Exercise training for clients at out-patient drug rehabilitation centers likely helps with coping skills. However, a better examination of the mechanisms producing changes may help identify effective interventions. PURPOSE: To test the effect of a vigorous exercise prescription on drug abstinence in voluntary rehabilitation patients. METHODS: 25 surveyed participants in a male drug treatment program underwent a 12-week minimum training program. The program included moderate-rigorous exercise and psychotherapy. Three days per week all subjects participated in EP for 90 minutes. Subjects also participated in ABIT 3 days per week where each session lasted 2 hours. Subjects also participated in ESM which ran for 90 minutes 5 days per week. Within each week, program participants also completed between 2-3 hours of psychotherapy (individual and/or group) per day, varying depending on level of care and phase of the treatment process. Exercise performance and adherence, sobriety and relapse rates, and emotional coping skills were collected. RESULTS: Subjects experienced frequent relapse (5±8 occurrences) prior to admission; however, 84% were currently sober on completion of the program, 8% relapsed during treatment, and 36% relapsed after treatment. The longest duration of sobriety a subject achieved was 273±111 days. Post-treatment survey results indicate 84% of subjects still exercised regularly, 68% continued to practice yoga or meditation, and 60% followed a diet that required disciplined awareness. Bench press max improved significantly throughout the program (39%; p<.001), as did squat (55% improvement; p<0.001) and deadlift (69.8%; p<0.001). On completion of the survey 91% of patients who exercised regularly were sober; 50% of patients who did not engage in regular exercise were sober on completion of the program (P=0.043). Owing to a small sample of patients who relapsed during treatment (N=2), the difference in exercisers who relapsed during treatment (5%) and non-exercisers who relapsed (25%) was not significant (P=0.171). Twenty-nine percent of exercisers relapsed after treatment; 75% of non-exercisers relapsed after treatment (P=0.076). The odds of managing adverse emotional states when they arose increased 20-fold among subjects who reported regular participation in exercise (Nagelkerke R2=0.333; P=0.036). Similarly, each additional day per week that a patient practiced yoga predicted a 20-day increase in duration of sobriety (R2=0.227; P=0.016). CONCLUSION: Exercise training exerts a statistically significant positive effect for sobriety and coping skills within a population that previously struggled with perpetual relapse.

<p>  </p> <p>Infections of dermal wounds is a growing burden for the healthcare industry, with a 2017 market exceeding $17.5 USD. As the number of patients with severe infections continues to increase year after year, there is an alarming downward trend in efficacy for traditional antibiotic treatments. In large part, this is due to the increasing development of antibiotic resistance within common bacteria strains. As microbes evolve to protect themselves from previously effective drugs, there is a growing need for new antimicrobial therapies. While alternatives exist in the market, they are largely impaired by non-selective toxicity which can cause further damage to the cells in the wound bed, as is the case with silver and other strong antiseptics, or the need for high energy, specialized equipment, as with cold atmospheric surface treatments. Gaseous ozone is a promising alternative therapy for treating these wound infections. Because ozone is a strong natural oxidant, it exhibits significant antimicrobial properties, and has also been shown to help stimulate natural wound healing in many cases. Herein is presented the design of a portable system for the topical delivery of gaseous ozone as an antimicrobial treatment for infected dermal wounds. This includes the design and characterization of the portable system and a custom ozone application dressing, the characterization of the safety and efficacy of the system using <em>in vitro</em> and <em>in vivo</em> models, and a disposable system for wound infection monitoring. The system utilizes a portable corona discharge generator to produce gaseous ozone from the ambient environment. The ozone gas is delivered through a dressing engineered to have a hydrophobic interface at the wound bed and disperse the ozone gas across the patch surface for more uniform application. The antimicrobial strength and biocompatibility of the system was optimized at varying ozone output levels. Additionally, an adjunct therapy of topical antibiotics was shown to significantly increase the strength of the treatment without leading to greater cytotoxicity. This synergistic effect between ozone and antibiotics was shown to circumvent natural bacterial resistances to antibiotics, which will have a major impact on the wound care industry. This adjunct treatment was then validated on a porcine animal model for safety and pilot results for efficacy testing. Finally, the pH sensor which can be incorporated with use of the ozone therapy enables objective monitoring of wound condition and is able to signal when appropriate infection therapy should begin. As it stands, this portable ozone wound treatment system shows great promise as an alternative therapy to improve the quality of live for millions of patients.</p>

