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Biomedical subjects

E C Lawrence

Publications and source records attributed to E C Lawrence.

At least 19 recordsLinked to original sources
PubMed2005

The SPINK1 N34S mutation is not associated with Type 2 diabetes mellitus in a population of the USA.

AIMS: Mutations in the serine protease inhibitor (SPINK1) gene have been associated with all forms of chronic pancreatitis. Recently, an association of SPINK1 mutations with early-onset Type 2 diabetes mellitus has been reported in patients from Bangladesh. Therefore, we determined the frequency of SPINK1 N34S mutations in patients with Type 2 diabetes mellitus from the USA. METHODS: The study population of Hispanic and non-Hispanic white people consisted of 387 patients with Type 2 diabetes and familial clustering of the disease, 232 family members without diabetes, 259 patients with Type 2 diabetes without a family history, and 302 ethnically matched healthy controls as part of the San Luis Valley Diabetes Study. We performed linkage- and association-analysis in 82 multiplex families with Type 2 diabetes mellitus. RESULTS: No significant linkage or allele sharing was detected between Type 2 diabetes mellitus and the SPINK1 locus. The frequency of the N34S mutation was determined by fluorescence polarization and was similar between patients (n = 14/387 patients with familial clustering; n = 2/259 patients without family history) and controls (n = 5/232 family members without diabetes; n = 10/302 individuals). Variables such as ethnicity, age of diabetes onset and percentage of individuals with impaired glucose tolerance did not differ significantly between carriers and homozygous normal individuals. CONCLUSION: The SPINK1 N34S mutation appears not to predispose Hispanic or non-Hispanic white people from the USA to the development of Type 2 diabetes mellitus.

Chronic Disease↗
PubMed2002

Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas.

BACKGROUND: Paragangliomas are rare and highly heritable tumours of neuroectodermal origin that often develop in the head and neck region. Germline mutations in the mitochondrial complex II genes, SDHB, SDHC, and SDHD, cause hereditary paraganglioma (PGL). METHODS: We assessed the frequency of SDHB, SDHC, and SDHD gene mutations by PCR amplification and sequencing in a set of head and neck paraganglioma patients who were previously managed in two otolaryngology clinics in the USA. RESULTS: Fifty-five subjects were grouped into 10 families and 37 non-familial cases. Five of the non-familial cases had multiple tumours. Germline SDHD mutations were identified in five of 10 (50%) familial and two of 37 ( approximately 5%) non-familial cases. R38X, P81L, H102L, Q109X, and L128fsX134 mutations were identified in the familial cases and P81L was identified in the non-familial cases. Both non-familial cases had multiple tumours. P81L and R38X mutations have previously been reported in other PGL families and P81L was suggested as a founder mutation. Allelic analyses of different chromosomes carrying these mutations did not show common disease haplotypes, strongly suggesting that R38X and P81L are potentially recurrent mutations. Germline SDHB mutations were identified in two of 10 (20%) familial and one of 33 ( approximately 3%) non-familial cases. P131R and M71fsX80 were identified in the familial cases and Q59X was identified in the one non-familial case. The non-familial case had a solitary tumour. No mutations could be identified in the SDHC gene in the remaining four families and 20 sporadic cases. CONCLUSIONS: Mutations in SDHD are the leading cause of head and neck paragangliomas in this clinic patient series. SDHD and SDHB mutations account for 70% of familial cases and approximately 8% of non-familial cases. These results also suggest that the commonness of the SDHD P81L mutation in North America is the result of both a founder effect and recurrent mutations.

Alleles↗
PubMed2001

A model for gene therapy of human hereditary lymphedema.

Primary human lymphedema (Milroy's disease), characterized by a chronic and disfiguring swelling of the extremities, is associated with heterozygous inactivating missense mutations of the gene encoding vascular endothelial growth factor C/D receptor (VEGFR-3). Here, we describe a mouse model and a possible treatment for primary lymphedema. Like the human patients, the lymphedema (Chy) mice have an inactivating Vegfr3 mutation in their germ line, and swelling of the limbs because of hypoplastic cutaneous, but not visceral, lymphatic vessels. Neuropilin (NRP)-2 bound VEGF-C and was expressed in the visceral, but not in the cutaneous, lymphatic endothelia, suggesting that it may participate in the pathogenesis of lymphedema. By using virus-mediated VEGF-C gene therapy, we were able to generate functional lymphatic vessels in the lymphedema mice. Our results suggest that growth factor gene therapy is applicable to human lymphedema and provide a paradigm for other diseases associated with mutant receptors.

Adenoviridae↗
PubMed2001

Truncating mutations in FOXC2 cause multiple lymphedema syndromes.

