The Impact of Opioid Prescribing Limits on Drug Usage in South Carolina: A Novel Geospatial and Time Series Data Analysis.

The opioid crisis in the United States has had devastating effects on communities across the country, leading many states to pass legislation that limits the prescription of opioid medications in an effort to reduce the number of overdose deaths. This study investigates the impact of South Carolina's prescription limit law (S.C. Code Ann. 44-53-360), which aims to reduce opioid overdose deaths, on opioid prescription rates. The study utilizes South Carolina Reporting and Identification Prescription Tracking System (SCRIPTS) data and proposes a distance classification system to group records based on proximity and evaluates prescription volumes in each distance class. Prescription volumes were found to be highest in classes with pharmacies located further away from the patient. An Interrupted Time Series (ITS) model is utilized to assess the policy impact, with benzodiazepine prescriptions as a control group. The ITS models indicate an overall decrease in prescription volume, but with varying impacts across the different distance classes. While the policy effectively reduced opioid prescription volumes overall, an unintended consequence was observed as prescription volume increased in areas where prescribers were located at far distances from patients, highlighting the limitations of state-level policies on doctors. These findings contribute to the understanding of the effects of prescription limit laws on opioid prescription rates and the importance of considering location and distance in policy design and implementation.

Protective Effects of Curcumin against Lipopolysaccharide-Induced Toxicity.

BACKGROUND: Lipopolysaccharide (LPS), a Gram-negative bacterial cell wall component, evokes intensive inflammatory responses in the human body. Naturally, inflammation is a part of the host immune response to an infection; nonetheless, an exaggerated response can lead to a series of pathophysiological consequences, collectively known as LPS toxicity or septic shock. OBJECTIVE: This review will explore the cellular and experimental investigations that mainly focus on Curcumin's therapeutic effects on the LPS-mediated inflammatory responses. METHOD: A literature review of all relevant studies was performed. CONCLUSION: Curcumin has been reported to exert anti-inflammatory properties by interfering with LPS-induced inflammatory pathways, including binding to cell surface receptors of LPS, NF-kB activation pathway, and inflammasome activation. Further clinical studies on the effect of Curcumin in reducing the pathophysiological consequences of LPS toxicity would substantiate the use of this molecule for future therapeutic approaches.

Reduced regulatory T lymphocytes in migraine patients.

Objectives: Migraine is a primary headache disorder with unknown pathophysiology. Recently, many studies have suggested the role of immune dysfunction in the pathophysiology of this disorder. In this study, we investigated the percentage of regulatory T cells (Treg cells) in different migraine categories.Methods: Peripheral blood samples of 40 newly diagnosed cases of migraine and 33 healthy individuals were collected for Treg cell analysis by flow cytometry.Results: The percentage of Treg cells in migraine patients with all subgroups including patients with or without auras and patients with chronic or episodic migraine was significantly lower than that of the control group. Also, a significant increase in the CD25 means fluorescence intensity (MFI) was observed in migraine without aura and chronic migraine groups, compared to the normal group.Conclusions: In this study, the number of Treg cells significantly decreased in new cases of migraine, which suggests that migraine is a result of an impairment in the immunological system or an autoimmune disease. Also, the insignificant difference in the number of Treg cells between the two categories of migraine suggests that there is no link between the reduced number of Treg cells and the emergence of aura symptoms or duration of the disease.

Helicobacter pylori Biofilm and New Strategies to Combat it.

Helicobacter pylori, the most frequent pathogen worldwide that colonizes around 50% of the world's population, causes important diseases such as gastric adenocarcinoma, chronic gastritis, and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. In recent years, various studies have reported that H. pylori biofilm may be one of the critical barriers to the eradication of this bacterial infection. Biofilms inhibit the penetration of antibiotics, increase the expression of efflux pumps and mutations, multiple therapeutic failures, and chronic infections. Nanoparticles and natural products can demolish H. pylori biofilm by destroying the outer layers and inhibiting the initial binding of bacteria. Also, the use of combination therapies destroying extracellular polymeric substances decreases coccoid forms of bacteria and degrading polysaccharides in the outer matrix that lead to an increase in the permeability and performance of antibiotics. Different probiotics, antimicrobial peptides, chemical substances, and polysaccharides by inhibiting adhesion and colonization of H. pylori can prevent biofilm formation by this bacterium. Of note, many of the above are applicable to acidic pH and can be used to treat gastritis. Therefore, H. pylori biofilm may be one of the major causes of failure to eradication of infections caused by this bacterium, and antibiotics are not capable of destroying the biofilm. Thus, it is necessary to use new strategies to prevent recurrent and chronic infections by inhibiting biofilm formation.

