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M Alexander

Publications and source records attributed to M Alexander.

At least 19 recordsLinked to original sources
PubMed2006

Activators of viral gene expression in polarized epithelial monolayers identified by rapid-throughput drug screening.

Epithelial polarity and tight junction formation limit the ability of adenovirus, retrovirus and adeno-associated virus (AAV) to deliver and express virally encoded genes. Using an extended half-life luciferase assay and high-throughput luminometry, we screened 23 000 compounds and natural product extracts as potentiators to overcome this barrier. Seven strong activators were discovered (up to several hundred fold above control) and two of these exhibited spectrum of activity in multiple cell types (HeLa (human cervical carcinoma), cystic fibrosis bronchial epithelial (human bronchial), HT29 (human colonic carcinoma), Calu3 (airway serous glandular)). Enhanced transduction by unrelated gene transfer vectors (adenovirus, lentivirus, AAV, liposomal) was also observed. These results establish a strategy for identifying compounds that improve viral gene transfer to resistant cell types, and provide new tools for examining epithelial defense against viral infection. The compounds should have broad usefulness in experimental therapies for cancer and genetic diseases.

Adenoviridae↗
PubMed2006

Fitness of hybrids between rapeseed (Brassica napus) and wild Brassica rapa in natural habitats.

Fitness of hybrids between genetically modified (GM) crops and wild relatives influences the likelihood of ecological harm. We measured fitness components in spontaneous (non-GM) rapeseed x Brassica rapa hybrids in natural populations. The F1 hybrids yielded 46.9% seed output of B. rapa, were 16.9% as effective as males on B. rapa and exhibited increased self-pollination. Assuming 100% GM rapeseed cultivation, we conservatively predict < 7000 second-generation transgenic hybrids annually in the United Kingdom (i.e. approximately 20% of F1 hybrids). Conversely, whilst reduced hybrid fitness improves feasibility of bio-containment, stage projection matrices suggests broad scope for some transgenes to offset this effect by enhancing fitness.

Brassica napus↗
PubMed2005

Once-daily ciclesonide 80 or 320 microg for 12 weeks is safe and effective in patients with persistent asthma.

The efficacy and safety of ciclesonide was assessed in this randomized, placebo-controlled study in patients with persistent asthma (randomized n=360) maintained on low to moderate doses of inhaled corticosteroids. Patients were randomized to receive ciclesonide 80 or 320 microg (ex-actuator doses, equivalent to 100 and 400 microg ex-valve, respectively) or placebo once daily in the morning via metered-dose inhaler for 12 weeks. Morning peak expiratory flow was maintained throughout the treatment period in patients treated with ciclesonide and decreased significantly in patients treated with placebo (P=0.0003). Ciclesonide (80 and 320 microg) significantly increased forced expiratory volume in 1s from baseline (0.13 and 0.19 L increases, respectively; P<0.01); improvements were superior versus placebo (P=0.0044 for 80 microg ciclesonide; P<0.0001 for 320 microg ciclesonide). The probability of losing efficacy decreased in a dose-dependent manner (55% for placebo, 38% for ciclesonide 80 microg, 23% for ciclesonide 320 microg). Asthma symptom scores and rescue medication use were unchanged with ciclesonide and significantly worsened with placebo. The incidence of adverse events was comparable in all treatment groups and no cortisol suppression was observed. Therefore, ciclesonide 80 and 320 microg administered once daily was a safe and effective maintenance treatment for patients with persistent asthma.

Administration, Inhalation↗
PubMed2005

Maintenance of asthma control by once-daily inhaled ciclesonide in adults with persistent asthma.

