Peptide deformylase (PDF), which is essential for normal growth of bacteria but not for higher organisms, is explored as an attractive target for developing novel antibiotics. Here, we present the crystal structure of Leptospira interrogans PDF (LiPDF) at 2.2A resolution. To our knowledge, this is the first crystal structure of PDF associating in a stable dimer. The key loop (named the CD-loop: amino acid residues 66-76) near the active-site pocket adopts "closed" or "open" conformations in the two monomers forming the dimer. In the closed subunit, the CD-loop and residue Arg109 block the entry of the substrate-binding pocket, while the active-site pocket of the open subunit is occupied by the C-terminal tail from the neighbouring molecule. Moreover, a formate group, as one product of deformylisation, is observed bound with the active-site zinc ion. LiPDF displays significant structural differences in the C-terminal region compared to both type-I and type-II PDFs, suggesting a new family of PDFs.

Peptide deformylase proteins (PDFs) participate in the N-terminal methionine excision pathway of newly synthesized peptides. We show that the human PDF (HsPDF) can deformylate its putative substrates derived from mitochondrial DNA-encoded proteins. The first structural model of a mammalian PDF (1.7 A), HsPDF, shows a dimer with conserved topology of the catalytic residues and fold as non-mammalian PDFs. The HsPDF C-terminus topology and the presence of a helical loop (H2 and H3), however, shape a characteristic active site entrance. The structure of HsPDF bound to the peptidomimetic inhibitor actinonin (1.7 A) identified the substrate-binding site. A defined S1' pocket, but no S2' or S3' substrate-binding pockets, exists. A conservation of PDF-actinonin interaction across PDFs was observed. Despite the lack of true S2' and S3' binding pockets, confirmed through peptide binding modeling, enzyme kinetics suggest a combined contribution from P2'and P3' positions of a formylated peptide substrate to turnover.

Two sets of wide-field neurons extend neurites into the fly's optic lamina, where monopolar cells receive photoreceptor input. They exhibit immunoreactivity to antibodies raised against either 5-hydroxytryptamine or the crustacean peptide PDH, respectively. Both are proposed whole-field neuromodulators of vision, apparently regulating a circadian rhythm of monopolar cell size. Seeking functional correlates, we have re-examined the electroretinogram for circadian rhythmicity, and for responses to locally injected 5-hydroxytryptamine and peptide. Long-term electroretinogram recordings from Calliphora entrained to a light/dark cycle and then transferred to constant darkness, uncovered a gradual, modest increase during the subjective night in the electroretinogram's ON- and OFF-transients, from the lamina's monopolar cells. Five to twenty nl of 5-hydroxytryptamine (10(-3) mol.1(-1)) injected into the head haemolymph strongly enhanced the electroretinogram transients, an action reversed by 5-hydroxytryptamine antagonists. Injected into the eye, 5-hydroxytryptamine (10(-4) mol.1(-1)) had the opposite effect; the rapid onset there suggests direct action, whilst the opposing effect from haemolymph injection suggests a different receptor site. Pigment-dispersing hormone (2.2 x 10(-5) mol.1(-1)) injected into the haemolymph increased the electroretinogram transients along a biphasic course, with a slow partial recovery; injected into the eye, it lacked effect.

1. A study of the historical development of the Weber-Fechner law shows that it fails to describe intensity perception; first, because it is based on observations which do not record intensity discrimination accurately, and second, because it omits the essentially discontinuous nature of the recognition of intensity differences. 2. There is presented a series of data, assembled from various sources, which proves that in the visual discrimination of intensity the threshold difference DeltaI bears no constant relation to the intensity I. The evidence shows unequivocally that as the intensity rises, the ratio See PDF for Equation first decreases and then increases. 3. The data are then subjected to analysis in terms of a photochemical system already proposed for the visual activity of the rods and cones. It is found that for the retinal elements to discriminate between one intensity and the next perceptible one, the transition from one to the other must involve the decomposition of a constant amount of photosensitive material. 4. The magnitude of this unitary increment in the quantity of photochemical action is greater for the rods than for the cones. Therefore, below a certain critical illumination-the cone threshold-intensity discrimination is controlled by the rods alone, but above this point it is determined by the cones alone. 5. The unitary increments in retinal photochemical action may be interpreted as being recorded by each rod and cone; or as conditioning the variability of the retinal cells so that each increment involves a constant increase in the number of active elements; or as a combination of the two interpretations. 6. Comparison with critical data of such diverse nature as dark adaptation, absolute thresholds, and visual acuity shows that the analysis is consistent with well established facts of vision.

