From Marine Venoms to Drugs: Efficiently Supported by a Combination of Transcriptomics and Proteomics.
The potential of marine natural products to become new drugs is vast; however, research is still in its infancy. The chemical and biological diversity of marine toxins is immeasurable and as such an extraordinary resource for the discovery of new drugs. With the rapid development of next-generation sequencing (NGS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), it has been much easier and faster to identify more toxins and predict their functions with bioinformatics pipelines, which pave the way for novel drug developments. Here we provide an overview of related bioinformatics pipelines that have been supported by a combination of transcriptomics and proteomics for identification and function prediction of novel marine toxins.


Diversity in the weapons of sexual selection: horn evolution in the beetle genus Onthophagus (Coleoptera: Scarabaeidae).
Both ornaments and weapons of sexual selection frequently exhibit prolific interspecific diversity of form. Yet, most studies of this diversity have focused on ornaments involved with female mate choice, rather than on the weapons of male competition. With few exceptions, the mechanisms of divergence in weapon morphology remain largely unexplored. Here, we characterize the evolutionary radiation of one type of weapon: beetle horns. We use partial sequences from four nuclear and three mitochondrial genes to develop a phylogenetic hypothesis for a worldwide sample of 48 species from the dung beetle genus Onthophagus (Coleoptera: Scarabaeidae). We then use these data to test for multiple evolutionary origins of horns and to characterize the evolutionary radiation of horns. Although our limited sampling of one of the world's most species-rich genera almost certainly underestimates the number of evolutionary events, our phylogeny reveals prolific evolutionary lability of these exaggerated sexually selected weapons (more than 25 separate gains and losses of five different horn types). We discuss these results in the context of the natural history of these beetles and explore ways that sexual selection and ecology may have interacted to generate this extraordinary diversity of weapon morphology.


Deagrarianisation and forest revegetation in a biodiversity hotspot on the Wild Coast, South Africa.
Deagraianisation is a worldwide phenomenon with widespread social, ecological and economic effects yet with little consensus on the local or higher level causes. There have been contested views on the causes and consequences of deagrarianisation on South Africa's Wild Coast, which is an international biodiversity hotspot. Using GIS, household interviews and ecological sampling, we compared the perspectives of current and former cultivators as to why some have abandoned farming, whilst also tracking the uses and woody plant cover and composition of fields abandoned at different periods. The GIS analysis showed that field abandonment had been ongoing over several decades, with a decline from 12.5 % field cover in 1961 to 2.7 % in 2009. The area of forests and woodlands almost doubled in the corresponding period. There was a distinct peak in field abandonment during the time of political transition at the national level in the early 1990 s. This political change led to a decrease in government support for livestock farming, which in turn resulted in reduced animal draught power at the household and community level, and hence reduced cropping. The study showed it is largely the wealthier households that have remained in arable agriculture and that the poorer households have abandoned farming. The abandoned fields show a distinct trend of increasing woody biomass and species richness with length of time since abandonment, with approximately three woody plant species added per decade. Most local respondents dislike the increases in forest and woodland extent and density because of anxiety about wild animals causing harm to crops and even humans, and the loss of an agricultural identity to livelihoods and the landscape.


Structural basis of GLUT1 inhibition by cytoplasmic ATP.
Cytoplasmic ATP inhibits human erythrocyte glucose transport protein (GLUT1)-mediated glucose transport in human red blood cells by reducing net glucose transport but not exchange glucose transport (Cloherty, E.K., D.L. Diamond, K.S. Heard, and A. Carruthers. 1996. Biochemistry. 35:13231-13239). We investigated the mechanism of ATP regulation of GLUT1 by identifying GLUT1 domains that undergo significant conformational change upon GLUT1-ATP interaction. ATP (but not GTP) protects GLUT1 against tryptic digestion. Immunoblot analysis indicates that ATP protection extends across multiple GLUT1 domains. Peptide-directed antibody binding to full-length GLUT1 is reduced by ATP at two specific locations: exofacial loop 7-8 and the cytoplasmic C terminus. C-terminal antibody binding to wild-type GLUT1 expressed in HEK cells is inhibited by ATP but binding of the same antibody to a GLUT1-GLUT4 chimera in which loop 6-7 of GLUT1 is substituted with loop 6-7 of GLUT4 is unaffected. ATP reduces GLUT1 lysine covalent modification by sulfo-NHS-LC-biotin by 40%. AMP is without effect on lysine accessibility but antagonizes ATP inhibition of lysine modification. Tandem electrospray ionization mass spectrometry analysis indicates that ATP reduces covalent modification of lysine residues 245, 255, 256, and 477, whereas labeling at lysine residues 225, 229, and 230 is unchanged. Exogenous, intracellular GLUT1 C-terminal peptide mimics ATP modulation of transport whereas C-terminal peptide-directed IgGs inhibit ATP modulation of glucose transport. These findings suggest that transport regulation involves ATP-dependent conformational changes in (or interactions between) the GLUT1 C terminus and the C-terminal half of GLUT1 cytoplasmic loop 6-7.


[Postnatal mortality in Brazilian territory: a literature review].
This is a systematic review regarding postnatal mortality, covering the period between 2004 and 2009. The objective was to identify how the causes of death and the relationship with socioeconomic conditions are stated in the literature. Twenty-seven articles were selected, 74.4% of which were published in public health journals, with 66.7% having an ecological study design. Nearly all articles addressed cause groups and their components (66.7%), followed by the remaining third, which addressed the identification of the determinant factors of the deaths. The Southeast region produced over 37% of the studies. In most Brazilians cities and states, there was a reduction of deaths by more than 50% by the end of the 1900s. Among the cause of death groups, the diarrhea-pneumonia group was predominant, followed by congenital abnormalities. The basic life conditions according to socioeconomic indicators - housing, basic sanitation, education, and accessibility to health - were determinants for the highest postnatal death rates due to reducible causes.


Environmental risk, precaution, and scientific rationality in the context of WTO/NAFTA trade rules.
This article considers the role of scientific rationality in understanding statements of risk produced by a scientific community. An argument is advanced that, while scientific rationality does impose constraints on valid scientific justifications for restrictions on products and practices, it also provides flexibility in the judgments needed to both develop and apply characterizations of risk. The implications of this flexibility for the understanding of risk estimates in WTO and NAFTA deliberations are explored, with the goal of finding an intermediate ground between the view that science unambiguously justifies or rejects a policy, and the view that science is yet another cultural tool that can be manipulated in support of any decision. The result is a proposal for a dialogical view of scientific rationality in which risk estimates are depicted as confidence distributions that follow from a structured dialogue of scientific panels focused on judgments of evidence, evidential reasoning, and epistemic analysis.


Tension-Band Wire Fixation of Olecranon Fractures.
Olecranon fractures account for approximately 20% of fractures of the proximal part of the forearm1. Clinicians may consider nonoperative management for elderly low-demand patients2, whereas operative fixation is recommended for active patients with a displaced fracture. Tension-band wire (TBW) fixation is commonly employed for simple isolated stable displaced fractures of the olecranon (type IIA according to the Mayo classification)3-5. In contrast, plate fixation is thought to provide superior outcomes for unstable comminuted olecranon fractures. Biomechanical principles of the TBW construct are based on the hypotheses of absolute fracture stability, exploiting functional limb movement, and converting tensile forces into compression through the actions of the triceps and brachialis. The surgical goals are to restore articular congruity, provide stable reliable fixation, and allow early mobilization to minimize joint stiffness. In a recent prospective randomized trial comparing plate fixation with TBW in 67 active adult patients, we found no difference between groups with respect to either patient or surgeon-reported outcome measures6. The overall complication rate was higher following TBW fixation, with implant removal required for 1 in 2 patients. However, it may still be the preferable procedure given that the more serious issues of infection and revision surgery occurred exclusively following plate fixation. The key steps of the procedure are (1) preoperative planning with careful assessment of radiographs; (2) positioning the patient supine and gaining exposure with a posterior longitudinal direct midline incision, raising lateral and medial fasciocutaneous flaps, and developing subperiosteal dissection in the interval between the flexor carpi ulnaris and extensor carpi ulnaris to visualize the fracture; (3) visual reduction maintained with a pointed reduction clamp, with joint congruity confirmed with an image intensifier if needed; (4) creation of the TBW construct with 2 parallel 1.6-mm Kirschner wires passed longitudinally from the proximal fragment into the distal part of the ulna, engaging the anterior cortex with care, and a 1.2-mm flexible cerclage wire placed through a transverse tunnel 3 to 4 cm distal to the fracture, passed posterior to the 2 Kirschner wires, and secured in a figure-of-8 configuration; (5) appropriate tensioning of the construct followed by trimming and burial of the wire ends; (6) layered wound closure according to surgeon preference; and (7) a postoperative protocol consisting of application of an above-the-elbow synthetic bandage, which is worn for 10 to 14 days, and gentle active mobilization under physiotherapy supervision. We advise against heavy lifting for at least 6 to 8 weeks and do not routinely remove implants unless they are symptomatic.


Risk stratification of prostate cancer in the modern era.
Novel tools have become available to the practicing urologist in recent years that endeavor to improve on commonly utilized prostate cancer (PCa) risk-stratification techniques. In this review, we provide an overview of these modalities in the context of active surveillance. Multiparametric MRI (MP-MRI) has a rapidly growing body of evidence that suggests it provides the necessary sensitivity and negative predictive value to rule out clinically significant disease. MRI-guided targeted biopsy has the potential to improve detection of clinically significant cancers and for rebiopsy of patients with continued suspicion for PCa. Prostate-specific antigen isoforms and Prostate Health Index outperform PSA alone and improve risk stratification when combined with the established criteria, but need further prospective studies using template and MRI-targeted biopsies. Urinary biomarkers tend to fall short in predicting adverse pathology when used alone, but improve risk stratification when used in conjunction and with the established criteria. Finally, tissue biomarkers and gene assays allow patient-specific molecular and genetic characterization of cancer phenotype, showing significant promise in predicting adverse pathology, and in some cases have already been incorporated into and altered clinical practice. These novel modalities show remarkable promise in improving the risk stratification of patients with PCa, and as the body of evidence grows will likely become incorporated into major oncologic guidelines and standard urologic practice. Further prospective clinical studies are needed, as well as analysis of cost-effectiveness.


