PubMed Health⌕ Search

Biomedical subjects

A Saltzman

Publications and source records attributed to A Saltzman.

At least 19 recordsLinked to original sources

Understanding human dendritic cell biology through gene profiling.

Dendritic cells are potent antigen presenting cells whose function has been associated with a variety of immunological disorders. Because of their relevance to human disease, extensive efforts have been made to gain a better understanding of their biology. One aspect of these efforts has been in the identification of pertinent molecules expressed in these cells through gene profiling experiments and proteomics. In this review, we summarize the results from the various profiling studies that have been done with human dendritic cells. We focus on molecules, which have been confirmed by other methods, such as quantitative PCR, or have been identified in multiple profiling studies to be expressed in the respective dendritic cell type. Through such profiling experiments and subsequent analysis, interesting molecules have been identified which can be further studied to determine their role in dendritic cell biology.

Dendritic Cells↗

Pyridoxine (vitamin B6) toxicity: enhancement by uremia in rats.

Pyridoxine is not completely innocuous. Large doses can cause a peripheral neuropathy despite renal excretion of this water-soluble vitamin. Renal failure patients are treated with pyridoxine to prevent a deficiency. The safety of pyridoxine treatment in the presence of renal dysfunction has not been studied. Our experiments on anephric rats show that the uremic state, in a mere 3 or 4 days, causes a 5- to 10-fold increase in susceptibility to pyridoxine-induced neuronopathy. These results suggest a need for caution in prescribing pyridoxine to uremic patients who will probably take the vitamin daily for many years.

Animals↗

Proliferation of glial cells induced by lithium in the neural lobe of the rat pituitary is enhanced by dehydration.

Rats dehydrated by 6 days of water deprivation had a low level of mitotic activity in the astrocytes ('pituicytes') of the neural lobe of the pituitary. Mitotic activity in the pituicytes was greatly increased when isotonic lithium was administered in the last 3 days of water deprivation. Rehydration on the last day of the experiment produced a further increase in mitoses. Isotonic solutions of sodium, potassium or rubidium chloride did not increase mitoses. This model of cell proliferation is of interest because the mitotic activity is related to a physiological attempt to maintain homeostasis rather than a response to injury or the development of neoplasia.

Animals↗

Prevention of chronic peritonitis caused by osmotic dysequilibrium in rats.

OBJECTIVE AND DESIGN: This study was done to determine whether peritonitis caused by osmotic dysequilibrium could be prevented by pretreatment. SUBJECTS: Young adult rats were used after induction of peritonitis by intraperitoneal injections of large volumes of pure water to create severe osmotic dysequilibrium. TREATMENT: During the 1 or 2 weeks before induction of peritonitis, the rats were pretreated by intraperitoneal injections of small volumes of pure water or large volumes of moderately hypotonic electrolytes to produce a slight degree of osmotic dysequilibrium. METHODS: Peritonitis was evaluated by macroscopic and microscopic study of peritoneal tissues. RESULTS: The severity of peritonitis was greatly reduced by the pretreatments. CONCLUSIONS: This study adds the peritoneum to the list of tissues in which adaptation to an injury can be accomplished by pretreatment with the same injurious agent, albeit in a less noxious form.

Animals↗

Are urea and creatinine uremic toxins in the rat?

Urea and creatinine are not generally considered to be important uremic toxins despite evidence from dialysis experiments to the contrary, and despite striking elevations of these nitrogenous waste products in uremia. In order to study this problem in acute uremia, we used a new dietary method for prolonging the survival of bilaterally nephrectomized rats. Urea or creatinine were injected on three successive days starting one day after the inception of uremia. Urea or creatinine injections shortened the survival time of acutely uremic rats, and increased the involution of thymus and spleen. The extra urea, but not creatinine, increased the serum osmolality. These data indicate that urea and creatinine are toxic in the acutely uremic rat. Hypertonicity of the serum may contribute to the toxicity of urea. Additional mechanisms of toxicity and additional toxins are not excluded.

Acute Disease↗

Pertussis vaccine and pertussis toxin increase lithium levels in rats: possible role of G-proteins.

A single dose of lithium was injected intravenously or intraperitoneally in rats. Lithium levels in serum and tissues 5 or 24 hours later were elevated when the rats were pretreated with pertussis vaccine (PV). The vaccine was effective whether given locally (subcutaneous) or systemically (intravenous). Tests of heated (inactivated) PV suggested that pertussis toxin might be responsible for the effects of PV. Injection of purified pertussis toxin (PT) confirmed this suggestion. Elevation of serum urea nitrogen suggested that lithium levels were increased because the combination of PV or PT with lithium reduced renal excretory function which could cause retention of lithium. Inasmuch as PV and PT are known to inactivate the inhibitory G-proteins, these data suggest G-protein involvement in the elevation of lithium levels by PV and PT.

