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Melanoma is one of the most sensitive tumors to immune modulation, and the major challenge for melanoma patients’ survival is immune checkpoint inhibitor (ICI) therapy. γδ T lymphocytes play an antitumoral role in a broad variety of tumors including melanoma and they are optimal candidates for cellular immunotherapy. Thus, a comprehensive analysis of the correlation between γδ T cells and immune checkpoint receptors in the context of melanoma was conducted, with the aim of devising an innovative combined immunotherapeutic strategy. In this study, using the GEPIA2.0 database, a significant positive correlation was observed between the expression of γδ T cell–related genes (TRGC1, TRGC2, TCRD) and immune checkpoint genes (PDCD1, HAVCR2, LAG3), highlighting the potential role of γδ T cells in the immune response within melanoma. Moreover, flow cytometry analysis unveiled a significant augmentation in the population of γδ T cells within melanoma lesions, which exhibited the expression of immune checkpoint receptors including LAG3, TIM3, and PD1. Analysis of single-cell RNA sequencing data revealed a significant enrichment and functional reprogramming of γδ T cell clusters in response to ICIs. Interestingly, the effects of ICI therapy varied between Vδ1 and Vδ2 γδ T cell subsets, with distinct changes in gene expression patterns. Last, a correlation analysis between γδ T cell abundance, immune checkpoint gene expression, and clinical outcomes in melanoma patients showed that low expression of immune checkpoint genes, including LAG3, HAVCR2, and PDCD1, was associated with improved 1-year overall survival, emphasizing the significance of these genes in predicting patient outcomes, potentially outweighing the impact of γδ T cell abundance. This study offers critical insights into the dynamic interaction between γδ T cells, immune checkpoint receptors, and melanoma, providing valuable perspectives for potential therapeutic avenues and predictive markers in this intricate interplay.A comprehensive analysis exploring the intricate correlation between γδ T cells and immune checkpoint receptors in melanoma is the focus of this study. Our findings provide a solid foundation for further exploration, suggesting the strategic combination of adoptive transfer or in vivo activation of γδ T cells with immune checkpoint inhibitor therapy as a compelling approach to enhance anti-tumor responses.

Zusammenfassung.Hintergrund:Vulväre Neoplasien sind gynäkologische Erkrankungen mit zum Teil einschneidenden Folgen für die Betroffenen. Neben physischen Komplikationen leiden die Frauen häufig unter psychischen Problemen. Die mit Scham besetzte Krankheit führt zu einer Verminderung der Lebensqualität und beeinträchtigt das Sozialleben. Es ist wenig bekannt darüber, was diese Frauen an sozialer Unterstützung erhalten. Ziel:Das Ziel dieser qualitativen Studie war, zu beschreiben, wie betroffene Frauen die Unterstützung durch das soziale Umfeld in der Zeit von der Diagnose bis sechs Monate postoperativ erleben bzw. vermissen. Methode:In der vorliegenden Sekundäranalyse wurde ein qualitatives Design gewählt. Es wurden 20 transkribierte Interviews aus der WOMAN-PRO-Studie mittels qualitativer Inhaltsanalyse nach Mayring ausgewertet. Ergebnisse:Die Analyse ergab vier Hauptkategorien: Eine schlimme Krankheit haben zeigt, wie die Frauen die Diagnose als Schock erlebten, mit welchen Tabuthemen sowie Schuldfragen sie sich auseinandersetzen mussten. Stark ausgeprägt war die Kategorie Sich allein fühlen, bedingt durch Nicht-Sprechen, Nicht-Hinschauen und Nicht-Handeln. In Selber anpacken wird beschrieben, welche Strategien den Frauen halfen, aus dem Alleinsein herauszufinden. In Hilfe erfahren wird deutlich, dass diejenigen Frauen, die von sich aus mit dem sozialen Umfeld in Kontakt traten, in der Regel soziale Unterstützung erhielten. Schlussfolgerungen:Diese Patientinnen haben einen hohen Bedarf an umfassenden Informationen sowie an emotionaler und praktischer Unterstützung durch das private Umfeld und besonders auch durch die Gesundheitsfachleute. Eine definierte Bezugs- und Vertrauensperson während des ganzen Behandlungsprozesses ist zu empfehlen.

This paper presents the methods deployed by the Horizon 2O2O SCIPPER project to characterize emission performance of vessels, mainly under the perspective of checking compliance to new emissions regulations. Various on-board and remote measurement techniques have been demonstrated within five experimental campaigns conducted at Europe's main sea areas and ports. Almost a thousand of ship plumes has been measured and crossed checked with various instrumentation, revealing the emission profile of ships during actual operation Accuracy of each measurement technique was also tested. Emission measurements are further exploited to assess the impact of shipping on air quality of coastal areas, by identifying the transformations of pollutants performed in the atmosphere as plume evolves and quantifying onshore pollutants concentrations attributed to shipping activity.

