[Financial advocacy: a true reality?].
It seems that in spite of soaring medical costs and a poor economic climate, financial advocacy for patients is not general practice. A question that arises is what part nurses play and what their perceptions on financial advocacy for patients are. A non-experimental descriptive study was done to determine what nurses' perceptions on financial advocacy are and how knowledgeable they are about the costs of disposable dispensary stock. Thirty patient accounts were analysed and questionnaires were completed by a convenience sample of thirty two registered nurses who had permanent appointments in high care or intensive care units. On average nurses control the utilization of 15.8% of each of the prescription accounts. Only 12.5% of respondents had formal education on their responsibility in keeping costs low. The majority (60%) of the 50% of respondents who had previously received information had performed financial advocacy although 94% agreed that they have the responsibility to do so. A mere 9% was achieved on the knowledge of the costs involved in using consumable products from the dispensary.


Proton pump for O2 reduction catalyzed by 5,10,15,20-tetraphenylporphyrinatocobalt(II).
The role of 5,10,15,20-tetraphenylporphyrinatocobalt(II) ([Co(tpp)]) as a catalyst on molecular oxygen (O(2)) reduction by ferrocene (Fc) and its two derivatives, 1,1'-dimethylferrocene (DFc) and decamethylferrocene (DMFc) at a polarized water|1,2-dichloroethane (DCE) interface has been studied. The water|DCE interface essentially acts as a proton pump controlled by the Galvani potential difference across the interface, driving the proton transfer from water to DCE. [Co(tpp)] catalyzed O(2) reduction by Fc, DFc and DMFc is then followed to produce hydrogen peroxide (H(2)O(2)). The catalytic mechanism is similar to that proposed by Fukuzumi et al. for bulk reactions. This interfacial system provides a platform for a very efficient collection of H(2)O(2), by extraction immediately after its formation in DCE to the adjacent water phase, thus decreasing the possibility of degradation and further reaction with ferrocene derivatives.


Two Training-Load Paradoxes: Can We Work Harder and Smarter, Can Physical Preparation and Medical Be Teammates?
The authors have observed that in professional sporting organizations the staff responsible for physical preparation and medical care typically practice in relative isolation and display tension as regards their attitudes toward training-load prescription (much more and much less training, respectively). Recent evidence shows that relatively high chronic training loads, when they are appropriately reached, are associated with reduced injury risk and better performance. Understanding this link between performance and training loads removes this tension but requires a better understanding of the relationship between the acute:chronic workload ratio (ACWR) and its association with performance and injury. However, there remain many questions in the area of ACWR, and we are likely at an early stage of our understanding of these parameters and their interrelationships. This opinion paper explores these themes and makes recommendations for improving performance through better synergies in support-staff approaches. Furthermore, aspects of the ACWR that remain to be clarified-the role of shared decision making, risk:benefit estimation, and clearer accountability-are discussed.


Specific chemopreventive agents trigger proteasomal degradation of G1 cyclins: implications for combination therapy.
There is a need to identify cancer chemoprevention mechanisms. We reported previously that all-trans-retinoic acid (RA) prevented carcinogenic transformation of BEAS-2B immortalized human bronchial epithelial cells by causing G(1) arrest, permitting repair of genomic DNA damage. G(1) arrest was triggered by cyclin D1 proteolysis via ubiquitin-dependent degradation. This study investigated which chemopreventive agents activated this degradation program and whether cyclin E was also degraded. This study examined whether: (a) cyclin E protein was affected by RA treatment; (b) cyclin degradation occurred in derived BEAS-2B-R1 cells that were partially resistant to RA; and (c) other candidate chemopreventive agents caused cyclin degradation. RA treatment triggered degradation of cyclin E protein, and ALLN, a proteasomal inhibitor, inhibited this degradation. Induction of the retinoic acid receptor beta, growth suppression, and cyclin degradation were each inhibited in BEAS-2B-R1 cells. Transfection experiments in BEAS-2B cells indicated that RA treatment repressed expression of wild-type cyclin D1 and cyclin E, but ALLN inhibited this degradation. Mutation of threonine 286 stabilized transfected cyclin D1, and mutations of threonines 62 and 380 stabilized transfected cyclin E, despite RA treatment. Specific chemopreventive agents triggered cyclin degradation. Nonclassical retinoids (fenretinide and retinoid X receptor agonists) and a synthetic triterpenoid (2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid) each suppressed BEAS-2B growth and activated this degradation program. However, a vitamin D3 analog (RO-24-5531), a cyclooxygenase inhibitor (indomethacin), and a peroxisome proliferator-activated receptor gamma agonist (rosiglitazone) each suppressed BEAS-2B growth, but did not cause cyclin degradation. BEAS-2B-R1 cells remained responsive to nonclassical retinoids and to 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid. Specific chemopreventive agents activate cyclin proteolysis. Yet, broad resistance did not occur after acquired resistance to a single agent. This provides a therapeutic rationale for combination chemoprevention with agents activating non-cross-resistant pathways.


Intratympanic aberrant and hypoplastic carotid artery.
Intratympanically aberrant internal carotid artery(ICA) is a rarely seen vascular abnormality. We present here the combination of aberration and prominent hypoplasia of the ICA in a case. Intratympanic aberrant ICA, which is rarely cited as a cause of tinnitus and hearing loss, should be known as a reason to be kept in mind as it may lead to life-threatening complications. Generally, it has been defined upon massive bleeding during myringotomy, ear surgery or biopsy procedure. In this article, the audiological and radiological studies confirmed with CT and MR angiography conducted on an aberrant and hypoplastic internal carotid artery that was identified under the manubrium mallei in a 28-year-old, young male patient who presented with complaints about hearing loss and fullness in the left ear were presented along with a literature review.


Clavicle and scapula fracture problems: functional assessment and current treatment strategies.
Historically, nonsurgical treatment was recommended for both clavicle and scapula fractures. Good functional outcomes were reported with nonsurgical treatment, whereas surgical treatment had a high complication rate. Recent studies have shown that the functional outcomes of nonsurgically treated fractures may not be as acceptable as had been previously believed. These studies also support the surgical treatment of clavicle and scapula fractures in certain circumstances. Relative indications for surgical treatment of clavicle fractures include skin compromise, neurologic or vascular injury, open fractures, high-energy closed fractures with greater than 15 to 20 mm of shortening, fractures with 100% displacement, and fractures with comminution. Relative indications for the surgical treatment of scapula fractures include displaced acromion or coracoid process fractures (> 10 mm), displaced intra-articular glenoid fractures (> 5 mm), and those associated with humeral subluxation.


