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Study objective: Widespread chest CT use in trauma evaluation may increase the diagnosis of minor sternal fracture (SF), making former teaching about SF obsolete. We sought to determine: (1) the frequency with which SF patients are diagnosed by CXR versus chest CT under current imaging protocols, (2) the frequency of surgical procedures related to SF diagnosis, (3) SF patient mortality and hospital length of stay comparing patients with isolated sternal fracture (ISF) and sternal fracture with other thoracic injury (SFOTI), and (4) the frequency and yield of cardiac contusion (CC) workups in SF patients. Methods: We analyzed charts and data of all SF patients enrolled from January 2009 to May 2013 in the NEXUS Chest and NEXUS Chest CT studies, two multi-centre observational cohorts of blunt trauma patients who received chest imaging for trauma evaluation. Results: Of the 14,553 patients in the NEXUS Chest and Chest CT cohorts, 292 (2.0%) were diagnosed with SF, and 94% of SF were visible on chest CT only. Only one patient (0.4%) had a surgical procedure related to SF diagnosis. Cardiac contusion was diagnosed in 7 (2.4%) of SF patients. SF patient mortality was low (3.8%) and not significantly different than the mortality of patients without SF (3.1%) [mean difference 0.7%; 95% confidence interval (CI) -1.0 to 3.5%]. Only 2 SF patient deaths (0.7%) were attributed to a cardiac cause. SFOTI patients had longer hospital stays but similar mortality to patients with ISF (mean difference 0.8%; 95% CI -4.7% to 12.0). Conclusions: Most SF are seen on CT only and the vast majority are clinically insignificant with no change in treatment and low associated mortality. Workup for CC in SF patients is a low-yield practice. SF diagnostic and management guidelines should be updated to reflect modern CT-driven trauma evaluation protocols.

Cancer treatment has transformed in recent years, with the introduction of immunotherapy providing substantial improvements in prognoses for certain cancers. However, traditional small molecule chemotherapeutics remain the major frontline of defence, and improving their delivery to solid tumors is of utmost importance for improving potency and reducing side effects. Here, length-controlled one-dimensional seed nanofibers ( ca. 25 nm, Đ L = 1.05) were generated from poly(fluorenetrimethylenecarbonate)- block -poly(dimethylaminoethylmethacrylate) via living crystallization-driven self-assembly. Paclitaxel, with an encapsulation content ranging from 1 to 100 wt%, was loaded onto the preformed nanoparticles by solvent addition and evaporation. Drug loading was quantified by dynamic light scattering and transmission electron microscopy. Drug-loaded vectors were then incubated with U87 MG glioblastoma cells in a 2D cell assay for up to 72 h, and their anticancer properties were determined. It was observed that seed nanofibers loaded with 20 wt% paclitaxel were the most advantageous combination (IC 50 = 0.48 μg mL -1 ), while pure seed nanofibers with no loaded drug displayed much lower cytotoxicity (IC 50 = 11.52 μg mL -1 ). The IC 50 of the loaded seed nanofibers rivaled that of the commercially approved Abraxane® (IC 50 = 0.46 μg mL -1 ). 3D tumor spheroids were then cultured and subjected to the same stresses. Live/dead cell staining revealed that once more, seed nanofibers with 20 wt% paclitaxel, Abraxane®, and paclitaxel all exhibited similar levels of potency (55% viability), whereas control samples exhibited much higher cell viability (70%) after 3 days. These results demonstrate that nanofibers contain great potential as biocompatible drug delivery vehicles for cancer treatment as they exert a similar anticancer effect to the commercially available Abraxane®.

Competing Interests: Competing interests: None declared.

Suspended hydrogel printing is a growing method for fabricating bioprinted hydrogel constructs, largely due to how it enables nonviscous hydrogel inks to be used in extrusion printing. In this work, a previously developed poly( N -isopropylacrylamide)-based thermogelling suspended bioprinting system was examined in the context of chondrocyte-laden printing. Material factors such as ink concentration and cell concentration were found to have a significant effect on printed chondrocyte viability. In addition, the heated poloxamer support bath was able to maintain chondrocyte viability for up to 6 h of residence within the bath. The relationship between the ink and support bath was also assessed by measuring the rheological properties of the bath before and after printing. Bath storage modulus and yield stress decreased during printing as nozzle size was reduced, indicating the likelihood that dilution occurs over time through osmotic exchange with the ink. Altogether this work demonstrates the promise for printing high-resolution cell-encapsulating tissue engineering constructs, while also elucidating complex relationships between the ink and bath, which must be taken into consideration when designing suspended printing systems.

Transition from traditional high-fiber to Western diets in urbanizing communities of Sub-Saharan Africa is associated with increased risk of non-communicable diseases (NCD), exemplified by colorectal cancer (CRC) risk. To investigate how urbanization gives rise to microbial patterns that may be amenable by dietary intervention, we analyzed diet intake, fecal 16 S bacteriome, virome, and metabolome in a cross-sectional study in healthy rural and urban Xhosa people (South Africa). Urban Xhosa individuals had higher intakes of energy (urban: 3,578 ± 455; rural: 2,185 ± 179 kcal/d), fat and animal protein. This was associated with lower fecal bacteriome diversity and a shift from genera favoring degradation of complex carbohydrates (e.g., Prevotella) to taxa previously shown to be associated with bile acid metabolism and CRC. Urban Xhosa individuals had higher fecal levels of deoxycholic acid, shown to be associated with higher CRC risk, but similar short-chain fatty acid concentrations compared with rural individuals. Fecal virome composition was associated with distinct gut bacterial communities across urbanization, characterized by different dominant host bacteria (urban: Bacteriodota; rural: unassigned taxa) and variable correlation with fecal metabolites and dietary nutrients. Food and skin microbiota samples showed compositional differences along the urbanization gradient. Rural-urban dietary transition in South Africa is linked to major changes in the gut microbiome and metabolome. Further studies are needed to prove cause and identify whether restoration of specific components of the traditional diet will arrest the accelerating rise in NCDs in Sub-Saharan Africa., (© 2024. The Author(s).)

Introduction: Recently published studies support the beneficial effects of consuming fibre-rich legumes, such as cooked dry beans, to improve metabolic health and reduce cancer risk. In participants with overweight/obesity and a history of colorectal polyps, the Fibre-rich Foods to Treat Obesity and Prevent Colon Cancer randomised clinical trial will test whether a high-fibre diet featuring legumes will simultaneously facilitate weight reduction and suppress colonic mucosal biomarkers of colorectal cancer (CRC)., Methods/design: This study is designed to characterise changes in (1) body weight; (2) biomarkers of insulin resistance and systemic inflammation; (3) compositional and functional profiles of the faecal microbiome and metabolome; (4) mucosal biomarkers of CRC risk and (5) gut transit. Approximately 60 overweight or obese adults with a history of noncancerous adenomatous polyps within the previous 3 years will be recruited and randomised to one of two weight-loss diets. Following a 1-week run-in, participants in the intervention arm will receive preportioned high-fibre legume-rich entrées for two meals/day in months 1-3 and one meal/day in months 4-6. In the control arm, entrées will replace legumes with lean protein sources (eg, chicken). Both groups will receive in-person and written guidance to include nutritionally balanced sides with energy intake to lose 1-2 pounds per week., Ethics and Dissemination: The National Institutes of Health fund this ongoing 5-year study through a National Cancer Institute grant (5R01CA245063) awarded to Emory University with a subaward to the University of Pittsburgh. The study protocol was approved by the Emory Institutional Review Board (IRB approval number: 00000563)., Trial Registration Number: NCT04780477., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

