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Back to Journals » Neuropsychiatric Disease and Treatment » Volume 11
Neurobehavioral burden of multiple sclerosis with nanotheranostics
Authors Sriramoju B, Kanwar R, Kanwar J
Received 12 February 2015
Accepted for publication 9 March 2015
Published 15 October 2015 Volume 2015:11 Pages 2675—2689
DOI https://doi.org/10.2147/NDT.S82768
Editor who approved publication: Dr Roger Pinder
Bhasker Sriramoju, Rupinder K Kanwar, Jagat R Kanwar
Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research (NLIMBR), School of Medicine, Molecular and Medical Research, Faculty of Health, Deakin University, VIC, Australia
Abstract: Multiple sclerosis (MS) is a chronic demyelinating neurological disorder affecting people worldwide; women are affected more than men. MS results in serious neurological deficits along with behavioral compromise, the mechanisms of which still remain unclear. Behavioral disturbances such as depression, anxiety, cognitive impairment, psychosis, euphoria, sleep disturbances, and fatigue affect the quality of life in MS patients. Among these, depression and psychosis are more common than any other neurological disorders. In addition, depression is associated with other comorbidities. Although anxiety is often misdiagnosed in MS patients, it can induce suicidal ideation if it coexists with depression. An interrelation between sleep abnormalities and fatigue is also reported among MS patients. In addition, therapeutics for MS is always a challenge because of the presence of the blood–brain barrier, adding to the lack of detailed understanding of the disease pathology. In this review, we tried to summarize various behavioral pathologies and their association with MS, followed by its conventional treatment and nanotheranostics.
Keywords: demyelination, behavioral disorders, behavioral tests
Multiple sclerosis (MS) is a chronic neurological autoimmune disease characterized by erosions of myelin, the protective nerve sheath, with a partial preservation or complete loss of axonal activity and nerve transmission.1 However, remyelination is often possible once inflammation subsides and is mediated by oligodendrocytes, which secrete myelin. Remyelination process can be explained as the phenomenon of newer myelin sheath formation around the damaged axons. It is better explained as more the number of oligodendrocytes around the affected neurons, the faster the process of remyeliantion. Inadequate number of oligodendrocytes may lead to improper or no myelin formation, resulting in abnormal neuronal functioning.2 MS has affected more than 1 million people worldwide. The symptoms of MS are weakness, loss of senses, shuffling gait, loss of vision, and cognition.3,4 The main driving force involved in the pathology of MS is inflammation, which enhances autoreactivity, followed by demyelination and neuronal damage.5 Histopathological studies have also confirmed multicentered inflammatory lesions, which spread throughout the brain and spinal cord.6 Autoreactive T-cells are the key players involved in disease generation, breaking down the margin of autoreactivity and self-tolerance, and multiple etiological factors are responsible for this activation. The existence of autoreactive T-cells is evident in both normal and MS patients, but they turn active and seem to be devastating only in MS.7 Among all the T-cell clones, CD8 subtype is found to be more associated with the disease, both in number and infiltration when assessed in the brain and spinal cord. CD8 T-cells were also found to be persistent in blood and cerebrospinal fluid (CSF), implying the fact that they were activated consistently by an antigen driving the long-lasting autoimmune reactivity.8
In brief, a group of activated T-cell subclones specific to the myelin protein will penetrate the blood–brain barrier (BBB), being potentiated by the existing inflammatory cytokines, while the resting T-cells have a restricted access to the BBB.9 The coupling of T-cell surface molecules – integrins, selectins, and cadherins – with the corresponding adhesion molecules present in brain capillary endothelial cells facilitates the entry of T-cells. Once the T-cells gain entry, they unleash the autoimmune reactions targeting the myelin antigen. The activation of antibody-producing B-cells further enhances this autoreactivity, thus driving the degeneration of neurons.10 Figure 1 shows MS pathogenesis. Symptom severity, disability levels, and rate of disease progression vary with each individual and even differs in the same patient with time.11 Significant sex differences were identified among MS patients, with a majority of females displaying the symptoms compared to males.
Figure 1 Pathogenesis of MS.
Notes: Lymphocytes activated due to various insults (inflammation, antigen presentation, free radicals, etc) will invade the blood–brain barrier. Initially, they bind with the cell adhesion molecules present on the capillary endothelium and gain access into the brain. Once inside, the reactive cells attract both the immune cell traffic (T- and B-cells) and mediate the devastating cascade. Cytotoxic T-cells release granzymes, and activated B-cells produce antibodies against the myelin sheath, thus mediating the demyelination process.
Abbreviations: MS, multiple sclerosis; Abs, antibodies.
Also, MS was found to affect women at an early age (18–30 years), while it affected men at a later stage of life (30–40 years). These dissimilarities were possibly due to the protective effects of testosterone in men. Another interesting aspect observed in MS was the cessation of disease symptoms in pregnant women who were in the third trimester. The elevated levels of estriol were anticipated to be responsible for the protective effect, and the same was observed in mice models as well.12 The introduction of biomarkers has revolutionized the understanding of the disease pathology and its diagnostics. Some of the recent advancements are the discovery of elevated levels of astrocyte and axonal cytoskeletal proteins, namely, glial fibrillary acidic protein and neurofilament light protein in the CSF corresponding to MS progression.13
The elevated levels of the 14-3-3 protein in the CSF corresponded to the disease progression and disability, while a close correlation was established with the downregulation of cystatin-C, a protease inhibitor that neutralizes the actions of lysosomal cathepsins modulating lymphocytic activation.14 Some other recently found potential biomarkers associated with the disease are osteopontin and pentosidine.15,16 Based on the symptoms, MS is categorized into four subtypes. Patients with relapsing remitting form recover with no symptoms following disease onset. Patients with persistent disability symptoms between the cycles of relapses and recoveries are termed as "secondary-progressive" patients. "Primary-progressive" MS is characterized by symptoms of only progression, but no signs of remission. In "progressive-relapsing" MS, patients display severe symptoms and attacks during the period of remission.17
MS is not only associated with neurological symptoms but also with a variety of behavioral disturbances such as depression, anxiety, cognitive loss, psychosis, euphoria, sleep disturbances, and fatigue. The impact of these psychological disturbances is such that MS at times is misdiagnosed, supposing it to be a behavioral disorder. In patients with MS, depression is the most common behavioral disorder followed by psychosis.18,19 The disease profession is highly variable with a majority of the neurological compromise following the relapses. In particular, RRMS is a critical subtype that always follows a prolonged deterioration and poses a serious threat of progressive disability. The symptoms of depression and anxiety are very common during the early course of the disease, though the correlation is poor toward the lesional load.
Cognitive impairment is often seen as a forerunner of MS, presenting the symptoms of hampered levels of memory, attention, and execution. According to magnetic resonance imaging (MRI) studies, the severity of cognition loss is relative to the cerebral white matter lesions associated with MS progression. Correlations also exist between the white matter lesions and the onset of psychosis, which is seldom seen in MS.20 Hence, early identification of these behavioral abnormalities would certainly help in diagnosing the onset of MS and can be invaluable for the disease management. Behavioral disorders and their association with MS are described as follows:
Depression and MS
Depression is the most common behavioral disorder prevailing among MS patients. The frequency of occurrence and tendency to develop depressive symptoms were higher in patients with MS compared to patients with other chronic neurological disorders. However, depression often remains undiagnosed and untreated in MS patients. Several factors related to genetics, psychology, immunology, and inflammation have a role in mediating the depressive pathology in MS. The higher prevalence of depression in MS could possibly be explained as: both depression and MS are central nervous system disorders and share multiple etiological factors in their pathophysiology. Also, elevated levels of proinflammatory cytokines and imbalances in monoaminergic neurotransmitter metabolism observed in MS were also reflected in depression.21 Likewise, a study reported genetic influence,22 while a brain MRI study showed the evidence of inflammatory markers in the lesions and pleocytosis in the CSF.
The symptoms of depression were found to be associated with the lesions seen in the arcuate fasciculus23 and medial orbitofrontal regions. They were also associated with poor perfusion rate in the left cerebral hemisphere, while in the right cerebral hemisphere, the frontal lesion load and temporal brain volume were involved.24
Similarities between MS and depression
There are some similarities between the pathologies of MS and depression. The lesions in arcuate fasciculus were found to detach few regions of the cerebral cortex. The lesions were evident in the frontotemporal region, while inflammation had an influence on the hypothalamic endocrine functioning, corroborating the coexistence of depression in MS compared to other neurological disorders.25 The symptoms of depression are not closely related to disease severity and its progression, but they are more prevalent during the relapses and in increased neurological disability.20 Though much progress has been made in identifying the depressive pathological origins, their specificity still remains as a question. When observed in a group of RRMS patients with depression, the proinflammatory cytokine interferon (IFN)-γ was excessively produced and was associated with symptom severity. However, when treated with antidepressive medication, the levels of IFN-γ were lowered, explaining its possible role in depressive pathology.26 Similarly, a case-controlled study observed exacerbations of depression in MS patients undergoing treatment with IFN-β.27 A few studies reported contradictory results revealing the uncertainty of MS medication-induced depression.28–31 The major consideration of depression in MS is that it is associated with other behavioral disturbances such as disturbed cognition. Depression may aggravate cognitive dysfunction, which may induce depression, thus worsening the quality of life in all aspects.32
