Showing papers by "University of Texas Health Science Center at San Antonio published in 2000"

Automated Talairach Atlas labels for functional brain mapping

Abstract: An automated coordinate-based system to retrieve brain labels from the 1988 Talairach Atlas, called the Talairach Daemon (TD), was previously introduced (Lancaster et al., 1997). In the present study, the TD system and its 3-D database of labels for the 1988 Talairach atlas were tested for labeling of functional activation foci. TD system labels were compared with author-designated labels of activation coordinates from over 250 published functional brain-mapping studies and with manual atlas-derived labels from an expert group using a subset of these activation coordinates. Automated labeling by the TD system compared well with authors' labels, with a 70% or greater label match averaged over all locations. Author-label matching improved to greater than 90% within a search range of 65 mm for most sites. An adaptive grey matter (GM) range-search utility was evaluated using individual activations from the M1 mouth region (30 subjects, 52 sites). It provided an 87% label match to Brodmann area labels (B A4&B A 6) within a search range of 65 mm. Using the adaptive GM range search, the TD system's overall match with authors' labels (90%) was better than that of the expert group (80%). When used in concert with authors' deeper knowledge of an experiment, the TD system provides consistent and comprehensive labels for brain activation foci. Additional suggested applications of the TD system include interactive labeling, anatomical grouping of activation foci, lesion-deficit analysis, and neuroanatomy education. Hum. Brain Mapping 10:120 -131, 2000. © 2000 Wiley-Liss, Inc.

Chronic Subclinical Inflammation as Part of the Insulin Resistance Syndrome The Insulin Resistance Atherosclerosis Study (IRAS)

Abstract: Background—Inflammation has been suggested as a risk factor for the development of atherosclerosis. Recently, some components of the insulin resistance syndrome (IRS) have been related to inflammatory markers. We hypothesized that insulin insensitivity, as directly measured, may be associated with inflammation in nondiabetic subjects. Methods and Results—We studied the relation of C-reactive protein (CRP), fibrinogen, and white cell count to components of IRS in the nondiabetic population of the Insulin Resistance Atherosclerosis Study (IRAS) (n=1008; age, 40 to 69 years; 33% with impaired glucose tolerance), a multicenter, population-based study. None of the subjects had clinical coronary artery disease. Insulin sensitivity (SI) was measured by a frequently sampled intravenous glucose tolerance test, and CRP was measured by a highly sensitive competitive immunoassay. All 3 inflammatory markers were correlated with several components of the IRS. Strong associations were found between CRP and measures of b...

Traumatic glenohumeral bone defects and their relationship to failure of arthroscopic Bankart repairs: significance of the inverted-pear glenoid and the humeral engaging Hill-Sachs lesion.

Abstract: Purpose: Our goal was to analyze the results of 194 consecutive arthroscopic Bankart repairs (performed by 2 surgeons with an identical suture anchor technique) in order to identify specific factors related to recurrence of instability. Type of Study: Case series. Materials and Methods: We analyzed 194 consecutive arthroscopic Bankart repairs by suture anchor technique performed for traumatic anterior-inferior instability. The average follow-up was 27 months (range, 14 to 79 months). There were 101 contact athletes (96 South African rugby players and 5 American football players). We identified significant bone defects on either the humerus or the glenoid as (1) “inverted-pear” glenoid, in which the normally pear-shaped glenoid had lost enough anterior-inferior bone to assume the shape of an inverted pear; or (2) “engaging” Hill-Sachs lesion of the humerus, in which the orientation of the Hill-Sachs lesion was such that it engaged the anterior glenoid with the shoulder in abduction and external rotation. Results: There were 21 recurrent dislocations and subluxations (14 dislocations, 7 subluxations). Of those 21 shoulders with recurrent instability, 14 had significant bone defects (3 engaging Hill-Sachs and 11 inverted-pear Bankart lesions). For the group of patients without significant bone defects (173 shoulders), there were 7 recurrences (4% recurrence rate). For the group with significant bone defects (21 patients), there were 14 recurrences (67% recurrence rate). For contact athletes without significant bone defects, there was a 6.5% recurrence rate, whereas for contact athletes with significant bone defects, there was an 89% recurrence rate. Conclusions: (1) Arthroscopic Bankart repairs give results equal to open Bankart repairs if there are no significant structural bone deficits (engaging Hill-Sachs or inverted-pear Bankart lesions). (2) Patients with significant bone deficits as defined in this study are not candidates for arthroscopic Bankart repair. (3) Contact athletes without structural bone deficits may be treated by arthroscopic Bankart repair. However, contact athletes with bone deficiency require open surgery aimed at their specific anatomic deficiencies. (4) For patients with significant glenoid bone loss, the surgeon should consider reconstruction by means of the Latarjet procedure, using a large coracoid bone graft. Key Words: Instability—Arthroscopic instability repair—Shoulder instability—Bone defect—Bone graft—Latarjet reconstruction.

Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle.

Abstract: The broad nature of insulin resistant glucose metabolism in skeletal muscle of patients with type 2 diabetes suggests a defect in the proximal part of the insulin signaling network. We sought to identify the pathways compromised in insulin resistance and to test the effect of moderate exercise on whole-body and cellular insulin action. We conducted euglycemic clamps and muscle biopsies on type 2 diabetic patients, obese nondiabetics and lean controls, with and without a single bout of exercise. Insulin stimulation of the phosphatidylinositol 3-kinase (PI 3-kinase) pathway, as measured by phosphorylation of the insulin receptor and IRS-1 and by IRS protein association with p85 and with PI 3-kinase, was dramatically reduced in obese nondiabetics and virtually absent in type 2 diabetic patients. Insulin stimulation of the MAP kinase pathway was normal in obese and diabetic subjects. Insulin stimulation of glucose-disposal correlated with association of p85 with IRS-1. Exercise 24 hours before the euglycemic clamp increased phosphorylation of insulin receptor and IRS-1 in obese and diabetic subjects but did not increase glucose uptake or PI 3-kinase association with IRS-1 upon insulin stimulation. Thus, insulin resistance differentially affects the PI 3-kinase and MAP kinase signaling pathways, and insulin-stimulated IRS-1-association with PI 3-kinase defines a key step in insulin resistance.

Practice parameter: Screening and diagnosis of autism Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Child Neurology Society

Abstract: Autism is a common disorder of childhood, affecting 1 in 500 children. Yet, it often remains unrecognized and undiagnosed until or after late preschool age because appropriate tools for routine developmental screening and screening specifically for autism have not been available. Early identification of children with autism and intensive, early intervention during the toddler and preschool years improves outcome for most young children with autism. This practice parameter reviews the available empirical evidence and gives specific recommendations for the identification of children with autism. This approach requires a dual process: 1) routine developmental surveillance and screening specifically for autism to be performed on all children to first identify those at risk for any type of atypical development, and to identify those specifically at risk for autism; and 2) to diagnose and evaluate autism, to differentiate autism from other developmental disorders.

Actions of melatonin in the reduction of oxidative stress

Abstract: Melatonin was discovered to be a direct free radical scavenger less than 10 years ago. Besides its ability to directly neutralize a number of free radicals and reactive oxygen and nitrogen species, it stimulates several antioxidative enzymes which increase its efficiency as an antioxidant. In terms of direct free radical scavenging, melatonin interacts with the highly toxic hydroxyl radical with a rate constant equivalent to that of other highly efficient hydroxyl radical scavengers. Additionally, melatonin reportedly neutralizes hydrogen peroxide, singlet oxygen, peroxynitrite anion, nitric oxide and hypochlorous acid. The following antioxidative enzymes are also stimulated by melatonin: superoxide dismutase, glutathione peroxidase and glutathione reductase. Melatonin has been widely used as a protective agent against a wide variety of processes and agents that damage tissues via free radical mechanisms.

