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Biomedical subjects

J M Gardner

Publications and source records attributed to J M Gardner.

At least 37 records · Page 2Linked to original sources
PubMed1997

The mouse pale ear (ep) mutation is the homologue of human Hermansky-Pudlak syndrome.

The recessive mutation at the pale ear (ep) locus on mouse chromosome 19 was found to be the homologue of human Hermansky-Pudlak syndrome (HPS). A positional cloning strategy using yeast artificial chromosomes spanning the HPS locus was used to identify the HPS gene and its murine counterpart. These genes and their predicted proteins are highly conserved at the nucleotide and amino acid levels. Sequence analysis of the mutant ep gene revealed the insertion of an intracisternal A particle element in a protein-coding 3' exon. Here we demonstrate that mice with the ep mutation exhibit abnormalities similar to human HPS patients in melanosomes and platelet-dense granules. These results establish an animal model of HPS and will facilitate biochemical and molecular analyses of the functions of this protein in the membranes of specialized intracellular organelles.

Albinism, Oculocutaneous↗
PubMed1997

Aggressive behaviour in children and adolescents. Part I: A review of the effects of child and family characteristics.

Interpersonal violence is a major public health concern throughout the West Indies, particularly in Jamaica. Many factors contribute to a youth's violent or aggressive behaviour, ranging from individual temperament, to family structure, to large sociocultural influences. In Part I, we review the incidence and severity of violence, and discuss the effects of individual characteristics, and of family structure and discipline. In Part II, the reported effects of school structure, peer relationships and interaction, corporal punishment and the media on violent behaviour in children and adolescents are reviewed, and potential policy implications are discussed.

Adolescent↗
PubMed1996

Complete short-term correction of canine hemophilia A by in vivo gene therapy.

Hemophilia A is a severe bleeding disorder caused by a deficiency in clotting factor VIII (FVIII). A canine model that closely mimics the human disease was used to determine if an adenoviral vector expressing a human FVIII cDNA could be used to correct the hemophilia A phenotype. Within 48 hours after peripheral vein administration of the vector to FVIII-deficient dogs, the hemophilic phenotype was corrected, based on determination of the activated clotting time, the activated partial thromboplastin time, and the cuticle bleeding time. Direct measurement of human FVIII in the dog plasma showed FVIII expression at amounts well above the human therapeutic level. FVIII expression in treated dogs was short-term, lasting 1 to 2 weeks, due to the development of a human FVIII-specific inhibitor antibody response. These data provide the first demonstration of in vivo gene therapy of hemophilia A.

Adenoviridae↗
PubMed1996

Sustained expression of therapeutic levels of human factor VIII in mice.

Deficiency of coagulation factor VIII (FVIII) results in hemophilia A, a common hereditary bleeding disorder. Using a human FVIII-encoding adenoviral vector, Av1ALAPH81, we have demonstrated expression of therapeutic levels of human FVIII in mice sustained for more than 5 months after vector administration. Administration of a high dose (4 x 10(9) plaque-forming units [pfu]) of Av1ALAPH81 to mice resulted in a peak expression of 2,063 ng/mL of human FVIII in the mouse plasma, with levels decreasing to background by weeks 15 to 17. Normal FVIII levels in humans range from 100 to 200 ng/mL and therapeutic levels are as low as 10 ng/mL. Alternatively, administration of 8- to 80-fold lower vector doses (5 x 10(8) pfu to 5 x 10(7) pfu) to normal adult mice resulted in expression of FVIII at therapeutic levels sustained for at least 22 weeks. Detailed analysis of vector toxicity indicated that the high vector dose caused a dramatic elevation of liver-specific enzyme levels, whereas an eight-fold lower vector dose was significantly less hepatotoxic. The data presented here demonstrate that administration of lower, less toxic vector doses allow long-term persistence of FVIII expression.

Adenoviruses, Human↗
PubMed1996

High-level tissue-specific expression of functional human factor VIII in mice.