Post-transplant lymphoproliferative disorder is a life-threatening complication of immunosuppression following transplantation mediated by failure of T cells to control Epstein–Barr virus (EBV)–infected and transformed B cells. Typically, a modification or reduction of immunosuppression is recommended, but insufficiently defined thus far. In order to help delineate this, we characterized EBV-antigen–specific T cells and lymphoblastoid cell lines from healthy donors and in patients with a kidney transplant in the absence or presence of the standard immunosuppressants tacrolimus, cyclosporin A, prednisolone, rapamycin, and mycophenolic acid. Phenotypes of lymphoblastoid cell-lines and T cells, T cell–receptor–repertoire diversity, and T-cell reactivity upon co-culture with autologous lymphoblastoid cell lines were analyzed. Rapamycin and mycophenolic acid inhibited lymphoblastoid cell-line proliferation. T cells treated with prednisolone and rapamycin showed nearly normal cytokine production. Proliferation and the viability of T cells were decreased by mycophenolic acid, while tacrolimus and cyclosporin A were strong suppressors of T-cell function including their killing activity. Overall, our study provides a basis for the clinical decision for the modification and reduction of immunosuppression and adds information to the complex balance of maintaining anti-viral immunity while preventing acute rejection. Thus, an immunosuppressive regime based on mTOR inhibition and reduced or withdrawn calcineurin inhibitors could be a promising strategy for patients with increased risk of or manifested EBV-associated post-transplant lymphoproliferative disorder.

The Alaskan Layered Pollution and Chemical Analysis (ALPACA) field campaign included deployment of a suite of atmospheric measurements in January–February 2022 with the goal of better understanding atmospheric processes and pollution under cold and dark conditions in Fairbanks, Alaska. We report on measurements of particle composition, particle size, ice nucleating particle (INP) composition, and INP size during an ice fog period (29 January–3 February). During this period, coarse particulate matter (PM10) concentrations increased by 150% in association with a decrease in air temperature, a stronger temperature inversion, and relatively stagnant conditions. Results also show a 18%–78% decrease in INPs during the ice fog period, indicating that particles had activated into the ice fog via nucleation. Peroxide and heat treatments performed on INPs indicated that, on average, the largest contributions to the INP population were heat‐labile (potentially biological, 63%), organic (31%), then inorganic (likely dust, 6%). Measurements of levoglucosan and bulk and single‐particle composition corroborate the presence of dust and aerosols from combustion sources. Heat‐labile and organic INPs decreased during the peak period of the ice fog, indicating those were preferentially activated, while inorganic INPs increased, suggesting they remained as interstitial INPs. In general, INP concentrations were unexpectedly high in Fairbanks compared to other locations in the Arctic during winter. The fact that these INPs likely facilitated ice fog formation in Fairbanks has implications for other high latitude locations subject to the hazards associated with ice fog. The Alaskan Layered Pollution and Chemical Analysis field campaign occurred January–February 2022 with the goal of better understanding the atmosphere and atmospheric pollution during the winter in Fairbanks, Alaska. We studied a rare subset of atmospheric particles called ice nucleating particles which facilitate the formation of ice fog by allowing water to freeze at temperatures above −38°C. During our study, there was an ice fog event that coincided with a pollution event. During this event, there was a significant increase in coarse particulate matter associated with a decrease in temperature and calm winds. Ice nucleating particle concentration in the air decreased during the ice fog event indicating that the INPs had activated into the ice fog and were not able to be captured. We determined that most INPs were heat‐labile (potentially biological), followed by organic. Very few INPs were inorganic. Inorganic INPs increased during the ice fog period while heat‐labile and organic INPs decreased indicating that they were being selectively activated into the fog. Overall, INP concentrations in Fairbanks were quite high compared to other Arctic locations and carries implications for ice fog formation in other high‐latitude locations. Fairbanks had higher wintertime ice nucleating particle (INP) concentrations than other high‐latitude locationsINP concentrations in Fairbanks decreased during the ice fog period, indicating that INPs were activated into the fogINP composition in Fairbanks was dominated by heat‐labile INPs Fairbanks had higher wintertime ice nucleating particle (INP) concentrations than other high‐latitude locations INP concentrations in Fairbanks decreased during the ice fog period, indicating that INPs were activated into the fog INP composition in Fairbanks was dominated by heat‐labile INPs

Background: Persistent infections with oncogenic human papillomavirus (HPV) types are causally related to cervical cancer. Little is known about the distribution of HPV types, independent risk factors of incidence and persistence, and patterns of persistence in sub-Saharan Africa. Methods: A cohort of 2040 Zimbabwean women was enrolled in a randomized trial assessing the effect of diaphragm/gel provision on human immunodeficiency virus and HPV acquisition. Data from the study arms were pooled for this analysis because diaphragm/gel provision did not affect HPV acquisition and clearance. Clinicians collected cervical samples for HPV testing at enrollment, 12 months, and exit (median 21 months). Results: HPV prevalence was 24.5% for any HPV type and 16.1% for oncogenic types. HPV incidence at 12 months was 23.3% for any HPV type and 11.4% for oncogenic types. HPV58 had the highest baseline prevalence (5.0%) and incidence (2.4%). Type-specific persistence was 29.8% among all HPV infections over a median of 21 months of follow-up. Baseline predictors of incident HPV infection were younger age, having more than 1 lifetime sexual partner, infrequent condom use, herpes simplex virus-2 positive serology, and having a sexually transmissible infection or a different HPV type at enrollment. Baseline predictors of persistent HPV infection were younger age, having more than 1 lifetime sexual partner, and having a high-risk partner. Conclusions: The novel association between herpes simplex virus-2 seropositivity and incident HPV infection warrants further investigation. Having a high-risk partner is a potentially modifiable risk factor for persistent HPV infection. The relatively high prevalence of HPV58 has implications for vaccine development.

