Epidemiology, Pathophysiology, and Treatment Strategies of Concussions: A Comprehensive Review.

A concussion is a particular manifestation of a traumatic brain injury, which is the leading cause of mortality and disabilities across the globe. The global prevalence of traumatic brain injury is estimated to be 939 instances per 100,000 individuals, with approximately 5.48 million people per year experiencing severe traumatic brain injury. Epidemiology varies amongst different countries by socioeconomic status with diverse clinical manifestations. Additionally, classifying concussions is an ambiguous process as clinical diagnoses are the only current classification method, and morbidity rates differ by demographic location as well as populations examined. In this article, we critically reviewed the pathophysiology of concussions, classification methods, treatment options available including both pharmacologic and nonpharmacologic intervention methods, etiologies as well as global etiologic differences associated with them, and clinical manifestations along with their associated morbidities. Furthermore, analysis of the current research regarding the incidence of concussion based traumatic brain injuries and future directions are discussed. Investigation on the efficacy of new therapeutic-related interventions such as exosome therapy and electromagnetic field stimulation are warranted to properly manage and treat concussion-induced traumatic brain injury.

Pulmonary Fibrosis and Diabetes Mellitus: Two coins with the same face.

Idiopathic pulmonary fibrosis (IPF) constitutes a long-term disease with a complex pathophysiology composed of multiple molecular actors that lead to the deposition of extracellular matrix, the loss of pulmonary function and ultimately the patient's death. Despite the approval of pirfenidone and nintedanib for the treatment of the disease, lung transplant is the only long-term solution to fully recover the respiratory capacity and gain quality of life. One of the risk factors for the development of IPF is the pre-existing condition of diabetes mellitus. Both, IPF and diabetes mellitus, share similar pathological damage mechanisms, including inflammation, endoplasmic reticulum stress, mitochondrial failure, oxidative stress, senescence and signaling from glycated proteins through receptors. In this critical review article, we provide information about this interrelationship, examining molecular mediators that play an essential role in both diseases and identify targets of interest for the development of potential drugs. We review the findings of clinical trials examining the progression of IPF and how novel molecules may be used to stop this process. The results highlight the importance of early detection and addressing multiple therapeutic targets simultaneously to achieve better therapeutic efficacy and potentially reverse lung fibrosis.

Osteopathic manipulative treatment in individuals with vertigo and somatic dysfunction: a randomized, controlled, comparative feasibility study.

CONTEXT: There is a paucity of research assessing the efficacy of osteopathic manipulative treatment (OMT) in patients with vertigo. OBJECTIVE: To assess the feasibility of conducting a randomized, controlled trial comparing OMT and vestibular rehabilitation therapy (VRT), alone or in combination, in patients with vertigo and somatic dysfunction. METHODS: Volunteers with vertigo who were also diagnosed with somatic dysfunction (SD) were prospectively enrolled in a blinded, randomized, controlled cohort comparative effectiveness study and assigned to 1 of 4 groups: OMT alone, VRT alone, a combination of OMT and VRT (OMT/VRT), or a nonintervention control group. Participants between 18 and 79 years of age were included if they had experienced symptoms of vertigo for at least 3 months' duration, demonstrated somatic dysfunction, and could participate in computerized dynamic posturography (CDP) testing, tolerate manual therapy and exercises, and communicate effectively in English or Spanish. A total of 3 treatments lasting 45 minutes each were administered 1 week apart to each participant. OMT in this study consisted of counterstrain, myofascial release, balanced ligamentous tension, soft tissue, HVLA, and articulatory techniques. Comparisons were made between composite scores (CS) assessed with computerized dynamic posturography (CDP), dizziness handicap inventory (DHI), optometric evaluation, and osteopathic structural examinations collected before the first treatment, after the third/final treatment, and 3 months after the final treatment. (ClinicalTrials.gov number NCT01529151). RESULTS: A total of 23 patients were included in the study: 7 in the OMT group, 5 in the VRT group, 6 in the OMT/VRT group, and 5 in the control group. The OMT/VRT group demonstrated significant improvement in DHI score (P=0.0284) and CS (P=0.0475) between pre- and 3-month posttreatment measures. For total severity, improvements were significant in the OMT group both from pretreatment to immediate posttreatment measures (P=0.0114) and from pretreatment to 3-month posttreatment measures (P=0.0233). There was a statistical difference between the OMT and control groups from pretreatment to 3-month posttreatment DHI scores (P=0.0332). Also, there was a statistical difference in DHI score between VRT and control from pre- to 3-month posttreatment scores (P=0.0338). OMT/VRT statistically and clinically improved visual acuity in patients' right eyes from pre- to posttreatment (P=0.0325). In all participants, vergence dysfunction was prevalent (5; 21.7%) in addition to vertical heterophoria (15; 65.2%). CONCLUSION: A combination of OMT and VRT significantly reduced vertigo and improved balance 3 months after treatment (P<0.05). There was a high prevalence in vergence and vertical heterophoria, which are not typical screening measurements used by physical therapists and physicians to assess vertigo patients. With a small sample size, this study demonstrated the feasibility of an interdisciplinary team evaluating and treating patients with vertigo in a community setting. A larger study is needed to assess the efficacy of OMT/VRT in vertigo patients.