Hemophilia A results from subnormal levels of blood coagulation factor VIII (FVIII) and is an attractive target for gene therapy. However, progress has been impeded by features of FVIII biology such as low mRNA accumulation and the instability of the protein. We have shown previously that a FVIII adenoviral vector, Av1ALH81, allowed high-level expression of human FVIII in mice sustained for several weeks. Here, we have generated a second FVIII adenoviral vector, Av1ALAPH81, in which an intron was introduced into the FVIII expression cassette. Administration of Av1ALAPH81 to mice resulted in significantly increased FVIII plasma levels, 1,046 +/- 163 ng/ml compared to 307 +/- 93 ng/ml of FVIII detected in mice that received Av1ALH81. Normal FVIII levels in humans are 100-200 ng/ml and therapeutic levels are as low as 10 ng/ml. Therapeutic levels are defined as the amount of FVIII necessary to convert severe hemophilia to a moderate or mild hemophiliac condition. The increased potency of the second FVIII adenoviral vector allowed the administration of significantly lower, less toxic vector doses, while retaining the potential for high FVIII expression. Furthermore, we demonstrate that adenoviral-mediated expression of human FVIII can be limited to the liver by inclusion of a liver-specific promoter, thereby achieving the first step in regulated expression of human FVIII in vivo.

Adenoviruses, Human↗
PubMed1996

Prenatal cocaine exposure effects on arousal-modulated attention during the neonatal period.

The organization of arousal and attention as a function of intrauterine cocaine exposure was investigated in 180 normal nursery infants prior to hospital discharge and at 1 month of age. This was done by studying visual looking preferences when infants were in three arousal conditions: less aroused (after feeding); more aroused-endogenous (before feeding); and more aroused-exogenous (after feeding but including 8-Hz visual stimulation prior to each visual preference trial). The stimuli were light panels illuminated at three temporal frequencies between 1 and 8 Hz presented in pairs using a balanced presentation series of trials. Infants not exposed to cocaine demonstrated strong arousal-modulated attention, preferring faster frequencies when less aroused and slower frequencies when more aroused in both endogenous and exogenous conditions. In contrast, cocaine-exposed infants showed a lack of arousal-modulated attention and preferred faster frequencies of stimulation regardless of arousal condition. Similar differences in arousal-modulated attention as a function of cocaine exposure were obtained at 1 month after birth, indicating that these effects lasted longer than would be reasonable to attribute to the active presence of cocaine or its metabolites. This form of stimulus-seeking behavior was shown to be independent of confounding factors associated with prenatal cocaine exposure such as the absence of prenatal care, alcohol use, minority status, or gender, as well as mediating factors associated with growth such as birthweight. A direct and more chronic effect of intrauterine cocaine exposure on arousal-modulated attention and presumably on the developing CNS therefore was supported.

Arousal↗
PubMed1996

Trichuris trichiura infection and cognitive function in Jamaican school children.

Trichuris trichiura is extremely prevalent worldwide and there is concern that this geohelminth may affect the cognitive function of children in developing countries. A random-controlled, double-blind, treatment trial was conducted in Jamaican children with light to moderate infections. This was part of a research programme involving several studies in Jamaica. Ninety-seven subjects, each with a minimum of 1200 T. trichiura eggs/g faeces, were randomly assigned to placebo (N = 48) or treatment (N = 49) groups. Each pair of infected children was matched with an uninfected classmate (N = 48). All children were given seven cognitive function tests: French-learning; digit spans (forwards and backwards), Corsi block span; fluency; picture search; and silly sentences. Albendazole was given to the treatment group and the other groups received a placebo. Three months later, these treatments were repeated, and the cognitive function battery was given again. On pre-test, the infected groups performed significantly poorer only in the silly-sentence test (analysis of variance F-value = 8.17; two degrees of freedom; P < 0.001). There was no significant improvement with treatment in any of the tests. Taking into account these findings and those of the other Jamaican studies, it is therefore probable that light to moderate Trichuris infections have little effect on cognitive functioning in school children who have adequate nutritional status.

Albendazole↗
PubMed1996

Arousal-modulated attention at four months as a function of intrauterine cocaine exposure and central nervous system injury.

CNS-compromised neonates are poor modulators tending to prefer less stimulation in all arousal conditions. Cocaine-exposed neonates also are poor modulators but tend to prefer more stimulation in all arousal conditions. Infants (N = 359, M = 4 months) were divided into 6 CNS injury groups and 1 cocaine-exposed, non-CNS-injured group and tested in three arousal conditions: less aroused (after feeding), more around-endogenous (before feeding), and more aroused-exogenous (after feeding with additional stimulation prior to each trial). Infants with CNS injuries still showed some degree of influence of arousal on attention that was now similar to that seen in normal neonates and 1-month-olds, while cocaine-exposed infants, 4-month-old normal and mild or moderate CNS-injury infants did not.

