Diesel exhaust particulate matter impairs Toll-like receptor signaling and host defense against staphylococcal cutaneous infection in mice.

Air pollution is an emerging cause of mortality, affecting nearly 5 million people each year. Exposure to diesel exhaust fine particulate matter (PM2.5) aggravates respiratory and skin conditions. However, its impact on the protective immunity of the skin remains poorly understood. This study aimed to investigate the underlying molecular mechanism for adverse effects of PM2.5 on the host protective immunity using in vitro cell and in vivo mouse model. Intracellular translocation of Toll-like receptor 9 (TLR9) and CpG-DNA internalization were assessed in dendritic cells without or with PM2.5 treatment using immunofluorescence staining. Cytokine and nitric oxide production were measured in dendritic cells and macrophages without or with PM2.5 treatment. NF-κB and MAPK signaling was determined using western blotting. Skin disease severity, bacterial loads, and cytokine production were assessed in cutaneous Staphylococcus aureus (S. aureus) infection mouse model. PM2.5 interfered with TLR9 activation by inhibiting both TLR9 trafficking to early endosomes and CpG-DNA internalization via clathrin-mediated endocytosis. In addition, exposure to PM2.5 inhibited various TLR-mediated nitric oxide and cytokine production as well as MAPK and NF-κB signaling. PM2.5 rendered mice more susceptible to staphylococcal skin infections. Our results suggest that exposure to PM impairs TLR signaling and dampens the host defense against staphylococcal skin infections. Our data provide a novel perspective into the impact of PM on protective immunity which is paramount to revealing air pollutant-mediated toxicity on the host immunity.

Reduced induction of human ß-defensins is involved in the pathological mechanism of cutaneous adverse effects caused by epidermal growth factor receptor monoclonal antibodies.

Epidermal growth factor receptor inhibitors (EGFRIs) frequently cause cutaneous adverse effects such as papulopustular eruptions. However, the mechanism of the reactions remains unclear. To assess the pathological mechanism of cutaneous adverse reactions caused by EGFRIs, we investigated whether EGFRIs have an influence on the innate immune response of the skin. Levels of human ß-defensins (hBDs), which serve as the first line of defence against infection by pathogenic microorganisms, in the stratum corneum samples of patients treated with EGFR. monoclonal antibodies were measured before and after starting therapy. There were no obvious trends in hBD production in patients without eruptions, whereas a significant decrease in hBD1 and hBD3 production and a nonsignficant decrease in hBD2 production were observed in patients who developed papulopustular eruptions. Our results suggest that a reduction in hBD contributes to the increased incidence of papulopustular eruptions.

Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Ankylosing spondylitis is a chronic immune-mediated inflammatory disease characterised by spinal inflammation, progressive spinal rigidity, and peripheral arthritis. Interleukin 17 (IL-17) is thought to be a key inflammatory cytokine in the development of ankylosing spondylitis, the prototypical form of spondyloarthritis. We assessed the efficacy and safety of the anti-IL-17A monoclonal antibody secukinumab in treating patients with active ankylosing spondylitis. METHODS: We did a randomised double-blind proof-of-concept study at eight centres in Europe (four in Germany, two in the Netherlands, and two in the UK). Patients aged 18-65 years were randomly assigned (in a 4:1 ratio) to either intravenous secukinumab (2×10 mg/kg) or placebo, given 3 weeks apart. Randomisation was done with a computer-generated block randomisation list without a stratification process. The primary efficacy endpoint was the percentage of patients with a 20% response according to the Assessment of SpondyloArthritis international Society criteria for improvement (ASAS20) at week 6 (Bayesian analysis). Safety was assessed up to week 28. This study is registered with ClinicalTrials.gov, number NCT00809159. FINDINGS: 37 patients with moderate-to-severe ankylosing spondylitis were screened, and 30 were randomly assigned to receive either intravenous secukinumab (n=24) or placebo (n=6). The final efficacy analysis included 23 patients receiving secukinumab and six patients receiving placebo, and the safety analysis included all 30 patients. At week 6, ASAS20 response estimates were 59% on secukinumab versus 24% on placebo (99·8% probability that secukinumab is superior to placebo). One serious adverse event (subcutaneous abscess caused by Staphylococcus aureus) occurred in the secukinumab-treated group. INTERPRETATION: Secukinumab rapidly reduced clinical or biological signs of active ankylosing spondylitis and was well tolerated. It is the first targeted therapy that we know of that is an alternative to tumour necrosis factor inhibition to reach its primary endpoint in a phase 2 trial. FUNDING: Novartis.

