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Biomedical subjects

S W Brusilow

Publications and source records attributed to S W Brusilow.

At least 19 recordsLinked to original sources
PubMed1995

Oral sodium phenylbutyrate therapy in homozygous beta thalassemia: a clinical trial.

Butyrate analogues have been shown to increase fetal hemoglobin (HbF) production in vitro and in vivo. Sodium phenylbutyrate (SPB), an oral agent used to treat individuals with urea-cycle disorders, has been shown to increase HbF in nonanemic individuals and in individuals with sickle cell disease. We have treated eleven patients with homozygous beta thalassemia (three transfusion dependent) and one sickle-beta-thalassemia patient with 20 g/d (forty 500-mg tablets) of SPB for 41 to 460 days. All patients showed an increase in the percent of F reticulocytes associated with treatment, but only four patients responded by increasing their Hb levels by greater than 1 g/dL (mean increase, 2.1 g/dL; range, 1.2 to 2.8 g/dL). None of the transfusion-dependent thalassemia subjects responded. Increase in Hb was associated with an increase in red blood cell number (mean increase, 0.62 x 10(12)/L), and mean corpuscular volume (mean increase, 6 fL). Changes in percent HbF, absolute HbF levels, or alpha- to non-alpha-globin ratios as measured by levels of mRNA and globin protein in peripheral blood did not correlate with response to treatment. Response to treatment was not associated with the type of beta-globin mutation, but baseline erythropoietin levels of greater than 120 mU/mL was seen in all responders and only two of eight nonresponders to SPB. Compliance with treatment was greater than 90% as measured by pill counts. Side effects of the drug included weight gain and/or edema caused by increase salt load in 2/12, transient epigastric discomfort in 7/12, and abnormal body odor in 3/12 subjects. Two splenectomized patients who were not on prophylactic antibiotics developed sepsis while on treatment. We conclude that SPB increases Hb in some patients with thalassemia, but the precise mechanism of action is unknown.

Adult↗
PubMed1995

Preservation of cerebral blood flow responses to hypoxia and arterial pressure alterations in hyperammonemic rats.

Acute hyperammonemia causes cerebral edema, elevated intracranial pressure and loss of cerebral blood flow (CBF) responsivity to CO2. Inhibition of glutamine synthetase prevents these abnormalities. If the loss of CO2 responsivity is secondary to the mechanical effects of edema, one would anticipate loss of responsivity to other physiological stimuli, such as hypoxia and changes in mean arterial blood pressure (MABP). To test this possibility, pentobarbital-anesthetized rats were subjected to either hypoxic hypoxia (PaO2 approximately 30 mm Hg), hemorrhagic hypotension (MABP approximately 70 and 50 mm Hg), or phenylephrine-induced hypertension (MABP approximately 125 and 145 mm Hg). CBF was measured with radiolabeled microspheres. Experimental groups received intravenous ammonium acetate (approximately 50 mumol min-1 kg-1) for 6 h to increase plasma ammonia to 500-600 microM. Control groups received sodium acetate plus HCl to prevent metabolic alkalosis. The increase in CBF during 10 min of hypoxia after 6 h of ammonium acetate infusion (84 +/- 19 to 259 +/- 52 ml min-1 100 g-1) was similar to that after sodium acetate infusion (105 +/- 20 to 265 +/- 76 ml min-1 100 g-1). Cortical glutamine concentration was elevated equivalently in hyperammonemic rats subjected to normoxia only or to 10 min of hypoxia. With severe hypotension, CBF was unchanged in both the ammonium (80 +/- 20 to 76 +/- 24 ml min-1 100 g-1) and the sodium (80 +/- 14 to 73 +/- 16 ml min-1 100 g-1) acetate groups. With moderate hypertension, CBF was unchanged. With the most severe hypertension, significant increases in CBF occurred in both groups, but there was no difference between groups. We conclude that hypoxic and autoregulatory responses are intact during acute hyperammonemia. The previously observed loss of CO2 responsivity is not the result of a generalized vasoparalysis to all physiological stimuli.

