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Biomedical subjects

J Belmont

Publications and source records attributed to J Belmont.

At least 19 recordsLinked to original sources
PubMed2006

Intraocular pressure alterations following intravitreal triamcinolone acetonide.

AIMS: To determine the prevalence of intraocular pressure (IOP) alterations following intravitreal injection of triamcinolone acetonide (IVTA) and to assess possible risk factors of IOP elevation in eyes receiving single and/or repeat injections. METHODS: Retrospective, consecutive case series. 570 consecutive eyes of 536 patients who received a single IVTA injection (4 mg/0.1 ml) and a second set of 43 eyes of 40 patients who received a second injection. Retrospective review of all IVTA cases performed by three vitreoretinal surgeons over a 42 month period beginning in 2000. The main outcome measure was change in IOP defined as absolute value of IOP elevation (5 mm Hg or higher, 10 mm Hg or higher), and percentage of baseline (30% or higher increase from baseline IOP). RESULTS: Of the 528 eyes receiving single injections, 281 (53.2%) had an IOP elevation; 267 eyes (50.6%) experienced an elevation of IOP of at least 30%, and 245 (45.8%) and 75 (14.2%) eyes had an increase of 5 mm Hg or 10 mm Hg or more, respectively. Baseline IOP greater than 16 mm Hg is a risk factor for post-injection IOP elevation. Of the 43 eyes which received a second injection, 28 (65.1%) experienced an increase in IOP of at least 30% of baseline. Filtering surgery was required in five (0.094%) of the single and one (2.3%) of repeat injection eyes. CONCLUSIONS: Elevated IOP after IVTA is common and patients should be monitored beyond 6 months post-injection. Patients with a baseline IOP more than 16 mm Hg or receiving a second injection should be carefully monitored for an elevated IOP.

Adolescent↗
PubMed2002

PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13.

We surveyed 16 subjects with the clinical diagnosis of Noonan Syndrome (NS1) from 12 families and their relevant family members for mutations in PTPN11/SHP2 using direct DNA sequencing. We found three different mutations among five families. Two unrelated subjects shared the same de novo missense substitution in exon 13 (S502T); an additional two unrelated families had a mutation in exon 3 (Y63C); and one subject had the amino acid substitution Y62D, also in exon 3. None of the three mutations were present in ethnically matched controls. In the mature protein model, the exon 3 mutants and the exon 13 mutant amino acids cluster at the interface between the N' SH2 domain and the phosphatase catalytic domain. Six of eight subjects with PTPN11/SHP2 mutations had pulmonary valve stenosis while no mutations were identified in those subjects (N = 4) with hypertrophic cardiomyopathy. An additional four subjects with possible Noonan syndrome were evaluated, but no mutations in PTPN11/SHP2 were identified. These results confirm that mutations in PTPN11/SHP2 underlie a common form of Noonan syndrome, and that the disease exhibits both allelic and locus heterogeneity. The observation of recurrent mutations supports the hypothesis that a special class of gain-of-function mutations in SHP2 give rise to Noonan syndrome.

Catalytic Domain↗
PubMed2001

BCR gene expression blocks Bcr-Abl induced pathogenicity in a mouse model.

