The Effects of Hyperoxia on Sea-Level Exercise Performance, Training, and Recovery: A Meta-Analysis

Abstract

Background

Acute exercise performance can be limited by arterial hypoxemia, such that hyperoxia may be an ergogenic aid by increasing tissue oxygen availability. Hyperoxia during a single bout of exercise performance has been examined using many test modalities, including time trials (TTs), time to exhaustion (TTE), graded exercise tests (GXTs), and dynamic muscle function tests. Hyperoxia has also been used as a long-term training stimulus or a recovery intervention between bouts of exercise. However, due to the methodological differences in fraction of inspired oxygen (F_iO₂), exercise type, training regime, or recovery protocols, a firm consensus on the effectiveness of hyperoxia as an ergogenic aid for exercise training or recovery remains unclear.

Objectives

The aims of this study were to (1) determine the efficacy of hyperoxia as an ergogenic aid for exercise performance, training stimulus, and recovery before subsequent exercise; and (2) determine if a dose–response exists between F_iO₂ and exercise performance improvements.

Data Source

The PubMed, Web of Science, and SPORTDiscus databases were searched for original published articles up to and including 8 September 2017, using appropriate first- and second-order search terms.

Study Selection

English-language, peer-reviewed, full-text manuscripts using human participants were reviewed using the process identified in the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement.

Data Extraction

Data for the following variables were obtained by at least two of the authors: F_iO₂, wash-in time for gas, exercise performance modality, heart rate, cardiac output, stroke volume, oxygen saturation, arterial and/or capillary lactate, hemoglobin concentration, hematocrit, arterial pH, arterial oxygen content, arterial partial pressure of oxygen and carbon dioxide, consumption of oxygen and carbon dioxide, minute ventilation, tidal volume, respiratory frequency, ratings of perceived exertion of breathing and exercise, and end-tidal oxygen and carbon dioxide partial pressures.

Data Grouping

Data were grouped into type of intervention (acute exercise, recovery, and training), and performance data were grouped into type of exercise (TTs, TTE, GXTs, dynamic muscle function), recovery, and training in hyperoxia.

Data Analysis

Hedges' g effect sizes and 95% confidence intervals were calculated. Separate Pearson's correlations were performed comparing the effect size of performance versus F_iO₂, along with the effect size of arterial content of oxygen, arterial partial pressure of oxygen, and oxygen saturation.

Results

Fifty-one manuscripts were reviewed. The most common F_iO₂ for acute exercise was 1.00, with GXTs the most investigated exercise modality. Hyperoxia had a large effect improving TTE (g = 0.89), and small-to-moderate effects increasing TTs (g = 0.56), GXTs (g = 0.40), and dynamic muscle function performance (g = 0.28). An F_iO₂ ≥ 0.30 was sufficient to increase general exercise performance to a small effect or higher; a moderate positive correlation (r = 0.47–0.63) existed between performance improvement of TTs, TTE, and dynamic muscle function tests and F_iO₂, but not GXTs (r = 0.06). Exercise training and recovery supplemented with hyperoxia trended towards a large and small ergogenic effect, respectively, but the large variability and limited amount of research on these topics prevented a definitive conclusion.

Conclusion

Acute exercise performance is increased with hyperoxia. An F_iO₂ ≥ 0.30 appears to be beneficial for performance, with a higher F_iO₂ being correlated to greater performance improvement in TTs, TTE, and dynamic muscle function tests. Exercise training and recovery supplemented with hyperoxic gas appears to have a beneficial effect on subsequent exercise performance, but small sample size and wide disparity in experimental protocols preclude definitive conclusions.

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One to two hours of exercise each week nearly halves long term risk of depression, finds study

Exercising for one to two hours every week reduces the risk of developing depression by 44% compared with no regular leisure time physical activity, a large follow-up study has found.1Several surveys...

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Correction to: Tripeptides Restore the Number of Neuronal Spines under Conditions of In Vitro Modeled Alzheimer’s Disease

Abstract

On the page 553 Acknowledgements should be as follows: The study was supported by the Russian Science Foundation (grant 14-25-00024-P).

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Correction to: Possibility of Aggravation of Tissue Sclerosis after Injection of Multipotent Mesenchymal Stromal Cells Near the Forming Cicatrix in the Experiment

Abstract

The author name G. A. Chastikina should read G. A. Chastikin.

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Attentional Modulation of Envelope-Following Responses at Lower (93–109 Hz) but Not Higher (217–233 Hz) Modulation Rates

Abstract

Directing attention to sounds of different frequencies allows listeners to perceive a sound of interest, like a talker, in a mixture. Whether cortically generated frequency-specific attention affects responses as low as the auditory brainstem is currently unclear. Participants attended to either a high- or low-frequency tone stream, which was presented simultaneously and tagged with different amplitude modulation (AM) rates. In a replication design, we showed that envelope-following responses (EFRs) were modulated by attention only when the stimulus AM rate was slow enough for the auditory cortex to track—and not for stimuli with faster AM rates, which are thought to reflect 'purer' brainstem sources. Thus, we found no evidence of frequency-specific attentional modulation that can be confidently attributed to brainstem generators. The results demonstrate that different neural populations contribute to EFRs at higher and lower rates, compatible with cortical contributions at lower rates. The results further demonstrate that stimulus AM rate can alter conclusions of EFR studies.

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Biochemical and histopathological changes of subacute cadmium intoxication in male rats

Abstract

Biochemical and histopathological effects of subacute intoxication of rats with cadmium (Cd) were studied in rats. Twenty adult healthy male albino rats were randomly divided into two duplicate groups (five rats in each cage); (1) control group where rats were provided with standard diet and water ad-libitum, (2) Cd group where rats were subjected to freshly prepared Cd chloride solution (CdCl2) 200 mg/l in drinking water daily for 8 weeks, the whole duration of experiment. Blood samples were obtained after 4 weeks, via retro-orbital bleeding for separation of serum. Five rats were killed, each sacrifice by decapitation for collection of kidneys and heart. Disturbed renal and cardiac functions were achieved after 4 weeks as indicated by the increase of most biochemical parameters measured in the serum, renal, and cardiac tissues. Histopathological examination of kidneys and hearts showed pathological alterations in Cd-intoxicated rats after 4 and 8 weeks with hematoxylin and eosin (H&E) and Masson trichrome stains. It was concluded that subacute exposure of rats to Cd (200 mg/l) in drinking water daily induced glomerular shrinkage, focal renal, and cardiac fibrosis at 4 and 8 weeks.

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Silver diamine fluoride: 38% more effective than 12% in arresting caries

This randomised controlled trial compared 12 and 38 % silver diamine fluoride applied annually and bi-annually to kindergarten children. . 38% applied bi-annually was most effective providing a 9% additional benefit over an annual application.

The post Silver diamine fluoride: 38% more effective than 12% in arresting caries appeared first on National Elf Service.

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Wnt Signaling Inhibition Promotes Apoptosis in Sarcomas--Response

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Retraction: EGFR-Mediated Reactivation of MAPK Signaling Induces Acquired Resistance to GSK2118436 in BRAF V600E-Mutant NSCLC Cell Lines

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The IGF1R/INSR Inhibitor BI 885578 Selectively Inhibits Growth of IGF2-Overexpressing Colorectal Cancer Tumors and Potentiates the Efficacy of Anti-VEGF Therapy

Clinical studies of pharmacologic agents targeting the insulin-like growth factor (IGF) pathway in unselected cancer patients have so far demonstrated modest efficacy outcomes, with objective responses being rare. As such, the identification of selection biomarkers for enrichment of potential responders represents a high priority for future trials of these agents. Several reports have described high IGF2 expression in a subset of colorectal cancers, with focal IGF2 amplification being responsible for some of these cases. We defined a novel cut-off value for IGF2 overexpression based on differential expression between colorectal tumors and normal tissue samples. Analysis of two independent colorectal cancer datasets revealed IGF2 to be overexpressed at a frequency of 13% to 22%. An in vitro screen of 34 colorectal cancer cell lines revealed IGF2 expression to significantly correlate with sensitivity to the IGF1R/INSR inhibitor BI 885578. Furthermore, autocrine IGF2 constitutively activated IGF1R and Akt phosphorylation, which was inhibited by BI 885578 treatment. BI 885578 significantly delayed the growth of IGF2-high colorectal cancer xenograft tumors in mice, while combination with a VEGF-A antibody increased efficacy and induced tumor regression. Besides colorectal cancer, IGF2 overexpression was detected in more than 10% of bladder carcinoma, hepatocellular carcinoma and non-small cell lung cancer patient samples. Meanwhile, IGF2-high non-colorectal cancer cells lines displayed constitutive IGF1R phosphorylation and were sensitive to BI 885578. Our findings suggest that IGF2 may represent an attractive patient selection biomarker for IGF pathway inhibitors and that combination with VEGF-targeting agents may further improve clinical outcomes. Mol Cancer Ther; 16(10); 2223–33. ©2017 AACR.

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Ormeloxifene Suppresses Prostate Tumor Growth and Metastatic Phenotypes via Inhibition of Oncogenic {beta}-catenin Signaling and EMT Progression

Ormeloxifene is a clinically approved selective estrogen receptor modulator, which has also shown excellent anticancer activity, thus it can be an ideal repurposing pharmacophore. Herein, we report therapeutic effects of ormeloxifene on prostate cancer and elucidate a novel molecular mechanism of its anticancer activity. Ormeloxifene treatment inhibited epithelial-to-mesenchymal transition (EMT) process as evident by repression of N-cadherin, Slug, Snail, vimentin, MMPs (MMP2 and MMP3), β-catenin/TCF-4 transcriptional activity, and induced the expression of pGSK3β. In molecular docking analysis, ormeloxifene showed proficient docking with β-catenin and GSK3β. In addition, ormeloxifene induced apoptosis, inhibited growth and metastatic potential of prostate cancer cells and arrested cell cycle in G₀–G₁ phase via modulation of cell-cycle regulatory proteins (inhibition of Mcl-1, cyclin D1, and CDK4 and induction of p21 and p27). In functional assays, ormeloxifene remarkably reduced tumorigenic, migratory, and invasive potential of prostate cancer cells. In addition, ormeloxifene treatment significantly (P < 0.01) regressed the prostate tumor growth in the xenograft mouse model while administered through intraperitoneal route (250 μg/mouse, three times a week). These molecular effects of ormeloxifene were also observed in excised tumor tissues as shown by immunohistochemistry analysis. Our results, for the first time, demonstrate repurposing potential of ormeloxifene as an anticancer drug for the treatment of advanced stage metastatic prostate cancer through a novel molecular mechanism involving β-catenin and EMT pathway. Mol Cancer Ther; 16(10); 2267–80. ©2017 AACR.