The preclinical candidate indole-2-carboxamide improves immune responses to Mycobacterium tuberculosis infection in healthy subjects and individuals with type 2 diabetes.

A novel group of agents known as the indole-2-carboxamides (often referred to as indoleamides) have been shown to demonstrate high antimycobacterial activity. Studies have demonstrated that the best indoleamides possess desirable ADME/Tox properties, with less adverse effects and increased efficacy against both MDR-TB (multi-drug resistant TB) and XDR-TB (extensively drug-resistant TB). The primary mechanism of killing Mycobacterium tuberculosis (Mtb) by indoleamides is by disrupting the function of the essential mycolic acid transporter MmpL3 protein (Mycobacterial membrane protein Large 3). Therefore, targeting this essential mycobacterial transporter by small molecules opens new possibility for the development of novel and effective anti-TB agents. In the present study, we characterized the effects of indoleamides in altering the viability of Mtb in an in vitro granuloma model using immune cells derived from healthy subjects and those with type 2 diabetes mellitus (T2DM). Our results indicate that treatment with the best indoleamide 3 resulted in a significant reduction in the viability of Mtb in both THP-1 macrophages as well as in granulomas derived from healthy individuals and subjects with T2DM. Graphical Abstract.

Flavonoid Mixture Inhibits Mycobacterium tuberculosis Survival and Infectivity.

BACKGROUND: Flavonoids have been shown to exert anti-pathogenic potential, but few studies have investigated their effects on Mycobacterium tuberculosis (Mtb) infectivity. We hypothesized that a flavonoid mixture would have a favorable influence on cell death and the resolution of Mtb infection in THP-1 macrophages and in granulomas derived from both healthy participants and those with type 2 diabetes mellitus (T2DM). METHODS: THP-1 macrophages, and in vitro granulomas from healthy participants (N = 8) and individuals with T2DM (N = 5) were infected with Mtb. A mixed flavonoid supplement (MFS) at a concentration of 0.69 mg per ml was added as treatment to Mtb infected THP-1 macrophages and granulomas for 8 to 15 days. RESULTS: MFS treatment significantly reduced the intracellular Mtb survival, increased cell density, aggregation, and granuloma formation, and increased glutathione (GSH) levels. IL-12 and IFN-γ levels tended to be higher and IL-10 lower when Mtb infected THP-1 macrophages and granulomas obtained from healthy subjects were treated with MFS compared to control. CONCLUSIONS: MFS treatment exerted a strong influence against Mtb infectivity in THP-1 macrophages and in granulomas including antimycobacterial effects, GSH enrichment, cytokine regulation, and augmented granuloma formation. Our data support the strategy of increased flavonoid intake for managing tuberculosis.

