Search

People's subjective response to any thermal environment is commonly investigated by using rating scales describing the degree of thermal sensation, comfort, and acceptability. Subsequent analyses of results collected in this way rely on the assumption that specific distances between verbal anchors placed on the scale exist and that relationships between verbal anchors from different dimensions that are assessed (e.g. thermal sensation and comfort) do not change. Another inherent assumption is that such scales are independent of the context in which they are used (climate zone, season, etc.). Despite their use worldwide, there is indication that contextual differences influence the way the scales are perceived and therefore question the reliability of the scales’ interpretation. To address this issue, a large international collaborative questionnaire study was conducted in 26 countries, using 21 different languages, which led to a dataset of 8225 questionnaires. Results, analysed by means of robust statistical techniques, revealed that only a subset of the responses are in accordance with the mentioned assumptions. Significant differences appeared between groups of participants in their perception of the scales, both in relation to distances of the anchors and relationships between scales. It was also found that respondents’ interpretations of scales changed with contextual factors, such as climate, season, and language. These findings highlight the need to carefully consider context-dependent factors in interpreting and reporting results from thermal comfort studies or post-occupancy evaluations, as well as to revisit the use of rating scales and the analysis methods used in thermal comfort studies to improve their reliability.

Approaches aimed at deconstructing PS by photocatalytic means struggle to generate high-energy species capable of cleaving the C-H and C-C bonds of PS. We show herein that 9-mesityl-10-methylacridinium perchlorate (MA) is capable of upcycling various grades of PS susbstrates into benzoic acid (BAc) up to 40%, with small proportions of acetophenone and formic acid, under visible light (456 nm) or through solar radiation. Time-resolved emission and absorption spectroscopy evidence that a reaction with oxygen is the primary photochemical step in oxygen-saturated solutions, accounting for 77% of the photons absorbed vs. 1% for the direct reaction with PS. These results suggest a mechanism in which MA-mediated photocycling of PS to BAc occurs through the abstraction of benzylic H atoms by reactive oxygen species generated by energy or electron transfer from the excited state of MA. Addition of triplet O2 to these radicals, followed by intra- or inter-molecular hydrogen atom transfer (HAT), generates C- or O-centered radicals then undergoing β-scission or hydroperoxide fragmentation. The formation of intermediate oligomers functionalized by terminal carbonyl groups is demonstrated by both infrared analysis and mass spectrometry. These oligomers undergo further photoinduced conversion in the absence of MA, as evidenced by size exclusion chromatography analysis., (© 2024 Wiley‐VCH GmbH.)

Background: Chikungunya virus (CHIKV) emerged in the Americas in 2013 and has caused approximately 2.1 million cases and >600 deaths. A retrospective investigation was undertaken to describe clinical, epidemiological, and viral genomic features associated with deaths caused by CHIKV in Ceará state, northeast Brazil., Methods: Sera, cerebrospinal fluid (CSF), and tissue samples from 100 fatal cases with suspected arbovirus infection were tested for CHIKV, dengue virus (DENV), and Zika virus (ZIKV). Clinical, epidemiological, and death reports were obtained for patients with confirmed CHIKV infection. Logistic regression analysis was undertaken to identify independent factors associated with risk of death during CHIKV infection. Phylogenetic analysis was conducted using whole genomes from a subset of cases., Results: Sixty-eight fatal cases had CHIKV infection confirmed by reverse-transcription quantitative polymerase chain reaction (52.9%), viral antigen (41.1%), and/or specific immunoglobulin M (63.2%). Co-detection of CHIKV with DENV was found in 22% of fatal cases, ZIKV in 2.9%, and DENV and ZIKV in 1.5%. A total of 39 CHIKV deaths presented with neurological signs and symptoms, and CHIKV-RNA was found in the CSF of 92.3% of these patients. Fatal outcomes were associated with irreversible multiple organ dysfunction syndrome. Patients with diabetes appear to die at a higher frequency during the subacute phase. Genetic analysis showed circulation of 2 CHIKV East-Central-South African (ECSA) lineages in Ceará and revealed no unique virus genomic mutation associated with fatal outcome., Conclusions: The investigation of the largest cross-sectional cohort of CHIKV deaths to date reveals that CHIKV-ECSA strains can cause death in individuals from both risk and nonrisk groups, including young adults., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Epidemiologic studies in diabetic patients as well as research in model organisms have indicated the potential of metformin as a drug candidate for the treatment of various types of cancer, including breast cancer. To date most of the anti-cancer properties of metformin have, in large part, been attributed either to the inhibition of mitochondrial NADH oxidase complex (Complex I in the electron transport chain) or the activation of AMP-activated kinase (AMPK). However, it is becoming increasingly clear that AMPK activation may be critical to alleviate metabolic and energetic stresses associated with tumor progression suggesting that it may, in fact, attenuate the toxicity of metformin instead of promoting it. Here, we demonstrate that AMPK opposes the detrimental effects of mitochondrial complex I inhibition by enhancing glycolysis at the expense of, and in a manner dependent on, pyruvate availability. We also found that metformin forces cells to rewire their metabolic grid in a manner that depends on AMPK, with AMPK-competent cells upregulating glycolysis and AMPK-deficient cell resorting to ketogenesis. In fact, while the killing effects of metformin were largely rescued by pyruvate in AMPKcompetent cells, AMPK-deficient cells required instead acetoacetate, a product of fatty acid catabolism indicating a switch from sugar to fatty acid metabolism as a central resource for ATP production in these cells. In summary, our results indicate that AMPK activation is not responsible for metformin anticancer activity and may instead alleviate energetic stress by activating glycolysis., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Brazil experienced a large dengue virus (DENV) epidemic in 2019, highlighting a continuous struggle with effective control and public health preparedness. Using Oxford Nanopore sequencing, we led field and classroom initiatives for the monitoring of DENV in Brazil, generating 227 novel genome sequences of DENV1-2 from 85 municipalities (2015-2019). This equated to an over 50% increase in the number of DENV genomes from Brazil available in public databases. Using both phylogenetic and epidemiological models we retrospectively reconstructed the recent transmission history of DENV1-2. Phylogenetic analysis revealed complex patterns of transmission, with both lineage co-circulation and replacement. We identified two lineages within the DENV2 BR-4 clade, for which we estimated the effective reproduction number and pattern of seasonality. Overall, the surveillance outputs and training initiative described here serve as a proof-of-concept for the utility of real-time portable sequencing for research and local capacity building in the genomic surveillance of emerging viruses.