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Epidermal Growth Factor Receptor (EGFR)-targeted Photoimmunotherapy (PIT) for the Treatment of EGFR-expressing Bladder Cancer

The use of light as a means of therapy for bladder cancer has a long history but has been hampered by a lack of tumor specificity and therefore, damage to the normal bladder mucosa. Here, we describe a targeted form of phototherapy called photoimmunotherapy (PIT), which targets EGFR-expressing bladder cancer. Anti-EGFR antibody panitumumab was labeled with the photoabsorber (PA), IRDye 700Dx (IR700), to create a panitumumab-IR700 antibody–PA conjugate that is activated by near-infrared radiation (NIR). Bladder cancer tissue microarray (TMA) and bladder cancer cell lines were analyzed for expression of EGFR. Mechanism of PIT-induced cell death was studied using proliferation assays, transmission electron microscopy (TEM), and production of reactive oxygen species. Finally, the in vivo effect was studied in xenografts. EGFR staining of TMAs showed that while most bladder cancers have expression of EGFR to a varying degree, squamous cell carcinomas (SCC) have the highest expression of EGFR. Panitumumab-IR700 activated by NIR light rapidly killed UMUC-5 cells, a bladder SCC line. Panitumumab alone, panitumumab-IR700 without NIR, or NIR alone had no effect on cells. TEM demonstrated that cell death is due to necrosis. Singlet oxygen species contributed toward cell death. NIR-PIT with panitumumab-IR700 reduced growth compared with only panitumumab-IR700–treated UMUC-5 xenograft tumors. PIT is a new targeted treatment for bladder cancer. Panitumumab-IR700–induced PIT selectively kills EGFR-expressing bladder cancer cells in vitro and in vivo and therefore warrants further therapeutic studies in orthotopic xenografts of bladder cancer and ultimately in patients. Mol Cancer Ther; 16(10); 2201–14. ©2017 AACR.

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The MET/AXL/FGFR Inhibitor S49076 Impairs Aurora B Activity and Improves the Antitumor Efficacy of Radiotherapy

Several therapeutic agents targeting HGF/MET signaling are under clinical development as single agents or in combination, notably with anti-EGFR therapies in non–small cell lung cancer (NSCLC). However, despite increasing data supporting a link between MET, irradiation, and cancer progression, no data regarding the combination of MET-targeting agents and radiotherapy are available from the clinic. S49076 is an oral ATP-competitive inhibitor of MET, AXL, and FGFR1-3 receptors that is currently in phase I/II clinical trials in combination with gefitinib in NSCLC patients whose tumors show resistance to EGFR inhibitors. Here, we studied the impact of S49076 on MET signaling, cell proliferation, and clonogenic survival in MET-dependent (GTL16 and U87-MG) and MET-independent (H441, H460, and A549) cells. Our data show that S49076 exerts its cytotoxic activity at low doses on MET-dependent cells through MET inhibition, whereas it inhibits growth of MET-independent cells at higher but clinically relevant doses by targeting Aurora B. Furthermore, we found that S49076 improves the antitumor efficacy of radiotherapy in both MET-dependent and MET-independent cell lines in vitro and in subcutaneous and orthotopic tumor models in vivo. In conclusion, our study demonstrates that S49076 has dual antitumor activity and can be used in combination with radiotherapy for the treatment of both MET-dependent and MET-independent tumors. These results support the evaluation of combined treatment of S49076 with radiation in clinical trials without patient selection based on the tumor MET dependency status. Mol Cancer Ther; 16(10); 2107–19. ©2017 AACR.

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Mechanisms of Resistance to NTRK Inhibitors and Therapeutic Strategies in NTRK1-Rearranged Cancers

Neurotrophic receptor tyrosine kinase 1 (NTRK1) gene rearrangement leads to constitutive activation of NTRK1, which induces high-transforming ability. NTRK-rearranged cancers have been identified in several cancer types, such as glioblastoma, non–small cell lung cancer, and colorectal cancer. Although there are currently no clinically approved inhibitors that target NTRK1, several tyrosine kinase inhibitors (TKI), such as entrectinib and LOXO-101, are in clinical trials. The purpose of this study was to identify potential mechanisms of resistance to NTRK inhibitors and find potential therapeutic strategies to overcome the resistance. We examined the sensitivity of TPM3-NTRK1-transformed Ba/F3 cells and TPM3-NTRK1-harboring KM12 cells to multiple NTRK inhibitors. Acquired NTRK inhibitor-resistant mutations were screened by N-ethyl-N-nitrosourea mutagenesis with Ba/F3-TPM3-NTRK1 cells or by the establishment of NTRK-TKI-resistant cells from KM12 cells continuously treated with NTRK-TKIs. We identified multiple novel NTRK-TKI resistance mutations in the NTRK1 kinase domain, including G595R, and insulin growth factor receptor type 1 (IGF1R) bypass pathway-mediated resistance. After identifying the resistance mechanisms, we performed drug screening with small-molecule inhibitors to overcome the resistance. As a result, we found that ponatinib and nintedanib effectively inhibited the survival of TPM3-NTRK1-G667C but not G595R mutants, both of which showed resistance to entrectinib or larotrectinib (LOXO-101). Furthermore, cabozantinib with an IGF1R inhibitor such as OSI-906 could overcome bypass pathway-mediated resistance. We developed a comprehensive model of acquired resistance to NTRK inhibitors in cancer with NTRK1 rearrangement and identified cabozantinib as a therapeutic strategy to overcome the resistance. Mol Cancer Ther; 16(10); 2130–43. ©2017 AACR.

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Dual Inhibition of NOX2 and Receptor Tyrosine Kinase by BJ-1301 Enhances Anticancer Therapy Efficacy via Suppression of Autocrine-Stimulatory Factors in Lung Cancer

NADPH oxidase–derived reactive oxygen species (ROS) potentiate receptor tyrosine kinase (RTK) signaling, resulting in enhanced angiogenesis and tumor growth. In this study, we report that BJ-1301, a hybrid of pyridinol and alpha-tocopherol, exerts anticancer effects by dual inhibition of NADPH oxidase and RTK activities in endothelial and lung cancer cells. BJ-1301 suppresses ROS production by blocking translocation of NADPH oxidase cytosolic subunits to the cell membrane, thereby inhibiting activation. The potency of RTK inhibition by BJ-1301 was lower than that of sunitinib (a multi-RTK inhibitor), but the inhibition of downstream signaling pathways (e.g., ROS generation) and subsequent biological changes (e.g., NOX2 induction) by BJ-1301 was superior. Consistently, BJ-1301 inhibited cisplatin-resistant lung cancer cell proliferation more than sunitinib did. In xenograft chick or mouse tumor models, BJ-1301 inhibited lung tumor growth, to an extent greater than that of sunitinib or cisplatin. Treatments with BJ-1301 induced regression of tumor growth, potentially due to downregulation of autocrine-stimulatory ligands for RTKs, such as TGFα and stem cell factor, in tumor tissues. Taken together, the current study demonstrates that BJ-1301 is a promising anticancer drug for the treatment of lung cancer. Mol Cancer Ther; 16(10); 2144–56. ©2017 AACR.

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Exposure-Response Analyses of Ramucirumab from Two Randomized, Phase III Trials of Second-line Treatment for Advanced Gastric or Gastroesophageal Junction Cancer

Ramucirumab is an IgG₁ monoclonal antibody specific for the vascular endothelial growth factor receptor-2. Ramucirumab, 8 mg/kg every 2 weeks, administered as monotherapy (REGARD) or in combination with paclitaxel (RAINBOW), was safe and effective in patients with previously treated advanced gastric or gastroesophageal junction (GEJ) cancer. We evaluated exposure–efficacy and exposure–safety relationships of ramucirumab from two randomized, placebo-controlled phase III trials. Sparse pharmacokinetic samples were collected, and a population pharmacokinetic analysis was conducted to predict ramucirumab minimum trough concentration at steady state (C_min,ss). Kaplan–Meier methods and Cox proportional hazards models were used to evaluate the ramucirumab exposure (C_min,ss)–efficacy relationship to overall survival (OS) and progression-free survival (PFS). Logistic regression analyses were used to evaluate exposure–safety relationships. Analyses included 321 ramucirumab + paclitaxel and 335 placebo + paclitaxel patients from RAINBOW and 72 ramucirumab and 35 placebo patients from REGARD. Exposure–efficacy analysis showed ramucirumab C_min,ss was a significant predictor of OS and PFS in both trials. Higher ramucirumab exposure was associated with longer OS and PFS. In RAINBOW, grade ≥3 hypertension, leukopenia, and neutropenia, but not febrile neutropenia, significantly correlated with C_min,ss, with increased exposure leading to increased incidence. Exploratory exposure–response analyses suggest a positive relationship between efficacy and ramucirumab exposure with manageable toxicities at exposures generated from a dose of 8 mg/kg ramucirumab given every 2 weeks for patients with advanced gastric/GEJ cancer. These findings suggest an opportunity to further optimize benefit versus risk profiles of ramucirumab treatment in patients with gastric/GEJ cancer. Mol Cancer Ther; 16(10); 2215–22. ©2017 AACR.