TO ACCOUNT FOR THE BEHAVIOR OF A SOLID PARTICLE IN THE INTERFACE BETWEEN TWO FLUIDS IT IS NECESSARY TO CONSIDER, AS INDICATED BY CLARK MAXWELL, THREE SURFACE TENSIONS: T(so), the tension in the interface between the solid particle and the organic phase; T(sw), the tension in the interface between solid particle and aqueous phase; and T(ow), the organic phase-water interfacial tension. If T(so)>> T(sw) + T(ow), (2), the stronger solid-organic phase tension should pull the line of intersection of the three phases around the periphery of the solid particle until the particle is completely enveloped in the water phase. If T(sw)>> T(ow) + T(ow) (3), the solid-water tension should pull the line of meeting of the phases about the particle until it is enveloped in the organic phase. If See PDF for Equation the particle should be stable in the interface, only leaving it when mechanical work overcomes the equilibrium due to the balance of interfacial tensions. The ordinary bacteria used have been stable in the interfaces between water or aqueous solutions and all organic liquids tested; i.e., condition (4) obtains. In preparations in which T(ow) is large, stability has been found by experiment to be greater than when T(ow) is small, as follows from condition (4). The force, dependent upon condition (4), which holds bacteria in the liquid-liquid interface, and the force, dependent upon unequal distribution of tension in the liquid-liquid interface, which causes bacteria to glide along the interface, prove to be of the same order of magnitude as the force due to bacterial flagella. Interfacial tensions or its own motility may dominate the movement of the bacterium, according to circumstances. When bacteria thresh their way out of the interface, escape is into the aqueous phase. Acid-fast bacteria possess very low or, in some cases, no stability in the interface, passing easily or even spontaneously into the organic phase. Good evidence has been advanced by other workers to indicate that the surfaces of ordinary bacteria contain many polar radicals; on the other hand, the acid-fast microorganisms are coated with predominantly non-polar substances. It follows from known principles, therefore, that T(sw) should be greater than T(sw) with ordinary bacteria, and T(sw) should be greater than T(so) with acid-fast bacteria. Consideration of relations (2) and (3) above will show that these conditions should result in the differences in behavior of acid-fast and ordinary bacteria actually found by experiment. The theoretical and experimental data here developed contradict the theoretical formulations of the surface tension factor in phagocytosis advanced by Rhumbler and by Tait and substantiate those of Fenn.

Peptide deformylase (PDF) catalyzes the hydrolytic removal of the N-terminal formyl group from nascent proteins. This is an essential step in bacterial protein synthesis, making PDF an attractive target for antibacterial drug development. Essentiality of the def gene, encoding PDF from Mycobacterium tuberculosis, was demonstrated through genetic knockout experiments with Mycobacterium bovis BCG. PDF from M. tuberculosis strain H37Rv was cloned, expressed, and purified as an N-terminal histidine-tagged recombinant protein in Escherichia coli. A novel class of PDF inhibitors (PDF-I), the N-alkyl urea hydroxamic acids, were synthesized and evaluated for their activities against the M. tuberculosis PDF enzyme as well as their antimycobacterial effects. Several compounds from the new class had 50% inhibitory concentration (IC50) values of <100 nM. Some of the PDF-I displayed antibacterial activity against M. tuberculosis, including MDR strains with MIC90 values of <1 microM. Pharmacokinetic studies of potential leads showed that the compounds were orally bioavailable. Spontaneous resistance towards these inhibitors arose at a frequency of < or =5 x 10(-7) in M. bovis BCG. DNA sequence analysis of several spontaneous PDF-I-resistant mutants revealed that half of the mutants had acquired point mutations in their formyl methyltransferase gene (fmt), which formylated Met-tRNA. The results from this study validate M. tuberculosis PDF as a drug target and suggest that this class of compounds have the potential to be developed as novel antimycobacterial agents.

OBJECTIVE

The purpose of this study was to characterize trends related to retracted publications within radiology journals.

METHODS

PubMed was queried to identify all articles with the publication type "retracted publication" or "notification of retraction." Articles published within radiology journals were identified using Journal Citation Reports' journal categories. Available versions of original articles and publication notices were accessed from journal websites. Citations to retracted publications were identified using Web of Science. Overall trends were assessed.

RESULTS

Forty-eight retracted original research articles were identified within radiology journals since 1983, which included 1.1% of all PubMed "retracted publication" entries. Distinct PubMed entries were available for the retracted publication and retraction notification in 39 of 48 articles. The original PDF was available for 37 articles, although the articles were not watermarked as retracted in 23 cases. In six cases with a watermarked PDF, further searches identified nonwatermarked versions. Original HTML versions were available for 13 articles but 11 were not watermarked. The mean (± SD) delay between publication and retraction was 2.7 ± 2.8 years (range, 0-16 years). The mean number of citations to retracted articles was 10.9 ± 17.1 (range, 0-94 citations). Reasons for retraction included problematic or incorrect methods or results (although it typically was unclear whether these represented honest errors or misconduct) in 33.3% of cases, complete or partial duplicate publication in 33.3% of cases, plagiarism in 14.6% of cases, a permission issue in 8.3% of cases, the publisher's error in 6.3% of cases, and no identified reason in 6.3% of cases. One or no retractions occurred annually from 1986 to 2001, although two or more retractions occurred annually in nine of the 12 years from 2002 through 2013.

