Clinical management of cystic echinococcosis: state of the art, problems, and perspectives.
Clinical management of cystic echinococcosis (CE) has evolved over decades without adequate evaluation of important features such as efficacy, effectiveness, rate of adverse reactions, relapse rate, and cost. CE occurs in health care environments as different as Europe/North America and resource-poor countries of the South and the East. This creates setting-specific problems in the management of patients. Furthermore, studies carried out in either of the two fundamentally different environments lack external validity, i.e., results obtained in one setting may be different from those in the other and practices that can work in one may not be applicable to the other. In this paper, we review the current management procedures of CE with particular emphasis on the evidence base and setting-specific problems.


In Vitro Activity of KBP-7072, a Novel Third-Generation Tetracycline, against 531 Recent Geographically Diverse and Molecularly Characterized Acinetobacter baumannii Species Complex Isolates.
KBP-7072 is a novel third-generation tetracycline (aminomethylcycline) antibacterial that overcomes common efflux and ribosomal protection resistance mechanisms that cause resistance in older-generation tetracyclines. KBP-7072 completed phase 1 clinical development studies for safety, tolerability, and pharmacokinetics (ClinicalTrials.gov identifier NCT02454361) and multiple ascending doses in healthy subjects (ClinicalTrials.gov identifier NCT02654626) in December 2015. Both oral and intravenous formulations of KBP-7072 are being developed. In this study, we evaluated the in vitro activities of KBP-7072 and comparator agents by CLSI document M07 (2018) broth microdilution against 531 recent geographically diverse and/or molecularly characterized Acinetobacter baumannii-A. calcoaceticus species complex (A. baumannii) isolates from the United States, Europe, Asia-Pacific (excluding China), and Latin America. A. baumannii isolates included carbapenem-resistant, colistin-resistant, tetracycline-resistant, and extended-spectrum-β-lactamase (ESBL)- and metallo-β-lactamase (MBL)-producing isolates. Overall, KBP-7072 (MIC50/90, 0.25/1 mg/liter) was comparable in activity to colistin (92.8%/92.8% susceptible [S] [CLSI/EUCAST]) against A. baumannii isolates, inhibiting 99.2% of isolates at ≤2 mg/liter and 97.6% of isolates at ≤1 mg/liter. KBP-7072 was equally active against A. baumannii isolates, including carbapenem-resistant, colistin-resistant, and tetracycline-resistant isolates, regardless of geographic location, and maintained activity against ESBL- and MBL-producing isolates. KBP-7072 outperformed comparator agents, including ceftazidime (40.3% S [CLSI]), gentamicin (48.2%/48.2% S [CLSI/EUCAST]), levofloxacin (39.5%/37.9% S [CLSI/EUCAST]), meropenem (42.0%/42.0% S [CLSI/EUCAST]), piperacillin-tazobactam (33.3% S [CLSI]), and all tetracycline-class comparator agents, which include doxycycline (67.3% S [CLSI]), minocycline (73.8% S [CLSI]), tetracycline (37.2% S [CLSI]), and tigecycline (79.5% inhibited by ≤2 mg/liter). The potent in vitro activity of KBP-7072 against recent geographically diverse, molecularly characterized, and drug-resistant A. baumannii isolates supports continued clinical development for the treatment of serious infections, including those caused by A. baumannii.


Comparison of General Anesthesia with Spinal Anesthesia in Laparoscopic Cholecystectomy Operations.
Laparoscopic cholecystectomy (LC) operations are being performed under general anesthesia (GA). Further studies are needed on the issue whether these operations can be performed under spinal anesthesia (SA). In this study we aimed to compare SA with (GA) in terms of efficacy and complications in patients who will undergo LC operations, and to investigate the effects of preemptive analgesia on the development of shoulder pain, transition to general anesthesia, and postoperative analgesia. Sixty patients in ASA I-II risk group between 18-65 years of age undergoing laparoscopic cholecystectomy were randomly divided into general anesthesia (GA, n=30) and spinal anesthesia (SA, n=30) groups. Patients were premedicated with i.v. midazolam and fentanyl preoperatively. Anesthesia was induced with propofol in the GA group, and maintained with Desflurane and remifentanil. In the SA group, spinal anesthesia was provided with intratechal administration of 15 mg bupivacaine at L2-3 level, and block level was increased to T4 by keeping the patient in Trendelenburg position for 7-10 minutes. Demographic data, hemodynamic parameters, operation time, visual analog scale (VAS) scores at postoperative 0th,1st, 4th, 8th,12th and 24th hours, patient-surgeon satisfaction, side effects, and occurrence of right shoulder pain in SA group were inquired and recorded. Effective anesthesia was produced in both groups. Hypotension was observed in 5, bradycardia requiring atropin administration in 4, and perioperative shoulder pain in 9 patients in Group SA, but none of them required general anesthesia. Hypotension developed in one patient in Group GA. The postoperative VAS scores were significantly lower in Group SA at 0th,1st, 4th hours. Patient satisfection scores were higher in Group SA. We concluded that spinal anesthesia may be an alternative method to general anesthesia in patients who will undergo laparoscopic cholecystectomy operations especially when the risk of general anesthesia is too high.


Acute resetting of arterial baroreflexes in hypertensive rats.
Acute baroreflex resetting was studied in one-kidney, one-clip renal hypertensive (HT) and normotensive (NT) control male Wistar-Kyoto rats. Systolic blood pressure (SBP) was monitored weekly in conscious rats by the indirect tail-cuff occlusion method. At the time of experimentation (4-6 wk after placement of the clip), SBP in the HT rats (238 +/- 9 mmHg) was elevated compared with NT rats (117 +/- 5 mmHg). Baroreflex control of lumbar sympathetic nerve activity (LSNA) was assessed in alpha-chloralose (120 mg/kg)-urethan (600 mg/kg)-anesthetized rats by raising and lowering mean arterial pressure (MAP) between 50 and 200 mmHg (phenylephrine and nitroprusside infusions). The baroreflexes of the hypertensive rats were less sensitive to increments in pressure compared with normotensive rats as evidenced by a decreased slope of the baroreflex curve (-0.396 +/- 0.064 HT vs. -0.637 +/- 0.042 NT). In both groups, curves were obtained before (control) and after (reset) base-line MAP was increased by 30-55 mmHg for 15 min. The MAP for 50% maximum inhibition of LSNA (EP50) was increased in both groups of rats after exposure to the elevated pressure (NT, control = 109 +/- 5.2, reset = 120 +/- 5.0 mmHg; HT, control = 114 +/- 6.5, reset = 131 +/- 10.0 mmHg) with no significant change in slope. There was no significant difference in degree of upward resetting between the two groups (NT, 21 +/- 4%; HT, 30 +/- 7%). Thus, although hypertensive rats exhibited the depressed baroreflex function associated with chronic resetting, the ability to reset acutely was maintained.


Characterization of the Porphyromonas gingivalis conjugative transposon CTnPg1: determination of the integration site and the genes essential for conjugal transfer.
In our previous study, extensive genomic rearrangements were found in two strains of the Gram-negative anaerobic bacterium Porphyromonas (Por.) gingivalis, and most of these rearrangements were associated with mobile genetic elements such as insertion sequences and conjugative transposons (CTns). CTnPg1, identified in Por. gingivalis strain ATCC 33277, was the first complete CTn reported for the genus Porphyromonas. In the present study, we found that CTnPg1 can be transferred from strain ATCC 33277 to another Por. gingivalis strain, W83, at a frequency of 10(-7) to 10(-6). The excision of CTnPg1 from the chromosome in a donor cell depends on an integrase (Int; PGN_0094) encoded in CTnPg1, whereas CTnPg1 excision is independent of PGN_0084 (a DNA topoisomerase I homologue; Exc) encoded within CTnPg1 and recA (PGN_1057) on the donor chromosome. Intriguingly, however, the transfer of CTnPg1 between Por. gingivalis strains requires RecA function in the recipient. Sequencing analysis of CTnPg1-integrated sites on the chromosomes of transconjugants revealed that the consensus attachment (att) sequence is a 13 bp sequence, TTTTCNNNNAAAA. We further report that CTnPg1 is able to transfer to two other bacterial species, Bacteroides thetaiotaomicron and Prevotella oralis. In addition, CTnPg1-like CTns are located in the genomes of other oral anaerobic bacteria, Porphyromonas endodontalis, Prevotella buccae and Prevotella intermedia, with the same consensus att sequence. These results suggest that CTns in the CTnPg1 family are widely distributed among oral anaerobic Gram-negative bacteria found in humans and play important roles in horizontal gene transfer among these bacteria.


Glutathione synthetase: similarities of the proteins from Schizosaccharomyces pombe and Arabidopsis thaliana.
Glutathione synthetase predicted from the reported gene sequence from Schizosaccharomyces pombe is substantially smaller than the equivalent protein predicted from the cDNAs sequenced from Arabidopsis thaliana, Saccharomyces cerevisiae and other eukaryotes. Sequence alignments of the proteins encoded by the cDNA clones for glutathione synthetase from Arabidopsis and S. pombe show that the Arabidopsis protein contains 200 extra amino acids at the N-terminus. In order to test if this sequence is essential in the function of the protein, the full-length Arabidopsis protein and as two N-terminal deletions (Delta67-71 and Delta67-200) were expressed in S. pombe mutant MN101, which lacks endogenous glutathione synthetase activity. Although the wild-type plant cDNA could complement the yeast mutation, neither deletion mutant was able to restore glutathione-dependent cadmium resistance. When the three proteins were expressed as fusion proteins in Escherichia coli, they accumulated to the same level, but only the plasmid containing the full-length cDNA, pFLAG222, produced detectable enzyme activity in vitro. These results suggested that the N-terminus of the Arabidopsis glutathione synthetase is essential for its function and opened up the possibility that there was a sequencing error in the reported S. pombe sequence. Therefore the gsh2 sequence from wild-type S. pombe and the mutant strain MN101 were determined. The wild-type S. pombe gsh2 encodes a protein that is about the same length as that found in Arabidopsis, and the MN101 mutation involves a frameshift mutation early in the glutathione synthetase reading frame.