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Efficacy of AKT Inhibitor ARQ 092 Compared with Sorafenib in a Cirrhotic Rat Model with Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related mortality worldwide. The AKT pathway has been found activated in 50% of HCC cases, making it a promising target. Therefore, we assess efficacy of the allosteric AKT inhibitor ARQ 092 compared with untreated control and standard treatment, sorafenib, in vitro and in vivo. ARQ 092 blocked phosphorylation of AKT in vitro and strongly inhibited cell growth with significantly higher potency than sorafenib. Similarly, apoptosis and cell migration were strongly reduced by ARQ 092 in vitro. To mimic human advanced HCC, we used a diethylnitrosamine-induced cirrhotic rat model with fully developed HCC. MRI analyses showed that ARQ 092 significantly reduced overall tumor size. Furthermore, number of tumors was decreased by ARQ 092, which was associated with increased apoptosis and decreased proliferation. Tumor contrast enhancement was significantly decreased in the ARQ 092 group. Moreover, on tumor tissue sections, we observed a vascular normalization and a significant decrease in fibrosis in the surrounding liver of animals treated with ARQ 092. Finally, pAKT/AKT levels in ARQ 092–treated tumors were reduced, followed by downregulation of actors of AKT downstream signaling pathway: pmTOR, pPRAS40, pPLC1, and pS6K1. In conclusion, we demonstrated that ARQ 092 blocks AKT phosphorylation in vitro and in vivo. In the HCC-rat model, ARQ 092 was well tolerated, showed antifibrotic effect, and had stronger antitumor effect than sorafenib. Our results confirm the importance of targeting AKT in HCC. Mol Cancer Ther; 16(10); 2157–65. ©2017 AACR.

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JAK1/STAT3 Activation through a Proinflammatory Cytokine Pathway Leads to Resistance to Molecularly Targeted Therapy in Non-Small Cell Lung Cancer

Molecularly targeted drugs have yielded significant therapeutic advances in oncogene-driven non–small cell lung cancer (NSCLC), but a majority of patients eventually develop acquired resistance. Recently, the relation between proinflammatory cytokine IL6 and resistance to targeted drugs has been reported. We investigated the functional contribution of IL6 and the other members of IL6 family proinflammatory cytokine pathway to resistance to targeted drugs in NSCLC cells. In addition, we examined the production of these cytokines by cancer cells and cancer-associated fibroblasts (CAF). We also analyzed the prognostic significance of these molecule expressions in clinical NSCLC samples. In NSCLC cells with acquired resistance to targeted drugs, we observed activation of the IL6–cytokine pathway and STAT3 along with epithelial-to-mesenchymal transition (EMT) features. In particular, IL6 family cytokine oncostatin-M (OSM) induced a switch to the EMT phenotype and protected cells from targeted drug-induced apoptosis in OSM receptors (OSMRs)/JAK1/STAT3–dependent manner. The cross-talk between NSCLC cells and CAFs also preferentially activated the OSM/STAT3 pathway via a paracrine mechanism and decreased sensitivity to targeted drugs. The selective JAK1 inhibitor filgotinib effectively suppressed STAT3 activation and OSMR expression, and cotargeting inhibition of the oncogenic pathway and JAK1 reversed resistance to targeted drugs. In the analysis of clinical samples, OSMR gene expression appeared to be associated with worse prognosis in patients with surgically resected lung adenocarcinoma. Our data suggest that the OSMRs/JAK1/STAT3 axis contributes to resistance to targeted drugs in oncogene-driven NSCLC cells, implying that this pathway could be a therapeutic target. Mol Cancer Ther; 16(10); 2234–45. ©2017 AACR.

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The DNA-Binding Polyamine Moiety in the Vectorized DNA Topoisomerase II Inhibitor F14512 Alters Reparability of the Consequent Enzyme-Linked DNA Double-Strand Breaks

Poisons of topoisomerase II (TOP2) kill cancer cells by preventing religation of intermediate DNA breaks during the enzymatic process and thus by accumulating enzyme–drug–DNA complexes called TOP2 cleavage-complex (TOP2cc). F14512 is a highly cytotoxic polyamine-vectorized TOP2 inhibitor derived from etoposide and currently in clinical trials. It was shown in vitro that F14512 has acquired DNA-binding properties and that the stability of TOP2cc was strongly increased. Paradoxically, at equitoxic concentrations in cells, F14512 induced less DNA breaks than etoposide. Here, we directly compared etoposide and F14512 for their rates of TOP2cc production and resolution in human cells. We report that targeting of TOP2α and not TOP2β impacts cell killing by F14512, contrary to etoposide that kills cells through targeting both isoforms. Then, we show that despite being more cytotoxic, F14512 is less efficient than etoposide at producing TOP2α cleavage-complex (TOP2αcc) in cells. Finally, we report that compared with TOP2αcc mediated by etoposide, those generated by F14512 persist longer in the genome, are not dependent on TDP2 for cleaning break ends from TOP2α, are channeled to a larger extent to resection-based repair processes relying on CtIP and BRCA1 and promote RAD51 recruitment to damaged chromatin. In addition to the addressing of F14512 to the polyamine transport system, the properties uncovered here would be particularly valuable for a therapeutic usage of this new anticancer compound. More generally, the concept of increasing drug cytotoxicity by switching the repair mode of the induced DNA lesions via addition of a DNA-binding moiety deserves further developments. Mol Cancer Ther; 16(10); 2166–77. ©2017 AACR.

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Drug-related problems identified during medication review before and after the introduction of a clinical decision support system

Summary

What is known and objective

To facilitate the identification of drug-related problems (DRPs) during medication review, several tools have been developed. Explicit criteria, like Beers criteria or STOPP (Screening Tool of Older Peoples' Prescriptions) and START (Screening Tool to Alert doctors to Right Treatment) criteria, can easily be integrated into a clinical decision support system (CDSS). The aim of this study was to investigate the effect of adding a CDSS to medication review software on identifying and solving DRPs in daily pharmacy practice.

Methods

Pre- to post-analysis of clinical medication reviews (CMRs) performed by 121 pharmacies in 2012 and 2013, before and after the introduction of CDSS into medication review software. Mean number of DRPs per patient, type of DRPs and their resolution rates were compared in the pharmacies pre- and post-CDSS using paired t tests.

Results and discussion

In total, 9151 DRPs were identified in 3100 patients pre-CDSS and 15 268 DRPs were identified in 4303 patients post-CDSS. The mean number of identified DRPs per patient (aggregated per pharmacy) was higher after the introduction of CDSS (3.2 vs 3.6 P < .01). The resolution rate was lower post-CDSS (50% vs 44%; P < .01), which overall resulted in 1.6 resolved DRPs per patient in both groups (P = .93). After the introduction of CDSS, 41% of DRPs were detected by the CDSS. The resolution rate of DRPs generated by CDSS was lower than of DRPs identified without the help of CDSS (29% vs 55%; P < .01). The two most prevalent DRP types were "Overtreatment" and "Suboptimal therapy" in both groups. The prevalence of "Overtreatment" was equal in both groups (mean DRPs per patient: 0.84 vs 0.77; P = .22), and "Suboptimal therapy" was more frequently identified post-CDSS (mean DRPs per patient: 0.54 vs 1.1; P < .01).

What is new and conclusion

The introduction of CDSS to medication review software generated additional DRPs with a lower resolution rate. Structural assessment including a patient interview elicited the most relevant DRPs. Further development of CDSS with more specific alerts is needed to be clinical relevant.

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Scientific misdemeanor—are we regulated enough?

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New bone formation and trabecular bone microarchitecture of highly porous tantalum compared to titanium implant threads: A pilot canine study

Abstract

Aim

This study evaluated new bone formation activities and trabecular bone microarchitecture within the highly porous region of Trabecular Metal™ Dental Implants (TM) and between the threads of Tapered Screw-Vent® Dental Implants (TSV) in fresh canine extraction sockets.

Materials and methods

Eight partially edentulated dogs received four implants (4.1 mmD × 13 mmL) bilaterally in mandibular fresh extraction sockets (32 TM, 32 TSV implants), and allowed to heal for 2, 4, 8, and 12 weeks. Calcein was administered to label mineralizing bone at 11 and 4 days before euthanasia for dogs undergoing all four healing periods. Biopsies taken at each time interval were examined histologically. Histomorphometric assay was conducted for 64 unstained and 64 stained slides at the region of interest (ROI) (6 mm long × 0.35 mm deep) in the midsections of the implants. Topographical and chemical analyses were also performed.

Results

Histomorphometry revealed significantly more new bone in the TM than in the TSV implants at each healing time (p = .0014, .0084, .0218, and .0251). Calcein-labeled data showed more newly mineralized bone in the TM group than in the TSV group at 2, 8, and 12 weeks (p = .045, .028, .002, respectively) but not at 4 weeks (p = .081). Histologically TM implants exhibited more bone growth and dominant new immature woven bone at an earlier time point than TSV implants. The parameters representing trabecular bone microarchitecture corroborated faster new bone formation in the TM implants when compared to the TSV implants. TM exhibited an irregular faceted topography compared to a relatively uniform microtextured surface for TSV. Chemical analysis showed peaks associated with each implant's composition material, and TSV also showed peaks reflecting the elements of the calcium phosphate blasting media.

Conclusions and clinical implications

Results suggest that the healing pathway associated with the highly porous midsection of TM dental implant could enable faster and stronger secondary implant stability than conventional osseointegration alone; however, prospective clinical studies are needed to confirm these potential benefits in patients with low bone density, compromised healing, or prior implant failure.

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Four Daily Steps Can Improve Overall Health

CHICAGO, October 2, 2017 - Did you know that four simple steps, performed daily, can lead to better overall health? The American Dental Hygienists' Association , in partnership with the Wrigley Oral Healthcare Program , has kicked off National Dental Hygiene Month with a simple message for all families: "Brush, Floss, Rinse and Chew" every day can make a difference not only to oral health but overall health. Known as the "Daily 4," this campaign arms dental hygienists with conversation starters and educational materials that encourage patients to brush teeth twice daily, floss daily, rinse with an antimicrobial mouthwash daily and chew sugarfree gum for 20 minutes after meals.

