IMID pathogenesis

Die, Drôme

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While Eddie Redmayne is good as Stephen Hawking, it's really just a performance that deceives the viewer and critic.

He looks like Hawking. His hair and clothes look like Hawking. He does the 'Hawking' smile and weird thinking stare face and frowns. Yes, he does a believable Hawking. But it's just a glorified impersonation. There's no actual great acting or stretch of a transformation or method or scenes that Redmayne is tested as an actor nor Hawking's character development.

The dialogue and interactions, aside from using actual Hawking quotes from speeches and writings, are awful and boring and redundant and derivative. The whole performance is mild and plain, and the story is weak. The story has generally been done before. There are no significant scenes or moments that go above and beyond anything generic, nor anything for Redmayne to truly bite into to 'perform. Mostly, the film fails miserably in exploring Hawking's internal thoughts, imagination, rituals, and inspirations.

It plays like a T. And quite frankly i'm tired of these Hollywood films doing biopics about an ENTIRE life, using montage and generic moments that aren't specific or significant enough. Biopics that are focused on a period on a life is more interesting than trying to do a whole life in two hours.

There's no sense of Hawking and his children in his life. Births are fast-tracked, montage child play and smiles. The film gives you an impression of just Jane, his wife, being a vessel for children. There's no sense of Hawkings personal life, interests, time spent, or anything underpinning the vast ideas he develops.

We see him on a beach or being pushed in a wheelchair by family as piano plays. The film is devoid of politics or popular culture and changing times of each decade other than clothes as lazy indicators, and the exception of pointing out Penthouse a few times as some recurring wink wink joke to convey Hawking as some sexual guy.

This 'sexualized' Hawking happens throughout the film in various ways In fact, Jane is in more scenes and gets more to act on screen than Stephen Hawking and Redmayne for that matter.

The story is more focused on tripe romance and affair rather than Hawking. And even when departing, a montage is set in again. No emotional development is organic. And, perhaps, maybe as brilliant as Hawking is and as tragic as his condition is, maybe he's just a boring guy and not much can be that interesting in terms of a character on film in scenes other than a guy sitting in a wheelchair mumbling and smiling and frowning.

The film would've done a better job with Hawking's imagination and space interpreted in shots, as well as the times he was living in and absorbing and watching as opposed to generic renderings of his domestic life which was still mild and safe compared to the actual reality and Jane's struggle and perspective. Everything is furthered by cued dramatic music and montage and shots of faces occasionally. By trying to cram in broad strokes in writing the film into a corner with Jane's story, the theory of everything becomes theory of nothing.

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It was once the see of a Roman Catholic diocese and its cathedral remains. Die is situated in a valley , surrounded by the Glandasse mountain feet , a massive and steep rocky barrier, which separates the area Pays Diois from the Vercors Plateau.

The territory of the commune of Die is part of the regional natural park of these regions. Clearly, there were inhabitants during the Neolithic age, this has been confirmed by Chanqueyras excavations. A big engraved standing stone and two small menhirs that are now in the Die museum were found near the wine cooperative, these also proved inhabitation in this area at that time. Lots of clues show the extension of urbanisation during the 1st century. At the beginning of the 2nd century, the city of Die constructs monuments and becomes a Roman capital, replacing Luc-en-Diois in that function for the Celtic people of northern Voconces.

While the Roman Empire was showing signs of weakness, between the years and , a fortified wall was constructed around the town, protecting an urbanised surface of 25 hectares 62 acres , this wall is slightly more than a mile long.

During its construction, fragments of burial monuments were reused. Die had two main gates: IL10, for example, is thought to be a potent downregulator of the Th 1 response, and although animal models have shown a strong link between IL10 deficiency and gut inflammation, the use of IL10 therapy in clinical trials has been disappointing.

Histologically, skin plaques and inflamed synovial tissue demonstrate an abundance of T cells and increased vascularity. NICE guidance has recently been issued for the use of etanercept in severe plaque psoriasis in patients who have failed conventional therapies, and for efalizumab as a second line agent to etanercept.

Benefit in psoriasis trials has also been seen with the T cell costimulation blocker, abatacept. The efficacy of infliximab has been well documented in randomised controlled trials RCTs. These data suggested that early aggressive treatment of RA may avert joint destruction.

Approval for infliximab in psoriasis was based on two large RCTs. Improvements in articular and dermatologic manifestations of PsA were sustained until study completion and significant benefits in health related QoL and physical function were noted.

Remarkably, clinical remission was achieved in almost half of those on active treatment. Importantly, infliximab maintenance therapy also reduced the number of hospitalisations and need for surgery. Based on success in RCTs, infliximab was the first biologic approved for the treatment of UC and a licence has also been granted for use in AS. Unlike infliximab, etanercept has not shown benefit in CD as mentioned previously. The efficacy of etanercept in RA was initially evaluated as monotherapy.