NDRC: A Disease-Causing Genes Prioritized Method Based on Network Diffusion and Rank Concordance.
Disease-causing genes prioritization is very important to understand disease mechanisms and biomedical applications, such as design of drugs. Previous studies have shown that promising candidate genes are mostly ranked according to their relatedness to known disease genes or closely related disease genes. Therefore, a dangling gene (isolated gene) with no edges in the network can not be effectively prioritized. These approaches tend to prioritize those genes that are highly connected in the PPI network while perform poorly when they are applied to loosely connected disease genes. To address these problems, we propose a new disease-causing genes prioritization method that based on network diffusion and rank concordance (NDRC). The method is evaluated by leave-one-out cross validation on 1931 diseases in which at least one gene is known to be involved, and it is able to rank the true causal gene first in 849 of all 2542 cases. The experimental results suggest that NDRC significantly outperforms other existing methods such as RWR, VAVIEN, DADA and PRINCE on identifying loosely connected disease genes and successfully put dangling genes as potential candidate disease genes. Furthermore, we apply NDRC method to study three representative diseases, Meckel syndrome 1, Protein C deficiency and Peroxisome biogenesis disorder 1A (Zellweger). Our study has also found that certain complex disease-causing genes can be divided into several modules that are closely associated with different disease phenotype.


The Combination of a Human Biomimetic Liver Microphysiology System with BIOLOGXsym, a Quantitative Systems Toxicology (QST) Modeling Platform for Macromolecules, Provides Mechanistic Understanding of Tocilizumab- and GGF2-Induced Liver Injury.
Biologics address a range of unmet clinical needs, but the occurrence of biologics-induced liver injury remains a major challenge. Development of cimaglermin alfa (GGF2) was terminated due to transient elevations in serum aminotransferases and total bilirubin. Tocilizumab has been reported to induce transient aminotransferase elevations, requiring frequent monitoring. To evaluate the clinical risk of biologics-induced liver injury, a novel quantitative systems toxicology modeling platform, BIOLOGXsym™, representing relevant liver biochemistry and the mechanistic effects of biologics on liver pathophysiology, was developed in conjunction with clinically relevant data from a human biomimetic liver microphysiology system. Phenotypic and mechanistic toxicity data and metabolomics analysis from the Liver Acinus Microphysiology System showed that tocilizumab and GGF2 increased high mobility group box 1, indicating hepatic injury and stress. Tocilizumab exposure was associated with increased oxidative stress and extracellular/tissue remodeling, and GGF2 decreased bile acid secretion. BIOLOGXsym simulations, leveraging the in vivo exposure predicted by physiologically-based pharmacokinetic modeling and mechanistic toxicity data from the Liver Acinus Microphysiology System, reproduced the clinically observed liver signals of tocilizumab and GGF2, demonstrating that mechanistic toxicity data from microphysiology systems can be successfully integrated into a quantitative systems toxicology model to identify liabilities of biologics-induced liver injury and provide mechanistic insights into observed liver safety signals.


Limits of learning enhancements with nicotine in old male rats.
Findings with young adult humans and animal models suggest that nicotine may serve both neuroprotective and cognition enhancing roles in old animals. A pair of experiments was conducted to examine drug-induced modification of the cholinergic nicotinic receptor subtype on rates of learning by young and aged rats. In experiment I males (4-7 months or 20-25 months old) were administered nicotine (0.0, 0.3 or 0.7 mg/kg injected s.c. daily) and tested in both a T-maze non-spatial discrimination paradigm and a hole board spatial task. Nicotine failed to improve acquisition by young animals on either task. Nicotine also failed to improve non-spatial learning by old animals. However, both dosages of nicotine improved performance by the old males in the spatial paradigm. In experiment II, a 5-choice serial discrimination paradigm designed to better evaluate visual attention and spatial working memory in aging was used. Groups of old male rats were administered nicotine or mecamylamine (2 or 8 mg/kg), an antagonist of the nicotinic cholinergic receptor. Results were that the 0.3 mg nicotine group learned the task fastest and achieved the highest learning asymptote. Both learning rates and final levels of performance were worst in the 8 mg mecamylamine group. However, the 2 mg mecamylamine rats were the equals of the control group and both reached a higher asymptote than the 0.7 mg nicotine group. These data suggest that healthy old animals can accrue benefits from nicotinic activation but that the benefits are complex, being limited to certain dosages and to specific cognitive skills.


In vitro susceptibility and cross-resistance of South African isolates of Neisseria gonorrhoeae to 14 antimicrobial agents.
One hundred isolates of Neisseria gonorrhoeae obtained from patients attending clinics in Johannesburg, South Africa, were tested by a broth dilution technique for their minimal inhibitory concentrations (MICs) of benzyl penicillin G, ampicillin, cefoxitin, cefuroxime, cefotaxime, ceftriaxone, ceftazidime, tetracycline, minocycline, doxycycline, spectinomycin, rosaramicin, chloramphenicol, and rosoxacin. None of the isolates tested produced beta-lactamase. The MICs of penicillin ranged from less than or equal to 0.007 to 0.5 micrograms/ml. The isolates were also very susceptible to rosaramicin (minimal concentration at which 50% of isolates were inhibited [MIC50] = 0.02 micrograms/ml) and to the new cephalosporins (cefotaxime MIC50 less than 0.007 micrograms/ml, ceftriaxone MIC50 less than 0.007 micrograms/ml, and ceftazidime MIC50 less than 0.007 micrograms/ml). By using regression analysis, good correlation was observed between the MICs of penicillin and those of the other agents, with the exception of ceftriaxone, spectinomycin, and rosaramicin. The MICs and the minimal bactericidal concentrations were within a log2 concentration of each other.


Allocation of resources for ambulatory care -a staffing model for outpatient clinics.
The enormous commitment of resources to ambulatory health care services requires that flexible and easily implementable management techniques be developed to improve the allocation of health manpower and funds. This article develops a feasible model for staffing outpatient clinics and thereby potentially provides an important analytical tool for allocating and monitoring the utilization of the most critical and expensive of ambulatory care resources-professional and nonprofessional clinic personnel. The model is simplistic, extremely flexible, and can be applied to many modes of delivering ambulatory care-from HMOs to traditional hospital outpatient clinics. To employ the model, certain decision variables must be specified so that the model can produce a least-cost staffing configuration to meet the demand for service in accordance with the desired mode and intensity of care. The key decision varables that require input from administrators and medical personnel include standards for physician-patient contact time, a desired ratio of staff time actually spent treating patients to total paid staff time, and the desired mix of various staff categories to achieve program objectives. Specific benefits of using the model include determining staffing for new, expanded, or existing outpatient clinics, determining budget requirements for such staffing needs, and providing quantitative productivity and utilization objectives and measurements.


The initiation of failure in cemented femoral components of hip arthroplasties.
We studied 16 femora retrieved at post-mortem from symptomless patients who had a satisfactory cemented total hip arthroplasty from two weeks to 17 years earlier, with the aim of delineating the initial mechanisms involved in loosening. Only one specimen showed radiographic evidence of loosening; the other 15 were stable to mechanical testing at 17.0 Nm of torque. In all 16 specimens, the cement-bone interface was intact with little fibrous tissue formation. By contrast, separation at the cement-prosthesis interface and fractures in the cement mantle were frequent. The most common early feature was debonding of the cement from the metal, seen at the proximal and distal ends of the prosthesis. Specimens which had been in place for longer also showed circumferential fractures in the cement, near the cement-metal interface, and radial fractures extending from this interface into the cement and sometimes to the bony interface. The most extensive cement fractures appeared to have started at or near sharp corners in the metal, or where the cement mantle was thin or incomplete. Fractures were also related to voids in the cement. The time relationship in this series suggested that long-term failure of the fixation of cemented femoral components was primarily mechanical, starting with debonding at the interface between the cement and the prosthesis, and continuing as slowly developing fractures in the cement mantle.


[The transitional survivorship in breast cancer: a narrative review].
This paper presents a review undertaken to explore the experiences of patients and families in the transition to breast cancer survivorship. The "transitional survivorship" is defined as the period immediately after the end of treatment. During this period, breast cancer survivors aim to return to their "new normality", but this time can be full of physical, emotional and social challenges for which the women may not feel prepared. A narrative review was conducted in the databases MEDLINE, CINAHL, PSYCHINFO and CancerLit for the period 2000-2010. The search terms "breast cancer", "transition", "survivorship", "family: and "experience" were combined. The main emerging categories that explained the experiences of breast cancer survivors during the "transitional survivorship" were "new normality", the sense of loss, uncertainty about the future, loneliness and self-transcendence. . This review shows the importance of knowing the experiences of women with breast cancer during the transitional survivorship in order to meet their needs during this stage of the illness, so as to facilitate their transition into the next phase of survival. There is a lack of knowledge about the experiences of families during this stage of survival and the impact of family relationship on the transitional experiences of breast cancer survivors. Therefore, it seems relevant to focus on this area in future exploratory studies.


[Treatment of subclinical hypothyroidism : an update of the evidence and the new Rapid Recommendations].
Subclinical hypothyroidism is frequent and its treatment by thyroid hormones is debated. Current guidelines tend to recommend a treatment for symptomatic adults or for thyrotropin (TSH) levels > 10 mIU/l. Nevertheless, new evidence from systematic review, -including 21 trials and 2192 participants, demonstrated that thyroid hormone replacement has no clinically relevant benefit on patients' symptoms or prognosis. An international and independent panel -including physicians, methodologists and patients issues a strong recommendation (BMJ Rapid Recommendation) against thyroid hormones therapy for adults with subclinical hypothyroidism. This recommendation does not apply to women who are pregnant or trying to conceive or to patients with TSH > 20 mIU/l.