North Carolina Medicaid's Healthy Opportunities Pilots program is the country's first comprehensive program to evaluate the impact of paying community-based organizations to provide eligible Medicaid enrollees with an array of evidence-based services to address four domains of health-related social needs, one of which is housing. Using a mixed-methods approach, we mapped the distribution of severe housing problems and then examined the design and implementation of Healthy Opportunities Pilots housing services in the three program regions. Four cross-cutting implementation and policy themes emerged: accounting for variation in housing resources and needs to address housing insecurity, defining and pricing housing services in Medicaid, engaging diverse stakeholders across sectors to facilitate successful implementation, and developing sustainable financial models for delivery. The lessons learned and actionable insights can help inform the efforts of stakeholders elsewhere, particularly other state Medicaid programs, to design and implement cross-sectoral programs that address housing-related social needs by leveraging multiple policy-based resources. These lessons can also be useful for federal policy makers developing guidance on addressing housing-related needs in Medicaid.

Demineralized bone matrix (DBM) has been widely used clinically for dental, craniofacial and skeletal bone repair, as an osteoinductive and osteoconductive material. 3D printing (3DP) enables the creation of bone tissue engineering scaffolds with complex geometries and porosity. Photoreactive methacryloylated gelatin nanoparticles (GNP-MAs) 3DP inks have been developed, which display gel-like behavior for high print fidelity and are capable of post-printing photocrosslinking for control of scaffold swelling and degradation. Here, novel DBM nanoparticles (DBM-NPs, ∼400 nm) were fabricated and characterized prior to incorporation in 3DP inks. The objectives of this study were to determine how these DBM-NPs would influence the printability of composite colloidal 3DP inks, assess the impact of ultraviolet (UV) crosslinking on 3DP scaffold swelling and degradation and evaluate the osteogenic potential of DBM-NP-containing composite colloidal scaffolds. The addition of methacryloylated DBM-NPs (DBM-NP-MAs) to composite colloidal inks (100:0, 95:5 and 75:25 GNP-MA:DBM-NP-MA) did not significantly impact the rheological properties associated with printability, such as viscosity and shear recovery or photocrosslinking. UV crosslinking with a UV dosage of 3 J/cm 2 directly impacted the rate of 3DP scaffold swelling for all GNP-MA:DBM-NP-MA ratios with an ∼40% greater increase in scaffold area and pore area in uncrosslinked versus photocrosslinked scaffolds over 21 days in phosphate-buffered saline (PBS). Likewise, degradation (hydrolytic and enzymatic) over 21 days for all DBM-NP-MA content groups was significantly decreased, ∼45% less in PBS and collagenase-containing PBS, in UV-crosslinked versus uncrosslinked groups. The incorporation of DBM-NP-MAs into scaffolds decreased mass loss compared to GNP-MA-only scaffolds during collagenase degradation. An in vitro osteogenic study with bone marrow-derived mesenchymal stem cells demonstrated osteoconductive properties of 3DP scaffolds for the DBM-NP-MA contents examined. The creation of photoreactive DBM-NP-MAs and their application in 3DP provide a platform for the development of ECM-derived colloidal materials and tailored control of biochemical cue presentation with broad tissue engineering applications., (© The Author(s) 2023. Published by Oxford University Press.)

The extracellular matrix (ECM) consists of a complex combination of proteins, proteoglycans, and other biomolecules. ECM-based materials have been demonstrated to have high biocompatibility and bioactivity, which may be harnessed for drug delivery and tissue engineering applications. Herein, nanoparticles incorporating ECM-based materials and their applications in drug delivery and tissue engineering are reviewed. Proteins such as gelatin, collagen, and fibrin as well as glycosaminoglycans including hyaluronic acid, chondroitin sulfate, and heparin have been employed for cancer therapeutic delivery, gene delivery, and wound healing and regenerative medicine. Strategies for modifying and functionalizing these materials with synthetic and natural polymers or to enable stimuli-responsive degradation and drug release have increased the efficacy of these materials and nano-systems. The incorporation and modification of ECM-based materials may be used to drive drug targeting and increase tissue-specific cell differentiation more effectively., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Three-dimensional bioprinting utilizes additive manufacturing processes that combine cells and a bioink to create living tissue models that mimic tissues found in vivo. Stem cells can regenerate and differentiate into specialized cell types, making them valuable for research concerning degenerative diseases and their potential treatments. 3D bioprinting stem cell-derived tissues have an advantage over other cell types because they can be expanded in large quantities and then differentiated to multiple cell types. Using patient-derived stem cells also enables a personalized medicine approach to the study of disease progression. In particular, mesenchymal stem cells (MSC) are an attractive cell type for bioprinting because they are easier to obtain from patients in comparison to pluripotent stem cells, and their robust characteristics make them desirable for bioprinting. Currently, both MSC bioprinting protocols and cell culturing protocols exist separately, but there is a lack of literature that combines the culturing of the cells with the bioprinting process. This protocol aims to bridge that gap by describing the bioprinting process in detail, starting with how to culture cells pre-printing, to 3D bioprinting the cells, and finally to the culturing process post-printing. Here, we outline the process of culturing MSCs to produce cells for 3D bioprinting. We also describe the process of preparing Axolotl Biosciences TissuePrint - High Viscosity (HV) and Low Viscosity (LV) bioink, the incorporation of MSCs to the bioink, setting up the BIO X and the Aspect RX1 bioprinters, and necessary computer-aided design (CAD) files. We also detail the differentiation of 2D and 3D cell cultures of MSC to dopaminergic neurons, including media preparation. We have also included the protocols for viability, immunocytochemistry, electrophysiology, and performing a dopamine enzyme-linked immunosorbent assay (ELISA), along with the statistical analysis. Graphical overview., Competing Interests: Competing interestsDr. Stephanie Willerth is the CEO and cofounder of Axolotl Biosciences, as well as a shareholder. She is also listed as an inventor on the pending patent entitled “MORPHOGENIC COMPOUND-RELEASING MICROSPHERES AND USE IN BIOINK.” Milena Restan Perez is currently employed by Axolotl Biosciences., (Copyright © 2023 The Authors; exclusive licensee Bio-protocol LLC.)

