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Several human-adapted Mycobacterium tuberculosis complex (Mtbc) lineages exhibit a restricted geographical distribution globally. These lineages are hypothesized to transmit more effectively among sympatric hosts, that is, those that share the same geographical area, though this is yet to be confirmed while controlling for exposure, social networks and disease risk after exposure. Using pathogen genomic and contact tracing data from 2,279 tuberculosis cases linked to 12,749 contacts from three low-incidence cities, we show that geographically restricted Mtbc lineages were less transmissible than lineages that have a widespread global distribution. Allopatric host-pathogen exposure, in which the restricted pathogen and host are from non-overlapping areas, had a 38% decrease in the odds of infection among contacts compared with sympatric exposures. We measure tenfold lower uptake of geographically restricted lineage 6 strains compared with widespread lineage 4 strains in allopatric macrophage infections. We conclude that Mtbc strain-human long-term coexistence has resulted in differential transmissibility of Mtbc lineages and that this differs by human population., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Severe mpox has been observed in people with advanced human immunodeficiency virus (HIV). We describe clinical outcomes of 13 patients with advanced HIV (CD4 <200 cells/μL), severe mpox, and multiorgan involvement. Despite extended tecovirimat courses and additional agents, including vaccinia immune globulin, cidofovir, and brincidofovir, this group experienced prolonged hospitalizations and high mortality., Competing Interests: Potential conflicts of interest. E. A. G. has received consulting fees from the American Society of Health-System Pharmacists and has received honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Southeast AIDS Education and Training Center (AETC). O. M. has received consulting fees from The Public Theatre and from Primary Care Development Corporation and has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Northeast Caribbean AETC, Infectious Diseases Society of New York, Columbia School of Social Work, Physicians’ Research Network, and State University of New York Downstate. J. Z. has received honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Rutgers New Jersey Medical School, Albany Medical Center, International Antiviral Society–USA, University of Rochester, Nassau University Medical Center, Memorial Sloan Kettering, East Tennessee Children's Hospital, and Stony Brook Medical Center. M. A. D. previously held stock with Gilead Sciences that was sold prior to starting work on this manuscript. All other authors report no potential conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Competing Interests: All authors declare that they have no competing interests in this manuscript and its publication.

Background & Aims: Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn's disease therapy; however, nonresponse and loss of response are common. As combination therapy with methotrexate may improve response, we performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare tumor necrosis factor inhibitors with oral methotrexate to tumor necrosis factor inhibitor monotherapy., Methods: Patients with pediatric Crohn's disease initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12-36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected., Results: Of 297 participants (mean age, 13.9 years, 35% were female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (hazard ratio, 0.69; 95% CI, 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19-0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49-1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24-2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs., Conclusions: Among adalimumab but not infliximab initiators, patients with pediatric Crohn's disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile., Clinicaltrials: gov, Number: NCT02772965., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Highly effective modulator therapy (HEMT) for cystic fibrosis (CF) has been touted as one of the greatest advances to date in CF care. As these therapies are now available for many older children and adults with CF, marked improvement of their nutritional status, pulmonary and gastrointestinal symptoms has been observed. However, most infants and younger children are not current candidates for HEMT due to age and/or cystic fibrosis transmembrane conductance regulator (CFTR) mutation. For these young children, it is essential to provide rigorous monitoring and care to avoid potential disease sequelae while awaiting HEMT availability. The following article highlights recent advances in the care of infants and young children with CF with regard to surveillance and treatment of nutritional, pulmonary, and gastrointestinal disorders. Recent clinical trials in this population are also reviewed., (© 2021 Wiley Periodicals LLC.)

Background: Postpartum depression (PPD) is a devastating mental illness associated with adverse health outcomes for mother, child, and family. Higher PPD prevalence in First American women suggests a racial/ethnic disparity, yet little is known about how PPD is experienced from their perspective., Purpose: To 1) describe First American women's PPD experiences and the meanings they ascribe to those experiences and 2) describe the cultural knowledge, influences, and practices during the perinatal period., Study Design and Methods: This phenomenological study used a community-based participatory research approach. Criterion and snowball sampling captured First American women who had PPD now or in the past (N = 8). Interviews used a semistructured guide and thematic analysis followed., Results: Mean age was 30.25 years. Most women were multigravidas (n = 7) and rated themselves as "very" (n = 4) or "mostly" (n = 3) Native American. Women were mostly of low socioeconomic status and had a history of depression (n = 7) and/or a history of prenatal depression (n = 6). Themes: 1) stressors that contributed to PPD; 2) how PPD made me feel; 3) what made my PPD better; 4) heritage-centered practices; 5) support through PPD; 6) how I felt after PPD; and 7) am I a good mother?, Clinical Implications: This study provides a better understanding of some First American women's PPD experiences that facilitates judgment of the importance of PPD within a cultural context. Clinicians need to create culturally appropriate responses to First American women's PPD needs., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The treatment of patients with multisuture craniosynostosis is complex and patient-dependent. Cranial distraction osteogenesis is a relatively new procedure for treatment of these patients, with its use increasing in many centers. With this increased use comes an expanding range of indications. Surgical management of multisuture craniosynostosis in therapeutically immunosuppressed patients following a solid organ transplant presents unique challenges. We describe our experience with posterior cranial vault distraction in two patients with multisuture craniosynostosis that had previously undergone organ transplantation., Methods: Two solid-organ transplant recipient patients with multisuture craniosynostosis were identified. A detailed examination of their medical/transplant history and perioperative details were recorded., Results: The first patient was a 3-year-old girl who received a kidney transplantation in infancy and subsequently presented with a symptomatic Chiari malformation and papilledema. Imaging revealed pansynostosis. She underwent posterior cranial vault distraction extending into a Chiari decompression. Her postoperative course was complicated by distractor site infection at the beginning of consolidation, necessitating early removal of distractors. The second patient was a 2-year-old boy who received a heart transplantation at the age of 3 months and subsequently presented with head shape concerns. Imaging revealed bicoronal and sagittal craniosynostosis. He underwent a posterior cranial vault distraction without complication. Following removal of the distractors, he developed an infection at one of the distractor sites with associated fever and leukocytosis, necessitating washout and drain placement. Both patients achieved successful cranial vault expansion with distraction osteogenesis and at a 2-year follow-up do not have evidence of elevated intracranial pressure., Conclusions: Immunosuppressive therapy has the potential to inhibit wound healing and place patients at risk for wound infection. Although we have demonstrated successful cranial vault expansion with distraction in two immunosuppressed children, extra care must be taken with these patients when placing semi-buried hardware. Specifically, prompt identification and proactive management of potential infectious complications is critical to applying this technique safely in these patients.

