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PepGen's enhanced delivery oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and nuclear uptake of therapeutic oligonucleotides. PGN-EDO51 is PepGen's investigational clinical candidate for the treatment of Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping. In nonclinical studies and a Phase 1 trial in healthy volunteers, PepGen's technology demonstrated significant improvement in the delivery of oligonucleotide resulting in higher levels of tissue concentrations and exon 51 skipping. Nuclear delivery of the EDO was confirmed in human tissue from the Phase 1 trial. The collective nonclinical and clinical data strongly suggest that repeat administration of PGN-EDO51 in people with DMD may lead to higher production of functional dystrophin, potentially resulting in improved clinical outcomes over time. PepGen's Phase 2 clinical program includes 2 studies: CONNECT1-EDO51, an open-label multiple-ascending dose (MAD) study being conducted in Canada, and CONNECT2-EDO51, a multinational randomized placebo-controlled MAD study. Participants who complete the MAD period in either study will have the opportunity to continue dosing in an open-label, long-term extension. The primary objectives of CONNECT2-EDO51 are to evaluate the safety and tolerability of PGN-EDO51 and to determine dystrophin levels following repeat dosing in male participants with DMD amenable to exon 51 skipping. Secondary objectives are plasma pharmacokinetics (PK) and concentration of PGN-EDO51 in muscle tissue. Muscle biopsies occur at Baseline and Week 25. Main inclusion criteria are age ≥6 years with a confirmed genetic diagnosis of DMD amenable to exon 51 skipping, and weight ≥25 kg. Participants will be randomized 3:1 to receive either PGN-EDO51 or placebo in multiple ascending doses across 3 cohorts. All participants (N=20) will receive 7 doses at approximately 4-week intervals over 24 weeks. The study design will be presented. [ABSTRACT FROM AUTHOR]

PepGen's enhanced delivery oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and nuclear uptake of therapeutic oligonucleotides. PGN-EDO51 is PepGen's investigational clinical candidate for the treatment of Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping. In nonclinical studies and a Phase 1 trial in healthy volunteers, PepGen's technology demonstrated significant improvement in the delivery of oligonucleotides resulting in higher levels of tissue concentrations and exon 51 skipping. Nuclear delivery of the EDO was confirmed in human tissue from the Phase 1 trial. Collective nonclinical and clinical data strongly suggest that repeat administration of PGN-EDO51 in people with DMD may lead to higher production of functional dystrophin, potentially resulting in improved clinical outcomes. PepGen's Phase 2 clinical program includes 2 studies: CONNECT1-EDO51, an open-label multiple-ascending dose (MAD) study being conducted in Canada (NCT06079736), and CONNECT2-EDO51, a multinational randomized placebo-controlled MAD study. Participants who complete the MAD period in either study will have the opportunity to continue dosing in a long-term extension. The CONNECT1-EDO51 study objective is to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) (dystrophin, exon skipping) of PGN-EDO51 following repeat dosing in male participants with DMD amenable to exon 51 skipping. Muscle biopsies are taken at Baseline and Week 13. Main inclusion criteria are age ≥8 years with a confirmed genetic diagnosis of DMD amenable to exon 51 skipping, and weight ≥25 kg. Participants will receive PGN-EDO51 in ascending doses across 3 cohorts. All participants (N=10) will receive 4 doses of PGN-EDO51 at approximately 4-week intervals over 12 weeks. Participants in the first cohort have received repeat doses of 5 mg/kg PGN-EDO51. Safety and initial dystrophin results from this cohort will be presented. [ABSTRACT FROM AUTHOR]

