Showing papers by "University of Texas Health Science Center at Houston published in 1996"
TL;DR: It is demonstrated that the benefit of cholesterol-lowering therapy extends to the majority of patients with coronary disease who have average cholesterol levels and was also greater in patients with higher pretreatment levels of LDL cholesterol.
Abstract: Background In patients with high cholesterol levels, lowering the cholesterol level reduces the risk of coronary events, but the effect of lowering cholesterol levels in the majority of patients with coronary disease, who have average levels, is less clear. Methods In a double-blind trial lasting five years, we administered either 40 mg of pravastatin per day or placebo to 4159 patients (3583 men and 576 women) with myocardial infarction who had plasma total cholesterol levels below 240 mg per deciliter (mean, 209) and low-density lipoprotein (LDL) cholesterol levels of 115 to 174 mg per deciliter (mean, 139). The primary end point was a fatal coronary event or a nonfatal myocardial infarction. Results The frequency of the primary end point was 10.2 percent in the pravastatin group and 13.2 percent in the placebo group, an absolute difference of 3 percentage points and a 24 percent reduction in risk (95 percent confidence interval, 9 to 36 percent; P = 0.003). Coronary bypass surgery was needed in 7.5 per...
7,272 citations
TL;DR: The results suggest that, after local damage to the motor cortex, rehabilitative training can shape subsequent reorganization in the adjacent intact cortex, and that the undamaged motor cortex may play an important role in motor recovery.
Abstract: Substantial functional reorganization takes place in the motor cortex of adult primates after a focal ischemic infarct, as might occur in stroke. A subtotal lesion confined to a small portion of the representation of one hand was previously shown to result in a further loss of hand territory in the adjacent, undamaged cortex of adult squirrel monkeys. In the present study, retraining of skilled hand use after similar infarcts resulted in prevention of the loss of hand territory adjacent to the infarct. In some instances, the hand representations expanded into regions formerly occupied by representations of the elbow and shoulder. Functional reorganization in the undamaged motor cortex was accompanied by behavioral recovery of skilled hand function. These results suggest that, after local damage to the motor cortex, rehabilitative training can shape subsequent reorganization in the adjacent intact cortex, and that the undamaged motor cortex may play an important role in motor recovery.
1,821 citations
TL;DR: This study provides the first evidence that osteocalcin is a determinant of bone formation, and generates osteocalin-deficient mice that develop a phenotype marked by higher bone mass and bones of improved functional quality.
Abstract: Vertebrates constantly remodel bone. The resorption of preexisting bone by osteoclasts and the formation of new bone by osteoblasts is strictly coordinated to maintain bone mass within defined limits. A few molecular determinants of bone remodelling that affect osteoclast activity have been characterized, but the molecular determinants of osteoblast activity are unknown. To investigate the role of osteocalcin, the most abundant osteoblast-specific non-collagenous protein, we have generated osteocalcin-deficient mice. These mice develop a phenotype marked by higher bone mass and bones of improved functional quality. Histomorphometric studies done before and after ovariectomy showed that the absence of osteocalcin leads to an increase in bone formation without impairing bone resorption. To our knowledge, this study provides the first evidence that osteocalcin is a determinant of bone formation.
1,666 citations
TL;DR: Elevations of blood pressure are a strong independent risk factor for end-stage renal disease; interventions to prevent the disease need to emphasize the prevention and control of both high-normal and high blood pressure.
Abstract: Background End-stage renal disease in the United States creates a large burden for both individuals and society as a whole. Efforts to prevent the condition require an understanding of modifiable risk factors. Methods We assessed the development of end-stage renal disease through 1990 in 332,544 men, 35 to 57 years of age, who were screened between 1973 and 1975 for entry into the Multiple Risk Factor Intervention Trial (MRFIT). We used data from the national registry for treated end-stage renal disease of the Health Care Financing Administration and from records on death from renal disease from the National Death Index and the Social Security Administration. Results During an average of 16 years of follow-up, 814 subjects either died of end-stage renal disease or were treated for that condition (15.6 cases per 100,000 person-years of observation). A strong, graded relation between both systolic and diastolic blood pressure and end-stage renal disease was identified, independent of associations between th...
