text:
Mechanisms of neurodegeneration
Immune cells involved in neurodegeneration
Mononuclear phagocytes
Major signaling molecules of CNS mononuclear phagocytes
Downstream inflammatory mediators of neurodegeneration
Immune-directed therapies for neurodegenerative diseases
Lessons learned and future directions
Review Series Free access | 10.1172/JCI90609
CNS inflammation and neurodegeneration
Tanuja Chitnis and Howard L. Weiner
Ann Romney Center for Neurological Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Address correspondence to: Tanuja Chitnis or Howard L. Weiner, Ann Romney Center for Neurological Diseases, Partners Multiple Sclerosis Center, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. Phone: 617.525.6550; Email: hweiner@rics.bwh.harvard.edu (H.L. Weiner); tchitnis@partners.org (T. Chitnis).
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First published September 5, 2017 - More info
Published in Volume 127, Issue 10 on October 2, 2017
J Clin Invest. 2017;127(10):3577–3587. https://doi.org/10.1172/JCI90609.
Copyright © 2017, American Society for Clinical Investigation
First published September 5, 2017 - Version history
There is an increasing recognition that inflammation plays a critical role in neurodegenerative diseases of the CNS, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and the prototypic neuroinflammatory disease multiple sclerosis (MS). Differential immune responses involving the adaptive versus the innate immune system are observed at various stages of neurodegenerative diseases, and may not only drive disease processes but could serve as therapeutic targets. Ongoing investigations into the specific inflammatory mechanisms that play roles in disease causation and progression have revealed lessons about inflammation-driven neurodegeneration that can be applied to other neurodegenerative diseases. An increasing number of immunotherapeutic strategies that have been successful in MS are now being applied to other neurodegenerative diseases. Some approaches suppress CNS immune mechanisms, while others harness the immune system to clear deleterious products and cells. This Review focuses on the mechanisms by which inflammation, mediated either by the peripheral immune response or by endogenous CNS immune mechanisms, can affect CNS neurodegeneration.
Increasing appreciation for the role of inflammation in neurodegenerative diseases of the CNS, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and the prototypic neuroinflammatory disease multiple sclerosis (MS), has identified differential immune responses involving the adaptive versus the innate immune systems at various stages of disease. These responses may not only drive disease processes but could serve as therapeutic targets. An increasing number of immunotherapeutic strategies that have been successful in MS are now being applied to other neurodegenerative diseases. Some approaches suppress CNS immune mechanisms, while others harness the immune system to clear deleterious products and cells. This Review focuses on the mechanisms, cellular functions, signaling molecules, immune responses, and mediators through which inflammation affects CNS neurodegeneration, and identifies the therapeutic opportunities within these processes.
Several basic mechanisms that drive neurodegeneration may be triggered by inflammatory cells and their mediators at various stages of the neurodegenerative cascade.
Apoptosis. Apoptosis is caspase-mediated programmed cell death (1) characterized by formation of membrane-enveloped apoptotic bodies that are rapidly phagocytosed by macrophages or neighboring cells. There is evidence of apoptotic mechanisms in animal models of several neurodegenerative diseases, but evidence in human tissues is limited. Caspase-1, -3, -8, and -9 activation and cytochrome c release seen in models of Huntington's disease (HD) were also demonstrated in human striatal brain tissue (2, 3). Similarly, caspase activation and neuronal apoptosis have been demonstrated in ALS (4) and HIV-associated neurodegeneration (5).
Necroptosis. Necroptosis represents a form of programmed cell death that is independent from the caspase activation and involves loss of plasma membrane integrity. Two main effector proteins of necroptosis are receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and mixed-lineage kinase domain–like (MLKL). Astrocytes release TNF-α, FasL, and TRAIL, which can trigger necroptosis through RIPK1 and MLKL activation, and this mechanism has been demonstrated in murine models of ALS (6). RIPK1-mediated axonal pathology was observed in pathological specimens from ALS patients (7). Necroptotic mechanisms were also observed in MS pathological samples (8).
Neuronal autophagy. Autophagy, also known as type II programmed cell death, is characterized by the accumulation of autophagic vacuoles during cell death, along with toxic components such as proteins or damaged organelles (9, 10). Excessive autophagy may lead to self-destruction and cell death. Autophagosomes were identified in affected neurons of patients with AD, HD, and PD (11–13). Many stimuli also induce autophagy, including nutrient starvation, mitochondrial toxins, hypoxia, and oxidative stress (14).
Retrograde degeneration. Retrograde degeneration of the proximal neuronal cell body may result from axonal injury or transection and may be associated with various pathological changes in the cell body, including apoptosis (15–17) and chromatolysis of the neuronal perikaryon (18, 19). The association of neuronal apoptosis with axonal damage suggests that inflammation-induced axotomy may produce retrograde (secondary) death of neuronal cell bodies via apoptosis.
Wallerian degeneration. Proximal damage to the neuron or axon may result in anterograde degeneration of the distal axon, termed Wallerian degeneration. Wallerian degeneration is a cascade of events that includes granular degeneration of the axonal cytoskeleton, accumulation of activated macrophages and microglia, and local changes in the immune environment. Evidence that Wallerian degeneration occurs in MS is seen in a histopathological study demonstrating inflammatory cervicomedullary junction lesion with distal axonal atrophy in the absence of demyelination (20), as well as in MRI studies (21, 22).
Demyelination. The relationship between the oligodendrocyte and axon is complex, with the provision of mutual support through trophic factors that can be disrupted in demyelinating diseases. In addition to protecting the axon from immune-mediated damage (23, 24), myelin integrity protects the integrity of the developing axon (25). Myelin-associated glycoprotein (26) and proteolipid protein (27) deliver essential myelin-derived trophic signals to axons (28). Mice lacking proteolipid protein developed axonal swellings and degeneration (27), suggesting that local oligodendroglial support is critical for axon survival.
Astrogliopathy. Dysfunction of astrocytes has broadly been termed astrogliopathy. Aging-related tau astrogliopathy (ARTAG) describes the pathological accumulation of abnormally phosphorylated tau protein in astrocytes that is found in AD, frontal temporal lobe dementias (29), and corticobasal degeneration (30). Neuromyelitis optica (NMO) presents with optic neuritis and myelitis and can mimic MS. NMO is associated with the presence of aquaporin-4 (AQP4) antibodies, which target astrocyte water channels. Pathologically NMO is characterized by extensive loss of immunoreactivity for the astrocytic proteins AQP4 and glial fibrillary acidic protein (GFAP), perivascular deposition of immunoglobulins, and activation of complement even within lesions with relative preservation of myelin (31).
Endogenous CNS immune cells. Inflammation-mediated neurodegeneration may result from dysfunction of endogenous or exogenous immune cells. The two major endogenous cells in the CNS that drive inflammation are astrocytes and mononuclear phagocytes, which include microglia and perivascular macrophages. The mechanisms by which astrocytes and macrophages/microglia drive the neurodegenerative process are outlined in Figure 1, A and B.
Immune-mediated attack on axons and myelin sheath. During MS and EAE, axonal damage and demyelination are initially mediated by the inflammatory response within the CNS. (i) CD4+ Th17 cells produce GM-CSF, which activates macrophages and microglia. (ii) CD4+ Th1 cells invade the CNS and produce IFN-γ, which activates macrophages and microglia to produce the cytokine IL-12 (the major promoter of Th1 cytokine production). (iii) Macrophages and microglia also produce nitric oxide (NO), peroxynitrite (ONOO–), and superoxide (O2–), which are each capable of mediating cellular damage. This capability is enhanced by microglia- and macrophage-derived TNF-α production. (iv) Activated macrophages and microglia may also consume damaged myelin sheaths and axons. (v) B cells produce antibodies that bind to myelin sheaths and may promote complement-mediated damage (C′). (vi) IFN-γ upregulates the expression of MHC class I by resident CNS cells, potentially inciting a CD8+ cytotoxic T cell response.