CONCLUSIONS

Retraction represents an uncommon, yet potentially increasing, issue within radiology journals that publishers have inconsistently and insufficiently addressed. Greater awareness and training in proper biomedical research conduct, as well as establishment and enforcement of standardized publishers' policies, are warranted.

OBJECTIVE

To determine whether sensitivity estimates from an individual's previous visual field tests can be incorporated into perimetric procedures to improve accuracy and reduce test-retest variability at subsequent visits.

METHODS

Computer simulation was used to determine the error, distribution of errors and presentation count for a series of perimetric algorithms. Baseline procedures were Full Threshold and Zippy Estimation by Sequential Testing (ZEST). Retest strategies were (1) allowing ZEST to continue from the previous test without reinitializing the probability density function [pdf]; (2) running ZEST with a Gaussian pdf centered about the previous result; (3) retest minimizing uncertainty (REMU), a new procedure combining suprathreshold and ZEST procedures incorporating prior test information. Empiric visual field data of 265 control and 163 patients with glaucoma were input into the simulation. Four error conditions were modeled: patients who make no errors, 15% false-positive (FP) with 3% false-negative (FN) errors, 15% FN with 3% FP errors, and 20% FP with 20% FN errors.

RESULTS

If sensitivity was stable from test to retest, all the retest algorithms were faster than the baseline algorithms by, on average, one presentation per location and are significantly more accurate (P < 0.05). When visual fields changed from test to retest, REMU was faster and more accurate than the other retest approaches and the baseline procedures. Relative to the baseline procedures, REMU showed decreased test-retest variability in impaired regions of visual field.

CONCLUSIONS

The obvious approaches to retest, such as continuing the previous procedure or seeding with previous values, have limitations when sensitivity changes between tests. REMU, however, significantly improves both accuracy and precision of testing and displays minimal bias, even when fields change and patients make errors.

Bacteriophages encode auxiliary metabolic genes that support more efficient phage replication. For example, cyanophages carry several genes to maintain host photosynthesis throughout infection, shuttling the energy and reducing power generated away from carbon fixation and into anabolic pathways. Photodamage to the D1/D2 proteins at the core of photosystem II necessitates their continual replacement. Synthesis of functional proteins in bacteria requires co-translational removal of the N-terminal formyl group by a peptide deformylase (PDF). Analysis of marine metagenomes to identify phage-encoded homologs of known metabolic genes found that marine phages carry PDF genes, suggesting that their expression during infection might benefit phage replication. We identified a PDF homolog in the genome of Synechococcus cyanophage S-SSM7. Sequence analysis confirmed that it possesses the three absolutely conserved motifs that form the active site in PDF metalloproteases. Phylogenetic analysis placed it within the Type 1B subclass, most closely related to the Arabidopsis chloroplast PDF, but lacking the C-terminal α-helix characteristic of that group. PDF proteins from this phage and from Synechococcus elongatus were expressed and characterized. The phage PDF is the more active enzyme and deformylates the N-terminal tetrapeptides from D1 proteins more efficiently than those from ribosomal proteins. Solution of the X-ray/crystal structures of those two PDFs to 1.95 Å resolution revealed active sites identical to that of the Type 1B Arabidopsis chloroplast PDF. Taken together, these findings show that many cyanophages encode a PDF with a D1 substrate preference that adds to the repertoire of genes used by phages to maintain photosynthetic activities.

BACKGROUND

The formation of glucose degradation products (GDPs) and accumulation of advanced glycation end products (AGEs) partly contribute to the bioincompatibility of peritoneal dialysis fluids (PDF). Aminoguanidine (AG) scavenges GDPs and prevents the formation of AGEs.

METHODS

In a peritoneal dialysis (PD) rat model, we evaluated the effects of the addition of AG to the PDF on microcirculation and morphology of the peritoneum, by intravital microscopy and quantitative morphometric analysis.

RESULTS

AG-bicarbonate effectively scavenged different GDPs from PDF. Daily exposure to PDF for 5 weeks resulted in a significant increase in leucocyte rolling in mesenteric venules, which could be reduced for approximately 50% by addition of AG-bicarbonate (P<0.02). Vascular leakage was found in rats treated with PDF/AG-bicarbonate, but not with PDF alone. Evaluation of visceral and parietal peritoneum showed the induction of angiogenesis and fibrosis after PDF instillation. PDF/AG-bicarbonate significantly reduced vessel density in omentum and parietal peritoneum (P<0.04), but not in mesentery. PDF-induced fibrosis was significantly reduced by AG (P<0.02). PDF instillation led to AGE accumulation in mesentery, which was inhibited by supplementation of AG. Since addition of AG-bicarbonate to PDF raised pH from 5.2 to 8.5, a similar experiment was performed with AG-hydrochloride that did not change the fluid acidity. We could reproduce most of the results obtained with AG-bicarbonate; however, AG-hydrochloride induced no microvascular leakage and had a minor effect on angiogenesis.