1,592 citations
TL;DR: Circulating levels of proinflammatory cytokines increase in patients as their functional heart failure classification deteriorates, and activation of the neurohumoral axis is unlikely to completely explain the elaboration of pro inflammatory cytokines in heart failure.
1,207 citations
TL;DR: The CATCH intervention was able to modify the fat content of school lunches, increase moderate-to-vigorous physical activity in PE, and improve eating and physical activity behaviors in children during 3 school years.
Abstract: grade intervention including school food service modifications, enhanced physical education (PE), and classroom health curricula. Twenty-eight additional schools received these components plus family education. Main Outcome Measures.\p=m-\Atthe school level, the two primary end points were changes in the fat content of food service lunch offerings and the amount of moderate-to-vigorous physical activity in the PE programs. At the level of the individual student, serum cholesterol change was the primary end point and was used for power calculations for the study. Individual level secondary end points included psychosocial factors, recall measures of eating and physical activity patterns, and other physiologic measures. Results.\p=m-\Inintervention school lunches, the percentage of energy intake from fat fell significantly more (from 38.7% to 31.9%) than in control lunches (from 38.9% to 36.2%)(P<.001 ). The intensity of physical activity in PE classes during the Child and Adolescent Trial for Cardiovascular Health (CATCH) intervention increased significantly in the intervention schools compared with the control schools (P<.02). Self-reported daily energy intake from fat among students in the intervention schools was significantly reduced (from 32.7% to 30.3%) compared with that among students in the control schools (from 32.6% to 32.2%) (P<.001). Intervention students reported significantly more daily vigorous activity than controls (58.6 minutes vs 46.5 minutes; P<.003). Blood pressure, body size, and cholesterol measures did not differ significantly between treatment groups. No evidence of deleterious effects of this intervention on growth or development was observed. Conclusion.\p=m-\TheCATCH intervention was able to modify the fat content of school lunches, increase moderate-to-vigorous physical activity in PE, and improve eating and physical activity behaviors in children during 3 school years.
1,054 citations
TL;DR: Monthly infusions of pamidronate provide significant protection against skeletal complications and improve the quality of life of patients with stage III multiple myeloma.
Abstract: Background Skeletal complications are a major clinical manifestation of multiple myeloma. These complications are caused by soluble factors that stimulate osteoclasts to resorb bone. Bisphosphonates such as pamidronate inhibit osteoclastic activity and reduce bone resorption. Methods Patients with stage III multiple myeloma and at least one lytic lesion received either placebo or pamidronate (90 mg) as a four-hour intravenous infusion given every four weeks for nine cycles in addition to antimyeloma therapy. The patients were stratified according to whether they were receiving first-line (stratum 1) or second-line (stratum 2) antimyeloma chemotherapy at entry into the study. Skeletal events (pathologic fracture, irradiation of or surgery on bone, and spinal cord compression), hypercalcemia (symptoms or a serum calcium concentration >12 mg per deciliter [3.0 mmol per liter]), bone pain, analgesic-drug use, performance status, and quality of life were assessed monthly. Results Among 392 treated patients, th...
1,024 citations
TL;DR: In this paper, pamidronate disodium (90 mg) was given to women with stage IV breast cancer who were receiving cytotoxic chemotherapy and had at least one lytic bone lesion.
Abstract: Background Bisphosphonates such as pamidronate disodium inhibit osteoclast-induced bone resorption associated with cancer that has metastasized to bone. Methods Women with stage IV breast cancer who were receiving cytotoxic chemotherapy and had at least one lytic bone lesion were given either placebo or pamidronate (90 mg) as a two-hour intravenous infusion monthly for 12 cycles. Skeletal complications, including pathologic fractures, the need for radiation to bone or bone surgery, spinal cord compression, and hypercalcemia (a serum calcium concentration above 12 mg per deciliter [3.0 mmol per liter] or elevated to any degree and requiring treatment), were assessed monthly. Bone pain, use of analgesic drugs, performance status, and quality of life were assessed throughout the trial. Results The efficacy of treatment was evaluated in 380 of 382 randomized patients, 185 receiving pamidronate and 195 receiving placebo. The median time to the occurrence of the first skeletal complication was greater in the pa...