Cytokines, key contributors to tumorigenesis, are mediators between inflammatory immune or nonimmune and cancer cells. Here, IL-6 production by tumor cells was assessed in a cohort of patients with lung adenocarcinoma treated with conventional therapy. IL-6 levels and neutrophil-lymphocyte ratio (NLR) or systemic immune-inflammation index (SII) markers were evaluated. Changes in pro- and anti-inflammatory cytokines, HMGB1 concentration, and CD4+ and CD8+ T-lymphocyte populations and their subpopulations were investigated. IL-6 expression was detected immunohistochemically in lung adenocarcinoma biopsies. Cytokines were quantified using the cytometric bead array, and TGF-β and HMGB-1 through ELISA. Clinical parameters were collected to assess NLR and SII. CD4+ and CD8+ T-lymphocytes and naïve, memory, and effector subpopulations were quantified by flow cytometry. The data obtained were associated with patients' median overall survival (OS). IL-6 showed the highest increase, probably because the lung adenocarcinoma cells produced IL-6. Patients with higher OS had lower NLR and SII from the third cycle of chemotherapy. Patients with lower OS had significantly lower percentages of CD8+ T-lymphocyte and its effector subpopulations, with a concomitant increase in the naïve subpopulation. This study suggests that in addition to the known inflammatory markers, IL-6, CD8+ T-lymphocytes and their effector and naïve subpopulations could be useful as predictive markers in lung adenocarcinoma.

Although infants with meconium ileus usually present with apparent symptoms shortly after birth, the diagnosis of meconium ileus and cystic fibrosis (CF) may be delayed, awaiting newborn screening (NBS) results. We present the case of an 11-day-old term girl with delayed passage of meconium at 48 hours who had 2 subsequent small meconium stools over the following week. There was a normal feeding history and no signs of abdominal distension or distress. She then presented with an acute abdomen, decompensated shock, bowel perforation, and peritonitis, requiring multiple intestinal surgeries. Her NBS for CF was positive, and CF was ultimately confirmed with mutation analysis. Her course was complicated by prolonged parenteral feedings and mechanical ventilation via tracheostomy. The infant was managed with soy oil, medium chain triglycerides, olive oil, fish oil lipids and experienced only transaminitis without cholestasis and no chronic liver sequelae, with subsequent normalization of her transaminases without treatment. Because her only symptom was decreased stool output and NBS results were unavailable, the CF diagnosis was delayed until she presented in extremis. Delayed meconium passage and decreased stool output during the first week of life should lead to suspicion and additional evaluation for CF while awaiting NBS results. Careful monitoring is indicated to prevent serious, life-threatening complications. The use of soy oil, medium chain triglycerides, olive oil, fish oil lipids for infants requiring prolonged parenteral nutrition may also be considered proactively to prevent cholestasis, particularly for high risk groups., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Purpose: The purpose of this study was to retrospectively investigate risk factors for chest port (port) infections within 30 days of placement (early port infections) in adult oncologic patients., Materials and Methods: This single-institution, three-center retrospective study identified 1,714 patients (868 males, 846 females; median age 60.0 years old) who underwent port placement between January 2013 and August 2017. All patients received an intravenous antibiotic prior to port placement. The median absolute neutrophil count was 5,260 cells/μL, the median white blood cell (WBC) count was 7,700 cells/μL, and the median serum albumin was 4.00 g/dL at the time of port placement. Double-lumen ports were most commonly implanted (74.85%) more frequently in an outpatient setting (72.69%). Risk factors for early port infections were elucidated using univariate and multivariate proportional subdistribution hazard regression analyses., Results: A total of 20 patients (1.2%) had early port infections; 15 patients (0.9%) had positive blood cultures. The mean time to infection was 20 days (range, 9-30 days). The port-related 30-day mortality rate was 0.2% (4 of 1,714 patients). Most bloodstream infections were attributed to Staphylococcus spp. (n = 11). In multivariate analysis, hematologic malignancy (hazard ratio [HR], 2.61; 95% confidence interval (CI), 1.15-5.92.; P = .02), hypoalbuminemia (albumin <3.5 g/dL; HR, 3.52; 95% CI: 1.48-8.36; P = .004), leukopenia (WBC <3,500 cells/μL; HR, 3.00; 95% CI: 1.11-8.09; P = .03), and diabetes mellitus (HR, 3.71; 95% CI: 1.57-8.83) remained statistically significant risk factors for early port infection., Conclusions: Hematologic malignancy, hypoalbuminemia, leukopenia, and diabetes mellitus at the time of port placement were independent risk factors for early port infections., (Copyright © 2020 SIR. Published by Elsevier Inc. All rights reserved.)

Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

Nocebo hyperalgesia is a clinically relevant phenomenon and may be formed as a result of associative learning, implemented by classical conditioning. This study explored for the first time distinct nocebo conditioning methods and their consequences for nocebo attenuation methods. Healthy participants (N = 140) were recruited and randomized to the following nocebo hyperalgesia induction groups: conditioning with continuous reinforcement (CRF), conditioning with partial reinforcement (PRF), and a sham-conditioning control group. In the attenuation phase, counterconditioning was compared with extinction. During induction, participants experienced increased thermal pain in 100% of nocebo trials in the CRF groups, while in only 70% of nocebo trials in the PRF groups. During evocation, pain stimulation was equivalent across all trials. During attenuation, pain stimulation was decreased on nocebo trials relative to control trials for the counterconditioning groups, while pain remained equivalent across all trials for the extinction groups. Results showed that both PRF and CRF significantly induced nocebo hyperalgesia, but CRF was a more potent nocebo induction method, as compared to PRF. Counterconditioning was more effective than extinction in attenuating nocebo hyperalgesia. Neither CRF nor PRF resulted in resistance to extinction. However, compared with CRF, conditioning with PRF resulted in more resistance to counterconditioning. These findings demonstrate that the more ambiguous learning method of PRF can induce nocebo hyperalgesia and may potentially explain the treatment resistance and chronification seen in clinical practice. Further research is required to establish whether attenuation with counterconditioning is generalizable to clinical settings.

