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Biomedical subjects

M Baker

Publications and source records attributed to M Baker.

At least 73 records · Page 4Linked to original sources
PubMed1999

5' splice site mutations in tau associated with the inherited dementia FTDP-17 affect a stem-loop structure that regulates alternative splicing of exon 10.

Missense and splice site mutations in the microtubule-associated protein tau gene were recently found associated with fronto-temporal dementia and parkinsonism linked to chromosome 17 (Poorkaj et al. (1998) Ann. Neurol. 43, 815-825; Hutton et al. (1998) Nature 393, 702-705; Spillantini et al. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 7737-7741). The mutations in the 5' splice site of exon 10 were shown to increase the ratio of tau mRNAs containing exon 10 and thus the proportion of Tau protein isoforms with 4 microtubule binding repeat domains, although how this increase leads to neurodegeneration is presently unclear. The mechanism by which these mutations increase tau exon 10 splicing was not determined, although the mutations were predicted to disrupt a potential stem-loop structure that was likely involved in the regulation of exon 10 alternative splicing. Here we describe in vitro splicing assays and RNA structural analysis that demonstrate that the mutations do indeed act through disruption of the stem-loop structure and that the stability of this secondary structure feature at least partially determines the ratio of tau exon 10+/- transcripts. In addition, we provide evidence that the stability of the stem-loop structure underlies the alternative splicing of this exon in other species.

Alternative Splicing↗
PubMed1999

A novel candidate presenilin-1 interacting protein containing tetratricopeptide repeats.

The yeast two-hybrid system, immunofluorescence and co-immunoprecipitation techniques were used to identify a novel candidate protein with which presenilin-1 (PS-1) interacts. This interacting protein, the gene of which is encoded on chromosome 16, contains two tetratricopeptide repeats (TPR) that are known to mediate interactions between proteins, appears to be primarily localized to the cytoplasm of transfected HEK293 cells, and is expressed in brain. Preliminary yeast two-hybrid data suggests this candidate may interact with both heat shock protein-90 and heat shock protein-70 and thus may be a novel member of TPR-containing proteins which interact with this complex.

Alzheimer Disease↗
PubMed1999

The 1996 pertussis epidemic in New Zealand: vaccine effectiveness.

AIM: To assess if reduced vaccine effectiveness may have accounted for increased hospitalisations in the 1996 pertussis epidemic. METHODS: Vaccine effectiveness was estimated by comparing vaccine coverage of the population (derived from a literature review) with that of cases (from notification data available from 1 June 1996) -- the screening method. Only three doses of pertussis vaccine were in the immunisation schedule until 1996, so vaccine effectiveness was calculated for three or more doses. RESULTS: Most likely estimates of vaccine effectiveness for Europeans were 88% (95% confidence interval 71 to 95%) for 5- to 14-month-olds, 80% for 15-month to 4-year-olds (66 to 88%) but lower for children aged 5 years and older with confidence limits including zero. Vaccine effectiveness estimates for Maori were less for each age group but based on few observations. CONCLUSIONS: The increase in hospitalisations for young children in the 1996 epidemic cannot be directly attributed to a reduced vaccine effectiveness, as vaccine effectiveness estimates for preschool Europeans are in line with international evidence. Additionally, the vaccine effectiveness estimates in this study are likely to be underestimates due to bias. The lower estimates for vaccine effectiveness among Maori are likely to reflect increased pressure of these biases, although a biological basis for the difference or clustering of factors that cause failure are also possible. The vaccine effectiveness estimates decrease with age, a likely combination of waning vaccine immunity and the cross-sectional nature of the screening method itself for determining vaccine effectiveness.

Child↗
PubMed1999

The 1996 pertussis epidemic in New Zealand: descriptive epidemiology.