Observations by Alajbegovic et al33 revealed some interesting results. They found that depression was common among the MS population studied, with a majority of them being young, educated, unemployed, and single.33 A longitudinal study also confirmed that the depression associated with MS is chronic and is usually episodic.34 Finally, the most interesting concept to understand is depression and its association with MS relapses. Though there are no substantiating data to support this issue, it definitely seems to pose a fascinating question to be answered. In summary, depression stands as the major behavioral disorder observed in MS, with a potential of aggravating other behavioral abnormalities. Hence, diagnosis and treatment of depression in MS will significantly improve the quality of life in patients.
Cognition and MS
Cognitive disturbances have been reported in 40%–60% of people with MS. Common manifestations include defects in recent memory and impaired attention, analyzing, visuospatial perception, and executional activities.35 Impairment of cognition can be a potential indicator for the demyelination process36 and is more common and severe in the progressive form of the disease rather than the relapses.37 The results of the study conducted by Deloire et al38 also hypothesized the symptoms of cognitive impairment as a forerunner for MS disability, which follows several years later. The precise pathology of cognitive disturbances in MS has not been identified, but inflammatory lesions, regional degeneration, and repetitive black holes somehow relate them to MS pathology.38
It has been previously reported that inflammatory cytokines tend to cause cognitive disturbances, and the association of MS with inflammation indicates the role of cytokines in correlating MS pathology with that of cognitive impairment.39 Loss of gray matter is quiet common among MS patients, and this also leads to the loss of cognitive function. Also, disruptions of the cerebral cortex regions and the thalamus strongly associate memory impairment with that of MS pathology.
Causes of cognitive imbalance in MS
Old age, male sex, ApoE, the gene encoding for apolipoprotein E, and variations in brain-derived neurotrophic factor were evaluated as major risk factors associated with cognitive impairment among MS patients.40 Some studies reported disability of recognizing emotions in MS patients, which were elusive, and associated it with memory impairment,41 while some other studies correlated disability of emotion recognition and perception of behavioral aspects and quality of life.42 Functional MRI studies have also proved that noticeable differences exist between MS patients and controls in emotion recognition, highlighting the point of disturbed brain function and cognition.43–45 Other manifestations that tend to associate disturbed cognition with MS include fatigue and depression, which are more common in MS than in any other neurological diseases. These symptoms are correlated in MS, assuming that they share some commonness in pathology.46 Also, the levels of fatigue and depression were noticeably high in cognitively impaired MS patients and were evident from the measures of attention and memory, respectively.47 Clinically, an interesting question regarding the correlation between depression and cognition loss arises: would the treatment for depression in MS alleviate memory impairment?
Currently, no data are available, but in traumatic brain injury, patients have displayed improved cognition when treated for depression.48 Other factors that have a correlation toward MS pathology and impaired cognition include dysregulation of the hypothalamopitutary–adrenal axis49 and hypercortisolemia. Corticosteroids administered for MS treatment were found to worsen memory, particularly in the relapsing–remitting form of the disease.50
Biomarker measurement
Though modest in correlating cognitive impairment in MS with MRI markers, MRI has been invaluable in the diagnosis of cognitive impairment. The identified MRI markers are T2 and T1 lesional loads, with the former showing a limited correlation, while the latter better related brain atrophy with cognitive loss.20 Also, MS patients showed cholinergic imbalances; hence, measuring the levels of choline acetyltransferase and acetylcholinesterase will be ideal for managing cognitive impairment.51 In conclusion, cognitive loss is identified as an important symptom of MS that is found to significantly hamper daily activities, inclusive of social and emotional functionings. Though the exact pathology remains unclear, the inflammatory and degenerative processes observed in MS can be the major contributors of cognition impairment with a higher impact on executive functions.
Anxiety in MS
Though not much studied in MS patients, anxiety cannot be ignored as it can be an important contributor to disability in them. As per published data, many MS patients exhibit the symptoms of anxiety; in some cases, it is more frequent than depression.52,53
Comparatively, the symptoms of anxiety are more prevalent in MS patients than in controls, and risk factors include female sex, lack of caring, coexisting depression, and ignorance of anxiety symptoms.54 Animal studies have also found the association of inflammation, which is default in MS pathology, and anxiety underlying the probable occurrence of anxious symptoms in MS.21 Anxiety among MS patients needs strict medical attention as it was found to disrupt executive functioning. Intriguingly, cognition was severely affected than when compared to depression among the patient population studied.55 Depression and anxiety run together in a few MS patients and importance should be given to anxiety as it may enhance suicidal tendencies in these patients compared to patients exhibiting little or no anxiety.52 A cross-sectional study also observed symptoms of depression and anxiety occurring twice and thrice, respectively, among MS patients with no sex indifference for depression, while anxiety was reported more in males.56 Another interesting feature reported was that some patients presented the symptoms of anxiety well before the diagnosis of MS.57,58 Considering the predominance of anxious symptoms among MS patients, attempts had been made to identify the connection of exact brain regions involved in this pathology. But still it has not been fruitful as correlation between anxious symptoms and brain MRI scans lacked correlation.24 The impact of anxiety in different forms of the disease was studied and contradictory results were observed. Some studies had reported that relapses in RRMS were more often associated with anxiety and disclosed higher levels of anxious symptoms,59 whereas studies by Noy et al53 and Brown et al60 reported the association of anxiety and relapses to be rather conflicting.
The advent of self-administered immunomodulatory drugs for MS has led to the induction of anxiety named "self-injection anxiety" and was reported to affect almost half of the MS population following this practice.61 Clinical studies have also revealed an increased prevalence of anxiety among the MS patients adding an interesting finding towards the MS associated behavioural compromise. Patients who were included in the study did not show severe neurological compromise but were certainly distressed as they were unable to cope up with the disease and get relief. Other reasons for developing anxiety were anticipated to be strong fear of developing personal and professional lagging, as the patients were emotionally preoccupied and compromised for a complete cure.62 In summary, it is quiet natural that people are concerned with health and become anxious, particularly, if affected with a chronic disease or a disease with no cure at all. Thus, MS, being a chronic disorder with incomplete cure, poses the symptoms of anxiety. The question to be answered in this scenario is to identify the pathologies that are common to MS and anxiety and to target them specifically.
Psychosis and its association with MS
Psychosis and MS share a common pathophysiology and the symptoms are displayed due to regional demyelination during the disease progression. The association was also exacerbated due to the medications for MS. IFN-β administered to lower autoimmunity in MS produced psychotic symptoms, while a reduction in these symptoms was noticed on administration of antipsychotic medication.63 Brain MRI has also not shown any significant changes pre- and post-IFN treatment, strengthening the fact of medication-induced psychosis.64
In a group of comparative studies among MS patients with psychosis and those devoid of psychosis, lesions were found to be more prominent in the MS psychotic patients than in those without psychosis.65,66 These lesions were more specific to the periventricular white matter of the temporal horn regions, and many studies have also associated psychotic symptoms in MS with lesions, substantiating the role of regional demyelination in the pathology of MS psychosis.67,68 There are also studies focusing on the involvement of other brain regions such as temporal, frontotemporal, and temporoparietal lesions, associating psychic symptoms in MS patients69,70 with temporal and frontotemporal and temporoparietal abnormalities.71 There is a growing interest to explore the exact relation between psychosis and MS pathology, as several large-scale studies have also pointed out the coexistence of them. It poses a serious challenge in terms of both treatment and diagnosis when these pathologies run together.72,73 Clinicians have also highlighted the point that psychic patients who do not respond to standard antipsychotic regimen should be diagnosed for the underlying MS pathology. Hence, preferably, MS needs differential diagnosis both for effective therapeutic outcome and ruling out psychotic symptoms.74,75
Euphoria affects approximately 10% of the MS population and is best described as the phase of cheerfulness without displaying the symptoms of motor hyperactivity. It is related to the frontal lobe pathology, which is common in several other personality disorders, along with the involvement of brainstem, pontine, and periventricular lesions. Interesting correlation was drawn from a study where the association of euphoric symptoms in MS was related to severe cognitive disturbances rather than to disease exacerbations, indicating extensive brain pathology.
This study also concluded that euphoric symptoms are predisposed regardless of the sex and are mostly associated with the progressive form of MS and its severity.76
Sleep and fatigue
As MS is associated with behavioral symptoms, it strongly influences sleep patterns and the associated disturbances. Sleep disturbances in MS patients were related to the degenerated regions involving the basal ganglia, thalamus, and limbic system.77 It has been reported that a majority of the MS patients display symptoms of insomnia, narcolepsy, sleep-related breathing abnormalities, and rapid eye movement sleep behavior disorder, thus significantly influencing quality of life.78,79 Clinical studies also revealed sleep disturbances in terms of onset and duration of sleep among MS patients.80
Fatigue in MS
