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Biomedical subjects

L Middleton

Publications and source records attributed to L Middleton.

At least 19 recordsLinked to original sources
PubMed2005

A randomised controlled trial of self-help interventions in patients with a primary care diagnosis of irritable bowel syndrome.

INTRODUCTION: Functional abdominal symptoms are very common and account for nearly two million primary care consultations in Britain every year and produce significant morbidity. The aims of this study were to evaluate the impact of two self-help interventions on consultation rates and symptom severity in patients with a primary care diagnosis of irritable bowel syndrome. METHODS: A total of 420 patients from 54 primary care centres were randomised either to receive self-help information in the form of a guidebook or the guidebook plus a "self-help" group meeting or to be in a control group receiving neither intervention. Data were collected using questionnaires and primary care records. RESULTS: At one year, patients in the guidebook group had a 60% reduction in primary care consultations (p < 0.001) and a reduction in perceived symptom severity (p < 0.001) compared with controls. Allocation to the self-help group conferred no additional benefit. Actual symptom scores did not change significantly in any group. Costs per patient were reduced by Pounds 73 (confidence interval Pounds 43, Pounds 103) or 40% per year. CONCLUSION: Introduction of a self-help guidebook results in a reduction in primary care consultations, a perceived reduction in symptoms, and significant health service savings. This suggests that patients attending their primary care physician with functional abdominal symptoms should be offered self-help information as part of their management.

Adult↗
PubMed2003

Cardiovascular pharmacogenetics in the SNP era.

In the past pharmacological agents have contributed to a significant reduction in age-adjusted incidence of cardiovascular events. However, not all patients treated with these agents respond favorably, and some individuals may develop side-effects. With aging of the population and the growing prevalence of cardiovascular risk factors worldwide, it is expected that the demand for cardiovascular drugs will increase in the future. Accordingly, there is a growing need to identify the 'good' responders as well as the persons at risk for developing adverse events. Evidence is accumulating to indicate that responses to drugs are at least partly under genetic control. As such, pharmacogenetics - the study of variability in drug responses attributed to hereditary factors in different populations - may significantly assist in providing answers toward meeting this challenge. Pharmacogenetics mostly relies on associations between a specific genetic marker like single nucleotide polymorphisms (SNPs), either alone or arranged in a specific linear order on a certain chromosomal region (haplotypes), and a particular response to drugs. Numerous associations have been reported between selected genotypes and specific responses to cardiovascular drugs. Recently, for instance, associations have been reported between specific alleles of the apoE gene and the lipid-lowering response to statins, or the lipid-elevating effect of isotretinoin. Thus far, these types of studies have been mostly limited to a priori selected candidate genes due to restricted genotyping and analytical capacities. Thanks to the large number of SNPs now available in the public domain through the SNP Consortium and the newly developed technologies (high throughput genotyping, bioinformatics software), it is now possible to interrogate more than 200,000 SNPs distributed over the entire human genome. One pharmacogenetic study using this approach has been launched by GlaxoSmithKline to identify the approximately 4% of patients who are predisposed to developing a hypersensitivity reaction to abacavir, an anti-HIV agent. Data collected thus far on the HLA locus on chromosome 6 indicate that this approach is feasible. Extended linkage disequilibrium can be detected readily, even across several haplotype blocks, thus potentially reducing the number of SNPs for future whole-genome scans. Finally, a modest number of cases and controls appears to be sufficient to detect genetic associations. There is little doubt that this type of approach will have an impact on the way cardiovascular drugs will be developed and prescribed in the future.

Genome, Human↗
PubMed2000

A novel form of distal hereditary motor neuronopathy maps to chromosome 9p21.1-p12.

