Supplementation of ginger root extract into broiler chicken diet: effects on growth performance and immunocompetence.

Ginger contains bioactive compounds that possess anti-inflammatory and antimicrobial properties. In this study, 432-day-old Ross 708 broiler male chicks were randomly allocated to 6 dietary treatments to investigate the effect of ginger root extract (GRE) on immunocompetence and growth performance to 6 wk of age. Treatment 1 (CON) consisted of chicks fed a corn-soybean meal (SBM), a base diet without GRE. Treatment 2 (MX) chicks were given basal diets containing bacitracin methylene disalicylate (BMD) at 0.055 g/kg. Treatments 3 (GRE-0.375%), 4 (GRE-0.75%), 5 (GRE-1.5%), and 6 (GRE-3%) were fed similar diet to control with GRE supplemented at 0.375%, 0.75%, 1.5%, and 3%, respectively. Moreover, HPLC analysis of GRE was carried out to determine the concentration of bioactive compounds found in GRE. Each treatment consisted of 6 replicate pens with 12 chicks/pen. Bodyweight (BW) and feed conversion ratio (FCR) were recorded. Results show that the concentration of bioactive compounds increased with increasing GRE supplementation. Likewise, dietary GRE supplementation did not have any detrimental effect on growth performance parameters up to 1.5%, as values for BWG was not different from CON and MX; however, 3% GRE had the poorest FCR and a lower BWG as compared to other treatments. On d 27 and d 41, fecal and cecal concentrations of total bacteria count (TBC), Escherichia coli, Lactobacillus spp., and Bifidobacterium spp enumerated using selective plating media showed that GRE supplementation significantly reduced (P < 0.05) the amount of TBC and E. coli but increased the number of beneficial microorganisms such as Lactobacillus spp. and Bifidobacterium spp. On d 20, no significant differences were observed (P > 0.05) among all treatments for antibody titer against Newcastle disease virus and total IgY antibodies; however, on d 27, GRE-0.75% had the highest value for both immune indicators and was not different from MX. Dietary supplementation of GRE up to 1.5% enhanced the immune system and suppressed E. coli while promoting the growth of healthy bacteria, without any detrimental effect on growth performance.

Effectiveness of various cacao pod husk extraction byproducts in promoting growth and immunocompetence in Litopenaeus vannamei.

Extracts from plant products can promote growth, can act as immunostimulants, and have antibacterial and antiparasitic properties. These extracts can be used as alternatives to the chemical treatments commonly used to prevent and control disease in aquatic species. Research on the subject has focused on identifying invasive plants or agricultural waste products that can be used as immunostimulants. The present study further identified an optimal means of extracting pectin from cacao pod husks to promote growth performance and immunocompetence in Litopenaeus vannamei that would both reduce production costs and enable waste recycling. The byproducts of pectin extraction from cacao pod husks, that is, dried cacao pod husk powder (DCP), steamed DCP (sDCP), hot water-treated cacao pod husk powder (HCP), hot water-treated cacao pod husk supernatant (HCS), and cacao pod husk pectin (CPH pectin), were used to create five experimental diets, which were administered to five groups. The control group was fed a basal diet. The growth and immunocompetence of the shrimp were determined after 30, 60, 90 and 120 days of feeding. To identify the most cost-effective means of obtaining dried cacao pod husks, this study firstly determined the costs and effectiveness of the sun-drying, dehumidification, and heated-wind drying techniques. According to the results of growth performance, the CPH pectin group had higher survival but lower weight gain than the DCP, sDCP, HCP, and HCS groups did. At 30, 60, and 90 days, the clearance efficiency of the experimental groups was higher than that of the control group. At 60 days, the experimental groups had significantly higher phagocytic activity than the control group did. However, at 30 and 90 days the HCP, HCS and CPH pectin group had higher phagocytic activity. The total hemocyte count, differential hemocyte count, phenoloxidase activity, and respiratory bursts of the CPH pectin group were higher at 30 days but the same as those of the control group at 60 and 90 days. After 120 days of feeding trial, the resistance of L. vannamei fed with diets containing byproducts of pectin extraction from cacao pod husks significantly enhanced compared to that in BD group when they were infected with Vibrio aliginolyticus for 168 h, and the related higher survival rate can be observed in HCP, HCS and CPH pectin groups. The study findings suggest that diet-administered HCP and HCS have long-term immunostimulant potential and that CPH pectin has potential in the early stages of feeding. In addition, when heated air drying was employed, a moisture level of below 10% was obtained within 12 h. The results of this study indicate that adding HCP obtained from heated air-dried cacao pod husks to the feed of L. vannamei is the most cost-effective and sustainable means of promoting long-term growth performance and immunocompetence in the species.

Clinical efficacy and safety of NSCLC ancillary treatment with compound Kushen injection through immunocompetence regulation: A systematic review and meta-analysis.

