PubMed Health⌕ Search

Biomedical subjects

L E Smith

Publications and source records attributed to L E Smith.

At least 19 recordsLinked to original sources
PubMed2003

Transanal endoscopic excision of rectal adenomas.

Transanal endoscopic microsurgery (TEM) is a minimally invasive surgical technique for performing local excision of rectal lesions in the mid and upper rectum that would otherwise be inaccessible for local excision by the direct transanal approach. In the absence of this approach, low anterior resection would be required, which is major abdominal surgery. The justification for excising adenomas of the colon and rectum is their malignant potential, which correlates with the size of the lesion. This retrospective review examines our experience using TEM for excision of adenomas of the rectum from February 1991 to the present. The decision for using TEM is based on a precise localization of the lesion with particular attention to the upper margin of the lesion and its diameter. A total of 56 adenomas were removed. The average diameter was 4.9 cm (range, 3-8 cm). The average distance from the anal verge was 7.92 cm (range, 5-12 cm). Carcinoma in situ was seen in 7 lesions, and the remaining lesions were benign. Morbidity was minimal, with one conversion to an open procedure for an intraperitoneal perforation that required a low anterior resection. No patient required transfusion and there was no mortality. The hospital stay was short, with half of the patients being discharged the same day. The average cost from July 1996 to December 1999 was 7775 dollars for TEM versus 34,018 dollars for LAR. Subsequent follow-up average was 38.8 months (range, 1-100 months), during which time two patients had recurrence of their adenomas. This was successfully treated with reexcision. In conclusion, TEM is an accurate, safe, and relatively inexpensive technique when compared to low anterior resection. This technique significantly reduces the proportion of adenomas requiring abdominal surgery.

Adenoma↗
PubMed2002

Study of the effectiveness of the US safety standard for child resistant cigarette lighters.

OBJECTIVE: The purpose of this research is to evaluate the effectiveness of the US Consumer Product Safety Commission's (CPSC) Safety Standard for Cigarette Lighters, which requires that disposable cigarette lighters be resistant to operation by children younger than age 5. METHODS: Fire data on children playing with lighters were solicited from selected US fire departments for incidents occurring from 1997-99, to identify the proportion of such fires caused by children younger than age 5 playing with cigarette lighters. These data were compared with similar data from 1985-87. An odds ratio was used to determine if there was a significant decrease in cigarette lighter fires caused by children younger than age 5 compared to children ages 5 and older. To estimate fires that would have occurred without the standard, the odds ratio, adjusted for population, was applied to 1998 national estimates of fires occurring. National estimates of 1998 fire losses were based on data from the National Fire Incident Reporting System and the National Fire Protection Association to which the 1997-99 age and lighter type distributions were applied. The difference between the fire losses that would have occurred and those that did occur represented fire losses prevented. RESULTS: In the post-standard study, 48% of the cigarette lighter fires were started by children younger than age 5, compared with 71% in the pre-standard study. The odds ratio of 0.42 was statistically significant (p<0.01). This represented a 58% reduction in fires caused by the younger age group compared to the older age group. When applied to national fire loss data, an estimated 3300 fires, 100 deaths, 660 injuries, and $52.5 million in property loss were prevented by the standard in 1998, totaling $566.8 million in 1998 societal savings. CONCLUSIONS: The CPSC standard requiring child resistant cigarette lighters has reduced fire deaths, injuries, and property loss caused by children playing with cigarette lighters and can be expected to prevent additional fire losses in subsequent years.

Burns↗
PubMed2001

Methylated CpG dinucleotides are the preferential targets for G-to-T transversion mutations induced by benzo[a]pyrene diol epoxide in mammalian cells: similarities with the p53 mutation spectrum in smoking-associated lung cancers.

