Ventilation-perfusion scintigraphy.
Ventilation-perfusion scintigraphy remains an important diagnostic tool in the evaluation of patients suspected of having PE. It is important for the emergency physician to be able to use the information from a lung scan appropriately in the diagnostic management of this elusive and life-threatening disorder. This requires a clear knowledge of how these scans are interpreted as well as a consultative approach between the physician ordering the lung scan and the nuclear medicine physician interpreting it. Each can ultimately contribute to the development of an effective management plan. It is important for the clinician to understand that a low-probability lung scan does not rule out PE, but in fact can have up to a 40% probability of PE when clinical suspicion is high.


Effects of diet and obesity on brown adipose metabolism.
The effect of diet-induced obesity on interscapular brown adipose tissue (IBAT) was assessed after feeding male Sprague-Dawley rats a high-fat diet for 3-5 mo beginning at 3 mo of age. IBAT pads in 6-mo-old obese rats were heavier (22%), had more lipid (71%), and larger unilocular cells (38%) than chow-fed controls. Mitochondrial morphology, beta-adrenergic receptor binding ([ 125I]iodocyanopindolol), and norepinephrine-stimulated lipolysis were similar in IBAT from obese and control rats. When 8-mo-old chow-fed rats were switched to the high-fat diet for 7-14 days, IBAT pads became hypercellular without cell hypertrophy and with a 70% increase in norepinephrine-induced lipolysis. However, when 8-mo-old obese rats that had been on the high-fat diet for 5 mo were switched to chow for 3 days, IBAT cellularity was unchanged, but norepinephrine-induced lipolysis was increased 70%. Therefore, in lean and obese 6- to 8-mo-old rats, short-term dietary manipulation led to metabolic activation, whereas chronic diet-induced obesity on a stable diet was associated with a return of IBAT metabolism to control levels.


Isolated metaphyseal injury influences unrelated bones.
Background and purpose - Fracture healing involves different inflammatory cells, some of which are not part of the traditional bone field, such as B-cells and cytotoxic T-cells. We wanted to characterize bone healing by flow cytometry using 15 different inflammatory cell markers in a mouse model of metaphyseal injury, and incidentally discovered a previously unknown general skeletal reaction to trauma. Material and methods - A bent needle was inserted and twisted to traumatize the cancellous bone in the proximal tibia of C57/Bl6 female mice. This is known to induce vivid bone formation locally in the marrow compartment. Cells were harvested from the injured region, the uninjured contralateral tibia, and the humerus. The compositions of the immune cell populations were compared to those in untraumatized control animals. Results - Tibial metaphyseal injury led to substantial changes in the cell populations over time. Unexpectedly, similar changes were also seen in the contralateral tibia and in the humerus, despite the lack of local trauma. Most leukocyte subsets were affected by this generalized reaction. Interpretation - A relatively small degree of injury to the proximal tibia led to systemic changes in the immune cell populations in the marrow of unrelated bones, and probably in the entire skeleton. The few changes that were specific for the injury site appeared to relate to modulatory functions.


Short term memory in the calcium messenger system. Evidence for a sustained activation of protein kinase C in adrenal glomerulosa cells.
If adrenal glomerulosa cells are treated with angiotensin II for a period of 20-30 min, their subsequent response to either a rechallenge with the same concentration of angiotensin II or treatment with BAY K 8644, a calcium channel agonist, differs from the responses of control cells. Perifusion of control cells with 10 nM-angiotensin II leads to an increase in aldosterone secretory rate from 44 +/- 7 to 166 +/- 9 pg/min per 10(6) cells, but perifusion of cells pretreated for a 20 min period with angiotensin II leads to an increase in secretory rate from 51 +/- 9 to 209 +/- 18 pg/min per 10(6) cells. Likewise, treatment of control cells with 10 nM-BAY K 8644 leads to no significant increase in aldosterone secretory rate, but treatment of previously exposed cells to angiotensin II leads to an increase in rate from 51 +/- 9 to 130 +/- 11 pg/min per 10(6) cells. This memory effect is time-dependent in two ways: cells must be exposed to angiotensin II for 20 min or more before it is apparent; the longer the time between removal of angiotensin II and the rechallenge, the less effect these agents have on aldosterone secretory rate. When cells are exposed to angiotensin II for 20 min and then treated with [Sar1,Ala8]angiotensin II, a competitive antagonist of angiotensin II action, the aldosterone secretory rate falls to basal with a half time of 5-7 min. If BAY K 8644 is added simultaneously with [Sar1,Ala8]angiotensin II, the secretory rate falls with a halftime of 35-60 min. BAY K 8644 increases Ca2+ influx rate to the same extent in the presence or absence of [Sar1,Ala8]angiotensin II, and does not alter the effect of either angiotensin II or [Sar1,Ala8]angiotensin II on the production of inositol tris-, bis-, or mono-phosphate. In cells treated with 10 nM-angiotensin II for either 20, 30 or 45 min, the extent of phosphorylation of four cellular proteins is increased. If cells treated for 20 min with angiotensin II are then treated with [Sar1,Ala8]angiotensin II, and examined 15 min later (35 min), there is no longer an increase in the extent of phosphorylation of any of the four proteins. If such cells are then treated with 10 nM-BAY K 8644 and re-examined 5 min later (40 min), all four patients show an increase in the extent of phosphorylation.(ABSTRACT TRUNCATED AT 400 WORDS)


Early-onset colorectal cancer: a sporadic or inherited disease?
Colorectal cancer is the third most common cancer diagnosed worldwide. Although epidemiology data show a marked variability around the world, its overall incidence rate shows a slow but steady decrease, mainly in developed countries. Conversely, early-onset colorectal cancer appears to display an opposite trend with an overall prevalence in United States and European Union ranging from 3.0% and 8.6%. Colorectal cancer has a substantial proportion of familial cases. In particular, early age at onset is especially suggestive of hereditary predisposition. The clinicopathological and molecular features of colorectal cancer cases show a marked heterogeneity not only between early- and late-onset cases but also within the early-onset group. Two distinct subtypes of early-onset colorectal cancers can be identified: a "sporadic" subtype, usually without family history, and an inherited subtype arising in the context of well defined hereditary syndromes. The pathogenesis of the early-onset disease is substantially well characterized in the inherited subtype, which is mainly associated to the Lynch syndrome and occasionally to other rare mendelian diseases, whereas in the "sporadic" subtype the origin of the disease may be attributed to the presence of various common/rare genetic variants, so far largely unidentified, displaying variable penetrance. These variants are thought to act cumulatively to increase the risk of colorectal cancer, and presumably to also anticipate its onset. Efforts are ongoing in the attempt to unravel the intricate genetic basis of this "sporadic" early-onset disease. A better knowledge of molecular entities and pathways may impact on family-tailored prevention and clinical management strategies.


Microsatellite instability and expression of hMLH-1 and hMSH-2 in sebaceous gland carcinomas as markers for Muir-Torre syndrome.
Sebaceous gland carcinomas (SGCs) are rare malignant skin tumors occurring sporadically or as a phenotypic feature of the Muir-Torre syndrome (MTS). A subset of patients with MTS have a variant of the hereditary nonpolyposis colorectal cancer syndrome caused by mutations in mismatch repair (MMR) genes, which lead to microsatellite instability (MSI). We evaluated the value of MSI and loss of expression of the MMR genes, hMLH-1 and hMSH-2, as a marker to identify and distinguish MTS from sporadic SGC. Using a nationwide pathology report database system, we identified patients with the MTS phenotype. SGCs from 10 MTS patients and the colorectal carcinomas from 3 additional MTS patients were collected. In addition, SGCs from eight patients without a history of visceral neoplasm were collected. MSI was detected in 9 of 13 MTS-associated tumors (69%) versus 0 of 8 sporadic SGCs (P = 0.002). Except for the age of onset of colorectal carcinoma [58 years in the MSI-positive group versus 69.8 years in the MSI-negative group (P = 0.17)], no differences were seen between the MSI-negative and the MSI-positive MTS patients. Loss of expression of hMLH-1 (n = 4) or hMSH-2 (n = 4) was found in MSI-positive patients only. MSI and loss of expression of MMR genes can be used as markers for MTS in patients with SGC. Consequently, MSI and loss of MMR gene expression in a patient presenting with SGC as the initial malignancy have important consequences for the patient and family. There are at least two variants of MTS with different molecular genetic mechanisms because 31% of the patients with the MTS phenotype had no MSI.


Improving the quality of automatic DNA sequence assembly using fluorescent trace-data classifications.
Virtually all large-scale sequencing projects use automatic sequence-assembly programs to aid in the determination of DNA sequences. The computer-generated assemblies required substantial hand-editing to transform them into submissions for GenBank. As the size of sequencing projects increases, it becomes essential to improve the quality of the automated assemblies so that this time consuming hand-editing may be reduced. Current ABI sequencing technology uses base calls made from fluorescently-labeled DNA fragments run on gels. We present a new representation for the fluorescent trace data associated with individual base calls. This representation can be used before, during, and after fragment assembly to improve the quality of assemblies. We demonstrate one such use-end-trimming of sub-optimal data-that results in a significant improvement in the quality of subsequent assemblies.


Pathophysiology of levodopa-induced dyskinesias in Parkinson's disease: problems with the current model.
The anatomical and physiological basis of levodopa-induced dyskinesias (LIDs) in patients with Parkinson's disease (PD) is reviewed in the light of the current model for the organization of the basal ganglia. This model, which was developed in the late 1980s, works relatively well in explaining the motor features of PD but, for example, it does not account for why tremor, rigidity, bradykinesia, gait dysfunction and postural instability present to differing degrees in different patients, and may respond differently to levodopa treatment or surgical procedures. Recent information suggests that LIDs develop as a consequence of pulsatile stimulation of dopamine receptors, with consequent dysregulation of genes and proteins in downstream neurons resulting in changes in neuronal firing patterns. A modified model of the basal ganglia in PD patients with LID is proposed, which incorporates more recent clinical and experimental data.


