Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke

Each year about 650,000 Europeans die from stroke and a similar number lives with the sequelae of multiple sclerosis (MS). Stroke and MS differ in their etiology. Although cause and likewise clinical presentation set the two diseases apart, they share common downstream mechanisms that lead to damage and recovery. Demyelination and axonal injury are characteristics of MS but are also observed in stroke. Conversely, hallmarks of stroke, such as vascular impairment and neurodegeneration, are found in MS. However, the most conspicuous common feature is the marked neuroinflammatory response, marked by glia cell activation and immune cell influx. In MS and stroke the blood-brain barrier is disrupted allowing bone marrow-derived macrophages to invade the brain in support of the resident microglia. In addition, there is a massive invasion of auto-reactive T-cells into the brain of patients with MS. Though less pronounced a similar phenomenon is also found in ischemic lesions. Not surprisingly, the two diseases also resemble each other at the level of gene expression and the biosynthesis of other proinflammatory mediators. While MS has traditionally been considered to be an autoimmune neuroinflammatory disorder, the role of inflammation for cerebral ischemia has only been recognized later. In the case of MS the long track record as neuroinflammatory disease has paid off with respect to treatment options. There are now about a dozen of approved drugs for the treatment of MS that specifically target neuroinflammation by modulating the immune system. Interestingly, experimental work demonstrated that drugs that are in routine use to mitigate neuroinflammation in MS may also work in stroke models. Examples include Fingolimod, glatiramer acetate, and antibodies blocking the leukocyte integrin VLA-4. Moreover, therapeutic strategies that were discovered in experimental autoimmune encephalomyelitis (EAE), the animal model of MS, turned out to be also effective in experimental stroke models. This suggests that previous achievements in MS research may be relevant for stroke. Interestingly, the converse is equally true. Concepts on the neurovascular unit that were developed in a stroke context turned out to be applicable to neuroinflammatory research in MS. Examples include work on the important role of the vascular basement membrane and the BBB for the invasion of immune cells into the brain. Furthermore, tissue plasminogen activator (tPA), the only established drug treatment in acute stroke, modulates the pathogenesis of MS. Endogenous tPA is released from endothelium and astroglia and acts on the BBB, microglia and other neuroinflammatory cells. Thus, the vascular perspective of stroke research provides important input into the mechanisms on how endothelial cells and the BBB regulate inflammation in MS, particularly the invasion of immune cells into the CNS. In the current review we will first discuss pathogenesis of both diseases and current treatment regimens and will provide a detailed overview on pathways of immune cell migration across the barriers of the CNS and the role of activated astrocytes in this process. This article is part of a Special Issue entitled: Neuro inflammation: A common denominator for stroke, multiple sclerosis and Alzheimer's disease, guest edited by Helga de Vries and Markus Swaninger.

Brain barriers: Crosstalk between complex tight junctions and adherens junctions

Unique intercellular junctional complexes between the central nervous system (CNS) microvascular endothelial cells and the choroid plexus epithelial cells form the endothelial blood-brain barrier (BBB) and the epithelial blood-cerebrospinal fluid barrier (BCSFB), respectively. These barriers inhibit paracellular diffusion, thereby protecting the CNS from fluctuations in the blood. Studies of brain barrier integrity during development, normal physiology, and disease have focused on BBB and BCSFB tight junctions but not the corresponding endothelial and epithelial adherens junctions. The crosstalk between adherens junctions and tight junctions in maintaining barrier integrity is an understudied area that may represent a promising target for influencing brain barrier function.