A large fraction of the p53 mutations in lung cancers from smokers are G-to-T transversions, a type of mutation that is infrequent in lung cancers from nonsmokers and in most other tumors. Previous studies have indicated that there is an association between G-to-T transversion hotspots in lung cancers and sites of preferential formation of polycyclic aromatic hydrocarbon adducts along the p53 gene. p53 codons containing methylated CpG sequences are preferential targets for formation of adducts by (+/-) anti-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE). To assess the role of CpG methylation in induction of mutations by BPDE, we analyzed BPDE mutagenesis in three CpG methylated target genes: a supF shuttle vector and the cII and lacI transgenes in embryonic mouse fibroblasts. After methylation of the shuttle vector at all CpG sequences, 42% of all G-to-T transversions were at CpG sites compared with 23% in unmethylated DNA. In the cII transgene, which is methylated at CpG sequences in vivo, 83 of 147 (56%) of the BPDE-induced mutations were G-to-T transversions, and 58% (48 of 83) of all G-to-T transversions occurred at methylated CpG sequences. In the lacI gene, 68% (75 of 111) of the BPDE-induced mutations were G-to-T events, and 58 of 75 (77%) of these occurred at methylated CpG sequences. The occurrence of transversion hotspots at methylated CpGs correlated with high levels of BPDE adducts formed at such sites. This situation mirrors the one in the p53 gene in lung cancers from smokers where 236 of 465 (51%) of the G-to-T transversions occurred at methylated CpG sites. These findings further strengthen a link between polycyclic aromatic hydrocarbons present in cigarette smoke and lung cancer mutations and provide evidence that mutational processes other than C-to-T transition mutations can occur selectively at methylated CpG sequences.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2001

Low IGF-I suppresses VEGF-survival signaling in retinal endothelial cells: direct correlation with clinical retinopathy of prematurity.

Retinopathy of prematurity is a blinding disease, initiated by lack of retinal vascular growth after premature birth. We show that lack of insulin-like growth factor I (IGF-I) in knockout mice prevents normal retinal vascular growth, despite the presence of vascular endothelial growth factor, important to vessel development. In vitro, low levels of IGF-I prevent vascular endothelial growth factor-induced activation of protein kinase B (Akt), a kinase critical for endothelial cell survival. Our results from studies in premature infants suggest that if the IGF-I level is sufficient after birth, normal vessel development occurs and retinopathy of prematurity does not develop. When IGF-I is persistently low, vessels cease to grow, maturing avascular retina becomes hypoxic and vascular endothelial growth factor accumulates in the vitreous. As IGF-I increases to a critical level, retinal neovascularization is triggered. These data indicate that serum IGF-I levels in premature infants can predict which infants will develop retinopathy of prematurity and further suggests that early restoration of IGF-I in premature infants to normal levels could prevent this disease.

Base Sequence↗
PubMed2001

In vivo modulation of FGF biological activity alters cranial suture fate.

Gain-of-function mutations in fibroblast growth factor receptors have been identified in numerous syndromes associated with premature cranial suture fusion. Murine models in which the posterior frontal suture undergoes programmed fusion after birth while all other sutures remain patent provide an ideal model to study the biomolecular mechanisms that govern cranial suture fusion. Using adenoviral vectors and targeted in utero injections in rats, we demonstrate that physiological posterior frontal suture fusion is inhibited using a dominant-negative fibroblast growth factor receptor-1 construct, whereas the normally patent coronal suture fuses when infected with a construct that increases basic fibroblast growth factor biological activity. Our data may facilitate the development of novel, less invasive treatment options for children with craniosynostosis.

Adenoviridae↗
PubMed2001

Angiogenesis as a potential biomarker in prostate cancer chemoprevention trials.

Prostate cancer is a multistep process in which progression rather than initiation may be the rate-limiting step. A strong possibility is that prostatic intraepithelial neoplasia lesions that switch to angiogenic phenotype eventually progress to cancer. However, it is a challenging task to quantitate angiogenesis in preneoplastic lesions. A promising approach to measuring angiogenesis involves real-time TaqMan polymerase chain reaction to quantitate mRNAs encoding a panel of angiogenesis markers. This highly sensitive molecular technique has potential for quantitating angiogenesis in clinical settings and can be used as a high-throughput screening procedure in prostate cancer clinical trials.

Animals↗
PubMed2001

Recent concepts in fecal incontinence.

Fecal incontinence is an inability to defer release of gas or stool from the anus and rectum by mechanisms of voluntary control. It is an important medical disorder affecting the quality of life of more than 2% of the US population. The most common contributing factors include previous vaginal deliveries, pelvic or perineal trauma, previous anorectal surgery, and rectal prolapse. Many physicians lack experience and knowledge related to pelvic floor incontinence disorders, but advancing technology has improved this knowledge. Increased experience with endoanal ultrasound and endoanal magnetic resonance imaging have given us better understanding of the anatomy of the anal canal, and new techniques with muscle translocation and artificial neosphincters and neuromodulation have expanded our armamentarium of options for restoring continence.

