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Biomedical subjects

N Leslie

Publications and source records attributed to N Leslie.

At least 19 recordsLinked to original sources
PubMed2006

Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease.

BACKGROUND: Pompe disease is a progressive metabolic neuromuscular disorder resulting from deficiency of lysosomal acid alpha-glucosidase (GAA). Infantile-onset Pompe disease is characterized by cardiomyopathy, respiratory and skeletal muscle weakness, and early death. The safety and efficacy of recombinant human (rh) GAA were evaluated in 18 patients with rapidly progressing infantile-onset Pompe disease. METHODS: Patients were diagnosed at 6 months of age and younger and exhibited severe GAA deficiency and cardiomyopathy. Patients received IV infusions of rhGAA at 20 mg/kg (n = 9) or 40 mg/kg (n = 9) every other week. Analyses were performed 52 weeks after the last patient was randomized to treatment. RESULTS: All patients (100%) survived to 18 months of age. A Cox proportional hazards analysis demonstrated that treatment reduced the risk of death by 99%, reduced the risk of death or invasive ventilation by 92%, and reduced the risk of death or any type of ventilation by 88%, as compared to an untreated historical control group. There was no clear advantage of the 40-mg/kg dose with regard to efficacy. Eleven of the 18 patients experienced 164 infusion-associated reactions; all were mild or moderate in intensity. CONCLUSIONS: Recombinant human acid alpha-glucosidase is safe and effective for treatment of infantile-onset Pompe disease. Eleven patients experienced adverse events related to treatment, but none discontinued. The young age at which these patients initiated therapy may have contributed to their improved response compared to previous trials with recombinant human acid alpha-glucosidase in which patients were older.

Dose-Response Relationship, Drug↗
PubMed2001

Evidence for alternate galactose oxidation in a patient with deletion of the galactose-1-phosphate uridyltransferase gene.

The persistent, dietary-independent elevation of galactose metabolites in patients with galactose-1-phosphate uridyltransferase (GALT) deficiency is probably secondary to de novo synthesis of galactose. Relatively constant steady-state levels of galactose metabolites in patients also suggest that non-GALT metabolic pathways must function to dispose of the galactose synthesized each day. The discovery of a patient with a rare deletion of the GALT gene provided a unique opportunity to examine the availability of any alternate galactose oxidative capacity both in vivo and in vitro. Utilizing genomic DNA from the patient, Southern blot data demonstrated that 10 of the 11 GALT exons were homozygously deleted. By measurement of 13CO2 in expired air for up to 24 h after an oral bolus of [1-13C]galactose, it was demonstrated that 17% of the galactose was metabolized, a value comparable to the 3-h elimination rate in a control subject. Furthermore, lymphoblasts prepared from the patient could also convert [1-14C]galactose to 14CO2. This unique study provides the first unambiguous evidence that another pathway exists in man that can be responsible for galactose disposal. Further knowledge of this alternate galactose oxidative route and its regulation may aid in formulating new strategies for the treatment of galactosemia.

Blotting, Southern↗
PubMed2001

Galactose metabolism in mice with galactose-1-phosphate uridyltransferase deficiency: sucklings and 7-week-old animals fed a high-galactose diet.

Mice deficient in galactose-1-phosphate uridyltransferase (GALT) demonstrate abnormal galactose metabolism but no obvious clinical phenotype. To further dissect the pathways of galactose metabolism in these animals, galactose oxidation and metabolite levels were studied in 16-day-old sucklings and the effect of a 4 week prior exposure to a 40% glucose or 40% galactose diet was determined in 7-week-old mice. Suckling GALT-deficient (G/G) mice slowly oxidized [1-14C]galactose to 14CO2, 4.0% of the dose when fed and 7.9% when fasted compared to normal animals 38.3 and 36.4% in 4 h, respectively. Plasma of G/G sucklings contained 11.1 mM galactose and erythrocyte galactose 1-phosphate levels were 28.2 and 31.9 mg/dl packed cells. Galactose, galactitol, galactonate, and galactose 1-phosphate were found in G/G suckling mouse tissues. The tissue galactose concentrations were 10% or less of that in plasma, suggesting that there was limited cellular entry of galactose. In 7-week-old fasted mice with 4 weeks prior exposure to glucose or galactose-containing diet, 4-h oxidation was 12.9 and 15.0% of the administered radiolabeled galactose, respectively. Normal animals oxidized 33.9 and 37.9% of the dose when fed the same diets, respectively. The ability of G/G mice to oxidize galactose in the absence of GALT activity suggests the presence of alternate metabolic pathways for galactose disposition. G/G mice fed the galactose-free 40% glucose diet had erythrocyte galactose 1-phosphate levels ranging from 6.4 to 17.7 mg/dl packed cells and detectable galactose and galactose metabolites in tissues, suggesting that these animals endogenously produced galactose. The plasma of 40% galactose-fed G/G mice contained 9.1 mM galactose with red blood cell galactose 1-phosphate averaging 43.6 mg/dl. Tissues of these animals also contained high levels of galactose and galactose 1-phosphate. Liver contained over 4 micromol/g galactonate but little galactitol. Despite the elevated galactose and galactose 1-phosphate, the animals tolerated the high-galactose diet and were indistinguishable from normal animals, exhibiting no manifestations of galactose toxicity seen in human GALT-deficient galactosemia. The data suggest that high galactose 1-phosphate levels do not cause galactose toxicity and that high galactitol in combination with galactose 1-phosphate may be a prerequisite. Absence of GALT appears necessary but insufficient to produce human galactosemic phenotype.

