Reduction In Severity Of Lesions Research Articles

Evaluation of alternative vaccination routes against paratuberculosis in goats.

Paratuberculosis is a chronic granulomatous enteritis, caused by Mycobacterium avium subspecies paratuberculosis (Map), that affects ruminants worldwide. Vaccination has been considered the most cost-effective method for the control of this disease in infected dairy herds. However, currently available vaccines do not provide complete protection and interfere with the diagnosis of both paratuberculosis and bovine tuberculosis, limiting its use. Because of that, efforts are being made for the development of new vaccines. The primary objective of this study was to evaluate the efficacy of two whole-cell inactivated experimental vaccines against paratuberculosis in goats, administered through the oral (OV) and intradermal (IDV) routes, and compare them with that of the commercial subcutaneous vaccine Gudair® (SCV). Over an 11-month period, the effect of vaccination and a subsequent Map challenge on the specific peripheral immune responses and Map-DNA fecal shedding were recorded. At the end of the experiment, tissue bacterial load and lesion severity were assessed. The experimental vaccines did not induce specific humoral immune responses and only elicited mild and delayed cellular immune responses. Although the OV reduced lesion severity, neither this vaccine nor the IDV prototype was able to reduce fecal shedding or tissue bacterial load. Moreover, although the SCV did not confer sterile immunity, it outperformed both experimental vaccines in all these parameters.

Effect of Omega-3 Polyunsaturated Fatty Acid Supplementation on Clinical Outcome of Atopic Dermatitis in Children.

The use of omega-3 fatty acids (omega-3 FA) in the treatment of atopic dermatitis (AD) is an area of ongoing research. Some studies suggest that dietary supplementation with omega-3 FA can help manage symptoms of AD by reducing lesion severity, skin inflammation, dryness and itching, while others show no significant beneficial effect. The aim of this study was to evaluate the effect of omega-3 FA from fish oil in combination with gamma-linolenic acid (GLA) from blackcurrant seed oil in children with AD. This is a longitudinal, prospective, randomized, triple blind, placebo-controlled parallel clinical trial. The study was conducted during the 2-year period throughout autumn, winter, and spring, avoiding the summer when AD usually improves. Children were randomized to receive the active study product (Mega Kid®) containing a specific blend of omega-3 and omega-6 fatty acids or placebo. The primary outcomes were changes in severity of AD measured using SCORing Atopic Dermatitis (SCORAD), patient-oriented SCORAD (PO-SCORAD) and the difference in topical corticosteroid (TCS) use. The secondary outcomes were changes in itch intensity, sleep quality and Family Dermatology Life Quality Index (FDLQI). Data were analyzed for 52 children (26 in the intervention group and 26 in the placebo group). In children receiving the active product, intention-to-treat analysis showed that after 4 months of treatment, there was a significant decrease in the SCORAD index (from median 42 to 25, p < 0.001) and the use of topical corticosteroids (from median 30 to 10 mg/month, p < 0.001), but also significant improvements in itch, sleep quality, and overall quality of life. Omega-3 fatty acids in combination with GLA and vitamin D may decrease symptoms and were associated with an improvement clinical picture of AD in children. Therefore, we can conclude that supplementation with this specific combination could be considered a safe and effective intervention that may significantly reduce the severity of AD in pediatric patients.

Herbivores can benefit both plants and their pathogens through selective herbivory on diseased tissue

