Alexandra Geusau

Activation of Nrf2 in keratinocytes causes chloracne (MADISH)‐like skin disease in mice

The transcription factor Nrf2 is a key regulator of the cellular stress response, and pharmacological Nrf2 activation is a promising strategy for skin protection and cancer prevention. We show here that prolonged Nrf2 activation in keratinocytes causes sebaceous gland enlargement and seborrhea in mice due to upregulation of the growth factor epigen, which we identified as a novel Nrf2 target. This was accompanied by thickening and hyperkeratosis of hair follicle infundibula. These abnormalities caused dilatation of infundibula, hair loss, and cyst development upon aging. Upregulation of epigen, secretory leukocyte peptidase inhibitor (Slpi), and small proline‐rich protein 2d (Sprr2d) in hair follicles was identified as the likely cause of infundibular acanthosis, hyperkeratosis, and cyst formation. These alterations were highly reminiscent to the phenotype of chloracne/“metabolizing acquired dioxin‐induced skin hamartomas” (MADISH) patients. Indeed, SLPI, SPRR2, and epigen were strongly expressed in cysts of MADISH patients and upregulated by dioxin in human keratinocytes in an NRF2‐dependent manner. These results identify novel Nrf2 activities in the pilosebaceous unit and point to a role of NRF2 in MADISH pathogenesis.

Identification of a Homozygous PSTPIP1 Mutation in a Patient With a PAPA-Like Syndrome Responding to Canakinumab Treatment

BACKGROUND Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome (OMIM 604416) is a rare autosomal dominant inherited autoinflammatory syndrome characterized by pyogenic sterile arthritis and less frequently accompanied by pyoderma gangrenosum and acne. It is associated with dominant missense mutations in the proline-serine-threonine phosphatase-interacting protein 1 gene (PSTPIP1) located on chromosome 15. The patient was diagnosed as having features of a PAPA-like syndrome in which cutaneous manifestations, such as pyoderma gangrenosum and acne fulminans, predominated. OBSERVATIONS Sequencing of the PSTPIP1 gene was performed in the patient and his extended family. The patients DNA analysis revealed a homozygous nucleotide exchange c.773G>C in the PSTPIP1 gene, leading to the substitution of glycine 258 by alanine (p.Gly258Ala), a previously reported heterozygous polymorphism. Heterozygous changes were identified in both of the patients parents and in 7 other family members, all of whom were asymptomatic. The patient was treated with canakinumab, a human anti-interleukin 1β monoclonal antibody, which led to rapid remission of the symptoms. CONCLUSIONS To our knowledge, this is the first reported case of the resolution of dermatological symptoms associated with a PAPA-like syndrome using canakinumab treatment. Further study of the p.Gly258Ala variant is warranted to determine whether this mutation has a role in causing an apparently recessive cutaneous syndrome resembling PAPA syndrome.

New Chlamydia trachomatis L2 strains identified in a recent outbreak of lymphogranuloma venereum in Vienna, Austria.

Background: Since 2003, an ongoing outbreak of lymphogranuloma venereum (LGV), caused by Chlamydia trachomatis biovar L2b, has been reported among men who have sex with men. Methods: Twenty-four samples positive for C. trachomatis were analyzed for specific biovars and genovariants by genotyping of the variable segment (VS) 4, VS2 and VS1 regions of the outer membrane protein (omp) A. In addition we assessed the patients’ sociodemographic background and clinical signs and symptoms. Results: Twenty-four men who have sex with men presented with either anorectal or inguinal symptoms and tested positive for C. trachomatis DNA. Of these, the L2 genotype accounted for 15 patients, with a high coinfection rate with HIV (73.3%) and other sexually transmitted infections (53.4%). Analysis of the VS1, VS2, and VS4 regions of the ompA gene revealed the variant L2b in 8 patients. In 4 patients, 3 new L2 sequences were identified with nucleotide changes in the VS1, VS2, and VS4 region, respectively, defining new strains designated L2c, d, e. Conclusions: This outbreak of LGV represents the further spread of C. trachomatis L2 infection. Sequence analysis of ompA regions shows heterogeneity of L2 variants, suggesting more than 1 source of the LGV infections diagnosed in Vienna.

