CNS myelin induces regulatory functions of DC-SIGN-expressing, antigen-presenting cells via cognate interaction with MOG.

Myelin oligodendrocyte glycoprotein (MOG), a constituent of central nervous system myelin, is an important autoantigen in the neuroinflammatory disease multiple sclerosis (MS). However, its function remains unknown. Here, we show that, in healthy human myelin, MOG is decorated with fucosylated N-glycans that support recognition by the C-type lectin receptor (CLR) DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) on microglia and DCs. The interaction of MOG with DC-SIGN in the context of simultaneous TLR4 activation resulted in enhanced IL-10 secretion and decreased T cell proliferation in a DC-SIGN-, glycosylation-, and Raf1-dependent manner. Exposure of oligodendrocytes to proinflammatory factors resulted in the down-regulation of fucosyltransferase expression, reflected by altered glycosylation at the MS lesion site. Indeed, removal of fucose on myelin reduced DC-SIGN-dependent homeostatic control, and resulted in inflammasome activation, increased T cell proliferation, and differentiation toward a Th17-prone phenotype. These data demonstrate a new role for myelin glycosylation in the control of immune homeostasis in the healthy human brain through the MOG-DC-SIGN homeostatic regulatory axis, which is comprised by inflammatory insults that affect glycosylation. This phenomenon should be considered as a basis to restore immune tolerance in MS.

Portal vein thrombosis in 33 dogs: 1998-2011.

BACKGROUND: Portal vein thrombosis (PVT) has been reported infrequently in dogs. OBJECTIVES: To characterize the presentation, associated disease conditions, and outcome in dogs with PVT. ANIMALS: Client-owned dogs with a diagnosis of PVT and a complete medical record. METHODS: Records were retrospectively analyzed for presentation, history, physical examination, clinicopathologic data, diagnostic imaging, treatment, and outcome. RESULTS: Thirty-three dogs were included. Common clinical signs were vomiting, diarrhea, abdominal pain, ascites, and signs of hypovolemic shock. Associated disease conditions included hepatic (14/33), neoplastic (7/33), immune (5/33), and infectious (4/33) diseases, protein-losing nephropathy (3/33), hyperadrenocorticism (2/33), protein-losing enteropathy (1/33), and pancreatitis (1/33). Fourteen dogs were receiving glucocorticoids at the time of diagnosis. Twenty-nine dogs had at least 1 predisposing condition for venous thrombosis, and 11 had 2 or more. Thrombocytopenia (24/33), increased liver enzyme activity (23/33), and hypoalbuminemia (20/33) were common laboratory abnormalities. Clinical syndromes at the time of PVT diagnosis included shock (16/33), systemic inflammatory response syndrome (SIRS), (13/33) and disseminated intravascular coagulation (3/33). Twenty-four dogs had acute and 9 had chronic PVT. Multiple thrombi were found in 17/33 dogs. Nineteen dogs survived to discharge. Dogs treated with anticoagulant therapy were more likely, whereas those with acute PVT, multiple thromboses or SIRS were less likely to survive. CONCLUSIONS AND CLINICAL IMPORTANCE: Hepatic disease is a common pre-existing condition in dogs with PVT. PVT should be considered in dogs with risk factors for venous thrombosis presenting with abdominal pain, ascites, and thrombocytopenia. Studies evaluating anticoagulant therapy in the management of PVT are warranted.

Complication rates of EUS-guided celiac plexus blockade and neurolysis: results of a large case series.

BACKGROUND AND STUDY AIMS: Complication rates for EUS-guided celiac plexus blockade (CPB) and celiac plexus neurolysis (CPN) have been largely derived from studies utilizing percutaneous or surgical techniques, with few studies specifically examining rates for EUS-guided CPB and CPN. This study aims to further describe the complication rates of EUS-guided CPB and CPN. PATIENTS AND METHODS: In a retrospective analysis of a prospectively collected EUS database, tracking patients and complications for a single endosonographer at a tertiary-care teaching hospital, data for consecutive patients between August 2003 and March 2008 undergoing either EUS-guided CPB or CPN were analyzed for indications, methods, and complications. Excellent follow-up data were available for all patients. RESULTS: 189 EUS-CPB and 31 EUS-CPN procedures were done in 128 and 30 patients, respectively (60 men, 98 women). Indications for blockades included chronic pancreatitis (122), relapsing pancreatitis with chronic pain (28), upper abdominal pain of suspected pancreatic origin (37), and suspected (yet unproven) pancreatic cancer with pain (2). Neurolyses were performed for refractory pain from cancer (21) or chronic pancreatitis (10). No prophylactic antibiotics were administered. Acid suppression was not withheld. Complications were defined as procedural side effects treated with anything beyond standard observation. Four complications were observed during clinical follow-up (three after CPB, one after CPN), giving an overall complication rate of 1.8 % (CPB 1.6 %, CPN 3.2 %). Complications included asymptomatic hypotension after neurolysis, retroperitoneal abscess after CPB, and severe self-limited postprocedural pain in two patients after CPB. CONCLUSIONS: EUS-guided CPB and CPN are reasonably safe procedures with tolerable side-effect profiles and low overall complication rates.