BACKGROUND: Inhaled corticosteroids (ICS) are recommended therapy for persistent asthma, although side effects can limit appropriate use. Ciclesonide, a novel ICS, is activated in the lung, thereby reducing systemic activity and side effects. This 12-week, double-blind, randomized, parallel-group, placebo-controlled study evaluated the efficacy and safety of ciclesonide in adults with persistent asthma. METHODS: After a 2-week baseline period in which current ICS treatment was continued, 329 patients were randomized to receive ciclesonide 160 microg (n = 107) or 640 microg (n = 112) (ex-actuator doses, equivalent to 200 and 800 microg ex-valve, respectively), or placebo (n = 110) once daily in the morning. Efficacy was monitored by asthma symptom scores, rescue medication use, morning and evening peak expiratory flow (PEF) measurements, spirometry, and probability of study completion without experiencing lack of efficacy. RESULTS: Morning PEF remained stable with either ciclesonide dose but decreased with placebo; the differences were significant (P < 0.0001) for both ciclesonide doses vs placebo. The forced expiratory volume in 1 s and forced vital capacity decreased significantly with placebo (P < 0.005), but were unchanged with ciclesonide. Lack of efficacy was significantly greater for patients switched to placebo (63%) than it was for those treated with ciclesonide 160 microg (30%) (P < 0.0001 vs placebo) or ciclesonide 640 microg (31%) (P < 0.0001 vs placebo). There were no significant differences between the two tested doses of ciclesonide with respect to efficacy and safety. Serum and 24-h urine cortisol were unaffected by ciclesonide treatment. Both doses of ciclesonide were well tolerated with no cases of oral candidiasis. CONCLUSION: Ciclesonide (160 or 640 microg) once daily in the morning effectively maintains asthma control, does not affect cortisol levels, and has an adverse event profile comparable with placebo in adults with primarily mild to moderate asthma.

Administration, Inhalation↗
PubMed2005

Cerebral venous sinus thrombosis presenting as subdural haematoma.

The authors report a 39-year-old woman who presented with intermittent, excruciating nuchal and occipital headache. Magnetic resonance imaging and magnetic resonance angiography scans showed bilateral subdural haematomas with veno-occlusive disease of the superficial and deep venous systems. There were bridging collaterals with scalp veins, bleeds from which could explain the subdural haematoma. There was acute on chronic veno-occlusive disease with an acute rise in intracranial pressure and a bleed from the vein of Galen.

Adult↗
PubMed2005

Clinical and laboratory features and response to treatment in patients presenting with vitamin B12 deficiency-related neurological syndromes.

AIMS AND OBJECTIVES: To study the clinical and laboratory features of patients admitted with vitamin B12 deficiency-related (B12def) neurological syndromes. SETTINGS AND DESIGN: A hospital-based retrospective and prospective study conducted at a referral teaching hospital. MATERIALS AND METHODS: Consecutive patients admitted with vitamin B12 deficiency-related neurological disorders during a three-year period from June 2000 to May 2003 were included. Data regarding clinical and laboratory features were obtained. Follow-up was done at least six months following treatment with parenteral vitamin B12. Chi-square test was used for statistical analysis. RESULTS: A total of 63 patients (52 males) with a mean age of 46.2 years were studied. The mean duration of symptoms at presentation was 10.3 months. Myeloneuropathy (54%) was the commonest neurological manifestation, followed by myeloneuropathy with cognitive dysfunction (34%), and peripheral neuropathy (9%). Neuropsychiatric manifestations and dementia were observed in 38% and 19% of patients respectively. All the patients had megaloblastic changes in the bone marrow smear. Eleven (17.5%) patients had both hemoglobin and the mean corpuscular volume (MCV) within the normal range. Follow-up after at least six months of therapy with parenteral B12 showed improvement in 54% patients. CONCLUSIONS: A high index of suspicion of B12def is required in patients presenting with myelopathy, cognitive decline, or neuropathy. A normal hemoglobin or MCV does not exclude B12def; therefore, other tests such as bone marrow smear and serum vitamin B12 assay are essential, as the condition is often reversible with treatment.

Adult↗
PubMed2004

Recent experience with Rett syndrome at a tertiary care center.

Rett syndrome (RS), a neurological developmental disorder, is one of the commonest causes of cognitive impairment in girls and women. These patients are often initially misdiagnosed as idiopathic mental retardation, cerebral palsy, or autism. Despite several reports from the West, there are very few reports from the Indian population. We present four female children with RS and emphasize the importance of early diagnosis.

Brain↗
PubMed2003

Linkage of a bipolar disorder susceptibility locus to human chromosome 13q32 in a new pedigree series.