The other major manifestation of MS is the perception of fatigue, and multiple factors are involved in its origin, which include elevated body temperature and cytokine levels, hyperactive hypothalamic–pituitary–adrenal axis, and some medications for associated disorders like depression and spasticity.78,81,82 Though fatigue is quiet common among MS patients, it is incompletely understood. However, two subtypes of fatigue have been reported. These are motor fatigue, which develops due to excess muscular stress, and mental fatigue, which develops due to the intense level of tiresomeness. The etiology of fatigue overlaps with that of other associated disorders and hence can be considered as both primary fatigue, which is purely associated with MS, and secondary fatigue, which is related to the comorbidity.
The symptoms of fatigue mainly arise due to neuronal demyelination, which severely hampers neurotransmission. In the recent past, fatigue in MS had been related to parietotemporal and frontal region lesions.83 Neurotransmitter imbalances, excessive muscular stress, lesions in other brain regions, coexisting disturbances, and medications for MS are other possibilities of fatigue generation.84
Sleep–fatigue correlation
Interesting correlations also exist between symptoms of sleep disturbances and fatigue in MS patients. A comparative study of healthy controls and MS patients concluded that sleep abnormalities were common among MS patients and showed a strong correlation with fatigue. However, this correlation was not observed in the healthy controls.85 Altogether, a precise relationship has not been established between sleep and fatigue; the published data suggest an interrelation between them. Thus, sleep disturbances and fatigue either independently or collectively influence the quality of life in MS patients. The association of pathology of all the behavioral disorders with that of MS is shown in Table 1.
Table 1 Association of MS with behavioral disorders
Abbreviations: MS, multiple sclerosis; -, not reported.
Behavioral screening studies for MS
Although several animal models exist for studying behavioral changes in MS, the experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein is the most widely accepted mouse model that mimics MS in humans.86 As MS is associated with several behavioral abnormalities, animal models serve as extremely useful tools for assessing and developing novel therapeutic approaches. For example, analyzing the locomotor activities in these animal models provide useful information on the involvement of specific pathologies. A brief introduction of them is as follows:
Open field test
This test screens for spontaneous locomotor activity. In this test, animals are allowed to move and explore freely in an enclosed square area while being monitored for their locomotor activity.21
Grid walk test
This test provides valuable information on the formation of lesions in the dorsal column and descending motor control abnormalities by analyzing an animal's ability to place its hindlimbs on bars. Animals are trained to walk on a runway consisting of bars placed at an elevation of 1 m above the ground. Comparatively, the number of falls were higher in the MS-induced animals than in the controls when they tried placing their hindlimbs firmly on the bars.87 Other tests for assessing locomotor activities include BBB open field locomotion score and narrow beam test.88
Rota rod analysis
This is the highly accepted test for assessing forced motor moments in rodents. Initially, animals are trained on a rotating rod at a speed of 4–40 rotations per minute and then the grip strength is analyzed by observing the animals' latency fall from the rotating rod.86
Learned helplessness paradigm
This test mainly aims at studying the depressive episodes in animal models conducted in a customized shuttle box equipped with a shock generator and the software for controlling, processing, and recording. Initially, the animal is conditioned with a phase of inescapable foot shocks and then placed in a testing chamber, from where it can escape to a shock-free chamber.
After sufficient training, the animal is subjected to the same escapable foot shocks, but this time, a light stimulus strikes before the shock is applied. The ability of the animal to avoid the shock with each light stimulus and to escape into the shock-free chamber is tested. If the animal fails to do so, it is assumed as learned helplessness behavior.89
Light/dark box
The light/dark box model measures anxiousness. In this model, animals (mice) are placed in a light and dark compartment, and exploratory behavior is monitored. The analysis is done based on the length of time spent by the animals and number of crossings they make into the lighted compartment, assuming these activities to be reflective of anxious behavior.21 A summary of behavioral screening in MS is shown in Figure 2.
Figure 2 MS and its associated behavioral tests.
Notes: MS is associated with several behavioral abnormalities, and the studies of these disorders involve the development of animal models mimicking them. These behavioral tests can serve as useful tools for evaluating and developing effective therapeutics against common behavioral disorders in MS.
Abbreviation: MS, multiple sclerosis.
MS therapeutics and applications of nanotechnology
The strategic treatment for MS is mainly concerned to alleviate its symptoms and associated disease progression. The first-line drugs considered for the treatment of MS are IFNs, particularly type 1 and include IFN-β1a and IFN-β1b, along with glatiramer acetate. Their mechanism is mainly targeted against the reactive T-cell activity with a strong inhibition of T-cell proliferation, migration, and antigen presentation.90 Interesting outcomes were seen when the first-line drugs were combined with a natural metabolite, methyl thioadenosine, that possessed potent immunomodulatory activity preclinically.91 Corticosteroids with a mechanistic activity of immune suppression were also effective against MS and its progression. Dexamethasone, prednisone, prednisolone, and methylprednisolone are some of the corticosteroids used to treat MS. However, indiscriminate and long-term use of these drugs is strictly discouraged on account of their severe side effects.92
Chemotherapeutics like cyclophosphamide and mitoxantrone with a background history of immune suppression were found to be efficacious in treating MS. With respect to the mechanism of action, cyclophosphamide showed activity against T and B lymphocytes, while mitoxantrone was found to be cytotoxic.93,94
Monoclonal antibodies (mAbs) have made significant contributions toward MS therapeutics. For instance, natalizumab, a humanized mAb, when tried in a patient population resulted in significant reduction in disease recurrence with an action against α-integrins (cell surface molecules essential for T-cell binding and entry). However, long-term use poses the risk of progressive multifocal leukoencephalopathy. mAbs under evaluation include alemtuzumab (Campath) and rituximab, which were observed to have a potential activity against the expression of CD52 and CD20 on leucocytes. When administered to a patient population, they resulted in a considerable reduction in the levels of inflammatory monocytes, lymphocytes, and dendritic cells.95,96 Daclizumab is a humanized mAb that acts against CD25 expression, thereby limiting the proliferation of reactive T-cell. This drug has recently finished its Phase II trial.97
Drug trials
The drug in trials with a prime motto of ameliorating disease progression and severity is the oral formulation BG00012. Its active principle is fumarate. It has the characteristic mechanisms of neuroprotection, relieving inflammatory cascade and oxidative stress.
Fingolimod is one of the class of MS therapeutics with an activity of lymphocyte complexatoin. BG00012 is in Phase II clinical trials,98 and fingolimod has recently received approval for human use.99 Firategrast, an antagonist for the very late antigen-4 (a cell adhesion molecule expressed on brain capillary cells) has finished its Phase II clinical trial and acts by inhibiting the entry of T-lymphocytes into the BBB. Laquinimod and teriflunomide are the representatives for drugs in Phase III trials, and their mechanisms include the immune response shift toward Th2 type and inhibition of lymphocytic expansion.16,100 A proprietary recombinant human IFN-β1b (NU 100) and an extended-release polyethylene glycol coated IFN-β1a (BII-B017) are in Phase III trials for the treatment of RRMS.101
Applications of nanotechnology
Nanotechnology has always been fascinating as it deals with ultrasmall particles with a dimension range of 1–100 nm. Specific advantages attributed to these nanoparticles (NPs) considering their size and durability are that they offer huge surface area, improving bioavailability and absorption, and enhanced physicochemical stability of theranostics (therapeutic + diagnostics). A unique feature of this technology is that NPs can be tailor-made for specific targets, thus nullifying unwanted biodistribution and achieving the maximum efficacy at a reduced drug dose.91 The same application would also benefit drug permeation through the complex BBB, which is viewed as a major hurdle for conventional drugs to pass through. When applied, this technology would certainly benefit the nervous system, promoting the viability and integrity of neurons that have a limited regenerative capacity. Hence, nanotechnology holds a strong future potential for theranostic applications against a variety of neurological disorders and thus overcome the limitations of existing therapeutics. The following is a brief description of NP application in MS. It is evident that matrix metallopeptidase-9 (MMP-9) plays a pivotal role in disrupting the BBB, thereby attracting peripheral T-cells and thus initiating the neuroinflammation cascade. A study has shown that the quantum dot complexed with MMP-9–small interfering RNA (nanoplex) has significantly blocked the expression of MMP-9 in brain microvascular endothelial cells and leukocytes. In addition, upregulation of extracellular matrix proteins like collagen types I, IV, and V was observed, indicating the successful delivery and efficacy of small interfering RNA nanoplex in vitro.102 Tissue inhibitor of matrix metalloproteinase-1 is a potent inhibitor of MMP-9, which is one of the main culprits associated with neuroinflammation. A study reported encapsulation of tissue inhibitor of matrix metalloproteinase-1 in poly(lactic-co-glycolic) acid NPs and strong neuroprotective activity in vitro by inhibiting the gelatinase-mediated MMP-9 activity.103 Interesting results were reported showing the antioxidant activity of fullerene (C60), where C60 suspension on administration showed strong protective activity against carbon tetrachloride intoxication in rats.104 This could be a potential application if tested against disorders such as MS that are associated with free radical toxicity. In an EAE model induced by the proteolipid protein PLP139–151 administration, significant improved tolerance was observed in mice that were administered in prior with the PLP139–151-coupled poly(lactic-co-glycolic) acid NPs. Antigen-presenting cells internalized these NPs via scavenger receptors and induced both T-cell anergy and enhanced T-reg activity. The disease improvement was also confirmed with the vascular (AngioSense 750EX) and protease-activatable cathepsin B (Cat B 680 FAST) near-infrared fluorescence imaging agents, which showed a respective decrease in the BBB breakdown and inflammation.105