Deep Learning for Automatic Segmentation of Hybrid Optoacoustic Ultrasound (OPUS) Images.
The highly complementary information provided by multispectral optoacoustics and pulse-echo ultrasound have recently prompted development of hybrid imaging instruments bringing together the unique contrast advantages of both modalities. In the hybrid optoacoustic ultrasound (OPUS) combination, images retrieved by one modality may further be used to improve the reconstruction accuracy of the other. In this regard, image segmentation plays a major role as it can aid improving the image quality and quantification abilities by facilitating modeling of light and sound propagation through the imaged tissues and surrounding coupling medium. Here, we propose an automated approach for surface segmentation in whole-body mouse OPUS imaging using a deep convolutional neural network (CNN). The method has shown robust performance, attaining accurate segmentation of the animal boundary in both optoacoustic and pulse-echo ultrasound images, as evinced by quantitative performance evaluation using Dice coefficient metrics.


Lujinxingia litoralis gen. nov., sp. nov. and Lujinxingia sediminis sp. nov., two new representatives in the order Bradymonadales.
In this study, two bacterial strains designated B210T and SEH01T, isolated from coastal sediment sampled in Weihai, PR China, were characterized using a polyphasic approach. Strains were Gram-stain-negative, facultative anaerobic, rod-shaped and motile. According to the results of phylogenetic analyses based on their 16S rRNA genes, these two strains should be classified under the order Bradymonadales and they both show <90 % sequence similarities with Bradymonas sediminis FA350T. Moreover, strain B210T showed 98.6 % sequence similarity to strain SEH01T. Genomic characteristics including average nucleotide identity and in silico DNA-DNA hybridization values clearly separated strain B210T from strain SEH01T. The sole quinone of these two strains was menaquinone MK-7, and the major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and an unidentified lipid. Iso-C15 : 0 was the major fatty acid in both strains B210T and SEH01T, and iso-C14 : 0 3-OH was also a major fatty acid for strain SEH01T. Based on the polyphasic analysis, these two strains represent two novel species of a new genus within the family Bradymonadaceae. Consequently, the novel genus Lujinxingia gen. nov. is proposed, containing two new species Lujinxingia litoralis gen. nov. sp. nov. and Lujinxingia sediminis sp. nov., with strain B210T (=KCTC 42951T=CGMCC 1.16770T) and strain SEH01T (=KCTC 42950T=DSM 101859T) as the type strains, respectively.


Somatostatin causes vasoconstriction, reduces blood flow and increases vascular permeability in the rat central nervous system.
Using radiolabeled microspheres, spinal cord blood flow was measured after spinal subarachnoid injections of 3.1- to 12.5-nmol doses of somatostatin through either indwelling i.t. catheters or acutely inserted intervertebral needles. With either injection technique, somatostatin caused significant dose-dependent reductions in thoracic and lumbosacral blood flow that could be partially blocked by a 5-min preinjection of the somatostatin receptor antagonist cyclo[7-aminoheptanoyl-Phe-D-Trp-Lys-Thr(Bzl)], which has previously been shown to block the hindlimb flaccidity produced by these doses of somatostatin in conscious rats. The duration of these blood flow changes were appreciably less in the rats injected through indwelling i.t. catheters. Somatostatin-induced reductions in spinal cord perfusion were accompanied by transient pressor responses, reduced cardiac output, 3-fold increases in spinal cord cerebrospinal fluid lactic acid concentrations and breakdown of the blood-spinal cord barrier, as reflected by significantly increased extravasation of [125I]bovine serum albumin. By 24 hr postinjection, a 12.5-nmol dose of somatostatin caused appreciable spinal cord cellular injury, as evidenced by significant elevations in cerebrospinal fluid concentrations of lactate dehydrogenase. After topical application to exposed pial vessels of the parietal cortex, comparable doses of somatostatin caused immediate intense dose-related arteriolar vasospasm and subsequent extravasation of the visible macromolecular tracer Evans blue dye. We conclude that somatostatin has significant vasoconstrictory effects on the blood vessels of the brain and spinal cord of the rat that must be recognized and appreciated when studying its neuropharmacological actions in vivo.


Smoking and the sudden infant death syndrome.
Maternal smoking has been shown to be a risk factor for sudden infant death syndrome (SIDS). The effect of smoking by the father and other household members has not previously been examined. A large nationwide case-control study. Four hundred eighty-five SIDS deaths in the postneonatal age group were compared with 1800 control infants. Infants of mothers who smoked during pregnancy had a 4.09 (95% confidence interval [CI] = 3.28, 5.11) greater risk of death than infants of mothers who did not smoke. Infants of mothers who smoked postnatally also had an increased risk of SIDS compared with infants of nonsmokers and, furthermore, the risk increased with increasing levels of maternal smoking. Smoking by the father and other household members increased the risk (odds ratio [OR] = 2.41, 95% CI = 1.92, 3.02 and OR = 1.54, 95% CI = 1.20, 1.99, respectively). Smoking by the father increased the risk of SIDS if the mother smoked, but had no effect if she did not smoke. In analyses controlled for a wide range of potential confounders, smoking by the mother and father was still significantly associated with an increased risk of SIDS. Passive tobacco smoking is causally related to SIDS.