1,008 citations
University of Texas Health Science Center at Houston1, National Institutes of Health2, University of Tennessee Health Science Center3, Rush University Medical Center4, Washington University in St. Louis5, University of California, San Francisco6, University of Minnesota7, University of Kentucky8, University of Alabama at Birmingham9, Veterans Health Administration10, Northwestern University11
TL;DR: Low-dose diuretic-based (chlorthalidone) treatment is effective in preventing major CVD events, cerebral and cardiac, in both non-insulin-treated diabetic and nondiabetic older patients with ISH.
Abstract: Objective. —To assess the effect of low-dose, diuretic-based antihypertensive treatment on major cardiovascular disease (CVD) event rates in older, non-insulintreated diabetic patients with isolated systolic hypertension (ISH), compared with nondiabetic patients. Design. —Double-blind, randomized, placebo-controlled trial: the Systolic Hypertension in the Elderly Program (SHEP). Setting. —Multiple clinical and support centers in the United States. Paticipants. —a total of 4736 men and women aged 60 years and older at baseline with ISH (systolic blood pressure [BP], ≥160 mm Hg; diastolic BP, Intervention. —The active treatment group received a low dose of chlorthalidone (12.5-25.0 mg/d) with a step-up to atenolol (25.0-50.0 mg/d) or reserpine (0.05-0.10 mg/d) if needed. The placebo group received placebo and any active antihypertensive drugs prescribed by patient's private physician for persistently high BP. Main Outcome Measures. —The 5-year rates of major CVD events, nonfatal plus fatal stroke, nonfatal myocardial infarction (MI) and fatal coronary heart disease (CHD), major CHD events, and all-cause mortality. Results. —The SHEP antihypertensive drug regimen lowered BP of both diabetic and nondiabetic patients, with few adverse effects. For both diabetic and nondiabetic patients, all outcome rates were lower for participants randomized to the active treatment group than for those randomized to the placebo group. Thus, 5-year major CVD rate was lower by 34% for active treatment compared with placebo, both for diabetic patients (95% confidence interval [CI], 6%-54%) and nondiabetic patients (95% CI, 21%-45%). Absolute risk reduction with active treatment compared with placebo was twice as great for diabetic vs nondiabetic patients (101/1000 vs 51/1000 randomized participants at the 5-year follow-up), reflecting the higher risk of diabetic patients. Conclusion. —Low-dose diuretic-based (chlorthalidone) treatment is effective in preventing major CVD events, cerebral and cardiac, in both non-insulin-treated diabetic and nondiabetic older patients with ISH.
914 citations
TL;DR: It is concluded that substantial functional reorganization occurs in primary motor cortex of adult primates following a focal ischemic infarct, but at least in the absence of postinfarct training, the movements formerly represented in the infarCTed zone do not reappear in adjacent cortical regions.
Abstract: 1. Intracortical microstimulation (ICMS) techniques were used to derive detailed maps of distal forelimb movement representations in primary motor cortex (area 4) of adult squirrel monkeys before and a few months after a focal ischemic infarct. 2. Infarcts caused a marked but transient deficit in use of the contralateral hand, as evidenced by increased use of the ipsilateral hand, and reduced performance on a task requiring skilled digit use. 3. Infarcts resulted in a widespread reduction in the areal extent of digit representations adjacent to the lesion, and apparent increases in adjacent proximal representations. 4. We conclude that substantial functional reorganization occurs in primary motor cortex of adult primates following a focal ischemic infarct, but at least in the absence of postinfarct training, the movements formerly represented in the infarcted zone do not reappear in adjacent cortical regions.
789 citations
TL;DR: Electrophysiologic data from intestinal mucosa showed that the NSP4 114–135 peptide potentiates chloride secretion by a calcium-dependent signaling pathway, and induced diarrhea in young (6 to 10 days old) CD1 mice.
Abstract: The rotavirus nonstructural glycoprotein NSP4 is an intracellular receptor that mediates the acquisition of a transient membrane envelope as subviral particles bud into the endoplasmic reticulum. NSP4 also causes an increase in intracellular calcium in insect cells. Purified NSP4 or a peptide corresponding to NSP4 residues 114 to 135 induced diarrhea in young (6 to 10 days old) CD1 mice. This disease response was age-dependent, dose-dependent, and specific. Electrophysiologic data from intestinal mucosa showed that the NSP4 114-135 peptide potentiates chloride secretion by a calcium-dependent signaling pathway. Diarrhea is induced when NSP4, acting as a viral enterotoxin, triggers a signal transduction pathway.