BACKGROUND: Compound Kushen injection (CKI) is a Chinese patented medicine that improves the immunity level of cancer patients and inhibits tumor cell proliferation and metastasis. Clinically, CKI is widely used in combination with platinum-based chemotherapy (PBC) for non-small cell lung cancer (NSCLC) treatment. This study attempted to systemically evaluate the efficacy and safety of a combination of CKI and PBC for NSCLC treatment by modulating the immune function. PURPOSE: To evaluate the clinical efficacy and safety of CKI in combination with PBC for NSCLC. MATERIALS AND METHODS: English and Chinese databases were retrieved for randomized controlled trials (RCTs) of NSCLC treatment using a combination of CKI and PBC, and the changes of peripheral blood T lymphocytes (such as CD3+ T cells, CD4+ T cells, CD8+ T cells), and CD4+/CD8+ T cell ratio among NSCLC patients were detected before and after treatment using CKI with PBC. The search deadline was set as November 2021. The systemic evaluation was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The methodology and quality of each study included in the systemic evaluation were assessed. Review Manager 5.4, Stata12.0, and trial sequential analysis (TSA) were used for data analysis. The outcome indicators were qualified using GRADEprofiler software. RESULTS: A total of 25 RCTs involving 2460 cases of patients were included. The results showed that the combination of CKI with PBC effectively increased the objective response rate (ORR) [relative risk (RR) = 1.31, 95% confidence interval (CI) (1.19, 1.44)] and disease control rate (DCR) [RR = 1.16, 95%CI (1.09,1.23)], regulated the expression of peripheral blood T lymphocytes (such as CD3+T cells, CD4+T cells, CD8+T cells, and CD4+/CD8+T cell ratio), upregulated the level of serum immunoglobulins (such as IgA, IgG, and IgM), and reduced the frequency of gastrointestinal reaction, marrow inhibition, hepatorenal toxicity, reduction of white blood cells and blood platelets, baldness, infection, neutrophilic granulocyte counts, diarrhea, or constipation. According to subgroup analysis results, chemotherapy cycles (1-2) had a more significant effect on DCR. A combination of CKI and GP regimens had better effects on improving CD3+T cell levels, and there were no significant changes among other chemotherapies regiments. CONCLUSION: A combination of CKI and PBC had a marked effect in improving tumor response, priming immune function, and decreasing the frequency of adverse reactions, which was safe for NSCLC treatment.

Timing of maternal supplementation of dried distillers grains during late gestation influences postnatal growth, immunocompetence, and carcass characteristics of Bos indicus-influenced beef calves.

This 2-yr study investigated the timing of dried distillers grains (DDG) supplementation during the third trimester of gestation of Bos indicus-influenced beef cows and its impact on their offspring performance. On day 0 of each year (84 d before calving), Brangus cows (n = 84/yr; cow age = 8 ± 3 yr) were stratified by initial body weight (BW; 482 ± 75 kg) and body condition score (BCS; 5.3 ± 0.8) and assigned randomly to one of six bahiagrass (Paspalum notatum) pastures (experimental units; 14 cows/pasture). Treatments were assigned randomly to pasture (2 pastures/treatment/yr) and consisted of no prepartum supplementation (CON), 2 kg/d of DDG from day 0 to 42 (LATE42), or 1 kg/d of DDG from day 0 to 84 (LATE84). Following calving (day 84), cow-calf pairs remained in their respective pastures, and cows were offered sugarcane molasses + urea (1.82 kg of dry matter/cow/d) from day 85 until the end of the breeding season (day 224). On day 347, steer calves (n = 38/yr; 11 to 15 steers/treatment/yr) were weaned and transported to the feedlot (1,193 km). Steers were penned according to cow prepartum pasture and managed similarly until the time of harvest. BCS at calving was greater (P < 0.01) for LATE42 and LATE84 vs. CON cows but did not differ (P = 0.16) between LATE42 and LATE84 cows. Calving date, calving percentage, and birth BW of the first offspring did not differ (P ≥ 0.22) among treatments. However, LATE42 cows calved their second offspring 8 d earlier (P = 0.04) compared with CON and LATE84 cows. At weaning (first offspring), LATE84 calves were the heaviest (P ≤ 0.05), CON calves were the lightest, and LATE42 calves had intermediate BW (P ≤ 0.05). Steer plasma concentrations of cortisol and haptoglobin and serum bovine viral diarrhea virus type-1 titers did not differ (P ≥ 0.21) between treatments. Steer serum parainfluenza-3 titers were greater (P = 0.03) for LATE42 vs. CON steers, tended to be greater (P = 0.10) for LATE84 compared with CON steers, and did not differ (P = 0.38) between LATE42 and LATE84 steers. Steer feedlot BW, average daily gain, dry matter intake, and hot carcass weight did not differ (P ≥ 0.36) between treatments. Marbling and the percentage of steers grading choice were greater (P ≤ 0.04) for LATE42 vs. CON steers, whereas LATE84 steers were intermediate. In summary, different timing of DDG supplementation during the third trimester of gestation could be explored to optimize cow BCS and offspring preweaning growth and carcass quality.

