Enhancement of the chondrogenic differentiation capacity of human dental pulp stem cells via chondroitin sulfate-coated polycaprolactone-MWCNT nanofibers.

Most of the conditions involving cartilaginous tissues are irreversible and involve degenerative processes. The aim of the present study was to fabricate a biocompatible fibrous and film scaffolds using electrospinning and casting techniques to induce chondrogenic differentiation for possible application in cartilaginous tissue regeneration. Polycaprolactone (PCL) electrospun nanofibrous scaffolds and PCL film were fabricated and incorporated with multi-walled carbon nanotubes (MWCNTs). Thereafter, coating of chondroitin sulfate (CS) on the fibrous and film structures was applied to promote chondrogenic differentiation of human dental pulp stem cells (hDPSCs). First, the morphology, hydrophilicity and mechanical properties of the scaffolds were characterized by scanning electron microscopy (SEM), spectroscopic characterization, water contact angle measurements and tensile strength testing. Subsequently, the effects of the fabricated scaffolds on stimulating the proliferation of human dental pulp stem cells (hDPSCs) and inducing their chondrogenic differentiation were evaluated via electron microscopy, flow cytometry and RT‒PCR. The results of the study demonstrated that the different forms of the fabricated PCL-MWCNTs scaffolds analyzed demonstrated biocompatibility. The nanofilm structures demonstrated a higher rate of cellular proliferation, while the nanofibrous architecture of the scaffolds supported the cellular attachment and differentiation capacity of hDPSCs and was further enhanced with CS addition. In conclusion, the results of the present investigation highlighted the significance of this combination of parameters on the viability, proliferation and chondrogenic differentiation capacity of hDPSCs seeded on PCL-MWCNT scaffolds. This approach may be applied when designing PCL-based scaffolds for future cell-based therapeutic approaches developed for chondrogenic diseases.

Individual Article: Evaluation of Efficacy and Tolerability of Two Over-the-Counter Eczema Itch Relief Products.

BACKGROUND: Study to compare efficacy, tolerability, and patient perception between an over-the-counter itch relief gel (IRG) and itch relief moisturizing cream (IRMC) after a single application.  Methods: Single-center, randomized, blinded, split-body study comparing IRG vs IRMC in adults with eczema-prone skin and mild-to-moderate itch. Assessments included itch relief duration upon application, itch severity (0=none to 9=severe at baseline [BL], 8, 12, and 24 hours), tolerability (0=none to 3=severe), and self-assessment questionnaire about product attributes and preference.  Results: Thirty-three females and males with a mean age of 49.7 completed the study. Average time to itch relief was 28.5 seconds for IRG vs 41.8 for IRMC (P<0.05), with first onset at 5 seconds. In the IRG group, itch severity was reduced from 4.4 at BL to 1.4 at 8 hours; in comparison, itch was reduced from 4.4 at BL to 2.6 at 8 hours in the IRMC group (P<0.05). Both products significantly relieved itch vs baseline at all time points. IRG had better tolerability, with burning/stinging going from 1.5 at BL to 0.8 at 24 hours vs 1.5 at BL to 1.2 at 24 hours for IRMC (P<0.05). There was a trend in favor of IRG vs IRMC on the patient satisfaction self-assessment questionnaire. CONCLUSIONS: IRG provided rapid itch relief and significantly outperformed IRMC. Both products significantly improved itch severity for up to 24 hours after application, with IRG outperforming IRMC at 8 hours. Additionally, IRG moderated stinging/burning sensations better than IRMC. Further, IRG was preferred by participants over IRMC.J Drugs Dermatol. 2023;22:10(Suppl 2):s10-15.  .

S100B and brain ultrasound: Novel predictors for functional outcome in acute ischemic stroke patients.

