Aluminium and phosphate uptake by Phragmites australis: the role of Fe, Mn and Al root plaques.
Aluminium, a potentially phytotoxic metal, is an important constituent of many mine water discharges but has largely been neglected in the literature. The behaviour of this element in the rhizosphere of the wetland plant Phragmites australis was investigated in the laboratory in the presence and absence of Mn and Fe root plaques. Electron microscopy and chemical extraction techniques were utilized to determine the physico-chemical properties of the plaques and any association of Al. Both Mn and Fe plaques occurred as amorphous coatings on root surfaces with uneven distributions. Al was not adsorbed onto the surface of either plaque type but formed a separate phosphate deposit closely resembling the Fe and Mn plaques. Phosphorus was also found to be adsorbed to the surface of the Fe plaques (but not the Mn plaques). Both mechanisms were found to immobilize P at the root surface but this did not significantly reduce the concentration of P in aerial plant tissues that was sufficient to ensure adequate growth.


[Follow-up of low birth weight infants: language acquisition].
The objective of this work was to follow-up language development of full-term infants/small for gestational age (RNT/PIG) and preterm infants/adequate for gestational age (RNPT/AIG). The assessments were done monthly, up to their 18th months of age. Twenty infants were evaluated, 10 of each group. The Ethical Committee of the institution approved the project. It was used the Protocol for Anamneses and the Early Language Milestone Scale - ELM Scale. Both groups were compared with 47 full term, adequate for gestational age infants. The results had shown that up to the 6th month, the infants showed a normal performance for their age. In the 9th month, there was a delay in babbling production. In the 12th month, infants of the RNT/PIG group showed a significant statistically delay expressing polysyllabic babbling and infants of the RNPT/AIG group showed delay in the production of the first words. In the 18th month, the delay persisted in one infant of the RNT/PIG group.


The interaction between eukaryotic initiation factor 1A and eIF5 retains eIF1 within scanning preinitiation complexes.
Scanning of the mRNA transcript by the preinitiation complex (PIC) requires a panel of eukaryotic initiation factors, which includes eIF1 and eIF1A, the main transducers of stringent AUG selection. eIF1A plays an important role in start codon recognition; however, its molecular contacts with eIF5 are unknown. Using nuclear magnetic resonance, we unveil eIF1A's binding surface on the carboxyl-terminal domain of eIF5 (eIF5-CTD). We validated this interaction by observing that eIF1A does not bind to an eIF5-CTD mutant, altering the revealed eIF1A interaction site. We also found that the interaction between eIF1A and eIF5-CTD is conserved between humans and yeast. Using glutathione S-transferase pull-down assays of purified proteins, we showed that the N-terminal tail (NTT) of eIF1A mediates the interaction with eIF5-CTD and eIF1. Genetic evidence indicates that overexpressing eIF1 or eIF5 suppresses the slow growth phenotype of eIF1A-NTT mutants. These results suggest that the eIF1A-eIF5-CTD interaction during scanning PICs contributes to the maintenance of eIF1 within the open PIC.


Preventing progression to first-episode psychosis in early initial prodromal states.
Young people with self-experienced cognitive thought and perception deficits (basic symptoms) may present with an early initial prodromal state (EIPS) of psychosis in which most of the disability and neurobiological deficits of schizophrenia have not yet occurred. To investigate the effects of an integrated psychological intervention (IPI), combining individual cognitive-behavioural therapy, group skills training, cognitive remediation and multifamily psychoeducation, on the prevention of psychosis in the EIPS. A randomised controlled, multicentre, parallel group trial of 12 months of IPI v. supportive counselling (trial registration number: NCT00204087). Primary outcome was progression to psychosis at 12- and 24-month follow-up. A total of 128 help-seeking out-patients in an EIPS were randomised. Integrated psychological intervention was superior to supportive counselling in preventing progression to psychosis at 12-month follow-up (3.2% v. 16.9%; P = 0.008) and at 24-month follow-up (6.3% v. 20.0%; P = 0.019). Integrated psychological intervention appears effective in delaying the onset of psychosis over a 24-month time period in people in an EIPS.


Influence of Modeling Choices on Value of Information Analysis: An Empirical Analysis from a Real-World Experiment.
Value of information (VOI) analysis often requires modeling to characterize and propagate uncertainty. In collaboration with a cancer clinical trial group, we integrated a VOI approach to assessing trial proposals. This paper aims to explore the impact of modeling choices on VOI results and to share lessons learned from the experience. After selecting two proposals (A: phase III, breast cancer; B: phase II, pancreatic cancer) for in-depth evaluations, we categorized key modeling choices relevant to trial decision makers (characterizing uncertainty of efficacy, evidence thresholds to change clinical practice, and sample size) and modelers (cycle length, survival distribution, simulation runs, and other choices). Using a $150,000 per quality-adjusted life-year (QALY) threshold, we calculated the patient-level expected value of sample information (EVSI) for each proposal and examined whether each modeling choice led to relative change of more than 10% from the averaged base-case estimate. We separately analyzed the impact of the effective time horizon. The base-case EVSI was $118,300 for Proposal A and $22,200 for Proposal B per patient. Characterizing uncertainty of efficacy was the most important choice in both proposals (e.g. Proposal A: $118,300 using historical data vs. $348,300 using expert survey), followed by the sample size and the choice of survival distribution. The assumed effective time horizon also had a substantial impact on the population-level EVSI. Modeling choices can have a substantial impact on VOI. Therefore, it is important for groups working to incorporate VOI into research prioritization to adhere to best practices, be clear in their reporting and justification for modeling choices, and to work closely with the relevant decision makers, with particular attention to modeling choices.


Using aversion learning techniques to assess the mental state, suffering, and welfare of farm animals.
The extent that handling farm animals causes them to suffer is a central concern when assessing their welfare. "Suffering" is a mental state, resulting from different emotions, such as fear, pain, or boredom, which have different causes and effects on the animal's behavior and physiology. What is common is that they are aversive; animals will seek to avoid such experiences. The degree of aversiveness can be measured using behavioral techniques, which are based on an animal's ability to learn the predictive relationships between events. Compared with physiological stress responses, aversion learning techniques are more easily interpreted in terms of animal suffering and are more able to discriminate between handling treatments. They can sometimes be used to predict physiological responses to handling. The outcome of experiments in aversion learning can be affected by factors influencing the learning ability and memory of animals, and researchers need be aware of potential confounding in experimental design. Such techniques have been used to compare sheep handling practices, examine which components of transport are aversive for pigs and poultry, and examine the relationship between animals and handlers.


Effects of a novel method of acute tryptophan depletion on plasma tryptophan and cognitive performance in healthy volunteers.
Disorders associated with low levels of serotonin (5-HT) are characterized by mood and cognitive disturbances. Acute tryptophan depletion (ATD) is an established method for lowering 5-HT levels and an important tool to study the effects of reduced 5-HT on mood and cognition in human subjects. The traditional ATD method, i.e., administration of separate amino acids (AAs), has several disadvantages. The AA mixture is costly, unpalatable and associated with gastrointestinal discomfort. The University of Maastricht developed a new and inexpensive method for ATD: a natural collagen protein (CP) mixture with low tryptophan (TRP) content. The reductions in plasma TRP after taking this CP mixture were compared with the reductions achieved taking the traditional AA mixture, and effects on memory and reversal learning were studied. Fifteen healthy young volunteers participated in a double-blind, counterbalanced within-subject study. Reversal learning, verbal memory and pattern recognition were assessed at baseline and 3-4 h after taking the CP mixture. The new ATD method significantly reduced plasma TRP by 74% and the ratio between TRP and the other large AAs (TRP/LNAA) by 82%. The placebo mixture did not change these measures. Delayed recognition reaction time on the verbal learning task was increased following ATD. No other cognitive effects were found. The CP mixture was shown to be an efficient tool for lowering plasma TRP in humans. The validity of this method with regard to behavioral changes remains to be established in healthy, vulnerable and clinical populations.


Samarosporin, a new peptide antibiotic. I. Fermentation, isolation ahd characterization.
A new antibiotic, samarosporin, was isolated in a crystalline state from a mycelial extract of a strain of Samarospora species (an ascomycete). Samarosporin is a neutral cyclopeptide and has a molecular formula of C72H111N15O19. Samarosporin shows a broad antimicrobial activity against various test microorganisms.


cPLA2α-/- sympathetic neurons exhibit increased membrane excitability and loss of N-Type Ca2+ current inhibition by M1 muscarinic receptor signaling.
Group IVa cytosolic phospholipase A2 (cPLA2α) mediates GPCR-stimulated arachidonic acid (AA) release from phosphatidylinositol 4,5-bisphosphate (PIP2) located in plasma membranes. We previously found in superior cervical ganglion (SCG) neurons that PLA2 activity is required for voltage-independent N-type Ca2+ (N-) current inhibition by M1 muscarinic receptors (M1Rs). These findings are at odds with an alternative model, previously observed for M-current inhibition, where PIP2 dissociation from channels and subsequent metabolism by phospholipase C suffices for current inhibition. To resolve cPLA2α's importance, we have investigated its role in mediating voltage-independent N-current inhibition (~40%) that follows application of the muscarinic agonist oxotremorine-M (Oxo-M). Preincubation with different cPLA2α antagonists or dialyzing cPLA2α antibodies into cells minimized N-current inhibition by Oxo-M, whereas antibodies to Ca2+-independent PLA2 had no effect. Taking a genetic approach, we found that SCG neurons from cPLA2α-/- mice exhibited little N-current inhibition by Oxo-M, confirming a role for cPLA2α. In contrast, cPLA2α antibodies or the absence of cPLA2α had no effect on voltage-dependent N-current inhibition by M2/M4Rs or on M-current inhibition by M1Rs. These findings document divergent M1R signaling mediating M-current and voltage-independent N-current inhibition. Moreover, these differences suggest that cPLA2α acts locally to metabolize PIP2 intimately associated with N- but not M-channels. To determine cPLA2α's functional importance more globally, we examined action potential firing of cPLA2α+/+ and cPLA2α-/- SCG neurons, and found decreased latency to first firing and interspike interval resulting in a doubling of firing frequency in cPLA2α-/- neurons. These unanticipated findings identify cPLA2α as a tonic regulator of neuronal membrane excitability.