Abstract Infectious disease can shape community structure, particularly when pathogens affect foundation species. Seagrasses are foundation species that form meadows along coasts worldwide, controlling sediment deposition and biogeochemical cycling while supporting a diverse community of fish and invertebrates. These plants are hosts to wasting diseases that cause necrotic tissue lesions, which could alter seagrass value as food, habitat and mediators of ecosystem processes. However, such biotic interactions and influences on disease dynamics are still not well understood. We investigated whether a common herbivore affected the development of wasting disease on eelgrass. We measured the severity and prevalence of eelgrass wasting disease in a meadow across two summers through repeated field surveys. We assessed the role of the eelgrass herbivore on disease spread and growth using microcosm and mesocosm experiments. We further explored herbivore feeding preferences in a choice trial, which was paired with chemical analysis of plant tissue and analysed using a structural equation model. While the herbivore facilitates the growth of new disease lesions among isolated leaves, on balance they reduce lesion severity by more than 50% in comparison with no‐herbivore controls in field‐realistic settings. This was likely because the herbivore strongly prefers to eat diseased rather than healthy tissue, consuming nearly twice as much lesion area in choice trials. This preference arises from pathogen‐driven changes in the host plant; lesioned tissue requires less force to penetrate than non‐lesioned tissue. Additionally, as lesions increase in size, their polyphenolic concentrations drop, which further increases the magnitude of preference for lesioned tissue. Synthesis: These results suggest that these herbivores could help maintain disease in this system at a high prevalence (by facilitating disease development) but low severity (through preferential consumption), which is consistent with our field observations of nearly 100% prevalence and low severity in a natural bed where herbivore density is high. Describing such multi‐species interactions in marine systems will advance our predictions of future disease states, as current understandings focus primarily on how environmental change contributes to pathogen outbreaks.

Inhibition of GATA3, ABCB1, and TYR by gallic acid: A real-world approach to uncovering a preventive agent against oral squamous cell carcinoma development

ObjectiveThis study aimed to the efficacy of gallic acid (GA) as a prospective prophylactic agent against the onset of oral squamous cell carcinoma (OSCC). MethodsWe conducted bioinformatic analyses to identify the molecular targets of GA. Subsequently, we employed the 4NQO-induced animal model to evaluate the therapeutic potential of GA in OSCC. ResultsOur analysis unveiled that only three genes, ABCB1, GATA3, and SERPINE1, were associated with survival outcomes in OSCC patients. Reduced expressions of ABCB1 and GATA3 correlated with hazard ratios of 1.53 and 2.06, respectively, for mortality, while elevated SERPINE1 expression carried a 1.42-fold increased risk of death in OSCC patients. Molecular docking simulations underscored the robust affinity between GA and these genes, revealing binding energies of −6.0 kcal/mol for ABCB1, − 6.1 kcal/mol for GATA3, and −5.9 kcal/mol for SERPINE1. Furthermore, GA treatment demonstrated statistically significant reductions in the histopathological grade of 4NQO-induced lesions (p = 0.006) and mitigated liver (p < 0.001) and kidney (p < 0.001) toxicity associated with 4NQO exposure. ConclusionThe current study highlights GA as a promising contender for OSCC prevention. Mainly, GA targets critical genes such as ABCB1, GATA3, and SERPINE1, substantially impacting patient survival. Furthermore, GA administration mitigates 4NQO-induced toxicity, indicating its potential to improve animal survival by reducing lesion severity. These findings carry significant implications for OSCC research and potential clinical applications.

Oxyresveratrol Attenuates Inflammation in Human Keratinocyte via Regulating NF-kB Signaling and Ameliorates Eczematous Lesion in DNCB-Induced Dermatitis Mice.

Oxyresveratrol (ORV) is one of the novel antioxidants having been extensively studied in recent years. One of the main sources of ORV is Artocarpus lakoocha, which has been used in traditional medicine in Thailand for decades. However, the role of ORV in skin inflammation has not been clearly demonstrated. Therefore, we investigated the anti-inflammatory effects of ORV on dermatitis model. The effect of ORV was examined on human immortalized and primary skin cells exposed to bacterial components including peptidoglycan (PGN) and lipopolysaccharide (LPS) and 2,4-Dinitrochlorobenzene (DNCB)-induced dermatitis mouse model. PGN and LPS were used to induce inflammation on immortalized keratinocytes (HaCaT) and human epidermal keratinocytes (HEKa). We then performed MTT assay, Annexin V and PI assay, cell cycle analysis, real-time PCR, ELISA and Western blot in these in vitro models. H&E staining, immunohistochemistry (IHC) staining with CD3, CD4 and CD8 markers were used to evaluate the effects of ORV in in vivo model of skin inflammation using BALB/c mice. Pretreatment of HaCaT and HEKa cells with ORV inhibited pro-inflammatory cytokine production through inhibition of NF-κB pathway. In DNCB-induced dermatitis mouse model, ORV treatment reduced lesion severity, and skin thickness and numbers of CD3, CD4 and CD8 T cells in the sensitized skin of mice. In conclusion, it has been demonstrated that ORV treatment can ameliorate inflammation in the in vitro models of skin inflammation and in vivo models of dermatitis, suggesting a therapeutic potential of ORV for treatment of skin diseases particularly eczema.

