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J P Kushner

Publications and source records attributed to J P Kushner.

At least 19 recordsLinked to original sources
PubMed1992

Evidence for cytokine-inducible nitric oxide synthesis from L-arginine in patients receiving interleukin-2 therapy.

An interferon-gamma, tumor necrosis factor, and interleukin-1-inducible, high-output pathway synthesizing nitric oxide (NO) from L-arginine was recently identified in rodents. High-dose interleukin-2 (IL-2) therapy is known to induce the same cytokines in patients with advanced cancer. Therefore, we examined renal cell carcinoma (RCC; n = 5) and malignant melanoma (MM; n = 7) patients for evidence of cytokine-inducible NO synthesis. Activity of this pathway was evaluated by measuring serum and urine nitrate (the stable degradation product of NO) during IL-2 therapy. IL-2 administration caused a striking increase in NO generation as reflected by serum nitrate levels (10- and 8-fold increase [P less than 0.001, P less than 0.003] for RCC and MM patients, respectively) and 24-h urinary nitrate excretion (6.5- and 9-fold increase [both P less than 0.001] for RCC and MM patients, respectively). IL-2-induced renal dysfunction made only a minor contribution to increased serum nitrate levels. Metabolic tracer studies using L-[guanidino-15N2]arginine demonstrated that the increased nitrate production was derived from a terminal guanidino nitrogen atom of L-arginine. Our results showing increased endogenous nitrate synthesis in patients receiving IL-2 demonstrate for the first time that a cytokine-inducible, high-output L-arginine/NO pathway exists in humans.

Adult↗
PubMed1991

Iron absorption in hypotransferrinemic mice.

We used a unique animal model, the hypotransferrinemic (Htx) mouse, to examine the role of transferrin (Tf) in gastrointestinal iron uptake. Despite the absence of Tf, Htx animals hyperabsorb iron. Transfusion of red blood cells sufficient to normalize the hematocrit and reticulocyte count resulted in a return of iron absorption to normal values. These studies indicate that Tf does not play an obligate role in iron absorption, either as a carrier or as a humoral signal regulating absorption. Transfer of plasma or whole blood from Htx mice or from other animal models of iron hyperabsorption to normal mice did not cause an increase in iron absorption in recipient animals. Using the plasma or blood transfer approach, we have been unable to detect a humoral regulator of gastrointestinal iron absorption.

Animals↗
PubMed1991

Comparison of stainable liver iron between symptomatic and asymptomatic hemochromatosis homozygotes and their homozygous relatives.

The authors compared the amount of hepatic parenchymal cell stainable iron in 159 hemochromatosis homozygotes. They were separated into four groups. Group 1: 59 symptomatic hemochromatosis probands with hemochromatosis (mean age 49 years) who were identified because of symptoms and signs of iron overload. Group 2: 38 asymptomatic probands with hemochromatosis (mean age 29 years) identified during population screening studies or during routine health maintenance evaluation. Group 3: 47 homozygous relatives (mean age 43 years) of Group 1 probands. Group 4: 15 homozygous relatives (mean age 30 years) of Group 2 probands. The symptomatic probands (Group 1) were 20 years older and had much more stainable hepatic iron (p less than 0.0001) than the asymptomatic probands (Group 2). The homozygous relatives (Group 3) of the symptomatic probands also were older and had much more stainable hepatic iron than the homozygous relatives (Group 4) of asymptomatic probands (p less than 0.0002). The results of this study suggest that population screening studies can result in early identification of individuals with hemochromatosis before massive hepatic iron overload occurs and before symptoms of iron overload develop.

Hemochromatosis↗
PubMed1991

Coincidental hemochromatosis and viral hepatitis.

A 35-year-old woman presented with liver failure, hepatic iron overload, and secondary amenorrhea due to hypogonadotropic hypogonadism. She had chronic inflammatory hepatitis which was considered to be due to post-transfusional viral hepatitis. Her hepatic iron overload was considered to be due to hemochromatosis. Her premature menopause was thought to be due to the severity of her liver disease, but her iron overload also could have contributed to gonadotrophin deficiency. She underwent liver transplantation and 5 months later, she experienced return of menstrual function. The distinction between hepatitis as a cause of iron loading, hemochromatosis as a cause of hepatic inflammation, the small influence of alcohol on increased iron stores, and other features of her history, physical examination, and laboratory evaluation are discussed.

Female↗
PubMed1990

Southern blood club symposium: an update on selected aspects of hemochromatosis.

Genetic epidemiology studies have indicated that hereditary hemochromatosis (HH) occurs in caucasians with a frequency of 3 to 13 per thousand. Clinical recognition however occurs far less frequently. The disparity is best resolved by defining HH as homozygosity for the HLA-linked hemochromatosis allele, regardless of the total body iron burden. Variability of clinical expression is explained in part by physiologic iron loss in women but variability in males may be due to environmental factors, gene-gene interactions or polymorphisms in mutated hemochromatosis alleles. Although clinical variability is great, the laboratory phenotype of HH is fairly constant and is marked by elevation of the transferrin saturation. The elevated transferrin saturation occurs early in life, before organ iron loading occurs and can be used as a screening tool to detect HH before organ damage occurs. Cloning and characterizing the HH gene, which is located within 1 centimorgan of the HLA-A locus should resolve some of the issues concerning clinical variability.