Animals↗
PubMed2000

Species-area curves, spatial aggregation, and habitat specialization in tropical forests.

The relationship between species diversity and sampled area is fundamental to ecology. Traditionally, theories of the species-area relationship have been dominated by random-placement models. Such models were used to formulate the canonical theory of species-area curves and species abundances. In this paper, however, armed with a detailed data set from a moist tropical forest, we investigate the validity of random placement and suggest improved models based upon spatial aggregation. By accounting for intraspecific, small-scale aggregation, we develop a cluster model which reproduces empirical species-area curves with high fidelity. We find that inter-specific aggregation patterns, on the other hand, do not affect the species-area curves significantly. We demonstrate that the tendency for a tree species to aggregate, as well as its average clump size, is not significantly correlated with the species' abundance. In addition, we investigate hierarchical clumping and the extent to which aggregation is driven by topography. We conclude that small-scale phenomena such as dispersal and gap recruitment determine individual tree placement more than adaptation to larger-scale topography.

Ecology↗
PubMed2000

Activation of peripheral mitochondrial benzodiazepine receptors in the hippocampus stimulates allopregnanolone synthesis and produces anxiolytic-like effects in the rat.

RATIONALE AND OBJECTIVES: Stimulation of the mitochondrial benzodiazepine receptor (MBR) in the brain activates the synthesis of neurosteroids that can act as positive modulators of the GABA(A) receptor complex. Allopregnanolone is a potent anxiolytic, anticonvulsant, sedative and hypnotic GABAergic neurosteroid. The anxiolytic-like effects of FGIN 1-27, an MBR agonist, were determined after microinjection into the dorsal hippocampus. METHODS: Behavior in the elevated plus-maze was assessed in adult male rats after bilateral injections of 0, 1.25, 2.5, or 5 microg FGIN 1-27. The behavioral effects of FGIN 1-27 were also determined in animals receiving intrahippocampal co-administration of 20 ng picrotoxin, 5 microg flumazenil, or 200 ng PK 11195. The effects of FGIN 1-27 on behavior in the elevated plus-maze and shock-probe burying test were measured in animals pretreated systemically with 10 mg/kg 4-MA, a 5alpha-reductase inhibitor. Hippocampal and blood plasma levels of allopregnanolone were measured in separate groups of animals pretreated with 4-MA and receiving an intrahippocampal injection of FGIN 1-27. RESULTS: Intrahippocampal injections of FGIN 1-27 produced anxiolytic-like effects in the plus-maze and in the shock-probe burying test. Hippocampal and blood levels of allopregnanolone were also increased by FGIN 1-27. The anxiolytic-like effects of FGIN 1-27 were attenuated by PK 11195 and were blocked by picrotoxin and 4-MA pretreatment, but remained unaffected by flumazenil pretreatment. The neurosteroidogenic effect of FGIN 1-27 was also eliminated by 4-MA. CONCLUSION: Activation of the MBR in the hippocampus leads to the synthesis of allopregnanolone, an anxiolytic neurosteroid that potentiates GABA(A) receptor function.

Analysis of Variance↗
PubMed2000

Galactose metabolism by the mouse with galactose-1-phosphate uridyltransferase deficiency.