Dopaminergic cells, derived from a high efficiency differentiation protocol from umbilical cord derived mesenchymal stem cells, alleviate symptoms in a Parkinson's disease rodent model.
Mesenchymal stem cells (MSCs) could be an alternative to foetal cells in the treatment of several neurodegenerative diseases, especially Parkinson's disease (PD). We have previously demonstrated the functional efficacy of the undifferentiated bone marrow MSCs (BMMSCs) cultured in a xenofree conditions in PD animal models. We now demonstrate isolation of MSCs from the umbilical cord matrix tissue and assess their safety and efficacy to improve Parkinsonian symptoms in an in vivo animal model. The efficacy of MSCs from BM and umbilical cord in the PD animal mode has also been studied, and more importantly the efficacy of using differentiated UCMSC (D-UCMSCs) to dopaminergic phenotype. Phenotypically, UCMSCs expressed higher levels of SSEA4 compared to BMMSCs. Analysis of differentiated cells showed that D-UCMSCs expressed significant levels of Tyrosine Hydroxyalse and Nurr1 compared to D-BMMSCs. The in vivo efficacy of the differentiated and undifferentiated cell types in the Parkinsonian rats showed that D-UCMSCs improved the symptoms throughout a year of study. Differentiated cell types are potentially better for clinical use than the undifferentiated type, provided they are made available at the site of action in adequate numbers. MSCs are less immunogenic and immunomodulatory, which opens up the further possibility of using these cells in allogeneic settings. This could be a novel cell therapy application, especially when getting autochthonous cells is difficult.


Interspecies Variation between Fish and Human Transthyretins in Their Binding of Thyroid-Disrupting Chemicals.
Thyroid-disrupting chemicals (TDCs) are xenobiotics that can interfere with the endocrine system and cause adverse effects in organisms and their offspring. TDCs affect both the thyroid gland and regulatory enzymes associated with thyroid hormone homeostasis. Transthyretin (TTR) is found in the serum and cerebrospinal fluid of vertebrates, where it transports thyroid hormones. Here, we explored the interspecies variation in TDC binding to human and fish TTR (exemplified by Gilthead seabream ( Sparus aurata)). The in vitro binding experiments showed that TDCs bind with equal or weaker affinity to seabream TTR than to the human TTR, in particular, the polar TDCs (>500-fold lower affinity). Crystal structures of the seabream TTR-TDC complexes revealed that all TDCs bound at the thyroid binding sites. However, amino acid substitution of Ser117 in human TTR to Thr117 in seabream prevented polar TDCs from binding deep in the hormone binding cavity, which explains their low affinity to seabream TTR. Molecular dynamics and in silico alanine scanning simulation also suggested that the protein backbone of seabream TTR is more rigid than the human one and that Thr117 provides fewer electrostatic contributions than Ser117 to ligand binding. This provides an explanation for the weaker affinities of the ligands that rely on electrostatic interactions with Thr117. The lower affinities of TDCs to fish TTR, in particular the polar ones, could potentially lead to milder thyroid-related effects in fish.


Characterization of a new human astrocytoma cell line SHG140: cell proliferation, cell phenotype, karyotype, STR markers and tumorigenicity analysis.
Background: Primary tumor Cell was an important tool for tumor research. Here, a new astrocytoma cell line SHG-140 was established and its proliferation, phenotype, karyotype, STR authentication, pathological characteristics, and characteristics of the cells' intrancranial xenografts of nude mice were studied. Methods: Primary SHG-140 culture was performed in DMEM/F12 medium with 10% FBS. Cell proliferation, karyotype analysis, cell immunofluorescence and STR authentication of SHG140 cells were performed. HE staining and immunohistochemistry, Whole oncogene high flux sequencing of the patient sample were carried out. SHG140 cells were injected into the brain of nude mice, HE staining and immunohistochemistry of intracranial xenograft tumor were detected. Results: Cell immunofluorescence demonstrated that SHG140 cells were positive for A2B5 (Glial precursors ganglioside), GFAP (Glial fibrillary acidic protein), Nestin, S-100 (Acid calcium bingding protein), Olig2 (Oligodendrocyte transcription factor 2) and Ki67 (Nuclear-associated antigen), cells negatively stained for Vimentin. Cell proliferation curve revealed that SHG140 proliferated slightly within 48 h, which then significantly proliferated to the fourth day. Karyotype analysis demonstrated its total number of chromosomes was 55, having trisomy of chromosome 6, 7, 8, 9 and X, and tetrad of chromosome 1 and 21, chromosomal deletion and rearrangement were observed. STR markers analysis showed the cells were derived from human male. SHG140 cells had tumorigenic properties - the intracranial injection of these cells into nude mice gave rise to growing tumors. We found that the glioma tissue was diffusively positive for GFAP, Nestin, slightly positive for Olig2, S-100; the positive rate of Ki-67 was 65% and negative for Vimentin. SHG140 cells were tumorigenic, GFAP, Nestin, S-100 Olig-2, the proliferation marker Ki-67 were expressed in its intracranial xenograft, Vimentin was negative expressed. Whole oncogene high flux sequencing of the patient tissue showed TP53, PTEN, IDH1 and PTCH1 mutation were existed. Conclusions: Our study showed that SHG140 was an astrocytoma glioma continuous cell line derived from a human adult male, having a strong tumorigenicity in nude mice, which made it wound be a useful model for the study of human glioblastoma multiforme.


Insulin-mimetic actions of wheat germ agglutinin and concanavalin A on specific mRNA levels.
Insulin has pleiotropic effects on sensitive cells, including the regulation of specific mRNA accumulation initiated by the binding of insulin to its plasma membrane receptor. Lectins, such as wheat germ agglutinin (WGA) and concanavalin A (Con A), are known to be insulin mimetic. It is thought that WGA and Con A interact with the insulin receptor or associated membrane glycoproteins which, when activated, lead to insulin-mimetic responses. We attempted to determine whether WGA and Con A could induce the accumulation of a specific messenger RNA (p33-mRNA). Insulin treatment of H4IIE (H4) hepatoma cells increased the concentration of p33-mRNA within 30 min after addition, with a maximum effect of 10- to 15-fold. WGA and Con A also exhibited time- and dose-dependent stimulatory effects on p33-mRNA accumulation with maximal effects of 30- to 40-fold. The effect of insulin was maximal by 1 h and plateaued thereafter, whereas lectins had maximal effects at 2 h after addition to cell cultures. Insulin, WGA, and Con A did not significantly alter the stability (half-life) of p33-mRNA. The addition of RNA synthesis inhibitors blocked the ability of insulin, WGA, and Con A to induce the amount of p33-mRNA. These data suggest that lectins, as well as insulin, induce the synthesis of p33-mRNA in acutely treated H4 hepatoma cells.


Benefit of combination β-blocker and endoscopic treatment to prevent variceal rebleeding: a meta-analysis.
To determine whether the association of β-blockers with endoscopic treatment is superior to endoscopic treatment alone for the secondary prophylaxis of oesophageal variceal bleeding. Randomised controlled trials comparing sclerotherapy (SCL) with SCL plus β-blockers (BB) or banding ligation (BL) with BL plus BB were identified. Main outcomes were overall and 6, 12 and 24 mo rebleeding rates, as well as overall and 6, 12 and 24 mo mortality. Two statistical methods were used: Yusuf-Peto, and Der Simonian and Laird. Inter-trial heterogeneity was systematically taken into account. Seventeen randomised controlled trials were included, 14 with SCL and 3 with BL. Combination β-blocker and endoscopic treatment significantly reduced rebleeding rates at 6, 12 and 24 mo and overall [odds ratio (OR): 2.20, 95% confidence interval (CI): 1.69-2.85, P < 0.0001] compared to endoscopic treatment alone. Mortality at 24 mo was significantly lower for the combined treatment group (OR: 1.83, 95% CI: 1.16-2.90, P = 0.009), as well as overall mortality (OR: 1.43, 95% CI: 1.03-1.98, P = 0.03). Combination therapy should thus be recommended as the first line treatment for secondary prophylaxis of oesophageal variceal bleeding.


A novel technique in a sheep model for evaluating prosthetic heart valve performance.
There have been many various animal studies to evaluate the structural integrity and antithrombogenicity of prosthetic heart valves. We were interested in developing a novel sheep model to study the thrombogenicity of mechanical heart valves placed into the systemic circulation but without the need for cardiac bypass. Also, we wanted to minimize the risk ofparaplegia from complete thoracic aortic clamping. Six sheep underwent left lateral thoracotomy for placement of a mechanical heart valve in parallel with the descending thoracic aorta. A valved conduit with a dacron tube graft sutured to the back end was fashioned. Employing partial aortic occlusion with a side-biting clamp, the proximal and distal ends were anastomosed in an end-to-side fashion. Once flow was confirmed through the graft, the native aorta was occulded with umbilical tape. The sheep received no postoperative anticoagulation. The median operative time and estimated blood loss (EBL) was 170 min and 250 cc, respectively. Patency of the valved conduits was confirmed during the initial procedure, and there was no incidence of paraplegia postoperatively. Two animals expired shortly after extubation and at necropsy the valved conduits were patent with preserved valve function. The four survivors were sacrificed a median of 37 days postoperatively. Prior to euthanasia, the valved conduits were evaluated in situ with ultrasound. In all cases, the valves had clot formation at the hinges, which prevented active movement of the leaflets. This novel in vivo technique provides an alternative in testing the thrombogenicity of prosthetic heart valves without cardiac bypass or the risk of paraplegia in an animal that is extremely sensitive to complete aortic cross-clamp.


Process for the fabrication of complex three-dimensional microcoils in fused silica.
The creation of complex three-dimensional (3D) microcoils has attracted significant attention from both scientific and applied research communities. However, it still remains challenging to build 3D microcoils with arbitrary configurations using conventional planar lithographic fabrication methods. This Letter presents a new facile method based on an improved femtosecond laser wet etch technology and metal microsolidifying process for the fabrication of on-chip complex 3D microcoils inside fused silica. The diameter of the microcoils is about 30 μm, and the effective length of the microchannel is about 13 mm. The aspect ratio of the microcoils can be larger than 400:1, and the microchannel exhibiting good uniformity and smoothness also has good flowability for high-viscosity conductive gallium metal. Based on this approach, we fabricated complex microcoils such as U-shaped and O-shaped microcoils that can be easily integrated into a "lab on a chip" platform or microelectric system inside fused-silica substrate.