In vivo therapeutic effects of colorectal cancer cell-derived exosomes.

OBJECTIVES: Exosomes are nano-sized structures with lipid bilayer membranes that can be secreted by cancer cells. They play an important role in the biology of the tumor extracellular matrix. Exosomes may contain and transfer tumor antigens to dendritic cells to trigger T cell-mediated anti-tumor immune responses. MATERIALS AND METHODS: BALB/c mice bearing CT26 colorectal cancer were treated subcutaneously with purified exosomes from analogous tumor cells. The mice were analyzed with respect to tumor size, survival, and anti-tumor immunity responses, including gene expression of cytokines and flowcytometry analysis of T lymphocytes. RESULTS: The rate of tumor size growth in the exosome-treated group significantly decreased (P<0.05), and the flow cytometry results showed a significant reduction in the spleen regulatory T cells (Tregs) count of the exosome-treated group, compared with the untreated group (P=0.02). Although the increase in the serum level of interferon-γ (IFN-γ) and the number of cytotoxic CD8 T lymphocytes (CTLs) in the spleen tissue was not significant (P>0.05), the gene expression of IFN-γ increased significantly (P=0.006). CONCLUSION: The present results revealed that subcutaneous administration of tumor-derived exosomes could effectively lead to the inhibition of tumor progression by decreasing the number of Treg cells and up-regulation of the IFN-γ gene. Therefore, tumor-derived exosomes can be used as potential vaccines in cancer immunotherapy.

Bacteriophage therapy against Pseudomonas aeruginosa biofilms: a review.

Multi-Drug Resistant (MDR) Pseudomonas aeruginosa is one of the most important bacterial pathogens that causes infection with a high mortality rate due to resistance to different antibiotics. This bacterium prompts extensive tissue damage with varying factors of virulence, and its biofilm production causes chronic and antibiotic-resistant infections. Therefore, due to the non-applicability of antibiotics for the destruction of P. aeruginosa biofilm, alternative approaches have been considered by researchers, and phage therapy is one of these new therapeutic solutions. Bacteriophages can be used to eradicate P. aeruginosa biofilm by destroying the extracellular matrix, increasing the permeability of antibiotics into the inner layer of biofilm, and inhibiting its formation by stopping the quorum-sensing activity. Furthermore, the combined use of bacteriophages and other compounds with anti-biofilm properties such as nanoparticles, enzymes, and natural products can be of more interest because they invade the biofilm by various mechanisms and can be more effective than the one used alone. On the other hand, the use of bacteriophages for biofilm destruction has some limitations such as limited host range, high-density biofilm, sub-populate phage resistance in biofilm, and inhibition of phage infection via quorum sensing in biofilm. Therefore, in this review, we specifically discuss the use of phage therapy for inhibition of P. aeruginosa biofilm in clinical and in vitro studies to identify different aspects of this treatment for broader use.

Bacteriophages, a New Therapeutic Solution for Inhibiting Multidrug-Resistant Bacteria Causing Wound Infection: Lesson from Animal Models and Clinical Trials.

Wound infection kills a large number of patients worldwide each year. Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa are the most important colonizing pathogens of wounds that, with various virulence factors and impaired immune system, causes extensive tissue damage and nonhealing wounds. Furthermore, the septicemia caused by these pathogens increases the mortality rate due to wound infections. Because of the prevalence of antibiotic resistance in recent years, the use of antibiotics to inhibit these pathogens has been restricted, and the topical application of antibiotics in wound infections increases antibiotic resistance. Therefore, finding a new therapeutic strategy against wound infections is so essential since these infections have a destructive effect on the patient's mental health and high medical costs. In this review, we discussed the use of phages for the prevention of multidrug-resistant (MDR) bacteria, causing wound infection and their role in wound healing in animal models and clinical trials. The results showed that phages have a high ability to inhibit different wound infections caused by MDR bacteria, heal the wound faster, have lower side effects and toxicity, destroy bacterial biofilm, and they are useful in controlling immune responses. Many studies have used animal models to evaluate the function of phages, and this study appears to have a positive impact on the use of phages in clinical practice and the development of a new therapeutic approach to control wound infections, although there are still many limitations.

