Interleukin-36 in hidradenitis suppurativa: evidence for a distinctive proinflammatory role and a key factor in the development of an inflammatory loop.

BACKGROUND: Possible regulatory involvement of the interleukin (IL)-36 family in inflammatory diseases has been suggested. OBJECTIVES: To analyse the expression of IL-36α, IL-36ß, IL-36γ and the antagonistic cytokines IL-36 receptor agonist (IL-36Ra), IL-37 and IL-38 in the skin of patients with hidradenitis suppurativa (HS). METHODS: Skin samples from lesional and corresponding perilesional HS skin, and from healthy controls were included in this study and analysed by quantitative real-time reverse-transcriptase polymerase chain reaction (PCR). To evaluate the PCR results of IL-36α, IL-36ß and IL-36γ, a subset of skin samples was studied by immunohistochemistry. RESULTS: Expression levels of IL-36α, IL-36ß, IL-36γ and IL-36Ra were all significantly higher in lesional HS skin than in healthy controls. IL-37 and IL-38 levels were significantly higher in perilesional HS skin than in healthy controls and were decreased in lesional HS skin. Limitations of the study are its descriptive nature and the small sample size. CONCLUSIONS: Our results showed a possible involvement of IL-36 cytokines in the inflammatory network of HS and a dysbalance between the agonistic and antagonistic cytokines in HS skin.

A Novel Porcine Circovirus Distantly Related to Known Circoviruses Is Associated with Porcine Dermatitis and Nephropathy Syndrome and Reproductive Failure.

Porcine circovirus-associated disease (PCVAD) is clinically manifested by postweaning multisystemic wasting syndrome (PMWS), respiratory and enteric disease, reproductive failure, and porcine dermatitis and nephropathy syndrome (PDNS). Porcine circovirus 2 (PCV2) is an essential component of PCVAD, although an etiologic role in PDNS is not well established. Here, a novel circovirus, designated porcine circovirus 3 (PCV3), was identified in sows that died acutely with PDNS-like clinical signs. The capsid and replicase proteins of PCV3 are only 37% and 55% identical to PCV2 and bat circoviruses, respectively. Aborted fetuses from sows with PDNS contained high levels of PCV3 (7.57 × 107 genome copies/ml), and no other viruses were detected by PCR and metagenomic sequencing. Immunohistochemistry (IHC) analysis of sow tissue samples identified PCV3 antigen in skin, kidney, lung, and lymph node samples localized in typical PDNS lesions, including necrotizing vasculitis, glomerulonephritis, granulomatous lymphadenitis, and bronchointerstitial pneumonia. Further study of archived PDNS tissue samples that were negative for PCV2 by IHC analysis identified 45 of 48 that were PCV3 positive by quantitative PCR (qPCR), with 60% of a subset also testing positive for PCV3 by IHC analysis. Analysis by qPCR of 271 porcine respiratory disease diagnostic submission samples identified 34 PCV3-positive cases (12.5%), and enzyme-linked immunosorbent assay detection of anti-PCV3 capsid antibodies in serum samples found that 46 (55%) of 83 samples tested were positive. These results suggest that PCV3 commonly circulates within U.S. swine and may play an etiologic role in reproductive failure and PDNS. Because of the high economic impact of PCV2, this novel circovirus warrants further studies to elucidate its significance and role in PCVAD. IMPORTANCE: While porcine circovirus 2 (PCV2) was first identified in sporadic cases of postweaning multisystemic wasting syndrome in Canada in the early 1990s, an epidemic of severe systemic disease due to PCV2 spread worldwide in the ensuing decade. Despite being effectively controlled by commercial vaccines, PCV2 remains one of the most economically significant viruses of swine. Here, a novel porcine circovirus (PCV3) that is distantly related to known circoviruses was identified in sows with porcine dermatitis and nephropathy syndrome (PDNS) and reproductive failure. PCV2, which has previously been associated with these clinical presentations, was not identified. High levels of PCV3 nucleic acid were observed in aborted fetuses by quantitative PCR, and PCV3 antigen was localized in histologic lesions typical of PDNS in sows by immunohistochemistry (IHC) analysis. PCV3 was also identified in archival PDNS diagnostic samples that previously tested negative for PCV2 by IHC analysis. The emergence of PCV3 warrants further investigation.