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Vascular dementia

Vascular dementia: A common form of dementia in older persons that is due to cerebrovascular disease, usually with stepwise deterioration from a series of small strokes and a patchy distribution of neurologic deficits affecting some functions and not others. Symptoms include confusion, problems with recent memory, wandering or getting lost in familiar places, loss of bladder or bowel control (incontinence), emotional problems such as laughing or crying inappropriately, difficulty following instructions, and problems handling money. The damage is typically so slight that the change is noticeable only as a series of small steps. However, over time, as more small blood vessels in the brain are blocked, there is noticeable gradual mental decline. Vascular dementia commonly begins between the ages of 60 and 75 and affects men more often than women. Also known as multi-infarct dementia. See also CADASIL.

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One to two hours of exercise each week nearly halves long term risk of depression, finds study

Exercising for one to two hours every week reduces the risk of developing depression by 44% compared with no regular leisure time physical activity, a large follow-up study has found.1Several surveys...

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Effects of prostaglandin lipid mediators on agonist-induced lung endothelial permeability and inflammation

Prostaglandins (PG), the products of cyclooxygenase-mediated conversion of arachidonic acid, become upregulated in many situations including allergic response, inflammation, and injury, and exhibit a variety of biological activities. Previous studies described barrier-enhancing and anti-inflammatory effects of PGE₂ and PGI₂ on vascular endothelial cells (EC). Yet, the effects of other PG members on EC barrier and inflammatory activation have not been systematically analyzed. This study compared effects of PGE₂, PGI₂, PGF_2α, PGA₂, PGJ₂, and PGD₂ on human pulmonary EC. EC permeability was assessed by measurements of transendothelial electrical resistance and cell monolayer permeability for FITC-labeled tracer. Anti-inflammatory effects of PGs were evaluated by analysis of expression of adhesion molecule ICAM1 and secretion of soluble ICAM1 and cytokines by EC. PGE₂, PGI₂, and PGA₂ exhibited the most potent barrier-enhancing effects and most efficient attenuation of thrombin-induced EC permeability and contractile response, whereas PGI₂ effectively suppressed thrombin-induced permeability but was less efficient in the attenuation of prolonged EC hyperpermeability caused by interleukin-6 or bacterial wall lipopolysaccharide, LPS. PGD₂ showed a modest protective effect on the EC inflammatory response, whereas PGF_2α and PGJ₂ were without effect on agonist-induced EC barrier dysfunction. In vivo, PGE₂, PGI₂, and PGA₂ attenuated LPS-induced lung inflammation, whereas PGF_2α and PGJ₂ were without effect. Interestingly, PGD₂ exhibited a protective effect in the in vivo model of LPS-induced lung injury. This study provides a comprehensive analysis of barrier-protective and anti-inflammatory effects of different prostaglandins on lung EC in vitro and in vivo and identifies PGE₂, PGI₂, and PGA₂ as prostaglandins with the most potent protective properties.

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Role of LTBP4 in alveolarization, angiogenesis, and fibrosis in lungs

Deficiency of the extracellular matrix protein latent transforming growth factor-β (TGF-β)-binding protein-4 (LTBP4) results in lack of intact elastic fibers, which leads to disturbed pulmonary development and lack of normal alveolarization in humans and mice. Formation of alveoli and alveolar septation in pulmonary development requires the concerted interaction of extracellular matrix proteins, growth factors such as TGF-β, fibroblasts, and myofibroblasts to promote elastogenesis as well as vascular formation in the alveolar septae. To investigate the role of LTBP4 in this context, lungs of LTBP4-deficient (Ltbp4^–/–) mice were analyzed in close detail. We elucidate the role of LTBP4 in pulmonary alveolarization and show that three different, interacting mechanisms might contribute to alveolar septation defects in Ltbp4^–/– lungs: 1) absence of an intact elastic fiber network, 2) reduced angiogenesis, and 3) upregulation of TGF-β activity resulting in profibrotic processes in the lung.

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The beginnings of cardiac catheterization and the resulting impact on pulmonary medicine

The early history of cardiac catheterization has many interesting features. First, although it would be natural to assume that the procedure was initiated by cardiologists, two of the three people who shared the Nobel Prize for the discovery were pulmonologists, while the third was a urologist. The primary objective of the pulmonologists André Cournand and Dickinson Richards was to obtain mixed venous blood from the right heart so that they could use the Fick principle to calculate total pulmonary blood flow. Cournand's initial catheterization studies were prompted by his reading of an account by Werner Forssmann, who catheterized himself 12 years before. His bold experiment was one of the most bizarre in medical history. In the earliest studies that followed, Cournand and colleagues first passed catheters into the right atrium, and then into the right ventricle, and finally, the pulmonary artery. At the time, the investigators did not appreciate the significance of the low vascular pressures, nor that what they had done would revolutionize interventional cardiology. Within a year, William Dock predicted that there would be a very low blood flow at the top of the upright lung, and he proposed that this was the cause of the apical localization of pulmonary tuberculosis. The fact that the pulmonary vascular pressures are very low has many implications in lung disease. Cardiac catheterization changed the face of investigative cardiology, and its instigators were awarded the Nobel Prize in 1956.

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Exhaled breath condensate biomarkers for the early diagnosis of lung cancer using proteomics

We explored whether the proteomic analysis of exhaled breath condensate (EBC) may provide biomarkers for noninvasive screening for the early detection of lung cancer (LC). EBC was collected from 192 individuals [49 control (C), 49 risk factor-smoking (S), 46 chronic obstructive pulmonary disease (COPD) and 48 LC]. With the use of liquid chromatography and tandem mass spectrometry, 348 different proteins with a different pattern among the four groups were identified in EBC samples. Significantly more proteins were identified in the EBC from LC compared with other groups (C: 12.4 ± 1.3; S: 15.3 ± 1; COPD: 14 ± 1.6; LC: 24.2 ± 3.6; P = 0.0001). Furthermore, the average number of proteins identified per sample was significantly higher in LC patients, and receiver operating characteristic curve (ROC) analysis showed an area under the curve of 0.8, indicating diagnostic value. Proteins frequently detected in EBC, such as dermcidin and hornerin, along with others much less frequently detected, such as hemoglobin and histones, were identified. Cytokeratins (KRTs) were the most abundant proteins in EBC samples, and levels of KRT6A, KRT6B, and KRT6C isoforms were significantly higher in samples from LC patients (P = 0.0031, 0.0011, and 0.0009, respectively). Moreover, the amount of most KRTs in EBC samples from LC patients showed a significant positive correlation with tumor size. Finally, we used a random forest algorithm to generate a robust model using EBC protein data for the diagnosis of patients with LC where the area under the ROC curve obtained indicated a good classification (82%). Thus this study demonstrates that the proteomic analysis of EBC samples is an appropriated approach to develop biomarkers for the diagnosis of lung cancer.

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Mitochondrial quality control in alveolar epithelial cells damaged by S. aureus pneumonia in mice

Mitochondrial damage is often overlooked in acute lung injury (ALI), yet most of the lung's physiological processes, such as airway tone, mucociliary clearance, ventilation-perfusion (Va/Q) matching, and immune surveillance require aerobic energy provision. Because the cell's mitochondrial quality control (QC) process regulates the elimination and replacement of damaged mitochondria to maintain cell survival, we serially evaluated mitochondrial biogenesis and mitophagy in the alveolar regions of mice in a validated Staphylococcus aureus pneumonia model. We report that apart from cell lysis by direct contact with microbes, modest epithelial cell death was detected despite significant mitochondrial damage. Cell death by TdT-mediated dUTP nick-end labeling staining occurred on days 1 and 2 postinoculation: apoptosis shown by caspase-3 cleavage was present on days 1 and 2, while necroptosis shown by increased levels of phospho- mixed lineage kinase domain-like protein (MLKL) and receptor-interacting serine/threonine-protein kinase 1 (RIPK1) was present on day 1. Cell death in alveolar type I (AT₁) cells assessed by bronchoalveolar lavage fluid receptor for advanced glycation end points (RAGE) levels was high, yet AT₂ cell death was limited while both mitochondrial biogenesis and mitophagy were induced. These mitochondrial QC mechanisms were evaluated mainly in AT₂ cells by localizing increases in citrate synthase content, increases in nuclear mitochondrial biogenesis regulators nuclear respiratory factor-1 (NRF-1) and peroxisome proliferator-activated receptor- coactivator-1α (PGC-1α), and increases in light chain 3B protein (LC3-I)/LC3II ratios. Concomitant changes in p62, Pink 1, and Parkin protein levels indicated activation of mitophagy. By confocal microscopy, mitochondrial biogenesis and mitophagy were often observed on day 1 within the same AT₂ cells. These findings imply that mitochondrial QC activation in pneumonia-damaged AT₂ cells promotes cell survival in support of alveolar function.

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Macrolides protect against Pseudomonas aeruginosa infection via inhibition of inflammasomes

Macrolides antibiotics have been effectively used in many chronic diseases, especially with Pseudomonas aeruginosa (P. aeruginosa) infection. The mechanisms underlying the therapeutic effects of macrolides in these diseases remain poorly understood. We established a mouse model of chronic lung infection using P. aeruginosa agar-beads, with azithromycin treatment or placebo. Lung injury, bacterial clearance, and inflammasome-related proteins were measured. In vitro, the inflammasomes activation induced by flagellin or ATP were assessed in LPS-primed macrophages with or without macrolides treatment. Plasma IL-18 levels were determined from patients who were diagnosed with bronchiectasis isolated with or without P. aeruginosa and treated with azithromycin for 3–5 days. Azithromycin treatment enhanced bacterial clearance and attenuated lung injury in mice chronically infected with P. aeruginosa, which resulted from the inhibition of caspase-1-dependent IL-1β and IL-18 secretion. In vitro, azithromycin and erythromycin inhibited NLRC4 and NLRP3 inflammasomes activation. Plasma IL-18 levels were higher in bronchiectasis patients with P. aeruginosa isolation compared with healthy controls. Azithromycin administration markedly decreased IL-18 secretion in bronchiectasis patients. The results of this study reveal that azithromycin and erythromycin exert a novel anti-inflammatory effect by attenuating inflammasomes activation, which suggests potential treatment options for inflammasome-related diseases.