The main aim is to compare oncological outcomes and patterns of recurrence of patients with early-stage endometrioid endometrial cancer according to lymphovascular space invasion (LVSI) status. The secondary objective is to determine preoperative predictors of LVSI. We performed a multicenter retrospective cohort study. A total of 3546 women diagnosed with postoperative early-stage (FIGO I-II, 2009) endometrioid endometrial cancer were included. Co-primary endpoints were disease-free survival (DFS), overall survival (OS), and pattern of recurrence. Cox proportional hazard models were used for time-to-event analysis. Univariate and multivariate logistical regression models were employed. Positive LVSI was identified in 528 patients (14.6%) and was an independent prognostic factor for DFS (HR 1.8), OS (HR 2.1) and distant recurrences (HR 2.37). Distant recurrences were more frequent in patients with positive LVSI (78.2% vs. 61.3%, p < 0.01). Deep myometrial invasion (OR 3.04), high-grade tumors (OR 2.54), cervical stroma invasion (OR 2.01), and tumor diameter ≥ 2 cm (OR 2.03) were independent predictors of LVSI. In conclusion, in these patients, LVSI is an independent risk factor for shorter DFS and OS, and distant recurrence, but not for local recurrence. Deep myometrial invasion, cervical stroma invasion, high-grade tumors, and a tumor diameter ≥ 2 cm are independent predictors of LVSI., Competing Interests: The authors declare no conflict of interest.

Objective: The presence of micropapillary and solid adenocarcinoma patterns leads to a worse survival and a significantly higher tendency to recur. This study aims to assess the impact of pT descriptor combined with the presence of high-grade components on long-term outcomes in early-stage lung adenocarcinomas., Methods: We retrospectively collected data of consecutive resected pT1-T3N0 lung adenocarcinoma from nine European Thoracic Centers. All patients who underwent a radical resection with lymph-node dissection between 2014 and 2017 were included. Differences in Overall Survival (OS) and Disease-Free Survival (DFS) and possible prognostic factors associated with outcomes were evaluated also after performing a propensity score matching to compare tumors containing non-high-grade and high-grade patterns., Results: Among 607 patients, the majority were male and received a lobectomy. At least one high-grade histological pattern was seen in 230 cases (37.9%), of which 169 solid and 75 micropapillary. T1a-b-c without high-grade pattern had a significant better prognosis compared to T1a-b-c with high-grade pattern (p = 0.020), but the latter had similar OS compared to T2a (p = 0.277). Concurrently, T1a-b-c without micropapillary or solid patterns had a significantly better DFS compared to those with high-grade patterns (p = 0.034), and it was similar to T2a (p = 0.839). Multivariable analysis confirms the role of T descriptor according to high-grade pattern both for OS (p = 0.024; HR 1.285 95% CI 1.033-1.599) and DFS (p = 0.003; HR 1.196, 95% CI 1.054-1.344, respectively). These results were confirmed after the propensity score matching analysis., Conclusions: pT1 lung adenocarcinomas with a high-grade component have similar prognosis of pT2a tumors., (© 2022. The Author(s).)

Background: Axillary surgical management in patients with node-positive breast cancer at the time of diagnosis converted to negative nodes through neoadjuvant chemotherapy (NAC) remains unclear. Removal of more than two sentinel nodes (SLNs) in these patients may decrease the false negative rate (FNR) of sentinel lymph node biopsies (SLNBs). We aim to analyse the detection rate (DR) and the FNR of SLNB assessment according to the number of SLNs removed., Methods: A retrospective study was performed from October 2012 to December 2018. Patients with invasive breast cancer who had a clinically node-positive disease at diagnosis and with a complete axillary response after neoadjuvant chemotherapy were selected. Patients included underwent SLNB and axillary lymph node dissection (ALND) after NAC. The SLN was considered positive if any residual disease was detected. Descriptive statistics were used to describe the clinicopathologic features and the results of SLNB and ALND. The DR of SLNB was defined as the number of patients with successful identification of SLN. Presence of residual disease in ALND and negative SLN was considered false negative., Results: A total of 368 patients with invasive breast cancer who underwent surgery after complete NAC were studied. Of them, 85 patients met the eligibility criteria and were enrolled in the study. The mean age at diagnosis was 50.8 years. Systematic lymphadenectomy was performed in all patients, with an average of 10 lymph nodes removed. The DR of SLNB was 92.9%, and the FNR was 19.1. The median number of SLNs removed was 3, and at least, three SLNs were obtained in 42 patients (53.2%). When at least three sentinel nodes were removed, the FNR decreased to 8.7%., Conclusions: In this cohort, the SLN assessment was associated with an adequate DR and a high FNR. Removing three or more SLNs decreased the FNR from 19.1% to 8.7%. Complementary approaches may be considered for axillary lymph node staging after neoadjuvant chemotherapy. The study was approved by our institution's ethics committee (Instituto de Investigacion Sanitaria Hospital 12 de Octubre (imas12), Universidad Complutense de Madrid, Madrid, Spain) (https://clinicaltrials.gov/ct2/show/NCEI:20/0048)., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Sofia Aragon-Sanchez et al.)

Background: The presence of psychosocial risks at work are associated with mental and physical health issues in workers. The study aim was to adapt the COPSOQ-ISTAS21 (Spanish version of the Copenhagen Psychosocial Questionnaire and Union Institute of Work, Environment and Health) Medium-Version to the Peruvian context and to develop a Short-Version of the instrument., Method: Cross-sectional design study. The COPSOQ-ISTAS21 Medium Version was used. A confirmatory factor analysis was performed to determine the internal structure of each subdimension (first-order) and dimension (second-order) using the Robust Maximum Likelihood estimation method, and classic fit indices in the literature (CFI, SRMR, RMSEA). Internal consistency was evaluated using the alpha and omega coefficients. A short version was developed based on the items with the highest factorial load and that reduce the factorial complexity., Results: A total of 1707 participants were evaluated. In the confirmatory factor analysis, the goodness-of-fit indices for seventeen of the 20 one-dimensional models (subdimensions) were identified; two subdimensions could not be evaluated because they presented only two items. When conducting a multidimensional analysis, we identified that all second-order models presented optimal goodness-of-fit indices, except "psychological demands at work". Finally, a short version of only 31 items was designed from the items with optimal fit indices., Conclusions: The new adapted versions of COPSOQ-ISTAS21 were renamed CENSOPAS-COPSOQ (National center of occupational health and environment protection for health -in Spanish- and Copenhagen Psychosocial Questionnaire). The CENSOPAS-COPSOQ is an instrument with sufficient evidence of validity and reliability in its medium and short version, which is why its use is recommended in Peruvian work centers to identify the evaluation and prevention of psychosocial risks at work in Peru., (© 2022. The Author(s).)

Volumetric muscle loss is a debilitating injury that can leave patients with long-lasting or permanent structural and functional deficits. With clinical treatments failing to address these shortcomings, there is a great need for tissue-engineered therapies to promote skeletal muscle regeneration. In this study, we aim to assess the potential for electrospun decellularized skeletal muscle extracellular matrix (dECM) to promote skeletal muscle regeneration in a rat partial thickness tibialis anterior defect model. Aligned electrospun scaffolds with varying degrees of crosslinking density were implanted into the defect site and compared to an empty defect control. After 8 weeks, muscles were harvested, weighed, and cellular and morphological analyses were performed via histology and immunohistochemistry. Cell infiltration, angiogenesis, and myogenesis were observed in the defect site in both dECM groups. However, favorable mechanical properties and slower degradation kinetics resulted in greater support of tissue remodeling in the more crosslinked scaffolds and preservation of existing myofiber area in both dECM groups compared to the empty defect control. More sustained release of pro-regenerative degradation products also promoted greater myofiber formation in the defect site. This study allowed for a greater understanding of how electrospun skeletal muscle scaffolds interact with existing skeletal muscle and can inform their potential as a therapy in a wide variety of soft tissue applications., (© 2022 Wiley Periodicals LLC.)

