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J A Morris

Publications and source records attributed to J A Morris.

At least 55 records · Page 3Linked to original sources
PubMed1999

The genomic organization and polymorphism analysis of the human Niemann-Pick C1 gene.

Niemann-Pick C (NP-C) is a fatal autosomal recessive storage disorder characterized by progressive neurodegeneration and variable hepatosplenomegaly. At the cellular level, cells derived from an affected individual accumulate unesterified cholesterol in lysosomes when cultured with low-density lipoprotein. The NP-C gene was identified at 18q11. The transcript is 4.9 kb encoding a 1278-amino-acid protein. We have defined the genomic structure of NPC1 along with the 5' flanking sequence. The NPC1 gene spans greater than 47 kb and contains 25 exons. Exons range in size from 74 to 788 bp with introns ranging in size from 0.097 to 7 kb. All intron/exon boundaries follow the GT/AG rule. The 5' flanking sequence has a CpG island containing multiple Sp1 sites indicative of a promoter region. The CpG island is located in the 5' flanking sequence, exon 1 and the 5' end of intron 1. We have also identified multiple single nucleotide polymorphisms in the coding and intronic sequences.

Base Sequence↗
PubMed1999

The common bacterial toxins hypothesis of sudden infant death syndrome.

The background to the common bacterial toxin hypothesis of sudden infant death syndrome is presented. The idea is that some cases of sudden infant death syndrome are due to the lethal effects of nasopharyngeal bacterial toxins which can act synergistically to trigger the events leading to death. The concept is consistent with the age distribution of sudden infant death syndrome, the winter excess of cases and the role of prone sleeping and passive exposure to cigarette smoke. A number of laboratory-based investigations are described. There is an increased isolation of staphylococci and Gram-negative bacilli from sudden infant death syndrome infants compared with age- and season-matched healthy infants. Bacteria from sudden infant death syndrome infants interact synergistically to cause sudden death in gnotobiotic weanling rats. Bacterial toxins implicated in sudden infant death syndrome interact synergistically to cause death in chick embryos. Nicotine in very low doses potentiates the lethal effect of toxin combinations in chick embryos. Staphylococcal toxins and endotoxins have been demonstrated in sudden infant death syndrome tissues, antibodies to endotoxins are low in sudden infant death syndrome cases and the prone sleeping position leads to pooling of secretions in the upper airways, increasing the risk of bacterial growth and toxin production. If the hypothesis is correct, then there is the possibility of a further reduction in the incidence of sudden infant death syndrome based on immunisation against the toxins involved.

Animals↗
PubMed1999

The nasopharyngeal bacterial flora in infancy: effects of age, gender, season, viral upper respiratory tract infection and sleeping position.

The aim of the investigation was to determine the effect of age, gender, viral upper respiratory tract infection (URTI), season and sleeping position on the composition of the nasopharyngeal bacterial flora in infancy. Seventy-two babies, 38 male and 34 female, whose birthdates were evenly spread throughout the year were followed from birth to 18 months of age. From 0 to 6 months nasopharyngeal swabs were obtained once a month in periods without URTI and daily for 3 days during episodes of URTI. From 12 to 18 months of age nasopharyngeal swabs were obtained in the early morning alter an overnight sleep and later in the day after the baby had been up for over 2 h. Swabs were obtained in prone and supine sleepers with and without infection. In infants aged 0-6 months URTI had little effect on the nasopharyngeal bacterial flora, but there was a marked effect of age and less marked effect of season and gender. In particular Staphylococcus aureus carriage decreased with age, was most common in the winter months and the density of colonisation was greater in males than females. In infants aged 12-18 months the combination of prone sleeping with URTI and an early morning swab led to increased carriage of staphylococci, streptococci. Haemophilus influenzae and Gram-negative bacilli which are not normally part of the nasopharyngeal flora. These results are relevant to sudden infant death syndrome (SIDS). The combination of prone sleeping and URTI reproduces the nasopharyngeal flora seen in SIDS. Gram-negative bacilli isolated from SIDS cases should not be dismissed as post-mortem contaminants. The features of S. aureus make it a prime candidate for a pathogenic role in SIDS.

