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Biomedical subjects

B Levy

Publications and source records attributed to B Levy.

At least 37 records · Page 2Linked to original sources
PubMed2000

Evidence for a Niemann-pick C (NPC) gene family: identification and characterization of NPC1L1.

Niemann-Pick type C1 (NPC1) disease is caused by defects in the NPC1 protein, which result in perturbation of subcellular cholesterol transport. To identify related proteins that may be involved in subcellular cholesterol trafficking, the expressed sequence tag (EST) database was searched to find homologues of human NPC1. A short, weakly similar EST was identified and used to obtain a full-length human cDNA of about 5 kb and two alternatively spliced transcripts. The gene, named NPC1L1, was mapped to chromosome 7p13, contained 20 exons, including an unusually large 1526-bp exon 2, and spanned approximately 29 kb. In contrast to NPC1, the NPC1L1 putative promoter region contained a sterol-regulatory element. The predicted protein shared 42% identity and 51% similarity with NPC1. Interestingly, NPC1L1 contains the conserved amino-terminal "NPC1 domain" and the putative sterol-sensing domain, providing strong evidence that it is related to human NPC1 and suggesting that these may comprise a new family of NPC1-related proteins. However, the two differ with respect to their putative intracellular targeting signals. Collectively, these data suggest that NPC1L1 and NPC1 form part of a family of related proteins that may have similar functions at different subcellular locations, perhaps at sequential steps of the same cholesterol transport pathway.

Amino Acid Sequence↗
PubMed2000

Cloning and characterization of human PREB; a gene that maps to a genomic region associated with trisomy 2p syndrome.

We have isolated the human homolog of a novel rodent gene that may be involved in the regulation of pituitary gene transcription. The human PREB gene encodes a predicted protein of 417 amino acids, exhibiting several sequences characteristic of the WD-motif protein family. PREB transcripts were detected in every human fetal and adult tissue examined, although a great variation in levels of expression was observed. PREB was mapped to human Chromosome 2p23, a region of the genome associated with partial trisomy 2p syndrome. Although variable, the common duplication phenotype includes facial abnormalities, skeletal defects, growth and mental retardation, congenital heart and neural tube defects, and abnormalities of the genitalia. We propose that PREB has a role during human development and that abnormal dosage of this transcription factor may be involved in some of the developmental abnormalities observed in patients with partial trisomy 2p.

Amino Acid Sequence↗
PubMed2000

Molecular cytogenetic analysis of uterine leiomyoma and leiomyosarcoma by comparative genomic hybridization.

Uterine leiomyomata are among the most common of human neoplasms and are associated with abnormal uterine bleeding, infertility, and abdominal pain. Uterine leiomyosarcomata are presumed to be the malignant counterpart to uterine leiomyomata and are very rare. Transformation of uterine leiomyoma (ULM) into uterine leiomyosarcoma (ULMS) is yet to be conclusively confirmed, and each type of tumor may represent a distinct genetic entity. We used comparative genomic hybridization (CGH) to evaluate DNA sequence copy-number changes in 12 specimens of ULM and 8 of ULMS. CGH analysis of ULM demonstrated chromosomal imbalances in 8 of 12 (66. 7%) specimens. The most frequent ULM gains were observed at 9q34 (a novel finding) and on chromosome 19. Other ULM imbalances included gains and losses of chromosome 1p, losses on 7q, and gains on 12q. All ULMS specimens demonstrated chromosomal aberrations. Chromosome 1 imbalances were very prominent. The most frequent losses were detected on 14q and 22q. Losses on 14q are rarely seen in other types of leiomyo-sarcoma and may be a distinctive feature of ULMS. Gains on chromosomes 8, 17, and X were observed in half the cases and were accompanied by high-level amplification. Other chromosome arms overrepresented included 12q and 19p. The absence of specific anomalies common to all ULM and ULMS argues against their being benign-malignant counterparts.

Chromosome Aberrations↗
PubMed2000

Cerebral mucormycosis: proton MR spectroscopy and MR imaging.

