Theraband Use Youtube Video

The Theraband (see it at Amazon) is a useful exercise tool that some people have utilized for injury rehabilitation, particularly for elbow problems

A YouTube video discussing the product can be seen here.

Screening For Factors Influencing Neurodegenerative Diseases

Screening for factors influencing neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal dementia, shows the importance of modifiers of an important mechanism of those diseases: hexanucleotide-repeat expansions in the C9ORF72 gene that result in toxic dipeptide-repeat proteins that aggregate – abnormal protein aggregation being a key feature of many nervous system-related diseases. This may have implications for treatment.  Abstract:

Hexanucleotide-repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). The nucleotide-repeat expansions are translated into dipeptide-repeat (DPR) proteins, which are aggregation prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons. We uncovered potent modifiers of DPR toxicity whose gene products function in nucleocytoplasmic transport, the endoplasmic reticulum (ER), proteasome, RNA-processing pathways, and chromatin modification. One modifier, TMX2, modulated the ER-stress signature elicited by C9ORF72 DPRs in neurons and improved survival of human induced motor neurons from patients with C9ORF72 ALS. Together, our results demonstrate the promise of CRISPR-Cas9 screens in defining mechanisms of neurodegenerative diseases.

Bacteriophages More Effective In The Presence Of Human Cells

Some good news: bacteriophage (viruses that infect and kill bacteria) can kill pathogenic bacteria better when in the presence of human cells than when just “in a test tube.”  Abstract:

Bacteriophage therapeutic development will clearly benefit from understanding the fundamental dynamics of in vivo phage-bacteria interactions. Such information can inform animal and human trials, and much can be ascertained from human cell-line work. We have developed a human cell-based system using Clostridium difficile, a pernicious hospital pathogen with limited treatment options, and the phage phiCDHS1 that effectively kills this bacterium in liquid culture. The human colon tumorigenic cell line HT-29 was used because it simulates the colon environment where C. difficile infection occurs. Studies on the dynamics of phage-bacteria interactions revealed novel facets of phage biology, showing that phage can reduce C. difficile numbers more effectively in the presence of HT-29 cells than in vitro. Both planktonic and adhered Clostridial cell numbers were successfully reduced. We hypothesise and demonstrate that this observation is due to strong phage adsorption to the HT-29 cells, which likely promotes phage-bacteria interactions. The data also showed that the phage phiCDHS1 was not toxic to HT-29 cells, and phage-mediated bacterial lysis did not cause toxin release and cytotoxic effects. The use of human cell lines to understand phage-bacterial dynamics offers valuable insights into phage biology in vivo, and can provide informative data for human trials.

CRISPR For HIV Treatment?

This paper is an analysis of the future potential of the CRISP gene editing method as a therapeutic approach against HIV infection.  It needs to be noted that there is nothing on the horizon, and methodologies, including delivery of the system to the relevant infected cells, needs to be worked out.  Nevertheless, I provide the abstract here for interested individuals who wish to delve deeper into the topic:

The huge success of current antiretroviral therapy is mediated by a triple effect: (i) Halting progression to AIDS in infected persons; (ii) reducing the risk of transmission to contacts (treatment as prevention); and (iii) minimizing the risk of HIV acquisition treating uninfected persons at risk (pre-exposure prophylaxis). However, UNAIDS has estimated that only 70% of infected people globally are diagnosed, only 53% are treated, and overall 44% have undetectable viral load, which is the necessary request for ensuring any antiretroviral benefit. Thus, with 37 million people currently living with HIV worldwide and more than 2 million new infections per year, the prospects for global HIV eradication are far on the horizon. Over the past couple of years, rapid development has been seen for technologies enabling modification of gene expression, either by direct inhibition by RNA interference (RNAi) or by genomic modification at DNA level. In particular, genome-editing endonucleases have significantly improved our ability to make precise changes in the DNA of eukaryotic cells. Notably, firstgeneration genome-editing technologies (i.e., ZFNs and TALENs) have been replaced by clustered regularly interspaced short palindromic repeats (CRISPR/Cas9), which work with a short guide RNA (gRNA) to hybridize to a target DNA site and recruit the Cas9 endonuclease. Once integrated into the host genome, HIV gene expression is regulated by the LTR promoter. Hypothetically, gene editing of the HIV promoter might have the potential to deactivate viral transcription by the introduction of mutations or fragment excision. HIV gene therapy progressed very slowly until recent breakthroughs in gene-editing methods using CRISPR/Cas9 (Liao et al. Nat Commun 2015;6:6413). Using a shorter version of the Cas9 endonuclease ensembled into an adenoviral vector, critical segments of thAQ!e viral DNA genome spanning between the LTR and gag regions were successfully removed in HIV transgenic mice. Excision was confirmed in all examined tissues as well as in circulating lymphocytes and resulted in a drastic reduction of HIV-RNA (Kaminski et al. Gene Ther 2016;23:690-5). Moreover, using latently infected CD4+ T lymphocytes from HIV-infected persons, lentiviral-delivered CRISPR/Cas9 precisely removed the entire HIV genome spanning between the 50 and 30 LTRs of integrated HIV proviral DNA (Kaminski et al., Sci Rep 2016;6:22555), providing a proof of concept of the high potential of genome-editing technologies. Before moving to the clinic, the CRISPR/Cas9 technology must solve several major issues in the HIV scenario. First, generation of resistance is a major concern. Mutations may occur surrounding the targeted site and result in the selection of strains that are no longer recognized nor cleaved by CRISPR (Badia et al. Curr Opin Virol 2017;24:46-54). The efficacy of the anti-HIV CRISPR/Cas9 strategy is highly dependent on the gRNA sequence, yet some mutant viral strains show poor or no cleavage at all. Higher CRISPR/Cas9 pressure could delay but not eliminate viral replication when using a combination of distinct gRNAs targeting distinct HIV proviral genes. In this case, although the reading frame may remain unaltered, an accumulation of insertions and/or deletions may occur in the target sequence, rendering new viral strains insensitive to CRISPR/Cas9 cleavage. Finally, double-strand breaks resulting from CRISPR/Cas9 activity and subsequent cellular non-homologous end joining machinery may introduce mutations in sequences that are no longer recognized by the gRNA, and therefore not susceptible to Cas9 cleavage. A second consideration is a need for developing safe and effective mechanisms of delivery. Adenoviral vectors have long been studied in gene therapy and represent an ideal viral vector for transduction at different tissues. However, the packaging size of adenoviral vectors is a limiting factor, especially for CRIPSR/Cas9. Third, HIV has a genome of about 10 kb while a gRNA generally only targets 20 bp of the DNA molecule, which means that there are thousands available targeting sites for the provirus in latently infected cells. To date, there is no platform established solely for gRNA candidate evaluation in HIV provirus eradication. A final consideration is an access to all tissues and cells potentially harboring the HIV provirus, including reservoirs as the central nervous system. In this regard, efforts are being focused in the development of Cas9/gRNA nanoparticle formulations. To overcome these problems, a group in Florida recently developed human transgenic cells that may be used for gene-editing studies and as platform for high-throughput screen of HIV provirus disrupters (Huang et al. Sci Rep 2017;7:5955). Of note, Cas9 protein instead of a Cas9 plasmid was used. Compared to a plasmid introduction, Cas9 protein agents could be easily quantitatively applied and standardized, mimicking better real clinic scenarios. In summary, RNAi-based technologies have widely dominated gene therapy research during the past decade, with overall slow progress. However, the advent of new gene-editing technologies, and especially the CRISPR/Cas9 system, has revolutionized the field. In the HIV context, CRISPR/Cas9 applications might go further than those of RNAi, for example, enabling excision of segments of integrated proviral DNA from latently infected cells and allowing complete provirus elimination, or it may be used to reverse HIV latency. Although important challenges still need to be overcome, a promising pathway to HIV cure seems to have been found.