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Distinct PKA regulatory subunits mediate PGE2 inhibition of TGF{beta}-1-stimulated collagen I translation and myofibroblast differentiation

Prostaglandin E₂ (PGE₂), via cAMP signaling, inhibits a variety of fibroblast functions relevant to fibrogenesis. Among these are their translation of collagen I protein and their differentiation to myofibroblasts. PKA is central to these actions, with cAMP binding to regulatory (R) subunits leading to the release of catalytic subunits. Here we examined the role of specific PKAR subunit isoforms in these inhibitory actions in transforming growth factor β-1 (TGFβ-1)-stimulated human lung fibroblasts (HLFs). HLFs expressed all four R subunit isoforms. siRNA-mediated knockdown of subunits PKARIα and PKARIIα had no effect on PGE₂ inhibition of either process. However, knockdown of PKARIβ selectively attenuated PGE₂ inhibition of collagen I protein expression, whereas knockdown of PKARIIβ selectively attenuated PGE₂ inhibition of expression of the myofibroblast differentiation marker, α-smooth muscle actin (α-SMA). cAMP analogs that selectively activate either PKARIβ or PKARIIβ exclusively inhibited collagen I synthesis or differentiation, respectively. In parallel, the PKARIβ agonist (but not a PKARIIβ agonist) reduced phosphorylation of two proteins involved in protein translation, protein kinase B (AKT) and mammalian target of rapamycin (mTOR). By contrast, the PKARIIβ agonist (but not a PKARIβ agonist) reduced levels of the differentiation-associated phosphorylated focal adhesion kinase (p-FAK) as well as the relative mRNA and protein expression of serum response factor (SRF), a transcription factor necessary for myofibroblast differentiation. Our results demonstrate that cAMP inhibition of collagen I translation and myofibroblast differentiation reflects the actions of distinct PKAR subunits.

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Pleural effusion and molecular response in dasatinib-treated chronic myeloid leukemia patients in a real-life Italian multicenter series

Abstract

Pleural effusion (PE) represents the leading cause of dasatinib (DAS) discontinuation. However, the pathogenic mechanism of this adverse event (AE) is unknown and its management unclear. We investigated if a DAS dose reduction after the first PE would prevent the recurrence of this AE. We retrospectively collected data on all the cases of PE in CML-chronic phase (CP) DAS-treated patients from November 2005 to February 2017 in 21 Italian hematological centers. We identified 196 cases of PE in a series of 853 CML-CP DAS-treated patients (incidence 23.0%). DAS starting dose was 100 mg/day in 70.4% of patients, less than 100 mg/day in 14.3%, and more than 100 mg/day in the remaining cases. Median time from DAS start to PE was 16.6 months. At first PE development, 28.6% of patients were in MMR, and 37.8% in deep molecular response (DMR). DAS was temporary interrupted in 71.9% of cases, with a dose reduction in 59.2%. Recurrence was observed in 59.4% of the cases. Treatment was definitively discontinued due to PE in 29.1% of the cases. Interestingly, among patients whose DAS dosage was reduced, 59.5% experienced PE recurrence. DAS dose reduction after the first episode of PE did not prevent recurrence of this AE. Therefore, once a MMR or a DMR is achieved, different strategies of DAS dose management can be proposed prior to the development of PE, such as daily dose reduction or, as an alternative option, an on/off treatment with a weekend drug holiday.

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【About us】"CSR Report 2017" has been updated.

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Impact of mesenchymal stem cells’ secretome on glioblastoma pathophysiology

Glioblastoma (GBM) is a highly aggressive primary brain cancer, for which curative therapies are not available. An emerging therapeutic approach suggested to have potential to target malignant gliomas has been...

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Report on the first SLFN11 monothematic workshop: from function to role as a biomarker in cancer

SLFN11 is a recently discovered protein with a putative DNA/RNA helicase function. First identified in association with the maturation of thymocytes, SLFN11 was later causally associated, by two independent gr...

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Pleural effusion and molecular response in dasatinib-treated chronic myeloid leukemia patients in a real-life Italian multicenter series

Abstract

Pleural effusion (PE) represents the leading cause of dasatinib (DAS) discontinuation. However, the pathogenic mechanism of this adverse event (AE) is unknown and its management unclear. We investigated if a DAS dose reduction after the first PE would prevent the recurrence of this AE. We retrospectively collected data on all the cases of PE in CML-chronic phase (CP) DAS-treated patients from November 2005 to February 2017 in 21 Italian hematological centers. We identified 196 cases of PE in a series of 853 CML-CP DAS-treated patients (incidence 23.0%). DAS starting dose was 100 mg/day in 70.4% of patients, less than 100 mg/day in 14.3%, and more than 100 mg/day in the remaining cases. Median time from DAS start to PE was 16.6 months. At first PE development, 28.6% of patients were in MMR, and 37.8% in deep molecular response (DMR). DAS was temporary interrupted in 71.9% of cases, with a dose reduction in 59.2%. Recurrence was observed in 59.4% of the cases. Treatment was definitively discontinued due to PE in 29.1% of the cases. Interestingly, among patients whose DAS dosage was reduced, 59.5% experienced PE recurrence. DAS dose reduction after the first episode of PE did not prevent recurrence of this AE. Therefore, once a MMR or a DMR is achieved, different strategies of DAS dose management can be proposed prior to the development of PE, such as daily dose reduction or, as an alternative option, an on/off treatment with a weekend drug holiday.

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Distinct roles of Cep192 and Cep152 in acentriolar MTOCs and spindle formation during mouse oocyte maturation [Research]

Mammalian oocytes lack a centriole that acts as a microtubule organization center (MTOC) in most somatic cells. During oocyte maturation, MTOCs undergo remodeling processes, including decondensation, fragmentation, and self-organization. However, the underlying mechanisms of MTOC remodeling in mouse oocytes are not well understood. We showed that two pericentriolar proteins, Cep192 and Cep152, play crucial roles during MTOC remodeling in mouse oocytes. Cep192 is present in MTOCs at all stages of oocyte maturation, and its depletion induces ablation of MTOCs, delay in spindle formation, and abnormal chromosomal alignment in spindles. In the case of Cep152, its localization on MTOCs is limited at the germinal vesicle stage and then disappears from the MTOCs after the germinal vesicle breakdown stage. Cep152 exclusion from MTOCs is involved in the fragmentation of MTOCs, and it is regulated by cyclin-dependent kinase 1 activity. Our results demonstrate the different roles of Cep192 and Cep152 in MTOC remodeling and a novel regulatory mechanism during meiotic spindle formation in mouse oocytes.—Lee, I.-W., Jo, Y.-J., Jung, S.-M., Wang, H.-Y., Kim, N.-H., Namgoong, S. Distinct roles of Cep192 and Cep152 in acentriolar MTOCs and spindle formation during mouse oocyte maturation.

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Dietary methionine restriction modulates renal response and attenuates kidney injury in mice [Research]

Methionine restriction (MR) extends the lifespan across several species, such as rodents, fruit flies, roundworms, and yeast. MR studies have been conducted on various rodent organs, such as liver, adipose tissue, heart, bones, and skeletal muscle, to elucidate its benefits to the healthspan; however, studies of the direct effect of MR on kidneys are lacking. To investigate the renal effects of MR, we used young and aged unilateral nephrectomized and 5/6 nephrectomized (5/6Nx) mice. Our studies indicated that MR mice experienced polydipsia and polyuria compared with control-fed counterparts. Urine albumin, creatinine, albumin-to-creatinine ratio, sulfur amino acids, and electrolytes were reduced in MR mice. Kidneys of MR mice up-regulated genes that are involved in ion transport, such as Aqp2, Scnn1a, and Slc6a19, which indicated a response to maintain osmotic balance. In addition, we identified renoprotective biomarkers that are affected by MR, such as clusterin and cystatin C. Of importance, MR attenuated kidney injury in 5/6Nx mice by down-regulating inflammation and fibrosis mechanisms. Thus, our studies in mice show the important role of kidneys during MR in maintaining osmotic homeostasis. Moreover, our studies also show that the MR diet delays the progression of kidney disease.—Cooke, D., Ouattara, A., Ables, G. P. Dietary methionine restriction modulates renal response and attenuates kidney injury in mice.

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Identification and characterization of hydrophobic gate residues in TRP channels [Research]

Transient receptor potential (TRP) channels, subdivided into 6 subfamilies in mammals, have essential roles in sensory physiology. They respond to remarkably diverse stimuli, comprising thermal, chemical, and mechanical modalities, through opening or closing of channel gates. In this study, we systematically substituted the hydrophobic residues within the distal fragment of pore-lining helix S6 with hydrophilic residues and, based on Xenopus oocyte and mammalian cell electrophysiology and a hydrophobic gate theory, identified hydrophobic gates in TRPV6/V5/V4/C4/M8. We found that channel activity drastically increased when TRPV6_{Ala616 or Met617} or TRPV5_{Ala576 or Met577}, but not any of their adjacent residues, was substituted with hydrophilic residues. Channel activity strongly correlated with the hydrophilicity of the residues at those sites, suggesting that consecutive hydrophobic residues TRPV6_{Ala616-Met617} and TRPV5_{Ala576-Met577} form a double-residue gate in each channel. By the same strategy, we identified a hydrophobic single-residue gate in TRPV4_Iso715, TRPC4_Iso617, and TRPM8_Val976. In support of the hydrophobic gate theory, hydrophilic substitution at the gate site, which removes the hydrophobic gate seal, substantially increased the activity of TRP channels in low-activity states but had little effect on the function of activated channels. The double-residue gate channels were more sensitive to small changes in the gate's hydrophobicity or size than single-residue gate channels. The unconventional double-reside gating mechanism in TRP channels may have been evolved to respond especially to physiologic stimuli that trigger relatively small gate conformational changes.—Zheng, W., Hu, R., Cai, R., Hofmann, L., Hu, Q., Fatehi, M., Long, W., Kong, T., Tang, J., Light, P., Flockerzi, V., Cao, Y., Chen, X.-Z. Identification and characterization of hydrophobic gate residues in TRP channels.