A Comparison of Glyburide and Insulin in Women with Gestational Diabetes Mellitus

Abstract: Background Women with gestational diabetes mellitus are rarely treated with a sulfonylurea drug, because of concern about teratogenicity and neonatal hypoglycemia. There is little information about the efficacy of these drugs in this group of women. Methods We studied 404 women with singleton pregnancies and gestational diabetes that required treatment. The women were randomly assigned between 11 and 33 weeks of gestation to receive glyburide or insulin according to an intensified treatment protocol. The primary end point was achievement of the desired level of glycemic control. Secondary end points included maternal and neonatal complications. Results The mean (±SD) pretreatment blood glucose concentration as measured at home for one week was 114±19 mg per deciliter (6.4±1.1 mmol per liter) in the glyburide group and 116±22 mg per deciliter (6.5±1.2 mmol per liter) in the insulin group (P=0.33). The mean concentrations during treatment were 105± 16 mg per deciliter (5.9±0.9 mmol per liter) in the glyburi...

Practice Guidelines for Diseases Caused by Aspergillus

Abstract: Aspergillosis comprises a variety of manifestations of infection. These guidelines are directed to 3 principal entities: invasive aspergillosis, involving several organ systems (particularly pulmonary disease); pulmonary aspergilloma; and allergic bronchopulmonary aspergillosis. The recommendations are distilled in this summary, but the reader is encouraged to review the more extensive discussions in subsequent sections, which show the strength of the recommendations and the quality of the evidence, and the original publications cited in detail. Invasive aspergillosis. Because it is highly lethal in the immunocompromised host, even in the face of therapy, work-up must be prompt and aggressive, and therapy may need to be initiated upon suspicion of the diagnosis, without definitive proof (BIII). Intravenous therapy should be used initially in rapidly progressing disease (BIII). The largest therapeutic experience is with amphotericin B deoxycholate, which should be given at maximum tolerated doses (e.g., 1-1.5 mg/kg/d) and should be continued, despite modest increases in serum creatinine levels (BIII). Lipid formulations of amphotericin are indicated for the patient who has impaired renal function or who develops nephrotoxicity while receiving deoxycholate amphotericin (AII). Oral itraconazole is an alternative for patients who can take oral medication, are likely to be adherent, can be demonstrated (by serum level monitoring) to absorb the drug, and lack the potential for interaction with other drugs (BII). Oral itraconazole is attractive for continuing therapy in the patient who responds to initial iv therapy (CIII). Therapy should be prolonged beyond resolution of disease and reversible underlying predispositions (BIII). Adjunctive therapy (particularly surgery and combination chemotherapy, also immunotherapy), may be useful in certain situations (CIII). Aspergilloma. The optimal treatment strategy for aspergilloma is unknown. Therapy is predominantly directed at preventing life-threatening hemoptysis. Surgical removal of aspergilloma is definitive treatment, but because of significant morbidity and mortality it should be reserved for high-risk patients such as those with episodes of life-threatening hemoptysis, and considered for patients with underlying sarcoidosis, immunocompromised patients, and those with increasing Aspergillus-specific IgG titers (CIII). Surgical candidates would need to have adequate pulmonary function to undergo the operation. Bronchial artery embolization rarely produces a permanent success, but may be useful as a temporizing procedure in patients with life-threatening hemoptysis. Endobronchial and intracavitary instillation of antifungals or oral itraconazole may be useful for this condition. Since the majority of aspergillomas do not cause life-threatening hemoptysis, the morbidity and cost of treatment must be weighed against the clinical benefit. Allergic bronchopulmonary aspergillosis (APBA). Although no well-designed studies have been carried out, the available data support the use of corticosteroids for acute exacerbations of ABPA (AII). Neither the optimal corticosteroid dose nor the duration of therapy has been standardized, but limited data suggest the starting dose should be approximately 0.5 mg/kg/d of prednisone. The decision to taper corticosteroids should be made on an individual basis, depending on the clinical course (BIII). The available data suggest that clinical symptoms alone are inadequate to make such decisions, since significant lung damage may occur in asymptomatic patients. Increasing serum IgE levels, new or worsening infiltrate on chest radiograph, and worsening spirometry suggest that corticosteroids should be used (BII). Multiple asthmatic exacerbations in a patient with ABPA suggest that chronic corticosteroid therapy should be used (BIII). Itraconazole appears useful as a corticosteroid sparing agent (BII). (ABSTRACT TRUNCATED)

