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Biomedical subjects

M Rees

Publications and source records attributed to M Rees.

At least 55 records · Page 3Linked to original sources
PubMed2000

Linkage analysis in an autosomal dominant 'zonular nuclear pulverulent' congenital cataract, mapped to chromosome 13q11-13.

PURPOSE: To determine by linkage analysis the chromosomal locus responsible for autosomal dominant congenital cataract (ADCC) in a four-generation Welsh pedigree. METHODS: The family pedigree was traced through two members of the family attending the hospital for treatment of their cataracts. Twenty-five members of the family were examined ophthalmologically and blood was collected with consent for genetic linkage analysis. RESULTS: Fifteen members of this family were known to have bilateral congenital cataracts, of whom 11 had a cataract extraction prior to examination. The youngest member of the pedigree was 5 years old and the oldest was 78 years old. Four children, unoperated at the time of this study, had a phenotypically identical morphology of their zonular pulverulent congenital cataracts. The known loci for congenital cataract were excluded. Significant lod scores for markers in the 13q11-13 region were detected with a Zmax of 3.59 D13S1236 (theta = 0.00). CONCLUSIONS: We report linkage of an ADCC of the zonular pulverulent type to chromosome 13q11-13 in a four-generation family.

Adolescent↗
PubMed1999

Bipolar disorder and the serotonin transporter gene: a family-based association study.

BACKGROUND: The human serotonin transporter gene (5-HTT) is a strong candidate for involvement in the pathogenesis of mood disorders. Two common polymorphisms have been identified in the gene: a VNTR in intron 2 and a functional deletion/insertion in the promoter region. In previous studies we proposed that allele 12 of the VNTR might increase susceptibility for bipolar disorder. METHODS: We have genotyped 122 parent-offspring trios of British Caucasian origin where the proband had DSM-IV Bipolar I disorder (BPI). The results were analysed with the transmission/ disequilibrium test (TDT), which examines whether particular alleles are preferentially transmitted from heterozygous parents to affected offspring. RESULTS: The 12 repeat in the VNTR in intron 2 was transmitted 72 times and not transmitted 56 times (chi2 = 2.0, 1 df, P = 0.16). If we exclude 24 families in which the proband was a case in our published case-control studies (Collier et al. 1996a; Rees et al. 1997), the excess transmission of allele 12 reaches conventional levels of statistical significance: chi2 = 3.85, 1 df, P < 0.05. The deletion/insertion polymorphism in the promoter region was not associated with BPI: 66 parents transmitted the inserted (L) allele and 59 parents transmitted the deleted (S) allele (chi2 = 0.39, 1 df, P = 0.53). CONCLUSIONS: The 12 repeat of the VNTR in intron 2 of the serotonin transporter gene might be a susceptibility factor in bipolar affective disorder. The genetic effect, if true, is likely to be small, and requires confirmation in further studies using parental controls.

Adult↗
PubMed1999

A new dimension to the Barker hypothesis: low birthweight and susceptibility to renal disease.

BACKGROUND: There is an epidemic of renal failure among Aborigines in the Australia's Northern Territory. The incidence is more than 1000 per million, and is doubling every three to four years. We evaluated the relationship of birthweight to renal disease in adults in one high-risk community. METHODS: We screened more than 80% of people in the community for renal disease, using the urine albumin/creatinine ratio (ACR, g/mol) as the marker, and reviewed records for birthweights. RESULTS: Birthweights were available with increasing frequency for people born after 1956. In 317 adults aged 20 to 38 years at screening, the mean birthweight (SD) was 2.712+/-0.4 kg, and 35% had been low birthweight (LBW, less than 2.5 kg). Birthweight was positively correlated with body mass index (BMI), blood pressure, and diabetes rates, but was inversely correlated with ACR. The odds ratio for overt albuminuria in LBW persons compared with those of higher birthweights was 2.82 (CI, 1.26 to 6.31) after adjusting for other factors, and LBW contributed to an estimated 27% (CI, 3 to 45%) of the population-based prevalence of overt albuminuria. Multivariate models suggest that increasing BMI and blood pressure and decreasing birthweight act in concert to amplify the increases in ACR that accompany increasing age. CONCLUSIONS: LBW contributes to renal disease in this high-risk population. The association might be mediated through impaired nephrogenesis caused by intrauterine malnutrition. The renal disease epidemic in Aborigines may partly be the legacy of greatly improved survival of LBW babies over the last four decades. Disease rates should eventually plateau as birthweights continue to improve, if postnatal risk factors can also be contained.