Gene expression of semaphorin-3A, semaphorin-7A, neuropilin-1, plexin-C1, and ß1 integrin in treated-multiple sclerosis patients.

OBJECTIVE: Recently, members of the semaphorin family have received major attention in various medical fields, especially autoimmunity. In this study, we selected semaphorin-3A (Sema3A), semaphorin-7A (Sema7A), and their receptors to determine the possible relationship between these molecules and multiple sclerosis (MS). METHOD: We measured the gene expression of Sema3A, Sema7A, neuropilin-1 (NP-1), plexin-C1, and ß1 integrin in the blood samples of relapsing-remitting multiple sclerosis (RRMS) patients, treated with high-dose interferon-ß1a (IFN-ß1a), low-dose IFN-ß1a, IFN-ß1b, and glatiramer acetate (GA) via quantitative real-time polymerase chain reaction (qRT-PCR) assay, and then, compared the results of treatment-naive patients with the healthy controls. RESULTS: The gene expression of Sema3A (P = 0.02), NP-1 (P < 0.001), and plexin-C1 (P < 0.01) significantly decreased in the treatment-naive group, compared to the healthy controls. Sema3A significantly increased in all treated patients, compared to the treatment-naive patients (P < 0.001). However, expression of NP-1 (P < 0.001), plexin-C1 (P < 0.001), and ß1 integrin (P < 0.05) only increased in patients receiving high-dose IFN-ß1a, IFN-ß1b, and GA. Expression of Sema7A increased in only two groups of patients treated with IFN-ß1b (P < 0.001) and GA (P = 0.018), without any significant decrease in the treatment-naive group, compared to the healthy controls (P > 0.05). CONCLUSION: Our findings confirm that the presence of Sema3A, Sema7A, and their receptors can play critical roles in the treatment of MS patients. Therefore, they can be potential target molecules for MS treatment in the future.

Increased expression of CD8 marker on T-cells in COVID-19 patients.

BACKGROUND: Cell-mediated immunity including T-cells (T helper and cytotoxic) plays an essential role in efficient antiviral responses against coronavirus disease-2019 (COVID-19). Therefore, in this study, we evaluated the ratio and expression of CD4 and CD8 markers in COVID-19 patients to clarify the immune characterizations of CD4 and CD8 T-cells in COVID-19 patients. METHODS: Peripheral blood samples of 25 COVID-19 patients and 25 normal individuals with similar age and sex as the control group were collected. White blood cells, platelets, and lymphocytes were counted and CD4 and CD8 T lymphocytes were evaluated by flow cytometry. RESULTS: The number of white blood cells, lymphocytes, and platelets were reduced significantly in COVID-19 patients (P < 0.05). The difference in CD4:CD8 ratio, CD4 T-cell frequency, CD8 T-cell frequency, and CD4 mean fluorescence intensity (MFI) was not significant between COVID-19 patients and healthy individuals (P > 0.05); however, the CD8 MFI increased significantly in COVID-19 infected patients (P < 0.05). CONCLUSION: Although, there is no significant difference in the ratio of CD4 to CD8 between two groups, the expression level of CD8 in COVID-19 patients was significantly higher than the normal individuals. This result suggested that the cellular immune responses triggered by COVID-19 infection were developed through overexpression of CD8 and hyperactivation of cytotoxic T lymphocytes.

Therapeutic effects of walnut oil on the animal model of multiple sclerosis.

