosphataemia markedly decreasing the number of proliferating cells. The application of basic science findings of how calcium, phosphate and 1,25(OH)2D3 regulate the parathyroids has led to an efficient and safe prescription for the management of the secondary hyperparathyroidism of chronic renal failure which is the maintenance of a normal serum calcium and phosphate and the careful use of bolus doses of 1,25(OH)2D3.

Animals↗
PubMed1996

Reduction of extraneural scarring by ADCON-T/N after surgical intervention.

The effects of ADCON-T/N (Gliatech, Inc., Cleveland, OH), a carbohydrate polymer gel, on peripheral nerve scarring and regeneration were studied in rodents undergoing three types of surgical intervention. Procedure I involved external neurolysis of the sciatic nerve from surrounding tissues and separation of its tibial and peroneal components. Procedure II involved the addition of an abrasive injury. Procedure III involved transection and suture anastomosis of the tibial component. ADCON-T/N or a control gel was locally applied in a blind fashion. Additional animals received no gel, as a further control. Animals underwent second operations 4 weeks after Procedures I and II and 6 weeks after Procedure III. The surgical sites were evaluated using a numerical grading scheme to assess wound healing, sciatic nerve adherence to surrounding tissues, and separability of its tibial and peroneal components. Animals receiving ADCON-T/N demonstrated reduced nerve adherence to surrounding tissues and enhanced separability of the tibial and peroneal components, compared with animals receiving control gel or no gel. Quantitative histological analysis revealed a statistically significant reduction in the amount of dense scar tissue surrounding nerves treated with ADCON-T/N. No evidence of nerve toxicity caused by ADCON-T/N was noted. Counts of regenerating myelinated axons in animals undergoing nerve transection and suture repair did not statistically differ in treated and untreated animals. In conclusion, ADCON-T/N seems to be both safe and effective in reducing extraneural scar formation after peripheral nerve surgery and local trauma.

Animals↗
PubMed1996

Bimodal down-regulation of CD4 in cells expressing human immunodeficiency virus type 1 Vpu and Env.

We analysed clones of HeLa cells stably expressing the human immunodeficiency virus (HIV-1) envelope gene (env) and the HIV-1 receptor, CD4. Surprisingly, individual clones were found to consist of two distinct populations of cells differing by about 10-fold in the level of surface CD4. When high and low CD4-expressing cells were separated by FACS, each subpopulation gave rise to a mixture of high and low CD4-expressing cells after several days in culture. High and low CD4-expressing subpopulations did not differ with respect to the amount of intracellular Env, but there was an inverse correlation between CD4 and another HIV-1 protein encoded by the same segment of the HIV genome, Vpu. High surface CD4 cells had high levels of intracellular CD4, largely in the perinuclear region, and low levels of Vpu with a diffuse staining pattern. Conversely, low surface CD4 cells had low levels of intracellular CD4 with a diffuse staining pattern, and high levels of Vpu, largely in the perinuclear region. Vectors containing mutant versions of either Env or Vpu failed to down-regulate surface CD4. The phenomenon of bimodal expression of a surface protein in cells derived from single clones provides a simple model of differentiation in vitro. We show how a hypothetical interaction between CD4 and a multimer of Vpu, the multimerization of which is cooperative, would lead to bimodal expression of CD4. This model may be generalized and could explain other cellular 'switches'.

CD4 Antigens↗
PubMed1996

Murine leukemia virus envelope protein in transgenic-mouse serum blocks infection in vitro.

Transgenic mice bearing a murine retroviral envelope transgene (Fv4) have Fv4 gp70env (SU) in their serum in amounts sufficient to block infection by ecotropic virus in vitro. Fv4 Env in serum is derived largely but not exclusively from hematopoietic cells. Tail cells from Fv4 mice and cell lines transduced with the Fv4 env transgene synthesize both components of the envelope protein (gp70 SU and p15E TM) but secrete the gp70 moiety, in the absence of retroviral particles. Blocking of the ecotropic viral receptor by secreted gp70 SU may contribute to resistance to retroviral infection in these mice.

3T3 Cells↗
PubMed1996

Parathyroid hormone mRNA levels are increased by progestins and vary during rat estrous cycle.

