Microstructure of bismuth centers in silicon before and after irradiation with 15 MeV protons.

A decrease of two-gamma annihilation rate of a positron in a strong spin-orbit field of the annihilation site of bismuth impurity center209Bi (J= 9/2) in silicon with natural isotope composition was revealed (Jis the nuclear spin). This decrease was observed along with increasing occupancy of Bi donor states (binding energyE{Bi} ≈ 69 meV). Atoms of29Si (J= 1/2) isotope are involved in spin interactions of positron with Bi impurity centers. The growth of occupancy of Bi donor states inhibits two-gamma annihilation rate. The estimated cross-section of positron trapping by the Bi impurity center isσ+≈ (1.23-1.5) × 10-13 cm2. Together with this surprisingly large value, the integral rate of two-gamma annihilation in a hypothetical polyelectron system of the Bi impurity center is by a factor of just Δ âˆ¼ 2.18 higher compared to the magnitude ≈2.09 × 109 s-1known for elemental isolated polyelectron, (e-e+e-). Possible formation of the positron-containing exciton-like states, (e+)D0X(D= Bi, P) is also discussed. Irradiation of material with 15 MeV protons results in decreasing the factor Δ by ∼11% due to forming the radiation complex in which Bi atom is in an open volume ambient it. Such complex is suggested to haveD3dsymmetry and be the deep donor. Low-temperature measurements of both the positron annihilation rate and Hall effect have been applied for studying the isochronal annealing of these point radiation defects which were found to be thermally stable up to ∼370 °C; they can be annealed at ∼430 °C - 470 °C. According to available data ofab initiocluster calculations, the complex of Bi atom with a simulated vacancy hasD3dsymmetry with the energy gain ∼0.92 eV, thus indicating qualitative agreement between experimental and theoretical data.

Squamous Cell Carcinoma In Situ Upstaged to Invasive Squamous Cell Carcinoma: A 5-Year, Single Institution Retrospective Review.

BACKGROUND: Shave biopsy may not be able to accurately distinguish squamous cell carcinoma in situ (SCCIS) from invasive squamous cell carcinoma (SCC). Information on the incidence of biopsy-proven SCCIS upstaged to SCC after a more complete histologic examination is limited. OBJECTIVE: To determine the incidence and clinical risk factors associated with upstaging the biopsy diagnosis of SCCIS into invasive SCC based on findings during Mohs micrographic surgery (MMS). METHODS: All MMS cases of SCCIS performed between March 2007 and February 2012 were identified, MMS operative notes were examined, and invasive dermal components were confirmed by the MMS slide review. Upstaged SCCIS was defined as biopsy-diagnosed SCCIS subsequently found to be an invasive SCC during MMS. RESULTS: From 566 cases with the preoperative diagnosis of SCCIS, 92 (16.3%) cases were SCCIS upstaged to SCC. Location of ears, nose, lips, and eyelids, preoperative diameter >10 mm, and biopsy report mentioning a transected base were significant predictors of upstaged SCCIS. CONCLUSION: Considering the possibility that over 16% of SCCIS may be truly invasive SCC, biopsy-proven SCCIS should be treated adequately with margin-assessed treatment modalities such as surgical excision or Mohs surgery when indicated.

Nonmelanoma Skin Cancer With Aggressive Subclinical Extension in Immunosuppressed Patients.

