Cytochrome P450 enzyme RosC catalyzes a multistep oxidation reaction to form the non-active compound 20-carboxyrosamicin

Abstract

The cytochrome P450 enzyme RosC catalyzes a two-step, hydroxylation and alcohol oxidation, oxidation reaction to form the C-20 formyl group in the biosynthesis of a 16-membered macrolide antibiotic rosamicin produced by Micromonospora rosaria IFO13697. RosC is presumed to be involved in the formation of 20-carboxyrosamicin because it has been isolated from the culture broth of M. rosaria. Here, we confirmed that RosC has catalytic activity, with Escherichia coli expressing RosC converting rosamicin into 20-carboxyrosamicin. Therefore, it was revealed that RosC is a multifunctional P450 that catalyzes a three-step oxidation reaction that leads to the formation of the hydroxyl group, formyl group, and carboxyl group at C-20 on the macrolactone ring in the rosamicin biosynthetic pathway. Moreover, the cytochrome P450 enzyme TylI, which is involved in formation of the formyl group of a 16-membered macrolide antibiotic tylosin produced by Streptomyces fradiae ATCC 19609, also converted rosamicin into 20-carboxyrosamicin.

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Changes in bacterial community after application of three different herbicides

Abstract

The native soil microbiota is very important to maintain the quality of that environment, but with the intensive use of agrochemicals, changes in microbial biomass and formation of large quantities of toxic waste were observed in soil, groundwater and surface water. Thereby, the goal of the present study was to evaluate if the selective pressure exerted by the presence of the herbicides atrazine, diuron and 2,4-Dchanges the bacterial community structure of an agricultural soil, using Denaturing Gradient Gel Electrophoresis (DGGE) technique. According to Permanova analysis, it was observed a greater effect of the herbicide persistence time in the soil, the effect of the herbicide class and the effect of interaction between these two factors (persistence time and herbicide class). In conclusion, the results showed that the selective pressure exerted by the presence of these herbicides altered the composition of the local microbiota, being atrazine and diuron that most significantly affected the bacterial community in soil and the herbicide 2,4-D was the one that less altered the microbial community and that bacterial community was reestablished first.

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Stress-responsively modulated ymdAB-clsC operon plays a role in biofilm formation and apramycin susceptibility in Escherichia coli

Abstract

The YmdB protein, an inhibitor of biofilm formation and an inducer of apramycin susceptibility in Escherichia coli (E. coli), is part of a putative operon. However, transcription of this operon and its subsequent effects on biological pathways has not been fully studied. Here, we characterized the operon in terms of promoter activity, transcription, and function. Promoter activity assays identified two new growth- and cold-shock-responsive upstream (PymdA) and inner (PclsC) promoters, respectively. Moreover, investigation of the operon-derived transcripts identified different polycistronic transcripts harboring multiple heterogeneous 3' ends. Overexpression of YmdA or ClsC proteins inhibited biofilm formation and affected apramycin susceptibility, a process dependent on the sucA gene, suggesting that the operon genes or their encoded proteins are functionally linked. Additional investigation of the effects of polycistronic transcripts on the response of E. coli cells to apramycin revealed that transcripts containing ymdA (-213 to + 27) are required for apramycin susceptibility. Thus, ymdAB-clsC is a new stress-responsive operon that plays a role in inhibiting undesired biofilm-forming and antibiotic-resistant bacterial populations.

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Retrospective Evaluation of Thromboembolism Risk in Ovarian Cancer Patients Treated with Bevacizumab

Abstract

Background

Bevacizumab is used in addition to standard, platinum-based chemotherapy to treat advanced-stage ovarian cancer patients. Thrombosis is a well-documented adverse effect of bevacizumab.

Objective

The aim of this study was to identify predictive parameters for thromboembolic events in ovarian cancer patients and to explain how bevacizumab increases the risk of these events.

Patients and Methods

Fifty-seven FIGO stage III ovarian cancer patients who underwent cytoreductive surgery and chemotherapy were identified and included in this retrospective study. Twenty-six patients were treated with carboplatin and paclitaxel (CP) only (control group), and 31 patients received CP with bevacizumab (study group). The two groups were compared with regard to thrombosis risk factors and laboratory parameters (total leukocytes, platelet count, hemoglobin, APTT, prothrombin time, INR, fibrinogen levels, D-dimer concentration) before treatment, after each course of chemotherapy, and during thromboembolic events.

Results

Only patients in the group receiving bevacizumab experienced venous thromboembolism (VTE) (p=0.03, χ² test). VTE occurred on average at the 13th cycle of chemotherapy. Patients who experienced VTE had increased BMI before chemotherapy as compared to patients with no thromboembolic event (27.2 vs. 23.3, p=0.005, Mann-Whitney test). D-dimer concentration before treatment was also elevated more in patients affected by VTE (3132.5) than in the non-VTE group (956.43) (p=0.0007, Mann-Whitney test). During the first four administrations of chemotherapy in patients with future VTE, there was a reduction in D-dimer concentration and an extension of APTT. A D-Dimer level higher than 485 ng/mL prior to first chemotherapy indicates for a risk of VTE with 94% sensitivity and 36% specificity.

Conclusions

An elevated D-dimer level and high BMI before chemotherapy are risk factors for VTE in ovarian cancer patients receiving bevacizumab. Bevacizumab possibly increases the risk for VTE.

http://ift.tt/2qOrxL0

Chlamydia muridarum Infection of Macrophages Stimulates IL-1β Secretion and Cell Death via Activation of Caspase-1 in an RIP3-Independent Manner

Chlamydiae are Gram-negative bacteria, which replicate exclusively in the infected host cells. Infection of the host cells by Chlamydiae stimulates the innate immune system leading to an inflammatory response, which is manifested not only by secretion of proinflammatory cytokines such as IL-1 from monocytes, macrophages, and dendritic cells, but also possibly by cell death mediated by Caspase-1 pyroptosis. RIP3 is a molecular switch that determines the development of necrosis or inflammation. However, the involvement of RIP3 in inflammasome activation by Chlamydia muridarum infection has not been clarified. Here, we assessed the role of RIP3 in synergy with Caspase-1 in the induction of IL-1β production in BMDM after either LPS/ATP or Chlamydia muridarum stimulation. The possibility of pyroptosis and necroptosis interplays and the role of RIP3 in IL-1 production during Chlamydia muridarum infection in BMDM was investigated as well. The data indicated that RIP3 is involved in NLRP3 inflammasome activation in LPS/ATP-stimulated BMDMs but not in Chlamydia muridarum infection. Pyroptosis occurred in BMDM after LPS/ATP stimulation or Chlamydia muridarum infection. Moreover, the results also illuminated the important role of the Caspase-1-mediated pyroptosis process which does not involve RIP3. Taken together, these observations may help shed new light on details in inflammatory signaling pathways activated by Chlamydia muridarum infection.

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Comment on “Intraoperative Contrast Enhanced Ultrasound Evaluates the Grade of Glioma”

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Blood assessment of the expression levels of matrix metalloproteinase 9 ( MMP9 ) and its natural inhibitor, TIMP1 genes in Iranian schizophrenic patients

Abstract

Schizophrenia (SCZ) is the most severe chronic mental disorder characterized by abnormal social behavior and disrupted emotions and thought. Like other complex neuropsychological disease, SCZ is caused by a combination of genetic and environmental factors but with a high concordance rate. So far, different genetic factors are revealed to be associated with increased risk of developing SCZ. One of the best ways to investigate the genetic basis of the complex disease is to discover the genetic underlying mechanisms of the defective clinical aspects of the patients. In this regard, genes involved in the developmental mechanisms of the brain such as long-term potentiation (LTP) process that is the basis of synaptic plasticity, memory and learning are considered as strong candidates for SCZ. The aim of the present study was to evaluate the expression levels of two genes that are involved in the LTP regulation in the developing and adult brain, Matrix metallopeptidase9 (MMP9) and TIMP metallopeptidase inhibitor 1 (TIMP1) genes in a blood assessment of schizophrenic patients in comparison to healthy controls by means of quantitative real time PCR. The results of the study showed a significant difference in MMP9/TIPM1 ratio between SCZ patients and healthy controls (P = 0.01). However, no significant difference was detected in the expression level of individual MMP9 and TIMP1 genes in SCZ patients versus healthy controls either in total numbers of subject or in sex based subgroups. Considering the relatively small sample size of the current study, there is a need to replicate this study with further investigations about the mechanism of association of these genes and their functions in the pathogenesis of the SCZ.

http://ift.tt/2sCConY

A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors [Research Briefs]

Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated histology-agnostic efficacy in patients with TRK fusion-positive cancers. While responses to TRK inhibition can be dramatic and durable, duration of response may eventually be limited by acquired resistance. LOXO-195 is a novel, selective TRK TKI designed to overcome acquired resistance mediated by recurrent kinase domain (solvent front and xDFG) mutations identified in multiple patients who have developed resistance to TRK TKIs. Activity against these acquired mutations was confirmed in enzyme and cell-based assays and in vivo tumor models. As clinical proof of concept, the first two patients with TRK fusion-positive cancers that developed acquired resistance mutations on larotrectinib were treated with LOXO-195 on a first-in-human basis, utilizing rapid dose titration guided by pharmacokinetic assessments. This approach led to rapid tumor responses and extended the overall duration of disease control achieved with TRK inhibition in both patients.

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Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy

The Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial recruits patients commencing long-term androgen-deprivation therapy (ADT; orchiectomy or gonadotropin-releasing hormone [GnRH] agonists or antagonists) for the first time for locally…

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Gastric inflammatory myofibroblastic tumor identified as ectopic pancreas and treated by endoscopic submucosal dissection

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Colovesical Fistula: Visualization of the Bladder During the Colonoscopy

http://ift.tt/2rEjbVp

Genome-wide Mapping of Protein-DNA Interactions with ChEC-seq in Saccharomyces cerevisiae

We describe chromatin endogenous cleavage coupled with high-throughput sequencing (ChEC-seq), a chromatin immunoprecipitation (ChIP)-orthogonal method for mapping protein binding sites genome-wide with micrococcal nuclease (MNase) fusion proteins.

http://ift.tt/2sqmzRI

Transfer of Mammary Gland-forming Ability Between Mammary Basal Epithelial Cells and Mammary Luminal Cells via Extracellular Vesicles/Exosomes

This protocol describes methods for purifying, quantitating, and characterizing extracellular vesicles (EVs)/exosomes from non-adherent/mesenchymal mammary epithelial cells and for using them to transfer mammary gland-forming ability to luminal mammary epithelial cells. EVs/exosomes derived from stem-like mammary epithelial cells can transfer this cell property to cells that ingest the EVs/exosomes.

http://ift.tt/2qLscZD

Breast cancer electron intraoperative radiotherapy: assessment of preoperative selection factors from a retrospective analysis of 758 patients and review of literature

Abstract

Purpose

To report our experience with full-dose 21 Gy IORT in early breast cancer patients after breast-conserving surgery to define most important selection factors.

Methods

Seven hundred and fifty eight patients, subjected to conserving surgery and IORT, were retrospectively analyzed evaluating most important clinical outcomes.