TL;DR: The cerebral organization of word identification processes in reading was examined using functional magnetic resonance imaging (fMRI) and a strategy of multiple subtractions was employed in order to validate relationships between structure and function.
Abstract: The cerebral organization of word identification processes in reading was examined using functional magnetic resonance imaging (fMRI). Changes in fMRI signal intensities were measured in 38 subjects (19 males and 19 females) during visual (line judgement), orthographic (letter case judgement), phonological (nonword rhyme judgement) and semantic (semantic category judgement) tasks. A strategy of multiple subtractions was employed in order to validate relationships between structure and function. Orthographic processing made maximum demands on extrastriate sites, phonological processing on a number of frontal and temporal sites, and lexical-semantic processing was most strongly associated with middle and superior temporal sites. Significant sex differences in the cerebral organization of reading-related processes were also observed.
TL;DR: The human genome is screened for susceptibility genes for NIDDM using non– and quasi-parametric linkage analysis methods in a group of Mexican American affected sib pairs and one marker, D2S725, showed significant evidence of linkage to NIDs and appears to be a major factor affecting the development of diabetes mellitus in Mexican Americans.
Abstract: Non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is a common disorder of middle-aged individuals characterized by high blood glucose levels which, if untreated, can cause serious medical complications and lead to early death. Genetic factors play an important role in determining susceptibility to this disorder. However, the number of genes involved, their chromosomal location and the magnitude of their effect on NIDDM susceptibility are unknown. We have screened the human genome for susceptibility genes for NIDDM using non-and quasi-parametric linkage analysis methods in a group of Mexican American affected sib pairs. One marker, D2S125, showed significant evidence of linkage to NIDDM and appears to be a major factor affecting the development of diabetes mellitus in Mexican Americans. We propose that this locus be designated NIDDM1.
TL;DR: This is the first randomized study to prove the value of surgical treatment for clinically occult regional metastases for intermediate-thickness melanomas, especially with nonulcerative melanoma and those with tumors 1 to 2 mm thick, may benefit.
Abstract: Objective A prospective multi-institutional randomized surgical trial involving 740 stage I and II melanoma patients was conducted by the Intergroup Melanoma Surgical Program to determine whether elective (immediate) lymph node dissection (ELND) for intermediate-thickness melanoma (1-4 mm) improves survival rates compared with clinical observation of the lymph nodes. A second objective was to define subgroups of melanoma patients who would have a higher survival with ELND. Methods The eligible patients were stratified according to tumor thickness, anatomic site, and ulceration, and then were prerandomized to either ELND or nodal observation. Femoral, axillary, or modified neck dissections were performed using standardized surgical guidelines. Results The median follow-up was 7.4 years. A multifactorial (Cox regression) analysis showed that the following factors independently influenced survival : tumor ulceration, trunk site, tumor thickness, and patient age. Surgical treatment results were first compared based on randomized intent. Overall 5.year survival was not significantly different for patients who received ELND or nodal observation. However, the 552 patients 60 years of age or younger (75% of total group) with ELND had a significantly better 5-year survival. Among these patients, 5-year survival was better with ELND versus nodal observation for the 335 patients with tumors 1 to 2 mm thick, the 403 patients without tumor ulceration, and the 284 patients with tumors 1 to 2 mm thick and no ulceration. In contrast, patients older than 60 years of age who had ELND actually had a lower survival trend than those who had nodal observation. When survival rates were compared based on treatment actually received (i.e., including crossover patients), the patients with significantly improved 5-year survival rates after ELND included those with tumors 1 to 2 mm thick, those without tumor ulceration, and those 60 years of age or younger with tumors 1 to 2 mm thick or without ulceration. Conclusion This is the first randomized study to prove the value of surgical treatment for clinically occult regional metastases. Patients 60 years of age or younger with intermediate-thickness melanomas, especially those with nonulcerative melanoma and those with tumors 1 to 2 mm thick, may benefit from ELND. However, because some patients still are developing distant disease, these results should be considered an interim analysis.