[A horse with Cushing's disease].
A thirteen-year-old Dutch warmblooded mare was referred to the Faculty of Veterinary Medicine because of a sinusitis. She was thin with a potbellied appearance. Her coat was dull with long wavy hair. Unilateral (left) purulent nasal discharge was evident. A cbc revealed leucopenia (3.9 G.L.-1) and plasma biochemical analysis revealed a plasma glucose concentration of 10.1 mmol.L-1. Thermostable alkaline phosphatase (at 65 degrees C during 2 minutes) could not be demonstrated. Basal plasma cortisol concentration was lowered (114 nmol.L-1) and basal plasma ACTH concentration was highly elevated (815 pg.ml-1), indicating adrenocortical insufficiency. A dexamethasone-suppression test was performed by intramuscular administering of 10 mg of dexamethasone showing a suppression of 32% instead of at least 50%. At necropsy a pituitary pars intermedia adenoma was found.


Effect of basis amino acids and aminoglycosides on 3H-gentamicin uptake in cortical slices of rat and human kidney.
The uptake of 3H-gentamicin was assessed in renal cortical slices of Fischer 344 male rats and four human cadaver kidneys not utilized for renal transplantation. In both species the uptake was maximal at 90 min and maintained a steady state thereafter. The characteristics of the energy-dependent component of 3H-gentamicin uptake were not altered by various basic amino acids, but competitive inhibition was induced by other aminoglycosides in a dose-dependent fashion. Thus aminoglycosides appear to share a transport process that is distinct from those of organic bases or other cationic substances. In addition, under the experimental conditions employed, the basolateral membrane of the tubular cell is capable of energy-dependent uptake of gentamicin. The role of this route of cellular uptake of aminoglycoside in clinical nephrotoxicity is speculative.


Creatine Supplementation Does Not Prevent the Development of Alcoholic Steatosis.
Alcohol-induced reduction in the hepatocellular S-adenosylmethionine (SAM):S-adenosylhomocysteine (SAH) ratio impairs the activities of many SAM-dependent methyltransferases. These impairments ultimately lead to the generation of several hallmark features of alcoholic liver injury including steatosis. Guanidinoacetate methyltransferase (GAMT) is an important enzyme that catalyzes the final reaction in the creatine biosynthetic process. The liver is a major site for creatine synthesis which places a substantial methylation burden on this organ as GAMT-mediated reactions consume as much as 40% of all the SAM-derived methyl groups. We hypothesized that dietary creatine supplementation could potentially spare SAM, preserve the hepatocellular SAM:SAH ratio, and thereby prevent the development of alcoholic steatosis and other consequences of impaired methylation reactions. For these studies, male Wistar rats were pair-fed the Lieber-DeCarli control or ethanol (EtOH) diet with or without 1% creatine supplementation. At the end of 4 to 5 weeks of feeding, relevant biochemical and histological analyses were performed. We observed that creatine supplementation neither prevented alcoholic steatosis nor attenuated the alcohol-induced impairments in proteasome activity. The lower hepatocellular SAM:SAH ratio seen in the EtOH-fed rats was also not normalized or SAM levels spared when these rats were fed the creatine-supplemented EtOH diet. However, a >10-fold increased level of creatine was observed in the liver, serum, and hearts of rats fed the creatine-supplemented diets. Overall, dietary creatine supplementation did not prevent alcoholic liver injury despite its known efficacy in preventing high-fat-diet-induced steatosis. Betaine, a promethylating agent that maintains the hepatocellular SAM:SAH, still remains our best option for treating alcoholic steatosis.


Effect of acyclovir [9-(2-hydroxyethoxymethyl)guanine] on Epstein-Barr virus DNA replication.
The effect of acyclovir [9-(2-hydroxyethoxymethyl)guanine] on Epstein-Barr virus (EBV) DNA replication in the lymphoblastoid cell lines P3HR-1 and Raji is reported. Acyclovir at a concentration of 100 microM completely inhibited EBV DNA synthesis in superinfected Raji cells, but did not inhibit DNA synthesis in mock-infected cells. The number of EBV genome equivalents per cell in the virus-producing cell line P3HR-1 was significantly reduced by acyclovir, whereas the number of latent EBV genomes in Raji cells was not affected by the drug. In situ cytohybridization performed on untreated P3HR-1 cultures revealed the presence of relatively large amounts of EBV DNA in 15 to 20% of the cells. After a 100 microM drug treatment, no P3HR-1 cells contained levels of EBV DNA detectable by in situ cytohybridization. Indirect immunofluorescence studies demonstrated that during treatment with 100 microM acyclovir for 7 days, the percentage of P3HR-1 cells expressing viral capsid antigen was reduced. The EBV DNA remaining in P3HR-1 cells after treatment with 100 microM acyclovir (approximately 14 genomes per cell) had the properties of covalently closed circular DNA with an average molecular weight of 108 X 10(6), as determined by contour length measurements.


Bronchial and nonbronchial systemic arteries at multi-detector row CT angiography: comparison with conventional angiography.
To retrospectively evaluate bronchial and nonbronchial systemic arteries at multi-detector row helical computed tomography (CT) compared with conventional angiography in patients undergoing endovascular treatment of hemoptysis. Neither institutional board approval nor informed consent was required. Forty-eight consecutive patients (39 men, nine women; mean age, 55.7 years; range, 20-82 years) with hemoptysis of bronchial and nonbronchial systemic artery origin underwent multi-detector row helical CT angiography of the thorax with use of a four-detector row (n = 31) or 16-detector row (n = 17) scanner prior to embolization. Findings on CT angiograms, including CT scans, maximum intensity projections, and three-dimensional volume-rendered images, were used to evaluate the depiction of bronchial and nonbronchial systemic arteries. Retrospective analysis of the ostium and the course of bronchial and/or nonbronchial systemic arteries on CT angiograms enabled evaluation of the accuracy of this technique in identification of the relevant vasculature. Among the 46 patients initially treated with bronchial artery embolization, 58 bronchial arteries were identified at CT and/or angiography. In 50 (86%) cases, concordant findings were observed with both modalities. In five (9%) cases, CT could not be used to identify the ostia of bronchial arteries. In three (5%) cases, CT depicted bronchial arteries that could not be selectively catheterized. Three-dimensional images were found to be superior to transverse CT scans in depicting the ectopic origin of the bronchial arteries, which enabled the interventional radiologists to perform successful embolization after direct catherization of the ectopic vessel in every case. In five (11%) patients, the nonbronchial systemic origin of bronchial bleeding was identified on CT angiograms. Multi-detector row helical CT angiography provides more precise depiction of bronchial and nonbronchial systemic arteries than does conventional angiography.


[Anthropology, ethnography, and narrative: intersecting paths in understanding the processes of health and sickness].
The article discusses anthropology, ethnographic method, and narrative as possible ways of coming to know subjects' experiences and the feelings they attribute to them. From an anthropological perspective, the sociocultural universe is taken as a point of reference in understanding the meaning of the processes of health and sickness, using a dense ethnographic description from an interpretivist analytical approach. In this context, narratives afford possible paths to understanding how subjective human experiences are shared and how behavior is organized, with a special focus on meaning, the process by which stories are produced, relations between narrator and other subjects, processes of knowledge, and the manifold ways in which experience can be captured.


Cigarette smoking and lung destruction. Accumulation of neutrophils in the lungs of cigarette smokers.
It has been hypothesized that lung destruction in persons with emphysema associated with cigarette smoking is mediated by elastase released by neutrophils that have migrated to the alveolar structures in response to cigarette smoke. To directly evaluate this hypothesis, cell suspensions, isolated from bronchoalveolar lavage fluid and from open lung biopsies of nonsmokers and cigarette smokers with normal lung parenchyma and from open lung biopsies of nonsmokers and cigarette smokers who have sarcoidosis were evaluated for the presence of neutrophils. A significantly increased number of neutrophils was present in the cell suspensions isolated from bronchoalveolar lavage fluid and from open lung biopsies of both normal and sarcoid cigarette smokers compared with that in the nonsmokers (p less than 0.01, each comparison). Evaluation of the alveolar macrophages present in lavage fluid suggested a mechanism by which neutrophils may be attracted to the lungs of cigarette smokers: alveolar macrophages of cigarette smokers release a chemotactic factor for neutrophils, whereas alveolar macrophages of nonsmokers do not. In addition, alveolar macrophages of nonsmokers, after exposure to cigarette smoke, in vitro, are stimulated to release this chemotactic factor. These studies demonstrate that an increased number of neutrophils are present in the lungs of cigarette smokers compared with that in nonsmokers and suggest that cigarette smoke may attract neutrophils to the lung by stimulating alveolar macrophages to release a potent chemotactic factor for neutrophils.


Prohedonic Effect of Cannabidiol in a Rat Model of Depression.
Accumulating evidence suggests that cannabidiol (CBD) may be an effective and safe anxiolytic agent and potentially also an antidepressant. The objective of this study was to further examine these properties of CBD using the 'depressive-like' Wistar-Kyoto (WKY) rat, focusing on the drug's effect on anhedonia-like behaviors. Forty-eight WKY and 48 control Wistar adult male rats were pretreated orally with CBD (15, 30 and 45 mg/kg) or vehicle. The saccharin preference test (SPT), the elevated plus maze (EPM) test and the novel object exploration (NOE) test were used. CBD showed a prohedonic effect on the WKY rats at 30 mg/kg in the SPT. In the NOE, CBD increased exploration of the novel object and locomotion at 45 mg/kg and increased locomotion at 15 mg/kg, indicating an improvement in the characteristically low motivation of WKY rats to explore. There was no similar effect at any dose in the EPM or in open-field behavior in the habituation to the NOE. These findings extend the limited knowledge on the antidepressant effect of CBD, now shown for the first time in a genetic animal model of depression. These results suggest that CBD may be beneficial for the treatment of clinical depression and other states with prominent anhedonia.


An acute pharyngeal-cervical-brachial (PCB) variant of Guillain-Barre syndrome presenting with isolated bulbar palsy.
Acute Guillain-Barre syndrome (GBS) is characterized by an acute onset of limb weakness and areflexia. There are a few rare variants that have been described and one of them is the pharyngeal-cervical-brachial (PCB) variant (oropharynx, neck, and proximal upper limb muscles). However, in this patient, the only presentation was bulbar involvement with fast recovery within days. This is likely to be the milder form of PCB that has rarely been described before. A 19-year-old Malay lady presented with progressive dysphagia associated with nasal voice for one week duration. There was no limb weakness. Examination showed generalized areflexia. Pharyngeal and palatal muscles were markedly weak. Cerebrospinal fluid (CSF) examination showed raised protein level. Nerve conduction studies revealed generalized demyelinating motor polyneuropathy consistent with GBS. The patient fully recovered within three days and was discharged well.