Context: During the 2016-2017 Zika virus outbreak in Puerto Rico, preventing unintended pregnancy was a primary strategy to reduce Zika-related adverse birth outcomes. The Zika Contraception Access Network (Z-CAN) was a short-term emergency response intervention that used contraception to prevent unintended pregnancy among women who chose to delay or avoid pregnancy., Objective: This analysis reports on the identified policy and practice change strategies to increase access to or provision of contraceptive services in Puerto Rico between 2015 and 2018., Methods: A policy review was conducted to document federal- and territorial-level programs with contraceptive coverage and payment policies in Puerto Rico and to identify policy and practice change. Semistructured interviews with key stakeholders in Puerto Rico were also conducted to understand perceptions of policy and practice change efforts following the Zika virus outbreak, including emergency response, local, and policy efforts to improve contraception access in Puerto Rico., Results: Publicly available information on federal and territorial programs with policies that facilitate access, delivery, and utilization of contraceptive coverage and family planning services in Puerto Rico to support contraceptive access was documented; however, interview results indicated that the implementation of the policies was often limited by barriers and that policy and practice changes as the result of the Zika virus outbreak were short-term., Conclusion: Consideration of long-term policy and practice changes related to contraceptive access is warranted. Similar analyses can be used to identify policies, practices, and perceptions in other settings in which the goal is to increase access to contraception or reduce unintended pregnancy., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Women who are obese have lower rates of breastfeeding initiation and duration and are less likely to breastfeed exclusively compared with women who are not obese. To develop programs to improve breastfeeding practices among this group of women, we investigated the association between maternal obesity and breastfeeding practices and problems in the first days postpartum. Methods: We analyzed medical records from postpartum women at a rooming-in maternity ward in State of São Paulo, Brazil, between 2016 and 2018. We included those who had intended to exclusively breastfeed, had given birth to a singleton and were admitted to rooming-in. We analyzed exclusive breastfeeding and nonexclusive breastfeeding each day of hospitalization and the presence of breastfeeding problems, comparing women in the obese category (body mass index [BMI] ≥30 kg/m 2 ) to normal and overweight women (≥18.6 to ≤29.9 kg/m 2 ). Results: Two hundred and twenty-four postpartum women participated, including 86 women in the obese category. More than 50% of women with obesity reported a breastfeeding problem in the first and second postpartum days ( p  = 0.026 and p  = 0.017, respectively) compared with the 41% and 38% nonobese group. Children of obese women were 2.8 times more likely to have poor latch during breastfeeding (95% confidence interval [CI]: 1.29-6.10) compared with the nonobese group on the third day. Conclusion: Maternal obesity increased the probability of breastfeeding difficulties and nonexclusive breastfeeding at discharge. Professionals need to support breastfeeding techniques in the days immediate after delivery to improve breastfeeding outcomes for mothers with obesity., Competing Interests: No competing financial interests exist., (© Marina Rico Perezet al., 2021; Published by Mary Ann Liebert, Inc.)

Objective: To analyze histological factors possibly associated with lymphovascular space invasion (LVSI) and to determine which of those can act as independent surrogate markers., Methods: Retrospective cohort study performed between January 2001 and December 2014. LVSI was defined as the presence of tumor cells inside a space completely surrounded by endothelial cells. Risk factors evaluated included myometrial invasion, tumor grade, size, location, and cervical invasion. Univariate logistical regression models were applied to study any possible association of LVSI with these factors. Values were adjusted by multivariate logistic regression analysis., Results: A total of 327 patients with endometrial carcinoma treated in our Centre were included. LVSI was observed in 120 patients (36.7%). Lower uterine segment involvement (OR 5.21, 95% CI:2.6-10.4, p < 0.001) and size ≥2 cm (OR 2.62, 95% CI: 1.14-6.1, p < 0.001) were independent factors for LSVI in multivariate analysis. In univariate analysis, LVSI was a surrogate marker in type 1 tumors with deep myometrial invasion (IB, 51.9% vs. IA, 16.0%; p < 0.001), grade 3 (G3 55.8% vs. G1 16.2%; p < 0.001), size ≥2 cm (37.9% vs. 16.1%, p = 0.005), those with involving the lower segment of the uterus (58.9% vs. 22.5%, p < 0.001) and/or with cervical stromal invasion (65.4% vs. 26.1%, p < 0.001), and in type 2 tumors (61.5% vs. 30.5%, p < 0.001). The use of uterine manipulator did not increase the rate of LVSI (35.5% vs. 40.5%, p = 0.612) as compared to no manipulator use., Conclusions: Size ≥2 cm and involvement of the lower uterine segment are independent factors for LSVI, in type 1 tumors, which can be used for surgical planning. LVSI is also more common in type 1 tumors with deep myometrial invasion, grade 3 and/or cervical stromal invasion, and also in type 2 tumors. The use of a uterine manipulator does not increase LVSI., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Various material compositions have been successfully used in 3D printing with promising applications as scaffolds in tissue engineering. However, identifying suitable printing conditions for new materials requires extensive experimentation in a time and resource-demanding process. This study investigates the use of Machine Learning (ML) for distinguishing between printing configurations that are likely to result in low-quality prints and printing configurations that are more promising as a first step toward the development of a recommendation system for identifying suitable printing conditions. The ML-based framework takes as input the printing conditions regarding the material composition and the printing parameters and predicts the quality of the resulting print as either "low" or "high." We investigate two ML-based approaches: a direct classification-based approach that trains a classifier to distinguish between low- and high-quality prints and an indirect approach that uses a regression ML model that approximates the values of a printing quality metric. Both modes are built upon Random Forests. We trained and evaluated the models on a dataset that was generated in a previous study, which investigated fabrication of porous polymer scaffolds by means of extrusion-based 3D printing with a full-factorial design. Our results show that both models were able to correctly label the majority of the tested configurations while a simpler linear ML model was not effective. Additionally, our analysis showed that a full factorial design for data collection can lead to redundancies in the data, in the context of ML, and we propose a more efficient data collection strategy.

The purpose of this study was to examine the role of traditional gender role value profiles on life satisfaction for Mexican descent youth. A latent profile analysis was conducted with 524 Mexican descent adolescents (53.1% girls and 46.9% boys; age M = 16.23 years, SD = 1.10 years) to examine endorsement of traditional gender role values. Analyses identified three profiles: modernist, pluralist, and traditionalist, reflecting the degree to which each group endorsed traditional gender roles. A multivariate analysis of variance of the latent profiles demonstrated differences in life satisfaction reports for boys and girls. Girls in the traditionalist profile reported greater overall life satisfaction compared to the pluralist and modernist profiles and greater environmental and friend satisfaction compared to the pluralist profile. For boys, the traditionalist gender value ratings reported greater overall, family, school, and environmental life satisfaction as compared to the pluralist and modernist groups. Results demonstrate that ascribing to more traditional gender role values may be protective for Mexican descent adolescents in regard to life satisfaction. We will discuss applications of our findings for practitioners working with Mexican descent youth focused on increasing positive aspects of emotional well-being.