Astrocytes. Astrocytes account for almost half of CNS volume. Their normal functions include providing trophic support for neurons, facilitating synapse formation and function, and synaptic pruning by phagocytosis. Astrocytes also help control extracellular ion and neurotransmitter concentrations and maintain the blood-brain barrier (32). One of their most important homeostatic functions is maintaining glutamine-glutamate balance. Glutamate transporters, including EAAT1–EAAT3, are predominantly expressed on astrocytes and neurons and regulate the glutamate uptake and metabolism. Downregulation of these transporters can result in increased extracellular glutamate, potentially enhancing neurotoxicity. Glial expression of these transporters is altered in MS (33) and ALS (34).
Glutaminase converts glutamine to glutamate and is present in astrocytes. Glutaminase is upregulated in MS lesions, colocalizing with infiltrating macrophages and microglia (33), and its expression is correlated with axonal damage. The astrocytic enzymes glutamine synthetase and glutamate dehydrogenase are responsible for glutamate degradation. Both are reduced in MS lesions (33) and spinal cords from mice with experimental autoimmune encephalomyelitis (EAE) (35). Dysfunctional or damaged astrocytes may not perform this function, resulting in increased concentrations of glutamate in the milieu, which may induce NMDA receptor–induced cell death.
Astrocyte function and gene expression are heterogeneous and dependent on local inflammatory milieu as well as region- and circuit-specific diversity (36–38). Inflamed astrocytes can produce proinflammatory cytokines and chemokines, including CCL2, which recruit monocytes into the CNS and may further activate astrocytes themselves (39). In EAE, astrocytes can have a different role depending on the stage of disease (40). Depletion of astrocytes during acute EAE worsens disease, as astrocytes play a protective role through glutamate metabolism. However, during chronic EAE, astrocytes become inflamed and acquire a pathogenic role; deletion of astrocytes at this stage improves EAE. Lactosylceramide synthesized by β-1,4-galactosyltransferase 6 is upregulated in the CNS, and lactosylceramide acted in an autocrine manner to control astrocyte transcriptional programs that promote neurodegeneration (40).
Recently, two distinct phenotypes of astrocytes have been described — A1 and A2 (41). A2 astrocytes were predominant in ischemia-induced CNS lesions, while A1 astrocytes predominated in inflammation-induced lesions. TLR4-activated microglia seem to be necessary for A1 astrocyte induction, which is dependent on IL-1α, TNF, and complement C1q in combination. A1 astrocytes expressing downstream complement C3 were identified in CNS specimens from MS, PD, AD, ALS, and HD and may play a key role as mediators of inflammation-induced neurodegeneration (41).
Perivascular and meningeal macrophages. The CNS contains an extensive network of bone marrow–derived (BMD) mononuclear phagocytes, including macrophages of the meninges, choroid plexus, and perivascular spaces. Perivascular macrophages differ from microglia and from BMD peritoneal macrophages or circulating monocytes. The transcriptional activator MYB is critical for development of BMD monocytes, but perivascular macrophage development depends on PU.1, IRF8, and CSF1R. The unique microenvironments of perivascular macrophages may work to shape their properties, including their CNS macrophage signatures (42–44). In MS, perivascular macrophages may function as antigen-presenting cells to T cells (45). The accumulation of perivascular macrophages observed in HIV encephalopathy may play an important role in the ensuing neurodegenerative process (46).
Microglia. Microglia are the resident macrophages of the CNS. Derived from the embryonic yolk sac, they migrate into the developing neural tube and subsequently colonize the brain parenchyma (47–49). Microglia turn over slowly and are present throughout the lifespan. They do not repopulate from the BMD myeloid precursors and are independent of blood-derived monocytes. Microglial precursors proliferate independently of MYB and myeloid-lineage hematopoietic stem cells (49). Unique markers and gene signatures that distinguish resident microglia from peripheral mononuclear cells/macrophages (50–52) include FSRSL, P2Y12, TMEM119, CX3CR1, Siglec-H, and the microRNAs miR-99a, miR-125-5p, and miR-342-3p, which are highly expressed in both mouse and human microglia (50, 53). Homeostatic microglia are dependent on TGF-β, and CNS-specific TGF-β–KO mice develop late-onset motor dysfunction (50), which may be due to impairment of microglia-associated glutamate recycling and synaptic plasticity (54). TMEM119 immunoreactivity is expressed exclusively on a subset of microglia with ramified and amoeboid morphologies in the brains of neurodegenerative diseases, such as AD, whereas infiltrating macrophages did not express TMEM11 9 (55) in demyelinating lesions of MS and necrotic lesions of cerebral infarction (56).
Although microglia have previously been classified as M1 (proinflammatory) and M2 (antiinflammatory), it is now clear that microglia are more complex than this simple dichotomy, as many microglia demonstrate characteristics of both phenotypes (refs. 57, 58, and Figure 2). A phagocytic program plays an important role in clearing aberrant proteins, particularly in AD, PD, and ALS. More recent work identifies a microglia subtype called "dark microglia" with ramified and thin processes and prominent staining for IBA1, CD11b, and microglia-specific 4D4, as well as TREM2 that associates with amyloid plaques (59). Future studies examining the molecular signatures of microglia in health and disease may identify novel targets for diagnosis and modulation of neurodegenerative diseases.
Secondary degeneration of the axon and neuronal cell body. Secondary degeneration may be mediated through several mechanisms. (i) Nitric oxide (NO) produced by macrophages and microglia may inhibit normal cellular respiration and mitochondrial ATP production. (ii) Reductions in neuronal ATP production may lead to failure of the Na+/K+ pump. The subsequent increases in intracellular concentrations of Na+ lead to reverse operation of the Na+/Ca2+ exchanger and opening of voltage-sensitive Ca2+ channels, resulting in a rise of intra-axonal Ca2+. (iii) This, in turn, may activate degradative enzymes, including proteases, phospholipases, and calpains, resulting in further neuronal or axonal damage and impaired ATP production. (iv) Microglia and macrophages recruited to the area produce glutamate, which can interact with NMDA or AMPA receptors, which also cause a rise in intracellular Ca2+. (v) Impaired glutamate uptake and degradation in the astrocyte, accompanied by downregulated expression of glutamine synthase (GS) and glutamate dehydrogenase (GDH), perpetuates increased extracellular glutamate levels. (vi) Astrocytes produce CCL2 and cytokines that further activate microglia and macrophages. In turn, microglia and macrophages consume damaged myelin sheaths and axons. (vii) Secondary neuronal cell body degradation can occur by apoptotic or necroptotic mechanisms, triggered in part by immune molecules (e.g., TNF-α, TRAIL) that are produced by microglia/macrophages or astrocytes.
Invading peripheral macrophages. Blood-derived monocytes can differentiate into macrophages and may invade the CNS to mediate CNS pathology, where they may be difficult to distinguish from resident microglial cells. Blood-derived macrophages associate with nodes of Ranvier and initiate demyelination, whereas microglia appear to clear debris (60). GM-CSF–activated mononuclear phagocytes that migrate into the CNS exhibit a more pathogenic signature than those that migrate to other organs, which may be due to the unique microenvironment of the CNS (61).
