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Biomedical subjects

L Hartley

Publications and source records attributed to L Hartley.

At least 19 recordsLinked to original sources
PubMed2005

Minicore myopathy with ophthalmoplegia caused by mutations in the ryanodine receptor type 1 gene.

BACKGROUND: Minicore myopathy (multi-minicore disease [MmD]) is a congenital myopathy characterized by multifocal areas with loss of oxidative activity on muscle biopsy. MmD is clinically heterogeneous and distinct phenotypes have been associated with recessive mutations in either the selenoprotein N (SEPN1) or the skeletal muscle ryanodine receptor (RYR1) gene, also implicated in central core disease and malignant hyperthermia. External ophthalmoplegia is an additional finding in a subset of patients with MmD. OBJECTIVE: To clinically and genetically examine families with MmD and external ophthalmoplegia. METHODS: The authors investigated 11 affected individuals from 5 unrelated families. Clinical, histopathologic, and imaging studies were performed and RYR1 haplotyping and mutational analysis were carried out. RESULTS: All patients had multiple cores involving the entire fiber diameter on longitudinal sections. Weakness and wasting in the shoulder girdle, scoliosis, moderate respiratory impairment, and feeding difficulties were prominent. In contrast to SEPN1-related myopathies, soleus was more severely affected than gastrocnemius on muscle MRI. Haplotyping suggested linkage to the RYR1 locus in informative families and mutational screening revealed four novel RYR1 mutations in three unrelated families; in addition, functional haploinsufficiency was found in one allele of two recessive cases. CONCLUSION: These findings expand the phenotypic spectrum associated with mutations in the skeletal muscle ryanodine receptor (RYR1) gene. Recessive mutations of domains commonly affected in malignant hyperthermia appear to be particularly prevalent in multi-minicore disease with external ophthalmoplegia and might suggest a different pathomechanism from that involved in central core disease.

Adolescent↗
PubMed2004

A case of severe congenital chronic inflammatory demyelinating polyneuropathy with complete spontaneous remission.

Chronic inflammatory demyelinating polyneuropathy (CIPD) is characterised by progressive weakness, hyporeflexia and electrophysiological evidence of demyelination with maximal neurological deficit reached after at least 8 weeks progression. CIPD rarely affects children. We present a neonate with clinical features compatible with congenital CIPD. A term male infant of non-consanguineous parents was referred to us at birth with weakness and contractures affecting his legs, suggesting a prenatal onset of immobility. He also had evidence of bulbar dysfunction with poor suck, recurrent aspiration and requiring nasogastric feeding. He had no antigravity movements in the legs, bilateral wrist drop, distal joint contractures and absent deep tendon reflexes. Electromyography showed neurogenic changes, with nerve conduction velocities markedly reduced, increased distal motor latency and dispersed compound muscle action potentials. Cerebrospinal fluid protein was raised. Sural nerve biopsy demonstrated decreased numbers of myelinated fibres and inflammatory cell infiltrates. Muscle biopsy showed denervation. He only received supportive treatment and by 6 months he had fully recovered, and all electrophysiological parameters had normalised.

Disease Progression↗
PubMed2004

Pilot trial of salbutamol in central core and multi-minicore diseases.

Several studies have documented positive effects of beta-adrenergic agonists on human skeletal muscle with regard to muscle mass and strength. The aim of this pilot study was to evaluate the effect of the beta2-agonist salbutamol (albuterol) in a group of children with central core disease and multi-minicore disease. Thirteen patients, 8 with central core disease (mean age 17.5 years) and 5 with minicore disease (mean age 13.6 years) received oral salbutamol at a dose of 2 mg four times a day. Measures of efficacy were the change from baseline at 3 and 6 months in muscle strength, assessed by MRC score, myometry, functional measures and forced vital capacity. Statistical analysis was performed using repeated measures ANOVA (significance level < 0.05). Two patients with central core disease stopped the medication after one month because they did not notice any improvement and another one with minicore disease after 4 months because of increased tremors and palpitations. The remaining ten (6 with central core and 4 with minicore disease) completed the course of salbutamol without any significant adverse effects. There were significant increases in myometry, MRC scores and forced vital capacity between baseline and the six-month assessments. For both myometry and MRC the difference was already significant at 3 months and this was associated with a significant increase in functional abilities assessed with a structured functional scale. Our results suggest that salbutamol was overall well tolerated and might be beneficial in both central core and minicore patients. Larger prospective randomised, double-blind, placebo-controlled trials with salbutamol will be needed to confirm these preliminary findings.