We herein report a high-resolution nanopatterning method using low voltage electromechanical spinning with a rotating collector to obtain aligned graphitized micro and nanowires for carbon nanomanufacturing. A small wire diameter and a small inter-wire spacing were obtained by controlling the electric field, the spinneret-to-collector distance, the pyrolysis parameters, the linear speed of the spinneret, the rotational speed of the collector. Using a simple scaling analysis, we show how the straightness and the diameter of the wires can be controlled by the electric field and the distance of the spinneret to the collector. A small inter-wire spacing, as predicted by a simple model, was achieved by simultaneously controlling the linear speed of the spinneret and the rotational speed of the collector. Rapid drying of the polymer nanowires enabled the facile fabrication of suspended wires over various structures. Patterned polyacrylonitrile wires were carbonized using standard stabilization and pyrolysis to obtain carbon nanowires. Suspended carbon nanowires with a diameter of <50 nm were obtained. We also established a method for making patterned, highly graphitized structures by using the aforementioned carbon wire structures as a template for chemical vapor deposition of graphite. This patterning technique offers high throughput for nano writing, which outperforms other existing nanopatterning techniques, making it a potential candidate for large-scale carbon nanomanufacturing., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Author(s) 2020.)

Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer that progresses without any symptom, and oftentimes, it is detected at an advanced stage. The lack of prior symptoms and effective treatments have created a knowledge gap in the management of this lethal disease. This issue can be addressed by developing novel noninvasive imaging-based biomarkers in PDAC. We explored in vivo hyperpolarized (HP) 13 C MRS of pyruvate to lactate conversion and ex vivo 1 H NMR spectroscopy in a panel of well-annotated patient-derived PDAC xenograft (PDXs) model and investigated the correlation between aberrant glycolytic metabolism and aggressiveness of the tumor. Real-time metabolic imaging data demonstrate the immediate intracellular conversion of HP 13 C pyruvate to lactate after intravenous injection interrogating upregulated lactate dehydrogenase (LDH) activity in aggressive PDXs. Total ex vivo lactate measurement by 1 H NMR spectroscopy showed a direct correlation with in vivo dynamic pyruvate-to-lactate conversion and demonstrated the potential of dynamic metabolic flux as a biomarker of total lactate concentration and aggressiveness of the tumor. Furthermore, the metabolite concentrations were very distinct among all four tumor types analyzed in this study. Overexpression of LDH-A and hypoxia-inducible factor (HIF-1α) plays a significant role in the conversion kinetics of HP pyruvate-to-lactate in tumors. Collectively, these data identified aberrant metabolic characteristics of pancreatic cancer PDXs and could potentially delineate metabolic targets for therapeutic intervention. Metabolic imaging with HP pyruvate and NMR metabolomics may enable identification and classification of aggressive subtypes of patient-derived xenografts. Translation of this real-time metabolic technique to the clinic may have the potential to improve the management of patients at high risk of developing pancreatic diseases.

Lumican is secreted by pancreatic stellate cells and inhibits cancer progression. Extracellular lumican inhibits cancer cell replication and restrains growth of early-stage pancreatic adenocarcinoma (PDAC) such that patients with tumors containing stromal lumican experience a three-fold longer survival after treatment. In the present study, patient tumor tissues, ex-vivo cultures of patient-derived xenografts (PDX), PDAC stellate and tumor cells were used to investigate whether hypoxia (1% O 2 ) within the tumor microenvironment influences stromal lumican expression and secretion. We observed that hypoxia significantly reduced lumican expression and secretion from pancreatic stellate cells, but not cancer cells. Although hypoxia enhanced lactate dehydrogenase A (LDHA) expression and lactate secretion from all cells, neither hypoxia-induced nor exogenous lactate influenced lumican expression. Autophagy was induced by hypoxia in ex vivo cultures of PDX and pancreatic stellate cells, but not cancer cells cultured in 2D. Autophagic flux inhibitors, bafilomycin A1, chloroquine diphosphate salt, and ammonium chloride prevented hypoxia-mediated reduction in lumican expression in stellate cells. Furthermore, inhibition of AMP-regulated protein kinase (AMPK) phosphorylation or hypoxia-inducible factor (HIF)-1α expression within hypoxic stellate cells restored lumican expression levels. Hypoxia did not affect lumican mRNA expression, indicating that hypoxia-induced reduction of lumican occurs post-transcriptionally; in addition, AMPK inhibition prevented hypoxia-reduced phosphorylation of the mTOR/p70S6K/4EBP signaling pathway, a key contributor to protein synthesis. Taken together, these findings demonstrate that hypoxia reduces stromal lumican in PDAC through autophagy-mediated degradation and reduction in protein synthesis within pancreatic cancer stellate cells.

We previously demonstrated that pancreatic stellate cells within pancreatic ductal adenocarcinoma (PDAC) stroma secrete lumican and its presence is associated with prolonged survival of patients with localized PDAC. Here, we observed that extracellular lumican decreases PDAC tumour cell growth in xenograft and syngeneic orthotopic animal models, and induces growth inhibition of low-passage human PDAC cells in a species-specific manner. PDAC cells grown in variant culture conditions and exposed to extracellular lumican display typical characterizations of cancer cell in a quiescent state, such as growth inhibition, apoptosis, G0/G1 arrest and chemoresistance. Importantly, extracellular lumican is associated with diminished ERK1/2 phosphorylation and increased p38 phosphorylation within PDAC cells. We further demonstrated that extracellular lumican physically binds with EGFR to trigger EGFR internalization and downregulation of EGFR and its downstream signal molecule ERK. Lumican enhances casitas B-lineage lymphoma expression, which stabilized the TGFβ Type II receptor sensitizing PDAC cells to TGFβ-mediated activation of p38 and SMAD signals. These provide a mechanism for the shift in signalling and phenotypic changes we observed after prolonged exposure to lumican. Together, our findings demonstrate that stromal lumican restrains PDAC cell growth through mediating cell entry into a quiescent state.

