Prophage-encoded methyltransferase drives adaptation of community-acquired methicillin-resistant Staphylococcus aureus.

We recently described the evolution of a community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) USA300 variant responsible for an outbreak of skin and soft tissue infections. Acquisition of a mosaic version of the Φ11 prophage (mΦ11) that increases skin abscess size was an early step in CA-MRSA adaptation that primed the successful spread of the clone. The present report shows how prophage mΦ11 exerts its effect on virulence for skin infection without encoding a known toxin or fitness genes. Abscess size and skin inflammation were associated with DNA methylase activity of an mΦ11-encoded adenine methyltransferase (designated pamA ). pamA increased expression of fibronectin-binding protein A ( fnbA ; FnBPA), and inactivation of fnbA eliminated the effect of pamA on abscess virulence without affecting strains lacking pamA . Thus, fnbA is a pamA -specific virulence factor. Mechanistically, pamA was shown to promote biofilm formation in vivo in skin abscesses, a phenotype linked to FnBPA's role in biofilm formation. Collectively, these data reveal a novel mechanism-epigenetic regulation of staphylococcal gene expression-by which phage can regulate virulence to drive adaptive leaps by S. aureus .

Quorum-sensing agr system of Staphylococcus aureus primes gene expression for protection from lethal oxidative stress.

The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H 2 O 2 , a crucial host defense against S. aureus . We now report that protection by agr surprisingly extends beyond post-exponential growth to the exit from stationary phase when the agr system is no longer turned on. Thus, agr can be considered a constitutive protective factor. Deletion of agr increased both respiration and fermentation but decreased ATP levels and growth, suggesting that Δ agr cells assume a hyperactive metabolic state in response to reduced metabolic efficiency. As expected from increased respiratory gene expression, reactive oxygen species (ROS) accumulated more in the agr mutant than in wild-type cells, thereby explaining elevated susceptibility of Δ agr strains to lethal H 2 O 2 doses. Increased survival of wild-type agr cells during H 2 O 2 exposure required sodA , which detoxifies superoxide. Additionally, pretreatment of S. aureus with respiration-reducing menadione protected Δ agr cells from killing by H 2 O 2 . Thus, genetic deletion and pharmacologic experiments indicate that agr helps control endogenous ROS, thereby providing resilience against exogenous ROS. The long-lived "memory" of agr -mediated protection, which is uncoupled from agr activation kinetics, increased hematogenous dissemination to certain tissues during sepsis in ROS-producing, wild-type mice but not ROS-deficient (Nox2 -/- ) mice. These results demonstrate the importance of protection that anticipates impending ROS-mediated immune attack. The ubiquity of quorum sensing suggests that it protects many bacterial species from oxidative damage.

Occupational Hand Dermatitis.

PURPOSE OF REVIEW: Occupational hand dermatitis is a common work-related disorder of the skin. Prevention and management of this disease is critical to improving workers' quality of life and for occupation-specific retention. RECENT FINDINGS: This is a critical review of the current literature on occupational hand dermatitis. Occupational dermatitis continues to have a high prevalence among workers although the overall incidence may be slowly decreasing. Irritant contact dermatitis due to wet work exposure is the most common cause of occupational hand dermatitis. Healthcare workers, hairdressers, and metal workers are at particularly high risk for this disease. While some prevention programs have been ineffective in mitigating occupational hand dermatitis, other more resource-intensive initiatives may have benefit. Continued research is needed on ways to manage wet work exposures and on scalable, effective prevention programs for occupational hand dermatitis. The spectrum of culprit contact allergens continues to evolve, and vigilance for potential occupation-specific allergens remains important.

Viral Venereal Diseases of the Skin.

Viral venereal diseases remain difficult to treat. Human papilloma virus (HPV) and herpes simplex virus (HSV) are two common viral venereal diseases. HPV infections are characterized by anogenital warts and less commonly by premalignant or malignant lesions. HSV infections classically present as grouped vesicles on an erythematous base with associated burning or pain; however, immunosuppressed patients may have atypical presentations with nodular or ulcerative lesions. This review discusses the epidemiology, diagnosis, and management of anogenital HPV and HSV infections with an emphasis on treatment modalities for the practicing dermatologist. Diagnosis of these diseases typically relies on clinical assessment, although multiple diagnostic techniques can be utilized and are recommended when diagnosis is uncertain or evaluating an individual with increased risk of malignancy. Management of HPV and HSV infections involves appropriate counseling, screening, and multiple treatment techniques. Particularly for HPV infections, a practitioner may need to use a combination of techniques to achieve the desired outcome.

NPM1 and FLT3-TKD mutations are enriched in patients with leukemia cutis.

Leukemia cutis (LC) is a dermatologic manifestation of leukemia. Its clinical implications for the patient and the biological mechanism behind the manifestation of LC are unknown. The oncology community is increasingly utilizing mutations to classify a number of malignancies to prognosticate outcomes and to choose targeted therapies. A single-center, retrospective analysis of dermatopathology cases with a diagnosis of leukemia cutis was performed. Patients with genetic testing using the Columbia Combined Cancer Panel (a targeted sequencing protocol of 467 genes) or Genoptix (targeted sequencing protocol of 44 genes) were identified. The frequency of the presence of genetic mutations in LC patients was compared to AML patients from the COSMIC (Catalogue of Somatic Mutations in Cancer) database. Twenty nine cases were confirmed to have leukemia cutis, 22 of which had acute myeloid leukemia (AML). Genetic testing was available in 11 patients. Twelve different mutations were observed with particular enrichment for NPM1 and FLT3-TKD. Our original hypothesis was that patients with LC would display a distinct mutation profile. Ultimately, the distribution of mutations observed in our cohort of LC patients largely reflects the mutational profile seen in AML patients in general.

