Big thanks to a mate, let's call him Mr W, for the heads up on this one.
All quotes below from the paper itself.
Link to the paper in reference 1 at the end.
INTRO
Chikungunya (CHIKV) is transmitted by pesky Mozzies. (err... I have nothing to do with that).
Symptoms can include:
High fever
Chills
Severe arthralgia
Myalgia
Maculopapular rash
General weakness
Headache
But it's also the painful rheumatic symptoms that can often affect large joints.These symptoms can last more than 3 months in some instances and even up to several years!
A CURIOUS INFLICTION
The paper goes on to suggest that due to the nature of the symptoms, many patients complain of symptoms that are very similar to Rheumatoid Arthritis (RA). MRI shows both conditions (CHIKV and RA) "cause joint effusions, bony erosions and synovial thickening, all of which contribute to the joint degeneration and pain".
Now there is a link and Paradigmers, these links intrigue me. No doubt there is a strong link between OA, RA and CHIKV at least in terms of symptomatic observations and possible pathways to meaningful treatment of these with iPPS. (My views)
PREVALENCE
Do we need to do a Mozz Quiz ® here? For sure...
How many countries have had cases of CHIKV and how many total cases are reported thus far?
A) Well it has to be a few more than a handful as it's a mainly tropical disease right? Let's go 5 countries, 50,000 cases?
B) 13 countries and 200,000 patients?
C) I'm getting warmer right?14 countries and 350,000 patients?
The answer is 45 countries and an incredible 2.9 million patients! The researchers stated that due to a number of factors including climate change and people travelling, cases will only increase. These figures aren't being pulled of a random site, they come from the peer review!
Let me quote from the report : "Over the last fifteen years, CHIKV has received significant attention due to its unprecedented spread and repetitive large outbreaks, including the most recent Caribbean outbreak where all islands were affected and over 800 000 cases (2% of the population) were diagnosed". The report goes on to state that local transmission has crossed into a number of countries.
Above graphic from Researchgate.net3
CURRENT REMEDIES?
Here is a quote from the paper: "To date, there are no licensed vaccines or specific therapeutics available for the treatment of CHIKV arthritides". NSAIDS are often prescribed but we already know the destructive nature of this class, the paper also affirms it: "however, long-term use of NSAIDs has unwanted side effects including gastric ulcers, cardiovascular complications, and renal impairment".
Corticosteroids have also been suggested but the researchers acknowledge these Corticosteroids aren't without problems, Corticosteroids " ...has been shown to increase the risk of developing infection, cataracts, glaucoma, diabetes and osteoporosis".
Not a viable solution.
SCENE IS SET
So what did these guys measure? Well more work for me down the track with some new measurements that I haven't come across such as Nanostring and PPI Network.
Grip Strength
Measurement
Chemokine and cytokine analysis (Yes I too am drawing parallels with Bond + 1 (008))
Histology
RNA Isolation and Nanostring and nCounter gene expression (Yep, this is new material for me)
Protein-Protein Interaction network ("Protein Protein"? See I told you my life is full of proteins these days...it's so important they repeated it?)
RESULTS
Right, let's get into it, how did WE perform then? Are we any good? How was the Magic in the magic juice?
So there were a few groups of mice that were analysed:
M1 Mock (Control) M2 PPS - PPS alone without CHIKV M3 CHIKV M4 CHIKV/PPS (Magic Juice Treatment)
M1 I can easily understand, a control to see how normal mice performed. Group M2 is interesting as that in my mind tests if the PPS drug is being counterproductive. ie you don't want hand grip strength to REDUCE if iPPS is used on a mouse that does not have CHIKV. That would be a warning of a potential destructive symptom. M3 is just the disease borne mice and M4 is what we all want to see and how it performs, ie Mice with CHIKV and are treated with iPPS.
Results?Mock increased by 22.8% (this possibly could be attributed due to normal growth of the mouse over the duration as was observed in foot swelling - see below). PPS (M2) alone increased by 3.5%. CHIKV-infected PPS-treated improved by 11.4% CHIKV-infected untreated mice had not recovered complete strength displaying a loss of 7.8%
In terms of foot swelling look at these results:Mock animals had a marginal increase of 3.2%, PPS alone had an increase of 8.2% and both of these groups "are attributed to normal mouse growth over time". The untreated mice? "CHIKV-infected untreated mice had an increase from baseline of 99.7%". And how did IPPS impact this? It brought it down to 45.4%, and in the words of the researchers; "This represented a significant reduction in swelling between CHIKV-infected untreated and CHIKV-infected PPS-treated mice (****P < 0.0001)".