Since introduction into Brazil in 2014, chikungunya virus (CHIKV) has presented sustained transmission, although much is unknown about its circulation in the midwestern states. Here, we analyze 24 novel partial and near complete CHIKV genomes from Cuiaba, an urban metropolis located in the Brazilian midwestern state of Mato Grosso (MT). Nanopore technology was used for sequencing CHIKV complete genomes. Phylogenetic and epidemiological approaches were used to explore the recent spatio-temporal evolution and spread of the CHIKV-ECSA genotype in Midwest Brazil as well as in the Americas. Epidemiological data revealed a reduction in the number of reported cases over 2018-2020, likely as a consequence of a gradual accumulation of herd-immunity. Phylogeographic reconstructions revealed that at least two independent introductions of the ECSA lineage occurred in MT from a dispersion event originating in the northeastern region and suggest that the midwestern Brazilian region appears to have acted as a source of virus transmission towards Paraguay, a bordering South American country. Our results show a complex dynamic of transmission between epidemic seasons and suggest a possible role of Brazil as a source for international dispersion of the CHIKV-ECSA genotype to other countries in the Americas., Competing Interests: The authors have declared that no competing interests exist.

Antimicrobial resistance (AMR) is a major public health threat of global proportions, which has the potential to lead to approximately ten million deaths per year by 2050. Pressured by this wicked problem, in 2014, the World Health Organization launched a call for member states to share AMR data through the implementation of the Global Antimicrobial Resistance Surveillance System (GLASS), to appropriately scale and monitor the general situation world-widely. In 2017, Brazil joined GLASS and, in 2018, started its own national antimicrobial surveillance program (BR-GLASS) to understand the impact of resistance in the country. We compiled data obtained from the complete routine of three hospitals' microbiology labs during the year of 2018. This pilot data sums up to 200,874 antimicrobial susceptibility test results from 11,347 isolates. It represents 119 different microorganisms recovered from 44 distinct types of clinical samples. Specimens came from patients originating from 301 Brazilian cities, with 4,950 of these isolates from presumed Healthcare-Associated Infections (HAIs) and the other 6,397 community-acquired cases. The female population offered 58% of the collected samples, while the other 42% were of male origin. The urinary tract was the most common topography (6,372/11,347 isolates), followed by blood samples (2,072/11,347). Gram-negative predominated the bacterial isolates: Escherichia coli was the most prevalent in general, representing 4,030 isolates (89.0% of these from the urinary tract). Coagulase-negative Staphylococci were the most prevalent bacteria in blood samples. Besides these two species, the ESKAPE group have consolidated their prevalence. Regarding drug susceptibility results, 141,648 (70.5%) were susceptible, 9,950 (4.9%) intermediate, and 49,276 (24.5%) resistant. Acinetobacter baumannii was the most worrisome microorganism, with 65.3% of the overall antimicrobial susceptibility tests showing resistance, followed by ESBL-producing Klebsiella pneumoniae , with a global resistance rate of 59%. Although this is a pilot project (still limited to one state), this database shows the importance of a nation-wide surveillance program,[153mm][-12mm] Q14 especially considering it already had patients coming from 301 distinct counties and 18 different states. The BR-GLASS Program is an ongoing project that intends to encompass at least 95 hospitals distributed in all five geographical regions in Brazil within the next 5 years., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pillonetto, Jordão, Andraus, Bergamo, Rocha, Onishi, Almeida, Nogueira, Dal Lin, Dias and Abreu.)