A "Pedi" Cures All: Toenail Trimming and the Treatment of Ulcerative Dermatitis in Mice.

Ulcerative Dermatitis (UD) is the most common cause of unplanned euthanasia in mice used in research, with prevalence rates reported between 4 and 21%. UD is characterized by a deep, ulcerative lesion that appears most commonly over the dorsal neck and is attendant with an intense pruritus. The underlying cause of UD is currently unknown, and as a consequence, there are no directed therapies that resolve lesions reliably. However, there is a growing body of evidence that suggests a behavioral component to the onset, maintenance, and progression of UD lesions. Scratching behavior in response to the intense pruritus associated with UD lesions may be an effective target for interventional therapies. We hypothesized that interfering with scratching behavior by trimming the toenails of mice with UD, would resolve UD lesions. To test this hypothesis, we first evaluated the efficacy of toenail trims with a single application of Vetericyn at the time of treatment versus our previous standard of care, topical Tresaderm applied daily. We found that toenail trims were significantly more effective at resolving lesions (n = 39 toenail trims, n = 100 Tresaderm, p<0.0001) with 93.3% of animals healing by 14 days (median time to lesion resolution). Furthermore, dorsal neck lesions did not recur by 42 days after a single toenail trim (n = 54); however, flank lesions did not resolve and the outcome of the two lesion distributions following treatment were significantly different (p<0.0001). Finally, we implemented toenail trims at an institutional level and found similar efficacies (approximately 90%) for toenail trims regardless of one-time topical supplement used (triple antibiotic ointment, Tresaderm, and Vetericyn, n = 55, 58, 18, p = 0.63). This is the first report of a highly effective treatment for one of the most serious welfare issues in laboratory mice.

Mast cells play a key role in host defense against herpes simplex virus infection through TNF-α and IL-6 production.

The essential contribution of mast cells (MCs) to bacterial host defense has been well established; however, little is known about their role in viral infections in vivo. Here, we found that intradermal injection with herpes simplex virus 2 (HSV-2) into MC-deficient Kit(W/Wv) mice led to increased clinical severity and mortality with elevated virus titers in HSV-infected skins. Ex vivo HSV-specific tetramer staining assay demonstrated that MC deficiency did not affect the frequency of HSV-specific cytotoxic T lymphocytes (CTLs) in draining lymph nodes. Moreover, the high mortality in Kit(W/W-v) mice was completely reversed by intradermal reconstitution with bone marrow-derived MCs (BMMCs) from wild-type, but not TNF(-/-) or IL-6(-/-) mice, indicating that MCs or, more specifically, MC-derived tumor necrosis factor (TNF) and IL-6 can protect mice from HSV-induced mortality. However, HSV did not directly induce TNF-α or IL-6 production by BMMCs; supernatants from HSV-infected keratinocytes induced the production of these cytokines by BMMCs without degranulation. Furthermore, IL-33 expression was induced in HSV-infected keratinocytes, and blocking the IL-33 receptor T1/ST2 on BMMCs significantly reduced TNF-α and IL-6 production by BMMCs. These results indicate the involvement of MCs in host defense at HSV-infected sites through TNF-α and IL-6 production, which is induced by keratinocyte-derived IL-33.

Mortality in red squirrels (Sciurus vulgaris) associated with exudative dermatitis.