Distal hereditary motor neuronopathies (dHMNs) form a heterogeneous group of rare disorders characterized by distal weakness and wasting in the limbs with no significant sensory involvement. Harding has classified dHMNs into seven categories based on clinical and genetic criteria. We report a novel form of autosomal recessive dHMN in 7 consanguineous families located in the Jerash region of Jordan. Onset of the disease is between 6 and 10 years of age and is characterized by weakness and atrophy of the lower limbs associated with pyramidal features. Within 2 years, symptoms progress to the upper limbs. Neurophysiological studies typically show normal conduction velocities, reduced compound motor action potential amplitudes, normal sensory nerve action potentials, and chronic neurogenic changes on needle electromyography. No significant abnormalities are seen on sural nerve biopsy. We call this novel form of dHMN Jerash hereditary motor neuronopathy. We studied the families at the molecular genetic level and mapped the Jerash hereditary motor neuronopathy gene to an approximately 0.54-cM region on chromosome 9p21.1-p12, flanked by microsatellite polymorphic marker loci D9S1845 and D9S1791. A maximum LOD score of 19.80 at theta = 0.001 was obtained between the disease and locus D9S1878.

Adolescent↗
PubMed1999

Chromosome 17p-linked myasthenias stem from defects in the acetylcholine receptor epsilon-subunit gene.

OBJECTIVE: To identify and to characterize functionally the mutational basis of congenital myasthenic syndromes (CMS) linked to chromosome 17p. BACKGROUND: A total of 37 patients belonging to 13 CMS families, 9 of them consanguineous, were investigated. All patients were linked previously to the telomeric region of chromosome 17p. Two candidate genes in this region encode synaptobrevin 2, a presynaptic protein, and the epsilon-subunit of the acetylcholine receptor (AChR). Direct sequencing of the synaptobrevin 2 gene revealed no mutations. The authors thus searched for mutations in the epsilon-subunit gene of AChR. METHODS: Direct sequencing of the AChR epsilon-subunit, restriction analysis, allele-specific PCR, and expression studies in human embryonic kidney cells were performed. RESULTS: The authors identified two previously characterized and five novel epsilon-subunit gene mutations, all homozygous, in the 13 kinships. Two of the novel mutations are truncating (epsilon723delC and epsilon760ins8), one is a missense mutation in the signal peptide region (epsilonV-13D), one is a missense mutation in the N-terminal extracellular domain (epsilonT51P), and one is a splice donor site mutation in intron 10 (epsilonIVS10+2T-->G). Unaffected family members have no mutations or are heterozygous. Expression studies indicate that the four novel mutations in the coding region of the gene and the most likely transcript of the splice-site mutation, which skips exon 10, are low-expressor or null mutations. CONCLUSIONS: Chromosome 17p-linked congenital myasthenic syndromes are caused by low-expressor/null mutations in the AChR epsilon-subunit gene. Mutations in this gene are a common cause of CMS in eastern Mediterranean countries.

Adolescent↗
PubMed1998

Neonatal screening for Duchenne muscular dystrophy: a novel semiquantitative application of the bioluminescence test for creatine kinase in a pilot national program in Cyprus.

The objectives of this study were to evaluate a novel semiquantitative application of the bioluminescence test for screening newborns for Duchenne muscular dystrophy (DMD) and to use this technique in a pilot national program. The study was performed on the island of Cyprus, which provides ideal conditions for maximizing the prevention rate due to the small size of the country, the well-defined population, and the high degree of awareness of the public concerning genetic diseases. Guthrie spots were obtained through the national screening center for phenylketonuria and congenital hypothyroidism. The bioluminescence method for measuring creatine kinase (CK) in dried blood spots was adapted for use in a semiquantitative way. During the first 6 years of the program (1992-1997), we screened 30,014 samples and found 43 with initially high CK values. We were able to obtain repeat specimens in 35 cases. Of the repeat samples, 30 were found to have normal activity, giving a false-positive rate of 0.10%. Five boys had persistent CK elevations and were confirmed to be DMD or Becker (BMD) cases by DNA analysis and/or dystrophin analysis. The semiquantitative application of the bioluminescence assay of CK that we have introduced has proved to be a fast and reliable method for screening large numbers of samples for DMD. It has a low rate of false positives, which compares favorably with that of other DMD screening programs. Although it is early to evaluate its impact fully, the program seems to be bringing about the anticipated benefits to affected families.

Creatine Kinase↗
PubMed1998

Hereditary motor and sensory neuropathy--Lom, a novel demyelinating neuropathy associated with deafness in gypsies. Clinical, electrophysiological and nerve biopsy findings.