Results

Median follow up was 5.2 years. Results from Cox analyses defined 2 groups of patients, "suitable" (age > 50 years, non lobular histology, tumour size ≤ 2 cm, pN0 or pNmic, ki67 ≤ 20%, non triple negative receptor status and G1-G2) and "unsuitable" for IORT, with a higher rate of breast related events moving from "suitable" to "unsuitable" group. The 5 year rate of IBR is 1.8% in suitable group with significant differences versus unsuitable (1.8 vs. 11.6%, p < 0.005). Same differences between two groups were evidenced in true local relapse (0.6 vs. 6.9%, p < 0.005) and in new ipsilateral BC (1.1 vs. 4.7%, p < 0.015).

Conclusions

In our current practice we consider the following preoperative factors to select patients suitable for IORT: age > 50 years, absence of lobular histology, tumor size ≤ 2 cm, pN0 or pNmic, according to APBI consensus statement, including also ki67 ≤ 20%, non triple negative receptor status and G1–G2.

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Precise Cellular Ablation Approach for Modeling Acute Kidney Injury in Developing Zebrafish

This work presents a new in vivo model of segmental kidney injury using kidney GFP transgenic zebrafish. The model allows for the induction of the targeted ablation of kidney epithelial cells to show the cellular mechanisms of nephron injury and repair.

http://ift.tt/2sqy37R

Prolonged Overall Treatment Time and Lack of Skin Rash Negatively Impact Overall Survival in Locally Advanced Head and Neck Cancer Patients Treated with Radiotherapy and Concomitant Cetuximab

Abstract

Background

Cetuximab, a chimeric monoclonal antibody against EGFR sensitizes tumors to radiotherapy (RT), but is associated with skin and mucosal toxicity.

Objective

We report outcomes and tolerance of definitive RT in association with cetuximab in patients with locally advanced squamous cell carcinoma (LASCC) of the head and neck.

Patients and Methods

Between 2006 and 2011, 92 consecutive patients with LASCC of the head and neck were treated with RT and concomitant weekly cetuximab. Median age was 61.7 years. Most patients presented with oropharyngeal tumors (52.2%) and stage IV disease (77.2%).

Results

Sixty-nine patients received at least 7 cycles of cetuximab. Cetuximab was stopped at the first infusion following allergic reactions in four patients. During RT, 37% of patients developed grade ≥ 3 dermatitis; grade ≥ 2 cetuximab-induced rash occurred in 43 patients (46.7%). Severe mucositis (grade ≥ 3) affected 57.6% of patients. Ten percent of patients did not receive the full course of RT, and temporary discontinuation due to acute toxicity was frequent and affected 37 patients (53%). The median RT overall treatment time (OTT) in patients with interrupted RT was 56 days (47–75) compared to 51 days (47–65) in patients who did not require toxicity-related radiation interruptions (p < 0.05). After a median follow-up of 17.5 months (1.3–107.6) for all patients, median overall survival was 17.9 months (95% CI: 12.7–23.2), and loco-regional control (LRC) was 9.2 months (95% CI: 3.9–14.4). On multivariate analysis, hemoglobin concentration and occurrence of rash grade ≥ 2 were independent prognostic factors for LRC (p = 0.023 and p = 0.006, respectively). Lack of rash and extended OTT negatively impacted overall survival (p = 0.048 and 0.052, respectively).

Conclusions

Skin and mucosal toxicity remains an issue in patients with LASCC of the head and neck treated with concomitant cetuximab and RT. Severe toxicity leads to treatment interruptions and prolonged overall treatment time, with consequent decreased overall survival in these patients.

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Fungal dysbiosis in cirrhosis

Objective

Cirrhotics have a high rate of infections, which are increasingly fungal or culture-negative in nature. While infected cirrhotics have bacterial dysbiosis, the role of fungi is unclear. We aimed to evaluate gut bacterial and fungal dysbiosis in cross-sectional and longitudinal analyses of outpatient and inpatient cirrhotics and prediction of hospitalisations.

Methods

Cross-sectional: Age-matched controls, outpatients (with/without antibiotics) and hospitalised uninfected, culture-negative and culture-positive cirrhotics were included and followed for 90 days. Longitudinal: Three studies were conducted: (1) cirrhotics followed over 6 months, (2) outpatient cirrhotics administered antibiotics per standard of care for 5 days and (3) cirrhotics and controls administered omeprazole over 14 days. In all studies, stool bacterial/fungal profiles were analysed.

Results

Cross-sectional: In 143 cirrhotics and 26 controls, bacterial and fungal diversities were significantly linked. Outpatients on antibiotics and patients with culture-positive infections had the lowest diversities. Bacterial and fungal correlations were complex in uninfected, outpatient and control groups but were markedly skewed in infected patients. 21% were admitted on 90-day follow-up. A lower Bacteroidetes/Ascomycota ratio was associated with lower hospitalisations. Longitudinal: Fungal and bacterial profiles were stable on follow-up (5 days and 6 months). After antibiotics, a significantly reduced bacterial and fungal diversity, higher Candida and lower autochthonous bacterial relative abundance were seen. After omeprazole, changes in bacterial diversity and composition were seen but fungal metrics remained stable.

Conclusion

There is a significant fungal dysbiosis in cirrhosis, which changes differentially with antibiotics and proton pump inhibitor use, but is otherwise stable over time. A combined bacterial–fungal dysbiosis metric, Bacteroidetes/Ascomycota ratio, can independently predict 90-day hospitalisations in patients with cirrhosis.

Clinical trial number

NCT01458990.

http://ift.tt/2qNcQI2

Effectiveness of various cleaning and disinfectant products on Clostridium difficile spores of PCR ribotypes 010, 014 and 027

In healthcare facilities, Clostridium difficile infections spread by transmission of bacterial spores. Appropriate sporicidal disinfectants are needed to prevent development of clusters and outbreaks. In this stu...

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Total disc replacement versus multidisciplinary rehabilitation in patients with chronic low back pain and degenerative discs: Eight-year follow-up of a randomized controlled multicenter trial

Publication date: Available online 2 June 2017
Source:The Spine Journal
Author(s): Håvard Furunes, Kjersti Storheim, Jens Ivar Brox, Lars Gunnar Johnsen, Jan Sture Skouen, Eric Franssen, Tore K Solberg, Leiv Sandvik, Christian Hellum
Background ContextLumbar total disc replacement is a treatment option for selected patients with chronic low back pain that is non-responsive to conservative treatment. The long-term results of disc replacement compared to multidisciplinary rehabilitation have not been reported previously.PurposeWe aimed to assess the long-term relative efficacy of lumbar total disc replacement compared to multidisciplinary rehabilitation.DesignWe undertook a multicenter randomized controlled trial at five university hospitals in Norway.Patient SampleThe sample consists of 173 patients aged 25-55 years with chronic low back pain and localized degenerative changes in the lumbar intervertebral discs.Outcome MeasuresThe primary outcome was self-reported physical function (Oswestry Disability Index, ODI) at eight-year follow-up in the intention to treat population. Secondary outcomes included self-reported low back pain (visual analogue scale, VAS), quality of life (EuroQol, EQ-5D), emotional distress (Hopkins Symptom Check List, HSCL-25), occupational status, patient satisfaction, drug use, complications and additional back surgery.MethodsPatients were randomly assigned to lumbar total disc replacement or multidisciplinary rehabilitation. Self-reported outcome measures were collected eight years after treatment. The study was powered to detect a difference of ten ODI points between the groups. The study has not been funded by the industry.Results605 patients were screened for eligibility, of whom 173 were randomly assigned treatment. 77 patients (90%) randomized to surgery and 74 patients (85%) randomized to rehabilitation responded at eight-year follow-up. Mean improvement on the ODI was 20.0 points (95% CI 16.4-23.6, p≤0.0001) in the surgery group and 14.4 points (95% CI 10.7-18.1, p≤0.0001) in the rehabilitation group. Mean difference between the groups at eight-year follow-up was 6.1 points (95% CI 1.2-11.0, p=0.02). Mean difference in favor of surgery on secondary outcomes were 9.9 points on VAS (95 % CI 0.6-19.2, p= 0.04) and 0.16 points on HSCL-25 (95 % CI 0.01-0.32, p=0.04). 18 patients (24 %) in the surgery group and four patients (6 %) in the rehabilitation group reported full recovery (p=0.002). There were no significant differences between the groups in EQ-5D, occupational status, satisfaction with care or drug use. In the per protocol analysis, the mean difference between groups was 8.1 ODI points (95 % CI 2.3-13.9, p=0.01) in favor of surgery. 43 of 61 patients (70 %) in the surgery group and 26 of 52 patients (50 %) in the rehabilitation group had a clinically important improvement (15 ODI points or more) from baseline (p=0.03). The proportion of patients with a clinically important deterioration (six ODI-points or more) were not significantly different between the groups. 21 patients (24 %) randomized to rehabilitation had crossed over and had undergone back surgery since inclusion. 12 patients (14 %) randomized to surgery had undergone additional back surgery. One serious adverse event after disc replacement is registered (<1%).ConclusionsSubstantial long-term improvement can be expected both after disc replacement and multidisciplinary rehabilitation. The difference between groups is statistically significant in favor of surgery, but smaller than the pre-specified clinical important difference of ten ODI points that the study was designed to detect. Future research should aim to improve selection criteria for disc replacement and multidisciplinary rehabilitation.



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Effect of 1- or 2-level posterior lumbar interbody fusion on global sagittal balance

Publication date: Available online 2 June 2017
Source:The Spine Journal
Author(s): Jae Hwan Cho, Youn-Suk Joo, Cheongsu Lim, Chang Ju Hwang, Dong-Ho Lee, Choon Sung Lee
Background ContextSagittal imbalance is associated with poor clinical outcomes in patients with degenerative lumbar disease. However, there is no consensus on the impact of posterior lumbar interbody fusion (PLIF) on local and global sagittal balance.PurposeTo reveal the effect of 1- or 2-level PLIF on global sagittal balance.Study Design/SettingA retrospective case-control study.Patients SampleThis study included 88 patients who underwent a 1- or 2-level PLIF for spinal stenosis with spondylolisthesis.Outcome MeasuresClinical and radiological parameters were measured pre- and postoperatively.MethodsAll patients were followed up for >2 years. Clinical outcomes included a visual analog scale, Oswestry Disability Index, and EuroQol 5-dimension questionnaire (EQ-5D). Radiological parameters were measured using whole-spine standing lateral radiographs. Fusion, loosening, subsidence rates, and adverse events were also evaluated. Patients were divided into two groups according to their preoperative C7–S1 sagittal vertical axis (SVA): group N: SVA ≤ 5 cm vs group I: SVA > 5 cm; they were also divided according to postoperative changes in C7–S1 SVA. Clinical and radiological outcomes were compared between the groups.ResultsAll clinical outcomes and radiological parameters improved postoperatively. C7–S1 SVA improved (−1.6 cm) after L3–4–5 fusion, but it was compromised (+3.6 cm) after L4–5–S1 fusion (p = 0.001). Preoperative demographic and clinical data showed no difference except in the anxiety/depression domain of EQ-5D. No differences were found in postoperative clinical outcomes. Lumbar lordosis, pelvic tilt, and thoracic kyphosis slightly improved in group N, whereas C7–S1 SVA decreased from 9.5 cm to 3.8 cm (p < 0.001) in group I. Furthermore, all sagittal parameters improved in group I. On comparing the postoperative changes in C7–S1 SVA, we found that the decreasing trend in the postoperative C7–S1 SVA was related to a larger preoperative C7–S1 SVA (p = 0.030) and a more proximal level fusion (L3–4–5 vs L4–5–S1, p = 0.033).ConclusionsGlobal sagittal balance improved after short-level lumbar fusion surgery in patients having spinal stenosis with spondylolisthesis who showed preoperative sagittal imbalance. Restoration of sagittal balance predominantly occurred after L3–4, L4–5, or L3–4–5 PLIF. However, no such restoration was observed after L5–S1 or L4–5–S1 PLIF. Thus, we could anticipate sagittal balance restoration after performing PLIF at L3–4 or L4–5 level. However, caution is required when planning for L5–S1 fusion if preoperative sagittal imbalance is present.