Users" Guides to the Medical Literature XXV. Evidence-Based Medicine: Principles for Applying the Users' Guides to Patient Care

Abstract: This series provides clinicians with strategies and tools to interpret and integrate evidence from published research in their care of patients. The 2 key principles for applying all the articles in this series to patient care relate to the value-laden nature of clinical decisions and to the hierarchy of evidence postulated by evidence-based medicine. Clinicians need to be able to distinguish high from low quality in primary studies, systematic reviews, practice guidelines, and other integrative research focused on management recommendations. An evidence-based practitioner must also understand the patient's circumstances or predicament; identify knowledge gaps and frame questions to fill those gaps; conduct an efficient literature search; critically appraise the research evidence; and apply that evidence to patient care. However, treatment judgments often reflect clinician or societal values concerning whether intervention benefits are worth the cost. Many unanswered questions concerning how to elicit preferences and how to incorporate them in clinical encounters constitute an enormously challenging frontier for evidence-based medicine. Time limitation remains the biggest obstacle to evidence-based practice but clinicians should seek evidence from as high in the appropriate hierarchy of evidence as possible, and every clinical decision should be geared toward the particular circumstances of the patient.

A Randomized, Placebo-Controlled 12-Month Trial of Divalproex and Lithium in Treatment of Outpatients With Bipolar I Disorder

Abstract: Background Long-term outcomes are often poor in patients with bipolar disorder despite treatment; more effective treatments are needed to reduce recurrences and morbidity. This study compared the efficacy of divalproex, lithium, and placebo as prophylactic therapy. Methods A randomized, double-blind, parallel-group multicenter study of treatment outcomes was conducted over a 52-week maintenance period. Patients who met the recovery criteria within 3 months of the onset of an index manic episode (n=372) were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2:1:1 ratio. Psychotropic medications were discontinued before randomization, except for open-label divalproex or lithium, which were gradually tapered over the first 2 weeks of maintenance treatment. The primary outcome measure was time to recurrence of any mood episode. Secondary measures were time to a manic episode, time to a depressive episode, average change from baseline in Schedule for Affective Disorders and Schizophrenia–Change Version subscale scores for depression and mania, and Global Assessment of Function scores. Results The divalproex group did not differ significantly from the placebo group in time to any mood episode. Divalproex was superior to placebo in terms of lower rates of discontinuation for either a recurrent mood episode or depressive episode. Divalproex was superior to lithium in longer duration of successful prophylaxis in the study and less deterioration in depressive symptoms and Global Assessment Scale scores. Conclusions The treatments did not differ significantly on time to recurrence of any mood episode during maintenance therapy. Patients treated with divalproex had better outcomes than those treated with placebo or lithium on several secondary outcome measures.

The rapamycin-sensitive signal transduction pathway as a target for cancer therapy

