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Biomedical subjects

S E Wilson

Publications and source records attributed to S E Wilson.

At least 37 records · Page 2Linked to original sources
PubMed2001

Results of a clinical trial of clinafloxacin versus imipenem/cilastatin for intraabdominal infections.

OBJECTIVE: Clinafloxacin is a novel quinolone with wide activity against the plethora of microorganisms encountered in intraabdominal infections. This trial was performed to examine its clinical efficacy. SUMMARY BACKGROUND DATA: Clinafloxacin is representative of a new class of quinolones with considerable antimicrobial activity resulting from their mechanisms of action and pharmacodynamics. There is, however, concern about specific potential toxicities, including photosensitivity. METHODS: This prospective, randomized, double-blind trial was conducted to compare clinafloxacin with imipenem/cilastatin as adjuncts in the management of complicated intraabdominal infections. RESULTS: Five hundred twenty-nine patients were included in the intent-to-treat population, with 312 meeting all criteria for the valid population. Patients with a wide range of infections were enrolled; perforated or abscessed appendicitis was the most common (approximately 50%). One hundred twenty-three of the 150 valid patients treated with clinafloxacin (82%) had successful outcomes, as did 130 of the 162 (80%) treated with imipenem. For the intent-to-treat groups, 219 of 259 patients treated with clinafloxacin (85%) had successful outcomes, as did 219 of 270 patients treated with imipenem/cilastatin (81%). Treatment failure occurred in 39 patients who underwent drainage. There were substantially more gram-negative organisms recovered from the patients with treatment failure who were initially treated with imipenem/cilastatin. CONCLUSIONS: The results of this study clearly demonstrate the safety and efficacy of clinafloxacin in the treatment of a range of intraabdominal infections, and in patients with a broad range of physiologic disturbances.

Abdomen↗
PubMed2001

Recovery of uncorrected visual acuity after laser in situ keratomileusis or photorefractive keratectomy for low myopia.

PURPOSE: To compare uncorrected visual acuity and refractive error in patients undergoing photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK) between 1 week and 6 months after surgery. METHODS: All eyes underwent PRK or LASIK with the VisX StarS2 excimer laser. We retrospectively analyzed data from 77 random eyes of 77 patients in the PRK group and 76 eyes of 76 patients in the LASIK group. All eyes had a low myopic refractive error (spherical equivalent range, -0.88 diopters (D) to -5.13 D; mean PRK. -2.8 +/- 0.20 D: LASIK, -2.5 +/- 0.22 D). Uncorrected visual acuity and manifest refractive error were evaluated 1 week, 1 month, and 6 months after surgery. RESULTS: Each eye undergoing PRK was paired with an eye undergoing LASIK for a similar level of spherical equivalent. Mean uncorrected visual acuity after 1 week was 0.85 +/- 0.06 (20/25, logMAR 0.12 +/- 0.04) for the PRK group and 1.01 +/- 0.06 (20/20, logMAR 0.01 +/- 0.03) for the LASIK group (p < 0.001). Mean spherical equivalent after 1 week was 0.23 +/- 0.12 D for the PRK group and -0.02 +/- 0.07 D for the LASIK group (p = 0.02). Mean uncorrected visual acuity after 1 month was 1.03 +/- 0.05 (20/20, logMAR 0.02 +/- 0.03) for the PRK group and 1.05 +/- 0.05 (20/20. -0.02 +/- 0.03) for the LASIK group (p = 0.16). Mean spherical equivalent after I month was 0.19 +/- 0.10 D for the PRK group and -0.02 +/- 0.09 D for the LASIK group. This difference was statistically significant (p = 0.02), but was unlikely to be clinically significant. Mean uncorrected visual acuity after 6 months was 1.05 +/- 0.06 (20/20, logMAR -0.01 +/- 0.03) for the PRK group and 1.06 +/- 0.05 (20/20, logMAR -0.14 +/- 0.03) for the LASIK group (p = 0.41). Mean spherical equivalent after 6 months was 0.02 +/- 0.08 D for the PRK group and 0.00 +/- 0.08 D for the LASIK group (p = 0.35). CONCLUSION: Uncorrected visual acuity 1 week after surgery is significantly better in eyes undergoing LASIK than in eyes undergoing PRK. Both procedures provide functional vision by 1 week after surgery. The difference does not relate to refractive error, which was similar between the two groups, but to differences in healing of the epithelium. By 1 month after surgery, there is no difference in mean uncorrected visual acuity between eyes that undergo PRK or LASIK for low myopia.