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Associated anomalies in cases with esophageal atresia

Esophageal atresia (EA) is a common type of congenital anomaly. The etiology of esophageal atresia is unclear and its pathogenesis is controversial. Infants with esophageal atresia often have other non-EA associated congenital anomalies. The purpose of this investigation was to assess the prevalence and the types of these associated anomalies in a defined population. The associated anomalies in cases with EA were collected in all livebirths, stillbirths, and terminations of pregnancy during 29 years in 387,067 consecutive births in the area covered by our population-based registry of congenital malformations. Of the 116 cases with esophageal atresia, representing a prevalence of 2.99 per 10,000, 54 (46.6%) had associated anomalies. There were 9 (7.8%) cases with chromosomal abnormalities including 6 trisomies 18, and 20 (17.2%) nonchromosomal recognized dysmorphic conditions including 12 cases with VACTERL association and 2 cases with CHARGE syndrome. Twenty five (21.6%) of the cases had multiple congenital anomalies (MCA). Anomalies in the cardiovascular, the digestive, the urogenital, the musculoskeletal, and the central nervous systems were the most common other anomalies. The anomalies associated with esophageal atresia could be classified into a recognizable malformation syndrome or pattern in 29 out of 54 cases (53.7%). This study included special strengths: each affected child was examined by a geneticist, all elective terminations were ascertained, and the surveillance for anomalies was continued until 2 years of age. In conclusion the overall prevalence of associated anomalies, which was close to one in two cases, emphasizes the need for a thorough investigation of cases with EA. A routine screening for other anomalies may be considered in infants and in fetuses with EA.

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Neuroradiographic findings in 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11.2DS) is a common genetic disorder with enormous phenotypic heterogeneity. Despite the established prevalence of developmental and neuropsychiatric issues in this syndrome, its neuroanatomical correlates are not as well understood. A retrospective chart review was performed on 111 patients diagnosed with 22q11.2DS. Of the 111 patients, 24 with genetically confirmed 22q11.2 deletion and brain MRI or MRA were included in this study. The most common indications for imaging were unexplained developmental delay (6/24), seizures of unknown etiology (5/24), and unilateral weakness (3/24). More than half (13/24) of the patients had significant radiographic findings, including persistent cavum septi pellucidi and/or cavum vergae (8/24), aberrant cortical veins (6/24), polymicrogyria or cortical dysplasia (4/24), inner ear deformities (3/24), hypoplastic internal carotid artery (2/24), and hypoplastic cerebellum (1/24). These findings reveal the types and frequencies of brain malformations in this case series, and suggest that the prevalence of neuroanatomical abnormalities in 22q11.2DS may be underestimated. Understanding indications for imaging and frequently encountered brain malformations will result in early diagnosis and intervention in an effort to optimize patient outcomes.

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Multiple supratentorial subependymomas causing obstructive hydrocephalus

Introduction

Subependymomas are benign intraventricular tumours that most often occur asymptomatically and are found incidentally on autopsy. Symptomatic examples requiring surgical intervention are exceedingly rare.

Case presentation

A 55-year-old man with no history of neurological symptoms presented with multiple episodes of loss of consciousness and increasing headaches. MRI revealed a lobulated intraventricular mass centred at the right Foramen of Monro. Obstructive hydrocephalus with localised midline shift and a second lesion were noted. Right frontal craniotomy with total removal via transcortical resection was performed.

Discussion

Symptomatic subependymomas generally present with signs of hydrocephalus due to obstruction of cerebrospinal fluid pathways. There is only one other reported case of multifocal subependymomas in a symptomatic patient. An example of multiple supratentorial subependymomas causing obstructive hydrocephalus has not been previously reported.

Conclusions

Multiple subependymomas are rare. Judicious surgical management with full excision led to symptomatic improvement in our patient.

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Multiple recurrent ischaemic strokes in a patient with cancer: is there a role for the initiation of anticoagulation therapy for secondary stroke prevention?

A 52-year-old woman with a medical history of cervical and thyroid cancer, hypertension, dyslipidaemia, uncontrolled diabetes and heavy smoking was diagnosed with a new metastatic cholangiocarcinoma. While undergoing palliative chemotherapy, she developed dysarthria and left-sided weakness. Imaging studies showed multiple bilateral ischaemic strokes. On hospital days 2 and 5, she developed worsening neurological symptoms and imaging studies revealed new areas of ischaemia on respective days. Subsequent workup did not revealed a clear aetiology for the multiple ischaemic events and hypercoagulability studies were only significant for a mildly elevated serum D-dimer level. Although guidelines are unclear, full-dose anticoagulation with low molecular weight heparin was initiated given her high risk of stroke recurrence. She was discharged to acute rehabilitation but, within a month, she experienced complications of her malignant disease progression and a new pulmonary thromboembolism. The patient died soon after being discharged home with hospice care.

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Corticosteroid treatment for traumatic acute subdural haematoma, maybe not such a good idea

Description

An 86-year-old woman with acute blunt head trauma (the patient's head was hit by a car) 10 days ago, associated with a right occipital fracture and an acute subdural haematoma (treated in the department of neurosurgery by oral prednisone 80 mg once a day) (figure 1), presented with focal left arm motor seizures. At that time, CT and MRI showed right cortical venous thrombosis (figure 1), absent on initial CT imaging. Corticosteroids were stopped and antiepileptic drugs and anticoagulation (warfarin) started. Three weeks later, CT showed complete resolution of the cortical venous thrombosis and spontaneous resorption of the subdural haematoma. Blood analyses in search of a prothrombotic state were negative in the absence of other blood test abnormalities (including normal metabolic profile).

Figure 1

Initial CT showing frontal (A) and temporal (B) acute subdural haematoma and right occipital fracture (C and D),...

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A 15-year-old Nepali boy with metastasised colorectal cancer

Nepal suffers from vast inequalities in modern healthcare. The low-income country wrestles with far-reaching insufficiencies in minimal preventative medicine, health awareness, limited infrastructure and difficult topography—all of which contribute to poor access and poor care-seeking behaviour. Our patient came from rural Nepal, where primary healthcare outposts are frequently understaffed and underequipped. He received supportive treatment in his village from the time symptoms presented until he was diagnosed 2 years later, at a tertiary medical centre, with colorectal cancer. An examination of the relevant literature indicates that younger patients often present in later stages of the disease due to initial misdiagnosis or overlooking colorectal cancer as a possibility. Beyond the rarity of the patient's condition, the logistical and financial obstacles he faced in Nepal, particularly outside of the capital of Kathmandu, deterred his access to a higher level of care and delayed his correct diagnosis and treatment.

http://ift.tt/2qL9hy0

Two-staged en bloc excision of a retinal haemangioma

A 31-year-old man presented to us with diminution of vision in the right eye which he noticed since 10 days, with a visual acuity of hand motions only. On examination, festooned pupil and a complicated cataract were noted with no view of the retina. Ultrasonography of the right eye showed retinal detachment in all quadrants with suspected areas of traction and membranes in the vitreous. Left eye examination revealed a normal anterior and posterior segment. Intraoperatively, he underwent a pars plana lensectomy following which an inferior large retinal haemangioma was noted with dilated and tortuous feeder artery and draining vein. The haemangioma was managed by a two-staged procedure including ligature of the feeder artery in the first surgery and the en bloc excision of the angioma at the time of the second procedure after significant shrinkage in size of the tumour.

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An unusual position of retromandibular vein: a surgical challenge in parotid surgeries

A 44-year-old man presented with swelling in the left parotid region. The swelling was firm and Fine Needle Aspiration Cytology report proved pleomorphic adenoma. In the CT scan, the tumour was confined to the superficial lobe of parotid. So, left superficial parotidectomy was planned. Modified Wilson Blair's incision was used. On course of identifying the facial nerve, a large calibre vein was identified running vertically through the parotid substance. Assuming it as retromandibular vein, further dissection was carried out more meticulously. Marginal mandibularbranch of facial nerve was identified near the angle of mandible and retrograde dissection showed the cervicofacial division running medial to retromandibular vein with the main facial nerve trunk lying unusually medial and posterior to it. Adding to it, the temporofacial division was found 'forked' between the branches of retromandibular vein. These variations in head and neck venous channels are not that rare as we believe. All these variations have an embryological basis. Therefore, knowledge and understanding of this complex anatomy will help us preventing devastating complications like bleeding and facial nerve injury in such cases.

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Orbital myositis presenting with only unilateral orbital pain

Description

A 24-year-old woman developed sudden severe periorbital pain characterised by severe, unilateral, pounding, short-lived, repetitive pain. Consequently, she was diagnosed with paroxysmal haemicrania at the first visit. There was no history of diplopia or other ophthalmic symptoms. Her physical and other neurological findings were normal. Anti-thyroid and antinuclear antibodies were negative. IgG4, soluble interleukin-2 receptor, C-reactive protein and creatine kinase levels; cerebrospinal fluid analysis; and CT scan were normal. MRI revealed enlargement and increased signal in the left medial rectus muscle on gadolinium-enhanced T1-weighted imaging suggesting orbital myositis (OM) (figure 1A,B). The patient was treated with three cycles of intravenous methylprednisolone (IVMP) followed by oral prednisolone 30 mg/day, resulting in rapid resolution of the symptoms. There was no relapse after reducing the prednisolone dosage, and MRI findings were almost resolved after 2 months of steroid therapy (figure 1C,D). The most frequently used medication of OM...

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Scanning of own- versus other-race faces in infants from racially diverse or homogenous communities

Abstract

We examined the role of community face experience on 6- and 8-month-old Caucasian infants' scanning of own- and other-race face scanning. We measured infants' proportional fixation time and scan path amplitudes as indices of face processing. Proportional fixation time to informationally rich face regions varied as a function of age and face race for infants living in a racially homogeneous community, whereas scan path amplitudes varied as a function of age and face race for infants living in a racially diverse community. In both communities 6-month-old infants did not show different responding to own- and other-race faces, whereas 8-month-old infants responded differently to own- and other-race faces. However, 8-month-old infants from the two communities showed different patterns of cross-race face scanning. Therefore, experience in the community beyond the home appears to contribute to the development of differential scanning of own- versus other-race faces between 6 and 8 months of age.

