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Biomedical subjects

M Baker

Publications and source records attributed to M Baker.

At least 91 records · Page 5Linked to original sources
PubMed1999

Susceptibility of beta-lactamase to core amino acid substitutions.

To determine which amino acids in TEM-1 beta-lactamase are important for its structure and function, random libraries were previously constructed which systematically randomized the 263 codons of the mature enzyme. A comprehensive screening of these libraries identified several TEM-1 beta-lactamase core positions, including F66 and L76, which are strictly required for wild-type levels of hydrolytic activity. An examination of positions 66 and 76 in the class A beta-lactamase gene family shows that a phenylalanine at position 66 is strongly conserved while position 76 varies considerably among other beta-lactamases. It is possible that position 76 varies in the gene family because beta-lactamase mutants with non-conservative substitutions at position 76 retain partial function. In contrast, position 66 may remain unchanged in the gene family because non-conservative substitutions at this location are detrimental for enzyme structure and function. By determining the beta-lactam resistance levels of the 38 possible mutants at positions 66 and 76 in the TEM-1 enzyme, it was confirmed that position 76 is indeed more tolerant of non-conservative substitutions. An analysis of the Protein Data Bank files for three class A beta-lactamases indicates that volume constraints at position 66 are at least partly responsible for the low tolerance of substitutions at this position.

Amino Acid Sequence↗
PubMed1999

Long-term outcome of achalasia treatment: the need for closer follow-up.

Treatment of achalasia includes pneumatic dilation (PD) and surgical myotomy (SM). Success rates range from 32% to 98% and are mostly based on symptomatic response. Our aims were to determine the long-term outcome of patients treated for achalasia and the adequacy of long-term follow-up. Patients treated with PD or SM between 1986 and 1990 were contacted by telephone after a minimum of 4 years after treatment, and asked about symptoms and need for retreatment since their discharge from our institution. Symptomatic response was classified as excellent/good or fair/poor using the Vantrappen score. Treatment was deemed a failure if patients were symptomatic on callback, needed retreatment, technical problems occurred during PD, or perforation occurred. Forty-seven PD patients and 15 SM patients were studied. There were no significant differences in clinical parameters between groups. Median time to callback was 82 and 73 months, respectively. Failure rates were high, respectively 74% and 67%. Importantly, 38% of PD and 33% of SM patients failed to seek help despite symptom recurrence. Achalasia treatment failures are higher than anticipated. This may be because of the lack of routine follow-up as well as patients' failure to seek help when symptoms recur. Achalasia patients need closer follow-up and may benefit from early intervention based on objective tests rather than symptoms alone.

Adult↗
PubMed1999

Analysis of vaginal cell populations during experimental vaginal candidiasis.

Studies with an estrogen-dependent murine model of vaginal candidiasis suggest that local cell-mediated immunity (CMI) is more important than systemic CMI for protection against vaginitis. The present study, however, showed that, compared to uninfected mice, little to no change in the percentage or types of vaginal T cells occurred during a primary vaginal infection or during a secondary vaginal infection where partial protection was observed. Furthermore, depletion of polymorphonuclear leukocytes (PMN) had no effect on infection in the presence or absence of pseudoestrus. These results indicate a lack of demonstrable effects by systemic CMI or PMN against vaginitis and suggest that if local T cells are important, they are functioning without showing significant increases in numbers within the vaginal mucosa during infection.

Animals↗
PubMed1999

Staff grade doctors and the consultant ladder: falling off or stepping off?

The majority of the doctors in staff grade posts surveyed had qualified overseas and a substantial proportion were dissatisfied with their posts. Very few doctors had received adequate careers counselling before starting their post and many were concerned at the lack of opportunities for career development.

Career Mobility↗
PubMed1999

The impact of nutritional status on the outcome of lung volume reduction surgery: a prospective study.