The ability of mice deficient in galactose-1-phosphate uridyltransferase (GALT) to metabolize galactose was determined in animals weaned to a mouse chow diet for a 4-wk period. When given [14C]galactose intraperitoneally, these animals slowly oxidized the sugar, excreting only 5.5% of the dose as 14CO2 in 4 h, whereas normal animals excreted 39.9%. These results mimic those seen in human galactosemic patients given isotopic galactose. When given 10 micromol of [1-13C]galactose, normal animals excrete small amounts of labeled galactose and galactonate but no galactitol in urine whereas GALT-deficient mice excrete significant amounts of all of these as labeled compounds in urine. When challenged with galactose, only about 20% of the dose is excreted in urine, and even on the chow diet, significant amounts of galactose, galactonate, and galactitol are excreted in urine. These compounds are also found to be present in liver, kidney, and brain, except that galactonate is not found in brain. Galactose-1-phosphate accumulates in red blood cells to levels found in humans exposed to large amounts of galactose, and galactose-1-phosphate is found in increased amounts in liver, kidney, and brain of GALT-deficient animals. There was no difference in the hepatic concentration of uridine diphosphate galactose and uridine diphosphate glucose between normal and GALT-deficient mice. The explanation for the presence of galactose and its conversion products in tissues and urine of affected mice appears to be related to the presence of approximately 1.75% of galactose-containing carbohydrates in the chow, which becomes bioavailable to mice. Despite the presence of galactose and its metabolites in tissues and urine and impaired ability to oxidize the sugar, the GALT-deficient animals are indistinguishable from normal animals and do not exhibit the phenotype of humans with GALT-deficiency galactosemia.

Animals↗
PubMed1999

Protein status of infants with phenylketonuria undergoing nutrition management.

OBJECTIVES: The objectives of this study were to determine if Phenex-1, amino-acid modified medical food with iron maintained normal indices of protein status in infants with phenylketonuria (PKU) and to investigate factors that influence plasma amino acid concentrations. METHODS: A study was conducted for six months in 35 infants with classical PKU diagnosed in the neonatal period. Diet diaries and plasma amino acid concentrations were obtained monthly. Blood for analysis of plasma albumin, blood urea nitrogen (BUN), retinol binding protein (RBP) and transthyretin was obtained at one, three and six months of study. RESULTS: Mean (+/-SEM) total daily intake of medical food and nutrients was 79+/-4 g; 17.3+/-0.6 g protein, 660+/-18 kcal, 255+/-10 mg phenylalanine (Phe), and 1423+/-56 mg tyrosine (Tyr). Mean concentrations of plasma amino acids, except cystine (during entire study), glycine (first month) and Phe were in the normal range. Mean concentrations of plasma Phe were in the treatment range (120 to 360 micromol/L). Plasma concentrations of arginine, methionine, Phe, tryptophan, Tyr, and valine were positively correlated with intakes at various months of study. Concentrations of aspartic and glutamic acids, Phe, and Tyr were positively correlated and 17 amino acids were negatively correlated with the interval between feeding and blood draw. At six months of study, concentration of plasma albumin was 4.1+/-0.1 g/dL, RBP was 3.74+/-0.2 mg/dL, transthyretin was 17.9+/-0.9 mg/dL, and urea nitrogen was 11.9+/-0.5 mg/dL. CONCLUSION: During study, all mean plasma indices of protein status were in normal reference ranges. Phenex-1 supports normal mean plasma amino acid, albumin, RBP, transthyretin, and BUN concentrations when fed in adequate amounts.

Amino Acids↗
PubMed1998

Both stroma and stem cell factor maintain long-term growth of ELM erythroleukemia cells, but only stroma prevents erythroid differentiation in response to erythropoietin and interleukin-3.

Defining how the stromal requirements of hematopoietic progenitors change during leukemia progression is an important topic that is not well understood at present. The murine ELM erythroleukemia is an interesting model because the erythroid progenitors retain dependence on bone marrow-derived stromal cells for long-term growth in vitro, and they also undergo erythroid differentiation in the presence of erythropoietin (EPO) and interleukin-3 (IL-3). In this report, we have shown using neutralizing antibodies that stem cell factor (SCF), insulin-like growth factor (IGF)-1, and integrin signaling pathways are all involved. We then determined whether ELM cells can be maintained long-term without stroma in various combinations of growth factors produced by stroma cells or growth factors for which ELM cells have receptors. This showed that ELM cells could be maintained with high efficiency in SCF alone; furthermore, the cells remained absolutely SCF-dependent and did not become more tumorigenic than cells maintained on stroma. In contrast, ELM cells underwent clonal extinction when serially cloned in IGF1; any cells that survived long-term growth in IGF-1 were found to be IGF1-independent. One important difference between maintaining ELM cells on stroma and growth in SCF is that stroma reversibly inhibits their differentiation in response to EPO and IL-3, whereas SCF does not.