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University study explores heart monitoring in vehicles

Researchers have teamed up with Toyota to examine whether new vehicle technology could predict emergencies

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Initial Stages of Angiogenesis after Acute Experimental Local Venous Outflow Disturbances and Application of Cell Technologies

The initial stages of angiogenesis in rats after transcutaneous injection of autologous bone marrow multipotent mesenchymal stromal cells transfected with GFP gene and stained cell membranes in the projection of ligated femoral vein were studied by fluorescent light and confocal laser microscopy. Large clusters of brightly fluorescing elongated fibroblast-like cells were seen in the paravasal tissue and in the postoperative scar and signs of angiogenesis were noted as soon as in 4 days. The injected cells not only formed new vessels, but also integrated into vessels formed by host cells. Some injected cells were phagocytizied by macrophages and the latter started to fluoresce due to the presence of the membrane dye. These macrophages within the specified period appeared in the regional inguinal lymph nodes where they formed clusters in the lymphoid parenchyma of the cortical substance.

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Neuromotor Activity, Anxiety and Cognitive Function in the In Vivo Model of Alimentary Hyperlipidemia and Obesity

Behavioral indicators characterizing specific features of the pathological process of alimentary-dependent diseases were studied using in vivo model of alimentary hyperlipidemia in rats and mice. Rats and mice of the control groups received balanced semisynthetic diet for 63 days; animals of the experimental groups received a diet with high fat content (30% dry weight), balanced or high-fat diet with fructose solution instead of water, balanced cholesterol-enriched diet (0.5% dry weight), or balanced cholesterol-enriched diet with fructose solution. During the experiment, the mass of food, consumed by the animals, was monitored daily. Muscle tone was assessed by the front paw grip strength on days 33 and 54 of the experiment. Anxiety was tested in the elevated plus maze on days 36 and 57. Behavior and memory were assessed by conditioned passive avoidance reflex on days 39, 40, and 61. A significant increase in muscle tone was revealed on day 54 in rats fed with a balanced diet with fructose, and in mice, that received a similar diet, supplemented with fructose and cholesterol. Anxiety in the second test (day 57) was significantly decreased in rats fed high-fat diet and increased in mice fed high fat diet and high fat diet with fructose. In the second test, additional amount of cholesterol in the diet was the factor that significantly improved both short-term and long-term memory in both species. In mice, in contrast to rats, addition of fructose, including combination with high-fat diet, significantly worsened short-term and long-term memory. Thus, dietary factors, contributing to alimentary dyslipidemia development in rats and mice, can significantly affect the indices of neuromotor activity, anxiety level and cognitive functions, and the nature and direction of these changes are largely species-specific.

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Estimation of Expression of Oral Fluid Biomarkers in the Diagnosis of Pretumor Diseases of Oral Mucosa

Complex clinical, dental, and morphological investigation, and ELISA of levels of MMP-2, 8, 9, and TIMP-1 and 2 in the saliva was performed during primary examination of patients with premalignant lesions of maxillofacial area and practically healthy volunteers. Levels of all study MMP in the saliva significantly differed (p≤0.05) in patients with premalignant lesions and the control. These patients were also characterized by a significant (0.1≤p≤0.05) changes in TIMP concentrations (toward pathological pattern) comparing to the control. Pattern of correlations between parameters of MMP-2 expression might be a marker for early diagnostics of a premalignant lesion independently on the dental health. Observed features of biomarker expression in patients with premalignant lesions might reflect the appearance of a cascade of biochemical reactions followed by the activation of production of proteinases and their inhibitors as a response to the exposure to etiological factors. Clinical and morphological diagnosis of a premalignant lesion in the maxillofacial area was confirmed by the immunological analysis of biomarker expression in the saliva, which can be used for monitoring and screening of population.

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Role of Cyclic Nucleotides in the Effect of Hydrogen Sulfide on Contractions of Rat Jejunum

We studied the role of cyclic nucleotides in the influence of hydrogen sulfide (H₂S) donor, sodium hydrosulfide (NaHS, 200 μM), on motor activity of rat jejunum. NaHS reduced spontaneous and carbachol-induced contractions of rat jejunum segment, which suggests that H₂S can act through mechanisms involving muscarinic receptor activation. Against the background of a membrane-penetrating non-hydrolyzable cAMP analogue or under conditions of adenylate cyclase blockade, the inhibitory effect of NaHS on the carbachol-induced contractions was maintained. Against the background of elevated cGMP concentration or guanylate cyclase inhibition, the reduction of carbachol-induced contractions upon exposure to NaHS was less pronounced than in control. It was hypothesized that H₂S induces relaxation of carbachol-induced jejunum contractions, affecting protein kinase G targets or activating cGMP synthesis.

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Effect of Concentration of Collagen Gel on Functional Activity of Bone Marrow Mesenchymal Stromal Cells

Collagen I gels with protein concentrations of 1, 2, and 3.5 mg/ml were prepared and embedded in a porous polylactide scaffold to reduce their contraction. Concentration of the gel did not affect its degradation. Collagen gels promoted the formation of cell networks. The cells in the collagen gel with a concentration of 1 mg/ml embedded in polylactide scaffold had elongated spindle-like shape, in contrast to flattened cells in collagen gel of the same concentration not embedded in the scaffold. Stabilization of the collagen gel in the polylactide scaffold promoted active synthesis of laminin and fibronectin by cells as soon as on day 5 of culturing in comparison with that in free collagen substrate.

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The Role of Endogenous Opioid System in the Regulation of Heart Tolerance to Stress-Induced Damage

In Wistar rats, stress was modeled by 24-h immobilization in a supine posture and stress-induced damage to the heart was assessed by accumulation of ^99mTc-pyrophosphate in the myocardium. The intensity of stress reaction was measured by serum levels of cortisol and insulin. Both stressinduced damage to the heart and intensity of stress reaction were examined under control conditions and in rats treated with opioid receptor antagonists naltrexone, methylnaltrexone bromide, MR2266, and ICI174.864. Activation of central μ-opioid receptors with endogenous opioids aggravated stress-induced cardiomyopathy, while stimulation of peripheral μ-opioid receptors produced a cardioprotective effect. The stress-induced damage to the heart was not directly related to up-regulation of cortisol secretion in response to 24-h immobilization. Blockade of the central opioid receptors promoted a decrease in cortisol level in stressed rats.

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Cytokine Production in Mixed Cultures of Mesenchymal Stromal Cells from Wharton’s Jelly and Peripheral Blood Lymphocytes

We compared the production of 19 humoral factors in mixed cultures of mesenchymal stromal cells from Wharton's jelly and allogenic peripheral blood lymphocytes. For evaluation of the specificity of immunosuppressive activity of mesenchymal stromal cells, comparative analysis of the production of these humoral factors in mixed cultures of lymphocytes and epithelial BxPC-3 cells was conducted. The production of soluble factors in both mono- and mixed cultures significantly correlated (p<0.05). The maximum production was found for proinflammatory chemokine IP-10 and IFN-γ and anti-inflammatory cytokine IL-10. The major difference of mesenchymal stromal cells from epithelial BxPC-3 cells was 7-fold higher production of IL-10, which can explain the immunosuppressive effect of mesenchymal stromal cells.

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Effects of Bone Marrow Multipotent Mesenchymal Stromal Cells and Their Secretory Products on Microcirculation in the Broad Ligament of the Uterus of Wistar Rats during Experimental Chronic Genital Inflammation

Effects of bone marrow multipotent mesenchymal stromal cells and their secretory products released into the conditioned medium on microcirculatory bed in the broad ligament of the uterus were studied in Wistar rats with chronic genital inflammation. Opposite changes in the parameters of microcirculation and lymphatic drainage in the broad ligament of the uterus were observed after administration of cells and conditioned medium via different routes, which should be taken into account during the treatment of inflammatory and degenerative processes in the pelvic organs.

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Internalization of Vectorized Liposomes Loaded with Plasmid DNA in C6 Glioma Cells

We studied internalization of vector nanocarriers loaded with plasmid DNA into C6 glioma cells. For improving selectivity of plasmid delivery, the liposomes were conjugated with monoclonal antibodies to VEGF and its receptor VEGFR2. Flow cytofluorometry and laser scanning confocal microscopy showed more intensive (more than 2-fold) internalization and accumulation of antibody-vectorized liposomes in C6 glioma cells in comparison with the control (liposomes conjugated with non-specific antibodies and non-vectorized liposomes). Using quantitative analysis of fluorescent signal, we showed that cationic immunoliposomes significantly more effective delivered pCop-Green-N plasmid DNA and ensured effective transfection of C6 glioma cells.

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Interaction of Constitutive Nitric Oxide Synthases with Cyclooxygenases in Regulation of Bicarbonate Secretion in the Gastric Mucosa

Neuronal NO synthase blocker 7-nitroindazole suppressed bicarbonate secretion in rat gastric mucosa induced by mild local irritation with 1 M NaCl (pH 2.0). Non-selective blocker of neuronal and endothelial synthases, Nω-nitro-L-arginine (L-NNA), did not affect HCO₃^– production, but inhibited secretion after pretreatment with omeprazole. Non-selective cyclooxygenase blocker indomethacin inhibited HCO₃^– production under conditions of normal synthase activity and in the presence of L-NNA, but was ineffective when co-administered with 7-nitroindazole. It was concluded that neuronal and endothelial synthases are involved in different mechanisms of regulation of HCO₃^– secretion in the gastric mucosa induced by mild irritation. Activation of neuronal synthase stimulated HCO₃^– production, which is mediated mainly through activation of cyclooxygenase. Theoretically, activation of endothelial synthase should suppress HCO₃^– production. The effect of endothelial synthase depends on acid secretion in the stomach and bicarbonate concentration in the submucosa, as it was demonstrated in experiments with intravenous NaHCO₃ infusion.

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The Content of Multipotent Stromal Cells in 3-4.5-Month Heterotopic Bone Marrow Transplants of CBA Mice Subjected to a Single Exposure to Osteogenic Stimuli (Curettage, BMP-2) or Antigens ( S. typhimurium antigenic complex, LPS)

At the early stages of development (3 months), transplants from bone marrow donors subjected to single in vivo stimulation (curettage, administration of BMP-2 or antigenic complex of S. typhimurium) 1 day before transplantation were characterized by significantly elevated content of nucleated cells (by 1.4, 1.9 and 2.9 times, respectively), efficiency of cloning of multipotent stromal cells (by 3.8, 3.8 and 7.2 times), and total number of multipotent stromal cells (by 5, 7 and 21 times) and osteogenic multipotent stromal cells (by 5, 9 and 15 times) in comparison with the control (intact donors); more rapid increase in the weight of bone capsules was also noted. At later terms, the difference by these parameters between the control and experimental groups became less pronounced, but even in 4.5 months, the total number of multipotent stromal cells in the transplant in experimental groups exceeded the control values by 1.4-1.7 times and osteogenic multipotent stromal cells by 2 times. In donors exposed to the specified stimulations, the content of multipotent stromal cells in the femoral bone marrow in 1 day increased by 2.1 times (curettage), 2.6 times (administration of S. typhimurium antigens), and 3.3 times (LPS); administration of BMP-2 reduced this value by 50%. The content of osteogenic bone marrow multipotent stromal cells at this term increased by 1.7 times (BMP-2) and 5.5 times (curettage), after administration of S. typhimurium antigens, this parameter corresponded to the control. The concentration of osteogenic multipotent stromal cells in the bone marrow of intact donors was 22%; the maximum values were observed after curettage (57%) and BMP-2 administration (74%) and minimum after treatment with S. typhimurium antigens (8%). However, this parameter in all groups of transplants little differed and leveled as soon as by 3-4 months, which can be due to regulatory influences of the recipient body. The initial advantage in the content of bone marrow multipotent stromal cells in donors exposed to osteogenic stimuli and administration of antigens ensured considerably more rapid growth of the transplants in comparison with the control. These results can be useful for the development of optimal protocols of tissue grafting.