AIM: To describe the 1996 pertussis epidemic. METHODS: Hospitalisation, notification and laboratory data were used to describe the 1996 pertussis epidemic and compare it with previous epidemics. RESULTS: The 1996 epidemic spanned 24 months. The crude hospitalisation rate from 1 June 1995 to 31 May 1997, was 10.1 per 100,000 person years, being highest for children aged six weeks to two months (42 to 90 days old inclusive; 1402 per 100,000). The 1996 epidemic involved more hospitalisations than the 1991 and 1986 epidemics, and a greater proportion for children under the age of one year (77%), compared to previous epidemics (60-70%). There were no deaths. Pertussis only became notifiable from 1 June 1996. The crude notification rate for the following twelve months was 19.8 per 100,000 (equivalent hospitalisation rate 6.7 per 100,000); children aged six weeks to two months of age had the highest notification rate (531 per 100,000; equivalent hospitalisation rate 1021 per 100,000). In 1996-97, children aged under 15 months accounted for 21% of notifications, but 82% of hospitalisations. Europeans tended to have higher rates of notifications than non-Europeans, but lower rates of hospitalisation. CONCLUSIONS: New Zealand continues to experience high rates of pertussis as a result of inadequate immunisation coverage. The increase in hospitalisations during the 1996 epidemic may reflect a real increase in the population-based incidence, or other changes (e.g. hospitalisation practice, increase in vulnerable children with poor access to primary care). Improved rates, accuracy and completeness of pertussis notifications will improve the ability of notification data to accurately describe future epidemics and estimate vaccine effectiveness. Further debate is required regarding the aims of pertussis immunisation; accelerating the timing of the first three doses and adding further doses of pertussis vaccine on the national immunisation schedule; and the role of acellular pertussis vaccines. In the meantime, the priority must be increasing on-time immunisation coverage.

Adolescent↗
PubMed1999

Low frequency of pathogenic mutations in the ubiquitin carboxy-terminal hydrolase gene in familial Parkinson's disease.

A coding substitution (I93M) in the ubiquitin carboxy-terminal L1 (UCH-L1) gene has recently been identified in a German family with Parkinson's disease. We have sequenced the entire coding region of the gene in 11 families who have a pattern of disease consistent with autosomal dominant inheritance. We found a polymorphism (S18Y) in exon 3, two polymorphisms in the 5' non-coding region, upstream of the transcription start, and an insertion/deletion polymorphism in intron 4. The S18Y allele is present on approximately 20% of chromosomes in a Caucasian population. These changes are, therefore, unlikely to be pathogenic. We conclude that the I93M variant must either be a rare cause of disease or a harmless substitution whose occurrence in the family reflects a chance co-occurrence.

Adult↗
PubMed1999

No pathogenic mutations in the persyn gene in Parkinson's disease.

The persyn (gamma-synuclein) gene is highly homologous to the alpha-synuclein gene and is highly expressed in the nervous system. It is therefore, an excellent candidate gene for Parkinson's disease. However, we have sequenced the gene in a large number of families with parkinsonism and failed to find pathogenic mutations.

Age of Onset↗
PubMed1999

The CD45 tyrosine phosphatase regulates CD3-induced signal transduction and T cell development in recombinase-deficient mice: restoration of pre-TCR function by active p56(lck).

The pre-TCR complex regulates the transition from CD4(-)CD8(-) double-negative (DN) to CD4(+)CD8(+) double-positive (DP) thymocytes during T cell development. In CD45(-/-) mice there is an accumulation of DN cells, suggesting a possible role for CD45 in pre-TCR signaling. We therefore crossed CD45(-/-) with Rag-1(-/-) mice to investigate the signaling functions of the CD3 complex in DN thymocytes. Remarkably, treatment of Rag-1(-/-)/CD45(-/-) mice with a CD3 mAb caused maturation to the DP stage at only 3% of the level measured in Rag-1(-/-) mice. Furthermore, ligation of the CD3 complex on Rag-1(-/-) /CD45(-/-) thymocytes in vitro induced less tyrosine phosphorylation in specific proteins when compared to Rag-1(-/-) thymocytes. CD45(-/-) mice were also crossed with pLGFA mice expressing a constitutively active form of the lck tyrosine kinase which restored the DN to DP transition to near normal levels. Our results are consistent with a model in which CD45-activated p56(lck) is critical for pre-TCR signal transduction.

Animals↗
PubMed1999

Frequency of tau mutations in three series of non-Alzheimer's degenerative dementia.