Proton magnetic resonance spectroscopy (MRS) was integrated with magnetic resonance imaging (MRI) in the evaluation of a case of cerebral mucormycosis. MRS showed markedly elevated lactate, depleted N-acetyl aspartate and metabolite resonances attributable to succinate and acetate. The spectroscopy profile is essentially similar to that of bacterial abscess but without the commonly seen resonances of the amino acids valine, leucine and isoleucine. Our extensive literature review did not yield any reports of MRS findings on cerebral mucormycosis. MRS prospectively limited the differential diagnoses given the otherwise nonspecific and complex MR imaging findings in our immunosuppressed patient.

Adult↗
PubMed2000

Evolution of lactate/pyruvate and arterial ketone body ratios in the early course of catecholamine-treated septic shock.

OBJECTIVES: To measure arterial lactate/pyruvate (L/P) and arterial ketone body ratios as reflection of cytoplasmic and mitochondrial redox state at different stages of catecholamine-treated septic shock and compare them with normal and pathologic values obtained in patients in shock who have decreased oxygen transport (cardiogenic shock), and to assess the relationship between the time course of lactate, L/P ratio, and mortality in septic shock. DESIGN: Prospective, observational human study. SETTING: A university intensive care unit. PATIENTS: Sixty consecutive adult patients who developed septic shock and lactic acidosis requiring the administration of vasopressors. Twenty patients in the intensive care unit without shock, sepsis, and hypoxia and with normal lactate values and 10 patients with cardiogenic shock were also studied. MEASUREMENTS: Hemodynamic measurements, arterial and mixed venous blood gases, arterial lactate and pyruvate concentrations, and arterial ketone body ratio were measured within 4 hrs after the introduction of catecholamine and 24 hrs later. MAIN RESULTS: Fifteen patients (25%) died within the first 24 hrs of septic shock, and these early fatalities had a higher blood lactate (12.2+/-3 versus 4.6+/-1.3 mmol/L; p<.01) concentration and a higher L/P ratio (37+/-4 versus 20+/-1; p<.01) than those who died later. No difference was found for arterial ketone body ratio (0.41+/-0.1 versus 0.50+/-0.06). Forty-five patients survived >24 hrs including 25 survivors and 20 nonsurvivors. Although there was no difference between survivors and nonsurvivors in initial lactate concentration (4.1+/-0.4 and 4.6+/-0.3, respectively), L/P ratio (19+/-1 and 20+/-1, respectively), and arterial ketone body ratio (0.5+/-0.06 and 0.52+/-0.07, respectively), blood lactate and L/P ratio significantly decreased during the first 24 hrs in the survivors (2.8+/-0.4 and 14+/-1, respectively; p<.05). and were stable in the nonsurvivors (4+/-0.3 and 22+/-1, respectively) Although returning to normal values after 24 hrs in survivors and nonsurvivors, arterial ketone body ratio was higher in survivors (1.72+/-0.17 versus 1.09+/-0.15; p<.05). Lactate and L/P ratio were closely correlated (r2 = .8, p<.0001). In the cardiogenic shock group, lactate concentration was 4+/-1 mmol/L, L/P ratio was 40+/-6, and arterial ketone body ratio was 0.2+/-0.05. The mortality rate was 60%. CONCLUSIONS: The main result of the present study is that hemodynamically unstable patients with sepsis needing catecholamine therapy had a lactic acidosis with an elevated L/P ratio and a decreased arterial ketone body ratio, suggesting a decrease in cytoplasmic and mitochondrial redox state. The duration of lactic acidosis is associated with the development of multiple organ failure and death.

Acidosis, Lactic↗
PubMed2000

Factors related to the progression of myopia in Singaporean children.