The relationship between inadvertent ingestion and dermal exposure pathways: a new integrated conceptual model and a database of dermal and oral transfer efficiencies.
Occupational inadvertent ingestion exposure is ingestion exposure due to contact between the mouth and contaminated hands or objects. Although individuals are typically oblivious to their exposure by this route, it is a potentially significant source of occupational exposure for some substances. Due to the continual flux of saliva through the oral cavity and the non-specificity of biological monitoring to routes of exposure, direct measurement of exposure by the inadvertent ingestion route is challenging; predictive models may be required to assess exposure. The work described in this manuscript has been carried out as part of a project to develop a predictive model for estimating inadvertent ingestion exposure in the workplace. As inadvertent ingestion exposure mainly arises from hand-to-mouth contact, it is closely linked to dermal exposure. We present a new integrated conceptual model for dermal and inadvertent ingestion exposure that should help to increase our understanding of ingestion exposure and our ability to simultaneously estimate exposure by the dermal and ingestion routes. The conceptual model consists of eight compartments (source, air, surface contaminant layer, outer clothing contaminant layer, inner clothing contaminant layer, hands and arms layer, perioral layer, and oral cavity) and nine mass transport processes (emission, deposition, resuspension or evaporation, transfer, removal, redistribution, decontamination, penetration and/or permeation, and swallowing) that describe event-based movement of substances between compartments (e.g. emission, deposition, etc.). This conceptual model is intended to guide the development of predictive exposure models that estimate exposure from both the dermal and the inadvertent ingestion pathways. For exposure by these pathways the efficiency of transfer of materials between compartments (for example from surfaces to hands, or from hands to the mouth) are important determinants of exposure. A database of transfer efficiency data relevant for dermal and inadvertent ingestion exposure was developed, containing 534 empirically measured transfer efficiencies measured between 1980 and 2010 and reported in the peer-reviewed and grey literature. The majority of the reported transfer efficiencies (84%) relate to transfer between surfaces and hands, but the database also includes efficiencies for other transfer scenarios, including surface-to-glove, hand-to-mouth, and skin-to-skin. While the conceptual model can provide a framework for a predictive exposure assessment model, the database provides detailed information on transfer efficiencies between the various compartments. Together, the conceptual model and the database provide a basis for the development of a quantitative tool to estimate inadvertent ingestion exposure in the workplace.


Mindful with Your Baby: Feasibility, Acceptability, and Effects of a Mindful Parenting Group Training for Mothers and Their Babies in a Mental Health Context.
Many mothers experience difficulties after the birth of a baby. Mindful parenting may have benefits for mothers and babies, because it can help mothers regulate stress, and be more attentive towards themselves and their babies, which may have positive effects on their responsivity. This study examined the effectiveness of Mindful with your baby, an 8-week mindful parenting group training for mothers with their babies. The presence of the babies provides on-the-spot practicing opportunities and facilitates generalization of what is learned. Forty-four mothers with their babies (0-18 months), who were referred to a mental health clinic because of elevated stress or mental health problems of the mother, infant (regulation) problems, or mother-infant interaction problems, participated in 10 groups, each comprising of three to six mother-baby dyads. Questionnaires were administered at pretest, posttest, 8-week follow-up, and 1-year follow-up. Dropout rate was 7%. At posttest, 8-week follow-up, and 1-year follow-up, a significant improvement was seen in mindfulness, self-compassion, mindful parenting, (medium to large effects), as well as in well-being, psychopathology, parental confidence, responsivity, and hostility (small to large effects). Parental stress and parental affection only improved at the first and second follow-ups, respectively (small to medium effects), and maternal attention and rejection did not change. The infants improved in their positive affectivity (medium effect) but not in other aspects of their temperament. Mindful with your baby is a promising intervention for mothers with babies who are referred to mental health care because of elevated stress or mental health problems, infant (regulation) problems, or mother-infant interaction problems.


Modified minimum-distance criterion for blended random and nonrandom encoding.
Two pixel-oriented methods for designing Fourier transform holograms--pseudorandom encoding and minimum-distance encoding-usually produce higher-fidelity reconstructions when combined than those produced by each method individually. In previous studies minimum-distance encoding was defined as the mapping from the desired complex value to the closest value produced by the modulator. This method is compared with a new minimum-distance criterion in which the desired complex value is mapped to the closest value that can be realized by pseudorandom encoding. Simulations and experimental measurements using quantized phase and amplitude modulators show that the modified approach to blended encoding produces more faithful reconstructions than those of the previous method.


Rapid image-segmentation and perceptual transparency share a process which utilises X-junctions generated by temporal integration in the visual system.
Perceptual transparency requires local same-polarity X-junctions, which can also be generated by temporal integration under natural dynamic conditions. In this study, segmentation performance and target appearance were measured for a uniform gray target embedded in a random-dot frame presented with a temporally adjacent mask. Although static cues for both segmentation and transparency were unavailable, transparency was observed only when collinear same-polarity edges reduced backward masking, in both the fovea and the perifovea. These results suggest that the visual system has a common underlying mechanism for rapid segmentation and transparency, which utilises same-polarity X-junctions generated by temporal integration.


Simulating Ideal Assistive Devices to Reduce the Metabolic Cost of Running.
Tools have been used for millions of years to augment the capabilities of the human body, allowing us to accomplish tasks that would otherwise be difficult or impossible. Powered exoskeletons and other assistive devices are sophisticated modern tools that have restored bipedal locomotion in individuals with paraplegia and have endowed unimpaired individuals with superhuman strength. Despite these successes, designing assistive devices that reduce energy consumption during running remains a substantial challenge, in part because these devices disrupt the dynamics of a complex, finely tuned biological system. Furthermore, designers have hitherto relied primarily on experiments, which cannot report muscle-level energy consumption and are fraught with practical challenges. In this study, we use OpenSim to generate muscle-driven simulations of 10 human subjects running at 2 and 5 m/s. We then add ideal, massless assistive devices to our simulations and examine the predicted changes in muscle recruitment patterns and metabolic power consumption. Our simulations suggest that an assistive device should not necessarily apply the net joint moment generated by muscles during unassisted running, and an assistive device can reduce the activity of muscles that do not cross the assisted joint. Our results corroborate and suggest biomechanical explanations for similar effects observed by experimentalists, and can be used to form hypotheses for future experimental studies. The models, simulations, and software used in this study are freely available at simtk.org and can provide insight into assistive device design that complements experimental approaches.


The nu(2) Bands of the Deuterated Species D(2)Se and HDSe.
For the first time D(2)Se and HDSe as (80)Se monoisotopic and natural material were studied in the region of the nu(2) fundamental vibration by high-resolution (0.0033 cm(-1)) Fourier transform infrared spectroscopy. For D(2)Se which is an asymmetric rotor with C(2v) symmetry the nu(2) band is of B type while for HDSe (C(s) symmetry) it is a hybrid band, and both A- and B-type transitions were observed. Depending on the isotopic abundances, 300-1000 lines were assigned for each of the isotopic (M)Se species (M = 76, 77, 78, 80, and 82). The corresponding (010) experimental rotational levels, obtained by adding the observed line positions to the ground state levels derived from J.-M. Flaud, Ph. Arcas, O. N. Ulenikov, G. A. Onopenko, N. E. Tyabaeva, W. Jerzembeck, and H. Bürger, (J. Mol. Spectrosc., in press) were fitted satisfactorily using a Watson-type Hamiltonian in A reduction and I(r)-representation: the rms deviations are ranging from 1.5 to 4.3 x 10(-4) cm(-1) depending on the isotopic species. Hamiltonian constants up to high order (octic terms) were determined for each isotopic species. For the most abundant Se isotopic species, namely (80)Se, the band centers are nu(0) (D(2)(80)Se) = 741.67503 cm(-1) and nu(0) (HD(80)Se) = 900.43820 cm(-1). Copyright 1999 Academic Press.


Antibodies against the Mycobacterium tuberculosis complex and Brucella spp. in captive and free-living European bison (Bison bonasus) in Poland.
The European bison (Bison bonasus), a symbol of Polish nature, is a protected species that requires active health monitoring. However, conservation efforts are made difficult by the zoonotic diseases such as brucellosis and tuberculosis. The aim of this study was to screen the Polish European bison population for exposure to the Mycobacterium tuberculosis complex (MTC) and Brucella spp. A total of 323 free-living and captive European bison from 13 localities were tested serologically for antibodies against the M. bovis P22 multi-protein complex (in-house ELISA) and against Brucella spp. (commercial ELISA). Antibodies against the MTC (P22) were detected in 7% (22/323) of the tested European bison. Anti-MTC antibody positivity was not significantly different by sex, age, and captive/free range status. Anti-MTC antibodies were found in six of 13 populations sampled, always in populations with larger sample sizes including the four free-living ones. Antibodies against Brucella spp. were detected in 36% (116/323) of the tested bison. While Brucella spp. antibody prevalence was not different by sex, it was significantly different by age (lower in adults) and captive/free-living status. Brucella spp. seroprevalence decreased with sample size and seropositive bison were found in 12 of 13 sampling populations. Our findings identify potential emerging threats to the European bison population and confirm the first serological response to P22 in European bison. As Poland is currently officially free of brucellosis and bovine tuberculosis, our results require careful interpretation. Further studies are needed to establish the presence of cross-reactions with atypical mycobacteria in the case of MTC and other bacteria (e.g. Yersinia enterocolitica O:9) in the case of Brucella spp.


Is it me or is it them? Factors that influence the passing of underperforming students.
Research has found that clinical assessments do not always accurately reflect medical student performance. Barriers to failing underperformance in students have been identified in other vocational settings. Is 'failure to fail' an issue for medical educators in the UK, and, if so, what are its determinants? We carried out a qualitative focus group study exploring the views of medical educators (general practitioners, hospital doctors and non-clinical tutors) from two different UK medical schools. To make sense of a potential multitude of factors impacting on failure to fail, we selected the integrative model of behavioural prediction to underpin our data collection and analysis. Ten focus groups were carried out with 70 participants. Using both theory and data-driven framework analysis, we identified six main themes relevant to the integrative model of behavioural prediction. These are: tutor attitudes towards an individual student; tutor attitudes towards failing a student; normative beliefs and motivation to comply; efficacy beliefs (self-efficacy); skills and knowledge, and environmental constraints. Many different factors impact on medical educators' failure to report underperformance in students. There are conflicts between these factors and the need to report competence accurately (i.e. duty to protect the public). Although some of the barriers identified are similar to those found in previous studies, using a theory-based approach added value in that it facilitated a richer exploration of failure to fail. Insights offered in this study will be used to plan a questionnaire study and subsequent intervention to support medical educators in accurately reporting underperformance in students.