Proof-of-concept study for liver-directed miQURE technology in a dyslipidemic mouse model

A gene-silencing platform (miQURE) has been developed and successfully used to deliver therapeutic microRNA (miRNA) to the brain, reducing levels of neurodegenerative disease-causing proteins/RNAs via RNA interference and improving the disease phenotype in animal models. This study evaluates the use of miQURE technology to deliver therapeutic miRNA for liver-specific indications. Angiopoietin-like 3 (ANGPTL3) was selected as the target mRNA because it is produced in the liver and because loss-of-function ANGPTL3 mutations and/or pharmacological inhibition of ANGPTL3 protein lowers lipid levels and reduces cardiovascular risk. Overall, 14 candidate miRNA constructs were tested invitro, the most potent of which (miAngE) was further evaluated in mice. rAAV5-miAngE led to dose-dependent (≤-77%) decreases in Angptl3 mRNA in WT mice with ≤-90% reductions in plasma ANGPTL3 protein. In dyslipidemic APOE∗3-Leiden.CETP mice, AAV5-miAngE significantly reduced cholesterol and triglyceride levelsvs. vehicle and scrambled (miSCR) controls when administrated alone, with greater reductions when co-administered with lipid-lowering therapy (atorvastatin). A significant decrease in total atherosclerotic lesion area (-58% vs. miSCR) was observed in AAV5-miAngE-treated dyslipidemic mice, which corresponded with the maintenance of a non-diseased plaque phenotype and reduced lesion severity. These results support the development of this technology for liver-directed indications.

Modulating disease phenotype in a songbird: A role for inflammation in disease tolerance?

Individual animals vary greatly in their responses to infection, either killing off the invading pathogen (resistance) or minimizing the per-pathogen costs of infection on host fitness (tolerance). Though we understand little about the physiological drivers of tolerance in wild animals, phenotypically, it manifests as milder clinical signs of disease. Here, we use a well-described disease system, finch mycoplasmosis, to evaluate the role of inflammation in disease tolerance. House finches (Haemorhous mexicanus) infected with the bacterial pathogen Mycoplasma gallisepticum (MG) develop conjunctival pathology that satisfies the cardinal signs of inflammation. We report on a captive trial performed in 2016 and replicated in 2018 that tested whether chemotherapeutics, specifically nonsteroidal anti-inflammatory drugs (NSAIDs), can reduce lesion severity, thus pushing individuals toward more tolerant phenotypes. Though birds treated with NSAIDs in the first trial developed milder pathology per unit pathogen load, we found no effect of treatment in the second trial, perhaps due to natural variation in baseline tolerance within the source population across years. Second-trial control birds developed markedly milder pathology than first-year controls, suggesting that the effect of trial swamped the effect of treatment in this study. Moving forward, using birds from a population in which the disease is absent or only recently emerged-and so tolerance has not yet been selected for-may better elucidate the role of pro-inflammatory mediators in disease tolerance.

Evaluation of the treatment of equine glandular gastric disease with either long‐acting‐injectable or oral omeprazole

BackgroundEquine glandular gastric disease (EGGD) is common in domesticated horses and can be challenging to treat. Oral omeprazole (ORLO) is used widely but the clinical response is frequently poor.ObjectivesTo compare rates of EGGD healing and improvement between ORLO and a long‐acting injectable omeprazole preparation (LAIO).Study designRetrospective clinical study.MethodsThe case records and gastroscopy images of horses presenting to masked for peer review over a 12‐month period were reviewed, with images blindly assessed by one of the authors. Treatment responses to 4 mg/kg LAIO administered every 7 days for 2 and 4 weeks were compared with ORLO 4 mg/kg PO q24hrs for 4 weeks. Data were compared using a Mann‐Whitney U test with post‐hoc Dunn's test, Chi‐squared test and a Fisher's exact test.ResultsThirty‐three horses that received LAIO and 12 that received ORLO were identified. Nine horses in the LAIO had received other treatments previously. The groups were comparable in signalment and EGGD lesion severity. Long‐acting injectable omeprazole was found to be non‐inferior to ORLO. LAIO was associated with better healing rates than ORLO at 4 weeks (LAIO‐80%; ORLO‐42%; p = 0.02), and reduction in lesion severity at 2 and 4 weeks in the LAIO group but not in the ORLO group at 4 weeks. Eighteen percent of horses in the LAIO group and 50% in the ORLO group did not heal at 4 weeks. There was no association between rate of healing or improvement and resolution or improvement of clinical signs. Six localised and self‐limiting injection site reactions were identified in 4 horses treated with LAIO (6.7%).Main limitationsRetrospective design, small numbers and the use of other treatments prior to use of LAIO.ConclusionsLAIO was found to be non‐inferior to oral omeprazole for EGGD. Larger blinded randomised clinical trials are justified.