The Synergistic Effects of the Glutathione Precursor, NAC and First-Line Antibiotics in the Granulomatous Response Against Mycobacterium tuberculosis.

Mycobacterium tuberculosis (M. tb), the causative bacterial agent responsible for tuberculosis (TB) continues to afflict millions of people worldwide. Although the human immune system plays a critical role in containing M. tb infection, elimination proves immensely more challenging. Consequently, there has been a worldwide effort to eradicate, and limit the spread of M. tb through the conventional use of first-line antibiotics. Unfortunately, with the emergence of drug resistant and multi-drug resistant strains of M. tb the archetypical antibiotics no longer provide the same ascendancy as they once did. Furthermore, when administered, these first-line antibiotics commonly present severe complications and side effects. The biological antioxidant glutathione (GSH) however, has been demonstrated to have a profound mycobactericidal effect with no reported adverse consequences. Therefore, we examined if N-Acetyl Cysteine (NAC), the molecular precursor to GSH, when supplemented in combination with suboptimal levels of standalone first-line antibiotics would be sufficient to completely clear M. tb infection within in vitro derived granulomas from healthy subjects and individuals with type 2 diabetes (T2DM). Our results revealed that by virtue of immune modulation, the addition of NAC to subprime levels of isoniazid (INH) and rifampicin (RIF) was indeed capable of inducing complete clearance of M. tb among healthy individuals.

Effects of ReadiSorb L-GSH in Altering Granulomatous Responses against Mycobacterium tuberculosis Infection.

Mycobacterium tuberculosis (M. tb), a rod-shaped acid-fast bacterium, is the causative agent of tuberculosis (TB). TB remains one of the leading causes of morbidity and mortality worldwide. Additionally, approximately one-third of the world's population has latent tuberculosis infection (LTBI) as a result of the body's primary mechanism of defense against M. tb infection, the formation of a granuloma. A granuloma is the aggregation of immune cells that encapsulate the bacteria to keep them localized to prevent further infection and thus the bacteria become quiescent. However, if an individual becomes immunocompromised, they become more susceptible to M. tb, which may lead to bacterial reactivation and an active infection, because the host is no longer able to generate adequate immune responses. In this study, we examined liposomal glutathione's (L-GSH) effectiveness in promoting the formation of solid, stable granulomas. We assessed this ability by generating in vitro human granulomas constructed from peripheral blood mononuclear cells (PBMCs) that were derived from healthy subjects and testing their granulomatous effector responses against both M. bovis bacille Calmette-Guérin (BCG) and the highly virulent Erdman strain of M. tb. Additionally, we measured the survival and immune characteristics of the Erdman strain of M. tb in THP-1 originated macrophages as well as in vitro granulomas generated from individuals from type 2 diabetes (T2DM). Our results demonstrate that L-GSH treatment can decrease the intracellular survival of both BCG and virulent M. tb, as well as downregulate the levels of overexpressed proinflammatory cytokines delegated from the granulomas derived from not only healthy subjects but also individuals with T2DM.

Use of the SMART Balance Master to quantify the effects of osteopathic manipulative treatment in patients with dizziness.