This 2-yr study evaluated the effect of the timing of dried distillers grains (DDG) supplementation during the last trimester of gestation in Bos indicus-influenced beef cows and the subsequent impact on their offspring. Brangus cows were allocated to one of the three prepartum treatments consisting of no prepartum supplementation, 2 kg/d of DDG for the first half of the last trimester of gestation, or 1 kg/d of DDG for the entire length of the last trimester of gestation. Prepartum supplementation, regardless of supplementation length, improved cow body condition scores at the time of calving. Calf birth weights were not affected by prepartum maternal treatment. Calves born to cows that received prepartum supplementation had greater weaning weight compared with no prepartum supplementation. However, weaning weights were improved to the greatest extent when calves were born to cows that received supplementation for the entire length of late gestation. Steer antibody response to parainfluenza-3 was improved with prepartum maternal supplementation, regardless of supplementation length. Furthermore, concentrating the total amount of supplement offered to the first half of the last trimester of gestation improved marbling and increased the percentage of steers grading choice compared with no prepartum supplementation or supplementation during the entire last trimester.

Synbiotic combination of prebiotic, cacao pod husk pectin and probiotic, Lactobacillus plantarum, improve the immunocompetence and growth of Litopenaeus vannamei.

To reach the sustainable development goals on waste recycling, cacao pod husk (CPH), produced as an agricultural waste byproduct during the cacao bean processing was applied to manufacture CPH pectin for developing the potential for diverse application in aquaculture, minimizing CPH impact to the environment and bringing benefits to the agriculture and aquaculture industries. In this study, CPH pectin (5 g/kg diet) and Lactobacillus plantarum (LP; 1010 cfu/kg diet) were separately introduced to the diets of Litopenaeus vannamei for a 56-day feeding trial, and two synbiotic combinations of CPH pectin and LP (CPH pectin at 5 g/kg diet + LP at 107 cfu/kg diet or at 1010 cfu/kg diet) were also conducted. After the 56-day feeding trial, significantly elevated percent weight gain, percent length gains and feeding efficiency in L. vannamei were only observed in synbiotic combination of CPH pectin at 5 g/kg diet and LP at 107 cfu/kg diet treatment, and the remainder of the treatments remained consistently similar to the control. Significantly increases in total haemocyte count, granular cells, phenoloxidase activity, and respiratory bursts were observed in L. vannamei fed with synbiotics at 7-28 days of feeding, accompanied by significant promotion of phagocytic activity and clearance efficiency in response to V. alginolyticus challenge during 56 days of feeding trial. Furthermore, at the end of the 56 days of feeding trial, shrimp receiving CPH pectin and/or LP treatments showed a significantly higher survival ratio against V. alginolyticus infection and hypothermal stress. It was therefore concluded that CPH pectin or LP was confirmed as an immunostimulant for L. vannamei to trigger immunocompetence through oral administration without negative effects within 56 days of feeding trial, and the synbiotic combination of CPH pectin and LP exhibited complementary and synergistic effects on growth performance and immunocompetence in L. vannamei.

Effects of Citrus Fruit Juices and Their Bioactive Components on Inflammation and Immunity: A Narrative Review.

The immune system provides defence to the host against pathogenic organisms. A weak immune system increases susceptibility to infections and allows infections to become more severe. One component of the immune response is inflammation. Where inflammation is excessive or uncontrolled it can damage host tissues and cause pathology. Limitation of oxidative stress is one means of controlling inflammation. Citrus fruit juices are a particularly good source of vitamin C and folate, which both have roles in sustaining the integrity of immunological barriers and in supporting the function of many types of immune cell including phagocytes, natural killer cells, T-cells and B-cells. Vitamin C is an antioxidant and reduces aspects of the inflammatory response. Important bioactive polyphenols in citrus fruit juices include hesperidin, narirutin and naringin. Hesperidin is a glycoside of hesperetin while narirutin and naringin are glycosides of naringenin. Hesperidin, hesperetin, naringenin, naringin and narirutin have all been found to have anti-inflammatory effects in model systems, and human trials of hesperidin report reductions in inflammatory markers. In humans, orange juice was shown to limit the post-prandial inflammation induced by a high fat-high carbohydrate meal. Consuming orange juice daily for a period of weeks has been reported to reduce markers of inflammation, including C-reactive protein, as confirmed through a recent meta-analysis. A newly emerging topic is whether polyphenols from orange juice have direct anti-viral effects. In summary, micronutrients and other bioactives present in citrus fruit juices have established roles in controlling oxidative stress and inflammation and in supporting innate and acquired immune responses. Trials in humans demonstrate that orange juice reduces inflammation; its effects on innate and acquired immunity require further exploration in well-designed trials in appropriate population sub-groups such as older people.