Andiroba oil and nanoemulsion (Carapa guianensis Aublet) reduce lesion severity caused by the antineoplastic agent doxorubicin in mice

Doxorubicin (DOX) is an anthracycline antibiotic used in the fight against many types of cancer. Although it is quite effective for this purpose, its clinical use is limited by its severe side effects, highlighting the relevance of efforts to identify substances that act to minimize these effects. In this work, we sought to verify the ability of andiroba oil (AO) and a nanoemulsion of andiroba oil (AN) to lessen the side effects of DOX. The animals were separated into 7 groups with 6 animals each: mice treated with AO (2000 mg/kg), AN (2000 mg/kg), the antineoplastic agent DOX (40 mg/kg), AO+DOX, AN+DOX and solvent controls was used of negative control (corn oil and nanoemulsion surfactant). AO and AN were administered for 14 consecutive days orally by gavage and on the 13th day, applied DOX by intraperitoneal route (i.p.), in order to evaluate the protective potential of andiroba. The animals were euthanized on the 15th day. Hematological, biochemical, histological, and immunohistochemical parameters were analyzed. Andiroba reduced several aspects of the severity of lesions caused by DOX, decreasing hematotoxicity and the severity of histological changes in the liver and kidneys, and reducing the frequency of apoptotic cell death. In many cases, AN showed greater efficacy than AO alone, reflecting the feasibility of using this nanotechnology to improve the pharmacokinetics of lipid compounds in the body. The study sheds new light on the therapeutic benefits of andiroba and suggests new ways for investigating how the quantity and quality of lipid compounds affect exposed organisms.

Phage therapy for treatment of virulent Klebsiella pneumoniae infection in a mouse model

ObjectivesKlebsiella pneumoniae is an important emerging pathogen of humans and animals leading to serious clinical consequences. Increased antibiotic use has promoted the emergence of carbapenem-resistant and extended-spectrum β-lactamase (ESBL)-producing K. pneumoniae strains. Recently, phage therapy has gained momentum as a possible alternative against emerging antimicrobial resistance. This study was performed to assess the therapeutic effects of a novel lytic phage (VTCCBPA43) in a pneumonic mouse model in order to explore the efficacy of phage therapy against virulent K. pneumoniae infection. MethodsThe tailed phage VTCCBPA43 was assessed for its growth kinetics, in vitro host range, and temperature and pH sensitivity. Protein constituents were analysed by SDS-PAGE and nLC-MS/MS. Therapeutic efficacy was observed 2 h post-challenge with virulent K. pneumoniae in a BALB/c mouse model. ResultsPhage VTCCBPA43 was found to be highly temperature-tolerant (up to 80 °C). It was most active at pH 5, had a burst size of 172 PFU/mL and exhibited a narrow host range. It was identified as a KP36-like phage by shotgun proteomics. Following intranasal application of a single dose (2 × 109 PFU/mouse) post-challenge with virulent K. pneumoniae, the presence of biologically active phage in vivo and a significant reduction in the lung bacterial load at all time points was observed. A reduction in lesion severity suggested overall beneficial effects of VTCCBPA43 phage therapy in the pneumonic mouse model. ConclusionThis research represents the first in vivo evidence of effective phage therapy against K. pneumoniae infection by the intranasal route.