PepGen's enhanced delivery oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and nuclear uptake of therapeutic oligonucleotides. PGN-EDODM1 is being evaluated for the treatment of myotonic dystrophy type 1 (DM1). PGN-EDODM1 binds to pathogenic CUG trinucleotide repeat expansions in DMPK mRNA, thereby liberating MBNL1 protein through steric blocking without degrading DMPK transcripts. Liberation of sequestered MBNL1 is hypothesized to restore splicing profiles of multiple downstream transcripts; a central cause of DM1 pathology. Nonclinical data demonstrate that PGN-EDODM1 reduces the number of myonuclear foci (DM1 cells), liberates MBNL1 (DM1 cells), corrects mis-splicing (DM1 cells, HSA-LR mouse), and normalizes myotonia (HSA-LR mouse). FREEDOM-DM1, a randomized, double-blind placebo-controlled single ascending dose study is underway (NCT06204809). The objective of the study is to evaluate safety and tolerability (primary objective) and plasma pharmacokinetics (secondary objective) following a single dose of PGN-EDODM1 in adults with DM1. Exploratory measurements include concentration of PGN-EDODM1 in skeletal muscle, pharmacodynamics (changes in splicing pattern of affected transcripts), as well as person-reported outcome (PRO) measures and functional assessments (including video hand opening time to assess myotonia). This study consists of three dose-ascending cohorts of participants (N=8), each randomized 3:1 investigational drug to placebo. A muscle needle biopsy will be performed at Baseline, Week 4, and Week 16 to measure tissue drug concentrations and evaluate splicing of selected transcripts. The design of this study and the subsequent FREEDOM2-DM1 multiple ascending dose study will be presented. The FREEDOM-DM1 and FREEDOM2-DM1 studies are designed to support and advance the clinical development of PGN-EDODM1. [ABSTRACT FROM AUTHOR]

Post-polio syndrome (PPS) is characterized by recrudescence or worsening of motor neuron disease symptoms decades after recovery from acute paralytic poliovirus infection, i.e., poliomyelitis. PPS afflicts between 25% and 40% of poliomyelitis survivors and mimics motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS), due to its selective impairment, degeneration, or death of motor neurons in the brainstem and spinal cord. Herein, we report a case of PPS in a 68-year-old man with a remote history of bulbar and cervical cord involvement by poliomyelitis, review the relevant literature, and contrast the salient histopathologic features that distinguish our case of PPS from ALS.

Background: Opicinumab is a human monoclonal antibody against LINGO-1, an inhibitor of oligodendrocyte differentiation and axonal regeneration. Previous findings suggested that opicinumab treatment might enhance remyelination in patients with CNS demyelinating diseases. We aimed to assess the safety and efficacy of opicinumab in patients with relapsing multiple sclerosis., Methods: We did a randomised, double-blind, placebo-controlled, dose-ranging, phase 2 study (SYNERGY) at 72 sites in 12 countries. Participants (aged 18-58 years) with relapsing multiple sclerosis (relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis with relapses) were randomised in a 1:2:2:2:2 ratio by an interactive voice and web response system to opicinumab 3 mg/kg, 10 mg/kg, 30 mg/kg, or 100 mg/kg, or placebo. An identical volume of study drug was administered intravenously once every 4 weeks. All participants self-administered intramuscular interferon beta-1a as background anti-inflammatory treatment once a week. The primary endpoint was the percentage of participants achieving confirmed disability improvement over 72 weeks, which was a multicomponent endpoint measured by the Expanded Disability Status Scale, the Timed 25-Foot Walk, the Nine-Hole Peg Test, and the 3 s Paced Auditory Serial Addition Test. The primary endpoint was analysed under intention-to-treat principles. This study is registered at ClinicalTrials.gov, number NCT01864148., Findings: Between Aug 13, 2013, and July 31, 2014, 419 patients were enrolled and randomly assigned either placebo (n=93) or opicinumab 3 mg/kg (n=45), 10 mg/kg (n=95), 30 mg/kg (n=94; one patient did not receive the assigned treatment), or 100 mg/kg (n=92). The last patient visit was on March 29, 2016. Confirmed disability improvement over 72 weeks was seen in 45 (49%) of 91 patients assigned to placebo, 21 (47%) of 45 assigned to opicinumab 3 mg/kg, 59 (63%) of 94 assigned to opicinumab 10 mg/kg, 59 (65%) of 91 assigned to opicinumab 30 mg/kg, and 36 (40%) of 91 assigned to opicinumab 100 mg/kg. A linear dose-response in the probability of confirmed disability improvement was not seen (linear trend test p=0·89). Adverse events occurred in 79 (85%) patients assigned placebo and in 275 (85%) assigned any dose of opicinumab. The most common adverse events of any grade in patients assigned any dose of opicinumab included influenza-like illness (140 [43%] with any dose of opicinumab vs 37 [40%] with placebo), multiple sclerosis relapses (117 [36%] vs 30 [32%]), and headache (51 [16%] vs 23 [25%]). Serious adverse events reported as related to treatment were urinary tract infection in one (1%) participant in the the placebo group, suicidal ideation and intentional overdose in one (1%) participant in the 30 mg/kg opicinumab group, bipolar disorder in one (1%) participant in the 100 mg/kg opicinumab group, and hypersensitivity in four (4%) participants in the 100 mg/kg opicinumab group. One patient in the opicinumab 30 mg/kg group died during the study due to a traffic accident, which was not considered related to study treatment., Interpretation: Our findings did not show a significant dose-linear improvement in disability compared with placebo in patients with relapsing multiple sclerosis. Further studies are needed to investigate whether some subpopulations identified in the study might benefit from opicinumab treatment at an optimum dose., Funding: Biogen., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Jaw clonus is an uncommon pathological reflex thought to indicate corticospinal tract dysfunction above the Vth cranial nerve. It is useful as a sign of upper motor neuron dysfunction above the spinal cord. One theory of self excitation posits an inverse and linear relationship between clonus frequency and the length of the reflex arc, to explain the higher frequency of clonus in the ankles than the wrist. Only two previous cases of jaw clonus have been published. One of these plus the present case suggest that an inverse and linear relationship is not correct.