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Heparanase regulates the M1 polarization of renal macrophages and their crosstalk with renal epithelial tubular cells after ischemia/reperfusion injury [Research]

Heparanase (HPSE) is part of the biologic network triggered by ischemia/reperfusion (I/R) injury, a complication of renal transplantation and acute kidney injury. During this period, the kidney or graft undergoes a process of macrophages recruitment and activation. HPSE may therefore control these biologic effects. We measured the ability of HPSE and its inhibitor, SST0001, to regulate macrophage polarization and the crosstalk between macrophages and HK-2 renal tubular cells during in vitro hypoxia/reoxygenation (H/R). Furthermore, we evaluated in vivo renal inflammation, macrophage polarization, and histologic changes in mice subjected to monolateral I/R and treated with SST0001 for 2 or 7 d. The in vitro experiments showed that HPSE sustained M1 macrophage polarization and modulated apoptosis, the release of damage associated molecular patterns in post-H/R tubular cells, the synthesis of proinflammatory cytokines, and the up-regulation of TLRs on both epithelial cells and macrophages. HPSE also regulated M1 polarization induced by H/R-injured tubular cells and the partial epithelial–mesenchymal transition of these epithelial cells by M1 macrophages. All these effects were prevented by inhibiting HPSE. Furthermore, the inhibition of HPSE in vivo reduced inflammation and M1 polarization in mice undergoing I/R injury, partially restored renal function and normal histology, and reduced apoptosis. These results show for the first time that HPSE regulates macrophage polarization as well as renal damage and repair after I/R. HPSE inhibitors could therefore provide a new pharmacologic approach to minimize acute kidney injury and to prevent the chronic profibrotic damages induced by I/R.—Masola, V., Zaza, G., Bellin, G., Dall'Olmo, L., Granata, S., Vischini, G., Secchi, M. F., Lupo, A., Gambaro, G., Onisto, M. Heparanase regulates the M1 polarization of renal macrophages and their crosstalk with renal epithelial tubular cells after ischemia/reperfusion injury.

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Cyanobacteria: promising biocatalysts for sustainable chemical production [Microbiology]

Cyanobacteria are photosynthetic prokaryotes showing great promise as biocatalysts for the direct conversion of CO2 into fuels, chemicals, and other value-added products. Introduction of just a few heterologous genes can endow cyanobacteria with the ability to transform specific central metabolites into many end products. Recent engineering efforts have centered around harnessing the potential of these microbial biofactories for sustainable production of chemicals conventionally produced from fossil fuels. Here, we present an overview of the unique chemistry that cyanobacteria have been co-opted to perform. We highlight key lessons learned from these engineering efforts and discuss advantages and disadvantages of various approaches.

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Role for Ribosome-Associated Complex and Stress-Seventy subfamily B (RAC-Ssb) in integral membrane protein translation [Protein Structure and Folding]

Targeting of most integral membrane proteins to the endoplasmic reticulum is controlled by the signal recognition particle (SRP), which recognizes a hydrophobic signal sequence near the protein N-terminus. Proper folding of these proteins is monitored by the unfolded protein response, and involves protein degradation pathways to ensure quality control. Here, we identify a new pathway for quality control of major facilitator superfamily transporters that occurs before the first transmembrane helix--the signal sequence recognized by SRP--is made by the ribosome. Increased rates of translation elongation of the N-terminal sequence of these integral membrane proteins can divert the nascent protein chains to the ribosome-associated complex (RAC) and Stress-Seventy Subfamily B (Ssb) chaperones. We also show that quality control of integral membrane proteins by RAC-Ssb couples translation rate to the unfolded protein response, which has implications for understanding mechanisms underlying human disease and protein production in biotechnology.

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Structural analyses of the MazEF4 toxin-antitoxin pair in Mycobacterium tuberculosis provide evidence for a unique extracellular death factor [Molecular Biophysics]

The bacterial toxin-antitoxin MazEF system in the tuberculosis (TB)-causing bacterium Mycobacterium tuberculosis is activated under unfavorable conditions, including starvation, antibiotic exposure, and oxidative stress. This system contains the ribonucleolytic enzyme MazF and has emerged as a promising drug target for TB treatments targeting the latent stage of M. tuberculosis infection and reportedly mediates a cell death process via a peptide called extracellular death factor (EDF). Although it is well established that the increase in EDFmediated toxicity of MazF drives a cell-killing phenomenon, the molecular details are poorly understood. Moreover, the divergence in sequences among reported EDFs suggests that each bacterial species has a unique EDF. To address these open questions, we report here the structures of MazF4 and MazEF4 complexes from M. tuberculosis, representing the first MazEF structures from this organism. We found that MazF4 possesses a negatively charged MazE4-binding pocket in contrast to the positively charged MazE-binding pockets in homologous MazEF complex structures from other bacteria. Moreover, using NMR spectroscopy and biochemical assays, we unraveled the molecular interactions of MazF4 with its RNA substrate and with a new EDF homolog originating from M. tuberculosis. The EDF homolog discovered here possesses a positively charged residue at the C-terminus, making this EDF distinct from previously reported EDFs. Overall, our results suggest that M. tuberculosis evolved a unique MazF and EDF and that the distinctive EDF sequence could serve as a starting point for designing new anti-tuberculosis drugs. We therefore conclude that this study might contribute to the development of a new line of anti-tuberculosis agents.

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A unique cysteine-rich Zn-finger domain present in a majority of class II ribonucleotide reductases mediates catalytic turnover [Enzymology]

Ribonucleotide reductases (RNRs) catalyze the reduction of ribonucleotides to the corresponding deoxyribonucleotides, used in DNA synthesis and repair. Two different mechanisms help deliver the required electrons to the RNR active site. Formate can be used as reductant directly in the active site, or gluta- or thioredoxins reduce a C-terminal cysteine pair, which then delivers the electrons to the active site. Here, we characterized a novel cysteine-rich C-terminal domain (CRD), which is present in most class II RNRs found in microbes. The NrdJd-type RNR from the bacterium Stackebrandtia nassauensis was used as a model enzyme. We show that the CRD is involved in both, higher oligomeric state formation and electron transfer to the active site. The CRD-dependent formation of high oligomers, such as tetramers and hexamers, was induced by addition of dATP or dGTP, but not of dTTP or dCTP. The electron transfer was mediated by an array of six cysteine residues at the very C-terminal end, which also coordinated a zinc atom. The electron transfer can also occur between subunits, depending on the enzyme's oligomeric state. An investigation of the native reductant of the system revealed no interaction with gluta- or thioredoxins, indicating that this class II RNR uses a different electron source. Our results are indicating that the CRD has a crucial role in catalytic turnover and a potentially new terminal reduction mechanism and suggest that the CRD is important for the activities of many class II RNRs.

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Sirtuin 5 is required for mouse survival in response to cardiac pressure overload [Molecular Bases of Disease]

In mitochondria, the sirtuin SIRT5 is an NAD+-dependent protein deacylase that controls several metabolic pathways. While a wide range of SIRT5 targets has been identified, the overall function of SIRT5 in organismal metabolic homeostasis remains unclear. Given that SIRT5 expression is highest in the heart and that sirtuins are commonly stress-response proteins, we used an established model of pressure overload-induced heart muscle hypertrophy caused by transverse aortic constriction (TAC) to determine SIRT5's role in cardiac stress responses. Remarkably, SIRT5KO mice had reduced survival upon TAC compared with wildtype mice, but exhibited no mortality when undergoing a sham control operation. The increased mortality with TAC was associated with increased pathological hypertrophy and with key abnormalities in both cardiac performance and ventricular compliance. By combining high-resolution MS-based metabolomic and proteomic analyses of cardiac tissues from wildtype and SIRT5KO mice, we found several biochemical abnormalities exacerbated in the SIRT5KO mice, including apparent decreases in fatty acid oxidation and glucose oxidation as well as an overall decrease in mitochondrial NAD+/NADH. Together, these abnormalities suggest that SIRT5 deacylates protein substrates involved in cellular oxidative metabolism to maintain mitochondrial energy production. Overall, the functional and metabolic results presented here suggest an accelerated development of cardiac dysfunction in SIRT5KO mice in response to TAC, explaining increased mortality upon cardiac stress. Our findings reveal a key role for SIRT5 in maintaining cardiac oxidative metabolism under pressure overload to ensure survival.

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Identification of the signals for glucose-induced insulin secretion in INS1 (832/13) {beta}-cells using metformin-induced metabolic deceleration as a model [Metabolism]

Metabolic deceleration in pancreatic β-cells is associated with inhibition of glucose-induced insulin secretion (GIIS), but only in the presence of intermediate/sub-maximal glucose concentrations. Here, we used acute metformin treatment as a tool to induce metabolic deceleration in INS1 (832/13) β-cells, with the goal of identifying key pathways and metabolites involved in GIIS. Metabolites and pathways previously implicated as signals for GIIS were measured in the cells at 2-25 mM glucose, with or without 5 mM metformin. We defined three criteria to identify candidate signals: 1) glucose-responsiveness, 2) sensitivity to metformin-induced inhibition of the glucose effect at intermediate glucose concentrations, and 3) alleviation of metformin inhibition by elevated glucose concentrations. Despite the lack of recovery from metformin-induced impairment of mitochondrial energy metabolism (glucose oxidation, O2 consumption and ATP production), insulin secretion was almost completely restored at elevated glucose concentrations. Meeting the criteria for candidates involved in promoting GIIS were the following metabolic indicators and metabolites: cytosolic NAD+/NADH ratio (inferred from the dihydroxyacetone phosphate:glycerol-3-phosphate ratio), mitochondrial membrane potential, ADP, Ca2+, 1-monoacylglycerol, diacylglycerol, malonyl-CoA, and HMG-CoA. On the contrary, most of the purine and nicotinamide nucleotides, acetoacetyl-CoA, H2O2, reduced glutathione and 2-monoacylglycerol were not glucose-responsive. Overall these results underscore the significance of mitochondrial energy metabolism-independent signals in GIIS regulation, in particular, the candidate lipid signaling molecules 1-monoacylglycerol, diacylglycerol and malonyl-CoA; the predominance of KATP/Ca2+ signaling control by low ADP.Mg2+ rather than by high ATP levels; and a role for a more oxidized state (NAD+/NADH) in the cytosol during GIIS that favors high glycolysis rates.