Adolescent↗
PubMed2004

Short-chain acyl-CoA dehydrogenase deficiency associated with early onset severe axonal neuropathy.

Two unusual cases of axonal neuropathy associated with short-chain acyl-CoA dehydrogenase (SCAD) deficiency are described. These two unrelated infants presented with profound generalised weakness, particularly affecting the upper limbs. Clinical examination revealed generalised peripheral hypotonia and weakness, with absent deep tendon reflexes. An axonal polyneuropathy was confirmed on electromyogram (EMG) and nerve conduction studies (NCS) and, following an extensive metabolic screen, an acylcarnitine and organic acid profile consistent with a short-chain fatty acid beta-oxidation defect was found. In both cases, SCAD deficiency was confirmed by enzyme analysis. Genetic analysis showed the presence of common gene variations in the SCAD gene. SCAD deficiency is a rare disorder with a wide clinical phenotype. SCAD deficiency associated with axonal neuropathy has not previously been reported. As highlighted in these cases, it may be necessary to include axonal neuropathy as a presenting feature of SCAD.

Age of Onset↗
PubMed2004

Speed choice by drivers: the issue of driving too slowly.

Quite correctly, the majority of road safety speeding initiatives focus on drivers travelling at excessive speeds. This study, however, focused on the potential problem of driving too slowly. Six thousand, four hundred and eighty vehicles from around the Perth metropolitan area in Western Australia had their speeds recorded; observations were also made of these vehicles to identify characteristics of the driver and vehicle. In addition, a community survey with 240 members of the public was conducted to examine their attitudes towards slow drivers. As expected, results showed that older drivers drove more slowly than the other age brackets, women drove more slowly than men, and that heavily laden vehicles drove more slowly than other types of vehicles. Additionally, the slowest days were weekdays and the quickest were Saturdays. Community attitudes, generally mirrored the observational findings, and indicated that the public believed that slow driving was sometimes a safety problem causing some accidents. These data are discussed, and some possible countermeasures are briefly introduced to address the problem.

Accidents, Traffic↗
PubMed2003

Parathyroid hormone venous sampling prior to reoperation for primary hyperparathyroidism.

BACKGROUND: The surgical cure rate for primary hyperparathyroidismis greater than 95%. For those who have recurrent or persistent disease, preoperative localization improves reoperation success rates. Selective parathyroid venous sampling (SPVS) for intact parathyroid hormone is particularly useful when non-invasive localization techniques are negative or inconclusive. METHODS: We present all known cases (n = 13)between 1994 and 2002 who had venous sampling for localization a tour institution prior to reoperation for recurrent or persistent primary hyperparathyroidism. Comparison was made with non-invasive localization procedures. Results of invasive and non-invasive localization were correlated with surgical findings. RESULTS: Of the nine reoperated cases, eight had positive correlations between SPVS and operative findings and histopathology. SPVS did not reveal the parathyroid hormone source in one case with negative non-invasive localization procedures. Comparisons between SPVS,computerized tomography (CT), and parathyroid scintigraphy (MIBI)as expressed in terms of true positive (TP), false positive (FP)and false negative (FN) were: SPVS - TP88.8%, FP 0%, FN 11.1%; CT - TP22.2%, FP 22.2%, FN 55.5%; and MIBI - TP33.3%, FP 0%, FN 66.6%. At least seven of the nine operated cases have been cured; another remained normocalcaemic 2 weeks after subtotal parathyroidectomy. CONCLUSION: In our institution SPVS has proven to be a valuable tool in cases with recurrent or persistent primary hyperparathyroidism and negative non-invasive localization procedures.