Hereditary lymphedemas are developmental disorders of the lymphatics resulting in edema of the extremities due to altered lymphatic flow. One such disorder, the lymphedema-distichiasis syndrome, has been reported to be caused by mutations in the forkhead transcription factor, FOXC2. We sequenced the FOXC2 gene in 86 lymphedema families to identify mutations. Eleven families were identified with mutations predicted to disrupt the DNA binding domain and/or C-terminal alpha-helices essential for transcription activation by FOXC2. Broad phenotypic heterogeneity was observed within these families. The phenotypes observed overlapped four phenotypically defined lymphedema syndromes. FOXC2 appears to be the primary cause of lymphedema-distichiasis syndrome and is also a cause of lymphedema in families displaying phenotypes attributed to other lymphedema syndromes. Our data demonstrates that the phenotypic classification of autosomal dominant lymphedema does not reflect the underlying genetic causation of these disorders.

Adolescent↗
PubMed2001

VEGFR3 gene structure, regulatory region, and sequence polymorphisms.

Vascular endothelial growth factor receptor 3 (VEGFR-3) is required for cardiovascular development during embryogenesis. In adults, this receptor is expressed in lymphatic endothelial cells, and mutant VEGFR3 alleles have been implicated in human hereditary lymphedema. To better understand the basis of its specific endothelial lineage-restricted expression, we have characterized the VEGFR3 gene and its regulatory 5' flanking region. The human gene contains 31 exons, of which exons 30a and 30b are alternatively spliced. The VEGFR3 proximal promoter is TATA-less and contains stretches of sequences homologous with the mouse Vegfr3 promoter region. In transfection experiments of cultured cells, the Vegfr3 promoter was shown to control endothelial cell-specific transcription of downstream reporter genes. This result was further confirmed in vivo; in a subset of transgenic mouse embryos, a 1.6 kb Vegfr3 promoter fragment directed weak lymphatic endothelial expression of the LacZ marker gene. This suggests that endothelial cell-specific elements occur in the proximal promoter, although further enhancer elements are probably located elsewhere. The sequence, organization, and variation in the VEGFR3 gene and its regulatory region provide important tools for the molecular genetic analysis of the lymphatic system and its disorders.

3T3 Cells↗
PubMed2000

Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.

Hereditary paraganglioma (PGL) is characterized by the development of benign, vascularized tumors in the head and neck. The most common tumor site is the carotid body (CB), a chemoreceptive organ that senses oxygen levels in the blood. Analysis of families carrying the PGL1 gene, described here, revealed germ line mutations in the SDHD gene on chromosome 11q23. SDHD encodes a mitochondrial respiratory chain protein-the small subunit of cytochrome b in succinate-ubiquinone oxidoreductase (cybS). In contrast to expectations based on the inheritance pattern of PGL, the SDHD gene showed no evidence of imprinting. These findings indicate that mitochondria play an important role in the pathogenesis of certain tumors and that cybS plays a role in normal CB physiology.

Alleles↗
PubMed2000

Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema.

Primary lymphoedema is a rare, autosomal dominant disorder that leads to a disabling and disfiguring swelling of the extremities and, when untreated, tends to worsen with time. Here we link primary human lymphoedema to the FLT4 locus, encoding vascular endothelial growth factor receptor-3 (VEGFR-3), in several families. All disease-associated alleles analysed had missense mutations and encoded proteins with an inactive tyrosine kinase, preventing downstream gene activation. Our study establishes that VEGFR-3 is important for normal lymphatic vascular function and that mutations interfering with VEGFR-3 signal transduction are a cause of primary lymphoedema.

Alleles↗
PubMed1999

Frequent sequence variation in the human myostatin (GDF8) gene as a marker for analysis of muscle-related phenotypes.

Myostatin is a recently identified member of the transforming growth factor-beta family of regulatory factors, also known as growth and differentiation factor 8 (GDF8). The nucleotide sequence of human myostatin was determined in 40 individuals. The invariant promoter contains a consensus MyoD binding site, and the coding sequence contains five missense substitutions in conserved amino acid residues (A55T, K153R, E164K, P198A, and I225T). Two of these, A55T in exon 1 and K153R in exon 2, are polymorphic in the general population with significantly different allele frequencies in Caucasians and African Americans (P < 0.001). Neither of the common polymorphisms had a significant impact on muscle mass response to strength training in either Caucasians or African Americans, although skewed allele frequencies preclude detection of small effects. These allelic variants provide markers for examining association between the myostatin gene and interindividual variation in muscle mass and differences in loss of muscle mass with aging.