Structure and 31P NMR spectroscopy of a new phosphate, Na8Ca1.5Mg12.5(PO4)12.
A new phosphate, sodium calcium magnesium tetrakis(phosphate), Na(8)Ca(1.5)Mg(12.5)(PO(4))(12), has been synthesized by a flux method. Its novel structure consists of MgO(x) (x = 5 and 6) polyhedra and MO(7) (M = Mg or Na) octahedra linked directly through common corners or edges to form a rigid three-dimensional skeleton, reinforced by corner-sharing between identical Mg(12)MO(48) units. The connection of these units by the PO(4) tetrahedra induces cavities and crossing tunnels where the Na(+) and Ca(2+) cations are located. This structural model was supported by a (31)P NMR spectroscopy study which confirmed the existence of 12 crystallographically independent sites for the P atoms.


The use of in vitro reconstituted human skin in dermotoxicity testing.
As they simulate the multilayer tissue architecture present in vivo, three-dimensional (3D) cultures of skin epithelial cells represent an attractive alternative for in vitro irritancy testing. In this study histology of non-commercial (Skin recombinant on de-epidermized dermis) and commercial models (Episkin, ZK 1300, Living Skin Equivalent) was compared. All 3D models possess a stratified epidermis with a differentiated stratum corneum. Their barrier function has been demonstrated by comparison of surfactants cytotoxicity on the 3D models and on human keratinocyte monolayer culture, and by the evaluation of the tritiated water penetration. All the 3D models showed permeability higher than fresh skin, the skin recombinant on DDED being the less permeable. However, reconstituted skin models possess several advantages for dermotoxicity testing, including the standardized nature of the epithelia and their suitability for testing water-insoluble compounds.


Motor assessment using the NIH Toolbox.
Motor function involves complex physiologic processes and requires the integration of multiple systems, including neuromuscular, musculoskeletal, and cardiopulmonary, and neural motor and sensory-perceptual systems. Motor-functional status is indicative of current physical health status, burden of disease, and long-term health outcomes, and is integrally related to daily functioning and quality of life. Given its importance to overall neurologic health and function, motor function was identified as a key domain for inclusion in the NIH Toolbox for Assessment of Neurological and Behavioral Function (NIH Toolbox). We engaged in a 3-stage developmental process to: 1) identify key subdomains and candidate measures for inclusion in the NIH Toolbox, 2) pretest candidate measures for feasibility across the age span of people aged 3 to 85 years, and 3) validate candidate measures against criterion measures in a sample of healthy individuals aged 3 to 85 years (n = 340). Based on extensive literature review and input from content experts, the 5 subdomains of dexterity, strength, balance, locomotion, and endurance were recommended for inclusion in the NIH Toolbox motor battery. Based on our validation testing, valid and reliable measures that are simultaneously low-cost and portable have been recommended to assess each subdomain, including the 9-hole peg board for dexterity, grip dynamometry for upper-extremity strength, standing balance test, 4-m walk test for gait speed, and a 2-minute walk test for endurance.


The untreated anterior cruciate ligament rupture.
Forty-nine patients (52 knees) with untreated anterior cruciate ligament (ACL) ruptures were evaluated an average of 14 years after injury. The results were compared with those of a ten-year follow-up study on the same patients. Eighty-six percent of the knees had one or both menisci removed. There had been little change in symptoms, except that the incidence of giving way had decreased. The incidence of anterior laxity and rotary instability continued to be high. Seventy-five percent of the patients continued to participate in strenuous sports. The incidence of degenerative changes on roentgenograms had increased, with one-third of the knees demonstrating joint space narrowing or unequivocal evidence of osteoarthritis. Development of degenerative changes was associated with varus deformity, meniscectomy, and relatively heavy body weight.


Salivary testing to reduce sugar consumption in school children.
A total of 423 elementary and middle school children participated in a project to see if it would be possible to reduce their sugar consumption. Children tested their salivary lactobacillus colony count and buffering capacity in their health/science class, and they used this information to measure their caries risk. Because the lactobacillus colony count is a good indicator of a person's recent sugar consumption, any change in sugar consumption will produce a change in the lactobacillus colony count. Children's saliva was tested four times, and an intensive dietary counseling program was provided in the classroom. Results showed that lactobacillus counts went down, and the children reduced their sugar consumption.


Critical Review of Health Impacts of Wildfire Smoke Exposure.
Wildfire activity is predicted to increase in many parts of the world due to changes in temperature and precipitation patterns from global climate change. Wildfire smoke contains numerous hazardous air pollutants and many studies have documented population health effects from this exposure. We aimed to assess the evidence of health effects from exposure to wildfire smoke and to identify susceptible populations. We reviewed the scientific literature for studies of wildfire smoke exposure on mortality and on respiratory, cardiovascular, mental, and perinatal health. Within those reviewed papers deemed to have minimal risk of bias, we assessed the coherence and consistency of findings. Consistent evidence documents associations between wildfire smoke exposure and general respiratory health effects, specifically exacerbations of asthma and chronic obstructive pulmonary disease. Growing evidence suggests associations with increased risk of respiratory infections and all-cause mortality. Evidence for cardiovascular effects is mixed, but a few recent studies have reported associations for specific cardiovascular end points. Insufficient research exists to identify specific population subgroups that are more susceptible to wildfire smoke exposure. Consistent evidence from a large number of studies indicates that wildfire smoke exposure is associated with respiratory morbidity with growing evidence supporting an association with all-cause mortality. More research is needed to clarify which causes of mortality may be associated with wildfire smoke, whether cardiovascular outcomes are associated with wildfire smoke, and if certain populations are more susceptible. Reid CE, Brauer M, Johnston FH, Jerrett M, Balmes JR, Elliott CT. 2016. Critical review of health impacts of wildfire smoke exposure. Environ Health Perspect 124:1334-1343; http://dx.doi.org/10.1289/ehp.1409277.


Acute small fiber neuropathy after Oxford-AstraZeneca ChAdOx1-S vaccination: A report of three cases and review of the literature.
Small fiber neuropathy usually presents with gradual and progressive chronic length-dependent pain. Acute small fiber neuropathy is rarely reported. Three patients with acute onset neuropathic pain after Oxford-AstraZeneca ChAdOx1-S vaccination are described. Two patients were identified at the Oxford University NHS Foundation Trust, Oxford, UK and one patient in Red de Salud UC Christus, Santiago, Chile. All patients underwent a clinical assessment that included a detailed neurological examination, laboratory investigations, nerve conduction studies, thermal threshold testing, and skin biopsy for intra-epidermal nerve fiber density. Patients seen in Oxford underwent MRI of the brain and spinal cord. Cerebrospinal analysis was not performed. Neuropathic symptoms (burning pain, dysaesthesias) developed in the hands and feet within 2 weeks of vaccination. On clinical examination, there was pinprick and thermal hyposensitivity in the area of neuropathic pain. Laboratory investigation, nerve conduction tests, sympathetic skin responses, and MRI showed no relevant abnormalities. Thermal thresholds were abnormal and intra-epidermal nerve fiber density in the lower leg was reduced. In two cases symptoms persist after several months. Three cases of definite acute small fiber neuropathy after Oxford-AstraZeneca ChAdOx1-S vaccination are described. At follow up, neuropathic pain was present in two of the patients.


Prevalence and factors associated with exclusive breastfeeding at 6 months of life in Tehran: a population-based study.
Exclusive breastfeeding is the best form of nutrition for infants in the first 6 months of life. The aim of this study was to determine the prevalence of exclusive breastfeeding in Tehran, Islamic Republic of Iran in the first 6 months of life, and the factors that influence it. In a population-based, cross-sectional study 538 mothers with children aged 6-24 months completed an interview questionnaire. Only 46.5% of mothers exclusively breastfed their infant in the first 6 months of life. In multivariate analysis formula supplementation in the hospital (OR = 0.41, 95% CI: 0.17-0.95) and mother receiving conflicting infant feeding advice (OR = 0.53, 95% CI: 0.37-0.78) had a negative effect on exclusive breastfeeding. Mother's intention to exclusively breastfeed (OR = 5.85, 95% CI: 2.88-11.9) and infant having first breast contact 6-30 minutes after delivery (OR = 2.35, 95% CI: 1.17-4.72) had positive effects on exclusive breastfeeding.


Dynamic exercise changes in venous pressure and liver stiffness in Fontan patients: effects of Treprostinil.
Systemic venous hypertension and low cardiac output are believed to be important mediators of liver injury after the Fontan procedure. Pulmonary vasodilators have the potential to improve such haemodynamics. The aim of this study was to assess the acute effects of exercise on liver stiffness and venous pressures and to assess the impact of inhaled Treprostinil on this response. In this prospective, double-blind, placebo-controlled, crossover trial, 14 patients with a Fontan circulation were randomised to inhalation of placebo and Treprostinil. Incremental and constant work rate exercise tests were performed to assess the effect of Treprostinil on exercise tolerance. Venous pressures were measured throughout and liver stiffness at rest and immediately after peak exercise. Mean age was 27.8 ± 7.9 years and 66% were females. Exercise acutely increased liver stiffness by 30% (mean shear wave speed: 2.38 ± 0.71 versus 2.89 ± 0.51 ms, p = 0.02). Peripheral venous pressures increased acutely during both incremental (12.1 ± 2.4 versus 22.6 ± 8.0 mmHg, p < 0.001) and constant work rate exercise (12.5 ± 2.5 versus 23.4 ± 5.2 mmHg, p < 0.001). Overall, Treprostinil failed to attenuate exercise-induced increases in liver stiffness. Compared with placebo, Treprostinil did not significantly impact venous pressure responses, VO2peak, nor exercise endurance times. Peripheral venous pressure increased acutely during exercise by an average of 88% above baseline and was not altered by administration of inhaled Treprostinil. Liver stiffness measured immediately post-exercise increased acutely by an average of 30%, with no attenuation following Treprostinil inhalation.