CD200-CD200R. CD200 is primarily expressed on the surface of neurons in both the CNS and the PNS, as well as thymocytes, recirculating B cells, activated B cells, and follicular dendritic cells (62). CD200 receptor (CD200R) initiates tyrosine phosphorylation (63) and is expressed only on cells of the microglia/macrophage lineage (63, 64). Administration of a CD200R-blocking antibody to Lewis rats exacerbated EAE (63), and CD200-deficient mice experienced earlier onset of EAE, with increased microglia/macrophage accumulation and activation in the CNS as demonstrated by increased expression of inducible NOS (iNOS) (65). We found that administration of a CD200R1 agonist attenuated disease in a chronic MS model (66). Enhanced CD200 expression was associated with reduced Wallerian degeneration in the slow Wallerian degeneration (Wlds) mouse (67), a spontaneously occurring mutant with the unique phenotype of protection against several forms of axonal injury (68–71). In vitro, Wlds neuronal cultures were protected from microglia-induced neurotoxicity, which was abrogated by anti-CD200 antibody treatment (67).
SIRPα-CD47. SIRPα (also known as SHPS-1, p84, and BIT) is a regulatory membrane glycoprotein expressed mainly by myeloid cells, stem cells, and neurons. It binds CD47 on microglia to deliver an inhibitory signal (72, 73). SIRPα activation was linked to the inhibition of cell activities, including decreased cytokine production, reduced monocyte adhesion to the extracellular matrix, reduced phagocytosis, and maturation arrest in dendritic cells (74–76). SIRPα engagement inhibits macrophage phagocytosis by recruiting SHP-1 (77). Fcγ receptor (FcγR) activation stimulates the association between SHP-1 and SIRPα, which in turn inhibits FcγR- and complement receptor–mediated phagocytosis (75, 78). CD47 expression is downregulated in MS brain lesions (79). Although CD47-deficient mice are resistant to EAE, primarily owing to lack of APC activation, blocking CD47 enhances disease progression by increasing myelin phagocytosis in the CNS (79).
TREM2. TREM2 (triggering receptor expressed on myeloid cells-2) is an activating phospholipid-binding receptor that couples with TYROBP, an adaptor protein, to attenuate inflammatory activation and increase phagocytic clearance of cell debris. DAP12 forms a receptor-signaling complex with TREM2 and triggers activation of immune responses to macrophages and microglia. A rare missense mutation in the gene encoding TREM2 confers risk of late-onset AD (80, 81) and frontotemporal dementia (82), possibly due to impaired clearance of proteins by macrophages and microglia.
CD33. CD33 is an immunoglobulin-like lectin that binds sialic acids and delivers inhibitory signals to human microglia. CD33 is increased in microglial cells in AD brain and inhibits uptake of amyloid by microglial cells (83). The minor allele of the CD33 SNP rs3865444 has been shown to confer protection against AD (84).
Purinergic metabolites. Dying cells in the brain may release extracellular purinergic metabolites such as ATP and NAD, leading to both innate and adaptive immune activation (85, 86). The uptake of double-stranded DNA can induce activation of TLRs. The purinergic receptor P2Y12 is a TGF-β–responsive molecule uniquely expressed on mouse and human microglia and not on perivascular macrophages or blood-derived monocytes (50), and is expressed predominantly in homeostatic-type microglia (87). ADP is the endogenous ligand of P2Y12, and homeostatic microglia have increased ligand-mediated calcium responses, which are blocked by selective P2Y12 antagonism (87).
GM-CSF. GM-CSF stimulates BMD stem cells to differentiate into granulocytes and monocytes. A variety of cells, including macrophages, T cells, mast cells, NK cells, endothelial cells, and fibroblasts, produce GM-CSF, and it can enhance ROS production as well as myeloid cell–mediated phagocytosis. GM-CSF was increased in the cerebrospinal fluid of MS patients (88). In EAE, GM-CSF production by Th17 cells activates effector mononuclear phagocytes (89). GM-CSF–activated mononuclear phagocytes that migrate into the CNS exhibit a more pathogenic signature than those that migrate to other organs, which may be due to the unique CNS microenvironment (61).
MicroRNAs. MicroRNAs (miRNAs) are small noncoding RNAs that function in RNA silencing and posttranscriptional regulation of gene expression (90). While the majority of miRNAs are located within the cell, some miRNAs, commonly known as circulating miRNAs or extracellular miRNAs, function in the extracellular environment. Several miRNAs are associated with microglial function. We have shown that in the SOD1 model of ALS, miR-155 expression was associated with loss of homeostatic microglia signature molecules including P2Y12, TMEM119, OLFM13, the transcription factors EGR1, ATF3, Jun, Fos, and MAFB, and the upstream regulators CSF1R, TGFB1, and TGFBR1, which are essential for microglial survival (91). miR-Let-7a participates in the reduction of nitrite production and the expression of iNOS and IL-6. It also increases expression of brain-derived neurotrophic factor (BDNF), IL-10, and IL-4 in microglia (92). The miRNA miR-181c controls microglia-mediated neuronal apoptosis by suppressing TNF (93).
T cells and neurodegeneration. Th1 and Th17 cells play a major role in the initiation of neurodegeneration in MS by creating an inflammatory milieu and recruiting inflammatory monocytes that lead to axonal damage. T cells may also have a neuroprotective role: we have shown that intranasal administration of anti-CD3 monoclonal antibody in chronic EAE induces an IL-10–secreting Tr1-like cell in the cervical lymph nodes that migrates to the brain, dampens astrocyte and microglial inflammation, and ameliorates neurodegeneration.
CD8+ T cells. CD8+ T cells can directly mediate neurodegeneration (Figure 1A). Under inflammatory conditions, IFN-γ can induce neuronal expression of MHC I molecules. This may be important in virally mediated reactions as well as in autoimmune diseases, including MS, in which CD8+ T cells are found in pathology specimens (94). CD8+ T cells may also mediate collateral killing of neurons, in part as a result of the release of perforin (and granzymes) independently of Fas/FasL signaling (95). Upon stimulation, CD8+ T cells can upregulate the molecular repertoire for vesicular glutamate release, including glutaminase, which is required to generate glutamate, vesicular proton-ATPase, and vesicular glutamate transporters (96), and thus may be key in immune-mediated neurodegeneration.
CD4+ T cells. Until recently, a direct role of CD4+ T cells in neurodegeneration was not appreciated, though they can indirectly initiate neurodegeneration by recruiting inflammatory monocytes. Thus, Th1 and Th17 may be targets to potentially minimize a hostile neuronal microenvironment. The ability of CD4+ T cells to directly mediate cytotoxicity was recently demonstrated in the MPTP-induced mouse model of PD (97). Similar attenuation of MPTP-induced dopaminergic cell death was seen in mice lacking CD4 as well as in Rag1–/– mice reconstituted with FasL-deficient splenocytes. However, CD8-deficient or Rag1–/– mice reconstituted with IFN-γ–deficient splenocytes were not protected.
Regulatory T cells. Regulatory T cells (Tregs) include FoxP3+CD25+CD4+ T cells as well as IL-10–producing Tregs and may play a role in dampening or controlling inflammatory processes within the CNS. Considerable evidence reveals that these cells play a role in the early stages of MS (98). More recent work found that Tregs from ALS patients were less effective in suppressing responder T lymphocyte proliferation and were increasingly dysfunctional with disease progression (99, 100).
Inflammatory mediators are known to enhance or affect several neurodegenerative mechanisms through key downstream mediators. Others may play neuroprotective roles, as discussed in the next section.