Red squirrels (Sciurus vulgaris) found dead or dying on the Isle of Wight and the island of Jersey were suffering from exudative, ulcerative dermatitis and superficial staphylococcal pyoderma. The principal gross lesions were on the lips, eyelids and feet and showed similarities to those of squirrelpox. The histopathological lesions were also similar and, although there was no ballooning degeneration of epidermal cells, intracytoplasmic inclusions resembling those seen in poxvirus infections were present. Examination of lesions by electron microscopy failed to identify any virions, and PCR analysis for squirrelpox virus proved negative. The skin lesions also resembled those of mange, but although numerous mites were present in the fur these were mostly Dermacarus sciurinus with small numbers of Metalistrophorus pagenstecheri. The occurrence of these species on red squirrels in Britain is confirmed, but neither is pathogenic and they were not considered to have been involved in the pathogenesis of the dermatitis, the primary cause of which was not established.

Dermatitis, branchitis and mortality in empire gudgeon Hypseleotris compressa exposed naturally to runoff from acid sulfate soils.

Severe dermatitis and branchitis are described in a wild population of empire gudgeon Hypseleotris compressa, an Australian eleotrid, exposed naturally to runoff from acid sulfate soils (ASS) in a drained estuarine embayment in eastern Australia. After at least 2 d exposure to pH < 4, and up to 7 d exposure to pH < 6, approximately 50% of the fish sampled had moderate to severe diffuse epidermal hyperplasia, usually at scale margins, and scattered areas of moderate to severe, focal to locally extensive, subacute, necrotising dermatitis. Saprolegnia spp. had invaded epidermis in some inflamed areas. In gills, there was moderate to severe hyperplasia and necrosis of secondary lamellar epithelium, with fusion of adjacent secondary lamellae. Inorganic monomeric aluminium and calcium concentrations in water at the site during the event were 27.7 and 16.6 mg l(-1), respectively. Large numbers of empire gudgeons at the study site had died after at least 8 d exposure to pH < 4, and up to 13 d exposure to pH < 6. These findings provide clear evidence that acidification of estuarine systems by runoff from ASS has deleterious effects on aquatic biota. Furthermore, study findings suggest a mechanism whereby lesions of epizootic ulcerative syndrome (EUS) may be initiated in estuarine fishes by a combination of sublethal exposure to ASS runoff and Aphanomyces invadans infection, a suggestion consistent with the geographic and temporal distribution of EUS outbreaks in Australian estuaries.

Differences in the pathogenicity of various bacterial isolates used in an induction model for gangrenous dermatitis in broiler chickens.

A gangrenous dermatitis model was developed in broiler chickens, in which birds previously vaccinated at 14 days of age with a bursal disease virus vaccine were challenged at 4 wk of age with various bacterial combinations with the combination of subcutaneous and intramuscular injection. Gangrenous dermatitis lesions were not produced in birds injected with one of the Staphylococcus aureus isolates, either alone or in combination with various Clostridium septicum isolates. Other S. aureus isolates produced significant levels of gangrenous dermatitis either alone or in combination with the same C. septicum isolates. These same C. septicum isolates when given alone did not produce gangrenous lesions. Data from this experiment show the highest level of mortality occurred in birds challenged with a mixture of C. septicum and S. aureus isolates, whereas lower or no mortality was associated with the same isolates given separately. The data clearly demonstrate that the pathogenicity of isolates responsible for gangrenous dermatitis varies widely, indicating that the frequency and severity of lesion production, as well as the occurrence of mortality, are largely dependent upon the specific isolate or isolates with which the birds are challenged.

Delayed onset of systemic bacterial dissemination and subsequent death in mice injected intramuscularly with Streptococcus pyogenes strains.

Streptococcus pyogenes causes severe invasive diseases in humans, including necrotizing fasciitis, sepsis, and streptococcal toxic shock syndrome (STSS). We found that mice infected intramuscularly (i.m.) with S. pyogenes strains developed bacteremia and subsequent sudden death after at least 10 days of a convalescent period. Mostly, it occurred more than 21 days after muscle infection. We provisionally designate this phenomenon as "delayed death." Just after muscle infection, all the mice lost weight and activity, but recovered completely within 3 days. They had kept good activity and a fine coat of fur till one or two days before their death. Some of the dead mice were found to have soft-tissue necrosis. There was no correlation between the virulence leading to the delayed death and the severity of diseases from which strains were isolated. It was also found that the production of neither streptococcal pyrogenic exotoxin (SPE) A nor B correlated to the virulence leading to delayed death. The bacteria obtained from the organs of the mice with delayed death expressed capsule. We suggest that the mice with delayed onset of systemic bacterial dissemination and subsequent death after muscle infection with S. pyogenes are the animal models of STSS, because the pathophysiology is extremely similar to that of human STSS.