Partial agonists and schizophrenia: theoretical developments for the development of mental health nursing.
People with schizophrenia have a significant impaired quality of life. The paper discusses how partial agonists could improve the quality of life with people with schizophrenia in comparison with treatment with second generation antipsychotics. The paper provides a framework as to how mental health nurses can utilize the clinical benefits of partial agonists through greater application of psychosocial interventions.


Degree of specialisation of the surgeon influences lymph node yield after right-sided hemicolectomy.
To investigate the degree to which specialisation or case-load of the surgeon is associated with the number of lymph nodes isolated from pathology specimens after right-sided hemicolectomy. Data from 6 hospitals with well-defined catchment areas included in the Uppsala/Örebro Regional Oncology Centre Colon Cancer Register 1997-2006 were used to assess 821 patients undergoing right-sided hemicolectomy for stages I-III colon cancer. Factors influencing the lymph node yield were evaluated. A surgeon with colorectal accreditation and a university pathology department were both associated with a significantly higher proportion of patients having 12 or more lymph nodes isolated from surgical specimens after right-sided hemicolectomy in both unadjusted and multivariate analyses. Emergency surgery did not affect the lymph node yield. The degree of specialisation of the surgeon influences the number of lymph nodes isolated from specimens obtained during routine right-sided colon cancer surgery.


Mesothelioma: Do asbestos and carbon nanotubes pose the same health risk?
Carbon nanotubes (CNTs), the product of new technology, may be used in a wide range of applications. Because they present similarities to asbestos fibres in terms of their shape and size, it is legitimate to raise the question of their safety for human health. Recent animal and cellular studies suggest that CNTs elicit tissue and cell responses similar to those observed with asbestos fibres, which increases concern about the adverse biological effects of CNTs. While asbestos fibres' mechanisms of action are not fully understood, sufficient results are available to develop hypotheses about the significant factors underlying their damaging effects. This review will summarize the current state of knowledge about the biological effects of CNTs and will discuss to what extent they present similarities to those of asbestos fibres. Finally, the characteristics of asbestos known to be associated with toxicity will be analyzed to address the possible impact of CNTs.


Generic substitution of drugs in hospitals
Nurses are frequently required to undertake generic substitution of drugs in hospitals. According to the prevailing regulations, nurses may only undertake such substitution based on the Norwegian Medicines Agency's substitution list or the local substitution list in the hospital's quality system. A total of 600 nurses in 23 surgical and 28 medical wards in three health trusts were invited to participate in an online questionnaire survey on the generic substitution of drugs in hospitals. The study was undertaken to assess how current practice functions with regard to risk factors, documentation and potential improvements. The response rate for the survey was 52 %. A total of 57 % of nurses undertook generic substitution of drugs on a daily basis, while 8 % equally often left the decision to the doctor. In six hypothetical examples of generic substitution, the median number of incorrect responses by the nurses was two; the local substitution list was used as the only source of information in 23 % of cases, and none of the nurses used the Norwegian Medicines Agency's online substitution list. Altogether 37 % responded that generic substitution was recorded in 80 % or more of cases, while 18 % responded that a double-check was performed in 80 % or more of cases. Generic substitution in hospitals entails a significant possibility of errors. Safety and documentation of generic substitution should primarily be taken care of by computerised solutions, with the introduction of an electronic medication chart. Alternatively, the approved substitution list should be the only source used for substitution.


Clinical characteristics of Group G streptococcal bacteremia in Taiwan.
The results of this retrospective study showed that Group G streptococcal bacteremia was an acute febrile disease with low mortality. Most patients were > 60 y old but there was a strong association between age < 60 y and malignancy. Cases clustered in summer and the most common port of entry was the skin.


Abdominal obesity and colorectal cancer risk: systematic review and meta-analysis of prospective studies.
The association between abdominal obesity (as measured by waist circumference (WC) and waist-to-hip ratio (WHR)) and colorectal cancer (CRC) has not been fully quantified, and the magnitude of CRC risk associated with abdominal obesity is still unclear. A meta-analysis of prospective studies was performed to elucidate the CRC risk associated with abdominal obesity. Pubmed and Embase were searched for studies assessing the association between abdominal obesity and CRC risk. Relative risks (RRs) with 95% confidence intervals (95% CIs) were pooled using random-effects model of meta-analysis. Nineteen prospective cohort studies from eighteen publications were included in this meta-analysis. A total of 12,837 CRC cases were identified among 1,343,560 participants. Greater WC and WHR were significantly associated with increased risk of total colorectal cancer (WC: RR 1.42, 95% CI 1.30, 1.55; WHR: RR 1.39, 95% CI 1.25, 1.53), colon cancer (WC: RR 1.53, 95% CI 1.36, 1.72; WHR: 1.39, 95% CI 1.18, 1.63), and rectal cancer (WC: RR 1.20, 95% CI 1.03, 1.39; WHR: RR 1.22, 95% CI 1.05, 1.42). Subgroup analyses further identified the robustness of the association above. No obvious risk of publication bias was observed. In summary, abdominal obesity may play an important role in the development of CRC.


Effect of trans-10 cis-12 conjugated linoleic acid on bovine oocyte competence and fatty acid composition.
The reproductive performance of dairy cows may be improved by feeding conjugated linoleic acid (CLA) supplements during early lactation. The mechanism of action of t10,c12 CLA is not clearly known. Our objective was to investigate the effect of t10,c12 CLA on oocyte maturation and lipid composition of cumulus oocyte complexes (COC). The developmental potential of oocytes incubated in in vitro maturation (IVM) medium supplemented with t10,c12 CLA to the blastocyst stage and embryo quality were also assessed. In experiment 1, abattoir-derived oocytes were matured in TCM199 + 10% serum supplemented with 100 μM t10,c12 CLA (t10,c12 CLA n = 672) or without it (control n = 672). Mature oocytes were either stained for chromatin configuration or inseminated and cultured for embryo development assessment. In experiment 2, COC and IVM culture media were subjected to fatty acid (FA) analysis prior and after maturation with t10,c12 CLA or without it (control). Total lipids and FA profiles in oocytes, cumulus cells and culture media were determined by gas chromatography. t10,c12 CLA supplementation to IVM medium improved (p = 0.05) embryo quality evaluated morphologically. This effect was associated with t10,c12 CLA presence (3.1 ± 0.7%, p = 0.04) and lower levels of arachidonic acid in FA profile of t10,c12 CLA mature oocytes (immature oocytes = 4.4 ± 1.9%, t10,c12 CLA mature oocytes = 1.0 ± 0.7%, p = 0.05). Differences in myristic and eicotrienoic acids, saturated and unsaturated FA concentrations between oocytes and cumulus cells were detected (p ≤ 0.05). In conclusion, the presence of t10,c12 CLA during maturation interfered on lipid metabolism improving bovine oocyte competence to develop into higher quality embryos.


Emerging role of extracellular vesicles in mediating cancer cachexia.
Cancer cachexia is a multifactorial metabolic syndrome characterized by the rapid loss of skeletal muscle mass with or without the loss of fat mass. Nearly 50-80% of all cancer patients' experience rapid weight loss results in ∼20% of cancer-related deaths. The levels of pro-inflammatory and pro-cachectic factors were significantly up-regulated in cachexia patients when compared with the patients who were without cachexia. It is becoming evident that these factors work synergistically to induce cancer cachexia. Extracellular vesicles (EVs) including exosomes and microvesicles are implicated in cell-cell communication, immune response, tissue repair, epigenetic regulation, and in various diseases including cancer. It has been reported that these EVs regulate cancer progression, metastasis, organotropism and chemoresistance. In recent times, the role of EVs in regulating cancer cachexia is beginning to unravel. The aim of this mini article is to review the recent knowledge gained in the field of EVs and cancer cachexia. Specifically, the role of tumour cell-derived EVs in promoting catabolism in distally located skeletal muscles and adipose tissue will be discussed.


Eggs-only diet: its implications for the toxin profile changes and ecology of the marbled sea snake (Aipysurus eydouxii).
Studies so far have correlated the variation in the composition of snake venoms with the target prey population and snake's diet. Here we present the first example of an alternative evolutionary link between venom composition and dietary adaptation of snakes. We describe a dinucleotide deletion in the only three finger toxin gene expressed in the sea snake Aipysurus eydouxii (Marbled Sea Snake) venom and how it may have been the result of a significant change in dietary habits. The deletion leads to a frame shift and truncation with an accompanying loss of neurotoxicity. Due to the remarkable streamlining of sea snake venoms, a mutation of a single toxin can have dramatic effects on the whole venom, in this case likely explaining the 50- to 100-fold decrease in venom toxicity in comparison to that of other species in the same genus. This is a secondary result of the adaptation of A. eydouxii to a new dietary habit--feeding exclusively on fish eggs and, thus, the snake no longer using its venom for prey capture. This was parallel to greatly atrophied venom glands and loss of effective fangs. It is interesting to note that a potent venom was not maintained for use in defense, thus reinforcing that the primary use of snake venom is for prey capture.


Developmental quotient at 24 months and fatty acid composition of diet in early infancy: a follow up study.
A follow up study of developmental quotient (DQ) at 24 months of toddlers whose diets in early infancy differed in fatty acid composition, and in whom an association between diet and DQ was observed at 4 months. 81 toddlers were distributed among three groups according to early type of diets standard infant formula (SFo, n = 30); long chain polyunsaturated fatty acid (LC-PUFA) enriched formula (LCPFo, n = 26); human milk (HM, n = 25). DQ at 24 months was assessed by Brunet-Léxine's psychomotor developmental test. A subgroup (n = 20; SFo 8; LCPFo 6; HM 6) was tested for erythrocyte phosphatidyicholine and phosphatidylethanolamine. No DQ differences were found by analysis of variance. Neither DQ nor erythrocyte docosahexaenoic acid at 4 months were predictors of DQ scores at 24 months. Phosphatidylcholine arachidonic and docosahexaenoic acid correlated positively, and phosphatidylcholine linoleic acid and phosphatidylethanolamine eicosapentaenoic acid negatively, with DQ. Multiple regression analysis including these variables explained 52% of inter-individual DQ variance. A strong association was found between the erythrocyte phosphatidylcholine arachidonic/ linoleic acid ratio and DQ (r = 0.75; p = 0.0001). The diet/DQ association found at 4 months was not predictive of DQ scores at 24 months. Irrespective of dietary or genetic factors, there appears to be a strong correlation between the LC-PUFA composition of the red cell membrane and higher neurodevelopmental performance.