Populations at risk for tuberculosis (TB) may have a low n-3 polyunsaturated fatty acid (PUFA) status. Our research previously showed that post-infection supplementation of n-3 long-chain PUFA (LCPUFA) in TB without TB medication was beneficial in n-3 PUFA sufficient but not in low-status C3HeB/FeJ mice. In this study, we investigated the effect of n-3 LCPUFA adjunct to TB medication in TB mice with a low compared to a sufficient n-3 PUFA status. Mice were conditioned on an n-3 PUFA-deficient (n- 3FAD) or n-3 PUFA-sufficient (n-3FAS) diet for 6 weeks before TB infection. Postinfection at 2 weeks, both groups were switched to an n-3 LCPUFA [eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA)] supplemented diet and euthanized at 4- and 14- days post-treatment. Iron and anemia status, bacterial loads, lung pathology, lung cytokines/chemokines, and lung lipid mediators were measured. Following 14 days of treatment, hemoglobin (Hb) was higher in the n-3FAD than the untreated n-3FAS group (p = 0.022), whereas the n-3FAS (drug) treated control and n-3FAS groups were not. Proinflammatory lung cytokines; interleukin-6 (IL-6) (p = 0.011), IL-1a (p = 0.039), MCP1 (p = 0.003), MIP1- a (p = 0.043), and RANTES (p = 0.034); were lower, and the antiinflammatory cytokine IL-4 (p=0.002) and growth factor GMCSF (p=0.007) were higher in the n-3FAD compared with the n-3FAS mice after 14 days. These results suggest that n-3 LCPUFA therapy in TB-infected mice, in combination with TB medication, may improve anemia of infection more in low n-3 fatty acid status than sufficient status mice. Furthermore, the low n-3 fatty acid status TB mice supplemented with n-3 LCPUFA showed comparatively lower cytokine-mediated inflammation despite presenting with lower pro-resolving lipid mediators.

Malaria accounts for 198 million cases worldwide; with a high mortality rate. 584000 deaths were reported in 2013. Malaria is a re-emerging disease globally due to drug resistance, parasite recrudescence and non-availability of a vaccine. Chloroquine, quinine and antifolates served as frontline antimalarial drugs for decades. Development of resistance to chloroquine and antifolates, and the decreased efficacy of mefloquine, and even quinine, in malaria-endemic regions, has led to artemisinin derivatives evolving as frontline drugs. Artemisinin is a potent antimalarial compound and clears around 104 parasites per cycle. Despite being a potent antimalarial, artemisinin derivatives suffer from poor pharmacokinetic properties and short half lives. This has led to the development of artemisinin-based combination therapies (ACTs) using a partner drug with a longer half-life. However, resistance to ACTs has been reported in the last few years, perhaps due to lack of adherence to prescribed regimens or suboptimal treatment and the use of counterfeit drugs. Therefore there is an urgent need to develop an alternative ACT which overcomes these limitations. This thesis entitled “Adjunct therapy with curcumin for the treatment of malaria: studies in a murine model” describes the antimalarial activity of curcumin and artemisinin and the adjunct role of curcumin in the prevention of parasite recrudescence and cerebral malaria. The thesis is divided into three chapters: The first chapter entitled “Introduction: Malaria and anti-malarial drugs” consists of a brief introduction of malaria, the parasite life cycle and currently known antimalarial drugs. During the course of infection, the Plasmodium undergoes sporogony in the mosquito, and merogony and schizogony in the human host. All these life cycle stages are briefly described with depictions. A major part of this chapter is dedicated to describe antimalarial compounds under the following headings 1. Quinoline derivatives 2. 