The trajectories of Prevention through Design in construction.

INTRODUCTION: Construction Hazards Prevention through Design (CHPtD) is a process in which engineers and architects explicitly consider the safety of construction workers during the design process. Although articles on CHPtD have appeared in top construction journals, the literature has not addressed technical principles underlying CHPtD to help designers better perform CHPtD, to facilitate the development of additional CHPtD tools, and to predict the future path of CHPtD. METHOD: This theoretical paper uses the existing literature on CHPtD and current action research associated with several CHPtD workgroups to analyze how CHPtD will likely evolve over the coming decades. RESULTS: There are four trajectories along which CHPtD will progress. (a) Designs will increasingly facilitate prefabricated construction; (b) designers will increasingly choose materials and systems that are inherently safer than alternatives; (c) designers will increasingly perform construction engineering; and (d) designers will increasingly apply spatial considerations to reduce worker hazards. IMPACT ON INDUSTRY: By understanding how CHPtD may be manifested in the engineering-procurement-construction (EPC) industry, practitioners can better prepare for adopting CHPtD within their organizations and construction and engineering educators can better prepare their graduates to perform CHPtD.

Portal vein thrombosis in cats: 6 cases (2001-2006).

BACKGROUND: Portal vein thrombosis (PVT) in cats is sparsely reported. PURPOSE OF STUDY: To evaluate the clinical signs and diseases associated with PVT in cats. ANIMALS: 6 client-owned cats. METHODS: Medical records for cats with a portal vein thrombus diagnosed on abdominal ultrasound or at necropsy were reviewed. Signalment, historical data, underlying disorders, clinical findings, clinicopathologic and histopathologic data, diagnostic imaging findings, treatment, and outcome were recorded. RESULTS: All 6 cats identified with PVT also had hepatic disease. Evidence of a congenital portosystemic shunt was present in 3/6 cats. Two cats had primary or metastatic hepatic neoplasia. One cat had acute cholangitis, acute pancreatitis, and locally extensive acute centrilobular hepatic necrosis. Two cats were suspected to have acute thrombi and 4 cats had chronic thrombi. CONCLUSION AND CLINICAL SIGNIFICANCE: PVT might be an important concurrent finding in cats with hepatic disease.

Large-scale quarantine following biological terrorism in the United States: scientific examination, logistic and legal limits, and possible consequences.

Concern for potential bioterrorist attacks causing mass casualties has increased recently. Particular attention has been paid to scenarios in which a biological agent capable of person-to-person transmission, such as smallpox, is intentionally released among civilians. Multiple public health interventions are possible to effect disease containment in this context. One disease control measure that has been regularly proposed in various settings is the imposition of large-scale or geographic quarantine on the potentially exposed population. Although large-scale quarantine has not been implemented in recent US history, it has been used on a small scale in biological hoaxes, and it has been invoked in federally sponsored bioterrorism exercises. This article reviews the scientific principles that are relevant to the likely effectiveness of quarantine, the logistic barriers to its implementation, legal issues that a large-scale quarantine raises, and possible adverse consequences that might result from quarantine action. Imposition of large-scale quarantine-compulsory sequestration of groups of possibly exposed persons or human confinement within certain geographic areas to prevent spread of contagious disease-should not be considered a primary public health strategy in most imaginable circumstances. In the majority of contexts, other less extreme public health actions are likely to be more effective and create fewer unintended adverse consequences than quarantine. Actions and areas for future research, policy development, and response planning efforts are provided.

Death due to bioterrorism-related inhalational anthrax: report of 2 patients.