Management of hemoptysis in patients with lung cancer.
Hemoptysis related to malignancy is common and accounts for nearly a quarter of all cases of hemoptysis in the US, and approximately 20% of patients with lung cancer will experience some degree of hemoptysis during their disease course. Both minor and massive hemoptysis come with diagnostic and treatment challenges and are associated with increased mortality. We will discuss the definition and epidemiology of hemoptysis related to malignancy, outline our approach to the initial evaluation and diagnostic workup, and extensively review the management of minor and massive hemoptysis. Specific emphasis will be on relevant signs and symptoms, imaging, and the role of bronchoscopy, and the differences in approach for minor hemoptysis compared to massive hemoptysis. While the role of surgical management is very limited in this patient population, the role of endobronchial and endovascular management will be discussed in detail.


Volume matters in the systemic treatment of metastatic pancreatic cancer: a population-based study in the Netherlands.
In pancreatic surgery, a relation between surgical volume and postoperative mortality and overall survival (OS) has been recognized, with high-volume centers reporting significantly better survival rates. We aimed to explore the influence of hospital volume on administration of palliative chemotherapy and OS in the Netherlands. Patients diagnosed between 2007 and 2011 with metastatic pancreatic cancer were identified in the Netherlands Cancer Registry. Three types of high-volume centers were defined: high-volume (1) incidence center, based on the number of patients diagnosed with metastatic pancreatic cancer, (2) treatment center based on number of patients with metastatic pancreatic cancer who started treatment with palliative chemotherapy and (3) surgical center based on the number of resections with curative intent for pancreatic cancer. Independent predictors of administration of palliative chemotherapy were evaluated by means of logistic regression analysis. The multivariable Cox proportional hazard model was used to assess the impact of being diagnosed or treated in high-volume centers on survival. A total of 5385 patients presented with metastatic pancreatic cancer of which 24 % received palliative chemotherapy. Being treated with chemotherapy in a high-volume chemotherapy treatment center was associated with improved survival (HR 0.76, 95 % CI 0.67-0.87). Also, in all patients with metastatic pancreatic cancer, being diagnosed in a high-volume surgical center was associated with improved survival (HR 0.74, 95 % CI 0.66-0.83). Hospital volume of palliative chemotherapy for metastatic pancreatic cancer was associated with improved survival, demonstrating that a volume-outcome relationship, as described for pancreatic surgery, may also exist for pancreatic medical oncology.


Characterization and localization of two ion-binding sites within the pore of cardiac L-type calcium channels.
L-type Ca channels from porcine cardiac sarcolemma were incorporated into planar lipid bilayers. We characterized interactions of permeant and blocking ions with the channel's pore by (a) studying the current-voltage relationships for Ca2+ and Na+ when equal concentrations of the ions were present in both internal and external solutions, (b) testing the dose-dependent block of Ba2+ currents through the channels by internally applied cadmium, and (c) examining the dose and voltage dependence of the block of Na+ currents through the channels by internally and externally applied Ca2+. We found that the I-V relationship for Na+ appears symmetrical through the origin when equal concentrations of Na+ are present on both sides of the channel (gamma = 90 pS in 200 mM NaCl). The conductance for outward Ca2+ currents with 100 mM Ca2+ on both sides of the channel is approximately 8 pS, a value identical to that observed for inward currents when 100 mM Ca2+ was present outside only. This provides evidence that ions pass through the channel equally well regardless of the direction of net flux. In addition, we find that internal Cd2+ is as effective as external Cd2+ in blocking Ba2+ currents through the channels, again suggesting identical interactions of ions with each end of the pore. Finally, we find that micromolar Ca2+, either in the internal or in the external solution, blocks Na+ currents through the channels. The affinity for internally applied Ca2+ appears the same as that for externally applied Ca2+. The voltage dependence of the Ca(2+)-block suggests that the sites to which Ca2+ binds are located approximately 15% and approximately 85% of the electric field into the pore. Taken together, these data provide direct experimental evidence for the existence of at least two ion binding sites with high affinity for Ca2+, and support the idea that the sites are symmetrically located within the electric field across L-type Ca channels.


Microelectrode array recordings from the ventral roots in chronically implanted cats.
The ventral spinal roots contain the axons of spinal motoneurons and provide the only location in the peripheral nervous system where recorded neural activity can be assured to be motor rather than sensory. This study demonstrates recordings of single unit activity from these ventral root axons using floating microelectrode arrays (FMAs). Ventral root recordings were characterized by examining single unit yield and signal-to-noise ratios (SNR) with 32-channel FMAs implanted chronically in the L6 and L7 spinal roots of nine cats. Single unit recordings were performed for implant periods of up to 12 weeks. Motor units were identified based on active discharge during locomotion and inactivity under anesthesia. Motor unit yield and SNR were calculated for each electrode, and results were grouped by electrode site size, which were varied systematically between 25 and 160 μm to determine effects on signal quality. The unit yields and SNR did not differ significantly across this wide range of electrode sizes. Both SNR and yield decayed over time, but electrodes were able to record spikes with SNR >2 up to 12 weeks post-implant. These results demonstrate that it is feasible to record single unit activity from multiple isolated motor units with penetrating microelectrode arrays implanted chronically in the ventral spinal roots. This approach could be useful for creating a spinal nerve interface for advanced neural prostheses, and results of this study will be used to improve design of microelectrodes for chronic neural recording in the ventral spinal roots.


Environmental regulation of the reproductive system in a flexibly breeding Sonoran Desert bird, the Rufous-winged Sparrow, Aimophila carpalis.
We investigated reproductive regulation in male Rufous-winged Sparrows, Aimophila carpalis, a Sonoran Desert passerine that breeds after irregular summer rains. Field and captive data demonstrate that increased photoperiod stimulates testicular development in March and maintains it until early September. Free-living birds caught in July and placed on captive long days (16L: 8D) maintained developed testes for up to 7 months, and free-living birds caught in September, during testicular regression, redeveloped testes when placed on captive long days, indicating that these birds were still photosensitive. Captive birds on long days maintained testicular development when exposed to temperatures mimicking those occurring during regression in free-living birds. In free-living birds, testicular development was observed during spring and summer, but unless this was associated with rainfall, breeding (indicated by juveniles) did not occur. Large increases in plasma luteinizing hormone (LH) in free-living males were correlated with heavy rainfall in July/August, when the birds bred, and in November, when they did not breed. In captive birds, plasma LH concentrations were unresponsive to photoperiodic changes, but may have responded to social cues. Plasma prolactin concentrations were directly correlated with photoperiod in free-living birds, but an effect of photoperiod on prolactin secretion was not seen in captive birds. It is concluded that male Rufous-winged Sparrows use long photoperiods to stimulate and maintain testicular development, but exposure to long photoperiods does not terminate breeding by inducing absolute photorefractoriness. The specific timing of reproductive behaviors is apparently determined by elevated plasma LH coinciding with long day stimulated gonad development.


Extracellular beta-D-glucosidase from Chaetomium thermophilum var. coprophilum: production, purification and some biochemical properties.
The thermophilic fungus Chaetomium thermophilum var. coprophilum produced large amounts of extracellular and intracellular beta-glucosidase activity when grown on cellulose or cellobiose as carbon sources. The presence of glucose in the culture medium drastically decreased the level of beta-glucosidase activity, while cycloheximide prevented the induction of the extracellular enzyme activity by cellobiose. An extracellular beta-glucosidase induced by avicel was purified by a procedure involving acetone precipitation and chromatography on two DEAE-cellulose columns. The purified enzyme was a basic protein, with a carbohydrate content of 73%. The deglycosylated enzyme exhibited a molecular mass of 43 kDa, with pH and temperature optima of 5.5 and 65 degrees C respectively. The beta-glucosidase hydrolysed only cellobiose and p-nitrophenyl-beta-D-glucopyranoside, exhibiting apparent Km values of 3.13 mM and 0.76 mM, respectively. The native purified enzyme was stable up to 2 hours at 60 degrees C, and its thermal stability was directly dependent on glycosylation.


[Suspected amyotrophic lateral sclerosis? Don't forget diagnostic imaging of the spine].
Two patients, men aged 35 and 72 years, had progressive muscle weakness, lower motor neuron signs in all extremities and upper motor neuron signs in the legs. There were no major sensory signs on examination. The clinical picture very much resembled amyotrophic lateral sclerosis (ALS), although there were never brain stem signs. Myelopathy and polyradiculopathies caused by a tandem cervical and lumbar spinal stenosis explained the clinical picture. Cervical MRI and lumbar CT confirmed this diagnosis. Laminectomy was done, after which both patients remained with unchanged symptoms. Tandem spinal stenosis should be part of the differential diagnosis of ALS. Imaging of the spine is necessary to confirm this diagnosis, and in the absence of bulbar signs always necessary prior to the diagnosis of ALS.


First results on patient dose measurements from conventional diagnostic radiology procedures in Serbia and Montenegro.
The objective of this work is to assess patient doses for the most frequent X-ray examinations for the first time in Serbia and Montenegro. A total of 510 procedures for 11 different examination categories in 3 general hospitals were analysed. Mean and median entrance surface air kerma (ESAK) and kerma area product (KAP) values followed by mean effective doses were reported. Using X-ray tube output data, ESAK for each radiographic examination was calculated, as well as the effective dose for each patient. Except for chest PA examination, all estimated doses are less than stated European and International Atomic Energy Agency (IAEA) reference levels for simple radiographic examinations. For complex examinations involving fluoroscopy and radiography total KAP was measured and contributions from fluoroscopy and radiography were assessed. The study of KAP confirms that the dose level for complex fluoroscopy investigations is closely related to the technique and individual patient variation in terms of fluoroscopy time and number of radiography exposures. The obtained values are comparable to those reported in the UK. Survey data are aimed aid development of a national quality control and radiation protection programme for medical exposures.


A Case Report of Delayed Diagnosed Chronic Aortocaval Fistula: A Rare Complication of Penetrating Trauma to the Abdomen.
Chronic aortocaval fistula (ACP) is a rare complication of penetrating trauma to the abdomen. We report a case of traumatic ACP presenting with pulmonary hypertension and right heart failure symptoms 15 years after the initial penetrating injury. Although symptoms of pulmonary hypertension started 5 years ago, it was wrongly diagnosed and treated as chronic obstructive pulmonary disease. The presence of a continuous abdominal bruit and history of penetrating abdominal trauma gave rise to suspicion of a fistula, which was confirmed by computed tomography and angiography. Percutaneous closure of ACP was planned, but the patient died of severe pneumonia. The clinical presentation of chronic ACP can vary from being asymptomatic to symptoms related to pulmonary hypertension, right heart failure, and pulmonary embolism; thus, definitive diagnosis can be challenging.