Cornea↗
PubMed2001

Laser in situ keratomileusis versus photorefractive keratectomy in the correction of myopic astigmatism.

PURPOSE: To evaluate retrospectively the effectiveness of astigmatism correction in eyes treated with laser in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK). METHODS: Patients with low to moderate myopia with astigmatism ranging from +0.25 to +4.50 diopters were included in the study. PRK was performed on 62 eyes and LASIK on 70 eyes. Six-month data were analyzed with regard to astigmatism power, astigmatism axis, spherical equivalent, uncorrected visual acuity, vector astigmatism change, and topographic corneal regularity. RESULTS: Mean astigmatism magnitude change was 0.54 +/- 0.76 in PRK-treated eyes and 0.60 +/- 0.67 in LASIK-treated eyes (61% versus 64% change, respectively, p = 0.61) at 6 months after surgery. Mean spherical correction change was -2.79 +/- 1.51 for PRK and -2.90 +/- 1.03 for LASIK (p = 0.63). Mean spherical equivalent change was -2.5 +/- 1.57 for PRK and -2.6 +/- 1.23 for LASIK (p = 0.73). Mean change in astigmatism axis was 20.8 +/- 73.1 for PRK and 33.8 +/- 81.7 for LASIK (p = 0.34). Mean change in uncorrected visual acuity (LogMar) was 0.84 +/- 0.26 for PRK and 0.89 +/- 0.23 for LASIK (p = 0.21). Mean vector-corrected astigmatism change was 0.88 +/- 0.66 for PRK and 0.95 +/- 0.59 for LASIK (p = 0.51). Mean vector-corrected astigmatism axis for PRK was 86.9 +/- 59 degrees and for LASIK 83.8 +/- -47.6 degrees (p = 0.75). CONCLUSION: There was no significant difference in astigmatism correction between PRK and LASIK at 6 months after surgery.

Adult↗
PubMed2001

Hyperopic laser in situ keratomileusis: primary and secondary treatments are safe and effective.

PURPOSE: To retrospectively analyze the safety and efficacy of hyperopic laser in situ keratomileusis (LASIK) treatment of eyes with primary hyperopia and consecutive hyperopia after initial myopic treatment. METHODS: Thirty-two eyes of 19 patients with primary hyperopia (group 1) and 37 eyes of 26 patients with consecutive hyperopia after initial myopic LASIK overcorrection (group 2) that had LASIK for hyperopia with the Hansatome microkeratome and VISX S2 Smoothscan excimer laser with 6 months' follow-up after surgery were analyzed. Uncorrected visual acuity, best spectacle-corrected visual acuity, fogged manifest refraction, and corneal topography with corneal irregularity measurement (CIM) were evaluated 1 month, 3 months, and 6 months after surgery. RESULTS: In group 1, the mean preoperative cycloplegic spherical equivalent was +4.0 +/- 4.5 diopters (D) (range, +1.5 to + 8.75 D) and the 6-month postoperative cycloplegic spherical equivalent was +0.26 +/- 1.74 D (range, -3.00 to +2.75 D). Fifty-three percent of eyes (n= 17) in group 1 were within 1 D of emmetropia. Sixty-six percent of eyes (n= 21) had uncorrected visual acuity of at least 20/40. Three eyes (9%) lost two lines of best spectacle-corrected visual acuity. Changes in uncorrected visual acuity, best spectacle-corrected visual acuity, spherical equivalent, and the CIM topographic index 6 months after surgery were statistically significant compared with the preoperative values. In group 2, the mean preoperative cycloplegic spherical equivalent was +1.58 +/- 0.35 D (range, +0.125 to +2.75 D), and the mean postoperative cycloplegic spherical equivalent was -0.48 +/- 0.46 (range, -2.75 to +0.38 D). Eighty-six percent of eyes (n= 32) were within 1 D of emmetropia. Eighty-four percent of eyes (n= 31) in group 2 had uncorrected visual acuity of at least 20/40. One eye (2.7%) lost two lines of best spectacle-corrected visual acuity. Complications included an epithelial nest that resolved 3 months after surgery in one eye in group 2. CONCLUSIONS: LASIK is a relatively safe treatment of primary hyperopia and hyperopia resulting from overcorrection after initial LASIK treatment of myopia (consecutive hyperopia). Patients with high hyperopia (>5 D) are at risk for loss of two lines of best spectacle-corrected visual acuity. A reduction in the level of attempted correction appears to be necessary in the treatment of consecutive hyperopia.