Adult↗
PubMed2003

Occipito-temporal polymicrogyria and subclinical muscular dystrophy.

We report a two-year-old Caucasian boy who had neonatal seizures and was found to have bilateral occipito-temporal polymicrogyria on neonatal brain MRI. The child had no additional neurological abnormality other than the neonatal seizures, but serum CK was found to be elevated (5 - 7 times normal values) and the muscle biopsy showed evidence of early muscular dystrophy. Detailed protein and genetic studies did not allow the identification of a known form of muscular dystrophy. The boy has been followed regularly and he currently has mild global developmental delay but no clinical signs of muscle involvement. The association of polymicrogyria and muscular dystrophy is known to occur in Fukuyama and Walker Warburg muscular dystrophies, in muscle-eye-brain disease and in some patients with merosin deficient CMD. However the absence of weakness and of eye involvement, the normal expression of merosin and alpha dystroglycan and the pattern of brain involvement make it very unlikely that the child is affected by one of these forms. As the pattern of brain involvement and the muscle pathology is not typical of one of the forms of neuronal migration disorders secondary to a known gene defect, we suspect that the combination of muscle and brain involvement found in this child is not coincidental. Our findings suggest that serum CK should be determined in children with undiagnosed polymicrogyria, even in the absence of weakness. This may lead to an expansion of our understanding of muscle dystrophies and cortical dysplasias.

Child, Preschool↗
PubMed2001

Placental defects and embryonic lethality in mice lacking suppressor of cytokine signaling 3.

Mice lacking suppressor of cytokine signaling 3 (SOCS3) exhibited embryonic lethality with death occurring between days 11 and 13 of gestation. At this stage, SOCS3(-/-) embryos were slightly smaller than wild type but appeared otherwise normal, and histological analysis failed to detect any anatomical abnormalities responsible for the lethal phenotype. Rather, in all SOCS3(-/-) embryos examined, defects were evident in placental development that would account for their developmental arrest and death. The placental spongiotrophoblast layer was significantly reduced and accompanied by increased numbers of giant trophoblast cells. Delayed branching of the chorioallantois was evident, and, although embryonic blood vessels were present in the labyrinthine layer of SOCS3(-/-) placentas, the network of embryonic vessels and maternal sinuses was poorly developed. Yolk sac erythropoiesis was normal, and, although the SOCS3(-/-) fetal liver was small at day 12.5 of gestation (E12.5), normal frequencies of erythroblasts and hematopoietic progenitor cells, including blast forming unit-erythroid (BFU-E) and, colony forming unit-erythroid (CFU-E) were present at both E11.5 and E12.5. Colony formation for both BFU-E and CFU-E from SOCS3(-/-) mice displayed wild-type quantitative responsiveness to erythropoietin (EPO), in the presence or absence of IL-3 or stem cell factor (SCF). These data suggest that SOCS3 is required for placental development but dispensable for normal hematopoiesis in the mouse embryo.

Animals↗
PubMed2001

Development and reorganization of corticospinal projections in EphA4 deficient mice.