Bipolar (BP) disorder or manic depressive illness is a major psychiatric disorder for which numerous family, twin and adoption studies support a substantial genetic contribution. Recently, we reported the results of a genome-wide search for BP disorder susceptibility loci in 20 pedigrees. Suggestive evidence for linkage was found in this study at three markers on 13q, representing possibly two peaks separated by 18 cM. We have now collected a second set of 32 pedigrees segregating BP disorder and have tested for evidence of linkage to markers on human chromosome 13q. In this sample, we have replicated the linkage result in 13q32 at D13S154 (lod=2.29), the more proximal of the two original peaks. When all 52 pedigrees were combined, the multipoint maximum lod score peaked approximately 7 cM proximal to D13S154 (lod=3.40), with a second peak occurring between D13S225 and D13S796 (lod=2.58). There have been several other reports of significant linkage to both BP disorder and schizophrenia in this region of chromosome 13. These pedigrees provide additional evidence for at least one locus for BP disorder in 13q32, and are consistent with other reports of a possible genetic overlap between these disorders.

Bipolar Disorder↗
PubMed2003

Evidence that a single nucleotide polymorphism in the promoter of the G protein receptor kinase 3 gene is associated with bipolar disorder.

In a genome-wide linkage survey, we have previously shown evidence suggesting that the chromosome 22q12 region contains a susceptibility locus for bipolar disorder (BPD). Two independent family sets yielded lod scores suggestive of linkage at markers in this region near the gene G protein receptor kinase 3 (GRK3). GRK3 is an excellent candidate risk gene for BPD since GRK3 is expressed widely in the brain, and since GRKs play key roles in the homologous desensitization of G protein-coupled receptor signaling. We have also previously shown GRK3 expression to be induced by amphetamine in an animal model of mania using microarray-based expression profiling. To identify possible functional mutations in GRK3, we sequenced the putative promoter region, all 21 exons, and intronic sequence flanking each exon, in 14-22 individuals with BPD. We found six sequence variants in the 5'-UTR/promoter region, but no coding or obvious splice variants. Transmission disequilibrium analyses of one set of 153 families indicated that two of the 5'-UTR/promoter variants are associated with BPD in families of northern European Caucasian ancestry. A supportive trend towards association to one of these two variants (P-5) was then subsequently obtained in an independent sample of 237 families. In the combined sample, the P-5 variant had an estimated allele frequency of 3% in bipolar subjects, and displayed a transmission to non-transmission ratio of 26 : 7.7 (chi(2)=9.6, one-sided P value=0.0019). Altogether, these data support the hypothesis that a dysregulation in GRK3 expression alters signaling desensitization, and thereby predisposes to the development of BPD.

Animals↗
PubMed2003

Effect of a multidisciplinary amyotrophic lateral sclerosis (ALS) clinic on ALS survival: a population based study, 1996-2000.

BACKGROUND: In recent years, there has been a paradigm shift in the method of healthcare delivery to amyotrophic lateral sclerosis (ALS) patients with the emergence of multidisciplinary ALS clinics that cater exclusively for patients with this condition. The impact of multidisciplinary management has not been previously evaluated. METHODS: Using data from the Irish ALS Register, we conducted a prospective, population based study of all ALS cases diagnosed in Ireland over a five year period to evaluate the effectiveness of a multidisciplinary clinic on ALS survival. RESULTS: Eighty two (24%) patients attended the multidisciplinary ALS clinic, with the remaining 262 (76%) cases followed in a general neurology clinic. The ALS clinic cohort was an average of five years younger (60.1 v 65.6 years) and were more likely to receive riluzole than the general neurology cohort (99% v 61%). The median survival of the ALS clinic cohort was 7.5 months longer than for patients in the general neurology cohort (logrank = 15.4, p < 0.0001). Overall, one year mortality was decreased by 29.7%. Prognosis of bulbar onset patients was extended by 9.6 months if they attended the ALS clinic. Using multivariate analysis, attendance at the ALS clinic was an independent covariate of survival (HR = 1.47, p = 0.02). CONCLUSIONS: ALS patients who received their care at a multidisciplinary clinic had a better prognosis than patients attending a general neurology clinic. The data suggest that active and aggressive management enhances survival, particularly among ALS patients with bulbar dysfunction. The effect of clinic type must be considered in future clinical trials design.

Adult↗
PubMed2002

Structure, dynamics, and optical properties of concentrated milk suspensions: an analogy to hard-sphere liquids.