Background: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are the treatment of choice for select patients with peritoneal surface malignancies; however, the traditional open approach may be associated with significant morbidity. We evaluated postoperative outcomes with minimally invasive (MI) CRS and HIPEC., Methods: Review of our institutional database identified 47 patients who underwent optimal cytoreduction (CC0 or CC1). Those with a PCI ≤ 15 and primary malignancy of gastrointestinal origin were then selected for subgroup analysis. Multivariable regression was performed to identify factors impacting postoperative outcomes., Results: Demographic data did not significantly differ between open (n = 24) and minimally invasive (n = 9) groups. The MI group had a mean age of 57.34 ± 14.92, BMI of 27.03 ± 4.27, Charlson comorbidity score of 1.78 ± 1.72, and PCI of 5.56 ± 5.08. Mean time to flatus (days) was 2.78 in the MI group and 5.04 in the open group (p < 0.001), and mean length of IV analgesic use (days) was 3.11 in the MI group compared to 6.00 in the open group (p = 0.006). Mean length of stay (days) was 5.11 in the MI group and 8.67 in the open group (p = 0.033). Surgical approach (p = 0.037) and BMI (p = 0.039) were the only factors impacting length of stay., Conclusions: Minimally invasive CRS and HIPEC is an excellent option for low volume peritoneal disease of gastrointestinal origin. A minimally invasive approach yields faster return of bowel function, reduced postoperative analgesia requirements, and shorter hospital stay., Competing Interests: Declaration of competing interest The authors have no commercial interest in the subject of study., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The re-emergence of smallpox is an increasing and legitimate concern due to advances in synthetic biology. Vaccination programs against smallpox using the vaccinia virus vaccine ceased with the eradication of smallpox and, unlike many other countries, Australia did not use mass vaccinations. However, vaccinated migrants contribute to population immunity. Testing for vaccinia antibodies is not routinely performed in Australia, and few opportunities exist to estimate the level of residual population immunity against smallpox. Serological data on population immunity in Australia could inform management plans against a smallpox outbreak. Vaccinia antibodies were measured in 2003 in regular plasmapheresis donors at the Australian Red Cross Blood Service from New South Wales (NSW). The data were analysed to estimate the proportion of Australians in NSW with detectable serological immunity to vaccinia. The primary object of this study was to measure neutralising antibody titres against vaccinia virus. Titre levels in donor samples were determined by plaque reduction assay. To estimate current levels of immunity to smallpox infection, the decline in geometric mean titres (GMT) over time was projected using two values for the antibody levels estimated on the basis of different times since vaccination. The results of this study suggest that there is minimal residual immunity to the vaccinia virus in the Australian population. Although humoral immunity is protective against orthopoxvirus infections, cell-mediated immunity and immunological memory likely also play roles, which are not quantified by antibody levels. These data provide an immunological snapshot of the NSW population, which could inform emergency preparedness planning and outbreak control, especially concerning the stockpiling of vaccinia vaccine.

Vasculogenic mimicry (VM) is a mechanism whereby cancer cells form microvascular structures similar to three-dimensional channels to provide nutrients and oxygen to tumors. Unlike angiogenesis, VM is characterized by the development of new patterned three-dimensional vascular-like structures independent of endothelial cells. This phenomenon has been observed in many types of highly aggressive solid tumors. The presence of VM has also been associated with increased resistance to chemotherapy, low survival, and poor prognosis. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are non-coding RNAs that regulate gene expression at the post-transcriptional level through different pathways. In recent years, these tiny RNAs have been shown to be expressed aberrantly in different human malignancies, thus contributing to the hallmarks of cancer. In this context, miRNAs and lncRNAs can be excellent biomarkers for diagnosis, prognosis, and the prediction of response to therapy. In this review, we discuss the role that the tumor microenvironment and the epithelial-mesenchymal transition have in VM. We include an overview of the mechanisms of VM with examples of diverse types of tumors. Finally, we describe the regulation networks of lncRNAs-miRNAs and their clinical impact with the VM. Knowing the key genes that regulate and promote the development of VM in tumors with invasive, aggressive, and therapy-resistant phenotypes will facilitate the discovery of novel biomarker therapeutics against cancer as well as tools in the diagnosis and prognosis of patients., (Copyright © 2020 Hernández de la Cruz, López-González, García-Vázquez, Salinas-Vera, Muñiz-Lino, Aguilar-Cazares, López-Camarillo and Carlos-Reyes.)

Objective: To implement a quality improvement based system to measure and improve data quality in an observational clinical registry to support a Learning Healthcare System., Data Source: ImproveCareNow Network registry, which as of September 2019 contained data from 314,250 visits of 43,305 pediatric Inflammatory Bowel Disease (IBD) patients at 109 participating care centers., Study Design: The impact of data quality improvement support to care centers was evaluated using statistical process control methodology. Data quality measures were defined, performance feedback of those measures using statistical process control charts was implemented, and reports that identified data items not following data quality checks were developed to enable centers to monitor and improve the quality of their data., Principal Findings: There was a pattern of improvement across measures of data quality. The proportion of visits with complete critical data increased from 72 percent to 82 percent. The percent of registered patients improved from 59 percent to 83 percent. Of three additional measures of data consistency and timeliness, one improved performance from 42 percent to 63 percent. Performance declined on one measure due to changes in network documentation practices and maturation. There was variation among care centers in data quality., Conclusions: A quality improvement based approach to data quality monitoring and improvement is feasible and effective., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2019 The Author(s).)

The determination of lineages from strain-based molecular genotyping information is an important problem in tuberculosis. Mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) typing is a commonly used molecular genotyping approach that uses counts of the number of times pre-specified loci repeat in a strain. There are three main approaches for determining lineage based on MIRU-VNTR data - one based on a direct comparison to the strains in a curated database, and two others, on machine learning algorithms trained on a large collection of labeled data. All existing methods have limitations. The direct approach imposes an arbitrary threshold on how much a database strain can differ from a given one to be informative. On the other hand, the machine learning-based approaches require a substantial amount of labeled data. Notably, all three methods exhibit suboptimal classification accuracy without additional data. We explore several computational approaches to address these limitations. First, we show that eliminating the arbitrary threshold improves the performance of the direct approach. Second, we introduce RuleTB, an alternative direct method that proposes a concise set of rules for determining lineages. Lastly, we propose StackTB, a machine learning approach that requires only a fraction of the training data to outperform the accuracy of both existing machine learning methods. Our approaches demonstrate superior performance on a training dataset collected in New York City over 10 years, and the improvement in performance translates to a held-out testing set. We conclude that our methods provide opportunities for improving the determination of pathogenic lineages based on MIRU-VNTR data., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Cancer patients who better benefit from neoadjuvant chemotherapy (NeoCh) are those who achieve a successful pathological complete response (pCR) represented by the absence of residual disease. Unfortunately, no highly sensitive and specific tumor biomarkers for predicting the clinical response to NeoCh have yet been defined. The aim of the present study was to ascertain whether miR‑145‑5p could discriminate between pCR and no‑pCR in triple‑negative breast cancer patients that received a cisplatin/doxorubicin‑based neoadjuvant treatment. miR‑145‑5p expression was determined in breast tumors by quantitative RT‑PCR. Our data showed that miR‑145‑5p had a significant low expression (P<0.005) in patients that achieved pCR in comparison to the non‑responder group. Kaplan Meier analysis indicated that low levels of miR‑145‑5p were associated with increased disease‑free survival. In addition, receiver operating characteristic (ROC) curve analysis suggested that miR‑145‑5p is a good predictor of pCR (P<0.003, AUC=0.7899, 95% CI, 0.6382‑0.9416). Quantitative RT‑PCR expression analysis also revealed that miR‑145‑5p was downregulated in four breast cancer cell lines relative to normal cells. To study the functions of miR‑145‑5p, its expression was restored in triple‑negative MDA‑MB‑231 cells and its effects in cell proliferation were evaluated by MTT assays and in apoptosis using Annexin V experiments. Data revealed that ectopic expression of miR‑145‑5p resulted in a significant inhibition of cell proliferation and also induced apoptosis. Moreover, miR‑145‑5p led to sensitization of breast cancer cells to cisplatin therapy. In addition, western blot assays indicated that miR‑145‑5p downregulated the TGFβR2 protein. In conclusion, miR‑145‑5p could be a potential biomarker of clinical response to NeoCh in triple‑negative breast cancer. Functionally miR‑145‑5p may regulate cell proliferation, at least in part, by targeting TGFβR2.