A previously unrecognized neuropathy was identified in Bulgarian gypsies, and was designated hereditary motor and sensory neuropathy-Lom (HMSNL) after the town where the initial cases were found. It was subsequently identified in other gypsy communities. The disorder, which is of autosomal recessive inheritance, was mapped to chromosome 8q24. It begins consistently in the first decade of life with gait disorder followed by upper limb weakness in the second decade and, in most subjects, by deafness which is most often first noticed in the third decade. Sensory loss affecting all modalities is present, both this and the motor involvement predominating distally in the limbs. Skeletal deformity, particularly foot deformity, is frequent. Severely reduced motor nerve conduction velocity indicates a demyelinating basis, which was confirmed by nerve biopsy. The three younger patients biopsied showed a hypertrophic 'onion bulb' neuropathy. The hypertrophic changes were not evident in the oldest individual biopsied and it is likely that they had regressed secondarily to axon loss. In the eight cases in which brainstem auditory evoked potentials could be recorded, the results suggested demyelination in the eighth cranial nerve and also abnormal conduction in the central auditory pathways in the brainstem. As no myelin genes are known to be located at chromosome 8q24, the disorder may involve a gene for a novel myelin protein or be due to an abnormality of axon-Schwann cell signalling.

Adolescent↗
PubMed1997

Multiple sclerosis in the Turkish- and Greek-speaking communities of Cyprus. A United Nations (UNHCR) Bicommunal Project.

A United Nations (UNHCR)-sponsored study has been undertaken, involving neurologists from the Turkish-speaking northern and Greek-speaking southern communities of Cyprus, to ascertain the prevalence of multiple sclerosis (MS) and to bring the medical personnel of the two communities to work together. The Turkish community includes both Turkish Cypriots and, since 1974, a big influx of immigrants from Turkey. The prevalence of MS among Turkish Cypriot men was significantly higher than in Turkish Cypriot women and was as high as has been found in men in recent studies in Northern Europe. It was also significantly higher than among Greek Cypriot men. The prevalence in Turkish Cypriot women was not significantly different to that found in Greek Cypriot women. Among the immigrants from mainland Turkey MS prevalence was significantly less for both men and women than among the Turkish Cypriots. In the Greek-speaking metropolitan area of Nicosia the prevalence of MS was 51 per 100,000, (males 43, females 59). The overall MS prevalence in four areas studied in Greek-speaking Cyprus, including three previously studied, was 42 per 100,000, (males 39, females 46 per 100,000).

Adolescent↗
PubMed1997

Small-area population estimates: a review of methods used in Britain in the 1990s.

"Population estimates are usually produced by local government administrations in Britain, for each small area within their authority. Increasing interest has been shown by commerce and by central government. Five main methods are identified: apportionment, ratio change, additive change, cohort survival, and local censuses. Estimation strategies also vary according to available data, the detail in which a population is estimated, and the precise combination of elements chosen from one or more of the main methods. The use of methods at the beginning of the 1990s is surveyed in this paper, and examples given. The accuracy of each main method is quantified from empirical data collated by the Estimating with Confidence project. Likely developments towards the end of the 1990s are reviewed."

Developed Countries↗
PubMed1997

Cytogenetic and fragile X molecular testing of individuals with mental retardation of unknown etiology.

The aim of this program was to investigate the patients with Mental Retardation Of Unknown Etiology (MROUE), on the island of Cyprus. The MROUE patients were examined cytogenetically for gross chromosomal abnormalities, and by molecular methods for the Fragile X syndrome pathology. Specialized physicians examined all institutionalized or non institutionalized patients throughout Cyprus. Cytogenetic analysis was carried out on 105 individuals, six of which showed various chromosomal aberrations. PCR and Southern blot analysis were carried out on 170 patients referred for exclusion of the Fragile X syndrome. Three patients had positive findings. Although the number of cases elucidated with this general approach was not spectacular, it allowed the resolution of a few clinically equivocal cases, to the satisfaction of the clinicians and, most importantly, the relatives involved. We believe that such screening programs should continue until all cases are thoroughly examined, thus providing definite genetic counseling and psychological support, at least in those cases that are clearly resolved. Equally important is the prospect for prevention through prenatal diagnostic programs, that are already available for such conditions.