A systematic study of the effects of volume fraction increment on the optical properties, the structure, and the dynamics of the casein micelles and fat droplets in milk was performed using diffusing wave spectroscopy. Four types of milk were investigated, NIDO full fat milk, fat-free milk, whey and fat-free milk, and finally lactose and fat-free milk. Independent measurements to calculate the dependence of the viscosity and the index of refraction of the milk serum and casein micelles as a function of the volume fraction were also performed. We compare the experimentally determined quantities photon transport mean free path (l*) and self-diffusion coefficient D(s) with the predictions from theoretical calculations using classical colloidal models such as a hard-sphere fluid. We demonstrate that all types of milk with and without fat content behave, structurally, like colloidal hard-sphere systems up to volume fractions well over 45%. In the case of dynamic measurements, both lactose- and fat-free and whey- and fat-free milk behave also like hard-sphere systems whereas fat-free milk and fat-containing NIDO milk deviate slightly at volume fractions over 35%. Finally, a comparative measurement and theoretical calculation of the casein micelle's size was performed.

Animals↗
PubMed2002

MMP-2, TIMP-2 and MT1-MMP are differentially expressed in lesional skin of melanocytic nevi and their expression is modulated by UVB-light.

BACKGROUND: In malignant melanoma, recent studies have demonstrated an important role of matrix-metalloproteinase 2 (MMP-2), its co-activating enzyme membrane-type matrix-metalloproteinase 1 (MT1-MMP), and the endogenous inhibitor of MMP-2, tissue-inhibitor of matrix metalloproteinase 2 (TIMP-2). Melanocytic nevi are benign neoplasms of the melanocytic lineage, but may exhibit dysplastic features that can be difficult to distinguish from early stage melanoma. As shown in earlier studies, nevi show important morphological and phenotypical changes in response to ultraviolet light (UVB) irradiation. OBJECTIVE: To clarify the role of MMP-2, TIMP-2 and MT1-MMP in UVB-irradiated vs. non-irradiated melanocytic nevi. METHODS: Immunohistochemical comparison of the MMP-2, TIMP-2 and MT1-MMP expression pattern. RESULTS: MMP-2 is expressed by lesional keratinocytes and its expression is up-regulated by UVB-irradiation. MMP-2 expression was not observed in melanocytic cells. TIMP-2, by contrast, is predominantly expressed by melanocytic nevus cells, and its expression is in part down-regulated by UVB-irradiation. MT1-MMP is expressed by basal keratinocytes and to a weaker extent by melanocytic nevus cells. CONCLUSIONS: MMP-2 expression by keratinocytes in nevi probably represents the result of activation of keratinocyte turnover in lesional epidermis. MMP-2 could play a role in the downward movement of junctional nevus cells into the dermis. The reduction of TIMP-2 expression in melanocytic cells by UV-light together with the enhanced expression of MMP-2 in the adjacent epidermis may promote basement membrane degradation. The expression pattern of MT1-MMP in close proximity to epithelial-mesenchymal interfaces underlines the synergistic role of MT1-MMP in this process.

Adult↗
PubMed2002

Segmental linkage disequilibrium within the dopamine transporter gene.

The dopamine transporter gene (DAT) has been implicated in a variety of disorders, including bipolar disorder, attention-deficit hyperactivity disorder, cocaine-induced paranoia, Tourette's syndrome, and Parkinson's disease. As no clear functional polymorphism has been identified to date, studies rely on linkage disequilibrium (LD) to assess the possible genetic contribution of DAT to the various disorders. A better understanding of the complex structure of LD across the gene is thus critical for an accurate interpretation of the results of such studies, and may facilitate the mapping of the actual functional variants. In the process of characterizing the extent of variation within the DAT gene, we have identified a number of single nucleotide polymorphisms (SNPs) suitable for LD studies, 14 of which have been analyzed, along with a 3' repeat polymorphism, in a sample of 120 parent-proband triads. Calculations of pairwise LD between the SNPs in the parental haplotypes revealed a high degree of LD (P < 0.00001) in the 5' (distal promoter through intron 6) and 3' (exon 9 through exon 15) regions of DAT. This segmental LD pattern is maintained over approximately 27 kb and 20 kb in these two regions, respectively, with very little significant LD between them, possibly due to the presence of a recombination hotspot located near the middle of the gene. These analyses of the DAT gene thus reveal a complex structure resulting from both recombination and mutation, knowledge of which may be invaluable to the design of future studies.

Dopamine Plasma Membrane Transport Proteins↗