Objective: Determine healthcare resource utilization in migraine patients prescribed preventive medications in the resident neurology clinic at Rhode Island Hospital., Background: Similar institutions have demonstrated that treatment with preventive migraine medications results in significant decreases in outpatient and ED visits, CT/ MRI scans and abortive medication usage., Methods: Retrospective chart review identified 166 patients based on icd-9 code. Resource utilization was defined as documented emergency room visits, MRI/CT, hospitalizations, outpatient visits and abortive medication usage., Results: There was no difference in resource utilization in those patients taking or not taking a preventive medication. Only 53% were on a level A recommended medication and of those 35.5% were treated with recommended doses., Conclusion: UNLIKE similar institutions, there was no difference in resource utilization in patients taking preventive medications. A possible explanation for this discrepancy may be that patients are sub-optimally treated with less effective medications and doses. Employment of appropriate preventive medications may result in a decrease in the utilization of healthcare resources.

The mechanisms of alcohol-related peripheral neuropathy (ALPN) are poorly understood. We hypothesize that, like alcohol-related liver and brain degeneration, ALPN may be mediated by combined effects of insulin/IGF resistance and oxidative stress. Adult male Long Evans rats were chronically pair-fed with diets containing 0% or 37% ethanol (caloric), and subjected to nerve conduction studies. Chronic ethanol feeding slowed nerve conduction in the tibial (p = 0.0021) motor nerve, and not plantar sensory nerve, but it did not affect amplitude. Histological studies of the sciatic nerve revealed reduced nerve fiber diameters with increased regenerative sprouts, and denervation myopathy in ethanol-fed rats. qRT-PCR analysis demonstrated reduced mRNA levels of insulin, IGF-1, and IGF-2 polypeptides, IGF-1 receptor, and IRS2, and ELISAs revealed reduced immunoreactivity for insulin and IGF-1 receptors, IRS-1, IRS-4, myelin-associated glycoprotein, and tau in sciatic nerves of ethanol-fed rats (all p < 0.05 or better). The findings suggest that ALPN is characterized by (1) slowed conduction velocity with demyelination, and a small component of axonal degeneration; (2) impaired trophic factor signaling due to insulin and IGF resistance; and (3) degeneration of myelin and axonal cytoskeletal proteins. Therefore, ALPN is likely mediated by molecular and signal transduction abnormalities similar to those identified in alcoholic liver and brain degeneration.