Adult↗
PubMed1999

Congenital trismus secondary to masseteric fibrous bands: endoscopically assisted exploration.

The authors present an 18-month-old female infant with congenital trismus. Computed tomography and magnetic resonance imaging were not helpful in determining the cause. A surgical endoscope was used to explore her temporomandibular joints and temporal fossae, thus avoiding the morbidity of a bicoronal incision. The cause was bilateral fibrous bands on the anterior border of the masseter muscles. Incision of these fibrous bands led to relief of the trismus. This finding is consistent with a previously described variant of the Hect-Beals-Wilson trismus-pseudocamptodactyly syndrome. This patient, however, had no evidence of the autosomal dominant inheritance pattern nor did she exhibit pseudocamptodactyly, both of which are generally ascribed to this syndrome. Unfortunately the trismus recurred 3 months postoperatively.

Abnormalities, Multiple↗
PubMed1999

Mouse models of spike-wave epilepsy.

The mouse is a well-established model for human genetic disorders. An increasing number of single-gene human diseases are being elucidated through the use of mouse models. Recently genes for three of the six well-characterised single locus models for human spike-wave epilepsy have been isolated and published. The tottering mouse has been shown to be due to mutations in the gene encoding the high voltage-activated alpha1A calcium channel subunit. The lethargic mouse has been shown to be due to mutations in the gene encoding another calcium channel subunit, beta4. The slow-wave epilepsy mouse phenotype is the result of loss of function of the ubiquitous sodium hydrogen exchanger NHEI. These genes and the pathways they are involved in are now candidates for human spike-wave epilepsy. The six mouse models and those genes underlying the spike-wave phenotype are discussed in conjunction with how these mutations were discovered and how they may give rise to the seizure phenotypes. Several nonepilepsy human neurologic disorders have been shown to be allelic with the tottering mouse. The question this raises as to the validity of these models for human spike-wave epilepsy is considered. Finally, the effect these discoveries will have on the understanding and treatment of human spike-wave epilepsy are discussed.

Animals↗
PubMed1999

Regulation of endometrial angiogenesis.

Bleeding problems are the most common reason for discontinuation of hormone replacement therapy. Human endometrium undergoes the unique process of benign angiogenesis under the control of ovarian steroids during reproductive life and it is presumed that similar processes occur when women take hormone replacement therapy. The key players in endometrial growth and angiogenesis are vascular endothelial growth factor, thymidine phosphorylase and adrenomedullin. Regulation of these angiogenic factors is described.

Adrenomedullin↗
PubMed1999

Studies of the lethargic (lh/lh) mouse model of absence seizures: regulatory mechanisms and identification of the lh gene.