Adult↗
PubMed2001

Computerized corneal topography and its importance to wavefront technology.

PURPOSE: To review the development and application of corneal topography in refractive surgery. METHODS: Review of the literature and discussion of recent developments in corneal topography and wavefront technology. RESULTS: Analysis of corneal topography provides critical information for the preoperative examination of patients before refractive surgery and for the evaluation and treatment of patients with complications after surgery. CONCLUSIONS: Corneal topography will continue to be a critical diagnostic modality for refractive surgery. Even with the advent of wavefront analysis designed to detect refractive error and aberrations of the eye, it will be necessary to have detailed corneal topographic information to understand the contribution the cornea makes to vision so that custom alteration of that surface can be used to optimize vision. This will be true of the normal eye, but it will be of special importance in eyes with abnormalities that were induced by corneal surgery.

Cornea↗
PubMed2001

Topical phenytoin treatment of stage II decubitus ulcers in the elderly.

OBJECTIVE: To compare the healing of stage II decubitus ulcers with topically applied phenytoin sodium with two other standard topical treatment procedures in a long-term care setting; and to assess the extent of systemic absorption after topical application in the phenytoin group. METHODS: Forty-seven nursing home patients with stage II decubitus ulcers were chosen for this study. The patients were matched for age, gender, and size and severity of wounds, and randomly assigned to each treatment group. Clinical assessment of decubitus ulcers was performed at the beginning of treatment and at each dressing change. Ulcers were examined for the presence of healthy granulation tissue, reduction in surface dimensions, and time to healing. Two phenytoin sodium plasma concentrations were to be obtained on all patients in the phenytoin group. RESULTS: Topical phenytoin therapy resulted in a shorter time to complete healing and formation of granulation tissue when compared with DuoDerm dressings or triple antibiotic ointment applications (p < or = 0.05). The mean +/- SD time to healing in the phenytoin group was 35.3 +/- 14.3 days compared with 51.8 +/- 19.6 and 53.8 +/- 8.5 days for the DuoDerm and triple antibiotic ointment groups, respectively. Healthy granulation tissue in the phenytoin group appeared within two to seven days in all subjects. Patients in the standard treatment groups required six to 21 days to produce new granulation tissue. Serum phenytoin sodium concentrations were nondetectable. No patient withdrew from the study secondary to adverse treatment effects. CONCLUSIONS: Both the phenytoin and standard treatment groups showed progress over the study period. However, the phenytoin group demonstrated more rapid results in all aspects of ulcer healing.

Administration, Topical↗
PubMed2001

Treatment of warfarin-associated coagulopathy: a physician survey.