PURPOSE: To examine the possible factors related to the progression of myopia in Singapore children. METHODS: One hundred fifty-three Singapore children aged 6 to 12 years were recruited to participate in a concurrent cohort study of the risk factors for the progression of myopia. Socioeconomic status, outdoor activity, and near-work activity were documented in a face-to-face clinic interview. The changes in cycloplegic subjective refraction and autorefraction were ascertained with the use of a Nidek ARK 900 over a 2-year period. RESULTS: The average rate of progression of myopia as measured by subjective refraction was -0.59 D per year (95% confidence interval -0.52, -0.66). Younger children and children who were more myopic at the beginning (refractive error worse than -2.0 D) of the study had higher myopia progression rates. CONCLUSIONS: Myopia progression was faster for younger children and for children who had more severe myopia at baseline. Socioeconomic status and near-work activity were not related to myopia progression.

Child↗
PubMed2000

Jumping translocations in spontaneous abortions.

Chromosome translocations involving one donor chromosome and multiple recipient chromosomes have been referred to as jumping translocations (JTs). Acquired JTs are commonly observed in cancer patients, mainly involving chromosome 1. Constitutional forms of JTs mostly involve the acrocentric chromosomes and their satellites and have been reported in patients with clinical abnormalities. Recognizable phenotypes resulting from these events have included Down, Prader-Willi, and DiGeorge syndromes. The presence of JTs in spontaneous abortions has not been previously described. The breakpoints of all JTs occur in areas rich in repetitive DNA (telomeric, centromeric, and nucleolus organizing regions). We report two different unstable chromosome rearrangements in samples derived from spontaneous abortions. The first case involved a chromosome 15 donor. The recipient chromosomes were 1, 9, 15, and 21, and the respective breakpoints were in either the heterochromatic regions or the centromeres. FISH studies confirmed that the breakpoints of the jumping 15 rearrangement did not involve the Prader-Willi region but originated at the centromere or in the proximal short arm. A second case of instability was observed with a rearrangement resulting from a presumed de novo 8;21 translocation. Three JT cell lines were observed. They consisted of a deleted 8p chromosome, a dicentric 8;21 translocation, and an 8q isochromosome. The instability regions appeared to be at the pericentromeric region of chromosome 8 and the satellite region of chromosome 21. Both cases proved to be de novo events. The unstable nature of the JT resulting in chromosomal imbalance most likely contributed to the fetal loss. It appears that JT events may predispose to chromosomal imbalance via nondisjunction and chromosomal rearrangement and, therefore, may be an unrecognized cause of fetal loss.

Abortion, Spontaneous↗
PubMed2000

Prenatal molecular cytogenetic diagnosis of partial tetrasomy 10p due to neocentromere formation in an inversion duplication analphoid marker chromosome.

Neocentromeres are fully functional centromeres found on rearranged or marker chromosomes that have separated from endogenous centromeres. Neocentromeres often result in partial tri- or tetrasomy because their formation confers mitotic stability to acentric chromosome fragments that would normally be lost. We describe the prenatal identification and characterization of a de novo supernumerary marker chromosome (SMC) containing a neocentromere in a 20-wk fetus by the combined use of comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH). GTG-banding of fetal metaphases revealed a 47,XY,+mar karyotype in 100% of cultured amniocytes; parental karyotypes were both normal. Although sequential tricolor FISH using chromosome-specific painting probes identified a chromosome 10 origin of the marker, a complete panel of chromosome-specific centromeric satellite DNA probes failed to hybridize to any portion of the marker. The presence of a neocentromere on the marker chromosome was confirmed by the absence of hybridization of an all-human-centromere alpha-satellite DNA probe, which hybridizes to all normal centromeres, and the presence of centromere protein (CENP)-C, which is associated specifically with active kinetochores. Based on CGH analysis and FISH with a chromosome 10p subtelomeric probe, the marker was found to be an inversion duplication of the distal portion of chromosome 10p. Thus, the proband's karyotype was 47,XY,+inv dup(10)(pter-->p14 approximately 15::p14 approximately 15-->neo-->pter), which is the first report of partial tetrasomy 10p resulting from an analphoid marker chromosome with a neocentromere. This study illustrates the use of several molecular strategies in distinguishing centric alphoid markers from neocentric analphoid markers.