4-aminoquinolines 3. Antifolates 4. Artemisinin derivatives 5. Antibiotics and 6. Curcumin. The second chapter is aimed at examining the ability of curcumin-arteether (a synthetic derivative of artemisinin) combination therapy in preventing parasite recrudescence in a murine model through immunomodulation employing various immunological, molecular biological, and biochemical techniques. The use of suboptimal doses of antimalarial drugs leads to recrudescence or relapse of malaria (reappearance of the parasite in blood after antimalarial regimen). In the present study we have addressed this issue by the use of curcumin as an adjunct molecule with α,β arteether (a synthetic derivative of artemisinin). We have studied recrudescence in a Swiss mice model. A suboptimal dose was standardized by the use of different doses of α,β arteether (AE) ranging from 250µg to 1500 µg. We found 750 µg to be a suboptimal dose and studied the adjunct nature of curcumin when animals were treated with AE suboptimal dose or AE+curcumin (AC) combination treatment and monitored the survival of animals. Our results clearly demonstrate that ~95% of animals treated with the suboptimal AE dose died of recrudescent malaria but there was almost 100% survival of AC-treated animals; these animals were under observation for at least 3 months. We have studied the effect of curcumin in a recrudescence model at the molecular level. Curcumin by itself has antimalarial activity, but only in combination with α,β arteether prevented recrudescence. Our results indicate that curcumin has immunomodulatory activity. Serum cytokine analysis and spleen mRNA analysis for proinflammatory and anti-inflammatory mediators indicate that AC treatment effectively reduced both mRNA and serum cytokine levels of IFNγ, TNFα, IL-12 and effectively increased both mRNA and serum levels IL-10 and antibodies of the IgG subclass. Using TLR2 and IL-10 knockout animals, we have conclusively demonstrated that TLR2 is involved in the production of IL-10, and IL-10 is required for the AC-mediated protection of animals during the recrudescence period. We conclude that curcumin is able to prevent parasite recrudescence essentially by switching the Th1 response to a Th2 response. The third chapter deals with the study the effect of areether-curcumin (AC) combination therapy in the prevention of Experimental Cerebral Malaria. Although malaria mortality rates have decreased by an impressive 47% between 2000 and 2013, it is still a major affliction of mankind (WHO 2014). Plasmodium falciparum infection causes human cerebral malaria (HCM). The mortality rate in HCM is unacceptably high (15–20%), despite the availability of artemisinin-based therapy. HCM is characterized by a rapid progression from headache, general malaise, and prostration to hemiparesis, ataxia, unrousable coma, and death. Paediatric HCM deaths are mostly due to respiratory arrest. Alternatively, death may be due to parasite-mediated injury to a sensitive location; a small lesion due to parasite in brain stem can cause sudden respiratory arrest. In HCM, cytoadherence of pRBCs in brain microvasculature has been implicated as a major contributing factor for CM pathology. The failure of a large number of adjunct therapies in HCM demands the development of new intervention strategies. An effective adjunct therapy is urgently needed. Experimental Cerebral Malaria (ECM) in mice manifests many of the neurological features of HCM. In this study, we have demonstrated the efficacy of curcumin and PLGA nanocurcumin in the treatment of Experimental Cerebral Malaria (ECM), using the Plasmodium berghei ANKA-infected mouse model (C57BL/6). Curcumin/PLGA nanocurcumin alone can prevent the onset of ECM. We have shown that curcumin/PLGA nanocurcumin can prevent CD8+ T cell, CXCR3+ CD8 T cell and parasite-infected RBC (pRBC) sequestration in the brain. These are also the essential parameters underlying HCM. We have also demonstrated that curcumin effectively inhibits T cell proliferation in spleen. We have explained the anti-inflammatory effects of curcumin by showing the inhibition of NF-B in both brain and spleen, which is a plausible explanation. But, curcumin/PLGA nanocurcumin treated animals died later due to build up of parasitemia in blood and subsequent anemia. Moreover, a combination therapy with arteether and curcumin given even after the onset of neurological symptoms can completely cure and protect the animals against mortality. We have tested AC-combination after the onset of symptoms to mimic patient conditions in HCM, since the murine regimens reported were not successful in the treatment of HCM. Our results clearly demonstrate that AC treatment even after the onset of symptoms ensures 100% survival. Since the bioavailability of curcumin is reported to be poor, we have also tested the efficacy of PLGA nanocurcumin and find that it is superior to native curcumin in terms of therapeutic effects. It is concluded that curcumin would be an ideal adjunct drug to be used with the artemisinin derivatives to treat malaria, including cerebral malaria.