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Structural insights into GDP-mediated regulation of a bacterial acyl-CoA thioesterase [Enzymology]

Thioesterases catalyze the cleavage of thioester bonds within many activated fatty acids and acyl-CoA substrates. They are expressed ubiquitously in both prokaryotes and eukaryotes and are subdivided into 25 thioesterase families according to their catalytic active site, protein oligomerization, and substrate specificity. While many of these enzyme families are well characterized in terms of function and substrate specificity, regulation across most thioesterase families is poorly understood. Here, we characterized a TE6 thioesterase from the bacterium Neisseria meningitidis. Structural analysis with X-ray crystallographic diffraction data to 2.0 Å revealed that each protein subunit harbors a hot dog fold and that the TE6 enzyme forms a hexamer with D3 symmetry. An assessment of thioesterase activity against a range of acyl-CoA substrates revealed greatest activity against acetyl-CoA, and structure-guided mutagenesis of putative active site residues identified Asn-24 and Asp-39 as being essential for activity. Our structural analysis revealed that six GDP nucleotides bound the enzyme in close proximity to an intersubunit disulfide bond interactions that covalently link thioesterase domains in a double hot dog dimer. Structure-guided mutagenesis of residues within the GDP-binding pocket identified Arg-93 as playing a key role in the nucleotide interaction and revealed that GDP is required for activity. All mutations were confirmed to be specific and not to have resulted from structural perturbations by X-ray crystallography. This is the first report of a bacterial GDP-regulated thioesterase and of covalent linkage of thioesterase domains through a disulfide bond, revealing structural similarities with ADP regulation in the human ACOT12 thioesterase.

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Preventive effect of oleate on palmitate-induced insulin resistance in skeletal muscle and its mechanism of action

Abstract

Insulin resistance in skeletal muscle is a feature associated with exposure to an excess of saturated fatty acids such as palmitate. Oleic acid has been shown to blunt palmitate-induced insulin resistance in muscle cells. However, there is no literature available regarding the effect of oleic acid on palmitate-induced insulin resistance in intact muscle. Therefore, this study investigated the effect of oleic acid on palmitate-induced insulin resistance in rat soleus muscle and its underlying mechanisms. For these purposes, oleic acid (1 mM) was administered for 12 h in the absence or presence of palmitate (2 mM). At the end of the experiment, plasmalemmal GLUT4, the phosphorylation of AS160 and Akt-2, and the total expression of these signaling proteins were examined. We found that treatment with palmitate for 12 h reduced insulin-stimulated GLUT4 translocation and the phosphorylation of AS160 and Akt-2. However, the administration of oleic acid fully restored insulin-stimulated GLUT4 translocation (P < 0.05), as well as AS160 and Akt-2 phosphorylation (P < 0.05) despite the continuous presence of palmitate. Wortmannin, an inhibitor of PI3-K, only slightly prevented the oleic acid-induced improvements in insulin-stimulated GLUT4 translocation, and AS160 phosphorylation. However, this treatment completely inhibited the oleic acid-induced improvement in insulin-stimulated Akt-2 phosphorylation. In contrast, the oleic acid-induced improvement in insulin signaling was not affected by compound C, an AMPK specific inhibitor. In conclusion, the results clearly indicate that oleic acid administration alleviates palmitate-induced insulin resistance by promoting GLUT4 translocation in muscle, at least in part, by activating the PI3K pathway.

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Relationship Between Problematic Internet Use and Time Management Among Nursing Students.

The Internet is an essential part of everyday life, particularly for the younger generation. The aims of this study were to evaluate nursing students' problematic Internet use and time management skills and to assess relationship between Internet use and time management. This descriptive study was conducted with 311 nursing students in Ankara, Turkey, from February to April 2016. The data were collected using the Problematic Internet Use Scale and Time Management Inventory. The Problematic Internet Use Scale and Time Management Inventory median scores were 59.58 +/- 20.69 and 89.18 +/- 11.28, respectively. There were statistically significant differences between both nursing students' Problematic Internet Use Scale and Time Management Inventory median scores and some variables (school grade, the time spent on the Internet). Fourth-year students were more prone to excessive use of the Internet and the resulting negative consequences than students from other year levels (P

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Medical Heat Sealers Market to Register Substantial Expansion by 2024

Effective packaging of medical devices and instruments is key in ensuring their sterility. There is a significant risk of product contamination during shipping and storage that could be dangerous if the packaging and seal closures of a medical pouch are compromised.

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Association between high risk for preterm birth and changes in gingiva parameters during pregnancy—a prospective cohort study

Abstract

Objectives

The objective of this study was to investigate clinical and microbiological gingival changes during pregnancy in women without periodontal disease. Additionally, these parameters were to be compared in women with high risk for preterm birth and women with a normal course of pregnancy.

Method and materials

Group I consisted of 40 subjects at high risk for preterm birth, while group II involved 49 subjects with a normal course of pregnancy. The control group (III) was made up of 50 non-pregnant women. Clinical parameters (plaque index, gingival index, probing pocket depths, gingival swelling, bleeding on probing) and microbiological changes were monitored during pregnancy and 2–4 weeks after parturition.

Results

In the high-risk preterm group (I), 19 women could be included in data analysis. This group was compared to 41 women in the normal pregnancy group (II) and 50 non-pregnant women (III). Gingival inflammation was significantly higher in women with high risk for preterm birth (I) compared to non-risk pregnant women (II, p < 0.05). In addition, in this group (I), the subgingival amounts of Fusobacterium nucleatum (> 10⁵) were found to be significantly higher after childbirth compared to non-pregnant women (p < 0.05).

Conclusions

Even without having periodontal disease, women with high risk for preterm birth showed worse clinical values compared to non-risk pregnant and non-pregnant women and an increased detection of Fusobacterium nucleatum after delivery.

Clinical relevance

High risk for preterm birth might be associated with the occurrence of increased gingival inflammation.

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Cryptic diversity, sympatry, and other integrative taxonomy scenarios in the Mexican Ceratozamia miqueliana complex (Zamiaceae)

Abstract

According to the integrative taxonomy (IT) framework, delimitation of taxonomic specimens into bona fide species requires the incorporation of multiple sources of biological evidence that jointly perform a role as systematic criteria. Here, we collected a combination of geographic, morphological (qualitative and quantitative), and molecular data sets from a group of specimens in the Ceratozamia miqueliana species complex. We analyzed them under methods suitable for each of these partitions and then synthesized results under the taxonomic circle—i.e., an operational tool for inference in IT. Taxonomic circle-based species delimitations in this Ceratozamia species complex have downstream taxonomic-nomenclatural consequences given that morphometric affinity between these specimens does not allow their species-level identification. However, joint patterns of qualitative morphological (i.e., diagnostics in standard sense) and molecular (i.e., character-based, DNA diagnostic or "bar coding") characters between the species suggest the following scenarios: (1) C. miqueliana is a morphologically diagnosable species that lacks DNA diagnostics; (2) Ceratozamia subroseophylla is diagnosable both in terms of morphological and molecular evidence and sympatric with C. miqueliana; (3) Ceratozamia euryphyllidia is diagnosable both in morphological and molecular terms; (4) Ceratozamia zoquorum and Ceratozamia santillanii are cryptic species, i.e., both have exclusive DNA diagnostics but are not diagnosable morphologically; and (5) Ceratozamia becerrae is not diagnosable by any criterion and should therefore fall in synonymy. The present work contributes to establish a robust platform for subsequent systematic assessments of Mexican cycad diversity, which could include new hypotheses on the evolutionary processes involved in their current biogeographic distribution, ecological relationships, and other life-history aspects, in turn useful for conservation biology concerns.

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The Sulphate Effect on Lijiaxia Concrete Dam (China) Gallery

The concrete degradation is one of the most serious problems for a dam construct during the normal operation, which determines the dam service life. Hence, it is very important to reduce the extent of the dam concrete degradation for the safety of the dam normal operation. Here, Lijiaxia hydroelectric station is taken as an example, and a comprehensive method to assess the sulphate effect on dam gallery is proposed. Eleven samples in total were taken from three difference locations by the drill bore. The microstructural investigations including X-ray fluorescence spectrometry (XRF), X-ray diffraction (XRD), scanning electron microscope (SEM), and energy dispersive spectroscopy (EDS) were conducted to assess the sulphate attack and the degradation degree. Meanwhile, the water chemical analysis was applied to reveal the mechanism of concrete degradation. The experimental and analysis results indicate that the concrete degradation degree varies with the location of the samples. The components of the concrete change and the content of SO3 increase dramatically during degradation. Moreover, the mineral facies of the concrete change correspondingly, with the cement paste substituted by the calcite, calcium vitriol, and gypsum. The reinforcement and precaution measures are suggested based on the results of the degradation assessment.

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Research on the Strength Variation of Root-Clay Systems under Freeze-Thaw Action

The aim of this paper is to study the influence of an effective root system of rhizome plants on the reinforcement of slope soil under freeze-thaw conditions. This study focused on the mechanical properties between roots and clay in the root system of four plant species from different regions of China (northeast, northern, central, and southern areas): Setaria viridis, Eleusine indica, Zoysia japonica, and Carex leucochlora. Based on the interfacial friction effects between the plant roots and the soil, pull-out tests and unconfined compressive strength tests were conducted on the reinforced soil system for varying numbers of freeze-thaw cycles. Several stages of the pull-out process of the root system in clay are explicitly proposed based on the interfacial friction test results. The results showed that the friction effect between Zoysia japonica roots and the soil was the most significant and that these roots had the best reinforcement effect. In contrast, the friction and reinforcement effects between Setaria viridis roots and the soil were the worst, and the resulting unconfined compressive strength was the smallest. However, the freeze-thaw resistance ability of the Setaria viridis and soil system was stronger than that of the Zoysia japonica system.