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Effect of Transplantation of Mesenchymal Stem Cells on the Density of Pial Microvascular Network in Spontaneously Hypertensive Rats of Different Age

Using a TV device for studying microcirculation (×40), we analyzed the density of the whole microvascular network and the density of arterioles in the pia mater of the sensorimotor cortex in SHR rats of different ages (3-4 and 12 months) after intracerebral transplantation of human mesenchymal stem cells. We found that the density of pial microvascular network in SHR rats receiving transplantation of human mesenchymal stem cells increased to a level observed in young Wistar-Kyoto rats.

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Association of Polymorphism in SCN5A , GJA5 , and KCNN3 Gene with Sudden Cardiac Death

We studied association of single-nucleotide SCN5A (rs1805124), GJA5 (rs35594137), and KCNN3 (rs13376333) polymorphisms and sudden cardiac death. Humans died suddenly from cardiac causes (N=379) and unrelated sex- and age-matched control subjects were genotyped. No significant intergroup differences were found in the frequency of rs1805124 and rs13376333 genotypes and alleles. In women under 50 years, enhanced risk of sudden cardiac death was associated with rs35594137 GG genotype (OR=3.6; 95%CI=1.2-10.4; p=0.022), while in older women it was associated with rs35594137 AA genotype (OR=3.0; 95%CI=2.3-3.9; p=0.041). In women under 50 years, GA rs35594137 genotype was associated with a protective effect against sudden cardiac death (OR=0.3; 95%CI=0.1-0.8; p=0.036). Thus, GJA5 gene rs35594137 polymorphism is significantly associated with sudden cardiac death in the examined group.

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Influence of ACTG 4-7 -PGP (Semax) on Morphofunctional State of Hepatocytes in Chronic Emotional and Painful Stress

We studied the effect of intraperitoneal administration of peptide ACTG_4-7-PGP to male Wistar rats in doses of 5, 50, 150, and 450 μg/kg on the morphofunctional state of hepatocytes in chronic emotional and painful stress. A dose-dependent stress-limiting effect of the peptide was observed: it normalized the protein synthesis function of the liver and serum activity of ALT. The anticytolytic effect of the peptide increased with increasing its dose against the background of the increase in the relative number of multinucleated and multinucleolated cells and deceleration of the recovery of serum protein concentration. The decrease of hepatocyte cytolysis against the background of more intense morphological signs of protein synthesis processes attests to activation of reparative processes in the liver parenchyma via enhanced constitutional synthesis of protein.

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Toxic Effects of Nanostructured Silicon Dioxide on Multipotent Mesenchymal Stromal Cells

We studied the effect of nanostructured silicon dioxide particles on functional activity and ultrastructure of rat multipotent mesenchymal stem cells. A dose-dependent decrease in cell adhesion to plastics and their proliferative potential, accumulation of apoptotic cells, a decrease in the electron density of cell cytoplasm due to swelling and degenerative changes of organelles, and intracellular accumulation of nanostructured of silicon dioxide particles were observed.

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Features of Blood Supply to Axillary Lymph Nodes in Breast Cancer Patients

Numerical density of vessels in axillary lymph node structures in breast cancer patients was studied by light microscopy with antibodies to CD34. The correlation between the stage of breast cancer and vascularization of lymph nodes was analyzed. The development of breast cancer was followed by rapid and significant increase in the number of blood vessel in axillary lymph nodes in general and in all their specific areas, especially in the paracortex and medullary substance. Strong or very strong positive correlation between the stage of tumor process and parameters of vascularization was observed in various areas of the axillary lymph nodes. No significant differences in node vascularization were observed between women without breast cancer and women with stage I breast cancer; the differences were found only starting from stage II. Considerable vascularization of lymph nodes can be a symptom of malignant tumor growth in the area of lymph collection. The duration of the tumor process and the size of the tumor can be indirectly evaluated by the increase in vessel number in lymph nodes.

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Level of Interleukins IL-6 and IL-15 in Blood Plasma of Mice after Forced Swimming Test

We measured the concentrations of IL-6 and IL-15 in blood plasma of mice at different terms after forced swimming, taking into account exercise intensity and preliminary training. It was shown that training was an important factor affecting blood plasma level of IL both at rest and after single forced swimming: in trained animals, the concentration of both myokines increased immediately after swimming, while in untrained animals, this increase was observed only after 5 h. Changes in cytokine production against the background of training can be associated with various factors, including neuroendocrine mechanisms, stress, modification of intracellular signaling, as well as reorganization of transcriptional mechanisms in muscle fibers. The most important factor is shift in the ratio of monovalent cations (sodium and potassium) in the cytoplasm.

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High Potassium Concentration during Culturing of Early Mammalian Embryos: Normal or Extreme Situation?

Analysis of the element composition of oviduct and uterine fluid in mammals showed high potassium concentrations in the early embryo microenvironment in vivo. The results of early embryogenesis of mammals in vitro in the presence of high potassium concentrations are discussed. The data are summarized in accordance with the conditions of experimentally modeled pre-implantation development. Comparative assessment of the quality of embryo development until the blastocyst stage in vitro proved the embryos more successfully developed at potassium concentrations close to those registered in the oviductal fluid.

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Circulating Proteasomes in the Pathogenesis of Head and Neck Squamous Cell Carcinoma

Increased proteasome activity was revealed in blood serum of patients with stage T1N0M0 head and neck squamous cell carcinoma in comparison with patients with chronic diseases of the larynx and laryngopharynx. This opens prospects of using chymotrypsin-like activity measurement for differential diagnosis of squamous cell carcinoma, screening for high-risk groups, and evaluation of the degree of tumor differentiation

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Effect of Atorvastatin Therapy on the Level of CD34 + CD133 + CD309 + Endothelial Progenitor Cells in Patients with Coronary Heart Disease

In 58 patients with coronary heart disease, the count of CD34⁺CD133⁺CD309⁺ endothelial progenitor cells in the blood was determined and the dynamics of the content of endothelial progenitor cells, angiogenic growth factors, and lipid parameters over 3 months of atorvastatin therapy was analyzed. Atorvastatin was administered in daily doses of 10 mg (26 patients) and 40 mg (32 patients). Control group comprised 15 healthy volunteers. In patients with coronary heart disease, the count of endothelial progenitor cells was lower by 4 times, the level of VEGF was higher by 52%, and the level of endostatin was lower by 13% than in healthy volunteers. Atorvastatin therapy significantly reduced the levels of VEGF (by 11%), C-reactive protein (by 26%), total cholesterol (by 30%), LDL cholesterol (by 35%), and triglycerides (by 18%); the levels of endostatin, MCP-1, and HDL cholesterol remained unchanged. The count of endothelial progenitor cells increased significantly by 72% irrespectively on the statin dose, but the changes were more pronounced in patients with lower initial endothelial progenitor cell counts and in patients with more drastic decrease in LDL cholesterol.

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ICORG 10-14: NEOadjuvant trial in Adenocarcinoma of the oEsophagus and oesophagoGastric junction International Study (Neo-AEGIS)

Abstract

Background

Neoadjuvant therapy is increasingly the standard of care in the management of locally advanced adenocarcinoma of the oesophagus and junction (AEG). In randomised controlled trials (RCTs), the MAGIC regimen of pre- and postoperative chemotherapy, and the CROSS regimen of preoperative chemotherapy combined with radiation, were superior to surgery only in RCTs that included AEG but were not powered on this cohort. No completed RCT has directly compared neoadjuvant or perioperative chemotherapy and neoadjuvant chemoradiation. The Neo-AEGIS trial, uniquely powered on AEG, and including comprehensive modern staging, compares both these regimens.

Methods

This open label, multicentre, phase III RCT randomises patients (cT2-3, N0-3, M0) in a 1:1 fashion to receive CROSS protocol (Carboplatin and Paclitaxel with concurrent radiotherapy, 41.4Gy/23Fr, over 5 weeks). The power calculation is a 10% difference in favour of CROSS, powered at 80%, two-sided alpha level of 0.05, requiring 540 patients to be evaluable, 594 to be recruited if a 10% dropout is included (297 in each group). The primary endpoint is overall survival, with a minimum 3-year follow up. Secondary endpoints include: disease free survival, recurrence rates, clinical and pathological response rates, toxicities of induction regimens, post-operative pathology and tumour regression grade, operative in-hospital complications, and health-related quality of life. The trial also affords opportunities for establishing a bio-resource of pre-treatment and resected tumour, and translational research.

Discussion

This RCT directly compares two established treatment regimens, and addresses whether radiation therapy positively impacts on overall survival compared with a standard perioperative chemotherapy regimen Sponsor: Irish Clinical Research Group (ICORG).

Trial registration

NCT01726452. Protocol 10-14. Date of registration 06/11/2012.

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Progressive resistance training in head and neck cancer patients during concomitant chemoradiotherapy -- design of the DAHANCA 31 randomized trial

Abstract

Background

Head and neck cancer patients undergoing concomitant chemoradiotherapy (CCRT) frequently experience loss of muscle mass and reduced functional performance. Positive effects of exercise training are reported for many cancer types but biological mechanisms need further elucidation. This randomized study investigates whether progressive resistance training (PRT) may attenuate loss of muscle mass and functional performance. Furthermore, biochemical markers and muscle biopsies will be investigated trying to link biological mechanisms to training effects.

Methods

At the Departments of Oncology at Herlev and Aarhus University Hospitals, patients with stage III/IV squamous cell carcinoma of the head and neck, scheduled for CCRT are randomized 1:1 to either a 12-week PRT program or control group, both with 1 year follow-up. Planned enrollment is 72 patients, and stratification variables are study site, sex, p16-status, and body mass index. Primary endpoint is difference in change in lean body mass (LBM) after 12 weeks of PRT, assessed by dual-energy X-ray absorptiometry (DXA). The hypothesis is that 12 weeks of PRT can attenuate the loss of LBM by at least 25%. Secondary endpoints include training adherence, changes in body composition, muscle strength, functional performance, weight, adverse events, dietary intake, self-reported physical activity, quality of life, labor market affiliation, blood biochemistry, plasma cytokine concentrations, NK-cell frequency in blood, sarcomeric protein content in muscles, as well as muscle fiber type and fiber size in muscle biopsies. Muscle biopsies are optional.

Discussion

This randomized study investigates the impact of a 12-week progressive resistance training program on lean body mass and several other physiological endpoints, as well as impact on adverse events and quality of life. Furthermore, a translational approach is integrated with extensive biological sampling and exploration into cytokines and mechanisms involved. The current paper discusses decisions and methods behind exercise in head and neck cancer patients undergoing concomitant chemoradiotherapy.

Trial registration

Approved by the Regional Ethics Committee for the Capital Region of Denmark (protocol id: H-15003725) and registered retrospectively at ClinicalTrials.gov (NCT02557529) September 11th 2015.