The recent emergence of a coronavirus (SARS-CoV-2), first identified in the Chinese city of Wuhan in December 2019, has had major public health and economic consequences. Although 61,888 confirmed cases were reported in Brazil by 28 April 2020, little is known about the SARS-CoV-2 epidemic in this country. To better understand the recent epidemic in the second most populous state in southeast Brazil - Minas Gerais (MG) - we sequenced 40 complete SARS-CoV-2 genomes from MG cases and examined epidemiological data from three Brazilian states. Both the genome analyses and the geographical distribution of reported cases indicate for multiple independent introductions into MG. Epidemiological estimates of the reproductive number (R) using different data sources and theoretical assumptions suggest the potential for sustained virus transmission despite a reduction in R from the first reported case to the end of April 2020. The estimated date of SARS-CoV-2 introduction into Brazil was consistent with epidemiological data from the first case of a returned traveller from Lombardy, Italy. These findings highlight the nature of the COVID-19 epidemic in MG and reinforce the need for real-time and continued genomic surveillance strategies to better understand and prepare for the epidemic spread of emerging viral pathogens..

Yellow fever virus (YFV) causes a clinical syndrome of acute hemorrhagic hepatitis. YFV transmission involves non-human primates (NHP), mosquitoes and humans. By late 2016, Brazil experienced the largest YFV outbreak of the last 100 years, with 2050 human confirmed cases, with 681 cases ending in death and 764 confirmed epizootic cases in NHP. Among affected areas, Bahia state in Northeastern was the only region with no autochthonous human cases. By using next generation sequence approach, we investigated the molecular epidemiology of YFV in NHP in Bahia and discuss what factors might have prevented human cases. We investigated 47 YFV positive tissue samples from NHP cases to generate 8 novel YFV genomes. ML phylogenetic tree reconstructions and automated subtyping tools placed the newly generated genomes within the South American genotype I (SA I). Our analysis revealed that the YFV genomes from Bahia formed two distinct well-supported phylogenetic clusters that emerged most likely of an introduction from Minas Gerais and Espírito Santo states. Vegetation coverage analysis performed shows predominantly low to medium vegetation coverage in Bahia state. Together, our findings support the hypothesis of two independent YFV SA-I introductions. We also highlighted the effectiveness of the actions taken by epidemiological surveillance team of the state to prevented human cases., Competing Interests: The authors have declared that no competing interests exist.

São Paulo, a densely inhabited state in southeast Brazil that contains the fourth most populated city in the world, recently experienced its largest yellow fever virus (YFV) outbreak in decades. YFV does not normally circulate extensively in São Paulo, so most people were unvaccinated when the outbreak began. Surveillance in non-human primates (NHPs) is important for determining the magnitude and geographic extent of an epizootic, thereby helping to evaluate the risk of YFV spillover to humans. Data from infected NHPs can give more accurate insights into YFV spread than when using data from human cases alone. To contextualise human cases, identify epizootic foci and uncover the rate and direction of YFV spread in São Paulo, we generated and analysed virus genomic data and epizootic case data from NHPs in São Paulo. We report the occurrence of three spatiotemporally distinct phases of the outbreak in São Paulo prior to February 2018. We generated 51 new virus genomes from YFV positive cases identified in 23 different municipalities in São Paulo, mostly sampled from NHPs between October 2016 and January 2018. Although we observe substantial heterogeneity in lineage dispersal velocities between phylogenetic branches, continuous phylogeographic analyses of generated YFV genomes suggest that YFV lineages spread in São Paulo at a mean rate of approximately 1km per day during all phases of the outbreak. Viral lineages from the first epizootic phase in northern São Paulo subsequently dispersed towards the south of the state to cause the second and third epizootic phases there. This alters our understanding of how YFV was introduced into the densely populated south of São Paulo state. Our results shed light on the sylvatic transmission of YFV in highly fragmented forested regions in São Paulo state and highlight the importance of continued surveillance of zoonotic pathogens in sentinel species., Competing Interests: The authors have declared that no competing interests exist.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

