Sulfhydryl oxidation modifies the calcium dependence of ryanodine-sensitive calcium channels of excitable cells

The calcium dependence of ryanodine-sensitive single calcium channels was studied after fusing with planar lipid bilayers sarcoendoplasmic reticulum vesicles isolated from excitable tissues. Native channels from mammalian or amphibian skeletal muscle displayed three different calcium dependencies, cardiac (C), mammalian skeletal (MS), and low fractional open times (low Po), as reported for channels from brain cortex. Native channels from cardiac muscle presented only the MS and C dependencies. Channels with the MS or low Po behaviors showed bell-shaped calcium dependencies, but the latter had fractional open times of <0.1 at all [Ca2+]. Channels with C calcium dependence were activated by [Ca2+] < 10 microM and were not inhibited by increasing cis [Ca2+] up to 0.5 mM. After oxidation with 2,2'-dithiodipyridine or thimerosal, channels with low Po or MS dependencies increased their activity. These channels modified their calcium dependencies sequentially, from low Po to MS and C, or from MS to C. Reduction with glutathione of channels with C dependence (native or oxidized) decreased their fractional open times in 0.5 mM cis [Ca2+], from near unity to 0.1-0.3. These results show that all native channels displayed at least two calcium dependencies regardless of their origin, and that these changed after treatment with redox reagents.     

Pharmacokinetics of 2-oxothiazolidine-4-carboxylate, a cysteine prodrug, and cysteine

The pharmacokinetics of both 2-oxothiazolidine-4-carboxylate (OTZ), a prodrug of cysteine, and total blood cysteine (cysteine plus cystine) were investigated in 18 healthy volunteers. OTZ was given either as a single, 2-hour intravenous infusion (56-66 mg/kg) or similarly infused (70-100 mg/kg) every 8 hours for four doses. Blood was assayed for OTZ, total blood cysteine, and glutathione. The pharmacokinetics of OTZ were analyzed alone and simultaneously with total cysteine using the NONMEM software package (University of California at San Francisco. The pharmacokinetics of OTZ were best described by Michaelis-Menten kinetics with parallel first-order elimination. OTZ was efficiently removed from the plasma. The Michaelis-Menten route of elimination was attributed to conversion of OTZ to total cysteine. At plasma OTZ concentrations equal to the Michaelis constant Km, 84% of OTZ was converted to total cysteine. These findings suggest that OTZ administered intravenously is an efficient means of increasing total blood cysteine.     

Persistent hyperinsulinemic hypoglycemia in the newborn and infants

Persistent hyperinsulinemic hypoglycaemia of infancy (PHHI) is the most frequent cause of hypoglycaemia in infancy. Clinical presentation is heterogeneous, with variable onset of hypoglycaemia and response to diazoxide, and presence of sporadic or familial forms. Underlying histopathological lesions can be focal or diffuse. Focal lesions are characterised by focal hyperplasia of pancreatic islet-like cells, whereas diffuse lesions implicate the whole pancreas. The distinction between the two forms is important because surgical treatment and genetic counselling are radically different. Focal lesions correspond to somatic defects which are totally cured by limited pancreatic resection, whereas diffuse lesions require a subtotal pancreatectomy exposing to high risk of diabetes mellitus. Diffuse lesions are due to functional abnormalities involving several genes and different transmission forms. Recessively inherited PHHI have been attributed to homozygote mutations for the beta-cell sulfonylurea receptor (SUR1) or the inward-rectifying potassium-channel (Kir6.2) genes. Dominantly inherited PHHI can implicate the glucokinase gene, particularly when PHHI is associated with diabetes, the glutamate dehydrogenase gene when hyperammonaemia is associated, or another locus.     

Primary leiomyosarcoma. A rare tumor of the adrenal gland

OBJECTIVE: To report on a rare case of primary leiomyosarcoma of the adrenal. To our knowledge, this is the fourth case reported in the literature. METHODS: A patient with primary leiomyosarcoma of the adrenal gland is presented. The clinical features are described, and the diagnostic and therapeutic aspects of this rare primary mesenchymal tumor are discussed. RESULTS/CONCLUSIONS: The aggressive nature and the poor prognosis of this rare tumor type are emphasized.     

Molecular and immunophenotypical characterization of a feline immunodeficiency virus (FIV)-associated lymphoma: a direct role for FIV in B-lymphocyte transformation?