Risk factors for nasal carriage of Staphylococcus aureus in infectious disease patients, including patients infected with HIV, and molecular typing of colonizing strains.

Nasal carriage is an important risk factor for Staphylococcus aureus infection, particularly in HIV-infected individuals. In this analytical cross-sectional study, a variety of probable risk factors associated with nasal carriage of Staphylococcus aureus were investigated. HIV-infected patients were examined within a larger cohort of infectious diseases patients. Staphylococcus aureus strains from HIV-infected and non-HIV-infected carriers were identified by molecular biological analysis. One hundred seventy infectious disease patients, 47 of them infected with HIV, were included. All patients were admitted to the University Hospital of Vienna, Austria, between January and July 1999. Independent significant effects on Staphylococcus aureus nasal carriage were found to be HIV status (OR 2.5, 95% CI 1.1–5.6; P=0.0303), history of operation or severe wound within 3 months prior to admission (OR 4.0, 95% CI 1.3–13.0; P=0.0208), presence of an intravenous device within 2 weeks prior to admission (OR 10.8, 95% CI 2.0–59.4; P=0.0065), and intake of antibiotics within 2 weeks prior to hospitalisation (OR 0.2, 95% CI 0.09–0.6; P=0.0016). Molecular analysis of the Staphylococcus aureus strains revealed that the strains in both groups resembled those of healthy nonhospitalized carriers in the community.

Prevalence of NSF following intravenous gadolinium-contrast media administration in dialysis patients with endstage renal disease

PURPOSE To evaluate the prevalence of nephrogenic systemic fibrosis (NSF) in a patient population being at highest risk for developing this disease and to evaluate possible risk factors. MATERIALS AND METHODS The radiological records of 552 patients with ESRD being on hemodialysis (HD) or peritoneal dialysis (PD) were retrospectively reviewed to identify whether the patients underwent MR-examinations with or without intravenous administration of GBCA. In case of exposure to GBCA, the number of contrast injections, the benchmark and the cumulative doses of GBCA, and possible cofactors regarding pathogenesis of NSF were recorded. Diagnosis of NSF was confirmed either by deep skin biopsy or by review of medical and histopathological records. Data of NSF patients were compared with data of dialysis patients who did not develop NSF after MR-examinations. RESULTS 146 dialysis patients underwent MRI without i.v.-administration of GBCA. No case of NSF was observed in this patient population. 195/552 patients proved to have a total number of 325 well-documented exposures to GBCA. Seven different types of GBCA were used during these MR-examinations. NSF prevalence rate was 1.6%. One patient died of NSF. Three different types of GBCA were involved in 6 NSF cases. 4/6 proved to be confounded cases. The cumulative dose of GBCA, history of thrombosis, recent surgery, and the combination of HD and PD proved to be significant cofactors for the development of NSF (p<.05). No significant difference regarding residual renal clearance (p=.898) and residual urine volume (p=.083) was found between NSF and non-NSF patients. CONCLUSION The prevalence of NSF proved to be much lower in this high risk patient group being exposed to GBCA compared to the literature. NSF was not observed in ESRD patients undergoing MRI without administration of GBCA. Our data support a positive association between cumulative dose of GBCA and development of NSF. No positive association was found between residual renal clearance and residual urine volume and NSF.

Neurosyphilis is unlikely in patients with late latent syphilis and a negative blood VDRL-test.

Patients with latent syphilis or syphilis of unknown duration should be evaluated for tertiary disease and neurosyphilis. The aim of this retrospective study was to determine relevant serological parameters for the identification of those individuals with syphilis who are most likely to have neurosyphilis and who therefore require lumbar puncture. After excluding repeated estimates and patients whose blood syphilis serology had either been negative or not been determined within 3 months of lumbar puncture, 265 out of 710 cerebrospinal fluids from 1988 to 2004 were analysed. In each of those patients the earliest available pairs of serum and cerebrospinal fluid samples were evaluated. The diagnosis of neurosyphilis was based on criteria according to established guidelines. Forty-three of 265 patients (16.2%; 5 women, 38 men; mean age 47+/-16 years) had neurosyphilis. Seven of 72 (9.7%) of those testing HIV-positive, fulfilled the criteria of neurosyphilis. Not a single patient with neurosyphilis tested Venereal Disease Research Laboratory test (VDRL)-negative in peripheral blood, an effect which was highly significant (p < 0.01, chi2-test). The median blood-VDRL titre was significantly higher in patients with neurosyphilis than in those without (1:32 vs. 1:0; p < 0.01, t-test, two-sided). Hence, neurosyphilis is very unlikely in patients with a negative blood-VDRL. Therefore, lumbar puncture is not recommended in these patients.