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Treatment strategies for DNA repair-deficient prostate cancer.

Related Articles

Treatment strategies for DNA repair-deficient prostate cancer.

Expert Rev Clin Pharmacol. 2017 Jun 02;:

Authors: Teply BA, Antonarakis ES

Abstract
INTRODUCTION: Common recurrent genetic alterations have been identified in prostate cancer through comprehensive sequencing efforts, and the prevalence of mutations in DNA repair pathway genes in patients with advanced and metastatic disease approaches 20-25%. Identification of these underlying DNA repair defects may present unique treatment opportunities for patients, both in terms of standard-of-care treatments and selected investigational agents. Areas Covered: We review our current understanding of the genomic landscape of prostate cancer, with special attention to alterations in DNA repair pathway genes in metastatic castration-resistant disease. For patients with tumors deficient in homologous recombination repair, potential opportunities for treatment include platinum chemotherapy, poly(ADP) ribose polymerase (PARP) inhibitors, bipolar androgen therapy, and maybe immune checkpoint blockade therapy. In addition, tumors with mismatch repair defects (i.e. microsatellite instability) may be particularly susceptible to checkpoint blockade immunotherapy. Expert Commentary: We anticipate that genomic profiling of tumors will become necessary to guide treatment of advanced prostate cancer treatment in the coming years. Work is needed to define the optimal tissue to test, and to define the national history of tumors with specific genetic defects. The prognostic and therapeutic importance of germline vs somatic DNA repair alterations, and mono-allelic vs bi-allelic inactivation, also remains unclear. Finally, optimal strategies to sequence or combine targeted agents for these patients with 'actionable' mutations are now needed.

PMID: 28573914 [PubMed - as supplied by publisher]

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Valuable contribution of magnetic resonance spectroscopy in differentiation of brain abscess from glioma

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Prevalence of hepatitis C and pre-testing awareness of hepatitis C status in 1500 consecutive PWID participants at the Stockholm needle exchange program

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First international consensus conference on standardization of oncoplastic breast conserving surgery

Abstract

Purpose

To obtain consensus recommendations for the standardization of oncoplastic breast conserving surgery (OPS) from an international panel of experts in breast surgery including delegates from the German, Austrian and Swiss societies of senology.

Methods

A total of 52 questions were addressed by electronic voting. The panel's recommendations were put into context with current evidence and the report was circled in an iterative open email process until consensus was obtained.

Results

The panelists considered OPS safe and effective for improving aesthetic outcomes and broadening the indication for breast conserving surgery (BCS) towards larger tumors. A slim majority believed that OPS reduces the rate of positive margins; however, there was consensus that OPS is associated with an increased risk of complications compared to conventional BCS. The panel strongly endorsed patient-reported outcomes measurement, and recommended selected scales of the Breast-Q™-Breast Conserving Therapy Module for that purpose. The Clough bi-level classification was recommended for standard use in clinical practice for indicating, planning and performing OPS, and the Hoffmann classification for surgical reports and billing purposes. Mastopexy and reduction mammoplasty were the only two recognized OPS procedure categories supported by a majority of the panel. Finally, the experts unanimously supported the statement that every OPS procedure should be tailored to each individual patient.

Conclusions

When implemented into clinical practice, the panel recommendations may improve safety and effectiveness of OPS. The attendees agreed that there is a need for prospective multicenter studies to optimize patient selection and for standardized criteria to qualify and accredit OPS training centers.

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Glowing Worms: Biological, Chemical, and Functional Diversity of Bioluminescent Annelids

Abstract

Bioluminescence, the ability to produce light by living organisms, has evolved independently in numerous lineages across the tree of life. Luminous forms are found in a wide range of taxonomic groups from bacteria to vertebrates, although the great majority of bioluminescent organisms are marine taxa. Within the phylum Annelida, bioluminescence is widespread, present in at least 98 terrestrial and marine species that represent 45 genera distributed in thirteen lineages of clitellates and polychaetes. The ecological diversity of luminous annelids is unparalleled, with species occupying a great variety of habitats including both terrestrial and marine ecosystems, from coastal waters to the deep-sea, in benthic and pelagic habitats from polar to tropical regions. This great taxonomic and ecological diversity is matched by the wide array of bioluminescent colors—including yellow light, which is very rare among marine taxa—different emission wavelengths even between species of the same genus, and varying patterns, chemical reactions and kinetics. This diversity of bioluminescence colors and patterns suggests that light production in annelids might be involved in a variety of different functions, including defensive mechanisms like sacrificial lures or aposematic signals, and intraspecific communication systems. In this review, we explore the world of luminous annelids, particularly focusing on the current knowledge regarding their taxonomic and ecological diversity and discussing the putative functions and chemistries of their bioluminescent systems.

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Butterflies Do Not Alter Conspecific Avoidance in Response to Variation in Density

Synopsis

High conspecific densities are associated with increased levels of intraspecific competition and a variety of negative effects on performance. However, changes in life history strategy could compensate for some of these effects. For instance, females in crowded conditions often have fewer total offspring, but they may invest more in each one. Such investment could include the production of larger offspring, more time spent engaging in parental care, or more choosy decisions about where offspring are placed. For animals that have a relatively immobile juvenile stage, the costs of competition can be particularly high. Females may be able to avoid such costs by investing more in individual reproductive decisions, rearing young or laying eggs in locations away from other females. We tested the hypothesis that conspecific density cues during juvenile and adult life stages lead to changes in life history strategy, including both reproduction and oviposition choices. We predicted that high-density cues during the larval and adult stages of female Pieris rapae butterflies lead to lower fecundity but higher conspecific avoidance during oviposition, compared to similar low-density cues. We used a 2×2 factorial design to examine the effects of low and high conspecific density during the larval and adult stages of butterflies on avoidance behavior and fecundity. We found that past information about conspecific density did not matter; all butterflies exhibited similar levels of fecundity and a low level of conspecific avoidance during oviposition regardless of their previous experience as larvae and adults. These results suggest that P. rapae females use a fixed, rather than flexible, conspecific avoidance strategy when making oviposition decisions, and past information about conspecific density has no effect on life history and current reproductive investment. We speculate that this may be partially because past conspecific density per se is not a reliable cue for predicting current density and levels of competition, and thus it does not affect the development of life history strategies in this system.

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Erratum to: Global skin colour prediction from DNA

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Real-World Impact of Cardiovascular Disease and Anemia on Quality of Life and Productivity in Patients with Non-Dialysis-Dependent Chronic Kidney Disease

Abstract

Introduction

Patients with chronic kidney disease (CKD) have an increased risk of comorbid conditions, including cardiovascular disease (CVD). Anemia is prevalent in the CKD population and worsens as kidney function declines, resulting in a diminished quality of life and increased morbidity/mortality. The purpose of this secondary analysis was to determine the real-world prevalence of CVD among patients with non-dialysis-dependent CKD (NDD-CKD), with and without comorbid anemia, and to assess the impact of these conditions on quality of life (QoL) and work productivity.

Methods

Data were drawn from the Adelphi CKD Disease-Specific Programme, conducted in France, Germany, Italy, Spain, and the UK (2012). Anonymized data were collected via patient record forms and patient-completed questionnaires. Patient data were stratified by anemic status and the presence of CVD comorbidity.

Results

Data were collected by physicians for 1993 patients, of whom 867 completed a patient-completed questionnaire. A total of 61.4% of patients had anemia, and the prevalence of anemia increased with CKD stage. Patients with anemia had a higher mean number of cardiovascular comorbidities than non-anemic patients (1.27 vs 0.95, respectively; P < 0.001). The presence of cardiovascular conditions was associated with a significantly reduced QoL (EuroQol EQ-5D-3L visual analog scale: coefficient, −5.68 in anemic patients; P = 0.028) and work productivity and activity impairment (WPAI activity impairment: coefficient, +8.04 in anemic patients; P = 0.032), particularly among anemic patients.

Conclusions

The presence of anemia in this cohort of NDD-CKD patients was high. The presence of concomitant cardiovascular conditions was more common in NDD-CKD patients with comorbid anemia, and was associated with reduced QoL and work productivity outcomes.

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Monitoring for and Characterizing Crizotinib Progression: A Chart Review of ALK -Positive Non-Small Cell Lung Cancer Patients

Abstract

Introduction

Crizotinib is recommended as first-line therapy for ALK-positive non-small cell lung cancer (NSCLC), but within a year of treatment initiation many patients develop resistance. With the recent approval of second-generation ALK inhibitors, this study assessed how physicians monitor for and diagnose progression and how they alter treatment following progression on crizotinib.

Methods

A panel of oncologists from the United States were surveyed regarding their monitoring practices and criteria for diagnosing progression on crizotinib. The physicians also retrospectively provided data (March–June 2016) from the medical charts of their adult patients with locally advanced or metastatic ALK-positive NSCLC who progressed on crizotinib after the approval (April 2014) of the first second-generation ALK inhibitor, ceritinib.

Results

A total of 28 physicians responded to the survey. Data was abstracted on 74 patients. In the physician survey, most physicians (71%) reported monitoring for radiographic progression every 3–4 months. When new lesions were detected, physician response varied. Following a symptomatic isolated lesion, most physicians (75%) would add local therapy and resume crizotinib. Following multiple symptomatic lesions, 96% and 64% of physicians would switch to a new therapy depending on whether the lesions were extracranial or isolated to the brain, respectively. For the patient cohort, physician-defined progression on crizotinib was diagnosed after a median of 10 months, and within 30 days of diagnosis, 86% of patients discontinued crizotinib. Among all patients who discontinued crizotinib, 77% switched to ceritinib, 14% to chemotherapy, and 1% to alectinib. The remaining 7% did not receive additional systemic antineoplastic therapy.

Conclusion

The findings from this physician survey and retrospective chart review study suggest that physician response to the development of new lesions in crizotinib-treated ALK-positive NSCLC patients varies with location and extent of the lesions. Once patients were considered to have progressed, most of them were immediately switched to ceritinib.

Funding

Novartis Pharmaceuticals Corporation.

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EVALUATION OF mONALDI’S APPROACH WITH REGARD TO NEEDLE DECOMPRESSION OF THE TENSION PNEUMOTHORAX − A CADAVER STUDY

Publication date: Available online 3 June 2017
Source:Injury
Author(s): G.M. Hohenberger, A. Schwarz, F. Hohenberger, T. Niernberger, R. Krassnig, N. Hörlesberger, A.H. Weiglein, V. Matzi
BackgroundAlthough needle decompression of tension pneumothorax through the second intercostal space in the midclavicular line (Monaldi's approach) is a life-saving procedure, severe complications have been reported after its implementation. We evaluated the procedure by comparing how it was performed on cadavers by study participants with different training levels.MethodsSix participants including one thoracic surgeon performed bilateral thoracic drainage after Monaldi on 82 torsos. After the thoraces were opened, the distances from the internal thoracic artery (A), the site of the puncture (B) and the midclavicular line (C) were measured bilaterally with reference to the median of the sternum. Further, it was determined whether the participants had correctly identified the second intercostal space. The differences between B-A and C-B were analysed.ResultsThe needle was placed in the second intercostal space in 136 hemithoraces (83%). The thoracic surgeon showed a hit rate of 0% laceration of adjacent vessels. All the other participants had hit rates between 10% and 15%. The interval B-A ranged from 2.88 to 5.06cm in right and from 3.00 to 5.00cm in left hemithoraces. The distance C-B lay between 1.03cm and 1.87cm (right side), and 0.84cm and 2.02cm (left side).ConclusionIn our collective, the main problem was failure to assess correctly the lateral extension of the clavicle. If this fact is emphasized during training, Monaldi's approach is a safe method for needle decompression of pneumothorax.