OBJECTIVE: Stroke is a leading cause of mortality and disability worldwide. This study aimed to assess the prognostic value of serum S100B protein, transcranial color-coded duplex sonography (TCCD), and optic nerve sheath diameter (ONSD) in predicting functional outcomes in critically ill patients with acute ischemic stroke (AIS). METHODS: In this prospective observational study, 80 adult AIS patients were evaluated. Serum S100B protein levels, ONSD, and middle cerebral artery pulsatility index (MCA PI) were measured on days 1 and 3. Functional outcomes at 90 days were assessed using the modified Rankin Scale (mRS) and categorized into favourable (mRS 0-2) or unfavourable (mRS 3-6) groups. The association of demographic, clinical, laboratory, and imaging parameters with mRS outcomes was analyzed. RESULTS: Poor mRS outcomes occurred in 82.5 % of patients. Factors significantly associated with poor outcomes were female sex, higher National Institutes of Health Stroke Scale (NIHSS) scores on days 1, 3, and 7, and larger stroke size. Receiver Operating Characteristic (ROC) curve analysis revealed that ONSD at days 1 and 3, serum S100B levels at day 1, and right MCA PI at day 1 had significant predictive value for poor mRS outcome. Multivariate analysis identified female sex, S100B on day 1, and NIHSS on days 1, 3, and 7 as independent predictors of poor mRS outcomes. CONCLUSIONS: The combination of S100B, ONSD, and MCA PI improved the prediction of functional outcomes in critically ill AIS patients. Early S100B measurement and brain ultrasound evaluation may serve as valuable prognostic tools for guiding therapeutic decision-making. This study provides novel insights into the role of S100B and brain ultrasound in stroke outcome prediction, particularly in critically ill AIS patients.

Pruritus in Keloid Scars: Mechanisms and Treatments.

Keloids are scars that extend beyond the margins of an insulting cutaneous injury. Keloids are often thought to be primarily a cosmetic issue, as they are typically quite raised and pigmented. However, these scars also present with functional symptoms of pruritus and pain that significantly impact quality of life. The symptom of pruritus is frequently overlooked by dermatologists, and treatments are often primarily focused on the gross appearance of the scar. This review describes the prevalence and importance of pruritus in keloids. In addition, the putative mechanisms underlying the development of keloid pruritus, which include neuronal and immunological mechanisms, are discussed. Furthermore, this review describes keloid treatments that have been shown to reduce pruritus, treatments that specifically target the itch, and emerging therapies.

The pruritogenic role of the type 2 immune response in diseases associated with chronic itch.

While there is a vast array of aetiologies that may lead to chronic pruritus, recent data suggests that many of these conditions share similar interactions between keratinocytes, nerves, and the immune system. Specifically, the type 2 immune response, including Th2 T Cells and their related cytokines, has been noted to play a major role in the development of pruritus in a variety of itchy conditions. To date, atopic dermatitis is the most striking example of this pathogenesis. However, the body of literature supporting its role in many other itchy conditions, including other inflammatory, bullous, as well as systemic diseases, continues to grow. In addition, new treatments targeting this type 2 immune system continue to be developed and investigated. In the current review, we present the current body of literature supporting the role of the type 2 immune response in itchy conditions beyond atopic dermatitis as well as potential therapeutic options that target this pathway for chronic itch.

The mechanism underlying transient weakness in myotonia congenita.

In addition to the hallmark muscle stiffness, patients with recessive myotonia congenita (Becker disease) experience debilitating bouts of transient weakness that remain poorly understood despite years of study. We performed intracellular recordings from muscle of both genetic and pharmacologic mouse models of Becker disease to identify the mechanism underlying transient weakness. Our recordings reveal transient depolarizations (plateau potentials) of the membrane potential to -25 to -35 mV in the genetic and pharmacologic models of Becker disease. Both Na+ and Ca2+ currents contribute to plateau potentials. Na+ persistent inward current (NaPIC) through NaV1.4 channels is the key trigger of plateau potentials and current through CaV1.1 Ca2+ channels contributes to the duration of the plateau. Inhibiting NaPIC with ranolazine prevents the development of plateau potentials and eliminates transient weakness in vivo. These data suggest that targeting NaPIC may be an effective treatment to prevent transient weakness in myotonia congenita.