Abstract: The high frequency of mutations in cancer cells which result in altered cell cycle regulation and growth signal transduction, conferring a proliferative advantage, indicates that many of these aberrant mechanisms may be strategic targets for cancer therapy. The macrolide fungicide rapamycin, a natural product with potent antimicrobial, immunosuppressant, and anti-tumor properties, inhibits the translation of key mRNAs of proteins required for cell cycle progression from G1 to S phase. Rapamycin binds intracellularly to the immunophilin FK506 binding protein 12 (FKBP12), and the resultant complex inhibits the protein kinase activity of a protein kinase termed mammalian target of rapamycin (mTOR). The inhibition of mTOR, in turn, blocks signals to two separate downstream pathways which control the translation of specific mRNAs required for cell cycle traverse from G1 to S phase. Blocking mTOR affects the activity of the 40S ribosomal protein S6 kinase (p70s6k) and the function of the eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), leading to growth arrest in the the G1 phase of the cell cycle. In addition to its actions on p70s6k and 4E-BP1, rapamycin prevents cyclin-dependent kinase activation, inhibits retinoblastoma protein (pRb) phosphorylation, and accelerates the turnover of cyclin D1 that leads to a deficiency of active cdk4/cyclin D1 complexes, all of which can inhibit cell cycle traverse at the G1/S phase transition. Both rapamycin and CCI-779, an ester analog of rapamycin with improved pharmaceutical properties and aqueous solubility, have demonstrated impressive activity against a broad range of human cancers growing in tissue culture and in human tumor xenograft models, which has supported the development of compounds targeting rapamycin-sensitive signal-transduction pathways. CCI-779 has completed several phase I clinical evaluations and is currently undergoing broad disease-directed efficacy studies. The agent appears to be well tolerated at doses that have resulted in impressive anti-tumor activity in several types of refractory neoplasms. Important challenges during clinical development include the definition of a recommended dose range associated with optimal biological activity and maximal therapeutic indices, as well as the ability to predict which tumors will be sensitive or resistant to CCI-779.

Minimally invasive treatment of malignant hepatic tumors: At the threshold of a major breakthrough

Abstract: Six existing minimally invasive techniques for the treatment of primary and secondary malignant hepatic tumors—radio-frequency ablation, microwave ablation, laser ablation, cryoablation, ethanol ablation, and chemoembolization—are reviewed and debated by noted authorities from six institutions from around the world. All of the authors currently believe that surgery remains the treatment of choice for patients with resectable hepatic tumors. However, the clinical results of each of the minimally invasive techniques presented have exceeded those obtained with conventional chemotherapy or radiation therapy. Thus, for nonsurgical patients, these techniques are becoming standard independent or adjuvant therapies. In addition, with continued improvement in technology and increasing clinical experience, one or more of these minimally invasive techniques may soon challenge surgical resection as the treatment of choice for patients with limited hepatic tumor.

Mortality from invasive pneumococcal pneumonia in the era of antibiotic resistance, 1995-1997.

Abstract: Objectives. This study examined epidemiologic factors affecting mortality from pneumococcal pneumonia in 1995 through 1997. Methods. Persons residing in a surveillance area who had communityacquired pneumonia requiring hospitalization and Streptococcus pneumoniae isolated from a sterile site were included in the analysis. Factors affecting mortality were evaluated in univariate and multivariate analyses. The number of deaths from pneumococcal pneumonia requiring hospitalization in the United States in 1996 was estimated. Results. Of 5837 cases, 12% were fatal. Increased mortality was associated with older age, underlying disease, Asian race, and residence in Toronto/Peel, Ontario. When these factors were controlled for, increased mortality was not associated with resistance to penicillin or cefotaxime. However, when deaths during the first 4 hospital days were excluded, mortality was significantly associated with penicillin minimum inhibitory concentrations of 4.0 or higher and cefotaxime minimum inhibitory concentrations of 2.0 or higher. In 1996, about 7000 to 12500 deaths occurred in the United States from pneumococcal pneumonia requiring hospitalization. Conclusions. Older age and underlying disease remain the most important factors influencing death from pneumococcal pneumonia. Mortality was not elevated in most infections with β-lactam‐resistant pneumococci. (Am J Public Health. 2000;90:223‐229) ABSTRA C T

Research criteria for subcortical vascular dementia in clinical trials.

Abstract: Vascular dementia (VaD) incorporate different vascular mechanisms and changes in the brain, and have different causes and clinical manifestations. Variation in defining the cognitive syndrome, in vascular etiologies, and allowable brain changes in current clinical definitions of VaD have resulted in variable estimates of prevalence, of groups of subjects, and of the types and distribution of putative causal brain lesions. Thus current criteria for VaD select an etiologically and clinically heterogeneous group. This definitional heterogeneity may have been a factor in “negative” clinical trials. An alternative for clinical drug trials is to focus on a more homogenous group, such as those with subcortical (ischemic) VaD. This designation incorporates two small vessel clinical entities “Binswanger’s disease” and “the lacunar state”. It comprises small vessel disease as the primary vascular etiology, lacunar infarct(s) and ischaemic white matter lesions as the primary type of brain lesions, and subcortical location as the primary location of lesions. The subcortical clinical syndrome is the primary clinical manifestation, a definition which still requires additional empirical data. We expect that subcortical VaD show a more predictable clinical picture, natural history, outcome, and treatment responses. We propose a modification of the NINDS-AIREN criteria as a new research criteria for subcortical VaD.