Amino Acid Substitution↗
PubMed1998

Hereditary lymphedema: evidence for linkage and genetic heterogeneity.

Hereditary or primary lymphedema is a developmental disorder of the lymphatic system which leads to a disabling and disfiguring swelling of the extremities. Hereditary lymphedema generally shows an autosomal dominant pattern of inheritance with reduced penetrance, variable expression and variable age at onset. Three multigeneration families demonstrating the phenotype of hereditary lymphedema segregating as an autosomal dominant trait with incomplete penetrance were genotyped for 366 autosomal markers. Linkage analysis yielded a two-point LOD score of 6.1 at straight theta = 0. 0 for marker D5S1354 and a maximum multipoint LOD score of 8.8 at marker D5S1354 located at chromosome 5q34-q35. Linkage analysis in two additional families using markers from the linked region showed one family consistent for linkage to distal chromosome 5. In the second family, linkage to 5q was excluded for all markers in the region with LOD scores Z < -2.0. The vascular endothelial growth factor C receptor ( FLT4 ) was mapped to the linked region, and partial sequence analysis identified a G-->A transition at nucleotide position 3360 of the FLT4 cDNA, predicting a leucine for proline substitution at residue 1126 of the mature receptor in one nuclear family. This study localizes a gene for primary lymphedema to distal chromosome 5q, identifies a plausible candidate gene in the linked region, and provides evidence for a second, unlinked locus for primary lymphedema.

Chromosomes, Human, Pair 5↗
PubMed1998

Ethical issues in lung transplantation.

Lung transplantation is now an accepted therapeutic option for many patients with incurable end-stage lung or pulmonary vascular disease processes for which other treatment options have been expended. However, as lung transplantation has evolved as a recognized discipline over the past decade, a variety of ethical issues related to the transplant process are emerging. This article considers those issues through a discussion of the four fundamental principles of biomedical ethics.

Ethics, Medical↗
PubMed1998

Lung transplantation: a current perspective.

Lung transplantation is a viable therapeutic option for patients with end-stage lung disease. Quality of life and survival are improved for most recipients. Donor availability remains an impediment to widespread application. The development of OB after lung transplantation continues to affect long-term survival. Clinical and basic science research will provide new strategies to further improve results.

Donor Selection↗
PubMed1996

Single lung transplantation followed by contralateral bullectomy for bullous emphysema.

BACKGROUND AND METHODS: Single lung transplantation for emphysema is now standard practice despite initial concerns, including the possibility that the compliant diseased lung would compress the transplanted lung as a result of hyperinflation. We describe a patient with severe bilateral bullous emphysema and alpha-1-antitrypsin deficiency who underwent single lung transplantation after which hyperinflation of the native lung led to significant compression of the pulmonary allograft. The patient subsequently underwent bullectomy of the contralateral lung with marked improvement in his functional status. RESULTS: After bullectomy, the patient's forced expiratory volume in 1 second increased from 1.77 to 2.82 L, his total lung capacity fell from 7.23 to 6.19 L, and his 6-minute walk increased from 724 to 1269 feet. However, 7 months after bullectomy, there was evidence that the bullous disease in the native lung was recurring. CONCLUSIONS: Significant hyperinflation of the native lung with compromise of the pulmonary allograft can occur after single lung transplantation for bullous emphysema. Bullectomy of the diseased lung after transplantation improved allograft function in our patient. Alternatively, bilateral lung transplantation for severe bilateral bullous emphysema may be considered.

Humans↗
PubMed1995

Early loss of passive measles antibody in infants of mothers with vaccine-induced immunity.

BACKGROUND: Maternally derived passive measles antibody may interfere with vaccine-induced immunity in infants less than 12 months of age. However, early loss of passive measles antibody may occur in infants of women who received measles vaccine because measles vaccine induces lower antibody titers than does natural infection. METHODS: Persistence of passive neutralizing measles antibody was studied longitudinally in a group of normal infants as a function of maternal measles titer at birth and maternal date of birth. Maternal serum and cord blood specimens were tested from 162 women and their newborns, from 51 of these infants at 9 months of age and from 63 at 12 months of age. RESULTS: Seventy-one percent of sera from 9-month-old infants (36 of 51, 95% confidence interval 68% to 84%) and 95% of samples from 12-month-old infants (60 of 63, 95% confidence interval 89% to 101%) had no detectable neutralizing measles antibody. Measles geometric mean titers were significantly higher at delivery in mothers whose infants were seropositive at 9 and 12 months compared with mothers whose infants were seronegative at 9 and 12 months. All infants with detectable measles antibody at 9 or 12 months had mothers born before 1963, before the vaccine era, and both material and cord blood measles geometric mean titers decreased significantly with decreasing maternal age. CONCLUSIONS: Persistence of passive measles antibody is uncommon by 12 months of age; earlier antibody loss is related to lower maternal age and maternal measles titer.