Animals↗
PubMed1998

Enzyme therapy for Gaucher disease: the first 5 years.

Gaucher disease was first described by Philippe Gaucher in his 1882 medical thesis. Gaucher's original concept was of an unusual epithelioma of the spleen. By the early 1900s, Mandelbaum recognized the systemic nature of the disease. Several children with Gaucher disease were described at the turn of the century, but Rusca described a rapidly progressive fatal neurodegenerative type of disease, i.e. type 2, in the 1920s. The 'juvenile' form (type 3) of the disease was described in Sweden in the 1950s. In 1965, the deficient enzyme, acid beta-glucosidase, was discovered and the lysosomal nature of the disease was elucidated. Currently, three variants of Gaucher disease have been defined clinically and are distinguished by the presence and severity of neuronopathic involvement (Table 1). Each of these clinical types has substantial phenotypic variation, but types 1 and 3 have significantly heterogeneous rates of disease progression and degrees of visceral organs involvement. The neuronopathic involvement in type 3 also has substantial variation in the age of onset and disease progression even within relatively isolated communities. An extensive review of the clinical and pathologic involvement by Gaucher disease is available.

Animals↗
PubMed1997

Adult psychosocial outcome in early-treated phenylketonuria.

Concerns about the psychosocial risk of adults with early-treated phenylketonuria (ETPKU) are predicated on four sources of scientific data: (1) consistent documentation of increased behavioural risk in children with ETPKU; (2) recent evidence of neurocognitive impairment in adults with ETPKU; (3) reports of neuroimaging abnormalities in adults with ETPKU; and (4) preliminary evidence of increased rates of psychiatric disturbance in this population. We studied the psychosocial adjustment of 25 patients, aged 18 years and older, with ETPKU. On most psychosocial outcome measures, patients were indistinguishable from 15 sibling controls. However, on a self-report inventory of psychiatric symptoms, 20% of the patients demonstrated significant morbidity. Psychosocial outcome of these patients was unrelated to concurrent or historical biological dietary disease factors, unlike neurocognitive outcome. A strong relationship was demonstrated, however, between neurocognitive measures and psychosocial morbidity. These findings indicate that a significant minority of patients with ETPKU develop psychosocial difficulties with multiple clinical elevations on a psychiatric inventory. However, most adults with ETPKU cope with the challenges of young adulthood with the same degree of success as their unaffected siblings. Neuropsychological surveillance during childhood and adolescence is important in identifying patients at risk for both neurocognitive and psychosocial morbidity.

Adult↗
PubMed1995

Site-specific recombination and circular chromosome segregation.

The Xer site-specific recombination system functions in Escherichia coli to ensure that circular plasmids and chromosomes are in the monomeric state prior to segregation at cell division. Two recombinases, XerC and XerD, bind cooperatively to a recombination site present in the E. coli chromosome and to sites present in natural multicopy plasmids. In addition, recombination at the natural plasmid site cer, present in ColEl, requires the function of two additional accessory proteins, ArgR and PepA. These accessory proteins, along with accessory DNA sequences present in the recombination sites of plasmids are used to ensure that recombination is exclusively intramolecular, converting circular multimers to monomers. Wild-type and mutant recombination proteins have been used to analyse the formation of recombinational synapses and the catalysis of strand exchange in vitro. These experiments demonstrate how the same two recombination proteins can act with different outcomes, depending on the organization of DNA sites at which they act. Moreover, insight into the separate roles of the two recombinases is emerging.

Bacterial Proteins↗
PubMed1994

Early-treated phenylketonuria: adult neuropsychologic outcome.

Twenty-five adults with phenylketonuria that was treated early were compared with 15 unaffected control siblings with respect to intellectual and neuropsychologic measures. Patients were found to have normal intelligence but were significantly lower than their control siblings on measures of intelligence, attention, and complex visuoconstructional ability. Stepwise multiple regression analyses found the patients' intellectual outcome to be best predicted by indexes reflecting early insult to the brain, whereas performance on a measure of novel problem solving was best predicted by concurrent serum phenylalanine level. Different pathophysiologic mechanisms may thus account for cognitive deficits in this population. These results provide further evidence of continuing benefits of dietary adherence into adulthood.