Epigenetic mechanisms control gene expression during normal development and their aberrant regulation may lead to human diseases including cancer. Natural phytochemicals can largely modulate mammalian epigenome through regulation of mechanisms and proteins responsible for chromatin remodeling. Phytochemicals are mainly contained in fruits, seeds, and vegetables as well as in foods supplements. These compounds act as powerful cellular antioxidants and anti-carcinogens agents. Several dietary compounds such as catechins, curcumin, genistein, quercetin and resveratrol, among others, exhibit potent anti-tumor activities through the reversion of epigenetic alterations associated to oncogenes activation and inactivation of tumor suppressor genes. In this review, we summarized the actual knowledge about the role of dietary phytochemicals in the restoration of aberrant epigenetic alterations found in cancer cells with a particular focus on DNA methylation and histone modifications. Furthermore, we discussed the mechanisms by which these natural compounds modulate gene expression at epigenetic level and described their molecular targets in diverse types of cancer. Modulation of epigenetic activities by phytochemicals will allow the discovery of novel biomarkers for cancer prevention, and highlights its potential as an alternative therapeutic approach in cancer.

Almost 55% to 80% of patients with breast cancer have an unfavorable pathological complete response to chemotherapy. MicroRNAs are small noncoding RNAs involved in cancer progression; however, their utility as predictors of pathological complete response to neoadjuvant chemotherapy is unclear. Here, we investigated if miR-143 could discriminate between pathological complete response and no-polymerase chain reaction of patients with locally advanced triple negative breast cancer that have received a fluorouracil-cisplatin/paclitaxel-based neoadjuvant treatment. Data showed that miR-143 exhibited a significant low expression ( P < .0006) in patients that achieved pathological complete response in comparison to nonresponder group. Receiver operating characteristic curve analysis suggested that miR-143 could be a good predictor of pathological complete response (area under curve = 0.849, P < .0006). Moreover, Kaplan-Meier analysis indicated that before neoadjuvant therapy low levels of miR-143 were associated to increased disease free survival. To gain insights into cellular functions of miR-143, we firstly showed that miR-143 was severely repressed in breast cancer cell lines and tumors in comparison to normal mammary cells and tissues. Ectopic restoration of miR-143 using RNA mimics inhibited both cell proliferation and migration and sensitized breast cancer cells to cisplatin therapy in vitro. To decipher the signaling networks regulated by miR-143, we used a high-throughput enzyme-linked immunosorbent assay-based phosphorylation antibody array. Phospho-proteomic profiling revealed that miR-143 coordinately reduced the protein levels and phosphorylation status of multiple oncoproteins involved in AKT, WNT/β-catenin, SAPK/JNK, FAK, and JAK/STAT signaling pathways. Moreover, low miR-143 and high GSK3-β, RAF1, paxillin, and p21CIP1 expression levels in a large cohort of patients with breast cancer were associated with worst outcome. In summary, miR-143 could be a potential predictor of response to neoadjuvant therapy and it may function as a divergent regulator of diverse signaling networks to suppress cell proliferation and migration in breast cancer.

RNA-based multi-target therapies focused in the blocking of signaling pathways represent an attractive approach in cancer. Here, we uncovered a miR-204 cooperative targeting of multiple signaling transducers involved in vasculogenic mimicry (VM). Our data showed that invasive triple negative MDA-MB-231 and Hs-578T breast cancer cells, but not poorly invasive MCF-7 cells, efficiently undergoes matrix-associated VM under hypoxia. Ectopic restoration of miR-204 in MDA-MB-231 cells leads to a potent inhibition of VM and reduction of number of branch points and patterned 3D channels. Further analysis of activation state of multiple signaling pathways using Phosphorylation Antibody Arrays revealed that miR-204 reduced the expression and phosphorylation levels of 13 proteins involved in PI3K/AKT, RAF1/MAPK, VEGF, and FAK/SRC signaling. In agreement with phospho-proteomic profiling, VM was impaired following pharmacological administration of PI3K and SRC inhibitors. Mechanistic studies confirmed that miR-204 exerts a negative post-transcriptional regulation of PI3K-α and c-SRC proto-oncogenes. Moreover, overall survival analysis of a large cohort of breast cancer patients indicates that low miR-204 and high FAK/SRC levels were associated with worst outcomes. In conclusion, our study provides novel lines of evidence indicating that miR-204 may exerts a fine-tuning regulation of the synergistic transduction of PI3K/AKT/FAK mediators critical in VM formation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: Because identification of intimate partner violence (IPV) in health care settings is low and strangulation increases lethality risk among women experiencing IPV, we examined the prevalence and correlates of nonfatal strangulation among 1,008 women survivors of IPV., Methods: Trained researchers conducted semistructured interviews with women survivors of IPV referred by police. Multinomial logistic regression examined differential correlates of attempted, completed, and multiple strangulation., Results: Interviews were conducted with 71.14% of eligible women contacted by researchers. A high proportion (79.66%) of the women interviewed experienced attempted (11.70%), completed (30.16%), or multiple (37.80%) strangulation. Each form of strangulation was independently significantly associated with sexual violence when compared with no strangulation. African American women were at increased risk of attempted (adjusted relative risk ratio [ARR], 2.02; p < .05), completed (ARR, 1.79; p < .05), and multiple strangulation (ARR, 2.62; p < .001). Compared with no strangulation, multiple strangulation was associated with more IPV injury and risk factors for homicide, including loss of consciousness (ARR, 2.95; p < .05) and miscarriage (ARR, 5.08; p < .05). Women who had lost consciousness owing to strangulation were more likely to seek medical care than those who had been strangled but had not lost consciousness (p < .01)., Conclusions: Strangulation is a prevalent form of IPV that presents significant health risks to women. Women's health practitioners are optimally positioned to identify subtle signs and symptoms of strangulation, help women to understand the delayed sequelae and potential future fatality associated with strangulation, and connect them with appropriate resources to reduce the risk of morbidity and mortality., (Copyright © 2017 Jacobs Institute of Women's Health. Published by Elsevier Inc. All rights reserved.)