IMPORTANCE: Immunosuppression (IS), such as in solid-organ transplant recipients (SOTRs) and patients with human immunodeficiency virus (HIV) or hematologic malignant neoplasms, increases the risk of developing nonmelanoma skin cancers (NMSCs). However, it is unknown whether IS patients are at increased risk of developing NMSCs with aggressive subclinical extensions (NMSC-ASE), which may extend aggressively far beyond conventional surgical margins. OBJECTIVE: To study clinical characteristics of NMSC-ASE among immunocompetent (IC) and various subgroups of IS patients and to suggest a predictive model for NMSC-ASE lesions. DESIGN, SETTING, AND PARTICIPANTS: A 6-year retrospective review of 2998 NMSC cases between February 26, 2007, and February 17, 2012, at the Dermatologic and Mohs Micrographic Surgery Unit of the University of California, San Diego, Medical Center. Nonmelanoma skin cancers that required at least 3 Mohs micrographic surgery stages with final surgical margins of at least 10 mm were defined as ASE lesions. All cases were categorized into 1 of 2 groups, IS or IC. Immunosuppressed cases were further subcategorized into 3 subgroups: SOTRs and patients with HIV or hematologic malignant neoplasm. The data were analyzed in December 2012. MAIN OUTCOMES AND MEASURES: We evaluated the odds ratio of having NMSC-ASE lesions in IS patients (SOTRs, HIV, hematologic malignant neoplasm) compared with IC patients. Other clinical characteristics and preoperative risks were analyzed and compared. RESULTS: Of all 2998 cases, we identified 805 NMSC-ASE cases: 137 IS and 668 IC. Immunosuppressed patients had an odds ratio of 1.94 of having ASE lesions compared with IC patients (95% CI, 1.54-2.44; P < .001). Additionally, the SOTR subgroup was associated with a 2.74 odds of having NSMC-ASE compared with non-SOTRs (95% CI, 2.00-3.76; P < .001), and the presence of hematologic malignant neoplasm was associated with 1.74 times the odds compared with IC patients (95% CI, 1.04-2.90; P = .04). Multivariate analysis found older age (P < .001), lesion locations such as zone 1 (OR, 1.39 [95% CI, 1.04-1.85]; P = .02) or zone 2 (OR, 1.45 [95% CI, 1.08-1.94]; P = .01), and IS status (OR, 1.94 [95% CI, 1.54-2.44]; P < .001) to be significant predictors of ASE. CONCLUSIONS AND RELEVANCE: The findings of this study suggest an increased risk for NMSC-ASE lesions in IS patients, especially in SOTRs and those with hematologic malignant neoplasm, but not patients with HIV. Statistically significant predictors of NMSC-ASE lesions such as age, location, and IS status can help physicians choose the most appropriate treatment modalities and optimize surgical planning.

Erythema induratum of Bazin presenting as peripheral neuropathy.

Erythema induratum of Bazin (EIB) is a rare tuberculid that typically affects middle-aged women. We report a unique case of EIB in a 57-year-old Hispanic woman who presented with recurrent painful plaques and nodules on the lower extremities, specifically on the pretibial area of the legs and dorsal aspect of the feet, with a severe burning sensation on the feet that resolved after antituberculosis therapy. We review the characteristics of EIB and examine how the unique presentation of peripheral neuropathy may relate to the pathophysiology of this disease.

Surgical smoke in dermatologic surgery.

BACKGROUND: Potential dangers associated with smoke generated during electrosurgery have been described. However, the use of smoke management in dermatology is unknown. There is no objective data showing the amount or the composition of the smoke generated in dermatologic surgeries. OBJECTIVE: To assess the use of smoke management in dermatologic surgery and provide data on the amount and chemical composition of surgical smoke. METHODS: A total of 997 surveys were sent to dermatologic surgeons across the United States to assess the use of smoke management. Amounts and concentrations of particulates and chemical composition were measured during electrosurgery using a particulate meter and the Environmental Protection Agency-standardized gas chromatography-mass spectrometry analysis. RESULTS: Thirty-two percent of the surgeons responded to the survey, and 77% of the respondents indicated no use of smoke management at all. Only approximately 10% of surgeons reported consistent use of smoke management. Active electrosurgery produced significant amounts of particulates. In addition, surgical smoke contained high concentrations of known carcinogens, such as benzene, butadiene, and acetonitrile. CONCLUSION: Surgical smoke contains toxic compounds and particulates. Most dermatologic surgeons do not use smoke management within their practices. Raising the awareness of the potential risks can help increase the use of smoke management.

Adverse events associated with mohs micrographic surgery: multicenter prospective cohort study of 20,821 cases at 23 centers.

IMPORTANCE: Detailed information regarding perioperative risk and adverse events associated with Mohs micrographic surgery (MMS) can guide clinical management. Much of the data regarding complications of MMS are anecdotal or report findings from single centers or single events. OBJECTIVES: To quantify adverse events associated with MMS and detect differences relevant to safety. DESIGN, SETTING, AND PARTICIPANTS: Multicenter prospective inception cohort study of 21 private and 2 institutional US ambulatory referral centers for MMS. Participants were a consecutive sample of patients presenting with MMS for 35 weeks at each center, with staggered start times. EXPOSURE: Mohs micrographic surgery. MAIN OUTCOMES AND MEASURES Intraoperative and postoperative minor and serious adverse events. RESULTS: Among 20 821 MMS procedures, 149 adverse events (0.72%), including 4 serious events (0.02%), and no deaths were reported. Common adverse events reported were infections (61.1%), dehiscence and partial or full necrosis (20.1%), and bleeding and hematoma (15.4%). Most bleeding and wound-healing complications occurred in patients receiving anticoagulation therapy. Use of some antiseptics and antibiotics and sterile gloves during MMS were associated with modest reduction of risk for adverse events. CONCLUSIONS AND RELEVANCE: Mohs micrographic surgery is safe, with a very low rate of adverse events, an exceedingly low rate of serious adverse events, and an undetectable mortality rate. Common complications include infections, followed by impaired wound healing and bleeding. Bleeding and wound-healing issues are often associated with preexisting anticoagulation therapy, which is nonetheless managed safely during MMS. We are not certain whether the small effects seen with the use of sterile gloves and antiseptics and antibiotics are clinically significant and whether wide-scale practice changes would be cost-effective given the small risk reductions.