Doxycycline decreases proteinuria in glomerulonephritis.

Treatment options for crescentic glomerulonephritis include the use of steroids, cytotoxic therapy, and, in severe cases, intravenous immunoglobulins and plasmapheresis. Injury and lysis of capillary glomerular basement membrane, which is made up of type IV collagen, laminin, fibronectin, and proteoglycans, by serine proteinases and matrix metalloproteinases (MMPs) likely is an important participant in the pathogenesis of crescentic glomerulonephritis. Tetracycline derivatives inhibit not only the activity of MMPs, but also their production, and have been investigated for the treatment of disorders in which the MMP system becomes amplified, such as degenerative osteoarthritis, periodontitis, cancer, and abdominal aortic aneurysm. We report an interesting case of crescentic glomerulonephritis in a young man who was treated with cyclophosphamide and prednisone. The patient developed steroid-induced acne that was treated with long-term oral doxycycline therapy. During the period the patient was administered doxycycline, proteinuria decreased by 70% and recurred when doxycycline was stopped. To our knowledge, this is the first report of possible benefits of a metalloproteinase inhibitor (doxycycline) in glomerulonephritis in humans. Future studies are urgently required to explore the option of metalloproteinase inhibitors in the treatment of proliferative glomerulonephritis.

Anthralin-corticosteroid combination therapy in the treatment of chronic plaque psoriasis.

A prospective randomized trial of anthralin in Lassar's paste compared with anthralin in 0.0125% clobetasol propionate in the treatment of chronic plaque psoriasis was undertaken. The psoriatic skin of patients treated with the corticosteroid-anthralin combination cleared significantly more quickly than those treated with anthralin alone, with a mean time to clearance of 14.9 days compared with 18.5 days, and with lower concentrations of anthralin. No significant difference was found in the rate of relapse of the two treatment groups, with relapse occurring in over 80% of patients within one year. Anthralin in 0.0125% clobetasol propionate was found to be an effective agent in the treatment of chronic plaque psoriasis, and one that was cosmetically acceptable to patients and nursing staff. An important disadvantage, however, was the development of a staphylococcal folliculitis in four of the 35 patients in which it was used. Because of this, anthralin in Lassar's paste remains our standard inpatient therapy, although the ease of use and cosmetic acceptability of anthralin in clobetasol propionate make it a useful remedy for outpatient use.

Susceptibility of various animals and cultured cells to exfoliative toxin produced by Staphylococcus hyicus subsp. hyicus.

In piglets inoculated with partially purified exfoliative toxin (pp-shET) produced by Staphylococcus hyicus subsp. hyicus, exfoliation was observed at 12 h after injection. Chickens inoculated with the same dose of pp-shET also showed exfoliation within 30 min of injection. However, exfoliation was not demonstrated in mouse, rat, guinea pig, hamster, dog or cat inoculated with pp-shET until 24 h after injection. In cultured cell lines, especially L-929 and Hep-2, the rounding effect occurred after incubation with pp-shET for 1 h. The rounding effect was also seen in five other cultured cells (NCTC 2544, HeLa/S3, HmLu-1, CHO and BHK-21) 6-24 h after exposure to pp-shET. These round cells survived for 72 h after inoculation and formed a monolayer 24 h after changeover to a toxin-free medium. The rounding effect was observed in cells after the formation of the monolayer, but not before. It was suggested that the rounding effect was not caused by the increase in cyclic AMP in cells inoculated with pp-shET but by the cleavage of intracellular contacts.

Healing of an MRSA-colonized, hydroxyurea-induced leg ulcer with honey.