Brevetoxin-induced neural insult in the retrosplenial cortex of mouse brain.
Brevetoxins (polyether breve toxins; PbTx) are polyether neurotoxins produced by the marine dinoflagellate Karenia brevis, an organism associated with red tide blooms in the Gulf of Mexico and along the Atlantic coast from Florida to North Carolina. Brevetoxin-3 (PbTx-3) is a major component of the array of brevetoxins found in marine aerosols measured along red tide affected beaches. Humans exposed to aerosolized brevetoxins for short periods of time often suffer a variety of adverse health effects. It was consequently of interest to assess the potential for aerosolized brevetoxin to produce a neurotoxic response. Female BALB/c mice were exposed nose-only for 2 consecutive days to PbTx-3 aerosol, with a 2-h exposure on the first day and a 4-h exposure on the second day. The average PbTx-3 exposure concentrations on days 1 and 2 were 312 +/- 113 mug brevetoxin 3/m3 and 278 +/- 24 mug brevetoxin 3/m3, respectively. The brevetoxin-containing aerosol had a mass median aerodynamic diameter of 0.92 mum with a geometric standard deviation of 1.38. Coronal sections of mouse brains were evaluated for neuronal damage using both silver and Fluoro-Jade B staining to identify degenerating neuronal elements. PbTx-3 inhalation exposure produced neuronal degeneration in the posterior cingulate/retrosplenial cortex of mice as evidenced by silver-positive degenerating neurons in this region. No staining was found in other regions of the PBTx-3-exposed mouse brains or in brains of control, sham-exposed mice. The existence of a neurotoxic insult in PbTx-3-exposed mice was confirmed using Fluoro-Jade B to label degenerating neurons. Fluro-Jade-positive neurons were observed in the retrosplenial cortex of PBTx-3 exposed, but not control, mice. These results suggest that subacute exposure to PbTx-3 for 2 days is sufficient to induce neuronal degeneration in a discrete region of the mouse cerebral cortex.


Attention deficit hyperactivity disorder: fine mapping supports linkage to 5p13, 6q12, 16p13, and 17p11.
We completed fine mapping of nine positional candidate regions for attention-deficit/hyperactivity disorder (ADHD) in an extended population sample of 308 affected sibling pairs (ASPs), constituting the largest linkage sample of families with ADHD published to date. The candidate chromosomal regions were selected from all three published genomewide scans for ADHD, and fine mapping was done to comprehensively validate these positional candidate regions in our sample. Multipoint maximum LOD score (MLS) analysis yielded significant evidence of linkage on 6q12 (MLS 3.30; empiric P=.024) and 17p11 (MLS 3.63; empiric P=.015), as well as suggestive evidence on 5p13 (MLS 2.55; empiric P=.091). In conjunction with the previously reported significant linkage on the basis of fine mapping 16p13 in the same sample as this report, the analyses presented here indicate that four chromosomal regions--5p13, 6q12, 16p13, and 17p11--are likely to harbor susceptibility genes for ADHD. The refinement of linkage within each of these regions lays the foundation for subsequent investigations using association methods to detect risk genes of moderate effect size.


Identification of the (183)RWTNNFREY(191) region as a critical segment of matrix metalloproteinase 1 for the expression of collagenolytic activity.
Matrix metalloproteinase 1 (MMP-1) cleaves types I, II, and III collagen triple helices into (3/4) and (1/4) fragments. To understand the structural elements responsible for this activity, various lengths of MMP-1 segments have been introduced into MMP-3 (stromelysin 1) starting from the C-terminal end. MMP-3/MMP-1 chimeras and variants were overexpressed in Escherichia coli, folded from inclusion bodies, and isolated as zymogens. After activation, recombinant chimeras were tested for their ability to digest triple helical type I collagen at 25 degrees C. The results indicate that the nine residues (183)RWTNNFREY(191) located between the fifth beta-strand and the second alpha-helix in the catalytic domain of MMP-1 are critical for the expression of collagenolytic activity. Mutation of Tyr(191) of MMP-1 to Thr, the corresponding residue in MMP-3, reduced collagenolytic activity about 5-fold. Replacement of the nine residues with those of the MMP-3 sequence further decreased the activity 2-fold. Those variants exhibited significant changes in substrate specificity and activity against gelatin and synthetic substrates, further supporting the notion that this region plays a critical role in the expression of collagenolytic activity. However, introduction of this sequence into MMP-3 or a chimera consisting of the catalytic domain of MMP-3 with the hinge region and the C-terminal hemopexin domain of MMP-1 did not express any collagenolytic activity. It is therefore concluded that RWTNNFREY, together with the C-terminal hemopexin domain, is essential for collagenolytic activity but that additional structural elements in the catalytic domain are also required. These elements probably act in a concerted manner to cleave the collagen triple helix.


Low brain ascorbic acid increases susceptibility to seizures in mouse models of decreased brain ascorbic acid transport and Alzheimer's disease.
Seizures are a known co-occurring symptom of Alzheimer's disease, and they can accelerate cognitive and neuropathological dysfunction. Sub-optimal vitamin C (ascorbic acid) deficiency, that is low levels that do not lead the sufferer to present with clinical signs of scurvy (e.g. lethargy, hemorrhage, hyperkeratosis), are easily obtainable with insufficient dietary intake, and may contribute to the oxidative stress environment of both Alzheimer's disease and epilepsy. The purpose of this study was to test whether mice that have diminished brain ascorbic acid in addition to carrying human Alzheimer's disease mutations in the amyloid precursor protein (APP) and presenilin 1 (PSEN1) genes, had altered electrical activity in the brain (electroencephalography; EEG), and were more susceptible to pharmacologically induced seizures. Brain ascorbic acid was decreased in APP/PSEN1 mice by crossing them with sodium vitamin C transporter 2 (SVCT2) heterozygous knockout mice. These mice have an approximately 30% decrease in brain ascorbic acid due to lower levels of SVCT2 that supplies the brain with ASC. SVCT2+/-APP/PSEN1 mice had decreased ascorbic acid and increased oxidative stress in brain, increased mortality, faster seizure onset latency following treatment with kainic acid (10 mg/kg i.p.), and more ictal events following pentylenetetrazol (50 mg/kg i.p.) treatment. Furthermore, we report the entirely novel phenomenon that ascorbic acid deficiency alone increased the severity of kainic acid- and pentylenetetrazol-induced seizures. These data suggest that avoiding ascorbic acid deficiency may be particularly important in populations at increased risk for epilepsy and seizures, such as Alzheimer's disease.


