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M P Johnson

Publications and source records attributed to M P Johnson.

At least 19 recordsLinked to original sources
PubMed2006

Identification of two novel quantitative trait loci for pre-eclampsia susceptibility on chromosomes 5q and 13q using a variance components-based linkage approach.

Pre-eclampsia/eclampsia (PE/E) is a common and serious disorder of human pregnancy that is associated with substantial maternal and perinatal morbidity and mortality. The suspected aetiology of PE/E is complex, with susceptibility being attributable to multiple environmental factors and a large genetic component. By assuming that the underlying liability towards PE/E susceptibility is inherently quantitative, any PE/E susceptibility gene would represent a quantitative trait locus (QTL). This assumption enables a more refined and powerful variance components procedure using a threshold model for our PE/E statistical analysis. Using this more efficient linkage approach, we have now re-analysed our previously completed Australian/New Zealand genome scan data to identify two novel PE/E susceptibility QTLs on chromosomes 5q and 13q. We have obtained strong evidence of linkage on 5q with a peak logarithm-of-odds (LOD) score of 3.12 between D5S644 and D5S433 [at approximately 121 centimorgan (cM)] and strong evidence of linkage on 13q with a peak LOD score of 3.10 between D13S1265 and D13S173 (at approximately 123 cM). Objective identification and prioritization of positional candidate genes using the quantitative bioinformatics program GeneSniffer revealed highly plausible PE/E candidate genes encoding aminopeptidase enzymes and a placental peptide hormone on the 5q QTL and two type IV collagens on the 13q QTL regions, respectively.

Analysis of Variance↗
PubMed2006

Objective prioritization of positional candidate genes at a quantitative trait locus for pre-eclampsia on 2q22.

Pre-eclampsia/eclampsia (PE/E) is a common, serious medical disorder of human pregnancy. Familial association of PE/E has been recognized for decades, but the genetics are complex and poorly understood. In an attempt to identify PE/E susceptibility genes, we embarked on a positional cloning strategy using 34 Australian and New Zealand PE/E pedigrees. An initial 10-cM resolution genome scan revealed a putative susceptibility locus spanning a broad region on chromosome 2 that overlaps an independently determined linkage signal seen in Icelandic PE pedigrees. Subsequent fine mapping using 25 additional short tandem repeat (STR) markers in this region and non-parametric multipoint linkage analysis did not change the overall position. Under a strict diagnosis of PE, we obtained significant evidence of linkage on 2q with a peak log-of-odds ratio score (LOD) of 3.43 near marker D2S151 at 155 cM. To prioritize positional candidate genes at the 2q locus for detailed analysis, we applied an objective prioritization strategy that integrates quantitative bioinformatics, assessment of differential gene expression and association analysis of single-nucleotide polymorphisms (SNPs). Highest priority was assigned to the activin receptor gene ACVR2. This gene also showed >10-fold differential gene expression in human decidual tissue from normotensive and PE individuals. We genotyped five known SNPs in this gene in our pedigrees and performed tests for association and linkage disequilibrium. One SNP (rs1424954) showed strong preliminary evidence of association with PE (P = 0.007), whereas two others (rs1364658 and rs1895694) exhibited nominal evidence (P < 0.05). Haplotype analysis revealed no additional association information. There was evidence of weak linkage disequilibrium among these SNPs. The highest observed LD occurred between the two strongest associated SNPs, suggesting that the observed signals may be the signature of an observed functional variant.

Activin Receptors, Type II↗
PubMed2005

A population genomics overview of the neuronal nitric oxide synthase (nNOS) gene and its relationship to migraine susceptibility.

The ubiquitous chemical messenger molecule nitric oxide (NO) has been implicated in a diverse range of biological activities including neurotransmission, smooth muscle motility and mediation of nociception. Endogenous synthesis of NO by the neuronal isoform of the nitric oxide synthase gene family has an essential role within the central and peripheral nervous systems in addition to the autonomic innervation of cerebral blood vessels. To investigate the potential role of NO and more specifically the neuronal nitric oxide synthase (nNOS) gene in migraine susceptibility, we investigated two microsatellite repeat variants residing within the 5' and 3' regions of the nNOS gene. Population genomic evaluation of the two nNOS repeat variants indicated significant linkage disequilibrium between the two loci. Z-DNA conformational sequence structures within the 5' region of the nNOS gene have the potential to enhance or repress gene promoter activity. We suggest that genetic analysis of this 5' repeat variant is the more functional variant expressing gene wide information that could affect endogenous NO synthesis and potentially result in diseased states. However, no association with migraine (with or without aura) was seen in our extensive case-control cohort (n = 579 affected with matched controls), when both the 5' and 3' genetic variants were investigated.