Adult↗
PubMed1999

The human acid ceramidase gene (ASAH): structure, chromosomal location, mutation analysis, and expression.

Acid ceramidase (AC) is the lysosomal enzyme that degrades ceramide into sphingosine and fatty acid. A deficiency in human AC activity leads to the lysosomal storage disorder, Farber disease (FD). The human AC gene (HGMW-approved symbol ASAH) was cloned and characterized, revealing an organization similar to that of the murine AC gene. The human gene spans about 30 kb in length and contains 14 exons ranging in size from 46 to 1201 bp. The exon/intron junctions were determined and found to follow the GT-AG rule. The putative promoter region had a GC content over 60%, lacked a TATA box, and contained several sequences matching transcription factor binding sites, including nine SP-1 sites, one AP-1 site, and three CACC boxes. The promoter activity of a 475-bp fragment from within this region was demonstrated by chloramphenicol acyltransferase assays. Northern blotting revealed variable expression of the human AC RNA; i.e., expression of the major 2.4-kb transcript was high in heart and kidney, followed by lung and placenta, but low in pancreas, liver, brain, and skeletal muscle. Two minor AC transcripts of 1.7 and 1.2 kb also were detected in heart and skeletal muscle. The human AC gene was mapped to the chromosomal region 8p21.3-p22 by in situ hybridization and FISH analyses, syntenic with the mouse chromosomal location. Finally, three new missense mutations, E138V, R254G, and P362R, were identified in the human AC gene from FD patients. Mutant AC cDNAs containing these point mutations were constructed and examined using the FLAG-tagged expression system. Although the levels of protein expression for these mutant ACs were about equivalent to that of the controls, their enzymatic activity was markedly reduced, confirming their authenticity.

3T3 Cells↗
PubMed1999

Molecular cloning and characterization of a human cDNA and gene encoding a novel acid ceramidase-like protein.

Computer-assisted database analysis of sequences homologous to human acid ceramidase (ASAH) revealed a 1233-bp cDNA (previously designated cPj-LTR) whose 266-amino-acid open reading frame had approximately 36% identity with the ASAH polypeptide. Based on this high degree of homology, we undertook further molecular characterization of cPj-LTR and now report the full-length cDNA sequence, complete gene structure (renamed human ASAHL since it is a human acid ceramidase-like sequence), chromosomal location, primer extension and promoter analysis, and transient expression results. The full-length human ASAHL cDNA was 1825 bp and contained an open-reading frame encoding a 359-amino-acid polypeptide that was 33% identical and 69% similar to the ASAH polypeptide over its entire length. Numerous short regions of complete identity were observed between these two sequences and two sequences obtained from the Caenorhabditis elegans genome database. The 30-kb human ASAHL genomic sequence contained 11 exons, which ranged in size from 26 to 671 bp, and 10 introns, which ranged from 150 bp to 6.4 kb. The gene was localized to the chromosomal region 4q21.1 by fluorescence in situ hybridization analysis. Northern blotting experiments revealed a major 2.0-kb ASAHL transcript that was expressed at high levels in the liver and kidney, but at relatively low levels in other tissues such as the lung, heart, and brain. Sequence analysis of the 5'-flanking region of the human ASAHL gene revealed a putative promoter region that lacked a TATA box and was GC rich, typical features of a housekeeping gene promoter, as well as several tissue-specific and/or hormone-induced transcription regulatory sites. 5'-Deletion analysis localized the promoter activity to a 1. 1-kb fragment within this region. A major transcription start site also was located 72 bp upstream from the ATG translation initiation site by primer extension analysis. Expression analysis of a green fluorescence protein/ASAHL fusion protein in COS-1 cells revealed a punctate, perinuclear distribution, although no acid ceramidase activity was detected in the transfected cells using a fluorescence-based in vitro assay system.

5' Untranslated Regions↗
PubMed1999

Myocardial infarction mediated by endothelin receptor signaling in hypercholesterolemic mice.