OBJECTIVES: To study the incidence and clinical significance of nutritional deficiencies in patients with emphysema undergoing lung volume reduction surgery (LVRS). DESIGN: Prospective observational study. SETTING: University-based teaching hospital. PATIENTS: Fifty-one consecutive patients with end-stage emphysema undergoing video-assisted thoracoscopic surgery for LVRS. INTERVENTIONS: All patients had their body mass index (BMI) and serum nutritional indexes (albumin, transferrin, total protein, cholesterol) measured preoperatively and postoperatively. Various clinical parameters were also compared between two groups. RESULTS: The BMI was normal in 24 patients (47%), and 27 patients (53%) had a below normal BMI. A preoperative analysis of the serum nutritional indexes revealed no clinically significant differences between the two groups, but postoperative levels were significantly lower in the low BMI group. Anthropometric measurements supported the designation of nutritional status by BMI. Clinically, 26% of the patients in the low BMI group required prolonged ventilatory support (> 24 h), compared to only 4% of the patients with a normal BMI. The hospital length of stay (LOS) also differed, averaging 15.9 days in the low BMI group, compared to an average of 11.8 days in the normal BMI group. CONCLUSION: Approximately 50% of patients undergoing LVRS for emphysema have a deficient nutritional status identifiable by BMI, but not by standard nutritional indexes. This impaired nutritional status is associated with increased morbidity following LVRS. We suggest that BMI is an accurate determinant of nutritional status in this patient population, and we speculate that preoperative repletion of nutritional deficiencies may decrease hospital morbidity, hospital LOS, and overall costs in the malnourished population undergoing LVRS.

Aged↗
PubMed1998

A measles epidemic controlled by immunisation.

AIM: In 1997, an immunisation campaign, using measles-mumps-rubella vaccine, was planned for children aged 2-10 years to prevent a measles epidemic predicted by mathematical modelling. The epidemic started before the campaign and is described here. METHOD: Measles hospitalisation, notification and laboratory data were combined. RESULTS: The epidemic started in April 1997 and was largely over by January 1998. No deaths were identified and only one hospitalisation was coded as measles encephalitis, compared to seven deaths and ten cases of measles encephalitis in the 1991 epidemic. For the 12 months from 1 March 1997 there were 2,169 (60 per 100,000) measles cases identified, 314 (9 per 100,000) of whom were hospitalised. Two-thirds of hospitalised cases were notified. The age-standardised measles incidence rates were 33, 34, and 174 per 100,000 for Europeans, Maori and Pacific people, respectively. The respective age-standardised hospitalisation rates were 4, 9 and 32 per 100,000. Measles incidence was highest for under one-year-olds (904 per 100,000) and low for 11-16 year-olds (27 per 100,000)--the cohort previously offered a second vaccine dose. Most cases were aged 10 years and under, and this group were the main drivers of virus transmission. CONCLUSIONS: The immunisation campaign prevented 90-95% of predicted cases. The campaign was appropriately targeted at children aged 10 years and under.

Adult↗
PubMed1998

Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17.

Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), historically termed Pick's disease. Most FTDP-17 cases show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule-associated protein Tau, although the Tau pathology varies considerably in both its quantity (or severity) and characteristics. Previous studies have mapped the FTDP-17 locus to a 2-centimorgan region on chromosome 17q21.11; the tau gene also lies within this region. We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon 10. The splice-site mutations all destabilize a potential stem-loop structure which is probably involved in regulating the alternative splicing of exon10. This causes more frequent usage of the 5' splice site and an increased proportion of tau transcripts that include exon 10. The increase in exon 10+ messenger RNA will increase the proportion of Tau containing four microtubule-binding repeats, which is consistent with the neuropathology described in several families with FTDP-17.

Alternative Splicing↗
PubMed1998

Exclusion of genetic linkage to 4q21-23 and 17q21 in a family with Lewy body parkinsonism.

Genetic analysis of markers from chromosomes 4q21-23 and 17q21 in a family with apparently autosomal dominant Lewy body parkinsonism is presented. This analysis shows that the locus leading to this disease is not allelic with that previously shown to lead to Lewy body parkinsonism on chromosome 4 or to the locus on chromosome 17 leading to frontotemporal dementia with parkinsonism. A brief clinical comparison of this family with families showing linkage to these loci is presented. The data suggest that at least one other major genetic determinant for Lewy body parkinsonism remains to be identified.

Adult↗
PubMed1998

Injecting behaviours and prevalence of hepatitis B, C and D markers in New Zealand injecting drug user populations.

