Rejected

Gulf War Illness (GWI) corresponds to an array of symptoms that includes chronic fatigue, musculoskeletal pain, cognitive dysfunction, sleep disturbance, gastrointestinal, respiratory, and dermatological symptoms that affect ~250,000 U.S. military veterans that served in Operation Desert Storm/Desert Shield (1990-1991). Mitochondrial function impairments have been shown in GWI patients. GWI patients report partial amelioration of chronic fatigue and brain fog after medicinal marijuana and CBD oils. Interestingly, cannabidiol (CBD) modulates mitochondrial physiology though this has not been characterized in detail. We hypothesize that GWI mitochondrial pathology can be recapitulated in dermal fibroblasts (DF) from subjects to help define and develop a cell-based model to study GWI and CBD treatment of DF promotes energy production by improving mitochondrial physiology. GWI patients (gender/age matched to healthy controls) were recruited to collect skin punch biopsy explants that were processed and cultured in DMEM FBS 10% for 30-days to obtain dermal fibroblasts. DF were treated with serial dilutions of Verséa™ CBD (50mg/mL) lipid formulation (VESIsorb that increases 4.4-fold C ). Using real time mitochondrial analysis by Seahorse, energy phenotype and mitochondrial function was analyzed in control and GWI DF. Mitochondrial networks and ultrastructure were studied by live-imaging using MitoTracker™ and transmission electron microscopy, respectively. Energy phenotype studies suggest that GWI DF present with lower mitochondrial metabolism and higher glycolytic activity, compared with controls. Additionally, mitochondrial stress suggests a significant reduction in mitochondrial maximal capacity. Such data establish GWI derived DF as a personalized model system to study mitochondrial pathology in GWI. After 18h treatment with Verséa™ CBD, GWI DF show a significant improvement in mitochondrial and glycolytic metabolism; control patients show no increases in mitochondrial metabolism but improved glycolysis. Verséa™ CBD treatment induced mitochondrial networks re-organization in DF. These findings suggest that CBD improves GWI DF mitochondrial physiology, thus improving energy homeostasis. Our data provide new evidence that will validate the potential of cannabinoids as a therapeutic strategy to mitigate energy imbalance that may contribute to detrimental symptomatology (i.e., chronic fatigue, brain fog, cognitive dysfunction, etc.) in GWI patients.

The esophagus is innervated by nociceptive sensory afferent nerve fibers originating from the vagus nerve. The nature of the vagal nociceptive fiber innervation, specifically which esophageal layers, however, remains unknown. We hypothesized that the vagal nociceptive TRPV1+ afferent fibers innervate the esophageal mucosa. We evaluated our hypothesis by using genetic neuronal tracing in several mutant mice, including two new strains we generated. The wholemount preparations of separated esophageal mucosa and muscle were immunostained for appropriate fluorescent proteins and imaged by spinning-disk confocal microscopy. In the TRPV1-Flp/RC: FLTG mice(N=8) in which TRPV1-expressing cells express tdTomato the TRPV1+ fibers with varicose appearance densely innervated both the mucosa and the muscle. In the mucosa the TRPV1+ fibers are located just beneath the epithelium, run in parallel registers of two or more fibers, have craniocaudal orientation and branch repeatedly. In the muscle the TRPV1+ fibers form a dense network in the myenteric plexus innervating virtually all myenteric ganglia forming intraganglionic varicose endings (IGVEs). Many TRPV1+ fibers connecting IGVEs run in parallel to the fibers of the outer and inner striated muscle. In the TRPV1-Flp/Tac1-Cre/RC:FLTG mice(N=4) in which GFP is selectively expressed in cells positive for both TRPV1 and Tac1 (the marker of esophageal nociceptors derived from neural crest) the esophageal innervation by TRPV1+/Tac1+ fibers mimicked the dense innervation by TRPV1+ fibers. In contrast, in the TRPV1-Flp/P2X2-Cre/RC:FLTG mice(N=4) in which GFP is selectively expressed in cells positive for both TRPV1 and P2X2 (the marker of esophageal nociceptors derived from placodes) the TRPV1+/P2X2+ fibers were almost absent in the esophagus. Consistent with this finding, in the P2X2-Cre mice unilaterally injected with AAV9-FLEX-EGFP virus into vagal ganglia(N=2) in which GFP is selectively expressed in vagal P2X2+ fibers, the nodose TRPV1-negative tension mechanosensor nerve terminals (intraganglionic laminar endings) were visualized in the esophageal muscle. Finally, in the TRPV1-Cre mice unilaterally injected with AAV9-FLEX-EGFP virus into vagal ganglia(N=3), in which only the vagal TRPV1+ fibers express GFP, the vagal TRPV1+ fibers had the same pattern as TRPV1+/Tac1+ fibers, but with lower density and patchy distribution. Our data indicate that vagal nociceptive TRPV1+ fibers innervate both the esophageal mucosa and myenteric ganglia and originate from neural crest-derived jugular portion of the vagal jugular-nodose ganglia complex.

Musculoskeletal disorders of the masticatory system impact the quality of life and have a high cost of diagnosis and treatment. Masseter muscle hyperactivity is a cause of pain in the chewing apparatus. Botulinum toxin type A (BoNTA) injection is widely used to induce paralysis of the masseter muscle, thereby decreasing impaired muscle activity. However, our laboratory has described in a preclinical model that the injection of BoNTA not only induces paralysis, but also muscle atrophy, which subsequently decreases bone quality. However, it is unknown whether apoptosis or autophagy mechanisms could contribute to muscle atrophy.