STUDY OBJECTIVES: (1) To determine physician preferences in the management of warfarin-induced excessive anticoagulation (AC); and (2) to assess compliance with the American College of Chest Physicians (ACCP) guidelines for the reversal of excessive AC. DESIGN: Cross-sectional physician survey. PARTICIPANTS: Members of the Canadian Society of Internal Medicine practicing in Ontario, Canada. MEASUREMENTS AND RESULTS: Physicians were asked to provide management preferences in six clinical scenarios describing warfarin-induced excessive AC. The scenarios represent various combinations of international normalized ratio (INR) value, treatment setting, and presence and severity of bleeding. In scenarios with INRs < 5.2 without bleeding, conservative approaches complying with the ACCP guidelines, such as withholding warfarin or reducing its dose, were most common. In scenarios with high INRs (ie, > 7.1) and/or bleeding, the selection of vitamin K in any form ranged between 71% and 82%. However, compliance with the ACCP-recommended doses and the routes of vitamin K administration ranged from 1 to 10%. In five of the six scenarios, subcutaneous injection, a route not recommended by the ACCP, was the most common method of vitamin K delivery. CONCLUSIONS: Physician preferences for the reversal of warfarin-induced excessive AC were highly variable and, in most cases, did not follow the recommendations of the ACCP consensus guidelines. Furthermore, the widespread reported use of subcutaneous vitamin K is concerning because this route of vitamin K administration has been demonstrated to be less effective than IV administration of vitamin K. These findings highlight the need for randomized controlled trials to compare the efficacy of different routes of administration of vitamin K for warfarin-associated coagulopathy.

Adult↗
PubMed2001

Socioeconomic status and the prevalence of health problems among married couples in late midlife.

OBJECTIVES: This study analyzed the association between socioeconomic status (SES) and the prevalence of mutually occurring health problems among married couples in late midlife. METHODS: Data consisted of 4746 married couples aged 51 to 61 years from the 1992 US Health and Retirement Study. Two health measures were used: (1) self-assessed health status and (2) an index of functional limitations and activity restrictions. SES indicators were household income, education, and insurance coverage. RESULTS: In general, after adjustment for age cohort, a strong association was found between the health of a married individual and the health of his or her spouse. SES was highly associated with the joint occurrence of health problems among marriage partners. CONCLUSIONS: Public health policy should pay particular attention to the interaction between health, SES, and interpersonal relationships.

Activities of Daily Living↗
PubMed2001

Characterization of human and mouse angiopoietin-like factor CDT6 promoters.

PURPOSE: Angiogenesis refers to the latter stage of vascular development. It has been reported that angiopoietin-like factor cornea-derived transcript 6 (CDT6) encodes a protein homologous to angiopoietins that could play a critical role in blocking a receptor of angiopoietin (Tie2) and therefore contribute to the avascularity and transparency of the cornea in the developing embryo and the adult. This study was focused on isolation and characterization of the CDT6 promoter. METHODS: Rapid amplification of cDNA ends (5'-RACE) was used to isolate the CDT6 promoter from an adaptor-ligated genomic DNA fragment library and to identify the transcription initiation site of the CDT6 gene. The RNase protection assay was performed to confirm the initiation site. The sequence similarity, binding sites for putative transcription factors, and transcriptional activity of human and mouse CDT6 promoters were compared. Corneal and noncorneal cells from humans and other animals were transiently transfected with CDT6 promoter-chloramphenicol acetyltransferase (CAT) reporter constructs to analyze the transcriptional activity of the promoter. RESULTS: A 2956-bp human CDT6 promoter fragment and a 3142-bp mouse CDT6 promoter fragment were isolated. The major transcription initiation sites of the human and mouse CDT6 genes were located at 224 and 168 bp, respectively, upstream of the translation initiation site. Human and mouse CDT6 promoter sequences were very similar. Both promoters were minus TATA and CAAT boxes close to the transcription initiation site. Transfection into human corneal and noncorneal cells and into nonhuman cells revealed that the human CDT6 promoter probably contains positive and negative cis-regulatory elements that modulate cell, tissue, and species specificity. The human CDT6 promoter contains four interferon (IFN)-stimulated response elements (ISREs). No ISREs could be identified in the mouse promoter. IFN-alpha stimulated transcriptional activity of the human promoter. CONCLUSIONS: The human and mouse CDT6 promoters have similar sequences and share many cis-regulatory elements. IFN-alpha appears to have an important role in regulating transcription of the human, but not the mouse, CDT6 promoter.