Animals↗

Proliferation of glial cells in vivo induced in the neural lobe of the rat pituitary by lithium.

Lithium salts are widely used for treatment of psychiatric illness. Lithium also affects cell proliferation. During investigation of the effect of lithium chloride on the central nervous system (CNS) of nephrectomized rats, we noted numerous mitotic figures in the neural lobe of the pituitary. Morphologic criteria established that the mitotic cells were astrocytes, the supporting glial cells of the CNS, also known as pituicytes. Equimolar doses of chlorides of chemically related cations (sodium, potassium, rubidium) had no such effect.

Animals↗

Feeding sugar overnight maintains metabolic homeostasis in rats and is preferable to overnight starvation.

Rats are often starved overnight for many different reasons. Overnight starvation causes loss of body and liver weights, depletion of liver glycogen, decrease of blood glucose and loss of amino acids because of gluconeogenesis. Providing pure sucrose cubes as the sole overnight nutrient is a simple, inexpensive way to empty the gastrointestinal (GI) tract, while minimizing liver changes and preventing decrease of blood glucose and loss of amino acids. Adding sugars to the overnight drinking water as the sole nutrient has the same beneficial effects, provided the type of sugar and its concentration allow for sufficient intake and provided hyponatremia is avoided. Feeding sucrose cubes or sugar solutions will empty the gastrointestinal tract as effectively as starvation. In all instances, simple precautions against coprophagy and pica should be taken in order to secure optimal benefit.

Animals↗

Effects of coprophagy on serum urea and the weight of the gastrointestinal tract of fed or fasted rats.

Coprophagy can be minimized by fitting rat cages with metal grids which allow faecal pellets to pass through to the floor of the cage. When bedding was omitted overnight, the extent of coprophagy could be estimated from the weight of the droppings on the cage floor or the weight of the gastrointestinal (GI) tract removed from rats housed with or without grids. The effect of coprophagy was also demonstrated by the elevation of serum urea nitrogen in rats that consumed faeces. Therefore, precautions against coprophagy, or their absence, should be specified in all experimental protocols and reports.

Animals↗

Transforming growth factor-beta-mediated apoptosis in the Ramos B-lymphoma cell line is accompanied by caspase activation and Bcl-XL downregulation.

Upon transforming growth factor-beta (TGF-beta) treatment, Ramos cells, a B-cell lymphoma cell line, undergo apoptosis, as measured by annexin V labeling, DNA fragmentation, and propidium iodide staining. Apoptosis could be observed by 24 h after TGF-beta exposure and occurred before the development of a significant blockage of cell cycle progression. TGF-beta-mediated apoptosis was also accompanied by a strong induction of caspase-3 subfamily activity. Incubation of cells with the caspase inhibitor Z-VAD.FMK at 20 microM, but not at 10 microM, prevented TGF-beta-induced apoptosis from occurring. By comparison, caspase-3 subfamily activity was 87% inhibited at 10 microM Z-VAD.FMK and completely inhibited at 20 microM. Because of TGF-beta's well-established role of regulating gene transcription, the mRNA levels for proteins associated with apoptosis (Fas- and Fas-associated proteins, Bcl-2 family members, IAP proteins, and I kappa B) were also studied. After 24 h of TGF-beta treatment, the most significant mRNA changes occurred with Bcl-XL (two-fold decrease) and Bik (twofold increase). TGF-beta treatment also resulted after 48 h in a fivefold decrease in Bcl-XL protein levels, based on immunoblotting analysis. Therefore, TGF-beta-mediated apoptosis involves the activation of caspases. In addition, TGF-beta transcriptionally regulates Bcl-2 family members, Bcl-XL and Bik, to further influence the apoptosis process.

Amino Acid Chloromethyl Ketones↗

Cloning and characterization of human Jak-2 kinase: high mRNA expression in immune cells and muscle tissue.

We report on the cloning and sequence analysis of the mRNA coding for full-length human Janus kinase 2 (Jak2). The human form of Jak2 is 1132 amino acids in length with a M(r) of 131 KDa. It has 95% sequence similarity to pig and rat Jak2. The highest level of mRNA expression was found in the spleen, peripheral blood leukocytes, and testis. Also a significantly high level of Jak2 mRNA was found in heart and skeletal muscle. Northern blot analysis showed three mRNA species in all tissues tested, except heart and skeletal muscle, of 7.6, 5.9, and 4.8 Kb. In skeletal muscle and heart, three mRNA species of 7.6, 4.8, and 3.9 Kb were identified. The catalytic domain of the human Jak2 was expressed and its specificity for phosphorylating peptide substrates derived from the gp130, STAT, and Jak3 molecules was determined and compared to that for human Jak1 and Jak3.

