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M J Higgins

Publications and source records attributed to M J Higgins.

At least 55 records · Page 3Linked to original sources
PubMed1996

A 1.5-megabase physical map encompassing the multiple endocrine neoplasia type-1 (MEN1) locus on chromosome 11q13.

Linkage analysis and loss of heterozygosity studies have shown that the gene responsible for the multiple endocrine neoplasia type-1 (MEN1) syndrome localizes to a small interval between D11S427 and D11S460 on chromosome 11q13. As an initial step to clone this tumor suppressor gene, our group is the first to map the MEN1 region physically using yeast artificial chromosome, bacterial artificial chromosome (BAC), and cosmid contigs. The 1.5-Mb high-resolution, contiguous map extends from PYGM to 300 kb telomeric of D11S460. Of this, the 1.2-Mb interval between PYGM and D11S460 is isolated in cosmids and BACs and will be useful for the development of genomic sequences and transcription maps of this important region. Nine new sequence-tagged sites (STS) are also characterized from this region. The physical map and the STSs will be valuable tools for the cloning of the MEN1 gene.

Chromosome Mapping↗
PubMed1996

Ascorbate attenuates the systemic kainate-induced neurotoxicity in the rat hippocampus.

The neuronal damage induced by systemic administration of kainic acid reproduces the cellular and regional pattern of damage produced by repeated seizures. The ability of kainic acid to induce lipid peroxidation, and the ability of free radical inhibitors to prevent ischaemically-induced cell death, has led us to examine the possible role of free radicals in kainate-induced injury. Ascorbic acid was able to reduce kainate-induced damage of the rat hippocampus, measured by means of the gliotic marker ligand [3H]PK11195. Ascorbate was significantly effective at doses of 30 mg kg-1 and above, with total protection against kainate at 50 mg kg-1. Histologically, ascorbate at 50 mg kg-1 was able to prevent kainate-induced neuronal loss in the hippocampal CA1 and CA3a cell layers. The antioxidant was also effective when administered simultaneously with, or 1 h before the kainate. Protection was also obtained by allopurinol, 175 mg kg-1 and by oxypurinol, 40 mg kg-1. Ascorbate did not modify synaptically evoked potentials or long-term potentiation in hippocampal slices, ruling out any blocking activity at glutamate receptors. It is concluded that the neuronal damage produced by systemically administered kainate involves the formation of free radicals.

Analysis of Variance↗
PubMed1996

Comparative sensitivity to adenosine of paired-pulse inhibition and single field potentials in the rat hippocampus.

If excitatory terminals onto inhibitory interneurones were more sensitive to adenosine than excitatory terminals onto pyramidal cells in the hippocampus it might explain the effect of adenosine to decrease paired-pulse inhibition and account for reported excitatory effects of low concentrations of adenosine. We have compared the concentration-response relationships for the effect of adenosine on single evoked field potentials and on paired-pulse inhibition in the CA1 area of the rat hippocampal slice in order to test this hypothesis. Adenosine caused a concentration-dependent decrease in both single evoked population spike size and in paired-pulse inhibition between potentials. The concentration-response relationships for both effects was very similar, ruling out the possibility that excitatory terminals onto inhibitory interneurones are more sensitive to adenosine than excitatory terminals onto pyramidal cells, and suggesting that the receptors located at the two sites may be indistinguishable.

Adenosine↗
PubMed1996

A high-resolution physical map of human chromosome 11.

The development of a highly reliable physical map with landmark sites spaced an average of 100 kbp apart has been a central goal of the Human Genome Project. We have approached the physical mapping of human chromosome 11 with this goal as a primary target. We have focused on strategies that would utilize yeast artificial chromosome (YAC) technology, thus permitting long-range coverage of hundreds of kilobases of genomic DNA, yet we sought to minimize the ambiguities inherent in the use of this technology, particularly the occurrence of chimeric genomic DNA clones. This was achieved through the development of a chromosome 11-specific YAC library from a human somatic cell hybrid line that has retained chromosome 11 as its sole human component. To maximize the efficiency of YAC contig assembly and extension, we have employed an Alu-PCR-based hybridization screening system. This system eliminates many of the more costly and time-consuming steps associated with sequence tagged site content mapping such as sequencing, primer production, and hierarchical screening, resulting in greater efficiency with increased throughput and reduced cost. Using these approaches, we have achieved YAC coverage for >90% of human chromosome 11, with an average intermarker distance of <100 kbp. Cytogenetic localization has been determined for each contig by fluorescent in situ hybridization and/or sequence tagged site content. The YAC contigs that we have generated should provide a robust framework to move forward to sequence-ready templates for the sequencing efforts of the Human Genome Project as well as more focused positional cloning on chromosome 11.