Mode of action of claudin peptidomimetics in the transient opening of cellular tight junction barriers

In epithelial/endothelial barriers, claudins form tight junctions, seal the paracellular cleft, and limit the uptake of solutes and drugs. The peptidomimetic C1C2 from the C-terminal half of claudin-1's first extracellular loop increases drug delivery through epithelial claudin-1 barriers. However, its molecular and structural mode of action remains unknown. In the present study, >100 μM C1C2 caused paracellular opening of various barriers with different claudin compositions, ranging from epithelial to endothelial cells, preferentially modulating claudin-1 and claudin-5. After 6 h incubation, C1C2 reversibly increased the permeability to molecules of different sizes; this was accompanied by redistribution of claudins and occludin from junctions to cytosol. Internalization of C1C2 in epithelial cells depended on claudin-1 expression and clathrin pathway, whereby most C1C2 was retained in recyclosomes >2 h. In freeze-fracture electron microscopy, C1C2 changed claudin-1 tight junction strands to a more parallel arrangement and claudin-5 strands from E-face to P-face association - drastic and novel effects. In conclusion, C1C2 is largely recycled in the presence of a claudin, which explains the delayed onset of barrier and junction loss, the high peptide concentration required and the long-lasting effect. Epithelial/endothelial barriers are specifically modulated via claudin-1/claudin-5, which can be targeted to improve drug delivery.

Diagnosing institutional barriers and opportunities for adaptation to climate change

Institutions are one of the decisive factors which enable, constrain and shape adaptation to the impacts of climate change, variability and extreme events. However, current understanding of institutions in adaptation situations is fragmented across the scientific community, evidence diverges, and cumulative learning beyond single studies is limited. This study adopts a diagnostic approach to elaborate a nuanced understanding of institutional barriers and opportunities in climate adaptation by means of a model-centred meta-analysis of 52 case studies of public climate adaptation in Europe. The first result is a novel taxonomy of institutional attributes in adaptation situations. It conceptually organises and decomposes the many details of institutions that empirical research has shown to shape climate adaptation. In the second step, the paper identifies archetypical patterns of institutional traps and trade-offs which hamper adaptation. Thirdly, corresponding opportunities are identified that enable actors to alleviate, prevent or overcome specific institutional traps or trade-offs. These results cast doubt on the validity of general institutional design principles for successful adaptation. In contrast to generic principles, the identified opportunities provide leverage to match institutions to specific governance problems that are encountered in specific contexts. Taken together, the results may contribute to more coherence and integration of adaptation research that we need if we are to foster learning about the role of institutions in adaptation situations in a cumulative fashion.

Tolerance of allografts across MHC barriers by allochimeric class I MHC proteins

Class I MHC proteins have been shown to induce accelerated rejection or prolong survival of allografts in various experimental models. These immunological effects have been attributed to the highly polymorphic alpha helical regions of the extracellular portions of the class I MHC molecule. The present experiments were designed to elucidate the immunomodulatory effects of these polymorphic regions and delineate the mechanisms involved. Soluble allochimeric class I MHC proteins were produced by substituting the PVG class I MHC RT1.Ac amino acid residues within the a 1 helical region with those of the donor BN ( a 1hn-RT1.Ac), the a 2 helical region of BN ( a 2hn-RT1.Ac), and both the a 1 and a 2 helical regions (RT1.An). The class I MHC proteins were produced in an E. coli protein expression system. The a 2hn-RT1.Ac and RT1.An proteins, when administered subcutaneously into PVG hosts 7 days prior to transplantation, resulted in accelerated rejection of BN cardiac allografts. The a 1hn-RT1.Ac construct did not demonstrate such immunogenic effects. Intra-portal administration of a 1hn-RT1.Ac or RT1.An, in combination with perioperative CsA, induced tolerance to BN cardiac allografts. The a 1hn-RT1.Ac protein was able to induce tolerance in a larger majority of the PVG recipients and at a lower dose of protein when compared to the RT1.An protein. RT1.An administered orally to PVG recipients also induced long term survival of cardiac allografts. In vitro analysis revealed that lymphocytes from tolerant hosts were hyporesponsive to donor splenocytes, but responsive to 3rd party splenocytes. Evaluation of T cell cytokine expression patterns revealed that rejector PVG hosts displayed a Type I T-cell response when re-challenged with donor splenocytes, in contrast to tolerant animals that displayed a Type II T-cell response. FACS analysis of the T cells revealed that the ratio of CD4 to CD8 cells was 3:1 and was consistent in the groups tested suggesting a complex interaction between the subsets of T cells, yielding the observed results. Histologic analysis of the cardiac allografts revealed that tolerant PVG hosts maintained BN cardiac allografts without any evidence of acute or chronic rejection after 300 days post transplant. This body of work has demonstrated that the use of soluble donor/recipient allochimeric class I MHC proteins with a short peri-operative course of CsA resulted in transplant tolerance. This treatment regimen proffers a clinically relevant approach to the induction of tolerance across MHC barriers. ^