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Demonstration of impaired neurovascular coupling responses in TG2576 mouse model of Alzheimer’s disease using functional laser speckle contrast imaging

Abstract

Increasing evidence from epidemiological, clinical, and experimental studies indicates that cerebromicrovascular dysfunction and microcirculatory damage play critical roles in the pathogenesis of many types of dementia in the elderly, including both vascular cognitive impairment (VCI) and Alzheimer's disease. Vascular contributions to cognitive impairment and dementia (VCID) include impairment of neurovascular coupling responses/functional hyperemia ("neurovascular uncoupling"). Due to the growing interest in understanding and pharmacologically targeting pathophysiological mechanisms of VCID, there is an increasing need for sensitive, easy-to-establish methods to assess neurovascular coupling responses. Laser speckle contrast imaging (LSCI) is a technique that allows rapid and minimally invasive visualization of changes in regional cerebromicrovascular blood perfusion. This type of imaging technique combines high resolution and speed to provide great spatiotemporal accuracy to measure moment-to-moment changes in cerebral blood flow induced by neuronal activation. Here, we provide detailed protocols for the successful measurement in neurovascular coupling responses in anesthetized mice equipped with a thinned-skull cranial window using LSCI. This method can be used to evaluate the effects of anti-aging or anti-AD treatments on cerebromicrovascular health.

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The beneficial effects of HMG-CoA reductase inhibitors in the processes of neurodegeneration

Abstract

Statins, cholesterol lowering drugs, have been demonstrated to exert beneficial effects in other conditions such as primary and progressing neurodegenerative diseases beyond their original role. Observation that statins ameliorate the neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS) and cerebral ischemic stroke, the neuroprotective effects of these drugs are thought to be linked to their anti-inflammatory, anti-oxidative, and anti-excitotoxic properties. Despite the voluminous literature on the clinical advantages of 3-hydroxy-3-methylglutaryl Co-enzyme A reductase (HMGCR) inhibitors (statins) in cardiovascular system, the neuroprotective effects and the underlying mechanisms are little understood. Hence, the present review tries to provide a critical overview on the statin-induced neuroprotection, which are presumed to be associated with the ability to reduce cholesterol, Amyloid-β and apolipoprotein E (ApoE) levels, decrease reactive oxygen and nitrogen species (ROS and RNS) formation, inhibit excitotoxicity, modulate matrix metalloproteinases (MMPs), stimulate endothelial nitric oxide synthase (eNOS), and increase cerebral blood perfusion. This review is also aimed to illustrate that statins protect neurons against the neuro-inflammatory processes through balancing pro-inflammatory/anti-inflammatory cytokines. Ultimately, the beneficial role of statins in ameliorating the development of PD, AD, MS and cerebral ischemic stroke has been separately reviewed.

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Apocynin Alleviates Renal Ischemia/Reperfusion Injury Through Regulating the Level of Zinc and Metallothionen

Abstract

The purpose of this research was to evaluate the protective effects of apocynin on renal ischemia/reperfusion (I/R) injury (RI/RI) in rats. Rats preconditioned with apocynin were subjected to renal I/R. Zinc levels in serum and renal tissues, blood urea nitrogen (BUN), and serum creatinine (Scr) were detected. We further measured the activity of superoxide dismutase (SOD); the content of malondialdehyde (MDA), IL-4, IL-6, IL-10, and TNF-α; and the expression of metallothionein (MT) in the renal tissues. Results indicated that the levels of MDA, IL-4, IL-6, IL-10, TNF-α, and MT in the kidney tissue and serum BUN and Scr levels in RI/RI group were significantly higher than those in sham-operated group, while the levels of serum Zn and kidney Zn and SOD were reduced in RI/RI group. Apocynin treatment further decreased the levels of MDA, IL-6, TNF-α, and serum BUN and Scr, whereas it significantly increased the levels of Zn, SOD, IL-4, IL-10, and MT in the kidney tissue and serum Zn. These findings suggest that apocynin might play a protective role against RI/RI in rats through regulating zinc level and MT expression involving in oxidative stress.

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Nanoselenium Supplementation of Heat-Stressed Broilers: Effects on Performance, Carcass Characteristics, Blood Metabolites, Immune Response, Antioxidant Status, and Jejunal Morphology

Abstract

An experiment was conducted to investigate the effects of dietary nanoselenium supplementation at 0, 0.6 and 1.2 mg/kg of diet on growth performance, serum biochemical parameters, immune response, antioxidant capacity, and jejunal morphology of 29-d-old male broilers subjected to heat stress at 37 ± 1°C for 14 d. Broilers were fed for 42 d on the experimental diets. The results showed that nanoselenium supplementation had no effect on growth performance, but it supplementation at the rate of 1.2 mg/kg diet decreased the serum concentration of cholesterol prior to the heat exposure. Further, dietary nanoselenium supplementation linearly increased the high-density lipoprotein cholesterol concentration, while linearly decreased those of low-density lipoprotein cholesterol and aspartate aminotransferase in the serum before applying heat stress. Compared with thermoneutral temperature, heat stress reduced body mass gain, feed intake, percentages of carcass, breast, leg, abdominal fat, bursa of Fabricius, thymus, antibody response against sheep red blood cells, serum concentration of protein, erythrocyte activities of glutathione peroxidase and superoxide dismutase, jejunal villus height, and villus height to crypt depth ratio, while increased feed conversion ratio, percentages of liver, gizzard, pancreas, gallbladder, heart, and the concentrations of aspartate aminotransferase and malondialdehyde. Dietary supplementation of nanoselenium linearly reduced the abdominal fat and liver percentages, while linearly increased the activity of glutathione peroxidase and villus height in heat-stressed broilers. Furthermore, the lower level of nanoselenium decreased the percentages of gizzard and heart in broilers under heat stress. The diet supplemented with 1.2 mg/kg nanoselenium improved feed conversion ratio and increased antibody response against sheep red blood cells, activity of superoxide dismutase, and villus height to crypt depth ratio, but decreased the serum concentrations of cholesterol, low-density lipoprotein cholesterol, and malondialdehyde in heat-stressed broilers. The results suggest that supplemental nanoselenium improved growth performance, internal organs health, immune response, and jejunal morphology by alleviating the oxidative stress induced by heat stress.

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Influence of Selenium on the Production of T-2 Toxin by Fusarium poae

Abstract

The objective of this study was to investigate the effects of selenium on the production of T-2 toxin by a Fusarium poae strain cultured in a synthetic medium containing different concentrations of selenium. The T-2 toxin contents in fermentative products were evaluated by a high performance liquid chromatography (HPLC). The results showed that the production of T-2 toxin was correlated with the concentration of selenium added to the medium. In all three treatments, the addition of 1 mg/L selenium to the medium resulted in a lower toxin yield than the control (0 mg/L); the yield of the toxin began to increase when selenium concentration was 10 mg/L, while it decreased again at 20 mg/L. In summary, T-2 toxin yield in the fermentative product was affected by the addition of selenium to the medium, and a selenium concentration of 20 mg/L produced the maximum inhibitory effect of T-2 toxin yield in the fermentative product of F. poae.

http://ift.tt/2rBXIws

The Influence of the Dietary Cu-Glycine Complex on the Histomorphology of Cancellous Bone, Articular Cartilage, and Growth Plate as well as Bone Mechanical and Geometric Parameters Is Dose Dependent

Abstract

Copper (Cu) is required for all basic biochemical and physiological processes. The objective of this study was to compare the effect of two different chemical forms (sulfates and glycinate chelates also below the recommended dose) of Cu administered to adult rats on the biomechanical and morphometric properties of femur. Male rats at the age of 12 weeks were used in the 12-week experiment. The control diet provided the required Cu level from sulfate (S-Cu), and the other diets were supplemented with Cu-glycine complex. The Cu-Gly-treatment, irrespective of its concentration, did not influence the bone mass and length. The Cu-Gly-treatment in 100 and 75% of daily demand increased mechanical endurance. The Cu-Gly-treatment (regardless of its concentration) increased the real bone volume in epiphysis and decreased the total thickness and zone I of the articular cartilage compared to the control group supplemented with S-Cu. The Cu-Gly-treatment enhanced the content of proteoglycans (except the OG50 group). Dietary Cu given to adult rats in the Cu-Gly complex covering the daily demand in 75% exerted a positive effect on bone metabolism and appeared to be the most effective among the investigated doses of the organic form.

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Erratum to: How Trace Element Levels of Public Drinking Water Affect Body Composition in Turkey

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Nickel Oxide Nanoparticles Induce Oxidative DNA Damage and Apoptosis in Kidney Cell Line (NRK-52E)

Abstract

Increasing use of nickel oxide (NiO) nanoparticles in different applications results in high occupational and environmental exposure to them. However, the effect of NiO nanoparticles on human health is still poorly documented. It was aimed to investigate the toxic potentials of NiO nanoparticles on NRK-52E kidney epithelial cells. The following assays were used: the nanoparticle characterization by transmission electron microscopy (TEM) and dynamic light scattering (DLS); the determination of cellular uptake and morphologic changes by TEM and inductively coupled plasma-mass spectrometry (ICP-MS); MTT and neutral red uptake (NRU) assays for cytotoxicity; comet assay for genotoxicity; the determination of malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), protein carbonyl (PC) and glutathione (GSH) levels by enzyme-linked immune sorbent assays (ELISA) for the potential of oxidative damage; and Annexin V-FITC apoptosis detection assay with propidium iodide (PI) for apoptosis. The nanoparticles were taken up by the cells and induced dose-dependent DNA damage by comet assay and oxidative damage evidenced by increasing levels of MDA, 8-OHdG, PC and depletion of GSH. At ≥294.0 μg/mL concentration, NiO nanoparticles caused 50% inhibition in cell viability by the cytotoxicity assays. Also, they showed apoptotic/necrotic effects on the cells as well as some morphological changes. We have indicated that their cellular damage effects should raise concern about the safety associated with their applications in consumer products.

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The Effect of Ketogenic Diet on Serum Selenium Levels in Patients with Intractable Epilepsy

Abstract

The aim of the present study was to evaluate serum selenium levels in children receiving olive oil-based ketogenic diet (KD) for intractable seizures for at least 1 year. Out of 320 patients who were initiated on KD, patients who continued receiving KD for at least 12 months were enrolled. Sixteen patients who had selenium deficiency at the time of starting KD were excluded. Finally, a total of 110 patients (mean age 7.3 ± 4.2 years) were included. Serum selenium levels were measured at baseline and at 3, 6, and 12 months after treatment initiation by using atomic absorption spectroscopy. Selenium deficiency was defined as a serum selenium level <48 μg/L at each visit. Repeated measure ANOVA with post hoc Bonferroni correction was used for data analysis. Mean duration of KD was 15.3 ± 4.3 months. Mean serum selenium levels were significantly lower at 6 and 12 months of KD treatment (66.2 ± 23.3 and 57.2 ± 16.2 μg/L, respectively) compared to pre-treatment levels (79.3 ± 25.7 μg/L) (p = 0.001). On the other hand, selenium levels did not show any significant difference at 3 months of KD treatment (70.0 ± 21.2 μg/L) compared to baseline levels (p = 0.076). A total of 54 patients (49.1%) were diagnosed with selenium deficiency, and oral selenium medication was initiated for these patients. No relevant clinical findings were detected, and echocardiographic findings were normal in all patients. The decline of the serum selenium concentrations after 6 and 12 months of ketogenic diet suggests that patients on this highly prescriptive dietary treatment need close monitoring of this trace element.