CONCLUSIONS

The supplementation of either AG reduced a number of PDF-induced alterations in our model, emphasizing the involvement of GDPs and/or AGEs in the PDF-induced peritoneal injury.

BACKGROUND

Chronic exposure to conventional peritoneal dialysis fluid (PDF) is associated with functional and structural alterations of the peritoneal membrane. The bioincompatibility of conventional PDF can be due to hypertonicity, high glucose concentration, lactate buffering system, presence of glucose degradation products (GDPs) and/or acidic pH. Although various investigators have studied the sole effects of hyperosmolarity, high glucose, GDPs and lactate buffer in experimental PD, less attention has been paid to the chronic impact of low pH in vivo.

METHODS

Rats received daily 10 ml of either conventional lactate-buffered PDF (pH 5.2; n=7), a standard bicarbonate/lactate-buffered PDF with physiological pH (n=8), bicarbonate/lactate-buffered PDF with acidic pH (adjusted to pH 5.2 with 1 N hydrochloride, n=5), or bicarbonate/lactate buffer, without glucose, pH 7.4 (n=7). Fluids were instilled via peritoneal catheters connected to implanted subcutaneous mini vascular access ports for 8 weeks. Control animals with or without peritoneal catheters served as control groups (n=8/group). Various functional (2 h PET) and morphological/cellular parameters were analyzed.

RESULTS

Compared with control groups and the buffer group, conventional lactate-buffered PDF induced a number of morphological/cellular changes, including angiogenesis and fibrosis in various peritoneal tissues (all parameters P<0.05), accompanied by increased glucose absorption and reduced ultrafiltration capacity. Daily exposure to standard or acidified bicarbonate/lactate-buffered PDF improved the performance of the peritoneal membrane, evidenced by reduced new vessel formation in omentum (P<0.02) and parietal peritoneum (P<0.008), reduced fibrosis (P<0.02) and improved ultrafiltration capacity. No significant differences were found between standard and acidified bicarbonate/lactate-buffered PDF. During PET, acidic PDF was neutralized within 15 to 20 min.

CONCLUSIONS

The bicarbonate/lactate-buffered PDF, acidity per se did not contribute substantially to peritoneal worsening in our in vivo model for PD, which might be explained by the buffering capacity of the peritoneum.

BACKGROUND

Peritoneal dialysis (PD) is associated with functional and structural alterations of the peritoneal membrane, particularly new vessel formation and fibrosis. In addition to anticoagulant effects, heparin displays anti-inflammatory and angiostatic properties. Therefore, the effects of administration of heparins on function and morphology of the peritoneal membrane were studied in a rat PD model.

METHODS

Rats received 10 mL conventional PD fluid (PDF) daily, with or without the addition of unfractionated heparin (UFH) or low molecular weight heparin (LMWH) in the PDF (1 mg/10 mL intraperitoneally) via a mini access port. Untreated rats served as controls. After 5 weeks, a 90-minute functional peritoneal transport test was performed and tissues and peritoneal leukocytes were taken.

RESULTS

PD treatment induced loss of ultrafiltration (p<0.01), a twofold increase in glucose absorption (p<0.03), increased urea transport (p<0.02), and loss of sodium sieving (p<0.03), which were also found in the PDF+heparin groups. Increased peritoneal cell influx and hyaluronan production (p<0.02) as well as an exchange of mast cells and eosinophils for neutrophils after PD treatment were observed in PD rats; addition of heparin did not affect those changes. Mesothelial regeneration, submesothelial blood vessel and matrix formation, and accumulation of tissue macrophages were seen in PD animals. Spindle-shaped vimentin-positive and cytokeratin-negative cells indicated either partial injury and denudation of mesothelial cells or epithelial-to-mesenchymal transition. Neither UFH nor LMWH affected any of these morphological changes.

CONCLUSIONS

Within 5 weeks, PD treatment induces a chronic inflammatory condition in the peritoneum, evidenced by high transport, leukocyte recruitment, tissue remodeling, and induction of spindle-shaped cells in the mesothelium. Addition of LMWH or UFH to the PDF did not prevent these adverse PDF-induced peritoneal changes.