TL;DR: This work examined the evolutionary history and functional convergence of the CAs encoded by members of three independent CA gene families, and found support for the "introns late" hypothesis by analysis of alpha-CA intron locations.
TL;DR: The most common and significant complications are respiratory and renal failure and failure to recognize and treat ACS is inevitably fatal.
TL;DR: The results indicate that PLGA 50:50 foams are not suitable for replacement of trabecular bone, however, the dependence of mechanical properties on porosity, pore size, and degree of degradation will aid in designing a biodegradable scaffold suitable for bone regeneration.
Abstract: We present a novel method for manufacturing three-dimensional, biodegradable poly(DLlactic-co-glycolic acid) (PLGA) foam scaffolds for use in bone regeneration. The technique involves the formation of a composite material consisting of gelatin microspheres surrounded by a PLGA matrix. The gelatin microspheres are leached out leaving an open-cell foam with a pore size and morphology defined by the gelatin microspheres. The foam porosity can be controlled by altering the volume fraction of gelatin used to make the composite material. PLGA 50 : 50 was used as a model degradable polymer to establish the effect of porosity, pore size, and degradation on foam mechanical properties. The yield strengths and moduli in compression of PLGA 50: 50 foams were found to decrease with increasing porosity according to power law relationships. These mechanical properties were however, largely unaffected by pore size. Foams with yield strengths up to 3.2 MPa were manufactured. From in vitro degradation studies we establishe...
TL;DR: Bipolar disorder has a strong relationship to a history of suicide attempts relative to unipolar disorder and other Axis I disorders.
TL;DR: The skewing in the distribution of Fc gamma RIIA alleles identifies this gene as a risk factor with pathophysiologic importance for the SLE diathesis in African Americans.
Abstract: Allelic variants of Fc gamma R confer distinct phagocytic capacities providing a mechanism for heritable susceptibility to immune complex disease Human Fc gamma RIIa has two codominantly expressed alleles, R131 and H131, which differ substantially in their ability to ligate human IgG2 The Fc gamma RIIa-H131 is the only human Fc gamma R which recognizes IgG2 efficiently and optimal IgG2 handling occurs only in the homozygous state Therefore, since immune complex clearance is essential in SLE, we hypothesized that Fc gamma RIIA genes are important disease susceptibility factors for SLE, particularly lupus nephritis In a two-stage cross-sectional study, we compared the distribution of Fc gamma RIIA alleles in African Americans with SLE to that in African American non-SLE controls A pilot study of 43 SLE patients and 39 controls demonstrated a skewed distribution of Fc gamma RIIA alleles, with only 9% of SLE patients homozygous for Fc gamma RIIa-H131 compared with 36% of controls (odds ratio, 018; 95% CI, 005-069, P = 0009) This was confirmed with a multicenter study of 214 SLE patients and 100 non-SLE controls The altered distribution of Fc gamma RIIA alleles was most striking in lupus nephritis Trend analysis of the genotype distribution showed a highly significant decrease in Fc gamma RIIA-H131 as the likelihood for lupus nephritis increased (P = 00004) consistent with a protective effect of the Fc gamma RIIA-H131 gene The skewing in the distribution of Fc gamma RIIA alleles identifies this gene as a risk factor with pathophysiologic importance for the SLE diathesis in African Americans
TL;DR: The GUSTO IIb study, a large, international, multicenter trial of heparin versus hirudin in patients with acute MI and unstable angina, presented the results of the study, where there was significant benefit with hirUDin in death or MI at 24 hours but with time, the relative benefits of hIRudin declined.