Close monitoring of nutritional status is critical to the overall health of a patient with CF. As part of routine CF care, measurement of weight and height (and calculation of weight/length or BMI as appropriate) should be performed and analyzed at each visit. Early recognition of nutritional risk is imperative and evaluation with a multidisciplinary team should be performed to assess for caloric intake, caloric malabsorption, and other causes of poor weight gain and growth. Many tools are available to use for intervention, including oral supplementation, behavioral interventions, medications, nutritional therapies, and enteral tube feeding., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Immunogenic cell death is a cell death modality that stimulates the immune system to combat cancer cells. IMMUNEPOTENT CRP (ICRP) is a mixture of substances of low molecular weight obtained from bovine spleens that exhibits in vitro cytotoxic activity on different tumor cell lines and modulates the immune response in vivo . The aim of the present study was to determine whether the cytotoxic effect of ICRP and its combination with oxaliplatin (OXP) on murine melanoma B16F10 cells was due to immunogenic cell death. The cytotoxic assay was performed using flow cytometry to detect Annexin V and propidium iodide staining, and calreticulin (CRT) exposure. Adenosine triphosphate, heat shock protein (HSP) 70, HSP90 and high mobility group box 1 (HMGB1) release were identified using bioluminescence, western blot and ELISA assays, respectively. The present in vitro study demonstrated that treatments with ICRP or OXP induced cell death in a time-dependent manner, but treatment with the combination of ICRP + OXP increased the cytotoxic effect following 24 h of treatment. CRT exposure and release of adenosine triphosphate (ATP), HSP70, HSP90 and HMGB1 were induced by treatment with ICRP, and the combination of ICRP + OXP increased the exposure and release of damage-associated molecular patterns (DAMPs), while OXP treatment only induced CRT exposure, ATP and HMGB1 release. The in vivo experiments demonstrated that administration of tumor-derived DAMP-rich cell lysates derived from B16F10 cells treated with ICRP and the combination of ICRP + OXP prevented melanoma growth; however, OXP treatment did not. These results suggested that IMMUNEPOTENT CRP may be used as an agent to increase the ability of antitumor drugs to induce immunogenic cell death and prevent the growth of melanoma.

Background: Meditation is increasingly showing beneficial effects for psychiatric disorders. However, learning to meditate is not straightforward as there are no easily discernible outward signs of performance and thus no direct feedback is possible. As meditation has been found to correlate with posterior cingulate cortex (PCC) activity, we tested whether source-space EEG neurofeedback from the PCC followed the subjective experience of effortless awareness (a major component of meditation), and whether participants could volitionally control the signal., Methods: Sixteen novice meditators and sixteen experienced meditators participated in the study. Novice meditators were briefly trained to perform a basic meditation practice to induce the subjective experience of effortless awareness in a progressively more challenging neurofeedback test-battery. Experienced meditators performed a self-selected meditation practice to induce this state in the same test-battery. Neurofeedback was provided based on gamma-band (40-57Hz) PCC activity extracted using a beamformer algorithm. Associations between PCC activity and the subjective experience of effortless awareness were assessed by verbal probes., Results: Both groups reported that decreased PCC activity corresponded with effortless awareness (P<0.0025 for each group), with high median confidence ratings (novices: 8 on a 0-10 Likert scale; experienced: 9). Both groups showed high moment-to-moment median correspondence ratings between PCC activity and subjective experience of effortless awareness (novices: 8, experienced: 9). Both groups were able to volitionally control the PCC signal in the direction associated with effortless awareness by practicing effortless awareness meditation (novices: median % of time=77.97, P=0.001; experienced: 89.83, P<0.0005)., Conclusions: These findings support the feasibility of using EEG neurofeedback to link an objective measure of brain activity with the subjective experience of effortless awareness, and suggest potential utility of this paradigm as a tool for meditation training., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Equilibrium and kinetic properties of cyanide and imidazole binding to the heme domains of Sinorhizobium meliloti and Bradyrhizobium japonicum FixL (SmFixLH and BjFixLH) have been investigated between pH5 and 11. KD determinations were made at integral pH values, with the strongest binding at pH9 for both ligands. KD for the cyanide complexes of BjFixLH and SmFixLH is 0.15±0.09 and 0.50±0.20μM, respectively, and 0.70±0.01mM for imido-BjFixLH. The association rate constants are pH dependent with maximum values of 443±8 and 252±61M(-1)s(-1) for cyano complexes of BjFixLH and SmFixLH and (5.0±0.3)×10(4) and (7.0±1.4)×10(4)M(-1)s(-1) for the imidazole complexes. The dissociation rate constants are essentially independent of pH above pH5; (1.2±0.3)×10(-4) and (1.7±0.3)×10(-4)s(-1) for the cyano complexes of BjFixLH and SmFixLH, and (73±19) and (77±14) s(-1) for the imidazole complexes. Two ionizable groups in FixLH affect the rate of ligand binding. The more acidic group, identified as the heme 6 propionic acid, has a pKa of 7.6±0.2 in BjFixLH and 6.8±0.2 in SmFixLH. The second ionization is due to formation of hydroxy-FixLH with pKa values of 9.64±0.05 for BjFixLH and 9.61±0.05 for SmFixLH. Imidazole binding is limited by the rate of heme pocket opening with maximum observed values of 680 and 1270s(-1) for BjFixLH and SmFixLH, respectively., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Coumarins have attracted intense interest in recent years due to their apoptogenic effects. The aim of the present study was to determine whether 7-hydroxycoumarin (7-HC) induces changes in caspase-3 (C-3) activity in A549 human lung carcinoma cells. A range of analytical techniques, including colorimetric and fluorometric assays, western blotting, single-cell microinjection, fluorescence microscopy and image analysis were conducted to elucidate the effects of 7-HC. A 24-h exposure to 1.85 mM 7-HC induced a 65% increase in C-3 activity, and a notable conversion of procaspase-3 to C-3, in addition to poly(ADP-ribose)polymerase cleavage. Furthermore, morphological changes associated with apoptosis were observed. Exposure of the cells to 7-HC for 3 or 6 h increased calcium conductance by 27%. By performing the single-cell microinjection of a specific fluorescent substrate of C-3 into previously 7-HC-exposed cells, a typical enzymatic kinetic profile of C-3 activation was identified a number of hours prior to the morphological and biochemical changes associated with apoptosis being observed. These results suggest that the rapid in vivo activation of C-3 is induced by 7-HC, the most relevant biotransformation product of coumarin in humans.

Background: Fructose intake is associated with non-alcoholic fatty liver disease (NAFLD) development., Objective: The objective of this study was to measure fructose absorption/metabolism in paediatric NAFLD compared with obese and lean controls., Methods: Children with histologically proven NAFLD, and obese and lean controls received oral fructose (1 g kg(-1) ideal body weight). Serum glucose, insulin, uric acid, and fructose, urine uric acid, urine fructose, and breath hydrogen levels were measured at baseline and multiple points until 360 min after fructose ingestion., Results: Nine NAFLD (89% Hispanic, mean age 14.3 years, mean body mass index [BMI] 35.3 kg m(-2)), six obese controls (67% Hispanic, mean age 12.7 years, mean BMI 31.0 kg m(-2)) and nine lean controls (44% Hispanic, mean age 14.3 years, mean BMI 19.4 kg m(-2)) were enrolled. Following fructose ingestion, NAFLD vs. lean controls had elevated serum glucose, insulin and uric acid (P < 0.05), higher urine uric acid (P = 0.001), but lower fructose excretion (P = 0.002) and lower breath hydrogen 180-min AUC (P = 0.04). NAFLD vs. obese controls had similar post-fructose serum glucose, insulin, urine uric acid and breath hydrogen, but elevated serum uric acid (P < 0.05) and lower urine fructose excretion (P = 0.02)., Conclusions: Children with NAFLD absorb and metabolize fructose more effectively than lean subjects, associated with an exacerbated metabolic profile following fructose ingestion., (© 2014 The Authors. Pediatric Obesity © 2014 World Obesity.)