BACKGROUND

As few data exist on treatment of peritonitis in patients on automated peritoneal dialysis (APD), and as pharmacokinetics of several antibiotics are reported to be unfavorable in APD, some favor switching to continuous ambulant PD (CAPD) while treating APD-related peritonitis. We explored whether treating peritonitis with patients continuing their usual PD modality had an effect on outcome.

METHODS

We performed a retrospective analysis of the 508 episodes of PD-associated peritonitis seen in 205 patients in our center from January 1993 to January 2007. During this period, the standard initial therapy for PD-related peritonitis was a combination of intraperitoneal gentamicin and rifampicin.

RESULTS

There was no difference in cure rate between CAPD and APD groups. Likewise, initial and maximal leukocyte counts in the PD fluid (PDF), relapse rates, catheter removal rates, and death during treatment of peritonitis were similar in the CAPD and APD groups. Median (interquartile range) duration of elevated leukocyte count in PDF was longer in APD: 5.0 (3.0 - 9.0) days versus 4.0 (2.5 - 7.0) days in CAPD (p <0.001). APD patients were treated with antibiotics longer than CAPD patients: 16.0 (12.5 - 21.0) versus 15.0 (12.0 - 18.0) days (p = 0.036). Also, after correction for possible confounders, odds ratios for death and for the combined end point death or catheter removal showed no difference when patients treated for peritonitis stayed on their own modality.

CONCLUSIONS

Regarding rate of relapse, mortality, or the combined end point mortality plus catheter removal, we found no difference between CAPD and APD patients continuing their own PD modality during treatment of PD-related peritonitis. Intermediate end points such as duration of elevated PDF leukocyte count and duration of antibiotic treatment were longer in APD patients.

Clinical indices of in vivo biocompatibility: The role of ex vivo cell function studies and effluent markers in peritoneal dialysis patients. Over the past 20 years, studies of the biocompatibility profile of peritoneal dialysis solutions (PDF) have evolved from initial in vitro studies assessing the impact of solutions on leukocyte function to evaluations of mesothelial cell behavior. More recent biocompatibility evaluations have involved assessments of the impact of PDF on membrane integrity and cell function in peritoneal dialysis (PD) patients. The development of ex vivo systems for the evaluation of in vivo cell function, and effluent markers of membrane integrity and inflammation in patients exposed both acutely and chronically to conventional and new PDF will be interpreted in the context of our current understanding of the biology of the dialyzed peritoneum. The available data indicate that exposure of the peritoneal environment to more biocompatible PDF is associated with improvements in peritoneal cell function, alterations in markers of membrane integrity, and reduced local inflammation. These data suggest that more biocompatible PDF will have a positive impact on host defense, peritoneal homeostasis, and the long-term preservation of peritoneal membrane function in PD patients.

Peptide deformylase (PDF) inhibitors have a strong potential to be used as a new class of antibiotics. However, recent studies have shown that the mitochondria of most eukaryotes, including humans, contain an essential PDF, PDFPDFPDFPDFPDFs. AtPDFPDF, the only other dimeric PDF identified to date. AtPDFPDF for which zinc has been identified as the catalytic ion. However, the zinc binding pocket does not differ from the binding pockets of PDFs with iron rather than zinc. The crystal structure of AtPDFPDFPDFPDFs. A true S3' pocket is created by the residues of a helical CD-loop, which is very long in PDFPDF inhibitors that will not target mitochondrial PDFs.

Inflammation of vascular cell wall is the key problem and proinflammatory cytokines and chemokines play a great role in it. These molecules, togheter with C-reactive protein (CRP) can predict risk of coronary events. It is questionable to what extend are CRP and pro-inflammatory cytokines purely acute phase markers and to what extend are they active inflammatory participants. Besides inflammation, other prominent mechanism in the pathogenesis of atherosclerosis and atherothrombosis--underlying causes of coronary events, is genetics. Gene polymorphisms including polymorphisms of inflammatory markers are studied and one of them, polymorphism of monocyte chemoattractant protein (MCP-1/CCL2) and its receptor CCR2 (key components of atherosclerosis) belong to most studied one. MCP-1/CCL2 and CCR2 polymorphisms have been implicated as susceptibility factors for chronic stable angina pectoris and myocardial infarction by several independent investigators. It seems that CCL2/CCR2 axis plays an important role both in post-ischemic and post-reperfusion inflammation and could become a new therapeutic goal in selected cardiovascular diseases as well as in stroke in future. Inhibition of this axis disrupts ischemic-reperfusion injury by decreasing edema, leucocyte infiltration and expression of inflammatory mediators. One can suppose that identifying genes influencing inflammatory biomarkers might improve understanding of genetic determinants of cardiovascular disease our management and prevention (Tab. 2, Fig. 1, Ref. 105). Full Text (Free, PDF) www.bmj.sk.