Splice-site and missense mutations have been identified in tau associated with frontotemporal dementia with parkinsonism linked to chromosome 17. In this study we assessed the genetic contribution of tau mutations to three patient series with non-Alzheimer's (non-AD) degenerative dementia. The groups included (1) a community-based dementia series from Minnesota, MN; (2) a referral series with clinicopathological tauopathy; and (3) a pathologically confirmed familial frontotemporal dementia series from Manchester, UK. Comparing the three clinical series: in the stringently diagnosed Manchester frontotemporal dementia series, tau mutations were present in 13.6% of cases (three splice-site mutations); in the clinicopathological referral series that used more general inclusion criteria, 3 cases with P301L mutations were observed, which represents a lower mutation frequency of 3.6% (9.4% in familial cases); in contrast, tau mutations were not detected in the Minnesota community-based dementia series, suggesting the occurrence of these mutations in dementia generally is rare (<0.2%). These data identify the prevalence of mutations in three different clinical settings and indicate that this figure is sensitive to the diagnostic criteria used in each patient series.

Adult↗
PubMed1999

The relationship between interleukin-6 and herpes simplex virus type 1: implications for behavior and immunopathology.

Cytokines are hormones once thought to be restricted to the immune system produced solely by hematopoietic-derived cells and acting on receptors expressed by cells of the immune system. However, it is now clear that many cytokines are produced not only by lymphocytes, monocytes, granulocytes, and dendritic cells but are also synthesized by cells outside the realm of the immune system in response to stimuli that may not be associated with immune homeostasis. In fact, there is evidence supporting a role of selected cytokines modifying behavior and neuroendocrine function. Recently, a potential relationship between the cytokine interleukin (IL)-6 and herpes simplex virus type 1 (HSV-1) reactivation has been found. This article discusses the relevance of these findings and considers the potential impact that HSV-1 infection has on behavior and chronic inflammatory processes that can occur in the nervous system during "latent" virus infection as a result of chronic IL-6 expression.

Herpes Simplex↗
PubMed1999

Safety of peripheral intravenous catheters in children.

OBJECTIVES: To determine the overall and per-day risk of complications of short peripheral intravenous (PIV) catheters placed for indefinite periods. DESIGN: During 5 months, general pediatric patients receiving intravenous therapy through short PIV catheters were monitored. Patient and catheter characteristics were recorded, complications were noted, and rolled semiquantitative cultures of removed catheters were performed. Major endpoints were infection and phlebitis. Per-day risk of complications and catheter colonization (>15 colony-forming units) were calculated. SETTING: University children's hospital. PATIENTS: General pediatric ward inpatients with PIV. RESULTS: We studied 642 Teflon catheters in place >24 hours (mean, 3.7 days) in 525 patients. There were no cases of catheter sepsis (0%; 95% confidence interval [CI95], 0%-0.6%), one possible insertion-site infection (0.2%; CI95, 0.004%-0.9%), and seven cases of phlebitis (1.1%; CI95, 0.4%-2.3%). Catheter colonization occurred in 92 (26%) of 348 catheters cultured. Neither the per-day risk of phlebitis nor of catheter colonization increased significantly with placement >3 days. CONCLUSION: Current guidelines recommend replacement of PIV catheters in adults within 2 to 3 days; no recommendations are made for children. Our findings and those of others indicate that the overall risk of PIV catheter complications in children is extremely low and would not be reduced substantially by routine catheter replacement.

Bacteria↗
PubMed1999

Association of an extended haplotype in the tau gene with progressive supranuclear palsy.

We describe two extended haplotypes that cover the human tau gene. In a total of approximately 200 unrelated caucasian individuals there is complete disequilibrium between polymorphisms which span the gene (which covers approximately 100 kb of DNA). This suggests that the establishment of the two haplotypes was an ancient event and either that recombination is suppressed in this region, or that recombinant genes are selected against. Furthermore, we show that the more common haplotype (H1) is significantly over-represented in patients with progressive supranuclear palsy (PSP), extending earlier reports of an association between an intronic dinucleotide polymorphism and PSP.

Aged↗
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↗