Arousal↗
PubMed1996

Slower economic growth affects the 1995 labor market.

As the pace of economic activity moderated in 1995, job growth slowed. Nonetheless, it was enough to absorb the small increase in the supply of labor, with the result that the unemployment rate remained at about the same level it had reached at the end of 1994. In the first quarter of 1995, employment grew at a brisk pace but, as the economy began to slow, job gains fell sharply. Employment growth continued at a much more moderate pace for the balance of the year, so that, by the fourth quarter, nearly 1.9 million jobs had been added to the Nation's payrolls. By comparison, in the fourth quarter of 1994 alone, payroll employment had grown by 1.1 million. Most of the job gains in 1995 were in the services industry group. Manufacturing employment, which had been rising since the fall of 1993, began to decline in the spring, and by the end of 1995, that industry group had lost nearly a quarter of a million jobs. Employment increased in most of the other major industry groups, even though declines in some of their component industries partly offset gains in others.

Adolescent↗
PubMed1996

Transient immunosuppression permits successful repetitive intravenous administration of an adenovirus vector.

The in vivo administration of adenovirus vectors frequently elicits a neutralizing antibody response which eliminates or substantially reduces the efficacy of subsequent treatments. Methods to overcome this significant barrier to repeat delivery will be required for the application of adenovirus-based gene therapy in the treatment of chronic disease. We have evaluated the relationship between the initial vector dose and the effectiveness of a second vector administration. C57BL/6 mice injected intravenously with up to 10(7) p.f.u. of a lacZ adenovirus vector, Av1lacZ4, expressed significant levels of human factor IX when injected with 2 x 10(8) p.f.u. of the factor IX vector, Av1H9F, 5 weeks later. An initial dose of 10(8) p.f.u. of Av1lacZ4 completely prevented expression of factor IX following the second administration due to the generation of neutralizing antibody. However, transient immunosuppression with deoxyspergualin (DSG) or cyclophosphamide at the time of initial exposure to 10(8) p.f.u. of Av1lacZ4 prevented the formation of anti-adenovirus neutralizing antibody and permitted an effective second administration of a factor IX vector. Furthermore, transient immunosuppression with cyclophosphamide concomitant with delivery of the factor IX vector enabled an effective administration of a third vector encoding human factor VIII. This approach, together with strategies to prolong the persistence of adenoviral vector expression, should permit long-term therapy with adenovirus-based vectors.

Adenoviruses, Human↗
PubMed1995

In vivo gene delivery and expression of physiological levels of functional human factor VIII in mice.

Hemophilia A is caused by blood coagulation factor VIII (FVIII) deficiency and is an attractive target for gene therapy. However, features of FVIII physiology, such as the instability of the mRNA and protein, have provided obstacles to the design of a feasible strategy for the transfer and expression of the human FVIII gene in vivo. We have constructed a recombinant adenoviral vector, Av1ALH81, that contains the human FVIII cDNA from which the B-domain has been deleted (BDD FVIII) and extensively characterized this vector in vitro and in vivo. In vitro, HepG2, human hepatoma cells, transduced with Av1ALH81 secreted high levels of biologically active human BDD FVIII measured by the Coatest bioassay (> 2,400 mU per 10(6) cells per 24 hr). Administration of Av1ALH81 to mice, via tail vein, resulted in expression of human BDD FVIII in the mouse plasma at levels averaging 307 +/- 93 ng/ml 1 week post-injection, measured by a sensitive human FVIII-specific ELISA. Normal FVIII levels in humans are 100-200 ng/ml, and therapeutic levels are as low as 10 ng/ml. Purification of the human FVIII from the mouse plasma, and subsequent Coatest analysis, revealed that the human FVIII produced in the mice was biologically active. In addition, the duration of FVIII expression in vivo was followed, and high-level FVIII expression was sustained over a period of several weeks. The finding that an adenoviral vector can mediate high-level expression of human FVIII in an animal model provides the basis for the development of gene therapy for hemophilia A.

Adenoviridae↗
PubMed1994

Identification of a melanosomal membrane protein encoded by the pink-eyed dilution (type II oculocutaneous albinism) gene.