It is well accepted that the Bcr-Abl oncoprotein encoded by the Philadelphia chromosome is responsible for causing chronic myelogenous leukemia (CML). We have previously demonstrated that expression of Bcr interferes with the oncogenic effects of Bcr-Abl. To examine the effects of increased Bcr expression on Bcr-Abl oncogenic effects in a more physiological system, we tested the leukemogenic potential of a clone of K562 cells (K6 K562) containing an inducible BCR gene in NOD/scid mice. In this clone, the BCR gene was placed under the control of a tetracycline (Tet) repression system with a cytomegalovirus (CMV) promoter. Induction of exogenous Bcr protein by removal of Tet from the culture medium caused a dramatic increase in Bcr serine kinase activity, yielding predominantly phosphoserine Bcr, despite the presence of Bcr-Abl in the kinase reaction mixture. Prior to induction, the endogenous Bcr was predominantly in the phosphotyrosine form because of phosphorylation by Bcr-Abl, which we previously have shown suppresses Bcr serine/threonine kinase activity. Injection of K6 K562 cells into NOD/scid mice under conditions where BCR expression was suppressed resulted in death or terminal illness in 100% of the mice within 35 days after injection. These mice had a severe wasting syndrome characterized by atrophy of bone marrow hematopoiesis, and/or neoplasia of liver, bone marrow and spleen. Neoplastic spleens from these mice usually contained b3a2 Bcr-Abl transcripts. In contrast, induction of BCR expression at the time of injection allowed 80% survival; these healthy mice had no detectable microscopic lesions in blood forming organs. This difference in survival was significant with P<0.0001. Of interest, mice that were fed Tet for 19 days to initiate the disease syndrome and then released from the BCR transcriptional block had a significantly better survival pattern than mice exposed to Tet throughout the entire period. Moreover, 30% of these mice (three mice) survived through day 50. We conclude from these findings that BCR gene expression strongly inhibits the oncogenic effects of Bcr-Abl in NOD/scid mice, yielding healthy mice in most cases.

Animals↗
PubMed2001

Enzyme-replacement therapy in mucopolysaccharidosis I.

BACKGROUND: Mucopolysaccharidosis I is a lysosomal storage disease caused by a deficiency of the enzyme alpha-L-iduronidase. We evaluated the effect of enzyme-replacement therapy with recombinant human alpha-L-iduronidase in patients with this disorder. METHODS: We treated 10 patients with mucopolysaccharidosis I (age, 5 to 22 years) with recombinant human alpha-L-iduronidase at a dose of 125,000 U per kilogram of body weight given intravenously once weekly for 52 weeks. The patients were evaluated at base line and at 6, 12, 26, and 52 weeks by detailed clinical examinations, magnetic resonance imaging of the abdomen and brain, echocardiography, range-of-motion measurements, polysomnography, clinical laboratory evaluations, measurements of leukocyte alpha-L-iduronidase activity, and urinary glycosaminoglycan excretion. RESULTS: Hepatosplenomegaly decreased significantly in all patients, and the size of the liver was normal for body weight and age in eight patients by 26 weeks. The rate of growth in height and weight increased by a mean of 85 and 131 percent, respectively, in the six prepubertal patients. The mean maximal range of motion of shoulder flexion and elbow extension increased significantly. The number of episodes of apnea and hypopnea during sleep decreased 61 percent. New York Heart Association functional class improved by one or two classes in all patients. Urinary glycosaminoglycan excretion decreased after 3 to 4 weeks of treatment; the mean reduction was 63 percent of base-line values. Five patients had transient urticaria during infusions. Serum antibodies to alpha-L-iduronidase were detected in four patients. CONCLUSIONS: In patients with mucopolysaccharidosis I, treatment with recombinant human alpha-L-iduronidase reduces lysosomal storage in the liver and ameliorates some clinical manifestations of the disease.

Adolescent↗
PubMed2000

Molecular determinants of left and right outflow tract obstruction.

Congenital heart defects represent the most common group of human birth defects; they occur in 0.8-1% of live births and in 10% of spontaneously aborted fetuses. Heart defects seen in newborns typically represent specific morphogenetic defects of individual chambers or regions of the heart, with the remaining portions of the heart developing relatively normally. These developmental defects are commonly compatible with the intrauterine circulation, where the pulmonary circulation and systemic circulation work in concert, resulting in adequate embryonic growth and development. After delivery, however, significant cardiac symptoms develop. In many of these disorders, cyanosis is the earliest feature, while in others, cardiovascular collapse occurs before diagnosis. In this review, obstruction of the left and right sides of the heart are discussed. In these disorders, ventricular hypoplasia resulting in single ventricle physiologic characteristics is typical. The unaffected ventricle in these cases is usually morphologically and physiologically normal. These conditions include hypoplastic left heart syndrome and aortic coarctation on the left side, pulmonary stenosis, tetralogy of Fallot, and other complex right ventricle obstructive disorders. Many of these disorders occur in association with genetic syndromes identifiable by dysmorphic features. In some cases, the gene(s) has been identified or the genetic pathway has been defined. The purpose of this review is to discuss the molecular determinants of these obstructive disorders.