Recurrent spontaneous pneumothoraces and vaping in an 18-year-old man: a case report and review of the literature.

BACKGROUND: Primary spontaneous pneumothorax is a common disorder occurring in young adults without underlying lung disease. Although tobacco smoking is a well-documented risk factor for spontaneous pneumothorax, an association between electronic cigarette use (that is, vaping) and spontaneous pneumothorax has not been noted. We report a case of spontaneous pneumothoraces correlated with vaping. CASE PRESENTATION: An 18-year-old Caucasian man presented twice with recurrent right-sided spontaneous pneumothoraces within 2 weeks. He reported a history of vaping just prior to both episodes. Diagnostic testing was notable for a right-sided spontaneous pneumothorax on chest X-ray and computed tomography scan. His symptoms improved following insertion of a chest tube and drainage of air on each occasion. In the 2-week follow-up visit for the recurrent episode, he was asymptomatic and reported that he was no longer using electronic cigarettes. CONCLUSIONS: Providers and patients should be aware of the potential risk of spontaneous pneumothorax associated with electronic cigarettes.

Use of "natural" oils for moisturization: Review of olive, coconut, and sunflower seed oil.

Despite the availability of effective medications for the management of atopic dermatitis and xerosis, patients may use nonconventional therapies such as topical oils. Patients choose these treatments because of the perceived lower risk of natural products and the fear of potential adverse effects of topical steroids. We review the use of topical olive, coconut, and sunflower seed oil in the treatment of atopic dermatitis and xerosis with a focus on children Currently available evidence suggests that olive oil may exacerbate xerosis and atopic dermatitis. Further studies are needed to make definitive recommendations regarding the use of coconut and sunflower seed oil.

Combination therapy with anti-HIV-1 antibodies maintains viral suppression.

Individuals infected with HIV-1 require lifelong antiretroviral therapy, because interruption of treatment leads to rapid rebound viraemia. Here we report on a phase 1b clinical trial in which a combination of 3BNC117 and 10-1074, two potent monoclonal anti-HIV-1 broadly neutralizing antibodies that target independent sites on the HIV-1 envelope spike, was administered during analytical treatment interruption. Participants received three infusions of 30 mg kg-1 of each antibody at 0, 3 and 6 weeks. Infusions of the two antibodies were generally well-tolerated. The nine enrolled individuals with antibody-sensitive latent viral reservoirs maintained suppression for between 15 and more than 30 weeks (median of 21 weeks), and none developed viruses that were resistant to both antibodies. We conclude that the combination of the anti-HIV-1 monoclonal antibodies 3BNC117 and 10-1074 can maintain long-term suppression in the absence of antiretroviral therapy in individuals with antibody-sensitive viral reservoirs.

Safety and antiviral activity of combination HIV-1 broadly neutralizing antibodies in viremic individuals.

Monotherapy of HIV-1 infection with single antiretroviral agents is ineffective because error-prone HIV-1 replication leads to the production of drug-resistant viral variants1,2. Combinations of drugs can establish long-term control, however, antiretroviral therapy (ART) requires daily dosing, can cause side effects and does not eradicate the infection3,4. Although anti-HIV-1 antibodies constitute a potential alternative to ART5,6, treatment of viremic individuals with a single antibody also results in emergence of resistant viral variants7-9. Moreover, combinations of first-generation anti-HIV-1 broadly neutralizing antibodies (bNAbs) had little measurable effect on the infection10-12. Here we report on a phase 1b clinical trial ( NCT02825797 ) in which two potent bNAbs, 3BNC11713 and 10-107414, were administered in combination to seven HIV-1 viremic individuals. Infusions of 30 mg kg-1 of each of the antibodies were well-tolerated. In the four individuals with dual antibody-sensitive viruses, immunotherapy resulted in an average reduction in HIV-1 viral load of 2.05 log10 copies per ml that remained significantly reduced for three months following the first of up to three infusions. In addition, none of these individuals developed resistance to both antibodies. Larger studies will be necessary to confirm the efficacy of antibody combinations in reducing HIV-1 viremia and limiting the emergence of resistant viral variants.

Antibody 10-1074 suppresses viremia in HIV-1-infected individuals.

Monoclonal antibody 10-1074 targets the V3 glycan supersite on the HIV-1 envelope (Env) protein. It is among the most potent anti-HIV-1 neutralizing antibodies isolated so far. Here we report on its safety and activity in 33 individuals who received a single intravenous infusion of the antibody. 10-1074 was well tolerated and had a half-life of 24.0 d in participants without HIV-1 infection and 12.8 d in individuals with HIV-1 infection. Thirteen individuals with viremia received the highest dose of 30 mg/kg 10-1074. Eleven of these participants were 10-1074-sensitive and showed a rapid decline in viremia by a mean of 1.52 log10 copies/ml. Virologic analysis revealed the emergence of multiple independent 10-1074-resistant viruses in the first weeks after infusion. Emerging escape variants were generally resistant to the related V3-specific antibody PGT121, but remained sensitive to antibodies targeting nonoverlapping epitopes, such as the anti-CD4-binding-site antibodies 3BNC117 and VRC01. The results demonstrate the safety and activity of 10-1074 in humans and support the idea that antibodies targeting the V3 glycan supersite might be useful for the treatment and prevention of HIV-1 infection.

Highly Potent, Chemically Stable Quorum Sensing Agonists for Vibrio Cholerae.

In the Vibrio cholerae pathogen, initiation of bacterial quorum sensing pathways serves to suppress virulence. We describe herein a potent and chemically stable small molecule agonist of V. cholerae quorum sensing, which was identified through rational drug design based on the native quorum sensing signal. This novel agonist may serve as a useful lead compound for the control of virulence in V. cholerae.