In emerging economies such as China, marked by profound regional disparities in terms of socio-economic wealth and technology, different regions use not only different levels of inputs into the innovation process, but also produce different outputs with qualitative diversity that is seldom sufficiently acknowledged. This paper uses structured expert interviews (AHP) to provide insights into the innovation profiles of four selected Chinese regions: Beijing, Shanghai, Chongqing and Kunming. It combines information on drivers of innovation as well as innovation characteristics and objectives to establish and compare regional innovation profiles.

The OH-initiated degradation of 2-amino-2-methyl-1-propanol [CH3C(NH2)(CH3)CH2OH, AMP] was investigated in a large atmospheric simulation chamber, employing time-resolved online high-resolution proton-transfer reaction-time-of-flight mass spectrometry (PTR-ToF-MS) and chemical analysis of aerosol online PTR-ToF-MS (CHARON-PTR-ToF-MS) instrumentation, and by theoretical calculations based on M06-2X/aug-cc-pVTZ quantum chemistry results and master equation modeling of the pivotal reaction steps. The quantum chemistry calculations reproduce the experimental rate coefficient of the AMP + OH reaction, aligning k(T) = 5.2 × 10–12× exp (505/T) cm3molecule–1s–1to the experimental value kexp,300K= 2.8 × 10–11cm3molecule–1s–1. The theoretical calculations predict that the AMP + OH reaction proceeds via hydrogen abstraction from the −CH3groups (5–10%), −CH2– group, (>70%) and −NH2group (5–20%), whereas hydrogen abstraction from the −OH group can be disregarded under atmospheric conditions. A detailed mechanism for atmospheric AMP degradation was obtained as part of the theoretical study. The photo-oxidation experiments show 2-amino-2-methylpropanal [CH3C(NH2)(CH3)CHO] as the major gas-phase product and propan-2-imine [(CH3)2C═NH], 2-iminopropanol [(CH3)(CH2OH)C═NH], acetamide [CH3C(O)NH2], formaldehyde (CH2O), and nitramine 2-methyl-2-(nitroamino)-1-propanol [AMPNO2, CH3C(CH3)(NHNO2)CH2OH] as minor primary products; there is no experimental evidence of nitrosamine formation. The branching in the initial H abstraction by OH radicals was derived in analyses of the temporal gas-phase product profiles to be BCH3/BCH2/BNH2= 6:70:24. Secondary photo-oxidation products and products resulting from particle and surface processing of the primary gas-phase products were also observed and quantified. All the photo-oxidation experiments were accompanied by extensive particle formation that was initiated by the reaction of AMP with nitric acid and that mainly consisted of this salt. Minor amounts of the gas-phase photo-oxidation products, including AMPNO2, were detected in the particles by CHARON-PTR-ToF-MS and GC×GC-NCD. Volatility measurements of laboratory-generated AMP nitrate nanoparticles gave ΔvapH= 80 ± 16 kJ mol–1and an estimated vapor pressure of (1.3 ± 0.3) × 10–5Pa at 298 K. The atmospheric chemistry of AMP is evaluated and a validated chemistry model for implementation in dispersion models is presented.

To avoid the middle-income trap, China’s leaders call for innovation to accelerate development in China. However, since it is not clear how innovation and (regional) development reinforce each other, there is no blueprint strategy for successful innovation capacity building throughout China. Due to resource scarcity in its “Western” regions, it is thus far from certain that innovation capacity building will support regional development. Departing from sociology of knowledge, narrations are constitutive of policy practice. This article analyses narrative patterns of policy experts to understand how innovation capacity building and regional development are negotiated in China’s lagging “West.” The comparison of Yunnan and Chongqing cases demonstrates that innovation capacity building is primarily infused with theoretical expectations: resource scarcity does not allow for grounding innovation as a strategy of regional development in the local context. This leads to narrations of “local” alternatives to innovation capacity building in centralist China.

Infection with human papillomavirus (HPV) is a risk factor for developing cervical neoplasia (tumors) that often develops into cancer. These tumors are presently screened for by the Pap smear, but this test is fairly insensitive, detecting only 50 to 80 percent of the cases of cervical neoplasia. A test that would identify those infected with HPV could be used to detect those at high risk for these tumors, who could then undergo the more time-consuming and more costly, but more accurate, colposcopy exam for these abnormalities. A test that identifies HPV DNA (hybridization) has been developed to detect infection with HPV. Studies have shown that not all infected with the virus have abnormal Pap smear results and vice versa. It is thought that a Pap smear in combination with an HPV DNA test may be most useful in determining who should be further examined by colposcopy. This study examined the association between HPV DNA results and Pap smear results to see if rescreening is useful for those that are HPV-positive. The tests were performed in 125 women. HPV results were not known by those examining the Pap smear results, two pathologists and a private cytologic laboratory. HPV DNA test results were positive for 24 subjects (19 percent). The private cytology laboratory read 6 of the 24 Pap smears from HPV-positive women as abnormal, but only 3 of 101 from HPV-negative individuals were read as abnormal. On the other hand, one pathologist read 15 of the 24 Pap smears from HPV-positive patients as abnormal, while 8 of 101 smears from HPV-negative individuals were considered atypical. A second pathologist read 11 of the 24 and 7 of the 101, respectively, as abnormal. Cervical epithelial neoplasia was diagnosed in none of the HPV-positive Pap smears by a private laboratory, in 40 percent by the first pathologist, and in 20 percent by the second. These results indicate that rescreening the Pap smear results of those who test positive for HPV-infection is useful and is likely to uncover a significant number of additional cases of cervical intraepithelial neoplasia. (Consumer Summary produced by Reliance Medical Information, Inc.)