Abnormalities, Multiple↗
PubMed1999

Prenatal diagnosis and treatment of holocarboxylase synthetase deficiency.

Holocarboxylase synthetase is one of two enzymes known to be involved in the metabolism of biotin. It catalyses the fixation of biotin to inactive apocarboxylases yielding active carboxylases. Deficiency of this enzyme leads to multiple carboxylase deficiency which is fatal in the absence of prompt diagnosis and treatment with biotin. In a pregnancy at risk for deficiency of holocarboxylase synthetase prenatal diagnosis was performed by assay of the enzyme in amniocytes. The Km for biotin was 62.8 nM which was 12 times the control value of 5.0 nM. The Vmax was 2 per cent of the control value. This was confirmed by assay of the activity of propionyl CoA carboxylase (20-26 per cent control), 3-methylcrotonyl CoA carboxylase (14-19 per cent control) and pyruvate carboxylase (12-30 per cent control) and demonstration of biotin responsiveness in vitro. All carboxylase activities were restored to 51-58 per cent of control when amniocytes were cultured in medium containing 1 microM biotin. Diagnosis was ultimately confirmed by assay of holocarboxylase synthetase in lymphocytes from the infant after birth. The Km for biotin of the holocarboxylase synthetase of the infant was 60.3 nM while that of a parallel control was 6.9 nM. Prenatal treatment of the mother with biotin led to a concentration of biotin of 240 nM in the serum of the infant at birth that was four times the Km of the enzyme for biotin. The infant was clinically well at birth, and organic acid analysis of the blood and urine revealed no accumulation of the characteristic metabolites.

Adult↗
PubMed1999

Characterization and mutation analysis of human LEFTY A and LEFTY B, homologues of murine genes implicated in left-right axis development.

Members of the transforming growth factor (TGF)-beta family of cell-signaling molecules have been implicated recently in mammalian left-right (LR) axis development, the process by which vertebrates lateralize unpaired organs (e.g., heart, stomach, and spleen). Two family members, Lefty1 and Lefty2, are expressed exclusively on the left side of the mouse embryo by 8.0 days post coitum. This asymmetry is lost or reversed in two murine models of abnormal LR-axis specification, inversus viscerum (iv) and inversion of embryonic turning (inv). Furthermore, mice homozygous for a Lefty1 null allele manifest LR malformations and misexpress Lefty2. We hypothesized that Lefty mutations may be associated with human LR-axis malformations. We now report characterization of two Lefty homologues, LEFTY A and LEFTY B, separated by approximately 50 kb on chromosome 1q42. Each comprises four exons spliced at identical positions. LEFTY A is identical to ebaf, a cDNA previously identified in a search for genes expressed in human endometrium. The deduced amino acid sequences of LEFTY A and LEFTY B are more similar to each other than to Lefty1 or Lefty2. Analysis of 126 human cases of LR-axis malformations showed one nonsense and one missense mutation in LEFTY A. Both mutations lie in the cysteine-knot region of the protein LEFTY A, and the phenotype of affected individuals is very similar to that typically seen in Lefty1-/- mice with LR-axis malformations.

Amino Acid Sequence↗
PubMed1997

Acute dopaminergic blockade augments the naloxone-induced LH rise in estrogen-treated postmenopausal women.