Adolescent↗
PubMed1996

Gene mapping in Gypsies identifies a novel demyelinating neuropathy on chromosome 8q24.

Founder effect and linkage disequilibrium have been successfully exploited to map single gene disorders, and the study of isolated populations is emerging as a major approach to the investigation of genetically complex diseases. In the search for genetic isolates ranging from Pacific islands to Middle East deserts, the 10 million Gypsies resident in Europe have largely escaped the attention of geneticists. Because of their geographical ubiquity, lack of written history and the presumed social and cultural nature of their isolation, Gypsies are construed as not meeting the criteria for a well defined founder population. Gypsy society has a complex structure with subdivisions and stratifications that are incomprehensible to the surrounding populations. Marginalization by the health care systems in most countries results in a lack of information on causes of morbidity and mortality and little is known about hereditary disorders or the population genetic characteristics of Gypsies. This study is the first example of mapping a disease gene in endogamous Gypsy groups. Using lod score analysis and linkage disequilibrium, we have located a novel demyelinating neuropathy to a narrow interval on chromosome 8q24. We show that the disease, occurring in Gypsy groups of different identity and history of migrations, is caused by a single mutation whose origin predates the divergence of these groups.

Adolescent↗
PubMed1996

Evaluation of an HIV risk reduction intervention among African-American homosexual and bisexual men.

OBJECTIVE: To provide the first data which evaluates an HIV risk reduction intervention designed to reduce HIV high-risk sexual behavior in African-American homosexual and bisexual men. SUBJECTS: Participants (n = 318) were recruited from bars, bathhouses, and erotic bookstores, and through homosexual African-American organizations, street out-reach, media advertisements, and personal referrals of individuals aware of the study. METHODS: Participants were randomized into a single or triple session experimental group or a wait-list control group. Both experimental interventions included AIDS risk education, cognitive-behavioral self-management training, assertion training, and attempts to develop self-identity and social support. Data collection involved assessments of self-reported changes in sexual behavior at 12- and 18-month follow-up. RESULTS: Participants in the triple session intervention greatly reduced their frequency of unprotected anal intercourse (from 46 to 20%) at the 12-month follow-up evaluation and (from 45% to 20%) at the 18-month follow-up evaluation. However, levels of risky behavior for the control group remained constant (from 26 to 23% and from 24 to 18%) at 12- and 18-month follow-up evaluations, respectively. In addition, levels of risky behavior for the single session intervention decreased only slightly (from 47 to 38% and from 50 to 38%) at the 12- and 18-month follow-up evaluations, respectively. CONCLUSIONS: Results were interpreted to demonstrate the superiority of a triple session over a single session intervention in reducing risky sexual behavior in this cohort.

Adult↗
PubMed1995

Mutations in the dystrophin-associated protein gamma-sarcoglycan in chromosome 13 muscular dystrophy.

Severe childhood autosomal recessive muscular dystrophy (SCARMD) is a progressive muscle-wasting disorder common in North Africa that segregates with microsatellite markers at chromosome 13q12. Here, it is shown that a mutation in the gene encoding the 35-kilodalton dystrophin-associated glycoprotein, gamma-sarcoglycan, is likely to be the primary genetic defect in this disorder. The human gamma-sarcoglycan gene was mapped to chromosome 13q12, and deletions that alter its reading frame were identified in three families and one of four sporadic cases of SCARMD. These mutations not only affect gamma-sarcoglycan but also disrupt the integrity of the entire sarcoglycan complex.

Amino Acid Sequence↗
PubMed1995

Underexpression of the apolipoprotein E2 and E4 alleles in the Greek Cypriot population of Cyprus.