Clinical and cost-effectiveness of compression hosiery versus compression bandages in treatment of venous leg ulcers (Venous leg Ulcer Study IV, VenUS IV): a randomised controlled trial.
Drawbacks exist with the standard treatment (four-layer compression bandages) for venous leg ulcers. We have therefore compared the clinical effectiveness and cost-effectiveness of two-layer compression hosiery with the four-layer bandage for the treatment of such ulcers. We undertook this pragmatic, open, randomised controlled trial with two parallel groups in 34 centres in England and Northern Ireland. The centres were community nurse teams or services, family doctor practices, leg ulcer clinics, tissue viability clinics or services, and wound clinics. Participants were aged 18 years or older with a venous leg ulcer and an ankle brachial pressure index of at least 0·8, and were tolerant of high compression. We randomly allocated participants (1:1) to receive two-layer compression hosiery or a four-layer bandage, using a remote randomisation service and prevalidated computer randomisation program. Participants were stratified by ulcer duration and ulcer area with permuted blocks (block sizes four and six). The primary endpoint was time to ulcer healing, with a maximum follow-up of 12 months. Although participants and health-care providers were not masked to treatment allocation, the primary endpoint was measured by masked assessment of photographs. Primary analysis was intention to treat with Cox regression, with adjustment for ulcer area, ulcer duration, physical mobility, and centre. This trial is registered with the ISRCTN register, number ISRCTN49373072. We randomly allocated 457 participants to the two treatment groups: 230 to two-layer hosiery and 227 to the four-layer bandage, of whom 453 (230 hosiery and 223 bandage) contributed data for analysis. Median time to ulcer healing was 99 days (95% CI 84-126) in the hosiery group and 98 days (85-112) in the bandage group, and the proportion of ulcers healing was much the same in the two groups (70·9% hosiery and 70·4% bandage). More hosiery participants changed their allocated treatment (38·3% hosiery vs 27·0% bandage; p=0·02). 300 participants had 895 adverse events, of which 85 (9·5%) were classed as serious but unrelated to trial treatment. Two-layer compression hosiery is a viable alternative to the four-layer bandage-it is equally as effective at healing venous leg ulcers. However, a higher rate of treatment changes in participants in the hosiery group than in the bandage group suggests that hosiery might not be suitable for all patients. NIHR Health Technology Assessment programme (07/60/26).


Lipids in human milk: a review. 1: Sampling, determination, and content.
A protocol for selection of donors of milk samples is presented. Various methods for the sampling of milk are critically reviewed and a tested procedure is described. The measurement of milk volume is reviewed. Analyses for milk lipids are presented and discussed. Results of the analyses relative to various factors affecting fat content are given. Depending upon the type of study, sampling of milk by the Egnell or similar pump is recommended. For field studies, the creamatocrit procedure for estimation of fat content is acceptable if calibrated. Satisfactory research methods are the Roese-Gottlieb, modified Folch, and dry column extractions followed by gravimetry.


Heterogeneous distribution of antithrombin-binding sites in rat brain heparan sulphate proteoglycans.
Heparan sulphates with high binding affinity for antithrombin (HA-HS), labelled in vivo with [35S]sulphate, were extracted from rat brains and purified by chromatography on DEAE-cellulose and on antithrombin-agarose. HA-HS proteoglycans (HA-HSPG) were then separated from HA-HS chains on Sepharose CL-6B. The total HA-HSPG product was rechromatographed on antithrombin-agarose. Six HA-HSPG subfractions with differing degrees of affinity for antithrombin were recovered and treated with NaOH to release their chains. Rechromatography of these six 35S-labelled HS chain preparations on antithrombin-agarose showed that their proportions of chains with no affinity for antithrombin (NA-HS chains) ranged from 36 to 71%. There was a reciprocal relationship between the proportion of NA-HS chains in each HA-HSPG subfraction and the degree of affinity for antithrombin of the rest of its chains (assessed relative to 3H-labelled HA-heparin chains with which they were co-chromatographed). Similar characteristics of antithrombin-binding-site distribution apply to HA-heparin proteoglycans from rat skin studied previously [Horner (1987) Biochem. J. 244, 693-698]. The data suggest that the sites at which 3-O-sulphation of some glucosamine N-sulphate residues occurs in the Golgi complex of brain cells (probably endothelial cells) which synthesize HA-HSPGs (as in mast cells, which synthesize HA-heparin PGs) are distributed sparsely but not randomly.


Alteration of nucleotide metabolism: a new mechanism for mitochondrial disorders.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease caused by loss-of-function mutations in the gene encoding thymidine phosphorylase (TP). TP deficiency alters the metabolism of the nucleosides thymidine and deoxyuridine, which, in turn, produces abnormalities of mitochondrial DNA (mtDNA) including depletion, deletions, and point mutations. MNGIE is the best characterized of the expanding number of mitochondrial disorders caused by alterations in the metabolism of nucleosides/nucleotides. Because mitochondria contain their own machinery for nucleoside and nucleotide metabolism and have physically separate nucleotide pools, it is not surprising that disorders of these pathways cause human diseases. Other diseases in this group include mtDNA depletion syndromes caused by mutations on the nuclear genes encoding the mitochondrial thymidine kinase and deoxyguanosine kinase; autosomal dominant progressive external ophthalmoplegia with multiple deletions of mtDNA due to mutations in the genes encoding the muscle-isoform of mitochondrial ADP/ATP translocator; and mitochondrial DNA depletion due to toxicities of nucleoside analogues. Mutations in the deoxynucleotide carrier, a transporter of deoxynucleoside diphosphates, have been identified as a cause of congenital microcephaly. However, alterations of mtDNA have not yet been established in this disorder. Future studies are likely to reveal additional diseases and provide further insight into this new subject.


Information systems for general practitioners for quality assessment: III. Suggested new prescribing profile.
The information that is supplied to general practitioners by the Prescription Pricing Authority and family practitioner committees has severe limitations if used for self audit of prescribing. We studied the demand for and the extent to which general practitioners would collaborate in developing a system for providing more pertinent information about patterns of personal and practice prescribing. One hundred and eighty two doctors (36% of respondents to a questionnaire) who wished to learn more about their repeat prescribing were invited to help to generate this information and to create profiles of their personal prescribing rates based on a denominator of doctor-patient contacts. Nearly all of them translated intention into participation and also recruited 28 more doctors, since all partners in a practice had to take part. Overall, 202 doctors (40%) took part, 83% of whom participated in the combined study of repeat prescribing and rate of prescribing and 17% in the repeat prescribing exercise only. The examples of the new profiles that are provided show a more accurate representation of personal and practice prescribing patterns, differentiate between face to face contacts and repeat prescriptions, and are likely to stimulate improvements in personal or practice prescribing. We believe that this system should be offered to all practices in the United Kingdom.


Analgesia for forceps delivery.
A forceps delivery may be indicated when a fetus fails to progress to delivery, or when delivery needs to be expedited in the second stage of labour. Effective analgesia is required to ensure that the woman is comfortable throughout the delivery, to allow the obstetrician to safely perform the procedure. It is currently unclear what the most effective and safe agent or method is to provide pain relief during forceps delivery. To assess the effectiveness and safety of different analgesic agents and methods available for forceps delivery for women and their babies. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 July 2013), reviewed published guidelines and searched the reference lists of review articles. Randomised controlled trials comparing an analgesic agent or method used for forceps delivery with placebo/no treatment or an alternative agent or method. Two review authors independently assessed study eligibility, extracted data and assessed the risk of bias of included studies. We included four trials involving 388 women that were judged to be at an unclear to high risk of bias overall. A variety of different agents for providing analgesia were assessed in the trials, and a number of different methods to measure pain relief were used, and thus results could not be combined in meta-analysis. Three trials compared diazepam with an alternative agent (ketamine; vinydan-ether; "other" anaesthesic agent) for the provision of general anaesthesia, and one trial compared spinal analgesia to pudendal nerve block (in both groups lignocaine was administered).With regard to the primary outcomes, women receiving diazepam for forceps delivery in one small trial were more likely to judge their pain relief as effective compared with women receiving vinydan-ether (risk ratio (RR) 1.13; 95% confidence interval (CI) 1.02 to 1.25; 101 women). In a further small trial, no significant difference was seen in the number of women judging their pain relief as effective when diazepam was compared with ketamine (RR 1.42; 95% CI 0.98 to 2.07; 26 women). In the trial that compared spinal analgesia to pudendal nerve block, women receiving spinal analgesia were significantly more likely to regard their analgesia as adequate (RR 3.36; 95% CI 2.46 to 4.60; 183 women) and were less likely to report severe pain during forceps delivery (RR 0.02; 95% CI 0.00 to 0.27; 183 women). No trials reported on the review's other two primary outcomes of serious maternal adverse effects or complications, and neonatal mortality or serious morbidity.In terms of secondary outcomes, women receiving diazepam compared with vinydan-ether, were significantly less likely to experience vomiting (RR 0.04; 95% CI 0.00 to 0.62; 101 women). No significant differences were seen for the few neonatal outcomes that were reported across any of the comparisons (including Agpar score of less than seven at five minutes and acidosis as defined by cord blood arterial pH less than 7.2). There is insufficient evidence to support any particular analgesic agent or method as most effective in providing pain relief for forceps delivery. Neonatal outcomes have largely not been evaluated.


Fetal Overnutrition and Adolescent Hepatic Fat Fraction: the Exploring Perinatal Outcomes in Children Study.
To determine if fetal overnutrition resulting from maternal obesity or gestational diabetes mellitus (GDM) is associated with increased liver fat during adolescence, adjusting for past and current metabolic risk factors. Data come from a historical prospective cohort study (Exploring Perinatal Outcomes in Children) of 254 mother-child pairs in Colorado who participated in 2 research visits at T1 (mean age 10.4, SD = 1.5 years) and at T2 (mean age 16.4, SD = 1.5 years), and had complete exposure and outcome data. Multiple linear regression was used to evaluate the effects of pre-pregnancy body mass index (BMI) and GDM on hepatic fat fraction (HFF) by magnetic resonance imaging at T2. Maternal pre-pregnancy obesity (BMI 30+) was significantly associated (β = 1.59, CI = 0.66, 2.52) with increased HFF relative to mothers with normal pre-pregnancy weight (BMI <25) independent of maternal GDM and sociodemographic factors. Moreover, this association was independent of T2 and T1 metabolic risk factors (acanthosis nigricans, BMI, fasting glucose) (β = 1.03, CI = 0.10, 1.97). Prenatal GDM exposure was not associated with HFF in either unadjusted or adjusted models. Maternal pre-pregnancy obesity was associated with increased HFF in offspring independent of childhood and adolescent adiposity. Intervention studies are needed to test the hypothesis that maternal obesity is a modifiable risk factor for childhood fatty liver disease.