The pink-eyed dilution (p) locus in the mouse is critical to melanogenesis; mutations in the homologous locus in humans, P, are a cause of type II oculocutaneous albinism. Although a cDNA encoded by the p gene has recently been identified, nothing is known about the protein product of this gene. To characterize the protein encoded by the p gene, we performed immunoblot analysis of extracts of melanocytes cultured from wild-type mice with an antiserum from rabbits immunized with a peptide corresponding to amino acids 285-298 of the predicted protein product of the murine p gene. This antiserum recognized a 110-kDa protein. The protein was absent from extracts of melanocytes cultured from mice with two mutations (pcp and p) in which transcripts of the p gene are absent or greatly reduced. Introduction of the cDNA for the p gene into pcp melanocytes by electroporation resulted in expression of the 3.3-kb mRNA and the 110-kDa protein. Upon subcellular fractionation of cultured melanocytes, the 110-kDa protein was found to be present in melanosomes but absent from the vesicular fraction; phase separation performed with the nonionic detergent Triton X-114 confirmed the predicted hydrophobic nature of the protein. These results demonstrate that the p gene encodes a 110-kDa integral melanosomal membrane protein and establish a framework by which mutations at this locus, which diminish pigmentation, can be analyzed at the cellular and biochemical levels.

Albinism, Oculocutaneous↗
PubMed1994

African origin of an intragenic deletion of the human P gene in tyrosinase positive oculocutaneous albinism.

Oculocutaneous albinism (OCA) is a genetically heterogeneous hypopigmentation disorder. One of the two major autosomal recessive forms involves the tyrosinase gene (OCA1), while the other form (OCA2) has recently been associated with alterations of the P gene on chromosome 15. OCA2 is about twice as common as OCA1 in African and African-American populations. We now describe an interstitial deletion that removes a single exon of the P gene. In a large family from an inbred population of tri-racial origin, all individuals with OCA2 were found to be homozygous for this allele. Moreover, the same mutant P allele was detected in several unrelated African American individuals with OCA2, but not in Caucasians with OCA2. The detection of the same allele in two unrelated Africans with OCA2 indicates an African origin for this allele.

Africa↗
PubMed1994

Weaning-food viscosity and energy density: their effects on ad libitum consumption and energy intakes in Jamaican children.

The effects of weaning-food viscosity and energy density on consumption and energy intake were determined in 15 non-breast-fed Jamaican children aged 7-15 mo under standardized conditions. We tested whether feeding thick, energy-dense porridge four times daily resulted in increased energy intakes and whether amylase treatment to reduce viscosity offered any advantage. When a traditional liquid, low-density porridge (2.15 kJ/g) was fed, the mean (+/- SD) daily consumption was 139 +/- 25 g/kg and the mean daily energy intake was 296 +/- 54 kJ/kg. When a semisolid high-density porridge (4.09 kJ/g) was fed, consumption was significantly lower (98 +/- 21 g/kg) but the daily energy intake was significantly higher--402 +/- 85 kJ/kg (P < 0.001). Amylase treatment of the thick energy-dense porridge did not increase intakes further. Meal duration for the thick porridge (12.9 +/- 4.0 min) was significantly longer than that for the low-density (7.4 +/- 2.6 min) or amylase-treated (6.4 +/- 1.8 min) porridges.

Amylases↗
PubMed1994

The mouse pink-eyed dilution gene: association with hypopigmentation in Prader-Willi and Angelman syndromes and with human OCA2.

Mutations at the mouse pink-eyed dilution locus, p, cause hypopigmentation. We have cloned the mouse p gene cDNA and the cDNA of its human counterpart, P. The region of mouse chromosome 7 containing the p locus is syntenic with human chromosome 15q11-q13, a region associated with Prader-Willi syndrome (PWS) and Angelman syndrome (AS), both of which involve profound imprinting effects. PWS patients lack sequences of paternal origin from 15q, whereas AS patients lack a maternal copy of an essential region from 15q. However, the critical regions for these syndromes are much smaller than the chromosomal region commonly deleted that often includes the P gene. Hypopigmentation in PWS and AS patients is correlated with deletions of one copy of the human P gene that is highly homologous with its mouse counterpart. A subset of PWS and AS patients also have OCA2. These patients lack one copy of the P gene in the context of a PWS or AS deletion, with a mutation in the remaining chromosomal homologue of the P gene. Mutations in both homologues of the P gene of OCA2 patients who do not have PWS or AS have also been detected.

Albinism, Oculocutaneous↗