BACKGROUND Despite efforts to mitigate the impact of dengue virus (DENV) epidemics, the virus remains a public health problem in tropical and subtropical regions around the world. Most DENV cases in the Americas between January and July 2019 were reported in Brazil. São Paulo State in the southeast of Brazil has reported nearly half of all DENV infections in the country. OBJECTIVES To understand the origin and dynamics of the 2019 DENV outbreak. METHODS Here using portable nanopore sequencing we generated20 new DENV genome sequences from viremic patients with suspected dengue infection residing in two of the most-affected municipalities of São Paulo State, Araraquara and São José do Rio Preto. We conducted a comprehensive phylogenetic analysis with 1,630 global DENV strains to better understand the evolutionary history of the DENV lineages that currently circulate in the region. FINDINGS The new outbreak strains were classified as DENV2 genotype III (American/Asian genotype). Our analysis shows that the 2019 outbreak is the result of a novel DENV lineage that was recently introduced to Brazil from the Caribbean region. Dating phylogeographic analysis suggests that DENV2-III BR-4 was introduced to Brazil in or around early 2014, possibly from the Caribbean region. MAIN CONCLUSIONS Our study describes the early detection of a newly introduced and rapidly-expanding DENV2 virus lineage in Brazil.

The recent reemergence of yellow fever virus (YFV) in Brazil has raised serious concerns due to the rapid dissemination of the virus in the southeastern region. To better understand YFV genetic diversity and dynamics during the recent outbreak in southeastern Brazil, we generated 18 complete and nearly complete genomes from the peak of the epidemic curve from nonhuman primates (NHPs) and human infected cases across the Espírito Santo and Rio de Janeiro states. Genomic sequencing of 18 YFV genomes revealed the estimated timing, source, and likely routes of yellow fever virus transmission and dispersion during one of the largest outbreaks ever registered in Brazil. We showed that during the recent epidemic, YFV was reintroduced from Minas Gerais to the Espírito Santo and Rio de Janeiro states multiple times between 2016 and 2019. The analysis of data from portable sequencing could identify the corridor of spread of YFV. These findings reinforce the idea that continued genomic surveillance strategies can provide information on virus genetic diversity and transmission dynamics that might assist in understanding arbovirus epidemics. IMPORTANCE Arbovirus infections in Brazil, including yellow fever, dengue, zika, and chikungunya, result in considerable morbidity and mortality and are pressing public health concerns. However, our understanding of these outbreaks is hampered by the limited availability of genomic data. In this study, we investigated the genetic diversity and spatial distribution of YFV during the current outbreak by analyzing genomic data from areas in southeastern Brazil not covered by other previous studies. To gain insights into the routes of YFV introduction and dispersion, we tracked the virus by sequencing YFV genomes sampled from nonhuman primates and infected patients from the southeastern region. Our study provides an understanding of how YFV initiates transmission in new Brazilian regions and illustrates that genomics in the field can augment traditional approaches to infectious disease surveillance and control., (Copyright © 2019 American Society for Microbiology.)

Thermal discomfort is one of the main triggers for occupants' interactions with components of the built environment such as adjustments of thermostats and/or opening windows and strongly related to the energy use in buildings. Understanding causes for thermal (dis-)comfort is crucial for design and operation of any type of building. The assessment of human thermal perception through rating scales, for example in post-occupancy studies, has been applied for several decades; however, long-existing assumptions related to these rating scales had been questioned by several researchers. The aim of this study was to gain deeper knowledge on contextual influences on the interpretation of thermal perception scales and their verbal anchors by survey participants. A questionnaire was designed and consequently applied in 21 language versions. These surveys were conducted in 57 cities in 30 countries resulting in a dataset containing responses from 8225 participants. The database offers potential for further analysis in the areas of building design and operation, psycho-physical relationships between human perception and the built environment, and linguistic analyses.

Mitochondrial superoxide dismutase (SOD2) suppresses tumor initiation but promotes invasion and dissemination of tumor cells at later stages of the disease. The mechanism of this functional switch remains poorly defined. Our results indicate that as SOD2 expression increases acetylation of lysine 68 ensues. Acetylated SOD2 promotes hypoxic signaling via increased mitochondrial reactive oxygen species (mtROS). mtROS, in turn, stabilize hypoxia-induced factor 2α (HIF2α), a transcription factor upstream of "stemness" genes such as Oct4, Sox2, and Nanog. In this sense, our findings indicate that SOD2 K68Ac and mtROS are linked to stemness reprogramming in breast cancer cells via HIF2α signaling. Based on these findings we propose that, as tumors evolve, the accumulation of SOD2 K68Ac turns on a mitochondrial pathway to stemness that depends on HIF2α and may be relevant for the progression of breast cancer toward poor outcomes., Competing Interests: The authors declare no competing interest.