3' Flanking Region↗
PubMed2004

Fetal head biometry following in-utero repair of myelomeningocele.

OBJECTIVE: To evaluate the impact of prenatal myelomeningocele repair on fetal head biometry. METHODS: Fifty fetuses underwent open fetal myelomeningocele repair at our institution between January 1998 and July 2002. All had serial head circumference (HC) and lateral ventricular diameter (VD) measurements taken preoperatively and weekly for 8 weeks after repair. Cortical index (CI) was defined as HC/VD. Measurements were compared with gestational age-matched values from nomograms. One-sample t-test, ANOVA and repeated measures analysis were used to assess HC, VD and CI after fetal repair. RESULTS: Preoperatively, the HC in fetuses with myelomeningocele was smaller than control values (186.4 vs. 198.8 mm, P = 0.0004). Eight weeks' postoperatively this difference had resolved (293 vs. 301.6 mm, P = 0.76). The mean increase in CI after repair was 20% (P = 0.02) compared with the predicted 51% in normal cases. The average increase in VD was 3.9 mm (38.8%, P < 0.001). CONCLUSIONS: Mid-gestational repair of myelomeningocele alters fetal head growth. Increased CI suggests HC changes are not due to ventriculomegaly alone.

Adult↗
PubMed2004

Allosteric modulators of metabotropic glutamate receptors: lessons learnt from mGlu1, mGlu2 and mGlu5 potentiators and antagonists.

Although relatively few G-protein-coupled receptors are Class C, in recent years, this small family of receptors has become a focal point for the discovery of new and exciting allosteric modulators. The mGlu (metabotropic glutamate) receptors are illustrative in the discovery of both positive and/or negative allosteric modulators with unique pharmacological properties. For instance, allosteric modulators of the mGlu2 receptor act as potentiators of glutamate responses in clonal expression systems and in native tissue assays. These potentiators act to increase the affinity of orthosteric agonists for the mGlu2 receptor and shift potency curves for the agonist to the left. In electrophysiological experiments, the potentiators show a unique activation-state-dependent presynaptic inhibition of glutamate release and significantly enhance the receptor-mediated increase in G-protein binding, as seen with autoradiography. Similarly, potentiators of mGlu5 have been described, as well as allosteric antagonists or inverse agonists of mGlu1 and mGlu5. Binding and activity of the modulators have recently indicated that positive and negative allosteric sites can be, but are not necessarily, overlapping. Compared with orthosteric ligands, these modulators display a unique degree of subtype selectivity within the highly conserved mGlu family of receptors and can have very distinct pharmacological properties, such as neuronal frequency-dependent activity. This short review describes some of the unique features of these mGlu1, mGlu2 and mGlu5 allosteric modulators.

Allosteric Regulation↗
PubMed2002

Modulation of stress-induced and stimulated hyperprolactinemia with the group II metabotropic glutamate receptor selective agonist, LY379268.