OBJECTIVES: To assess the effect of estrogen replacement on the simultaneous blockade of the dopaminergic (DA) and opioidergic neural control of hypothalamic-gonadotropic function in postmenopausal women. METHODS: Twenty healthy postmenopausal women, 48-55 years old were randomly assigned to receive either a 4-h naloxone infusion at 2 mg/h (group 1, n = 7) or a 10 mg i.v. bolus of metoclopramide (group 2, n = 7) or both drugs, simultaneously (group 3, n = 6) before and after 3 weeks of transdermal estradiol (100 microg/day). Blood samples were obtained at 30-min intervals during 4 h and duplicate determinations of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2) and prolactin (PRL) were performed in all samples. RESULTS: In group 1 only a mild but significant LH rise after but not before estrogen replacement was seen. In group 2 PRL had a greater rise after than before estrogen therapy, without other hormonal changes. In group 3 a greater rise in PRL occurred after than before estrogen administration and serum LH had a sustained rise throughout the test only after estrogen replacement (greater than in group 1). No FSH changes were observed. The after-estradiol PRL response was nearly similar in groups 2 and 3. CONCLUSIONS: Our results indicate that in the untreated postmenopausal women, the dopaminergic system has little and the opioidergic system has no significant input in the control of gonadotropin or prolactin release. However, following estrogen replacement, opioids are involved in the inhibition of LH release and stimulating PRL release, while the dopaminergic system acts to inhibit PRL release and modulates LH release or inhibition, depending on the levels of circulating estrogens.

Dopamine↗
PubMed1993

Aqueous tube-shunt implantation and pars plana vitrectomy in eyes with refractory glaucoma.

We reviewed the surgical outcome of 20 eyes of 20 consecutive patients who had undergone combined aqueous tube-shunt implantation and vitrectomy for complicated glaucoma associated with vitreoretinal disorders. After a mean follow-up of 10.39 +/- 5.43 months, visual acuity remained stable or improved in 13 patients (65%), and intraocular pressure was controlled (< 22 mm Hg) in 15 (75%). The most common complications were corneal edema (seven eyes) and choroidal effusion (three eyes). Combined tube-shunt implantation and pars plana vitrectomy may successfully control intraocular pressure and maintain preoperative visual acuity in refractory glaucoma associated with vitreoretinal disorders.

Adolescent↗
PubMed1993

The use of perfluorophenanthrene in the removal of intravitreal lens fragments.

We used perfluorophenanthrene as an aid during pars plana vitrectomy in removing lens fragments dislocated posteriorly into the vitreous cavity. We reviewed the records of all patients (nine patients, nine eyes) referred with dislocated lenses who underwent pars plana vitrectomy with perfluorophenanthrene for removal of the lens material at Wills Eye Hospital from July 1, 1991, through Nov. 30, 1991. The lens was dislocated during cataract extraction in eight eyes. One eye had a history of nonpenetrating trauma and lens dislocation. In one eye a retinal tear was noted intraoperatively and treated. Six eyes had postoperative visual acuity of 20/50 or better. In all eyes the lens was removed without further complications. Perfluorocarbon liquids such as perfluorophenanthrene may enhance current techniques by allowing easier and safer removal of displaced lens fragments through the pars plana.

Cataract Extraction↗
PubMed1993

Fatal infantile encephalopathy with olivopontocerebellar hypoplasia and micrencephaly. Report of three siblings.

We report three siblings born with severe neonatal encephalopathy, manifested clinically by microcephaly, myoclonus, and muscular hypertonus. Karyotypic analyses and all biochemical investigations were unrevealing. All three patients died during infancy. Postmortem examination of the brain in one child disclosed severe neuronal loss in the inferior olives and the pontine nuclei. There was also severe hypoplasia of the cerebellum and micrencephaly. There was diffuse gliosis of the white matter in all areas of the brain. We believe this may represent a previously undescribed form of familial infantile encephalopathy with olivopontocerebellar hypoplasia.