Risk factors for candidemia in neonatal intensive care unit patients

Abstract: Background.Candidaspecies are important nosocomial pathogens in neonatal intensive care unit (NICU) patients.Methods.A prospective cohort study was performed in six geographically diverse NICUs from 1993 to 1995 to determine the incidence of and risk factors for candidemia, including the rol

Significance of melatonin in antioxidative defense system: reactions and products.

Abstract: Melatonin is a potent endogenous free radical scavenger, actions that are independent of its many receptor-mediated effects In the last several years, hundreds of publications have confirmed that melatonin is a broad-spectrum antioxidant Melatonin has been reported to scavenge hydrogen peroxide (H2O2), hydroxyl radical (HO·), nitric oxide (NO·), peroxynitrite anion (ONOO–), hypochlorous acid (HOCl), singlet oxygen (1O2), superoxide anion (O2–·) and peroxyl radical (LOO·), although the validity of its ability to scavenge O2–· and LOO· is debatable Regardless of the radicals scavenged, melatonin prevents oxidative damage at the level of cells, tissues, organs and organisms The antioxidative mechanisms of melatonin seem different from classical antioxidants such as vitamin C, vitamin E and glutathione As electron donors, classical antioxidants undergo redox cycling; thus, they have the potential to promote oxidation as well as prevent it Melatonin, as an electron-rich molecule, may interact with free radicals via an additive reaction to form several stable end-products which are excreted in the urine Melatonin does not undergo redox cycling and, thus, does not promote oxidation as shown under a variety of experimental conditions From this point of view, melatonin can be considered a suicidal or terminal antioxidant which distinguishes it from the opportunistic antioxidants Interestingly, the ability of melatonin to scavenge free radicals is not in a ratio of mole to mole Indeed, one melatonin molecule scavenges two HO· Also, its secondary and tertiary metabolites, for example, N1-acetyl-N2-formyl-5-methoxykynuramine, N-acetyl-5-methoxykynuramine and 6-hydroxymelatonin, which are believed to be generated when melatonin interacts with free radicals, are also regarded as effective free radical scavengers The continuous free radical scavenging potential of the original molecule (melatonin) and its metabolites may be defined as a scavenging cascade reaction Melatonin also synergizes with vitamin C, vitamin E and glutathione in the scavenging of free radicals Melatonin has been detected in vegetables, fruits and a variety of herbs In some plants, especially in flowers and seeds (the reproductive organs which are most vulnerable to oxidative insults), melatonin concentrations are several orders of magnitude higher than measured in the blood of vertebrates Melatonin in plants not only provides an alternative exogenous source of melatonin for herbivores but also suggests that melatonin may be an important antioxidant in plants which protects them from a hostile environment that includes extreme heat, cold and pollution, all of which generate free radicals

Screening techniques to identify people at high risk for diabetic foot ulceration: a prospective multicenter trial.