Kinetic modeling of stem cell transcriptome dynamics to identify regulatory modules of normal and disturbed neuroectodermal differentiation.
Thousands of transcriptome data sets are available, but approaches for their use in dynamic cell response modelling are few, especially for processes affected simultaneously by two orthogonal influencing variables. We approached this problem for neuroepithelial development of human pluripotent stem cells (differentiation variable), in the presence or absence of valproic acid (signaling variable). Using few basic assumptions (sequential differentiation states of cells; discrete on/off states for individual genes in these states), and time-resolved transcriptome data, a comprehensive model of spontaneous and perturbed gene expression dynamics was developed. The model made reliable predictions (average correlation of 0.85 between predicted and subsequently tested expression values). Even regulations predicted to be non-monotonic were successfully validated by PCR in new sets of experiments. Transient patterns of gene regulation were identified from model predictions. They pointed towards activation of Wnt signaling as a candidate pathway leading to a redirection of differentiation away from neuroepithelial cells towards neural crest. Intervention experiments, using a Wnt/beta-catenin antagonist, led to a phenotypic rescue of this disturbed differentiation. Thus, our broadly applicable model allows the analysis of transcriptome changes in complex time/perturbation matrices.


Keeping pace with CYP2D6 haplotype discovery: innovative methods to assign function.
The discovery of haplotypes with unknown or uncertain function in the CYP2D6 pharmacogene is outpacing the capabilities of traditional in vitro and in vivo approaches to characterize their function. This challenge will undoubtedly grow as pharmacogenomic research becomes more inclusive of globally diverse populations. As accurate phenotypic assignment is paramount to the utility of pharmacogenomics, high-throughput technologies are needed for this complex pharmacogene. We describe the evolving landscape of innovative approaches to assign function to CYP2D6 haplotypes and possibilities for adopting these technologies into cohesive processes. Promising approaches include ADME-optimized prediction frameworks, machine learning algorithms, deep mutational scanning and phenoconversion predictions. Implementing these approaches will lead to improved personalization of treatment for patients.


Review of the safety and efficacy of long-term NSAID use in the treatment of canine osteoarthritis.
The published, peer-reviewed literature was systematically searched for information on the safety and efficacy of long-term (defined as 28 days or more of continuous therapy) NSAID use in the treatment of canine osteoarthritis. Online databases were reviewed in June 2008 and papers were selected based on their relevance. Fifteen papers were identified and evaluated. Six of seven papers indicated a benefit of long-term treatment over short-term treatment in terms of the reduction of clinical signs or lameness; one study showed no benefit. Fourteen papers evaluated safety with calculated experimental (adverse) event rates (EER) between 0 and 0.31, but there was no correlation between study length and EER (rs=-0.109, P=0.793). The balance of evidence for the efficacy of NSAIDs supports longer-term use of these agents for increased clinical effect. There is no indication in the literature that such an approach is associated with a reduction in safety, although robust data on the safety of long-term NSAID use are lacking in large numbers of dogs.


Mechanisms of beta-lactam resistance in British isolates of Pseudomonas aeruginosa.
The mechanisms of resistance to beta-lactam antibiotics in 191 isolates of Pseudomonas aeruginosa were examined. These represented the most resistant organisms of 1866 isolates collected during a national survey of antibiotic resistance in this species. One hundred and seventy-two isolates were selected because they were resistant to carbenicillin (MIC greater than 128 mg/L) and 19 because the MICs of cefotaxime were greater than the MICs of carbenicillin. Of the carbenicillin-resistant isolates, 35 produced plasmid-mediated beta-lactamases known to be active against carbenicillin and seven produced unusual beta-lactamases; in 131 strains, resistance could not be attributed to beta-lactamase production and was considered to be intrinsic. The unusual antibiogram in which the MIC of cefotaxime was greater than the MIC of carbenicillin was associated with overproduction of the chromosomally-determined Sabath and Abrahams ' beta-lactamase. Selection of strains with this last mechanism represents a novel resistance problem and one which may increase with increased use of newer antipseudomonal beta-lactams.


Enzymatic engineering of the porcine genome with transposons and recombinases.
Swine is an important agricultural commodity and biomedical model. Manipulation of the pig genome provides opportunity to improve production efficiency, enhance disease resistance, and add value to swine products. Genetic engineering can also expand the utility of pigs for modeling human disease, developing clinical treatment methodologies, or donating tissues for xenotransplantation. Realizing the full potential of pig genetic engineering requires translation of the complete repertoire of genetic tools currently employed in smaller model organisms to practical use in pigs. Application of transposon and recombinase technologies for manipulation of the swine genome requires characterization of their activity in pig cells. We tested four transposon systems- Sleeping Beauty, Tol2, piggyBac, and Passport in cultured porcine cells. Transposons increased the efficiency of DNA integration up to 28-fold above background and provided for precise delivery of 1 to 15 transgenes per cell. Both Cre and Flp recombinase were functional in pig cells as measured by their ability to remove a positive-negative selection cassette from 16 independent clones and over 20 independent genomic locations. We also demonstrated a Cre-dependent genetic switch capable of eliminating an intervening positive-negative selection cassette and activating GFP expression from episomal and genome-resident transposons. We have demonstrated for the first time that transposons and recombinases are capable of mobilizing DNA into and out of the porcine genome in a precise and efficient manner. This study provides the basis for developing transposon and recombinase based tools for genetic engineering of the swine genome.


TPMT, COMT and ACYP2 genetic variants in paediatric cancer patients with cisplatin-induced ototoxicity.
Cisplatin ototoxicity affects 42-88% of treated children. Catechol-O-methyltransferase (COMT), thiopurine methyltransferase (TPMT) and AYCP2 genetic variants have been associated with ototoxicity, but the findings have been contradictory. The aims of the study were as follows: (a) to investigate these associations in a carefully phenotyped cohort of UK children and (b) to perform a systematic review and meta-analysis. We recruited 149 children from seven UK centres using a retrospective cohort study design. All participants were clinically phenotyped carefully. Genotyping was performed for one ACYP2 (rs1872328), three TPMT (rs12201199, rs1142345 and rs1800460) and two COMT (rs4646316 and rs9332377) variants. For CTCAE grading, hearing loss was present in 91/120 (75.8%; worst ear) and 79/120 (65.8%; better ear). Using Chang grading, hearing loss was diagnosed in 85/119 (71.4%; worst ear) versus 75/119 (63.0%; better ear). No TPMT or COMT single-nucleotide polymorphisms (SNPs) were associated with ototoxicity. ACYP2 SNP rs1872328 was associated with ototoxicity (P=0.027; worst ear). Meta-analysis of our data with that reported in previous studies showed the pooled odds ratio (OR) to be statistically significant for both the COMT SNP rs4646316 (OR: 1.50; 95% confidence interval: 1.15-1.95) and the ACYP2 SNP rs1872328 (OR: 5.91; 95% confidence interval: 1.51-23.16). We showed an association between the ACYP2 polymorphism and cisplatin-induced ototoxicity, but not with the TPMT and COMT. A meta-analysis was statistically significant for both the COMT rs4646316 and the ACYP2 rs1872328 SNPs. Grading the hearing of children with asymmetric hearing loss requires additional clarification.


[Allogenic transplantation of sterilised bones and halfjoints (author's transl)].
The bones and halfjoints were gained under non-sterile conditions. They were sterilised using 1% formaldehyde solution and preserved with 2% formaldehyde--sugar solution or 50% honey solution. 102 allogenic transplants were performed in 100 patients. The results are very satisfying. The method described is effective, of universal practicability and guarentees constant available high class bone material for transplantation.


Policy and system change and community coalitions: outcomes from allies against asthma.
Objectives. We assessed policy and system changes and health outcomes produced by the Allies Against Asthma program, a 5-year collaborative effort by 7 community coalitions to address childhood asthma. We also explored associations between community engagement and outcomes. Methods. We interviewed a sample of 1,477 parents of children with asthma in coalition target areas and comparison areas at baseline and 1 year to assess quality-of-life and symptom changes. An extensive tracking and documentation procedure and a survey of 284 participating individuals and organizations were used to ascertain policy and system changes and community engagement levels. Results. A total of 89 policy and system changes were achieved, ranging from changes in interinstitutional and intrainstitutional practices to statewide legislation. Allies children experienced fewer daytime (P = .008) and nighttime (P = .004) asthma symptoms than comparison children. In addition, Allies parents felt less helpless, frightened, and angry (P = .01) about their child's asthma. Type of community engagement was associated with number of policy and system changes. Conclusions. Community coalitions can successfully achieve asthma policy and system changes and improve health outcomes. Increased core and ongoing community stakeholder participation rather than a higher overall number of participants was associated with more change.