Reactive oxygen and nitrogen species. ROS are chemically reactive chemicals containing oxygen and include peroxides and superoxides. Activated immune cells, particularly macrophages, can produce ROS, which contributes to mitochondrial dysfunction and ultimately neuronal apoptosis. Superoxide dismutase (SOD) binds free superoxide radicals for conversion into molecular oxygen and hydrogen peroxide, the latter of which is then broken down by catalase (101). Over 160 mutations in the SOD gene have been found in forms of ALS (102, 103).
Nitric oxide (NO) is a key mediator of neurotoxicity with multiple roles in the CNS. NO is synthesized from l-arginine by NOS and can potently inhibit mitochondrial respiration (Figure 1B). Constitutive forms of NOS are produced by endothelial cells (eNOS) and neurons (nNOS), while the inducible form (iNOS) is produced by a variety of cell types, including macrophages and microglia, in response to inflammatory stimuli. iNOS accounts for the majority of NO production. NO can regulate a variety of cellular processes, including the generation of the highly cytotoxic superoxide anion (O2·–) and peroxynitrite anion (ONOO–) (104, 105). Collectively, NO and its products have been shown to mediate neurotoxicity in vitro (106–108), and selective inhibitors of iNOS reduce microglia/macrophage-mediated neurotoxicity (109).
NO appears to act in concert with other factors in increasing susceptibility to neurotoxicity. In a cerebral ischemia model, the combination of TNF-α and IL-1β was neurotoxic in the presence of iNOS, while in the absence of iNOS, this combination mediated neuroprotection and plasticity (110). Conversely, TNF-α increased neuronal sensitivity toward NO (111). NO inhibits neuronal respiration, which in turn enhances release of glutamate, causing excitotoxic death of neurons (112). Inhibition of iNOS blocked NMDA-mediated neurotoxicity (113, 114), reinforcing the concept that NO plays a role in excitotoxicity. Further, arginase can compete with NOS for their common substrate, l-arginine, and thus inhibit NO production. This regulatory mechanism may be important when the extracellular supply of l-arginine is limited (115). Electrically active axons exposed to high concentrations of NO have enhanced susceptibility to persistent conduction block and axonal degeneration (116, 117).
Cytokine-mediated neurodegeneration. It is now well recognized that cytokines secreted by immune cells may have direct neurotoxic properties.
IL-1 is produced by the activated mononuclear phagocyte and upregulated in the CNS during EAE induction (118–120). Injection of its isoform, IL-1β, into the rat brain at the time of experimental ischemia or traumatic injury caused increased neuronal cell death and edema (121). Overexpression of IL-1 receptor antagonists in the CNS blocked these effects (122). Addition of IL-1 in vitro results in neuronal apoptosis (123), and its neurotoxic effects appear to be dependent on iNOS expression (124, 125). Thus, IL-1, alone or in combination with iNOS, may be an important factor in neuronal and axonal damage in the CNS. However, IL-1 has also been shown to induce the production of nerve growth factor (NGF) in vitro (126, 127), suggesting some neuroprotective effects.
IL-3 is a cytokine growth factor produced by CD4+ T cells and microglia. It exerts both trophic (128) and toxic effects on neurons (129, 130). Systemic overexpression of IL-3 in the CNS of mice results in severe neurological dysfunction characterized by degenerated, vacuolated neurons (131), predominantly motor neurons of the spinal cord, with an increase in inflammatory infiltrates surrounding neurons in the absence of demyelination. In contrast, transgenic IL-3 expression under the astrocytic GFAP promoter resulted in a predominantly demyelinating disease with minimal axonal pathology (132).
IL-6 is secreted by mononuclear phagocytes, T cells, vascular endothelial cells, and fibroblasts in response to IL-1 and TNF-α. Overexpression of IL-6 in the CNS resulted in neurodegenerative pathology characterized by dendritic vacuolization (133, 134). IL-6 orchestrates the transition between innate and adaptive immune responses through the recruitment of monocytes and T cells. In particular, IL-6 in the presence of TGF-β induces Th17 cells (135). IL-6 also enhances astrogliosis and angiogenesis needed for the tissue remodeling (136).
TNF-α is a proinflammatory cytokine. Local TNF production in the CNS induces oligodendrocyte apoptosis and demyelination in EAE models (137, 138). However, TNF-α may play either neuroprotective or neurotoxic roles, depending on expression of other factors including NO (111, 123, 124), upregulation of NF-κB (139), timing of exposure of damaged neurons to TNF (139), and the presence of excess NMDA receptor agonists (127). In addition, TNF-α may exert neurotoxic effects through inhibition of growth factors such as IGF (140). Interaction of TNF-α with TNF receptor 1 (TNFR1) versus TNFR2 may result in different and even opposite effects. This may explain the unexpected finding that TNF-α–deficient mice develop a more severe form of EAE than controls (141). In addition, TNF-α has been shown to promote the proliferation of oligodendrocyte progenitors (142).
Antibody- and complement-mediated neurodegeneration. Antibodies can induce neurodegeneration through two mechanisms, antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). In ADCC, effector immune cells lyse a target cell, whose membrane-surface antigens have been bound or opsonized by specific antibody. The effector cells in this case are typically NK cells, but macrophages, neutrophils, and eosinophils can also mediate ADCC. CDC is a function of the complement system that kills without the involvement of antibodies or cells. Three pathways of complement activation lead to the deposition of membrane attack complexes onto the target, which eventually causes colloid-induced osmotic swelling and lethal membrane damage.
Several studies have demonstrated that complement activation may have neuroprotective effects in specific situations. C3a protects neurons against NMDA toxicity (143). In an in vivo mouse model, C5a protected neurons from kainic acid–induced apoptosis, which was associated with the inhibition of glutamate-mediated caspase induction (144). Some neuronal subtypes, including dentate gyrus granule cells, hippocampal pyramidal hilar cells, and cerebellar Purkinje cells, constitutively express receptors for C3a and C5a (145, 146), which may play a role in development.
Neurons express particularly low levels of CD59 and DAF, molecules that normally confer cellular resistance to complement-mediated damage in other organs. Complement deposition is noted in several neuroinflammatory conditions, including NMO (147) and subtypes of MS (148), and may be a downstream therapeutic target.
Immune-directed therapies for neurodegenerative diseases generally fall into two categories: (a) therapies that target components or cells of the immune system determined to cause disease, such as T cells in MS and microglia in ALS; and (b) therapies that utilize the immune system to clear or target aberrant proteins, including vaccine or passive antibody therapies for AD and more recently PD. As outlined above, the immune system, and particularly CNS immunity, is composed of many complex interrelated and dependent pathways. Therefore, consideration of upstream and downstream effects of immune-directed therapies is important and can affect a therapy's mechanism of action as well as the risk of adverse events. Below, we discuss lessons learned from the successes and failures of specific immunotherapies for neurodegenerative diseases that provided important insights for developing specific targets of therapy.
Multiple sclerosis. In MS, the initial target is the myelin sheath in the CNS; however, later stages are characterized by microglial activation, astrocytic dysfunction, and secondary neurodegeneration (149). Current immunotherapies for MS target a diverse array of immune cell types of the peripheral immune system, including those of the lymphoid lineage (T cells and B cells) and those of the myeloid lineage (macrophages and dendritic cells). These therapies are most effective during the early relapsing-remitting stage of disease and have only limited efficacy during the later secondary progressive stage of disease, which is thought to be mediated by intrinsic CNS inflammatory and neurodegenerative mechanisms (149) including oxidative stress and axonal degeneration. Some oral immunotherapies, including S1P1 modulators, may penetrate into the CNS, and a recent trial has demonstrated effects in secondary progressive MS (150). S1P1 receptors on astrocytes suppress astrocyte- and microglia-mediated inflammatory pathways (151, 152). B cell–directed therapies have a modest effect in primary progressive MS, but it is unclear whether this is due to effects within the CNS or potent modulation of peripheral immune mechanisms (153). An ongoing clinical trial in secondary progressive MS evaluates ibudilast, which inhibits macrophage migration inhibitor factor and phosphodiesterase-4 and -10 and thus may modulate microglia and macrophage function (154). A challenge for halting progressive MS is successful targeting of multiple immune-dependent and immune-independent neurodegenerative cascades initiated within the CNS.