Myocardial infarction is linked to atherosclerosis, yet the sequence leading from silent coronary atherosclerosis to acute myocardial infarction has remained unclear. Here we show that hypercholesterolemic apolipoprotein E-/- low density lipoprotein receptor-/- mice develop not only coronary atherosclerosis but also myocardial infarction. Exposure of mice to mental stress or hypoxia led to acute ischemia, which, in a large proportion of the mice, was followed by electrocardiographic changes, leakage of troponin T, and loss of dehydrogenase from the myocardium, all indicative of acute myocardial infarction. Apoptotic death of cardiomyocytes was followed by inflammation and fibrosis in the heart. All these pathological changes could be prevented by a blocker of the endothelin type A receptor. Thus, stress elicits myocardial infarction through endothelin receptor signaling in coronary atherosclerosis caused by hypercholesterolemia.

Animals↗
PubMed1999

Human cathepsins F and W: A new subgroup of cathepsins.

Human cathepsin F is a recently described papain-like cysteine protease of unknown function. To investigate the evolutionary relatedness to other human cathepsins, we determined the genomic organization and the chromosomal localization of cathepsin F and isolated its putative promoter region. The gene of human cathepsin F (CTSF) is composed of twelve exons and eleven introns and was found to be similar to that of cathepsin W but different from the cathepsins K, S, L, O, B, and C. The splice sites of nine out of the eleven introns were identical to those determined in the cathepsin W gene (CTSW), whereas introns one and ten were unique for CTSF. The 4. 7 kb gene was mapped to the long arm of chromosome 11 at position q13.1-3, a locus shared with CTSW. Phylogenetic analysis of human cathepsin protein sequences demonstrated that (i) cathepsins F and W are evolutionarily separated from other human cathepsins, and (ii) cysteine proteases closely related to human cathepsin W and F are also expressed in parasites and mammals. Based on these phylogenetic findings, on the presence of a particular protein motif ("ERFNAQ") in the propeptides of cathepsins F and W as well as the genomic organization and chromosomal localization of their genes, we concluded that F and W form a novel subgroup of cathepsin proteases. We suggest the naming "cathepsin F-like" proteases distinct from the previously described cathepsins "L- and B-like" subgroups.

Cathepsin F↗
PubMed1999

Neonatal gene transfer leads to widespread correction of pathology in a murine model of lysosomal storage disease.

For many inborn errors of metabolism, early treatment is critical to prevent long-term developmental sequelae. We have used a gene-therapy approach to demonstrate this concept in a murine model of mucopolysaccharidosis type VII (MPS VII). Newborn MPS VII mice received a single intravenous injection with 5.4 x 10(6) infectious units of recombinant adeno-associated virus encoding the human beta-glucuronidase (GUSB) cDNA. Therapeutic levels of GUSB expression were achieved by 1 week of age in liver, heart, lung, spleen, kidney, brain, and retina. GUSB expression persisted in most organs for the 16-week duration of the study at levels sufficient to either reduce or prevent completely lysosomal storage. Of particular significance, neurons, microglia, and meninges of the central nervous system were virtually cleared of disease. In addition, neonatal treatment of MPS VII mice provided access to the central nervous system via an intravenous route, avoiding a more invasive procedure later in life. These data suggest that gene transfer mediated by adeno-associated virus can achieve therapeutically relevant levels of enzyme very early in life and that the rapid growth and differentiation of tissues does not limit long-term expression.

Animals↗
PubMed1999

Comparison of systemic and regional effects of dobutamine and dopexamine in norepinephrine-treated septic shock.