AIM: To determine the seroprevalence of hepatitis C virus (HCV), hepatitis B virus (HBV) & hepatitis D virus (HDV) markers of infection among injecting drug user populations in New Zealand and to examine the relationship between demographic features, risk behaviours and infection. METHODS: A total of 323 current injecting drug users completed a questionnaire that explored their needle and syringe using behaviours. Information was collected on injection pattern, sharing behaviours and methods of cleaning needles and syringes. Two hundred and forty-one respondents gave blood samples which were tested for hepatitis B, C and D markers. RESULTS: Over half the respondents (59%) were male and 41% were female. Most (89%) identified as European. Sixty-four percent were anti-HCV positive. The likelihood of infection increased with age and duration of injecting. Forty-one percent (33/81) of those aged 25 or under, sixty-four percent (45/70) of those aged 26-30 and eighty-seven percent (78/90) over 30 were anti-HCV positive. Those who tested anti-HCV positive had been injecting for an average of 12.0 years compared to 6.0 years for those were anti-HCV negative. The results for hepatitis B are to be reported fully at a later date. Sharing behaviour was also a factor although this was less important as an independent factor. Comparisons with earlier surveys suggested that there has not been a significant decline in the rate of sharing needles and syringes since the initial period following introduction of the needle exchange programme. CONCLUSION: The prevalence of hepatitis C infection is common among injecting drug users of all ages. Without a significant reduction in sharing behaviour, particularly among younger injecting drug users, it is unlikely that the prevalence of hepatitis C among injecting drug users will decline in the future. Evidence suggests that the carriage of hepatitis C is higher than that of hepatitis B which would help explain the differing rates of prevalence. However, the risk of future transmission of other parenterally transmitted diseases remains high without a further significant decline in sharing behaviour.

Adolescent↗
PubMed1998

ApoE genotype is a risk factor in nonpresenilin early-onset Alzheimer's disease families.

The apolipoprotein E (ApoE) genotype is a significant risk factor and modulator of age of onset of Alzheimer's disease (AD). We analyzed the effect of the ApoE genotype in two distinct early-onset familial AD groups: families with a mutation in the presenilin-1 gene (PS-1) on chromosome 14, and families without a mutation detectable in the PS-1, presenilin-2 (PS-2), and the amyloid precursor protein (APP) gene (non-PS early-onset familial AD). The ApoE genotype is clearly shown not to modulate age of onset in families with a mutation in the PS-1 gene and families with no lesion detectable in either the presenilin or APP gene. The effects of a double dose of ApoE4 on age of onset were not assessed in the PS-1 AD families due to the lack of any affected ApoE4 homozygotes in the sample set; this insufficiency will need to be assessed in further studies. There was no association between the ApoE4 allele and AD in the PS-1 families. Non-PS early-onset AD families were shown to have a significantly higher frequency of ApoE4 compared to controls and the PS-1 AD group. These observations are important and suggest that 1) other genetic and environmental factors modify the AD phenotype in PS-1 and non-PS early-onset families; and 2) the ApoE4 allele is a significant risk factor in the etiology of non-PS early-onset AD and will be a useful adjunct in the diagnosis of unaffected family members.

Alleles↗
PubMed1998

Cloning and characterization of the presenilin-2 gene promoter.

Mutations in the presenilin-2 (PS-2) have been shown to cause early onset Alzheimer's disease (AD) in a series of families known as the Volga Germans and in an unrelated Italian kindred. Expression of the PS-2 gene is regulated during AD, aging, development and brain injury. Although expressed primarily in neurons, enhanced levels of PS-2 have been reported in astrocytes activated by neuronal damage. Understanding the regulation of the PS-2 gene may thus provide an insight into its role in AD. We have isolated a 3635 bp DNA fragment that contains 2934 bp of DNA sequence upstream from the PS-2 gene. Primer extension analysis was used to map three major transcriptional start sites within the PS-2 gene. The promoter sequence, upstream of each transcriptional start site, does not contain TATA or CAAT boxes but does contain several GC rich sites (Sp-1 and AP-2). A reporter gene construct containing the PS-2 promoter (PS2P, -2934 to +702) transfected into M17 cells drives basal transcription to 20% of the levels of the SV-40 viral promoter. Addition of NGF to PC-12 cells was found to upregulate the PS2P promoter and an NGF-responsive element was localized by deletional analysis between -403 and +13 within the promoter. Since the PS-2 gene has multiple start sites and the upstream sequence is GC rich with no TATA box, the PS-2 promoter is consistent with the GC class of 'housekeeping' genes.

5' Untranslated Regions↗
PubMed1998

Accuracy of CT biopsy: laser guidance versus conventional freehand techniques.