Aged↗
PubMed2000

Targeting of lung cancer mutational hotspots by polycyclic aromatic hydrocarbons.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in combustion products of organic matter, including cigarette smoke. Metabolically activated diol epoxides of these compounds, including benzo[a]pyrene diol epoxide (B[a]PDE), have been suggested as causative agents in the development of lung cancer. We previously mapped the distribution of B[a]PDE adducts within the p53 tumor suppressor gene (also known as TP53), which is mutated in 60% of human lung cancers, and found that B[a]PDE adducts preferentially form at lung cancer mutational hotspots (codons 154, 157, 158, 245, 248, and 273). Other PAHs may be important in lung cancer as well. METHODS: Here we have mapped the distribution of adducts induced by diol epoxides of additional PAHs: chrysene (CDE), 5-methylchrysene (5-MCDE), 6-methylchrysene (6-MCDE), benzo[c]phenanthrene (B[c]PDE), and benzo[g]chrysene (B[g]CDE) within exons 5, 7, and 8 of the p53 gene in human bronchial epithelial cells. RESULTS: CDE exposure produced only low levels of adducts. Exposure of cells to the other activated PAHs resulted in DNA damage patterns similar to those previously observed with B[a]PDE but with some distinct differences. 5-MCDE, 6-MCDE, B[g]CDE, and B[c]PDE efficiently induced adducts at guanines within codons 154, 156, 157, 158, and 159 of exon 5, codons 237, 245 and 248 of exon 7, and codon 273 of exon 8, but the relative levels of adducts at each site varied for each compound. B[g]CDE, B[c]PDE, and 5-MCDE induced damage at codon 158 more selectively than 6-MCDE or B[a]PDE. The sites most strongly involved in PAH adduct formation were also the sites of highest mutation frequency (codons 157, 158, 245, 248, and 273). CONCLUSION: The data suggest that PAHs contribute to the mutational spectrum in human lung cancer.

Base Sequence↗
PubMed2000

The spectrum of mutations in erythrokeratodermias--novel and de novo mutations in GJB3.

Intercellular channels in skin are a complex and functionally diverse system formed by at least eight connexins (Cx). Our recent molecular studies implicating Cx defects in inherited skin disorders emphasize the critical role of this signaling pathway in epidermal differentiation. Erythrokeratodermia variabilis (EKV) is an autosomal dominant genodermatosis with a striking phenotype characterized by the independent occurrence of transient localized erythema and hyperkeratosis. The disease maps to 1p34-p35, and recently we identified the causative gene GJB3 encoding Cx31. We have now investigated GJB3 in two families and three sporadic cases with EKV, and report three new heterozygous mutations. In a sporadic case, we detected a mutation leading to substitution of a conserved phenylalanine (F137L) in the third transmembrane domain, which likely interferes with the proper assembly or gating properties of connexons. In another family, all three affected individuals carried two distinct mutations on the same GJB3 allele. However, only a de novo heterozygous missense mutation replacing arginine 42 with proline (R42P) co-segregated with the disease, while a 12 bp deletion predicted to eliminate four amino acid residues in the variable carboxy terminal domain of Cx31 was also found in clinically unaffected relatives but not in 90 unaffected controls. Including the previously published mutations, in toto, five different missense mutations have now been detected in 6 out of 17 families investigated by our laboratory, all of which presumably affect the cytoplasmic amino terminal and transmembrane domains of Cx31. In contrast, two mutations linked to progressive high-tone hearing impairment were located in the second extracellular domain, suggesting that the character and position of Cx mutations determine their phenotypic expression in different tissues. However, the phenotypic spectrum of GJB3 mutations seems not to include progressive symmetric erythrokeratodermia, another dominant genodermatosis with overlapping features, since no mutations were found in six unrelated families tested.

Connexins↗
PubMed2000

Septic arthritis of the hip secondary to rat bite fever: a case report.

Rat bite fever is a rare infection typically caused by Streptobacillus moniliformis. The mode of transmission is most commonly through a bite or scratch from an infected rat. This disease is characterized by polyarthritis, fever, and a delayed onset erythematous maculopapular rash of the extremities. The authors report a case of rat bite fever, which led to septic arthritis of the hip. To the authors' knowledge, the complication of hip sepsis requiring an arthrotomy has not been reported in the literature. The orthopaedist should be aware of not only Streptobacillus moniliformis, but also of other zoonotic organisms, which potentially can cause septic arthritis and warrant treatment with specific antibiotics.