Gut Microbiota As Effectors Of Cell Physiology And As Potential Therapeutic Vectors

By Darryl Leja, NHGRI - http://www.genome.gov/dmd/img.cfm?node=Photos/Graphics&id=85320, Public Domain, https://commons.wikimedia.org/w/index.php?curid=29534265

It is known that microbiota, particularly gastrointestinal bacteria, can have a profound effect on human health.  This study (linked here) shows another mechanism by which this occurs – the bacteria can produce compounds that affect signaling pathways in human cells, potentially regulating metabolic hormones and glucose levels. Thus, bacteria can produce factors that mimic human equivalents, affecting human cell physiology, and thus influencing human health. The authors propose “microbiome-biosynthetic gene therapy” – leveraging this ability of microbes to have them produce factors that can promote therapeutic changes in the human system.  Abstract:

Commensal bacteria are believed to have important roles in human health. The mechanisms by which they affect mammalian physiology remain poorly understood, but bacterial metabolites are likely to be key components of host interactions. Here we use bioinformatics and synthetic biology to mine the human microbiota for N-acyl amides that interact with G-protein-coupled receptors (GPCRs). We found that N-acyl amide synthase genes are enriched in gastrointestinal bacteria and the lipids that they encode interact with GPCRs that regulate gastrointestinal tract physiology. Mouse and cell-based models demonstrate that commensal GPR119 agonists regulate metabolic hormones and glucose homeostasis as efficiently as human ligands, although future studies are needed to define their potential physiological role in humans. Our results suggest that chemical mimicry of eukaryotic signalling molecules may be common among commensal bacteria and that manipulation of microbiota genes encoding metabolites that elicit host cellular responses represents a possible small-molecule therapeutic modality (microbiome-biosynthetic gene therapy).

Treating My Golfer's Elbow and Tennis Elbow

I’ve had both golfer’s elbow (medial epicondylitis) and tennis elbow (lateral epicondylitis). Of the two, golfer’s was the worse for me, it was more painful, lasted longer, impeded more activities, and was more difficult to treat.  I was taking Advil for months for the golfer’s elbow. However, both maladies are nasty.  Also, in my case, the pain was not from gripping (as it is with many people) but with elbow flexion and extension.  With golfer’s elbow, I had the most pain from activities that entailed lifting weight, exerting force with the palm up (e.g., curling a weight); with tennis elbow, the major pain was with extending the elbow as in a dumbbell triceps curl.  In my case I think both golfer’s and tennis elbow was principally localized on the muscle-tendon units along the ring finger axis, from ring finger to elbow.

Current thought suggests the initial problem is a tendinitis which over time can evolve into a long-lasting tendonosis, involving damage and degeneration to the elbow tendons, with golfer’s involving flexor tendons (e.g., palm up wrist curl) and tennis involving the extensor tendons (e.g., palm down wrist curl).  The initiating event is likely a small tear or multiple tears in the tendon. However, in my experience I believe an important component is tightness, particularly for golfer’s, while tightness and weakness is a problem for tennis. So, stretching can be important, but, in my opinion and experience, for golfer’s elbow, the classic “extend your arm palm up and push your hand down” stretch made the problem worse. However, slow stretching as part of the eccentric part of an exercise, as those explained below, helped to elongate the tendon-muscle unit under weight, which helped. While I see the stretching under weight as important, the literature suggests that eccentric exercises stimulate the tendon to remodel itself, synthesize healthy tissue, etc. Just resting is not enough. Once the initial tendinitis part of the problem with inflammation, etc. is done (at that early point, rest and ice may be useful), work needs to be done to stimulate tendon remodeling and to relieve the stress on the injured point by the stretching of the area.

What is eccentric?   Eccentric is the lowering part of a muscle movement, while concentric is the lifting part. For a barbell curl, concentric is lifting the bar up, curling it up, while eccentric is lowering it back down to the starting position. And when I talk about “therapy” here I mean doing the exercises when you have an active case of golfer’s/tennis elbow; “maintenance” is doing preventive exercises when you are feeling better.

Note that I do the following regularly now, as preventive maintenance. I consider my elbow problems currently 95% better, in the sense that usually it is fine, but with too much work (like too much barbell curls), I can get some flare-ups (so far minor).  When that happens I increase the therapeutic exercises described below, and go easy on the aggravating activities for a while.