We report on a new method for analyzing atmospheric submicrometer particulate organic matter which combines direct particle sampling and volatilization with online chemical ionization mass spectrometric analysis. Technically, the method relies on the combined use of a CHARON (“Chemical Analysis of Aerosol Online”) particle inlet and a proton-transfer-reaction time-of-flight mass spectrometer (PTR-ToF-MS). Laboratory studies on target analytes showed that the ionization conditions in the PTR-ToF-MS lead to extensive fragmentation of levoglucosan and cis-pinonic acid, while protonated oleic acid and 5α-cholestane molecules remain intact. Potential problems and biases in quantitative and qualitative analyses are discussed. Side-by-side atmospheric comparison measurements of total particulate organic mass and levoglucosan with an aerosol mass spectrometer (AMS) were in good agreement. Complex and clearly distinct organic mass spectra were obtained from atmospheric measurements in three European cities (Lyon, Valencia, Innsbruck). Data visualization in reduced-parameter frameworks (e.g., oxidation state of carbon vs carbon number) revealed that the CHARON-PTR-ToF-MS technique adds significant analytical capabilities for characterizing particulate organic carbon in the Earth’s atmosphere. Positive matrix factorization (PMF) was used for apportioning sources of atmospheric particles in late fall in Innsbruck. The m/zsignatures of known source marker compounds (levoglucosan and resin acids, polycyclic aromatic hydrocarbons, nicotine) in the mass spectra were used to assign PMF factors to biomass burning, traffic, and smoking emission sources.

The OH-initiated photo-oxidation of piperidine and the photolysis of 1-nitrosopiperidine were investigated in a large atmospheric simulation chamber and in theoretical calculations based on CCSD(T*)-F12a/aug-cc-pVTZ//M062X/aug-cc-pVTZ quantum chemistry results and master equation modeling of the pivotal reaction steps. The rate coefficient for the reaction of piperidine with OH radicals was determined by the relative rate method to be kOH-piperidine= (1.19 ± 0.27) × 10–10cm3molecule–1s–1at 304 ± 2 K and 1014 ± 2 hPa. Product studies show the piperidine + OH reaction to proceed via H-abstraction from both CH2and NH groups, resulting in the formation of the corresponding imine (2,3,4,5-tetrahydropyridine) as the major product and in the nitramine (1-nitropiperidine) and nitrosamine (1-nitrosopiperidine) as minor products. Analysis of 1-nitrosopiperidine photolysis experiments under natural sunlight conditions gave the relative rates jrel= j1-nitrosoperidine/jNO2= 0.342 ± 0.007, k3/k4a= 0.53 ± 0.05 and k2/k4a= (7.66 ± 0.18) × 10–8that were subsequently employed in modeling the piperidine photo-oxidation experiments, from which the initial branchings between H-abstraction from the NH and CH2groups, kN–H/ktot= 0.38 ± 0.08 and kC2–H/ktot= 0.49 ± 0.19, were derived. All photo-oxidation experiments were accompanied by particle formation that was initiated by the acid–base reaction of piperidine with nitric acid. Primary photo-oxidation products including both 1-nitrosopiperidine and 1-nitropiperidine were detected in the particles formed. Quantum chemistry calculations on the OH initiated atmospheric photo-oxidation of piperidine suggest the branching in the initial H-abstraction routes to be ∼35% N1, ∼50% C2, ∼13% C3, and ∼2% C4. The theoretical study produced an atmospheric photo-oxidation mechanism, according to which H-abstraction from the C2position predominantly leads to 2,3,4,5-tetrahydropyridine and H-abstraction from the C3position results in ring opening followed by a complex autoxidation, of which the first few steps are mapped in detail. H-abstraction from the C4position is shown to result mainly in the formation of piperidin-4-one and 2,3,4,5-tetrahydropyridin-4-ol, whereas H-abstraction from N1under atmospheric conditions primarily leads to 2,3,4,5-tetrahydropyridine and in minor amounts of 1-nitrosopiperidine and 1-nitropiperidine. The calculated rate coefficient for the piperidine + OH reaction agrees with the experimental value within 35%, and aligning the theoretical numbers to the experimental value results in k(T) = 2.46 × 10–12× exp(486 K/T) cm3molecule–1s–1(200–400 K).