Amyotrophic lateral sclerosis. Motor neuron death in ALS often occurs in association with protein inclusions. Familial ALS accounts for 10% of cases and has been associated with mutations in the SOD1 gene and ubiquitin-related genes (155). Glutamate levels are elevated in ALS patient cerebrospinal fluid, possibly because of aberrant expression of the astrocytic glutamate transporter EAAT2 (156). Glutamate inhibition is the mechanism of riluzole, the first approved therapy for ALS. There is evidence for both central and peripheral immune system activation in ALS. In early disease, there is evidence of homeostatic microglia and Treg infiltration, while in later disease stages, M1 microglia and activated astrocytes predominate (157). Tregs themselves are defective in ALS (99, 100). TLR4, which activates microglia, is upregulated in the spinal cord of ALS patients, and could thereby mediate neurodegeneration (158). Immune-directed therapeutic trials to date have largely targeted microglia, and include minocycline, masitinib, NP001 (a modulator of NF-κB function on monocytes), and celecoxib. Of these, only masitinib, a tyrosine-kinase inhibitor targeting microglia and mast cells, has demonstrated positive results. Interim analysis showed that masitinib met both its primary endpoint, a change in the ALS function rating scale revised score, and its secondary endpoint, which included respiratory function and combined assessment of function and survival (159). Minocycline modulated microglial function and delayed disease progression in a mouse model of ALS but failed to demonstrate benefit in human studies. A potential explanation was later demonstrated in animal models: in later stages of ALS, in the setting of activated microglia, minocycline induces end-stage GFAP-biophotonic signals and increases connexin-43 expression levels, thereby altering astrocyte function and inducing microgliosis (160). Edaravone is a free radical scavenger with antioxidant effects that was approved for ALS in the US in 2017 based on a small randomized controlled clinical trial with people with early-stage ALS in Japan. It failed two earlier trials in people with all stages of ALS. Other immune-directed strategies currently under investigation include ibudilast, anti–IL-6 (tocilizumab), and IL-1 receptor antagonist (anakinra) therapies (157). We have found that both microglia and peripheral monocytes have an inflammatory phenotype in the SOD model and in ALS and that targeting miR-155 ameliorates disease in this model (91); targeting of miR-155 is now being evaluated in clinical trials.
Alzheimer's disease. AD is characterized by the presence of extracellular amyloid plaques, formed mainly from amyloid-β (Aβ) 1–42 peptide and intracellular neurofibrillary tangles that contain hyperphosphorylated tau, both of which are neurotoxic. Additional pathological changes include gliosis, inflammation, neuritic dystrophy, neuronal loss, and changes in neurotransmitter levels. Solomon et al. demonstrated that monoclonal antibodies could dissolve Aβ plaques in vitro (161, 162). Schenk et al. attenuated and prevented disease in Aβ-transgenic mice by administering Aβ antibodies (163). Over the past 10 years, Aβ immunotherapy has transitioned from preclinical studies to human studies, with at least 13 different trials stratified into passive antibody administration and active vaccination with Aβ. In the first vaccine trial, using AN1792Aβ, 6% of patients developed meningoencephalitis (164), likely because of increased Th1 cell responses to Aβ (165, 166). Eight vaccinated patients died, and autopsy examinations revealed profound reductions in amyloid load; however, they exhibited severe dementia at the time of death, suggesting that vaccination may not be sufficient to stop ongoing neurodegenerative processes. Newer active-immunization trials have either modified the Aβ peptide to be less immunogenic or used only the B cell–reactive epitope (167).
At least seven trials using passive transfer of Aβ antibodies have been performed. Post hoc analysis demonstrated marked cognitive benefits largely in patients who did not carry the apolipoprotein E (APOE) ε4 allele; however, only a trend toward benefit was observed in APOE ε4 carriers, possibly because of accelerated pathogenesis in these individuals (167). Vasogenic edema and cerebral hemorrhage have occurred in cases after passive anti-Aβ immunotherapy (168). A large phase III clinical trial of the anti-amyloid antibody aducanumab is under way based on encouraging initial results (169).
Newer strategies for AD aim to enhance microglial phagocytosis of Aβ, for instance by targeting TREM2 and CD33, but limit potentially deleterious microglial responses. We have found that nasal administration of a proteosome-based adjuvant (Protollin) induced monocytes that cleared fibrillar amyloid, insoluble Aβ, and soluble Aβ fragments successfully in aged amyloid precursor protein–transgenic (APP-transgenic) mice (170). A clinical trial in AD subjects is planned.
(a) Treat early: It is clear that immune-targeting therapeutics for MS and AD are most effective when targeting patients early in their disease course, when neurodegeneration and activation of secondary inflammatory pathways are not pronounced. Immunotherapy for AD has been more successful in earlier patients with minimal cognitive decline, but there is evidence from imaging that Aβ deposition has already occurred at this point (171).
(b) Different immune mechanisms predominate depending on the stage of disease and thus require different approaches: This is exemplified in ALS, in which minocycline was ineffective in the later stages of disease and may have even triggered astrogliosis in the setting of diffuse CNS inflammation. In MS, antiinflammatory medications have little effect in the secondary progressive phase of disease, which is mediated by innate and CNS-compartmentalized immune mechanisms.
(c) Microglia, macrophages, and astrocytes play important roles: As with T cell subsets, it is becoming clear that microglial, astrocyte, and macrophage subsets with unique molecular signatures can have both pathogenic and disease-ameliorating functions in neurodegeneration. Further work is required to elucidate the role of molecules involved in these subsets to target them therapeutically.
(d) Use caution in interpreting animal studies: One shortcoming of animal studies is the testing of therapies at early disease stages, which is unlike the situation in human clinical trials, where disease is only recognized in later stages.
(e) Precision medicine approaches will enhance immune-based therapeutics: Given the heterogeneity of disease course as well as key pathogenic differences according to disease stage, precision approaches combining genomics, biomarkers, imaging markers, and targeted therapeutics may enhance immune-based management for CNS diseases.
In conclusion, inflammatory processes play an important role in neurodegeneration, both in triggering and amplifying degeneration and in providing avenues to limit neurodegeneration. Immune processes that impinge on neurodegeneration exist in both the periphery and the CNS. Because immune cells traffic to the CNS, some therapies can access periphery inflammatory processes to affect the CNS. It is more difficult to target local CNS inflammatory processes, such as microglia and astrocytes. It was recently shown that microglia (44) and astrocytes (172) may be affected by the microbiome, providing a potential new avenue to modulate CNS inflammation and degeneration. It must be realized, however, that neurodegenerative processes may become inflammation-independent, especially in later stages. There is great promise in ongoing studies of inflammation-targeted neuroprotective strategies, which may ultimately be used across neurodegenerative diseases.
We thank the Ann Romney Center for Neurological Diseases for support of this work. We thank Belinda Kaskow for assistance with the figures.