I liked the P value representing degree of significance. So we more than halved the swelling.
INFILTRATES IN HIND LIMBS
Stick with me here Paradigmers, didn't get bamboozled or bored by any of the science, Infiltrates is just a sciency way of saying a substance or observation like inflammation of a cell or tissue.Firstly, how did PPS affect mice that didn't have CHIKV?"... staining of mock and PPS alone treatment groups displayed no observable inflammation".
So this mean PPS on its own didn't do any damage or cause any inflammation. What about PPS's CHIKV mice?How about a quote?
" In contrast, CHIKV-infected PPS-treated mice displayed a visible reduction in the overall number of infiltrates in these structures of the hind limbs".
Key Quote time??
"Interestingly, at day 21, histological analyses showed complete disease resolution".
What else did PPS do?
"...treatment of PPS protected muscle fibres from damage".
If I have a drug that results in at least some chance of complete disease resolution AND protects muscle fibres from damage....well I'm interested.
MORE?
"Furthermore, PPS treatment appeared to accelerate the inflammatory repair processes with evidence of an increase in the number of regenerating myocytes".
Naysayers? Do you think the results could have been swayed by the fact that the disease was slowly dissipating and remedying itself anyway over time? The researchers covered this scenario:
"Additionally, the reduction in clinical disease score and joint inflammation was not a result of reduced viral load in CHIKV-infected PPS-treated mice. "
Paradigmers, some fairly awesome results...take a look at the next subheading, it's not a Mozz sub heading this time, it was a subheading in the paper itself:
PPS TREATMENT REDUCES JOINT DESTRUCTION
As a testimony of this disease, "CHIKV-infected untreated mice showed a marked depletion of sulfated GAGs...with corresponding cartilage shrinkage"...but this "was significantly improved with PPS treatment". The CHIKV infected mice had less severe cartilage changes even up to day 21 after the initial infection of CHIKV. The researchers concluded that PPS treatment protects joint cartilage during CHIKV infection.
SERUM LEVELS OF CHEMOKINES AND CYTOKINES
Well as we know our 008 is under way. This study looked at such biomarkers as CCL2, CCL7 and a few others. The observation were stated clearly: " Compared to CHIKV-infected untreated mice, CHIKV-infected PPS-treated mice showed significant reductions in serum biomarkers for the chemokines."
How important is just one of these biomarkers known as CCL2?Let me quote "CCL2 has been well characterised in atherosclerosis and arthritis development". In a recent meta-analysis study, CCL2 was identified as an important marker for the progression of osteoarthritis (OA) with the authors concluding that it may serve as a potential biomarker for the diagnosis of OA".
A number of new and novel observations were highlighted just in the conclusion. Lots of food for thought here.
Red circle - we have seen this biomarker before, TNF-Alpha, plays a crucial role in inflammation. Green Circle - this biomarker has been linked to Interstitial Lung Disease.2
NANOSTRINGS?
Using a technique called NanoString™ the researchers came up with a number of observations in terms of gene expressions:
I can't pretend to know each and every one of the above gene expressions, what I can point out is that quite simply the PPS played a significant role in changing the said expressions and this contributed to the overall results. We can easily take any of these expressions and simply learn more about what they are and what effect they can have.
CONCLUSION
Perhaps the most telling statements can be found in this area, here is one such quote:"Furthermore, we have shown for the first time, that CHIKV-infected untreated mice experience a prolonged and significant decrease in grip strength, an important rheumatological function test ". And further, "PPS treatment not only attenuated local inflammation in this animal model but was shown to prevent limb dysfunction as evidenced by reduced foot swelling and grip strength respectively. "
Final statements in the publication were "Overall, our study has demonstrated for the first time that PPS is an effective treatment against CHIKV-induced arthritis through investigation of a number of parameters." and further "PPS was shown to exert effect on growth factor signalling, lymphocyte activation and pathogen response, all which likely contribute to the amelioration of CHIKV-induced arthritic disease".
Much more can be gleaned from the report itself. Quite a read and a possible insight on what's to come.
Next step? Well it may just be a new round of discussions with certain interested parties? Did someone say the DOD? (Spec comment, only my thoughts).
(20min delay)