Adult↗
PubMed1989

Fever and petechiae in children.

A prospective study of patients with fever and petechiae was performed. Of 190 patients enrolled in the 1-year study, 13 (7%) had meningococcal disease. The most common bacterial association was Streptococcus pyogenes (19 patients). Viral infections were documented in 28 patients. Patients with invasive bacterial disease (group I) appeared more sick, were more likely to have signs of meningeal irritation, and were more likely to have petechiae on the lower extremities than those with less serious, nonbacteremic disease (group II). No patient in group I had petechiae only above the nipple line. Patients in group I had a significantly higher peripheral white blood cell count and absolute band form count. Although no laboratory test or physical finding was sufficiently sensitive to detect all patients with serious disease, the patient with abnormal cerebrospinal fluid, elevated white blood cell count, or elevated absolute band form count was at increased risk for invasive, bacterial disease. Conversely, the risk of serious disease was small if all of these values were in the normal range in the nonill-appearing child or if sore throat and clinical pharyngitis were present in the patient older than 3 years of age.

Adolescent↗
PubMed1986

Amantadine prophylaxis during an institutional outbreak of type A (H1N1) influenza.

In January 1984, an outbreak of influenza caused by A/Victoria/7/83-like virus, a new H1N1 variant, occurred in an institution for mentally handicapped children and adults. During the first 18 days of the outbreak, 35 (81%) of 43 residents in two housing modules became ill, nearly all of whom had received influenza vaccine the previous autumn. Amantadine hydrochloride prophylaxis was initiated in two other housing modules and was continued for 28 days. While factors influencing the risk of introduction and secondary spread of influenza virus were comparable in all four modules, only ten (16%) of 63 residents who received amantadine were infected, only one of whom became symptomatic. Most side effects associated with amantadine were mild, but residents with active, preexisting major-motor seizure disorders demonstrated an increase in seizure activity compared with the previous eight-month period; those who took the maximum daily dose of amantadine hydrochloride (200 mg) and those who were also taking anticonvulsants other than phenobarbital were at highest risk.

Adolescent↗
PubMed1985

Combination chemotherapy followed by radiation therapy in patients with regional stage III unresectable non-small cell lung cancer.

A chemotherapy combination of cyclophosphamide, doxorubicin, and cisplatin (CAP) was administered to 30 patients with stage III M0 or M1 (supraclavicular nodes) unresectable non-small cell lung cancer before and after radiotherapy. All patients had mediastinal metastases and most had T2 or T3 primary lesions. The response rate (complete plus partial) after two cycles of CAP was 47%, which increased to 66% (24% complete response rate) following radiotherapy. The overall median survival from initiation of chemotherapy was 9 months. CNS relapse occurred in five (26%) of 19 responding patients who did not receive prophylactic cranial irradiation in the early part of the study.

Adenocarcinoma↗
PubMed1984

Fetal-perinatal catecholamine secretion: role in perinatal glucose homeostasis.

Secretion of catecholamines may play an important role in several of the adaptations that characterize the transition from intra- to extrauterine life including cardiovascular, respiratory, and metabolic events, specifically the initiation of endogenous glucose production following curtailment of the transplancental maternal supply of glucose. Maturation of neural and enzymatic pathways involved in catecholamine secretion occurs late in gestation; fetal hypoxia can produce a 20- and 125-fold increase in plasma epinephrine (E) and norepinephrine (NE), respectively. Estimates of turnover (approximately 2,000 pg X kg-1 X min-1) and metabolic clearance rates (20-40 ml X kg-1 X min-1) indicate active secretion and metabolism of E from fetal sources with negligible transfer from the mother. Simultaneously, there is maturation of functional alpha- and beta-adrenergic receptors. At birth, plasma E and NE rise three- to tenfold; plasma levels are higher in hypoxic infants and lower in prematures. Concurrently, glucagon increases three- to fivefold; cortisol and growth hormone also are high, whereas insulin remains low and poorly responsive to stimuli; the number of glucagon receptors increases, whereas that of insulin decreases. Acting in concert these hormonal changes activate glycogenolysis, gluconeogenesis, lypolysis, and ketogenesis. Glucose production and gluconeogenesis, absent in utero, become evident within hours of birth in both humans and sheep. The spontaneous surge in catecholamine secretion at birth may be the key event because infusion of E or NE to fetal sheep in late gestation simulates the metabolic and hormonal profile of glucagon and insulin as well as glucose production that normally only occur with separation of the placenta.

Animals↗