Aging↗
PubMed1999

Sleeping position in infants over 6 months of age: implications for theories of sudden infant death syndrome.

The aim of this study was to determine the prevalence of prone and supine sleeping in infants aged 0-12 months and relate this to changes in the number of cases of sudden infant death syndrome (SIDS) since 1985. Seventy-two babies, 38 male and 34 female, were followed for the first 18 months of life with regular home visits and sleeping position was recorded. In addition, data on the number of cases of SIDS in England and Wales between 1985 and 1995 were analysed. All babies slept supine for the first 5 months of life, but once they could turn over in their cots (mean age 7.34 months, range 5-11 months) the majority slept prone. By 11 months of age, 53 regularly slept prone (73%), 95% CI +/- 19.8%), while 11 slept supine, three adopted the side position and five varied from night to night. The number of cases of SIDS in infants aged 7-11 months has fallen significantly (P<0.0001) in a period in which the prevalence of prone sleeping, in that age group, has not changed. The most plausible explanation for this paradoxical result is that supine sleeping in the first 5 months of life reduces the absolute risk of SIDS in the second 6 months of life even though most babies are then sleeping prone. It is suggested that reduced exposure to nasopharyngeal bacterial superantigens in babies sleeping prone might explain this effect.

Adult↗
PubMed1999

Effect of time post mortem on the concentration of endotoxin in rat organs: implications for sudden infant death syndrome (SIDS).

The aim of the study was to test the following hypotheses: (i) that endotoxin injected 40 min prior to death can be detected in rat organs post mortem and (ii) that endotoxin levels do not change with increasing time post mortem. Rats were injected with or without endotoxin in buffered saline, 40 min prior to being killed. Endotoxin levels in rat organs were assessed using a Limulus amoebocyte assay. The effect of storage time post mortem was assessed by following various storage regimes at 25 degrees C and 8 degrees C. Significant differences (P = < 0.001) in endotoxin levels of all samples tested were found between rats injected with and without endotoxin. A significant increase in detectable endotoxin was observed between 0 h and 6 h post mortem in rats injected with or without endotoxin. No difference in detectable endotoxin levels in the kidney, liver and spleen was observed from 30 h to 102 h post mortem in rats injected with or without endotoxin. In rats injected with endotoxin, detectable endotoxin levels in the heart were raised between 0 h and 6 h, 6 h and 54 h, and 30 h and 78 h. Endotoxin injected into rats 40 min prior to death can be detected post mortem. For rats injected with saline or endotoxin prior to death levels in the kidney, liver and spleen were not affected by storage at 8 degrees C for 30-102 h, after initial storage at room temperature for 6 h. Levels of endotoxin detected in the hearts of rats injected with saline were not affected by storage up to 102 h. In rats injected with endotoxin prior to death, detectable levels in the heart were significantly affected by increasing time in storage.

Animals↗
PubMed1999

Endotoxin in blood and tissue in the sudden infant death syndrome.

Although the explanation for sudden infant death syndrome (SIDS) remains unknown, an increasing body of evidence now exists to suggest a possible role for bacterial toxins in the aetiology, and a number of investigators have considered that endotoxaemia could explain some of the associated features. Following the development of an animal model which confirmed that endotoxaemia could be detected after death, we studied endotoxin levels in blood and tissue samples taken at autopsy from SIDS infants, child controls and adult controls. There were significant correlations between endotoxin levels in blood and the various organs sampled particularly in SIDS cases and child controls, and blood endotoxin levels in SIDS cases were higher in those infants where there was histological evidence of mild to moderate inflammation. However, overall no significant differences were found between endotoxin levels in blood or tissue in the three study groups. Further studies into possible actions or interactions of endotoxin in SIDS are required.

Adult↗
PubMed1999

The kinetics of epithelial cell generation: its relevance to cancer and ageing.