Diagnosis and management of contact dermatitis.
Contact dermatitis is a common inflammatory skin condition characterized by erythematous and pruritic skin lesions that occur after contact with a foreign substance. There are two forms of contact dermatitis: irritant and allergic. Irritant contact dermatitis is caused by the non-immune-modulated irritation of the skin by a substance, leading to skin changes. Allergic contact dermatitis is a delayed hypersensitivity reaction in which a foreign substance comes into contact with the skin; skin changes occur after reexposure to the substance. The most common substances that cause contact dermatitis include poison ivy, nickel, and fragrances. Contact dermatitis usually leads to erythema and scaling with visible borders. Itching and discomfort may also occur. Acute cases may involve a dramatic flare with erythema, vesicles, and bullae; chronic cases may involve lichen with cracks and fissures. When a possible causative substance is known, the first step in confirming the diagnosis is determining whether the problem resolves with avoidance of the substance. Localized acute allergic contact dermatitis lesions are successfully treated with mid- or high-potency topical steroids, such as triamcinolone 0.1% or clobetasol 0.05%. If allergic contact dermatitis involves an extensive area of skin (greater than 20 percent), systemic steroid therapy is often required and offers relief within 12 to 24 hours. In patients with severe rhus dermatitis, oral prednisone should be tapered over two to three weeks because rapid discontinuation of steroids can cause rebound dermatitis. If treatment fails and the diagnosis or specific allergen remains unknown, patch testing should be performed.


Survival assessment of the extended-wear insulin infusion set featuring lantern technology in adults with type 1 diabetes by the glucose clamp technique.
Maintaining good glycaemic control with the same infusion set for longer than 3 days may improve the quality of life of insulin pump users. The aim of the current study was to assess the efficacy and safety of the novel, extended-wear infusion set over 7 days of wear in adults with type 1 diabetes. Sixteen participants completed three identical 8-hour euglycaemic clamp experiments on Days 1, 4 and 7 of infusion set wear. Between the experiments, the participants were discharged home for routine diabetes management while wearing the same extended-wear infusion set throughout the study. Time to reach the maximum glucose infusion rate (TGIRmax ) on Day 7 was reduced by 67% compared with Day 1 (p < .001). The corresponding area under the glucose infusion rate curve (AUCGIR ) was comparable for the first 2 h of the clamp (p = .891) but decreased by 28% over time (p < .008). While the extent of insulin absorption decreased with prolonged wear, it was accompanied by an increase in insulin absorption rate. The infusion set survival rate was 100% without leakages, occlusion alarms, severe hypoglycaemia or ketoacidosis. The extended-wear infusion set proved safe and effective during prolonged wear in real-life conditions.


Bosniak classification of cystic renal masses, version 2019: interpretation pitfalls and recommendations to avoid misclassification.
The purpose of this review is to describe the potential sources of variability or discrepancy in interpretation of cystic renal masses under the Bosniak v2019 classification system. Strategies to avoid these pitfalls and clinical examples of diagnostic approaches are also presented. Potential pitfalls in the application of Bosniak v2019 are divided into three categories: interpretative, technical, and mass related. An organized, comprehensive review of possible discrepancies in interpreting Bosniak v2019 cystic masses is presented with pictorial examples of difficult clinical cases and proposed solutions. The scheme provided can guide readers to consistent, precise application of the classification system. Radiologists should be aware of the possible sources of misinterpretation of cystic renal masses when applying Bosniak v2019. Knowing which features and types of cystic masses are prone to interpretive errors, in addition to the inherent trade-offs between the CT and MR techniques used to characterize them, can help radiologists avoid these pitfalls.


Hierarchical electrohydrodynamic structures for surface-enhanced Raman scattering.
Surface enhanced Raman scattering (SERS) is a well-established spectroscopic technique that requires nanoscale metal structures to achieve high signal sensitivity. While most SERS substrates are manufactured by conventional lithographic methods, the development of a cost-effective approach to create nanostructured surfaces is a much sought-after goal in the SERS community. Here, a method is established to create controlled, self-organized, hierarchical nanostructures using electrohydrodynamic (HEHD) instabilities. The created structures are readily fine-tuned, which is an important requirement for optimizing SERS to obtain the highest enhancements. HEHD pattern formation enables the fabrication of multiscale 3D structured arrays as SERS-active platforms. Importantly, each of the HEHD-patterned individual structural units yield a considerable SERS enhancement. This enables each single unit to function as an isolated sensor. Each of the formed structures can be effectively tuned and tailored to provide high SERS enhancement, while arising from different HEHD morphologies. The HEHD fabrication of sub-micrometer architectures is straightforward and robust, providing an elegant route for high-throughput biological and chemical sensing.


Recommendations for the medical evaluation of children prior to adoption in South Africa.
The current legislative framework in South Africa (SA) supports adoption as the preferred form of care for children with inadequate or no parental or family support. There are an estimated 3.8 million orphans in SA, with approximately 1.5 - 2 million children considered adoptable. As a means of improving services, newly drafted adoption guidelines from the National Department of Social Development will in future require both non-profit and private sector adoption agencies to obtain a medical report on a child prior to placement. However, no local guidelines specify what an appropriate medical examination entails or how it should be reported. For the purposes of proposing and developing such guidelines, an open forum was convened at the Institute of Pathology, University of Pretoria, in March 2013. These 'Recommendations for the medical evaluation of children prior to adoption in South Africa' emanate from this meeting.


Factors implicated in the decision whether or not to join the tamoxifen trial in women at high familial risk of breast cancer.
Why, given similar medical circumstances-high familial risk of breast cancer-will some women elect to join a trial of drugs designed to reduce that risk but others choose not to take part? The aim of this study was to identify measurable differences between women who elect to join a placebo-controlled, double-blind randomised trial of the drug tamoxifen and women who elect not to join. One hundred and six women attending a breast care clinic completed questionnaires covering demographic details, health locus of control, perception of risk and adequacy of medical communication. All were eligible for inclusion in the tamoxifen trial. Only half (n=53) of the sample elected to join, the other half (n=53) declined. Those who declined the trial were significantly more aware of lifestyle factors thought to influence the development of cancers-diet, exercise and oestrogen-prolonging activities (p<0.001), and they also appeared to find the information given by the hospital about tamoxifen harder to understand than did the group who had joined the trial (p=0.01). They could think of significantly fewer positive reasons for joining (p<0.001) and were significantly younger (p=0.001). Participants in both groups significantly overestimated the relative risks of breast cancer. The average estimation of risk for women aged 30 with a family history of breast cancer was 22 times higher than that given by their consultant. This gives rise to considerable concerns about the information underpinning informed consent.