It is well recognized that glutamate is an integral excitatory neurotransmitter in the neuroendocrine control of several hormonal factors. While the ability of pharmacological agents acting at ionotropic glutamate receptors to modulate the levels of serum prolactin levels has been investigated, there have been few reports of the effects mediated by the G-protein coupled, metabotropic glutamate (mGlu) receptors. The present work was undertaken to investigate the role of the Group II mGlu receptors, mGlu2 and mGlu3 in the regulation of serum polactin levels. LY379268, a Group II selective agonist, did not alter basal levels of circulating prolactin in young (36-40 day old) male rats. However, when an immobilization stress-induced hyperprolactinemia was examined, 10 mg/kg s.c. of LY379268 significantly lowered serum prolactin levels. Similarly, pretreatment with LY379268 was able to reverse the hyperprolactinemia induced with the catecholamine synthesis inhibitor, alpha-methyl-p-tyrosine (aMPT). This inhibition of hyperprolactinemia could be prevented by pretreatment with LY341495, a Group II mGlu receptor antagonist. The Group II antagonist alone had no effect on either basal nor stimulated prolactin levels. The agonist LY379268 was able to prevent the transient hyperprolactinemia associated with stimulation of serotonin 5-HT2A receptors by 2,5-dimethoxy-4-iodoamphetamine (DOI), but did not alter the high levels of circulating prolactin induced with the D2 antagonist, haloperidol. When treatment with LY379268 was delayed until 1 h after aMPT, a time demonstrated to show a full effect of aMPT on serum prolactin levels, the Group II agonist was similarly able to reverse hyperprolactinemia, suggesting LY379268 did not act by preventing the partial catecholamine depletion by aMPT. Similarly, high doses of amphetamine, a dopamine (DA) releaser, were able to reverse the aMPT-induced hyperprolactinemia, consistent with sufficient levels of dopamine remaining after aMPT treatment to modulate prolactin levels. LY379268 did not alter the hyperprolactinemia seen in estrogen-primed, ovariectomized female rats. Taken together the results indicate that stimulation of mGlu2/3 has an indirect inhibitory action on pituitary prolactin release. It is speculated that disinhibition of tubero-infundibular DA release by presynaptic Group II mGlu receptors located on inhibitory inputs to the arcuate hypothalamic nucleus is a possible explanation for the findings.

Amino Acids↗
PubMed2002

The implications of unfulfilled expectations and perceived pressure to attend the birth on men's stress levels following birth attendance: a longitudinal study.

Men's stress and their experiences of reproduction have yet to be fully explored. This study aims to examine the subjective stress experienced by men during their partner's pregnancy, at the time of the birth and six weeks postpartum by means of a longitudinal study of 53 men's reproductive experience. Further, it aims to examine the role birth attendance, unfulfilled expectations and perceived pressure to attend the birth have on levels of stress. Men were measured on the Impact of Event Scale three times during the pregnancy, at the time of the birth and six weeks postpartum. Findings indicate that compared to non-psychiatric norms, overall levels of stress were elevated during the pregnancy, at birth and postpartum. The highest levels of stress were found at the time of the birth in the men who were in birth attendance. Stress levels were particularly high amongst men who felt they did not fulfill their role expectation, or they perceived pressure to be present at the birth. Confirming findings from phenomenological studies, there appears to be some confusion as to the nature and purpose of men's presence at childbirth. Expectant fathers may not anticipate the psychological and emotional realities of childbirth/becoming a father and there remains a possibility that raised stress following childbirth may impact on father/child bonding.

Adolescent↗
PubMed2001

Buoyant balaenids: the ups and downs of buoyancy in right whales.

A variety of marine mammal species have been shown to conserve energy by using negative buoyancy to power prolonged descent glides during dives. A new non-invasive tag attached to North Atlantic right whales recorded swim stroke from changes in pitch angle derived from a three-axis accelerometer. These results show that right whales are positively buoyant near the surface, a finding that has significant implications for both energetics and management. Some of the most powerful fluke strokes observed in tagged right whales occur as they counteract this buoyancy as they start a dive. By contrast, right whales use positive buoyancy to power glides during ascent. Right whales appear to use their positive buoyancy for more efficient swimming and diving. However, this buoyancy may pose added risks of vessel collision. Such collisions are the primary source of anthropogenic mortality for North Atlantic right whales, whose population is critically endangered and declining. Buoyancy may impede diving responses to oncoming vessels and right whales may have a reduced ability to manoeuvre during free ascents. These risk factors can inform efforts to avoid collisions.

Animals↗
PubMed2001

Chromosome 17 and the inducible nitric oxide synthase gene in human essential hypertension.