The OH-initiated photo-oxidation of piperazine and 1-nitropiperazine as well as the photolysis of 1-nitrosopiperazine were investigated in a large atmospheric simulation chamber. The rate coefficient for the reaction of piperazine with OH radicals was determined by the relative rate method to be kOH-piperazine= (2.8 ± 0.6) × 10–10cm3molecule–1s–1at 307 ± 2 K and 1014 ± 2 hPa. Product studies showed the piperazine + OH reaction to proceed both via C–H and N–H abstraction, resulting in the formation of 1,2,3,6-tetrahydropyrazine as the major product and in 1-nitropiperazine and 1-nitrosopiperazine as minor products. The branching in the piperazinyl radical reactions with NO, NO2, and O2was obtained from 1-nitrosopiperazine photolysis experiments and employed analyses of the 1-nitropiperazine and 1-nitrosopiperazine temporal profiles observed during piperazine photo-oxidation. The derived initial branching between N–H and C–H abstraction by OH radicals, kN–H/(kN–H+ kC–H), was 0.18 ± 0.04. All experiments were accompanied by substantial aerosol formation that was initiated by the reaction of piperazine with nitric acid. Both primary and secondary photo-oxidation products including 1-nitropiperazine and 1,4-dinitropiperazine were detected in the aerosol particles formed. Corroborating atmospheric photo-oxidation schemes for piperazine and 1-nitropiperazine were derived from M06-2X/aug-cc-pVTZ quantum chemistry calculations and master equation modeling of the pivotal reaction steps. The atmospheric chemistry of piperazine is evaluated, and a validated chemical mechanism for implementation in dispersion models is presented.

IMPORTANCE: The standard of care for refeeding inpatients with anorexia nervosa, starting with low calories and advancing cautiously, is associated with slow weight gain and protracted hospital stay. Limited data suggest that higher-calorie refeeding improves these outcomes with no increased risk of refeeding syndrome. OBJECTIVE: To compare the short-term efficacy, safety, and cost of lower-calorie vs higher-calorie refeeding for malnourished adolescents and young adults with anorexia nervosa. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter randomized clinical trial with prospective follow-up conducted at 2 inpatient eating disorder programs at large tertiary care hospitals, 120 adolescents and young adults aged 12 to 24 years hospitalized with anorexia nervosa or atypical anorexia nervosa and 60% or more of median body mass index were enrolled from February 8, 2016, to March 7, 2019. The primary analysis was a modified intent-to-treat approach. INTERVENTIONS: Higher-calorie refeeding, beginning at 2000 kcal/d and increasing by 200 kcal/d vs lower-calorie refeeding, beginning at 1400 k/cal and increasing by 200 kcal every other day. MAIN OUTCOMES AND MEASURES: Main outcomes were end-of-treatment outcomes; the primary end point of this trial will be clinical remission over 12 months. Short-term efficacy was defined a priori as time to restore medical stability in the hospital, measured by the following 6 indices: 24-hour heart rate of 45 beats/min or more, systolic blood pressure of 90 mm Hg or more, temperature of 35.6 °C or more, orthostatic increase in heart rate of 35 beats/min or less, orthostatic decrease in systolic blood pressure of 20 mm Hg or less, and 75% or more of median body mass index for age and sex. The prespecified safety outcome was incidence of electrolyte abnormalities; cost efficacy was defined as savings associated with length of stay. RESULTS: Because 9 participants withdrew prior to treatment, the modified intention-to-treat analyses included 111 participants (93%; 101 females [91%]; mean [SD] age, 16.4 [2.5] years). Higher-calorie refeeding restored medical stability significantly earlier than lower-calorie refeeding (hazard ratio, 1.67 [95% CI, 1.10-2.53]; P = .01). Electrolyte abnormalities and other adverse events did not differ by group. Hospital stay was 4.0 days shorter (95% CI, −6.1 to −1.9 days) among the group receiving higher-calorie refeeding, which was associated with a savings of $19 056 (95% CI, −$28 819 to −$9293) in hospital charges per participant. CONCLUSIONS AND RELEVANCE: In the first randomized clinical trial in the US to compare refeeding approaches in patients with anorexia nervosa and atypical anorexia nervosa, higher-calorie refeeding demonstrated short-term efficacy with no increase in safety events during hospitalization. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02488109

Small studies reported poor post-partum outcomes among young women living with perinatal HIV infection who are now ageing into adulthood and becoming pregnant. For targeted clinical intervention, we sought to identify women in this population at risk of poor post-partum virological control.

Hand and face transplants are becoming increasingly common, recording progressively more penile, uterus, abdominal wall, and allotransplantation cases reported worldwide. Despite current protocols allow long-term survival of the allografts, the ultimate goal of donor-specific tolerance has not been achieved yet. In fact, the harmful adverse effects related to the lifelong administration of immunosuppressive agents are the main drawbacks for vascularized composite allotransplantations. Research is very active in investigating alternative methods to induce greater tolerance while minimizing toxicity. Adipose-derived stem cells (ASCs) represent promising cell therapies for immunomodulation in preclinical and clinical settings. Their clinical appeal is due to their easy harvest in large quantities through a noninvasive and well-accepted approach; they may well promote donor-specific tolerance and potentially reduce immunosuppression. Several experimental studies exist, but lacking review articles reporting current evidence. This work proposes a literature review on the immunomodulatory role of ASCs in vascularized composite allotransplantations. In vitro and in vivo evidence will be summarized. The role that cell passaging and upstream progenitors—the so-called spheroid ASCs—may play in modulating the immune response will also be discussed. Finally, this article will summarize current knowledge on biodistribution, migration, and homing of injected stem cells. This review may well provide useful information for preclinical and clinical studies, aiming at a breakthrough for donor-specific tolerance.