Wedelolactone suppresses IL-1β maturation and neutrophil infiltration in Aspergillus fumigatus keratitis

PurposeWedelolactone, a chemical compound extracted from Wedelia calendulacea or Eclipta alba, has been reported to regulate key steps in inflammation. However, the effects of wedelolactone on fungal keratitis are not known. Hence, we aimed to characterize the impact of wedelolactone in Aspergillus fumigatus keratitis. MethodsAspergillus fumigatus was used to establish an in vivo mouse model of fungal keratitis and an in vitro model of THP-1 macrophages. Mice and THP-1 macrophages were pre-treated with wedelolactone. Clinical evaluation, myeloperoxidase (MPO) assay, neutrophil staining, western blot and quantitative polymerase chain reaction (qRT-PCR) were used to assess the effect of wedelolactone on A. fumigatus infection. Therapeutic effect of natamycin treatment with or without wedelolactone was measured via slit lamp microscopy. ResultsWe confirmed that wedelolactone attenuated the infiltration of neutrophils and decreased MPO level at earlier time points in mice with A. fumigatus keratitis. Pre-treatment with wedelolactone decreased pro-inflammatory cytokine interleukin 1 beta (IL-1β) maturation by inhibiting caspase-1 activity. Combined with natamycin, wedelolactone protected corneal transparency in mouse with fungal keratitis. ConclusionPresent findings indicated that wedelolactone reduced host immune responses by attenuating neutrophil recruitment and IL-1β maturation in Aspergillus fumigatus keratitis. Wedelolactone combined with an antifungal medicine could be a potential therapy for reducing lesion severity in fungal keratitis.

English

The objective of the present study was to assess the anti-fungal activity of medicinal plant extracts on inhibition of Colletotrichum gloesporioides mycelial growth, sporulation and germination and on anthracnose control in Heliconia psitacorum cv. Golden Torch and Heliconia rostrata. Extracts of garlic, lemon grass, cinnamon, lemon balm, eucalyptus, ginger, mint, bitter melon and black pepper were used. The, mycelial were assessed in vitro by measuring their growth in Petri dishes. Sporulation was assessed by counting spores in a Neubauer chamber. Germination was observed based on germination tube emission. In the in vitro tests, the inflorescences were treated with the plant extracts and inoculated with the pathogen 24 h later. The results showed that all the extracts presented anti-fungal activity, in greater or lesser intensity, compared to the control. The garlic extract resulted in the highest mycelial growth inhibition rate. Regarding sporulation, the bitter melon, ginger, mint, popcorn eucalyptus and bitter melon extracts were more efficacious, interfering in spore formation; while the ginger extract most reduced spore germination inhibiting germination tube emission. For the in vivo tests, it was observed that all the plant extracts tested were efficient in reducing lesion severity in the inflorescence, showing that the use of plant extracts may be a promising alternative for managing the diseases that affect helconia post-harvest. Key words: Alternative control, fungi, Colletotrichum gloesporioides, tropical flowers. &nbsp

Biological Control of Mango Dieback Disease Caused by Lasiodiplodia theobromae Using Streptomycete and Non-streptomycete Actinobacteria in the United Arab Emirates.

Dieback caused by the fungus Lasiodiplodia theobromae is an important disease on mango plantations in the United Arab Emirates (UAE). In this study, 53 actinobacterial isolates were obtained from mango rhizosphere soil in the UAE, of which 35 (66%) were classified as streptomycetes (SA) and 18 (34%) as non-streptomycetes (NSA). Among these isolates, 19 (12 SA and 7 NSA) showed antagonistic activities against L. theobromae associated with either the production of diffusible antifungal metabolites, extracellular cell-wall-degrading enzymes (CWDEs), or both. Using a “novel” mango fruit bioassay, all isolates were screened in vivo for their abilities to reduce lesion severity on fruits inoculated with L. theobromae. Three isolates, two belonging to Streptomyces and one to Micromonospora spp., showed the strongest inhibitory effect against this pathogen in vitro and were therefore selected for tests on mango seedlings. Our results revealed that the antifungal action of S. samsunensis UAE1 was related to antibiosis, and the production of CWDEs (i.e., chitinase) and siderophores; whilst S. cavourensis UAE1 and M. tulbaghiae UAE1 were considered to be associated with antibiotic- and CWDE-production, respectively. Pre-inoculation in greenhouse experiments with the most promising actinobacterial isolates resulted in very high levels of disease protection in mango seedlings subsequently inoculated with the pathogen. This was evident by the dramatic reduction in the estimated disease severity indices of the mango dieback of individual biocontrol agent (BCA) applications compared with the pathogen alone, confirming their potential in the management of mango dieback disease. L. theobromae-infected mango seedlings treated with S. samsunensis showed significantly reduced number of defoliated leaves and conidia counts of L. theobromae by 2- and 4-fold, respectively, in comparison to the other two BCA applications. This indicates that the synergistic antifungal effects of S. samsunensis using multiple modes of action retarded the in planta invasion of L. theobromae. This is the first report of BCA effects against L. theobromae on mango seedlings by microbial antagonists. It is also the first report of actinobacteria naturally existing in the soils of the UAE or elsewhere that show the ability to suppress the mango dieback disease.