Background: Uterine leiomyosarcomas are very rare and highly aggressive tumors that have a high rate of recurrence and poor prognosis, even when early diagnosed. Due to their relative rarity, there is limited research on optimal management strategies., Case Presentation: A 60-year-old woman with a history of an asymptomatic uterine leiomyoma presented in October 2015 with postmenopausal bleeding and a friable vaginal cyst that bled when palpated. A partial cystectomy was performed, and malignant-like cystic and solid components were identified. Histopathology diagnosed an unclassifiable malignant epithelioid tumor. Subsequent imaging studies identified a malignant uterine tumor, a metabolically active vaginal lesion, and two benign leiomyomas. An anterior pelvic exenteration (colpectomy, hysterectomy, bilateral adnexectomy, total cystectomy, and cutaneous ureteroileostomy ad modum Bricker) were performed by laparotomy in March 2016. Examination of the surgical specimens identified a 75 × 75-mm leiomyoma, an 80 × 30-mm infiltrating mesenchymal uterine lesion with vascular invasion and tumor emboli, and a 60 × 30-mm perivascular vaginal tumor. Immunohistochemistry indicated a phenotypic transition from a uterine leiomyosarcoma to a vaginal epithelioid lesion; marker expression changed from the uterine tumor actin+/desmin+/caldesmon+/CD10- phenotype, through the tumor emboli, to an actin-/desmin-/caldesmon-/CD10+ phenotype in the vaginal lesion. A high-grade uterine mesenchymal tumor and vaginal metastasis were diagnosed. Adjuvant chemotherapy with docetaxel, gemcitabine, and doxorubicin commenced in May 2016 and treatment has been well tolerated., Conclusions: Differentiating leiomyosarcoma from leiomyoma is challenging and few tools other than microscopic evaluation are available. Vaginal compromise in leiomyosarcoma usually results from tumor extension, not hematogenous metastasis. A vaginal metastasis is a very rare initial presentation. We have found only two cases like this described on published literature. The atypical clinical and histological presentation in our case complicated diagnosis and delayed treatment. An early diagnosis and complete surgical clearance gives the best chance of survival, and imaging tools should be applied early in instances of new suspicious malignant lesions.

At present, there is no effective screening of ovarian cancer. Primary prevention may be the only strategy to decrease the mortality from ovarian cancer, not only in women at high risk but also at low risk. Several recent studies have identified the distal fimbriae end of the fallopian tubes as primary precursor of High-grade serous carcinoma. Serous tubal intraepithelial carcinomas and occult invasive serous carcinomas have been identified in 2-17% of the fallopian tubes of BRCA1/2 positive women undergoing risk-reducing salpingo-oophorectomy. Removal of the fallopian tubes with ovarian preservation has been suggested as a reasonable strategy that could reduce the risk of developing ovarian carcinoma in both low and high-risk women. It has been proposed after childbearing in women at high risk to be followed by bilateral oophorectomy at a later date. Bilateral salpingectomy is also suggested for low risk women, at the time of other benign gynaecologic surgery as a primary preventive strategy. Some studies have shown a risk reduction of ovarian cancer in women with bilateral prophylactic salpingectomy. Current research regarding bilateral salpingoophorectomy as primary prevention approach of ovarian cancer is reviewed here. In addition, the potential use of bilateral salpingectomy as prevention approach of ovarian cancer is discussed., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: Infants with congenital diaphragmatic hernia (CDH) have variable degrees of pulmonary hypoplasia at birth. Few reports of lung function over the first years of life exist in this group of children., Hypothesis: Pulmonary function abnormalities correlate with severity of neonatal disease and intensity of neonatal therapies needed. We also hypothesized that longitudinal measurements of lung function over the usual period of rapid lung growth would lend some insight into how the lung remodels in CDH infants., Methodology: Ninety-eight infants with CDH between 11 days and 44 months of age underwent pulmonary function testing (PFT) on 1-5 occasions using the raised volume rapid thoracic compression technique. Demographic data were also collected., Main Results: Forced expiratory flows were below normal. Total lung capacity was normal, but residual volume and functional residual capacity were elevated. Children requiring patch closure, ECMO, or pulmonary vasodilators generally had lower lung functions at follow up. Additionally, longer duration of mechanical ventilation correlated with worse lung function., Conclusions: Lung functions of survivors of CDH remain abnormal throughout the first 3 years of life. The degree of pulmonary function impairment correlated both with markers of the initial degree of pulmonary hypoplasia and the duration of mechanical ventilation. Understanding the relationship between the phenotypic presentation of CDH and the potential for subsequent lung growth could help refine both pre- and postnatal therapies to optimize lung growth in CDH infants., (© 2014 Wiley Periodicals, Inc.)

Growing concern about water quality issues, along with a series of fish kills in 1997, prompted Maryland, Delaware, and Virginia to adopt regulations to reduce nutrient pollution from agricultural nonpoint sources. All three states required farmers to follow a state-certified nutrient management plan that would "optimize crop yields and minimize environmental losses," although the policy-making processes in each state were different. The objective of this political and policy analysis research was to determine if the policy-making process affected farmer compliance and whether nutrient management practices have improved. Sixty farmers on the Delmarva Peninsula, which includes all three states, who grew corn and used poultry manure as a nutrient source were interviewed, as were 68 policy stakeholders. Analysis of state regulatory agency data indicated that the contentious policy-making process in Maryland resulted in initially poor administrative compliance (i.e., obtaining a plan), whereas collaborative approaches in Delaware resulted in very good initial compliance. Interviews with farmers indicated good adoption of four practices: possessing a current plan, taking soil and manure nutrient tests, and split-applying nitrogen fertilizer. Farmers reported poor adoption (60% or less) across all three states of other practices: taking residual nitrogen credits for previous use of legumes or manure, keeping manure-free setbacks next to surface waters, avoiding manure application in winter, and frequent calibration of manure spreaders. Although nutrient management plans were required, many aspects of implementation and enforcement meant that adherence to plans was largely voluntary. This research helped identify successes, shortcomings, and lessons learned about regulating farmers., (Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.)

Background: Neurofibromatosis type 1 can rarely present in the larynx. Patients typically do not present with complete obstructive symptoms, but partial obstruction and stridor. We review our health centers' case series of two patients, the first of whom presented with persistent sleep apnea post tonsillectomy and adenoidectomy, and the second who presented with noisy breathing. Additionally, we will review the literature on the management and treatment options for children with this rare clinical entity., Methods: Retrospective case review., Case Report & Results: A two-year old male underwent a sleep endoscopy following persistent evidence of obstructive sleep apnea on polysomnography after initial tonsillectomy and adenoidectomy. Family elicited concerns about noisy breathing at night and an accompanying video documented stridor while sleeping during the monitored polysomnography. Flexible fiberoptic laryngoscopy in the operating room revealed what appeared to be a cystic mass along the right aryepiglottic fold causing deviation of the laryngeal introitus towards the contralateral side. Subsequent direct laryngoscopy and excisional biopsy revealed pathology results consistent with a plexiform neurofibroma. A six-month-old patient with stertor and stridor was found to have a laryngeal mass, subglottic stensosis, and progressive airway obstruction due to plexiform neurofirboma in the supraglottis, subglottis, and trachea. We present a series of two patients incidentally diagnosed with neurofibromatosis type 1 by way of a laryngeal neurofibroma and review the literature on management options. Both patients were found to have accompanying café au lait spots. Both patients required tracheostomy for airway management, and one was successfully decannulated., Conclusion: Laryngeal neurofibroma is a rare anomaly that can manifest with airway obstruction. Both patients presented here subsequently were noted to have café au lait spots on physical examination. The Otolaryngologist should be reminded of this anomaly when evaluating a child with evidence of a submucosal laryngeal mass. We present our series including that of a patient whose diagnosis was prompted by persistent sleep apnea following adenotonsillectomy tonsillectomy and a patient with airway obstruction and subglottic stenosis due to a neurofibroma. The treatment of choice is complete excision of the neurofibroma while maintaining functionality of the larynx. This can lead to successful decannulation., (Published by Elsevier Inc.)