The T-cell regulatory activity was also improved in an autoimmune model, wherein the authors fabricated disease-relevant self-peptides and the class I peptide–major histocompatibility complex-coated iron oxide NPs.106 Thus, the antigen-specific T-reg cell expansion can be a potential approach if modified using the MS specific antigen. Similar results were also reported where gold NPs carrying 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester and myelin oligodendrocyte glycoprotein showed significant disease remission. NP-treated dendritic cells showed a tolerogenic phenotype and induced the differentiation of T-reg cells, which significantly abrogated disease generation.107 The monolayer mannosylated liposomes packed with various immunodominant myelin basic protein (MBP) fragments showed significant reduction in the level of anti-MBP antibodies. This nanoformulation showed a synergetic therapeutic effect, wherein disease scores were reduced showing a first EAE wave inhibition followed by subsequent remission in vivo.108 Gold NPs encapsulated with potential antioxidant compounds epigallocatechin gallate, and α-lipoic acid were found to have strong wound healing and migration along with an increase in the antioxidant activity in vivo. This could be a future application for evaluating against MS pathology.109 Cerium oxide (CeO) NPs are regarded as potent antioxidants on account of their ability to either donate or receive electrons. It was also reported that CeO NPs showed an extremely small size of 2.9 nm with enhanced brain uptake and reduced reactive oxygen species in vivo. The authors claim that custom-made CeO NPs provide protection against autoimmune diseases associated with free radical toxicity.110 Further to this, a novel pH-sensitive IFN-β microparticle was synthesized using trimethyl-chitosan, poly(ethylene glycol)-D-methacrylate, and methacrylic acid. These microparticles showed effective drug release over 24 hours both in vitro and in vivo.111
Neuroprotection was also made possible with the implication of fullerenol (polyhydroxylated C60), which mitigated neuronal excitotoxicity antagonizing the glutamate receptors in amyotrophic lateral sclerosis model.112 This function of fullerenol also holds potential application for MS too. The implication of nanosurgery is underway and is at the threshold of revolutionizing neurological disorders. Earlier, nanosurgery was only a dream, but now the current nano tools have made the dream come true. The introduction of quantum dots for imaging, multipartite NPs for neuromodulations, and nano manipulations mediated by atomic force microscopy cantilever have all made it possible.113 A study reported the use of atomic force microscopy tip as nanoscissors for indenting the cell wall by only 1 μm, which otherwise is inevitably difficult employing conventional techniques.114 This kind of applications opens up new avenues for single-cell and chromosomal surgeries operating at submicron levels and would highly benefit the MS brain where damaged neurons can be successfully treated without affecting the healthy ones. NPs not only have a role in therapeutic application, but have also improvised the diagnostic strategy with enhanced sensitivity, enabling early detection of the disease. Likewise, the titanium dioxide nanocomposite film modified with alginate coat has been immobilized with MBP, and when tested for antigen detection, it showed an astounding sensitivity of 0.18 ng/mL. Thus, NPs have improved MS diagnosis, wherein a blood sample is sufficient instead of CSF samples.115 MS diagnosis was even improved with the application of very small superparamagnetic iron oxide particles, which showed a characteristic accumulation in the inflammatory lesions. The very small superparamagnetic iron oxide particles were also successful in discriminating inflammatory events between control and established EAE, with clear demarcation of the central nervous system alterations preceding immune cell infiltration.116
Similarly, detection sensitivity was enhanced using the streptavidin antibody-conjugated superparamagnetic iron oxide particles, as they are superior contrast agents because of their T2* relaxation properties. These target-specific NPs were able to visualize CD3+ T-cell infiltrates in a murine MS model, confirming the diagnostic potential of NPs.117 Some recent advancements were made with the introduction of gadolinium–diethylene triamine pentaacetic acid and ultrasmall superparamagnetic particles of iron oxide (USPIO). Gadolinium–diethylene triamine pentaacetic acid is a routinely employed inflammatory marker,118 while USPIO can detect cellular infiltration and inflammation progression in MS.119 The application of stem cell therapeutics has also garnered significant attention; it was found that patients administered with autologous hematopoietic stem cells showed much improved outcome in Phase II trials.120,121 Further, coupling nanotechnology platforms would improvise the stem cell-based theranostics. For instance, carbon nanotube substrates regulate growth and neurite regeneration, which can find potential application for neural regeneration.122 Intriguingly, USPIOs can label stem cells and help in tracking the fate of these cells using MRI.123 Table 2 summarizes the list of nanotechnology applications in MS.
Table 2 Various nanotechnology applications in MS
Abbreviations: CeO, cerium oxide; DTPA, diethylene triamine pentaacetic acid; EAE, encephalomyelitis; H. pylori, Helicobacter pylori; IFN, interferon; ITE, 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester; MBP, myelin basic protein; MMP, matrix metalloproteinase; MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis; NPs, nanoparticles; PLGA, poly(lactic-co-glycolic) acid; PLP, proteolipid protein; pMHC, class I peptide–major histocompatibility complex; siRNA, small interfering RNA; SPIO, superparamagnetic iron oxide; TiO2, titanium dioxide; USPIO, ultrasmall superparamagnetic particles of iron oxide; VSOP, very small superparamagnetic iron oxide particles.
What is in the pipeline?
Agents possessing neuroprotective activity are worth considering as treatment for MS, and histone deacetylase inhibitors is one such class possessing strong anti-immune activity.124 Inflammatory insults play a major role in the onset and progression of MS, and hence therapeutics acting against it can be invaluable. Likewise, inhibitors of midkine (a cytokine that drives T-cell traffic followed by inflammatory cascade) are under development, as they have shown a remission preclinically in an MS model.125
Physiologically, carbon monoxide has some anti-inflammatory and cytoprotective activities. Interestingly, when carbon monoxide-releasing molecules were tested preclinically in the EAE model, they were found to alleviate the pathologic disease scores, driving the need for clinical evaluation.126 The potential immunomodulatory role of vitamin D is also being evaluated in a Phase II trial.127 Table 3 gives a summary of the drugs included.
Table 3 Current drugs in trials for MS treatment
Abbreviations: FDA, US Food and Drug Administration; IFN, interferon; MS, multiple sclerosis.
As per the data published, there is commonness in the pathologies of MS and some behavioral disorders. Hence, selectively identifying and targeting the events of MS will also prove to be potential for the alleviation of comorbidities. Some of our own results are discussed here. We have adopted the principle of neuroprotection and observed anti-inflammatory effects of anti-mucosal addressin cell adhesion molecule-1 (MAdCAM-1) mAb, which protected oligodendrocytes. Also, simultaneous administration of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate/kainate antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline and the neuroprotector glycine–proline–glutamic acid (N-terminal tripeptide of insulin-like growth factor) resulted in strong neuroprotector activity, confirmed with the significant reduction in impaired neurological scores in vivo.4 More rapid disease remittance was observed in mice when a combination of anti-MAdCAM-1, vascular cell adhesion molecule-1, intercellular cell adhesion molecule-1, and ligand for lymphocyte function-associated antigen integrin mAbs was administered.128 Also, the contribution of integrin (α4β7 and αEβ7)-mediated inflammation in MS was significantly remitted, administering antibodies against them.129
Thus, after the analysis of the results, we assume that the antibodies targeting the inflammatory ligands involved in MS may also impede the inflammatory component of the depressive episodes and cognitive impairment followed by their remission. Hence, it is postulated that identifying and targeting the pathological events specific to MS can definitely prove to be beneficial for relieving the comorbid behavioral symptoms as well. This is because of the findings of commonness in the pathologies of MS and behavioral disorders. Future also holds an interesting question to answer: shall the treatments initiated for behavioral symptoms improve MS too? Figure 3 shows strategic treatment options for MS.
Figure 3 Strategic treatment for MS.
Notes: (A) Permeation inhibitors bind either with cell adhesion molecules present on the capillary endothelium or cell surface molecules of the reactive T-cells and prevent them from gaining access into the brain (eg, IFN-β1a, natalizumab). (B) mAbs particularly target the T- and B-cells based on their surface markers and eventually deplete them (eg, daclizumab and rituximab target CD25 and CD20 expressed on T- and B-cells, respectively, and deplete them). (C) Immunomodulators such as corticosteroids, chemotherapeutics, and the lead compound laquinimod act against immunity by suppressing it or shift the immune response to Th2 type. (D) Neuroprotectors such as BG00012 and histone deacetylase inhibitors (under evaluation) and protect neurons from the insults of inflammation and free radical stress.
Abbreviations: IFN, interferon; mAbs, monoclonal antibodies; MS, multiple sclerosis; BBB, blood–brain barrier.
Behavioral disturbances are found to be common among MS patients, irrespective of the severity and the course of disease progression. Depression seems to be the most common neuropsychiatric abnormality observed in MS compared to any other neurological disorders. It is also associated with cognitive impairment in few of the MS patients, raising the question of commonness in their pathology. It is worthwhile to identify the early symptoms of this memory loss, as it is considered to be a forerunner of MS in a group of patients. Psychosis, euphoric symptoms, sleep disturbances, and fatigue are other influential comorbidities associated with MS that will drastically affect the quality of a patient's life. Hence, identifying disease-specific targets and coupling them with NPs will result in the effective diagnosis and treatment of the disease. This would also positively affect and help overcome the associated behavioral symptoms in MS. "The better the quality of life, the better the recovery".
Jagat R Kanwar acknowledges the funding received from the Department of Innovation Industry Science, Research and Commonwealth Australia (BF030016/42), and National Health and Medical Research Council.
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E.L.I.'s pale pink cotton-blend tank top is a soft base for layering under your everyday edit. It's crafted in Peru, and cut to a relaxed silhouette with a scoop neckline. Pair it with a matching E.L.I. cardigan for a perfectly polished weekend look.
Length 22.5" 23" 23.5" 24" 25.5"
Shoulder Width 12" 12.5" 13.5" 13.75" 14"
Bust 34" 35" 37" 39" 42"
Waist 32" 33" 35.5" 38" 42"
Hip 37" 38" 39.5" 42" 47"


