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Biomedical subjects

R A Lewis

Publications and source records attributed to R A Lewis.

At least 55 records · Page 3Linked to original sources
PubMed2001

Evaluation of the G protein coupled receptor-75 (GPR75) in age related macular degeneration.

BACKGROUND: A long term project was initiated to identify and to characterise genes that are expressed exclusively or preferentially in the retina as candidates for a genetic susceptibility to age related macular degeneration (AMD). A transcript represented by a cluster of five human expressed sequence tags (ESTs) derived exclusively from retinal cDNA libraries was identified. METHODS: Northern blot and RT-PCR analyses confirmed preferential retinal expression of the gene, which encodes a G protein coupled receptor, GPR75. Following isolation of the full length cDNA and determination of the genomic organisation, the coding sequence of GPR75 was screened for mutations in 535 AMD patients and 252 controls from Germany, the United States, and Italy. Employed methods included single stranded conformational polymorphism (SSCP) analysis, denaturing high performance liquid chromatography (DHPLC), and direct sequencing. RESULTS: Nine different sequence variations were identified in patients and control individuals. Three of these (-30A>C, 150G>A, and 346G>A) likely represent polymorphic variants. Each of six alterations (-4G>A, N78K, P99L, S108T, T135P, and Q234X) were found once in single AMD patients and were considered variants that could affect the protein function and potentially cause retinal pathology. CONCLUSION: The presence of six potential pathogenic variants in a cohort of 535 AMD patients alone does not provide statistically significant evidence for the association of sequence variation in GPR75 with genetic predisposition to AMD. However, a possible connection between the variants and age related retinal pathology cannot be discarded. Functional studies are needed to clarify the role of GPR75 in retinal physiology.

Adult↗
PubMed2001

A prospective, open-label treatment trial to compare the effect of IFNbeta-1a (Avonex), IFNbeta-1b (Betaseron), and glatiramer acetate (Copaxone) on the relapse rate in relapsing--remitting multiple sclerosis: results after 18 months of therapy.

We previously reported results of a 12 month prospective, non-randomized, open-label treatment trial of immunomodulatory therapy in patients with relapsing-remitting multiple sclerosis (RRMS). We now report the results after 18 months of follow-up. Our primary objective was to compare the effect of IFNbeta-1a (Avonex), IFNbeta-1b (Betaseron), and Glatiramer Acetate (GA, Copaxone) to no treatment on the relapse rate in patients with RRMS. One hundred and fifty-six consecutive patients with clinically definite RRMS with a Kurtzke scale (EDSS) score of 4 or less were followed for 18 months. Prior 2-year relapse history and available chart information was carefully reviewed at the time of enrollment Thirty-three of 156 elected no treatment at enrollment; 40 elected IFNbeta-1a, 41 IFNbeta-1b, and 42 chose GA. There were no statistically significant differences among the four groups at enrollment. After 18 months of treatment 122 patients remained in their original treatment group. Compared to the untreated group (1.02), mean annualized number of relapses was significantly reduced only in the GA (0.49, P>0.0001) and IFNbeta-1b groups (0.55, P=0.001) in contrast to the IFNbeta-1a treated patients (0.81, P=0.106) who did not show a significant reduction. Despite limitations of the study design, the results provide helpful clinical information regarding the relative efficacy of each therapy in mildly affected treatment naive RRMS patients.

Adjuvants, Immunologic↗
PubMed2001

Outpatient shoulder surgery: a prospective analysis of a perioperative protocol.

During a 10-month period, 106 consecutive outpatient shoulder procedures were done in 102 patients who were followed up prospectively for a minimum of 6 months. The procedures included arthroscopic surgery alone (60%) and open surgeries with or without associated arthroscopy (40%). The anesthetic protocol included propofol and nitrous oxide, without scalene block augmentation, and local 0.5% bupivacaine. Patients were discharged with oral analgesics. Ninety-five percent of the patients successfully underwent their procedure as an outpatient; only 5% required admission on the day of surgery, and none required readmission. There were no short- or long-term postoperative complications attributable to the protocol. Ninety-six percent of the patients were satisfied with their pain management, and all patients were satisfied with their overall experience.

Ambulatory Surgical Procedures↗
PubMed2001

Null missense ABCR (ABCA4) mutations in a family with stargardt disease and retinitis pigmentosa.