Ammonia↗
PubMed1994

Fetal hemoglobin induction by acetate, a product of butyrate catabolism.

Butyrate induces fetal hemoglobin (HbF) synthesis in cultures of erythroid progenitors, in primates, and in man. The mechanism by which this compound stimulates gamma-globin synthesis is unknown. In the course of butyrate catabolism, beta oxidation by mitochondrial enzymes results in the formation of two acetate molecules from each molecule of butyrate. Studies were performed to determine whether acetate itself induces HbF synthesis. In erythroid burst-forming unit (BFU-E) cultures from normal persons, and individuals with sickle cell disease and umbilical-cord blood, dose-dependent increases in gamma-globin protein and gamma mRNA were consistently observed in response to increasing acetate concentrations. In BFU-E cultures from normal adults and patients with sickle cell disease, the ratio of gamma/gamma + beta mRNA increased twofold to fivefold in response to acetate, whereas the percentage of BFU-E progeny staining with an anti-gamma monoclonal antibody (MoAb) increased approximately twofold. Acetate-induced increases in gamma-gene expression were also noted in the progeny of umbilical cord blood BFU-E, although the magnitude of change in response to acetate was less because of a higher baseline of gamma-chain production. The effect of acetate on HbF induction in vivo was evaluated using transgenic mouse and primate models. A transgenic mouse bearing a 2.5-kb mu locus control region (mu LCR) cassette linked to a 3.3-kb A gamma gene displayed a near twofold increase in gamma mRNA during a 10-day infusion of sodium acetate at a dose of 1.5 g/kg/d. Sodium acetate administration in baboons, in doses ranging from 1.5 to 6 g/kg/d by continuous intravenous infusion, also resulted in the stimulation of gamma-globin synthesis, with the percentage of HbF-containing reticulocytes (F reticulocytes) approaching 30%. Surprisingly, a dose-response effect of acetate on HbF induction was not observed in the baboons, and HbF induction was not sustained with prolonged acetate administration. These results suggest that both two-carbon fatty acids (acetate) and four-carbon fatty acids (butyrate) stimulate synthesis of HbF in vivo.

Acetates↗
PubMed1992

Plasma glutamine concentration: a guide in the management of urea cycle disorders.

Because increases in plasma glutamine concentrations are almost always associated with hyperammonemia in patients with urea cycle disorders, we determined the correlation between these two variables for 2 years in a child with ornithine transcarbamylase deficiency. A correlation coefficient of 0.77 (p less than 0.0001) was found. Hyperammonemia was rarely observed when plasma glutamine levels were near normal. These data suggest that one goal of therapy is the maintenance of plasma glutamine levels at or near normal values.

Amino Acid Metabolism, Inborn Errors↗
PubMed1992

Restoration of cerebrovascular CO2 responsivity by glutamine synthesis inhibition in hyperammonemic rats.

Hyperammonemia increases brain glutamine levels, causes astrocytic swelling, and depresses cerebral blood flow (CBF) responsivity to CO2. Methionine sulfoximine (MSO) inhibition of glutamine synthetase activity, known to be enriched in astrocytes, prevents ammonia-induced increases in brain glutamine and water content. We tested the hypothesis that inhibition of glutamine accumulation restores CBF responsivity to CO2 during acute hyperammonemia. Pentobarbital-anesthetized rats treated with either vehicle or MSO (150 mg/kg i.p.) received a 6-hour intravenous infusion of either sodium or ammonium acetate. With subsequent induction of hypercapnia, CBF increased from 113 +/- 14 (mean +/- SEM) to 194 +/- 9 ml/min per 100 g in control rats but was unchanged from 107 +/- 13 to 79 +/- 10 ml/min per 100 g in hyperammonemic rats. Treatment with MSO in hyperammonemic rats restored the CBF response to hypercapnia (from 73 +/- 8 to 141 +/- 14 ml/min per 100 g). With induction of hypocapnia, CBF decreased from 114 +/- 11 to 88 +/- 11 ml/min per 100 g in control rats but increased from 112 +/- 13 to 142 +/- 19 ml/min per 100 g in hyperammonemic rats. Treatment with MSO in hyperammonemic rats did not fully restore the response to hypocapnia but prevented the paradoxical increase in CBF (from 80 +/- 8 to 80 +/- 8 ml/min per 100 g). In control rats, MSO did not affect CO2 responsivity. Treatment with MSO prevented ammonia-induced increases in intracranial pressure. Hyposmotic-induced increases in brain water content and intracranial pressure attenuated the CBF response to hypercapnia but, unlike hyperammonemia, did not attenuate the response to hypocapnia. In contrast to hypercapnia, vasodilation in response to arterial hypotension was intact in hyperammonemic rats. We conclude that the grossly abnormal CBF responsivity to CO2 alterations during hyperammonemia is linked to glutamine accumulation rather than ammonia per se. Cerebral edema secondary to glutamine accumulation may contribute in part to abnormal CBF responses, although other aspects of astrocyte dysfunction are likely to be important.