Outdoor scene image segmentation based on background recognition and perceptual organization.
In this paper, we propose a novel outdoor scene image segmentation algorithm based on background recognition and perceptual organization. We recognize the background objects such as the sky, the ground, and vegetation based on the color and texture information. For the structurally challenging objects, which usually consist of multiple constituent parts, we developed a perceptual organization model that can capture the nonaccidental structural relationships among the constituent parts of the structured objects and, hence, group them together accordingly without depending on a priori knowledge of the specific objects. Our experimental results show that our proposed method outperformed two state-of-the-art image segmentation approaches on two challenging outdoor databases (Gould data set and Berkeley segmentation data set) and achieved accurate segmentation quality on various outdoor natural scene environments.


Kidney function and volume progression in unilateral autosomal dominant polycystic kidney disease with contralateral renal agenesis or hypoplasia: a case series.
The occurrence of unilateral autosomal dominant polycystic kidney disease (ADPKD) with absence of the contralateral kidney has been described only rarely in the literature. Whether unilateral ADPKD is associated with faster disease progression is not known. Case series. In a prospective cohort of 182 patients with ADPKD, we identified 3 patients with ADPKD and unilateral renal agenesis (2 patients) or severe hypoplasia (1 patient). Genetic analysis of the PKD1 and PKD2 genes was performed for all 3 patients. Serum creatinine levels and kidney volumes based on magnetic resonance imaging were determined twice, with a 6-month interval between measurements. Characteristics of the 3 patients were compared with age- and sex-matched controls from the full cohort. Genotyping of the 3 patients indicated that each had a different [corrected] mutation in the PKD1 gene that is predicted to cause frameshift and/or truncation of the protein product. [corrected] All 3 patients with unilateral ADPKD had renal volumes and progression rates greater than the mean values of their matched control groups. However, their glomerular filtration rates were well preserved, with estimated single-kidney creatinine clearances much greater than their controls. The number of cases in this study is small and time of follow-up was limited. Unilateral renal agenesis or hypoplasia in patients with ADPKD might not be as rare as previously thought. Glomerular filtration rate was preserved despite unilateral renal absence, suggesting that renal compensatory mechanisms are well conserved in patients with ADPKD.


Phytophthora suppressor of RNA silencing 2 is a conserved RxLR effector that promotes infection in soybean and Arabidopsis thaliana.
The genus Phytophthora consists of notorious and emerging pathogens of economically important crops. Each Phytophthora genome encodes several hundreds of cytoplasmic effectors, which are believed to manipulate plant immune response inside the host cells. However, the majority of Phytophthora effectors remain functionally uncharacterized. We recently discovered two effectors from the soybean stem and root rot pathogen Phytophthora sojae with the activity to suppress RNA silencing in plants. These effectors are designated Phytophthora suppressor of RNA silencing (PSRs). Here, we report that the P. sojae PSR2 (PsPSR2) belongs to a conserved and widespread effector family in Phytophthora. A PsPSR2-like effector produced by P. infestans (PiPSR2) can also suppress RNA silencing in plants and promote Phytophthora infection, suggesting that the PSR2 family effectors have conserved functions in plant hosts. Using Agrobacterium rhizogenes-mediated hairy roots induction, we demonstrated that the expression of PsPSR2 rendered hypersusceptibility of soybean to P. sojae. Enhanced susceptibility was also observed in PsPSR2-expressing Arabidopsis thaliana plants during Phytophthora but not bacterial infection. These experiments provide strong evidence that PSR2 is a conserved Phytophthora effector family that performs important virulence functions specifically during Phytophthora infection of various plant hosts.


Patterns of errors contributing to trauma mortality: lessons learned from 2,594 deaths.
To identify patterns of errors contributing to inpatient trauma deaths. All inpatient trauma deaths at a high-volume level I trauma center from 1996 to 2004 inclusive were audited. Data were collected with daily trauma registry chart abstraction, weekly morbidity and mortality reports, hospital quality assurance reports, and annual trauma registry analyses of risk of death using TRISS and HARM methodology. Deaths that met criteria for low to medium probability of mortality or those with quality of care concerns were analyzed for errors and then subjected to 3-stage peer review at weekly departmental, monthly hospital, and annual regional forums. Patterns of errors were constructed from the compiled longitudinal data. In 9 years, there were 44,401 trauma patient admissions and 2,594 deaths (5.8%), of which 601 met low to medium mortality risks. Sixty-four patients (0.14% admissions, 2.47% deaths) had recognized errors in care that contributed to their death. Important error patterns included: failure to successfully intubate, secure or protect an airway (16%), delayed operative or angiographic control of acute abdominal/pelvic hemorrhage (16%), delayed intervention for ongoing intrathoracic hemorrhage (9%), inadequate DVT or gastrointestinal prophylaxis (9%), lengthy initial operative procedures rather than damage control surgery in unstable patients (8%), over-resuscitation with fluids (5%), and complications of feeding tubes (5%). Resulting data-directed institutional and regional trauma system policy changes have demonstrably reduced the incidence of associated error-related deaths. Preventable deaths will occur even in mature trauma systems. This review has identified error patterns that are likely common in all trauma systems, and for which policy interventions can be effectively targeted.


Impact of high-risk cytogenetics on outcomes for children and young adults receiving CD19-directed CAR T-cell therapy.
Chimeric antigen receptor (CAR) T-cell therapy can induce durable remissions of relapsed/refractory B-acute lymphoblastic leukemia (ALL). However, case reports suggested differential outcomes mediated by leukemia cytogenetics. We identified children and young adults with relapsed/refractory CD19+ ALL/lymphoblastic lymphoma treated on 5 CD19-directed CAR T-cell (CTL019 or humanized CART19) clinical trials or with commercial tisagenlecleucel from April 2012 to April 2019. Patients were hierarchically categorized according to leukemia cytogenetics: High-risk lesions were defined as KMT2A (MLL) rearrangements, Philadelphia chromosome (Ph+), Ph-like, hypodiploidy, or TCF3/HLF; favorable as hyperdiploidy or ETV6/RUNX1; and intermediate as iAMP21, IKZF1 deletion, or TCF3/PBX1. Of 231 patients aged 1 to 29, 74 (32%) were categorized as high risk, 28 (12%) as intermediate, 43 (19%) as favorable, and 86 (37%) as uninformative. Overall complete remission rate was 94%, with no difference between strata. There was no difference in relapse-free survival (RFS; P = .8112), with 2-year RFS for the high-risk group of 63% (95% confidence interval [CI], 52-77). There was similarly no difference seen in overall survival (OS) (P = .5488), with 2-year OS for the high-risk group of 70% (95% CI, 60-82). For patients with KMT2A-rearranged infant ALL (n = 13), 2-year RFS was 67% (95% CI, 45-99), and OS was 62% (95% CI, 40-95), with multivariable analysis demonstrating no increased risk of relapse (hazard ratio, 0.70; 95% CI, 0.21-2.90; P = .7040) but a higher proportion of relapses associated with myeloid lineage switch and a 3.6-fold increased risk of all-cause death (95% CI, 1.04-12.75; P = .0434). CTL019/huCART19/tisagenlecleucel are effective at achieving durable remissions across cytogenetic categories. Relapsed/refractory patients with high-risk cytogenetics, including KMT2A-rearranged infant ALL, demonstrated high RFS and OS probabilities at 2 years.