Estrogen increases parathyroid hormone (PTH) mRNA levels in vivo in ovariectomized rats. We now show that the 19-norprogestin R-5020 given to weanling rats or mature ovariectomized rats led to a twofold increase in thyroparathyroid PTH mRNA levels. This increase in PTH mRNA occurred at 24 and 48 h after progesterone but not at 72 h. There were no changes in serum calcium. In vitro, in primary cultures of bovine parathyroid cells, progesterone increased PTH mRNA levels threefold at 10(-8) M and twofold at 10(-9) M after 24 h. Progesterone receptor (PR) mRNA was demonstrated in rat parathyroid tissue by in situ hybridization and in human parathyroid adenoma by immunohisto-chemistry. Changes in PTH mRNA levels during the rat estrous cycle were also studied. At proestrus and estrus PTH mRNA levels were increased significantly by three- and fourfold compared with diestrus. Our results confirm that the parathyroid gland is a target organ for the ovarian sex steroids estrogen and progesterone and are of physiological relevance as shown by the changes during estrus.

Animals↗
PubMed1996

Carnitine palmitoyltransferase deficiency: an underdiagnosed condition?

Two apparently healthy adults were admitted because of acute muscle cramps, severe weakness, and red urine excretion. Patient No. 1 developed the symptoms following intense exercise and patient No. 2 during a febrile infection. Both of them experienced such episodes in the past, but these were medically misinterpreted. Their present manifestations were accompanied by renal failure which subsided gradually and was found to be a result of rhabdomyolsis and myoglobinuria. Further investigations yielded a deficiency of carnitine palmitoyltransferase as a background to the acute muscular destruction. Examination of a sister of patient No. 2 who had a similar past history revealed the same metabolic disorder. Carnitine palmitoyltransferase deficiency, as a cause of nontraumatic rhabdomyolysis, is a distinct entity in the pathogenesis of acute renal failure. Our experience (3 patients within 2 years) makes us presume that this condition is not as rare as hitherto reported and should rather be considered in cases of 'nonhematuric' red urine and acute renal failure.

Acute Kidney Injury↗
PubMed1995

Overexpressed tau protein in cultured cells is phosphorylated without formation of PHF: implication of phosphoprotein phosphatase involvement.

Pyramidal neurons in affected regions of Alzheimer's disease (AD) brain contain neurofibrillary tangles (NFT), aggregates of paired helical filaments (PHF) composed mainly of phosphorylated microtubule-associated protein tau. To explore the role of tau phosphorylation in the aggregation of tau into PHF, we constructed mammalian cell culture systems producing high levels of intracellular phosphorylated tau. COS-1 fibroblast-like cells were transiently transfected to simultaneously express tau, MAP kinase (MAPK), and MAP kinase kinase (MAPKK), or alternatively to express tau and glycogen synthase kinase 3 (GSK3). B103 neuron-like cells (which contain MAPK but little tau or GSK3) were stably transfected to express tau or tau and GSK3. In both systems, GSK3-transfected cells contained tau AT8/M (defined by AT8 staining and tau PHF-like mobility), but MAPK-transfected cells required phosphatase inhibitors, such as okadaic acid (OKA) or calyculin (CAL), to produce tau AT8/M. In vitro, the same concentrations of CAL and OKA inhibit phosphatases 1 and 2A (PP1 and PP2A), except that 100-1000 times as much OKA is needed to inhibit PP1. Inducing tau phosphorylation at the AT8 site in MAPK-transfected cells required 2-10 times more OKA than CAL, suggesting both PP1 and PP2A helped block the phosphorylation. Though levels of tau AT8/M reached 2-8% of total cellular proteins in COS-1 cells, the ratio of particulate to supernatant tau levels did not increase, and no tangles were observed; perhaps post-translational modifications or co-aggregating proteins are needed to induce PHF.

Animals↗
PubMed1995

CD14-independent responses to LPS require a serum factor that is absent from neonates.