Abstract: OBJECTIVE: Diabetic foot ulceration is a preventable long-term complication of diabetes. A multicenter prospective follow-up study was conducted to determine which risk factors in foot screening have a high association with the development of foot ulceration. RESEARCH DESIGN AND METHODS: A total of 248 patients from 3 large diabetic foot centers were enrolled in a prospective study. Neuropathy symptom score, neuropathy disability score (NDS), vibration perception threshold (VPT), Semmes-Weinstein monofilaments (SWFs), joint mobility, peak plantar foot pressures, and vascular status were evaluated in all patients at the beginning of the study. Patients were followed-up every 6 months for a mean period of 30 months (range 6-40), and all new foot ulcers were recorded. The sensitivity, specificity, and positive predictive value of each risk factor were evaluated. RESULTS: Foot ulcers developed in 95 feet (19%) or 73 patients (29%) during the study. Patients who developed foot ulcers were more frequently men, had diabetes for a longer duration, had nonpalpable pedal pulses, had reduced joint mobility, had a high NDS, had a high VPT, and had an inability to feel a 5.07 SWE NDS alone had the best sensitivity, whereas the combination of the NDS and the inability to feel a 5.07 SWF reached a sensitivity of 99%. On the other hand, the best specificity for a single factor was offered by foot pressures, and the best combination was that of NDS and foot pressures. Univariate logistical regression analysis yielded a statistically significant odds ratio (OR) for sex, race, duration of diabetes, palpable pulses, history of foot ulceration, high NDSs, high VPTs, high SWFs, and high foot pressures. In addition, 94 (99%) of the 95 ulcerated feet had a high NDS and/or SWF which resulted in the highest OR of 26.2 (95% CI 3.6-190). Furthermore, in multivariate logistical regression analysis, the only significant factors were high NDSs, VPTs, SWFs, and foot pressures. CONCLUSIONS: Clinical examination and a 5.07 SWF test are the two most sensitive tests in identifying patients at risk for foot ulceration, especially when the tests are used in conjunction with each other. VPT measurements are also helpful and can be used as an alternative. Finally, foot pressure measurements offer a substantially higher specificity and can be used as a postscreening test in conjunction with providing appropriate footwear.

Modulation of Vascular Inflammation In Vitro and In Vivo by Peroxisome Proliferator–Activated Receptor-γ Activators

Abstract: Background—Peroxisome proliferator–activated receptor-γ (PPARγ) is expressed in atherosclerotic plaques and in endothelial cells. The possible effects of PPARγ activators on endothelial activation and inflammatory response within the plaque are currently unknown. Methods and Results—We tested the hypothesis that PPARγ activators inhibit vascular cell adhesion molecule (VCAM-1) and intercellular adhesion molecule (ICAM-1) expression in cultured endothelial cells (evaluated by flow cytometry) and homing of monocyte/macrophages to atherosclerotic plaques in vivo. In endothelial cells, the PPARγ agonists troglitazone at 100 μmol/L and 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) at 20 μmol/L markedly attenuated the tumor necrosis factor–induced expression of VCAM-1 and ICAM-1. A significant inhibition of VCAM-1 expression was also evident at 5 and 10 μmol/L 15d-PGJ2 and 20 μmol/L troglitazone. Expression of E-selectin and PECAM-1 was not altered. To confirm the biological relevance of these results, we assesse...

Blood-derived angioblasts accelerate blood-flow restoration in diabetic mice

Abstract: Endothelial cell progenitors, angioblasts, have been detected in the peripheral blood of adult humans, mice, and rabbits. These cells have been shown to incorporate into the endothelium of newly forming blood vessels in pathological and nonpathological conditions. Here we investigated the possibility that the CD34-expressing leukocytes (CD34+ cells) that appear to be enriched for angioblasts could be used to accelerate the rate of blood-flow restoration in nondiabetic and diabetic mice undergoing neovascularization due to hindlimb ischemia. CD34+ cells did not accelerate the restoration of flow in nondiabetic mice, but dramatically increased it in diabetic mice. Furthermore, CD34 + cells derived from type 1 diabetics produced fewer differentiated endothelial cells in culture than did their type 2 diabetic‐ or nondiabetic-derived counterparts. In vitro experiments suggest that hyperglycemia per se does not alter the ability of angioblasts to differentiate or of angioblast-derived endothelial cells to proliferate. In contrast, hyperinsulinemia may enhance angioblast differentiation but impair angioblast-derived endothelial cell survival or proliferation. Our findings suggest that CD34+ cells may be a useful tool for therapeutic angiogenesis in diabetics.