A new goatfish of the genus Upeneus (Mullidae) from Angoche, northern Mozambique.
A new goatfish, Upeneus saiab n. sp. (Mullidae), is described from six specimens collected off Angoche, northern Mozambique, during a research cruise of the RV Dr. F. Nansen in August 2009. Upeneus saiab n. sp. differs from all congeneric species in the following combination of characteristics: seven dorsal-fin spines, 29 total gill rakers, body depth at anal-fin origin 17-19% SL, and pectoral-fin length 20-21% SL. Detailed comparisons with the eight other species of the japonicus group are made and a key for Western Indian Ocean species is provided. A new record of Upeneuspori for Kwa-Zulu-Natal, South Africa, is reported based on in situ photographs. The need for further exploration of the rather long and ecologically diverse Mozambican coast and adjacent areas of southeastern Africa for the occurrence of yet undescribed or unreported goatfish species is emphasized.


Characterizing Highly Benefited Patients in Randomized Clinical Trials.
Physicians and patients may choose a certain treatment only if it is predicted to have a large effect for the profile of that patient. We consider randomized controlled trials in which the clinical goal is to identify as many patients as possible that can highly benefit from the treatment. This is challenging with large numbers of covariate profiles, first, because the theoretical, exact method is not feasible, and, second, because usual model-based methods typically give incorrect results. Better, more recent methods use a two-stage approach, where a first stage estimates a working model to produce a scalar predictor of the treatment effect for each covariate profile; and a second stage estimates empirically a high-benefit group based on the first-stage predictor. The problem with these methods is that each of the two stages is usually agnostic about the role of the other one in addressing the clinical goal. We propose a method that characterizes highly benefited patients by linking model estimation directly to the particular clinical goal. It is shown that the new method has the following two key properties in comparison with existing approaches: first, the meaning of the solution with regard to the clinical goal is the same, and second, the value of the solution is the best that can be achieved when using the working model as a predictor, even if that model is incorrect. In the Citalopram for Agitation in Alzheimer's Disease (CitAD) randomized controlled trial, the new method identifies substantially larger groups of highly benefited patients, many of whom are missed by the standard method.


Native cysteine residues are dispensable for the structure and function of all five yeast mitotic septins.
Budding yeast septins assemble into hetero-octamers and filaments required for cytokinesis. Solvent-exposed cysteine (Cys) residues provide sites for attaching substituents useful in assessing assembly kinetics and protein interactions. To introduce Cys at defined locations, site-directed mutagenesis was used, first, to replace the native Cys residues in Cdc3 (C124 C253 C279), Cdc10 (C266), Cdc11 (C43 C137 C138), Cdc12 (C40 C278), and Shs1 (C29 C148) with Ala, Ser, Val, or Phe. When plasmid-expressed, each Cys-less septin mutant rescued the cytokinesis defects caused by absence of the corresponding chromosomal gene. When integrated and expressed from its endogenous promoter, the same mutants were fully functional, except Cys-less Cdc12 mutants (which were viable, but exhibited slow growth and aberrant morphology) and Cdc3(C124V C253V C279V) (which was inviable). No adverse phenotypes were observed when certain pairs of Cys-less septins were co-expressed as the sole source of these proteins. Cells grew less well when three Cys-less septins were co-expressed, suggesting some reduction in fitness. Nonetheless, cells chromosomally expressing Cys-less Cdc10, Cdc11, and Cdc12, and expressing Cys-less Cdc3 from a plasmid, grew well at 30°C. Moreover, recombinant Cys-less septins--or where one of the Cys-less septins contained a single Cys introduced at a new site--displayed assembly properties in vitro indistinguishable from wild-type.


Local recurrence rates after radiofrequency ablation or resection of colorectal liver metastases. Analysis of the European Organisation for Research and Treatment of Cancer #40004 and #40983.
The aim of this study is to describe local tumour control after radiofrequency ablation (RFA) and surgical resection (RES) of colorectal liver metastases (CLM) in two independent European Organisations for Research and Treatment of Cancer (EORTC) studies. Only 10-20% of patients with newly diagnosed CLM are eligible for curative RES. RFA has found a place in daily practice for unresectable CLM. There are no prospective trials comparing RFA to RES for resectable CLM. The CLOCC trial randomised 119 patients with unresectable CLM between RFA (±RES)+adjuvant FOLFOX (±bevacizumab) versus FOLFOX (±bevacizumab) alone. The EPOC trial randomised 364 patients with resectable CLM between RES±perioperative FOLFOX. We describe the local control of resected patients with lesions ≤4 cm in the perioperative chemotherapy arm of the EPOC trial (N=81) and the RFA arm of the CLOCC trial (N=55). Local recurrence (LR) rate for RES was 7.4% per patient and 5.5% per lesion. LR rate for RFA was 14.5% per patient and 6.0% per lesion. When lesion size was limited to 30 mm, LR rate for RFA lesions was 2.9% per lesion. Non-local hepatic recurrences were more often observed in RFA patients than in RES patients, 30.9% and 22.3% respectively. Patients receiving RFA had a more advanced disease. LR rate after RFA for lesions with a limited size is low. The local control per lesion does not appear to differ greatly between RFA and surgical resection. This study supports the local control of RFA in patients with limited liver metastases. Future studies should evaluate in which patients RFA could be an equal alternative to liver resection.


Active case finding of tuberculosis in Europe: a Tuberculosis Network European Trials Group (TBNET) survey.
Tuberculosis control depends on successful case finding and treatment of individuals infected with Mycobacterium tuberculosis. Passive case finding is widely practised: the present study aims to ascertain the consensus and possible improvements in active case finding across Europe. Recommendations from national guidelines were collected from 50 countries of the World Health Organization European region using a standard questionnaire. Contacts are universally screened for active tuberculosis and latent tuberculosis infection (LTBI). Most countries (>70%) screen those with HIV infection, prisoners and in-patient contacts. Screening of immigrants is related to their contribution to national rates of tuberculosis. Only 25 (50%) out of 50 advise a request for symptoms in their guidelines. A total of 36 (72%) out of 50 countries recommend sputum examination for those with a persistent cough; 13 countries do not, even if the chest radiograph suggests tuberculosis. Nearly all countries (49 out of 50) use tuberculin skin testing (TST); 27 (54%) out of 50 countries also perform chest radiography irrespective of the TST result. Interpretation of the TST varies widely. All countries use 6-9 months of isoniazid for treatment of LTBI, with an estimated median (range) uptake of 55% (5-92.5%). Symptoms and sputum examination could be used more widely when screening for active tuberculosis. Treatment of latent tuberculosis infection might be better focused by targeted use of interferon-gamma release assays.


Dependence of silicon position-detector bandwidth on wavelength, power, and bias.
We have developed a two-LED wobbler system to generate the spatial displacement of total light intensity on a detector surface, facilitating the acquisition of frequency responses up to 600 kHz with high accuracy. We have used this setup to characterize the low-pass filtering behavior of silicon-based position detectors for wavelengths above 850 nm by acquiring the frequency responses of several quadrant detectors and position-sensitive detectors as functions of wavelength, applied bias voltage, and total light power. We observed an increase in bandwidth for an increase in applied bias voltage and incident-light intensity. The combined effect of these parameters is strongly dependent on the detector used and has significant implications for the use of these detectors in scanning probe and optical tweezers applications.


Translational regulation of acetylcholinesterase by the RNA-binding protein Pumilio-2 at the neuromuscular synapse.
Acetylcholinesterase (AChE) is highly expressed at sites of nerve-muscle contact where it is regulated at both the transcriptional and post-transcriptional levels. Our understanding of the molecular mechanisms underlying its regulation is incomplete, but they appear to involve both translational and post-translational events as well. Here, we show that Pumilio-2 (PUM2), an RNA binding translational repressor, is highly localized at the neuromuscular junction where AChE mRNA concentrates. Immunoprecipitation of muscle cell extracts with a PUM2 specific antibody precipitated AChE mRNA, suggesting that PUM2 binds to the AChE transcripts in a complex. Gel shift assays using a bacterially expressed PUM2 RNA binding domain showed specific binding using wild type AChE 3'-UTR RNA segment that was abrogated by mutation of the consensus recognition site. Transfecting skeletal muscle cells with shRNAs specific for PUM2 up-regulated AChE expression, whereas overexpression of PUM2 decreased AChE activity. We conclude that PUM2 binds to AChE mRNA and regulates AChE expression translationally at the neuromuscular synapse. Finally, we found that PUM2 is regulated by the motor nerve suggesting a trans-synaptic mechanism for locally regulating translation of specific proteins involved in modulating synaptic transmission, analogous to CNS synapses.


The Short Synacthen (Corticotropin) Test Can Be Used to Predict Recovery of Hypothalamo-Pituitary-Adrenal Axis Function.
The 250-μg short Synacthen (corticotropin) test (SST) is the most commonly used tool to assess hypothalamo-pituitary-adrenal (HPA) axis function. There are many potentially reversible causes of adrenal insufficiency (AI), but no data to guide clinicians as to the frequency of repeat testing or likelihood of HPA axis recovery. To use the SST results to predict adrenal recovery. A retrospective analysis of 1912 SSTs data. Seven hundred seventy-six patients with reversible causes of AI were identified who had at least two SSTs performed. A subgroup analysis was performed on individuals previously treated with suppressive doses of glucocorticoids (n = 110). Recovery of HPA axis function. SST 30-minute cortisol levels above or below 350 nmol/L (12.7 μg/dL) best predicted HPA axis recovery [area under the curve (AUC) receiver operating curve (ROC) = 0.85; median recovery time: 334 vs 1368 days, P = 8.5 × 10-13]: 99% of patients with a 30-minute cortisol >350 nmol/L recovered adrenal function within 4 years, compared with 49% in those with cortisol levels <350 nmol/L. In the subgroup analysis, delta cortisol (30-minute-basal) best predicted the recovery (AUC ROC = 0.77; median recovery time: 262 vs 974 days, P = 7.0 × 10-6). No patient with a delta cortisol <100 nmol (3.6 μg/dL) and a subsequent 1-year random cortisol <200 nmol/L (7.3 μg/dL) recovered HPA axis function. Cortisol levels across an SST can be used to predict recovery of AI and may guide the frequency of repeat testing and inform both clinicians and patients as to the likelihood of restoration of HPA axis function.