To understand the cellular and molecular mechanisms that underlie generalized absence seizures sufficiently well to design rational, efficacious new therapies for patients, it is necessary to turn to animal models to gain insights into these mechanisms. The lethargic (lh/lh) mutant mouse expresses spontaneous absence seizures that share behavioral, electrographic, and anticonvulsant profiles with absence seizures in patients. This validates its use to study the mechanisms that underlie absence seizures. This chapter discusses two scientific approaches that involve the use of lh/lh mice. The first part of the chapter discusses neurobiologic approaches used to investigate critical mechanisms that regulate the synchronized burst firing within the thalamocortical network that generates absence seizures. Two of these critical mechanisms have been studied in detail with lh/lh mice. The first critical mechanism involves the required activation of gamma-aminobutyric acid B (GABAB) receptors to generate absence seizures. Because the numbers of GABAB receptors are increased in thalamocortical populations among lh/lh mice compared with littermates without epilepsy, these receptors appear to play a pathophysiologic role in the expression of absence seizures among lh/lh mice. Moreover, there may be a role for GABAB receptors in the generation of absence seizures among humans, because administration of compounds that activate GABAB receptors can produce absence seizures among humans. These findings suggest that GABAB receptor antagonists may represent a new class of antiabsence compounds that will be efficacious against absence seizures among patients. A second critical mechanism that regulates generation of absence seizures involves GABAA receptors in the nucleus reticularis thalami (NRT), a nucleus that sends GABA-ergic afferents to thalamic relay nuclei. Activation of GABAA receptors in the NRT appears to suppress the generation of absence seizures among lh/lh mice and in other models. Moreover, clonazepam may exert its antiabsence actions through this mechanism. Together, these findings suggest that compounds that selectively activate GABAA receptor isoforms expressed in NRT may represent a class of antiabsence drugs that could have fewer side effects than compounds currently used to treat patients. The second part of the chapter discusses a molecular genetic approach to delineation of the mechanisms that underlie absence seizures. Absence seizures among lh/lh mice are caused by a single-gene defect on chromosome 2. If positional cloning and gene isolation techniques are successful, it will be possible to identify the lh disease gene. Subsequent studies of the lh gene product should greatly increase not only our understanding of the pathophysiologic basis for absence seizures among lh/lh mice but also our ability to seek similar mutations in homologous genes in human families that express absence seizures. Accordingly, strategies and progress in cloning and identifying the lh disease gene are presented.

Animals↗
PubMed1999

Chemistry and structure activity relationships of bafilomycin A1, a potent and selective inhibitor of the vacuolar H+-ATPase.

Bafilomycin A1, a macrolide antibiotic isolated from the fermentation of Streptomyces spp., is a potent and selective inhibitor of vacuolar-type proton translocating ATP-ases (V-ATPases) and was used to study the physiological role of this class of enzymes. An extensive chemical effort on the unusual structure of this macrolide led to the synthesis of significantly different bafilomycin derivatives. None of the new analogues was more potent than the parent compound but provided a significant amount of information about the structural requirements for the inhibitory activity of bafilomycin A1 in particular on chicken osteoclast (cOc) ATPase. The vinylic methoxy group adjacent to a carbonyl function, the dienic system and the hydroxy group at position 7 were recognized to be essential features for bafilomycin V-ATPase-inhibitory activity. This information was utilized to design simplified novel derivatives as inhibitors of bone resorption.

Animals↗
PubMed1998

The evolution of diapause in a coupled host-parasitoid system.

Diapause of part of a population during a breeding opportunity is widespread among insects. We explore the evolution of such diapause in a coupled host-parasitoid system, using a discrete-generation population dynamic model that incorporates diapause. We show that diapause in the host tends to be a stabilizing factor while diapause in the parasitoid does not affect the stability boundaries. We then allow the frequency of diapause in the host and parasitoid to evolve, and find the joint population and evolutionary dynamic equilibrium by numerical methods. At the equilibrium, population dynamics exhibit cycles and host diapause always occurs. Parasitoid diapause often occurs, though this depends on exact parameter values. Thus, intrinsically generated fluctuations in fitness (due to cyclical population dynamics) lead to the evolution of diapause as a bet-hedging mechanism.

Animals↗
PubMed1998

Cloning and characterization of alpha1H from human heart, a member of the T-type Ca2+ channel gene family.