Isolation of orbiviruses and uukuviruses from puffin ticks.
Two viruses were isolated from a pool of three female Ixodes uriae ticks found on a dead puffin (Fratercula arctica) on a beach at Arbroath, Scotland. Complement fixation tests showed that one of the viruses was an orbivirus belonging to the Kemerovo serogroup and was related to Cape Wrath virus. Cross-reactions did not occur in neutralisation tests with 4 Kemerovo group viruses previously isolated from I. uriae collected in British seabird colonies. The orbivirus was therefore named Arbroath virus. The other virus was of the Uukuniemi serogroup (family Bunyaviridae) and reacted in complement fixation and neutralisation tests with a virus isolated from I. uriae collected from a seabird colony at St Abb's Head, Scotland. Both the orbi- and the uukuviruses replicated in a tick (Rhipicephalus appendiculatus) cell line, RA-243.


The effect of road and sea transport on inflammatory, adrenocortical, metabolic and behavioural responses of weanling heifers.
The objective was to investigate the effect of transport on inflammatory, adrenocortical, metabolic and behavioural responses of weanling heifers transported from Ireland to Spain. At the end of the grazing season, 60 Charolais x beef heifers (mean live weight 245, s.e. 4.3 kg and mean weaning age 219, s.e. 4.9 days) were abruptly weaned from their dams on day 0. The animals were assigned by live weight to two treatments, transport (T) (n = 40) (mean 246, s.e. 5.4 kg) and control (C) (n = 20) (mean 247, s.e. 7.2 kg) on day 0. The T animals were transported from Ireland to France on a roll-on roll-off ferry at a stocking density of 0.93 m2/animal and then by road for 9 h to a French lairage while C animals remained in Ireland and were not transported. On arrival at the French lairage (d 2), 20 T animals were unloaded (ULT) and rested for 12 h in the French lairage and 20 animals rested (RT) on the transporter. All animals had access to hay and water. After the rest period, the ULT animals were re-loaded. The subsequent journey by road from France to Spain was 9 h travel, 7 h rest (on the transporter) and a further 7 h travel by road. All T animals were blood sampled prior to transport (day (d) 0; baseline), on arrival in the French lairage (d 2), after 12 h rest in the French lairage (d 2), on arrival at the feedlot in Spain (d 4) and on d 6, d 8, d 10 and d 34. Control animals were blood sampled at the same times as T animals. ULT and RT animals had lower (P < 0.05) live weight than C animals on d 6. WBC number was lower (P < 0.05) in control animals on d 10 and greater on d 34 compared with baseline values. RT and ULT animals had greater (P < 0.05) WBC number than baseline on d 2 (arrival in France) to d 34. Neutrophil % was unchanged in RT, ULT and control animals compared with baseline. Control, RT and ULT animals had lower haematocrit % (P < 0.05) throughout the study compared with d 0. There was no difference (P > 0.05) in plasma protein concentration between RT and ULT animals from day 2 to d 34. Plasma concentrations of urea were higher (P < 0.05) in RT animals from d 2 to d 34 compared with C animals. RT and ULT animals had lower (P < 0.05) non-esterified fatty acid (NEFA) and betaeta-hydroxy-butyrate (ssHB) concentrations on d 10 and d 34 compared with d 0. It is concluded that, within the conditions of the present study, the performance of the animals that remained on the transporter during the 12 h lairage period in France was not different post-transport from the transported animals that were unloaded and lairaged in France.


A disorder of anger and aggression: children's perspectives on attention deficit/hyperactivity disorder in the UK.
This article investigates the social and moral dimensions of Attention Deficit/Hyperactivity Disorder (ADHD) diagnosis, asking what ADHD means in UK children's everyday lives, and what children do with this diagnosis. Drawing on interviews with over 150 children, the analysis examines the influence of a UK state school-based culture of aggression on the form and intensity of diagnosed children's difficulties with behavioral self-control. Diagnosed children's mobilization of ADHD behaviors and their exploitation of the diagnosis shows how children's active moral agency can support and compromise cognitive, behavioral and social resilience. The findings support a proposal for a complex sociological model of ADHD diagnosis and demonstrate the relevance of this model for national policy initiatives related to mental health and wellbeing in children.


Outside the box--novel therapeutic strategies for glioblastoma.
Standard approaches to therapy for malignant glioma provide modest improvement of progression-free survival and overall survival. Almost all patients experiencing glioblastoma eventually progress, and no cure is currently available. During the last decade, we have witnessed a 30% improvement in 2-year overall survival rates, yet glioblastoma continues to cause approximately 13,000 cancer-related deaths in the United States annually. Thus, novel therapies need to be investigated alongside continued development of currently available radiotherapy and chemotherapy options. Because glioblastoma does not typically metastasize outside the brain, development of unique local therapies that are not available for other cancers is feasible. Experimental agents, like scorpion venom-derived chlorotoxin, have been successfully applied in local therapy for glioblastoma. In addition, multiple new gene therapy approaches are emerging for both local and systemic glioblastoma therapy. Lastly, alternating electric fields are being introduced to cancer therapy. This review will discuss these "nonstandard"--outside the box--modalities for therapy for malignant glioma.


Zoonoses-with friends like this, who needs enemies?
Zoonoses are infections that are spread from animals to humans. Most often, humans are "dead-end" hosts, meaning that there is no subsequent human-to-human transmission. If one considers most of the emerging infections that were recognized at the end of the last century and the beginning of this century, they would fall into the category of zoonoses. One of the most important common traits exhibited by infections that have been or can be eliminated from the face of the earth (e.g. smallpox, measles, polio) is the absence of any host other than humans. Therefore, zoonses represent infections that can never be eliminated and must be considered as permanent and recurrent factors to be dealt with in protecting human health.