Essential hypertension is a common multifactorial trait that results in a significantly increased risk for heart attack and stroke. The condition has a genetic basis, although at present the number of genes is unknown. In order to identify such genes, we are utilising a linkage scanning approach using microsatellite markers and affected sibships. Here we provide evidence for the location of at least one hypertension susceptibility locus on chromosome 17. Analysis of 177 affected sibpairs gave evidence for significant excess allele sharing to D17S949 (SPLINK: P=0.0029; MAPMAKER SIBS: P=0.0033; ASPEX: P=0.0061; GENEHUNTER: P=0.0096; ANALYZE (SIBPAIR): P=0.0025) on 17q22-24, with significant allele sharing also indicated for an additional marker, D17S799 (SPLINK: P=0.025; MAPMAKER SIBS: P=0.025) located close to the centromere. Since these two genomic regions are well separated, our results indicate that there may be more than one chromosome 17 locus affecting human blood pressure. Moreover, further investigation of this chromosome, utilizing a polymorphism within the promoter of the iNOS candidate gene, NOS2A, revealed both increased allele sharing among sibpairs (SPLINK: P=0.02; ASPEX: P=0.00004) and positive association (P=0.034) of NOS2A to essential hypertension. Hence these results indicate that chromosome 17 and, more specifically, the NOS2A gene may play a role in human essential hypertension.

Alleles↗
PubMed2001

Changes in rat serum corticosterone after treatment with metabotropic glutamate receptor agonists or antagonists.

From previous work, it appears that glutamate can activate the hypothalamic-pituitary-adrenocortical (HPA) axis by an interaction at either ionotopic or metabotropic (G-protein coupled) receptors. For example, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (ACPD), a metabotropic glutamate (mGlu) receptor agonist, has been shown to increase the levels of serum corticosterone in rats. The present study was undertaken to further characterize which of the mGlu receptors are substantially involved in control of the HPA axis. The group I mGlu receptor agonists, 3,5-dihydroxyphenylglycine (DHPG), 1S,3R-ACPD, and 2-chloro-5-hydroxyphenylglycine (CHPG) but not the inactive isomer 1R,3S-ACPD were found to dose-dependently increase serum corticosterone 1 h after intracerebroventricular (i.c.v.) injection in male rats. The relative potency, DHPG (EC50 = 520 nmol) > 1S,3R-ACPD (1.4 micromol) = CHPG (2.7 micromol) >> 1R,3S-ACPD (>> 3 micromol) is consistent with activation of group I (mGlu1/5) receptors. The effects of DHPG were long lasting with substantial elevations in corticosterone remaining for at least 3 h. In a similar manner, the group III mGlu receptor agonists, L-AP4 (4-phosphono-2-aminobutyric acid) and L-SOP (serine-O-phosphate), were found to increase serum corticosterone levels at 1 h. In contrast, the mGlu group II selective agonists LY354740 (10 mg/kg, i.p.) and subtype-selective doses of the group II antagonist LY341495 (1 mg/kg, i.p.) did not significantly elevate serum corticosterone. Given the group I agonists results, it was surprising to find that group I selective and mGlu1 selective antagonists given alone also increased serum corticosterone. As with the agonists, the rise in serum corticosterone with LY393675 (an mGlu1/5 antagonist, EC50 = 20 nmol, i.c.v.) and LY367385 (an mGlu1 antagonist, 325 nmol, i.c.v.) were dose-dependent and consistent with their relative affinity for the group I mGlu receptors. The selective mGlu5 antagonist MPEP [2-methyl-6-(phenylethylnyl)pyridine] increased serum corticosterone but only at high doses (> 30 mg/kg, i.p.). A model involving the high glutamatergic tone on GABAergic interneurons in the paraventricular nucleus of the hypothalamus is discussed as a possible explanation for these results.

Adrenalectomy↗
PubMed2001

New method to assess scapular upward rotation in subjects with shoulder pathology.