Abstract: Dr Frans Van de Werf, from the University Hospital Gasthuisberg in Leuven, Belgium, Drs Robert Califf and Christopher Granger from Duke University, Durham, NC, and Dr Eric Topol, from the Cleveland (Ohio) Clinic, presented the results of the GUSTO IIb study, a large, international, multicenter trial of heparin versus hirudin in patients with acute MI and unstable angina. A total of 12 142 qualifying patients (onset of symptoms within 12 hours and ischemic ECG changes) were stratified into two groups on the basis of whether or not ST-segment elevation was present and randomized to receive heparin or hirudin. The primary end point of the study was the 30-day incidence of death and MI. Because of prior experience with a high level of bleeding complications in GUSTO IIa, the doses of study drug (both heparin and hirudin) used in GUSTO IIb were significantly reduced from GUSTO IIa. Patients treated with hirudin were noted to require fewer adjustments to maintain therapeutic levels (a mean of two adjustments versus four with heparin), and there were more hirudin patients who did not require any dose adjustments (28.5% versus 5.4% with heparin). In the ST-segment elevation group (n=4131), there was marked benefit of hirudin at 24 hours in the incidence of death and MI but no significant differences between the hirudin and heparin groups in terms of severe bleeding events (1.1% with hirudin, 1.5% with heparin), stroke (1.3% with hirudin, 0.8% with heparin), death at 30 days (5.9% versus 6.3%), and reinfarction at 30 days (5.0% versus 6.0%). In the overall population, there was significant benefit with hirudin in death or MI at 24 hours (1.3% with hirudin and 2.1% with heparin, a 37% relative decrease; P <.001). However, with time, the relative benefits of hirudin declined. By 48 hours, the incidence of death or MI …
University of Texas Health Science Center at Houston1, NewYork–Presbyterian Hospital2, University of South Alabama3, University of Texas Southwestern Medical Center4, Washington University in St. Louis5, Harborview Medical Center6, University of Cincinnati7, Louisiana State University8, University of Alabama at Birmingham9, University of Texas Medical Branch10
TL;DR: Wound assessment over time showed that thin split-thickness autografts plus allograft dermal matrix were equivalent to thicker split- Thirteen-day take rates of the dermal Matrix were statistically equivalent to the control autografteds.
Abstract: A multicenter clinical study assessed the ability of an acellular allograft dermal matrix to function as a permanent dermal transplant in full-thickness and deep partial-thickness burns. The study consisted of a pilot phase (24 patients) to identify the optimum protocol and a study phase (43 patients) to evaluate graft performance. Each patient had both a test and a mirror-image or contiguous control site. At the test site, the dermal matrix was grafted to the excised wound base and a split-thickness autograft was simultaneously applied over it. The control site was grafted with a split-thickness autograft alone. Fourteen-day take rates of the dermal matrix were statistically equivalent to the control autografts. Histology of the dermal matrix showed fibroblast infiltration, neovascularization, and neoepithelialization without evidence of rejection. Wound assessment over time showed that thin split-thickness autografts plus allograft dermal matrix were equivalent to thicker split-thickness autografts.
TL;DR: The implementation of a standardized curriculum and staff development program increased children's MVPA in existing school PE classes in four geographic and ethnically diverse communities, meeting the established Year 2000 objective of 50.
TL;DR: It is postulated that both types of thrombotic events may be predicted by heat released by activated macrophages either on the plaque surface or under a thin cap, which raises the possibility that an infrared catheter or other techniques that can localise heat or metabolic activity might be able to identify plaques at high risk of rupture orThrombosis.
TL;DR: The first population-based study that determined the magnitude of the risk and identified the factors predictive of developing seizure disorders after cerebral infarction found that early seizure occurrence predisposed those with initial late seizures to develop epilepsy.
Abstract: We performed the first population-based study that determined the magnitude of the risk and identified the factors predictive of developing seizure disorders after cerebral infarction. Five hundred thirty-five consecutive persons without prior unprovoked seizures were followed from their first cerebral infarctions until death or migration out of Rochester, Minnesota. Thirty-three patients (6%) developed early seizures (within 1 week), 78% of which occurred within the first 24 hours after infarction. Using multivariate analysis, the only factor predictive of early seizure occurrence was anterior hemisphere location of infarct (odds ratio 4.0, 95% CI 1.2 to 13.7). Twenty-seven patients developed an initial late seizure (past 1 week), whereas 18 developed epilepsy (recurrent late seizures). Compared with the population in the community, the risk during the first year was 23 times higher for initial late seizures and 17 times higher for epilepsy. The cumulative probability of developing initial late seizures was 3.0% by 1 year, 4.7% by 2 years, 7.4% by 5 years, and 8.9% by 10 years. Independent predictive factors on multivariate analysis for initial late seizures were early seizure occurrence (hazard ratio of 7.8 [95% CI 2.8 to 21.7]) and stroke recurrence (3.1 [1.2 to 8.3]). Both early seizure occurrence (16.4 [5.5 to 49.2]) and stroke recurrence (3.5 [1.2 to 10.5]) independently predicted the development of epilepsy as well. We also found that early seizure occurrence predisposed those with initial late seizures to develop epilepsy. NEUROLOGY 1996; 46 350-355
TL;DR: Endothelium produces and secretes von Willebrand factor, which mediates platelet adhesion and shear-stress-induced aggregation, and releases prostacyclin and nitric oxide, potent inhibitors of platelet and monocyte activation and vasodilators.