The link between high-risk human Papillomavirus (HR-HPV) and other sexually transmitted diseases (STDs) in the risk of developing cervical cancer still unclear. Thus, in this report we investigated the rates of co-infections between HPV and other important non-HPV STDs in different cervical findings using a multiplex polymerase chain reaction (M-PCR) to simultaneously detect Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, Trichomonas vaginalis, HSV-1 and -2, and Treponema pallidum. A total of 838 women aged 18 to 68 years were screened using Papanicolaou smears for cervical abnormalities, HPV and non-HPV STDs using PCR and M-PCR methods. A total of 614 (73.3%) of the women had normal cytology (NILM) and 224 (26.7%) women exhibited abnormal cytology (≥ ASC-US). HPV-DNA prevalence was 33.9%, and HPV-16 was the most prevalent genotype in women with NILM and ≥ ASC-US cytology. Non-HPV STDs were detected in 30.4% women and T. vaginalis was the most prevalent one (11.6%). A higher increased risk of ≥ ASC-US and HSIL occurred in co-infections of HR-HPV with C. trachomatis and N. gonorrhoeae. Co-infections of HPV-DNA and HR-HPV with HSV-2 exhibited a similar increased risk but only with ≥ ASC-US. Co-infections of HPV-DNA and HR-HPV with T. vaginalis demonstrated a similar increased risk of ≥ ASC-US and HSIL. We found that C. trachomatis and N. gonorrhoeae were the primary pathogens associated with HR-HPV for the increased risk for all grades of cervical abnormalities but mainly for HSIL, suggesting a possible synergistic action in cervical lesions progression. Our results reinforce the hypothesis that some non-HPV STDs might play a role as co-factors in HPV-mediated cervical carcinogenesis. These data improve our understanding of the etiology of SCC and may also be useful for disease prevention.

Background: Ligation of the mesovarium in female dogs may be cumbersome with risk of complications and is associated with intense noxious stimuli. A resorbable implant, a self-locking loop designed for surgery, was developed as an alternative to traditional ligation. The study aimed to test the feasibility of ligating the canine ovarian pedicle with the implant and to compare its performance to traditional suture ligation., Results: In total 45 intact female dogs destined for elective ovariohysterectomy and adoption were included. In 21 dogs the new resorbable implant was used to ligate the mesovarium, and in 24 control dogs traditional suture was used with one encircling ligature. Mean weight of implant dogs was 10.7 ± 5.6 kg (range 3.5-22.0), and mean weight of control dogs was 12.8 ± 6.4 kg, (range 4.1-27.0). The body weight of dogs did not differ between groups (P = 0.25). In total, 42 ovarian pedicles were successfully ligated with the implant. In one control dog, intraoperative haemorrhage from the left ovarian pedicle was diagnosed. The mesovarium was re-ligated and haemostasis was confirmed. All dogs recovered uneventfully. The ligation time of the mesovarium was significantly shortened (P = 0.02) by using the self-locking implant versus a single ligature (3'28'' ± 1'05'' and 5'29'' ± 3'54'', respectively). Total duration of surgery differed between the groups (P = 0.02) with a shortened duration of surgery when using the self-locking implant (15'56'' ± 2'47'' and 20'39'' ± 8'58'', study group versus control group, respectively). In both groups, duration of surgery and time required to ligate the ovarian pedicle were longer in larger dogs than smaller dogs., Conclusion: The results of this feasibility study suggested the implant can be used to ligate the canine mesovarium. Compared with traditional suture ligation, the results suggested that time to ligate the ovarian pedicle and duration of surgery were significantly reduced with the implant. More time was required to perform surgeries in larger dogs.

