Inflammasome Activators Induce Interleukin-1α Secretion via Distinct Pathways with Differential Requirement for the Protease Function of Caspase-1

Bortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature

Background: Cow's milk allergy (CMA) is one of the leading causes of food allergy in children. Understanding the mechanisms involved in the development of CMA has been hampered by the lack of suitable animal models. Objective: We sought to develop a mouse model of IgE-mediated cow's milk hypersensitivity (CMH) that mimics the clinical features of immediate CMA in humans. Methods: Three-week-old C3H/HeJ mice were sensitized by intragastric administration of cow's milk (CM) plus cholera toxin and boosted 5 times at weekly intervals. Results: CM-specific IgE antibody levels were significantly increased at 3 weeks and peaked at 6 weeks after the initial feeding. Intragastric challenge with CM at week 6 elicited systemic anaphylaxis accompanied by vascular leakage, significantly increased plasma histamine, and increased intestinal permeability to casein. Histologic examination of intestinal tissue revealed marked vascular congestion, edema, and sloughing of enterocytes. The role of IgE in mediating CMH was confirmed by abrogation of passive cutaneous anaphylaxis reactions by heat inactivation of immune sera. Development of IgE-mediated CMH in this model is likely to be T H2 cell mediated because in vitro stimulation of spleen cells from mice allergic to CM induced significant increases in the levels ofIL-4 and IL-5, but not IFN-γ. Conclusion: This model should provide a useful tool for evaluating the immunopathogenic mechanisms involved in CMA and for exploring new therapeutic approaches. (J Allergy Clin Immunol 1999;103:206-14.)

A murine model of IgE-mediated cow's milk hypersensitivity.

Moderately elevated plasma total homocysteine (tHcy) is a strong modifiable risk factor for vascular dementia and Alzheimer's disease. Prospectively, elevated tHcy is associated with cognitive decline, white matter damage, brain atrophy, neurofibrillary tangles, and dementia. Most homocysteine-lowering trials with folate and vitamins B6 and/or B12 tested as protective agents against cognitive decline were poorly designed by including subjects unlikely to benefit during the trial period. In contrast, trials in high-risk subjects, which have taken into account the baseline B vitamin status, show a slowing of cognitive decline and of atrophy in critical brain regions, results that are consistent with modification of the Alzheimer's disease process. Homocysteine may interact with both risk factors and protective factors, thereby identifying people at risk but also providing potential strategies for early intervention. Public health steps to slow cognitive decline should be promoted in individuals who are at r...

Homocysteine, B Vitamins, and Cognitive Impairment

Pyridoxal phosphate is the cofactor for over 100 enzyme-catalysed reactions in the body, including many involved in the synthesis or catabolism of neurotransmitters. Inadequate levels of pyridoxal phosphate in the brain cause neurological dysfunction, particularly epilepsy. There are several different mechanisms that lead to an increased requirement for pyridoxine and/or pyridoxal phosphate. These include: (i) inborn errors affecting the pathways of B(6) vitamer metabolism; (ii) inborn errors that lead to accumulation of small molecules that react with pyridoxal phosphate and inactivate it; (iii) drugs that react with pyridoxal phosphate; (iv) coeliac disease, which is thought to lead to malabsorption of B(6) vitamers; (v) renal dialysis, which leads to increased losses of B(6) vitamers from the circulation; (vi) drugs that affect the metabolism of B(6) vitamers; and (vii) inborn errors affecting specific pyridoxal phosphate-dependent enzymes. The last show a very variable degree of pyridoxine responsiveness, from 90% in X-linked sideroblastic anaemia (delta-aminolevulinate synthase deficiency) through 50% in homocystinuria (cystathionine beta-synthase deficiency) to 5% in ornithinaemia with gyrate atrophy (ornithine delta-aminotransferase deficiency). The possible role of pyridoxal phosphate as a chaperone during folding of nascent enzymes is discussed. High-dose pyridoxine or pyridoxal phosphate may have deleterious side-effects (particularly peripheral neuropathy with pyridoxine) and this must be considered in treatment regimes. None the less, in some patients, particularly infants with intractable epilepsy, treatment with pyridoxine or pyridoxal phosphate can be life-saving, and in other infants with inborn errors of metabolism B(6) treatment can be extremely beneficial.

B6-responsive disorders: a model of vitamin dependency.

A procedure for inducing sustained hyperlipemia in rats by administration of a surfactant.

Large doses of pyridoxine cause injury to the primary sensory neurons in trigeminal and dorsal root ganglia of animals and patients subjected to megavitamin therapy. The increased hazard to subjects with reduced renal excretory function has been explored previously. In the present work, the neurotoxicity of pyridoxine for rats was found to be increased by dietary protein deficiency. A mere 3 or 7 days of pretreatment with either of two protein-deficient diets were sufficient to accelerate and intensify the clinical neurological signs and histological lesions from pyridoxine injections. These results are caused, at least in part, by loss of body weight, decreased protein binding in serum and decreased consumption of water and decreased volume of urine, which reduce the urinary losses of the toxicant. The vitamers related to pyridoxine (pyridoxal, pyridoxamine) and the coenzyme (pyridoxal 5-phosphate) did not cause clinical signs or lesions similar to those produced by pyridoxine even when injected in maximum tolerated doses. Neither a protein-deficient diet nor bilateral nephrectomy changed the results with the vitamers.

Pyridoxine (vitamin B6) neurotoxicity: enhancement by protein-deficient diet.

http://cdr.rfmh.org/Publications/PDFs_Levy/Levine%202009%20Exp%20Mol%20Pathol.pdf

Systemic pathology in aged mouse models of Down's syndrome and Alzheimer's disease.

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.

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

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.

Arthur Saltzman

Papers

A procedure for inducing sustained hyperlipemia in rats by administration of a surfactant.

Pyridoxine (vitamin B6) neurotoxicity: enhancement by protein-deficient diet.

Systemic pathology in aged mouse models of Down's syndrome and Alzheimer's disease.

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

Are urea and creatinine uremic toxins in the rat