The Eph family of receptor tyrosine kinases and their ligands, the ephrins, are important regulators of axon guidance and cell migration in the developing nervous system. Inactivation of the EphA4 gene results in axon guidance defects of the corticospinal tract, a major descending motor pathway that originates in the cortex and terminates at all levels of the spinal cord. In this investigation, we report that although the initial development of the corticospinal projection is normal through the cortex, internal capsule, cerebral peduncle, and medulla in the brain of EphA4 deficient animals, corticospinal axons exhibit gross abnormalities when they enter the gray matter of the spinal cord. Notably, many corticospinal axons fail to remain confined to one side of the spinal cord during development and instead, aberrantly project across the midline, terminating ipsilateral to their cells of origin. Given the possible repulsive interactions between EphA4 and one of its ligands, ephrinB3, this defect could be consistent with a loss of responsiveness by corticospinal axons to ephrinB3 that is expressed at the spinal cord midline. Furthermore, we show that EphA4 deficient animals exhibit ventral displacement of the mature corticospinal termination pattern, suggesting that developing corticospinal axons, which may also express ephrinB3, fail to be repelled from areas of high EphA4 expression in the intermediate zone of the normal spinal cord. Taken together, these results suggest that the dual expression of EphA4 on corticospinal axons and also within the surrounding gray matter is very important for the correct development and termination of the corticospinal projection within the spinal cord.

Age Factors↗
PubMed2001

Cloning of rat interleukin 11 and interleukin 11 receptor alpha chain and analysis of their expression in rat uterus in the peri-implantation period.

Studies in mice have shown that interleukin 11 (IL-11) signalling is required for female fertility. In the absence of IL-11, decidualization is markedly retarded and implantation fails. IL-11 acts via a heterodimeric receptor composed of a ligand-specific receptor alpha chain (IL-11R alpha) and the signalling moiety gp130. This study reports the cloning of genes encoding rat IL-11 and IL-11R alpha. RNase protection was used to demonstrate that expression of IL-11 is upregulated in the rat uterus at the initiation of implantation at 5.5 days after mating. Expression of the genes encoding the two receptor components, IL11Ra and gp130, did not change throughout the peri-implantation period. In situ hybridization studies revealed that, as in mice, expression of IL-11 was high in the primary decidual zone at the time of the attachment reaction, whereas IL11Ra was expressed throughout primary and secondary decidua. Conservation of the temporal and spatial expression of IL-11 and IL-11R alpha in the uterus of the mouse and rat during the peri-implantation period will facilitate future studies investigating the role of IL-11 in fertility.

Amino Acid Sequence↗
PubMed2000

The development of fatal myocarditis and polymyositis in mice heterozygous for IFN-gamma and lacking the SOCS-1 gene.

Mice lacking the gene encoding the suppressor of cytokine signaling-1 (SOCS-1 -/-) and heterozygous for the IFN-gamma gene (IFN-gamma +/-) avoided the IFN-gamma-dependent preweaning death of SOCS-1 -/- IFN-gamma +/+ mice but did not exhibit the good health of young adult SOCS-1 -/- IFN-gamma -/- mice. SOCS-1 -/- IFN-gamma +/- mice died within 160 days of birth with massive T lymphocyte, macrophage, and eosinophil infiltration of all skeletal muscles and a similar severe myocarditis. The cornea also developed inflammatory infiltration and often a corneal ulcer. The mice exhibited evidence of selective CD8 T lymphocyte activation in populations in the thymus, spleen, and lymph nodes and focal T- and B-lymphoid infiltrates developed in the lung and salivary gland without apparent tissue damage. Comparison of SOCS-1 -/- IFN-gamma +/- mice with various control mice indicated that the development of tissue-damaging T lymphocyte, macrophage, and eosinophil infiltrates required loss of SOCS-1 and the presence of some IFN-gamma, but that the lung lymphoid infiltrates required only loss of SOCS-1 to develop.

Animals↗
PubMed2000

Targeted insertion of a lacZ reporter gene into the mouse Cer1 locus reveals complex and dynamic expression during embryogenesis.