Purpose: The persistence of high-risk oncogenic human papillomavirus (HR-HPV) infection and its integration into the host genome are key steps in the induction of malignant alterations. c-MYC chromosome region is a frequent localization for HPV insertion that has been observed in chromosome band 8q24 by fluorescence in situ hybridization (FISH). We report the HPV viral integration and amplification patterns of the c-MYC gene in cytological smears with FISH as a potential biomarker for the progression of squamous intraepithelial lesions (SIL)., Methods: HPV detection and genotyping by polymerase chain reaction (PCR) and FISH analysis by "Vysis Cervical FISH Probe" kit (ABBOTT Molecular Inc.) were performed in 37 cervical samples including 8 NILM, 7 ASC-US, 7 LSIL, 3 ASC-H, 7 HSIL and 5 SCC., Results: The results show concordance between FISH and PCR techniques for HPV detection. The majority of the samples contained HR-HPV, the majority being -16 and -18 genotypes. HPV integration as determined by FISH was most frequent in high-risk lesions. The c-MYC gene amplification was found only in HPV-positive samples and was detected primarily in high-risk lesions and in cells with an integrated form of HPV., Conclusions: HPV integration and c-MYC gene amplification detected by FISH could be an important biomarker for use in clinical practice to determine SIL with a risk of progression.

To determine the prevalence of human papillomavirus (HPV) among women with atypical squamous cells of undetermined significance (ASC-US) referred to colposcopy and the implications for clinical management in low- and middle-income countries (LMIC), the present study was conducted. We included 200 women living in Maringa÷Brazil referred to colposcopy service between August 2012 and March 2013 due to an abnormal cytology from ASC-US until high-grade intraepithelial lesion (HSIL). HPV was detected and genotyped by polymerase chain reaction (PCR). The mean age was 36.8±10.5 years, and women with and without ASC-US had similar mean ages (37.4±11.5 and 36.4±9.96 years, respectively). The highest prevalence of ASC-US occurred at 20-24 years (40%). HPV-DNA was positive in 164 (82.0%) women.Of the 57 women with ASC-US, 30 (52.6%) were HPV-DNA-positive and 21 (70%) were high-risk HPV-positive (HR-HPV); the latter was similar to women without ASC-US (76.9%) but with other abnormal cytological findings present. Our data demonstrated that performing tests for HR-HPV can be used for management of women with ASC-US to support the decision of which women should be referred for an immediate or later colposcopy. The same conclusions can be applied to other LMICs for which HPV testing for primary screening has not been adopted.

The NF-κB pathway is central to the regulation of inflammation. Here, we demonstrate that the low-output nitric oxide (NO) synthase 1 (NOS1 or nNOS) plays a critical role in the inflammatory response by promoting the activity of NF-κB. Specifically, NOS1-derived NO production in macrophages leads to proteolysis of suppressor of cytokine signaling 1 (SOCS1), alleviating its repression of NF-κB transcriptional activity. As a result, NOS1(-/-) mice demonstrate reduced cytokine production, lung injury, and mortality when subjected to two different models of sepsis. Isolated NOS1(-/-) macrophages demonstrate similar defects in proinflammatory transcription on challenge with Gram-negative bacterial LPS. Consistently, we found that activated NOS1(-/-) macrophages contain increased SOCS1 protein and decreased levels of p65 protein compared with wild-type cells. NOS1-dependent S-nitrosation of SOCS1 impairs its binding to p65 and targets SOCS1 for proteolysis. Treatment of NOS1(-/-) cells with exogenous NO rescues both SOCS1 degradation and stabilization of p65 protein. Point mutation analysis demonstrated that both Cys147 and Cys179 on SOCS1 are required for its NO-dependent degradation. These findings demonstrate a fundamental role for NOS1-derived NO in regulating TLR4-mediated inflammatory gene transcription, as well as the intensity and duration of the resulting host immune response., (© 2015 Baig et al.)

Manganese superoxide dismutase (MnSOD/SOD2) is a mitochondria-resident enzyme that governs the types of reactive oxygen species egressing from the organelle to affect cellular signalling. Here we demonstrate that MnSOD upregulation in cancer cells establishes a steady flow of H2O2 originating from mitochondria that sustains AMP-activated kinase (AMPK) activation and the metabolic shift to glycolysis. Restricting MnSOD expression or inhibiting AMPK suppresses the metabolic switch and dampens the viability of transformed cells indicating that the MnSOD/AMPK axis is critical to support cancer cell bioenergetics. Recapitulating in vitro findings, clinical and epidemiologic analyses of MnSOD expression and AMPK activation indicated that the MnSOD/AMPK pathway is most active in advanced stage and aggressive breast cancer subtypes. Taken together, our results indicate that MnSOD serves as a biomarker of cancer progression and acts as critical regulator of tumour cell metabolism.