text:
1997 Natatanging Gawad Urian
FELIPE SACDALAN
FELIPE SACDALAN: Unflagging Proponent of the Invisible Camera
Agustin Sotto
"The camera should be invisible!" : this is a dictum Felipe Sacdalan, swears by. "If the cinematography gets noticed, if the audience leaves the moviehouse swooning over the shots -or if they said bad things about it — then the cinematographer has not done his job."
For thirty four years, from 1946 to 1979, "Ka Ipe", his nickname in the industry, has been pushing the storytelling function of the camera. Because he doesn't believe in flashy, attention-calling cinematography, Ka Ipe works on images that contribute to the overall film design. Compared to those of other cameramen, his work is subtle, never intrusive, and hence, even more powerful because it is wholly integrated with the story.
A corollary dictum is his insistence on reading the script. "The cinematographer must know what is going on in order to make decisions on the shots. He must read the script beforehand." It is only after Ka Ipe has familiarized himself with the material that he starts working on the angles and selecting the filters and lenses that would effectively bring out the heart and soul of the film.
This is not to say that Ka Ipe is merely dexterous; for his films are compelling accounts of the larger than life occurrences, the fantastic, and the surprises that make the quotidian sometimes indelible in the mind. Gerardo de Leon's The Day of the Trumpet and Kulay Dugo Ang Gabi, Eddie Romero's Man on the Run and Escape to Paradise, John Cromwell's The Scavengers : these are but a few of the films whose engaging storytelling and screen power have been shaped by his craft.
Ka Ipe was born in Calumpit, Bulacan on April 30, 1916. At the age of seven, he became an orphan and thus had to push hard to get to his status. He remembers he was so poor that he was not able to pay for his high school diploma. However, he was not without luck; his uncle, fellow cinematographer Higino Fallorina's dad, ran a photography studio and got young Ipe to work in the lab.
Because he was acquainted with the basics of photography, he was hired by Filippine Films in 1939, first to work in the photo lab, later as stillman and then as assistant cameraman. But Ka Ipe wanted to improve on his knowledge and subscribed to a correspondence course with the Motion Picture Institute in Birmingham, Michigan.
During the war, when film production was grinding to a halt, he found himself in the lab again — this time, a motion picture lab. He became active in the processing of prints until raw stock finally ran out.
After the war, he became a full-fledged cameraman for Fernando Poe's Royal Productions, starting with Dugo ng Bayan in 1946. He shot several films for Poe's studio. In the Fifties, he transferred to Premiere Productions where he worked with some of Philippine cinema's major directors: Gerardo de Leon, Eddie Romero, Chat Gallardo, Efren Reyes. Some of the films he shot on the lot: Aawitan Kita, Singing Idol, I Believe, Huling Mandirigma, Lagalag, Darna at ang Babaeing Tuod, Batang Angustia.
He won the FAMAS five times.- May Bakas ang Lumipas (1954); Mga Yapak na Walang Bakas (1961); Ito ang Filipino (1966); Dalawang Mukha ng Tagumpay(1973);and Krimen( 1974).
Because of his expertise, he was often chosen as the cinematographer for many of the international co-productions. In 1956, he shot The Day of the Trumpet, with John Agar, Premiere's first production intended for worldwide release. This was followed by many of Eddie Romero's international joint ventures: Man on the Run with Burgess Meredith and Escape to Paradise. He also shot Hollywood director John Cromwell's Scavengers with Vince Edwards.
He was also the favorite cinematographer of local producers when they decided to shoot abroad. For Premiere, he did Arizona Kid, Lollipops and Roses at Burong Talangka in the United States and El Pinoy Matador in Spain. For Regal Films, he did Elwood Perez's Pinay — American Style, his last film before his self-imposed retirement.
"I was often chosen because of my other skills. I could be counted on to repair the camera in case something happened. Also, I am a judo champion twice in a row, a 2nd Dan conferred by the Kodokan Institute. I could also be a bodyguard to the stars in case the teeming crowds watching the shoot became unruly."
Ka Ipe is a fervent Seventh Day Adventist who adheres to the principles of a sound mind and a healthy body. As with his craft, Ka Ipe is very zealous with his health and eats only fish and vegetables. Already 81, his sturdy physique belies his age. He has a daily routine which prescribes daily excercises and forbids him to eat in-between meals.
Ka Ipe now runs a camera rental company. "Many of our cinematographers do not really know the constitution of a camera. They keep blaming the camera for their own lack of understanding. I took it upon myself to know the camera inside out and to learn the equations by heart. Some of our cameramen just don't have the patience to do this."
Asked what his favorite films are, Ka Ipe Sacdalan protests, "I don't have any favorites, I pour myself into every film I do, every shot I make. Maybe that's why I choose the people whom I work with. If I cannot function in this manner, I'd rather not do it. No amount of money can make me."
It is this total commitment to the job that has made Ka Ipe Sacdalan's career a proud and distinguished one in the history of Philippine film industry.
Back to Natatanging Gawad Urian