Economic evaluation of telephone-based concussion management for combat-related mild traumatic brain injury.
Introduction Mild traumatic brain injury (mTBI) is an unfortunately common repercussion of military service in a combat zone. The CONTACT study tested an individualized telephone support intervention employing problem solving therapy (PST) for mTBI in soldiers recently returned from deployment. We sought to determine the cost effectiveness of this intervention from a military healthcare system perspective. Methods We conducted an intent-to-treat post-hoc analysis by building a decision analytic model that evaluated the choice between using PST or education only (EO). The model included cost-minimization and cost-effectiveness analyses. The incremental cost-effectiveness ratios (ICERs) were calculated as the differences in costs of PST versus EO relative to the differences in the outcomes of participants. Results The PST intervention resulted in an annual per-enrolee cost of $1027 (95% CI: $836 to $1248), while EO costs were $32 (95% CI: $25 to $39), resulting in a net incremental cost of $996 per enrolee (95% CI: $806 to $1,217). The ICERs were $68,658/QALY based on EQ-5D (95% CI: -$463,535 to $596,661) and $49,284/QALY based on SF-6D (95% CI: $26,971 to $159,309). Estimates of treatment costs in a real-world setting were accompanied by substantially lower ICERs that are within accepted thresholds for willingness-to-pay. Discussion Although the intervention had short-term benefits sufficient to yield acceptable ICERs, there was no long-term effect of PST over EO observed in the study. Consequently, we suggest that future studies examine the use of low-cost approaches, such as booster relapse-prevention calls, that may lead to a sustained treatment benefit for this population.


Citizen sensors for SHM: use of accelerometer data from smartphones.
Ubiquitous smartphones have created a significant opportunity to form a low-cost wireless Citizen Sensor network and produce big data for monitoring structural integrity and safety under operational and extreme loads. Such data are particularly useful for rapid assessment of structural damage in a large urban setting after a major event such as an earthquake. This study explores the utilization of smartphone accelerometers for measuring structural vibration, from which structural health and post-event damage can be diagnosed. Widely available smartphones are tested under sinusoidal wave excitations with frequencies in the range relevant to civil engineering structures. Large-scale seismic shaking table tests, observing input ground motion and response of a structural model, are carried out to evaluate the accuracy of smartphone accelerometers under operational, white-noise and earthquake excitations of different intensity. Finally, the smartphone accelerometers are tested on a dynamically loaded bridge. The extensive experiments show satisfactory agreements between the reference and smartphone sensor measurements in both time and frequency domains, demonstrating the capability of the smartphone sensors to measure structural responses ranging from low-amplitude ambient vibration to high-amplitude seismic response. Encouraged by the results of this study, the authors are developing a citizen-engaging and data-analytics crowdsourcing platform towards a smartphone-based Citizen Sensor network for structural health monitoring and post-event damage assessment applications.


Progenitor cells in healing after pterygium excision.
Bone marrow derived progenitor cells were reported to be involved in the pathogenesis of pterygium and have been suggested to be important in angiogenesis and the repair process after tissue damage. In order to investigate the involvement of these cells in wound healing after a pterygium excision, immunohistochemical staining was performed with a temporary amniotic membrane, applied to the bare sclera, after a pterygium excision using various progenitor cell markers, including CD34, c-kit, STRO-1, and AC133, to determine the expression levels of the participating cells. CD34-positive cells were observed along with some round or spindle-shaped mononuclear cells on the stromal side of the amniotic membrane. Some CD34-positive, large, and round or spindle-shaped cells formed clusters resembling small vessels in some regions of the amniotic membrane. c-kit was expressed in the epithelium that had grown over the amniotic membrane and in the spindle-shaped or round mononuclear cells in the stroma. Many stellate- to spindle-shaped fibroblast like cells expressed STRO-1, and AC133 was expressed in some round and ovoid cells. Overall, these results suggest that adult bone marrow- derived progenitor cells, such as endothelial progenitor cells and mesenchymal stem cells, are involved in the wound healing process post-excision in patients with pterygium.


Prevalence of presenteeism among workers of an industrial company.
Attending work when sick for fear of losing the job is common among workers. Presenteeism is a rising problem, which has called the attention of researchers from different fields; being difficult to notice, it also raised concerns among managers. To establish the prevalence of presenteeism at a food industrial company. Cross-sectional epidemiological study conducted with 1,224 workers, with application of Stanford Presenteeism Scale (SPS-6) as method to investigate presenteeism. Presenteeism was adopted by 30.6% of the analyzed workers along the previous 12 months. The prevalence of presenteeism detected through SPS-6 was 50.9% for the full sample. Significant association was found between presenteeism and sedentarism, overweight and some self-reported symptoms. The detected high prevalence of presenteeism and its association with sedentary lifestyle and musculoskeletal symptoms confirm the relevance of presenteeism and its negative impact on the health of workers.


[Prevention of sudden infant death syndrome in children in preventive-treatment institutions in the Odessa region].
The sudden infant death syndrome (SIDS) is one of the most prevalent causes of infant mortality in European countries. SIDS is a sudden but not violent death in those infants aged between 7 to 365 days. Whether or not the case can be diagnosed as having had SIDS remains uncertain even after an in-depth study of the autopsy material, previous history, and death concurrent events. The study into infant care was made within the framework of the ICCPS (International child care practical study) program with 21 countries from all the corner of the globe having taken part in it. SIDS incidence in Ukraine estimated with the aid of the model of the Odessa Region has been found out to come up to 0.5-0.85%. Measures have been instituted designed to prevent SIDS as a stage of our work at women health centres, mother and child outpatient and in-patient departments of the relevant institutions. Monitoring of children at risk for SIDS is not a sufficient enough measure capable of reducing SIDS incidence as evidenced by a one-year follow-up but combined with the parents' education as to risk factors for SIDS in a preventive-treatment setting such a monitoring permitted reducing SIDS frequency from 0.85 to 0.60% in the Odessa Region.


PI3K/Akt Cooperates with Oncogenic Notch by Inducing Nitric Oxide-Dependent Inflammation.
The PI3K/Akt signaling pathway, Notch, and other oncogenes cooperate in the induction of aggressive cancers. Elucidating how the PI3K/Akt pathway facilitates tumorigenesis by other oncogenes may offer opportunities to develop drugs with fewer side effects than those currently available. Here, using an unbiased in vivo chemical genetic screen in Drosophila, we identified compounds that inhibit the activity of proinflammatory enzymes nitric oxide synthase (NOS) and lipoxygenase (LOX) as selective suppressors of Notch-PI3K/Akt cooperative oncogenesis. Tumor silencing of NOS and LOX signaling mirrored the antitumor effect of the hit compounds, demonstrating their participation in Notch-PI3K/Akt-induced tumorigenesis. Oncogenic PI3K/Akt signaling triggered inflammation and immunosuppression via aberrant NOS expression. Accordingly, activated Notch tumorigenesis was fueled by hampering the immune response or by NOS overexpression to mimic a protumorigenic environment. Our lead compound, the LOX inhibitor BW B70C, also selectively killed human leukemic cells by dampening the NOTCH1-PI3K/AKT-eNOS axis.


A new approach to quantifying the EEG during walking: Initial evidence of gait related potentials and their changes with aging and dual tasking.
The electroencephalogram (EEG) can be a useful tool to investigate the neurophysiology of gait during walking. Our aims were to develop an approach that identify and quantify event related potentials (ERPs) during a gait cycle and to examine the effects of aging and dual tasking on these gait related potentials (GRPs). 10 young and 10 older adults walked on a treadmill while wearing a wireless 20-channels EEG and accelerometers on the ankles. Each heel strike extracted from the accelerometers was used as an event to which the electrical brain activity pattern was locked. The subjects performed usual and dual task walking that included an auditory oddball task. GRPs amplitude and latency were computed, and a new measure referred to as Amplitude Pattern Consistency (APC) was developed to quantify the consistency of these GRP amplitudes within a gait cycle. The results were compared between and within groups using linear mixed model analysis. The electrical pattern during a gait cycle consisted of two main positive GRPs. Differences in these GRPs between young and older adults were observed in Pz and Cz. In Pz, older adults had higher GRPs amplitude (p = 0.006, p = 0.010), and in Cz lower APC (p = 0.025). Alterations were also observed between the walking tasks. Both groups showed shorter latency during oddball walking compared to usual walking in Cz (p = 0.040). In addition, the APC in Cz was correlated with gait speed (r = 0.599, p = 0.011) in all subjects and with stride time variability in the older adults (r = -0.703, p = 0.023). This study is the first to define specific gait related potentials within a gait cycle using novel methods for quantifying waveforms. Our findings show the potential of this approach to be applied broadly to study the EEG during gait in a variety of contexts. The observed changes in GRPs with aging and walking task and the relationship between GRPs and gait may suggest the neurophysiologic foundation for studying walking and for developing new approaches for improving gait.


Ezrin is an actin binding protein that regulates sertoli cell and spermatid adhesion during spermatogenesis.
During spermatogenesis, the transport of spermatids and the release of sperms at spermiation and the remodeling of the blood-testis barrier (BTB) in the seminiferous epithelium of rat testes require rapid reorganization of the actin-based cytoskeleton. However, the mechanism(s) and the regulatory molecule(s) remain unexplored. Herein we report findings that unfold the functional significance of ezrin in the organization of the testis-specific adherens junction at the spermatid-Sertoli cell interface called apical ectoplasmic specialization (ES) in the adluminal compartment and the Sertoli cell-cell interface known as basal ES at the BTB. Ezrin is expressed at the basal ES/BTB in all stages, except from late VIII to IX, of the epithelial cycle. Its knockdown by RNA interference (RNAi) in vitro perturbs the Sertoli cell tight junction-permeability barrier via a disruption of the actin microfilaments in Sertoli cells, which in turn impeded basal ES protein (eg, N-cadherin) distribution, perturbing the BTB function. These findings were confirmed by a knockdown study in vivo. However, the expression of ezrin at the apical ES is restricted to stage VIII of the cycle and limited only between step 19 spermatids and Sertoli cells. A knockdown of ezrin in vivo by RNAi was found to impede spermatid transport, causing defects in spermiation in which spermatids were embedded deep inside the epithelium, and associated with a loss of spermatid polarity. Also, ezrin was associated with residual bodies and phagosomes, and its knockdown by RNAi in the testis also impeded the transport of residual bodies/phagosomes from the apical to the basal compartment. In summary, ezrin is involved in regulating actin microfilament organization at the ES in rat testes.