Phosphoproteomic analysis of human mitotic chromosomes identified a chromokinesin KIF4A.
Protein phosphorylation is the prime post-translational modification to drive cell division. Identification of phosphorylated proteins and their related kinases has uncovered molecular networks underlying mitotic processes, including chromosome assembly. Here we aimed to identify phosphoproteins from a mitotic chromosome-enriched lysate biochemically using mass spectrometry. We employed the Polo-box domain (PBD) of Polo-like kinase to tether phosphorylated proteins in the lysate. Resulting candidates included a number of chromosomal proteins that would not be identified unless using chromosome-enriched fractions. Among them, we focused to a chromokinesin KIF4A which becomes concentrated along the longitudinal axis of mitotic condensed chromatids. We found that KIF4A is phosphorylated specifically during mitosis, depending on the activity of Cdk1 and Aurora B, which turned out to be required for KIF4A to interact with condensin I. The molecular link between KIF4A and condensin raises an interesting possibility that the interaction of two distantly related ATPases is triggered by mitotic phosphorylation.


Computational prediction of drug solubility in lipid based formulation excipients.
To investigate if drug solubility in pharmaceutical excipients used in lipid based formulations (LBFs) can be predicted from physicochemical properties. Solubility was measured for 30 structurally diverse drug molecules in soybean oil (SBO, long-chain triglyceride; TGLC), Captex355 (medium-chain triglyceride; TGMC), polysorbate 80 (PS80; surfactant) and PEG400 co-solvent and used as responses during PLS model development. Melting point and calculated molecular descriptors were used as variables and the PLS models were validated with test sets and permutation tests. Solvation capacity of SBO and Captex355 was equal on a mol per mol scale (R (2) = 0.98). A strong correlation was also found between PS80 and PEG400 (R (2) = 0.85), identifying the significant contribution of the ethoxylation for the solvation capacity of PS80. In silico models based on calculated descriptors were successfully developed for drug solubility in SBO (R (2) = 0.81, Q (2) = 0.76) and Captex355 (R (2) = 0.84, Q (2) = 0.80). However, solubility in PS80 and PEG400 were not possible to quantitatively predict from molecular structure. Solubility measured in one excipient can be used to predict solubility in another, herein exemplified with TGMC versus TGLC, and PS80 versus PEG400. We also show, for the first time, that solubility in TGMC and TGLC can be predicted from rapidly calculated molecular descriptors.


Ectopic pregnancy: exploration of its global research architecture using density-equalising mapping and socioeconomic benchmarks.
About 2% of all pregnancies are complicated by the implantation of the zygote outside the uterine cavity and termed ectopic pregnancy. Whereas a multitude of guidelines exists and related research is constantly growing, no thorough assessment of the global research architecture has been performed yet. Hence, we aim to assess the associated scientific activities in relation to geographical and chronological developments, existing research networks and socioeconomic parameters. Retrospective, descriptive study. On the basis of the NewQIS platform, scientometric methods were combined with novel visualising techniques such as density-equalising mapping to assess the scientific output on ectopic pregnancy. Using the Web of Science, we identified all related entries from 1900 to 2012. 8040 publications were analysed. The USA and the UK were dominating the field in regard to overall research activity (2612 and 723 publications), overall citation numbers and country-specific H-Indices (US: 80, UK: 42). Comparison to economic power of the most productive countries demonstrated that Israel invested more resources in ectopic pregnancy-related research than other nations (853.41 ectopic pregnancy-specific publications per 1000 billlion US$ gross domestic product (GDP)), followed by the UK (269.97). Relation to the GDP per capita index revealed 49.3 ectopic pregnancy-specific publications per US$1000 GDP per capita for the USA in contrast to 17.31 for the UK. Semiqualitative indices such as country-specific citation rates ranked Switzerland first (24.7 citations per ectopic pregnancy-specific publication), followed by the Scandinavian countries Finland and Sweden. Low-income countries did not exhibit significant research activities. This is the first in-depth analysis of global ectopic pregnancy research since 1900. It offers unique insights into the global scientific landscape. Besides the USA and the UK, Scandinavian countries and Switzerland can also be regarded as leading nations with regard to their relative socioeconomic input.


Redox-sensitive signaling in inflammatory T cells and in autoimmune disease.
Reactive oxygen species (ROS) are byproducts of oxygen metabolism best known for their damaging potential, but recent evidence has exposed their role as secondary messengers, which regulate cell function through redox-activatable signaling systems. In immune cells, specifically in T cells, redox-sensitive signaling pathways have been implicated in controlling several functional domains; including cell cycle progression, T effector cell differentiation, tissue invasion and inflammatory behavior. T cells from patients with the autoimmune disease rheumatoid arthritis (RA) have emerged as a valuable model system to examine the functional impact of ROS on T cell function. Notably, RA T cells are distinguished from healthy T cells based on reduced ROS production and undergo "reductive stress". Upstream defects leading to the ROSlow status of RA T cells are connected to metabolic reorganization. RA T cells shunt glucose away from pyruvate and ATP production towards the pentose phosphate pathway, where they generate NADPH and consume cellular ROS. Downstream consequences of the ROSlow conditions in RA T cells include insufficient activation of the DNA repair kinase ATM, bypassing of the G2/M cell cycle checkpoint and biased differentiation of T cells into IFN-γ and IL-17-producing inflammatory cells. Also, ROSlow T cells rapidly invade into peripheral tissue due to dysregulated lipogenesis, excessive membrane ruffling, and overexpression of a motility module dominated by the scaffolding protein Tks5. These data place ROS into a pinnacle position in connecting cellular metabolism and protective versus auto-aggressive T cell immunity. Therapeutic interventions for targeted ROS enhancement instead of ROS depletion should be developed as a novel strategy to treat autoimmune tissue inflammation.


The association of acute alcohol use and dynamic suicide risk with variation in onward care after psychiatric crisis.
Despite the association of alcohol use with recurrent suicidal acts, individuals attempting suicide after drinking alcohol face barriers accessing crisis care following emergency assessment, demonstrated by higher odds of inpatient admission for those whose suicide attempt did not feature alcohol. This disparity may be due to suicidality dissipating more rapidly after a suicide attempt involving alcohol. We investigated the effect of acute alcohol use and ongoing suicidality on onward care decisions after emergency assessment. We analysed electronic health records of 650 suicidal adults detained under Section 136 of the Mental Health Act (1983, amended 2007) for up to 36 h at a London psychiatric emergency care centre. We used logistic regression to estimate the association of acute alcohol use and ongoing suicidality (including their interaction) with admission to psychiatric hospital. Fifteen percent of previously intoxicated detainees expressed suicidal intent at detention end, compared to 24% of detainees who had not used alcohol prior to detention. Compared to those who were not previously intoxicated and not suicidal at detention end, acute alcohol use was associated with reduced odds of admission amongst those no longer suicidal (AOR 0.4, 95% CI 0.2, 0.6). Where suicidality persisted, odds of admission rose; however, the magnitude of increase when in combination with prior alcohol use (AOR 3.6, 95% CI 1.9, 7.1) was under half that of when alcohol was not involved (AOR 8.2, 95% CI 3.5, 19.1). Acute alcohol use is associated with transient suicidality, but this only partially accounts for disparities in care following suicide attempts.


Post-transcriptional regulation of human breast cancer cell proteome by unliganded estrogen receptor β via microRNAs.
Estrogen receptor β (ERβ) is a member of the nuclear receptor family of homeostatic regulators that is frequently lost in breast cancer (BC), where its presence correlates with a better prognosis and a less aggressive clinical outcome of the disease. In contrast to ERα, its closest homolog, ERβ shows significant estrogen-independent activities, including the ability to inhibit cell cycle progression and regulate gene transcription in the absence of the ligand. Investigating the nature and extent of this constitutive activity of ERβ in BC MCF-7 and ZR-75.1 cells by means of microRNA (miRNA) sequencing, we identified 30 miRNAs differentially expressed in ERβ+ versus ERβ- cells in the absence of ligand, including up-regulated oncosuppressor miRs such miR-30a. In addition, a significant fraction of >1,600 unique proteins identified in MCF-7 cells by iTRAQ quantitative proteomics were either increased or decreased by ERβ, revealing regulation of multiple cell pathways by ligand-free receptors. Transcriptome analysis showed that for a large number of proteins regulated by ERβ, the corresponding mRNAs are unaffected, including a large number of putative targets of ERβ-regulated miRNAs, indicating a central role of miRNAs in mediating BC cell proteome regulation by ERβ. Expression of a mimic of miR-30a-5p, a direct target and downstream effector of ERβ in BC, led to the identification of several target transcripts of this miRNA, including 11 encoding proteins whose intracellular concentration was significantly affected by unliganded receptor. These results demonstrate a significant effect of ligand-free ERβ on BC cell functions via modulation of the cell proteome and suggest that miRNA regulation might represent a key event in the control of the biological and clinical phenotype of hormone-responsive BC by this nuclear receptor.


Professional identity and sense of coherence affect the between compassion fatigue and work engagement among Chinese hospital nurses.
With the continuous improvement of people's health needs, the public's requirements for medical care are also getting higher and higher. Work engagement is a positive psychological state related to the work. It is very important to maintain nurses' work engagement, however, due to many factors, the level of nurses' work engagement is not high and nursing managers should identify the influencing factors of work engagement, and take positive measures to fully improve nurses' work engagement. To explore the influence of compassion fatigue, professional identity and sense of coherence on nurses' work engagement. From January 2022 to June 2022, convenience sampling was used to select clinical nurses from 9 tertiary hospitals in Henan Province of China as the research objects for a questionnaire survey. Statistical methods included descriptive statistical analysis, Pearson correlation analysis and the PROCESS Macro Model 4 and 7 in regression analysis. The results showed that compassion fatigue was significantly negatively correlated with sense of coherence, professional identity and work engagement (P<0.01), professional identity was significantly positively correlated with sense of coherence and work engagement (P<0.01), and there was a significant positive correlation between sense of coherence and work engagement (P<0.01). Professional identity played a partial mediating role between compassion fatigue and work engagement, accounting for 46.40% of the total effect; meanwhile, sense of coherence moderated the effect of compassion fatigue on professional identity and formed a moderated mediation model. Compassion fatigue has a negative predictive effect on nurses' work engagement. Professional identity and sense of coherence further explained the relationship of compassion fatigue on compassion fatigue and work engagement through mediating and moderating effects.