STUDY DESIGN: Test-retest repeated measures and correlational design. OBJECTIVES: To examine the reliability and validity of a "modified" digital inclinometer to assess scapular upward rotation during humeral elevation in the scapular plane BACKGROUND: Evidence exists that scapular motion is related to shoulder pathology; however, evaluation and treatment planning for shoulder rehabilitation often fails to include an objective assessment of scapular motion. METHODS AND MEASURES: Two-dimensional measurements by the inclinometer were taken with the arm in a static position. These data were compared to 3-dimensional measurements obtained using a magnetic tracking device with the arm fixed and during arm movement. Both methods were used to assess scapular upward rotation positions with the arm at rest and at 60 degrees , 90 degrees , and 120 degrees of humeral elevation in the scapular plane. Both scapulae were tested on a total of 39 subjects, 16 with shoulder pathology and 23 without. Reliability was assessed using repeated measurements from the inclinometer. Validity was assessed using 2 separate comparisons: inclinometer and magnetic tracking device under static arm conditions and inclinometer and magnetic tracking device during active arm elevation. Reliability and validity were assessed at all 4 arm positions. RESULTS: Intraclass correlation coefficients (ICC [3,1]) varied from 0.89 to 0.96. Pearson Product Moment correlation coefficients, used to assess validity of the static inclinometer, varied from r = 0.74 to 0.92 compared with the static magnetic tracking measures, and from r = 0.59 to 0.73 compared with the active magnetic tracking measures taken during arm elevation. CONCLUSIONS: The "modified" digital inclinometer demonstrated good to excellent intrarater reliability and good to excellent validity when measuring scapular upward rotation during static positions of humeral elevation in the scapular plane.

Adult↗
PubMed2000

Temporally explicit habitat ecology and the coexistence of species.

Habitats may have dynamics that exist independently of the population densities of species occupying the habitat. For example, ephemeral habitat patches may disappear regardless of whether a particular species is present or not. Such habitat dynamics are frequently modelled by ignoring age-related variation in patch turnover rates. This can be thought of as a temporally implicit approach. An alternative, temporally explicit approach involves using age-structured models in order to describe variations in habitat dynamics. Simple models of coexistence between competing species show that temporally implicit models may be misleading where there is age-related variation in patch dynamics. Changing the shape of the patch survivorship function but not the average patch survivorship can result in mutual extinction, monocultures or coexistence of an inferior and a superior competitor. An explicit treatment of habitat demography may therefore offer improved predictive models and alternative landscape management strategies.

Animals↗
PubMed2000

Blockade of pilocarpine-induced cerebellar phosphoinositide hydrolysis with metabotropic glutamate antagonists: evidence for an indirect control of granule cell glutamate release by muscarinic agonists.

The ability in vivo of the muscarinic agonist, pilocarpine, to increase phosphoinositol (PI) hydrolysis in lithium pretreated rats was investigated by measuring the accumulation of [(3)H]inositol phosphates (IP). As expected, 20 mg/kg s.c. pilocarpine, a muscarinic agonist, increased PI hydrolysis in the striatum, frontal cortex and hippocampus. Somewhat surprisingly, an increase in IP was also found in the cerebellar homogenates. In all four tissues the pilocarpine-induced effect could be completely inhibited by pretreatment with the muscarinic antagonist scopolamine (1.2 mg/kg i. p.). It was also found that the cerebellar but not the hippocampal pilocarpine-induced rise in PI hydrolysis could be blocked by the metabotropic glutamate (mGlu) receptor antagonist, LY341495 (100 nmol, i.c.v.). The same dose of LY341495 was found to also block both the cerebellar and hippocampal increase in IP formed by stimulation with the group I mGlu receptor agonist 3, 5-dihydroxyphenylglycine (1 micromol, i.c.v.). Given this data and the current information on the distribution of muscarinic and mGlu receptors in the cerebellum, it is suggested that these results may be a reflection of pilocarpine acting at M(2) receptors to indirectly increase glutamate release from parallel fibers by inhibition of gamma-aminobutyric acid-releasing Golgi cells.

Amino Acids↗
PubMed2000

Routine prenatal diagnosis of aneuploidy by FISH studies in high-risk pregnancies.

This study is a prospective clinical trial with fluorescent in situ hybridization (FISH) as a "routine" test for prenatal detection of the most common aneuploidies in high-risk pregnancies. Since April 1996, FISH studies with multicolor, commercially available, specific probes for chromosomes 13, 18, 21, X, and Y have been routinely performed in our cytogenetic laboratory on uncultured chorionic villous samplings (CVS), amniotic fluid samples, or fetal blood obtained by cordocentesis from patients with major or minor fetal anomalies detected by ultrasonography. Among the 4,193 prenatal samples analyzed between April 1996 and June 1998, routine FISH studies were ordered by the referring physicians on 301 (7.2%) cases. Aneuploidies were detected in 32 (10.6%) samples. Fourteen trisomy-21, 10 trisomy-18, 3 trisomy-13, 4 monosomies of X, and 1 case of triploidy were diagnosed by FISH. All 1,505 hybridizations were informative, and all 301 results were available and reported to the referring physicians in 24-48 hr. All relevant FISH results were confirmed by subsequent cytogenetic analysis. In 10 (3.8%) cases with normal FISH results, the final cytogenetic analysis revealed abnormal chromosomal rearrangements that could not be detected by the routine FISH studies. We conclude that rapid FISH analysis of interphase, uncultured fetal cells is an accurate and very sensitive method for routine prenatal diagnosis of the most common aneuploidies in high-risk pregnancies.