PURPOSE: To determine the type of ABCR mutations that segregate in a family that manifests both Stargardt disease (STGD) and retinitis pigmentosa (RP), and the functional consequences of the underlying mutations. METHODS: Direct sequencing of all 50 exons and flanking intronic regions of ABCR was performed for the STGD- and RP-affected relatives. RNA hybridization, Western blot analysis, and azido-adenosine triphosphate (ATP) labeling was used to determine the effect of disease-associated ABCR mutations in an in vitro assay system. RESULTS: Compound heterozygous missense mutations were identified in patients with STGD and RP. STGD-affected individual AR682-03 was compound heterozygous for the mutation 2588G-->C and a complex allele, [W1408R; R1640W]. RP-affected individuals AR682-04 and-05 were compound heterozygous for the complex allele [W1408R; R1640W] and the missense mutation V767D. Functional analysis of the mutation V767D by Western blot and ATP binding revealed a severe reduction in protein expression. In vitro analysis of ABCR protein with the mutations W1408R and R1640W showed a moderate effect of these individual mutations on expression and ATP-binding; the complex allele [W1408R; R1640W] caused a severe reduction in protein expression. CONCLUSIONS: These data reveal that missense ABCR mutations may be associated with RP. Functional analysis reveals that the RP-associated missense ABCR mutations are likely to be functionally null. These studies of the complex allele W1408R; R1640W suggest a synergistic effect of the individual mutations. These data are congruent with a model in which RP is associated with homozygous null mutations and with the notion that severity of retinal disease is inversely related to residual ABCR activity.

ATP-Binding Cassette Transporters↗
PubMed2000

Pharmacological inhibition of phosphatidylcholine biosynthesis is associated with induction of phosphatidylinositol accumulation and cytolysis of neoplastic cell lines.

De novo production of phosphatidic acid (PA) in tumor cells is required for phospholipid biosynthesis and growth of tumor cells. In addition, PA production by phospholipase D has been cited among the effects of certain oncogenes and growth factors. In this report, it has been demonstrated that enhanced phospholipid metabolism through PA in tumor cells can be exploited pharmacologically for development of anticancer agents, such as CT-2584, a cancer chemotherapeutic drug candidate currently in Phase II clinical trials. By inhibiting CTP:choline-phosphate cytidylyltransferase (CT), CT-2584 caused de novo phospholipid biosynthesis via PA to be shunted away from phosphatidylcholine (PC) and into phosphatidylinositol (PI), the latter of which was doubled in a variety of CT-2584-treated tumor cell lines. In contrast, cytotoxic concentrations of cisplatin did not induce accumulation of PI, indicating that PI elevation by CT-2584 was not a general consequence of chemotherapy-induced cell death. Consistent with this mechanism of action, propranolol, an inhibitor of PA phosphohydrolase and phosphatidylcholine biosynthesis, was also cytotoxic to tumor cell lines, induced PI accumulation, and potentiated the activity of CT-2584 in cytotoxicity assays. As expected from biophysical properties of anionic phospholipids on cellular membranes, CT-2584 cytotoxicity was associated with disruption and swelling of endoplasmic reticulum and mitochondria. We conclude that CT-2584 effects a novel mechanism of cytotoxicity to cancer cells, involving a specific modulation of phospholipid metabolism.

Adrenergic beta-Antagonists↗
PubMed2000

Breast cancer diagnosis using scattered X-rays.

Small-angle X-ray diffraction data has been collected from 99 ;core-cut' breast tissue specimens representing a number of different pathologies. Data in the range 75-1390 A have been compared with controls from patients with no breast disease. Bessel functions and Bragg maxima resulting from the fibrillar structure of collagen have been identified. The Bragg maxima indexed onto a 649 A lattice. Systematic differences in the intensities and D-spacings between the collagen of malignant, benign and normal tissue groups have been clearly demonstrated and quantified. These differences appear to be due to a significantly lower structural order within the malignant tissues. Possible explanations for this are discussed and the potential for utilizing this observation in cancer diagnosis is considered.

Journal Article↗
PubMed2000

Macular degeneration: the emerging genetics.

Discovery of the gene responsible for a recessive, early-onset maculopathy has focused attention on a biomolecular pathway in which subtle metabolic flaws become toxic to irreplaceable retinal cells. The pathway's identification points toward specific ways of intervening. Among patients with age-related macular degeneration, carriers of single mutations in the same gene are proving to be remarkably common.

ATP-Binding Cassette Transporters↗
PubMed2000

Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium.