The circadian clock plays an important role in adaptation in time and space by synchronizing changes in physiological, developmental, and behavioral traits of organisms with daily and seasonal changes in their environment. We have studied some features of the circadian activity and clock organization in a northern Drosophila species, Drosophila montana, at both the phenotypic and the neuronal levels. In the first part of the study, we monitored the entrained and free-running locomotor activity rhythms of females in different light-dark and temperature regimes. These studies showed that D. montana flies completely lack the morning activity component typical to more southern Drosophila species in an entrained environment and that they are able to maintain their free-running locomotor activity rhythm better in constant light than in constant darkness. In the second part of the study, we traced the expression of the PDF neuropeptide and the CRY protein in the neurons of the brain in D. montana adults and found differences in the number and location of PDF- and CRY-expressing neurons compared with those described in Drosophila melanogaster. These differences could account, at least in part, for the lack of morning activity and the reduced circadian rhythmicity of D. montana flies in constant darkness, both of which are likely to be adaptive features during the long and dark winters occurring in nature.

OBJECTIVE

What is the chance of a live birth following one or more linked complete cycles of IVF (including ICSI)?

CONCLUSIONS

The chance of a live birth after three complete cycles of IVF was 42.3% for treatment commencing from 1999 to 2007.

BACKGROUND

IVF success has generally been reported on the basis of live birth rates after a single episode of treatment resulting in the transfer of a fresh embryo. This fails to capture the real chance of having a baby after a number of complete cycles-each involving the replacement of fresh as well as frozen-thawed embryos.

METHODS

Population-based observational cohort study of 178 898 women between 1992 and 2007.

METHODS

Participants included all women who commenced IVF treatment at a licenced clinic in the UK as recorded in the Human Fertilisation and Embryology Authority (HFEA) national database. Exclusion criteria included women whose treatment involved donor insemination, egg donation, surrogacy and the transfer of more than three embryos. Cumulative rates of live birth, term (>37 weeks) singleton live birth, and multiple pregnancy were estimated for two time-periods, 1992-1998 and 1999-2007. Conservative estimates assumed that women who did not return for IVF would not have the outcome of interest while optimal estimates assumed that these women would have similar outcome rates to those who continued IVF.

RESULTS

A total of 71 551 women commenced IVF treatment during 1992-1998 and an additional 107 347 during 1999-2007. After the third complete IVF cycle (defined as three fresh IVF treatments-including replacement of any surplus frozen-thawed embryos), the conservative CLBR in women who commenced IVF during 1992-1998 was 30.8% increasing to 42.3% during 1999-2007. The optimal CLBRs were 44.6 and 57.1%, respectively. After eight complete cycles the optimal CLBR was 82.4% in the latter time period. The conservative rate for multiple pregnancy per pregnant woman fell from 31.9% during the earlier time period to 26.2% during the latter.

UNASSIGNED

Linkage of all IVF treatments to individual women was conducted. However, it was not possible to identify with certainty in all cases the episode of ovarian stimulation which generated some of the frozen embryos. Cumulative live birth rates could not be calculated for women who started treatment beyond 2007 as follow-up data were incomplete in some of them. Following a change in legislation in 2008, linked data were only made available for research in women who gave formal consent for this purpose. BMI and ethnicity could not be reported: these demographics are not recorded in the HFEA database.

CONCLUSIONS

Our results demonstrate, at a national level, the chances of live birth in couples undergoing a number of complete (fresh and frozen) IVF cycles. They reflect improvements in reproductive technology and a more conservative embryo transfer policy. Although most couples in the UK still do not receive three complete IVF cycles; assuming no barriers to continuation of IVF treatment, around 83% of women receiving IVF would achieve a live birth by the eighth complete cycle, similar to the natural live birth rate in a non-contraception practising population. Our results support the call from NICE to develop consistent IVF policies based on three complete cycles.

BACKGROUND

This work was funded by a Chief Scientist Office Postdoctoral Training Fellowship in Health Services Research and Health of the Public Research (Ref PDF/12/06). The views expressed here are those of the authors and not necessarily those of the Chief Scientist Office. S.B. reports grants from Chief Scientist Office Scotland during the conduct of the study. His institution has received support from Pharmaceutical companies (for educational seminars), which is not related to the submitted work. D.J.M., A.M. and A.J.L. have no conflicts of interest to declare.

BACKGROUND

Patients' health related quality of life (HRQoL) has rarely been systematically monitored in general practice. Electronic tools and practice training might facilitate the routine application of HRQoL questionnaires. Thorough piloting of innovative procedures is strongly recommended before the conduction of large-scale studies. Therefore, we aimed to assess i) the feasibility and acceptance of HRQoL assessment using tablet computers in general practice, ii) the perceived practical utility of HRQoL results and iii) to identify possible barriers hindering wider application of this approach.