Ammonia↗
PubMed1991

First report of management and outcome of pregnancies associated with hereditary orotic aciduria.

Two pregnancies in a 25-year-old woman with hereditary orotic aciduria who was managed prenatally on uridine therapy are described. The first pregnancy resulted in an infant with multiple congenital anomalies and a 47,xx,inv(4)(p12q25), +der(22)t(11;22)(p23;q11) karyotype. The proposita was found to be a carrier of a de novo 11;22 translocation and a pericentric inversion of chromosome 4. Subsequently, several carriers of orotic aciduria in this family were identified with the inverted chromosome 4. The second pregnancy resulted in a normal male with an inverted chromosome 4.

Abnormalities, Multiple↗
PubMed1991

Prospective treatment of urea cycle disorders.

We present a diagnostic and therapeutic protocol designed to prevent clinical expression of inborn errors of urea synthesis in the neonatal period, and discuss the long-term developmental outcome of survivors. The families of 32 infants, among 43 identified prenatally as being at risk for a urea cycle disorder, chose to have their infants treated according to a diagnostic and therapeutic protocol, beginning at birth. The therapy was effective in avoiding neonatal hyperammonemic coma and death in seven patients with carbamoyl phosphate synthetase deficiency, argininosuccinate synthetase deficiency, and argininosuccinate lyase deficiency. When treated prospectively, five of eight patients with ornithine transcarbamylase deficiency avoided severe hyperammonemia and survived the neonatal period. Two patients with carbamoyl phosphate synthetase deficiency and two with ornithine transcarbamylase deficiency have subsequently died; three additional patients with the latter disorder have received orthotopic liver transplants. Our experience suggests that these surviving patients have had a more favorable neurologic outcome than patients rescued from neonatal hyperammonemic coma. However, all of them require a burdensome medical regimen and may have handicaps that include impairment of development and recurrent episodes of hyperammonemia. Further, those with deficiency of carbamoyl phosphate synthetase or ornithine transcarbamylase have a high mortality rate.

Amino Acid Metabolism, Inborn Errors↗
PubMed1991

Inhibition of brain glutamine accumulation prevents cerebral edema in hyperammonemic rats.

The mechanism of brain swelling during hyperammonemia is not understood, but glutamine accumulation is consistently observed. We tested the hypothesis that brain swelling associated with hyperammonemia is a consequence of the osmotic effect of intracellular glutamine accumulation in brain. Increases in plasma ammonium levels from 31 +/- 3 to 601 +/- 38 mumol/l (+/- SE) were produced by 6 h of infusion of ammonium acetate in anesthetized rats. Hyperammonemia resulted in increased brain water content accompanied by more than a tripling of brain glutamine concentration compared with control rats receiving sodium acetate (5.6 +/- 0.4 vs. 18.8 +/- 0.4 mmol/kg). Inhibition of glutamine synthetase activity by pretreatment with L-methionine sulfoximine prevented both the increase in brain glutamine levels and the increase in brain water content despite elevated plasma ammonium levels (908 +/- 196 mumol/l). Thus cerebral edema during hyperammonemia is associated with glutamine accumulation. We suggest that accumulated glutamine may serve as an idiogenic osmole causing swelling. Because brain swelling eventually leads to increased intracranial pressure and tissue hypoxia, these data suggest a unifying mechanism to account for the many pathophysiological abnormalities found during coma associated with various forms of liver disease, inborn errors of metabolism, and Reye's syndrome.