Objective: The optimal management of fingertip injuries is a much debated topic. Surgical and nonsurgical options, including treatment with dressings alone, have comparable results. IV3000 is a semi-occlusive dressing with a high reactive moisture vapour transmission rate (MVTR) compared to its alternatives. As the fingertip is crucial to hand function, determining the optimal dressing to treat these injuries is of clinical importance. The aim of this study is to collect preliminary data on the IV dressing when used to treat fingertip injuries., Method: Patients were recruited from the department of orthopaedic surgery outpatient clinic. Inclusion criteria were a fingertip injury with skin loss and emergency department treatment consistent with the study protocol, including washing the fingertip, simple debridement as required, administration of antibiotics, tetanus prophylaxis, and fingertip dressed with the IV dressing., Results: Fingertip injuries (15) from 13 male patients were identified. With the exception of one, all injuries were treated with the IV dressing and were included in the analysis. The treatment outcome of 13 injuries was rated as 'satisfactory' by the patients, while one was rated 'indifferent'. The latter was on one of two patients with injuries to two digits. No patient reported their outcome as 'unsatisfactory'. At the 18-24 months' follow-up, seven of the 14 affected digits had some degree of hypersensitivity, eight regained normal pulp thicknesses, one had thickened padding, and five had reduced pulp volume. All but one patient reported some degree of numbness. Nail involvement was seen in 11 injuries, all of which continued to have some degree of nail deformity., Conclusion: The IV dressing provides satisfactory outcomes when used to treat fingertip injuries. As the dressing possesses properties that suggest it would result in a superior healing environment compared to other semi-occlusive dressings, a prospective, randomised control trial should be conducted to determine whether these properties translate into superior outcomes when used to treat fingertip injuries.

Background: Patients with prior positive tuberculin skin test (TST) results may benefit from prophylaxis after repeat exposure to infectious tuberculosis (TB)., Objective: To evaluate factors associated with active TB disease among persons with prior positive TST results named as contacts of persons with infectious TB., Design: Population-based retrospective cohort study., Participants: A total of 2,933 contacts with prior positive TST results recently exposed to infectious TB identified in New York City's TB registry during the period from January 1, 1997 through December 31, 2003., Main Measurements: Contacts developing active TB disease ≤ 4 years after exposure were identified and compared with those who did not, using Poisson regression analysis. Genotyping was performed on selected Mycobacterium tuberculosis-positive isolates., Key Results: Among contacts with prior positive TST results, 39 (1.3 %) developed active TB disease ≤ 4 years after exposure (≤ 2 years: 34). Risk factors for contacts that were independently associated with TB were age < 5 years (adjusted prevalence ratio [aPR] = 19.48; 95 % confidence interval [CI] = 7.15-53.09), household exposure (aPR = 2.60;CI = 1.30-5.21), exposure to infectious patients (i.e., cavities on chest radiograph, acid-fast bacilli on sputum smear; aPR = 1.9 3; CI = 1.01-3.71), and exposure to a U.S.-born index patient (aPR = 4.04; CI = 1.95-8.38). Receipt of more than 1 month of treatment for latent TB infection following the current contact investigation was found to be protective (aPR = 0.27; CI =  .08-0.93). Genotype results were concordant with the index patients among 14 of 15 contacts who developed active TB disease and had genotyping results available., Conclusions: Concordant genotype results and a high proportion of contacts developing active TB disease within 2 years of exposure indicate that those with prior positive TST results likely developed active TB disease from recent rather than remote infection. Healthcare providers should consider prophylaxis for contacts with prior TB infection, especially young children and close contacts of TB patients (e.g., those with household exposure).

Genotyping results and epidemiologic investigation were used to confirm tuberculosis transmission from a cadaver to an embalmer. This investigation highlights the utility of genotyping in identifying unsuspected epidemiologic links and unusual transmission settings. In addition, the investigation provides additional evidence for the occupational risk of tuberculosis among funeral service workers and indicates a need for education about tuberculosis risk and the importance of adhering to appropriate infection control measures among funeral service workers., (Copyright © 2015 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

The glucose transporter GLUT1 at the blood-brain barrier (BBB) mediates glucose transport into the brain. Alzheimer's disease is characterized by early reductions in glucose transport associated with diminished GLUT1 expression at the BBB. Whether GLUT1 reduction influences disease pathogenesis remains, however, elusive. Here we show that GLUT1 deficiency in mice overexpressing amyloid β-peptide (Aβ) precursor protein leads to early cerebral microvascular degeneration, blood flow reductions and dysregulation and BBB breakdown, and to accelerated amyloid β-peptide (Aβ) pathology, reduced Aβ clearance, diminished neuronal activity, behavioral deficits, and progressive neuronal loss and neurodegeneration that develop after initial cerebrovascular degenerative changes. We also show that GLUT1 deficiency in endothelium, but not in astrocytes, initiates the vascular phenotype as shown by BBB breakdown. Thus, reduced BBB GLUT1 expression worsens Alzheimer's disease cerebrovascular degeneration, neuropathology and cognitive function, suggesting that GLUT1 may represent a therapeutic target for Alzheimer's disease vasculo-neuronal dysfunction and degeneration.