Histidines 578 and 587 in the S5-S6 linker of the human Ether-a-gogo Related Gene-1 K+ channels confer sensitivity to reactive oxygen species.
The K(+) channels encoded by the human Ether-a-gogo Related Gene-1 (hERG1) are crucially involved in controlling heart and brain excitability and are selectively influenced by reactive oxygen species (ROS). To localize the molecular regions involved in ROS-induced modulation of hERG1, segmental exchanges between the ROS-sensitive hERG1 and the ROS-insensitive bovine ether-a-gogo gene (bEAG) K(+) channels were generated, and the sensitivity of these chimeric channels to ROS was studied with the two-microelectrode voltage-clamp technique upon their expression in Xenopus oocytes. Substitution of the S(5)-S(6) linker of hERG1 with the corresponding bEAG region removed channel sensitivity to ROS, whereas the reverse chimeric exchange introduced ROS sensitivity into bEAG. Mutation of each of the two hERG1 histidines at positions 578 and 587 within the S(5)-S(6) linker generated K(+) channels insensitive to modulation by ROS. In addition, the two iron chelators desferrioxamine (1 mm) and o-phenanthroline (0.2 mm) significantly inhibited hERG1 outward K(+) currents and prevented hERG1 inhibition induced by the ROS-scavenging enzyme catalase (1000 units/ml). Finally, the hERG1-inhibitory effect exerted by the iron chelators was prevented by the hERG1 H578D/H587Y double mutation. Collectively, the results obtained suggest that histidines at positions 578 and 587 in the S(5)-S(6) linker region of hERG1 K(+) channels are crucial players in ROS-induced modulation of hERG1 K(+) channels.


Results of an economic model to assess the cost-effectiveness of enoxaparin, a low-molecular-weight heparin, versus warfarin for the prophylaxis of deep vein thrombosis and associated long-term complications in total hip replacement surgery in the United States.
Premature death due to pulmonary embolism is a short-term complication of deep vein thrombosis (DVT). The long-term clinical course after DVT can be further complicated by excess mortality, recurrent venous thromboembolism (VTE), and the post-thrombotic syndrome (PTS), which may produce sizable long-term economic burdens. The goal of this study was to determine the cost-effectiveness of the low-molecular-weight heparin (LMWH) enoxaparin versus warfarin for the universal prophylaxis of DVT and associated long-term complications in US patients undergoing total hip replacement surgery (THRS). A model was constructed to assess the long-term cost-effectiveness of the 2 treatments. Patients undergoing THRS were exposed to a short-term risk of developing a DVT. Patients surviving a DVT were exposed to increased risk of long-term complications of DVT, including PTS, recurrent VTE, and increased mortality. Published literature, augmented by expert opinion, served as input for the model's resource use and costs for DVT prophylaxis, clinical diagnosis, and treatment of DVT, VTE, and PTS. When the analysis included only the short-term consequences of DVT, therapy with enoxaparin resulted in a net cost of $133 per patient and a net increase of 0.04 quality-adjusted life-years (QALYs) per patient. Thromboprophylaxis with enoxaparin versus warfarin resulted in $3733 per QALY saved. In contrast, when the long-term consequences of DVT were included, enoxaparin resulted in net lifetime savings of $89 per patient and net QALY benefits of 0.16 per patient. To the best of our knowledge, this is the first US economic analysis comparing DVT prophylaxis with the LMWH enoxaparin versus warfarin that included the long-term complications of DVT. Our model suggests that use of enoxaparin in patients undergoing THRS reduces the economic burden associated with these long-term complications.


Gas-phase structure of 1,8-bis[(trimethylsilyl)ethynyl]anthracene: cog-wheel-type vs. independent internal rotation and influence of dispersion interactions.
The gas-phase structure of 1,8-bis[(trimethylsilyl)ethynyl]anthracene (1,8-BTMSA) was determined by a combined gas electron diffraction (GED)/mass spectrometry (MS) experiment as well as by quantum-chemical calculations (QC). DFT and dispersion corrected DFT calculations (DFT-D3) predicted two slightly different structures for 1,8-BTMSA concerning the mutual orientation of the two -C-C[triple bond, length as m-dash]C-SiMe3 units: away from one another or both bent to the same side. An attempt was made to distinguish these structures by GED structural analysis. To probe the structural rigidity, a set of Born-Oppenheimer molecular dynamics (BOMD) calculations has been performed at the DFT-D level. Vibrational corrections Δr = ra - re were calculated by two BOMD approaches: a microcanonically (NVE) sampled ensemble of 20 trajectories (BOMD(NVE)) and a canonical (NVT) trajectory thermostated by the Noose-Hoover algorithm (BOMD(NVT)). In addition, the conventional approach with both, rectilinear and curvilinear approximations (SHRINK program), was also applied. Radial distribution curves obtained with models using both MD approaches provide a better description of the experimental data than those obtained using the rectilinear (SHRINK) approximation, while the curvilinear approach turned out to lead to physically inacceptable results. The electronic structure of 1,8-BTMSA was investigated in terms of an NBO analysis and was compared with that of the earlier studied 1,8-bis(phenylethynyl)anthracene. Theoretical and experimental results lead to the conclusion that the (trimethylsilyl)ethynyl (TMSE) groups in 1,8-BTMSA are neither restricted in rotation nor in bending at the temperature of the GED experiment.


The human cathelicidin LL-37 preferentially promotes apoptosis of infected airway epithelium.
Cationic host defense peptides are key, evolutionarily conserved components of the innate immune system. The human cathelicidin LL-37 is an important cationic host defense peptide up-regulated in infection and inflammation, specifically in the human lung, and was shown to enhance the pulmonary clearance of the opportunistic pathogen Pseudomonas aeruginosa in vivo by as yet undefined mechanisms. In addition to its direct microbicidal potential, LL-37 can modulate inflammation and immune mechanisms in host defense against infection, including the capacity to modulate cell death pathways. We demonstrate that at physiologically relevant concentrations of LL-37, this peptide preferentially promoted the apoptosis of infected airway epithelium, via enhanced LL-37-induced mitochondrial membrane depolarization and release of cytochrome c, with activation of caspase-9 and caspase-3 and induction of apoptosis, which only occurred in the presence of both peptide and bacteria, but not with either stimulus alone. This synergistic induction of apoptosis in infected cells was caspase-dependent, contrasting with the caspase-independent cell death induced by supraphysiologic levels of peptide alone. We demonstrate that the synergistic induction of apoptosis by LL-37 and Pseudomonas aeruginosa required specific bacteria-epithelial cell interactions with whole, live bacteria, and bacterial invasion of the epithelial cell. We propose that the LL-37-mediated apoptosis of infected, compromised airway epithelial cells may represent a novel inflammomodulatory role for this peptide in innate host defense, promoting the clearance of respiratory pathogens.