Environmental distribution of two widespread uncultured freshwater Euryarchaeota clades unveiled by specific primers and quantitative PCR.
Quantitative environmental distribution of two widely distributed uncultured freshwater Euryarchaeota with unknown functional role was explored by newly designed quantitative PCR primers targeting the 16S rRNA gene of clades Miscellaneous Euryarchaeota Group (MEG, containing the groups pMC2A384 and VALII/Eury4) and Deep-Sea Euryarchaeotal Groups (DSEG, targeting the cluster named VALIII containing the DHVE-3/DSEG, BC07-2A-27/DSEG-3 and DSEG-2 groups), respectively. The summer surface plankton of 28 lakes was analysed, and one additional dimictic deep alpine lake, Lake Redon, was temporally and vertically surveyed covering seasonal limnological variability. A trophic range between 0.2 and 5.2 μg l(-1) Chl a, and pH span from 3.8 to 9.5 was explored at altitudes between 632 and 2590 m above sea level. The primers showed to be highly selective with c. 85% coverage and 100% specificity. Only pH significantly explained the changes observed in gene abundances and environment. In Lake Redon, DSEG bloomed in deep stratified waters both in summer and early spring, and MEG at intermediate depths during the ice-cover period. Overall, MEG and DSEG showed a differential ecological distribution although correlational analyses indicated lack of coupling of both Euryarchaeota with phytoplankton (chlorophyll a). However, an intriguing positive and significant relationship was found between DSEG and putative ammonia oxidizing thaumarchaeota.


In vitro effects and in vivo efficacy of a novel cyclooxygenase-2 inhibitor in dogs with experimentally induced synovitis.
To determine cyclooxygenase-2 (COX-2) selectivity, pharmacokinetic properties, and in vivo efficacy of ML-1,785,713 in dogs. 21 healthy male and female mixed-breed dogs and 24 healthy male Beagles. Selectivity of ML-1,785,713 for inhibiting COX-2 was determined by comparing the potency for inhibiting cyclooxygenase-1 (COX-1) with that of COX-2 in canine blood. Pharmacokinetic properties were determined after i.v. (2 mg/kg) and oral (8 mg/kg) administration in female mixed-breed dogs. In vivo efficacy was evaluated in male mixed-breed dogs with urate crystal-induced synovitis. Prophylactic efficacy was evaluated by administering ML-1,785,713 two hours before induction of synovitis whereas therapeutic efficacy was determined by administering ML-1,785,713 one hour after induction of synovitis. Blood concentrations that resulted in 50% inhibition of COX-1 and COX-2 activity in vitro were 119.1 microM and 0.31 microM, respectively, and selectivity ratio for inhibiting COX-2 relative to COX-1 was 384. ML-1,785,713 had high oral bioavailability (101%), low systemic clearance (77 mL/min/kg), and an elimination half-life of 5.9 hours. ML-1,785,713 was efficacious when administered prophylactically and therapeutically to dogs with urate crystal-induced synovitis. ML-1,785,713 is a novel, potent COX-2 inhibitor that is the most selective COX-2 inhibitor described for use in dogs to date. ML-1,785,713 has oral bioavailability and low systemic clearance that is comparable to other non-steroidal anti-inflammatory drugs. It is effective after prophylactic and therapeutic administration in attenuating lameness in dogs with urate crystal-induced synovitis. Drugs that specifically inhibit COX-2 and not COX-1 at therapeutic doses may have an improved tolerability profile, compared with nonselective non-steroidal anti-inflammatory drugs.


Amplification of a cloned Chinese hamster dihydrofolate reductase gene after transfer into a dihydrofolate reductase-deficient cell line.
We have transformed a dihydrofolate reductase (DHFR)-deficient Chinese hamster ovary cell line to the DHFR+ phenotype with a recombinant cosmid (cH1) containing a functional Chinese hamster DHFR gene (J.D. Milbrandt et al., Mol. Cell. Biol. 3:1266-1273, 1983). After exposure of cells to successive increases in methotrexate, we have isolated a resistant cell line (JSH-1) that grows in 1 microM methotrexate. We show here that JSH-1 contains 300 to 500 copies of the integrated cosmid and that these copies are located predominantly at one position on a chromosome identified as Z5a. Hybridization analysis of restriction digests of genomic DNA indicates that the cosmid has been integrated intact into the genome and that upon amplification, the original cosmid/genomic junction fragments are also amplified in JSH-1. Furthermore, the pattern of amplified bands observed in ethidium bromide-stained gels indicates that the unit amplified sequence (amplicon) may be as large as 120 to 135 kilobases and therefore includes considerable amounts of flanking DNA in addition to the 45 kilobases of integrated cosmid. We also show that the protein overproduced by the amplified cosmid in JSH-1 comigrates with the 21,000-dalton polypeptide characteristic of the methotrexate-resistant cell line (CHOC 400) from which cH1 was cloned. However, the DHFR mRNA species overproduced in JSH-1 appear to be larger than those detected in CHOC 400, indicating that not all of the normal transcription and processing signals are preserved in the integrated recombinant cosmid.


Relation between negligent adverse events and the outcomes of medical-malpractice litigation.
We have previously shown that in New York State the initiation of malpractice suits correlates poorly with the actual occurrence of adverse events (injuries resulting from medical treatment) and negligence. There is little information on the outcome of such lawsuits, however. To assess the ability of malpractice litigation to make accurate determinations, we studied 51 malpractice suits to identify factors that predict payment to plaintiffs. Among malpractice claims that we reviewed independently in an earlier study, we identified 51 litigated claims and followed them over a 10-year period to determine whether the malpractice insurer had closed the case. We obtained detailed summaries of the cases from the insurers and reviewed the litigation files if the outcome of a case differed from the outcome predicted in our original review. Of the 51 malpractice cases, 46 had been closed as of December 31, 1995. Among these cases, 10 of 24 that we originally identified as involving no adverse event were settled for the plaintiffs (mean payment, $28,760), as were 6 of 13 cases classified as involving adverse events but no negligence (mean payment, $98,192) and 5 of 9 cases in which adverse events due to negligence were found in our assessment (mean payment, $66,944). Seven of eight claims involving permanent disability were settled for the plaintiffs (mean payment, $201,250). In a multivariate analysis, disability (permanent vs. temporary or none) was the only significant predictor of payment (P=0.03). There was no association between the occurrence of an adverse event due to negligence (P = 0.32) or an adverse event of any type (P=0.79) and payment. Among the malpractice claims we studied, the severity of the patient's disability, not the occurrence of an adverse event or an adverse event due to negligence, was predictive of payment to the plaintiff.


Age and reasons for first dental visit among children in Lagos, Nigeria.
An early first dental clinic appointment offers the prospect of prompt preventative care and parental education regarding the oral health of the child. The evidence-based recommendation by dental professionals all over the world is that a child should visit a dentist before or by 1 year of age. This study aimed to determine the chronological age at and the purpose for a first dental clinic visit amongst children aged 16 years and below attending the Paediatric Dental Clinic at the Lagos University Teaching Hospital (LUTH). This was a retrospective study conducted amongst children who attended the Paediatric Dental Clinic at the LUTH between January 2017 and December 2018. Data on age at first dental visit, reasons for attending and other information relevant to the study were collected. Descriptive statistics and Chi-square analysis were conducted, and the level of significance was set at P < 0.05. A total of 1157 children were studied, comprising 580 (50.5%) males and 577 (49.9%) females. Their mean age on their first dental visit was 7.9 ± 3.7 years. Most of the children (31.4%) had their first dental visits at 7 and 9 years, and 0.8% of the children had their first dental visit below the age of 1 year. The most common reason for visiting the dental clinic was dental pain (33.1%). A higher proportion of the children (911 [79.0%]) had their first dental visit for therapeutic purposes, whereas 246 (21.0%) children visited the dental clinic for preventive care. Sex and age at first dental visit were statistically significantly associated with the reason for attendance (P < 0.001). Most children had their first dental visit between the ages of 7 and 9 years, mainly because of pain. It is necessary to create more awareness among parents/caregivers and to establish the concept of dental home.


Molecular signaling mechanisms of axon-glia communication in the peripheral nervous system.
In this article we discuss the molecular signaling mechanisms that coordinate interactions between Schwann cells and the neurons of the peripheral nervous system. Such interactions take place perpetually during development and in adulthood, and are critical for the homeostasis of the peripheral nervous system (PNS). Neurons provide essential signals to control Schwann cell functions, whereas Schwann cells promote neuronal survival and allow efficient transduction of action potentials. Deregulation of neuron-Schwann cell interactions often results in developmental abnormalities and diseases. Recent investigations have shown that during development, neuronally provided signals, such as Neuregulin, Jagged, and Wnt interact to fine-tune the Schwann cell lineage progression. In adult, the signal exchange between neurons and Schwann cells ensures proper nerve function and regeneration. Identification of the mechanisms of neuron-Schwann cell interactions is therefore essential for our understanding of the development, function and pathology of the peripheral nervous system as a whole.


DAT1 VNTR polymorphisms in a European and an African population: identification of a new allele.
Polymorphism frequencies of the dopamine transporter gene (DAT1) hypervariable region have been analyzed in a sample of Italian and Ivory Coast individuals. The 3' untranslated region (UTR) of DAT1 includes a variable number of tandem repeats (VNTR) of a 40-bp monomer, ranging from 3 to 13 repeats in Caucasian and African populations. In our sample we found alleles with 3 to 16 repeats, and the most common alleles were the 10-repeat (DAT1*10) and the 9-repeat (DAT1*9) alleles. We also found two rare alleles in the Italian population and four in the Ivory Coast population. For the first time the new allele DAT1*16 is described in the Ivorians. The Ivory Coast population was not in Hardy-Weinberg equilibrium for the DAT1 locus because of a deficit of heterozygote genotypes. The observed heterozygosity of the Ivorian population was half that of the Italians. The lower observed heterozygosity and deviation from Hardy-Weinberg equilibrium could be the result of microevolutionary trends, such as genetic drift and/or inbreeding, acting on the relatively small and isolated population sampled for this study, although some sort of selective pressures acting against the shorter alleles cannot be excluded. This evidence, in association with the reduced polymorphism shown by the DAT1 VNTR compared to other VNTRs, seems to indicate that the DAT1 locus may be under some selective pressure.


Mobile in situ obstetric emergency simulation and teamwork training to improve maternal-fetal safety in hospitals.
Evidence from other high-risk industries has demonstrated that teamwork skills can be taught and effective teamwork may improve safety. Increasingly, health care providers, hospital administrators, and quality and safety professionals are considering simulation as a strategy to improve quality and patient safety. A mobile obstetric emergency simulation and team training program was created to bring simulation technology and teamwork training used routinely in other high reliability fields directly to health care institutions. A mobile unit constituted a practical approach, given the expense of simulation equipment, the time required for staff to develop educational materials and simulation scenarios, and the need to have a standardized program to promote consistent evaluation across sites. Between 2007 and 2009, in situ simulation of obstetric emergencies and teamwork training was tested with more than 150 health care professionals in labor and delivery units across four rural and two community hospitals in Oregon. HOW DO ORGANIZATIONS DETERMINE WHICH TYPE OF SIMULATION IS BEST FOR THEM? Because simulation technologies are relatively costly to start and maintain, it can be challenging for hospitals and health care professionals to determine which format (send staff to a simulation center, develop in-house simulation program, develop a consortium of hospitals that run a simulation program, or use a mobile simulation program) is best for them. In situ simulation is an effective way to develop new skills, to maintain infrequently used clinical skills even among experienced clinical teams, and to uncover and address latent safety threats in the clinical setting.