Golfer’s elbow plan:

I did the following for golfer’s elbow. During this time I avoided weight-lifting exercises that aggravated the condition (normal palm-up curls) and instead did alternatives like hammer curls (palms facing toward body).

I would divide the work I did into the three most important (major) exercises and two auxiliary (minor) exercises which are still important.

Major:

1. See this. Load up a dumbbell rod or a broomstick with weights at the end and go to it. I would do sets of 20 reps. For maintenance I only do I set each arm. When you have the problem, do more than one set. It will take time. I saw progress when I got up to five pounds at a hand-weight distance of five inches.  Today, I use 7.5 pounds with the left arm at around 4-5 inches and the right 5-9 inches.

This is a great exercise. I believe it both stimulates tendon remodeling AND slowly stretches the tendon-muscle unit, so the area is less tight, so that the muscle is not constantly “tugging” at the painful area. Try and do 20 reps per set. One set twice per day 4-5 days per week for maintenance; do at least two sets twice per day for therapy. Start light and work up the weight and distance.

2. Use the Flextend glove. This is a great tool. Again, be patient, it takes time. I started seeing improvement once I got to two strands used at a time for each hand.  The massage did not help, and the stretching I think made me worse. But the actual exercise is great, and the fellow in the video really explains well the double action of stretching and strengthening. The utility of these exercises underscores the importance of tightness in the development of golfer’s elbow, and how dynamic stretching – stretching against resistance (weights or bands) can be helpful.  Do this twice per day, 4-5 days per week. Try and get to 20 reps per set, do as in video.

3. Eccentric dumbbell wrist curls. Start light, work up the weight. I use 20 lbs. now.  Put dumbbell in hand of affected arm, palm up, arm on leg, dumbbell over knee. Use the other hand (of unaffected arm) to lift the dumbbell to the up position (don’t do the concentric lift with the affected arm).  Then, using the affected arm only, slowly lower the dumbbell all the way down to the full down position, with wrist fully bent downward. Then use the unaffected hand/arm to life the weight up and repeat. Do 20 reps per set, once per day, 4-5 days per week.  One set for maintenance. Multiple sets (up to three) for therapy, or you can sometimes try one long set (up to 50 reps). You can also do it twice per day for therapy.

Minor.

4. Expand Your Hand Bands. Twice per week, once per day, three sets of 25 reps. Build up to increasing intensity of the bands; I use the red ones now. Try and open your hands wide and get a good stretch.

5. Eccentric dumbbell curls. With the same dumbbell you use for the eccentric wrist curls, do this exercise, one set once per week.  Standing, hold dumbbell at arm’s length, palm up in hand of affected arm. Using the unaffected hand, raise the dumbbell up to the top, fully curled position. Very slowly lower – the same principle as the eccentric wrist curl, but here you are stretching the entire arm, all the flexors. This also acclimates your arm to accept the stress of doing curls again. Do 4-10 reps, depending on the weight and how you feel. Probably 6-8 reps would be best.

Tennis elbow plan:

Some of the exercises outlined above for golfer’s elbow can work for tennis elbow, if suitably modified. For example, the Flextend glove has a tennis elbow program.

The Expand Your Hand Bands are helpful here as well.  The exercise with the weighted rod used for golfer’s elbow (# 1, above) can be adapted for tennis elbow, just lower in the opposite direction (I do a couple of sets per week of that for tennis elbow prevention now).

Many people are very happy with results from the Flexbar for tennis elbow. I believe it can be effective for most people; I have one myself which I sometimes use for maintenance to prevent future tennis elbow, or to use when I feel some twinges there. The exercise can also be used in reverse fashion for golfer’s elbow, but I am less optimistic about that based on my own experience – the range of motion for me is much more limited for medial elbow Flexbar exercises. But for lateral elbow problems – tennis elbow – Flexbar can be a very effective addition to your therapy regimen.

But I had tennis elbow long before I heard of that, and I cured it with exercises of my own invention, coupled with stretching. Yes, the sort of stretching I did not find helpful for golfer’s elbow. The interesting thing is, you can find people saying online that the sort of “pull one hand with the other” type stretching is good for golfer’s but not tennis, but I found the opposite for myself – this is what worked for me, specifically.

