Disorders of Transepidermal Elimination

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65203/1/j.1365-4362.1985.tb05799.x.pd

The impact of provider-initiated (opt-out) HIV testing and counseling of patients with sexually transmitted infection in Cape Town, South Africa: a controlled trial

<p>Abstract</p> <p>Background</p> <p>The effectiveness of provider-initiated HIV testing and counseling (PITC) for patients with sexually transmitted infection (STI) in resource-constrained settings are of particular concern for high HIV prevalence countries like South Africa. This study evaluated whether the PITC approach increased HIV testing amongst patients with a new episode of sexually transmitted infection, as compared to standard voluntary counseling and testing (VCT) at the primary care level in South Africa, a high prevalence and low resource setting.</p> <p>Methods</p> <p>The design was a pragmatic cluster-controlled trial with seven intervention and 14 control clinics in Cape Town. Nurses in intervention clinics integrated PITC into standard HIV care with few additional resources, whilst lay counselors continued with the VCT approach in control clinics. Routine data were collected for a six-month period following the intervention in 2007, on new STI patients who were offered and who accepted HIV testing. The main outcome measure was the proportion of new STI patients tested for HIV, with secondary outcomes being the proportions who were offered and who declined the HIV test.</p> <p>Results</p> <p>A significantly higher proportion of new STI patients in the intervention group tested for HIV as compared to the control group with (56.4% intervention versus 42.6% control, p = 0.037). This increase was achieved despite a significantly higher proportion intervention group declining testing when offered (26.7% intervention versus 13.5% control, p = 0.0086). Patients were more likely to be offered HIV testing in intervention clinics, where providers offered the HIV test to 76.8% of new STI patients versus 50.9% in the control group (p = 0.0029). There was significantly less variation in the main outcomes across the intervention clinics, suggesting that the intervention also facilitated more consistent performance.</p> <p>Conclusions</p> <p>PITC was successful in three ways: it increased the proportion of new STI patients tested for HIV; it increased the proportion of new STI patients offered HIV testing; and it delivered more consistent performance across clinics. Recommendations are made for increasing the impact and feasibility of PITC in high HIV prevalence and resource-constrained settings. These include more flexible use of clinical and lay staff, and combining PITC with VCT and other community-based approaches to HIV testing.</p> <p>Trial registration</p> <p>Controlled trial ISRCTN93692532</p

Competitive and Cooperative Interactions Mediate RNA Transfer from Herpesvirus Saimiri ORF57 to the Mammalian Export Adaptor ALYREF

The essential herpesvirus adaptor protein HVS ORF57, which has homologs in all other herpesviruses, promotes viral mRNA export by utilizing the cellular mRNA export machinery. ORF57 protein specifically recognizes viral mRNA transcripts, and binds to proteins of the cellular transcription-export (TREX) complex, in particular ALYREF. This interaction introduces viral mRNA to the NXF1 pathway, subsequently directing it to the nuclear pore for export to the cytoplasm. Here we have used a range of techniques to reveal the sites for direct contact between RNA and ORF57 in the absence and presence of ALYREF. A binding site within ORF57 was characterized which recognizes specific viral mRNA motifs. When ALYREF is present, part of this ORF57 RNA binding site, composed of an a-helix, binds preferentially to ALYREF. This competitively displaces viral RNA from the a-helix, but contact with RNA is still maintained by a flanking region. At the same time, the flexible N-terminal domain of ALYREF comes into contact with the viral RNA, which becomes engaged in an extensive network of synergistic interactions with both ALYREF and ORF57. Transfer of RNA to ALYREF in the ternary complex, and involvement of individual ORF57 residues in RNA recognition, were confirmed by UV cross-linking and mutagenesis. The atomic-resolution structure of the ORF57-ALYREF interface was determined, which noticeably differed from the homologous ICP27-ALYREF structure. Together, the data provides the first site-specific description of how viral mRNA is locked by a herpes viral adaptor protein in complex with cellular ALYREF, giving herpesvirus access to the cellular mRNA export machinery. The NMR strategy used may be more generally applicable to the study of fuzzy protein-protein-RNA complexes which involve flexible polypeptide regions

KRIT1 Regulates the Homeostasis of Intracellular Reactive Oxygen Species

KRIT1 is a gene responsible for Cerebral Cavernous Malformations (CCM), a major cerebrovascular disease characterized by abnormally enlarged and leaky capillaries that predispose to seizures, focal neurological deficits, and fatal intracerebral hemorrhage. Comprehensive analysis of the KRIT1 gene in CCM patients has suggested that KRIT1 functions need to be severely impaired for pathogenesis. However, the molecular and cellular functions of KRIT1 as well as CCM pathogenesis mechanisms are still research challenges. We found that KRIT1 plays an important role in molecular mechanisms involved in the maintenance of the intracellular Reactive Oxygen Species (ROS) homeostasis to prevent oxidative cellular damage. In particular, we demonstrate that KRIT1 loss/down-regulation is associated with a significant increase in intracellular ROS levels. Conversely, ROS levels in KRIT1−/− cells are significantly and dose-dependently reduced after restoration of KRIT1 expression. Moreover, we show that the modulation of intracellular ROS levels by KRIT1 loss/restoration is strictly correlated with the modulation of the expression of the antioxidant protein SOD2 as well as of the transcriptional factor FoxO1, a master regulator of cell responses to oxidative stress and a modulator of SOD2 levels. Furthermore, we show that the KRIT1-dependent maintenance of low ROS levels facilitates the downregulation of cyclin D1 expression required for cell transition from proliferative growth to quiescence. Finally, we demonstrate that the enhanced ROS levels in KRIT1−/− cells are associated with an increased cell susceptibility to oxidative DNA damage and a marked induction of the DNA damage sensor and repair gene Gadd45α, as well as with a decline of mitochondrial energy metabolism. Taken together, our results point to a new model where KRIT1 limits the accumulation of intracellular oxidants and prevents oxidative stress-mediated cellular dysfunction and DNA damage by enhancing the cell capacity to scavenge intracellular ROS through an antioxidant pathway involving FoxO1 and SOD2, thus providing novel and useful insights into the understanding of KRIT1 molecular and cellular functions

Contact and photocontact allergy to musk ambrette.

Musk ambrette, a contact and photocontact allergen, is a synthetic fragrance present in aftershave lotions and many toiletries. Thirty-four patients with contact and photocontact allergy to musk ambrette were studied. All had a facial eczema. Four distinctive clinical pictures were seen. These were plaques of eczema, jawline (mandibular) dermatitis, acute contact dermatitis and chronic actinic dermatitis. Twenty-six patients were light sensitive by history and 10 were diagnosed by clinical criteria as having chronic actinic dermatitis. Patch and photopatch testing to musk ambrette showed that seven patients had pure photocontact dermatitis to musk ambrette. Eight patients had contact dermatitis to musk ambrette but this was exacerbated by irradiation. Cross reaction with moskene occurred. Scrupulous avoidance of musk ambrette has resulted in clinical resolution in most patients