Investigating tumor perfusion and metabolism using multiple hyperpolarized (13)C compounds: HP001, pyruvate and urea.
The metabolically inactive hyperpolarized agents HP001 (bis-1,1-(hydroxymethyl)-[1-(13)C]cyclopropane-d(8)) and urea enable a new type of perfusion magnetic resonance imaging based on a direct signal source that is background-free. The addition of perfusion information to metabolic information obtained by spectroscopic imaging of hyperpolarized [1-(13)C]pyruvate would be of great value in exploring the relationship between perfusion and metabolism in cancer. In preclinical normal murine and cancer model studies, we performed both dynamic multislice imaging of the specialized hyperpolarized perfusion compound HP001 (T(1)=95 s ex vivo, 32 s in vivo at 3 T) using a pulse sequence with balanced steady-state free precession and ramped flip angle over time for efficient utilization of the hyperpolarized magnetization and three-dimensional echo-planar spectroscopic imaging of urea copolarized with [1-(13)C]pyruvate, with compressed sensing for resolution enhancement. For the dynamic data, peak signal maps and blood flow maps derived from perfusion modeling were generated. The spatial heterogeneity of perfusion was increased 2.9-fold in tumor tissues (P=.05), and slower washout was observed in the dynamic data. The results of separate dynamic HP001 imaging and copolarized pyruvate/urea imaging were compared. A strong and significant correlation (R=0.73, P=.02) detected between the urea and HP001 data confirmed the value of copolarizing urea with pyruvate for simultaneous assessment of perfusion and metabolism.


BCL-2 Inhibitor Venetoclax Induces Autophagy-Associated Cell Death, Cell Cycle Arrest, and Apoptosis in Human Breast Cancer Cells.
Venetoclax (VCX) is a selective BCL-2 inhibitor approved for the treatment of leukemia and lymphoma. However, the mechanisms of anti-cancer effect of VCX either as a monotherapy or in combination with other chemotherapeutic agents against breast cancer need investigation. Breast cancer cell lines with different molecular subtypes (MDA-MB-231, MCF-7, and SKBR-3) were treated with different concentrations of VCX for indicated time points. The expression of cell proliferative, apoptotic, and autophagy genes was determined by qRT-PCR and Western blot analyses. In addition, the percentage of MDA-MB-231 cells underwent apoptosis, expressed higher oxidative stress levels, and the changes in the cell cycle phases were determined by flow cytometry. Treatment of human breast cancer cells with increasing concentrations of VCX caused a significant decrease in cells growth and proliferation. This effect was associated with a significant increase in the percentage of apoptotic MDA-MB-231 cells and in the expression of the apoptotic genes, caspase 3, caspase 7, and BAX, with inhibition of anti-apoptotic gene, BCL-2 levels. Induction of apoptosis by VCX treatment induced cell cycle arrest at G0/G1 phase with inhibition of cell proliferator genes, cyclin D1 and E2F1. Furthermore, VCX treatment increased the formation of reactive oxygen species and the expression level of autophagy markers, Beclin 1 and LC3-II. Importantly, these cellular changes by VCX increased the chemo-sensitivity of MDA-MB-231 cells to doxorubicin. The present study explores the molecular mechanisms of VCX-mediated inhibitory effects on the growth and proliferation of TNBC MDA-MB-231 cells through the induction of apoptosis, cell cycle arrest, and autophagy. The study also explores the role of BCL-2 as a novel targeted therapy for breast cancer.


The flexible linker and CotG were more effective for the spore surface display of keratinase KERQ7.
Feather, horn, hoof, and other keratin waste are protein-rich but limited by natural keratinase synthesis, activity, pH, and temperature stability. It is challenging to realize its large-scale application in industries. Bacillus subtilis spores are a safe, efficient, and highly resistant immobilized carrier, which can improve target proteins' resistance. In this research, KERQ7, the keratinase gene of Bacillus tequilensis strain Q7, was fused to the Bacillus subtilis genes coding for the coat proteins CotG and CotB, respectively, and displayed on the surface of B. subtilis spores. Compared with the free KERQ7, the immobilized KERQ7 showed a greater pH tolerance and heat resistance on the spore surface. The activity of CotG-KERQ7 is 1.25 times that of CotB-KERQ7, and CotG-KERQ7 is more stable. When the flexible linker peptide L3 was used to connect CotG and KERQ7, the activity was increased to 131.2 ± 3.4%, and the residual enzyme activity was still 62.5 ± 2.2% after being kept at 60 ℃ for 4 h. These findings indicate that the flexible linker and CotG were more effective for the spore surface display of keratinase to improve stress resistance and promote its wide application in feed, tanning, washing, and other industries.


Meta-EHR: A meta-learning approach for electronic health records with a high imbalanced ratio and missing rate.
Data imbalance is a practical and crucial issue in deep learning. Moreover, real-world datasets, such as electronic health records (EHR), often suffer from high missing rates. Both issues can be understood as noises in data that may lead to bad generalization results for standard deep-learning algorithms. This paper introduces a novel meta-learning approach to deal with these noise issues in an EHR dataset for a binary classification task. This meta-learning approach leverages the information from a selected subset of balanced, low-missing rate data to automatically assign proper weight to each sample. Such weights would enhance the informative samples and suppress the opposites during training. Furthermore, the meta-learning approach is model-agnostic for deep learning-based architectures that simultaneously handle the high imbalanced ratio and high missing rate problems. Through experiments, we demonstrate that this meta-learning approach is better in extreme cases. In the most extreme one, with an imbalance ratio of 172 and a 74.6% missing rate, our method outperforms the original model without meta-learning by as much as 10.3% of the area under the receiver-operating characteristic curve (AUROC) and 3.2% of the area under the precision-recall curve (AUPRC). Our results mark the first step towards training a robust model for extremely noisy EHR datasets.


A pipeline to translate glycosaminoglycan sequences into 3D models. Application to the exploration of glycosaminoglycan conformational space.
Mammalian glycosaminoglycans are linear complex polysaccharides comprising heparan sulfate, heparin, dermatan sulfate, chondroitin sulfate, keratan sulfate and hyaluronic acid. They bind to numerous proteins and these interactions mediate their biological activities. GAG-protein interaction data reported in the literature are curated mostly in MatrixDB database (http://matrixdb.univ-lyon1.fr/). However, a standard nomenclature and a machine-readable format of GAGs together with bioinformatics tools for mining these interaction data are lacking. We report here the building of an automated pipeline to (i) standardize the format of GAG sequences interacting with proteins manually curated from the literature, (ii) translate them into the machine-readable GlycoCT format and into SNFG (Symbol Nomenclature For Glycan) images and (iii) convert their sequences into a format processed by a builder generating three-dimensional structures of polysaccharides based on a repertoire of conformations experimentally validated by data extracted from crystallized GAG-protein complexes. We have developed for this purpose a converter (the CT23D converter) to automatically translate the GlycoCT code of a GAG sequence into the input file required to construct a three-dimensional model.


Cross-species and tissue imputation of species-level DNA methylation samples across mammalian species.
DNA methylation data offers valuable insights into various aspects of mammalian biology. The recent introduction and large-scale application of the mammalian methylation array has significantly expanded the availability of such data across conserved sites in many mammalian species. In our study, we consider 13,245 samples profiled on this array encompassing 348 species and 59 tissues from 746 species-tissue combinations. While having some coverage of many different species and tissue types, this data captures only 3.6% of potential species-tissue combinations. To address this gap, we developed CMImpute (Cross-species Methylation Imputation), a method based on a Conditional Variational Autoencoder, to impute DNA methylation for non-profiled species-tissue combinations. In cross-validation, we demonstrate that CMImpute achieves a strong correlation with actual observed values, surpassing several baseline methods. Using CMImpute we imputed methylation data for 19,786 new species-tissue combinations. We believe that both CMImpute and our imputed data resource will be useful for DNA methylation analyses across a wide range of mammalian species.


Prevention of osteoporosis: cost-effectiveness of different pharmaceutical treatments.
The cost-effectiveness of different pharmaceutical programmes to prevent osteoporosis has been compared. The following pharmaceutical treatments were analysed and compared: calcium supplementation, etidronate and calcitonin. As a benchmark for comparison, oestrogen replacement therapy, in the form of both pills and plaster, was also included in the analysis. The cost-effectiveness of different strategies for particular age groups was analysed. Finally, the cost-effectiveness of population-based prevention programmes was compared with the cost-effectiveness of programmes based on screening followed by treatment of women with low bone mineral density (BMD). A cost-effectiveness analysis (CEA) was carried out. The cost/effectiveness ratio computed was net costs per hip fracture avoided. The evaluation was based on a simulation model in which 1000 women were followed from the age of 50 years. The model was based on Danish epidemiological data and Danish health care cost figures. Assumptions concerning the health effect of the pharmaceutical methods of prevention were based on results from existing studies. As different results have been reported, 'optimistic' and 'pessimistic' alternatives were simulated in the model. The analysis revealed large differences in the cost-effectiveness of different pharmaceutical methods; however, the cost-effectiveness is highly sensitive to the treatment effect assumed. Treatment will be more cost-effective the higher the fracture risk of the group treated, so cost-effectiveness will therefore increase the later in life the intervention takes place, and if only women screened for low BMD are treated. However, the overall effect from a general screening programme will be low and highly sensitive to compliance. As compliance with pharmaceutical treatment seems to be low, and as the effectiveness--and thereby the cost-effectiveness--is encumbered with much uncertainty, prevention of osteoporosis through screening for low BMD should not be recommended at present.