RATIONALE AND OBJECTIVES: The purpose of this study was to determine whether laser-guided computed tomographic (CT) biopsy is more accurate than CT-guided biopsy with conventional freehand techniques. MATERIALS AND METHODS: Two independent operators performed an equal number of freehand and laser-guided needle passes at varying single and double angles (0 degree, 30 degrees, 60 degrees, 25 degrees/30 degrees, and 25 degrees/60 degrees) on targets within six pork and beef phantoms. A total of 180 biopsy passes were performed, and error distances of needle tip to target were tabulated. Data were analyzed by means of repeated measures analysis of variance (ANOVA) to compare the accuracy of laser guidance with freehand passes. ANOVA and correlation analysis were also used to confirm the relative equivalency of phantom targets and biopsy parameters. RESULTS: Overall, laser-guided passes were statistically significantly more accurate than freehand passes. Mean error with laser guidance was 5.01 mm (standard error [SE] = 0.41 mm), whereas mean error with freehand techniques was 10.58 mm (SE = 0.82 mm) (F = 52.0, df = 1.17, P = .0001). Ninety-three percent of laser-guided passes and 56% of freehand passes were within 1 cm of the intended target. Error increased for both laser-guided and freehand techniques with larger angles or double-angle biopsies, but the increases were greater with freehand technique. No statistically significant differences existed between the targets themselves or biopsy parameters for the two operators. CONCLUSION: Laser-guided CT biopsies were more accurate than freehand CT biopsies. Practical advantages of laser guidance over freehand CT biopsy methods may include decreased procedure times and reduced patient morbidity.

Animals↗
PubMed1998

A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1.

We describe a novel variant of Alzheimer's disease (AD) in a Finnish pedigree with 17 affected individuals of both sexes in three generations. The disease is characterized by progressive dementia which is, in most cases, preceded by spastic paraparesis. Neuropathological investigations revealed numerous, distinct, large, round and eosinophilic plaques as well as neurofibrillary tangles and amyloid angiopathy throughout the cerebral cortex. The predominant plaques resembled cotton wool balls and were immunoreactive for Abeta but lacked a congophilic dense core or marked plaque-related neuritic pathology. Molecular genetic analysis revealed that the disease was caused by a deletion of exon 9 (delta9) of the presenilin 1 (PS1) gene from the mRNA: unlike previous examples of the delta9 variant, the deletion was not caused by a splice acceptor site mutation.

Age of Onset↗
PubMed1998

Comparative tolerance of adapalene 0.1% gel and six different tretinoin formulations.

Adapalene 0.1% gel (Differin gel) is a recently introduced topical treatment for mild to moderate acne which has been demonstrated to be much better tolerated and at least as effective as tretinoin 0.025% gel. We compared the tolerance of adapalene 0.1% gel with six different formulations and concentrations of tretinoin. A total of 55 healthy human subjects were enrolled in two controlled, randomized, observer blinded, intraindividual comparison studies. In the first study, adapalene 0.1% gel was evaluated for its 21-day cumulative irritation potential compared with tretinoin 0.025%, 0.05% and 0.1% cream, tretinoin 0.01% and 0.025% gel, and petrolatum (control). In the second study, adapalene 0.1% gel was evaluated for its 21-day cumulative irritation potential compared with tretinoin 0.025%, 0.05% and 0.1% cream, tretinoin 0.1% gel microsphere, and petrolatum (control). In both studies, cumulative irritation scores helped to define three groups of common irritancy potential, with significant differences between each group. In study A, the three groups were in descending order of irritancy: tretinoin 0.1% cream and tretinoin 0.05% cream; tretinoin 0.025% gel, tretinoin 0.01% gel and tretinoin 0.025% cream; adapalene 0.1% gel and petrolatum (control). In study B, the three groups were in descending order of irritancy: tretinoin 0.1% cream; tretinoin 0.05% cream, tretinoin 0.025% cream and tretinoin 0.1% gel microsphere; adapalene 0.1% gel and petrolatum (control). The experimental results show that adapalene 0.1% gel is significantly better tolerated than any of six formulations of tretinoin, including two gels, three creams and a microsphere formulation, ranging in potency from 0.01% to 0.1%.

Acne Vulgaris↗
PubMed1998

Comparison of adapalene 0.1% solution and tretinoin 0.025% gel in the topical treatment of acne vulgaris.

A multicentre study was conducted to compare clinical safety and efficacy of adapalene 0.1% solution and tretinoin 0.025% gel, both topical treatments for acne, in a once-daily dosage regimen for 12 weeks. A total of 297 patients were enrolled by eight investigators in this randomized, investigator-masked study in a parallel group design. An open label period using adapalene followed this study to assess the long-term safety of adapalene solution. Adapalene and tretinoin proved to be clinically and statistically effective in treating acne by reducing inflammatory (47% and 50%, respectively) and non-inflammatory lesions (57% and 54%) as compared to baseline. When comparing patients who had 75% or greater improvement in open comedones, adapalene was shown to be significantly more effective than tretinoin. No serious adverse event was reported during this study, including during the long-term period. The reactions that occurred were similar between treatments, i.e. burning, pruritus, scaling, dryness and erythema.

Acne Vulgaris↗