Global experience in cervical carotid artery stent placement

Abstract: The purpose of this article is to review and update the current status of carotid artery stent placement in the world. Surveys to major interventional centers in Europe, North and South America, and Asia were initially completed in June 1997. Subsequent information from these 24 centers in addition to 12 new centers has been obtained to update the information. The survey asked the various questions regarding the patients enrolled, procedure techniques, and results of carotid stenting, including complications and restenosis. The total number of endovascular carotid stent procedures that have been performed worldwide to date included 5,210 procedures involving 4,757 patients. There was a technical success of 98.4% with 5,129 carotid arteries treated. Complications that occurred during the carotid stent placement or within a 30-day period following placement were recorded. Overall, there were 134 transient ischemic attacks (TIAs) for a rate of 2.82%. Based on the total patient population, there were 129 minor strokes with a rate of occurrence of 2.72%. The total number of major strokes was 71 for a rate of 1.49%. There were 41 deaths within a 30-day postprocedure period resulting in a mortality rate of 0.86%. The combined minor and major strokes and procedure-related death rate was 5.07%. Restenosis rates of carotid stenting have been 1.99% and 3.46% at 6 and 12 months, respectively. The rate of neurologic events after stent placement has been 1.42% at 6-12-month follow-up. Endovascular stent treatment of carotid artery atherosclerotic disease is growing as an alternative for vascular surgery, especially for patients that are high risk for standard carotid endarterectomy. The periprocedure risks for major and minor strokes and death are generally acceptable at this early stage of development and have not changed significantly since the first survey results. Cathet. Cardiovasc. Intervent. 50:160-167, 2000.

Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products

Abstract: Ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS) are recessive genetic disorders with susceptibility to cancer and similar cellular phenotypes1. The protein product of the gene responsible for A-T, designated ATM, is a member of a family of kinases characterized by a carboxy-terminal phosphatidylinositol 3-kinase-like domain2,3. The NBS1 protein is specifically mutated in patients with Nijmegen breakage syndrome and forms a complex with the DNA repair proteins Rad50 and Mre114,5,6,7. Here we show that phosphorylation of NBS1, induced by ionizing radiation, requires catalytically active ATM. Complexes containing ATM and NBS1 exist in vivo in both untreated cells and cells treated with ionizing radiation. We have identified two residues of NBS1, Ser 278 and Ser 343 that are phosphorylated in vitro by ATM and whose modification in vivo is essential for the cellular response to DNA damage. This response includes S-phase checkpoint activation, formation of the NBS1/Mre11/Rad50 nuclear foci and rescue of hypersensitivity to ionizing radiation. Together, these results demonstrate a biochemical link between cell-cycle checkpoints activated by DNA damage and DNA repair in two genetic diseases with overlapping phenotypes.

A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)

Abstract: Hypohidrotic ectodermal dysplasia (HED), a congenital disorder of teeth, hair, and eccrine sweat glands, is usually inherited as an X-linked recessive trait, although rarer autosomal dominant and recessive forms exist. We have studied males from four families with HED and immunodeficiency (HED-ID), in which the disorder segregates as an X-linked recessive trait. Affected males manifest dysgammaglobulinemia and, despite therapy, have significant morbidity and mortality from recurrent infections. Recently, mutations in IKK-gamma (NEMO) have been shown to cause familial incontinentia pigmenti (IP). Unlike HED-ID, IP affects females and, with few exceptions, causes male prenatal lethality. IKK-gamma is required for the activation of the transcription factor known as “nuclear factor kappa B” and plays an important role in T and B cell function. We hypothesize that “milder” mutations at this locus may cause HED-ID. In all four families, sequence analysis reveals exon 10 mutations affecting the carboxy-terminal end of the IKK-gamma protein, a domain believed to connect the IKK signalsome complex to upstream activators. The findings define a new X-linked recessive immunodeficiency syndrome, distinct from other types of HED and immunodeficiency syndromes. The data provide further evidence that the development of ectodermal appendages is mediated through a tumor necrosis factor/tumor necrosis factor receptor–like signaling pathway, with the IKK signalsome complex playing a significant role.