Brain↗
PubMed1992

Use of cell-free retroviral vector preparations for transduction of cells from the marrow of chronic phase and blast crisis chronic myelogenous leukemia patients and from normal individuals.

Marrow cells were exposed to the LNL6 or G1N safety-modified variants of the N2 retrovirus, which contain the G418 bacterial resistance gene neo. The frequency of acquisition of the G418 resistance phenotype following exposure to LNL6 or G1N was compared among hematopoietic progenitor cells from the marrow of patients with chronic phase chronic myelogenous leukemia (CML), blast crisis CML, or from nonleukemic individuals. Under the conditions of our experiments, the myeloid committed progenitor cells from 3 of 6 nonleukemic individuals, 9 of 18 chronic-phase CML patients, and 2 of 4 blast crisis CML patients acquired resistance to at least 1 mg/ml G418 following incubation with cell-free supernatants from the PA317 LNL6 or PA317 G1N producer cell lines. Ten of the 32 colonies growing up in 0.8 mg/ml G418 from chronic-phase marrow exposed to LNL6 were shown to contain the neo gene by polymerase chain reaction (PCR) assay of DNA. These results were consistent with estimates of the transduction frequency based on acquisition of resistance to G418 as the number of colonies growing under G418 selection was always greater at 0.8 mg/ml G418 than at higher concentrations of G418 (1.0-1.4 mg/ml). The average transduction frequency at each G418 concentration (1.0, 1.2, and 1.4 mg/ml) in cells from blast crisis CML cells ranged from 2 to 14%, as measured by acquisition of G418 resistance. Chronic-phase CML showed slightly lower average frequencies of transduction (0.6-2.8% of the colonies are G418 resistant). The average transduction frequency of cells from nonleukemic marrow was as high as that seen from the marrow of chronic-phase CML individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1992

Pediatric cardiology: auscultation from 280 miles away.

New long-distance audio/video and data communications links among health-care facilities promise to reduce rural patients' travel time and waiting time for subspecialty consultations. To offer a satisfactory alternative to face-to-face examination, the long-distance system must meet the subspecialty's minimum criteria. For pediatric cardiology in particular, the system has to permit satisfactory cardiac auscultation. A preliminary test of remote auscultation that uses an electronic stethoscope involved two pediatric cardiologists, one listening hands-on with an acoustic stethoscope, the other listening independently at long distance with the electronic instrument. Taking the acoustic findings as the reference standard, the electronic stethoscope did not miss the one case of heart disease, correctly recommended echocardiogram follow-up in the two cases requiring it, and agreed on 80% of the murmurs' qualitative specifics. The patients' parents also indicated that the system was highly acceptable. We are following up these results with a full-scale study of the effectiveness and parental acceptance of remote auscultation.

Cardiology↗
PubMed1988

Hormone release by primary amniotic fluid cell cultures.

Amniotic fluid cells have been widely used in prenatal diagnosis; however, there is great heterogeneity of the cells and their origin. In this study we analyze the karyotype and release of human chorionic gonadotropin (hCG), human chorionic somatomammotropin (hCS), free estriol (E 3), prolactin (PRL) and progesterone (P) of amniotic fluid cells from primary cultures of six normal and two anencephalic fetuses. In all the amniotic fluid samples there was release of hCG; in one amniotic fluid, in which several tetraploid colonies were found. PRL and P were also released. The heterogeneity of amniotic fluid cell morphology and their hormone release in culture was confirmed. The presence of hormones like hCG supports the trophoblastic origin of some amniotic fluid cells from normal and anencephalic fetuses. Other hormones, such as PRL and P could be used in the differential diagnosis between the karyotype of fetal membranes and the true fetal karyotype. Amniotic fluid cell cultures used in prenatal diagnosis yielded second trimester placental cells without any elaborate methods that could be used as cell models for hormone studies.

Amniotic Fluid↗