Conflict of interest: T. Chitnis has received research funding from Verily, Serono, and Biogen. She has served as a consultant or on the advisory board for Novartis, Sanofi, Genentech, Bayer, and Biogen. H.L. Weiner has received research funding from Verily, Serono, Biogen, Genentech, and Sanofi-Genzyme. He serves on the scientific advisory board for Tiziana and MedDay.
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Dolgin E. Therapies: progressive steps. Nature. 2016;540(7631):S7–S9.
Rothhammer V, et al. Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation. Proc Natl Acad Sci U S A. 2017;114(8):2012–2017.
Choi JW, et al. FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc Natl Acad Sci U S A. 2011;108(2):751–756.
Montalban X, et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017;376(3):209–220.
Fox RJ, et al. Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis. Contemp Clin Trials. 2016;50:166–177.
Taylor JP, Brown RH, Cleveland DW. Decoding ALS: from genes to mechanism. Nature. 2016;539(7628):197–206.
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Crisafulli SG, Brajkovic S, Cipolat Mis MS, Parente V, Corti S. Therapeutic strategies under development targeting inflammatory mechanisms in amyotrophic lateral sclerosis. [published online ahead of print April 28, 2017]. Mol Neurobiol. https://doi.org/10.1007/s12035-017-0532-4.
Casula M, et al. Toll-like receptor signaling in amyotrophic lateral sclerosis spinal cord tissue. Neuroscience. 2011;179:233–243.
Petrov D, Mansfield C, Moussy A, Hermine O. ALS Clinical Trials Review: 20 years of failure. Are we any closer to registering a new treatment? Front Aging Neurosci. 2017;9:68.
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Version 1 (September 5, 2017): Electronic publication
Version 2 (October 2, 2017): Print issue publication
Glia and Neurodegeneration
Microglia in steady state
Katrin Kierdorf et al.
Transcriptional control of microglia phenotypes in health and disease
Inge R. Holtman et al.
Microglia in prion diseases
Adriano Aguzzi et al.
Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia
Deepti Lall et al.
Cell biology of spinal cord injury and repair
Timothy M. O'Shea et al.
Tanuja Chitnis et al.
Understanding the functions and relationships of the glymphatic system and meningeal lymphatics
Antoine Louveau et al.
Microglia in Alzheimer's disease
Heela Sarlus et al.
Oligodendroglia: metabolic supporters of neurons
Thomas Philips et al.


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The FlexrStep allows for easier entry onto the trampoline without introducing a hard surface to the jumping area. It comes with a lock to restrict unsupervised jumping.
The Spring free Trampoline Ground Anchor secures your trampoline to the ground. Two anchors are positioned on either side of the legs to properly secure the trampoline. Each box includes two anchors (4 anchors are required for the S155).
The wheels slip easily under the legs to make moving a Springfree Trampoline easy and quick. They come as a pair; only one set is required for any model.


text:
Procedure rules
Rules & Practice Directions
PRACTICE DIRECTION – PRE-ACTION CONDUCT AND PROTOCOLS
Introduction Para. 1
Objectives of pre-action conduct and protocols Para. 3
Proportionality Para. 4
Steps before issuing a claim at court Para. 6
Experts Para. 7
Settlement and ADR Para. 8
Stocktake and list of issues Para. 12
Compliance with this practice direction and the protocols Para. 13
Limitation Para. 17
Protocols in force Para. 18
1. Pre-action protocols explain the conduct and set out the steps the court would normally expect parties to take before commencing proceedings for particular types of civil claims. They are approved by the Master of the Rolls and are annexed to the Civil Procedure Rules (CPR). (The current pre-action protocols are listed in paragraph 18.)
2. This Practice Direction applies to disputes where no pre-action protocol approved by the Master of the Rolls applies.A person who knowingly makes a false statement in a pre-action protocol letter or other document prepared in anticipation of legal proceedings may be subject to proceedings for contempt of court.
Objectives of pre-action conduct and protocols
3. Before commencing proceedings, the court will expect the parties to have exchanged sufficient information to—
(a) understand each other's position;
(b) make decisions about how to proceed;
(c) try to settle the issues without proceedings;
(d) consider a form of Alternative Dispute Resolution (ADR) to assist with settlement;
(e) support the efficient management of those proceedings; and
(f) reduce the costs of resolving the dispute.
Proportionality
4. A pre-action protocol or this Practice Direction must not be used by a party as a tactical device to secure an unfair advantage over another party. Only reasonable and proportionate steps should be taken by the parties to identify, narrow and resolve the legal, factual or expert issues.
5. The costs incurred in complying with a pre-action protocol or this Practice Direction should be proportionate (CPR 44.3(5)). Where parties incur disproportionate costs in complying with any pre-action protocol or this Practice Direction, those costs will not be recoverable as part of the costs of the proceedings.
Steps before issuing a claim at court
6. Where there is a relevant pre-action protocol, the parties should comply with that protocol before commencing proceedings. Where there is no relevant pre-action protocol, the parties should exchange correspondence and information to comply with the objectives in paragraph 3, bearing in mind that compliance should be proportionate. The steps will usually include—
(a) the claimant writing to the defendant with concise details of the claim. The letter should include the basis on which the claim is made, a summary of the facts, what the claimant wants from the defendant, and if money, how the amount is calculated;
(b) the defendant responding within a reasonable time - 14 days in a straight forward case and no more than 3 months in a very complex one. The reply should include confirmation as to whether the claim is accepted and, if it is not accepted, the reasons why, together with an explanation as to which facts and parts of the claim are disputed and whether the defendant is making a counterclaim as well as providing details of any counterclaim; and
(c) the parties disclosing key documents relevant to the issues in dispute.
7. Parties should be aware that the court must give permission before expert evidence can be relied upon (see CPR 35.4(1)) and that the court may limit the fees recoverable. Many disputes can be resolved without expert advice or evidence. If it is necessary to obtain expert evidence, particularly in low value claims, the parties should consider using a single expert, jointly instructed by the parties, with the costs shared equally.
Settlement and ADR
8. Litigation should be a last resort. As part of a relevant pre-action protocol or this Practice Direction, the parties should consider whether negotiation or some other form of ADR might enable them to settle their dispute without commencing proceedings.
9. Parties should continue to consider the possibility of reaching a settlement at all times, including after proceedings have been started. Part 36 offers may be made before proceedings are issued.
10. Parties may negotiate to settle a dispute or may use a form of ADR including—
(a) mediation, a third party facilitating a resolution;
(b) arbitration, a third party deciding the dispute;
(c) early neutral evaluation, a third party giving an informed opinion on the dispute; and
(d) Ombudsmen schemes.
(Information on mediation and other forms of ADR is available in the Jackson ADR Handbook (available from Oxford University Press) or at—
https://www.gov.uk/guidance/a-guide-to-civil-mediation
11. If proceedings are issued, the parties may be required by the court to provide evidence that ADR has been considered. A party's silence in response to an invitation to participate or a refusal to participate in ADR might be considered unreasonable by the court and could lead to the court ordering that party to pay additional court costs.
Stocktake and list of issues
12. Where a dispute has not been resolved after the parties have followed a pre-action protocol or this Practice Direction, they should review their respective positions. They should consider the papers and the evidence to see if proceedings can be avoided and at least seek to narrow the issues in dispute before the claimant issues proceedings.
Compliance with this Practice Direction and the Protocols
13. If a dispute proceeds to litigation, the court will expect the parties to have complied with a relevant pre-action protocol or this Practice Direction. The court will take into account non-compliance when giving directions for the management of proceedings (see CPR 3.1(4) to (6)) and when making orders for costs (see CPR 44.3(5)(a)). The court will consider whether all parties have complied in substance with the terms of the relevant pre-action protocol or this Practice Direction and is not likely to be concerned with minor or technical infringements, especially when the matter is urgent (for example an application for an injunction).