METHODS

Two HRQoL questionnaires (St. George's Respiratory Questionnaire SGRQ and EORTC QLQ-C30) were electronically presented on portable tablet computers. Wireless network (WLAN) integration into practice computer systems of 14 German general practices with varying infrastructure allowed automatic data exchange and the generation of a printout or a PDF file. General practitioners (GPs) and practice assistants were trained in a 1-hour course, after which they could invite patients with chronic diseases to fill in the electronic questionnaire during their waiting time. We surveyed patients, practice assistants and GPs regarding their acceptance of this tool in semi-structured telephone interviews. The number of assessments, HRQoL results and interview responses were analysed using quantitative and qualitative methods.

RESULTS

Over the course of 1 year, 523 patients filled in the electronic questionnaires (1-5 times; 664 total assessments). On average, results showed specific HRQoL impairments, e.g. with respect to fatigue, pain and sleep disturbances. The number of electronic assessments varied substantially between practices. A total of 280 patients, 27 practice assistants and 17 GPs participated in the telephone interviews. Almost all GPs (16/17 = 94%; 95% CI = 73-99%), most practice assistants (19/27 = 70%; 95% CI = 50-86%) and the majority of patients (240/280 = 86%; 95% CI = 82-91%) indicated that they would welcome the use of electronic HRQoL questionnaires in the future. GPs mentioned availability of local health services (e.g. supportive, physiotherapy) (mean: 9.4 +/- 1.0 SD; scale: 1 - 10), sufficient extra time (8.9 +/- 1.5) and easy interpretation of HRQoL results (8.6 +/- 1.6) as the most important prerequisites for their use. They believed HRQoL assessment facilitated both communication and follow up of patients' conditions. Practice assistants emphasised that this process demonstrated an extra commitment to patient centred care; patients viewed it as a tool, which contributed to the physicians' understanding of their personal condition and circumstances.

CONCLUSIONS

This pilot study indicates that electronic HRQoL assessment is technically feasible in general practices. It can provide clinically significant information, which can either be used in the consultation for routine care, or for research purposes. While GPs, practice assistants and patients were generally positive about the electronic procedure, several barriers (e.g. practices' lack of time and routine in HRQoL assessment) need to be overcome to enable broader application of electronic questionnaires in every day medical practice.

We propose a novel approach for surface electromyogram (sEMG) signal classification. This approach utilizes higher order statistics of sEMG signal to classify four primitive motions, i.e., elbow flexion, elbow extension, forearm supination, and forearm pronation. In documented research, the sEMG signal generated during isometric contraction is modeled by a stationary process whose probability density function (pdf) is assumed to be either Gaussian or Laplacian. In this paper, using Negentropy, we demonstrate that the level of non-Gaussianity of sEMG signal recorded in muscular forces below 25% of maximum voluntary contraction (MVC) is significant. Therefore, application of higher order statistics in sEMG signal processing is justified, due to the fact that more useful information can be extracted from the corresponding higher order statistics. An accurate classification is achieved by using the sequential forward selection (SFS) method for reducing of the dimensionality of feature space and the K-nearest neighbor (KNN) classifier. The results indicate that the proposed approach provides higher sEMG correct classification rates as compared to the existing methods.

The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for amphetamines to cause adverse effects on reproduction and development in humans. Amphetamines evaluated were D- and D,L-amphetamine and methamphetamine. Amphetamine is approved by the U.S. Food and Drug Administration for the treatment of attention deficit hyperactivity disorder (ADHD) in persons over 3 years of age and narcolepsy; methamphetamine is approved for the treatment of ADHD in persons 6 years of age and older and for short-term treatment of obesity. Amphetamines were selected for evaluation because of 1) widespread usage in children, 2) availability of developmental studies in children and experimental animals, and 3) public concern about the effect of this stimulant on child development. The results of this evaluation on amphetamines are published in an NTP-CERHR monograph which includes: 1) the NTP Brief, 2) the Expert Panel Report on the Reproductive and Developmental Toxicity of Methylphenidate, and 3) public comments received on the Expert Panel Report. As stated in the NTP Brief, the NTP reached the following conclusions regarding the possible effects of exposure to methylphenidate on human development and reproduction. First, there is some concern for developmental effects, specifically for potential neurobehavioral alterations, from prenatal amphetamine exposure in humans both in therapeutic and non-therapeutic settings. After prenatal exposure to therapeutic doses of amphetamine, rat pups demonstrated neurobehavioral alterations. Data from human and animal studies were judged insufficient for an evaluation of the effect of amphetamine exposure on growth and other related developmental effects. Second, there is concern for methamphetamine-induced adverse developmental effects, specifically on growth and neurobehavioral development, in therapeutic and non-therapeutic settings. This conclusion is based on evidence from studies in experimental animals that prenatal and postnatal exposures to methamphetamine produce neurobehavioral alterations, small litter size, and low birth weight. Results from studies in humans suggest that methamphetamine may cause low birth weight and shortened gestation, but study confounders such as possible multiple drug usage prevent a definite conclusion. NTP-CERHR monographs are transmitted to federal and state agencies, interested parties, and the public and are available in electronic PDF format on the CERHR web site (http://cerhr.niehs.nih.gov) and in printed text or CD-ROM from the CERHR (National Institute of Environmental Health Sciences, P.O. Box 12233, MD EC-32, Research Triangle Park, NC; fax: 919-316-4511).