A hierarchical model of epithelial cell generation is proposed, in which even in extreme old age mature epithelial cells in humans are only a limited number of cell divisions from the zygote (60-120). This contrasts with conventional models in which regularly cycling stem cells can be several thousands of cell divisions from the zygote. The hierarchical model is supported by data on the rate of telomere shortening both in vivo and in vitro, and by data on the rate of synonymous substitutions in Y-linked, X-linked and autosomal genes in rodents. Limiting the number of cell generations leads to a vast reduction in the risk of cancer and reduces the rate of ageing. It is suggested that longer-lived animals need stricter control of the hierarchy than do shorter-lived animals and this difference has implications for theories of ageing.

Aging↗
PubMed1999

The Niemann-Pick C1 protein resides in a vesicular compartment linked to retrograde transport of multiple lysosomal cargo.

Niemann-Pick C disease (NP-C) is a neurovisceral lysosomal storage disorder. A variety of studies have highlighted defective sterol trafficking from lysosomes in NP-C cells. However, the heterogeneous nature of additional accumulating metabolites suggests that the cellular lesion may involve a more generalized block in retrograde lysosomal trafficking. Immunocytochemical studies in fibroblasts reveal that the NPC1 gene product resides in a novel set of lysosome-associated membrane protein-2 (LAMP2)(+)/mannose 6-phosphate receptor(-) vesicles that can be distinguished from cholesterol-enriched LAMP2(+) lysosomes. Drugs that block sterol transport out of lysosomes also redistribute NPC1 to cholesterol-laden lysosomes. Sterol relocation from lysosomes in cultured human fibroblasts can be blocked at 21 degrees C, consistent with vesicle-mediated transfer. These findings suggest that NPC1(+) vesicles may transiently interact with lysosomes to facilitate sterol relocation. Independent of defective sterol trafficking, NP-C fibroblasts are also deficient in vesicle-mediated clearance of endocytosed [14C]sucrose. Compartmental modeling of the observed [14C]sucrose clearance data targets the trafficking defect caused by mutations in NPC1 to an endocytic compartment proximal to lysosomes. Low density lipoprotein uptake by normal cells retards retrograde transport of [14C]sucrose through this same kinetic compartment, further suggesting that it may contain the sterol-sensing NPC1 protein. We conclude that a distinctive organelle containing NPC1 mediates retrograde lysosomal transport of endocytosed cargo that is not restricted to sterol.

Amino Acid Sequence↗
PubMed1999

Family psychiatric history, cerebrospinal fluid monoamine metabolites, and temperament in infants.

BACKGROUND: Variations in cerebrospinal fluid (CSF) levels of the monoamine metabolites 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxyphenylglycol, and homovanillic acid have been associated with behavioral abnormalities in nonhuman primates, and with psychopathology in studies of children and adults. METHODS: We assayed monoamine metabolites in "left-over" spinal fluid from 167 neurologically normal newborn infants (0-3 months of age), and later (at age 18-21 months of age) obtained their family psychiatric histories and assessed their temperament using the Colorado Childhood Temperament Inventory (CCTI). RESULTS: Family history of antisocial personality disorder predicted significantly lower scores for soothability (p = .003) at 18-21 months. There were no statistically significant associations between newborn monoamine metabolite levels and any aspect of temperament on the CCTI. CONCLUSIONS: These findings suggest complex relationships between genetic liability for psychiatric disorders and CSF monoamine metabolite levels; those relationships do not seem to be mediated by infant temperament. It appears likely that interindividual differences in monoamine metabolite levels change over the course of development in humans.

Antisocial Personality Disorder↗
PubMed1999

Effects of nitroglycerin and indomethacin on fetal-maternal circulation and on fetal cerebral blood flow and metabolism in sheep.