OBJECTIVES: To compare the effects of dobutamine and dopexamine on systemic hemodynamics, lactate metabolism, renal function and the intramucosal-arterial PCO(2) gap in norepinephrine-treated septic shock. DESIGN: A prospective, interventional, randomized clinical trial. SETTING: Adult medical/surgical intensive care unit in a university hospital. PATIENTS: After volume resuscitation, 24 patients were treated with norepinephrine alone titrated to obtain a mean arterial pressure of 75 mmHg and a cardiac index greater than 3. 5 l/min(-1). m(-2). INTERVENTIONS: Patients were randomized to receive an infusion of dobutamine (n = 12) (5 microg/kg per min) or dopexamine (n = 12) (1 microg/kg per min). MEASUREMENTS AND MAIN RESULTS: Baseline measurements included: hemodynamic parameters, renal parameters (diuresis, creatinine clearance and urinary sodium excretion), gastric mucosal-arterial PCO(2) gap, arterial and mixed venous gases and arterial lactate and pyruvate levels. These measurements were repeated after 1 (H(1)), 4 (H(4)) and 24 (H(24)) h. No difference was found between dobutamine and dopexamine among H(0) and H(1), H(4) and H(24) values for hemodynamics. Dobutamine and dopexamine at low doses had no significant effect on mean arterial pressure, heart rate, cardiac index, oxygen delivery, oxygen consumption and pulmonary artery occlusion pressure. No patients developed arrhythmia or electrocardiographic signs of myocardial ischemia. After 4 and 24 h lactate concentration decreased in the dobutamine group from 2.4 +/- 1 mmol/l to 1.7 +/- 0. 7 mmol/l and 1.5 +/- 0.4 mmol/l, respectively, while it increased in the dopexamine group from 2.3 +/- 1 mmol/l to 2.7 +/- 1 mmol/l after 4 h and returned to baseline values after 24 h (2.2 +/- 0.6). After 24 h the lactate/pyruvate ratio decreased in the dobutamine group from 15 +/- 5 to 12 +/- 3 (p < 0.05) while it was unchanged in the dopexamine group (from 16 +/- 6 to 17 +/- 4). Arterial pH increased in the dobutamine group from 7.35 +/- 0.05 to 7.38 +/- 0.07 (p < 0. 05) while it was unchanged in the dopexamine group (from 7.34 +/- 0. 01 to 7.35 +/- 0.10). The PCO(2) gap decreased after 1 and 4 h in both the dobutamine and dopexamine groups (p < 0.05 with respect to baseline). When looking at individual responses, however, patients from both groups exhibited an increased gastric PCO(2) gap. No difference was found between dobutamine and dopexamine for renal parameters. CONCLUSIONS: In norepinephrine-treated septic shock, low doses of neither dobutamine nor dopexamine caused significant effects on systemic hemodynamics and renal function and both dobutamine and dopexamine inconsistently improved the PCO(2) gap. The present results support the need for individual measurement of the effects of catecholamine on the PCO(2) gap.

Analysis of Variance↗
PubMed1999

The role of religion and ethnicity in the help seeking of family caregivers of elders with Alzheimer's disease and related disorders.

Stages of help seeking during illness have been identified as follows: disease experience, symptom attribution, decision to seek care, and contact with care providers. These stages have not been evaluated amongst family caregivers of elders affected with Alzheimer's disease and related disorders (ADRD). Since minority families typically care for ADRD elders at home, it seems important to understand the help seeking of minority family caregivers in particular, and the role of religious/ethnic factors. Thematic analyses were conducted on in-depth interviews from 10 caregivers from 4 groups (total n = 40): African-American, Chinese-American, Puerto Rican, and Irish-American. Aside from the disease experience stage, where religious/ethnic themes were negligible, between-group differences existed in these themes at other stages. For example, themes of extended family support emerged around decision making, with much between-group variation. At the contact with providers stage themes of contacting religious or ethnic service organizations were present, again with between-group variation. Chinese-American and Puerto Rican narratives contained themes of language barriers to care, and a lack of culturally-competent services. Both Irish-American and African-American narratives showed themes of alienation from religious groups on the one hand, and using prayer to cope on the other. Narratives from all groups contained themes of religious and/or ethnic imperatives for providing care. Overall, findings reveal that religious/ethnic factors may both aid and impede the help seeking of caregivers.

Journal Article↗
PubMed1999

Beneficial effects of L-canavanine, a selective inhibitor of inducible nitric oxide synthase, on lactate metabolism and muscle high energy phosphates during endotoxic shock in rats.