Alcohol-related peripheral neuropathy (ALN) is a potentially debilitating complication of alcoholism that results in sensory, motor, and autonomic dysfunction. Unfortunately, ALN is rarely discussed as a specific disease entity in textbooks because it is widely assumed to primarily reflect consequences of nutritional deficiency. This hypothesis is largely based on observations first made over eight decades ago when it was demonstrated that thiamine deficiency (beriberi) neuropathy was clinically similar to ALN. In recent studies, failure of thiamine treatment to reverse ALN, together with new information demonstrating clinical and electrophysiological distinctions between ALN and nutritional deficiency neuropathies, suggests that alcohol itself may significantly predispose and enhance development of neuropathy in the appropriate clinical setting. We reviewed the evidence on both sides and conclude that ALN should be regarded as a toxic rather than nutritional neuropathy., (Copyright © 2011 Wiley Periodicals, Inc.)

Though common, myofascial pain syndrome can be difficult to recognize and distinguish from underlying entities. It is often confused with fibromyalgia. Diagnosis hinges on the identification of painful muscle trigger points that, when palpated, create local twitch responses and refer pain in predictable patterns. With appropriate treatment, such as stretch and spray, trigger point injections, or massage therapy, prognosis is good. Perpetuating factors, such as poor posture or workplace ergonomics, also need to be addressed.

Sever's disease, or apophysitis of the calcaneus, is a common but frequently undiagnosed source of heel pain in young athletes. This condition frequently occurs before or during the peak growth spurt in boys and girls, often shortly after they begin a new sport or season. Sever's disease often occurs in running and jumping sports, particularly soccer. Patients present with intermittent or continuous heel pain occurring with weight bearing. Findings include a positive squeeze test and tight heel cords. Sever's disease cannot be diagnosed radiographically. The condition usually resolves two weeks to two months after the initiation of conservative treatment, which may include rest, ice application, heel lifts, stretching and strengthening exercises, and, in more severe cases, nonsteroidal anti-inflammatory drugs.

Exercise-induced asthma (EIA) is a very common and troublesome disease frequently impairing optimal athletic performance. Although described as early as the second century A.D. and widely known since 1972, EIA often goes unrecognized by both patient and physician. The goals of treatment are to minimize symptoms thus allowing the athlete to participate fully in a broad array of activities and to utilize the most effective pharmacologic drugs available. The recognition and treatment of exercise-induced asthma (EIA) have made significant progress since 1972 when United States swimmer, Rick Demont had his Olympic gold medal award rescinded because of traces of ephedrine were detected in his urine. Lessons from this episode paid dividends subsequently; in preparation for the 1984 Olympic games in Los Angeles, the U.S. Olympic Committee developed a screening program which identified 67 U.S. team members with EIA. Astoundingly, several of these world-class athletes did not realize they had asthma. Affected individuals were counseled on the prevention of asthma and also on the effective use of medications; 41 won medals in various competitions including track and field, wrestling, basketball, cycling, swimming and rowing. Despite this resounding success, many athletes at all levels of competition still suffer from unrecognized or under-treated EIA despite knowledge of the problem since the second century A.D.(ABSTRACT TRUNCATED AT 250 WORDS)

Topical nasal sprays, especially steroids, have regained favor as treatment for allergic rhinitis. Nasal steroids are widely used and are as safe and effective as antihistamines in controlling symptoms of rhinitis. However, if improperly used, steroids can have side effects. It is essential that patients learn correct techniques for administering nasal steroids and understand complications that can result from nasal steroid use. New steroid drugs, such as budesonide, tripedane and fluticasone, are being evaluated and will be available in the near future. Other topical drugs, such as cromolyn and ipratropium, are also effective. Over-the-counter decongestants are helpful in reducing nasal congestion and allowing other topical medicines to penetrate effectively into the nasal cavity, but their use should be limited to no more than three days. Prolonged use of topical nasal decongestants has no place in the treatment of allergic rhinitis and can be associated with significant side effects.