Arthritis, Infectious↗
PubMed1999

Oligonucleotide-based inhibition of embryonic gene expression.

We describe a technique to define gene function using antisense oligonucleotide (AS-ODN) inhibition of gene expression in mice. A single intravenous injection of an AS-ODN targeting vascular endothelial growth factor (VEGF) into pregnant mice between E7.5-8.5 resulted in a lack of primary angiogenesis. This enabled us to define the critical window required to inhibit VEGF expression and recapitulate the primary loss of function phenotype observed in VEGF (-/-) embryos. This phenotype was sequence-specific and time- and dose-dependent. Injection of an AS-ODN targeting a second gene, E-cadherin, into pregnant mice at E10 confirmed a hypothesized secondary phenotype. This is the first report of AS-ODN inhibition of gene expression in utero and provides a new strategy for target validation in functional genomics.

Animals↗
PubMed1999

Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor.

Although insulin-like growth factor 1 (IGF-1) has been associated with retinopathy, proof of a direct relationship has been lacking. Here we show that an IGF-1 receptor antagonist suppresses retinal neovascularization in vivo, and infer that interactions between IGF-1 and the IGF-1 receptor are necessary for induction of maximal neovascularization by vascular endothelial growth factor (VEGF). IGF-1 receptor regulation of VEGF action is mediated at least in part through control of VEGF activation of p44/42 mitogen-activated protein kinase, establishing a hierarchical relationship between IGF-1 and VEGF receptors. These findings establish an essential role for IGF-1 in angiogenesis and demonstrate a new target for control of retinopathy. They also explain why diabetic retinopathy initially increases with the onset of insulin treatment. IGF-1 levels, low in untreated diabetes, rise with insulin therapy, permitting VEGF-induced retinopathy.

Animals↗
PubMed1998

Functional defects of Cx26 resulting from a heterozygous missense mutation in a family with dominant deaf-mutism and palmoplantar keratoderma.

Mutations in GJB2 encoding the gap junction protein connexin-26 (Cx26) have been established as the basis of autosomal recessive non-syndromic hearing loss. The involvement of GJB2 in autosomal dominant deafness has also been proposed, although the putative mutation identified in one family with both deafness and palmoplantar keratoderma has recently been suggested to be merely a non-disease associated polymorphism. We have observed a similar phenotype in an Egyptian family that segregated with a heterozygous missense mutation of GJB2, leading to a non-conservative amino acid substitution (R75W). The deleterious dominant-negative effect of R75W on gap channel function was subsequently demonstrated in the paired oocyte expression system. Not only was R75W alone incapable of inducing electrical conductance between adjacent cells, but it almost completely suppressed the activity of co-expressed wildtype protein. The Cx26 mutant W77R, which has been implicated in autosomal recessive deafness, also failed to form functional gap channels by itself but did not significantly interfere with the function of wildtype Cx26. These data provide compelling evidence for the serious functional consequences of Cx26 mutations in dominant and recessive deafness.

Amino Acid Sequence↗
PubMed1998

Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis.

Erythrokeratodermia variabilis (EKV, OMIM 133200) is an autosomal dominant genodermatosis with considerable intra- and interfamilial variability. It has a disfiguring phenotype characterized by the independent occurrence of two morphologic features: transient figurate red patches and localized or generalized hyperkeratosis. Both features can be triggered by external factors such as trauma to the skin. After initial linkage to the RH locus on 1p, EKV was mapped to an interval of 2.6 cM on 1p34-p35, and a candidate gene (GJA4) encoding the gap junction protein alpha-4 (connexin 31, Cx31) was excluded by sequence analysis. Evidence in mouse suggesting that the EKV region harbours a cluster of epidermally expressed connexin genes led us to characterize the human homologues of GJB3 (encoding Cx31) and GJB5 (encoding Cx31.1). GJB3, GJB5 and GJA4 were localized to a 1.1-Mb YAC in the candidate interval. We detected heterozygous missense mutations in GJB3 in four EKV families leading to substitution of a conserved glycine by charged residues (G12R and G12D), or change of a cysteine (C86S). These mutations are predicted to interfere with normal Cx31 structure and function, possibly due to a dominant inhibitory effect. Our results implicate Cx31 in the pathogenesis of EKV, and provide evidence that intercellular communication mediated by Cx31 is crucial for epidermal differentiation and response to external factors.

Amino Acid Sequence↗