Adolescent↗
PubMed1990

Uroporphyrinogen decarboxylase: a splice site mutation causes the deletion of exon 6 in multiple families with porphyria cutanea tarda.

Uroporphyrinogen decarboxylase (URO-D) is a cytosolic heme-biosynthetic enzyme that converts uroporphyrinogen to coproporphyrinogen. Defects at the uroporphyrinogen decarboxylase locus cause the human genetic disease familial porphyria cutanea tarda. A splice site mutation has been found in a pedigree with familial porphyria cutanea tarda that causes exon 6 to be deleted from the mRNA. The intron/exon junctions on either side of exon 6 fall between codons, so the resulting protein is shorter than the normal protein, missing only the amino acids coded by exon 6. The shortened protein lacks catalytic activity, is rapidly degraded when exposed to human lymphocyte lysates, and is not detectable by Western blot analysis in lymphocyte lysates derived from affected individuals. The mutation was detected in five of 22 unrelated familial porphyria cutanea tarda pedigrees tested, so it appears to be common. This is the first splice site mutation to be found at the URO-D locus, and the first mutation that causes familial porphyria cutanea tarda to be found in more than one pedigree.

Amino Acid Sequence↗
PubMed1990

Neonatal hemochromatosis. Genetic analysis of transferrin-receptor, H-apoferritin, and L-apoferritin loci and of the human leukocyte antigen class I region.

Neonatal hemochromatosis (NH), a generally fatal disorder of infancy, is characterized by severe hepatic insufficiency of intrauterine onset and by marked organ iron loading. Its cause is unknown. It has been suggested that NH may represent an unusual manifestation of hereditary hemochromatosis (HH), which is human leukocyte antigen (HLA) linked. Evidence for major rearrangements or deletions at the HLA class I region and at three loci directly involved in iron metabolism (H- and L-apoferritin and the transferrin receptor [TfR]) was sought. The population studied included five probands with NH and 14 first-degree family members in a total of six kindreds. Also sought were HLA associations with NH by collating the results of HLA serotyping in these 19 persons and in 17 members of 7 additional kindreds in which NH has occurred, including 5 probands with NH and 12 first-degree family members. We found no evidence for major rearrangements or deletions in H- or L-apoferritin genes, in TfR genes, or within the HLA locus. We found no evidence for linkage of NH to HLA serotypes. We conclude that while NH and HH are similar in their patterns of iron loading, they are not genetically related.

Adult↗
PubMed1989

HLA-linked hemochromatosis alleles in sporadic porphyria cutanea tarda.

We tested the hypothesis that the hepatic siderosis that characterizes sporadic porphyria cutanea tarda is due to the presence of HLA-linked hemochromatosis alleles. We studied 21 probands with sporadic porphyria cutanea tarda and 135 of their relatives by determining HLA haplotypes and measuring transferrin saturation and serum ferritin concentration. Liver biopsies were performed in all probands and in relatives when appropriate. Seventeen pedigrees were available and were studied by both likelihood analysis and by a gene counting method. We estimated that 10 of the 17 probands with available living relatives possessed at least one hemochromatosis allele. Thirteen of the 21 probands (62%) possessed at least one HLA-A3 alloantigen. Eighteen of 69 relatives who shared an HLA haplotype with a proband (26%) had an elevation of transferrin saturation or serum ferritin concentration. Only one first-degree relative not sharing an HLA haplotype with a proband had an elevated transferrin saturation or serum ferritin concentration. These findings indicate that HLA-linked hemochromatosis alleles are far more common in patients with sporadic porphyria cutanea tarda than in individuals in the general population and may be responsible for the hepatic siderosis associated with most cases of sporadic porphyria cutanea tarda.

Adult↗
PubMed1989

Twenty-four hour variation of transferrin saturation in treated and untreated haemochromatosis homozygotes.

We studied 43 haemochromatosis homozygotes and seven normal individuals to test the hypothesis that there is an almost continuous relative deficiency of apotransferrin in treated and untreated homozygotes. Transferrin saturation was measured at 2-h intervals for 24 h while all subjects ate their usual diet. Subjects with haemochromatosis were separated into four groups based on sex and whether or not they had been iron-depleted. Nineteen treated and 11 untreated male homozygotes had mean transferrin saturation values of 70 and 81%, respectively. Five treated and eight untreated female homozygotes had mean transferrin saturation values of 71 and 69%. Normal subjects had mean transferrin saturation values of 29% (3 males) and 21% (4 females). These data demonstrate continuously high transferrin saturation values, greater than 69% in most treated and untreated male and female homozygotes, resulting in hepatic iron accumulation of non-transferrin-bound iron from the portal circulation.