On October 9, 2001, a letter containing anthrax spores was mailed from New Jersey to Washington, DC. The letter was processed at a major postal facility in Washington, DC, and opened in the Senate's Hart Office Building on October 15. Between October 19 and October 26, there were 5 cases of inhalational anthrax among postal workers who were employed at that major facility or who handled bulk mail originating from that facility. The cases of 2 postal workers who died of inhalational anthrax are reported here. Both patients had nonspecific prodromal illnesses. One patient developed predominantly gastrointestinal symptoms, including nausea, vomiting, and abdominal pain. The other patient had a "flulike" illness associated with myalgias and malaise. Both patients ultimately developed dyspnea, retrosternal chest pressure, and respiratory failure requiring mechanical ventilation. Leukocytosis and hemoconcentration were noted in both cases prior to death. Both patients had evidence of mediastinitis and extensive pulmonary infiltrates late in their course of illness. The durations of illness were 7 days and 5 days from onset of symptoms to death; both patients died within 24 hours of hospitalization. Without a clinician's high index of suspicion, the diagnosis of inhalational anthrax is difficult during nonspecific prodromal illness. Clinicians have an urgent need for prompt communication of vital epidemiologic information that could focus their diagnostic evaluation. Rapid diagnostic assays to distinguish more common infectious processes from agents of bioterrorism also could improve management strategies.

Phase I trial of lobradimil (RMP-7) and carboplatin in children with brain tumors.

PURPOSE: To determine the maximum tolerated dose (MTD), the incidence and severity of toxicities, and the pharmacokinetics of lobradimil administered intravenously over 10 min in combination with carboplatin in children with refractory brain tumors. METHODS: A group of 25 children with primary brain tumors received carboplatin and lobradimil on two consecutive days every 28 days. The 10-min lobradimil infusion began 5 min before the end of the carboplatin infusion. Four lobradimil dose levels (100, 300, 450 and 600 ng/kg ideal body weight, IBW) were studied in cohorts of 4 to 13 patients. Carboplatin was adaptively dosed based on the glomerular filtration rate to achieve a target plasma area under the concentration-time curve (AUC) of 7.0 mg min/ml per course (5.0 mg min/ml for patients who had previously received craniospinal radiation or myeloablative chemotherapy). RESULTS: Lobradimil toxicity was immediate, tolerable and rapidly reversible. The most frequent toxicities were hypotension, flushing, headache and gastrointestinal complaints. One patient on the 600 ng/kg dose level had a seizure during the lobradimil infusion. The incidence and severity of lobradimil toxicities were not dose-related and the lobradimil dose was not escalated beyond the 600 ng/kg IBW dose level. Two patients had partial responses and ten patients had stable disease. Myelosuppression (thrombocytopenia more prominent than neutropenia) was the primary toxicity attributed to carboplatin. Lobradimil pharmacokinetics were characterized by rapid clearance from the plasma compartment and substantial interpatient variability. CONCLUSIONS: The combination of carboplatin and lobradimil is safe and tolerable. An MTD for lobradimil was not defined because toxicity was not dose-related. The recommended pediatric phase II dose of lobradimil is 600 ng/kg IBW.

Anthrax as a biological weapon: medical and public health management - consensus statement.

It presents recommendations are made regarding the diagnosis of anthrax, indications for vaccination, therapy for those exposed, postexposure prophylaxis, decontamination of the environment, and additional research needs. Published in JAMA, 281:1735-1745, 1999. Document in pdf format; Acrobat Reader required.

Primary care office policies regarding care of uninsured adult patients.

OBJECTIVE: To describe primary care office policies regarding care of uninsured patients. DESIGN: Telephone survey of all adult primary care sites advertising in the area telephone directory. Sites were defined by ownership status, number of physicians, use of physician-extenders, and location. Policies assessed were whether the site was accepting new uninsured patients, billing policies, the availability of free or discounted care, and payment plans. SETTING: Allegheny County, Pennsylvania. PARTICIPANTS: Of the 359 sites identified, 240 (66.9%) responded, representing 794 physicians. Survey respondents included receptionists (40.4%), office managers (36.2%), and physicians (22.9%). RESULTS: While the majority of all sites reported accepting new patients without health insurance (87.5%), policies regarding these patients varied significantly by ownership status and the number of physicians. Sites with 3 or fewer physicians were more likely to accept uninsured patients. Self-owned practices were more likely to require payment at the time of service, and provide discounted care, free care, and payment plans compared with hospital/health system practices or multisite group practices. CONCLUSIONS: Willingness to accept uninsured patients does not always equate to affordable or accessible care. Office policies have the potential to be substantial obstacles to primary care.

Tularemia as a biological weapon: medical and public health management.

