E. Macnamara - Academia.edu (original) (raw)

Papers by E. Macnamara

British journal of cancer, Jan 26, 2004

There has been interest in the literature in the possible existence of a gene that predisposes to... more There has been interest in the literature in the possible existence of a gene that predisposes to both breast cancer (BC) and colorectal cancer (CRC). We describe the detailed characterisation of one kindred, MON1080, with 10 cases of BC or CRC invasive cancer among 26 first-, second- or third-degree relatives. Linkage analysis suggested that a mutation was present in BRCA2. DNA sequencing from III: 22 (diagnosed with lobular BC) identified a BRCA2 exon 3 542G>T (L105X) mutation. Her sister (III: 25) had BC and endometrial cancer and carries the same mutation. Following immunohistochemical and microsatellite instability studies, mutation analysis by protein truncation test, cDNA sequencing and quantitative real-time PCR revealed a deletion of MSH2 exon 8 in III: 25, confirming her as a double heterozygote for truncating mutations in both BRCA2 and MSH2. The exon 8 deletion was identified as a 14.9 kb deletion occurring between two Alu sequences. The breakpoint lies within a seque...

Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery, 2005

Previous studies have established the efficacy of post-thyroidectomy hypocalcemia monitoring usin... more Previous studies have established the efficacy of post-thyroidectomy hypocalcemia monitoring using parathyroid hormone (PTH) and corrected calcium levels at 1 and 6 hours. The goal of this study was to measure the impact of managing patients based on the above findings with respect to: duration of hospital stays, rates of transient hypocalcemia, number of blood tests, cost savings, and discharge from the hospital as early as 8 hours post-thyroidectomy without compromising safety. This is a prospective study involving 95 total thyroidectomy patients using historical data as controls. The previous protocol was modified in that all blood tests ceased for patients meeting the 6-hour critical level of PTH > or = 28 ng/L and simultaneous corrected calcium > or = 2.14 mmol/L (8.56 mg/dL). Furthermore, patients with 1-hour PTH levels < or = 8 ng/L were prophylactically treated with calcium and vitamin D supplementation. This study demonstrates lower rates of transient hypocalcemia ...

Otolaryngology - Head and Neck Surgery, 2008

OBJECTIVES: A 1-hour post-thyroidectomy parathyroid hormone (PTH) level of Յ8 ng/L is predictive ... more OBJECTIVES: A 1-hour post-thyroidectomy parathyroid hormone (PTH) level of Յ8 ng/L is predictive of patients who will develop hypocalcemia and guides early supplementation with calcium and vitamin D. However, most hypocalcemic patients fail to meet this criterion. The goal of this study was to determine whether PTH Յ 15 ng/L could be used as a better predictor of hypocalcemia. STUDY DESIGN, SUBJECTS, AND METHODS: This retrospective study involved 270 thyroidectomy patients (2004)(2005)(2006). PTH and calcium levels, length of admission, supplementation, and rates of hypocalcemia were recorded. RESULTS: Forty-three percent (26/60) of patients developing hypocalcemia met the PTH Յ 8 ng/L cut-off. In contrast, 80% (48/60) of patients developing hypocalcemia had a PTH Յ 15 ng/L. Two point two percent of patients had a 1-hour PTH Յ 15 ng/L and failed to develop hypocalcemia, for a specificity of 97%. CONCLUSIONS: A 1-hour PTH cut-off of Յ15 ng/L for prophylactic supplementation should allow the prevention of the majority of cases of hypocalcemia, leading to significant cost savings by shortening hospital stays.

Otolaryngology - Head and Neck Surgery, 2007

OBJECTIVES: Previous studies have demonstrated that a one-hour post-thyroidectomy PTH level of&lt... more OBJECTIVES: Previous studies have demonstrated that a one-hour post-thyroidectomy PTH level of<= 8ng/L was predictive of patients who would eventually develop hypocalcemia. This finding resulted in significant cost savings at the presenters' institution, since ...

Otolaryngology -- Head and Neck Surgery, 2011

Objectives. The goal of the present study is to determine whether a decline in the 1-hour postope... more Objectives. The goal of the present study is to determine whether a decline in the 1-hour postoperative parathyroid hormone (PTH) level relative to the preoperative level is predictive of hypocalcemia.