Editorial: Current status and perspective on drug targets in tubercle bacilli and drug design of antituberculous agents based on structure-activity relationship.
Worldwide, tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death. However, the development of new drugs for the treatment and prophylaxis of TB, particularly those truly active against dormant and persistent types of tubercle bacilli, has been slow, although some promising drugs, such as diarylquinoline TMC207, nitroimidazopyran PA-824, nitroimidazo-oxazole Delamanid (OPC-67683), oxazolidinone PNU-100480, ethylene diamine SQ-109, and pyrrole derivative LL3858, are currently under phase 1 to 3 clinical trials. Therefore, novel types of antituberculous drug, which act on unique drug targets in Mycobacterium tuberculosis (MTB) pathogens, particularly drug targets related to the establishment of mycobacterial dormancy in the host's macrophages, are urgently needed. In this context, it should be noted that current anti-TB drugs mostly target the metabolic reactions and proteins which are essential for the growth of MTB in extracellular milieus. It may also be promising to develop another type of drug that exerts an inhibitory action against bacterial virulence factors which cross-talk and interfere with signaling pathways of MTB-infected immunocompetent host cells, such as lymphocytes, macrophages, and NK cells, thereby changing the intracellular milieus that are favorable to intramacrophage survival and the growth of infected bacilli. This special issue contains ten review articles, dealing with recent approaches to identify and establish novel drug targets in MTB for the development of new and unique antitubercular drugs, including those related to mycobacterial dormancy and crosstalk with cellular signaling pathways. In addition, this special issue contains some review papers with special reference to the drug design based on quantitative structure-activity relationship (QSAR) analysis, especially three-dimensional (3D)-QSAR. New, critical information on the entire genome of MTB and mycobacterial virulence genes is promoting the elucidation of the molecular structures of drug targets in MTB, and are consequently markedly useful for the design of new, promising antituberculous drugs using QSAR techniques. In this issue, we review the following areas. Firstly, Dr. Li M. Fu reviews the perspective that combines machine learning and genomics for drug discovery in tuberculosis, in relation to the problem that the exhaustive search for useful drug targets over the entire MTB genome would not be as productive as expected in practice [1]. Secondly, the review article by Drs. R. S. Chauhan. S. K. Chanumolu, C. Rout, and R. Shrivastava focuses on analysis of the current state of MTB genomic resources, host-pathogen interaction studies in the context of mycobacterial persistence, and drug target discovery based on the utilization of computational tools and metabolic network analyses [2]. Thirdly, Drs. Daria Bottai, Agnese Serafini, Alessandro Cascioferro, Roland Brosch, and Riccardo Manganelli review the current knowledge on MTB T7SS/ESX secretion systems and their impact on MTB physiology and virulence, and the possible approaches to develop T7SS/ESX inhibitors [3]. Fourthly, Drs. E. Jeffrey North, Mary Jackson, and Richard E. Lee review and analyze new and emerging inhibitors of the mycolic acid biosynthetic pathway, including mycobacterial enzymes for fatty acid synthesis, mycolic acid-modifying enzymes, fatty acid-activating and -condensing enzymes, transporters, and transferases, that have been discovered in the post-genomic era of tuberculosis drug discovery [4]. Fifthly, Drs. Katarina Mikusova, Vadim Makarov, and Joao Neres review the mycobacterial enzyme DprE1, which catalyzes a unique epimerization reaction in the biosynthesis of decaprenylphosphoryl arabinose, a single donor of the arabinosyl residue for the build-up of arabinans, one of the mycobacterial cell wall components, as an important drug target especially for the development of benzothiazinones [5]. Sixthly, I review the present status of global research on novel drug targets related to the Toll-like receptor in the MTB pathogen, with special reference to mycobacterial virulence factors that cross-talk and interfere with signaling pathways of host macrophages [6]. The following four review articles deal with drug design of novel anti-TB agents employing QSAR techniques. Firstly, Drs. Nidhi and Mohammad Imran Siddiqi review 2D and 3D QSAR approaches and the recent trends of these methods integrated with virtual screening using the 3D pharmacophore and molecular docking approaches for the identification and design of novel antituberculous agents, by presenting a comprehensive overview of QSAR studies reported for newer antituberculous agents [7]. Secondly, Drs. Filomena Martins, Cristina Ventura, Susana Santos, and Miguel Viveiros review the current status of different QSAR-based strategies for the design of novel anti-TB drugs based upon the most active anti-TB agent, isoniazid, from the viewpoint of the development of promising derivatives that are active against isoniazid- resistant strains with katG mutations [8]. Thirdly, Drs. Sanchaita Rajkhowa and Ramesh C. Deka review current studies concerning 2D and 3D QSAR models that contain density-functional theory (DFT)-based descriptors as their parameters [9]. Notably, DFT-based descriptors such as atomic charges, molecular orbital energies, frontier orbital densities, and atom-atom polarizabilities are very useful in predicting the reactivity of atoms in molecules. Fourthly, Drs. Renata V. Bueno, Rodolpho C. Braga, Natanael D. Segretti, Elizabeth I. Ferreira, Gustavo H. G. Trossini, and Carolina H. Andrade review the current progress and applications of QSAR analysis for the discovery of innovative tuberculostatic agents as inhibitors of ribonucleotide reductase, DNA gyrase, ATP synthase, and thymidylate kinase enzymes, highlighting present challenges and new opportunities in TB drug design [10]. The aim of this issue is to address the future prospects for the development of new antituberculous drugs. There are a number of difficulties in computational drug-design for the development of new drug formulations with potential antimycobacterial effects, especially therapeutic and prophylactic efficacy against infection due to dormant-type MTB pathogens. In addition, it should be emphasized that the most urgent goal of TB chemotherapy is develop highly active, low-cost drugs which can be used not only in industrialized but also in developing countries, because most global TB incidence occurs in the latter. I am sincerely grateful to the individuals who contributed to this work. All authors are experts in their fields and they made earnest efforts to perform these in-depth reviews. I thank them all.


Recent advances in the oral delivery of insulin.
Insulin was discovered over 90 years ago. However oral insulin still remains a challenging and elusive goal. Extensive efforts are being made worldwide for developing noninvasive drug delivery systems, mainly via oral route as it is the most widely accepted means of administration. The main barriers faced in oral protein delivery are the enzymatic degradation and poor permeability across the intestinal wall. The approaches for developing an oral insulin delivery system mainly focus on overcoming these barriers. To overcome the gastro-intestinal barriers various types of formulations such as insulin conjugates, permeation enhancers, micro/nanoparticles, liposomes etc. are investigated. In the recent years a number of advances have taken place in understanding the needs and workable mechanisms of improved oral peptide delivery systems. In this review the recent patents on oral insulin is focused. Emphasis is on the technologies based on permeation enhancers and nanoparticle based carrier systems.


Longitudinal observation and outcome of nonfamilial childhood haemophagocytic syndrome receiving etoposide-containing regimens.
The long-term outcome of 22 children treated with etoposide-containing regimens for haemophagocytic syndrome (HS) were longitudinally studied; none of them had a family history of the disease. All patients received etoposide-containing (150 mg/m2/d) regimens, combined, in 16 cases, with intravenous immunoglobulin (IVIG) and prednisolone. Complete remission (CR) was achieved in 12 patients, partial remission in seven, and early mortality occurred in three. Of the 12 CR patients, only four remain alive and disease-free, with a median follow-up of 47.4 months; one CR patient died due to infection and the remaining seven had relapsed diseases. Three patients with a partial response or with relapsed disease progressed to T-cell lymphoma, characterized, in the two cases tested, by clonal chromosomal abnormalities. Epstein-Barr virus (EBV) infection was implicated in disease pathogenesis in 15/22 patients. The overall survival was 45.5%, 40.9% and 40.9% at 1, 3 and 5 years, respectively, and disease-free survival for CR patients at these same times was 45.5%, 36.4% and 36.4%. The etoposide-containing regimen would appear to be an effective initial therapeutic option for childhood HS. However, in view of the frequency of partial remissions and relapsed disease, a more intensive chemotherapy or bone marrow transplantation should be applied. The progression to EBV-containing T-cell lymphoma in three patients is consistent with the previous observation that EBV-associated HS is a potentially malignant disease.


Virtual screening against Mycobacterium tuberculosis dihydrofolate reductase: suggested workflow for compound prioritization using structure interaction fingerprints.
In this study, we suggest a new workflow for the identification and prioritization of potential compounds targeted against Mycobacterium tuberculosis dihydrofolate reductase, an important folate cycle enzyme and a validated target for the development of anti-tubercular agents. First, we have performed an integrated pharmacophore and structure-based virtual screening using Maybridge small molecule database, subsequently interaction patterns from known actives to the receptor were applied for scoring and ranking the virtual screening hits using structure interaction fingerprint (SIFt)-based similarity approach. In addition, agglomerative hierarchical clustering of the structure interaction fingerprints permits the easy separation of active from inactive binding modes. Using this approach we screened 59275 Maybridge compounds and 20 compounds were prioritized as promising virtual screening hits. Though using a receptor interaction scoring approach, the results were not biased toward the chemical classes of the known actives and the proposed compounds were structurally diverse with low molecular weights and structural complexities. Our results suggest that structure-based virtual screening coupled with the SIFt should be a valuable tool for prioritization of virtual screening hits.


Spirituality in recovery: a lagged mediational analysis of alcoholics anonymous' principal theoretical mechanism of behavior change.
Evidence indicates Alcoholics Anonymous (AA) can play a valuable role in recovery from alcohol use disorder. While AA itself purports it aids recovery through "spiritual" practices and beliefs, this claim remains contentious and has been only rarely formally investigated. Using a lagged, mediational analysis, with a large, clinical sample of adults with alcohol use disorder, this study examined the relationships among AA, spirituality/religiousness, and alcohol use, and tested whether the observed relation between AA and better alcohol outcomes can be explained by spiritual changes. Adults (N = 1,726) participating in a randomized controlled trial of psychosocial treatments for alcohol use disorder (Project MATCH) were assessed at treatment intake, and 3, 6, 9, 12, and 15 months on their AA attendance, spiritual/religious practices, and alcohol use outcomes using validated measures. General linear modeling (GLM) and controlled lagged mediational analyses were utilized to test for mediational effects. Controlling for a variety of confounding variables, attending AA was associated with increases in spiritual practices, especially for those initially low on this measure at treatment intake. Results revealed AA was also consistently associated with better subsequent alcohol outcomes, which was partially mediated by increases in spirituality. This mediational effect was demonstrated across both outpatient and aftercare samples and both alcohol outcomes (proportion of abstinent days; drinks per drinking day). Findings suggest that AA leads to better alcohol use outcomes, in part, by enhancing individuals' spiritual practices and provides support for AA's own emphasis on increasing spiritual practices to facilitate recovery from alcohol use disorder.