Toward optimizing a self-creating neural network.
This paper optimizes the performance of the growing cell structures (GCS) model in learning topology and vector quantization. Each node in GCS is attached with a resource counter. During the competitive learning process, the counter of the best-matching node is increased by a defined resource measure after each input presentation, and then all resource counters are decayed by a factor alpha. We show that the summation of all resource counters conserves. This conservation principle provides useful clues for exploring important characteristics of GCS, which in turn provide an insight into how the GCS can be optimized. In the context of information entropy, we show that performance of GCS in learning topology and vector quantization can be optimized by using alpha=0 incorporated with a threshold-free node-removal scheme, regardless of input data being stationary or nonstationary. The meaning of optimization is twofold: (1) for learning topology, the information entropy is maximized in terms of equiprobable criterion and (2) for leaning vector quantization, the use is minimized in terms of equi-error criterion.


[Study of the interaction of proflavine and isomeric diribonucleoside monophosphates CpG and GpC by proton magnetic resonance].
A comparative study of the interaction of proflavine with isomeric diribonucleoside monophosphates CpG and GpC has been made by the method of 1H NMR (270 MHz). A method of calculation of the parameters of complex formation from the concentration dependences of proton chemical shifts of the dye has been proposed. The equilibrium constants of 1:1 and 1:2 complexes association of these molecules and the most probable structures of the complexes have been determined.


Pravastatin for the prevention of preeclampsia in high-risk pregnant women.
Preeclampsia complicates approximately 3-5% of pregnancies and remains one of the major causes of maternal and neonatal morbidity. It shares pathogenic similarities with adult cardiovascular disease as well as many risk factors. Attempts at prevention of preeclampsia using various supplements and classes of medications have failed or had limited success, and they were not convincing enough to lead to widespread adoption of any particular strategy. Contrary to the experience with preeclampsia, prevention of cardiovascular mortality and other cardiovascular events in nonpregnant patients using 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, or statins, is widely accepted. Pravastatin and other statins have been shown to reverse various pathophysiologic pathways associated with preeclampsia, such as angiogenic imbalance, endothelial injury, inflammation, and oxidative stress. These beneficial effects are likely to contribute substantially to preventing preeclampsia and provide biological plausibility for the use of pravastatin in this setting. Pravastatin has favorable safety and pharmacokinetic profiles. In addition, animal studies and human pregnancy exposure data do not support teratogenicity claims for pravastatin. Therefore, the Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric--Fetal Pharmacology Research Units Network started a pilot trial to collect maternal--fetal safety data and to evaluate pravastatin pharmacokinetics when used as a prophylactic daily treatment in high-risk pregnant women (identifier NCT01717586, clinicaltrials.gov).


Tomato leaf curl Kerala virus (ToLCKeV) AC3 protein forms a higher order oligomer and enhances ATPase activity of replication initiator protein (Rep/AC1).
Geminiviruses are emerging plant viruses that infect a wide variety of vegetable crops, ornamental plants and cereal crops. They undergo recombination during co-infections by different species of geminiviruses and give rise to more virulent species. Antiviral strategies targeting a broad range of viruses necessitate a detailed understanding of the basic biology of the viruses. ToLCKeV, a virus prevalent in the tomato crop of Kerala state of India and a member of genus Begomovirus has been used as a model system in this study. AC3 is a geminiviral protein conserved across all the begomoviral species and is postulated to enhance viral DNA replication. In this work we have successfully expressed and purified the AC3 fusion proteins from E. coli. We demonstrated the higher order oligomerization of AC3 using sucrose gradient ultra-centrifugation and gel-filtration experiments. In addition we also established that ToLCKeV AC3 protein interacted with cognate AC1 protein and enhanced the AC1-mediated ATPase activity in vitro. Highly hydrophobic viral protein AC3 can be purified as a fusion protein with either MBP or GST. The purification method of AC3 protein improves scope for the biochemical characterization of the viral protein. The enhancement of AC1-mediated ATPase activity might lead to increased viral DNA replication.


Phylogeny of Rozites, Cuphocybe and Rapacea inferred from ITS and LSU rDNA sequences.
Phylogenetic relationships of Rozites, Cuphocybe, and Rapacea were assessed using molecular phylogenetic approaches. These three genera are placed in Cortinariaceae and have been regarded as closely related to Cortinarius. Rozites includes more than 20 species, which are characterized by having both a membranaceous partial veil in the form of a persistent annulus and a membranaceous universal veil. Cuphocye (4 species) lacks an annulus or cortina, but has pigmented veil fibrils or scales. The monotypic genus Rapacea accommodates a distinct taxon with pale, nearly smooth and thick-walled basidiospores. We analyzed 56 sequences of the internal transcribed spacer region (ITS1, ITS2, and the intervening 5.8S rRNA gene) for nine species of Rozites, three species of Cuphocybe, 28 species of Cortinarius, Rapacea mariae and Protoglossum luteum. Two species of Hebeloma were used as outgroup. Large subunit (LSU) rDNA sequences from selected taxa were also analyzed. The results clearly demonstrate that Rozites species are nested within the clade/Cortinarius, and that Rozites is polyphyletic, suggesting that membranaceous veils have evolved several times in the genus Cortinarius. Also Rapacea and Cuphocybe are nested within Cortinarius, making the latter genus paraphyletic. Based on phylogenetic studies, Rozites, Cuphocybe and Rapacea are artificial genera and do not reflect natural relationships.


Prospective study of measles in hospitalized, human immunodeficiency virus (HIV)-infected and HIV-uninfected children in Zambia.
Measles in persons coinfected with human immunodeficiency virus (HIV) has been reported to be unusual in its presentation and frequently fatal. To determine the effect of HIV coinfection on the clinical features and outcome of measles, a prospective study of hospitalized children with measles was conducted between January 1998 and October 2000 in Lusaka, Zambia. One-sixth (17%) of 546 children hospitalized with laboratory-confirmed measles were coinfected with HIV. One-third of the HIV-infected children hospitalized with confirmed measles were <9 months old, compared with 23% of HIV-uninfected children (P=.03). Few differences in clinical manifestations, complications, or mortality were found between HIV-infected and HIV-uninfected children with measles. HIV-infected children constitute a significant proportion of children hospitalized with measles in countries with high HIV prevalence and are more likely to be younger than the age for routine measles immunization.


Anti-Bacterial Effect of Cannabidiol against the Cariogenic Streptococcus mutans Bacterium: An In Vitro Study.
Dental caries is caused by biofilm-forming acidogenic bacteria, especially Streptococcus mutans, and is still one of the most prevalent human bacterial diseases. The potential use of cannabidiol (CBD) in anti-bacterial therapies has recently emerged. Here we have studied the anti-bacterial and anti-biofilm activity of CBD against S. mutans. We measured minimum inhibitory concentration (MIC) and minimum biofilm inhibitory concentration (MBIC). The bacterial growth and changes in pH values were measured in a kinetic study. The biofilm biomass was assessed by Crystal Violet staining and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) metabolic assay. Spinning Disk Confocal Microscopy (SDCM) was used to assess biofilm structure, bacterial viability and extracellular polysaccharide (EPS) production. CBD inhibited S. mutans planktonic growth and biofilm formation in a dose-dependent manner, with similar MIC and MBIC values (5 µg/mL). CBD prevented the bacteria-mediated reduction in pH values that correlated with bacterial growth inhibition. SDCM showed a decrease of 50-fold in live bacteria and EPS production. CBD significantly reduced the viability of preformed biofilms at 7.5 µg/mL with an 80 ± 3.1% reduction of metabolic activity. At concentrations above 20 µg/mL, there was almost no bacterial recovery in the CBD-treated preformed biofilms even 48 h after drug withdrawal. Notably, precoating of the culture plate surfaces with CBD prior to incubation with bacteria inhibited biofilm development. Additionally, CBD was found to induce membrane hyperpolarization in S. mutans. Thus, CBD affects multiple processes in S. mutans including its cariogenic properties. In conclusion, we show that CBD has a strong inhibitory effect against cariogenic bacteria, suggesting that it is a potential drug adjuvant for reducing oral pathogenic bacterial load as well as protecting against dental caries.


A clinical evaluation of the electric pulp tester as an indicator of local anesthesia.
Local anesthesia is the primary method in dentistry to control patients' pain. However, several studies have shown that profound anesthesia is not always achieved. The electric pulp tester has been used to measure the level of local dental anesthesia during endodontic therapy. However, no study has been performed that evaluates the ability of the electric pulp tester to predict the efficacy of local anesthesia prior to as operative procedure. If ineffective anesthesia could be predicted, supplemental injections could be administered to alleviate the anesthetic problem. The purpose of this study was to evaluate the ability of the electric pulp tester to measure the level of local anesthesia prior to operative treatment. The study was performed in vivo on patients requiring operative therapy. All teeth were pulp tested preoperatively for vitality using the electric pulp tester. After injection of local anesthetic, traditional parameters of dental anesthesia were verified (lip numbness, mucosal sticks). Teeth were then retested with the electric pulp tester and the results recorded. The teeth were them prepared for restoration using conventional instrumentation, and the patient's level of anesthesia evaluated using a visual analog scale. The electric pulp tester readings were compared to the patient's responses using Fisher's Exact test (two-tail). The results indicate that the electric pulp tester can be a valuable tool in predicting potential anesthetic problems in operative (restorative) dentistry.


Selective adsorption of nitrate over chloride in microporous carbons.
Activated carbon is the most common electrode material used in electrosorption processes such as water desalination with capacitive deionization (CDI). CDI is a cyclic process to remove ions from aqueous solutions by transferring charge from one electrode to another. When multiple salts are present in a solution, the removal of each ionic species can be different, resulting in selective ion separations. This ion selectivity is the result of combined effects, such as differences in the hydrated size and valence of the ions. In the present work, we study ion selectivity from salt mixtures with two different monovalent ions, chloride and nitrate. We run adsorption experiment in microporous carbons (i.e., without applying a voltage), as well as electrosorption experiments (i.e., based on applying a voltage between two carbon electrodes). Our results show that i) during adsorption and electrosorption, activated carbon removes much more nitrate than chloride; ii) at equilibrium, ion selectivity does not depend strongly on the composition of the water, but does depend on charging voltage in CDI; and iii) during electrosorption, ion selectivity is time-dependent. We modify the amphoteric Donnan model by including an additional affinity of nitrate to carbon. We find good agreement between our experimental results and the theory. Both show very high selectivity towards nitrate over chloride, [Formula: see text] ∼10, when no voltage is applied, or when the voltage is low. The selectivity gradually decreases with increasing charging voltage to [Formula: see text] ∼6 at Vch = 1.2 V. Despite this decrease, the affinity-effect for nitrate continues to play an important role also at a high voltage. In general, we can conclude that our work provides new insights in the importance of carbon-ion interactions for electrochemical water desalination.