Efficacy and complication rates of full-thickness skin graft repair of lower extremity wounds after Mohs micrographic surgery.

BACKGROUND: Repair of below-the-knee lower extremity defects after Mohs micrographic surgery (MMS) that are not amenable to primary closure can be challenging given the high propensity for complications. No criterion standard exists for management of these wounds, but secondary-intention healing, partial- and full-thickness skin grafts (FTSGs), and various flaps are possible options to manage these wounds. Few data exist on the efficacy of FTSG repairs for lower extremity wounds. OBJECTIVES: Assess the efficacy and complications rates of FTSG repairs for lower extremity wounds after MMS. METHODS: This was a retrospective review of 80 FTSG repairs performed after MMS. Data were derived from 45 cases at Beth Israel Deaconess Medical Center and 35 cases at University of California, San Diego (UCSD) Medical Center. RESULTS: Seventy-two of 80 cases (90%) had full graft survival, six (7.5%) had partial failure, and two (2.5%) had complete failure. In the cases where grafts had failed, wounds healed by secondary intention without further complications. Other complications included infections in nine (11%) cases and hematoma formation in two (2.5%). CONCLUSION: FTSG is a consistent and safe reconstructive option for the management of lower extremity wounds after MMS.

Single treatment of non-melanoma skin cancers using a pulsed-dye laser with stacked pulses.

BACKGROUND AND OBJECTIVE: Non-melanoma skin cancers are the most common cause of cancer worldwide. Within this grouping, the most common skin cancer is basal cell carcinoma (BCC) followed by squamous cell carcinoma (SCC). Recent evidence has shown that BCCs can be cleared by a pulsed-dye laser after multiple treatments using a single pass setting. Given the necessity for multiple treatments in the prior studies, we sought to determine whether tumor clearance could instead be achieved using a single treatment of the pulsed-dye laser in a stacked pulse setting. STUDY DESIGN/MATERIALS AND METHODS: Twenty patients with 23 biopsy-proven BCCs and SCCIS that measured 0.4-3 cm in size and located on the trunk and extremities were recruited for this study. The lesions were randomized into three study arms: a control group (no treatment), first treatment group (S1), and second treatment group (S2). The S1 group was treated using a 595 nM pulsed-dye laser (PDL) at pulse energy of 15 J/cm(2), 3-millisecond pulse length, with no dynamic cooling, using a 7-mm spot size with 10% overlap of pulses and two passes. The S2 group was treated using the same 595 nM PDL at 7.5 J/cm(2), 3-millisecond pulse length, with no dynamic cooling, using a 10-mm spot size with 10% overlap of pulses and double stacked pulses. All the treated lesions were treated with a 4 mm margin of clinically normal skin. The lesions were subsequently surgically excised and examined by histopathology. RESULTS: There was no significant difference in the dimensions of the tumors between the three study arms, with a mean area of 94 mm(2) [SEM ± 15.2] for the control group, 88 mm(2) [SEM ± 12.1] for the S1 treatment group, and 105 mm(2) [SEM ± 23.6] for the S2 treatment group. In the control group, there were two out seven lesions with no residual tumors, representing a background tumor clearance rate of approximately 28%. The S1 treatment group had two out of eight lesions with no residual lesion representing a clearance rate of 25%, similar to the background clearance rate. The S2 treatment group had a clearance rate of five out seven lesions, representing a clearance rate of 71%. The two lesions with residual tumors were noted to be beyond the central treatment zone by histopathology and if excluded, results in a clearance rate of 100%. By the Fisher's exact test with a Bonferroni correction, there is a trend towards significance between the S2 treatment group and the control group with a P-value of 0.028. CONCLUSIONS: The results of our pilot study suggest that BCCs and SCCIS can be cleared in a single treatment using a pulsed-laser in a stacked pulse setting. However, given the small sample size of this pilot study, further larger scale studies will be needed to determine statistical significance and long-term recurrence rate and to further validate these findings.