Journal of Medical Genetics, 2002

Background: The mismatch repair gene, MLH1, appears to occur as two main haplotypes at least in w... more Background: The mismatch repair gene, MLH1, appears to occur as two main haplotypes at least in white populations. These are referred to as A and G types with reference to the A/G polymorphism at IVS14-19. On the basis of preliminary experimental data, we hypothesised that deviations from the expected frequency of these two haplotypes could exist in carriers of disease associated MLH1 germline mutations. Methods: We assembled a series (n=119) of germline MLH1 mutation carriers in whom phase between the haplotype and the mutation had been conclusively established. Controls, without cancer, were obtained from each contributing centre. Cases and controls were genotyped for the polymorphism in IVS14. Results: Overall, 66 of 119 MLH1 mutations occurred on a G haplotype (55.5%), compared with 315 G haplotypes on 804 control chromosomes (39.2%, p=0.001). The odds ratio (OR) of a mutation occurring on a G rather than an A haplotype was 1.93 (95% CI 1.29 to 2.91). When we compared the haplotype frequencies in mutation bearing chromosomes carried by people of different nationalities with those seen in pooled controls, all groups showed a ratio of A/G haplotypes that was skewed towards G, except the Dutch group. On further analysis of the type of each mutation, it was notable that, compared with control frequencies, deletion and substitution mutations were preferentially represented on the G haplotype (p=0.003 and 0.005, respectively). Conclusion: We have found that disease associated mutations in MLH1 appear to occur more often on one of only two known ancient haplotypes. The underlying reason for this observation is obscure, but it is tempting to suggest a possible role of either distant regulatory sequences or of chromatin structure influencing access to DNA sequence. Alternatively, differential behaviour of otherwise similar haplotypes should be considered as prime areas for further study.

Familial Cancer, 2006

Hereditary non-polyposis colorectal cancer (HNPCC) is a dominantly inherited cancer syndrome caus... more Hereditary non-polyposis colorectal cancer (HNPCC) is a dominantly inherited cancer syndrome caused by a mutation in one of the mismatch repair genes, most frequently MLH1 or MSH2. The rate of mutation detection is influenced by many factors, including the diagnostic methods used. Large deletions, which occur frequently in MLH1 and MSH2, are not detected by exon-by-exon screening methods. Here, we describe three mutations in mismatch repair genes detected using a screening protocol that combines protein truncation test (PTT) analysis and multiplex ligation-dependent probe amplification (MLPA) with genomic and cDNA sequencing. Two of these mutations consist of large deletions in MLH1 that were detected by both MLPA and PTT but that would have been missed by genomic DNA sequencing. The third is a large deletion in MSH2 that could not be detected by PTT because of its location relative to the primers used to amplify the cDNA, or by sequencing. This mutation was detected by MLPA.

Diseases of the Colon & Rectum, 2001

Genetic tests are available for familial adenomatous polyposis and hereditary nonpolyposis colore... more Genetic tests are available for familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer. The goal of this review was to develop an algorithm for application of molecular diagnostic techniques to the management of hereditary colorectal carcinoma and to familiarize the clinician with the vocabulary of molecular genetic testing for hereditary colorectal carcinoma. Studies examining the clinical use of genetic testing for hereditary colorectal carcinoma syndromes are evaluated. Recent advances in molecular genetic technology are reviewed, and clinical management as practiced here and elsewhere is outlined. This review is a guide to the most reliable molecular diagnostic techniques. Three key questions are answered: who, when, and how to test. When integrated with existing testing protocols for colorectal carcinoma and when applied with appropriate caveats, particularly regarding interpretation of negative results, genetic testing can result in improved management of patients and families.

Clinical Genetics, 2004

Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common inherited cancer syn... more Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common inherited cancer syndromes, accounting for 3-5% of all cases of colorectal cancer. In most HNPCC families, the disease is caused by a germline mutation in MLH1 or MSH2. In some populations, founder mutations appear to explain a substantial fraction of HNPCC. We report here the identification and preliminary characterization of two putative MLH1 founder mutations. The mutation MLH1c.1831delAT was shown to segregate in two Quebec families of Italian origin who fulfilled the Amsterdam criteria for HNPCC. Haplotype analysis using five intragenic microsatellite/single nucleotide polymorphism markers spanning MLH1 on chromosome 3 showed that these two unrelated families share an identical haplotype. In addition, two other Italian kindred whose affected members carry MLH1g.IVS6 + 3A&amp;gt;G also share a common haplotype, suggesting that, similarly, the latter mutation has a common origin. These mutations are the first putative founder MLH1 mutations to be identified in HNPCC kindred of Italian origin.