Abstract: Vascular endothelium is strategically located at the interface between tissue and blood. It is pivotal for protecting against vascular injury and maintaining blood fluidity. Normal endothelium releases prostacyclin and nitric oxide, potent inhibitors of platelet and monocyte activation and vasodilators. Their syntheses are governed by isoforms of enzymes. Normal endothelial surface expresses ecto-adenosine diphosphatase, which degrades adenosine diphosphate and inhibits platelet aggregation; thrombomodulin, which serves as a binding site for thrombin to activate protein C; and heparin-like molecules, which serve as a cofactor for antithrombin III. Normal endothelium secretes tissue plasminogen activator, which activates the fibrinolysis system. Endothelium produces and secretes von Willebrand factor, which mediates platelet adhesion and shear-stress-induced aggregation. Injury to endothelium is accompanied by loss of protective molecules and expression of adhesive molecules, procoagulant activities, and mitogenic factors, leading to development of thrombosis, smooth muscle cell migration, and proliferation and atherosclerosis.
TL;DR: The data suggest that venous involvement is a function of tumor location rather than an indicator of aggressive tumor biology, and when necessary, segmental resection of the SMPV confluence may be performed safely during pancreaticoduodenectomy for periampullary malignant tumors.
Abstract: OBJECTIVE: Tumor invasion of the superior mesenteric-portal vein (SMPV) confluence is often considered a contraindication to pancreaticoduodenectomy for patients with malignant tumors of the pancreas or periampullary region. The authors sought to determine whether pancreaticoduodenectomy with en bloc resection of the SMPV confluence could be safely performed and whether tumors involving the SMPV confluence were associated with pathologic parameters suggesting poor prognosis. SUMMARY BACKGROUND DATA: Several centers have reported high rates of retroperitoneal margin positivity after pancreaticoduodenectomy for tumors of the pancreatic head and periampullary region. Positive-margin or incomplete resection is associated with early tumor recurrence and no survival benefit compared with palliative therapy. Tumor adherence to the lateral of posterior wall of the SMPV confluence often represents the only barrier to complete tumor resection at the time of pancreaticoduodenectomy. METHODS: Data on all patients undergoing pancreaticoduodenectomy for adenocarcinoma of the pancreas or periampullary region over a 3.5-year period were entered prospectively in a pancreatic tumor database. To be considered for surgery, patients were required to fulfill the following computed tomography criteria for resectability: 1) the absence of extrapancreatic disease, 2) no tumor encasement of the superior mesenteric artery or celiac axis, and 3) a patent SMPV confluence. Tumor adherence to the superior mesenteric vein or SMPV confluence was assessed intraoperatively, and en bloc venous resection was performed when necessary to achieve complete tumor extirpation. Data on operative characteristics, morbidity, mortality, tumor size, nodal metastases, margin positivity, perineural invasion, and tumor DNA content were compared for patients who did and did not receive venous resection. RESULTS: Fifty-nine patients underwent pancreaticoduodenectomy, 36 without venous resection and 23 with en bloc resection of the SMPV confluence. No differences in median hospital stay, morbidity, mortality, tumor size, margin positivity, nodal positivity, or tumor DNA content were observed between groups. CONCLUSIONS: When necessary, segmental resection of the SMPV confluence may be performed safely during pancreaticoduodenectomy for periampullary malignant tumors. Tumors invading the SMPV confluence are not associated with histologic parameters suggesting a poor prognosis. Our data suggest that venous involvement is a function of tumor location rather than an indicator of aggressive tumor biology.
TL;DR: This gene shows striking sequence similarity to the EXT1 gene, and a four base deletion segregating with the phenotype is identified, defining a new multigene family of proteins with potential tumour suppressor activity.