OBJECTIVES: Therapeutic approaches for multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), are accompanied by various undesirable side effects. Owing to the anti-inflammatory and antioxidant effects of walnut, we investigated its effects on the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. METHODS: After EAE induction in mice, the treated group was gavaged daily with walnut oil. The weights and clinical symptoms were monitored daily for 21 days following the onset of symptoms. The spleens and brains of the mouse were removed and used for ELISA and histological studies. RESULTS: The average disease severity and plaque formation in the brains of the walnut oil-treated group were significantly lower (P < 0.05) than those of the untreated group. Stimulated splenocytes of the treated group expressed significantly less INF-γ and interleukin (IL)-17 than the untreated group with no significant differences in IL-10 or IL-5 production. In serum from the treated group, IL-17 expression was also significantly less than in the untreated group, while IL-10 was greater (P < 0.05). CONCLUSION: Walnut oil significantly reduced disease severity, inhibited plaque formation, and altered cytokine production. More studies are required to identify the mechanism of action of walnut oil as a valuable supplement in the treatment of MS.

Artemisinin therapeutic efficacy in the experimental model of multiple sclerosis.

CONTEXT: The immune system through T-helper 1 (Th1) and Th17 cells play a critical role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), whereas the Th2 responses inhibit myelin degeneration. Artemisinin, as an anti-malaria as its agent, has been used widely in the treatment of malaria, shifts the lymphocyte responses from Th1 to Th2. OBJECTIVE: In this study, we have investigated the therapeutic effects of artemisinin on the EAE treatment. MATERIALS AND METHODS: EAE was induced in the inbred C57BL6 mice. High and low doses of prednisolone and artemisinin were injected daily with the control and test groups, respectively. The spleen and the brain of the mice were removed and used for ELISA and histological studies. RESULTS: The mean weight of mice was significantly (p value < .05) higher in artemisinin-treated group compared with the untreated group, whereas, the mean EAE score of mice was significantly (p value < .05) lower in the artemisinin-treated group compared with the untreated group. The brain histology shows the absence of plaque formation in the artemisinin treated group. The concentration of IFN-γ in the low dose of artemisinin treated group showed significantly (p value < .05) lower in comparison to the untreated group. IL-4 concentration was significantly (p value < .05) higher in the treated groups than the control group. CONCLUSIONS: Since, artemisinin can shift the immune responses from Th1 to Th2, therefore, it can be helpful in the treatment of MS after more investigation.

Frequency of seropositivity against infectious agents amongst pemphigus vulgaris patients: a case-control study on Strongyloides stercoralis, Helicobacter pylori, Toxoplasma gondii, Leishmania major, and Epstein-Barr virus.

BACKGROUND: Environmental and genetic factors may contribute to the pathogenesis of pemphigus vulgaris (PV) as an autoimmune disease. We aimed to determine rates of seropositivity for immunoglobulin G (IgG) antibodies against a number of infectious agents in untreated and treated PV patients and in healthy individuals. METHODS: Eighty-two newly diagnosed untreated PV patients (34 men and 48 women; mean ± standard deviation [SD] age: 44.18 ± 14.43 years) and 36 previously diagnosed patients under immunosuppressive therapy (16 men and 20 women; mean ± SD age: 38.53 ± 9.96 years) were enrolled in the study. The clinical diagnosis of PV was confirmed by histopathology and direct immunofluorescence findings. As a control group, 131 healthy individuals (68 men and 63 women; mean ± SD age: 42.56 ± 19.69 years) were recruited. In all patients and controls, serum IgG antibodies against Strongyloides stercoralis, Helicobacter pylori, Epstein-Barr virus (EBV) capsid antigen, and Leishmania major were measured using enzyme-linked immunosorbent assays. The indirect immunofluorescence test was used to detect IgG antibodies against Toxoplasma gondii. RESULTS: Newly-diagnosed untreated PV patients had significantly higher rates of seropositivity of IgG antibodies against S. stercoralis and H. pylori compared with the control group (69.5% vs. 16.0% [P < 0.001] and 79.3% vs. 59.5% [P = 0.004], respectively). For the other agents, namely T. gondii, L. major, and EBV capsid antigen, the differences between groups in seropositivity for IgG antibodies were not statistically significant. CONCLUSIONS: Significant associations between S. stercoralis and H. pylori seropositivity rates and untreated disease led to the hypothesis that these pathogenic agents may contribute to the pathogenesis of PV.

Salivary desmoglein enzyme-linked immunosorbent assay for diagnosis of pemphigus vulgaris: a noninvasive alternative test to serum assessment.