[In-patient treatment concept for acute crises of borderline patients on the basis of dialectical-behavioral therapy].
Whereas the Dialectical-Behavioral Therapy (DBT) by Marsha Linehan for chronic suicidal female patients with borderline personality disorder has also been successfully implemented for in-patient treatment, the management of recurrent crisis has continued to be a significant challenge especially for hospitals taking part in the mandatory health coverage. Therefore, we have established an acute, short-term crisis treatment concept for both genders on a locked unit which takes the different circumstances of acute crisis into account. It ought to be used under the conditions of acute psychiatry and at the same time meet psychotherapeutic demands of borderline treatment. The treatment basis is DBT. The treatment focus is to improve stress-tolerance, especially by skills-training, regarding the individual situation and problems at time of admittance. The in-patient treatment should not take more than three weeks. The short-time aim is a fast reintegration in ambulant treatment or motivation for a specific therapy as DBT, middle- and long-time aims are the improvement of the ability to cope with crises and to demand less in-patient care.


Prediction of neural excitation during magnetic stimulation using passive cable models.
A method for predicting neural excitation during magnetic stimulation using passive cable models has been developed. This method uses the information of the threshold capacitor voltage for magnetic stimulation coils to determine the equivalent excitation thresholds for the passive transient (PT) and passive steady-state (PSS) cable models as well as for the activating function. The threshold values for the PT, PSS models, and the activating function vary only with the pulsewidth of the stimulus for a variety of coils at different locations and orientations. Furthermore, the excitation threshold for the PSS model is also independent of axon diameter and best fitted to a simple mathematical function. By comparing the transmembrane potential of the PSS model with the corresponding threshold, the prediction of excitation during magnetic stimulation can be made. Similarly, it is also possible to predict excitation using the PT model and the activating function with the corresponding thresholds provided. By taking advantage of the weighted pulsewidth, this method can even predict the excitation for stimuli with various waveforms, greatly simplifying the determination of neural excitation for magnetic stimulation.


Estimating the number of required nurses in different types of hospitals: An application of the workload indicators of staffing needs (WISNS) method.
Health system performance depends on the availability, accessibility, acceptability, and quality of health workforces. Policymakers seek whether the number of nurses is optimally matched based on patients' needs. This study aimed to assess the workforce stock, workload activities, activity standards, and workload pressure to determine the number of required nurses in different types of hospitals in Iran. This study applied the workload indicators of staffing needs (WISNs) method and was conducted in 22 surgical and internal medicine wards at five hospitals in the southwest of Iran during six months. A time-motion study, and several group discussions, interviews were used to extract the required data. Descriptive statistics were used for data analysis. All selected hospitals faced nursing shortages. The highest shortage (-47) and workload pressure (WISN ratio 0.45) were observed in the general-educational hospitals. In the specialized hospitals, the workload pressure was high (WISN ratio 0.49). The lowest shortage belonged to the private hospital. Based on our assessment, in all of the hospitals, nurses typically worked overtime due to high workload. The studied hospitals covered an average of 25% of their shortage with nursing overtime working. We noted that nurses were predominantly occupied with health service and supportive activities (≈90% of their time). Based on the WISN method, all of the hospitals faced nursing shortages from moderate to high. However, it would be essential to consider current labor market analysis based on accurate data to adopt appropriate policies in HRH planning.


Reflex cardiovascular response during injection of capsaicin into skeletal muscle.
In an anesthetized dog, injections of capsaicin, a potent stimulator of small myelinated and unmyelinated fibers that originate as free nerve endings, into a neurally intact donor-perfused hindlimb produced a significant (P less than 0.05) increase in mean aortic pressure (20%), heart rate (12%), cardiac output (28%), and respiratory minute volume (97%). Organ blood flows were measured with 25-micrometers radioactive microspheres. During the injection of capsaicin, there was a decrease in renal blood flow (-25%), but liver, spleen, brain, heart, and skeletal muscle flows remained near control values. After section of the afferent neural connection from the donor perfused hindlimb, the responses to the injection of capsaicin were abolished. These reflex cardiovascular and respiratory responses and changes in organ flow caused by stimulation of capsaicin-sensitive receptors in skeletal muscle are similar to those that occur during induced isometric exercise in the hindlimb.


MAOA-VNTR genotype affects structural and functional connectivity in distributed brain networks.
Previous studies have linked the low expression variant of a variable number of tandem repeat polymorphism in the monoamine oxidase A gene (MAOA-L) to the risk for impulsivity and aggression, brain developmental abnormalities, altered cortico-limbic circuit function, and an exaggerated neural serotonergic tone. However, the neurobiological effects of this variant on human brain network architecture are incompletely understood. We studied healthy individuals and used multimodal neuroimaging (sample size range: 219-284 across modalities) and network-based statistics (NBS) to probe the specificity of MAOA-L-related connectomic alterations to cortical-limbic circuits and the emotion processing domain. We assessed the spatial distribution of affected links across several neuroimaging tasks and data modalities to identify potential alterations in network architecture. Our results revealed a distributed network of node links with a significantly increased connectivity in MAOA-L carriers compared to the carriers of the high expression (H) variant. The hyperconnectivity phenotype primarily consisted of between-lobe ("anisocoupled") network links and showed a pronounced involvement of frontal-temporal connections. Hyperconnectivity was observed across functional magnetic resonance imaging (fMRI) of implicit emotion processing (pFWE = .037), resting-state fMRI (pFWE = .022), and diffusion tensor imaging (pFWE = .044) data, while no effects were seen in fMRI data of another cognitive domain, that is, spatial working memory (pFWE = .540). These observations are in line with prior research on the MAOA-L variant and complement these existing data by novel insights into the specificity and spatial distribution of the neurogenetic effects. Our work highlights the value of multimodal network connectomic approaches for imaging genetics.


Skin tolerance to cleansing agents.
The types of surfactants used for skin cleansing are discussed. Methods for the evaluation of the relative irritant potential of skin cleansers are reviewed.


Defining cancer risk in dermatomyositis. Part I.
The idiopathic inflammatory myopathies (IIMs) comprise polymyositis, myositis overlapping with another connective tissue disease, dermatomyositis (DM) and inclusion-body myositis (IBM). IIMs are characterized by the presence of proximal muscle weakness, increased levels of muscle-specific enzymes, specific electromyographic abnormalities, and the presence of inflammatory cell infiltrates in skeletal muscle. Clinical, serological and histological criteria can be used to define individual IIM subtypes. In the first of this two-part review series, we examine the evidence for the existence of cancer-associated myositis (CAM), and in part 2, we discuss recent discoveries that provide insight into identification of patients with DM, who may be most at risk of developing CAM.


Has the introduction of direct oral anticoagulants (DOACs) in England increased emergency admissions for bleeding conditions? A longitudinal ecological study.
There is concern about long-term safety of direct oral coagulants (DOACs) in clinical practice. Our aim was to investigate whether the introduction of DOACs compared with vitamin-K antagonists in England was associated with a change in admissions for bleeding or thromboembolic complications. 5508 General practitioner (GP) practices in England between 2011 and 2016. All GP practices in England with a registered population size of greater than 1000 that had data for all 6 years. The rate of emergency admissions to hospital for bleeding or thromboembolism, per 100 000 population for each GP practice in England. The annual number of DOAC items prescribed for each GP practice population as a proportion of all anticoagulant items prescribed. This longitudinal ecological study used panel regression models to investigate the association between trends in DOAC prescribing within GP practice populations and trends in emergency admission rates for bleeding and thromboembolic conditions, while controlling for confounders. For each additional 10% of DOACs prescribed as a proportion of all anticoagulants, there was a 0.9% increase in bleeding complications (rate ratio 1.008 95% CI 1.003 to 1.013). The introduction of DOACs between 2011 and 2016 was associated with additional 4929 (95% CI 2489 to 7370) emergency admissions for bleeding complications. Increased DOAC prescribing was associated with a slight decline in admission for thromboembolic conditions. Our data show that the rapid increase in prescribing of DOACs after changes in National Institute for Health and Care Excellence guidelines in 2014 may have been associated with a higher rate of emergency admissions for bleeding conditions. These consequences need to be considered in assessing the benefits and costs of the widespread use of DOACs.


Anti-Inflammatory Diet in Clinical Practice: A Review.
Recently, there has been an increase in the research regarding the impact of acute and chronic inflammation on health and disease. Specific foods are now known to exert strong effects on inflammatory pathways within the body. Carefully selecting foods that are anti-inflammatory in nature while avoiding foods that are proinflammatory is central to an anti-inflammatory diet plan. Ultimately, the plan models a pattern of eating that (1) focuses on eating whole, plant-based foods that are rich in healthy fats and phytonutrients and (2) maintains a stable glycemic response.


Relationship between adiponectin and fertility in the female pig.
Adiponectin isoforms may mediate different aspects of the pleiotropic function of the protein, including the reproductive process. We examined the pattern of circulating adiponectin and adiponectin system expression in fat and ovarian tissues of hyperfertile and subfertile sows. We demonstrated the presence of five different isoforms of adiponectin (90, 158, 180, 250 and >250kDa) in the circulation and identified a subgroup of subfertile females that displayed reduced abundance of all adiponectin isoforms as well as a lack of the 250-kDa adiponectin isoform in both serum and follicular fluid. Subfertility in these animals was associated with fewer large follicles and corpora lutea in the ovaries, as well as lower concentrations of 17β-oestradiol in the follicular fluid of large follicles. In addition, subfertile females showed higher adiponectin mRNA in fat tissue and altered mRNA and protein expression of adiponectin and its receptors in the ovary. Changes in the abundance and pattern of circulating adiponectin isoforms have been associated with reproductive disorders in animals and humans, including polycystic ovarian syndrome (PCOS). Our findings suggest that the adiponectin system may play an important role in controlling ovarian function and influencing porcine fertility.


Minimally invasive harvesting of the quadriceps tendon: Technical note.
The quadriceps tendon is gaining preference as an autograft over conventional grafts for the primary reconstruction of the anterior and posterior cruciate ligaments and of the medial patello-femoral ligament. In the past, the use of the quadriceps tendon was associated with considerable morbidity and less favourable outcomes compared to other grafts, specifically due to post-operative weakness of the quadriceps and other complications such as patellar fracture and rupture of the extensor apparatus. These problems are partially ascribable to the graft harvesting method used (large incision, bone block>2cm, and full-thickness tendon harvesting). Recent technical advancements have made reproducible harvesting of quadriceps grafts possible, thereby largely preventing the complications. In this study we describe an original quadriceps tendon harvesting technique in which a minimally invasive approach allows the collection of a sufficiently long graft, while sparing the deep layer of the quadriceps tendon. This technique decreases intra-operative morbidity and improves the post-operative outcomes.