Myotonia is a neuromuscular condition that causes problems with the relaxation of muscles following voluntary movements. One type of myotonia is Becker disease, also called recessive myotonia congenita. This is a genetic condition that causes muscle stiffness as a result of involuntary muscle activity. Patients may also suffer transient weakness for a few seconds or as long as several minutes after initiating a movement. The cause of these bouts of temporary weakness is still unclear, but there are hints that it could be linked to the muscle losing its excitability, the ability to respond to the stimuli that make it contract. However, this is at odds with findings that show that muscles in Becker disease are hyperexcitable. Muscle excitability depends on the presence of different concentrations of charged ions (positively charged sodium, calcium and potassium ions and negatively charged chloride ions) inside and outside of each muscle cells. These different concentrations of ions create an electric potential across the cell membrane, also called the 'membrane potential'. When a muscle cell gets stimulated, proteins on the cell membrane known as ion channels open. This allows the flow of ions between the inside and the outside of the cell, which causes an electrical current that triggers muscle contraction. To better understand the causes behind this muscle weakness, Myers et al. used mice that had either been genetically manipulated or given drugs to mimic Becker disease. By measuring both muscle force and the electrical currents that drive contraction, Myers et al. found that the mechanism underlying post-movement weakness involved a transient change in the concentrations of positively charged ions inside and outside the cells. Further experiments showed that proteins that regulate the passage of both sodium and calcium in and out of the cell ­ called sodium and calcium channels ­ contributed to this change in concentration. In addition, Myers et al. discovered that using a drug called ranolazine to stop sodium ions from entering the cell eliminated transient weakness in live mice. These findings suggest that in Becker disease, muscles cycle rapidly between being hyperexcited or not able to be excited, and that targeting the flow of sodium ions into the cell could be an effective treatment to prevent transient weakness in myotonia congenita. This study paves the way towards the development of new therapies to treat Becker disease as well as other muscle ion channel diseases with transient weakness such as periodic paralysis.

Treatment of myotonia congenita with retigabine in mice.

Patients with myotonia congenita suffer from muscle stiffness caused by muscle hyperexcitability. Although loss-of-function mutations in the ClC-1 muscle chloride channel have been known for 25 years to cause myotonia congenita, this discovery has led to little progress on development of therapy. Currently, treatment is primarily focused on reducing hyperexcitability by blocking Na+ current. However, other approaches such as increasing K+ currents might also be effective. For example, the K+ channel activator retigabine, which opens KCNQ channels, is effective in treating epilepsy because it causes hyperpolarization of the resting membrane potential in neurons. In this study, we found that retigabine greatly reduced the duration of myotonia in vitro. Detailed study of its mechanism of action revealed that retigabine had no effect on any of the traditional measures of muscle excitability such as resting potential, input resistance or the properties of single action potentials. Instead it appears to shorten myotonia by activating K+ current during trains of action potentials. Retigabine also greatly reduced the severity of myotonia in vivo, which was measured using a muscle force transducer. Despite its efficacy in vivo, retigabine did not improve motor performance of mice with myotonia congenita. There are a number of potential explanations for the lack of motor improvement in vivo including central nervous system side effects. Nonetheless, the striking effectiveness of retigabine on muscle itself suggests that activating potassium currents is an effective method to treat disorders of muscle hyperexcitability.

Open-label trial of ranolazine for the treatment of paramyotonia congenita.