BACKGROUND: Serum desmoglein enzyme-linked immunosorbent assay (ELISA) is used for the diagnosis and monitoring of pemphigus diseases. OBJECTIVES: To compare the diagnostic accuracy of salivary antidesmoglein (Dsg) 1 and 3 ELISA in the diagnosis of pemphigus vulgaris (PV) patients with that of serum desmogleins ELISA. METHODS: Eighty-six untreated PV patients and 180 age- and sex-matched PV-free controls were recruited in this case-control study. PV was diagnosed based on clinical, histopathological, and direct immunofluorescence findings. After processing, serum and salivary anti-Dsg 1 and 3 were measured by the ELISA method using Euroimmun kit (Lübeck, Germany). RESULTS: Using the cut-off point of 20 relative units (RU)/mL, the serum anti-Dsg 1 and 3 ELISA were positive in 62 (72.1%) and 83 (96.5%) patients, respectively, and the salivary anti-Dsg 1 and 3 ELISA were positive in 31 (36.1%) and 63 (73.3%) patients, respectively. The specificity of salivary anti-Dsg 1 and anti-Dsg 3 were both 98.9%. Optimal cut-off values of 7.7 and 13.4 RU/mL were determined for the salivary anti-Dsg 1 and anti-Dsg 3 ELISA, respectively. CONCLUSION: Salivary anti-Dsg 1 and 3 ELISA with high specificities (98.9%) could be suggested as safe and noninvasive methods for the diagnosis of PV when obtaining a blood sample is difficult.

The effect of conventional immunosuppressive therapy on cytokine serum levels in pemphigus vulgaris patients.

Pemphigus vulgaris is an autoimmune disease, in which the role of Th17 cytokines needs to be further explored. This study was performed to assess serum levels of three interleukins (IL) required for Th17 differentiation (IL-1ß, IL-6 and IL-23) and two specific Th17 cytokines (IL-17 and IL-22) in a group of patients with pemphigus vulgaris, at baseline, 3 weeks and 6 months after treatment. Correlations between anti-desmogleins and cytokines with disease severity as well as the influence of therapy on the above factors were assessed. Forty-three first-admitted pemphigus vulgaris patients with the active disease entered the study, but only 31 completed the study. Forty-five healthy volunteers were recruited as a control group. The patients were treated with conventional immunosuppressive therapy (oral prednisolone and azathioprine). Cytokines and anti-desmogleins were measured, using enzyme-linked immunosorbent assay. General linear model was used to evaluate the changes over time. In patients at baseline, mean serum level of IL-6 was higher, while mean levels of IL-1ß and IL-22 were lower than the controls. After 3 weeks of therapy, IL-1ß and IL-6 levels showed a decreasing trend, whereas IL-22 showed an increasing trend. Mean anti-desmogleins 1 and 3 values decreased significantly during the time. Anti-desmoglein values were significantly correlated with disease severity. In conclusion, IL-1ß and IL-6 could be involved in the pathogenesis of pemphigus vulgaris. The positive trend of IL-22 is a new finding and should be confirmed by further studies.

Pemphigus vulgaris and infections: a retrospective study on 155 patients.

Background. Autoimmune process and immunosuppressive therapy of pemphigus vulgaris would predispose the patients to infections. Aim. We aimed to study the prevalence of infection and pathogenic agents in pemphigus vulgaris patients admitted to dermatology service. Material and methods. This retrospective study was conducted on 155 pemphigus vulgaris patients (68 males, 87 females) admitted to dermatology service between 2009 and 2011. In this study, the diagnosis of pemphigus vulgaris was confirmed by light microscopic and direct immunofluorescence findings. Data were collected through a questionnaire. Results. Of 155 pemphigus vulgaris patients, 33 had infection at admission and 9 acquired nosocomial infection. In addition, 37 cases of oral candidiasis and 15 cases of localized herpes simplex were recorded. Totally, 94 cases of infection were recorded. The occurrence of infection was significantly related to the severity of disease, number of hospital admissions, and presence of diabetes mellitus. The most common pathogenic germs isolated from cultures were Staphylococcus aureus and Escherichia coli. Conclusion. Severity of pemphigus vulgaris and diabetes were directly related with tendency to infections. Staphylococcus aureus and Escherichia coli were the most common pathogenic agents. Due to limitations of retrospective study, a prospective study is recommended.