Chimera↗
PubMed1996

Relationship between serum concentrations, hemodynamic effects, and cardiovascular lesions in dogs treated with minoxidil.

The threshold hemodynamic changes associated with the cardiovascular (CV) toxicity of minoxidil (MNX) in the dog, characterized by subendocardial necrosis, right atrial hemorrhagic lesions, and coronary vascular medial hemorrhage and necrosis, have not been defined. To determine the relationship between serum concentration, hemodynamic effects [heart rate (HR) and mean arterial pressure (MAP)] and CV toxicity, groups of female Beagle dogs were treated with a continuous iv infusion of dextrose (control) or 0.05, 0.14, 0.43, 1.44, or 4.32 mg/kg/day of MNX for 3 days. Serum concentration of free MNX increased in a dose-related manner and reached steady state within 4 hr after the initiation of infusion. There was a time-dependent, apparently dose-related increase in HR at all doses. MAP was decreased at > or = 0.14 mg/kg/day in a time- and dose-related manner. The doses or steady-state serum concentrations of MNX that showed no significant hemodynamic effects and CV toxicity were approximately 0.05 mg/kg or 3.0 +/- 0.6 ng/ml and 0.14 mg/kg or 7.3 +/- 2.0 ng/ ml, respectively. CV toxicity occurred at a serum concentration of 16.6 +/- 1.9 ng/ml where HR was increased by 65 +/- 11 beats/min and MAP was decreased by 34 +/- 2 mm Hg. A serum concentration of 7.3 +/- 2 ng/ml of MNX that increased HR by 47 +/- 14 beats/min and decreased MAP by 17 +/- 8 mm Hg was not associated with CV toxicity. This study suggests that the threshold hemodynamic effects associated with the CV toxicity of MNX in the dog are a function of an increase in HR by at least 55 beats/min and a decrease in MAP by at least 30 mm Hg. In conclusion, the safety margin of drugs like MNX, where the mechanisms of toxicity are known to be related to their pharmacologic effects, should be based on the ratio of the pharmacokinetically and metabolically adjusted dose/serum concentration of the drug that evokes comparable pharmacologic effects in the animal model and humans rather than on the ratio of the nontoxic dose/serum concentration in animals to the efficacious dose in humans.

Animals↗
PubMed1996

Abscedation of posterior fossa dermoid cysts.

Dermoid cysts of the posterior fossa are uncommon. When associated with a dermal sinus, these cysts are often diagnosed during early childhood. The main risk of such an association is contamination of the cyst leading to abscedation of the dermoid itself or formation of daughter abscesses within the cerebellar hemisphere. We recently treated a 20-month-old girl who had a congenital dermal sinus leading to an intradural dermoid cyst. In addition to the midline dermoid cyst, computerized tomography revealed an enhancing lesion extending into the adjacent left cerebellar hemisphere. Suboccipital craniectomy was undertaken after 2 days of external ventricular drainage, and the infected dermoid and adjacent cerebellar abscess were excised. Cultures of the operative specimen revealed Corynobacterium aquaticum, Enterobacter sakazakii and Enterobacter cloacae, requiring 6 weeks of intravenous antibiotic therapy consisting of ceftriaxone, penicillin and gentamicin. A diligent literature search revealed only 24 sporadic cases reported over a period of 56 years. All 24 cases were in children (mean age 17 months), and one-third were in infants under the age of 1 year. All but 1 of these patients underwent posterior fossa surgery, with mortality and morbidity rates of 13% and 10%, respectively. Eleven (40%) children had suppuration within the cerebellar parenchyma, while the rest had abscedation of the dermoid cyst alone. Among the cases reviewed S. aureus was the most common agent, occurring with a probability of 64%. Key issues for appropriate management of these benign lesions are discussed.