Nano-selenium on reproduction and immunocompetence: an emerging progress and prospect in the productivity of poultry research.

Nanotechnology, an emerging and promising technology, has been implicated to revolutionize the poultry industry. The main aspect of nanotechnology was to modify or alter the particle size into nanometers and thereby alter the physical as well as chemical features of the particular molecules. Selenium (Se), an essential trace element, can play an immense role in the maintenance of diverse physiological functions, body metabolism and cellular homeostasis, and the performance of poultry. Selenium nanoparticles (Se-NPs) are of growing importance due to its nutrients digestibility, medicinal therapy, targeted drug delivery system, and production of vaccines. Se-nanoparticles are having importance due to its high bioavailability and digestive efficiency. Se-NPs have been implicated to increase relative weights of immune-related organs (burse and thymus) to enhance immunity and thereby modulate egg production as well as the reproductive performance of birds. The present review is highlighted on the significant role of nano-selenium on reproductive performance and immunocompetence in poultry as comparative advantages over conventional sources of Se in poultry diets.

10 ns PEFs induce a histological response linked to cell death and cytotoxic T-lymphocytes in an immunocompetent mouse model of peritoneal metastasis.

PURPOSE: The application of nanosecond pulsed electric fields (nsPEFs) could be an effective therapeutic strategy for peritoneal metastasis (PM) from colorectal cancer (CRC). The aim of this study was to evaluate in vitro the sensitivity of CT-26 CRC cells to nsPEFs in combination with chemotherapeutic agents, and to observe the subsequent in vivo histologic response. METHODS: In vitro cellular assays were performed to assess the effects of exposure to 1, 10, 100, 500 and 1000 10 ns pulses in a cuvette or bi-electrode system at 10 and 200 Hz. nsPEF treatment was applied alone or in combination with oxaliplatin and mitomycin. Cell death was detected by flow cytometry, and permeabilization and intracellular calcium levels by fluorescent confocal microscopy after treatment. A mouse model of PM was used to investigate the effects of in vivo exposure to pulses delivered using a bi-electrode system; morphological changes in mitochondria were assessed by electron microscopy. Fibrosis was measured by multiphoton microscopy, while the histological response (HR; hematoxylin-eosin-safran stain), proliferation (KI67, DAPI), and expression of immunological factors (CD3, CD4, CD8) were evaluated by classic histology. RESULTS: 10 ns PEFs exerted a dose-dependent effect on CT-26 cells in vitro and in vivo, by inducing cell death and altering mitochondrial morphology after plasma membrane permeabilization. In vivo results indicated a specific CD8+ T cell immune response, together with a strong HR according to the Peritoneal Regression Grading Score (PRGS). CONCLUSIONS: The effects of nsPEFs on CT-26 were confirmed in a mouse model of CRC with PM.

Immune Competence and Minimizing Susceptibility to COVID-19 and Other Immune System Threats.

Exposure to viruses, bacteria, and other pathogens is unavoidable. Yet, the mere presence of these threats is not enough to automatically predispose to illness. The susceptibility of an individual to viral or bacterial infections is dependent upon immune competence. Many factors can interfere with the functioning of the immune system. Epigenetic alterations in the form of lifestyle or environmental factors can lead to impaired immunity. For example, exposure to air pollution can increase the risk of complications and mortality from COVID-19. Obesity can also exacerbate the damaging effects of air pollution on the lungs and may enhance the association between air pollution and increased COVID-19 severity. Poor sleep is another factor leading to impaired immunity, likely due to the coinciding melatonin depletion. Melatonin has been found to have antiviral and immune-enhancing effects, and it has been proposed that this hormone may be beneficial in COVID-19 patients. Zinc and vitamins D and C have also been well studied for their ability to shorten the duration of upper respiratory infections, and vitamin D has been found to reduce mortality in COVID-19 patients. Cannabidiol can both directly and indirectly improve immunity by enhancing natural killer cell activity, reducing inflammation, and relieving stress. Other dietary supplements backed by solid scientific evidence to show they act as immune enhancers are astragalus, a yeast fermentate (EpiCor®), olive leaf extract, berberine, N-acetyl cysteine, and garlic.

Therapeutic candidates for the Zika virus identified by a high-throughput screen for Zika protease inhibitors.

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Of onions and men: Report of cavitary community acquired pneumonia due to Burkholderia cepacia complex in an immunocompetent patient and review of the literature.

Burkholderia cepacia complex consists of highly antibiotic resistant gram negative bacilli that are plant symbionts and also potential agents of human infection.  This bacterial family's claim to fame in clinical medicine is as the scourge of cystic fibrosis patients, in whom it is a notorious respiratory pathogen.  Outside of cystic fibrosis, it rarely comes to mind as an etiology of community acquired pneumonia with or without lung cavitation in immunocompetent hosts.  We describe a case of an otherwise healthy, community-dwelling man who presented with subacute cavitary lung disease, the causative organism of which turned out to be Burkholderia cepacia complex.  Our report is accompanied by a review of the literature, which identified an additional eleven cases in the same category.  We analyze all of the available cases for the emergence of any identifiable patterns or peculiarities.