Angiogenesis Inducing Agents↗
PubMed2001

Proinflammatory chemokine induction in keratocytes and inflammatory cell infiltration into the cornea.

PURPOSE: To determine the effect of interleukin (IL)-1alpha and tumor necrosis factor (TNF)-alpha on cytokine, chemokine, and receptor expression in corneal stromal cells; the effect of corneal scrape injury on monocyte chemotactic and activating factor (MCAF) expression and monocyte-macrophage influx into the stroma; and the effect of MCAF and granulocyte colony-stimulating factor (G-CSF) microinjection on inflammatory cell infiltration into the stroma. METHODS: Gene array technology was used to evaluate changes in cytokine, chemokine, and receptor gene expression in stromal fibroblasts in response to IL-1alpha and TNFalpha. Expression of MCAF mRNA and protein was monitored with an RNase protection assay and Western blot analysis, respectively. Keratocyte MCAF protein expression in the rabbit cornea was detected with immunocytochemistry. After epithelial scrape injury, monocytes-macrophages were detected in rabbit corneas, by immunocytochemistry for monocyte-macrophage antigen. Inflammatory cell infiltration after MCAF and G-CSF microinjection into the stroma of mouse corneas was monitored with hematoxylin and eosin staining. RESULTS: IL-1alpha or TNFalpha upregulated the expression of several proinflammatory chemokines in stromal fibroblasts in culture. These included G-CSF, MCAF, neutrophil-activating peptide (ENA-78), and monocyte-derived neutrophil chemotactic factor (MDNCF). MCAF mRNA upregulation was confirmed by RNase protection assay, and MCAF protein was detected by Western blot analysis. MCAF protein was detected in keratocytes at 4 hours and 24 hours after epithelial injury, but not in keratocytes in the unwounded cornea. Corneal epithelial injury triggered the influx of monocytes-macrophages into the corneal stroma in the rabbit. Microinjection of MCAF and G-CSF into mouse cornea resulted in the influx of monocytes-macrophages and granulocytes, respectively, into the stroma. CONCLUSIONS: Proinflammatory chemokine induction in keratocytes is mediated by IL-1alpha and TNFalpha. The proinflammatory chemokines produced by the keratocytes probably trigger the influx of inflammatory cells into the stroma after epithelial injury associated with corneal surgery, contact lenses, or trauma.

Blotting, Western↗
PubMed2001

The histone deacetylase inhibitor sodium butyrate induces DNA topoisomerase II alpha expression and confers hypersensitivity to etoposide in human leukemic cell lines.

The differentiating agent and histone deacetylase inhibitor, sodium butyrate (NaB), was shown previously to cause a transient, 3-17-fold induction of human DNA topoisomerase II alpha (topo II alpha) gene promoter activity and a 2-fold increase in topo II alpha protein early in monocytic differentiation of HL-60 cells. This observation has now been extended to other short chain fatty acids and aromatic butyrate analogues, and evidence is presented that human topo II alpha promoter induction correlates closely with histone H4 acetylation status. Because increased topo II alpha expression is associated with enhanced efficacy of topo II-poisoning antitumor drugs such as etoposide, the hypothesis tested in this report was whether NaB pretreatment could sensitize HL-60 myeloid leukemia and K562 erythroleukemia cells to etoposide-triggered DNA damage and cell death. A 24-72 h NaB treatment (0.4-0.5 mM) induced topo II alpha 2-2.5-fold in both HL-60 and K562 cells and caused a dose-dependent enhancement of etoposidestimulated, protein-linked DNA complexes in both cell lines. At concentrations with minimal effects on cell cycle kinetics (0.4 mM in HL-60; 0.5 mM in K562), NaB pretreatment also modestly enhanced etoposidetriggered apoptosis in HL-60 cells, as determined morphologically after acridine orange/ethidium bromide staining, and substantially increased K562 growth inhibition and poly(ADP-ribose)polymerase cleavage after etoposide exposure. Therefore, a temporal window may exist whereby a differentiating agent may sensitize experimental leukemias to a cytotoxic antitumor agent. These results indicate that histone deacetylase inhibitors should be investigated for etoposide sensitization of other butyrate-responsive hematopoietic and nonhematopoietic tumor lines in vitro and in vivo.