The mouse Cer1 (mCer1, Cer-l, Cerr1) gene encodes one member of a family of cytokines structurally and functionally related to the Xenopus head-inducing factor, Cerberus (xCer). We generated a mouse line in which the Cer1 gene was inactivated by replacing the first coding exon with a lacZ reporter gene. Mice homozygous for this allele (Cer1(lacZ)) showed no apparent perturbation of embryogenesis or later development. However, the lacZ reporter revealed a number of hitherto uncharacterised sites of Cer1 expression in late fetal and adult tissues. Preliminary analysis suggests that Cer1 is not essential for their morphogenesis, differentiation, or homeostasis.

Animals↗
PubMed2000

Cloning, expression analysis, and chromosomal localization of murine and human homologues of a Xenopus mix gene.

We report the cloning and chromosomal localization of murine and human Mix genes, members of a subclass of paired-like homeobox genes of which the Xenopus laevis Mix.1 gene is the founding member. The murine Mix gene was mapped to the distal region of chromosome 1 and the human region to the syntenic region 1q41-42. Northern analysis and RT-PCR of murine adult and embryonic tissues demonstrated that Mix expression was restricted to the early embryo. Whole-mount in situ hybridization revealed patchy but symmetrical Mix expression in visceral endoderm of embryonic day (E)5.5 embryos. In slightly older embryos, the expression was skewed to one side of the embryo and by E6.5, at the onset of gastrulation, expression was seen in the epiblast, visceral endoderm, nascent mesoderm, and the primitive streak. This expression pattern was maintained in mid- and late-streak embryos. In early bud-stage embryos, expression was strongest in the proximal two thirds of the streak, extending to the base of the allantois. By the headfold-stage, expression was confined to the remnant of the primitive streak in the caudal region of the embryo and, after E8.0, in the caudal notochord and tail bud mesoderm. Mix transcripts were no longer detectable after embryonic day 9.5.

Amino Acid Sequence↗
PubMed2000

Identification of somatic mutations of the MEN1 gene in sporadic endocrine tumours.

Endocrine tumours of the pancreas, anterior pituitary or parathyroids arise either sporadically in the general population, or as a part of inherited syndromes such as multiple endocrine neoplasia type 1 (MEN 1). The mechanisms responsible for the development of sporadic endocrine lesions are not well understood, although loss of heterozygosity (LOH) of the MEN1 locus on chromosome 11q13 and somatic mutation of the MEN1 gene have been frequently associated with the development of MEN 1-type sporadic endocrine lesions. To further investigate the role of the MEN1 gene in sporadic endocrine tumorigenesis, we analysed DNA from 14 primary parathyroid lesions, 8 anterior pituitary tumours and 3 pancreatic tumours for the presence of somatic MEN1 gene mutations and LOH of seven microsatellite markers flanking the MEN1 locus. In addition, we similarly analysed 8 secondary parathyroid lesions which arose in patients with chronic renal failure. None of the patients studied had a family history of MEN 1. Three primary parathyroid lesions and one pancreatic tumour (glucagonoma) were found to have lost one allele at the MEN1 locus. Somatic mutations were identified by SSCP and sequence analysis in one of these parathyroid lesions (P320L) and in the glucagonoma (E179V). These results support previous findings that inactivation of the MEN1 tumour suppressor gene contributes to the development of sporadic MEN 1-type endocrine lesions but is not associated with the development of parathyroid hyperplasia seen in some renal failure patients.

Adenoma↗
PubMed2000

Structure-activity studies on gossypol in tumor cell lines.