Apolipoprotein E (APOE) plays an important role in the multifactorial etiology of both cardiovascular disease and Alzheimer's disease. Polymerase chain reaction (PCR) was used to investigate the APOE gene polymorphism in 335 unrelated Greek Cypriots living on the island of Cyprus. For the most common APOE genotypes, the Greek Cypriots followed the general Caucasian European pattern of having higher genotypic frequencies of E3/3, followed by E3/4, and then E2/3. Among the European populations compared, Greek Cypriots exhibited the lowest relative frequency of the E3/4 genotype (12.83%). Also, the relative frequencies of the E2 and E4 alleles in Greek Cypriots were among the lowest around the world (5.4% and 7.0%, respectively). This was also demonstrated by using the complete and the average clustering methods of analysis where the APOE allele relative frequencies in Greek Cypriots were compared to 46 other populations. The Greek Cypriot population in these analyses clustered with populations mainly from south Europe and Japan which have low E2 and E4 allele frequencies. The Greek Cypriot population will be studied further for elucidating the effect(s) and the role of APOE in cardiovascular disease and the APOE4 allele as a possible metabolic factor affecting the rate of expression of both Alzheimer's disease and vascular dementia.

Adolescent↗
PubMed1995

Help-seeking for AIDS high-risk sexual behavior among gay and bisexual African-American men.

Help-seeking for AIDS high-risk sexual behavior and its association with HIV status were examined among 318 gay and bisexual men in the San Francisco Bay Area who participated in the African American Men's Health Project, a longitudinal survey of gay and bisexual African-American men. A third (36%) of the sample reported seeking help regarding their concerns about HIV high-risk sexual behavior. Peers and professionals were the most widely sought sources of help and the sources perceived to be the most helpful. Men (39%) who had received the HIV antibody test and who were HIV seropositive were more likely to seek help than men who were HIV seronegative or did not know their HIV status (25%). Furthermore, gay men who were HIV seropositive or who knew their serostatus were more likely to seek help from professionals and peers. Explanations for the differences in help-seeking by HIV-seropositive men are discussed with implications for the development of social support for HIV risk reduction among gay and bisexual African-American men.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Molecular genetic detection of Xp21 muscular dystrophy carriers in Cyprus.

Multiplex Polymerase Chain Reaction (PCR) for 18 different exons of the dystrophin gene was used to characterize the mutations in 29 Cypriot families with Duchenne or Becker Muscular Dystrophy. Deletions were detected in 21 out of 28 families from which DNA was available for an affected patient (75%). Quantitative Multiplex PCR further enabled the identification of a duplication in one of our families (3.6%). Quantitative Multiplex PCR also enabled carrier diagnosis in families where a deletion or a duplication was detectable in an affected patient. Out of 69 at-risk females examined in these families, 20 were shown by Quantitative Multiplex PCR to be carriers, including three obligatory carriers. In the remaining six families with a surviving patient, carrier diagnosis was based on haplotype analysis using microsatellite polymorphisms from the 5'- and 3'-ends of the dystrophin gene. Haplotype analysis was informative in three of the above families (10.7%). Thus, deletions or duplications were detected in 78.6% of our families with a surviving patient, while carrier diagnosis was possible in 89.3% of these families. In the single family without a surviving patient, Quantitative Multiplex PCR indicated the absence of a deletion or duplication in the mother, while haplotype analysis could not be carried out in the absence of an affected patient. The high rate of new mutations in the dystrophin gene of which only about 80% are directly detectable by Quantitative Multiplex PCR, and the difficulty of haplotype analysis in some of our families, restricts the usefulness of these techniques to about 90% of our families.

Cyprus↗
PubMed1994

Dystrophinopathy presenting as congenital muscular dystrophy.

We report a 3 1/2-year-old boy with congenital hypotonia, calf pseudohypertrophy, markedly delayed motor milestones and joint contractures. He was initially diagnosed to have congenital muscular dystrophy on the basis of the age of onset, a myopathic EMG, an elevated creatine kinase and a dystrophic muscle biopsy. Subsequently, dystrophin immunocytochemistry and immunoblot analysis showed complete absence of dystrophin. We suggest that male cases of CMD should undergo dystrophin analysis, if there is calf hypertrophy and markedly elevated CK (> 2000 U/l).

Biopsy↗