The role of regulatory T cells in multiple sclerosis

The dysregulation of inflammatory responses and of immune self-tolerance is considered to be a key element in the autoreactive immune response in multiple sclerosis (MS). Regulatory T (T(REG)) cells have emerged as crucial players in the pathogenetic scenario of CNS autoimmune inflammation. Targeted deletion of T(REG) cells causes spontaneous autoimmune disease in mice, whereas augmentation of T(REG)-cell function can prevent the development of or alleviate variants of experimental autoimmune encephalomyelitis, the animal model of MS. Recent findings indicate that MS itself is also accompanied by dysfunction or impaired maturation of T(REG) cells. The development and function of T(REG) cells is closely linked to dendritic cells (DCs), which have a central role in the activation and reactivation of encephalitogenic cells in the CNS. DCs and T(REG) cells have an intimate bidirectional relationship, and, in combination with other factors and cell types, certain types of DCs are capable of inducing T(REG) cells. Consequently, T(REG) cells and DCs have been recognized as potential therapeutic targets in MS. This Review compiles the current knowledge on the role and function of various subsets of T(REG) cells in MS and experimental autoimmune encephalomyelitis. We also highlight the role of tolerogenic DCs and their bidirectional interaction with T(REG) cells during CNS autoimmunity.     

EEG markers of future cognitive performance in the elderly

This exploratory follow-up study investigated whether EEG parameters can predict future cognitive performance. Forty elderly subjects, ranging from cognitively unimpaired to those with Alzheimer disease underwent EEG registration at baseline and neuropsychological examination at both baseline and follow-up. We assessed relations between EEG measures and future cognitive performance (i.e., global cognition, memory, language, and executive functioning) controlling for age, follow-up time, and baseline cognitive performance. Regression models were constructed to predict performance on the Cambridge Cognitive Examination, a widely used tool within dementia screenings. Baseline EEG measures, i.e., increased theta activity (4-8 Hz) during eyes closed and less alpha reactivity (8-13 Hz) during eyes open and memory activation, indicated lower global cognitive, language (trend significant), and executive performance at follow-up. A regression model combining baseline cognitive and EEG measures provided the best prediction of future Cambridge Cognitive Examination performance (93%). EEG and cognitive measures alone predicted, respectively, 43% and 92% of variance. EEG and cognitive measures combined provided the best prediction of future cognitive performance. Although the "cognition only" model showed similar predictive power, the EEG provided significant additional value. The added value of EEG registration in the diagnostic work-up of dementia should be further assessed in larger samples.     

Community-associated methicillin-resistant Staphylococcus aureus skin and soft tissue infections at a public hospital: do public housing and incarceration amplify transmission?

BACKGROUND: Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections have emerged among patients without health care-associated risk factors. Understanding the epidemiology of CA-MRSA is critical for developing control measures. METHODS: At a 464-bed public hospital in Chicago and its more than 100 associated clinics, surveillance of soft tissue, abscess fluid, joint fluid, and bone cultures for S aureus was performed. We estimated rates of infection and geographic and other risks for CA-MRSA through laboratory-based surveillance and a case-control study. RESULTS: The incidence of CA-MRSA skin and soft tissue infections increased from 24.0 cases per 100,000 people in 2000 to 164.2 cases per 100,000 people in 2005 (relative risk, 6.84 [2005 vs 2000]). Risk factors were incarceration (odds ratio [OR], 1.92; 95% confidence interval [CI], 1.00-3.67), African American race/ethnicity (OR, 1.91; 95% CI, 1.28-2.87), and residence at a group of geographically proximate public housing complexes (OR, 2.50; 95% CI, 1.25-4.98); older age was inversely related (OR, 0.89; 95% CI, 0.82-0.96 [for each decade increase]). Of 73 strains tested, 79% were pulsed-field gel electrophoresis type USA300. CONCLUSIONS: Clonal CA-MRSA infection has emerged among Chicago's urban poor. It has occurred in addition to, not in place of, methicillin-susceptible S aureus infection. Epidemiological analysis suggests that control measures could focus initially on core groups that have contributed disproportionately to risk, although CA-MRSA becomes endemic as it disseminates within communities.     

Establishing mild, moderate, and severe scores for cancer-related symptoms: how consistent and clinically meaningful are interference-based severity cut-points?