Significant improvements were found in all ACR responder indices and QoL measures in the etanercept groups compared with placebo. Furthermore, many patients were able to discontinue MTX and corticosteroid therapy. Approval for the use of etanercept in psoriasis was based on data from two large phase III trials involving over patients.

NICE appraisals are in development for all these indications. Although clinical responses were comparable when either adalimumab and MTX were used alone, impressive results were seen when the two drugs were combined. The drug has since been investigated in a variety of IMIDs in which B cells have been suggested to play a role. Convincing evidence of efficacy comes from trials in RA with significant benefit being demonstrated when using rituximab either alone or in combination with MTX or cyclophosphamide.

The use of rituximab has not been limited to RA. In the clinical setting, two pivotal efficacy studies have now been published for RA. Success with abatacept has been noted in psoriasis, with early studies showing a clear clinical and biochemical improvement in addition to a quantitative reduction of T cells infiltrating the skin. Two additional agents have been approved for the treatment of plaque psoriasis. This produces a drug that can remain in circulation longer and can be conveniently administered once a month via subcutaneous injection.

Not surprisingly, certolizumab has also demonstrated efficacy in RA with outcomes comparable to that of etanercept and infliximab. There were however more opportunistic infections, such as histoplasmosis, and more skin and soft tissue infections in the cohort on biologic therapy.

The possible increased risk for the development of solid malignancy is far from clear. The tolerability of rituximab and abatacept in clinical trials has been very favourable with integrated safety data indicating that adverse events, such as malignancy and serious infections, are rare. Although neutropaenia has been noted in clinical trials with the IL1 blocker, the rate of serious infection is comparable to control patients.

In an RA study comparing the combined efficacy of anakinra and etanercept, however, no added benefit was seen and there was an unacceptably high incidence of serious infections. The precise relationship between several of these complications and biologic therapy is unknown, partly due to underreporting but also due to lack of comparison cohorts.

It may be that several of these comorbidities are associated with the disease itself, or perhaps due to extended exposure to standard DMARD therapy. Robust safety data will emerge from the numerous biologic registries established across Europe and the US. Due to the infrastructure required to manufacture these agents, the prices are unlikely to plummet following patent expiry. This cost, however, must be balanced against the significant economic burden IMIDs can pose to the individual patient and to society as a whole.

Biologics have revolutionised the treatment of autoimmune diseases due to their efficacy, speed of onset and tolerability. For the medical profession, this represents an important breakthrough in the way we classify pathology. Traditionally, IMIDs are treated by doctors who specialise in the organ most affected, however given that CD shares similar cytokine dysregulation to both RA and psoriasis, these systemic disorders may in the future be grouped as one disorder.

Although biologics provide a very useful addition to our therapeutic armamentarium, evidence suggests that they should not be considered a panacea. Furthermore, a substantial number of patients demonstrate a poor response to these agents, confirming that our understanding of IMID immunopathogenesis is far from complete. The current challenge is to identify exactly when to introduce biologics into the therapeutic algorithm.

Traditionally they have been used in those least likely to respond, that is, those who have failed multiple DMARDs and still have active disease. Certainly in rheumatology, the prevailing philosophy is to treat as early as possible in order to avoid the potential sequelae of joint destruction and functional loss.

If we could identify the patients most likely to respond, it may be possible to save time and expense and to avert potential toxic reactions. The field of pharmacogenetics will address this. Overall, biologic therapies represent an exciting advance in the treatment of autoimmune diseases. For millions of patients, treatment success may translate to rapid suppression of inflammation, prevention of disability, improved quality of life, and the goal of complete disease remission — something unthinkable a decade ago.

Dr Annabel Kuek declares no conflicts of interest. National Center for Biotechnology Information , U. Journal List Postgrad Med J v. Author information Article notes Copyright and License information Disclaimer. Received Aug 24; Accepted Nov This article has been cited by other articles in PMC. Open in a separate window. Rheumatoid arthritis Rheumatoid arthritis RA is a systemic inflammatory condition that primarily affects the synovial membrane of affected joints.

Alefacept and efalizumab Two additional agents have been approved for the treatment of plaque psoriasis. Biologic agents improve the signs and symptoms and quality of life of patients with rheumatoid arthritis, Crohn's disease, psoriasis and many orphan inflammatory conditions. Conclusions Biologics have revolutionised the treatment of autoimmune diseases due to their efficacy, speed of onset and tolerability.

Convincing evidence of efficacy comes from trials in RA with significant benefit being demonstrated when using rituximab either alone or in combination with MTX or cyclophosphamide.

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