Voltage-activated Ca2+ channels exist as multigene families that share common structural features. Different Ca2+ channels are distinguished by their electrophysiology and pharmacology and can be classified as either low or high voltage-activated channels. Six alpha1 subunit genes cloned previously code for high voltage-activated Ca2+ channels; therefore, we have used a database search strategy to identify new Ca2+ channel genes, possibly including low voltage-activated (T-type) channels. A novel expressed sequence-tagged cDNA clone of alpha1G was used to screen a cDNA library, and in the present study, we report the cloning of alpha1H (or CavT.2), a low voltage-activated Ca2+ channel from human heart. Northern blots of human mRNA detected more alpha1H expression in peripheral tissues, such as kidney and heart, than in brain. We mapped the gene, CACNA1H, to human chromosome 16p13.3 and mouse chromosome 17. Expression of alpha1H in HEK-293 cells resulted in Ca2+ channel currents displaying voltage dependence, kinetics, and unitary conductance characteristic of native T-type Ca2+ channels. The alpha1H channel is sensitive to mibefradil, a nondihydropyridine Ca2+ channel blocker, with an IC50 of 1.4 micromol/L, consistent with the reported potency of mibefradil for T-type Ca2+ channels. Together with alpha1G, a rat brain T-type Ca2+ channel also cloned in our laboratory, these genes define a unique family of Ca2+ channels.

Amino Acid Sequence↗
PubMed1998

Molecular characterization of a neuronal low-voltage-activated T-type calcium channel.

The molecular diversity of voltage-activated calcium channels was established by studies showing that channels could be distinguished by their voltage-dependence, deactivation and single-channel conductance. Low-voltage-activated channels are called 'T' type because their currents are both transient (owing to fast inactivation) and tiny (owing to small conductance). T-type channels are thought to be involved in pacemaker activity, low-threshold calcium spikes, neuronal oscillations and resonance, and rebound burst firing. Here we report the identification of a neuronal T-type channel. Our cloning strategy began with an analysis of Genbank sequences defined as sharing homology with calcium channels. We sequenced an expressed sequence tag (EST), then used it to clone a full-length complementary DNA from rat brain. Northern blot analysis indicated that this gene is expressed predominantly in brain, in particular the amygdala, cerebellum and thalamus. We mapped the human gene to chromosome 17q22, and the mouse gene to chromosome 11. Functional expression of the channel was measured in Xenopus oocytes. Based on the channel's distinctive voltage dependence, slow deactivation kinetics, and 7.5-pS single-channel conductance, we conclude that this channel is a low-voltage-activated T-type calcium channel.

Amino Acid Sequence↗
PubMed1998

Properties of human glycine receptors containing the hyperekplexia mutation alpha1(K276E), expressed in Xenopus oocytes.

1. Inherited defects in human glycine receptors give rise to hyperekplexia (startle disease). We expressed human glycine receptors in Xenopus oocytes, in order to examine the pharmacological and single-channel properties of receptors that contain a mutation, alpha1(K276E), associated with an atypical form of hyperekplexia. 2. Equilibrium concentration-response curves showed that recombinant human alpha1(K276E)beta receptors had a 29-fold lower glycine sensitivity than wild-type alpha1beta receptors, and a greatly reduced Hill coefficient. The maximum response to glycine also appeared much reduced, whereas the equilibrium constant for the glycine receptor antagonist strychnine was unchanged. 3. Both wild-type and mutant channels opened to multiple conductance levels with similar main conductance levels (33 pS) and weighted mean conductances (41.5 versus 49.8 pS, respectively). 4. Channel openings were shorter for the alpha1(K276E)beta mutant than for the wild-type alpha1beta, with mean overall apparent open times of 0.82 and 6.85 ms, respectively. 5. The main effect of the alpha1(K276E) mutation is to impair the opening of the channel rather than the binding of glycine. This is shown by the results of fitting glycine dose-response curves with particular postulated mechanisms, the shorter open times of mutant channels, the properties of single-channel bursts, and the lack of an effect of the mutation on the strychnine-binding site.