IRF3-dependent type I interferon response in B cells regulates CpG-mediated antibody production.

Hypomethylated CpG oligonucleotides (CpG) are not only potent adjuvants for enhancing adaptive immune responses but may also play a critical role in the development of autoimmune diseases such as Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). Here we provide evidence that, in addition to dendritic cells, murine B lymphocytes also exhibit a type I IFN response to CpG-B. Unlike dendritic cells, B cell-mediated type I IFN induction depended on the transcription factor IRF3, but similar to dendritic cells this pathway was independent of the IRF3 kinase TBK1. Utilizing type I IFN receptor-deficient mice, we were able to demonstrate that this IFN pathway enhanced Syndecan-1 expression and IgM production and was required for IgG2a production following CpG-B stimulation. Overall, our findings identify a unique IFN pathway in B cells that may play a central role in mediating B cell biology in response to CpG, potentially implicating this pathway in autoantibody production and the pathogenesis of certain autoimmune diseases.

TRAF3 and its biological function.

Tumor necrosis factor receptor associated factor 3 (TRAF3) is one of the most enigmatic members in the TRAF family that consists of six members, TRAF1 to 6. Despite its similarities with other TRAFs in terms of structure and protein-protein association, overexpression of TRAF3 does not induce activation of the commonly known TRAF-inducible signaling pathways, namely NF-kappaB and JNK. This lack of a simple functional assay in combination with the mysterious early lethality of the TRAF3-deficient mice has made the study of the biological function of TRAF3 challenging for almost ten years. Excitingly, TRAF3 has been identified recently to perform two seemingly distinct roles. Namely, TRAF3 functions as a negative regulator of the NF-kappaB pathway and separately, as a positive regulator of type I IFN production, placing itself as a critical regulator of both innate and adaptive immune responses.

Rescue of TRAF3-null mice by p100 NF-kappa B deficiency.

Proper activation of nuclear factor (NF)-kappaB transcription factors is critical in regulating fundamental biological processes such as cell survival and proliferation, as well as in inflammatory and immune responses. Recently, the NF-kappaB signaling pathways have been categorized into the canonical pathway, which results in the nuclear translocation of NF-kappaB complexes containing p50, and the noncanonical pathway, which involves the induced processing of p100 to p52 and the formation of NF-kappaB complexes containing p52 (Bonizzi, G., and M. Karin. 2004. Trends Immunol. 25:280-288). We demonstrate that loss of tumor necrosis factor (TNF) receptor-associated factor 3 (TRAF3) results in constitutive noncanonical NF-kappaB activity. Importantly, TRAF3-/- B cells show ligand-independent up-regulation of intracellular adhesion molecule 1 and protection from spontaneous apoptosis during in vitro culture. In addition, we demonstrate that loss of TRAF3 results in profound accumulation of NF-kappaB-inducing kinase in TRAF3-/- cells. Finally, we show that the early postnatal lethality observed in TRAF3-deficient mice is rescued by compound loss of the noncanonical NF-kappaB p100 gene. Thus, these genetic data clearly demonstrate that TRAF3 is a critical negative modulator of the noncanonical NF-kappaB pathway and that constitutive activation of the noncanonical NF-kappaB pathway causes the lethal phenotype of TRAF3-deficient mice.

Regulation of antiviral responses by a direct and specific interaction between TRAF3 and Cardif.

Upon recognition of viral infection, RIG-I and Helicard recruit a newly identified adapter termed Cardif, which induces type I interferon (IFN)-mediated antiviral responses through an unknown mechanism. Here, we demonstrate that TRAF3, like Cardif, is required for type I interferon production in response to intracellular double-stranded RNA. Cardif-mediated IFNalpha induction occurs through a direct interaction between the TRAF domain of TRAF3 and a TRAF-interaction motif (TIM) within Cardif. Interestingly, while the entire N-terminus of TRAF3 was functionally interchangeable with that of TRAF5, the TRAF domain of TRAF3 was not. Our data suggest that this distinction is due to an inability of the TRAF domain of TRAF5 to bind the TIM of Cardif. Finally, we show that preventing association of TRAF3 with this TIM by mutating two critical amino acids in the TRAF domain also abolishes TRAF3-dependent IFN production following viral infection. Thus, our findings suggest that the direct and specific interaction between the TRAF domain of TRAF3 and the TIM of Cardif is required for optimal Cardif-mediated antiviral responses.

Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response.

Type I interferon (IFN) production is a critical component of the innate defence against viral infections. Viral products induce strong type I IFN responses through the activation of Toll-like receptors (TLRs) and intracellular cytoplasmic receptors such as protein kinase R (PKR). Here we demonstrate that cells lacking TRAF3, a member of the TNF receptor-associated factor family, are defective in type I IFN responses activated by several different TLRs. Furthermore, we show that TRAF3 associates with the TLR adaptors TRIF and IRAK1, as well as downstream IRF3/7 kinases TBK1 and IKK-epsilon, suggesting that TRAF3 serves as a critical link between TLR adaptors and downstream regulatory kinases important for IRF activation. In addition to TLR stimulation, we also show that TRAF3-deficient fibroblasts are defective in their type I IFN response to direct infection with vesicular stomatitis virus, indicating that TRAF3 is also an important component of TLR-independent viral recognition pathways. Our data demonstrate that TRAF3 is a major regulator of type I IFN production and the innate antiviral response.

Key molecular contacts promote recognition of the BAFF receptor by TNF receptor-associated factor 3: implications for intracellular signaling regulation.

B cell-activating factor belonging to the TNF family receptor (BAFF-R), a member of the TNFR superfamily, plays a role in autoimmunity after ligation with BAFF ligand (also called TALL-1, BLyS, THANK, or zTNF4). BAFF/BAFF-R interactions are critical for B cell regulation, and signaling from this ligand-receptor complex results in NF-kappaB activation. Most TNFRs transmit signals intracellularly by recruitment of adaptor proteins called TNFR-associated factors (TRAFs). However, BAFF-R binds only one TRAF adaptor, TRAF3, and this interaction negatively regulates activation of NF-kappaB. In this study, we report the crystal structure of a 24-residue fragment of the cytoplasmic portion of BAFF-R bound in complex with TRAF3. The recognition motif (162)PVPAT(166) in BAFF-R is accommodated in the same binding crevice on TRAF3 that binds two related TNFRs, CD40 and LTbetaR, but is presented in a completely different structural framework. This region of BAFF-R assumes an open conformation with two extended strands opposed at right angles that each make contacts with TRAF3. The recognition motif is located in the N-terminal arm and intermolecular contacts mediate TRAF recognition. In the C-terminal arm, key stabilizing contacts are made, including critical hydrogen bonds with Gln(379) in TRAF3 that define the molecular basis for selective binding of BAFF-R solely to this member of the TRAF family. A dynamic conformational adjustment of Tyr(377) in TRAF3 occurs forming a new intermolecular contact with BAFF-R that stabilizes the complex. The structure of the complex provides a molecular explanation for binding affinities and selective protein interactions in TNFR-TRAF interactions.

Unique CD40-mediated biological program in B cell activation requires both type 1 and type 2 NF-kappaB activation pathways.

B lymphocytes can be activated by many different stimuli. However, the mechanisms responsible for the signaling and functional specificities of individual stimuli remain to be elucidated. Here, we have compared the contribution of the type 1 (p50-dependent) and type 2 (p52-dependent) NF-kappaB activation pathways to cell survival, proliferation, homotypic aggregation, and specific gene regulation of murine primary B lymphocytes. Whereas lipopolysaccharide (LPS) and B cell activation factor (BAFF) mainly activate the type 1 or type 2 pathways, respectively, CD40 ligand (CD40L) strongly activates both. Rescue of spontaneous apoptosis is diminished in p52(-/-) B cells after BAFF stimulation and in p50(-/-)c-Rel(-/-) B cells after LPS stimulation. Interestingly, significant CD40-induced B cell survival is still observed even in p50(-/-)c-Rel(-/-)p65(-/+) B cells, which is correlated with the ability of CD40L to up-regulate Bcl-x(L) expression in these cells. CD40L- and LPS-induced B cell proliferation, as well as up-regulation of proliferation-related genes, however, are greatly reduced in c-Rel(-/-) and p50(-/-)c-Rel(-/-) B cells but are normal in p52(-/-) B cells. We have further demonstrated that both c-Rel and p52 are required for CD40-mediated B cell homotypic aggregation, which explains well why neither LPS nor BAFF has this function. Overall, our studies suggest that both type 1 and type 2 NF-kappaB pathways contribute to the gene expression and biological program unique for CD40 in B cell activation.