14. The court may decide that there has been a failure of compliance when a party has—
(a) not provided sufficient information to enable the objectives in paragraph 3 to be met;
(b) not acted within a time limit set out in a relevant protocol, or within a reasonable period; or
(c) unreasonably refused to use a form of ADR, or failed to respond at all to an invitation to do so.
15. Where there has been non-compliance with a pre-action protocol or this Practice Direction, the court may order that
(a) the parties are relieved of the obligation to comply or further comply with the pre-action protocol or this Practice Direction;
(b) the proceedings are stayed while particular steps are taken to comply with the pre-action protocol or this Practice Direction;
(c) sanctions are to be applied.
16. The court will consider the effect of any non-compliance when deciding whether to impose any sanctions which may include—
(a) an order that the party at fault pays the costs of the proceedings, or part of the costs of the other party or parties;
(b) an order that the party at fault pay those costs on an indemnity basis;
(c) if the party at fault is a claimant who has been awarded a sum of money, an order depriving that party of interest on that sum for a specified period, and/or awarding interest at a lower rate than would otherwise have been awarded;
(d) if the party at fault is a defendant, and the claimant has been awarded a sum of money, an order awarding interest on that sum for a specified period at a higher rate, (not exceeding 10% above base rate), than the rate which would otherwise have been awarded.
17. This Practice Direction and the pre-action protocols do not alter the statutory time limits for starting court proceedings. If a claim is issued after the relevant limitation period has expired, the defendant will be entitled to use that as a defence to the claim. If proceedings are started to comply with the statutory time limit before the parties have followed the procedures in this Practice Direction or the relevant pre-action protocol, the parties should apply to the court for a stay of the proceedings while they so comply.
Protocols in force
18. The table sets out the protocols currently in force and from which date.
Came into force
Personal Injury 6 April 2015
Resolution of Clinical Disputes 6 April 2015
Construction and Engineering 9 November 2016 2nd Edition
Defamation 02 October 2000
Professional Negligence 16 July 2000
Judicial Review 6 April 2015
Disease and Illness 8 December 2003
Housing Disrepair 6 April 2015
Possession Claims by Social Landlords 6 April 2015
Possession Claims for Mortgage Arrears 6 April 2015
Dilapidation of Commercial Property 1 January 2012
Low Value Personal Injury Road Traffic Accident Claims 30 April 2010 extended from 31 July 2013
Low Value Personal Injury Employers' and Public Liability Claims 31 July 2013
Updated: Thursday, 19 August 2021
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Discussion in 'Gear & Equipment Discussion' started by Markovich, Dec 15, 2012.
I was thinking about buying some Twins gloves for my next purchase. I'm interested in the dark green color, but it seems the muay thai fighting website doesn't have it, nor does muay thai stuff. The only place that seems to have it, is the official Twins Special site. I may have missed something. You guys know anywhere else to get some dark green Twins gloves? I am not gonna buy the bright green ones, to bright for me, plus its not the right shade of green I like.
Have you tried sending muay thai fighting an email to confirm which green they have in stock.
Haven't done that, but I would assume what the depict in the site is what they actually have.
Shoot them an email, sometimes they miss to update colours especially if they're relatively new. Before, their Fairtex BGV1(BR) didn't have a yellow option and so I emailed them. They double checked with factory and have since updated.
Agreed. MuayThaiFighting always updates their products and gets everything straight from the factory if it's not in stock. I did the same thing when I saw that Fairtex released these new Superior Curved Thai Pads (KPLS2). I sent an email asking if they could make a special order for me and they shortly listed the item on their site apologizing for the delay in updating.
Give it a shot! It's worth a try.
I got a pair from MMAHQ, maybe MAS sells them?


When you join CCJR-NH you support the important work that we do and we keep you updated with newsletters and emails. You will also receive Action Alerts and updates on pending legislation and CCJR-NH campaigns on the local and national level.
When we receive your membership information we will mail you a welcome letter with an official Membership Card as shown below, and a CCJR brochure for you to share with someone else. (Members receive all mailings and newsletters).
With almost 500 members it is an overwhelming task to contact each and every member on their annual renewal date. To simplify the membership fee system the board voted on March 28, 2017 to implement a new policy. We are asking every member "to submit their annual membership fee between January 1st and March 31st in order to maintain active member status. Please take care of this as soon as possible.
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Banner week for SFist as the site's new editor introduced himself — hooray for Brock! While the NY Times weighed in on SF's mayoral race, only SFist had the (insert tongue firmly into cheek) hard-hitting latest on candidate/activist Josh Wolf. Coverage of a protest vs. gentrification spawned a fantastic debate amongst SFist's readers. Finally, from the sublime to the ridiculous: video of a man that confused a Board of Supes meeting with "open mic night" and sang a custom version of Madonna's "Borderline" to a much-beleaguered board member.
Phillyist has had a busy week, looking for power outlets while liveblogging the First Annual Blog Philadelphia "unconference." (Here's day 1 and day 2 of their coverage, and a video from the event.) They also interviewed Chris Funk of the Decemberists (since those guys are in town this weekend to play with a local orchestra), reviewed that little indie film about the wizard child, and helped out with tips on how to act if you run into that annoying ex of yours. Finally, they warned the suburbs to Beware of the Blob!
For LAist, it was a week of new beginnings. Soccer Star, David Beckham, made his official move to Los Angeles just in time for LAist's Neighborhood Project, which will cover the 170+ neighborhoods in the city. They interviewed the Los Angeles Fire Department and found that they may be the most Web 2.0 savvy government office in the world. In other government fun, a bill in the state senate is being pushed through to ensure that a particular person remains in office indefinitely. Speaking of things that remain forever, you have probably seen TV shows and movies that were shot at the rickety-almost-alling-over Lacy Street Studios.
You might have Duck Tours in your city by now, Bostonist has been watching them roll the streets and rivers for years – now there are two, and a court case. A couple weeks ago news came out that former governor, now presidential hopeful Mitt Romney strapped his dog to the roof on family vacations, now blogs have gone to the dogs. A new name for a subway stop has Bostonist coming up with their own suggestions. They said goodbye to a beloved by some, hated by others, personality. Oh, and, as usual in Boston, Sox fans believe.
Torontoist had a busy week yet again. They investigated some monkey business (literally) in its east end; dissed the Blue Jays, much to a mother's chagrin; invited its users to call a lonely Irish woman; and hooked its readers up with some great coverage of their local Fringe Festival. They realized that karaoke maybe isn't all that great, dissed their city's most brutal example of Brutalism and covered the Polaris Prize shortlist announcement. They explored their city's downtown walkways and wondered about the future of their transit system's signage. It wasn't all shiny happy people holding hands, however: this week, they had to bid farewell to a local legend, "Honest Ed" Mirvish.
For Gothamist, the week started off on a sad note, as two police officers were shot during a traffic stop; the suspected shooters were all captured by the end of the week. Readers debated over whether a large flag should still hang in Grand Central Terminal as Brooklyn's Park Slope neighborhood was examined for its child friendliness while the trend of "New Victorian" living was alarmingly noted. There was excitement over seeing dragon fruit at stores and sharing – not stealing – bikes. Finally, Miss NJ's "racy" photographs were totally hilarious, but ultimately pretty tame.
gin-flavoured, terribly exciting Olympics. Butlers across the city have been pressing tweed suits and tennis flannels all week.