Familial incontinentia pigmenti (IP; MIM 308310) is a genodermatosis that segregates as an X-linked dominant disorder and is usually lethal prenatally in males. In affected females it causes highly variable abnormalities of the skin, hair, nails, teeth, eyes and central nervous system. The prominent skin signs occur in four classic cutaneous stages: perinatal inflammatory vesicles, verrucous patches, a distinctive pattern of hyperpigmentation and dermal scarring. Cells expressing the mutated X chromosome are eliminated selectively around the time of birth, so females with IP exhibit extremely skewed X-inactivation. The reasons for cell death in females and in utero lethality in males are unknown. The locus for IP has been linked genetically to the factor VIII gene in Xq28 (ref. 3). The gene for NEMO (NF-kappaB essential modulator)/IKKgamma (IkappaB kinase-gamma) has been mapped to a position 200 kilobases proximal to the factor VIII locus. NEMO is required for the activation of the transcription factor NF-kappaB and is therefore central to many immune, inflammatory and apoptotic pathways. Here we show that most cases of IP are due to mutations of this locus and that a new genomic rearrangement accounts for 80% of new mutations. As a consequence, NF-kappaB activation is defective in IP cells.

Exons↗
PubMed2000

Multiple CYP1B1 mutations and incomplete penetrance in an inbred population segregating primary congenital glaucoma suggest frequent de novo events and a dominant modifier locus.

Primary congenital glaucoma (PCG) is an autosomal recessive disorder associated with unknown developmental defect(s) in the anterior chamber. Recently, we reported three distinct mutations in CYP1B1, the gene for cytochrome P4501B1, in 25 Saudi families segregating PCG. For this report, we analyzed 37 additional families and confirmed the initial finding of decreased penetrance. Mutations and intragenic single-nucleotide polymorphisms (SNPs) were also analyzed from direct sequencing of all CYP1B1 coding exons. Eight distinct mutations were identified: G61E, R469W and D374N, the most common Saudi mutations, account for 72, 12 and 7%, respectively, of all the PCG chromosomes. Five additional homozygous mutations (two deletions and three missense mutations) were detected, each in a single family. Affected individuals from five families had no CYP1B1 coding mutations, and each family had a unique SNP profile. The identification of eight distinct mutations in a single gene, on four distinct haplotypes, suggests a relatively recent occurrence of multiple mutations in CYP1B1 in Saudi Arabia. These data demonstrate decreased penetrance of the PCG phenotype in the Saudi population, because 40 apparently unaffected individuals in 22 families have mutations and haplotypes identical to their affected siblings. Two individuals were subsequently diagnosed with glaucoma and two others had abnormal ocular findings that are consistent with milder forms of glaucoma. Analysis of these 22 kindreds suggests the presence of a dominant modifier locus that is not linked genetically to CYP1B1. Linkage and Southern analyses excluded three candidate modifier loci.

Amino Acid Sequence↗
PubMed2000

Electrophysiological features of inherited demyelinating neuropathies: A reappraisal in the era of molecular diagnosis.

The observation that inherited demyelinating neuropathies have uniform conduction slowing and that acquired disorders have nonuniform or multifocal slowing was made prior to the identification of mutations in myelin-specific genes which cause many of the inherited disorders involving peripheral nerve myelin. It is now clear that the electrophysiological aspects of these disorders are more complex than previously realized. Specifically, certain mutations appear to induce nonuniform slowing of conduction which resemble the findings in acquired demyelinating neuropathies. It is clinically important to recognize the different electrodiagnostic patterns of the various inherited demyelinating neuropathies. In addition, an understanding of the relationship between mutations of specific genes and their associated neurophysiological findings is likely to facilitate understanding of the role of these myelin proteins in peripheral nerve function and of how abnormalities in myelin proteins lead to neuropathy. We therefore review the current information on the electrophysiological features of the inherited demyelinating neuropathies in hopes of clarifying their electrodiagnostic features and to shed light on the physiological consequences of the different genetic mutations.

Electrophysiology↗
PubMed2000

Ziprasidone for schizophrenia and severe mental illness.