Successful treatment of an aciclovir-resistant herpes simplex type 2 infection with cidofovir in an AIDS patient

Summary Management of the increasing frequency of aciclovir‐resistant herpes simplex virus (HSV) infections among immunocompromised human immunodeficiency virus‐infected people demands additional treatment options. We report the case of a 38‐year‐old patient with acquired immune deficiency syndrome who suffered from a perianal butterfly ulcer, which was HSV‐2 positive by polymerase chain reaction (PCR) analysis. The ulcer appeared during treatment of a cytomegalovirus (CMV) pneumonitis with ganciclovir. Despite additional valaciclovir therapy the lesion gradually progressed in size. Investigations including histology, PCR analysis and in situ hybridization of a biopsy from the growing ulcer margin confirmed the presence of HSV‐2 infection. Importantly, HSV isolates from this specimen were resistant to aciclovir. Based on a report about the successful treatment of aciclovir‐resistant HSV infection with cidofovir, our patient received this drug intravenously at a dose of 5 mg kg−1 body weight once weekly for a total of 3 weeks. Concomitant oral probenecid and prehydration were administered to minimize nephrotoxicity. Within 30 days of treatment the ulcer had almost (> 95%) completely healed. We conclude that cidofovir is a potent antiviral drug with a potential usefulness in the treatment of aciclovir‐resistant HSV‐2 infection. It deserves further investigation in clinical trials.

Psoriasin (S100A7) is a major Escherichia coli -cidal factor of the female genital tract

The female urogenital tract requires an efficient defense against bacteria, potentially derived from the adjacent intestinal tract. We have thus sought to identify the factors that protect against Escherichia coli (E. coli) in the female genital tract. Vaginal fluid from healthy human donors consistently killed E. coli in vitro and vaginal epithelium strongly expressed and secreted psoriasin. Psoriasin was constitutively produced in an organotypic vaginal epithelium model, and exposure of these cells to supernatants of E. coli cultures led to an enhanced psoriasin expression. Secreted psoriasin in vaginal fluids accounted for approximately 2.5–3% of total protein. Fractionation of vaginal fluids by high performance liquid chromatography (HPLC) showed that psoriasin co-eluted with a peak of E. coli killing activity. Our data show that normal vaginal fluid contains a powerful intrinsic antimicrobial defense against E. coli and that psoriasin contributes to the innate immune response of the female genital tract.

Pemphigoid gestationis: treatment with immunoapheresis

Background: Pemphigoid (herpes) gestationis is a rare blistering disease of pregnancy. Topical and systemic corticosteroids and antihistamines are usually sufficient for treatment.

Punctate keratoderma-like lesions on the palms and soles in a patient with chloracne: a new clinical manifestation of dioxin intoxication?

We report what we believe to be a novel skin manifestation of dioxin intoxication. A 30‐year‐old woman with 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin levels of 144,000 pg g−1 blood fat presented with severe chloracne that affected the entire integument. She also exhibited acral granuloma annulare‐like lesions and distal onycholysis and, at a later time point, showed signs of hypertrichosis, as well as brownish‐grey hyperpigmentation of the face. In addition, she developed punctate keratoderma‐like lesions on the palms and soles. These lesions were negative for human papillomavirus and histologically characterized by cone‐shaped hyperkeratoses invaginating, but not penetrating, into the dermis. Squamous syringometaplasia of the eccrine glands was observed in the immediate vicinity of these lesions. Both clinically and histologically these alterations are essentially indistinguishable from what is described as keratosis punctata palmaris et plantaris (KPPP). Although a fortuitous coincidence of chloracne and KPPP cannot be formally excluded, the possibility exists that in our patient toxic levels of dioxin were causally involved in this disorder of keratinization.