Standardized botanical formulations have often yielded promising results in the treatment of debilitating joint pains such as those encountered in Osteoarthritis (OA) and Rheumatoid Arthritis (RA). We report a novel formulation of essentials oils made from the Generally Recognized as Safe (GRAS) family of plants widely used in Ayurveda namely Kattrna (CC-Cymbopogon citratus) (3.0%), Sati (Hedychium spicatum) (1.0%) and Tumuru (ZA- Zanthoxylum alatum) oil (1.0%) along with Menthol (M- Mentha arvensis) (1.3%) in a non-greasy cream base which can provide relief against joint pains arising out of arthritis. The formulation was designed as a topical cream for applying around the affected joint. Its purity was confirmed through HPLC and GC-MS analysis by comparing with identifiable marker components. The formulation patented as HerboJoint was able to substantially bring down the levels of inflammatory cytokines TNF-α, IL-6 and IL-1β in a Type II collagen induced mouse arthritis model. In human clinical trials, the formulation significantly decreased joint pain, joint swelling and joint stiffness arising out of Osteoarthritis and Rheumatoid Arthritis by 2.2, 2.7 and 3.6 times respectively and provided relief to about 90% of patients selected randomly. The corresponding TNF-α levels in the sera of patients also decreased substantially thus indicating that the formulation was effective in management of both OA and RA. The present invention based on synergistic action of Essential Oils and Menthol is believed to provide a significant relief to these extremely painful and potentially incurable medical conditions.

Kratom is a tropical evergreen tree indigenous to Southeast Asia whose leaves and decoctions have long been used in traditional folk medicine for the relief of pain and enhancement of vitality. In recent years kratom use has increased in the United States, where an estimated 10-15 million people use the herb for the self-management of pain and opioid withdrawal. Kratom leaves contain over 40 active alkaloids, with the most important being mitragynine, 7-hydroxymitragynine and paynantheine. To further explore the possible anti-inflammatory actions of these kratom alkaloids, we examined their effects on cortisol secretion in a human adrenocortical cell line. HAC15 cells were exposed to vehicle or mitragynine, 7-hydroxymitragynine, and paynantheine (10 μM). After 24, 48, 72, and 96 h, cortisol secretion was examined. Basal cortisol secretion was significantly increased by mitragynine at all timepoints, with maximal effect at 96 h (in ng/mL: vehicle, 8.9±1.1; 10 μM mitragynine, 47.3±0.7; n=4). Alternatively, 7-hydroxymitragynine only significantly increased basal cortisol levels at the 96 h timepoint (in ng/mL: vehicle, 8.9±1.1; 10 μM 7-hydroxymitragynine, 17.4±1.2; n=4), while paynantheine only significantly increased basal cortisol levels at the 24 h timepoint (in ng/mL: vehicle, 23.4±1.0; 10 μM paynantheine, 32.8±2.2; n=4). Additional studies are currently being done to characterize effects on cellular viability and concentration responses for each of these kratom alkaloids on cortisol secretion. These data indicate that mitragynine can enhance cortisol secretion in vitro and suggest that such a mechanism may contribute to the possible analgesic actions of kratom in vivo.

To study assessed adherence to 11 chronic medications and one medication class with high medical necessity in people with cognitive impairment (CIM) and identified clinical characteristics associated with nonadherence. This was a retrospective cohort study. 180-day adherence was calculated as the percent of days covered (PDC). Multi-variable logistic regression modeling was used to identify clinical factors associated with a PDC less than 80% (ie, nonadherence) to one or more studied chronic medication(s). Primary care in an integrated health care delivery system. People with CIM 65 years of age or older who were dispensed five or more chronic medications in one month between March 1, 2019, and October 31, 2019. Overall, the 1,109 patients included were older (mean age = 79.8 years of age), female (54.1%), White (78.6%), had a high burden of chronic disease, and 396 (35.7%) were nonadherent to one or more study medication(s). Two medications (tiotropium and venlafaxine) and one medication class (direct oral anticoagulants) had a mean PDC less than 80%. Alzheimer's disease and related dementias (ADRD), chronic pain, chronic obstructive pulmonary disease (COPD), male, nonwhite race, and one or more mental health visits were associated independently with nonadherence. Chronic pain, COPD, ADRD, male sex, nonwhite race, and mental health care use were associated with nonadherence. These findings can help guide clinicians as they navigate medication therapy in people with CIM.

The literature describes a few case reports of bilateral accessory popliteus muscle, a rare variant of the popliteus muscle. We report a case of a 24-year-old male patient with acute pain and inability to flex the left knee, without a traumatic event. Additionally, the patient reported mild sensitive symptoms in the left calf region and no pain in the right knee. The patient underwent a series of other examinations which culminated in a Magnetic Resonance Imaging (MRI) that showed an accessory popliteus muscle. The comparative study of the contralateral knee showed no evidence of this anatomic variant.

Patients with temporomandibular disorder (TMD) often have orofacial pain and may use medication without professional prescription. Self-medication and inappropriate drug intake may cause serious health problems. This cross-sectional study evaluated the self-medication profile of TMD patients, the most used medications and their effect, and the relation between self-medication and socioeconomic factors.

Acute calcific tendinitis of the longus colli muscle (LCM) also called acute calcific prevertebral tendinitis or retropharyngeal tendinitis is an inflammatory process of the LCM that results in acute and debilitating symptoms. Although the imaging appearances of this uncommon condition are specific, due to the rarity of this entity and lack of familiarity, it can be sometimes misdiagnosed as a retropharyngeal abscess. This case report presents characteristic radiological features of the acute calcific tendinitis of the LCM, which may be helpful for the emergency radiologist to accurately diagnose this condition to avoid unnecessary surgical interventions.