An experimental and computational study of correlations between solid-state structure and optical/electronic properties of cyclotrimeric gold(I) carbeniates, [Au3(RN═COR')3] (R, R' = H, Me, (n)Bu, or (c)Pe), is reported. Synthesis and structural and photophysical characterization of novel complexes [Au3(MeN═CO(n)Bu)3], [Au3((n)BuN═COMe)3], [Au3((n)BuN═CO(n)Bu)3], and [Au3((c)PeN═COMe)3] are presented. Changes in R and R' lead to distinctive variations in solid-state stacking, luminescence spectra, and conductive properties. Solid-state emission and excitation spectra for each complex display a remarkable dependence on the solid-state packing of the cyclotrimers. The electronic structure of [Au3(RN═COR')3] was investigated via molecular and solid-state simulations. Calculations on [Au3(HN═COH)3] models indicate that the infinitely extended chain of eclipsed structures with equidistant Au--Au intertrimer aurophilic bonding can have lower band gaps, smaller Stokes shifts, and reduced reorganization energies (λ). The action of one cyclotrimer as a molecular nanowire is demonstrated via fabrication of an organic field effect transistor and shown to produce a p-type field effect. Hole transport for the same cyclotrimer-doped within a poly(9-vinylcarbazole) host-produced a colossal increase in current density from ∼1 to ∼1000 mA/cm(2). Computations and experiments thus delineate the complex relationships between solid-state morphologies, electronic structures, and optoelectronic properties of gold(I) carbeniates.

We report the structure-based design and synthesis of a unique NOS inhibitor, called nanoshutter NS1, with two-photon absorption properties. NS1 targets the NADPH site of NOS by a nucleotide moiety mimicking NADPH linked to a conjugated push-pull chromophore with nonlinear absorption properties. Because NS1 could not provide reducing equivalents to the protein and competed with NADPH binding, it efficiently inhibited NOS catalysis. NS1 became fluorescent once bound to NOS with an excellent signal-to-noise ratio because of two-photon excitation avoiding interference from the flavin-autofluorescence and because free NS1 was not fluorescent in aqueous solutions. NS1 fluorescence enhancement was selective for constitutive NOS in vitro, in particular for endothelial NOS (eNOS). Molecular dynamics simulations suggested that two variable residues among NOS isoforms induced differences in binding of NS1 and in local solvation around NS1 nitro group, consistent with changes of NS1 fluorescence yield. NS1 colocalized with eNOS in living human umbilical vein endothelial cells. Thus, NS1 constitutes a unique class of eNOS probe with two-photon excitation in the 800-950-nm range, with great perspectives for eNOS imaging in living tissues.

EDTA modified layered double hydroxides (LDHs) were investigated as potential sorbents to remediate heavy metals pollution. The polidentate ligand was introduced by an exchange method in a Zn-Al-LDH, which takes place with partial erosion of the layers, causing the intercalation of [Zn(EDTA)](2-) complex instead of the ligand. [Cu(H(2)O)(6)](2+) cation was selected as a model cation to study the uptake mechanism, exploring the elimination kinetics from the first minutes up to the steady state. A flow injection analysis system coupled to an amperometric detector (FIA-AM) was applied to perform fast and reliable [Cu(H(2)O)(6)](2+) determinations in monodisperse solid-aqueous solution systems. Furthermore, the sorbent stability was determined as a function of the pH and the nitrate concentration. The [Cu(H(2)O)(6)](2+) elimination is produced by an exchange reaction with [Zn(EDTA)](2-) anions placed either in the solid interlayer or in the aqueous solution, this last being released from the sorbent. Additional [Cu(H(2)O)(6)](2+) removal is produced by Cu(OH)(2) precipitation at high copper concentrations due to the LDHs high pH buffering capacity. The sorbent removes [Cu(H(2)O)(6)](2+) with high affinity in a wide concentration range. The elimination process reaches equilibrium in less than 30 min and leaves metal cation concentrations lower than 0.05 ppm in the supernatants.

Background: : On the basis of logistic benefits of colloids over crystalloids, the U.S. military selected Hextend for resuscitation of combat casualties in the field. We investigated the effects of resuscitation with this fluid, as well as other colloids, on coagulation and uncontrolled bleeding in rabbits subjected to a splenic injury., Methods: : Anesthetized male New Zealand white rabbits (3.3 kg +/- 0.2 kg) were divided into three groups and subjected to hypothermia (35 degrees C +/- 0.5 degrees C) and approximately 40% isovolemic blood exchange (hemodilution) with Hextend (H); Dextran70 (D); or 5% human albumin (A) solution (n = 8/group). Complete blood count, arterial blood gas, and coagulation values were measured before and after hemodilution. Laparotomy was performed and a standard splenic injury causing uncontrolled hemorrhage was made. Rabbits were resuscitated (25 mL/kg) with the same colloid used for hemodilution to restore baseline blood pressure. Animals were monitored for 2 hours or until death. Blood loss and survival times were measured., Results: : There were no differences among groups in pH, Hct, fibrinogen, or platelets before or after hemodilution. Hct, fibrinogen, and platelets were reduced by 45% to 60% in all groups. Prothrombin time (PT) and activated partial thromboplastin time were prolonged in all the rabbits with the greatest increase in A group. Thrombelastograph (TEG) analysis showed longer initial reaction (R) and clotting (K) times, slower clotting rate and lower clot strength in H and D than A diluted blood. R time was faster and K time remained unchanged in A group after hemodilution. Thrombin generation potential and peak concentration of thrombin were unchanged in A samples but significantly reduced in H and D diluted samples. Subsequent splenic injury led to almost equal blood losses ( approximately 54 +/- 1 mL/kg) in H and D groups, which were higher (p < 0.01) than in A rabbits (37 +/- 4 mL/kg). This resulted in death of 100% (H), 75% (D), and 50% (A) of the rabbits with significant difference in survival time among the groups., Conclusion: : TEG and thrombin generation assays identified more severe coagulopathy development with H and D than A dilution, whereas plasma PT and activated partial thromboplastin time measurements did not differentiate between these colloids. These results suggest that resuscitation with albumin maintained coagulation function, decreased blood loss, and improved survival time compared with the synthetic colloids.

Voltage-gated K(+) channels of the Kv7 family underlie the neuronal M current that regulates action potential firing. Suppression of M current increases excitability and its enhancement can silence neurons. We here show that three of five Kv7 channels undergo strong enhancement of their activity by oxidative modification induced by physiological concentrations of hydrogen peroxide. A triple cysteine pocket in the channel S2-S3 linker is critical for this effect. Oxidation-induced enhancement of M current produced a hyperpolarization and a dramatic reduction of action potential firing frequency in rat sympathetic neurons. As hydrogen peroxide is robustly produced during hypoxia-induced oxidative stress, we used an oxygen/glucose deprivation neurodegeneration model that showed neuronal death to be severely accelerated by M current blockade. Such blockade had no effect on survival of normoxic neurons. This work describes a novel pathway of M-channel regulation and suggests a role for M channels in protective neuronal silencing during oxidative stress.