Background: Regulatory T-(Treg) and pro-inflammatory T-helper 17 (Th17) cells have been reported to be involved in the pathogenesis of pleural effusions caused by lung cancer. However, the presence of these subsets might not be a consequence of tumor pathogenesis, but rather a result of the pleural effusion itself, irrespective of its origin. In the present study, we analyzed the balance between these CD4+ T-cell subsets and compared them with those in non-malignant pleural effusions., Patients and Methods: We detected the frequencies of Treg and Th17 cells, identified as cluster of differentiation (CD)3+CD4+CD25+CD127low/- and CD3+CD4+ retinoid-related orphan receptor γt (RORγt)+ cells respectively, and proportions of interleukin (IL)17A-producing CD4+ cells in pleural effusions of patients with lung cancer, tuberculous and non-chronic pathologies by flow cytometry. The cytokine profile of stimulated CD4+ T-cells from tuberculosis and cancer groups was compared., Results: The proportion of Th17 cells were increased whereas Tregs were decreased in both tuberculosis and cancer, but not in non-chronic pathologies. Nevertheless, CD4+ T-cells from lung cancer effusions secreted interferon (IFN)γ, IL6 and IL17A, whereas CD4+ T-cells from tuberculous effusions secreted IL10 and low levels of IFNγ., Conclusion: Although effusions from patients with chronic pathologies presented higher proportions of Th17 cells in comparison to those with non-chronic pathologies, only Th17 cells from malignant effusions maintained their proinflammatory profile after stimulation. Thus, in the pleural compartment of patients with lung cancer, a proinflammatory environment might be favored and possibly maintained by Th17 response., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Lung cancer is the leading cause of cancer death worldwide. Adenocarcinoma, the most commonly diagnosed histologic type of lung cancer, is associated with smoking. Cigarette smoke promotes inflammation on the airways, which might be mediated by Th17 cells. This inflammatory environment may contribute to tumor development. In contrast, some reports indicate that tumors may induce immunosuppressive Treg cells to dampen immune reactivity, supporting tumor growth and progression. Thus, we aimed to analyze whether chronic inflammation or immunosuppression predominates at the systemic level in lung adenocarcinoma patients, and several cytokines and Th17 and Treg cells were studied. Higher proportions of IL-17-producing CD4(+) T-cells were found in smoking control subjects and in lung adenocarcinoma patients compared to nonsmoking control subjects. In addition, lung adenocarcinoma patients increased both plasma concentrations of IL-2, IL-4, IL-6, and IL-10, and proportions of Latency Associated Peptide (LAP) TGF-β subset of CD4(+)CD25(+)CD127(-) Treg cells, which overexpressed LAP TGF-β. This knowledge may lead to the development of immunotherapies that could inhibit the suppressor activity mediated by the LAP TGF-β subset of CD4(+)CD25(+)CD127(-) Treg cells to promote reactivity of immune cells against lung adenocarcinoma cells.

We have previously reported that Vivax Malaria Protein 001 (VMP001), a vaccine candidate based on the circumsporozoite protein of Plasmodium vivax, is immunogenic in mice and rhesus monkeys in the presence of various adjuvants. In the present study, we evaluated the immunogenicity and efficacy of VMP001 formulated with a TLR9 agonist in a water-in-oil emulsion. Following immunization, the vaccine efficacy was assessed by challenging Aotus nancymaae monkeys with P. vivax sporozoites. Monkeys from both the low- and high-dose vaccine groups generated strong humoral immune responses to the vaccine (peak median titers of 291,622), and its subunits (peak median titers to the N-term, central repeat and C-term regions of 22,188; 66,120 and 179,947, respectively). 66.7% of vaccinated monkeys demonstrated sterile protection following challenge. Protection was associated with antibodies directed against the central repeat region. The protected monkeys had a median anti-repeat titer of 97,841 compared to 14,822 in the non-protected monkeys. This is the first report demonstrating P. vivax CSP vaccine-induced protection of Aotus monkeys challenged with P. vivax sporozoites.

Behavioral issues are a frequent problem in the pediatric population. Often, these are evaluated and considered to be psychiatric in origin. We report on a pediatric patient who presented with severe behavioral disturbance and developed organic symptoms including hypoventilation and dysautonomia and who was ultimately diagnosed with ROHHADNET syndrome, a syndrome of rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation associated with a neuroendocrine tumor. Autopsy findings revealed novel findings of the syndrome, including hypothalamic encephalitis., (Copyright © 2014 by the American Academy of Pediatrics.)

Background: The use of plasma-derived immunoglobulin G (IgG) is increasing, and the number of diseases, including immunodeficiencies, neurological diseases and autoimmune conditions, treated with intravenous IgG (IVIG) is expanding. Consequently, there is a great need for high-yield production processes for plasma-derived IgG. The aim of this work was to develop a high-yield process leading to a highly purified, liquid, ready-to-use IgG for intravenous use., Methods: Plasma from healthy, voluntary, non-remunerated donors was fractionated by ethanol precipitation. IgG was extracted from fraction II + III using a phosphate/acetate buffer, pH 4, and purified by chromatography., Results: Precipitation with 6% polyethylene glycol at pH 7 removed high molecular-weight contaminating proteins, aggregates and contaminating viruses. Ion exchange chromatography at pH 5.7 on serially connected anion and cation exchange columns allowed for elution of IgG from the cation exchange column in good yield and high purity. Further safety was achieved by solvent/detergent treatment and repeated ion exchange chromatography. The product consisted of essentially only IgG monomers and dimers, and had a high purity with very low levels of IgM and IgA., Conclusion: A process providing highly purified IVIG in good yield was developed.

Background: Elderly people do not mount strong immune responses to vaccines. We compared 23-valent capsular polysaccharide (23vPPV) alone versus 7-valent conjugate (PCV7) vaccine followed by 23vPPV 6 months later in hospitalized elderly., Methods: Participants were randomized to receive 23vPPV or PCV7-23vPPV. Antibodies against serotypes 3, 4, 6A, 6B, 9V, 14, 18C, 19A, 19F, 23F were measured by enzyme-linked immunosorbent (ELISA) and opsonophagocytic (OPA) assays at baseline, 6 months and 12 months., Results: Of 312 recruited, between 40% and 72% of subjects had undetectable OPA titres at baseline. After one dose, PCV7 recipients had significantly higher responses to serotypes 9V (both assays) and 23F (OPA only), and 23vPPV recipients had significantly higher responses to serotype 3 (ELISA), 19F and 19A (OPA only). In subjects with undetectable OPA titres at baseline, a proportionately greater rise in OPA titre (P<0.01) was seen for all serotypes after both vaccines. The GMT ratio of OPA was significantly higher at 12 months in the PCV7-23vPPV group for serotypes 6A, 9V, 18C and 23F. OPA titre levels for these serotypes increased moderately after 6 months, whereas immunity waned in the 23vPPV only arm., Conclusion: We did not show overwhelming benefit of one vaccine over the other. Low baseline immunity does not preclude a robust immune response, reiterating the importance of vaccinating the frail elderly. A schedule of PCV7-23vPPV prevents waning of antibody, suggesting that both vaccines could be useful in the elderly. Follow up studies are needed to determine persistence of immunity., Trial Registration: The Australian Clinical Trials Registry ACTRN12607000387426.