Interventions for American cutaneous and mucocutaneous leishmaniasis.

BACKGROUND: On the American continent, cutaneous and mucocutaneous leishmaniasis (CL and MCL) are diseases associated with infection by several species of Leishmania parasites. Pentavalent antimonials remain the first-choice treatment. There are alternative interventions, but reviewing their effectiveness and safety is important as availability is limited. This is an update of a Cochrane Review first published in 2009. OBJECTIVES: To assess the effects of interventions for all immuno-competent people who have American cutaneous and mucocutaneous leishmaniasis (ACML). SEARCH METHODS: We updated our database searches of the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, LILACS and CINAHL to August 2019. We searched five trials registers. SELECTION CRITERIA: Randomised controlled trials (RCTs) assessing either single or combination treatments for ACML in immuno-competent people, diagnosed by clinical presentation and Leishmania infection confirmed by smear, culture, histology, or polymerase chain reaction on a biopsy specimen. The comparators were either no treatment, placebo only, or another active compound. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our key outcomes were the percentage of participants 'cured' at least three months after the end of treatment, adverse effects, and recurrence. We used GRADE to assess evidence certainty for each outcome. MAIN RESULTS: We included 75 studies (37 were new), totalling 6533 randomised participants with ATL. The studies were mainly conducted in Central and South America at regional hospitals, local healthcare clinics, and research centres. More male participants were included (mean age: roughly 28.9 years (SD: 7.0)). The most common confirmed species were L. braziliensis, L. panamensis, and L. mexicana. The most assessed interventions and comparators were non-antimonial systemics (particularly oral miltefosine) and antimonials (particularly meglumine antimoniate (MA), which was also a common intervention), respectively. Three studies included moderate-to-severe cases of mucosal leishmaniasis but none included cases with diffuse cutaneous or disseminated CL, considered the severe cutaneous form. Lesions were mainly ulcerative and located in the extremities and limbs. The follow-up (FU) period ranged from 28 days to 7 years. All studies had high or unclear risk of bias in at least one domain (especially performance bias). None of the studies reported the degree of functional or aesthetic impairment, scarring, or quality of life. Compared to placebo, at one-year FU, intramuscular (IM) MA given for 20 days to treat L. braziliensis and L. panamensis infections in ACML may increase the likelihood of complete cure (risk ratio (RR) 4.23, 95% confidence interval (CI) 0.84 to 21.38; 2 RCTs, 157 participants; moderate-certainty evidence), but may also make little to no difference, since the 95% CI includes the possibility of both increased and reduced healing (cure rates), and IMMA probably increases severe adverse effects such as myalgias and arthralgias (RR 1.51, 95% CI 1.17 to 1.96; 1 RCT, 134 participants; moderate-certainty evidence). IMMA may make little to no difference to the recurrence risk, but the 95% CI includes the possibility of both increased and reduced risk (RR 1.79, 95% CI 0.17 to 19.26; 1 RCT, 127 participants; low-certainty evidence). Compared to placebo, at six-month FU, oral miltefosine given for 28 days to treat L. mexicana, L. panamensis and L. braziliensis infections in American cutaneous leishmaniasis (ACL) probably improves the likelihood of complete cure (RR 2.25, 95% CI 1.42 to 3.38), and probably increases nausea rates (RR 3.96, 95% CI 1.49 to 10.48) and vomiting (RR 6.92, 95% CI 2.68 to 17.86) (moderate-certainty evidence). Oral miltefosine may make little to no difference to the recurrence risk (RR 2.97, 95% CI 0.37 to 23.89; low-certainty evidence), but the 95% CI includes the possibility of both increased and reduced risk (all based on 1 RCT, 133 participants). Compared to IMMA, at 6 to 12 months FU, oral miltefosine given for 28 days to treat L. braziliensis, L. panamensis, L. guyanensis and L. amazonensis infections in ACML may make little to no difference to the likelihood of complete cure (RR 1.05, 95% CI 0.90 to 1.23; 7 RCTs, 676 participants; low-certainty evidence). Based on moderate-certainty evidence (3 RCTs, 464 participants), miltefosine probably increases nausea rates (RR 2.45, 95% CI 1.72 to 3.49) and vomiting (RR 4.76, 95% CI 1.82 to 12.46) compared to IMMA. Recurrence risk was not reported. For the rest of the key comparisons, recurrence risk was not reported, and risk of adverse events could not be estimated. Compared to IMMA, at 6 to 12 months FU, oral azithromycin given for 20 to 28 days to treat L. braziliensis infections in ACML probably reduces the likelihood of complete cure (RR 0.51, 95% CI 0.34 to 0.76; 2 RCTs, 93 participants; moderate-certainty evidence). Compared to intravenous MA (IVMA) and placebo, at 12 month FU, adding topical imiquimod to IVMA, given for 20 days to treat L. braziliensis, L. guyanensis and L. peruviana infections in ACL probably makes little to no difference to the likelihood of complete cure (RR 1.30, 95% CI 0.95 to 1.80; 1 RCT, 80 participants; moderate-certainty evidence). Compared to MA, at 6 months FU, one session of local thermotherapy to treat L. panamensis and L. braziliensis infections in ACL reduces the likelihood of complete cure (RR 0.80, 95% CI 0.68 to 0.95; 1 RCT, 292 participants; high-certainty evidence). Compared to IMMA and placebo, at 26 weeks FU, adding oral pentoxifylline to IMMA to treat CL (species not stated) probably makes little to no difference to the likelihood of complete cure (RR 0.86, 95% CI 0.63 to 1.18; 1 RCT, 70 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Evidence certainty was mostly moderate or low, due to methodological shortcomings, which precluded conclusive results. Overall, both IMMA and oral miltefosine probably result in an increase in cure rates, and nausea and vomiting are probably more common with miltefosine than with IMMA. Future trials should investigate interventions for mucosal leishmaniasis and evaluate recurrence rates of cutaneous leishmaniasis and its progression to mucosal disease.