INTRODUCTION: Paramyotonia congenita (PMC) is a nondystrophic myotonic disorder that is believed to be caused by a defect in Nav 1.4 sodium channel inactivation. Ranolazine, which acts by enhancing slow inactivation of sodium channels, has been proposed as a therapeutic option, but in vivo studies are lacking. METHODS: We conducted an open-label, single-center trial of ranolazine to evaluate efficacy and tolerability in patients with PMC. Subjective symptoms of stiffness, weakness, and pain as well as clinical and electrical myotonia were evaluated. Baseline measures were compared with those after 4 weeks of treatment with ranolazine. RESULTS: Ranolazine was tolerated well without any serious adverse events. Both subjective symptoms and clinical myotonia were significantly improved. Duration of myotonia was reduced according to electromyography, but this change was not statistically significant in all tested muscles. DISCUSSION: Our findings support the use of ranolazine as a treatment for myotonia in PMC and suggest that a randomized, placebo-controlled trial is warranted. Muscle Nerve 59:240-243, 2019.

Myocardial damage on SPECT imaging among patients treated with radiotherapy for left-sided breast cancer: Systematic review with meta-analysis and narrative synthesis.

PURPOSE: With advancements in radiation oncology techniques, the use of radiation therapy (RT) as a treatment modality for cancer has been steadily increasing. Incidental radiation exposure to surrounding tissue during breast cancer treatment has been known to cause myocardial damage, the extent of which can be detected with single-photon emission computed tomography (SPECT) perfusion studies. We undertook a systematic review and meta-analysis to investigate the impact of RT on myocardial perfusion. METHODS: A systematic review of the literature was conducted to identify 17 studies, of which 4 were included in this meta-analysis and 13 were included in the narrative synthesis. RESULTS: The incidence of post-radiation cardiac perfusion defects on SPECT was significantly higher in patients who received RT for left-sided breast cancer compared to those who had RT for right-sided breast cancer (OR=3.10, 95% CI 1.35-7.08, p=0.007). CONCLUSION: In patients who undergo RT for left-sided breast cancer, the incidence of post-radiation cardiac perfusion defects on SPECT is higher compared to patients who undergo RT for right-sided breast cancer.

Inhibiting persistent inward sodium currents prevents myotonia.

OBJECTIVE: Patients with myotonia congenita have muscle hyperexcitability due to loss-of-function mutations in the ClC-1 chloride channel in skeletal muscle, which causes involuntary firing of muscle action potentials (myotonia), producing muscle stiffness. The excitatory events that trigger myotonic action potentials in the absence of stabilizing ClC-1 current are not fully understood. Our goal was to identify currents that trigger spontaneous firing of muscle in the setting of reduced ClC-1 current. METHODS: In vitro intracellular current clamp and voltage clamp recordings were performed in muscle from a mouse model of myotonia congenita. RESULTS: Intracellular recordings revealed a slow afterdepolarization (AfD) that triggers myotonic action potentials. The AfD is well explained by a tetrodotoxin-sensitive and voltage-dependent Na+ persistent inward current (NaPIC). Notably, this NaPIC undergoes slow inactivation over seconds, suggesting this may contribute to the end of myotonic runs. Highlighting the significance of this mechanism, we found that ranolazine and elevated serum divalent cations eliminate myotonia by inhibiting AfD and NaPIC. INTERPRETATION: This work significantly changes our understanding of the mechanisms triggering myotonia. Our work suggests that the current focus of treating myotonia, blocking the transient Na+ current underlying action potentials, is an inefficient approach. We show that inhibiting NaPIC is paralleled by elimination of myotonia. We suggest the ideal myotonia therapy would selectively block NaPIC and spare the transient Na+ current. Ann Neurol 2017;82:385-395.

Open-label trial of ranolazine for the treatment of myotonia congenita.