Barriers and facilitators to nurses' acceptance of and implications for injury rates of an IV catheter safety device

This study has the purpose of determining the barriers and facilitators to nurses' acceptance of the Johnson and Johnson Protectiv®* Plus IV catheter safety needle device and implications for needlestick injuries at St. Luke's Episcopal Hospital, Houston, Texas. A one-time cross-sectional survey of 620 responding nurses was conducted by this researcher during December, 2000. The study objectives were to: (1) describe the perceived (a) organizational and individual barriers and facilitators and (b) acceptance of implementation of the IV catheter device; (2) examine the relative importance of these predictors; (3) describe (a) perceived changes in needlestick injuries after implementation of the device; (b) the reported incidence of injuries; and (c) the extent of underreporting by nurses; and (4) examine the relative importance of (a) the preceding predictors and (b) acceptance of the device in predicting perceived changes in needlestick injuries. Safety climate and training were evaluated as organizational factors. Individual factors evaluated were experience with the device, including time using it and frequency of use, and background information, including nursing unit, and length of time as a nurse in this hospital and in total nursing career. The conceptual framework was based upon the safety climate model. Descriptive statistics and multiple and logistic regression were utilized to address the study objectives. ^ The findings showed widespread acceptance of the device and a strong perception that it reduced the number of needlesticks. Acceptance was notably predicted by adequate training, appropriate time between training and device use, solid safety climate, and short length of service, in that order. A barrier to acceptance was nurses' longtime of use of previous needle technologies. Over four-fifths of nurses were compliant in always using the device. Compliance had two facilitators: length of time using device and, to a lesser extent, safety climate. Rates of compliance tended to be lower among nurses in units in which the device was frequently used. ^ High quality training and an atmosphere of caring about nurse safety stand out as primary facilitators that other institutions would need to adopt in order to achieve maximum success in implementing safety programs involving utilization of new safety devices. ^

Barriers to Influenza Immunization: The Role of Physician Training on Influenza Vaccine Utilization in Six to Twenty-Three Month Old Infants

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Barriers to Timely Screening Colonoscopy

Objective: Colorectal cancer (CRC) can be largely prevented or effectively treated in its early stages, yet disparities exist in timely screening. The aim of this study was to explore the disparities in CRC screening on the basis of health insurance status including private, Medicare, Medicaid, and State Administered General Assistance (SAGA). Methods: A retrospective chart review for the period January 2000 to May 2007 (95 records) was conducted at two clinic sites; a private clinic and a university hospital clinic. All individuals at these sites who met study criteria (>50 years old with screening colonoscopy) were included. Age, gender, date of first clinic visit when screening referral was made, and date of completed procedure (screening colonoscopy) were recorded. Groups were dichotomized between individuals with private health insurance and individuals with public health insurance. Individuals with any history of CRC, known pre-cancerous conditions as well as family history of CRC requiring frequent colonoscopy were excluded from the study. Linear model analysis was performed to compare the average waiting time to receiving screening colonoscopy between the groups. T-test was performed to analyze age or gender related differences between the two groups as well as within each group. Results: The average waiting time (33 days) for screening colonoscopy in privately insured individuals was significantly lower than publicly insured individuals (200 days). The time difference between the first clinic visit and the procedure was statistically significant (p < 0.0001) between the two groups. There was no statistical difference (p=0.089) in gender between these groups (public vs. private). There were also no statistically significant gender or age related differences found within each group. Conclusions: Disparities exist in timely screening for CRC and one of the barriers leading to delayed CRC screening includes health insurance status of an individual. Even within the insured group, type of insurance plays major role. There is a negative correlation between public health insurance status and timely screening. Differences in access to medical care and delivery of care experienced by patients who are publicly insured through Medicaid, Medicare, and SAGA, suggests that the State of Connecticut needs to implement changes in health care policies that would provide timely screening colonoscopy. It is evident that health insurance coverage facilitates timely access to healthcare. Therefore, there is a need for increased efforts in advocacy for policy, payment and physician participation in public insurance programs. A state-wide comprehensive program involving multiple components targeting different levels of change such as provider, patients and the community should help reduce some of the observed causes of healthcare disparities based on the insurance status.