Prevalence of hibernating myocardium in patients with severely impaired ischaemic left ventricles.
Severe impairment of left ventricular (LV) contraction is associated with an adverse prognosis in patients with ischaemic heart disease. Revascularisation may improve the impaired LV contraction if hibernating myocardium is present. The proportion of patients likely to benefit from this intervention is unknown. Therefore, the prevalence of hibernating myocardium in patients with ischaemic heart disease and severe impairment of LV contraction was assessed. From a consecutive series of patients undergoing coronary angiography for the investigation of chest pain or LV impairment, all patients with ischaemic heart disease and an LV ejection fraction (LVEF) < or = 30% were identified. These patients underwent positron emission tomography (PET) to detect hibernating myocardium, identified by perfusion metabolism mismatch. A teaching hospital directly serving 500,000 people. Of a total of 301 patients, 36 had ischaemic heart disease and an LVEF < or = 30%. Twenty-seven patients had PET images, while nine patients were not imaged because of emergency revascularisation (three), loss to follow up (one), inability to give consent (four), and age < 50 years (one, ethics committee guidelines). Imaged and non-imaged groups were similar in LV impairment, demographic characteristics, and risk factor profile. Fourteen patients (52% of the imaged or 39% of all patients with ischaemic heart disease and LVEF < or = 30%) had significant areas of hibernating myocardium on PET. It is possible that up to 50% of patients with ischaemic heart disease and severely impaired left ventricles have hibernating myocardium.


Molecular Dynamics Simulation on Thin-Film Lubrication of a Mixture of Three Alkanes.
We used the COMPASS forcefield to perform molecular dynamics (MD) simulation of a mixture composed of three alkanes as the lubricant for the thin-film lubrication. The viscosity of the lubrication film in the non-working state, the final film thickness, and density distribution were investigated. The results reveal that the viscosity error among different initial film thicknesses in the non-working state is within 5%, which confirms the applicability of the model and the forcefield. The viscosity decreases oscillating as temperature increases. Whatever the initial film thickness is, the film thickness change rate with respect to pressure load is almost the same. When pressure increases, the density peaks increase. As the initial film thickness increases, the normalized thicknesses of adsorption and ordered layers decrease. In nanoscale, the density predicted by the MD simulation is higher than the prediction of the Tait equation, even if the adsorption layers is excluded.


Youth Exposure and Response to the FDA Health Warning Label on Electronic Cigarettes Packaging: Policy Implications.
Youth represent a high-priority group for e-cigarette health communication. This study examined youth exposure to the FDA e-cigarette warning label over four years and its association with change in youth harm perception and intention. We pooled data from the 2018-2021 National Youth Tobacco Survey (age 10-17; n=67,159). Participants were divided into four groups: never users (58.5%), susceptible nonusers (16.3%), former users (12.7%), and current users (12.5%). We examined the prevalence, time-trend, correlates, and association of youth exposure to the warning with addictiveness and harm perception, intention to use e-cigarettes, and intention to quit all tobacco products. Only 24.5% of youth were exposed to the warning. Exposure increased from 14.9% in 2018 to 30.8% in 2019, then declined to 25.2% in 2021. Hispanic (aOR=0.76 [95 % CI=0.641 - 0.89]) and non-Hispanic Black current users (0.53 [0.40 - 0.69]) were less likely to be exposed to the warning than White current users. Youth exposure was positively associated with a higher perception of e-cigarette addictiveness (1.12 [1.04 - 1.19]) and intention to quit all tobacco products (1.28 [1.13 - 1.46]). However, exposure was negatively associated with harm perception (0.91 [0.85 - 0.96]) and intention to use e-cigarettes among e-cigarette nonusers (2.38 [1.99 - 2.84]). The decline in youth exposure to the warning indicates wear-out effects. Strengthening the label by using compelling designs, adding themes on e-cigarette harm to youth, periodically rotating warning content, and using culturally tailored messaging may improve its impact on youth and address the racial/ethnic disparities. The FDA e-cigarette label reached only 24.5% of youth, and exposure to the warning declined to indicate wear-out effects. Exposure was significantly lower among minorities. Exposure was associated with a higher perception of e-cigarette addictiveness and intention to quit all tobacco products. Still, it did not increase harm perception or reduce intention to use e-cigarettes among nonusers. Strengthening the label by using more compelling designs, including diverse themes focusing on e-cigarette harm relevant to youth, and periodically rotating warning content may improve its impact on youth. Continued surveillance of the implementation of e-cigarette policies is needed to ensure that they equally affect youth across racial/ethnic subpopulations.


Brain Activity Associated With Regulating Food Cravings Predicts Changes in Self-Reported Food Craving and Consumption Over Time.
Neural patterns associated with viewing energy-dense foods can predict changes in eating-related outcomes. However, most research on this topic is limited to one follow-up time point, and single outcome measures. The present study seeks to add to that literature by employing a more refined assessment of food craving and consumption outcomes along with a more detailed neurobiological model of behavior change over several time points. Here, a community sample of 88 individuals (age: M = 39.17, SD = 3.47; baseline BMI: M = 31.5, SD = 3.9, range 24-42) with higher body mass index (BMI) performed a food craving reactivity and regulation task while undergoing functional magnetic resonance imaging. At that time-and 1, 3, and 6 months later-participants reported craving for and consumption of healthy and unhealthy foods via the Food Craving Inventory (FCI) and ASA24 (N at 6 months = 52-55 depending on the measure). A priori hypotheses that brain activity associated with both viewing and regulating personally desired unhealthy, energy-dense foods would be associated with self-reported craving for and consumption of unhealthy foods at baseline were not supported by the data. Instead, regression models controlling for age, sex, and BMI demonstrated that brain activity across several regions measured while individuals were regulating their desires for unhealthy food was associated with the self-reported craving for and consumption of healthy food. The hypothesis that vmPFC activity would predict patterns of healthier eating was also not supported. Instead, linear mixed models controlling for baseline age and sex, as well as changes in BMI, revealed that more regulation-related activity in the dlPFC, dACC, IFG, and vmPFC at baseline predicted decreases in the craving for and consumption of healthy foods over the course of 6 months.


Socioeconomic trends in hospitalization for multiple sclerosis.
Multiple sclerosis (MS) is a neurological disorder with a high burden on patient quality of life and medical rehabilitation services. Little is known about the acute hospitalization costs and characteristics. We examined the trends in MS hospitalizations from 1993 to 2006. The Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project was searched using the ICD-9 code 340 (MS). Diagnostic, treatment and administrative data were analyzed using basic statistical software. A total of 288,454 hospital admissions with the primary diagnosis of MS occurred between 1993 and 2006, an average of 20,604 admissions annually. The percentage admitted from the emergency department (ED) increased from 19.4 to 60.0% during 1993-2006. The mean cost for each inpatient increased from USD 7,965 to 20,076. The percentage of discharges to home health care increased from 8.6 to 14.9%, and the percentage of discharges to nursing homes and rehabilitation services increased from 8.3 to 22.6%. In 2006, Medicaid patients were significantly more likely to be admitted from the ED (p < 0.001). Medicare payers were significantly more likely to be discharged to a nursing home/rehabilitation (p < 0.0001). National health insurance policies have made measurable effects on MS disease management. MS is becoming more expensive to treat acutely, and improved treatment modalities geared toward decreasing acute flare-ups may provide substantial cost savings by reducing ED visits, inpatient hospitalizations and the need for rehabilitation.


[Rare cases of severe heart rhythm disturbances during the hypoxic function test].
Cases of severe rhythm disorders of cardiac activity--the syncope developing lasting up to 34 seconds, are described in practically healthy individuals undergoing the hypoxic functional test. It is concluded that the hypoxic functional tests require a specially trained physician who must not only stop the test, but also give the patient immediate aid.


Involvement of gangliosides in rabies virus infection.
The role of gangliosides in rabies virus infection of chick embryo-related (CER) cells was investigated. Cultured cells were pretreated with neuraminidase to render the cells transiently non-susceptible to viral infection. Incubation of these desialylated cells with gangliosides allowed them to incorporate exogenous gangliosides and they recovered their susceptibility to rabies virus infection. Infection of CER cells was monitored by specific fluorescence 24 h after virus inoculation. The use of individual purified gangliosides or mixtures of two gangliosides to restore cellular susceptibility to viral infection showed that GT1b and GQ1b were the most effective. The disialogangliosides were also active, principally GD1b, whereas GM1, GM3 were poorly active and GD3 inactive. Incubation of rabies virus with gangliosides prior to virus infection reduced the percentage of infected cells. The results indicate that highly sialylated gangliosides are part of the cellular membrane receptor structure for the attachment of infective rabies virus. However, it is possible that other glycoconjugates such as glycoproteins or glycolipids also participate as components of a receptor structure for rabies virus.


Identification of regions of the chromosome of Neisseria meningitidis and Neisseria gonorrhoeae which are specific to the pathogenic Neisseria species.
Neisseria meningitidis and Neisseria gonorrhoeae give rise to dramatically different diseases. Their interactions with the host, however, do share common characteristics: they are both human pathogens which do not survive in the environment and which colonize and invade mucosa at their port of entry. It is therefore likely that they have common properties that might not be found in nonpathogenic bacteria belonging to the same genetically related group, such as Neisseria lactamica. Their common properties may be determined by chromosomal regions found only in the pathogenic Neisseria species. To address this issue, we used a previously described technique (C. R. Tinsley and X. Nassif, Proc. Natl. Acad. Sci. USA 93:11109-11114, 1996) to identify sequences of DNA specific for pathogenic neisseriae and not found in N. lactamica. Sequences present in N. lactamica were physically subtracted from the N. meningitidis Z2491 sequence and also from the N. gonorrhoeae FA1090 sequence. The clones obtained from each subtraction were tested by Southern blotting for their reactivity with the three species, and only those which reacted with both N. meningitidis and N. gonorrhoeae (i.e., not specific to either one of the pathogens) were further investigated. In a first step, these clones were mapped onto the chromosomes of both N. meningitidis and N. gonorrhoeae. The majority of the clones were arranged in clusters extending up to 10 kb, suggesting the presence of chromosomal regions common to N. meningitidis and N. gonorrhoeae which distinguish these pathogens from the commensal N. lactamica. The sequences surrounding these clones were determined from the N. meningitidis genome-sequencing project. Several clones corresponded to previously described factors required for colonization and survival at the port of entry, such as immunoglobulin A protease and PilC. Others were homologous to virulence-associated proteins in other bacteria, demonstrating that the subtractive clones are capable of pinpointing chromosomal regions shared by N. meningitidis and N. gonorrhoeae which are involved in common aspects of the host interaction of both pathogens.