Acetates↗
PubMed1991

Phenylacetylglutamine may replace urea as a vehicle for waste nitrogen excretion.

Phenylacetylglutamine (PAG), the amino acid acetylation product of phenylacetate (or phenylbutyrate after beta-oxidation) was evaluated as a waste nitrogen product in patients with inborn errors of urea synthesis. A boy with carbamyl phosphate synthetase deficiency receiving a low nitrogen intake excreted 80-90% of administered phenylacetate or phenylbutyrate as PAG. The amount of PAG nitrogen excreted varied from 38-44% of his dietary nitrogen, similar to the relationship between urea nitrogen and dietary nitrogen found in normal subjects receiving low dietary nitrogen. With few exceptions, neither phenylacetate nor phenylbutyrate accumulated in plasma. Treatment with relatively high dose phenylacetate or phenylbutyrate (0.5-0.6 g/kg/d) resulted in normal daytime levels of glutamine. These data suggest that PAG may replace urea as a waste nitrogen product when phenylbutyrate is administered at a dose that yields PAG nitrogen excretion equal to 40-44% of a low nitrogen intake.

Adolescent↗
PubMed1990

Allopurinol-induced orotidinuria. A test for mutations at the ornithine carbamoyltransferase locus in women.

Ornithine carbamoyltransferase is an X-linked mitochondrial enzyme expressed in hepatocytes and enterocytes. A deficiency of this enzyme results in central nervous system dysfunction, which may be fatal in newborn boys. Milder forms are seen in older boys and girls and in adults. Establishing the carrier status of women at risk for ornithine carbamoyltransferase deficiency is important for determining reproductive and medical risks for affected women. We report a test to establish the carrier status of women at risk for ornithine carbamoyltransferase deficiency. This test relies on the allopurinol-induced accumulation of orotidine, whose synthesis is stimulated by carbamoyl phosphate, a substrate that accumulates in ornithine carbamoyltransferase deficiency. We used anion-exchange, high-performance liquid chromatography to measure urinary orotidine and orotic acid excretion after the administration of a 300-mg oral dose of allopurinol in 25 [corrected] women who were obligate heterozygotes, 13 who were probable heterozygotes, 15 mothers of affected boys from monoplex families (families with only one affected member), 12 mothers of affected girls from monoplex families, and 21 [corrected] normal, unrelated women who were not carriers. Urinary orotidine excretion was increased 3 SD or more above the mean value for the normal women in 95.8 percent of the obligate heterozygotes, 84.6 percent of the probable heterozygotes, 73.3 percent of the mothers of affected boys in monoplex families, and 33.3 percent of the mothers of affected girls in monoplex families, thus establishing that these women were carriers of a mutant ornithine carbamoyltransferase allele. The presence of allopurinol-induced orotic aciduria was not as sensitive or specific an indicator of carrier status as the presence of orotidinuria. We conclude that measurement of urinary orotidine excretion after the administration of allopurinol is a simple and reliable test for the identification of women who are heterozygous for ornithine carbamoyltransferase deficiency.

Adult↗
PubMed1990

Glutamine synthetase inhibition prevents cerebral oedema during hyperammonemia.

The relationship between cerebral oedema and cerebral glutamine accumulation was investigated during acute hyperammonemia in anesthetized rats. Six hours of ammonium acetate infusion resulted in an increase in cortical glutamine concentration and a decrease in specific gravity. Pretreatment with methionine sulfoximine inhibited glutamine synthetase, prevented the increase in glutamine during hyperammonemia, and prevented the decrease in specific gravity. We conclude that the increase in brain water content is linked to the glutamine accumulation derived from the detoxification of ammonia by glutamine synthetase.