Antigens, Neoplasm↗
PubMed2000

The aneurysm detection and management study screening program: validation cohort and final results. Aneurysm Detection and Management Veterans Affairs Cooperative Study Investigators.

BACKGROUND: We previously reported the prevalence and associations of abdominal aortic aneurysm (AAA) in 73451 veterans aged 50 to 79 years who underwent ultrasound screening. OBJECTIVE: To understand the prevalence of and principal positive and negative risk factors for AAA, and to assess reproducibility of our previous findings. METHODS: In the new cohort of veterans undergoing screening, 52 745 subjects aged 50 to 79 without history of AAA underwent successful ultrasound screening for AAA, after completing a questionnaire on demographics and potential risk factors. RESULTS: We detected AAA of 4.0 cm or larger in 613 participants (1.2%; compared with 1.4% in the earlier cohort). The direction and magnitude of the important associations reported in the first cohort were confirmed. Respective odds ratios for the major associations with AAA for the second and for the combined cohorts were as follows: 1.81 and 1.71 for age (per 7 years), 0.12 and 0. 18 for female sex, 0.59 and 0.53 for black race, 1.94 and 1.94 for family history of AAA, 4.45 and 5.07 for smoking, 0.50 and 0.52 for diabetes, and 1.60 and 1.66 for atherosclerotic diseases. The excess prevalence associated with smoking accounted for 75% of all AAAs of 4.0 cm or larger in the total population of 126 196. Associations for AAA of 3.0 to 3.9 cm were similar but tended to be somewhat weaker. CONCLUSIONS: Our findings confirm our previous cohort findings. Age, smoking, family history of AAA, and atherosclerotic diseases remained the principal positive associations with AAA, and female sex, diabetes, and black race remained the principal negative associations.

Aged↗
PubMed2000

Yield of repeated screening for abdominal aortic aneurysm after a 4-year interval. Aneurysm Detection and Management Veterans Affairs Cooperative Study Investigators.

BACKGROUND: Little is known about the rate at which new abdominal aortic aneurysms (AAAs) develop or whether screening older men for AAA, if undertaken, should be limited to once in a lifetime or repeated at intervals. METHODS: A large population of veterans, aged 50 through 79 years, completed a questionnaire and underwent ultrasound screening for AAA. Of these, 5151 without AAA on the initial ultrasound (defined as infrarenal aortic diameter of 3.0 cm or larger) were selected randomly to be invited for a second ultrasound screening after an interval of 4 years. Local records and national databases were searched to identify deaths and AAA diagnoses made during the study interval in subjects who did not attend the rescreening. RESULTS: Of the 5151 subjects selected for a second screening, 598 (11.6%) had died (none due to AAA), and 20 (0.4%) had an interim diagnosis of AAA. A second screening was performed on 2622 (50.9%), of whom 58 (2.2%; 95% confidence interval, 1.6%-2.8%) had new AAA. Three new AAAs were 4.0 to 4.9 cm, 10 were 3.5 to 3.9 cm, and 45 were 3.0 to 3.4 cm. Independent predictors of new AAA at the second screening included current smoker (odds ratio, 3.09; 95% confidence, 1.74-5.50), coronary artery disease (odds ratio, 1.81; 95% confidence interval, 1.07-3.07), and, in a separate model using a composite variable, any atherosclerosis (odds ratio, 1.97; 95% confidence interval, 1.16-3.35). Adding the interim and rescreening diagnosis rates suggests a 4-year incidence rate of 2.6%. Rescreening only in subjects with infrarenal aortic diameter of 2.5 cm or greater on the initial ultrasound would have missed more than two thirds of the new AAAs. CONCLUSIONS: A second screening is of little practical value after 4 years, mainly because the AAAs detected are small. However, the incidence that we observed suggests that a second screening after longer intervals (ie, more than 8 years) may provide yields similar to those seen in initial screening and therefore warrants further study.