Purpose: To evaluate the safety and efficacy of a novel robotic tissue ablation system (PROCEPT Aquablation(™) System), in performing prostate ablation in a survival canine model., Materials and Methods: This novel technology uses a high-velocity saline stream that aims to selectively ablate prostatic glandular tissue while sparing collagenous structures such as blood vessels and capsule. Once the ablation is complete, a laser beam is captured by a low-pressure water jet to produce surface hemostasis. The extent and depth of ablation is predetermined by endoscopic and transrectal ultrasonography guidance. The procedure was performed in eight noncastrated male beagles aged 6 years or older (Acute 2, Chronic 6) through a previously created perineal urethrostomy., Results: Aquablation time ranged from 40 to 84 seconds (mean 60.5 sec). There was no active bleeding in any of the dogs during or after Aquablation. Water jet-guided laser coagulation was used for purposes of monitoring its safety and efficacy. Five of the six dogs reached the predetermined 6-week mark. Complications included two dogs with infection successfully treated with antibiotics, a false passage created during catheter placement, and two bladder neck perforations (from mechanical insertion), one leading to euthanasia. Histologic evaluation at 6 weeks revealed a normal cellular architecture and full reepithelialization of the treatment cavity., Conclusions: We report the initial survival data in the animal model of a novel robotic device developed for managing symptomatic benign prostatic hyperplasia (BPH). Aquablation produces ablation of adenomatous elements while preserving collagenous structures and is a promising technology for surgical management of symptomatic BPH.

While persistent infection with oncogenic types of human Papillomavirus (HPV) is required for cervical epithelial cell transformation and cervical carcinogenesis, HPV infection alone is not sufficient to induce tumorigenesis. Only a minor fraction of HPV infections produce high-grade lesions and cervical cancer, suggesting complex host-virus interactions. Based on its pronounced immunoinhibitory properties, human leukocyte antigen (HLA)-G has been proposed as a possible prognostic biomarker and therapeutic target relevant in a wide variety of cancers and viral infections, but to date remains underexplored in cervical cancer. Given the possible influence of HLA-G on the clinical course of HPV infection, cervical lesions and cancer progression, a better understanding of HLA-G involvement in cervical carcinogenesis might contribute to two aspects of fundamental importance: 1. Characterization of a novel diagnostic/prognostic biomarker to identify cervical cancer and to monitor disease stage, critical for patient screening; 2. Identification of HLA-G-driven immune mechanisms involved in lesion development and cancer progression, leading to the development of strategies for modulating HLA-G expression for treatment purposes. Thus, this systematic review explores the potential involvement of HLA-G protein expression and polymorphisms in cervical carcinogenesis., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objectives: To present time-efficiency data during our initial experience with intracorporeal urinary diversion and technical tips that may shorten operative time early in the learning curve., Patients and Methods: Data were analyzed in the initial 37 consecutive patients undergoing robotic radical cystectomy and intracorporeal urinary diversion in whom detailed stepwise operative time data were available. Median age was 65 years and median body mass index was 27. Neoadjuvant chemotherapy was administered in 6 patients and 11 patients had clinical evidence of T3 or lymph node-positive disease. Each component of the operation was subdivided into specific steps and operative time for each step was prospectively recorded. Peri-operative and follow-up data up to 90 days and final pathological data were recorded., Results: All procedures were completed intracorporeally and robotically without need for conversion to open surgery or extracorporeal diversion. Median total operative time was 387 vs 386 minutes (p=0.2) and median total console time was 361 vs 295 minutes (p<0.007) for orthotopic neobladder and ileal conduit, respectively. Median time for radical cystectomy was 77 minutes, extended pelvic lymph node dissection was 63 minutes, and diversion was 111 minutes (ileal conduit 92 minutes and orthotopic neobladder 124 minutes). Median estimated blood loss was 250 mL, and median hospital stay was 9 days. High grade (Clavien grade 3-5) complications at 30 and 90 days follow-up were recorded in 6 (16%) and 9 (24%) patients, respectively. Over a median follow-up of 16 months, 12 (32%) patients experienced disease recurrence and 9 (24%) died from bladder cancer. These correspond to 1-year recurrence-free and overall survival of 64% and 70%, respectively., Conclusions: Intracorporeal urinary diversion following robotic radical cystectomy can be safely performed and reproducible in a time-efficient manner even during the early learning curve.