Animals↗
PubMed1998

The multidimensional nature of renal disease: rates and associations of albuminuria in an Australian Aboriginal community.

BACKGROUND: An epidemic of end-stage renal disease (ESRD) is accompanying the rising rates of hypertension, type 2 diabetes and cardiovascular disease among Aborigines in the Northern Territory of Australia. Incidence rates are now 21 times those of nonAboriginal Australians and are doubling every four years. We describe the rates and associations of renal disease in one remote community, which has a current ESRD incidence of 2700 per million, and cardiovascular mortality among the highest in Australia. METHODS: Between 1992 and 1995 a community-wide screening program was conducted, in which the urinary albumin/creatinine ratio (ACR) was used as the chief renal disease marker. More than 90% of the population ages five and older participated. RESULTS: Albuminuria was evident in early childhood and increased dramatically with age; 26% of adults had microalbuminuria and 24% had overt albuminuria. All renal failure developed out of a background of overt albuminuria. ACR was significantly correlated with the presence of scabies at screening, with a history of poststreptococcal glomerulonephritis, which is epidemic and endemic in the community, with increasing body wt, blood pressure, glucose, insulin and lipid levels, and with evidence of heavy drinking. ACR was also significantly and inversely correlated with birth weight. As a result of its association with deteriorating hemodynamic and metabolic profiles, increasing ACR was also correlated with increasing cardiovascular risk score. Direct observations showed, and multivariate models predicted, progressive amplification of ACR when multiple risk factors were present simultaneously. Albuminuria also clustered in families. CONCLUSION: Renal disease in this population is multifactorial, with risk factors related to whole-of-life nutrition, metabolic and hemodynamic profiles, infections, health behaviors, and possibly a family predisposition. Its relationship to low birth weight, and its associations with deteriorating metabolic and hemodynamic profiles, suggest that renal disease is, in part, a component of Syndrome X, which explains the simultaneous increase in metabolic, cardiovascular and renal disease in Aboriginal people. The family clustering might have both environmental and genetic causes, and is under further investigation. Most of the identified risk factors arise out of poverty, disadvantage and accelerated lifestyle change, and the current epidemic can be explained by the confluence of many risk factors in the last few decades. The introduction of effective and sustained programs to address social, economic and educational inequities in all Aboriginal communities, and of screening and renal- and cardiovascular-protective treatment programs for those already afflicted are matters of great urgency.

Adolescent↗
PubMed1998

A randomized controlled trial of an intervention designed to improve the care given in general practice to Type II diabetic patients: patient outcomes and professional ability to change behaviour.

AIM: Our objective was to evaluate the effect of training in a patient-centred intervention for GPs and practice nurses on outcomes for patients with Type II diabetes. METHODS: We carried out a randomized controlled trial within general practices as the basis for randomization and a before-and-after design for measures of patient outcome. A parallel process study examined the use of the method by professionals. The study was carried out in 29 general practices in South Glamorgan who had participated for at least 2 years in a local scheme of audit and CME in relation to Type II diabetes care. The subjects were 252 Type II diabetic patients recruited by 15 experimental and 14 control practices. The main outcome measures were changes in glycosylated haemoglobin, patient satisfaction with care and treatment, functional health status and professional ability to apply the intervention. RESULTS: Professionals adopted the innovative method with enthusiasm, but after 2 years only 19% continued to apply the method systematically. The trial was, therefore, unable to demonstrate significant biochemical or functional improvements. This highlights the need to understand the factors associated with professional uptake and subsequent ability to sustain changes in behaviour. CONCLUSIONS: The efficacy of this behavioural intervention remains unproved, despite its acceptability to professional staff. Detailed and prolonged development and testing of behavioural interventions is an essential first step before embarking on randomized controlled trials which involve complex behavioural changes in professionals or patients.

Adult↗