Aneuploidy↗
PubMed2000

Ultrasound screening for fetal chromosome anomalies.

Ultrasound evidence for aneuploidy may be found in almost every organ of the fetus and can be used to modify the risk of aneuploidy. The diagnosis of these minor anomalies on second-trimester ultrasonography will increase the risk of an abnormal karyotype whereas the absence of these findings may reduce this danger. The most specific and most ominous isolated markers for fetal aneuploidy are nuchal findings (edema or cysts), indicating the need to obtain a fetal karyotype in all cases irrespective of maternal age or results of biochemical serum screening. Hyperechoic fetal bowel is apparently also a strong indicator of fetal aneuploidy. Other isolated sonographic markers may increase the risk of an abnormal karyotype three- to ninefold. Most sonographic markers for aneuploidy specify an increased risk for Down syndrome, but choroid plexus cysts are apparently more specific for trisomy 18. Along with other screening methods, ultrasound screening for fetal aneuploidy should be used routinely to identify additional pregnancies at need for evaluation of fetal karyotype.

Aneuploidy↗
PubMed2000

Fetal therapy for obstructive uropathy: past, present.future?

Antenatal treatment of obstructive uropathy, although widely performed, remains controversial. An overview of prenatal therapy for obstructive uropathy, the limitations of the early published experience, advances of recent years, and future directions for treatment are reviewed. The clinical approach and outcomes of the Fetal Treatment Program of Hutzel Hospital and Wayne State University are presented. Patient selection for antenatal treatment is based on the existence of a significant threat of neonatal death due to pulmonary hypoplasia, pending exclusion criteria such as anatomical structural anomalies and chromosomal defects. Ultrasonography, karyotyping, and sequential urinary electrolyte analysis are essential. Current treatment involves the placement under ultrasonic guidance of a Rodeck vesicoamniotic shunt. Recent technical advances include the use of amnioinfusion for fetal visualization, temporary fetal paralysis, routine antibiotics, and more-precise catheter placement. The establishment of standardized short- and long-term outcome measures and the documentation of fetal and maternal complications are in progress. Procedural refinement, development of fetoscopic techniques and equipment, identification of urinary markers to aid patient selection, and the collection of multicenter outcome data will assist the future management of prenatally detected obstructive uropathy.

Animals↗
PubMed2000

Comparative evaluation of Tuned Aperture Computed Tomography for the detection of mandibular fractures.

OBJECTIVES: To compare the diagnostic efficacy of Tuned Aperture Computed Tomography (TACT) with conventional imaging modalities for detection of fractures of the mandible. METHODS: Fractures were induced using blunt trauma in human defleshed mandibles. Conventional extra-oral and indirect digital images, unprocessed TACT images reconstructed from eight and 16 basis images (BI) and iteratively restored TACT images from eight and 16 BI were used for fracture evaluation. Twelve observers recorded their diagnoses using a five-point confidence rating scale. The data were analysed using ROC curve analysis. RESULTS: Significant differences were found (P < 0.0001) in the areas under the curve (Az): film, 0.6954; digital images 0.6169; TACT unprocessed images using 8 BI, 0.7420; TACT unprocessed images using 8 BI, 0.7667; TACT unprocessed images using 16 BI, 0.7730; TACT iteratively restored images using 16 BI, 0.8143. No observer-based differences were found. Fractures in the condylar and coronoid regions were more difficult to detect than those in the ramus and body of the mandible. CONCLUSIONS: Iteratively restored TACT images generated using 16 BI had a superior diagnostic performance to all the other imaging modalities. Studies are in order to evaluate its in vivo potential.

Analysis of Variance↗