redpajama_set_name: RedPajamaCommonCrawl


Guyana Tourism Authority head, Mitra Ramkumar (extreme left) looks on as Roddy Carr (center) and Aleem Hussain (right) sign the $20b deal.
"Norton says gov't in the dark on $20b golf project." The photograph published, was an old photograph which depicted Banks DIH Limited officials, who have in the past sponsored golf tournaments. Stabroek Sports apologises to Banks DIH Limited and Citizens Bank Inc., and its officials, who are not in any way associated with the project or the story, for the error. Below is the correct photo and caption.


text:
Diplomas Awarded to Veterans in Red-White-and-Blue Celebration
SCOE Holds Sixth Operation Recognition Event
Sacramento County Office of Education / Sacramento County Office of Education News / Diplomas Awarded to Veterans in Red-White-and-Blue Celebration
Operation Recognition diploma recipients pose with the Sacramento County Board of Education.
Thirteen local veterans and a World War II internee were awarded their belated high school diplomas in a ceremony held May 24 by the Sacramento County Office of Education (SCOE).
The diplomas were presented by the Sacramento County Board of Education through a program called Operation Recognition. The program acknowledges veterans who missed graduating with their high school class because they enlisted in World War II, Korean War or Vietnam War military service, and Japanese American citizens whose internment in World War II relocation camps prevented them from graduating with their hometown high school class.
"This program is our humble way of paying tribute and acknowledging those who put their personal lives on hold, who put their plans on the shelf, in order to serve our country. This is our modest way of thanking them," said Marty Cavanaugh, Sacramento County Deputy Superintendent of Schools.
Honorees in attendance, joined by family members and friends, gathered with County Board of Education Trustees at Sacramento's Hilton Hotel for a pre-ceremony reception. A flag ceremony presented by the Folsom Joint Veterans Organization Color Guard opened the event. Board President Sylvia J. Ruiz conducted a brief meeting of the Board, during which Trustees unanimously voted to bestow diplomas.
"This is a gesture of our society's gratitude for the sacrifices these individuals made in the name of freedom," Ruiz said.
Student speaker Connor Sweeney of El Camino High School gave a special tribute to veterans and Japanese Americans who made sacrifices during times of war.
"Congratulations to our recipients. We should not only give these honored guests their diplomas; we should also give them our supreme gratitude and utmost respect for everything they have endured in the name of freedom," Sweeney said.
Diploma Recipients
Sakaye Ishihara Aoki is a resident of Woodland and was interned in a relocation camp in Tule Lake, California during World War II. Prior to being relocated, she attended Sacramento High School in Sacramento.
Richard Dale Balak is a resident of Rescue, California. Mr. Balak served in the Marines during the Vietnam War.
Floyd Edward Carney is a resident of the South Sacramento area and served in the Army as a Sharpshooter during the Vietnam War. Prior to enlisting in the service, he attended Luther Burbank High School in Sacramento.
Carlos Cervantes is a resident of Sacramento who served in the Navy during World War II. Prior to enlisting in the service, he attended Woodland High School in Woodland, California.
Lewis Wayne Easter is a resident of the Hollywood Park Area of Sacramento and served in the Navy during the Korean and Vietnam Wars. Prior to enlisting in the service, he attended C.K. McClatchy High School in Sacramento.
Frank Junior Garavito is a resident of Orangevale and served in the Army as a medic during the Vietnam War. Prior to enlisting in the service, he attended Tennyson High School in Hayward, California.
Richard C. Garlinghouse is a resident of Rancho Murieta and served in the Navy onboard the USS Antietam Aircraft Carrier during the Korean War. Prior to enlisting in the service, he attended Marysville High School in Marysville, California.
Frank William Loscutoff is a resident of South Sacramento who served in the army as a paratrooper during the Vietnam War. He was awarded the National Defense Service Medal and has an Expert M-16 Bar. Prior to enlisting in the service, he attended Luther Burbank High School in Sacramento, CA.
Rex T. Rice, Sr., is a resident of Rancho Cordova who served in the Army during World War II. Prior to enlisting in the service, he attended Gerstmeyer High School in Terre Haute, Indiana. Mr. Rice was issued the Purple Heart for his service in the Battle of the Bulge.
Gordon Roberts is a resident of Orangevale and served in the Navy during World War II and the Korean War. Prior to enlisting in the service, he attended Sulphur Springs High School in Tampa, Florida.
Donald Edward Strassburg is a resident of Elk Grove and served in the Navy during the Vietnam War.
Floyd A. Van Dyke is a resident of Folsom who served in the Navy during World War II and the Korean War. He is one of 5 boys in his family who served our country during WWII. Prior to enlisting in the service, Mr. Van Dyke attended Danesfield High School in Minnesota.
Jay B. Wiley is a resident of Folsom and served in the Marine Corps during the Korean War. He was part of the First Marine's Provisional Brigade of which he served in the 5th Marine Regiment. Prior to enlisting in the service, he attended Luther Burbank High School in San Antonio, Texas.
Danny Leon Willyard is a resident of Orangevale who served in the Coast Guard during the Vietnam War. Prior to enlisting in the service, he attended Casa Roble High School in Orangevale, California.
The Sheldon High School Jazz Band provided entertainment for the reception's 100 guests, as well as performing a musical tribute during the diploma ceremony. The honorees posed for photos with their families and were interviewed by local media.
Operation Recognition was adopted unanimously in October 2001 by the Sacramento County Board of Education and has since expanded to include recognition of qualifying Vietnam War veterans. Operation Recognition high school diplomas are authorized by the California Education Code (§ 51430 and § 51440).
The Sacramento County Board of Education has thus far provided Operation Recognition high school diplomas to 84 individuals, including four posthumous awards. A photo gallery is available on SCOE's Operation Recognition website.
Those interested in applying for an Operation Recognition diploma for themselves or a qualifying family member should call (916) 228-2449.