Nutraceuticals against Neurodegeneration: A Mechanistic Insight.
The mechanisms underlying neurodegenerative disorders are complex and multifactorial; however, accumulating evidences suggest few common shared pathways. These common pathways include mitochondrial dysfunction, intracellular Ca2+ overload, oxidative stress and inflammation. Often multiple pathways co-exist, and therefore limit the benefits of therapeutic interventions. Nutraceuticals have recently gained importance owing to their multifaceted effects. These food-based approaches are believed to target multiple pathways in a slow but more physiological manner without causing severe adverse effects. Available information strongly supports the notion that apart from preventing the onset of neuronal damage, nutraceuticals can potentially attenuate the continued progression of neuronal destruction. In this article, we i) review the common pathways involved in the pathogenesis of the toxicants-induced neurotoxicity and neurodegenerative disorders with special emphasis on Alzheimer`s disease (AD), Parkinson`s disease (PD), Huntington`s disease (HD), Multiple sclerosis (MS) and Amyotrophic lateral sclerosis (ALS), and ii) summarize current research advancements on the effects of nutraceuticals against these detrimental pathways.


The interaction between Beta-lactoglobulin and sodium N-dodecyl sulphate.
1. The binding of sodium n-dodecyl sulphate to beta-lactoglobulin was studied in the pH range 3.5-7.0 by equilibrium dialysis, ultracentrifugation and microcalorimetry. 2. At low binding concentrations (less than 30 bound surfactants anions per protein molecule) the complexes formed aggregates in solution. 3. At higher binding concentrations aggregation does not occur at low ionic strength (0.01 mol/litre), but continues at high ionic strength (0.1 mol/litre). 4. At 25 degrees C the enthalpy of interaction of sodium n-dodecyl sulphate with beta-lactoglobulin can be interpreted as the sum of the enthalpies of formation of a complex with 2 bound surfactant anions, with an enthalpy change of -9.5 kJ-mol-1 of bound surfactant, and complexes containing at least 22 bound surfactant anions, with limiting enthalpies per bound surfactant anion of -12.4 kJ-mol-1 at pH 3.5 and -3.25 kJ-mol-1 at pH 5.5. 5. The binding of surfactant and the enthalpy of interaction at pH 3.5 ARE NOT SIGNIFICANTLY AFFECTED BY THE ADDITION Of 8 M-urea. 6. The data indicate that at low binding concentrations the interaction is of an ionic nature, and is accompanied by a conformational change in the protein.


[Treatment of borderline D/IIIa hip in newborn infants with the Graf-Mittelmeier abduction harness under close ultrasound control].
By retrospective analysis we investigated the treatment of "congenital" dysplasia of the hip (D/IIIa-type according to Graf) in newborn infants with the Graf-Mittelmeier-Aktivspreizhose (abduction harness). Between 1990 and 1997 twenty of twenty-three newborn infants with the IIIa-type were treated with the abduction harness by short-term ultrasound monitoring. We started the therapy in the first days of life, if we could identify a IIIa-type with an alpha-angle close to type D and with only minor tendency to decentration. Eighteen infants (90%) treated by abduction harness developed "mature" hips. At the beginning the mean-value of the alpha-angle was 41 degrees. In the first weeks a rapid hip maturation was observed. The alpha-angles of the 25 and 75 percentiles crossed the 60 degrees at the control of twelve weeks. A modification of the treatment by cast application was necessary in one case only. The results show, that dysplastic hip joints of newborn infants show a rapid maturation under therapy. Initial treatment with an abduction harness can improve decentered D/IIIa-hips.


Role of the Chinese herbal medicine xianhuayin on the reversal of premalignant mucosal lesions in the golden hamster buccal pouch.
To investigate the role of the Chinese herbal medicine Xianhuayin on the reversal of 7,12-dimethylbenz[a]anthracene (DMBA)-induced premalignant mucosal lesions in the oral buccal pouch of golden hamsters. The animals were randomly divided into a non-diseased control group (n=5) and an experimental group including 50 animals in which the buccal mucosa had been painted with DMBA (0.5% in acetone) to generate an oral mucosa premalignant lesion. Animals in the experimental group were further divided into Xianhuayin-treated group (n=30), untreated premalignant lesion group (n=10) and normal saline (NS)-treated group (n=10). The cheek (buccal) pouch mucosa of the golden hamsters in each group was observed with light and electron microscopy eight weeks after intragastric administration with NS or Xianhuayin. In the non-diseased control group, the buccal mucosa was keratinized and stratified squamous epithelium under a light microscope. In the untreated premalignant lesion group, variable degrees of epithelial dysplasia was observed. The irregular epithelial mucosa gradually became distinct in the Xianhuayin-treated group. Scanning electronic microscopic (SEM) analysis showed that surface of the cells exhibited honeycomb structures in the hamster of untreated-group. The cells were morphologically irregular, overlapped and loosened in the untreated premalignant lesion group. Most of the cell surface exhibited honeycomb structure in the Xianhuayin-treated group. Transmission electronic microscopic (TEM) analysis showed that buccal mucosal epithelial cells were morphologically regular in the non-diseased control group. Desmosomes and tonofibrils were reduced and the nucleus was morphologically irregular in the untreated premalignant lesion group. In the Xianhuayin-treated group, the widening intercellular gap was gradually reduced, desmosomes and the cells becoming morphologically regular. No significant difference was observed between the hamsters in NS-treated group and those in the untreated premalignant lesion group. Significant therapeutic efficacy was observed in the group receiving Xianhuayin. Xianhuayin is effective in the reversal of DMBA-induced premalignant lesions in the buccal pouch of golden hamsters.


Bipartite functional map of the E. coli RNA polymerase alpha subunit: involvement of the C-terminal region in transcription activation by cAMP-CRP.
The alpha subunit of Escherichia coli RNA polymerase plays a major role in the subunit assembly. Carboxyterminal deletion derivatives lacking 73 or 94 amino acid residues were assembled in vitro into enzyme molecules. Core enzymes consisting of these C-terminal-truncated alpha subunits were as active in RNA synthesis as native core enzyme. By the addition of sigma 70 subunit, these mutant enzymes initiated transcription from certain promoters. The mutant RNA polymerases, however, did not show cAMP-CRP activated transcription. These results demonstrate that the N-terminal region of the alpha subunit is involved in the formation of active enzyme molecule, while the C-terminal region plays an essential role in response to transcription activation by cAMP-CRP.


Analysis of injury in complex organ preservation.
A biochemical assay of renal viability previously described for rabbits is validated in a canine model using anoxia, hypothermia, and hypothermic perfusion. The assay correlated well with the decree of anoxic injury and protective effect of hypothermia. It was found to be unable to document significant injury when pulsatile perfusion was added to the system and resulted in nonviable canine kidneys. Apparent vascular damage with interstitial hemorrhage occurred after the perfusion and was not predictable by the use of the assay system. The limitations of any assay for organ viability after complex preservation maneuvers is the result of a multiplicity of injurious factors surrounding the preservation or as a consequence of the preservation. No single assay system will be adequate for protection of organ viability during or after preservation as long as the types of injury are multiple. Is is suggested that great care be used in defining possible injurious factors associated with given preservation maneuver and that specific assays be utilized to document the effects of each of these factors. The more complex the preservation system employed; the more complex the assay system needed.


A pointing sign for localization in early pneumonia.
In a study of the first 48 hours of 500 consecutive cases of early pneumonia mostly complicating the influenzal syndrome in Benin City, Nigeria, radiological examination which shows opacities in 12--18 hours confirmed accurate localization in 50 per cent of cases localized by physical examination alone, and in 90 per cent of cases cross-checked by the pointing sign--asking the patient to cough hard and point to the side where pain is clearly felt.


The organism fate of inland freshwater system under micro-/nano-plastic pollution: A review of past decade.
Micro- and nano-plastics (MPs/NPs) are characterized by their small size and extensive surface area, making them global environmental pollutants with adverse effects on organisms at various levels, including organs, cells, and molecules. Freshwater organisms, such as microalgae, emerging plants, zooplankton, benthic species, and fish, experience varying impacts from MPs/NPs, which are prevalent in both terrestrial and aquatic inland environments. MPs/NPs significantly impact plant physiological processes, including photosynthesis, antioxidant response, energy metabolism, and nitrogen removal. Extended exposure and ingestion to MPs/NPs might cause metabolic and behavioral deviations in zooplankton, posing an extinction risk. Upon exposure to MPs/NPs, both benthic organisms and fish display behavioral and metabolic disturbances, due to oxidative stress, neural toxicity, intestinal damage, and metabolic changes. Results from laboratory and field investigations have confirmed that MPs/NPs can be transported across multiple trophic levels. Moreover, MPs/NPs-induced alterations in zooplankton populations can impede energy transfer, leading to food scarcity for filter-feeding fish, larvae of benthic organism and fish, thus jeopardizing aquatic ecosystems. Furthermore, MPs/NPs can harm the nervous systems of aquatic organisms, influencing their feeding patterns, circadian rhythms, and mobility. Such behavioral alterations might also introduce unforeseen ecological risks. This comprehensive review aims to explore the consequences of MPs/NPs on freshwater organisms and their interconnected food webs. The investigation encompasses various aspects, including behavioral changes, alterations in physiology, impacts on metabolism, transgenerational effects, and the disruption of energy transfer within the ecosystem. This review elucidated the physiological and biochemical toxicity of MPs/NPs on freshwater organisms, and the ensuing risks to inland aquatic ecosystems.


Interaction of kinesin motor domains with alpha- and beta-tubulin subunits at a tau-independent binding site. Regulation by polyglutamylation.
Interaction of rat kinesin and Drosophila nonclaret disjunctional motor domains with tubulin was studied by a blot overlay assay. Either plus-end or minus-end-directed motor domain binds at the same extent to both alpha- and beta-tubulin subunits, suggesting that kinesin binding is an intrinsic property of each tubulin subunit and that motor directionality cannot be related to a preferential interaction with a given tubulin subunit. Binding features of dimeric versus monomeric rat kinesin heads suggest that dimerization could drive conformational changes to enhance binding to tubulin. Competition experiments have indicated that kinesin interacts with tubulin at a Tau-independent binding site. Complementary experiments have shown that kinesin does not interact with the same efficiency with the different tubulin isoforms. Masking the polyglutamyl chains with a specific monoclonal antibody leads to a complete inhibition of kinesin binding. These results are consistent with a model in which polyglutamylation of tubulin regulates kinesin binding through progressive conformational changes of the whole carboxyl-terminal domain of tubulin as a function of the polyglutamyl chain length, thus modulating the affinity of tubulin for kinesin and Tau as well. These results indicate that microtubules, through tubulin polymorphism, do have the ability to control microtubule-associated protein binding.