OBJECTIVE

The aim of this study was to evaluate the learning and memory-enhancing effect of Bacopa monniera in neonatal rats.

BACKGROUND

Learning is an acquisition and storage of information as a consequence of experience. Memory is a relatively permanent storage form of the learned information. In the process of 'learning', activation of neurons occurs in specific areas or specific memory systems of the brain concerned with the processing of the specific modality of sensory information. Rasayana plants are said to prevent ageing, re-establish youth, strengthen life, brain power and prevent diseases. Bacopa monniera (BM) is shown to be very useful in improving learning and memory.

METHODS

In the present study neonatal rat pups (10 days old) were given different doses of BM extract orally for different periods of time. These rats were then subjected to spatial learning (T- Maze) and passive avoidance tests along with the age matched normal and gum acacia control rats. The data were compared with those of control rats.

RESULTS

The results showed improvement in spatial learning performance and enhanced memory retention in neonatal rats treated with extract of BM.

CONCLUSIONS

We conclude that treatment with BM extract during growth spurt period of neonatal rats enhances learning and memory (Tab. 3, Fig. 3, Ref. 45). Full Text in free PDF www.bmj.sk.

Iron oxide nanoparticles are magnetic nanoparticles which have widespread application in MRI and heat therapy of cancer as contrast elements. They are also used effectively for drug and gene delivery because of effective penetrating to the cells and tissues. However, these features cause Fe2O3 nanoparticles have toxic effects that are not completely understood yet. In this study, effects of iron oxide nanoparticles on lung tissue in adult male Wistar rats were studied. We used pulmonary inhalation method for nanoparticle administration and used ether as a helper. Our results showed administered nanoparticles penetrated to the circulation and rapidly reached to liver and created serious inflammation in lung and liver tissues. This study used two different nanoparticle doses (20 and 40 mg/kg) and two exposing numbers (7 and 14 times). Results showed significant enhancement of free radicals and reduction of the GSH in lung tissue. Histological studies showed nanoparticle treatment of rats caused pulmonary emphysema, interstitial hyperemia and inflammation in lungs. By increasing the administrated dose lung tissue showed all of the mentioned symptoms with increased intensity. Nanoparticle exposition causes presence of neutrophils, lymphocytes and eosinophils in the lung tissue that confirmed there is a serious pathologic condition. Hepatic cells injuries cause penetration of the hepatic enzymes in to the blood serum (Tab. 2, Fig. 4, Ref. 32). Text in PDF www.elis.sk.

This article has been corrected. The original version (PDF) is appended to this article as a Supplement.

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Although consumption of tea at high temperatures has been suggested as a risk factor for esophageal cancer, an association has not been observed consistently, and whether any relationship is independent of alcohol and tobacco exposure has not been evaluated.

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To examine whether high-temperature tea drinking, along with the established risk factors of alcohol consumption and smoking, is associated with esophageal cancer risk.

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China Kadoorie Biobank, a prospective cohort study established during 2004 to 2008.

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10 areas across China.

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456 155 persons aged 30 to 79 years. Those who had cancer at baseline or who reduced consumption of tea, alcohol, or tobacco before baseline were excluded.

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The usual temperature at which tea was consumed, other tea consumption metrics, and lifestyle behaviors were self-reported once, at baseline. Outcome was esophageal cancer incidence up to 2015.

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During a median follow-up of 9.2 years, 1731 incident esophageal cancer cases were documented. High-temperature tea drinking combined with either alcohol consumption or smoking was associated with a greater risk for esophageal cancer than hot tea drinking alone. Compared with participants who drank tea less than weekly and consumed fewer than 15 g of alcohol daily, those who drank burning-hot tea and 15 g or more of alcohol daily had the greatest risk for esophageal cancer (hazard ratio [HR], 5.00 [95% CI, 3.64 to 6.88]). Likewise, the HR for current smokers who drank burning-hot tea daily was 2.03 (CI, 1.55 to 2.67).

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Tea consumption was self-reported once, at baseline, leading to potential nondifferential misclassification and attenuation of the association.

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Drinking tea at high temperatures is associated with an increased risk for esophageal cancer when combined with excessive alcohol or tobacco use.

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National Natural Science Foundation of China and National Key Research and Development Program.