Active fragments obtained by cyanogen bromide cleavage of ovomucoid.
Cleavage of the two methionine residues in the glycoprotein trypsin inhibitor ovomucoid, variant O1, with CNBr resulted in two fragments whose mol.wts. were approx. 16 600 (fragment LS) and 11 000 (fragment M). Both fragments formed precipitates with antisera to ovomucoid. Fragment LS retained 56% of the trypsin-inhibitory activity of ovomucoid, but fragment M did not inhibit. After reduction and alkylation, the molecular weight of fragment M was unchanged, but fragment LS could be resolved into two segments of peptide chain with mol.wts. of approx. 12000 (fragment L) and 4700 (fragment S). Each of these peptides contained carbohydrate. Marked heterogeneity was observed in the hexose and hexosamine contents of fragment L. This may account for much of the heterogeneity in neutral carbohydrate occurring in ovomucoid preparations. It was found that fragment M was located at the N-terminal end, fragment S was in the centre and fragment L made up the C-terminal portion of the molecule.


H pylori (CagA) and Epstein-Barr virus infection in gastric carcinomas: correlation with p53 mutation and c-Myc, Bcl-2 and Bax expression.
To investigate the interrelationship between H pylori and Epstein-Barr virus (EBV) infection in the gastric carcinogenesis having in focus the p53 mutation and the c-Myc, Bcl-2 and Bax expression. seventy-one gastric carcinoma tissues were assessed by polymerase chain reaction (PCR) for H pylori and in situ hybridization for EBV. c-Myc, Bcl-2 and Bax expression were detected by immunohistochemistry and single-stranded conformational polymorphism (SSCP) for p53 mutation. The positivity rates for H pylori and EBV were 94.4% and 8.45%, respectively. The majority of the cases displayed only the H pylori presence. All EBV positive cases were also H pylori positive. None infectious agent was observed in 5.55% of the cases. The intestinal type tumor was more frequent in the co-infected and non-infected groups. The female predominated in the non-infected group showing statistical significance (70.4% vs 29.6%, P = 0.039). The Bcl-2 was only detected in the group exclusively infected by H pylori. However, c-Myc and Bax were detected in the three groups but with a low frequency in the co-infected group. Mutation of p53 was present in all groups, with the highest frequencies in the H pylori positive groups. The frequency of H pylori infection in gastric carcinomas was high. The presented data indicated that gastric carcinogenesis has different pathways depending of the presence of the two investigated infectious agents, suggesting a possible involvement of H pylori with apoptotic process. The low expression of c-Myc and Bax in the EBV-positive groups suggests that EBV may inhibit the expression of these proteins. Nevertheless, p53 mutation shows to be a relevant alteration, independent of both infectious agents.


Low-latency and efficient retiming and equalizing scheme for a 112-Gbps bandwidth-limited optical PAM-4 system.
The bandwidth limitation of optoelectronic devices is a key constraint for realizing higher capacity short-reach optical communication systems. In this work, we show that the performance of the timing recovery algorithm will significantly impact the performance of bandwidth-limited optical PAM-4 signals. To address this problem, we introduce a moving average filter (MAF) into the Gardner retiming loop to realize ultra-stable retiming without any pilot symbols. It enables a significantly reduced timing jitter, especially for bandwidth-limited conditions. Based on simulations, we show that the proposed retiming scheme will give a stable sampling phase, which is beneficial to the performance of the decision feedback equalizer. Compared to the system based on the traditional Gardner timing synchronization algorithm, the 2-dB power budget gain is realized. The proposed method improves the equalization performance of short-reach optical communication systems where complexity and processing latency are important concerns.


Centromeric DNA replication reconstitution reveals DNA loops and ATR checkpoint suppression.
Half of the human genome is made up of repetitive DNA. However, mechanisms underlying replication of chromosome regions containing repetitive DNA are poorly understood. We reconstituted replication of defined human chromosome segments using bacterial artificial chromosomes in Xenopus laevis egg extract. Using this approach we characterized the chromatin assembly and replication dynamics of centromeric alpha-satellite DNA. Proteomic analysis of centromeric chromatin revealed replication-dependent enrichment of a network of DNA repair factors including the MSH2-6 complex, which was required for efficient centromeric DNA replication. However, contrary to expectations, the ATR-dependent checkpoint monitoring DNA replication fork arrest could not be activated on highly repetitive DNA due to the inability of the single-stranded DNA binding protein RPA to accumulate on chromatin. Electron microscopy of centromeric DNA and supercoil mapping revealed the presence of topoisomerase I-dependent DNA loops embedded in a protein matrix enriched for SMC2-4 proteins. This arrangement suppressed ATR signalling by preventing RPA hyper-loading, facilitating replication of centromeric DNA. These findings have important implications for our understanding of repetitive DNA metabolism and centromere organization under normal and stressful conditions.


'ALSPAC' infant morbidity and Council Tax Band: doctor consultations are higher in lower bands.
The discrepancy between the occurrence of disease and the risk of consulting a doctor is well known, but whether or not it is socially governed is uncertain and could have important implications for primary care manpower and resource allocation. The aim of the study was to investigate whether (i) reported occurrence of common symptoms in infancy and (ii) consulting rates for those symptoms, are associated with socio-economic status as marked by Council Tax Valuation Band (CTVB). Compound cross-sectional analysis of data was obtained from sequential parental questionnaires. Data were taken from Avon Longitudinal Study of Parents and Children of over 14,000 responders from Avon county since 1991. Comparative analyses by CTVB and other covariables were carried out. Final study group of nearly 10 000: diarrhoea, wheeze and accidental injuries moderately associated with CTVB but consulting behaviour for all morbidity bar earache strongly associated with CTVB, the lower the band the higher the clinical burden. The children from more modest homes are more likely to be taken to a doctor for everyday symptoms: for infant morbidity, the lower the CTVB of home address, the higher the clinical burden for UK general practices.


Multiphoton stimulation of neurons.
We pulsed the activation of neurons using a femtosecond laser. Pyramidal neurons are depolarized and fire action potentials when high intensity mode-locked infrared light irradiates somatic membranes and axon initial segments. This depolarization is reversible, does not occur with CW laser light, and appears to be due to multiphoton excitation. We describe two regimes of multiphoton optical stimulation. Low intensity, long duration laser irradiation produces a sustained depolarization, insensitive to sodium channel blockers yet sensitive to antioxidants. On the other hand, high intensity, short duration irradiation can induce fast depolarizations, which appear due to different mechanism. The combination of multiphoton stimulation and optical probing could enable systematic analysis of circuits.


Early diagnosis of oesophageal cancer.
Squamous cell carcinoma and adenocarcinoma of the oesophagus are cancers that develop from distinct epithelial sub-types; however, they are both related to chronic inflammation of differing aetiologies. Inflammation leads to somatically inherited genetic mutations altering control of the cell cycle, DNA replication and apoptosis, which together result in autonomous and uncontrolled proliferation. These cancers have often metastasised to lymph nodes and distant organs before symptomatic presentation and therefore carry a poor prognosis. It is therefore vital to diagnose oesophageal cancer at an early stage, before the development of symptoms, when treatment can dramatically improve prognosis. Understanding the pathogenesis of these cancers is vital to guide early diagnostic strategies.


Opposing effects of warming on the stability of above- and belowground productivity in facing an extreme drought event.
Climate warming, often accompanied by extreme drought events, could have profound effects on both plant community structure and ecosystem functioning. However, how warming interacts with extreme drought to affect community- and ecosystem-level stability remains a largely open question. Using data from a manipulative experiment with three warming treatments in an alpine meadow that experienced one extreme drought event, we investigated how warming modulates resistance and recovery of community structural and ecosystem functional stability in facing with extreme drought. We found warming decreased resistance and recovery of aboveground net primary productivity (ANPP) and structural resistance but increased resistance and recovery of belowground net primary productivity (BNPP), overall net primary productivity (NPP), and structural recovery. The findings highlight the importance of jointly considering above- and belowground processes when evaluating ecosystem stability under global warming and extreme climate events. The stability of dominant species, rather than species richness and species asynchrony, was identified as a key predictor of ecosystem functional resistance and recovery, except for BNPP recovery. In addition, structural resistance of common species contributed strongly to the resistance changes in BNPP and NPP. Importantly, community structural resistance and recovery dominated the resistance and recovery of BNPP and NPP, but not for ANPP, suggesting the different mechanisms underlie the maintenance of stability of above- versus belowground productivity. This study is among the first to explain that warming modulates ecosystem stability in the face of extreme drought and lay stress on the need to investigate ecological stability at the community level for a more mechanistic understanding of ecosystem stability in response to climate extremes.


Youth Suicide in Korea Across the Educational Stages.
Background: Youth suicides have diverse characteristics according to the young people's developmental stages. Warning signs and communication of suicidal intent can be vague among early adolescents, while mental health problems may be more evidently related to suicidal ideation in older adolescents. Understanding the developmental characteristics of youth suicide is necessary for effective suicide prevention. Aims: We explored the differences between children and adolescents who died by suicide and the characteristics of these young people as observed by their school teachers. Method: We analyzed teachers' mandatory postmortem reports of suicides among 308 Korean students. We compared: suicide-related information including personal, familial, and school factors; stressful life events; and participation in interventions among elementary, middle, and high school students who died by suicide. We also assessed the distribution of student suicides per month. Results: Suicide among elementary school students increased during school vacations, and suicide among middle and high school students increased during the school semester. According to the teachers' reports, elementary school students who died by suicide were more extroverted and had better academic achievements than their high school peers, and had significantly lower levels of substance/tobacco use. Elementary school students who died by suicide showed significantly less academic stress and use of external professional help than did other groups. Limitations: Because this research is based on mandatory teacher reports, the subjective opinions of teachers may have affected the reliability of the data. Suicide by out-of-school youth was not included. Conclusion: School-based suicide prevention should be implemented in accordance with young people's developmental characteristics.