Gay Parenthood and the Revolution of the Modern Family: An Examination of the Unique Barriers Confronting Gay Adoptive Parents

Abstract: In recent decades, the structure of the American family has been revolutionized to incorporate families of diverse and unconventional compositions. Gay and lesbian couples have undoubtedly played a crucial role in this revolution by establishing families through the tool of adoption. Eleven adoptive parents from the state of Connecticut were interviewed to better conceptualize the unique barriers gay couples encounter in the process adoption. Both the scholarly research and the interview data illustrate that although gay couples face enormous legal barriers, the majority of their hardship comes through social interactions. As a result, the cultural myths and legal restrictions that create social hardships for gay adoptive parents forge a vicious and discriminatory cycle of marginalization that American legal history illustrates is best remedied through judicial intervention at the Supreme Court level. While judicial intervention, alone, cannot change the reality of gay parenthood, I argue that past judicial precedent illustrates that such change can serve as a tool of individual, political, and legal validation for the gay community for obtaining equal rights.

Depression, interpersonal violence and lack of social support as barriers to cervical cancer screening among recently immigrated Latinas

Background. Various psychosocial factors have been demonstrated to be barriers for cervical cancer screening among Latinas in the United States, but few studies have researched whether depression and interpersonal violence act as psychosocial barriers to cervical cancer screening. ^ Methods. The proposed study assessed whether depression, interpersonal violence, lack of social support and demographic characteristics such as age, income, education and years in the United States acted as barriers to cervical cancer screening among cantineras in Houston, TX. This secondary data analysis utilized data from a previous cross-sectional study called Project GIRASOL- Community Outreach to Prevent Cervical Cancer among Latinas. The data from the baseline survey (sample size 331) was analyzed using Pearson chi-square and multiple logistic regression. ^ Results. Multiple logistic regression indicates that none and low levels of social support from relatives, depression, and total IPV are significant predictors of non-compliance to cervical cancer screening. ^ Conclusions. Future health interventions or physicians that promote cervical cancer screening among cantineras or recently immigrated Latinas with similar socio-demographic characteristics should try to identify whether Latinas are suffering from depression, interpersonal violence or lack of social support and provide proper referrals to alleviate the problems and positively influence screening behavior. ^

Barriers to cross-border research projects: A prelude to improving professional collaborations between the United States and Mexico

Study objective. This was a secondary data analysis of a study designed and executed in two phases in order to investigate several questions: Why aren't more investigators conducting successful cross-border research on human health issues? What are the barriers to conducting this research? What interventions might facilitate cross-border research? ^ Methods. Key informant interviews and focus groups were used in Phase One, and structured questionnaires in Phase Two. A multi-question survey was created based on the findings of focus groups and distributed to a wider circle of researchers and academics for completion. The data was entered and analyzed using SPSS software. ^ Setting. El Paso, TX located on the U.S-Mexico Border. ^ Participants. Individuals from local academic institutions and the State Department of Health. ^ Results. From the transcribed data of the focus groups, eight major themes emerged: Political Barriers, Language/Cultural Barriers, Differing Goals, Geographic Issues, Legal Barriers, Technology/Material Issues, Financial Barriers, and Trust Issues. Using these themes, the questionnaire was created. ^ The response rate for the questionnaires was 47%. The largest obstacles revealed by this study were identifying a funding source for the project (47% agreeing or strongly agreeing), difficulties paying a foreign counterpart (33% agreeing or strongly agreeing) and administrative changes in Mexico (31% agreeing or strongly agreeing). ^ Conclusions. Many U.S. investigators interested in cross-border research have been discouraged in their efforts by varying barriers. The majority of respondents in the survey felt financial issues and changes in Mexican governments were the most significant obstacles. While some of these barriers can be overcome simply by collaboration among motivated groups, other barriers may be more difficult to remove. Although more evaluation of this research question is warranted, the information obtained through this study is sufficient to support creation of a Cross-Border Research Resource Manual to be used by individuals interested in conducting research with Mexico. ^