BACKGROUND: With the everincreasing emergence of antibiotic-resistant pathogens, in particular methicillin-resistant Staphylococcus aureus (MRSA) in leg ulcers, a means of reducing the bacterial bioburden of such ulcers, other than by the use of either topical or systemic antibiotics, is urgently required. METHODS: We report the case of an immunosuppressed patient who developed a hydroxyurea-induced leg ulcer with subclinical MRSA infection which was subsequently treated with topical application of manuka honey, without cessation of hydroxyurea or cyclosporin. RESULTS: MRSA was eradicated from the ulcer and rapid healing was successfully achieved. CONCLUSION: Honey is recognized to have antibacterial properties, and can also promote effective wound healing. A traditional therapy, therefore, appears to have enormous potential in solving new problems.

Management of recurrent cutaneous abscesses during therapy with infliximab.

BACKGROUND: Infliximab is a chimeric monoclonal antibody, belonging to the class of anti-tumor necrosis factor-α (TNF-α) agents, approved for the treatment of psoriasis and psoriatic arthritis. Drugs of this class are known to be associated with an infective risk, probably because they interfere with inflammatory and immune response at different levels. Although cutaneous Staphylococcus aureus infections seem to be more frequent than any other infection in the course of anti-TNF-α treatment, only a few case reports in the literature deal with this side effect, and, in particular, with its management. OBJECTIVE: Our aim was to report a case of recurrent methicillin-sensitive S aureus (MSSA) cutaneous abscesses during therapy with infliximab and successful management. CASE SUMMARY: In July 2009, a 53-year-old white woman (weighing 85 kg) affected by psoriasis and psoriatic arthritis was administered infliximab (5 mg/kg IV), based upon clinical appearance and previous unsuccessful treatment with cyclosporine, methotrexate, etanercept, and adalimumab. Three days after the first 3 infusions (at weeks 0, 2, and 6) she complained about the recurrent onset of painful, erythematous, indurated, and pus-draining cutaneous nodules located on her abdomen. The swab always revealed the presence of MSSA, and antibiotic oral therapy with amoxicillin + clavulanic acid (875 + 125 mg BID for 7 days) was established, with complete resolution of the abscesses. Routine laboratory findings were in normal ranges, with the exception of an elevated erythrosedimentation rate and an increased white blood cell count (range, 13,000-15,000/mm(3)) with neutrophilia (range, 75%-80%). HIV infection was ruled out. In agreement with the infectious disease consultant, 1 day before the fourth infusion, a prophylactic antibiotic therapy with amoxicillin + clavulanic acid (875 + 125 mg BID for 5 days) was added to the therapeutic regimen. This treatment schedule was successfully repeated at each following infusion (every 8 weeks), and no recurrence of skin abscesses was observed. The patient provided signed authorization for publication of this case. CONCLUSIONS: This case report describes a woman with psoriasis and psoriatic arthritis who developed MSSA skin abscesses after each of the first 3 infliximab infusions, which did not recur for the next 6 infusions after amoxicillin + clavulanic acid was added to her regimen, pre- and 4 days postinfusion. Adequately designed, placebo-controlled, double-blind trials are needed to determine whether such prophylactic antibiotic treatment is well tolerated or effective for this common complication of therapy with anti-TNF-α agents, when withdrawal of the drug is not advisable, as in this case.

Counterfeiting in performance- and image-enhancing drugs.

The current drastic escalation in obesity may be contributing to the exponential rise in drugs used for image enhancement. Drugs such as anabolic-androgenic steroids (AAS) are perceived as a viable method of achieving a perfect physique. They are also the most widely abused drugs in sport. The Internet has encouraged the abuse of expensive drugs, particularly human growth hormone (hGH), resulting in increased importation for personal use. The substantial increase in this market has opened up avenues for counterfeiting, estimated as a multi-million pound business. The acute adverse effects from contaminated vials may result in a variety of pathologies including communicable diseases. In 2007, in the UK, a series of intramuscular abscesses, requiring surgical treatment, led us to study samples obtained from the underground market. The analysis of 38 parenteral samples and 19 oral samples of tablets was performed by a World Anti-Doping Agency (WADA) accredited laboratory, in an attempt to establish the extent of available counterfeit products. Fifty-three per cent (20) of the injectable AAS esters and 21% (4) of the oral tablets were counterfeit. Culture and sensitivity revealed the presence of skin commensal organisms, which may have contributed to the development of the abscesses. Users of AAS and hGH for sport, including bodybuilding, are currently risking their health because of counterfeit and poorly controlled products.