DCist was busy throwing their biggest Unbuckled concert yet, featuring rising local band Le Loup, but they still made time to find out what's up with the scaffolding around the Statue of Freedom on top of the Capitol Dome, wonder why anyone would want to swim in the Potomac river, and indulge in the latest D.C. Madam scandal revelations.
Also read some more posts from Austinist, Chicaogist, Houstonist, Seattlest, Shanghaiist, and Sampaist.


Are you moving to another country and don't know to whom you should entrust the shipment of your dogs? Are you worried about the journey and want to make sure that it is taken care of with the maximum comfort and peace of mind?
Bliss Pet Services has the right service for you!
Since we are aware of the strong relationship existing between a person and his/her four-legged friend, we handle the shipment of dogs in Europe and worldwide with the maximum care, ensuring reliable and qualified services.
The fact that we are driven by a mission aimed at ensuring the welfare and safety of our furry friends, we operate in full compliance with the regulations of the destination countries and deal with all the technical, bureaucratic and health care aspects required for the shipment of your dog abroad, in order to make sure it arrives safely.
The regulations governing air transport and medical prophylaxis required for the shipment of a dog abroad may vary from country to country.
In such a complex and diversified bureaucratic viewpoint, Bliss Pet Services is an ideal partner for the organization of the trip and to carry out the procedure for the completion and production of certificates and documents.
Thanks to qualified experts in this field, who share the love for animals, we will provide all the assistance and advice you may need for the transportation of your dog into another country.
Shipping a dog overseas through a serious and reliable agency as Bliss Pets Services is a guarantee of thorough and qualified services mainly focused on the safety of the animal and, consequently, on reassuring its owner.
In addition to the air transfer and the supply of approved pet kennels, we offer hospitality services and accommodation at the destination countries through affiliated animal homes, carefully selected among IPATA members based on strict quality parameters.
Like every dog mom, the prospect of moving home from our overseas station in Naples, Italy was beyond stressful. To add to that, my dog Baron is a giant breed and the recent increase in restrictions made it nearly impossible for me to find the right crate and an airline that would accept him. After reading some reviews I decided to go with Bliss. I had them build a custom crate and plan Baron's itinerary in conjunction with my flight home. While I wanted to fly with Baron, it wasn't possible because the only airline that would accept him for our itinerary was Lufthansa (which I was happy about), and this required an overnight stay at the Animal Lounge in Frankfurt (cue more dog mom stress!) Bliss (specifically Annamaria who managed Baron's move) was unbelievably patient with my 1 million questions, my stress from reading negative reviews of the animal lounge (which are by far the exception, not the norm) and my panic in the days before our departure.
Never once did she make me feel poorly for asking questions and she was extremely timely in her responses. Fast forward to the day of travel, we met with our Bliss travel representative at the Cargo City in Rome. Baron's crate fit perfectly and was very well constructed. He was treated with kindness and care.
Annamaria texted me updates on Baron's status every step of the way and aside from the expected anxiety, my fears and concerned were managed. Fast forward to picking Baron up, while he was a bit shaken he still happily greeted his sister Luna (who is small enough to fly with us) and was back to himself the next day. Baron seems happy, healthy and excited to be back stateside, and so am I. Thank you Bliss!!
What are you waiting for?Bliss Pets is your right partner!
Choose the best for your pet, choose Bliss!


text:
Cognitive technologies: The real opportunities for business
David Schatsky, Deloitte University Press
Artificial intelligence (AI) may sound like science fiction, but it is real, and becoming increasingly important to companies in every sector. The field of artificial intelligence has produced a wide variety of "cognitive technologies" that simulate human reasoning and perceptual skills, giving businesses entirely new capabilities and enabling organizations to break prevailing tradeoffs between speed, cost, and quality.
Aimed at a general business audience, this course demystifies artificial intelligence, provides an overview of a wide range of cognitive technologies, and offers a framework to help you understand their business implications. Some experts have called artificial intelligence "more important than anything since the industrial revolution." That makes this course essential for professionals working in business, operations, strategy, IT, and other disciplines. Throughout the course, participants will build a knowledge base on cognitive technologies to equip them to engage in discussions with colleagues, customers, and suppliers and help them shape cognitive technology strategy in their organization.
During the course, participants will learn from leading thinkers in the field including Professor Eric Nyberg, Professor and Director, Master's Program in Computational Data Science in the School of Computer Science at Carnegie Mellon University, and Professor Tom Davenport, President's Distinguished Professor of Information Technology and Management at Babson College, a Fellow of the MIT Center for Digital Business, and senior advisor to Deloitte Analytics. They will help address the questions:
What is artificial intelligence, and how did the field attain the importance it has today?
What are cognitive technologies? Dig below the surface and gain a basic understanding of the technologies that simulate language understanding, seeing, and reasoning.
How will cognitive technologies impact my business? Explore the types of applications that cognitive technologies may be suited for, and discover a framework that can help you conceptualize whether and where you might deploy them in your organization.
What is the impact of cognitive technologies on work? Cut through the hype and understand what leaders and workers need to know now to prepare for the changes these technologies will bring to work, workers, and organizations.
What does the future hold for cognitive technologies? David, Eric and Tom discuss the technological, legal and ethical factors that may influence the evolution and further adoption of cognitive technologies.
Check out course highlights »
David Schatsky
Deloitte University Press publishes original articles, reports and periodicals that provide insights for businesses, the public sector and NGOs. Our goal is to draw upon research and experience from throughout our professional services organization, and that of coauthors in academia and business, to advance the conversation on a broad spectrum of topics of interest to executives and government leaders.
Deloitte University Press is an imprint of Deloitte Development LLC.
The Course Artificial intelligence (AI) may sound like science fiction, but...
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Signalling poetry in Morse code from the top floor executive suite of the Hilton Liverpool. Looking over the docks, the torchlight makes the hotel into a poetry lighthouse.
The poem speaks from the top floor to a poem I buried three metres under the hotel entrance after a storm a year ago. Looking across the river to Bidston Observatory, the three points make a poetry triangulation inspired by mountain triangulation used in early mountain range measurements and trig points.
Using the room in change over times between one set of guests leaving and the next set checking in, I inhabit the space in an unseen and unregistered parallel universe. Partly inspired by Haruki Murakami's Sheep Man, a shamanic character who inhabits a hidden floor in the Dolphin Hotel.
The torchlight makes the hotel into a huge sculpture, a lighthouse of poetry using a slight and temporary gesture.


The Expert Panel on Acute and Critical Care focuses on informing health policy and practices related to acute and critical care. Goals are achieved by the creation and dissemination of knowledge related to the practice and care of acute or critically ill patients, their health care environment, and treatment processes.
Policy Brief: Admit to observation. Nursing Outlook 64 (November/December 2016) 604-606.
Policy Brief: Reconsideration of do not resuscitate orders in the surgical/procedural setting. Nursing Outlook 63 (May 2015) 370-373.
Policy Brief: Improving health and health care systems with advanced practice registered nurse practice in acute and critical care settings. Nursing Outlook 62 (September 2014) 366-370.
The Acute and Critical Care Expert Panel was established to inform health policy and influence relevant issues related to acute and critical care. Members of the panel have diverse areas of expertise to provide leadership and expert opinion on a variety of issues. The panel facilitates networking, and fosters research and scholarship among members. It also promotes exchange of information and ideas with other nursing and professional groups. Opportunities for future projects include integration of technology into practice to promote quality and safety, identification of care delivery models that incorporate and maximize the advanced practice nurse role, and addressing futile and/or palliative care issues as they relate to care of the acute or critically ill patient.
How do I join an Expert Panel?
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