CONTEXT: Dizziness is the third most common complaint among outpatients and the most common complaint in patients aged 75 years or older. It can be incapacitating for patients, affecting both productivity and quality of life. OBJECTIVE: To evaluate the effect of osteopathic manipulative treatment (OMT) for spinal somatic dysfunction in patients with dizziness lasting longer than 3 months. DESIGN: A prospective clinical cohort study that took place in 2011. SETTING: Department of Physical Therapy laboratory at the Western University of Health Sciences College of Osteopathic Medicine in Pomona, California. PATIENTS: Sixteen participants (2 male, 14 female; mean [range] age, 49 [13-75] years) with dizziness lasting at least 3 months (mean duration of symptoms, 84 months) and spinal somatic dysfunction, but no history of known stroke or brain disease, were recruited from the local community and evaluated for postural balance control before, immediately after, and 1 week after OMT. INTERVENTION: Four osteopathic physicians board certified in neuromusculoskeletal medicine/osteopathic manipulative medicine provided OMT, including muscle energy; high-velocity, low-amplitude; counterstrain; myofascial release; balanced ligamentous release; and cranial OMT techniques. MAIN OUTCOME MEASURES: Outcomes were assessed with the SMART Balance Master (NeuroCom), a validated instrument that provides graphic and quantitative analyses of sway and balance, and the Dizziness Handicap Inventory (DHI), a self-assessment inventory designed to assess precipitating physical factors associated with dizziness and functional and emotional consequences of vestibular disease. RESULTS: Paired t tests, performed to assess changes in mean composite scores for all challenge tests, revealed that balance was significantly improved both immediately and 1 week after OMT (both P<.001), with no significant difference between immediate and 1-week post-OMT scores (P=.20). The DHI scores, both total and subscale, improved significantly after OMT (P<.001), and changes in composite and DHI scores were correlated with each other (P=.047). CONCLUSION: Osteopathic manipulative treatment for spinal somatic dysfunction improved balance in patients with dizziness lasting at least 3 months.

Role of the musculoskeletal system and the prevention of falls.

Approximately 30% of older adults fall at least once per year, with falls being the leading cause of fatal and nonfatal injuries for individuals in this age group. Because of projected increases in the older adult population, the annual cost of fatal and nonfatal fall-related injuries is estimated to reach $32.4 billion in 2020. Falls in older adults are likely due to an interaction of multiple risk factors, including vitamin D deficiency, diminished strength and coordination, depression, multiple medications, and home hazards. Ultimately, the evidence supports a multifaceted approach to screening for fall-related risk factors and targeting treatment to address specific risks for each patient. While keeping in mind that the patient is the product of the dynamic interaction of body, mind, and spirit, the osteopathic physician is well suited to provide comprehensive, patient-centered care.

Osteopathic manipulative treatment and vertigo: a pilot study.

OBJECTIVE: To assess the safety and feasibility of studying osteopathic manipulative treatment and its potential effectiveness for patients with vertigo. DESIGN: A nonrandomized pilot study. SETTING: Outpatient clinic affiliated with a teaching hospital and osteopathic medical school. PATIENTS: The subjects were older than 18 years of age, with the diagnosis of vertigo for longer than 3 months. INTERVENTION: The patients were treated with osteopathic manipulative treatment (OMT). MAIN OUTCOME MEASUREMENTS: Treatment effectiveness was measured with the use of the Dizziness Handicap Inventory (DHI), a validated symptom inventory. Intensity and duration of adverse effects after OMT were used to measure study safety. RESULTS: Of the 18 patients who were recruited all 18 (100%) met the inclusion criteria and were enrolled in the study. Sixteen patients (88.9%) completed the treatment course with OMT, and data with respect to the DHI were obtained from all 16 (100%). Significant improvement (P<.001) in total and subcomponent DHI scores was observed after completion of treatment. Of the 8 patients with moderate pretest scores, 7 (87.5%) had mild post-test scores after undergoing OMT, and of the 8 patients with severe pretest scores, 4 (50%) had mild post-test scores. Of the 18 enrolled patients, 3 (16.7%) experienced an exacerbation of their vertigo, and 5 (27.8%) experienced muscle soreness after OMT. These adverse effects were mild and transient, not lasting longer than 24 hours. CONCLUSIONS: This study showed that OMT is generally well tolerated in patients with vertigo. It also demonstrated that it is feasible to recruit a population of patients with vertigo who can complete a course of OMT and collect data by using the DHI. A randomized control trial that examines the efficacy of OMT in patients with vertigo is warranted, given that OMT may be a reasonable treatment for vertigo and the functional impairment associated with it.