Abstract: Hereditary multiple exostoses (EXT) is an autosomal dominant condition characterized by short stature and the development of bony protuberances at the ends of all the long bones. Three genetic locl have been identified by genetic linkage analysis at chromosomes 8q24.1, 11p11-13 and 19p. The EXT1 gene on chromosome 8 was recently identified and characterized. Here, we report the isolation and characterization of the EXT2 gene. This gene shows striking sequence similarity to the EXT1 gene, and we have identified a four base deletion segregating with the phenotype. Both EXT1 and EXT2 show significant homology with one additional expressed sequence tag, defining a new multigene family of proteins with potential tumour suppressor activity.
TL;DR: It is shown that in the developing mouse retina, Brn-3b protein is first observed in presumptive ganglion cell precursors as they begin to migrate from the zone of dividing neuroblasts to the future ganglION cell layer, and that targeted disruption of the Brn -3b gene leads in the homozygous state to a selective loss of 70% of retinal ganglions.
Abstract: The three members of the Brn-3 family of POU domain transcription factors are found in highly restricted sets of central nervous system neurons. Within the retina, these factors are present only within subsets of ganglion cells. We show here that in the developing mouse retina, Brn-3b protein is first observed in presumptive ganglion cell precursors as they begin to migrate from the zone of dividing neuroblasts to the future ganglion cell layer, and that targeted disruption of the Brn-3b gene leads in the homozygous state to a selective loss of 70% of retinal ganglion cells. In Brn-3b (-/-) mice other neurons within the retina and brain are minimally or not at all affected. These experiments indicate that Brn-3b plays an essential role in the development of specific ganglion cell types.
Journal Article•
TL;DR: Sentrin is a novel protein of 101 amino acids with homology to ubiquitin, Nedd8, and a Saccharomyces cerevisiae protein, Smt3, which interacts with Fas/APO-1 and TNF receptor 1 but not with FADD/MORT1 or CD40.
Abstract: Fas/APO-1 and TNF receptor 1 share a common signaling motif in their cytoplasmic tail called the "death domain." Using the death domain as bait in the yeast two-hybrid system, several death domain-containing proteins that participate in cell death signaling have been identified. Here we report the isolation of a novel protein, sentrin, which interacts with Fas/APO-1 and TNF receptor 1 but not with FADD/MORT1 or CD40. Two-hybrid interaction assays reveal that sentrin associates only with the signal-competent forms of Fas/APO-1 or TNF receptor 1 death domains. Sentrin is a novel protein of 101 amino acids with homology to ubiquitin, Nedd8, and a Saccharomyces cerevisiae protein, Smt3. When overexpressed, sentrin provides protection against both anti-Fas/APO-1 and TNF-induced cell death.
Journal Article•
TL;DR: Findings suggest that individuals with reduced DNA repair capacity (DRC) are at an increased risk of developing lung cancer.
Abstract: Although lung cancer is the paradigm of a tobacco-induced malignancy, host-specific factors modulate susceptibility to tobacco carcinogenesis. Variations in DNA repair may influence the rate of removal of DNA damage and of fixation of mutations. To test the hypothesis that genetically determined DNA repair capacity (DRC) modulates lung cancer susceptibility, we conducted a pilot case-control study of 51 patients with newly diagnosed, previously untreated lung cancer and 56 controls identified from local community centers and frequency matched to the cases on age, sex, and ethnicity. The subjects were ascertained and interviewed for an ongoing molecular epidemiological investigation of lung cancer susceptibility. We measured DRC in the subjects' peripheral blood lymphocytes by using the host-cell reactivation assay, which measures cellular reactivation of a reporter gene damaged by exposure to 75 microM benzo(a)pyrene diol epoxide. The mean level of DRC in cases (3.3%) was significantly lower than that in controls (5.1%) (P < 0.01). Only nine cases (18%) had DNA repair levels greater than the median value of repair in the controls. This median level of DRC in controls was used as the cutoff value for calculating the odds ratios. After adjustment for age, sex, ethnicity, and smoking status, the cases were five times more likely than the controls to have reduced DRC (odds ratio, 5.7; 95% confidence interval, 2.1-15.7). Younger cases (< 65 years) and smokers were more likely than controls to have reduced DRC. These findings suggest that individuals with reduced DRC are at an increased risk of developing lung cancer.