OBJECTIVE: To determine open-label, pilot study whether ranolazine could improve signs and symptoms of myotonia and muscle stiffness in patients with myotonia congenita (MC). METHODS: Thirteen participants were assessed at baseline and 2, 4, and 5 weeks. Ranolazine was started after baseline assessment (500 mg twice daily), increased as tolerated after week 2 (1,000 mg twice daily), and maintained until week 4. Outcomes included change from baseline to week 4 in self-reported severity of symptoms (stiffness, weakness, and pain), Timed Up and Go (TUG), hand grip and eyelid myotonia, and myotonia on EMG. RESULTS: Self-reported severity of stiffness (p < 0.0001) and weakness (p < 0.01) was significantly improved compared with baseline. TUG and grip myotonia times were reduced (p = 0.03, p = 0.01). EMG of the abductor digiti minimi and tibialis anterior showed significantly reduced myotonia duration (p < 0.001, p < 0.01) at week 4. No participant discontinued ranolazine because of side effects. CONCLUSIONS: Ranolazine appeared to be well tolerated over a period of 4 weeks in individuals with MC, and ranolazine resulted in improvement of signs and symptoms of muscle stiffness. The findings of this study suggest that ranolazine should be investigated in a larger controlled study. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that ranolazine improves myotonia in myotonia congenita.

The effects of 15 Hz trans-spinal magnetic stimulation on locomotor control in mice with chronic contusive spinal cord injury.

The effects of repetitive trans-spinal magnetic stimulation (rTSMS), combined with acrobatic exercise on functional locomotor recovery in chronic spinal-contused mice were tested. The exposure to magnetic stimulation was initiated 3 weeks after injury, when the animals entered chronic stage. The rTSMS was applied for a total of 4 weeks over a 9-week duration trial. Seventeen mice with the spinal cord contusion injured at level T13 were separated into two groups. While one group consisting of 10 animals was exposed to rTSMS (15 Hz), the other seven animals served as controls. Functional recovery measured with Basso mouse scale and horizontal ladder scale showed significantly better functional recovery in rTSMS-treated animals. The progress in recovery continued even after cessation of magnetic stimulation. In vitro experiments revealed that the release of glutamate analog, radioactive D-aspartate from the segments of the spinal cord exposed to rTSMS was significantly elevated. In conclusion, the exposure to rTSMS, applied to injured spinal cord during chronic post-surgery stage remarkably improves the functional recovery. This recovery may be correlated by magnetically induced elevation in the release of major excitatory neurotransmitter, glutamate from injured tissue.

Chemoprevention in colorectal cancer--where we stand and what we have learned from twenty year's experience.

INTRODUCTION: Colorectal chemoprevention is a strategy aimed at preventing tumour progression before irreversible changes to the proteome are in full progress. Chemoprevention is not a new concept. In fact, medical practitioners since the early 19th century have tried various herbal and medicinal products as methods that could prevent tumours. The current understanding of tumourigenesis and cellular signalling focuses on a more targeted approach and paves the way for better understanding of colorectal chemoprevention. METHODS: The online databases PubMed, Medline, Medscape Oncology and Scirrus were searched for articles of relevance. The Keyword involved the following words: "Colorectal Cancer Chemoprevention", "Colorectal Cancer", "Chemoprevention", "Adenoma-Carcinoma Sequence" and "Colorectal Polyps". The search was started from the period of June 1995 until September 2010 inclusive. RESULTS: More than 50 natural and synthetic compounds have been shown to have chemotherapeutic effect but the majority of these agents are still in their early experimental stages and hence far from our subject of discussion. Our discussion will focus on large scale randomised trials on human subjects or established compounds. Within the context of chemoprevention, Non-steroidal anti-inflammatory agents have undergone extensive research and have shown promising results with large scale randomised trials. Additionally, metformin, resveratrol, Histone deacetylase inhibitors, Src kinases as well monoclonal antibodies have shown promising results as well. CONCLUSION: Colorectal cancer is the fourth most common cancer in the world. In the UK alone the number of cases reported in 2008 was almost 40,000 which make it the third most common tumour nationwide. Curative intent surgery or Colectomy is the treatment of choice for most cases of bowel cancer; however, in a select subpopulation of patients who have been colonoscopically diagnosed to harbour pre-malignant lesions, have a family history of colorectal cancer, or have been genetically diagnosed and treated surgically for colorectal tumours; chemoprevention might play a crucial role in deterring further tumour progression. The very latest studies that are in publication or are just accruing results are giving us encouraging data that might suggest whether mass scale ingestion of a specific medication might deter colorectal tumour progression.