Biochemical and Biophysical Research Communications, 2005

This study was designed to determine if soluble Tie2 (sTie2) expression inhibits and regresses co... more This study was designed to determine if soluble Tie2 (sTie2) expression inhibits and regresses corneal neovascularization, and if VEGF contributes to its effect. The corneas of BALB/c mice were scraped and the mice were injected with either an adenovirus expressing soluble Tie2 (Ad.sTie2) or an empty adenoviral vector. When injected at the inhibition timepoint (one day prior to corneal injury), the mean percentage of neovascularized corneal area two weeks later in Ad.sTie2-treated mice vs. controls was 56.37 ± 9.15% vs. 85.79 ± 3.55% (p = 0.04). At the regression timepoint (4 weeks after corneal scrape), the mean area of corneal neovascularization in Ad.sTie2-treated mice was 42.89 ± 4.74% vs. 75.01 ± 3.22% in the control group (p = 0.007). VEGF expression was significantly higher in Ad.sTie2-treated mice at the inhibition timepoint and there was no significant difference at the regression timepoint. These findings suggest that sTie2 inhibits and regresses corneal neovascularization in a VEGF-independent manner.

The American Journal of Human Genetics, 2002

We report here the identification and characterization of a founder mutation in MSH2 in the Ashke... more We report here the identification and characterization of a founder mutation in MSH2 in the Ashkenazi Jewish population. We identified a nucleotide substitution, MSH2*1906GrC, which results in a substitution of proline for alanine at codon 636 in the MSH2 protein. This allele was identified in 15 unrelated Ashkenazi Jewish families with HNPCC, most of which meet the Amsterdam criteria. Genotype analysis of 18 polymorphic loci within and flanking MSH2 suggested a single origin for the mutation. All colorectal cancers tested showed microsatellite instability and absence of MSH2 protein, by immunohistochemical analysis. In an analysis of a population-based incident series of 686 Ashkenazi Jews from Israel who have colorectal cancer, we identified 3 (0.44%) mutation carriers. Persons with a family history of colorectal or endometrial cancer were more likely to carry the mutation than were those without such a family history ( ), and those with colorectal cancer who carried the mutation P p .042 were, on average, younger than affected individuals who did not carry it ( ). The mutation was not detected P p .033 in either 566 unaffected Ashkenazi Jews from Israel or 1,022 control individuals from New York. In hospital-based series, the 1906C allele was identified in 5/463 Ashkenazi Jews with colorectal cancer, in 2/197 with endometrial cancer, and in 0/83 with ovarian cancer. When families identified by family history and in case series are included, 25 apparently unrelated Ashkenazi Jewish families have been found to harbor this mutation. Although this pathogenic mutation is not frequent in the Ashkenazi Jewish population (accounting for 2%-3% of colorectal cancer in those whose age at diagnosis is !60 years), it is highly penetrant and accounts for approximately one-third of HNPCC in Ashkenazi Jewish families that fulfill the Amsterdam criteria.

Journal of Parenteral and Enteral Nutrition, 2003

N-acetyl-L-tyrosine (NAT) is commonly used in place of tyrosine in parenteral nutrition, but huma... more N-acetyl-L-tyrosine (NAT) is commonly used in place of tyrosine in parenteral nutrition, but human studies carried out to date indicate considerable amounts of it are excreted unchanged in the urine. NAT retention has not been well studied in parenterally fed adults. NAT retention was measured in 13 adults receiving continuous parenteral nutrition with Aminosyn II 15% (Abbott Laboratories, Abbott Park, IL). Approximately 35% of administered NAT was excreted unchanged in the urine, with no important effect of infusion rate, N balance, or level of renal function on this value. Sufficient NAT was retained that the prescription of 1 g total amino acids/kg x day(-1) using this product exceeded the combined recommended dietary allowance for aromatic amino acids As used in the clinical setting, the phenylalanine and NAT composition of Aminosyn II is sufficient to meet the combined aromatic amino acid needs of adults with normal phenylalanine hydroxylase activity.