Overproduction of NO by an inducible NO synthase (iNOS) plays a role in the pathophysiology of septic shock. In such situations, NOS inhibition might be of therapeutic value, although detrimental side effects possibly related to inhibition of constitutive NOS have been reported. The use of L-canavanine, a selective inhibitor of iNOS, might be more suitable. The aim of the study was to compare in a rodent endotoxic shock the effects of saline (2 mL/h), N(G)-methyl-L-arginine(L-NMMA) (10 mg/kg/h) and L-canavanine (100 mg/kg/h) on muscle intracellular pH (pHi) and intracellular bioenergetic patterns (ATP, phosphocreatine/inorganic phosphate ratio) using in vivo 31P magnetic resonance spectroscopy (31P MRS). Three groups of anesthetized, mechanically ventilated and paralyzed rats received an intravenous infusion of 15 mg/kg of endotoxin. A fourth time-matched control group (n = 8) received 2 mL/h of saline. Mean arterial pressure, femoral blood flow, arterial blood gases, lactate, nitrate level, and 31P nuclear magnetic resonance (31P MRS) measurements were acquired at onset (T = 0), 90 min (T = 90), and 180 min (T180) after the endotoxin challenge. Femoral oxygen delivery was calculated as the product of femoral blood flow (mL/min) and arterial oxygen content. Endotoxin induced a marked decrease in arterial pressure and femoral oxygen delivery and an increase in lactate level. Intracellular pH and phosphocreatine/inorganic phosphate ratio decreased. ATP level did not change. Both L-NMMA and L-canavanine reversed the endotoxin-induced decrease in arterial pressure. L-NMMA attenuated the decrease in femoral oxygen delivery and the increase in lactate level while these were corrected by L-canavanine. Considering 31P MRS derived bioenergetic indices, the endotoxin-induced decrease in pHi and Pcr/Pi was attenuated by L-NMMA and corrected by L-canavanine. In conclusion, in a rodent model of endotoxinic shock, the continuous infusion of L-canavanine, a selective iNOS inhibitor, improved the systemic hemodynamic parameters and the intracellular bio-energetic patterns estimated by in vivo 31P MRS. To the contrary, the continuous infusion of both constitutive and inducible NOS inhibitor L-NMMA was not followed by the same achievement.

Adenosine Triphosphate↗
PubMed1999

Enzyme replacement in murine mucopolysaccharidosis type VII: neuronal and glial response to beta-glucuronidase requires early initiation of enzyme replacement therapy.

We have previously shown that mucopolysaccharidosis type VII (MPS VII) mice receiving six weekly injections of recombinant beta-glucuronidase from birth had improved cognitive ability and reduced central nervous system lysosomal storage. However, a single beta-glucuronidase injection at 5 wk of age did not correct neuronal storage. We define the age at which central nervous system storage in MPS VII mice becomes resistant to beta-glucuronidase therapy and determine the effect of enzyme on other tissues by comparing the histology of mice begun on therapy at various times after birth. MPS VII mice received injections on the day of birth and then weekly for 5 wk with 16,000U/g beta-glucuronidase had reduced lysosomal storage in brain. The same therapy begun on d 14 of life or thereafter failed to correct neuronal storage, even when treatment was continued for six doses. Glial responsiveness or accessibility to enzyme also depended on early treatment. In contrast, leptomeningeal, osteoblast, and retinal pigment epithelial storage reduction depended on enzyme dose rather than age at initiation of therapy. Fixed tissue macrophage storage was reduced in all treated MPS VII mice, even those receiving a single dose. These observations indicate that fixed tissue macrophages in MPS VII mice remain sensitive to enzyme replacement therapy well into adulthood although neurons are responsive or accessible to enzyme therapy early in life. Because early initiation of enzyme replacement is important to achieve a central nervous system response, these studies emphasize the importance of newborn screening for lysosomal storage diseases so that early treatment can maximize the likelihood of a favorable therapeutic response.

Anaphylaxis↗