I was staying with a friend in Boston for, oh, a week and a half, so I decided to buy a $12 train ticket to Concord to visit Walden Pond. (I'm currently in Western New York spending time with family.) I've been to Walden Pond before (and wrote about it here), but I've uploaded some new images below.
Here's a bronzey sculpture of Thoreau, which, for some reason, is slightly smaller than human scale--and behind the sculpture is his "replica" cabin. The original was long ago used as firewood.
The Pond. It was a pretty dreary day and I got thoroughly (or Thoreauly?) soaked when eating a banana at the site of his original cabin. No moments of transcendence, unfortunately.
Lots of rails and wire to keep foot traffic from harming the land. Supposedly it gets pretty busy here in the normal months.


US magazine Game Informer revealed Enemy Unknown, saying it "introduces a wider console audience to what made the storied franchise great in the first place". It launches on PC, PlayStation 3 and Xbox 360 this autumn.
"Unlike 2K Marin's previously announced XCOM shooter, which sparked tempers among longtime fans for turning its back on the series' cerebral roots, this title is a full-on strategy game that puts players in command of a global anti-alien defense force," Game Informer said.
Firaxis boss Steve Martin added: "It's been a dream of ours to recreate X-COM with our unique creative vision. We're huge fans of the original game and it's a once in a lifetime opportunity to re-envision a game that is as beloved as X-COM.
Firaxis' XCOM will have destructible tactical environments, and fuses a real-time strategic view with turn-based combat.


THE NATURAL HAVEN: If your hair had a voice what would it say?
If your hair had a voice what would it say?
Ok this one has been doing the blog and forum rounds and I like it!! So what would your hair say???
"You need to drink more water, I'm thirsty"
"OK, I'll drink more tomorrow"
"NO! YOU'LL DRINK RIGHT NOW!!"
"Yeah, and I need a wash and style. What the hell is wrong with you, can't you see I'm in a state??"
"Well, I did have a baby not so long ago"
"THAT WAS TEN WEEKS AGO!! HOW MUCH LONGER DO YOU EXPECT ME TO PUT UP WITH THIS NEGLECT??!!!"
"OK, I'll wash and style you tomorrow *sigh*"
"Yeah, you'd better or I'll up and fall right out of your head - that would show you!!"
Do I sound like I have a guilty conscience? LOL!!!
"Stop touching me!" Not gonna happen.... even if it all breaks off, lol.


A hot fashion rivalry is underway thousands of miles from the runways of Milan and Paris. It has nothing to do with couture houses or red carpets. It does not involve a luxury brand poaching the designer du jour from a competitor. The clash arises from recent claims made by boosters for Nashville and Columbus. Each city, it seems, considers itself the fashion capital of the United States, with the very notable exceptions of New York and Los Angeles. Each city, in other words, is vying for third place.
"Columbus is ranked the No. 3 largest metro for fashion designers and is rapidly becoming known as the region to live, work and play everything fashion," goes a line from an email sent by the publicity firm DCI on behalf of Ohio's most populous city.
After puzzling over the dueling claims, I set out to determine which city is worthy of fashion bronze. I quickly found during my travels that both places have a lot going for them. As part of my investigation, I dined at hip restaurants, pawed through the racks at luxury boutiques and met with fashion powers and prospects in both towns.
Over dinner at the Margot Cafe & Bar in Nashville, in the stylish company of Van Tucker, the chief executive of the Nashville Fashion Alliance, and Libby Callaway, a fashion reporter turned Nashville publicist, I learned that Minnie Pearl, the hillbilly granny on "Hee Haw," was, in real life, a chic Diana Vreeland of the South.
But it wasn't all gossipy expense-account dinners. I had work to do. My aim was to judge Columbus and Nashville in various categories and, whenever possible, award a winner for each. The final tally would settle the matter. There can be only one third-place finisher, after all.
For the evidence and my ruling, please read on.
Nashville "My take on Nashville fashion is there's pre-Imogene and Willie and post Imogene and Willie," said Ms. Callaway, who once covered the industry for The New York Post. "They changed the conversation here." Indeed, fashion obsessives flipped for the heritage denim label founded in 2009 by Matt and Carrie Eddmenson. So did Gwyneth Paltrow, who became a fit model. The flagship store occupies a converted auto repair shop in the 12 South district, where I saw millennials gingerly handling pairs of $200 straight-leg, cardboard-stiff selvedge-denim jeans. But these days the store is mostly symbolic. In 2015, the Eddmensons moved to Los Angeles, to be closer to their manufacturers. What does it say about a local industry when the most successful brand had to leave to grow?
Nashville Nicole Kidman, one of numerous local celebrities, may have to do her serious shopping elsewhere. For all of its entertainment-industry wealth, there is no luxury department store in the city's downtown area. But a bustling independent retail scene has sprung up to fill the void, including H. Audrey, Peter Nappi and Billy Reid. But for my money, the city's saving grace is its three locations of United Apparel Liquidators, the only-in-the-South off-price retailer that sells Chanel, Prada and other luxury goods at ridiculous markdowns.
Columbus You may have heard that shopping malls are going extinct in a retail apocalypse. But that wasn't the feeling I experienced at Polaris Fashion Place, where two levels of stores hummed with consumerist joy as if it were 1989. Perhaps that's why brands treat Columbus as Test Market, U.S.A., trying out products there before rolling them out nationwide. After my mall visit, I stopped by Rowe Boutique, an independent shop in the trendy Short North neighborhood. The owner, Maren Roth, worked in the fashion trenches on both coasts before returning to her Ohio roots in 2007, "to bring a little of New York and L.A. to Columbus," she said. Next month, Ms. Roth and her fiancé, Marc Desrosiers, plan to open KILN, a men's store, nearby.
Columbus For the job seeker, this city resembles a fashion version of "Field of Dreams." At the Abercrombie & Fitch headquarters in nearby New Albany, Ohio, modern shedlike buildings spread across 500 meadowed acres, with stylish young employees zooming on razor scooters toward the mess hall. "There's a youthful, campus feeling here," said Lisa Lowman, a senior vice president of Hollister Design, one of the 2,500 or so employees who work there. Ms. Lowman moved two years ago from Los Angeles, where she worked for Lucky Brand Jeans. Her co-workers are from London, Australia, New York and, yes, Columbus. L Brands (Victoria's Secret, Bath & Body Works, Henri Bendel) also has its own campus and a work force of more than 7,000 in the Columbus area.
Nashville Savannah Yarborough studied design at Central Saint Martins in London and worked as head men's wear designer for Billy Reid before setting up shop here. She hand-stitches leather jackets for Wall Street bankers and musicians who can afford to pay $5,000 and up. Her Atelier Savas studio would be impossible in New York, she said: "I'd be on the eighth floor of some building in the garment district with no electricity." The handbag designer Ceri Hoover started with no apparel background, but, she said, Nashville residents are "friendly, supportive, collaborative." Ms. Hoover won a local grant to study leather production in Italy.
Winner: They are both winners.
Nashville Every serious fashion town needs hip places to stay, and in recent years, boutique hotels here have become, well, a boutique industry. The first to gain acclaim was the 404 Hotel & Kitchen, with five guest rooms and an adjoining restaurant inside a reclaimed shipping container. Then there is the Germantown Inn, with its six suites in a historic 1870s house; Urban Cowboy, a branch of the bed-and-breakfast that started in Williamsburg, Brooklyn; and in the Gulch neighborhood, not far from Jack White's Third Man Records, is the newly opened Thompson Nashville, which has 224 rooms and three restaurants, including a rooftop cafe that doubles as an Instagram backdrop.
Columbus Le Meridien Columbus, the Joseph hotel opened not long ago in the Short North district. And Columbus residents talk up their first boutique hotel the way new parents gush over their firstborn. "You've got to see the Joseph." "When are you gonna see the Joseph?" O.K., O.K., we saw the Joseph. We stayed there, in fact. There is a bar in the lobby with Illy coffee and an adjoining restaurant, the Guild House, that serves an excellent snapper. But Jack White isn't likely to walk through that door any time soon.
Nashville What's a fashion city without a fashion week? Nashville Fashion Week has been happening for seven years, and, at the showing in April, the event featured a mix of locals, like the women's wear designer Cavanagh Baker and the jewelry maker Judith Bright, and national brands, like Vineyard Vines and Madewell.
Columbus Fashion Week Columbus is scheduled for this October. It appears to have one runway show, a casting call for models and some mixers. But the city also holds Alternative Fashion Week in July, which in past years has included a drag-queen-and-wine pairing. That's the spirit that once made fashion shows fun. One of the organizers is Kelli Martin, a former "Project Runway" contestant who came back to her hometown and started making "pretty-slash-ugly" punk rock clothes under the name Anti.Label. She reminded me of Iona from "Pretty in Pink." Ms. Martin, who designs in a downtown office building behind a frosted-glass door, keeps Columbus weird.
Columbus During my stay, I hit up Pistacia Vera in German Village four times. It was as much a testament to the excellent coffee and croissants as to the limited options in a town that is not yet a go-to place for cold-pressed juices or restaurants serving ingredients grown on the roof. Where Columbus excels, though, is high-culture: an opera company that features vocalists from Juilliard, an arts center at Ohio State University and a museum that has long treated fashion as art.
Nashville When fashion people talk about the man in black, they mean Karl Lagerfeld. To Nashville people, that sobriquet conjures Johnny Cash, whose style was heavy on substance. "I wear the black for the poor and the beaten down," he sang in "Man in Black." The city has also had its share of transgressive style icons. Think of Dolly Parton in her wigs and rouge, an inspiration to drag queens and Vogue editors alike. Or Waylon Jennings, who modeled the "outlaw" look — greasy long hair, rough beard, black leather vest — years before fashion players like Oliver Zahm made sleaze cool. If today's country stars have opted for a more toned-down look, at least the designer Manuel still has his shop in the heart of town. The tailor known as the "Rhinestone Rembrandt," who made the famous gold lamé suit for Elvis Presley, has also duded up Gram Parsons, Keith Richards, Dwight Yoakam and Neil Young.
Columbus Charlotte Curtis, the New York Times fashion and society editor who wrote "The Rich and Other Atrocities," was a Columbus native. The American designer known for his work in the couture tradition, Charles Kleibacker, the "Master of the Bias," taught fashion design at Ohio State and curated shows at the Columbus Museum of Art. And Leslie Wexner, the billionaire founder of the Limited (now L Brands), "single-handedly changed how America shops," according to Forbes. But maybe the coolest Columbus fashion icons are fictional — Veronica Sawyer and Jason Dean, the high-school students played by Winona Ryder and Christian Slater in "Heathers." The 1989 film, set at a fictional suburban Ohio school, is a cult favorite (perhaps especially among the fashion set) for its celebration of '80s looks and its mean-girl quotability.
I enjoyed my stay in each city so much that it is no easy task for me to name a winner. But the numbers don't lie: Nashville edged out Columbus, 4 to 3, with a tie in the Indie Talent category.
Perhaps Columbus is Milan to Nashville's Paris. While the more workaday Ohio city has a flourishing apparel industry, Nashville has more of what a fashion city needs, for good or ill: glamour.
An article last Thursday about the fashion rivalry between Nashville and Columbus misidentified a type of eco-conscious wool product that the Columbus designer Celeste Malvar-Stewart makes. She creates rugs, not blankets. The article also referred imprecisely to the kind of shopping available in Nashville. While there is no luxury department store in downtown Nashville, there are some within the city limits, at the Mall at Green Hills; it is not the case that there are no luxury department stores in Nashville.