So, I did the following for tennis elbow therapy:

1. Find a relatively light dumbbell (or even a heavy soup can).  Do a few (palm down) reverse wrist curls to warm up.  Then do this: standing up, hold the weight at arm’s length in the hand of the affected arm, palm down.  Then bend your arm at the elbow (and only the elbow, try and keep the shoulder straight), until the arm is completely bent and the weight is next to your chin. If necessary, you can support that arm with your other arm to prevent stress to the shoulder supporting the weight (you don’t want to cause shoulder problems while treating tennis elbow! Anyway, start with a light weight and support the arm as indicated if that is easier and more comfortable). Then, with your arm bent in that position, do reverse wrist curls with the weight under your chin. Go slow and get a good stretch. With ALL of the exercise listed in this post, if it is too painful, during or after, you can go to a lighter weight. However, in my case, I did feel discomfort at the beginning (I used a three pound dumbbell for 20+ reps; today for maintenance I have worked up to an eight pound dumbbell for 20 or so reps), not extremely bad, but with your elbow in that stretched position, you are putting stress on the painful tendon and then doing exercises. My idea was to strengthen the area in its position of maximal weakness, so that if I worked it to a point where I could do high reps in that position with no pain (eventually) then I was getting better. This exercise I think stretches the area under dynamic stress and may stimulate tendon remodeling (?). Note though that this is NOT a strictly eccentric exercise, I was doing the full reverse wrist curl, concentric (up) as well as eccentric (down).

2. Then after one or multiple sets of the exercise above, I would put the hand of the affected arm against a wall, palm against wall and fingers up, and slowly lower myself to the wall, essentially doing the eccentric phase of a one-handed push-up against the wall. Body weight would be on the bent arm (note: I was someone what had been doing years of weight training, for others, they may need to at least partially support themselves with the other arm as well). This too causes some discomfort, but my opinion was, again, if I could acclimate my arm to this stress, and if I could eventually do this without pain, then I would be getting better.

3. I immediately followed the above exercises with the standard tennis elbow stretch, affected arm straight out, palm down, and then pulling the hand down with the other hand and holding for 20-30 seconds.  After than I would sometimes just move my arm up and down (with no weight) in a reverse curl motion, to loosen things up and I would sometimes feel a faint “rubber band snapping” in the extensors of the forearm, and sometimes would feel as if the pain was moving from an intense pain at the lateral epicondyle to a fainter soreness in the muscles. It felt almost as if the pain was being "pulled" off the joint into the muscles and lessening. I suspect that by stretching the entire region, the tight pulling on the tendon was decreased, allowing for healing.

I can imagine some medical professional may disapprove of my tennis elbow exercises because of the significant stress on the elbow. If your doctors, nurses, therapists, etc. disapprove, then you should of course listen to them. Alternatively, they may say give it a chance, but, always listen to the medical experts. In my case, the therapists I went to were useless, and I decided I needed more intensive work. But what was useful to me may not be for you (and vice versa).

For maintenance to prevent future tennis elbow, I do the bent arm reverse wrist curl several times per week, and also do the weighed rod exercise for tennis elbow, as well as for golfer’s elbow, several times per week.

So, that is what worked for me. As always, if you are interested, consult your medical professional. These things take time. While my tennis elbow responded relatively quickly to the therapy routine (and I mean by “relatively quickly” 3-4 months), the golfer’s elbow took about six months to show significant improvement and longer to get to the point it is today.  But I had waited a long time before doing these routines. For me, rest was useless; in my case, it had likely already progressed to tendonosis – tendon damage – and the only way to reverse it was to actively engage in therapy. Keep in mind my conditions were relatively severe; in the case of the golfer’s elbow, even closing a car door or washing my hair hurt. With the tennis elbow, tooth brushing and flossing hurt. And yet, I’ve been able to get to the 95% better condition, with regular function at 100% and only the occasional mild flare-up to deal with so far. So, in my case, these routines worked, and still work as prevention.