Gossypol [(2,2'-binaphthalene)-8,8'-dicarboxaldehyde-1,1',6,6',7,7'-hexahydroxy-5,5'-diisopropyl-3,3'-dimethyl] 1a is a naturally occurring compound extracted from the cotton plant and has been extensively studied as an oral male contraceptive. Its favorable toxicity profile, and the more recent demonstration of anti-tumor activity in animals and humans, prompted us to investigate the role of the aldehyde groups in a structure-activity study in cultured tumor cells. Four racemic compounds were evaluated: gossypol 1a, gossypolone 2, the bis Schiff's base of L-phenylalanine methyl ester with gossypol (bis Schiff's base) 1c and apogossypol 1b. The former two compounds both retain the aldehyde functional groups at positions 8 and 8' of the molecule whilst in the latter two compounds the aldehydes are blocked or absent, respectively. In addition, the l- and d-isomers of gossypol 1a, the bis Schiff's base 1c and the half Schiff's base 1d (one aldehyde blocked) were tested. The cell lines studied included melanoma (SK-mel-19), cervix (Sihas), small cell lung (H69) and myelogenous leukemia (K562). Cytotoxicity was measured using the MTT and flow cytometric viability assays. Racemic gossypol 1a and gossypolone 2 induced similar dose-dependent decreases in cell viability in all the cell lines with IC50 values of 23-46 and 28-50 microM, respectively. In contrast, the racemic bis Schiff's base derivative of gossypol 1c and apogossypol 1b showed minimal activity in any cell line up to 50 microM. The l-enantiomer of gossypol 1a was significantly more active than the d-enantiomer (IC50 of 20 versus > 50 microM, respectively). When one aldehyde of either enantiomer was blocked 1d cytoxicity was comparable to the l-enantiomer of gossypol. The data suggest that only one aldehyde group is required for the cytotoxicity of gossypol 1a, irrespective of the stereoconfiguration.

Antineoplastic Agents↗
PubMed1999

SCL expression in the mouse embryo detected with a targeted lacZ reporter gene demonstrates its localization to hematopoietic, vascular, and neural tissues.

The helix-loop-helix transcription factor SCL (TAL1) is indispensable for blood cell formation in the mouse embryo. We have explored the localization and developmental potential of cells fated to express SCL during murine development using SCL-lacZ mutant mice in which the Escherichia coli lacZ reporter gene was 'knocked in' to the SCL locus. In addition to the hematopoietic defect associated with SCL deficiency, the yolk sac blood vessels in SCL(lacZ/lacZ) embryos formed an abnormal primary vascular plexus, which failed to undergo subsequent remodeling and formation of large branching vessels. Intraembryonic vasculogenesis in precirculation SCL(lacZ/lacZ) embryos appeared normal but, in embryos older than embryonic day (E) 8.5 to E9, absolute anemia leading to severe hypoxia precluded an accurate assessment of further vascular development. In heterozygous SCL(lacZ/w) embryos, lacZ was expressed in the central nervous system, vascular endothelia, and primitive and definitive hematopoietic cells in the blood, aortic wall, and fetal liver. Culture of fetal liver cells sorted for high and low levels of beta galactosidase activity from SCL(lacZ/w) heterozygous embryos indicated that there was a correlation between the level of SCL expression and the frequency of hematopoietic progenitor cells.

Animals↗
PubMed1999

Suckling defect in mice lacking the soluble haemopoietin receptor NR6.

Cytokines control a variety of cellular responses including proliferation, differentiation, survival and functional activation, via binding to specific receptors expressed on the surface of target cells [1]. The cytokine receptors of the haemopoietin family are defined by the presence of a conserved 200 amino acid extracellular domain known as the haemopoietin domain [2]. We report here the isolation of NR6, a haemopoietin receptor that, like the p40 subunit of interleukin-12 (IL-12) [3] and the EBI3 gene induced by Epstein-Barr virus infection in lymphocytes [4], contains a typical haemopoietin domain but lacks transmembrane and cytoplasmic domains. Although in situ hybridisation revealed NR6 expression at multiple sites in the developing embryo, mice lacking NR6 did not display obvious abnormalities and were born in the expected numbers. Neonatal NR6(-/-) mice failed to suckle, however, and died within 24 hours of birth, suggesting that NR6 is necessary for the recognition or processing of pheromonal signals or for the mechanics of suckling itself. In addition, NR6(-/-) mice had reduced numbers of haemopoietic progenitor cells, suggesting a potential role in the regulation of primitive haemopoiesis.

Amino Acid Sequence↗