In vivo predictors of plaque erosion in patients with ST-segment elevation myocardial infarction: a clinical, angiographical, and intravascular optical coherence tomography study.

Plaque erosion is a significant substrate of acute coronary thrombosis. This study sought to determine in vivo predictors of plaque erosion in patients with ST-segment elevation myocardial infarction (STEMI). A prospective series of 822 STEMI patients underwent pre-intervention optical coherence tomography. Using established diagnostic criteria, 209 had plaque erosion (25.4%) and 564 had plaque rupture (68.6%). Plaque erosion was more frequent in women <50 years when compared with those ≥50 years of age (P = 0.009). There was a similar, but less striking, trend in men (P = 0.011). Patients with plaque erosion were more frequently current smokers but had fewer other coronary risk factors (dyslipidaemia, hypertension, chronic kidney disease, and diabetes mellitus) than those with plaque rupture. There was a preponderance of plaque erosion in the left anterior descending artery (LAD; 61.2%), whereas plaque rupture was more equally distributed in both the LAD (47.0%) and right coronary artery (43.3%). Despite the similar spatial distribution of erosions and ruptures over the lengths of the coronary arteries, plaque erosion occurred more frequently near a bifurcation (P < 0.001). In the multivariable analysis, age <50 years, current smoking, absence of other coronary risk factors, lack of multi-vessel disease, reduced lesion severity, larger vessel size, and nearby bifurcation were significantly associated with plaque erosion. Nearby bifurcation and current smoking were especially notable in men, while age <50 years was most predictive in women. Plaque erosion was a predictable clinical entity distinct from plaque rupture in STEMI patients, and gender-specific role of risk factors in plaque erosion should be considered.

The Preventive Effects of Different Doses of Glucomannan on Experimental Aflatoxicosis in Japanese Quails

ABSTRACT This experimental study was performed to investigate whether there is a protective effect of different doses of Glucomannan using against aflatoxicosis in Japanese quail, and pathological changes and relative organ weights were compared. In the experiment, 60 one-day old male Japanese quails were used as divided into six different groups. Experimental groups were designated as Control(C), aflatoxin(A), glucomannan(GM), 2-fold dose of glucomannan(2GM), aflatoxin+glucomannan(A+GM) and aflatoxin+2-fold dose of glucomannan(A+2GM). While control group quails fed the standard ration as ad libitum, other groups were fed with the administrations additionally to standard diet respectively; 2mg/kg of aflatoxin to group A, 1g/kg of glucomannan to group GM, 2g/kg of glucomannan to group 2GM, 2mg/kg of aflatoxin and 1g/kg glucomannan to group A+GM, 2mg/kg of aflatoxin and 2g/kg glucomannan to group A+2GM. All quails were euthanized at day 21 of the study and organs, (liver, spleen, kidney, thymus and bursa of Fabricius) were removed, weighed and subjected to routine histopathological procedures. Although any important macroscopic changes were not observed in the C, GM and 2GM groups, significant pathological changes were found in the groups of A, A+GM and A+2GM. In the A+GM group, the partial reduction in the severity of microscopic lesions were seen in liver, bursa of Fabricius, thymus and spleen, however a significant reduction in severity of lesions was noticed in A+2GM group. As a result of the study, 2g/kg of glucomannan has been found pathologically to be more effective than 1g/kg glucomannan in terms of the protection against aflatoxicosis by giving orally.