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Increased Serum Al Levels in Hemodialysis Patients Kept Enhanced during a 2-Year Prospective Study

Abstract

The regulation of mineral homeostasis is altered in hemodialysis patients with renal insufficiency, producing increased risk for secondary diseases like cardiovascular ones. We hypothesized that risen serum aluminum (Al) concentration in hemodialysis patients kept enhanced during a 2-year longitudinal study is associated with enhanced cardiovascular risk and influenced by medical treatments. This study reports the prospective monitoring of serum Al levels in six-monthly samplings over 2 years in 116 hemodialysis patients and a control group of 50 healthy adults. The influence of other factors like sex, age, kidney transplant, disease etiology, and drug consumption was also considered. At each sampling, serum Al levels were significantly higher in the patients than in the healthy controls (P < 0.05). Levels in the patient group were statistically significantly lower at the third and fourth versus first and second samplings, which may be related to Al accumulation in tissues. Increased Al levels in patients were positively and significantly related to serum calcium (Ca) and uric acid levels. Serum Al concentrations were significantly lower in patients receiving vasodilators and diuretics. Higher serum Al levels in hemodialyzed patients administered with phosphate binders or anti-hyperkalemics are attributable to their usual Al salt content. The consumption of antianemic drugs increases Al absorption by forming more bioavailable complexes with the compounds in these drugs. In conclusion, this is the first study to indicate that cardiovascular problems associated with elevated serum Al levels in hemodialysis patients may be in part mitigated by administrating vasodilators and diuretics, which reduce these levels.

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Effects of Chromium-Loaded Chitosan Nanoparticles on Glucose Transporter 4, Relevant mRNA, and Proteins of Phosphatidylinositol 3-Kinase, Akt2-Kinase, and AMP-Activated Protein Kinase of Skeletal Muscles in Finishing Pigs

Abstract

The study was conducted to evaluate the effects of chromium-loaded chitosan nanoparticles (Cr-CNP) on glucose transporter 4 (GLUT4), relevant messenger RNA (mRNA), and proteins involved in phosphatidylinositol 3-kinase (PI3K), Akt2-kinase, and AMP-activated protein kinase (AMPK) of skeletal muscles in finishing pigs. A total of 120 crossbred barrows (BW 65.00 ± 1.26 kg) were randomly allotted to four dietary treatments, with three pens per treatment and 10 pigs per pen. Pigs were fed the basal diet supplemented with 0, 100, 200, or 400 μg/kg of Cr from Cr-CNP for 35 days. After the feeding trials, 24 pigs were slaughtered to collect longissimus muscle samples for analysis. Cr-CNP supplementation increased GLUT4 messenger RNA (mRNA) (quadratically, P < 0.01) and total and plasma membrane GLUT4 protein contents (linearly and quadratically, P < 0.001) in skeletal muscles. Glycogen synthase kinase 3β (GSK-3β) mRNA was decreased linearly (P < 0.001) and quadratically (P < 0.001). Supplemental Cr-CNP increased insulin receptor (InsR) mRNA quadratically (P < 0.01), Akt2 total protein level linearly (P < 0.01) and quadratically (P < 0.001), and PI3K total protein was increased significantly (P < 0.05) in 200 μg/kg treatment group. The mRNA of AMPK subunit gamma-3 (PRKAG3) and protein of AMPKα₁ was significantly increased (P < 0.001) with the addition of Cr-CNP. The results indicate that dietary supplementation of Cr-CNP may promote glucose uptake by leading to recruitment of GLUT4 to the plasma membrane in skeletal muscles, and these actions may be associated with the insulin signal transduction and AMPK.

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N-Acetyl-L-Cysteine Protects Liver and Kidney Against Chromium(VI)-Induced Oxidative Stress in Mice

Abstract

Acute hexavalent chromium [Cr(VI)] compound exposure may lead to hepatotoxic and nephrotoxic effects. Cr(VI) reduction may generate reactive intermediates and radicals which might be associated with damage. We investigated effects of N-acetyl-l-cysteine (NAC) pre- or post-treatment on oxidative stress and accumulation of Cr in liver and kidney of Cr(VI)-exposed mice. Intraperitoneal potassium dichromate injection (20 mg Cr/kg) caused a significant elevation of lipid peroxidation in both tissues as compared to control (p < 0.05). Significant decreases in non-protein sulfhydryl (NPSH) level, as well as enzyme activities of catalase (CAT) and superoxide dismutase (SOD) along with significant accumulation of Cr in the tissues (p < 0.05) were of note. NAC pre-treatment (200 mg/kg, ip) provided a noticeable alleviation of lipid peroxidation (p < 0.05) in both tissues, whereas post-treatment exerted significant effect only in kidney. Similarly, Cr(VI)-induced NPSH decline was restored by NAC pre-treatment in both tissues (p < 0.05); however, NAC post-treatment could only replenish NPSH in liver (p < 0.05). Regarding enzyme activities, in liver tissue NAC pre-treatment provided significant restoration on Cr(VI)-induced CAT inhibition (p < 0.05), while SOD enzyme activity was regulated to some extent. In kidney, SOD activity was efficiently restored by both treatments (p < 0.05), whereas CAT enzyme alteration could not be totally relieved. Additionally, NAC pre-treatment in both tissues and post-treatment in liver exerted significant tissue Cr level decreases (p < 0.05). Overall, especially NAC pre-treatment seems to provide beneficial effects in regulating pro-oxidant/antioxidant balance and Cr accumulation caused by Cr(VI) in liver and kidney. This finding may be due to several mechanisms including extracellular reduction or chelation of Cr(VI) by readily available NAC.

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Comment on "Stories of an Emigrant Physician: What It Has Been Like to Practice in Canada Compared With the United States".

No abstract available

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Precise Target Site of Ultrasound-Guided C5 Cervical Root Block.

No abstract available

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Restless ‘rest’: intrinsic sensory hyperactivity and disinhibition in post-traumatic stress disorder

Abstract

Post-traumatic stress disorder is characterized by exaggerated threat response, and theoretical accounts to date have focused on impaired threat processing and dysregulated prefrontal-cortex-amygdala circuitry. Nevertheless, evidence is accruing for broad, threat-neutral sensory hyperactivity in post-traumatic stress disorder. As low-level, sensory processing impacts higher-order operations, such sensory anomalies can contribute to widespread dysfunctions, presenting an additional aetiological mechanism for post-traumatic stress disorder. To elucidate a sensory pathology of post-traumatic stress disorder, we examined intrinsic visual cortical activity (based on posterior alpha oscillations) and bottom-up sensory-driven causal connectivity (Granger causality in the alpha band) during a resting state (eyes open) and a passive, serial picture viewing state. Compared to patients with generalized anxiety disorder (n = 24) and healthy control subjects (n = 20), patients with post-traumatic stress disorder (n = 25) demonstrated intrinsic sensory hyperactivity (suppressed posterior alpha power, source-localized to the visual cortex—cuneus and precuneus) and bottom-up inhibition deficits (reduced posterior→frontal Granger causality). As sensory input increased from resting to passive picture viewing, patients with post-traumatic stress disorder failed to demonstrate alpha adaptation, highlighting a rigid, set mode of sensory hyperactivity. Interestingly, patients with post-traumatic stress disorder also showed heightened frontal processing (augmented frontal gamma power, source-localized to the superior frontal gyrus and dorsal cingulate cortex), accompanied by attenuated top–down inhibition (reduced frontal→posterior causality). Importantly, not only did suppressed alpha power and bottom-up causality correlate with heightened frontal gamma power, they also correlated with increased severity of sensory and executive dysfunctions (i.e. hypervigilance and impulse control deficits, respectively). Therefore, sensory aberrations help construct a vicious cycle in post-traumatic stress disorder that is in action even at rest, implicating dysregulated triangular sensory-prefrontal-cortex-amygdala circuitry: intrinsic sensory hyperactivity and disinhibition give rise to frontal overload and disrupt executive control, fuelling and perpetuating post-traumatic stress disorder symptoms. Absent in generalized anxiety disorder, these aberrations highlight a unique sensory pathology of post-traumatic stress disorder (ruling out effects merely reflecting anxious hyperarousal), motivating new interventions targeting sensory processing and the sensory brain in these patients.

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HSCT Based Approaches for Tolerance Induction in Renal Transplant.

Renal transplantation has become the preferred treatment for end stage kidney failure. Although short-term graft survival has significantly improved as advances in immunosuppression have occurred, long term patient and graft survival have not. Approximately only 50% of renal transplant recipients are alive at 10 years due to the toxicities of immunosuppression and alloimmunity. Emerging research on cell-based therapies is opening a new door for patients to receive the organs they need without sacrificing quality of life and longevity because of drug based immunosuppression. Research has focused upon inducing tolerance, a state in which the body accepts the transplant and graft function is stable. Cell-based therapies to facilitate chimerism and achieve tolerance in MHC-disparate recipients have been developed in mouse, swine, canine, and nonhuman primate models. These finding are now being translated into the clinic in several trials currently underway. Protocols that utilize a combination of traditional therapeutic agents paired with cell populations including hematopoietic stem cells (HSC), regulatory T cells (Treg), and facilitating cells (FCRx) are being conducted with the objective to harness the donor immune system to protect the transplanted tissue. The benefits and feasibility of the clinical application of cell-based therapy has been demonstrated and promising results have been achieved. Here we discuss the preclinical work that has led to the clinical application of the various approaches and a summary of the most current clinical data from groups throughout the world. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Advanced Donation Programs and Deceased Donor Initiated Chains - 2 Innovations in Kidney Paired Donation.

Kidney paired donation strategies have facilitated compatible living-donor kidney transplants for end stage renal disease patients with willing but incompatible living donors. Success has inspired further innovations that expand opportunities for kidney-paired donation. Two such innovations are the advanced donation strategy in which a donor provides a kidney before their recipient is matched, or even in need of, a kidney transplant, and deceased donor initiated chains in which chains are started with deceased donors rather than altruistic living donors. While these innovations may expand kidney paired donation, they raise several ethical issues. Specific concerns raised by advanced donation include the management of uncertainty, the extent of donor and recipient consent, the scope of the obligation that the organization has to the kidney exchange paired recipient, the naming of alternative recipients, and the potential to unfairly advantage the recipient. Use of deceased donors for chain initiating kidneys raises ethical issues concerning the consent process for each involved party, the prioritization of deceased donor kidneys, the allocation of chain ending kidneys, and the value of a living donor kidney versus a deceased donor kidney. We outline each ethical issue and discuss how it can be conceptualized and managed so that these kidney paired donation innovations programs are ultimately successful. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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