Cannabis in the Time of Coronavirus Disease 2019: The Yin and Yang of the Endocannabinoid System in Immunocompetence.

Editor's Note: For those whose response to COVID-19 includes exploring beyond vaccines, conventional pharmaceuticals, and the watchful or healthy waiting until such tools might arrive, interest in cannabinoids has been high - and controversial. It has already stimulated one journal, the Liebert Cannabis and Cannabinoid Research, to issue a call for papers on COVID-19. The unique place of cannabis in the culture seems to always mark the herb with an exponential asterisk whenever basketed with the other natural health strategies that are both widely used, and as broadly derided. In this invited commentary, JACM Editorial Board member Michelle Sexton, ND starts by describing the multiple immune modulating effects associated with the herb. The University of California San Diego Assistant Adjunct Professor in Anesthesiology then asks: "Given these effects, can phytocannabinoids be either helpful, or harmful for immune competency, in the context of the current COVID-19 pandemic?" A skilled edge-walker, Sexton lets the research fall where it may in wending a path through this evidentiary maze. -John Weeks, Editor-in-Chief, JACM.

Hepatic Ablation Promotes Colon Cancer Metastases in an Immunocompetent Murine Model.

OBJECTIVE: To determine the impact of radiofrequency (RF) and microwave (MW) energy compared to direct cautery on metatstatic colon cancer growth. BACKGROUND: Hepatic ablation with MW and RF energy creates a temperature gradient around a target site with temperatures known to create tissue injury and cell death. In contrast, direct heat application (cautery) vaporizes tissue with a higher site temperature but reduced heat gradient on surrounding tissue. We hypothesize that different energy devices create variable zones of sublethal injury that may promote tumor recurrence. To test this hypothesis we applied MW, RF, and cautery to normal murine liver with a concomitant metastatic colon cancer challenge. METHODS: C57/Bl6 mice received hepatic thermal injury with MW, RF, or cautery to create a superficial 3-mm lesion immediately after intrasplenic injection of 50K MC38 colon cancer cells. Thermal imaging recorded tissue temperature during ablation and for 10 seconds after energy cessation. Hepatic tumor location and volume was determined at day 7. RESULTS: Cautery demonstrated the highest maximum tissue temperatures (129°C) with more rapid return to baseline compared to MW or RF energy. All mice had metastasis at the ablation site. Mean tumor volume was significantly greater in the MW (95.3 mm; P = 0.007) and RF (55.7 mm; P = 0.015) than cautery (7.13 mm). There was no difference in volume between MW and RF energy (P = 0.2). CONCLUSIONS: Hepatic thermal ablation promotes colon cancer metastasis at the injury site. MV and RF energy result in greater metastatic volume than cautery. These data suggest that the method of energy delivery promotes local metastasis.

Pharmacotherapy Approaches in Nontuberculous Mycobacteria Infections.

Nontuberculous mycobacteria (NTM) comprise a heterogeneous group of organisms, with only a small subset known to cause disease in humans. Although NTM infection is not a reportable disease, both the increasing clinical recognition and recent advancements in laboratory diagnostic capabilities of NTM infections in immunocompromised and immunocompetent patients are rapidly evolving. We reviewed antimicrobial agents used to treat the most frequently encountered NTM infections and examined optimized drug dosing strategies, toxicity profiles, drug-drug interactions, and the role of therapeutic drug monitoring. Antimicrobial susceptibility testing and patient monitoring on therapy were also examined. We used PubMed to review the published literature on the management of select NTM pathogens, the common syndromes encountered since 2000, and select pharmacokinetic principles of select antimicrobial agents used since 1990. We included select clinical trials, systematic reviews, published guidelines, and observational studies when applicable. The prolonged duration and the necessity for combination therapy for most forms of NTM disease can be problematic for many patients. A multidisciplinary care team that includes pharmacy engagement may help increase rates of optimal patient tolerability and successful treatment completion.