Monocytes/macrophages and neutrophils can respond to endotoxin via a high-affinity receptor (CD14), requiring low levels of LPS (< 1 ng/ml) as well as through another pathway(s) that requires high levels of LPS (> 10 ng/ml). Both pathways result in the secretion of high levels of cytokines, such as TNF-alpha, and the up-regulation of various other effector molecules. To further define the activation of cells by LPS via a pathway that does not involve CD14, we have used an experimental model that distinguishes CD14-dependent from CD14-independent responses using saturating amounts of an anti-CD14 Ab to block the CD14-dependent response. Analysis of the ability of various individuals to respond to LPS via via both the CD14-dependent and CD14-independent pathways shows that adults can respond via both pathways; furthermore, in the presence of 100 ng of LPS/ml, the primary response is CD14 independent. In contrast to the response by adults, neonates can only respond via the CD14-dependent pathway. Further analysis has shown that the CD14-independent pathway requires a non-CD14 plasma protein present in adult plasma that is either missing or nonfunctional in neonate (cord) plasma.

Adult↗
PubMed1995

Cell and molecular analysis of the developing and adult mouse subventricular zone of the cerebral hemispheres.

The subventricular zone (SVZ) of the lateral ventricle remains mitotically active in the adult mammalian central nervous system (CNS). Recent studies have suggested that this region may contain neuronal precursors (neural stem cells) in adult rodents. A variety of neuronal and glial markers as well as three extracellular matrix (ECM) markers were examined with the hope of understanding factors that may affect the growth and migration of neurons from this region throughout development and in the adult. This study has characterized the subventricular zone of late embryonic, postnatal, and adult mice using several neuronal markers [TuJ1, nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d), neuron-specific enolase (NSE)], glial markers [RC-2, vimentin, glial fibrillary acidic protein (GFAP), galactocerebroside (Gal-C)], ECM markers [tenascin-C (TN-C), chondroitin sulfate, a chondroitin sulfate proteoglycan termed dermatan sulfate-dependent proteoglycan-1 (DSD-1-PG)], stem-cell marker (nestin), and proliferation-specific marker [bromodeoxyuridine (BrdU)]. TuJ1+ and nestin+ cells (neurons and stem cells, respectively) persist in the region into adulthood, although the numbers of these cells become more sparse as the animal develops, and they appear to be immature compared to the cells in surrounding forebrain structures (e.g., not expressing NSE and having few, if any, processes). Likewise, NADPH-d+ cells are found in and around the SVZ during early postnatal development but become more sparse in the proliferative zone through maturity, and, by adulthood, only a few labeled cells can be found at the border between the SVZ and surrounding forebrain structures (e.g., the striatum), and even smaller numbers of positive cells can be found within the adult SVZ proper. BrdU labeling also seems to decrease significantly after the first postnatal week, but it still persists in the SVZ of adult animals. The disappearance of RC-2+ (radial) glia during postnatal development and the persistence of glial-derived ECM molecules such as tenascin and chondroitin sulfate proteoglycans (as well as other "boundary" molecules) in the adult SVZ may be associated with a persistence of immaturity, cell death, and a lack of cell emigration from the SVZ in the adult.

Aging↗
PubMed1995

Mutational analysis of two DR alpha residues involved in dimers of HLA-DR molecules.

Crystallographic analysis of HLA-DR1 molecules reveals a "dimer of dimers" with two reciprocal salt bridges between Glu 88 and Lys 111 of the two DR alpha chains. To determine whether these amino acids are critical for Ag presentation, we generated a panel of human B cell transfectants expressing DR alpha chains with mutations at residues 88, 111, or both. The mutant DR alpha chains, paired with endogenous DR3 beta chain, form cell surface dimers that retain epitopes recognized by a panel of anti-DR3 Abs. Replacement of Glu 88 with Ala (88A) selectively eliminates the ability to activate an alloreactive (anti-DR3) T cell clone. Mutant DR molecules with Lys substituted for Glu 88 (88K) fail to activate an alloreactive, an Ag-specific, and a peptide-specific T cell line. The DR alpha 88 mutants bind an exogenously supplied DR3-specific peptide and the mutant DR molecules migrate as dimers on SDS-PAGE, implying that their defective Ag presentation is not due to an inability to bind antigenic peptides. In contrast, substitution of Lys 111 with either Ala (111A) or Glu (111E) does not abrogate Ag presentation. Further, the defect introduced by Glu 88 to Lys mutation (88K) is not overcome by compensatory Lys to Glu mutation at position 111 (111E). Taken together, these results indicate an important functional or structural role for position 88 of the DR alpha chain, but argue against a requirement for interaction between DR alpha 88 and 111 during Ag-specific T cell stimulation.

Antigen Presentation↗