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Background and Objectives: In adolescents and young adults, multiple studies have identified sexual activity and behaviors as significant risk factors for acquiring both human cytomegalovirus (HCMV) and hepatitis B virus (HBV). However, there are no reports on the prevalence or risk factors for infection of these viruses and hepatitis C virus (HCV) in an adolescent population with sexually acquired HIV. Goals: To examine the seroprevalence and risk factors of HBV, HCV, and HCMV infection in a population of HIV-infected male and female adolescents and in an age- and risk behavior-matched HIV-uninfected cohort. Study Design: A cross-sectional analysis of HBV, HCV, and HCMV infections in a cohort of HIV-infected and HIV-uninfected adolescents. Results: Adolescent males infected with HIV were more likely to have evidence of HBV and HCMV infection than HIV-uninfected males (23.7% versus 0%, respectively, for HBV, P = 0.008; 79.7% versus 50%, respectively, for HCMV, P = 0.004). HIV-infected females were more likely to have evidence of HCMV infection (78.5% versus 61.4%, P = 0.003) than HIV-uninfected females. No significant difference was found for HBV infection in the two groups of females. The rate of HCV infection (1.6%) was too small to make comparisons between the groups. To determine whether the differences in infection rates for HBV and HCMV could be explained by factors other than HIV status, a variety of possible risk factors were examined using univariate and multivariate analyses. A significant risk factor for HBV and HCMV infections for males was a homosexual or bisexual orientation. For females, a risk factor for HBV infection was having more than 10 lifetime sexual partners; for HCMV infection, HIV infection was the only risk factor. In addition, in the HIV-infected cohort, 15% of females and 36% of males who were seropositive for HBV had evidence of active HBV infection. Conclusions: These results emphasize the need for continued development of primary and secondary prevention programs and clinical screening and treatment for HBV and HCMV in adolescents., HIV-infected teenagers are at risk of hepatitis B and cytomegalovirus infection. In men, homosexuality or bisexuality was a risk factor for both infections. In women, having more than 10 lifetime sexual partners was a risk factor for hepatitis B and HIV infection was a risk factor for cytomegalovirus infection

Context: Data suggest that in adults, human papillomavirus (HPV) infections and their sequalae, squamous intraepithelial lesions (SILs), occur more commonly among human immunodeficiency (HIV)-infected women because of the HIV-associated [CD.sup.+] T-cell immunosuppression. Since adolescents are more likely to be early in the course of HIV and HPV infections, the study of both infections in this age group may help elucidate their initial relationship. Objective: To examine the prevalence of and risks for cervical HPV infection and SILs by HIV status in a population of adolescent girls. Participants: Subjects recruited at each of the 16 different US sites participating in a national study of HIV infection in adolescents. Main Outcome Measures: Cervical HPV DNA findings using polymerase chain reaction detection techniques and Papanicolaou smear from baseline visits. Infection with HPV was categorized into low- (rarely associated with cancer) and high- (commonly associated with cancers) risk types. Results: Of 133 HIV-infected girls, 103 (77.4%) compared with 30 (54.5%) of 55 noninfected girls were positive for HPV (relative risk [RR], 1.4; 95% confidence interval ICI], 1.1-1.8). The risk was for high-risk (RR, 1.8; 95% CI, 1.2-2.7) but not low-risk (RR, 1.2; 95% CI, 0.4-3.9) HPV types. Among the girls with HPV infection, 21 (70.0%) of the non-HIV-infected girls had normal cytologic findings compared with only 29 (29.9%) of the HIV-infected girls (P [is less than] .001). Multivariate analysis showed that HIV status was a significant risk for HPV infection (odds ratio [OR], 3.3; 95% CI, 1.6-6.7) and SIL (OR, 4.7; 95% CI, 1.8-14.8), but CD4 cell count and viral load were not associated with infection or squamous intraepithelial lesions. Only 9 girls had a [CD.sup.+] T-cell count of less than 0.2 cell x [10.sup.9]/L. Conclusions: High prevalence of HPV infection in both groups underscores the risky sexual behavior in this adolescent cohort. Rates of HPV infection and SILs were higher among HIV-infected girls, despite similar sexual risk behaviors and the relatively healthy state of our HIV-infected group. Infection with HIV may enhance HPV proliferation through mechanisms other than CD4 immunosuppression, particularly early in the course of HIV infection. Arch Pediatr Adolesc Med. 2000;154:12 7-134, HIV infection in adolescent girls may enhance active human papillomavirus (HPV) proliferation and the presence of HPV-associated squamous intrepithelial lesions (SILs), even early in the course of HIV infection. HPV has been established as a necessary component in the development of squamous cell cervical cancers. Of 197 adolescent girls tested, the incidence of HPV was 56% among those who were HIV positive and 31% among those who were not infected with the HIV virus. The high prevalence of HPV-associated SILs in the HIV-infected girls suggests that the host immune response may play a significant role in the development of HPV-associated cancers.