Efficient purification of GP-1D8 glycoprotein from human breast carcinoma tissue by immunoaffinity chromatography.
Anti-GP-1D8 monoclonal antibody was produced in our laboratory. Immunoaffinity purification of GP-1D8 glycoprotein from human breast carcinoma tissues, on column with the monospecific antibody, is developed. The procedure permits purification of GP-1D8 to a highly purified state. It appeared as a single band in sodium dodcyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The molecular mass of GP-1D8 was determined to be 66 kDa by mass spectrometry. Its antigenicity was stable between 0 and 70 degrees C. It was breast cancer specific, as determined by immunohistochemistry and immunocytochemistry. The preparation of anti-GP-1D8 monoclonal antibody will facilitate further detection of, and functional study on, GP-1D8. The study also provides a simple, economical, and efficient method for affinity purification of target proteins from human or animal tissues.


Effects of physical activity on placental analytes in nulliparous persons.
Physical activity during pregnancy has long been investigated for its role in preeclampsia prevention. The mechanism of this relationship is unknown, although some studies suggest physical activity may affect placental analytes throughout pregnancy. The objective of this study was to determine the effect of physical activity on preeclampsia-associated placental analytes using a prospective cohort of pregnant nulliparous patients. This was a secondary analysis of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be. Frequency and duration of up to three leisure activities was reported in the first and second trimesters and was analyzed, with participants either meeting or not meeting the recommended exercise of 150 min per week. Levels of the following placental analytes, placental growth factor, soluble endoglin, and soluble fms-like tyrosine kinase-1 (sFLT1), were analyzed stratified by the physical activity level. A total of 1,956 participants were included in the analysis. The level of sFLT1 in the first trimester was lower in the group that had ≥ 150 min per week of physical activity, compared to the group that had < 150 min (846.3 [821.6, 871,8] versus 893.0 [864.5,922.5], p = 0.017). There were no significant sFLT1 changes in the second trimester based on physical activity. After controlling for maternal demographic and clinical factors, sFLT1 levels in the second trimester were significantly lower (p = 0.049) in participants that had ≥ 150 min of physical activity per week. Our findings of decreased sFLT1 levels suggest this could be the mechanism explaining the association between PA in pregnancy and lower risk of preeclampsia.


Prevention and treatment of dislocation after total hip replacement using large diameter balls.
The purpose of this study was to review safety and efficacy of total hip arthroplasty using large-diameter femoral heads in treatment and prevention of dislocation. One hundred forty hips in 135 patients were replaced using femoral heads at least 36 mm in diameter. The average age of the patients was 61.6 years. The patients were grouped into three categories depending on their diagnoses: recurrent dislocations from previous total hip replacements (Group 1; 29 hips); revision surgeries not including revisions for dislocations (Group 2; 54 hips); and primary surgeries (Group 3; 57 hips). The average followup was 5.5 years (range, 1-17 years). A total of 16 hips were revised: six for instability, four for fracture or disassociation of a conventional polyethylene liner, three for aseptic loosening of the socket, and three for sepsis. One hip from Group 1 dislocated at 12.5 years postoperatively, was treated with closed reduction, and since has been nonrecurring. UCLA hip scores all improved significantly. The prevalence of dislocation varied among the three groups, with 13.7% for Group 1, 1.8% for Group 2, and 3.5% for Group 3. The failure in the six cases that required revision for instability was attributable to poor socket orientation. All the hips became stable after revision without the use of a constrained acetabular liner. Large-diameter femoral heads provide additional stability not only for patients with recurrent dislocations, but also for patients having revision. The new, more wear-resistant bearings now enable the surgeon to extend the use of big femoral heads to primary total hip arthroplasty. Metal-on-metal seems to be the material of choice for a bone-conserving reconstruction with large femoral heads.


Analysis and computational dissection of molecular signature multiplicity.
Molecular signatures are computational or mathematical models created to diagnose disease and other phenotypes and to predict clinical outcomes and response to treatment. It is widely recognized that molecular signatures constitute one of the most important translational and basic science developments enabled by recent high-throughput molecular assays. A perplexing phenomenon that characterizes high-throughput data analysis is the ubiquitous multiplicity of molecular signatures. Multiplicity is a special form of data analysis instability in which different analysis methods used on the same data, or different samples from the same population lead to different but apparently maximally predictive signatures. This phenomenon has far-reaching implications for biological discovery and development of next generation patient diagnostics and personalized treatments. Currently the causes and interpretation of signature multiplicity are unknown, and several, often contradictory, conjectures have been made to explain it. We present a formal characterization of signature multiplicity and a new efficient algorithm that offers theoretical guarantees for extracting the set of maximally predictive and non-redundant signatures independent of distribution. The new algorithm identifies exactly the set of optimal signatures in controlled experiments and yields signatures with significantly better predictivity and reproducibility than previous algorithms in human microarray gene expression datasets. Our results shed light on the causes of signature multiplicity, provide computational tools for studying it empirically and introduce a framework for in silico bioequivalence of this important new class of diagnostic and personalized medicine modalities.


Age--an independent prognostic factor of clinical outcome in renal malignancies: results of a large study over two decades.
Age has been linked to outcome in renal cancer patients, but mainly in North American cohorts. In this study, we hypothesized that age is correlated with metastasis and cancer-specific survival in a German cohort regardless of types of treatments. A total of 1,538 patients treated for renal malignancies between 1991 and 2010 were evaluated. Mean age and median age are 61.9 ± 11.6 and 62.6 years. Clinicopathologic [tumor type, size, grade, stage and treatment (surgery, chemotherapy, radiation, immunotherapy)] and outcome parameters (metastasis and survival) were examined for an association with age using logistic regression and Cox proportional hazard model, and Kaplan-Meier plots. Age was associated with stage, metastasis, treatment, cancer-specific and overall mortality (p < 0.01). The metastasis-free and cancer-free survival rates for patients >63 years were lower than those for patients ≤63 years (p < 0.0001). In a multivariate analysis, age was an independent prognostic factor of metastasis, cancer-specific and overall mortality (p < 0.0001) even when data were stratified in different decades and treatment was included as one of the parameters. Patients >63 years of age had 29-35% higher risk of metastasis and cancer-specific mortality than younger patients. Median metastasis-free and cancer-specific survival for patients >63 years of age (months: 84.4; 70.3) was ~50% shorter than in patients ≤63 years (months: 151; 144.6). This large study shows that, despite advances in surgical and non-surgical treatment modalities over the two decades, age is an independent prognostic indicator of metastasis and cancer-specific mortality in renal cancer patients. Patients >63 years have ~30% increased risk for metastasis and ~50% shorter cancer-specific survival.


Spatial and Temporal Variation of Physico-chemical Parameters in the Merbok Estuary, Kedah, Malaysia.
In this study, factor analysis (FA) was applied to extract the hidden factors responsible for water quality variations during both wet and dry seasons. Water samples were collected from six sampling stations (St. 1 Lalang River, St. 2 Semeling River, St. 3 Jagung River, St. 4 Teluk Wang River, St. 5 Gelam River and St. 6 Derhaka River) in the Merbok estuary, Malaysia from January to December 2011; the samples were further analysed in the laboratory. Correlation analysis of the data sets showed strong correlations between the parameters. Nutrients such as nitrate (NO3 (-)), nitrite (NO2 (-)), ammonia (NH3) and phosphate (PO4 (3-)) were determined to be critical indicators of water quality throughout the year. Influential water quality parameters during the wet season were conductivity, salinity, biochemical oxygen demand (BOD), dissolved oxygen (DO) and chlorophyll a (Chla), whereas total suspended solid (TSS) and pH were critical water quality indicators during the dry season. The Kruskal-Wallis H test showed that water quality parameters were significantly different among the sampling months and stations (p<0.05), and Mann-Whitney U tests further revealed that the significantly different parameters were temperature, pH, DO, TSS, NO2 (-) and BOD (p<0.01), whereas salinity, conductivity, NO3 (-), PO4 (3-), NH3 and Chla were not significantly different (p>0.05). Water quality parameters in the estuary varied on both temporal and spatial scales and these results may serve as baseline information for estuary management, specifically for the Merbok estuary.


Function of specific K(+) channels in sustained high-frequency firing of fast-spiking neocortical interneurons.
Fast-spiking GABAergic interneurons of the neocortex and hippocampus fire high-frequency trains of brief action potentials with little spike-frequency adaptation. How these striking properties arise is unclear, although recent evidence suggests K(+) channels containing Kv3.1-Kv3.2 proteins play an important role. We investigated the role of these channels in the firing properties of fast-spiking neocortical interneurons from mouse somatosensory cortex using a pharmacological and modeling approach. Low tetraethylammonium (TEA) concentrations (</=1 mM), which block only a few known K(+) channels including Kv3.1-Kv3.2, profoundly impaired action potential repolarization and high-frequency firing. Analysis of the spike trains evoked by steady depolarization revealed that, although TEA had little effect on the initial firing rate, it strongly reduced firing frequency later in the trains. These effects appeared to be specific to Kv3.1 and Kv3.2 channels, because blockade of dendrotoxin-sensitive Kv1 channels and BK Ca(2+)-activated K(+) channels, which also have high TEA sensitivity, produced opposite or no effects. Voltage-clamp experiments confirmed the presence of a Kv3.1-Kv3.2-like current in fast-spiking neurons, but not in other interneurons. Analysis of spike shape changes during the spike trains suggested that Na(+) channel inactivation plays a significant role in the firing-rate slowdown produced by TEA, a conclusion that was supported by computer simulations. These findings indicate that the unique properties of Kv3.1-Kv3.2 channels enable sustained high-frequency firing by facilitating the recovery of Na(+) channel inactivation and by minimizing the duration of the afterhyperpolarization in neocortical interneurons.