Methods are presented to separate 16 frequently occurring cancer symptoms measured on 10-point symptom severity rating scales into mild, moderate, and severe categories that are clinically interpretable and significant for use in oncology practice settings. At their initial intervention contact, 588 solid tumor cancer patients undergoing chemotherapy reported severity on a standard 11-point rating scale for 16 symptoms. All reporting a one or higher were asked to rate on an 11-point scale how much the symptom interfered with enjoyment of life, relationship with others, general daily activities, and emotions. Factor analysis revealed that these items tapped into the same dimension, and the items were summed to form an interference scale. Cut-points for mild, moderate, and severe categories of symptom severity were defined by comparing the differences in interference scores corresponding to each successive increases in severity for each symptom. The cut-points differed among symptoms. Pain, fatigue, weakness, cough, difficulty remembering, and depression had lower cut-points for each category compared to other symptoms. Cut-points for each symptom were not related to site or stage of cancer, age, or gender but were associated with a global depression measure. Cut-points were related to limitations in physical function, suggesting differences in the quality of patients' lives. The resulting cut-points summarize severity ratings into clinically significant and useful categories that clinicians can use to assess symptoms in their practices.     

Zwitterionic Polymer Brushes and Core-Shell Particles Based thereon for Control of Biofouling

Biofilm formation on material surfaces – biofouling – has a significant economic impact on a wide range of applications and industries. There is a huge need for the prevention of undesired interactions of coatings with proteins, cells, and bacteria in biomaterials, biosensors, and other applications. In this work, the preparation and characterization as well as the comparison of bio-fouling properties of surfaces based on planar zwitterionic polymer brushes made of poly(sulfobetaine methacrylate) P(SBMA-3), poly(carboxybetaine methacrylate) P(CBMA-2), or poly(2-methacryloyloxyethyl phosphorylcholine) P(MPC-2) are reported. Since polymer brushes on planar surfaces have disadvantages with regard to layer stability, industrial scaling, and the coating of complex geometries, nano- and microstructured coatings based on polymer-functionalized core-shell particles are subsequently produced. It is found that coatings based on poly(phosphorylcholine) P(MPC-2) modified particles with a diameter of 100 nm have the lowest bioadhesion compared to other particle sizes and chemical compositions. The particle-based coatings developed can pave the way for developing scalable anti-fouling coatings in the future.     

Semaphorin 6D regulates the late phase of CD4+ T cell primary immune responses

The semaphorin and plexin family of ligand and receptor proteins provides important axon guidance cues required for development. Recent studies have expanded the role of semaphorins and plexins in the regulation of cardiac, circulatory and immune system function. Within the immune system, semaphorins and plexins regulate cell–cell interactions through a complex network of receptor and ligand pairs. Immune cells at different stages of development often express multiple semaphorins and plexins, leading to multivariate interactions, involving more than one ligand and receptor within each functional group. Because of this complexity, the significance of semaphorin and plexin regulation on individual immune cell types has yet to be fully appreciated. In this work, we examined the regulation of T cells by semaphorin 6D. Both in vitro and in vivo T cell stimulation enhanced semaphorin 6D expression. However, semaphorin 6D was only expressed by a majority of T cells during the late phases of activation. Consequently, the targeted disruption of semaphorin 6D receptor–ligand interactions inhibited T cell proliferation at late but not early phases of activation. This proliferation defect was associated with reduced linker of activated T cells protein phosphorylation, which may reflect semaphorin 6D regulation of c-Abl kinase activity. Semaphorin 6D disruption also inhibited expression of CD127, which is required during the multiphase antigen-presenting cell and T cell interactions leading to selection of long-lived lymphocytes. This work reveals a role for semaphorin 6D as a regulator of the late phase of primary immune responses.     

A Rare p.T599dup BRAF Mutant NSCLC in a Non-Smoker

V-RAF murine sarcoma viral oncogene homolog B1 (BRAF) mutated non-small-cell lung cancer (NSCLC) is an exceptionally rare form of lung cancer, found only in one to two percent of patients with an NSCLC diagnosis. BRAF NSCLC traditionally affects former or active smokers. BRAF mutations have always been of special interest to the oncological community, as they offer potential for targeted therapies. BRAF mutation spectrum includes mutations that are of both V600 and non-V600 types. BRAF V600 is an activating mutation, which results in high kinase activity and overproduction of active oncoproteins such as rapidly accelerated fibrosarcoma (RAF). This makes them susceptible to targeted therapies with RAF inhibitors. There has been little evidence, however, regarding efficacy of RAF inhibitors towards non-activating mutations that have intermediate to low kinase activity, such as non-V600 BRAF mutations. While several approaches have been investigated to overcome the limitations of RAF inhibitors, such as use of mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) inhibitors or combination of MEK and RAF inhibitors, none of them have been proven to have a superior efficacy for low kinase activity non-V600 BRAF tumors. We present a case of an extremely rare variant of NSCLC BRAF p.T599dup mutation in a non-smoker that responded to a targeted combination therapy with RAF and MEK inhibitors. The patient responded well to therapy that usually targets high kinase activity V600 mutations. Our hope is to bring more attention to non-V600 mutations and document their responses to existing and new therapies.