It is important for the physician to understand bicycle safety equipment in order to prevent and treat bicycle-related injuries effectively. The physician should understand (1) the basic design and function of bicycles, (2) the relationship of improper bicycle fit to injuries, (3) the potential of the various forms of serious riding and racing for injury, and (4) bicycle safety equipment and the standards involved in its fit, manufacture, and care. A decision to use bicycle safety equipment is a decision to control the risk of injury. Physicians should accept a share of the responsibility for decreasing bicycling-related injuries, because they are viewed by the public as credible sources of information regarding the prevention of accidents and injuries.

Back and neck problems in bicyclists should be managed by a combination of bicycle adjustment or modification, technique change, and medical treatment. The bicycle should be checked for proper fit. Often it is necessary to relieve the rider's extended position by using handlebars with less drop, using a stem with a shorter extension, raising the stem, or moving the seat forward. Changing hand positions on the handlebars frequently, riding with the elbows "unlocked," varying head position, using padded gloves and handlebars, and riding on wider tires all reduce the effects of road shock. Initial medical management includes ice, massage stretching, and nonsteroidal anti-inflammatory drugs or acetaminophen. Definitive treatment is neck and back rehabilitation based on dynamic muscular stabilization. It involves three progressive and overlapping parts: (1) establishing range of motion, (2) finding and stabilizing the neutral position, and (3) adapting the neutral position to exercise.

Exercise-induced asthma affects approximately 10 percent of the exercising population but often goes undiagnosed. Diagnosis is generally simple if the physician is aware of the subtle symptoms that may present during or after exercise. Preventive treatment, using a combination of exercise strategies and inhaled medications, is often successful. For patients with underlying chronic asthma that is exacerbated by exercise, long-term medication with preexercise doses is recommended.

The purpose of this study was to determine the accuracy of the American College of Sports Medicine's equation for estimating the oxygen cost of exercise performed on a cycle ergometer. Sixty healthy males, ages 19-39 yr old, performed a five stage (30, 60, 90, 120, and 150 W) submaximal cycle ergometer test while their oxygen uptake was measured. Results indicated the standard error of estimate for the predicted oxygen values ranged from 0.11 to 0.22 l.min-1, with correlations between the actual and predicted values ranging from r = 0.22 to r = 0.50. Total errors ranged from 0.23 to 0.31 l.min-1. The actual oxygen cost was underestimated from 0.16 to 0.29 l.min-1 (P less than 0.05) by the equation at each workload. A revised equation was developed based upon the actual VO2-power relationship. The resulting slope was lower and the intercept higher when compared with the current ACSM equation. The slope and intercept of the revised equation are more consistent with values published in the literature. This equation appears as: VO2 (ml.min-1) = kgm.min-1 x 1.9 ml.min-1) + ((3.5 ml.kg-1.min-1 x kg body weight) + 260 ml.min-1). Predicted values from the revised equation were more accurate as reflected by slightly higher correlations, lower total errors, and lower mean differences from actual VO2 measurements than those from the current equation.

Exercise-induced asthma is a common but frequently undiagnosed problem. The patient may not wheeze, but rather have shortness of breath, chest tightening, and coughing. The coach and the physician must be particularly alert to the signs and symptoms of exercise-induced asthma to recognize this syndrome. Proper conditioning, warming up, inducing refractoriness, participating in sports less likely to provoke exercise-induced asthma, and the aggressive use of appropriate medications allow patients to enjoy sports and compete effectively. A rare but potentially fatal syndrome is exercise-induced anaphylaxis. Accurate diagnosis and differentiation from other exertion-related syndromes are critical, and appropriate precautions are necessary. A third clinical entity, exercise-induced cholinergic urticaria, although not life-threatening, can be quite annoying. Aggravating factors, such as increased heat, compound the problems. In summary, exercise-induced allergic phenomena are common and should be recognized by the practicing physician.