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Effect of Heat Drawing Process on Mechanical Properties of Dry-Jet Wet Spun Fiber of Linear Low Density Polyethylene/Carbon Nanotube Composites

Polyethylene is one of the most commonly used polymer materials. Even though linear low density polyethylene (LLDPE) has better mechanical properties than other kinds of polyethylene, it is not used as a textile material because of its plastic behavior that is easy to break at the die during melt spinning. In this study, LLDPE fibers were successfully produced with a new approach using a dry-jet wet spinning and a heat drawing process. The fibers were filled with carbon nanotubes (CNTs) to improve the strength and reduce plastic deformation. The crystallinity, degree of orientation, mechanical properties (strength to yield, strength to break, elongation at break, and initial modulus), electrical conductivity, and thermal properties of LLDPE fibers were studied. The results show that the addition of CNTs improved the tensile strength and the degree of crystallinity. The heat drawing process resulted in a significant increase in the tensile strength and the orientation of the CNTs and polymer chains. In addition, this study demonstrates that the heat drawing process effectively decreases the plastic deformation of LLDPE.

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MicroRNA-93 Regulates Hypoxia-Induced Autophagy by Targeting ULK1

The expression of the core autophagy kinase, Unc51-like kinase 1 (ULK1), is regulated transcriptionally and translationally by starvation-induced autophagy. However, how ULK1 is regulated during hypoxia is not well understood. Previously, we showed that ULK1 expression is induced by hypoxia stress. Here, we report a new ULK1-modulating microRNA, miR-93; its transcription is negatively correlated with the translation of ULK1 under hypoxic condition. miR-93 targets ULK1 and reduces its protein levels under hypoxia condition. miR-93 also inhibits hypoxia-induced autophagy by preventing LC3-I to LC3-II transition and P62 degradation; these processes are reversed by the overexpression of an endogenous miR-93 inhibitor. Re-expression of ULK1 without miR-93 response elements restores the hypoxia-induced autophagy which is inhibited by miR-93. Finally, we detected the effects of miR-93 on cell viability and apoptosis in noncancer cell lines and cancer cells. We found that miR-93 sustains the viability of MEFs (mouse embryonic fibroblasts) and inhibits its apoptosis under hypoxia. Thus, we conclude that miR-93 is involved in hypoxia-induced autophagy by regulating ULK1. Our results provide a new angle to understand the complicated regulation of the key autophagy kinase ULK1 during different stress conditions.

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MCMC-Based Fatigue Crack Growth Prediction on 2024-T6 Aluminum Alloy

This work aims to make the crack growth prediction on 2024-T6 aluminum alloy by using Markov chain Monte Carlo (MCMC). The fatigue crack growth test is conducted on the 2024-T62 aluminum alloy standard specimens, and the scatter of fatigue crack growth behavior was analyzed by using experimental data based on mathematical statistics. An empirical analytical solution of Paris' crack growth model was introduced to describe the crack growth behavior of 2024-T62 aluminum alloy. The crack growth test results were set as prior information, and prior distributions of model parameters were obtained by MCMC using OpenBUGS package. In the additional crack growth test, the first test point data was regarded as experimental data and the posterior distribution of model parameters was obtained based on prior distributions combined with experimental data by using the Bayesian updating. At last, the veracity and superiority of the proposed method were verified by additional crack growth test.

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Association between high risk for preterm birth and changes in gingiva parameters during pregnancy—a prospective cohort study

Abstract

Objectives

The objective of this study was to investigate clinical and microbiological gingival changes during pregnancy in women without periodontal disease. Additionally, these parameters were to be compared in women with high risk for preterm birth and women with a normal course of pregnancy.

Method and materials

Group I consisted of 40 subjects at high risk for preterm birth, while group II involved 49 subjects with a normal course of pregnancy. The control group (III) was made up of 50 non-pregnant women. Clinical parameters (plaque index, gingival index, probing pocket depths, gingival swelling, bleeding on probing) and microbiological changes were monitored during pregnancy and 2–4 weeks after parturition.

Results

In the high-risk preterm group (I), 19 women could be included in data analysis. This group was compared to 41 women in the normal pregnancy group (II) and 50 non-pregnant women (III). Gingival inflammation was significantly higher in women with high risk for preterm birth (I) compared to non-risk pregnant women (II, p < 0.05). In addition, in this group (I), the subgingival amounts of Fusobacterium nucleatum (> 10⁵) were found to be significantly higher after childbirth compared to non-pregnant women (p < 0.05).

Conclusions

Even without having periodontal disease, women with high risk for preterm birth showed worse clinical values compared to non-risk pregnant and non-pregnant women and an increased detection of Fusobacterium nucleatum after delivery.

Clinical relevance

High risk for preterm birth might be associated with the occurrence of increased gingival inflammation.

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Magnetotactic Bacteria Powered Biohybrids Target E. coli Biofilms

ACS Nano

DOI: 10.1021/acsnano.7b04128

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Crystallization, Reentrant Melting, and Resolubilization of Virus Nanoparticles

ACS Nano

DOI: 10.1021/acsnano.7b03131

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Preventing new sensitization and asthma onset by allergen immunotherapy: the current evidence.

Purpose of review: Specific allergen immunotherapy is considered a key candidate for a successful preventive intervention in atopic diseases. The strong association of atopic manifestations such as rhinitis and asthma with atopic sensitizations (specific serum IgE) provide a rationale for early intervention in childhood and adolescence. Recent findings: Currently, the documentation of the disease-modifying intervention effects is limited to the secondary prevention of asthma symptoms in children with allergic rhinoconjunctivitis. These effects appear to be rather allergen specific than nonspecific. Summary: Documentation on disease modification including a reduction of asthma symptoms in children, particularly with grass pollen tablets has become quite robust. It is not clear up to now, if the new onset of allergic sensitizations can be modified. So far data on primary prevention are not conclusive. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Approaches to the removal of T-lymphocytes to minimize graft-versus-host disease in patients with primary immunodeficiencies who do not have a matched sibling donor.

Purpose of review: Since the advent of T-lymphocyte depletion in hematopoietic stem cell transplantation (HSCT) for primary immunodeficiency, survival following this procedure has remained poor compared to results when using matched sibling or matched unrelated donors, over the last 40 years. However, three new techniques are radically altering the approach to HSCT for those with no matched donor, particularly those with primary immunodeficiencies which are not severe combined immunodeficiency. Recent findings: Three main techniques of T-lymphocyte depletion are altering donor choice for patients with primary immunodeficiencies and have improved transplant survival for primary immunodeficiencies to over 90%, equivalent to that for matched sibling and matched unrelated donor transplants. CD3+ T cell receptor (TCR)[alpha][beta]+ CD19+ depletion, CD45RA depletion and use of posttransplant cyclophosphamide give similar overall survival of 90%, although viral reactivation remains a concern. Further modification of CD3+ TCR[alpha][beta]+ CD19+ depletion by adding back inducible caspase-9 suicide gene-modified CD3+ TCR[alpha][beta]+ T-lymphocytes may further improve outcomes for patients with systemic viral infection. Summary: Over the last 5 years, the outcomes of HSCT using new T-lymphocyte depletion methods have improved to the extent that they are equivalent to outcomes of matched sibling donors and may be preferred in the absence of a fully matched sibling donor, over an unrelated donor to reduce the risk of graft versus host disease. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Critical appraisal of the unmet needs in the treatment of chronic spontaneous urticaria with omalizumab: an Italian perspective.

Purpose of review: The humanized anti-IgE antibody omalizumab has been available for patients with chronic spontaneous urticaria (CSU) in Italy since 2015. This review summarizes the unresolved issues and unmet therapeutic needs associated with omalizumab and discusses practical recommendations for its use in the management of CSU. Recent findings: Although modern second-generation H1-antihistamines are the standard of care for patients with CSU, adjunctive treatments (including omalizumab) may be required for effective control of symptoms in many patients. Evidence from clinical trials and experience from daily clinical practice suggest that the use of omalizumab in patients with CSU who have inadequate response to H1-antihistamines remains challenging. Summary: Based on current international guidelines, omalizumab labelling information and our experience in clinical practice, we provide treatment recommendations regarding the use of omalizumab in patients with CSU. These include: optimal treatment duration, the use of concomitant antihistamine therapy, the definition and management of disease relapse after treatment, and the management of patients with late or no response to treatment. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Malignant Ectomesenchymoma: A Potential Pitfall of Diagnosis in the Spectrum of Pediatric Small Blue Round Cell Tumors.

No abstract available

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Immature Terminal Deoxynucleotidyl Transferase Positive B Cells are Detected in a Subset of Adult and Pediatric Liver Biopsies.

Terminal deoxynucleotidyl transferase (TdT) is a nuclear enzyme restricted to precursor lymphoid cells and their malignant counterparts; immunohistochemical TdT labeling is helpful in recognition of lymphoblasts, which can resemble mature lymphocytes. The diagnosis of B-lymphoblastic leukemia/lymphoma (B-ALL) is occasionally first encountered on liver core biopsy, but TdT immunostain specificity for B-ALL is not clearly established in this setting, which can be problematic when only a few TdT-positive cells are identified. In this study, we evaluated the incidence and distribution of immature B lymphocytes coexpressing TdT and PAX-5, in pediatric and adult liver biopsies, to determine whether a normal complement of hepatic immature B cells can be detected, which must be recognized in a workup to exclude B-ALL. We selected 41 pediatric and adult liver biopsies with a significant portal and/or sinusoidal hematolymphoid infiltrate and performed immunohistochemical stains for TdT and PAX-5 to identify and categorize distribution of immature B cells. TdT-positive cells were detected in 40% of pediatric liver biopsies with a significant hematolymphoid infiltrate (4/10), which included all biopsies from neonates (and infants under 9 wk of age). In adults, immature B-cell infiltrates were less common (6%, 2/31). Dual immunostaining was performed on 2 cases of neonatal hepatitis, which documented B-cell lineage in at least a subset of TdT-positive cells and there was no colabeling with CD3. Immature B cells can be detected in liver biopsies in a variety of clinical settings, most commonly in children, and presence of a few TdT-positive cells cannot be considered entirely specific for involvement by B-ALL. Further workup for B-ALL can be warranted if there is more extensive multifocal portal and/or sinusoidal involvement by blasts with TdT labeling. Copyright 2017 Wolters Kluwer Health, Inc. All rights reserved.

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