Background: Human Papillomavirus (HPV) infection is particularly burdensome for women infected with human immunodeficiency virus (HIV), which increases their risk of developing cervical lesions and cancer (CC). We conducted a molecular study of the distribution of cervical HPV genotypes and the risk factors for this infection in HIV-infected Brazilian women., Findings: Cervical and endocervical samples for Papanicolaou screening and HPV detection were collected from 178 HIV-infected women using highly active antiretroviral therapy (HAART) of Maringá city/Brazil. Risk factors were assessed using a standardized questionnaire, and the data regarding to HIV infection from medical records. HPV was detected by polymerase chain reaction (PCR), and genotyping using PCR-restriction fragment length polymorphism analysis. HIV infection was well controlled, but women with a current CD4+ T lymphocyte count between 200-350 cells/mm3 (37.6%) had a two-fold greater risk of HPV infection than those with > 350 cells/mm3 (26.4%). HPV was associated with parity ≥3, hormonal contraceptive use and current smoker. HPV infection occurred with high frequency (46.6%) but a low frequency of cervical abnormalities was detected (7.30%), mainly low-grade squamous intraephitelial cervical lesions (LSIL) (84.6%). A high frequency of multiple HPV infections was detected (23.0%), and the most frequent HPV genotype was HPV-72 (6.7%), followed by -16, -31 and -51 (6.14% each)., Conclusions: We showed that HAART use does not protect HIV-infected women from HPV, but appear to exert some protection against cervical lesions development. This study provides other important information about risk factors and cervical HPV in HIV-infected women, which can contribute to planning protocols.

We determined the prevalence of seven clinically important pathogens that cause sexually transmitted infections (STIs) (Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, Trichomonas vaginalis, herpes simplex virus 1 [HSV-1], HSV-2, and Treponema pallidum), by using a multiplex polymerase chain reaction (M-PCR) in samples from Brazilian woman infected with human immunodeficiency virus 1 (HIV-1) and uninfected Brazilian women (controls). The M-PCR assay identified all STIs tested for and surprisingly, occurred association between the control and STIs. This association was probably caused by excellent HIV infection control and regular monitoring in these women established by public health strategies in Brazil to combat HIV/acquired immunodeficiency syndrome. Studies using this M-PCR in different populations may help to better elucidate the roles of STIs in several conditions.

Background: Human Papillomavirus (HPV) infection is a serious problem for human immunodeficiency virus (HIV)-infected women, increases their risk of cervical lesions and cancer. In cervical carcinogenesis, mutations in the p53 gene occur most frequently within exons 5-8. To our knowledge, no previous studies have analyzed mutations in exons 5-8 of the p53 gene in HIV- and HPV-infected women. In our study, we verified these mutations in women with and without cervical abnormalities., Findings: The study included 160 women, divided into three groups: (1) 83 HPV- and HIV-infected women (HIV group); (2) 37 HPV-infected/HIV-uninfected (control group); and (3) 40 normal cytology/DNA-HPV negative/HIV-uninfected women (negative control p53 reactions). HPV-DNA was detected using polymerase chain reaction (PCR) and genotyping by PCR-restriction fragment length polymorphism analysis. Using primers for exons 5-8, the mutation of the p53 gene was verified by PCR-single strand conformational polymorphism. The total mutation of the p53 gene in exons 5-8 was not significantly associated with the HIV and control groups. The mutations in exon 7 were the highest in the HIV group (43.8%) and in exon 6 in the control group (57.2%) (p = 0.0793) suggesting a tendency toward differential mutation in exon 7 in the HIV group., Conclusions: Our study provides preliminary evidence that the mutation in exon 7 might be an important differentiating factor for cervical carcinogenesis in HIV-infected women. This aspect deserves an additional cross-sectional and longitudinal study using a larger sample size with a higher number of High-grade squamous intraephitelial lesion (HSIL) to observe the evolution of cervical lesions.

The question of whether Chlamydia trachomatis (Ct) is a cofactor for human Papillomavirus (HPV) in cervical carcinogenesis is still controversial. We conducted a molecular detection study of both infections in 622 Brazilian women, including 252 women with different grades of abnormal cervical cytology and cervical cancer (CC; cases) and 370 women with normal cytology (controls). Although Ct infection did not seem related to CC carcinogenicity, women with abnormal cytology had a significant high rate of Ct infection. Therefore, it is important to adopt protocols for diagnosis and treatment of this bacterium in conjunction with screening for CC in this population.

Purpose: To test the use of intraluminal protection in colonic anastomosis without intestinal cleansing. The intraluminal liner was fashioned from porcine submucosa preserved in glycerin and then fixed 10 cm anteriorly to the anastomotic site. This technique was compared with the one used in termino-terminal colonic anastomosis without intraluminal protection., Methods: Twenty-eight dogs were divided into two groups of fourteen animals each. Clinical and histopathological tests were performed on the fourth and twenty-first postoperative days., Results: The morbidity and mortality rates were higher in animals that did not receive the intraluminal liner. Histopathological examinations in animals in which the intraluminal liner was used showed better healing, characterized by milder inflammation and increased amount of collagen., Conclusion: It can be concluded that the use of intraluminal protection decreases complication rates in colonic anastomosis and promotes better healing.