Aged↗
PubMed2000

Defective keratocyte apoptosis in response to epithelial injury in stat 1 null mice.

Defects in apoptosis have been noted in signal transducer and activator of transcription (Stat) 1-null cells in vitro. The purpose of this study was to analyse the keratocyte apoptosis response that occurs in vivo in response to corneal epithelial injury in Stat 1null compared with control mice and to determine whether Stat 1null corneal fibroblasts have a defective response to death receptor activation in vitro. Corneal epithelial scrape injuries were performed in Stat 1-null and wild-type mice. Keratocyte apoptosis was monitored with the quantitative TUNEL assay and confirmed using transmission electron microscopy. Corneal fibroblast apoptosis in response to tumor necrosis factor (TNF) alpha, with and without inhibitors of nuclear factor kappa B (NF-kappaB) activation, was monitored using DNA laddering and the methylene blue assay. Significantly less keratocyte apoptosis was noted in Stat 1-null mice compared with wild-type controls. TNF alpha-induced apoptosis only occurred in wild-type mice in the presence of inhibitors of NF-kappaB activation. Corneal fibroblast TNF alpha-induced apoptosis was defective in Stat 1null corneal fibroblasts whether NF-kappaB activation was blocked or not. Stat 1 has an important role in the keratocyte apoptosis that occurs in response to corneal epithelial injury. Previous studies suggest that the defect is due to a lack of constitutive expression of caspases. This study demonstrates that this defect in apoptosis in Stat 1-null mice is present in vivo in Stat 1-null mice and suggests that Stat 1 could be a therapeutic target for transient inhibition of keratocyte apoptosis to modulate corneal wound healing.

Animals↗
PubMed2000

Caspase inhibitor z-VAD-FMK inhibits keratocyte apoptosis, but promotes keratocyte necrosis, after corneal epithelial scrape.

The purpose of this study was to determine whether the caspase inhibitor z-VAD-FMK could be applied topically prior to epithelial scrape injury to inhibit keratocyte apoptosis. Rabbit corneas were treated with z-VAD-FMK or vehicle alone prior to epithelial scrape injury. Cell fate was analysed at 4 hr after epithelial scrape using quantitative TUNEL assay, propidium iodide staining, and transmission electron microscopy. Less stained anterior stromal keratocytes were detected with the quantitative TUNEL assay in corneas pre-treated with z-VAD-FMK than in corneas pretreated with vehicle at 4 hr after epithelial scrape. This difference appeared to be confirmed by propidium iodide staining of keratocyte nuclei. It was observed that fewer nuclei were stained with propidium iodide in the DMSO vehicle treated corneas compared to the z-VAD-FMK treated corneas. Analysis of corneas with transmission electron microscopy, however, indicated that many anterior stromal keratocytes in corneas pretreated with z-VAD-FMK, but not vehicle, had cell morphologic changes more consistent with necrosis. Although pretreatment of corneas with the caspase inhibitor z-VAD-FMK inhibited keratocyte apoptosis detected with the TUNEL assay, transmission electron microscopy revealed that many anterior stromal keratocytes in z-VAD-FMK-treated corneas instead died by necrosis. Thus, z-VAD-FMK is unlikely to be useful to modulate corneal would healing through inhibition of keratocyte apoptosis induced by epithelial injury. The TUNEL assay should not be used to monitor cell fate without confirmation using analyses that also detect necrosis.