Catherine Milneand colleagues present the findings of their review, ccna2@juno.com

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The incidence of invasive cervical cancer is decreasing in Western countries but precancerous cervical lesions are a major cause of disease in women. Low-grade cervical intraepithelial cell neoplasia (CIN, abnormal cell growth) is increasing, particularly in women aged 20 to 29 years. Adolescents have a lower CIN rate, but the rate for adolescent women is nevertheless significant. Increases in adolescent CIN may be due to an increase in sexually transmitted diseases (STDs), younger age of first sexual intercourse, or having multiple sexual partners. The rapid physiologic change in the lining of the cervix, the epithelium, during puberty is another possible risk factor for adolescent CIN. Researchers report the results of a study of risk factors for CIN in adolescent subjects who were seen in the University of California at San Francisco Colposcopy Clinic from April to September, 1986. The results of the study suggest that physiologic changes in the cervical epithelium are an important risk factor influencing the development of CIN. Other important cofactors which influence cervical vulnerability are smoking, sexual promiscuity, and the STDs Chlamydia trachomatis infection and human papilloma virus infection (HPV, venereal warts).

ABSTRACTStudies of the natural history of human papillomavirus (HPV) infection require reproducible, type-specific testing of the viral types that infect cervical tissue; Linear Array (LA) is one method that has been widely used. We sought to develop a cost-effective, high-throughput alternative using the same PGMY09/11 primer/probe system and offering sensitivity and specificity comparable to those with LA to ensure continuity in longitudinal studies. We report here on a Luminex-based approach, PGMY-LX, that offers type-specific detection of 33 oncogenic and nononcogenic types. Detection of HPV type-specific plasmid DNA was highly specific, with high signal-to-noise ratios for all types except nononcogenic type 40 and no cross-reactivity between types. Cohen's unweighted ? values for 378 clinical samples tested by both LA and PGMY-LX were =0.8 (range, 0.80 to 1.0) for 25 types, including oncogenic HPV types 16, 31, 33, 39, 45, 58, and 59 and possibly oncogenic types 53, 66, 73, and 82) and >0.7 (range, 0.74 to 0.79) for oncogenic types 18, 35, 51, and 56 and probable oncogenic type 68b, indicating substantial or better type-specific agreement between the two methods. The reproducibility by PGMY-LX of the types detected by LA varied from 94% when a single HPV type was present to 66% when multiple types were present. The interrun reproducibility for PGMY-LX varied from 98% for single-type infections to 85% for multiple-type infections. The high reproducibility of PGMY-LX and the type-specific agreement with LA allows PGMY-LX to be incorporated into longitudinal, cohort studies that have historically relied on LA.

Marine ecosystems are important drivers of the global climate system. They emit volatile species into the atmosphere, involved in complex reaction cycles that influence the lifetime of greenhouse gases. Sea spray and marine biogenic aerosols affect Earth's climate by scattering solar radiation and controlling cloud microphysical properties. Here we show larger than expected marine biogenic emissions of butenes, three orders of magnitude higher than dimethyl sulfide, produced by the coastal part of the Benguela upwelling system, one of the most productive marine ecosystems in the world. We show that these emissions may contribute to new particle formation in the atmosphere within the marine boundary layer through production of Criegee intermediates that oxidize SO2to H2SO4. Butene emissions from the marine biota may affect air quality and climate through ozone, secondary organic aerosol, and cloud condensation nuclei formation even in pristine regions of the world. Our results indicate a potentially important role of butene emissions in marine particle formation that requires investigation in other regions. Marine biogenic emissions of volatile organic compounds (VOCs) are key drivers of the Earth's climatic system, but they are not considered in climate models, except for dimethyl sulfide (DMS). We observed massive concentrations of reactive VOCs, especially butenes, in ambient air at a pristine coastal site on the west coast of the southern African continent. These strong emissions originated from the coastal part of the Benguela ecosystem and may have contributed to new particle formation in the marine boundary layer. According to our observations, butenes can be found at concentrations orders of magnitude larger than DMS in highly productive coastal environments and thus their climatic impact requires investigation. Marine biogenic emissions of reactive volatile organic compounds previously thought to be anthropogenicMassive emissions of butenes from the coastal part of the Benguela upwelling systemEmissions of butenes may contribute to new particle formation in the marine boundary layer Marine biogenic emissions of reactive volatile organic compounds previously thought to be anthropogenic Massive emissions of butenes from the coastal part of the Benguela upwelling system Emissions of butenes may contribute to new particle formation in the marine boundary layer