Azacytidine Treatment Inhibits the Progression of Herpes Stromal Keratitis by Enhancing Regulatory T Cell Function.

Ocular infection with herpes simplex virus 1 (HSV-1) sets off an inflammatory reaction in the cornea which leads to both virus clearance and chronic lesions that are orchestrated by CD4 T cells. Approaches that enhance the function of regulatory T cells (Treg) and dampen effector T cells can be effective to limit stromal keratitis (SK) lesion severity. In this report, we explore the novel approach of inhibiting DNA methyltransferase activity using 5-azacytidine (Aza; a cytosine analog) to limit HSV-1-induced ocular lesions. We show that therapy begun after infection when virus was no longer actively replicating resulted in a pronounced reduction in lesion severity, with markedly diminished numbers of T cells and nonlymphoid inflammatory cells, along with reduced cytokine mediators. The remaining inflammatory reactions had a change in the ratio of CD4 Foxp3+ Treg to effector Th1 CD4 T cells in ocular lesions and lymphoid tissues, with Treg becoming predominant over the effectors. In addition, compared to those from control mice, Treg from Aza-treated mice showed more suppressor activity in vitro and expressed higher levels of activation molecules. Additionally, cells induced in vitro in the presence of Aza showed epigenetic differences in the Treg-specific demethylated region (TSDR) of Foxp3 and were more stable when exposed to inflammatory cytokines. Our results show that therapy with Aza is an effective means of controlling a virus-induced inflammatory reaction and may act mainly by the effects on Treg.IMPORTANCE HSV-1 infection has been shown to initiate an inflammatory reaction in the cornea that leads to tissue damage and loss of vision. The inflammatory reaction is orchestrated by gamma interferon (IFN-γ)-secreting Th1 cells, and regulatory T cells play a protective role. Hence, novel therapeutics that can rebalance the ratio of regulatory T cells to effectors are a relevant issue. This study opens up a new avenue in treating HSV-induced SK lesions by increasing the stability and function of regulatory T cells using the DNA methyltransferase inhibitor 5-azacytidine (Aza). Aza increased the function of regulatory T cells, leading to enhanced suppressive activity and diminished lesions. Hence, therapy with Aza, which acts mainly by its effects on Treg, can be an effective means to control virus-induced inflammatory lesions.

Minimal In Vivo Efficacy of Iminosugars in a Lethal Ebola Virus Guinea Pig Model.

The antiviral properties of iminosugars have been reported previously in vitro and in small animal models against Ebola virus (EBOV); however, their effects have not been tested in larger animal models such as guinea pigs. We tested the iminosugars N-butyl-deoxynojirimycin (NB-DNJ) and N-(9-methoxynonyl)-1deoxynojirimycin (MON-DNJ) for safety in uninfected animals, and for antiviral efficacy in animals infected with a lethal dose of guinea pig adapted EBOV. 1850 mg/kg/day NB-DNJ and 120 mg/kg/day MON-DNJ administered intravenously, three times daily, caused no adverse effects and were well tolerated. A pilot study treating infected animals three times within an 8 hour period was promising with 1 of 4 infected NB-DNJ treated animals surviving and the remaining three showing improved clinical signs. MON-DNJ showed no protective effects when EBOV-infected guinea pigs were treated. On histopathological examination, animals treated with NB-DNJ had reduced lesion severity in liver and spleen. However, a second study, in which NB-DNJ was administered at equally-spaced 8 hour intervals, could not confirm drug-associated benefits. Neither was any antiviral effect of iminosugars detected in an EBOV glycoprotein pseudotyped virus assay. Overall, this study provides evidence that NB-DNJ and MON-DNJ do not protect guinea pigs from a lethal EBOV-infection at the dose levels and regimens tested. However, the one surviving animal and signs of improvements in three animals of the NB-DNJ treated cohort could indicate that NB-DNJ at these levels may have a marginal beneficial effect. Future work could be focused on the development of more potent iminosugars.

Hidradenitis suppurativa: epidemiology, clinical features, associated comorbidities and treatment.