Corynebacterium↗
PubMed1996

Changes in hippocampal gene expression associated with the induction of long-term potentiation.

The expression of four genes: zif/268, c-fos, tubulin and alpha Ca2+/calmodulin-dependent protein kinase II (alpha CAMKII) was studied following the induction of LTP in Schaffer collateral CA1 neurone synapses in rat hippocampal slices maintained in vitro. Levels of c-fos mRNA and tubulin (T26) mRNA in area CA1 were unchanged after induction of LTP, however, zif/268 and alpha CAMKII mRNA levels showed a significant increase compared to non-potentiated controls. It is possible, therefore, to measure changes in gene expression using in situ hybridisation following induction of LTP in vitro and these results strengthen the theory that zif/268 and alpha CAMKII are involved in some aspect of the induction or maintenance of hippocampal LTP.

Animals↗
PubMed1996

Dorsal brain stem lipomas: case report.

Intracranial lipomas are uncommon and rarely symptomatic lesions accounting for 0.06 to 0.46% of intracranial lesions. The management of symptomatic dorsal brain stem lipomas was once limited to cerebrospinal fluid diversion, but with recent advances in microsurgery, they now may be directly treated. We report three patients with dorsal brain stem lipomas, two of which involved the quadrigeminal cistern and one of which was in the cisterna magna region. Antenatal documentation by ultrasound examination in one patient represents the first reported in utero diagnosis of quadrigeminal cistern lipoma. Computed tomographic and magnetic resonance imaging scans were diagnostic. The surgical experience in two symptomatic patients is discussed. Microsurgical decompression was performed in each without neurological deficit, and clinical symptoms postoperatively subsided. No patient required a permanent cerebrospinal fluid shunt. The management of symptomatic dorsal brain stem lipomas is discussed, and an algorithm is proposed.

Adolescent↗
PubMed1996

Posttraumatic gas-containing brain abscess caused by Clostridium perfringens with unique simultaneous fungal suppuration by Myceliophthora thermophila: case report.

OBJECTIVE AND IMPORTANCE: Gas-containing brain abscesses are rare, and the vast majority are caused by Clostridium perfringens. Significant simultaneous fungal infection in a bacterial abscess is even rarer. We present such a case and review the literature. CLINICAL PRESENTATION: A 21-month-old male patient sustained a penetrating head injury in a barnyard, developed a gas-containing left parietal brain abscess, and presented with high fever, galeal swelling, and seizure. INTERVENTION: The patient initially underwent debridement of his wound and then repeated aspirations. The initial cultures revealed pure growth of Clostridium perfringens. Despite appropriate antibiotic therapy, serial neuroimaging did not demonstrate a decrease in the size of the cavity. An excision had to be undertaken 6 weeks after the injury. The culture from the excised specimen revealed an unexpected growth of a saprophytic and opportunistic fungus, Myceliophthora thermophila. Antifungal treatment consisting of the administration of liposomal amphotericin B and itraconazole was then performed. The child was well and neurologically intact 6 months after the excision. CONCLUSION: Our review revealed 38 cases of clostridial brain abscess in the literature. Despite the reputation of the organism, the outcome with clostridial brain abscesses was relatively benign. The main characteristics of clostridial brain abscesses are highlighted, with reference to their optimal treatment. Our review also revealed that fungal infection after a penetrating head injury is extremely rare and often fatal. Our case seems to be the first in the medical literature with growth of M. thermophila as a causative agent for intracranial suppuration.

Amphotericin B↗
PubMed1995

Rapid construction of integrated maps using inner product mapping: YAC coverage of human chromosome 11.