We describe the histopathological, immunohistochemical, and molecular characterization of a lymphoma arising in a 7-year-old cat following experimental infection with feline immunodeficiency virus (FIV). The tumor was high grade and of B-cell lineage. The transformed cell had an immature phenotype (CD79a+, CD79b-, CD21-, immunoglobulin heavy and light chain negative), confirmed by antigen receptor gene analysis, which showed germ line configuration. Single-copy, clonally integrated FIV provirus was detected in tumor genomic DNA. FIV p24 antigen was not detected in tumor cells by immunostaining. This study provides the first evidence that the feline lentivirus may play a direct role in cell transformation under certain circumstances.     

Controlled clinical assay in Clonidine, arginine aspartate, alpha-ketoglutarate of Ornithine and Ciproheptadine as growth stimulants in children with short stature

Eighty-one healthy prepubertal children of short stature, between two and twelve years of age, were divided into four homogeneous groups. Each group was treated with a placebo for one year and for a second year with one of the following drugs (double blind): clonidine (CI), arginine asprate (AA), ornithine alphaketoglutare (OKG), or cyproheptadine (Cp). CI and OKG did not better the standard deviation of height. AA and Cp did, but to no greater extent than the placebo. The growth rate did not change in any group. The ratio of bone age/chronological age was significantly higher at the end of the OKG year than at the end of the year with placebo, a difference that was not found in any other group. The prognosis of adult height (TW2) did not change in any group. The standard deviation of weight increased in all groups, both with the placebo and the various drugs, without significant differences between the groups. The CI caused frequent clinical side effects, including a reversible increase in transaminases in one child. The Cp stimulated hunger. The AA and OKG did not produce side-effects and the placebo increased appetite in 11% of the children. Somatomedin C was significantly higher after one year with Cp than after one year with the placebo, significantly higher after the placebo than after CI and AA and there was no difference between the treatment with the placebo and OKG. Growth hormone values in a 24 hour urine sample were so scattered that we do not consider them helpful.(ABSTRACT TRUNCATED AT 250 WORDS)     

The immunology of corneal graft rejection

Corneal transplantation is the most successful of organ transplants due to the fact that the eye is an immunologically privileged site, and the cornea is an immunologically privileged tissue. The factors responsible for this include presence of the blood-aqueous barrier, the avascularity of the cornea, the absence of classic antigen-presenting cells (APCs) in the central cornea, inhibitory factors in the aqueous humor, the phenomenon known as anterior chamber-associated immune deviation (ACAID), and the intraocular expression of Fas ligand. Loss of ocular immune privilege can occur with breaching of the blood-ocular barrier, corneal neovascularization, migration of classic APCs to the center of the cornea, loss of inhibitory factors in aqueous humor, abrogation of ACAID, and loss of Fas ligand expression within the anterior chamber. The purpose of this review is to analyze these events and how they relate to corneal graft rejection. A discussion on future research and therapeutic modalities is provided.     

In vivo neurochemistry of the brain in schizophrenia as revealed by magnetic resonance spectroscopy

Magnetic resonance spectroscopy (MRS), an application of the methods of nuclear magnetic resonance (NMR), is a functional imaging modality that provides a view of localized biochemistry in vivo. A number of studies applying MRS to the neurochemistry of schizophrenia have been reported, which encompass a range of patient populations, states of medication, anatomic regions, nuclear species, and MRS techniques. A brief review of the history and methodology of NMR and MRS is presented. Comparison is made of MRS capabilities with other functional imaging modalities. Aspects of the neurochemistry of schizophrenia relevant to MRS studies are reviewed, as are the reported MRS studies involving patients with schizophrenia. Areas of consistent findings include decreased phosphomonoesters and increased phosphodiesters in frontal lobes, and decreases in the putative neuronal cell marker, N-acetylaspartate, in temporal lobes. Studies of neurotransmitters such as glutamate, gamma-aminobutyric acid, and glutamine have generated inconsistent results. New insights into alterations in neurochemistry in schizophrenia have been provided by MRS. Studies of neurotransmitters have future potential with improvements in field strength and in spectral editing techniques. MRS has the potential to measure brain medication levels and simultaneous effects on neurochemistry. MRS may assist in characterizing high-risk populations, and ultimately guide medication use.