OBJECTIVE: The Working Group on Civilian Biodefense has developed consensus-based recommendations for measures to be taken by medical and public health professionals if tularemia is used as a biological weapon against a civilian population. PARTICIPANTS: The working group included 25 representatives from academic medical centers, civilian and military governmental agencies, and other public health and emergency management institutions and agencies. EVIDENCE: MEDLINE databases were searched from January 1966 to October 2000, using the Medical Subject Headings Francisella tularensis, Pasteurella tularensis, biological weapon, biological terrorism, bioterrorism, biological warfare, and biowarfare. Review of these references led to identification of relevant materials published prior to 1966. In addition, participants identified other references and sources. CONSENSUS PROCESS: Three formal drafts of the statement that synthesized information obtained in the formal evidence-gathering process were reviewed by members of the working group. Consensus was achieved on the final draft. CONCLUSIONS: A weapon using airborne tularemia would likely result 3 to 5 days later in an outbreak of acute, undifferentiated febrile illness with incipient pneumonia, pleuritis, and hilar lymphadenopathy. Specific epidemiological, clinical, and microbiological findings should lead to early suspicion of intentional tularemia in an alert health system; laboratory confirmation of agent could be delayed. Without treatment, the clinical course could progress to respiratory failure, shock, and death. Prompt treatment with streptomycin, gentamicin, doxycycline, or ciprofloxacin is recommended. Prophylactic use of doxycycline or ciprofloxacin may be useful in the early postexposure period.

Emerging illness and bioterrorism: implications for public health.

Biological weapons have the potential to inflict deliberate, potentially devastating epidemics of infectious disease on populations. The science and technology exist to create deliberate outbreaks of human disease, as well as disease among plants and animals, crops, and livestock. A new awareness among policymakers of the link between public health and national security requires the attention of public health professionals. The issues posed by biological weapons are likely to challenge the political assumptions of many progressive public health professionals and will demand new coalitions. The prospect of bioterrorism may offer new opportunities for improving the public health infrastructure and its capabilities.

Activation-enhanced alpha(IIb)beta(3)-integrin-cytoskeleton interactions outside of focal contacts require the alpha-subunit.

Integrins link the cell's cytoskeleton to the extracellular matrix, as well as to receptors on other cells. These links occur not only at focal contacts but also at smaller integrin-containing protein complexes outside of focal contacts. We previously demonstrated the importance of focal contact-independent integrin-cytoskeleton interactions of beta(2) integrins: activation of adhesion resulted from a release of integrins from cytoskeletal constraints. To determine whether changes in integrin-cytoskeleton interactions were related to activation of the integrin, we used single particle tracking to examine focal contact-independent cytoskeletal associations of alpha(IIb)beta(3)-integrin, in which activation results in a large conformational change. Direct activation of alpha(IIb)beta(3) by mutation did not mimic activation of lymphocytes with phorbol ester, because it enhanced integrin-cytoskeleton interactions, whereas activation of lymphocytes decreased them. Using additional integrin mutants, we found that both alpha- and beta-cytoplasmic domains were required for these links. This suggests that 1) both beta(2)- and beta(3)-integrins interact with the cytoskeleton outside of focal contacts; 2) activation of a cell and activation of an integrin are distinct processes, and both can affect integrin-cytoskeleton interactions; and 3) the role of the alpha-subunit in integrin-cytoskeleton interactions in at least some circumstances is more direct than generally supposed.

Relationships between patient characteristics and unsuccessful substance abuse detoxification.

OBJECTIVE: History and laboratory evaluations are common for patients entering substance abuse detoxification programs. We sought to identify if patient history and laboratory characteristics entering a detoxification program were associated with unsuccessful detoxification. DESIGN: Retrospective cohort study of 186 patients of a residential-inpatient short-term medical detoxification facility. Unsuccessful detoxification was defined as leaving for urgent medical referral or against program advice. RESULTS: Patients were predominantly male, middle-aged, minority, unemployed, and poly-substance users. Twenty-four patients (13%) did not complete the detoxification program (4 left for urgent medical referral, 20 left against program advice). Unsuccessful detoxification was associated with nausea and/or vomiting (p = 0.032), Caucasian race (p = 0.002), and opiates as a drug of choice (p = 0.018). Laboratory abnormalities were common but none were associated with unsuccessful detoxification. CONCLUSIONS: For patients admitted to a medically monitored detoxification facility, few patient characteristics were associated with detoxification outcome. Routine admission laboratories without clinical correlation may be unwarranted.

The WD protein Rack1 mediates protein kinase C and integrin-dependent cell migration.