> we try to send a P2P frame we get following issue.
> Can somebody explain why we are getting this some times?
>>This can only come from your driver, the stack never returns that value.
Understood. So the frame does travers to the driver and this rejection is not in cfg80211/mac80211. Am I  correct?


text:
Q: Can a "User Assigned Managed Identity" be used locally? I am trying to use a User Assigned Managed Identity in one of our applications. I also read about the differences between System Assigned Managed Identity and User Assigned Managed Identity.
It is very clear to me that a System Assigned Managed Identity cannot be used locally as there you're assigning an identity to an Azure Resource.
However I am not clear if a User Assigned Managed Identity can be used locally. Only thing I could find is the following:

In my scenario, I would like to read some secrets from an Azure Key Vault. I have created a User Assigned Managed Identity and configured access policies on the Key Vault to give necessary permissions to this identity. Considering I am using this identity to access Azure Key Vault (which is an Azure resource), my expectation is that it should work regardless of the location (using JetBrains Rider as my IDE) from where my code is running.
However when I try to do something like:
var managedIdentityCredential = new ManagedIdentityCredential("managed-identity-id");
SecretClient secretClient = new(new Uri("https://mykeyvault.vault.azure.net/"), managedIdentityCredential);
KeyVaultSecret secret = await secretClient.GetSecretAsync(key);

I get the Azure.Identity.CredentialUnavailableException with ManagedIdentityCredential authentication unavailable. No Managed Identity endpoint found error message when I run the code locally:
Azure.Identity.CredentialUnavailableException: ManagedIdentityCredential authentication unavailable. No Managed Identity endpoint found.
   at Azure.Identity.ManagedIdentityClient.AuthenticateAsync(Boolean async, TokenRequestContext context, CancellationToken cancellationToken)
   at Azure.Identity.ManagedIdentityCredential.GetTokenImplAsync(Boolean async, TokenRequestContext requestContext, CancellationToken cancellationToken)
   at Azure.Identity.CredentialDiagnosticScope.FailWrapAndThrow(Exception ex)
   at Azure.Identity.ManagedIdentityCredential.GetTokenImplAsync(Boolean async, TokenRequestContext requestContext, CancellationToken cancellationToken)
   at Azure.Identity.ManagedIdentityCredential.GetTokenAsync(TokenRequestContext requestContext, CancellationToken cancellationToken)
   at Azure.Security.KeyVault.ChallengeBasedAuthenticationPolicy.AuthenticateRequestAsync(HttpMessage message, Boolean async, AuthenticationChallenge challenge)
   at Azure.Security.KeyVault.ChallengeBasedAuthenticationPolicy.ProcessCoreAsync(HttpMessage message, ReadOnlyMemory`1 pipeline, Boolean async)
   at Azure.Core.Pipeline.RetryPolicy.ProcessAsync(HttpMessage message, ReadOnlyMemory`1 pipeline, Boolean async)
   at Azure.Core.Pipeline.RetryPolicy.ProcessAsync(HttpMessage message, ReadOnlyMemory`1 pipeline, Boolean async)
   at Azure.Core.Pipeline.HttpPipeline.SendRequestAsync(Request request, CancellationToken cancellationToken)
   at Azure.Security.KeyVault.KeyVaultPipeline.SendRequestAsync(Request request, CancellationToken cancellationToken)
   at Azure.Security.KeyVault.KeyVaultPipeline.SendRequestAsync[TResult](RequestMethod method, Func`1 resultFactory, CancellationToken cancellationToken, String[] path)
   at Azure.Security.KeyVault.Certificates.CertificateClient.GetCertificateAsync(String certificateName, CancellationToken cancellationToken)

Any insights into this will be highly appreciated.

A: No. User managed identity is also not supported with ManagedIdentityCredential in the local environment.
You should use DefaultAzureCredential for the code to work in local environment.
See the Note tip here.

Note
The ManagedIdentityCredential works only in Azure environments of
services that support managed identity authentication. It doesn't work
in the local environment. Use DefaultAzureCredential for the code
to work in both local and Azure environments as it will fall back to a
few authentication options including managed identity.
In case you want to use a user-asigned managed identity with the
DefaultAzureCredential when deployed to Azure, specify the
clientId.

redpajama_set_name: RedPajamaStackExchange