Directly probing spin dynamics in a molecular magnet with femtosecond time-resolution.
We show that a vanadium-chromium Prussian blue analogue, which is a room-temperature molecule-based magnet, displays a fast magnetic response on a femtosecond timescale that is attributed to the super-exchange interaction between the metal ions. These dynamics are obtained from femtosecond Faraday magneto-optical (MO) measurements, performed at 50 and 300 K. Exciting at the ligand-to-metal charge-transfer (LMCT) band results in the formation of the 2E excited state on the Cr ion via intersystem crossing (ISC) from the 4LMCT state in less than 250 fs. Subsequent vibrational relaxation in the 2E state occurs on a 0.78 ± 0.05 ps timescale at 50 K and 1.1 ± 0.1 ps at 300 K. The MO measurements can detect the formation of the 2E state on the Cr ion from the change in the super-exchange interaction taking place as a result of the corresponding spin flip associated with the formation of the 2E state. These results open up a new avenue to study molecular magnets using a powerful method that is capable of directly probing spin dynamics on a sub-picosecond timescale in thin film environments.


[Social representations of municipal counselors regarding social control in health in the Brazilian Unified Health System (SUS)].
This study seeks to analyze the social representations of municipal health counselors regarding social control in health. Sixty interviews were conducted with counselors of nineteen counties within the Integrated Federal District Region and Surrounding Areas (RIDE-DF). Data analysis was conducted with the use of French Alceste software, which included two thematic groups. The first dealt with the weaknesses of health councils, consisting of four categories: limitations in decision-making powers, bureaucratization of everyday practices, weaknesses in social participation and limitations in the practice of representation. The second dealt with the health system in RIDE-DF, consisting of only one category that expresses the precarious organization of health care in RIDE-DF. Social representation of social control, with a focus on social participation appears to be constrained by a ritual, namely the bureaucratization of policies and practices in the councils. This form of hierarchical and bureaucratic organization and operation of the council, based on a centralizing management model, has distanced the counselors from discussing health needs geared to the construction of public Health Projects.


A new rapid method for the identification of reducible collagen cross-links in small tissue samples.
A normal-phase high-pressure liquid-chromatography system was used with amino-propyl-bonded silica as the column packing in order to resolve amino acids, reduced amino acid derivatives and reduced cross-links of collagen. The method utilized a solvent system comprising acetonitrile and 10 mM-potassium phosphate buffer, pH 4.3, as described by Schuster [(1980) Anal. Chem. 52, 617-620]. With modifications to the original gradient elution it was possible to resolve fully the radiolabelled components of reduced collagen in one run of less than 80 min. The method is very sensitive, and small biopsy samples can readily be investigated. Although solute retention times gradually decreased with repeated use, little loss of resolution of the reducible cross-links of collagen occurred during a 30-day trial period.


Evaluation of commercial HPV assays in the context of post-treatment follow-up: Scottish Test of Cure Study (STOCS-H).
Human papillomavirus (HPV) testing is more sensitive than cytology for detection of residual/recurrent cervical disease after lesion treatment. Several HPV test comparison studies have been performed within triage and screening populations, but data on their comparative performance in a test of cure context is lacking. This study aims to address this gap. We compared the technical and clinical performance of Abbott RealTime High risk (HR)-HPV, Genprobe Aptima PV, Hologic Cervista HPV-HR, Qiagen Hybrid Capture 2 and Roche cobas HPV in the Early Implementation phase of a 'test of cure' service within the Scottish Cervical Screening Programme. Valid results with all five HPV Tests from 1020 first samples taken ∼6 months post-treatment showed HPV positivity ranging from 17.84% to 26.96%. There was perfect agreement in 74%, and greatest variation between assays was observed in cytologically negative samples. Clinical performance was judged on cumulative incidence of cervical intraepithelial neoplasia 2+ (CIN2+) during follow-up (mean: 13.2 months). There were 23 cases of CIN2+ of which 14 were CIN3+. All assays, including cytology, were 100% sensitive for detection of CIN3+. Of the nine cases of residual CIN2, three assays detected all, one assay missed one and one assay missed two cases. Specificity ranged from 75% to 84% according to assay. All assays were sensitive for detection of CIN2+ at 6 months post-treatment. The range of positivity equated to a 50% increase between assays with the lowest and highest positivity rates. The relevance of HPV positivity in the absence of cytological abnormalities requires longer follow-up to determine whether additional tools for risk stratification are required.


[Relation between changes in the blood levels of beta-endorphin and various hormones during physical exercise].
Dynamics of beta-endorphin, corticotropin, cortisol, somatotropin, insulin and triiodothyronine content were studied using bicycle ergometer in blood of 22 persons during 2 hrs exercises. After an initial increase the beta-endorphin content was subsequently decreased. At the same time, the decrease in the neuropeptide content was accompanied by repeated elevation within the second hr of the exercise, mainly in persons exhibiting high working capacity, while in other persons the hormone concentration decreased below the initial level at the end of the exercise. These alterations in the content of beta-endorphin correlated distinctly with dynamics of pituitary-adrenocortical hormones variation. In untrained persons the initial increase in beta-endorphin content was especially distinctly related to the elevation in somatotropin and to a decrease in insulin content in blood. Concentration of triiodothyronine in blood was altered independently of the alterations of other hormones.


Soft substrate maintains proliferative and adipogenic differentiation potential of human mesenchymal stem cells on long-term expansion by delaying senescence.
Human mesenchymal stem cells (hMSCs), during in vitro expansion, gradually lose their distinct spindle morphology, self-renewal ability, multi-lineage differentiation potential and enter replicative senescence. This loss of cellular function is a major roadblock for clinical applications which demand cells in large numbers. Here, we demonstrate a novel role of substrate stiffness in the maintenance of hMSCs over long-term expansion. When serially passaged for 45 days from passage 3 to passage 18 on polyacrylamide gel of Young's modulus E=5 kPa, hMSCs maintained their proliferation rate and showed nine times higher population doubling in comparison to their counterparts cultured on plastic Petri-plates. They did not express markers of senescence, maintained their morphology and other mechanical properties such as cell stiffness and cellular traction, and were significantly superior in adipogenic differentiation potential. These results were demonstrated in hMSCs from two different sources, umbilical cord and bone marrow. In summary, our result shows that a soft gel is a suitable substrate to maintain the stemness of mesenchymal stem cells. As preparation of polyacrylamide gel is a well-established, and well-standardized protocol, we propose that this novel system of cell expansion will be useful in therapeutic and research applications of hMSCs.


No Time Like the Present: Thinking About the Past and the Future Is Related to State Dissociation Among Individuals With High Levels of Psychopathological Symptoms.
Several short-term pathways have been implicated in relation to dissociative experiences, among them are daily stress, sleepiness, and rumination. In addition, it has been claimed that mechanisms contributing to dissociative experiences may differ, according to specific psychopathological symptoms. Accordingly, this study had two aims. The first was to sample moment-to-moment increases or decreases in current stress, sleepiness, and rumination, in order to assess their temporal relations with state dissociation. Rumination was broken down to its basic two subcomponents: the negative value of the thoughts and thinking about the past (in comparison to present or future), in order to differentiate it from other repetitive thought patterns (e.g., worry). The second goal was to explore whether depression, anxiety, and obsessive-compulsive symptoms may moderate the links between the three mechanisms and specific state dissociation scales [specifically, depersonalization-derealization (DEP-DER) and absorption (ABS)]. Ninety-nine undergraduate students completed trait questionnaires and then answered state items four times a day for 4 days. These experience sampling data were analyzed using multilevel linear modeling (MLM) with Level 1 state measurements and Level 2 demographic and trait variables of the participants. Moments of stress, sleepiness, thinking about the past and negative thoughts were all associated both with state DEP-DER and with state ABS. Dissociation, negative thinking, stress, and sleepiness were positively associated with moments of thinking about the past and the future but inversely associated with moments of thinking about the present. Finally, in accordance with our expectations, the links between DEP-DER and hypothesized mechanisms were mostly moderated by depression and anxiety symptoms, whereas the links between ABS and hypothesized mechanisms were moderated mainly by obsessive-compulsive symptoms. Our findings are in accordance with literature on the efficacy of mindfulness as well as the maladaptive correlates of mind-wandering, as they suggest that dissociative detachment from one's present occupation is associated with decreased well-being.


New testosterone derivatives as semi-synthetic anticancer agents against prostate cancer: synthesis and preliminary biological evaluation.
Prostate cancer (PC) is a major health issue in the world. Treatments of localized PC are quite efficient and usually involve surgery, radiotherapy and/or hormonal therapy. Metastatic PC is however rarely curable to this day. Treatments of metastatic PC involve radiotherapy, chemotherapy and hormonal treatment such as orchiectomy, antiandrogens and luteinizing hormone-releasing hormone agonists. The suppression of tumor growth by hormonal treatment is efficient but overtime resistance still occurs and the disease progresses. Thus, more urgently than ever there is a need for discovery of new treatment options for castration-resistant PC (CRPC). Hence, we designed and tested a series of amide derivatives located at position 7α of testosterone as prospective "natural" or "semisynthetic" anticancer agents against CRPC with the goal of discovering therapeutic alternatives for the disease. This manuscript describes an efficient path towards the target molecules that are made in only 6 or 7 chemical steps from testosterone in good overall yields. This strategy can be used to make several compounds of interest that present higher biological activity than the classic antiandrogen; cyproterone acetate (3). The best testosterone-7α-amide was the N-2-pyridylethylamide (25) which was as active as the antiandrogen cyproterone acetate (3) on androgen-dependent LNCaP cells and 2.7 times more active on androgen-independent PC3 prostate cancer cells. The results obtained show the synthetic feasibility and the potential for future development of this unique class of semi-synthetic anticancer agents that offer the premise of new treatment modalities for patients afflicted with CRPC.


Genome-wide identification and expression profiling of the fatty acid desaturase gene family in the silkworm, Bombyx mori.
Fatty acid desaturases exist in all living organisms and play important roles in many different biologic processes, such as fatty acid metabolism, lipid biosynthetic processes, and pheromone biosynthetic processes. Using the available silkworm genome sequence, we identified 14 candidate fatty acid desaturase genes. Eleven genes contain 3 conserved histidine cluster motifs and 4 transmembrane domains, but their N-terminal residues exhibit obvious diversity. Phylogenetic analysis revealed that there are 6 groups; Bmdesat1 and Bmdesat5-8 were clustered into group 2, which is involved in Δ11 desaturation activity, and Bmdesat3-4 were grouped in group 1, which is involved in Δ9 desaturation activity. Twelve of the 14 genes have expressed sequence tag evidence. Microarray data and reverse transcription polymerase chain reaction analysis demonstrated that Bmdesat3-4 and Bmdesat10 were expressed from the larval to moth stages and in multiple tissues on day 3 of 5th instar larvae. Bmdesat9, Bmdesat11, and Bmdesat14 were expressed during the pupal and late-embryonic stage, suggesting that they may take part in fatty acid metabolism to provide energy. These results provide some insights into the functions of individual fatty acid desaturases in silkworm.