OBJECTIVE: Our purpose was to evaluate the effects of maternal administration of nitroglycerin and indomethacin on maternal and fetal hemodynamics and on fetal cerebral blood flow and metabolism in sheep. STUDY DESIGN: Invasive vascular and fetal carotid flow monitoring was established in 12 gravid ewes. Isotonic sodium chloride solution, nitroglycerin, and indomethacin were infused maternally, and maternal and fetal heart rate, blood pressure, blood gas values, fetal carotid blood flow, and flow variability were measured. Fetal cerebral uptake of oxygen, glucose, and lactate were calculated. RESULTS: Nitroglycerin infusion caused a significant increase in maternal and fetal heart rate and a significant decrease in maternal and fetal mean arterial pressure at a dosage of 10 microram/kg per minute, without a change in blood gas values. Neither drug had any effect on fetal carotid blood flow, flow variability, or cerebral substrate metabolism. CONCLUSION: Maternal administration of nitroglycerin and indomethacin caused no adverse maternal or fetal circulatory changes and did not alter fetal carotid blood flow or substrate metabolism.

Animals↗
PubMed1999

Information and redundancy: key concepts in understanding the genetic control of health and intelligence.

A model is proposed in which information from the environment is analysed by complex biological decision-making systems which are highly redundant. A correct response is intelligent behaviour which preserves health; incorrect responses lead to disease. Mutations in genes which code for the redundant systems will accumulate in the genome and impair decision-making. The number of mutant genes will depend upon a balance between the new mutation rate per generation and systems of elimination based on synergistic interaction in redundant systems. This leads to a polygenic pattern of inheritance for intelligence and the common diseases. The model also gives a simple explanation for some of the hitherto puzzling aspects of work on the genetic basis of intelligence including the recorded rise in IQ this century. There is a prediction that health, intelligence and socio-economic position will be correlated generating a health differential in the social hierarchy. Furthermore, highly competitive societies will place those least able to cope in the harshest environment and this will impair health overall. The model points to a need for population monitoring of somatic mutation in order to preserve the health and intelligence of future generations.

Genetic Predisposition to Disease↗
PubMed1999

Niemann-Pick C1 disease: the I1061T substitution is a frequent mutant allele in patients of Western European descent and correlates with a classic juvenile phenotype.

Niemann-Pick type C (NPC) disease is an autosomal recessive lipid-storage disorder usually characterized by hepatosplenomegaly and severe progressive neurological dysfunction, resulting from mutations affecting either the NPC1 gene (in 95% of the patients) or the yet-to-be-identified NPC2 gene. Our initial study of 25 patients with NPC1 identified a T3182-->C transition that leads to an I1061T substitution in three patients. The mutation, located in exon 21, affects a putative transmembrane domain of the protein. PCR-based tests with genomic DNA were used to survey 115 unrelated patients from around the world with all known clinical and biochemical phenotypes of the disease. The I1061T allele constituted 33 (14.3%) of the 230 disease-causing alleles and was never found in controls (>200 alleles). The mutation was particularly frequent in patients with NPC from Western Europe, especially France (11/62 alleles) and the United Kingdom (9/32 alleles), and in Hispanic patients whose roots were in the Upper Rio Grande valley of the United States. The I1061T mutation originated in Europe and the high frequency in northern Rio Grande Hispanics results from a founder effect. All seven unrelated patients who were homozygous for the mutation and their seven affected siblings had a juvenile-onset neurological disease and severe alterations of intracellular LDL-cholesterol processing. The mutation was not found (0/40 alleles) in patients with the severe infantile neurological form of the disease. Testing for this mutation therefore has important implications for genetic counseling of families affected by NPC.

Adolescent↗
PubMed1999

Injury experience of temporary workers in a manufacturing setting. Factors that increase vulnerability.

An apparent two to three times higher injury frequency rate for temporary employees compared to permanent workers was identified in one manufacturing setting. Data were collected using demographic surveys (N = 20) and three focus group interviews (n = 13), with a convenience sample of temporary employees as well as four structured interviews with temporary agency owners and managers to explore factors which increase the vulnerability of temporary employees to workplace injuries. Several physical and psychological stressors were identified as well as a perception by the temporary employees that the reporting of work injuries could lead to loss of a temporary work assignment or the opportunity for permanent employment. In contrast, the agency owners and managers were concerned that reported injuries were not always legitimate. All of them actively used strategies to control their injury experience but faced the challenge of lacking day to day control of both the work environment and employee work behaviors. This preliminary study cannot be generalized to manufacturing worksites. Additional research is needed to document the injury experience of temporary employees, identify training needs, and design interventions.