Amino Acid Sequence↗

hUBC9 associates with MEKK1 and type I TNF-alpha receptor and stimulates NFkappaB activity.

hUBC9, an E2 ubiquitin conjugating enzyme, was identified by yeast two-hybrid screening and coprecipitation studies to interact with MEKK1 and the type I TNF-alpha receptor, respectively. Because both of these proteins regulate NFkappaB activity, the role of hUBC9 in modulating NFkappaB activity was investigated. Overexpression of hUBC9 in HeLa cells stimulated the activity of NFkappaB as determined by NFkappaB reporter and IL-6 secretion assays. hUBC9 also synergized with MEKK1 to activate NFkappaB reporter activity. Thus, hUBC9 modulates NFkappaB activity which, at least in part, can be attributed to its interaction with MEKK1 and the type I TNF-alpha receptor.

Antigens, CD↗

Prevention of lithium nephrotoxicity in a novel one-hour model in rats.

It is well established that lithium can cause morphologically visible damage to the kidneys of humans and animals. Although the clinical significance of its nephrotoxicity is debatable, it would be desirable to find a method to prevent lithium's effect on the kidneys. Toward this end, we have developed a novel method for producing nephrotoxicity that will be useful for research on prevention. A single, large, toxic dose of lithium chloride (LiCl) caused necrosis of the distal convoluted tubules, which was visible by light microscopy in 30 min, had fully developed in 1 h, and had disappeared by the next day. The lesions were seen after i.p. or i.v. injections of fasted rats of three different strains. Equivalent doses of NaCl, KCl, MgCl2 and combinations thereof had no such effect, nor did they inhibit nephrotoxicity when incorporated into the LiCl solution. However, relatively small doses of LiCl injected by any route 3 or 24 h beforehand prevented the nephrotoxicity. The mechanism of prevention is not known, but it does not involve reduction of lithium levels in the kidneys.

Animals↗

Distribution of small intestinal lesions in anaphylaxis of rats.

Hemorrhage and congestion were not uniformly distributed along the small intestine during systemic anaphylaxis in rats. Duodenum had little hemorrhage and congestion and the terminal ileum had even less. Maximum involvement occurred in jejunum of 13% of rats, in ileum of 47%, and in both jejunum and ileum of 40%. Sequential scoring along the entire length of small intestine revealed different patterns of distribution with more than one peak of intensity in some of the rats. Within a lesioned area, banding was common except where hemorrhage and congestion were so severe as to obliterate all patterns. Banding represented a gradient of injury with respect to the vascular supply. The pale stripes (less severe hemorrhage) contained the penetrating vessels derived from the terminal mesenteric arcades. The dark stripes (more severe hemorrhage) did not contain such vessels. In addition, the mesenteric side of the intestine was less affected than the antimesenteric side. This constituted a second gradient that might also be related to the distance from the vascular supply. In both instances, proximity to larger blood vessels had a protective effect. These two gradients and the variable sites and patterns of distribution have not been described previously in intestinal anaphylaxis. Gradients and the variability of the distribution of lesions in intestinal anaphylaxis should be considered in experiments on pathogenesis and altered function.

Anaphylaxis↗

Petechial hemorrhages in the small intestinal Peyer's patches: a new manifestation of systemic anaphylaxis.

Systemic anaphylaxis in the rat has major manifestations in the small intestine. In August rats, but not in other strains, intestinal anaphylaxis was accompanied by petechial hemorrhages in Peyer's patches. The occurrence of petechiae was not proportional to the intensity of prostration, cyanosis or gut congestion. No hemorrhages were found in other organs. The petechiae occurred in August rats of either sex after sensitization and challenge with any of several antigens and adjuvants and after passive sensitization with antiserum. The number of Peyer's patches with hemorrhage varied from one to all 20 in individual rats. The occurrence of petechiae was not influenced significantly by the route of sensitization or challenge, by the presence or absence of pinworms in the cecum, or by ancillary treatment at time of challenge with normal serum, normal blood, heparin, pertussis vaccine or lipopolysaccharide. The intestinal mast cells of the susceptible August rats were not different from the mast cells of the resistant strains. Furthermore, mast cells did not reside in the lymphoid follicles of Peyer's patches which was the site of the petechial hemorrhages in anaphylactic August rats. Nor did injections of histamine, serotonin or both cause hemorrhages in Peyer's patches.

Anaphylaxis↗

Influence of body size on lithium levels in rats.

Lithium chloride was injected into rats by the intraperitoneal or intravenous route. The dose was proportional to body weight, in the conventional manner. Lithium levels in blood serum and organs were determined after 3-24 h. Within a given strain, large rats had higher levels than small rats. The size of the rats, and not their age, was the determining factor. The large rats had more adipose tissue than the small rats. Inasmuch as lithium distributes in body water, the excess fat in large rats reduces its volume of distribution, which may be responsible for raising the lithium levels in aqueous compartments, including serum. Male and female rats of equal body size developed equal lithium levels in serum.

Age Factors↗