Recent progress especially in the field of gene identification and expression has attracted greater attention to the genetic and epigenetic susceptibility to cancer, possibly enhanced by ionising radiation. This issue is especially important for radiation therapists since hypersensitive patients may suffer from adverse effects in normal tissues following standard radiation therapy, while normally sensitive patients could receive higher doses of radiation, offering a better likelihood of cure for malignant tumours. Although only a small percentage of individuals are "hypersensitive" to radiation effects, all medical specialists using ionising radiation should be aware of the aforementioned progress in medical knowledge. The present paper, the second of two parts, reviews human disorders known or strongly suspected to be associated with hypersensitivity to ionising radiation. The main tests capable of detecting such pathologies in advance are analysed, and ethical issues regarding genetic testing are considered. The implications for radiation protection of possible hypersensitivity to radiation in a part of the population are discussed, and some guidelines for nuclear medicine professionals are proposed.

Recent progress especially in the field of gene identification and expression has attracted greater attention to genetic and epigenetic susceptibility to cancer, possibly enhanced by ionising radiation. It has been proposed that the occurrence and severity of the adverse reactions to radiation therapy are also influenced by such genetic susceptibility. This issue is especially important for radiation therapists since hypersensitive patients may suffer from adverse effects in normal tissues following standard radiation therapy, while normally sensitive patients could receive higher doses of radiation offering a better likelihood of cure for malignant tumours. This paper, the first of two parts, reviews the main mechanisms involved in cell response to ionising radiation. DNA repair machinery and cell signalling pathways are considered and their role in radiosensitivity is analysed. The implication of non-targeted and delayed effects in radiosensitivity is also discussed.

Pregnant Wistar rats were exposed on day 17 of gestation to 1 Gy gamma irradiation from a Co(60) source. Even though it is established that gamma radiation-dependent damage is mainly due to free radical generation neither the ascorbyl radical/ascorbate ratio nor the lipid radical content in developing rat brain were affected by prenatal irradiation. A distinctive EPR signal for the adduct NO-Fe-MGD (g=2.03 and a(N)=12.5 G) was detected in brain homogenates prepared from irradiated rats. Nitric oxide (NO)-dependent EPR signal increased in a time-dependent manner up to 2h post-irradiation. NO concentration in unirradiated brains was 37+/-4 pmol/g brain and 45+/-2, 77+/-5 and 216+/-6 after 30, 60 and 120 min post-irradiation, respectively. Total nitric oxide synthase activity was increased by 77 and 51% after 30 and 60 min post-irradiation, respectively, and returned to control values after 120 min. Thus, increased NO steady-state concentration could be ascribed to an increase in NOS activity. Taken as a whole, these results suggest that NO might act to protect the developing brain from the cytotoxicity of reactive species.

Measurements were made of trans-sarcolemmal Ca(2+) fluxes and intracellular [Ca(2+)](i) in rat ventricular myocytes loaded with Indo-1 to determine how the n-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) suppresses spontaneous waves of Ca(2+) release. We report that in 10 microM EPA, the Ca(2+) efflux generated by individual waves increased by 11.3 +/- 4.9 % over control levels. However, wave-generated efflux per unit time fell overall by 19 +/- 5.3 %. On removal of EPA, wave frequency increased transiently such that Ca(2+) efflux was greater than normal and the cell lost 28.0 +/- 10.6 micromol l(-1) Ca(2+). This probably represents the loss of extra Ca(2+) accumulated by the sarcoplasmic reticulum (SR), while Ca(2+) release was inhibited. These results are evidence of inhibition of the SR Ca(2+)-release mechanism and reduced availability of Ca(2+) to the SR. From the relationship between average intracellular Ca(2+) and the frequency of spontaneous waves, we have calculated the relative contributions of these different mechanisms to the lower frequency of waves. In EPA, the frequency of spontaneous waves fell by 37.5 +/- 8.1 %, the majority of this (29.2 +/- 8.8 %) is due to inhibition of the Ca(2+)-release mechanism. In EPA, the rate of fall of Ca(2+) in the caffeine response (an indicator of surface membrane Ca(2+) efflux pathway activity) was not altered. We conclude, therefore, that the lower resting level of Ca(2+) observed in EPA is due to a lower influx of Ca(2+) across the surface membrane rather than increased activation of efflux pathways. How these effects might contribute to the anti-arrhythmic actions of EPA is discussed.

1. We have studied the effects of two polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on spontaneous and electrically stimulated contractions in single, isolated ventricular myocytes from rat hearts. 2. The frequency of spontaneous waves of calcium release and contraction (induced by elevation of the bathing calcium concentration) is reduced in the presence of EPA. At the same time the resting level of intracellular calcium falls, the resting cell length increases and the amplitude of shortening decreases. All these effects are reversed on removal of EPA. 3. Imaging of the waves of calcium release shows that the amplitude and the rate of propagation of the wave is increased in EPA. Consistent with the increased amplitude, integration of the caffeine-induced Na+-Ca2+ exchange current (a measure of the sarcoplasmic reticulum (SR) calcium content) is increased by both EPA and DHA. 4. EPA has a maintained negative inotropic effect on voltage clamped myocytes. This seems to be entirely due to inhibition of the L-type calcium current. Smaller depolarising pulses in control conditions that elicit the same calcium current as in EPA also activate the same level of contraction. This is in spite of the increased SR calcium content in EPA. 5. It is concluded that PUFAs have two effects on the SR; they reduce the availability of calcium for uptake and they inhibit the release mechanism. Both of these effects should lower the frequency of spontaneous waves of calcium release. As spontaneous release of calcium can initiate arrhythmias, some of the anti-arrhythmic action of PUFAs must be exerted at the level of the SR.

Background/aims: In our area most of the human immunodeficiency virus (HIV) infected patients are intravenous drug users; HIV and hepatitis C virus infections often coexist in these patients. Due to the repercussions of both infections, we designed a trial to evaluate the efficacy, response-related factors and tolerance during an eight-month regime of recombinant interferon alpha-2b on hepatitis C virus infection., Methodology: We included 79 patients in an open, prospective and multicentric trial with zidovudine and interferon alpha-2b. Response to interferon treatment was evaluated by biochemical and histopathological criteria., Results: A complete response (alanine aminotransferase normalization) was obtained in 57.4% of patients. The significant response-related factors were: degree of histopathological activity, CD4+ cell number and initial leukocyte number., Conclusions: Recombinant interferon therapy seems to be effective for chronic hepatitis C in HIV infected patients; the best response was in those with active chronic hepatitis and CD4+ cell counts > or = 200/mm3. General tolerance was variable, although side effects were not different from those seen in non-HIV patients. The most common side effect was flu-like syndrome (constitutional manifestations), with no interference on treatment continuity; however, hematological toxicity prevents the indiscriminate use of interferon.

Four of 83 patients undergoing percutaneous transhepatic cholangiography were demonstrated to have hepatic abscesses communicating with the biliary tract. The abscesses resulted from obstruction of the common bile duct. The etiologies of the obstructions were chronic pancreatitis, recurrent cholangiocarcinoma. Radiographic demonstration of suppurative cholangitis is associated with a very poor prognosis.