[Serological activity of vaccine and circulating Bordetella pertussis strains].
To study activity of vaccine and circulating strains of Bordetella pertussis in serological reactions with serum samples from healthy vaccinated children and children with pertussis infection. One hundred forty-six serum samples from children with pertussis infection as well as 158 samples from healthy vaccinated children aged 3 - 5 years old were studied. Serologic activity of 3 vaccine strains and 7 strains of B. pertussis isolated from patients with pertussis in 2001 - 2005 against sera of children with pertussis infection or vaccinated children was assessed with hemagglutination assay (HA), radial gel immunodiffusion (RGI), and immunoelectrophoresis (IEP). In HA both serum samples of infected and vaccinated children were equally active in agglutination of microbial preparations prepared from vaccine or recently isolated strains of B. pertussis. RGI assay showed that 81 - 84% of serum samples from infected children and 17 -19% of samples from healthy vaccinated children reacted with vaccine strains, and 81 - 85% of samples from infected children and 16 - 20% of samples from healthy vaccinated children reacted with circulating strains: Sera from patients with pertussis formed identical lines of precipitation with vaccine and circulating strains in RGI assay and three types of precipitation arches profile in IEP. Sera from healthy vaccinated children formed identical precipitation arches with vaccine and circulating strains in RGI assay and one type of precipitation arches profile in IEP. Antibodies of patients with pertussis were equally active against vaccine and circulating strains of B. pertussis. Antibodies of vaccinated children were also equally active against vaccine and circulating strains although revealed more narrow spectrum of antigens compared to children with pertussis infection.


Effect of severe hyperemesis gravidarum on maternal vascular endothelial health: evaluation of soluble adhesion molecules.
Purpose: This study aimed to clarify the effect of severe hyperemesis gravidarum (sHG) on maternal vascular endothelial health with evaluation of soluble adhesion molecules.Method: The study population consisted of two groups of pregnant participants between 18 and 35 years of age who were between 5 and 13 weeks of gestation: sHG group and a healthy control group. A group of 26 participants whose pregnancies were complicated by sHG was compared with 26 healthy participants regarding serum levels of the soluble adhesion molecules such as E-selectin, soluble intracellular cell adhesion molecule 1 (sICAM-1), and soluble vascular cell adhesion molecule one (sVCAM-1), as well as other biochemical markers. The two groups had similar baseline characteristics.Results: Maternal baseline characteristics were similar in both groups. Serum levels of E-selectin (p < .001), sICAM-1 (p < .001), and sVCAM-1 (p < .001) were higher in the sHG group compared with the control group. Higher blood urea nitrogen, creatinine, and sodium levels, serum osmolarity, and urine density (p < .001, < .001, .006, .041, and .001, respectively) were also observed in the sHG group compared with the control group.Conclusions: The findings of this study indicated that sHG could impact endothelial cell function and these changes represented hypovolemia and dehydration caused by severe vomiting. Large-scale studies are required to understand the clinical importance of this finding regarding the long-term consequences and underlying mechanisms of elevated sICAM-1, sVCAM-1, and sE-selectin synthesis.


The alpha6beta4 integrin can regulate ErbB-3 expression: implications for alpha6beta4 signaling and function.
The integrin alpha(6)beta(4) has been shown to facilitate key functions of carcinoma cells, including their ability to migrate, invade, and evade apoptosis. The mechanism involved seems to be a profound effect of alpha(6)beta(4) on specific signaling pathways, especially the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. An intimate relationship between alpha(6)beta(4) and growth factor receptors may explain this effect of alpha(6)beta(4) on signaling. Previously, we showed that alpha(6)beta(4) and ErbB-2 can function synergistically to activate the PI3K/Akt pathway. Given that ErbB-2 can activate PI3K only when it heterodimerizes with other members of the epidermal growth factor receptor family, these data imply that other receptors cooperate in this process. Here, we report that alpha(6)beta(4) can regulate the expression of ErbB-3 using several different models and that the consequent formation of an ErbB-2/ErbB-3 heterodimer promotes the alpha(6)beta(4)-dependent activation of PI3K/Akt and the ability of this integrin to impede apoptosis of carcinoma cells. Our data also support the hypothesis that alpha(6)beta(4) can regulate ErbB-3 expression at the translational level as evidenced by the findings that alpha(6)beta(4) does not increase ErbB-3 mRNA significantly, and that this regulation is both rapamycin sensitive and dependent on eukaryotic translation initiation factor 4E. These findings provide one mechanism to account for the activation of PI3K by alpha(6)beta(4) and they also provide insight into the regulation of ErbB-3 in carcinoma cells.


Care of children isolated for infection control: a prospective observational cohort study.
Patients with community-acquired or nosocomial infections are often managed in a hospital with isolation precautions. Given the high prevalence and substantial inconvenience associated with implementation of isolation precautions in pediatric settings, we explored the impact of this intervention on the care provided to children and their families. The purpose of this work was to compare the quantity and quality of care received by isolated patients relative to nonisolated patients. Sixty-five consecutive newly admitted inpatients in private rooms (24 isolated, 41 nonisolated) were recruited from the general pediatric service at the Hospital for Sick Children. Interactions between a medical team with patients and their families were observed. All of the participants were blinded to the study objectives. The medical team was observed during its morning rounds, and data were collected on the quantity and quality of care. Quantity of care was determined by the amount of time that the medical team spent interacting with the patient and parents and the number of organ systems examined by the attending physician during morning rounds. Quality of care was determined by using parental completion of the Pediatric Family Satisfaction Questionnaire. We found no significant difference in the average amount of time spent interacting with isolated compared with nonisolated patients (516 vs 480 seconds) or the number of organ systems examined in isolated compared with nonisolated patients (3 vs 4). Isolated and nonisolated groups gave high ratings to all of the items pertaining to the facility, doctors, and nurses. No large differences in quality or quantity of care were observed between isolated and nonisolated patients in the first 2 days of admission to a pediatric ward.


Superresolution of ultrasound images using the first and second harmonic signal.
This paper presents a new method of blind two-dimensional (2-D) homomorphic deconvolution and speckle reduction applied to medical ultrasound images. The deconvolution technique is based on an improved 2-D phase unwrapping scheme for pulse estimation. The input images are decomposed into minimum-phase and allpass components. The 2-D phase unwrapping is applied only to the allpass component. The 2-D phase of the minimum-phase component is derived by a Hilbert transform. The accuracy of 2-D phase unwrapping is also improved by processing small (16 x 16 pixels) overlapping subimages separately. This takes the spatial variance of the ultrasound pulse into account. The deconvolution algorithm is applied separately to the first and second harmonic images, producing much sharper images of approximately the same resolution and different speckle patterns. Speckle reduction is made by adding the envelope images of the deconvolved first and second harmonic images. Neither the spatial resolution nor the frame rate decreases, as the common compounding speckle reduction techniques do. The method is tested on sequences of clinical ultrasound images, resulting in high-resolution ultrasound images with reduced speckle noise.


Evolution of urticaria pigmentosa into indolent systemic mastocytosis: abnormal immunophenotype of mast cells without evidence of c-kit mutation ASP-816-VAL.
Mastocytosis comprises a heterogeneous group of hematological disorders which are morphologically defined by proliferation and accumulation of tissue mast cells in one or more organs. Clinical manifestations of mastocytosis range from disseminated maculopapular skin lesions (= urticaria pigmentosa [UP]) that may spontaneously regress to highly aggressive neoplasms like mast cell leukemia or mast cell sarcoma. Recently, it could be shown that systemic mastocytosis (SM) is a clonal disorder often exhibiting mutations of c-kit, a protooncogene encoding the tyrosine kinase receptor for stem cell factor (SCF). Mutations of c-kit are considered to play a key role in the pathogenesis of mastocytosis. Therefore, we investigated the unique case of a 36 year-old male patient with indolent systemic mastocytosis (ISM) evolving from UP (cutaneous mastocytosis) by means of histology, immunophenotyping and molecular biology. At the time of initial diagnosis the bone marrow showed only a mild diffuse increase in mast cells but compact infiltrates were missing. The serum tryptase levels were normal. Five years later, however, the bone marrow histology displayed patchycompact mast cell infiltrates, which now allowed to establish the diagnosis of an ISM. The serum tryptase levels at this time were markedly elevated. At both time points, mast cells were analyzed by immunohistochemistry using anti-tryptase antibody AA1, by flow cytometry using antibodies against CD2 and CD25, and nested polymerase chain reaction (PCR) on laser-microdissected, single pooled mast cells. Immunohistochemistry revealed strong tryptase-positivity of mast cells in both cutaneous and bone marrow infiltrates. Flow cytometry yielded an aberrant expression of CD2 and CD25 on bone marrow mast cells. However, repeated thorough PCR analysis failed to unveil c-kit mutation in atypical mast cells of skin and bone marrow samples of both dates. These findings clearly show that ISM can evolve from UP. Moreover, our study provides further evidence that the c-kit mutation Asp-816-Val is not invariably present in ISM.


APOBEC3H Subcellular Localization Determinants Define Zipcode for Targeting HIV-1 for Restriction.
APOBEC enzymes are DNA cytosine deaminases that normally serve as virus restriction factors, but several members, including APOBEC3H, also contribute to cancer mutagenesis. Despite their importance in multiple fields, little is known about cellular processes that regulate these DNA mutating enzymes. We show that APOBEC3H exists in two distinct subcellular compartments, cytoplasm and nucleolus, and that the structural determinants for each mechanism are genetically separable. First, native and fluorescently tagged APOBEC3Hs localize to these two compartments in multiple cell types. Second, a series of genetic, pharmacologic, and cell biological studies demonstrate active cytoplasmic and nucleolar retention mechanisms, whereas nuclear import and export occur through passive diffusion. Third, APOBEC3H cytoplasmic retention determinants relocalize APOBEC3A from a passive cell-wide state to the cytosol and, additionally, endow potent HIV-1 restriction activity. These results indicate that APOBEC3H has a structural zipcode for subcellular localization and selecting viral substrates for restriction.