Inner product mapping (IPM) has been proposed as a hybridization-based method for achieving low-cost, high-throughput, high-resolution radiation hybrid (RH) mapping of clones. Using Alu-PCR products of chromosome 11-specific clones, we serially hybridized a set of RHs against gridded filters of YACs having an average size of 350 kb. We then combined these hybridization data with preexisting RH map data to build an inner product map. This binning of 865 YACs provides the first high-resolution large-scale (> twofold redundancy) clonal coverage of human chromosome 11 and is the first inner product map ever constructed. We verified the accuracy and precision of this chromosome 11 map by performing a novel likelihood analysis on independent YAC hybridization data. These results establish that IPM is a highly rapid, inexpensive, accurate, and precise large-scale long-range mapping method, particularly when preexisting RH maps are available, and that IPM can replace or complement more conventional short-range mapping methods. IPM may enable the rapid construction of sequence-ready maps and the binning of expressed sequences.

Chromosome Mapping↗
PubMed1995

Modulation by adenosine of a neuronal inhibitory interaction in the rat hippocampus.

Adenosine is acknowledged to have a primarily inhibitory function in the central nervous system, but is believed to have little effect on inhibitory neurones themselves. It is, however, difficult to determine the effect of adenosine on inhibitory synaptic potentials since adenosine directly depresses evoked potentials and, in the presence of bicuculline to block GABAA-mediated inhibition, the bicuculline-resistant fraction of paired-pulse inhibition (ppi) is greater between pairs of small potentials than between pairs of larger potentials. Here, adenosine increased bicuculline-resistant ppi when stimulus strength was constant between adenosine and control but ppi of responses in adenosine was markedly less than ppi of control responses of the same size. Adenosine had less effect on the size of 'conditioned' potentials than on control potentials. It is concluded that adenosine can reduce the bicuculline-resistant fraction of paired-pulse inhibition in the hippocampus. Further quantitative comparison of the effects of adenosine on ppi and on single evoked potentials excluded a difference in the potency of adenosine at excitatory and inhibitory terminals as an explanation for this activity. The results suggest that adenosine may diminish bicuculline-resistant paired-pulse inhibition by enhancing a simultaneous facilitatory component of the neuronal responses.

Adenosine↗
PubMed1995

Micronuclei in mice treated with monocrotaline with and without phenobarbital pretreatment.

Monocrotaline is a very potent toxin, producing significant effects of pneumotoxicity, hepatotoxicity, and teratogenicity, as well as carcinogenicity. In addition, the compound has been clearly shown to be mutagenic after metabolic activation. The goal of the experiments reported here was to confirm the reported clastogenesis induced by this agent in vivo and to evaluate the impact of modulation of metabolic activity by phenobarbital, a potent P-450 inducer (both Phase I and Phase II enzymes). The method used in addressing this problem relied on a new technique for monitoring clastogenesis in vivo, i.e., the acridine orange micronucleus assay method originally exploited by Hayashi et al. [1990]. The result of our experiments confirmed monocrotaline to be an effective clastogen in vivo, using the acridine orange method of assessment. The peak in induction of micronuclei occurred on the second day following intraperitoneal administration of the drug. Administration of phenobarbital prior to monocrotaline did appear to modulate the micronucleus induction. At 30 mg/kg bw monocrotaline, the pretreatment with phenobarbital appears to increase the intensity of monocrotaline clastogenesis, while the effect at higher doses (60 and 125 mg/kg bw) is a reduction in potency, presumably reflecting increased importance of Phase II metabolism for monocrotaline at these doses. Thus the study reported here confirms the potent in vivo clastogenesis of monocrotaline, and provides evidence for a dose-related shift in mechanism for the phenomenon.

Analysis of Variance↗
PubMed1995

Effect of adenosine on bicuculline-resistant paired-pulse inhibition in the rat hippocampal slice.