The scaffolding protein, Rack1, is a seven-WD-domain-containing protein that has been implicated in binding to integrin beta subunit cytoplasmic domains and to members of two kinase families (src and protein kinase C, PKC) that mediate integrin bidirectional signaling. To explore the role of Rack1 in integrin function we have transfected this protein in Chinese hamster ovary (CHO) cells. We have observed no effect of Rack1 overexpression on inside-out signaling as the ligand binding properties of CHO cells also expressing constitutively active or inactive integrins were not affected. In contrast, we observed that cells stably or transiently overexpressing Rack1 had decreased migration compared to mock transfected cells. Stable Rack1 transfectants also demonstrated an increased number of actin stress fibers and focal contacts. These effects on motility and cytoskeletal organization did not appear to result from Rack1 inhibition of src function as downstream substrates of this kinase were phosphorylated normally. In addition, expression of an active src construct did not reverse the migratory deficit induced by Rack1 overexpression. On the other hand when we overexpressed a Rack1 variant with alanine substitutions in the putative PKC binding site in its third WD domain, we observed no deficit in migration. Thus the ability of Rack1 to bind, localize and stabilize PKC isoforms is likely to be involved in aspects of integrin outside-in signaling.

Botulinum toxin as a biological weapon: medical and public health management.

OBJECTIVE: The Working Group on Civilian Biodefense has developed consensus-based recommendations for measures to be taken by medical and public health professionals if botulinum toxin is used as a biological weapon against a civilian population. PARTICIPANTS: The working group included 23 representatives from academic, government, and private institutions with expertise in public health, emergency management, and clinical medicine. EVIDENCE: The primary authors (S.S.A. and R.S.) searched OLDMEDLINE and MEDLINE (1960-March 1999) and their professional collections for literature concerning use of botulinum toxin as a bioweapon. The literature was reviewed, and opinions were sought from the working group and other experts on diagnosis and management of botulism. Additional MEDLINE searches were conducted through April 2000 during the review and revisions of the consensus statement. CONSENSUS PROCESS: The first draft of the working group's consensus statement was a synthesis of information obtained in the formal evidence-gathering process. The working group convened to review the first draft in May 1999. Working group members reviewed subsequent drafts and suggested additional revisions. The final statement incorporates all relevant evidence obtained in the literature search in conjunction with final consensus recommendations supported by all working group members. CONCLUSIONS: An aerosolized or foodborne botulinum toxin weapon would cause acute symmetric, descending flaccid paralysis with prominent bulbar palsies such as diplopia, dysarthria, dysphonia, and dysphagia that would typically present 12 to 72 hours after exposure. Effective response to a deliberate release of botulinum toxin will depend on timely clinical diagnosis, case reporting, and epidemiological investigation. Persons potentially exposed to botulinum toxin should be closely observed, and those with signs of botulism require prompt treatment with antitoxin and supportive care that may include assisted ventilation for weeks or months. Treatment with antitoxin should not be delayed for microbiological testing.

A plague on your city: observations from TOPOFF.

The United States Congress directed the Department of Justice to conduct an exercise engaging key personnel in the management of mock chemical, biological, or cyberterrorist attacks. The resulting exercise was called "TOPOFF," named for its engagement of top officials of the United States government. This article offers a number of medical and public health observations and lessons discovered during the bioterrorism component of the exercise. The TOPOFF exercise illuminated problematic issues of leadership and decision-making; the difficulties of prioritization and distribution of scarce resources; the crisis that contagious epidemics would cause in health care facilities; and the critical need to formulate sound principles of disease containment. These lessons should provoke consideration of future directions for bioterrorism planning and preparedness at all levels of government and among the many communities and practitioners with responsibilities for national security and public health.

Integrin activation controls metastasis in human breast cancer.

Metastasis is the primary cause of death in human breast cancer. Metastasis to bone, lungs, liver, and brain involves dissemination of breast cancer cells via the bloodstream and requires adhesion within the vasculature. Blood cell adhesion within the vasculature depends on integrins, a family of transmembrane adhesion receptors, and is regulated by integrin activation. Here we show that integrin alpha v beta 3 supports breast cancer cell attachment under blood flow conditions in an activation-dependent manner. Integrin alpha v beta 3 was found in two distinct functional states in human breast cancer cells. The activated, but not the nonactivated, state supported tumor cell arrest during blood flow through interaction with platelets. Importantly, activated alpha v beta 3 was expressed by freshly isolated metastatic human breast cancer cells and variants of the MDA-MB 435 human breast cancer cell line, derived from mammary fat pad tumors or distant metastases in severe combined immunodeficient mice. Expression of constitutively activated mutant alpha v beta 3(D723R), but not alpha v beta 3(WT), in MDA-MB 435 cells strongly promoted metastasis in the mouse model. Thus breast cancer cells can exhibit a platelet-interactive and metastatic phenotype that is controlled by the activation of integrin alpha v beta 3. Consequently, alterations within tumors that lead to the aberrant control of integrin activation are expected to adversely affect the course of human breast cancer.