Antibodies, Viral↗
PubMed1993

The diagnosis of CMV pneumonitis in lung and heart/lung transplant patients by PCR compared with traditional laboratory criteria.

Polymerase chain reaction (PCR) amplification of CMV DNA recovered from bronchial alveolar lavage (BAL) and peripheral blood samples was compared with tissue culture, cytology, and/or histology for the earlier detection of CMV pneumonitis in 12 recipients of single-lung or heart/lung transplants. In patients with confirmed CMV pneumonitis, cytological evidence of CMV disease in BAL samples was detected 38 +/- 14 days posttransplantation, while tissue culture and PCR-positive results were noted as early as 30 +/- 4.0 days and 18 +/- 4.6 days, respectively. While PCR was positive earlier than culture in a number of cases, culture-positive results were subsequently obtained in each case, consistent with earlier detection of viral replication by PCR as opposed to detection of latent virus. CMV was detected by PCR in 6 of 24 blood samples from patients with confirmed or suspected CMV pneumonitis, while results of all 24 blood samples were negative when assayed by tissue culture. PCR-based testing was more sensitive than traditional tests, allowing detection of viral replication earlier than tissue culture in the posttransplant period. PCR could provide a powerful means of monitoring the immunocompromised patients in whom preemptive therapeutic intervention for CMV disease is desirable.

Biopsy↗
PubMed1992

Semiquantitative measurement of cytomegalovirus DNA in lung and heart-lung transplant patients by in vitro DNA amplification.

We report the cases of two lung transplant recipients (one heart-lung and one single lung) who eventually developed cytomegalovirus (CMV) pneumonitis after documentation of increasing CMV DNA titers in sequential bronchoalveolar lavage (BAL) specimens by polymerase chain reaction (PCR) amplification. To our knowledge, this is the first report that semiquantitation of PCR-amplified DNA can detect an increase in CMV DNA titer in BAL specimens prior to the onset of clinical symptoms or detection of infection by traditional techniques in lung transplant patients. The results obtained in these two cases suggest that DNA titer measurement on sequential BAL samples may differentiate latency from active viral replication and, thus, provide an opportunity for clinical intervention before the development of overt clinical symptoms.

Adult↗
PubMed1991

Inability of isolated soluble interleukin-2 receptor levels to predict biopsy rejection scores after heart transplantation.

Successful cardiac transplantation requires suppression of rejection, and endomyocardial biopsy is generally used to quantify this and guide immunotherapy. Biopsy, however, is an invasive, costly, cardiac catheterization with repetition limited. Since rejection requires lymphocyte activation, an alternative method of assessing rejection dynamics might be ELISA determination of soluble interleukin-2 receptor (sIL-2R) levels since induction of the interleukin-2 ligand and its receptor is required. Reports suggest that sIL-2R levels rise during kidney, liver, and heart-lung allograft rejection and heart recipients have an adverse prognosis if sIL-2R is elevated postoperatively. It is unclear, however, if serial measurements or single determinations are sufficient or if change from a baseline assessment is important. The purpose of this study was to determine if an isolated sIL-2R level after heart transplant predicted endomyocardial biopsy score at that moment. To do this, we prospectively followed 60 consecutive patients after orthotopic heart transplant and correlated 479 endomyocardial biopsy scores (McAllister scale 0-10) with matched sIL-2R levels. Regression analysis demonstrated minimal relationship between sIL-2R level and biopsy score (r =.11, r2 =.01, P=.009). When the maximum sIL-2R level for each individual patient was compared with the matched biopsy score, regression analysis revealed r=.04, r2=.001, P=.8. Likewise, when all biopsy scores and sIL-2R levels for each patient were meaned, analysis showed r=.14, r2=.02, P=.26. Thus in heart transplant patients, there is poor correlation between an isolated biopsy score and matched sIL-2R level. However, when mean +/- SEM sIL-2R was determined for severe rejection (score 7-10) and compared with sIL-2R for all other grades, it was significantly higher (1600 +/- 257 vs. 423 +/- 57 U/ml; P=.012). Still, the sensitivity, specificity, and predictive value of an sIL-2R level above 1000 U/ml predicting severe rejection was only 52%, 63%, and 8%. It would be difficult, therefore, to use a single sIL-2R determination after heart transplant to foretell the endomyocadial biopsy score. Serial measurements or quantification of a change in sIL-2R level from baseline might be more predictive of rejection severity.

Biomarkers↗