This study extends previous investigations into the effect of adenosine on bicuculline-resistant paired-pulse inhibition between field potentials evoked 300 ms apart in the CA1 area of the rat hippocampal slice. A direct assessment of the effect of adenosine on paired-pulse inhibition is complicated by the facts that adenosine directly depresses evoked potentials and bicuculline-resistant paired-pulse inhibition is greater between pairs of small potentials than between pairs of larger potentials. Adenosine increased bicuculline-resistant paired-pulse inhibition when stimulus strength was constant between adenosine and control but paired-pulse inhibition of responses in adenosine was markedly less than paired-pulse inhibition of control responses of the same size. Furthermore, adenosine decreased the size of conditioned potentials to a significantly lesser extent than unpaired potentials of the same initial size. Taken together the results indicate that adenosine can decrease bicuculline-resistant paired-pulse inhibition in the hippocampus. A possible mechanism for this effect is that adenosine is suppressing transmission at excitatory terminals onto interneurones which would suggest that these receptors are more sensitive to adenosine than those on the Schaffer collateral/CA1 pyramidal cell synapses. In this case adenosine should reduce paired-pulse inhibition at lower concentrations than are required for depression of single evoked potentials. A comparison of the concentration-response relationships for the effects of adenosine on paired-pulse inhibition and on single evoked potentials ruled out greater sensitivity of adenosine receptors at excitatory terminals onto interneurones as an explanation for adenosine's action on bicuculline-resistant paired-pulse inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1994

A YAC contig spanning the ataxia-telangiectasia locus (groups A and C) at 11q22-q23.

Ataxia-telangiectasia (A-T) is an autosomal recessive disease involving cerebellar degeneration, immunodeficiency, cancer predisposition, chromosomal instability and radiosensitivity. A-T is heterogeneous, and the majority of A-T cases are associated with two complementation groups, A and C. The ATA and ATC loci are closely linked at chromosome 11q22-q23. Recombination mapping and linkage disequilibrium analysis have confined both loci between the markers D11S1817 and D11S927, spaced approximately 3.5 Mb apart. Isolation in yeast artificial chromosomes of the genomic segment defined by these loci is essential to identify the gene or genes containing the ATA and ATC mutations. A YAC contig spanning 4.5 Mb, which includes the D11S1817-D11S927 interval, was constructed using two whole genome libraries (ICRF and St. Louis), and a chromosome 11-specific library. Construction of this contig was expedited by prior generation of a region-specific ICRF sublibrary using Alu-PCR products derived from a radiation hybrid. The contig was expanded further by screening the libraries with Alu-PCR products derived from YAC clones and with STSs from YAC ends. YAC clones were aligned by fingerprinting with moderately repetitive probes.

Ataxia Telangiectasia↗
PubMed1994

An ordered NotI fragment map of human chromosome band 11p15.

An ordered NotI fragment map containing over 60 loci and encompassing approximately 17 Mb has been constructed for human chromosome band 11p15. Forty-two probes, including 11 NotI-linking cosmids, were subregionally mapped to 11p15 using a subset of the J1-deletion hybrids. These and 23 other probes defining loci previously mapped to 11p15 were hybridized to genomic DNA digested with NotI and 5 other infrequently cleaving restriction enzymes and separated by pulsed-field gel electrophoresis. Thirty-nine distinct NotI fragments were detected encompassing approximately 85% of the estimated length of 11p15. The predicted order of the gene loci used is cen-MYOD1-PTH-CALCA-ST5-RBTN1-HPX-HBB-RRM1 -TH/INS/IGF2-H19-CTSD-MUC2-DRD4-HRAS - RNH-tel. This map will allow higher resolution mapping of new 11p15 markers, facilitate positional cloning of disease genes, and provide a framework for the physical mapping of 11p15 in clone contigs.

Cells, Cultured↗
PubMed1994

Release and actions of adenosine in the central nervous system.

Adenosine is released from active neurons into the extracellular fluid at a concentration of about 1 mumol/l. Neither the precise cellular origin nor the biochemical form of release has been firmly established, though the nucleotide is probably released partly directly, as a result of raised intracellular levels, and partly as nucleotides, which are subsequently hydrolysed. Once in the extracellular medium, adenosine markedly inhibits the release of excitatory neurotransmitters and modulatory peptides and has direct inhibitory effects on postsynaptic excitability via A1 receptors. A population of A2 receptors may mediate depolarization and enhanced transmitter release. Adenosine also modulates neuronal sensitivity to acetylcholine and catecholamines, all these effects probably contributing to the behavioural changes observed in conscious animals. As a result of their many actions, adenosine analogues are being intensively investigated for use as anticonvulsant, anxiolytic, and neuroprotective agents.

Acetylcholine↗