Occurrence and challenges in the management of severe chronic plaque type psoriasis in a limited resourced setting: a case report.

Plaque-type psoriasis is a major dermatosis with significant effects on quality of life. Case complexity is often high in low-resourced settings such as in Africa where the incidence has been on the rise. Despite major advancements and newer therapeutic modalities over the last decade, an insight into the real-life, day to day challenges in low resourced settings reveal an interplay between the difficulty in obtaining these drugs and use of alternative traditional indigenous agents. We report the case of a 50 year old immunocompetent male who presented with chronic and extensive well demarcated plaques covered with silver-white scales occupying about 61% of his body surface area. Patient was however lost to follow up for about 8 months during which time, the lesions responded to some unknown homemade indigenous medications which was preferred to a systemic medication. Paramount importance on proper counselling and the need to retain patients in care is warranted by physicians and allied health personnel. Also, incentives aimed at subsidizing the newer systemic agents for patients in low resourced cohorts will go a long way to combat this multi-faceted disorder which is often unrecognized and under diagnosed.

Growth performance and immune status in common carp Cyprinus carpio as affected by plant oil-based diets complemented with ß-glucan.

Omnivorous fish species such as the common carp (Cyprinus carpio) are able to biosynthesise long chain polyunsaturated fatty acids (LC-PUFAs) from plant oil PUFA precursors, but the influence of the amount and quality of the LC-PUFAs biosynthesised from these oils on the immunocompetence status of the fish has received little attention. This study aims to evaluate whether the conversion of PUFA by carp induces a sufficient biosynthesis of LC-PUFA to maintain a good immunocompetence status in this species. Six iso-nitrogenous (crude protein = 39.1%) and iso-lipidic (crude lipids = 10%) diets containing three different lipid sources (cod liver oil (CLO) as fish oil; linseed oil (LO) and sunflower oil (SFO) as plant oils) were formulated with or without ß-glucan supplementation at 0.25 g/kg diet. Juvenile carp (16.3 ±â€¯0.6 g initial body weight) were fed a daily ration of 4% body weight for 9 weeks and then infected at day 64 with the bacteria Aeromonas hydrophyla. No significant differences in survival rate, final body weight, specific growth rate and feed conversion rate were observed between diets. After bacterial infection, mortality rate did not differ between fish fed CLO and plant oil-based diets, indicating that the latter oils did not affect the overall immunocompetence status of common carp. Plant oil-based diets did not alter lysozyme activity in healthy and infected fish. No negative effects of plant oils on complement activity (ACH50) were observed in healthy fish, even if both plant oil-based diets induced a decrease in stimulated fish two days after infection. Furthermore, the levels of various immune genes (nk, lys, il-8, pla, pge, alox) were not affected by plant oil-based diets. The expression of pla and pge genes were higher in SFO-fed fish than in CLO ones, indicating that this plant oil rich in linoleic acid (LA) better stimulated the eicosanoid metabolism process than fish oil. In response to ß-glucan supplementation, some innate immune functions seemed differentially affected by plant oil-based diets. LO and SFO induced substantial LC-PUFA production, even if fish fed CLO displayed the highest EPA and DHA levels in tissues. SFO rich in LA induced the highest ARA levels in fish muscle while LO rich in α-linolenic acid (ALA) sustained higher EPA production than SFO. A significantly higher fads-6a expression level was observed in SFO fish than in LO ones, but this was not observed for elovl5 expression. In conclusion, the results show that common carp fed plant oil-based diets are able to produce substantial amounts of LC-PUFA for sustaining growth rate, immune status and disease resistance similar to fish fed a fish oil-based diet. The differences in the production capacity of LC-PUFAs by the two plant oil-based diets were associated to a differential activation of some immune pathways, explaining how the use of these oils did not affect the overall immunocompetence of fish challenged with bacterial infection. Moreover, plant oil-based diets did not induce substantial negative effects on the immunomodulatory action of ß-glucans, confirming that these oils are suitable for sustaining a good immunocompetence status in common carp.

Fluconazole plus flucytosine is a good alternative therapy for non-HIV and non-transplant-associated cryptococcal meningitis: A retrospective cohort study.