Hidradenitis suppurativa (HS) is a chronic relapsing suppurativa skin disease localized in the apocrine-gland-bearing areas of the body, predominantly in the axillae and groin. Although important risk factors have been identified, the pathomechanisms of the disease have not been fully understood. In the absence of proper treatment, chronic inflammation results in debilitating, and sometimes life-threatening complications. This severe and chronic disease can have detrimental effects on self-esteem and quality of life and is associated with high comorbidity, such as the metabolic syndrome and its components. Early detection and treatment in patients with HS may prevent late direct complications, such as severe scarring, and indirect complications, i.e. cardio-vascular disease. Thus appropriate screening and treatment should be prompt. No definitive treatment has been recognized, but several therapies have been found to reduce lesion severity and improve symptoms of HS. Additional research is needed for evaluation of the comparative effectiveness of topical and systemic treatments and for better understanding of the pathogenesis, natural history, and subtypes of HS.

BCG lowers plasma cholesterol levels and delays atherosclerotic lesion progression in mice

Background and aimsBacille-Calmette-Guérin (BCG), prepared from attenuated live Mycobacterium bovis, modulates atherosclerosis development as currently explained by immunomodulatory mechanisms. However, whether BCG is pro- or anti-atherogenic remains inconclusive as the effect of BCG on cholesterol metabolism, the main driver of atherosclerosis development, has remained underexposed in previous studies. Therefore, we aimed to elucidate the effect of BCG on cholesterol metabolism in addition to inflammation and atherosclerosis development in APOE*3-Leiden.CETP mice, a well-established model of human-like lipoprotein metabolism. MethodsHyperlipidemic APOE*3-Leiden.CETP mice were fed a Western-type diet containing 0.1% cholesterol and were terminated 6 weeks after a single intravenous injection with BCG (0.75 mg; 5 × 106 CFU). ResultsBCG-treated mice exhibited hepatic mycobacterial infection and hepatomegaly. The enlarged liver (+53%, p = 0.001) coincided with severe immune cell infiltration and a higher cholesterol content (+31%, p = 0.03). Moreover, BCG reduced plasma total cholesterol levels (−34%, p = 0.003), which was confined to reduced nonHDL-cholesterol levels (−36%, p = 0.002). This was due to accelerated plasma clearance of cholesterol from intravenously injected [14C]cholesteryl oleate-labelled VLDL-like particles (t½ −41%, p = 0.002) as a result of elevated hepatic uptake (+25%, p = 0.05) as well as reduced intestinal cholestanol and plant sterol absorption (up to −37%, p = 0.003). Ultimately, BCG decreased foam cell formation of peritoneal macrophages (−18%, p = 0.02) and delayed atherosclerotic lesion progression in the aortic root of the heart. BCG tended to decrease atherosclerotic lesion area (−59%, p = 0.08) and reduced lesion severity. ConclusionsBCG reduces plasma nonHDL-cholesterol levels and delays atherosclerotic lesion formation in hyperlipidemic mice.

Host Transcriptional Profiles and Immunopathologic Response following Mycobacterium avium subsp. paratuberculosis Infection in Mice.

Paratuberculosis or Johne’s disease is a chronic granulomatous enteropathy in ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP) infection. In the present study, we examined the host response to MAP infection in spleens of mice in order to investigate the host immunopathology accompanying host-pathogen interaction. Transcriptional profiles of the MAP-infected mice at 3 and 6 weeks p.i. showed severe histopathological changes, whereas those at 12 weeks p.i. displayed reduced lesion severity in the spleen and liver. MAP-infected mice at 3 and 6 weeks p.i. showed up-regulation of interferon-related genes, scavenger receptor, and complement components, suggesting an initial innate immune reaction, such as macrophage activation, bactericidal activity, and macrophage invasion of MAP. Concurrently, MAP-infected mice at 3 and 6 weeks p.i. were also suggested to express M2 macrophage phenotype with up-regulation of Mrc1, and Marco and down-regulation of MHC class II, Ccr7, and Irf5, and canonical pathways related to the T cell response including ICOS-ICOSL signaling in T helper cells, calcium-induced T lymphocyte apoptosis, and CD28 signaling in T helper cell. These results provide information which furthers the understanding of the immunopathologic response to MAP infection in mice, thereby providing insights valuable for research into the pathogenesis for MAP infection.