Acetates↗
PubMed1990

Use of denaturing gradient gel electrophoresis for detection of mutation and prospective diagnosis in late onset ornithine transcarbamylase deficiency.

Ornithine transcarbamylase (ornithine carbamoyltransferase, EC 2.1.3.3) deficiency is an X-linked inborn error of metabolism with considerable phenotypic variability in affected males. Using a combination of the polymerase chain reaction and denaturing gradient gel electrophoresis (DGGE), we defined a mutation in a family in whom affected males have significant residual enzyme activity. A C----T change in the first nucleotide of codon 277 resulted in the substitution of a tryptophan for an arginine at amino acid 245 of the mature protein. This change appears to represent a deleterious mutation rather than a polymorphism on the basis of several factors: the change occurs at a highly conserved arginine residue, significant size and change differences exist between arginine and tryptophan, and this change was not seen on DGGE screening of 26 unrelated individuals representing 43 chromosomes. Diagnosis of an at-risk male newborn in this family was performed using direct mutational analysis. In families with partial enzyme deficiencies in whom biochemical data may be difficult to evaluate, direct detection of mutations at the OTC locus permits definitive diagnosis. This represents the first description of a mutation in late onset OTC deficiency and demonstrates direct mutational analysis by DGGE for prospective diagnosis in a genetic disorder.

Amino Acid Sequence↗
PubMed1990

Late-onset ornithine transcarbamylase deficiency in male patients.

We report on 21 male patients who presented after 28 days of age with ornithine transcarbamylase (OTC) deficiency, which we define as late-onset OTC deficiency. These patients appeared normal at birth, but irritability, vomiting, and lethargy, which were often episodic, later developed. The age at presentation ranged from 2 months to 44 years. Biochemical testing revealed hyperammonemia, hyperglutaminemia, hypocitrullinemia, increased urinary orotate excretion, and decreased liver OTC activity measured in vitro, which ranged from 0% to 15% of normal. Male patients who were older at presentation had a somewhat different pattern of presenting symptoms and were more likely to die. These data illustrate the phenotypic variability of OTC deficiency. Unexplained episodes of repetitive or protracted vomiting in association with progressive alterations in behavior or neurologic findings should suggest the diagnosis of a urea cycle defect (or another symptomatic inborn error of metabolism), regardless of the age or medical history of the patient.

Adolescent↗
PubMed1990

Arterial pH modulation of regional cerebral blood flow during hyperammonemia in dogs.

Acute hyperammonemia at normal arterial pH causes selective increases in midbrain blood flow in dogs. Unexpectedly, further increases occur with hypocapnia. We investigated whether metabolic acidemia and alkalemia modulate the distribution of ammonium across the blood-brain barrier and if, in turn, midbrain blood flow is effectively modulated. In dogs anesthetized with pentobarbital sodium, hyperammonemia (approximately 940 microM) was produced by a 210-min infusion of ammonium acetate. Concurrent infusion of NaHCO3 increased arterial pH to 7.53 +/- 0.02 (SE), whereas HCl infusion decreased pH to 7.11 +/- 0.01. Normocapnia was maintained. Cerebrospinal fluid [HCO3-] increased 5 mM with alkalemia (one-half of the increase in blood) and was unchanged with acidemia. Thus cerebrospinal fluid [H+]/blood [H+] was greater with alkalemia than acidemia. The corresponding ratio for ammonium was likewise greater with alkalemia (0.70 +/- 0.06) than acidemia (0.44 +/- 0.08). Microsphere-determined blood flow to midbrain more than doubled in the alkalemic group but was unchanged in the acidemic group. No other region along the neuraxis or in cerebrum showed increased blood flow in either hyperammonemic group. Alkalemia without hyperammonemia did not increase midbrain blood flow. Thus metabolic acidemia-alkalemia significantly alters ammonium partitioning into cerebrospinal fluid, and this alteration is sufficiently great to exert a specific physiological effect manifested by changes in midbrain blood flow.

Ammonia↗