Aqueous Phase Synthesis of Cu2-x S Nanostructures and Their Photothermal Generation Study.
Size- and shape-dependent features of plasmonic nanocrystals govern the development of their applications. In the past decades, gold nanostructures, such as gold nanorods and nanoshells, have been well studied and applied for sensing, bioimaging, and photothermal generation. However, knowledge of copper chalcogenide, a new generation of plasmonic nanomaterials, is limited, especially about their preparation and size- and shape-dependent photothermal properties. In this work, controllable size and shape Cu2-x S nanocrystals (NCs) are synthesized by a facile aqueous route. Using low-molecular-weight polyethylenimine (PEI) as the reducing and capping agents, the size and shape of Cu2-x S NCs can be controlled with lengths from 6.5 to 46.5 nm and the aspect ratio from 2.2 to 7.5 by adjusting the concentration of PEI. The plasmonic peak of Cu2-x S experiences a redshift (from 1145 to 1369 nm) when the length increases from 6.5 to 44.5 nm. Under the irradiation of 1064 nm laser with 1.33 W/cm2, an excellent photothermal conversion rate (from 34.9 to 49.0%) is obtained. The characterization of Cu2-x S NCs is conducted with a UV-vis spectrometer, transmission electron microscopy, powder X-ray diffraction measurements, and 1064 nm laser.


Common Reasons That Asymptomatic Patients Who Are 65 Years and Older Receive Carotid Imaging.
National guidelines do not agree on the role of carotid screening in asymptomatic patients (ie, patients who have not had a stroke or transient ischemic attack). Recently, several physician organizations participating in the Choosing Wisely campaign have identified carotid imaging in selected asymptomatic populations as being of low value. However, the majority of patients who are evaluated for carotid stenosis and subsequently revascularized are asymptomatic. To better understand why asymptomatic patients who undergo revascularization receive initial carotid imaging. Retrospective cohort study of 4127 Veterans Health Administration patients 65 years and older undergoing carotid revascularization for asymptomatic carotid stenosis between 2005 and 2009. Indications for carotid ultrasounds were extracted using trained abstractors. Frequency of indications and appropriateness of initial carotid ultrasound imaging for patients within each rating category after the intervention were reported. The mean (SD) age of this cohort of 4127 patients was 73.6 (5.9) years; 4014 (98.8%) were male. Overall, there were 5226 indications for 4063 carotid ultrasounds. The most common indications listed were carotid bruit (1578 [30.2% of indications]) and follow-up for carotid disease (stenosis/history of carotid disease) in patients who had previously documented carotid stenosis (1087 [20.8% of indications]). Multiple vascular risk factors were the next most common indication listed. Rates of appropriate, uncertain, and inappropriate imaging were 5.4% (227 indications), 83.4% (3387 indications), and 11.3% (458 indications), respectively. Among the most common inappropriate indications were dizziness/vertigo and syncope. Among the 4063 patients, 3373 (83.0%) received a carotid endarterectomy. Overall, 663 procedures were performed in patients 80 years and older. Carotid bruit and follow-up for carotid disease accounted for approximately half of all indications provided by physicians for carotid testing. Strong consideration should be given to improving the evidence base around carotid testing, especially around monitoring stenosis over long periods and evaluating carotid bruits. Targeting carotid ultrasound ordering with decision support tools may also be an important step in reducing use of low-value imaging.


Complete remission of ovarian endometrioid adenocarcinoma associated with hyperamylasemia and liver metastasis treated by paclitaxel and carboplatin chemotherapy: a case report.
Complete remission in the case of a 45-year-old woman with ovarian endometrioid adenocarcinoma associated with hyperamylasemia and liver metastasis is described. Ultrasound examination and CT scan revealed several large solid and cystic intra-abdominal tumors and a metastatic liver tumor. The serum amylase was 600 micro/l (normal value: 60-200 micro/l), and electrophoresis identified isoamylases of the salivary type. A total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed for invasive carcinoma of the left ovary. The histology of the left ovary showed endometrioid adenocarcinoma. Immunohistochemically, the adenocarcinoma cells were diffusely and strongly positive for amylase. The patient received six courses of paclitaxel and carboplatin combination chemotherapy. Two years later, the patient is alive and well, without evidence of disease. The prognosis of patients with ovarian cancer metastatic to the liver is uniformly poor. This represents the first report of complete remission of such a patient in the literature.


HLA-DQ molecules form alpha-beta heterodimers of mixed allotype.
Retroviral vectors with an internal cytomegalovirus major immediate-early gene enhancer/promoter regulating HLA class II gene expression were used to transfer HLA cDNA into human EBV-transformed B-lymphoblastoid cell lines. HLA-DQ2 beta and DQ3.2 beta cDNA were transferred into DQ3.2 and DQ2 homozygous lymphoblastoid cell lines, respectively. Serologic analysis of the infected cell lines with allospecific mAb demonstrated surface expression of these exogenous DQ molecules implying that DQ alpha-chains from DR3, DQ2-positive cells can pair with DQ3.2 beta-chains and, similarly, DQ alpha-chains from DR4, DQ3.2-positive cells can pair with DQ2 beta-chains. Immunoprecipitation of the introduced DQ3.2 beta molecule resulted in co-purification of the allotype-mismatched endogenous DQ2 alpha polypeptide. We also show that vectors with a cytomegalovirus major immediate-early gene enhancer/promoter result in higher levels of expression of the transduced gene compared to previously described HLA vectors with either the SV-40 early enhancer/promoter or the lymphotropic papovavirus-enhanced SV-40 promoter. Although deletion of HLA cDNA did sometimes occur in the process of generating virus-producing clones, the HLA cDNA is stably maintained in virus-producing clones, once it is generated. This retroviral expression system is a highly efficient way to study HLA gene function.


Current utilization, interpretation, and recommendations: the musculoskeletal function assessments (MFA/SMFA).
The development of patient-oriented health status measurements has resulted in the emergence of several generic condition-specific and anatomic-specific instruments. These instruments are generally designed to measure the function of the individual as a whole from the individual's own point of view. They are not intended to replace traditional physician-oriented clinical outcome measures, such as complication rates, ranges of motion, or time to fracture union; instead, they are an attempt to measure the results of a treatment or condition from the patient's perspective. Over the past decade, the Musculoskeletal Function Assessment (MFA) instrument has been developed and used as one of the primary generic musculoskeletal functional assessment tools, in part because of its validity, reliability, and responsiveness. Despite the numerous publications reporting the MFA/SMFA, we are unaware of any publications that have used those results to subsequently affect patient care. We hope that this special interest article highlights the current underutilization of the available data and encourages the orthopedic community to maximize the clinical and research potential of the MFA/SMFA (Short Musculoskeletal Function Assessment).


Amplitude modulation of EPSPs in motoneurons in response to a frequency-modulated train in single la afferent fibers.
In anesthetized cats, single group Ia fibers were activated with a train of 52 stimuli whose interspike intervals were obtained from the discharge of a group Ia fiber in a walking cat (courtesy of Dr. G. E. Loeb, NIH). The EPSPs recorded in motoneurons to which the afferents projected were averaged in register (EPSP1, EPSP2, ..., EPSP52) in response to multiple presentations of the train at a rate (0.77 Hz) similar to the stepping rate of the cat. Amplitudes of these averaged EPSPs were found to be highly variable, depending both on afferent discharge rate and history of activation. The initial EPSP was generally potentiated, and EPSPs in the high-frequency (greater than 200 Hz) middle portion of the train were generally reduced in amplitude. Connections at which the first EPSP was most potentiated tended to be those which showed the most depression of EPSP amplitude during the high-frequency portion of the train. Thus, at some connections, modulation of EPSP amplitude during the frequency-modulated train was much greater than at other connections. In general, the extent of modulation was greater on low-rheobase motoneurons than on high-rheobase motoneurons. We suggest that these differences in transmission permit type S (i.e., low-rheobase) motoneurons, which on average generate the largest EPSPs, to reach threshold at low levels of input (size principle) but prevent excessive depolarization due to temporal summation during high-frequency stimulation.


Ecosystem restoration strengthens pollination network resilience and function.
Land degradation results in declining biodiversity and the disruption of ecosystem functioning worldwide, particularly in the tropics. Vegetation restoration is a common tool used to mitigate these impacts and increasingly aims to restore ecosystem functions rather than species diversity. However, evidence from community experiments on the effect of restoration practices on ecosystem functions is scarce. Pollination is an important ecosystem function and the global decline in pollinators attenuates the resistance of natural areas and agro-environments to disturbances. Thus, the ability of pollination functions to resist or recover from disturbance (that is, the functional resilience) may be critical for ensuring a successful restoration process. Here we report the use of a community field experiment to investigate the effects of vegetation restoration, specifically the removal of exotic shrubs, on pollination. We analyse 64 plant-pollinator networks and the reproductive performance of the ten most abundant plant species across four restored and four unrestored, disturbed mountaintop communities. Ecosystem restoration resulted in a marked increase in pollinator species, visits to flowers and interaction diversity. Interactions in restored networks were more generalized than in unrestored networks, indicating a higher functional redundancy in restored communities. Shifts in interaction patterns had direct and positive effects on pollination, especially on the relative and total fruit production of native plants. Pollinator limitation was prevalent at unrestored sites only, where the proportion of flowers producing fruit increased with pollinator visitation, approaching the higher levels seen in restored plant communities. Our results show that vegetation restoration can improve pollination, suggesting that the degradation of ecosystem functions is at least partially reversible. The degree of recovery may depend on the state of degradation before restoration intervention and the proximity to pollinator source populations in the surrounding landscape. We demonstrate that network structure is a suitable indicator for pollination quality, highlighting the usefulness of interaction networks in environmental management.


Effects of pindolol and propranolol on beta adrenergic receptors on human lymphocytes.
The cardiovascular supersensitivity observed after discontinuation of administration of beta adrenergic receptor antagonists may be explained by an increase in the density of beta adrenergic receptors. Thus, a change in the density of receptors has been observed in human lymphocytes after administration of propranolol (Aarons et al., 1980). The effects of pindolol, a beta adrenergic receptor antagonist with intrinsic sympathomimetic activity, were compared with those of propranolol or placebo. Pindolol (10 mg q.i.d.), propranolol (40 mg q.i.d.) or placebo were administered to 12 subjects for 8 days. The density of beta adrenergic receptors was determined by Scatchard analysis of the specific binding of [125I]iodopindolol on membranes prepared from human lymphocytes. Administration of pindolol resulted in a 30 to 50% decrease in the density of beta adrenergic receptors. This decrease was apparent within 1 day of beginning pindolol administration and it persisted for at least 8 days after discontinuation of drug administration. The reversibility of the decrease in receptors observed after pindolol administration was studied in 27 subjects given propranolol, pindolol or placebo for 4 days in a double-blind cross-over trial. Propranolol consistently induced a small increase in the density of beta adrenergic receptors. The density of receptors returned to predrug values within 2 days after discontinuation of propranolol administration. Pindolol induced a 30 to 50% decrease in the density of receptors which, as observed previously, persisted for at least 10 days after discontinuation of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)


Poly[bis-(μ-2-amino-4-nitro-benzoato)di-μ-aqua-dirubidium].
In the structure of the title salt, [Rb2(C7H5N2O4)2(H2O)2] n , the asymmetric unit comprises two independent and different seven-coordinate Rb(+) cations, one forming an RbO7 polyhedron, the other a RbO6N polyhedron, each of which is considerably distorted. The RbO7 polyhedron comprises bridging O-atom donors from two water mol-ecules, three carboxyl-ate groups, and two nitro groups. The RbO6N polyhedron comprises the two bridging water mol-ecules, one monodentate amine N-atom donor, one carboxyl O-atom donor and three O-atom donors from nitro groups (one from the chelate bridge). The extension of the dinuclear unit gives a three-dimensional polymeric structure which is stabilized by both intra- and inter-molecular amine N-H⋯O and water O-H⋯O hydrogen bonds to carboxyl and water O-atom acceptors, as well as a number of inter-ring π-π inter-actions [minimum centroid-centroid separation = 3.364 (2) Å]. The title salt is isostructural with the analogous caesium salt.