Objective: To determine whether obstructive sleep apnea (OSA) and/or nocturnal hypoxemia are associated with the severity of liver injury in patients with pediatric nonalcoholic fatty liver disease (NAFLD)., Study Design: Obese children aged 10-18 years with liver biopsy-proven NAFLD were enrolled. Demographic, clinical, and laboratory data were collected, polysomnography was performed, and liver histology was scored. Subjects were divided into those with OSA/hypoxemia and those without OSA/hypoxemia for analysis., Results: Of 25 subjects with NAFLD, OSA/hypoxemia was present in 15 (60%) (mean age, 12.8 ± 1.9 years; 68% male; 88% Hispanic; mean body mass index z-score, 2.3 ± 0.3). Subjects with and without OSA/hypoxemia had similar levels of serum aminotransferases, serum lipids, and inflammatory and insulin resistance markers. Although there were no differences between groups in the histological severity of steatosis, inflammation, ballooning degeneration, NAFLD activity score, or histological grade, subjects with OSA/hypoxemia had significantly more severe hepatic fibrosis. Moreover, oxygen saturation nadir during polysomnography was related to hepatic fibrosis stage (r = -0.49; P = .01) and aspartate aminotransferase level (r = 0.42; P < .05). Increasing percentage of time with oxygen saturation ≤90% was related to NAFLD inflammation grade (r = 0.44; P = .03), degree of hepatic steatosis (r = -0.50; P = .01), NAFLD activity score (r = 0.42; P = .04), aspartate aminotransferase level (r = 0.56; P = .004), and alanine aminotransferase level (r = 0.44; P = .03)., Conclusion: Moderate OSA/hypoxemia is common in pediatric patients with biopsy-proven NAFLD. OSA and the severity/duration of hypoxemia are associated with biochemical and histological measures of NAFLD severity., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Humans with ALS and transgenic rodents expressing ALS-associated superoxide dismutase (SOD1) mutations develop spontaneous blood-spinal cord barrier (BSCB) breakdown, causing microvascular spinal-cord lesions. The role of BSCB breakdown in ALS disease pathogenesis in humans and mice remains, however, unclear, although chronic blood-brain barrier opening has been shown to facilitate accumulation of toxic blood-derived products in the central nervous system, resulting in secondary neurodegenerative changes. By repairing the BSCB and/or removing the BSCB-derived injurious stimuli, we now identify that accumulation of blood-derived neurotoxic hemoglobin and iron in the spinal cord leads to early motor-neuron degeneration in SOD1(G93A) mice at least in part through iron-dependent oxidant stress. Using spontaneous or warfarin-accelerated microvascular lesions, motor-neuron dysfunction and injury were found to be proportional to the degree of BSCB disruption at early disease stages in SOD1(G93A) mice. Early treatment with an activated protein C analog restored BSCB integrity that developed from spontaneous or warfarin-accelerated microvascular lesions in SOD1(G93A) mice and eliminated neurotoxic hemoglobin and iron deposits. Restoration of BSCB integrity delayed onset of motor-neuron impairment and degeneration. Early chelation of blood-derived iron and antioxidant treatment mitigated early motor-neuronal injury. Our data suggest that BSCB breakdown contributes to early motor-neuron degeneration in ALS mice and that restoring BSCB integrity during an early disease phase retards the disease process.

The ribonucleoproteins (hnRNPs) have important roles in multiple aspects of nucleic acid metabolism and in the regulation of different cellular processes. Abnormal expression of hnRNPs has been reported in several types of cancer including lung, pancreatic, and gastric carcinomas. Heterogenous tumor cell populations generate a tumor microenvironment that can present normoxic, hypoxic, or acidic regions. The analysis of hnRNP transcriptional responses considering the changing nature of the tumor microenvironment is important to understand tumor cell survival under stress conditions. We analyzed the transcriptional response of hnRNPA0, A1, A2, B1, and A3 in lung tumor cell lines under acidosis, hypoxia, and serum deprivation conditions. We used qRT-PCR to obtain a relative quantification of the hnRNPA/B transcript levels. We found that the hnRNPA2 transcript was the most abundant, followed by B1, A0, and A1. Expression of hnRNPA3 was the lowest, although its transcript levels were the most constant. hnRNPA/B transcript levels in lung tumor cell lines responded to changes in the microenvironment; however, hnRNPB1 transcript levels relative to hnRNPA2 expression did no change in all tested stress conditions, indicating that the alternative splicing between these isoforms was constant. hnRNPA1, A2, and B1 transcript levels were upregulated under serum deprivation conditions; possibly to promote a migration phenotype. Our data provide new insights into the transcriptional responses of ribonucleoproteins that might favor tumor cell survival and migration.

This study focuses on the relationship between women's risk of homicide as measured by the Danger Assessment and 13 protective actions. Participants (N = 432) experienced an incident of police involved intimate partner violence (IPV) and subsequently completed a structured telephone interview. Most women in this sample experienced severe violence and were classified as being at high risk for homicide. Participants engaged in an average of 3.81 (SD = 2.73) protective actions. With the exception of the use of formal domestic violence services, women in the high-risk category were significantly more likely than women in the lower risk category to have used each of the protective actions examined. Implications for research and practice are discussed.

Background: Athletes suspected of being concussed are frequently evaluated on the side-line for self-reported symptoms which guide subsequent management and return-to-play decisions. Concussion-like symptoms have been shown to be influenced by prior participation in physical activity; however, the potential contribution of acute exercise on symptoms is not well understood., Objective: The purpose of this study was to systematically review the literature in order to further understand the acute effects of exercise on documented self-reported symptoms in both concussed and non-concussed individuals., Design: Systematic narrative review., Methods: Nine electronic databases were systematically searched using keywords and MeSH terms that included; self-reported symptoms, sports-related concussion, brain concussion, exercise and athletic injuries. In addition, an extensive search of the grey literature was conducted., Results: Of the 785 articles retrieved, only five met the inclusion criteria comprising a total of 295 concussed and non-concussed participants. In general, the mean symptom scores increased from pre-exercise to post-exercise levels immediately following acute bouts of exercise in both concussed and non-concussed individuals., Conclusion: Although the symptom scores increased following exercise in both concussed and non-concussed participants, this increase was only maintained for a relatively short duration. Thus, the application to real world situation is still to be established., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Neurovascular dysfunction contributes to Alzheimer's disease (AD). Cerebrovascular abnormalities and blood-brain barrier (BBB) damage have been shown in AD. The BBB dysfunction can lead to leakage of potentially neurotoxic plasma components in brain that may contribute to neuronal injury. Pericytes are integral in maintaining the BBB integrity. Pericyte-deficient mice develop a chronic BBB damage preceding neuronal injury. Moreover, loss of pericytes was associated with BBB breakdown in patients with amyotrophic lateral sclerosis. Here, we demonstrate a decrease in mural vascular cells in AD, and show that pericyte number and coverage in the cortex and hippocampus of AD subjects compared with neurologically intact controls are reduced by 59% and 60% (P < 0.01), and 32% and 33% (P < 0.01), respectively. An increase in extravascular immunoglobulin G (IgG) and fibrin deposition correlated with reductions in pericyte coverage in AD cases compared with controls; the Pearson's correlation coefficient r for the magnitude of BBB breakdown to IgG and fibrin vs. reduction in pericyte coverage was -0.96 (P < 0.01) and -0.81 (P < 0.01) in the cortex, respectively, and -0.86 (P < 0.01) and -0.98 (P < 0.01) in the hippocampus, respectively. Thus, deficiency in mural vascular cells may contribute to disrupted vascular barrier properties and resultant neuronal dysfunction during AD pathogenesis., (© 2012 The Authors; Brain Pathology © 2012 International Society of Neuropathology.)