IMiDs prime myeloma cells for daratumumab-mediated cytotoxicity through loss of Ikaros and Aiolos.
Recent studies have demonstrated that the immunomodulatory drugs (IMiDs) lead to the degradation of the transcription factors Ikaros and Aiolos. However, why their loss subsequently leads to multiple myeloma (MM) cell death remains unclear. Using CRISPR-Cas9 genome editing, we have deleted IKZF1/Ikaros and IKZF3/Aiolos in human MM cell lines to gain further insight into their downstream gene regulatory networks. Inactivation of either factor alone recapitulates the cell intrinsic action of the IMiDs, resulting in cell cycle arrest and induction of apoptosis. Furthermore, evaluation of the transcriptional changes resulting from their loss demonstrates striking overlap with lenalidomide treatment. This was not dependent on reduction of the IRF4-MYC "axis," as neither protein was consistently downregulated, despite cell death occurring, and overexpression of either factor failed to rescue for Ikaros loss. Importantly, Ikaros and Aiolos repress the expression of interferon-stimulated genes (ISGs), including CD38, and their loss led to the activation of an interferon-like response, contributing to MM cell death. Ikaros/Aiolos repressed CD38 expression through interaction with the nucleosome remodeling and deacetylase complex in MM. IMiD-induced loss of Ikaros or treatment with interferon resulted in an upregulation of CD38 surface expression on MM cells, priming for daratumumab-induced NK cell-mediated antibody-dependent cellular cytotoxicity. These results give further insight into the mechanism of action of the IMiDs and provide mechanistic rationale for combination with anti-CD38 monoclonal antibodies.


[Characteristics of locomotion regulation in man].
It has been found by transforming experimental kinematic data to normal coordinates with calculating of muscle force moments during walking that the locomotor movements are regulated almost discontinuously at each degree of freedom of leg, so two piece constant parameters of control are switched few times during gait cycle. Therefore musculature acts like switched elastic constraints, and energy expenditure depends on the trajectories of movements essentially less than on the kinematic conditions displayed during fixed switchings.


Characterization of stanniocalcin 2, a novel target of the mammalian unfolded protein response with cytoprotective properties.
Accumulation of misfolded proteins in the endoplasmic reticulum (ER) induces a highly conserved homeostatic response in all eukaryotic cells, termed the unfolded-protein response (UPR). Here we describe the characterization of stanniocalcin 2 (STC2), a mammalian homologue of a calcium- and phosphate-regulating hormone first identified in fish, as a novel target of the UPR. Expression of STC2 gene is rapidly upregulated in cultured cells after exposure to tunicamycin and thapsigargin, by ATF4 after activation of the ER-resident kinase PERK. In addition, STC2 expression is also activated in neuronal cells by oxidative stress and hypoxia but not by several cellular stresses unrelated to the UPR. In contrast, expression of another homologue, STC1, is only upregulated by hypoxia independent of PERK or ATF4 expression. In vivo studies revealed that rat cortical neurons rapidly upregulate STC2 after transient middle cerebral artery occlusion. Finally, siRNA-mediated inhibition of STC2 expression renders N2a neuroblastoma cells and HeLa cells significantly more vulnerable to apoptotic cell death after treatment with thapsigargin, and overexpression of STC2 attenuated thapsigargin-induced cell death. Consequently, induced STC2 expression is an essential feature of survival component of the UPR.


Helping Carers Care: An Exploratory Study of Factors Impacting Informal Family Carers and Their Use of Aged Care Services.
This exploratory study considered the role of informal carers and their decision-making regarding various aged care services that supposedly support their ageing relatives. Consideration was given to the stressors and overall well-being of informal carers and the support services they did or did not receive during their time of caregiving. A questionnaire was utilised to gain exploratory quantitative and qualitative data plus basic demographic information from informal carers who connected with a single caregiver association based in Victoria, Australia. Several themes emerged from the analysis of data regarding carer well-being, carer decision-making and carer relationships-particularly with respect to the various authorities and organisations ostensibly responsible for supporting carers. While the majority of participants indicated a religious association, nevertheless spiritual considerations were not stress factors paramount in their decision-making or their criticism of carer support services. Other concerns dominated such as the need of having appropriate practical support, better case management, organisational transparency and greater recognition of the role of informal carers. Although this research was isolated to a particular locality, carers in similar situations globally have indicated comparable stresses and challenges further indicating that greater accountability and improved organisation are required for the support of carers internationally. Recommendations are suggested for how service providers can support carers-most importantly, the need for ongoing government assessment and government service improvement in order to help carers care into the future.


Dynamic network participation of functional connectivity hubs assessed by resting-state fMRI.
Network studies of large-scale brain connectivity have demonstrated that highly connected areas, or "hubs," are a key feature of human functional and structural brain organization. We use resting-state functional MRI data and connectivity clustering to identify multi-network hubs and show that while hubs can belong to multiple networks their degree of integration into these different networks varies dynamically over time. The extent of the network variation was related to the connectedness of the hub. In addition, we found that these network dynamics were inversely related to positive self-generated thoughts reported by individuals and were further decreased with older age. Moreover, the left caudate varied its degree of participation between a default mode subnetwork and a limbic network. This variation was predictive of individual differences in the reports of past-related thoughts. These results support an association between ongoing thought processes and network dynamics and offer a new approach to investigate the brain dynamics underlying mental experience.


Cetuximab plus irinotecan in pretreated metastatic colorectal cancer patients: the ELSIE study.
To evaluate the efficacy and safety of cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer (mCRC) patients from South-East Asia and Australia. In this open-label, phase II study, the main eligibility criteria were epidermal growth factor receptor-positive mCRC with progressive disease within 3 mo of an irinotecan-based regimen as the most recent chemotherapy. Patients received cetuximab 400 mg/m2 initially, then 250 mg/m2 every week, with the same regimen of irinotecan on which the patients had progressed (4 pre-defined regimens allowed). The primary objective was evaluation of progression-free survival (PFS) at 12 wk. Secondary objectives included a further investigation of PFS, and an assessment of the overall response rate (ORR), duration of response, time to treatment failure (TTF), overall survival and the safety profile. One hundred and twenty nine patients were enrolled from 25 centers in the Asia-Pacific region and of these 123 received cetuximab plus irinotecan. The most common recent irinotecan regimen used was 180 mg/m2 every 2 wk which had been used in 93 patients (75.6%). The PFS rate at 12 wk was 50% (95% confidence interval (CI, 41-59) and median PFS time was 12.1 wk (95% CI: 9.7-17.7). The ORR was 13.8% (95% CI: 8.3-21.2) and disease control rate was 49.6% (95% CI: 40.5-58.8). Median duration of response was 31.1 wk (95% CI: 18.0-42.6) and median overall survival was 9.5 mo (95% CI, 7.5-11.7). The median TTF was 11.7 wk (95% CI: 9.1-17.4). Treatment was generally well tolerated. The most common grade 3/4 adverse events were diarrhea (13.8%), neutropenia (8.9%), rash (5.7%) and vomiting (5.7%). In patients from Asia and Australia, this study confirms the activity and safety of cetuximab plus irinotecan observed in previous studies in Europe and South America.


Glutamate-positive neurons in the somatic sensory cortex of rats and monkeys.
The morphology and laminar distribution of neurons labeled with an antiserum prepared against glutamic acid (Glu) conjugated to keyhole limpet hemocyanin have been studied in the somatic sensory cortex of rats and monkeys. In both species, the vast majority of immunostained neurons are pyramidal; some nonpyramidal neurons are also present. Positive neurons are observed in all cortical layers, although variations are found in the percentage of Glu-positive neurons in the different layers. In rats they are most numerous in layer V (36%), followed by layer II (33%), layer III (32%), and layer VI (29%). In layer IV, 13% of all neurons are positive. Immunoreactive neurons are very sparse in layer I. In monkeys, Glu-positive neurons represent 51% of all neurons in layer V, 49% in layer III, 40% in layers II and VI, and 19% in layer IV. No differences are evident in the laminar distribution of Glu-positive neurons among cytoarchitectonic areas 3a, 3b, 1, and 2. As in rats, Glu-positive neurons are very sparse in layer I. Since Glu and GABA metabolisms are closely related, double-labeling experiments were performed in which thin, adjacent paraffin sections were stained alternately with the anti-Glu serum and with an anti-GABA serum. The 2 populations are almost completely segregated, even though a small fraction of neurons (less than 5%) are labeled by the antisera against both antigens.(ABSTRACT TRUNCATED AT 250 WORDS)


The emergence of 'hypervirulence' in Clostridium difficile.
The impact of Clostridium difficile-associated disease (CDAD) in healthcare settings throughout the developed world is considerable in terms of mortality, morbidity, and disease management. The incidence of CDAD has risen dramatically since the turn of this century, concomitant with the emergence of so-called hypervirulent strains which are thought to cause a more severe disease, higher relapse rates, and increased mortality. Pre-eminent amongst hypervirulent strains are those belonging to ribotype 027, which were first reported in Canada in 2003 and shortly thereafter in the UK. Since its arrival in Europe, it has spread rapidly and has now been reported in 16 member states and Switzerland. The physiological factors responsible for the rapid emergence of hypervirulent C. difficile strains remain unclear. It is known that they produce a binary toxin (CDT) in addition to toxins A and B, that they are resistant to fluoroquinolones due to mutations in gyrA, and that they are resistant to erythromycin. Representative strains have been suggested to produce more toxin A and B in the 'laboratory flask' (most likely due to a frameshift mutation in the repressor gene tcdC), to be more prolific in terms of spore formation, and also exhibit increased adherence to human intestinal epithelial cells due to altered surface proteins. However, the contribution of these and other as yet unidentified factors to the rapid spread of certain C. difficile variants (e.g., ribotypes 027 and 078) remains unclear at present. The advent of ClosTron technology means that it is now possible to construct genetically stable isogenic mutants of C. difficile and carry out reverse genetic studies to elucidate the role of specific gene loci in causing disease. The identification of virulence factors using this approach should help lead to the rational development of therapeutic countermeasures against CDAD.