BACKGROUND: Typical antipsychotic drugs are widely used as the first line treatment for people with schizophrenia. However, the atypical class of antipsychotic drugs are making important inroads into this approach. Atypical is a widely used term used to describe some antipsychotics which have a low propensity to produce movement disorders, sedation and raised serum prolactin. There is some suggestion that the different adverse effect profiles of the atypical antipsychotic group make them more acceptable to people with schizophrenia. Ziprasidone is one of the newer atypicals with a high serotonin/dopamine receptor affinity. OBJECTIVES: To determine the effects of ziprasidone compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia and related psychoses. SEARCH STRATEGY: Electronic searches of Biological Abstracts (1980-1999), The Cochrane Library (Issue 1, 1999), The Cochrane Schizophrenia Group's Register (January 1999), EMBASE (1980-1999), MEDLINE (1966-1999), LILACS (1982-1996), PSYNDEX (1977-1995) and PsycLIT (1974-1999) were undertaken. In addition, pharmaceutical databases on the Dialog Corporation Datastar and Dialog services were searched. References of all identified studies were searched for further trials. Pharmaceutical companies and authors of trials were contacted. SELECTION CRITERIA: All randomised controlled trials that compared ziprasidone to other treatments for schizophrenia and schizophrenia-like psychoses were included by independent assessment. DATA COLLECTION AND ANALYSIS: Citations and, where possible, abstracts were independently inspected by reviewers, papers ordered, re-inspected and quality assessed. Data were independently extracted. Data were excluded if loss to follow up was greater than 50%. For homogeneous dichotomous data the risk ratio (RR), 95% confidence interval (CI) and, where appropriate, the number needed to treat (NNT) were calculated on an intention-to-treat basis. For continuous data, weighted mean differences were calculated (WMD). All data were inspected for heterogeneity. MAIN RESULTS: Data for this compound range from very short (1 week) studies of the intramuscular preparation, to trials lasting over six months. For measures of mental state ziprasidone seems more effective than placebo (RR 0.8 CI 0.7-0.9) and as effective as haloperidol (RR 0.8 CI 0.7-1). It is less likely than haloperidol to cause movement disorders (RR 0.4 CI 0.2-0.6), but may cause more nausea and vomiting (RR 2.1 CI 1.2-3.8). The injected form of the drug may cause more pain at the injection site than haloperidol (RR 5.3 CI 1.3-22). REVIEWER'S CONCLUSIONS: Currently data are limited. Ziprasidone may be an effective antipsychotic with less extrapyramidal effects than haloperidol. It also may, however, cause more nausea and vomiting than the typical drugs, and, at present, there is no data suggesting that it is different to other atypical compounds. Well planned, conducted and reported long term randomised trials are needed if ziprasidone is to be accepted into everyday use.

Antipsychotic Agents↗
PubMed2000

Complex inheritance of ABCR mutations in Stargardt disease: linkage disequilibrium, complex alleles, and pseudodominance.

Stargardt disease is a recessively transmitted disease caused by mutations in the ABCR gene. Linkage disequilibrium has recently been reported between a polymorphism, 2828 A, and a common Western European founder mutation, 2588 C. Here, we confirm this linkage disequilibrium in a North American population. We also describe two complex alleles involving the 2828 A and 2588 C alterations and suggest a possible order of clinical severity of mutations identified in trans to the complex alleles. Finally, we report pseudodominance of Stargardt disease in a family with the 2588 C mutation, further supporting a high frequency of carriers for ABCR mutations in our population.

ATP-Binding Cassette Transporters↗
PubMed2000

Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder predominantly characterized by obesity, retinal dystrophy, polydactyly, learning difficulties, hypogenitalism and renal malformations, with secondary features that include diabetes mellitus, endocrinological dysfunction and behavioural abnormalities. Despite an initial expectation of genetic homogeneity due to relative clinical uniformity, five BBS loci have been reported, with evidence for additional loci in the human genome; however, no genes for BBS have yet been identified. We performed a genome screen with BBS families from Newfoundland that were excluded from BBS1-5 and identified linkage with D20S189. Fine-mapping reduced the critical interval to 1.9 cM between D20S851 and D20S189, encompassing a chaperonin-like gene. Mutations in this gene were recently reported to be associated with McKusick-Kaufman syndrome (MKKS; ref. 8). Given both the mapping position and clinical similarities of these two syndromes, we screened MKKS and identified mutations in five Newfoundland and two European-American BBS pedigrees. Most are frameshift alleles that are likely to result in a non-functional protein. Our data suggest that a complete loss of function of the MKKS product, and thus an inability to fold a range of target proteins, is responsible for the clinical manifestations of BBS.

Alleles↗
PubMed2000

Charcot-Marie-Tooth disease type 1: molecular pathogenesis to gene therapy.

Charcot-Marie-Tooth disease type 1 (CMT1) is caused by mutations in the peripheral myelin protein, 22 kDa (PMP22) gene, protein zero (P0) gene, early growth response gene 2 (EGR-2) and connexin-32 gene, which are expressed in Schwann cells, the myelinating cells of the peripheral nervous system. Although the clinical and pathological phenotypes of the various forms of CMT1 are similar, including distal muscle weakness and sensory loss, their molecular pathogenesis is likely to be quite distinct. In addition, while demyelination is the hallmark of CMT1, the clinical signs and symptoms of the disease are probably produced by axonal degeneration, not demyelination itself. In this review we discuss the molecular pathogenesis of CMT1, as well as approaches to an effective gene therapy for this disease.

Charcot-Marie-Tooth Disease↗