Mortality of captive Canadian toads from Basidiobolus ranarum mycotic dermatitis.

Twenty-six adult free-ranging Canadian toads (Bufo hemiophrys) were collected from northeastern North Dakota (USA) during the last week of August 1994 and placed in captivity. During late December and January 1995, 21 Canadian toads died. Clinical signs included increased time sitting in water bowls, darkened dorsal skin, constant arching of their backs, and hyperemia and sloughing of ventral epidermis. The condition progressively worsened until death occurred within 5 to 7 days after onset of clinical disease. Mycotic dermatitis due to Basidiobolus ranarum was diagnosed in all toads and the fungus was isolated from 11 (52%) of 21 toads. Histology of the ventral skin and digits revealed numerous fungal spherules and occasional hyphae without significant inflammatory reaction. This condition clinically resembled red leg associated with Aeromonas hydrophila and many other bacterial organisms, and the diseases could be confused without appropriate diagnostic tests. This also is the first report of B. ranarum causing clinical disease in a toad species.

The feeding of raw, fermented poultry byproducts: using mink as a model.

In this study, the safety of fermentation as a method of preservation of raw animal byproducts used for animal nutrition was tested. Two feeding trials with mink, as a model for nonruminant animals, were carried out. In the first trial mink were given a fermented diet composed of raw poultry and fish byproducts supplemented with cereals, glucose, lactic acid, premix, and starter culture (Lactobacillus plantarum and Enterococcus faecium). These mink failed to deliver kits, and 7 of the 30 females in the test group died. At autopsy no specific cause of death could be diagnosed, although all the dead mink showed symptoms of cachexia. In a second trial, a group of mink kits, during the growth period, was given a diet composed of fermented poultry byproducts, just before feeding mixed with raw fish. The weight gain of the mink in the test group decreased statistically compared with that of the control group, mainly for the male members of the group. From the end of October until the beginning of November, during pelt priming, some mink showed symptoms of severe weight loss. It is suggested that the measured increase of amino acid breakdown, and(or) the acidic pH of the fermented diet, caused these unfavorable results. To examine the effect of the fermented diet on the gut flora, fecal samples were analyzed. The fermented diet changed the composition of the gut flora significantly. In the group that received the fermented diet the number of lactobacilli and the mesophilic aerobic count increased and the number of Enterobacteriaceae and enterococci decreased compared with the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Exudative epidermitis in pigs. Clinical studies and preliminary transmission trials.

Four outbreaks of an infectious, exudative skin disease of 6 to 10 week-old weaned pigs, are described. The disease was seen in fattening barns where weanlings from several sources were mixed. The disease was characterized in the peracute form by the formation, over the entire body, of a brown, greasy, odorous exudate, by loosening of the hoofs, by severe depression, dehydration and death in 3 to 5 days. In the acute form the lesions were identical, but their evolution slower, the mortality was high, and survivors severely stunted. Secondary infections seemed largely responsible for mortality in the acute form. Subacute infections were frequent and characterized by the formation of few to many circular exudative foci which became dry and cleared up completely in about 2 weeks. Antibiotics and mineral supplements were of no value in controlling or preventing the development of lesions or mortality.Minimal-disease pigs were exposed to diseased pigs from 3 of the 4 outbreaks studied and in all cases they developed typical lesions and could transmit the infection to other pigs. Bacteriological examination of field and experimentally produced cases gave inconclusive results pending further study.