Die Betreuung von chronisch kranken Kindern und Jugendlichen mit multiplen Einschränkungen ist komplexer geworden und stellt Gesundheitseinrichtungen und Fachpersonen vor Herausforderungen. Neue Versorgungsmodelle wie die Implementierung von Advanced Practice Nursing sind angemessen, um auch zukünftig qualitativ hochstehende Versorgung zu gewährleisten. Im Kinderspital Zürich sichern Advanced Practice Nurses (APNs) die komplexe Betreuung der betroffenen Familien. Ziel dieser Studie ist, die Tätigkeiten der APNs Kontinenz und Wundpflege aus interdisziplinärer Sicht auf ihre Qualität und ihren Nutzen zu untersuchen. Einem Mixed Method-Ansatz folgend wurden Handlungen und Nutzen der APNs anhand von zehn qualitativen Interviews und einer parallelen Fragebogenerhebung (N = 96) evaluiert. Die Resultate zeigen die Umsetzung zentraler APN-Kompetenzen und weisen eine hohe Qualität der Tätigkeiten aus. Der Nutzen umfasst positive Auswirkungen auf die betroffenen Kinder und Familien und das interdisziplinäre Fachpersonal. Eine professionelle Wundversorgung und das Erlangen von Kontinenz wurden als Effekte identifiziert.

ABSTRACTDaptomycin (DAP) is a cyclic lipopeptide that disrupts the functional integrity of the cell membranes of Gram-positive bacteria in a Ca2+-dependent manner. Here we present genetic, genomic, and phenotypic analyses of an evolved DAP-resistant isolate, DapR1, from the model bacterium Bacillus subtilis168. DapR1 was obtained by serial passages with increasing DAP concentrations, is 30-fold more resistant than the parent strain, and displays cross-resistance to vancomycin, moenomycin, and bacitracin. DapR1 is characterized by aberrant septum placement, notably thickened peptidoglycan at the cell poles, and pleiotropic alterations at both the transcriptome and proteome levels. Genome sequencing of DapR1 revealed 44 point mutations, 31 of which change protein sequences. An intermediate isolate that was 20-fold more resistant to DAP than the wild type had only three of these point mutations: mutations affecting the cell shape modulator gene mreB, the stringent response gene relA, and the phosphatidylglycerol synthase gene pgsA. Genetic reconstruction studies indicated that the pgsA(A64V) allele is primarily responsible for DAP resistance. Allelic replacement with wild-type pgsArestored DAP sensitivity to wild-type levels. The additional point mutations in the evolved strain may contribute further to DAP resistance, serve to compensate for the deleterious effects of altered membrane composition, or represent neutral changes. These results suggest a resistance mechanism by which reduced levels of phosphatidylglycerol decrease the net negative charge of the membrane, thereby weakening interaction with the positively charged Ca2+-DAP complex.

Menopause affects women most commonly after 40 years of age. At this time there is higher risk of myocardial infarction, hypertension, high cholesterol level, diabetes, overweight, osteoporosis as well as balance disorders and vertigo.

ABSTRACTDaptomycin is the first of a new class of cyclic lipopeptide antibiotics used against multidrug-resistant, gram-positive pathogens. The proposed mechanism of action involves disruption of the functional integrity of the bacterial membrane in a Ca2+-dependent manner. We have used transcriptional profiling to demonstrate that treatment of Bacillus subtiliswith daptomycin strongly induces the liaoperon including the autoregulatory LiaRS two-component system (homologous to Staphylococcus aureusVraSR). The liaoperon protects against daptomycin, and deletion of liaH, encoding a phage-shock protein A (PspA)-like protein, leads to threefold increased susceptibility. Since daptomycin interacts with the membrane, we tested mutants with altered membrane composition for effects on susceptibility. Deletion mutations of mprF(lacking lysyl-phosphatidylglycerol) or des(lipid desaturase) increased daptomycin susceptibility, whereas overexpression of MprF decreased susceptibility. Conversely, depletion of the cell for the anionic lipid phosphatidylglycerol led to increased resistance. Fluorescently labeled daptomycin localized to the septa and in a helical pattern around the cell envelope and was delocalized upon the depletion of phosphatidylglycerol. Together, these results indicate that the daptomycin-Ca2+complex interacts preferentially with regions enriched in anionic phospholipids and leads to membrane stresses that can be ameliorated by PspA family proteins.

The kinetics of the heterogeneous reaction between gas-phase ozone and chlorophyll present at the air−salt water interface are altered in the presence of actinic radiation. Under dark conditions, a Langmuir−Hinshelwood mechanism is followed, but actinic illumination brings about a large enhancement in the rate and a change to a linear dependence on ozone concentration. This change is observed through the entire near-UV and visible spectrum but reverts to that seen in darkness with illumination >800 nm. The excitation spectrum of chlorophyll on the salt-water surface is only somewhat different than that observed with a pure-water substrate. However, the photochemical loss rate of chlorophyll in the absence of ozone is much greater on the surface of salt solutions than upon pure water. In salt solutions, a transient absorption feature assignable to Cl2−is observed following laser excitation of chlorophyll. Also, absorptions due to the chlorophyll cation or triplet state and due to solvated electrons are seen in illuminated salt- and fresh-water chlorophyll solutions. Altogether, these results suggest that Cl atoms are formed in this system via the reduction of the photoformed chlorophyll cation by chloride anions. The yield of Cl is enhanced in the presence of ozone, perhaps through the oxidation of Cl2−. The chlorine atoms thus formed are responsible for the enhanced chlorophyll loss at the surface of illuminated salt-water substrates. The formation of Cl atoms also has implications for gas-phase oxidative chemistry in the marine boundary layer.