Promoting positive human development and social justice: Integrating theory, research and application in contemporary developmental science.
The bold claim that developmental science can contribute to both enhancing positive development among diverse individuals across the life span and promoting social justice in their communities, nations and regions is supported by decades of theoretical, methodological and research contributions. To explain the basis of this claim, I describe the relational developmental systems (RDS) metamodel that frames contemporary developmental science, and I present an example of a programme of research within the adolescent portion of the life span that is associated with this metamodel and is pertinent to promoting positive human development. I then discuss methodological issues associated with using RDS-based models as frames for research and application. Finally, I explain how the theoretical and methodological ideas associated with RDS thinking may provide the scholarly tools needed by developmental scientists seeking to contribute to human thriving and to advance social justice in the Global South.


The induction of melanogenesis by ultraviolet light in the pigmentary system of Rhesus monkeys.
Except for the face, eyelids, friction surfaces, and lips, the epidermis of the rhesus monkey contains no discernible melanocytes. After ultraviolet irradiation, however, dopa-positive dendritic cells appeared. With daily sequential irradiation, the number of histochemically demonstrable dopa-positive dendritic cells peaked after 30 exposures, then declined to a basal level which was maintained for the duration of the experiment (216 exposures or 43 weeks). Pigment cells can be restimulated by shading part of the irradiated area and then reirradiating after 3 months. While shaded, dopa-positive cells disappeared; but when reirradiated, they reappeared, increased, then declined again to a basal level. These melanocytes, unlike those in other primates, require high threshold levels of irradiation to produce a response, have a definite period during which they are active, and transfer very little melanin to the surrounding keratinocytes. Long-term ultraviolet irradiation has no discernible effect on dermal pigment-containing cells.


Endovascular Treatment with Platinum Coils. Recanalization is Associated with Early Increased von Willebrand Factor mRNA.
Recanalization after coil occlusion is a concern for long-term results of endovascular treatment. Knowledge of molecular events following coil occlusion and recanalization could help design specific strategies to promote permanent occlusion. Platinum coils were implanted into canine maxillary, vertebral or lingual arteries. Coil occlusion (treatment 1), routinely followed by recanalization was compared with two strategies to prevent recanalization: beta radiation using (32)P coils (treatment 2) and endothelial denudation, using an endovascular device, followed by coil occlusion (treatment 3). The evolution of initial complete occlusions was followed by angiography and pathology at three months. Levels of messenger RNA of vWF (von Willebrand factor), SMA (smooth muscle actin), CD14, CD31 (or PECAM-1: Platelet Endothelial Cell Adhesion Molecule-1), PDGFBB (platelet-derived growth factor), TGF-b1 (transforming growth factor), MCP-1 (macrophage chemoattractant protein), Angiopoietins, Metalloproteinases-9, 14 and inhibitors (TIMP- 2, 4) were followed by Reverse Transcription and Polymerase Chain Reaction (RT-PCR). Analyses were performed one, four, seven and 14 days after coiling, and levels of expression after the three treatments were compared using ANOVAs. Intact arteries treated with platinum coils routinely recanalize (100%), but arteries treated by denudation and coiling or with radioactive coils recanalize in only 17% and 4% respectively (P<.001). Recanalization was associated with increased levels of vWF mRNA at seven days, a finding that was not observed with denudation or radiation (P=.015). There was no other significant difference. Recanalization is associated with early vWF expression, perhaps reflecting the development of endothelialized channels through thrombus formed after coil occlusion.


Procedure for chromatography involving sample solvent with higher elution strength than the mobile phase.
In preparative chromatography, often the solubility of the sample in the mobile phase is limited, making the mobile phase unsuitable as a solvent for preparation of load. Generally, solvents that have high solubility for the sample also have higher elution strengths than the mobile phase. Additionally, at high loading volumes, these strong sample solvents are known to adversely affect the band profiles leading to poor chromatographic performance. Here, we show that controlling the mobile phase strength during loading and post-load elution resulted in improved band profiles when the sample solvent was stronger than the mobile phase. Such an approach improves performance in preparative chromatography by allowing either higher sample loading or higher organic content in mobile phase (without loss of yield). Alternately, the approach can be used for improvement in performance by increase in yield or product purity.


Cumulative fluid balance predicts mortality and increases time on mechanical ventilation in ARDS patients: An observational cohort study.
Acute respiratory distress syndrome (ARDS) is characterized by acute, diffuse, inflammatory lung injury leading to increased pulmonary vascular permeability, pulmonary oedema and loss of aerated tissue. Previous literature showed that restrictive fluid therapy in ARDS shortens time on mechanical ventilation and length of ICU-stay. However, the effect of intravenous fluid use on mortality remains uncertain. We investigated the relationship between cumulative fluid balance (FB), time on mechanical ventilation and mortality in ARDS patients. Retrospective observational study. Patients were divided in four cohorts based on cumulative FB on day 7 of ICU-admission: ≤0 L (Group I); 0-3.5 L (Group II); 3.5-8 L (Group III) and ≥8 L (Group IV). In addition, we used cumulative FB on day 7 as continuum as a predictor of mortality. Primary outcomes were 28-day mortality and ventilator-free days. Secondary outcomes were 90-day mortality and ICU length of stay. Six hundred ARDS patients were included, of whom 156 (26%) died within 28 days. Patients with a higher cumulative FB on day 7 had a longer length of ICU-stay and fewer ventilator-free days on day 28. Furthermore, after adjusting for severity of illness, a higher cumulative FB was associated with 28-day mortality (Group II, adjusted OR (aOR) 2.1 [1.0-4.6], p = 0.045; Group III, aOR 3.3 [1.7-7.2], p = 0.001; Group IV, aOR 7.9 [4.0-16.8], p<0.001). Using restricted cubic splines, a non-linear dose-response relationship between cumulative FB and probability of death at day 28 was found; where a more positive FB predicted mortality and a negative FB showed a trend towards survival. A higher cumulative fluid balance is independently associated with increased risk of death, longer time on mechanical ventilation and longer length of ICU-stay in patients with ARDS. This underlines the importance of implementing restrictive fluid therapy in ARDS patients.


Tuberculosis vaccines: present and future.
There has never been a greater need for a new protective tuberculosis vaccine. Bacille Calmette-Guerin remains the cornerstone of any vaccine strategy, but improving its immunogenicity and efficacy has now become an urgent global health priority. This review discusses the main vaccines currently in clinical development and other novel vaccine strategies in the pipeline. It addresses the key questions in vaccine design, including antigen selection, route of vaccine delivery and immune correlates of vaccine-induced protection. There is an opportunity to identify such correlates from ongoing and future Phase II/III trials and, as these emerge, they can be used to validate the most relevant and predictive animal models with which to develop the next generation of new vaccines.


Complete chloroplast genome of Oncidium Gower Ramsey and evaluation of molecular markers for identification and breeding in Oncidiinae.
Oncidium spp. produce commercially important orchid cut flowers. However, they are amenable to intergeneric and inter-specific crossing making phylogenetic identification very difficult. Molecular markers derived from the chloroplast genome can provide useful tools for phylogenetic resolution. The complete chloroplast genome of the economically important Oncidium variety Onc. Gower Ramsey (Accession no. GQ324949) was determined using a polymerase chain reaction (PCR) and Sanger based ABI sequencing. The length of the Oncidium chloroplast genome is 146,484 bp. Genome structure, gene order and orientation are similar to Phalaenopsis, but differ from typical Poaceae, other monocots for which there are several published chloroplast (cp) genome. The Onc. Gower Ramsey chloroplast-encoded NADH dehydrogenase (ndh) genes, except ndhE, lack apparent functions. Deletion and other types of mutations were also found in the ndh genes of 15 other economically important Oncidiinae varieties, except ndhE in some species. The positions of some species in the evolution and taxonomy of Oncidiinae are difficult to identify. To identify the relationships between the 15 Oncidiinae hybrids, eight regions of the Onc. Gower Ramsey chloroplast genome were amplified by PCR for phylogenetic analysis. A total of 7042 bp derived from the eight regions could identify the relationships at the species level, which were supported by high bootstrap values. One particular 1846 bp region, derived from two PCR products (trnHGUG -psbA and trnFGAA-ndhJ) was adequate for correct phylogenetic placement of 13 of the 15 varieties (with the exception of Degarmoara Flying High and Odontoglossum Violetta von Holm). Thus the chloroplast genome provides a useful molecular marker for species identifications. In this report, we used Phalaenopsis. aphrodite as a prototype for primer design to complete the Onc. Gower Ramsey genome sequence. Gene annotation showed that most of the ndh genes inOncidiinae, with the exception of ndhE, are non-functional. This phenomenon was observed in all of the Oncidiinae species tested. The genes and chloroplast DNA regions that would be the most useful for phylogenetic analysis were determined to be the trnHGUG-psbA and the trnFGAA-ndhJ regions. We conclude that complete chloroplast genome information is useful for plant phylogenetic and evolutionary studies in Oncidium with applications for breeding and variety identification.


Minimally invasive total knee arthroplasty: comparison of jig-based technique versus computer navigation for clinical and alignment outcome.
Correct alignment of the leg and positioning of the components are important factors in good long-term outcome of total knee arthroplasty (TKA). Computer-assisted navigation systems were introduced to improve component alignment accuracies. The three main hypotheses of this study were that the navigated compared to jig-based patient will show the following: (1) No difference in clinical outcomes. (2) Better alignment in the frontal and sagittal plane. (3) Better rotational positioning of components. The authors evaluated 100 patients who had minimally invasive TKA using either an image-free computer-assisted navigation system (n=50) or a jig-based technique (n=50). Six months postoperatively, clinical and radiological evaluations were performed using full-length standing anteroposterior and lateral radiographs and CT scans of the knee. Knee Society knee score, function score, and range of motion were comparable in the two groups after surgery. The percentage of patients with a frontal tibiofemoral angle within ±3° of the ideal was significantly higher in the navigated group than in the jig-based group (94% vs. 78%, respectively; P=0.041). No significant differences were found between groups in terms of the frontal and sagittal planes as well as rotational alignment of the femoral or tibial components. Computer-assisted TKA gives a better correction of alignment of the leg compared with jig-based TKA when combined with a minimally invasive surgical approach.