The purpose of this study was to describe and compare cardiac structure and function in adult male weight trainers, runners, and those who do both activities. Subjects had actively participated in the various training programs for the previous five years. Age ranged from 28.4 to 31.3 years in the three groups. Echocardiography was used to assess selected heart diameters, volumes, indices of contractility, and thicknesses, while VO2 max and percent body fat were measured using standard methods. Heart structure and function were expressed in absolute terms and relative to total body weight. An alpha level of .05 was used in all comparisons. Results indicated the runners demonstrated significantly greater relative LVIDd, LVIDs, and LVPW than the weight trainers. The runner/weight trainers possessed significantly greater relative LVIDd, LVIDs, LVPW, IVS, and LVEDV than the weight trainers. No significant differences, absolute or relative, existed between the runner and runner/weight trainer groups in any of the myocardial structure and function variables. It was concluded that men who run or run and weight train have similar structural and functional characteristics of the heart and possess greater relative internal diameter and left ventricular wall thickness than men who only weight train.

The increasing participation in the athletic forms of bicycling warrants expanded physician attention to the traumatic and overuse injuries experienced by cyclists. The modern bicycle consists of a frame with various components, including handlebars, brakes, wheels, pedals, and gears, in various configurations for the various modes of cycling. For high performance cycling the proper fit of the bicycle is critical. The most efficient method to provide an accurate fit is the Fitkit, but proper frame selection and adjustment can be made by following simple guidelines for frame size, seat height, fore and aft saddle position, saddle angle, reach and handlebar height. The human body functions most effectively in a narrow range of pedal resistance to effort. Riding at too much pedal resistance is a major cause of overuse problems in cyclists. Overuse injuries are lower using lower gear ratios at a higher cadence. Cycling injuries account for 500,000 visits per year to emergency rooms in the US. Over half the accidents involve motor vehicles, and road surface and mechanical problems with the bicycle are also common causes of accidents. Head injuries are common in cyclists and account for most of the fatal accidents. Despite good evidence of their effectiveness, victims with head injuries have rarely worn helmets. Contusions, sprains and fractures may occur throughout the body, most commonly to the hand, wrist, lower arm, shoulder, ankle and lower leg. The handlebar and seat have been implicated in a wide variety of abdominal and genital injuries. Abrasions, lacerations and bruises of the skin are the most common traumatic injuries. Trauma may be prevented or reduced by proper protective safety equipment and keeping the bike in top mechanical condition. Anticipation of the errors of others and practising and adopting specific riding strategies also help to prevent traumatic injuries. Management of overuse injuries in cycling generally involves mechanical adjustment as well as medical management. Neck and back pain are extremely common in cyclists, occurring in up to 60% of riders. Ulnar neuropathy, characterised by tingling, numbness and weakness in the hands is common in serious cyclists after several days of riding. Managing saddle-related injuries or irritations may also involve adjusting seat height, angle and fore and aft position in addition to changing the saddle. Padding in the saddle and shorts play an important part in saddle problems. Saddle-related problems include chafing, perineal folliculitis and furuncles, subcutaneous perineal nodules, pudendal neuropathy, male impotence, traumatic urethritis and a variety of vulva trauma.(ABSTRACT TRUNCATED AT 400 WORDS)

In brief Gastrointestinal (GI) bleeding has been well documented in long-distance runners but not in cyclists. The disorder is thought to occur in other strenuous endurance sports as well. The purpose of the present study was to identify the incidence of occult GI bleeding in a large group of endurance cyclists who participated in the 7-day Bike Ride Across Nebraska. Of 500 participants, 35 submitted 163 stool specimens during the first 6 days of the ride; only two specimens, from two riders (1.2%), were positive for occult blood. GI bleeding deserves further research to determine the incidence and cause or causes of this intriguing problem among athletes who engage in strenuous sports.