Accidents, Occupational↗
PubMed1998

Binding of factor VIII to von willebrand factor is enabled by cleavage of the von Willebrand factor propeptide and enhanced by formation of disulfide-linked multimers.

von Willebrand factor (vWF) is a multimeric adhesive glycoprotein with one factor VIII binding site/subunit. Prior reports suggest that posttranslational modifications of vWF, including formation of N-terminal intersubunit disulfide bonds and subsequent cleavage of the propeptide, influence availability and/or affinity of factor VIII binding sites. We found that deletion of the vWF propeptide produced a dimeric vWF molecule lacking N-terminal intersubunit disulfide bonds. This molecule bound fluorescein-labeled factor VIII with sixfold lower affinity than multimeric vWF in an equilibrium flow cytometry assay (approximate KDs, 5 nmol/L v 0.9 nmol/L). Coexpression of propeptide-deleted vWF with the vWF propeptide in trans yielded multimeric vWF that displayed increased affinity for factor VIII. Insertion of an alanine residue at the N-terminus of the mature vWF subunit destroyed binding to factor VIII, indicating that the native mature N-terminus is required for factor VIII binding. The requirement for vWF propeptide cleavage was shown by (1) a point mutation of the vWF propeptide cleavage site yielding pro-vWF that was defective in factor VIII binding and (2) correlation between efficiency of intracellular propeptide cleavage and factor VIII binding. Furthermore, in a cell-free system, addition of the propeptide-cleaving enzyme PACE/furin enabled factor VIII binding in parallel with propeptide cleavage. Our results indicate that high-affinity factor VIII binding sites are located on N-terminal disulfide-linked vWF subunits from which the propeptide has been cleaved.

Binding Sites↗
PubMed1998

Differential interaction of coagulation factor VIII and factor V with protein chaperones calnexin and calreticulin.

Factor VIII (FVIII) and factor V (FV) are homologous coagulation cofactors sharing a similar domain organization (A1-A2-B-A3-C1-C2) and are both extensively glycosylated within their B-domains. In mammalian cell expression systems, compared with FV, the FVIII primary translation product is inefficiently transported out of the endoplasmic reticulum. Here we show that FVIII is degraded within the cell by a lactacystin-inhibitable pathway, implicating the cytosolic 20 S proteasome machinery. Protein chaperones calnexin (CNX) and calreticulin (CRT) preferentially interact with glycoproteins containing monoglucosylated N-linked oligosaccharides and are proposed to traffic proteins through degradative and/or secretory pathways. Utilizing co-immunoprecipitation assays, intracellular FVIII was detected in association with CNX maximally within 30 min to 1 h following synthesis, whereas FV could not be detected in association with CNX. In contrast, both FVIII and FV displayed interaction with CRT during transit through the secretory pathway. B-domain deleted FVIII significantly reduced the CNX and CRT interaction, indicating the B-domain may represent a primary CNX and CRT interaction site. In the presence of inhibitors of glucose trimming, the interactions of FVIII with CNX, and of FVIII and FV with CRT, were significantly reduced whereas the secretion of FVIII, and not FV, was inhibited. In addition, transfection in a glucosidase I-deficient Chinese hamster ovary cell line (Lec23) demonstrated that both degradation and secretion of FVIII were inhibited, with little effect on the secretion of FV. These results support that CNX and CRT binding, mediated at least in part by the B-domain of FVIII, is required for efficient FVIII degradation and secretion. In contrast, FV does not require CNX interaction for efficient secretion. The results suggest a unique requirement for carbohydrate processing and molecular chaperone interactions that may limit the productive secretion of FVIII.

Animals↗