Bloodletting↗
PubMed1989

The HLA class I locus: analysis of RFLPs in hereditary hemochromatosis.

The gene for hereditary hemochromatosis is linked to the HLA locus on chromosome 6. Four cloned DNA probes originating from the HLA class I region were used to detect seven restriction fragment length polymorphisms (RFLPs). Allele frequencies and segregation of each RFLP was determined. Analysis of RFLPs in 38 unrelated homozygotes with hemochromatosis revealed differences in allele frequencies between the control and the hemochromatotic groups but these differences did not reach statistical significance. Some differences persisted, however, even when only controls with the A3 antigen were compared with A3 hemochromatotics. Since both control and hemochromatotic groups were small, further studies will be necessary to ascertain whether these RFLPs could serve to locate the gene responsible for hereditary hemochromatosis.

Adult↗
PubMed1989

A point mutation in the coding region of uroporphyrinogen decarboxylase associated with familial porphyria cutanea tarda.

Familial porphyria cutanea tarda (PCT) is inherited as an autosomal dominant trait caused by decreased activity of uroporphyrinogen decarboxylase (URO-D). In most families with PCT, URO-D mRNA levels are normal but both catalytic activity and immunologic reactivity of URO-D are half normal. We have cloned and sequenced 8 URO-D cDNA transcripts derived from a pedigree member with familial PCT. Three of the cDNAs had sequences encoding normal URO-D but five cDNA's contained a point mutation resulting in a gly----val substitution at amino acid position 281. An oligonucleotide probe complementary to the mutant sequence hybridized to DNA from affected individuals within the pedigree, but not to DNA from normal individuals. Measurements of pulse labeled URO-D in Epstein-Barr virus transformed lymphocytes indicated that the mutant protein has a half-life in vivo of less than four hours. In vitro measurements utilizing labeled URO-Ds generated in a reticulocyte lysate system revealed a 12-hour half-life for the mutant protein compared with a 102-hour half-life for normal URO-D. This is the first URO-D mutation to be characterized in a pedigree with familial PCT. This mutation was not detected in affected individuals from seven other PCT pedigrees, suggesting that PCT can result from different mutations.

Carboxy-Lyases↗
PubMed1979

Idiopathic refractory sideroblastic anemia: incidence and risk factors for leukemic transformation.

The clinical course of 29 patients with idiopathic refractory sideroblastic anemia studied by us was reviewed. Four patients developed acute leukemia. We were able to find 27 out of 268 cases of idiopathic refractory sideroblastic anemia reported in the literature which terminated in acute leukemia. Nine of these were well described. The overall incidence of acute leukemia is 10%. In an attempt to identify the risk factors for the development of acute leukemia, the clinical and laboratory features of this group of thirteen well-described cases which terminated in acute leukemia were compared to the remaining 25 of our cases which did not undergo leukemic transformation. The patients who died of acute leukemia tended to have a more severe anemia, a lower reticulocyte count, and increased transfusion requirement, and thrombocytopenia. Thrombocytosis appears to be a relatively good prognostic sign.

Adult↗
PubMed1979

Acquired myeloperoxidase deficiency and recurrent infections in a patient with acute myelomonocytic leukemia.

Acquired myeloperoxidase deficiency has been reported in several hematological malignancies. The clinical course of a patient with acute myelomonocytic leukemia is described which was characterized by staphylococcal infections prior to therapy and again during a period of relapse. Neutropenia was not a feature of these two periods but in vitro studies revealed decreased bacterial killing capacity and decreased neutrophil myeloperoxidase activity. Infectious complications were not observed during drug-induced remission when bacterial killing capacity and myeloperoxidase activity were improved toward normal. These observations suggest that the myeloperoxidase deficient neutrophils were derived from leukemic progenitors.

Cytotoxicity, Immunologic↗
PubMed1978

Porphyria cutanea tarda in three generations of a single family.

We examined conjugal and blood relatives of one kindred for evidence of porphyria cutanea tarda. The disease was identified in eight family members in three generations. Four were classified as having overt porphyria cutanea tarda because of four criteria: photo-enhanced dermatosis; excessive urinary excretion of uroporphyrins; characteristic thin-layer chromatographic pattern of urinary porphyrins; and decreased activity of erythrocyte uroporphyrinogen decarboxylase. Two patients with excessive excretion of uroporphyrins or characteristic chromatograms, or both, and decreased uroporphyrinogen decarboxylase activity were classified as having subclinical porphyria cutanea tarda, and two with decreased uroporphyrinogen decarboxylase activity only were classified as having latent porphyria cutanea tarda. This study provides further evidence that prophyria cutanea tarda can be a familial disease inherited in an autosomal dominant fashion. We propose a reclassification of porphria cutanea tarda as an overt, subclinical or latent disorder.

Adult↗