Cryptococcal meningitis (CM) carries a high risk of mortality with increasing incidences in immune competent hosts. Current treatments are not well tolerated, and evaluation of other treatments is needed. Fluconazole and 5-flucytosine in treating immune competent hosts have not been characterised. To evaluate the efficacy of fluconazole and 5-flucytosine in treating non-HIV- and non-transplant-associated CM. We performed a retrospective cohort study of the outcomes in immune competent patients with CM treated with fluconazole and 5-flucytosine or deoxycholate-amphotericin B and 5-flucytosine. The primary outcome was treatment response evaluated at the 12th week after initiation of antifungal therapy. A total of 43 and 47 patients received amphotericin B deoxycholate and 5-flucytosine or fluconazole and 5-flucytosine, respectively. A total of 38 (88.4%) patients cannot tolerate recommended doses of amphotericin B deoxycholate and 5-flucytosine (patients needed dose reduction during the treatment). Patients given fluconazole and 5-flucytosine had higher baseline cryptococcal burdens (median 3632 versus 900 cryptococci/mL, P = 0.008). No significant differences were seen in cryptococcus clearance (74.4% vs 70.2%, P = 0.814), treatment time (39 days, 20-69 days vs 21 days, 7-63 days, P = 0.107) and successful response (including complete and partial responses) rates (69.7% vs 72.3%, P = 0.820). Fluconazole and 5-flucytosine treatment had lower total adverse events (19.1% vs 90.7%, P < 0.001). Fluconazole and 5-flucytosine had relatively high efficacy with few adverse events in treating CM. Fluconazole and 5-flucytosine therapy is promising in patients that do not tolerate or are not suited for amphotericin B deoxycholate treatment.

Baloxavir marboxil, a novel cap-dependent endonuclease inhibitor potently suppresses influenza virus replication and represents therapeutic effects in both immunocompetent and immunocompromised mouse models.

Baloxavir marboxil (BXM) is an orally available small molecule inhibitor of cap-dependent endonuclease (CEN), an essential enzyme in the initiation of mRNA synthesis of influenza viruses. In the present study, we evaluated the efficacy of BXM against influenza virus infection in mouse models. Single-day oral administration of BXM completely prevented mortality due to infection with influenza A and B virus in mice. Moreover, 5-day repeated administration of BXM was more effective for reducing mortality and body weight loss in mice infected with influenza A virus than oseltamivir phosphate (OSP), even when the treatment was delayed up to 96 hours post infection (p.i.). Notably, administration of BXM, starting at 72 hours p.i. led to significant decrease in virus titers of >2-log10 reduction compared to the vehicle control within 24 hours after administration. Virus reduction in the lung was significantly greater than that observed with OSP. In addition, profound and sustained reduction of virus titer was observed in the immunocompromised mouse model without emergence of variants possessing treatment-emergent amino acid substitutions in the target protein. In our immunocompetent and immunocompromised mouse models, delayed treatment with BXM resulted in rapid and potent reduction in infectious virus titer and prevention of signs of influenza infection, suggesting that BXM could extend the therapeutic window for patients with influenza virus infection regardless of the host immune status.

Involvement of a novel protein kinase C (nPKC) in immunocompetence in hemocytes of white shrimp, Litopenaeus vannamei.

Complementary (c)DNA encoding novel protein kinase C (PKC) messenger (m)RNA of the white shrimp Litopenaeus vannamei, consisted of 2454-bp cDNA containing an open reading frame (ORF) of 2232 bp, belonging to the novel (n)PKC family of proteins characterized by their containing two phorbol ester/diacylglycerol-binding domains (C1 domain), a C2 domain, and a catalytic domain of the serine/threonine kinase, designated LvnPKC. A comparison of amino acid sequences showed that LvnPKC was closely related to arthropod nPKC. LvnPKC cDNA was detected in all tested tissues with a real-time PCR including the hepatopancreas, gills, muscles, subcuticular epithelium, abdominal nerve, thoracic nerve, brain, the stomach, heart, and especially in hemocytes and the intestines. Moreover, significantly upregulated LvnPKC expression was only observed in the eyestalk, brain, and hepatopancreas of shrimp transferred from 28 °C to 18 °C for 30 min. Induction of LvnPKC expression in hemocytes of L. vannamei injected with Vibrio alginolyticus at 105 cfu shrimp-1 was detected earlier than in those injected with 103 cfu shrimp-1. Shrimp received LvnPKC-dsRNA for 1 days specifically depleted the expression of LvnPKC mRNA in hemocytes compared those of diethylpyrocarbonate water treatment. After that, significantly decreased expressions of lipopolysaccharide - and ß-1,3-glucan-binding protein, prophenoloxidase-activating enzyme, peroxinectin, prophenoloxidase I, and prophenoloxidase II in the prophenoloxidase-activating system; lysozyme and cytosolic manganese superoxide dismutase and mitochondrial manganese superoxide dismutase in the antioxidant system were observed. We therefore concluded that LvnPKC is involved in immune defense of L. vannamei exposed to hypothermal stress or infected with V. alginolyticus.