Echocardiography of Right Ventriculoarterial Coupling Combined With Cardiopulmonary Exercise Testing to Predict Outcome in Heart Failure.
Pulmonary hypertension, which is related to right ventricular (RV) failure, indicates a poor prognosis in heart failure (HF). Increased ventilatory response and exercise oscillatory ventilation (EOV) also have a negative impact. We hypothesized that the severity classification of HF and risk prediction could be improved by combining functional capacity with cardiopulmonary exercise testing (CPET) and RV-pulmonary circulation coupling, as evaluated by the tricuspid annular plane systolic excursion (TAPSE)-pulmonary artery systolic pressure (PASP) relationship. Four hundred fifty-nine patients with HF were assessed with Doppler echocardiography and CPET and were tracked for outcome. The subjects were followed for major cardiac events (cardiac mortality, left ventricular assist device implant, or heart transplant). Cox regression and Kaplan-Meier analyses were performed with TAPSE and PASP as individual measures that were then combined into a ratio form. The TAPSE/PASP ratio (TAPSE/PASP) was the strongest predictor, whereas the New York Heart Association classification and EOV added predictive value. A four-quadrant group prediction risk was created based on TAPSE (< 16 mm or ≥ 16 mm) vs PASP (< 40 mm Hg or ≥ 40 mm Hg) thresholds and the CPET variables distribution as follows: group A (TAPSE > 16 mm and PASP < 40 mm Hg) presented the lowest risk (hazard ratio, 0.17) and best ventilation; group B exhibited a low risk (hazard ratio, 0.88) with depressed TAPSE (< 16 mm) and normal PASP, a preserved peak oxygen consumption (V.o2), but high ventilation. Group C had an increased risk (hazard ratio, 1.3; TAPSE ≥ 16 mm, PASP ≥ 40 mm Hg), a reduced peak V.o2, and a high EOV prevalence. Group D had the highest risk (hazard ratio, 5.6), the worse RV-pulmonary pressure coupling (TAPSE < 16 and PASP ≥ 40 mm Hg), the lowest peak V.o2, and the highest EOV rate. TAPSE/PASP, combined with exercise ventilation, provides relevant clinical and prognostic insights into HF. A low TAPSE/PASP with EOV identifies patients at a particularly high risk of cardiac events.


Necrotizing fasciitis in a woman with a diabetic foot infection and peripheral neuropathy.
We report the case of a 62-year-old African American woman with poorly controlled diabetes who presented with the complaint of not being able to remove her stockings from her left foot. The patient had long-standing peripheral neuropathy from diabetes. Her physical examination in the emergency department was challenging because of extensive infection in her left lower extremity. Careful removal of the stockings resulted in the debridement of the lower third of her left leg and entire foot. Her laboratory findings were notable for a white blood cell count of 11.7 x 10(3) cells/mm(3) with 18% bands, an erythrocyte sedimentation rate of 100 mm/hour, and glycated hemoglobin of 11.5%. This case is unique in that the patient presented with both wet and dry gangrene of her lower extremities. We discuss the spectrum of infectious processes in diabetic foot infections and discuss the management of patients with necrotizing fasciitis.


Histopathological Effects of Titanium Dioxide Nanoparticles and The Possible Protective Role of N-Acetylcysteine on The Testes of Male Albino Rats.
Titanium dioxide (TiO2) is a white pigment which is used in paints, plastics, etc. It is reported that TiO2 induces oxidative stress and DNA damage. N-acetylcysteine (NAC) has been used to fight oxidative stress-induced damage in different tissues. The objective of this study was to evaluate the toxic effects of orally administered TiO2 nanoparticles and the possible protective effect of NAC on the testes of adult male albino rats. In this experimental study, 50 adult male albino rats were classified into five groups. Group I was the negative control, group II was treated with gum acacia solution , group III was treated with NAC, group IV was treated with TiO2 nanoparticles, and group V was treated with 100 mg/kg of NAC and 1200 mg/kg TiO2 nanoparticles. Total testosterone, glutathione (GSH), and serum malondialdehyde (MDA) levels were estimated. The testes were subjected to histopathological, electron microscopic examinations, and immunohistochemical detection for tumor necrosis factor (TNF)-α. Cells from the left testis were examined to detect the degree of DNA impairment by using the comet assay. TiO2 nanoparticles induced histopathological and ultrastructure changes in the testes as well as positive TNF-α immunoreaction in the testicular tissue. Moreover, there was an increase in serum MDA while a decrease in testosterone and GSH levels in TiO2 nanoparticles-treated group. TiO2 resulted in DNA damage. Administration of NAC to TiO2- treated rats led to improvement of the previous parameters with modest protective effects against DNA damage. TiO2-induced damage to the testes was mediated by oxidative stress. Notably, administration of NAC protected against TiO2's damaging effects.


Sex differences in forearm vasoconstrictor response to voluntary apnea.
Clinical evidence indicates that obstructive sleep apnea is more common and more severe in men compared with women. Sex differences in the vasoconstrictor response to hypoxemia-induced sympathetic activation might contribute to this clinical observation. In the current laboratory study, we determined sex differences in the acute physiological responses to maximal voluntary end-expiratory apnea (MVEEA) during wakefulness in healthy young men and women (26 ± 1 yr) as well as healthy older men and women (64 ± 2 yr). Mean arterial pressure (MAP), heart rate (HR), brachial artery blood flow velocity (BBFV, Doppler ultrasound), and cutaneous vascular conductance (CVC, laser Doppler flowmetry) were measured, and changes in physiological parameters from baseline were compared between groups. The breath-hold duration and oxygen-saturation nadir were similar between groups. In response to MVEEA, young women had significantly less forearm vasoconstriction compared with young men (ΔBBFV: 2 ± 7 vs. -25 ± 6% and ΔCVC: -5 ± 4 vs. -31 ± 4%), whereas ΔMAP (12 ± 2 vs. 16 ± 3 mmHg) and ΔHR (4 ± 2 vs. 6 ± 3 bpm) were comparable between groups. The attenuated forearm vasoconstriction in young women was not observed in postmenopausal women (ΔBBFV -21 ± 5%). We concluded that young women have blunted forearm vasoconstriction in response to MVEEA compared with young men, and this effect is not evident in older postmenopausal women. These data suggest that female sex hormones dampen neurogenic vasoconstriction in response to apnea-induced hypoxemia.


An Epithelioid Gastrointestinal Stromal Tumor of the Stomach With Strong Expression of Keratin: Clinicopathologic Correlation and Follow-up Post-Imatinib Therapy.
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasms of the digestive tract. They are relatively rare neoplasms compared with gastrointestinal carcinomas and usually can readily be differentiated from carcinomas based on the morphology of the neoplastic cells that are typically spindled (70%), pure epithelioid, or mixed type. GISTs in general lack expression of cytokeratin and exhibit immunoreactivity toward CD117, CD34, or DOG1. GISTs can demonstrate a pure epithelioid morphology that can appear similar histologically to a carcinoma. Very few epithelioid GISTs have been reported to express cytokeratin, which can lead to diagnostic challenges especially in cases with pure epithelioid morphology. Epithelioid GISTs should be considered in the differential diagnosis when evaluating gastrointestinal neoplasms with overlapping epithelioid and carcinoma-like morphology. An accurate diagnosis can be made using additional immunohistochemical studies directed against CD117, CD34, or DOG1. Advanced investigations such as mutation analysis of KIT using molecular pathology methods can further assist in confirming the diagnosis.


Validation of a Novel Telehealth Administration Protocol for the NIH Toolbox-Cognition Battery.
Cognition is an important outcome in many clinical trials. The NIH Toolbox-Cognition Battery (NIHTB-CB) is a computerized cognitive assessment designed for clinical research that is administered in-person. Here, we evaluated the equivalency of a novel videoconference protocol for administering the NIHTB-CB. Since our protocol required repeated assessments, we further explored the NIHTB-CB's practice effect. Twenty-five healthy participants completed the NIHTB-CB under two separate conditions 4 weeks apart. The standard condition followed the recommended administration protocol, whereas the videoconference condition had the examiner and participant in separate rooms but able to communicate over videoconference. A linear mixed-model analysis was performed to explore the fixed effect of testing condition and time on NIHTB-CB performance. Across all three NIHTB-CB composite scores (total, fluid, and crystallized cognition), no significant fixed effect of administration condition was found. A significant practice effect was observed for the fluid and total cognition composite scores over a 29.0 (±2.1) day test-retest interval. Our novel videoconference protocol for the NIHTB-CB is equivalent to the standard protocol in healthy participants, and may provide a solution for researchers seeking to engage study participants at remote sites. If the NIHTB-CB is used longitudinally to monitor patients, corrections for repeated measures may be required.


To estimate prostate cancer (PC) survival in Mexico and explore survival disparities according to the marginalization level of residence place. A nationwide administrative claims database (4 110 men) whose PC treatment was financed by Seguro Popular between 2012-2016, was cross-linked to the National Mortality Registry up to December 2019. Patients were classified according to their oncological risk at diagnosis and the marginalization level of the residence municipality. Cox proportional hazards regression was used to estimate multivariable survival functions. Five-years PC survival (69%; 95%CI: 68,71%) ranged from 72% to 54% at very low and very high marginalization, respectively (p for trend<0.001). The lowest PC survival was observed in men with high-risk PC (47%; 95%CI: 33,66%) residents in very high marginalization municipalities. Overall, PC survival was lower than that reported in other Latin American countries. The distribution of oncologic risk and survival differences across marginalization levels suggests limited early detection and cancer health disparities.