Defining barriers in caring for seriously-ill children in a resource-limited setting: An observational study of 2 children's hospitals in Haiti

Background. According to the WHO 2007 country report, Haiti lags behind the Millennium Development Goal of reducing child mortality and maintains the highest under-5 mortality rate in the Western hemisphere. 3 Overall, few studies exist that seek to better grasp barriers in caring for a seriously ill child in a resource-limited setting and only a handful propose sustainable, effective interventions. ^ Objectives. The objectives of this study are to describe the prevalence of serious illnesses among children hospitalized at 2 children's hospitals in Port au Prince, to determine the barriers faced when caring for seriously ill children, and to report hospital outcomes of children admitted with serious illnesses. ^ Methods. Data were gathered from 2 major children's hospitals in Port au Prince, Haiti (Grace Children's Hospital [GCH] and Hopital d l'Universite d'Etat d'Haiti [HUEH]) using a triangulated approach of focus group discussions, physician questionnaires, and retrospective chart review. 23 pediatric physicians participated in focus group discussions and completed a self-administered questionnaire evaluating healthcare provider knowledge, self-efficacy, and perceived barriers relating to the care of seriously ill children in a resource-limited setting. A sample of 240 patient charts meeting eligibility criteria was abstracted for pertinent elements including sociodemographics, documentation, treatment strategies, and outcomes. Factors associated with mortality were analyzed using χ2 test and Fisher exact test [Minitab v.15]. ^ Results. The most common primary diagnoses at admission were gastroenteritis with moderate dehydration (35.5%), severe malnutrition (25.8%), and pneumonia (19.3%) for GCH, and severe malnutrition (32.6%), sepsis (24.7%), and severe respiratory distress (18%) for HUEH. Overall, 12.9% and 27% of seriously ill patients presented with shock to GCH and HUEH, respectively. ^ Shortage of necessary materials and equipment represented the most commonly reported limitation (18/23 respondents). According to chart data, 9.4% of children presenting with shock did not receive a fluid bolus, and only 8% of patients presenting with altered mental status or seizures received a glucose check. 65% of patients with meningitis did not receive a lumbar puncture due to lack of materials. ^ Hospital mortality rates did not differ by gender or by institution. Children who died were more likely to have a history of prematurity (OR 4.97 [95% CI 1.32-18.80]), an incomplete vaccination record (OR 4.05 [95% CI 1.68-9.74]), or a weight for age ≤3rd percentile (OR 6.1 [95% CI 2.49-14.93]. Case-fatality rates were significantly higher among those who presented with signs of shock compared with those who did not (23.1% vs. 10.7%, RR=2.16, p=0.03). Caregivers did not achieve shock reversal in 21% of patients and did not document shock reversal in 50% of patients. ^ Conclusions. Many challenges face those who seek to optimize care for seriously ill children in resource-limited settings. Specifically, in Haiti, qualitative and quantitative data suggest major issues with lack of supplies, pre-hospital factors, including malnutrition as a comorbidity, and early recognition and management of shock. A tailored intervention designed to address these issues is needed in order to prospectively evaluate improvements in child mortality in a high-risk population.^

Identifying and removing barriers to cycling as a viable means of transportation in Houston, Texas

The citizens of Houston, Texas, spend much time commuting. It has repeatedly been named among the “Fattest Cities” by Men’s Fitness Magazine (The fittest and fattest cities in America – Men’s Fitness. ). Obesity is one of its major public health problems as Houstonians often do not engage in enough physical activity to help them maintain their ideal weights. The use of bicycles provides a healthy and ecological alternative to commuting by driving. However, because urban cyclists must often share the roads with motorized vehicles, cyclists are often exposed to high levels of emissions. As vulnerable users of the roadways, urban cyclists also face the threat of injury. Nevertheless, there are some programs that encourage the use of bicycles. Laws and ordinances not only reveal public policy relating to bicycling but are a means to develop policy which can encourage bicycling. ^