Chitosan microparticle preparation for controlled drug release by response surface methodology.
The objectives were to investigate the effects of formulation variables on the release of drug and to optimize the formulation of chitosan microparticles loaded with drug for controlled release using response surface methodology. Chitosan microparticles were prepared by dropping a chitosan solution into sodium tripolyphosphate (TPP) through ionic cross-linking. The release behaviour of felodipine as a model drug was affected by preparation variables. A central composite design was used to evaluate and optimize the effect of preparation variables, chitosan concentration (X1), the pH of the TPP solution (X2) and cross-linking time (X3) on the cumulative per cent drug release (Y) in 24 h. Chitosan concentration and cross-linking time affected negatively the release of felodipine, while the pH of the TPP did so positively and was the highest influential factor. The optimum rate of drug release, 100% in 24 h, was achieved at 1.8% chitosan concentration, a pH 8.7 for the TPP solution and 9.7 min cross-linking time.


Effects of phosphorothioate modifications on precursor tRNA processing by eukaryotic RNase P enzymes.
The cleavage mechanism has been studied for nuclear RNase P from Saccharomyces cerevisiae, Homo sapiens sapiens and Dictyostelium discoideum, representing distantly related branches of the Eukarya. This was accomplished by using precursor tRNAs (ptRNAs) carrying a single Rp or Sp-phosphorothioate modification at the normal RNase P cleavage site (position -1/+1). All three eukaryotic RNase P enzymes cleaved the Sp-diastereomeric ptRNA exclusively one nucleotide upstream (position -2/-1) of the modified canonical cleavage site. Rp-diastereomeric ptRNA was cleaved with low efficiency at the modified -1/+1 site by human RNase P, at both the -2/-1 and -1/+1 site by yeast RNase P, and exclusively at the -2/-1 site by D. discoideum RNase P. The presence of Mn(2+ )and particularly Cd(2+) inhibited the activity of all three enzymes. Nevertheless, a Mn(2+ )rescue of cleavage at the modified -1/+1 site was observed with yeast RNase P and the Rp-diastereomeric ptRNA, consistent with direct metal ion coordination to the (pro)-Rp substituent during catalysis as observed for bacterial RNase P enzymes. In summary, our results have revealed common active-site constraints for eukaryotic and bacterial RNase P enzymes. In all cases, an Rp as well as an Sp-phosphorothioate modification at the RNase P cleavage site strongly interfered with the catalytic process, whereas substantial functional interference is essentially restricted to one of the two diastereomers in other RNA and protein-catalyzed hydrolysis reactions, such as those catalyzed by the Tetrahymena ribozyme and nuclease P1.


Perioperative Complications and Radiographic Outcomes Following Cervical Laminoplasty: A Review of 105 Cases from a Single Academic Center.
To assess complications and to compare preoperative and postoperative radiographic measures in patients who underwent cervical laminoplasty. We evaluated patients undergoing cervical laminoplasty between 2011 and 2022 at an academic medical center. Patient demographics, intraoperative and postoperative complications, and preoperative and postoperative radiographic parameters were recorded. Of 150 patients undergoing cervical laminoplasty during 2011-2022, 105 met the inclusion criteria. We identified 22 (21.0%) adverse events in 20 patients: 4 intraoperative (3.8%), 10 perioperative (9.5%), and 8 delayed postoperative (7.6%). Among adverse events, 13 (12.4%) were judged to be minor and 9 (8.6%) were judged to be major complications. Revision surgery was required in 6 (5.7%) patients. Both preoperative and postoperative cervical spine radiographic imaging was available in 47 (44.8%) of the 105 patients. Mean preoperative and postoperative C2-7 Cobb angles were 14.7° and 12.3°, respectively (P = 0.04). Mean preoperative and postoperative sagittal vertical axis measurements were 29.2 mm and 33.3 mm, respectively (P = 0.07). Mean preoperative and postoperative T1 slopes were 32.3° and 30.2°, respectively (P = 0.07). Cervical laminoplasty carries a significant risk of adverse events, the majority of which are minor, and has a low rate of reoperation (5.7%). The procedure does not result in significant changes in sagittal vertical axis or T1 slope. Cervical laminoplasty remains a valuable surgical option for selected patients with cervical myelopathy.


Intracranial haemorrhage and use of selective serotonin reuptake inhibitors.
In the past few years an increasing number of bleeding disorders have been reported in association with the use of selective serotonin reuptake inhibitors (SSRIs), including serious cases of intracranial haemorrhage, raising concerns about the safety of this class of drugs. The present study was performed to test the hypothesis of an increased risk of intracranial haemorrhage associated with the use of SSRIs. We carried out a case-control study nested in a cohort of antidepressants users with the UK-based General Practice Research Database (GPRD) as the primary source of information. The study cohort encompassed subjects aged between 18 and 79 years who received a first-time prescription for any antidepressant from January, 1990 to October, 1997. Patients with presenting conditions or treatments that could be associated with an increased risk of intracranial haemorrhage were excluded from the cohort. Patients were followed-up until the occurrence of an idiopathic intracranial haemorrhage. Up to four controls per case, matched on age, sex, calendar time and practice were randomly selected from the study cohort. We estimated adjusted odds ratios and 95% confidence intervals of intracranial haemorrhage with current use of SSRIs and other antidepressants as compared with nonuse using conditional logistic regression. We identified 65 cases of idiopathic intracranial haemorrhage and 254 matched controls. Current exposure to SSRIs was ascertained in 7 cases (10. 8%) and 24 controls (9.7%) resulting in an adjusted OR (95%CI) of 0. 8 (0.3,2.3). The estimate for 'other antidepressants' was 0.7 (0.3,1. 6). The effect measures were not modified by gender or age. No effect related to dose or treatment duration was detected. The risk estimates did not change according to the location of bleeding (intracerebral or subarachnoid). Our results are not compatible with a major increased risk of intracranial haemorrhage among users of SSRIs or other antidepressants at large. However, smaller but still relevant increased risks cannot be ruled out.


Assessment of the Fragment Docking Program SEED.
The fragment docking program solvation energy for exhaustive docking (SEED) is evaluated on 15 different protein targets, with a focus on enrichment and the hit rate. It is shown that SEED allows for consistent computational enrichment of fragment libraries, independent of the effective hit rate. Depending on the actual target protein, true positive rates ranging up to 27% are observed at a cutoff value corresponding to the experimental hit rate. The impact of variations in docking protocols and energy filters is discussed in detail. Remaining issues, limitations, and use cases of SEED are also discussed. Our results show that fragment library selection or enhancement for a particular target is likely to benefit from docking with SEED, suggesting that SEED is a useful resource for fragment screening campaigns. A workflow is presented for the use of the program in virtual screening, including filtering and postprocessing to optimize hit rates.


Can Chronic Ankle Instability Be Prevented? Rethinking Management of Lateral Ankle Sprains.
OBJECTIVE: To pose the question, "Can chronic ankle instability be prevented?" The evaluation and treatment of chronic ankle instability is a significant challenge in athletic health care. The condition affects large numbers of athletes and is associated with reinjury and impaired performance. The management of acute injuries varies widely but in athletic training has traditionally focused on initial symptom management and rapid return to activity. A review of practice strategies and philosophies suggests that a more detailed evaluation of all joints affected by the injury, correction of hypomobility, and protection of healing structures may lead to a more optimal long-term outcome. BACKGROUND: Sprains to the lateral ankle are common in athletes, and the reinjury rate is high. These injuries are often perceived as being isolated to the anterior talofibular and calcaneofibular ligaments. It is, however, becoming apparent that a lateral ankle sprain can injure other tissues and result in joint dysfunction throughout the ankle complex. DESCRIPTION: We begin by addressing the relationship between mechanical and functional instability. We then discuss normal ankle mechanics, sequelae to lateral ankle sprains, and abnormal ankle mechanics. Finally, tissue healing, joint dysfunction, and the management of acute lateral ankle sprain are reviewed, with an emphasis on restoring normal mechanics of the ankle-joint complex. A treatment model based on assessment of joint function, treatment of hypomobile segments, and protection of healing tissues at hypermobile segments is described.


Ni-catalyzed stereoselective arylation of inert C-O bonds at low temperatures.
A Ni-catalyzed arylation of inert C-O bonds that operates at temperatures as low as -40 °C is described. Unlike other methods for C-O bond cleavage utilizing organometallic species, this protocol operates at low temperatures, thus allowing the presence of sensitive functional groups with exquisite site-selectivity and stereoselectivity.


[Influence of prothrombin cleavage products on platelet activation and aggregation].
Meizothrombin efficiently activates mechanically triggered platelets and enhance collagen-, ADP- and adrenalin-induced aggregation of platelet-rich blood plasma. Thus, in clotting system activation zone meizothrombin is able to enhance process of involving platelets in clotformation. Pre-thrombin 1 inhibits collagen-, ADP- and adrenalin-induced aggregation of platelet-rich blood plasma and so regulates not only plasm but platelet hemostasis by reverse negative relation.


Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis.
Transcutaneous auricular vagus nerve stimulation (taVNS) has been investigated as a novel neuromodulation tool. Although taVNS is generally considered safe with only mild and transient adverse effects (AEs), those specifically caused by taVNS have not yet been investigated. This systematic review and meta-analysis on taVNS aimed to (1) systematically analyze study characteristics and AE assessment, (2) characterize and analyze possible AEs and their incidence, (3) search for predictable risk factors, (4) analyze the severity of AE, and (5) suggest an evidence-based taVNS adverse events questionnaire for safety monitoring. The articles searched were published through April 7, 2022, in Medline, Embase, Web of Science, Cochrane, and Lilacs databases. In general, we evaluated 177 studies that assessed 6322 subjects. From these, 55.37% of studies did not mention the presence or absence of any AEs; only 24.86% of the studies described that at least one adverse event occurred. In the 35 studies reporting the number of subjects with at least one adverse event, a meta-analytic approach to calculate the risk differences of developing an adverse event between active taVNS and controls was used. The meta-analytic overall adverse events incidence rate was calculated for the total number of adverse events reported on a 100,000 person-minutes-days scale. There were no differences in risk of developing an adverse event between active taVNS and controls. The incidence of AE, in general, was 12.84/100,000 person-minutes-days of stimulation, and the most frequently reported were ear pain, headache, and tingling. Almost half of the studies did not report the presence or absence of any AEs. We attribute this to the absence of AE in those studies. There was no causal relationship between taVNS and severe adverse events. This is the first systematic review and meta-analysis of transcutaneous auricular stimulation safety. Overall, taVNS is a safe and feasible option for clinical intervention.