Administration, Topical↗
PubMed2000

Impaired elastogenesis in Hurler disease: dermatan sulfate accumulation linked to deficiency in elastin-binding protein and elastic fiber assembly.

Hurler disease resulting from a deficiency in alpha-L-iduronidase, which causes an accumulation of dermatan sulfate and heparan sulfate glycosaminoglycans, is characterized by connective tissue and skeletal deformations, cardiomyopathy, cardiac valve defects, and progressive coronary artery stenosis. In this report, we present evidence that accumulation of dermatan sulfate but not heparan sulfate moieties is linked to impaired elastic fiber assembly that, in turn, contributes substantially to the development of the clinical phenotype in Hurler disease. Our data suggest that dermatan sulfate-bearing moieties bind to and cause functional inactivation of the 67-kd elastin-binding protein, a molecular chaperone for tropoelastin, which normally facilitates its secretion and assembly into elastic fibers. We demonstrate that, in contrast to normal skin fibroblasts and cells from Sanfilippo disease, which accumulate heparan sulfate, Hurler fibroblasts show reduced expression of elastin-binding protein and do not assemble elastic fibers, despite an adequate synthesis of tropoelastin and sufficient production of a microfibrillar scaffold of elastic fibers. Because cultured Hurler fibroblasts proliferate more quickly than their normal counterparts and the addition of exogenous insoluble elastin reduces their proliferation, we suggest that cell contacts with insoluble elastin play an important role in controlling their proliferation.

Adolescent↗
PubMed2000

Angioplasty and stent placement in chronic occlusion of the superficial femoral artery: technique and results.

PURPOSE: To improve the patency rate for angioplasty in chronic occlusion of the superficial femoral artery by deploying stents after angioplasty. MATERIALS AND METHODS: Angioplasty and stent placement were performed in 61 arteries in 48 male patients. The mean occlusion length was 13.5 cm and the mean stent length was 30 cm. Patency rates were analyzed at 6 months and at 1, 2, 3, and 4 years. The predictors of restenosis were analyzed by univariate and multiple logistic regression. RESULTS: Patency rates were 87% at 6 months, consisting of 74% primary, 6% primary assisted, and 7% secondary; 79% at 1 year, consisting of 47% primary, 19% primary assisted, and 13% secondary; 72% at 2 years, consisting of 36% primary, 26% primary assisted, and 10% secondary; 70% at 3 years, consisting of 26% primary, 22% primary assisted, and 22% secondary; and 63% at 4 years, consisting of 25% primary, 0% primary assisted, and 38% secondary. There was a 15% morbidity rate and one mortality as a result of retroperitoneal bleeding. Better patency rates were noted at all time intervals in diabetic limbs, 7-mm-diameter versus 10-mm-diameter stents, shorter obstructions and shorter stents, nonsmokers, in limbs in which urokinase was not necessary after stent deployment, and in limbs with an International Society of Cardiovascular Surgery (ISCVS) classification under 3. Patency rates were not affected by age, race, number of trifurcation vessels patent, experience in performing the procedures, and procedures requiring less time. By multivariate logistic analysis, the independent predictors of patency at 6 months were postprocedure ankle/brachial index (ABI) and shorter stent length; at 1 year, preprocedure ABI, shorter stent length, and the presence of diabetes; at 2 years, preprocedure ABI and the presence of diabetes; and at 3 years, the preprocedure ABI. CONCLUSIONS: The techniques used to reestablish antegrade flow in these superficial femoral arteries yielded a high success rate. In addition, the use of angioplasty with stents may improve patency rates over angioplasty without stents.

Adult↗