Spontaneous splenic rupture in polyarteritis nodosa.
A 28 year old man presented with haematuria and renal failure. Renal arteriography revealed bleeding into the pelvis of a solitary right kidney from a hilar artery. Multiple aneurysms were noted in the splenic artery. The spleen subsequently ruptured spontaneously and was removed at laparotomy together with the right kidney. Histological examination of the spleen and kidney revealed an acute necrotizing vasculitis involving medium-sized and smaller arteries confirming a diagnosis of polyarteritis nodosa. An area of infarction involved a subcapsular area of the spleen. Spontaneous splenic rupture is a rare but important complication of systemic vasculitides.


Contribution of large scale biases in decoding of direction-of-motion from high-resolution fMRI data in human early visual cortex.
Previous studies have demonstrated that the perceived direction of motion of a visual stimulus can be decoded from the pattern of functional magnetic resonance imaging (fMRI) responses in occipital cortex using multivariate analysis methods (Kamitani and Tong, 2006). One possible mechanism for this is a difference in the sampling of direction selective cortical columns between voxels, implying that information at a level smaller than the voxel size might be accessible with fMRI. Alternatively, multivariate analysis methods might be driven by the organization of neurons into clusters or even orderly maps at a much larger scale. To assess the possible sources of the direction selectivity observed in fMRI data, we tested how classification accuracy varied across different visual areas and subsets of voxels for classification of motion-direction. To enable high spatial resolution functional MRI measurements (1.5mm isotropic voxels), data were collected at 7T. To test whether information about the direction of motion is represented at the scale of retinotopic maps, we looked at classification performance after combining data across different voxels within visual areas (V1-3 and MT+/V5) before training the multivariate classifier. A recent study has shown that orientation biases in V1 are both necessary and sufficient to explain classification of stimulus orientation (Freeman et al., 2011). Here, we combined voxels with similar visual field preference as determined in separate retinotopy measurements and observed that classification accuracy was preserved when averaging in this 'retinotopically restricted' way, compared to random averaging of voxels. This insensitivity to averaging of voxels (with similar visual angle preference) across substantial distances in cortical space suggests that there are large-scale biases at the level of retinotopic maps underlying our ability to classify direction of motion.


Alteration in Nasopharyngeal Microbiota Profile in Aged Patients with COVID-19.
Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) is an infectious virus that causes coronavirus disease 2019 (COVID-19) transmitted mainly through droplets and aerosol affecting the respiratory tract and lungs. Little is known regarding why some individuals are more susceptible than others and develop severe symptoms. In this study, we analyzed the nasopharyngeal microbiota profile of aged patients with COVID-19 (asymptomatic vs. symptomatic) vs. healthy individuals. We examined the nasopharynx swab of 84 aged-matched patients, out of which 27 were negative asymptomatic (NegA), 30 were positive asymptomatic (PA), and 27 patients were positive symptomatic (PSY). Our analysis revealed the presence of abundant Cyanobacterial taxa at phylum level in PA (p-value = 0.0016) and PSY (p-value = 0.00038) patients along with an upward trend in the population of Litoricola, Amylibacter, Balneola, and Aeromonas at the genus level. Furthermore, to know the relationship between the nasal microbiota composition and severity of COVID-19, we compared PA and PSY groups. Our data show that the nasal microbiota of PSY patients was significantly enriched with the signatures of two bacterial taxa: Cutibacterium (p-value = 0.045) and Lentimonas (p-value = 0.007). Furthermore, we also found a significantly lower abundance of five bacterial taxa, namely: Prevotellaceae (p-value = 7 × 10-6), Luminiphilus (p-value = 0.027), Flectobacillus (p-value = 0.027), Comamonas (p-value = 0.048), and Jannaschia (p-value = 0.012) in PSY patients. The dysbiosis of the nasal microbiota in COVID-19 positive patients might have a role in contributing to the severity of COVID-19. The findings of our study show that there is a strong correlation between the composition of the nasal microbiota and COVID-19 severity. Further studies are needed to validate our finding in large-scale samples and to correlate immune response (cytokine Strome) and nasal microbiota to identify underlying mechanisms and develop therapeutic strategies against COVID-19.


Towards the new normal: Transcriptomic convergence and genomic legacy of the two subgenomes of an allopolyploid weed (Capsella bursa-pastoris).
Allopolyploidy has played a major role in plant evolution but its impact on genome diversity and expression patterns remains to be understood. Some studies found important genomic and transcriptomic changes in allopolyploids, whereas others detected a strong parental legacy and more subtle changes. The allotetraploid C. bursa-pastoris originated around 100,000 years ago and one could expect the genetic polymorphism of the two subgenomes to follow similar trajectories and their transcriptomes to start functioning together. To test this hypothesis, we sequenced the genomes and the transcriptomes (three tissues) of allotetraploid C. bursa-pastoris and its parental species, the outcrossing C. grandiflora and the self-fertilizing C. orientalis. Comparison of the divergence in expression between subgenomes, on the one hand, and divergence in expression between the parental species, on the other hand, indicated a strong parental legacy with a majority of genes exhibiting a conserved pattern and cis-regulation. However, a large proportion of the genes that were differentially expressed between the two subgenomes, were also under trans-regulation reflecting the establishment of a new regulatory pattern. Parental dominance varied among tissues: expression in flowers was closer to that of C. orientalis and expression in root and leaf to that of C. grandiflora. Since deleterious mutations accumulated preferentially on the C. orientalis subgenome, the bias in expression towards C. orientalis observed in flowers indicates that expression changes could be adaptive and related to the selfing syndrome, while biases in the roots and leaves towards the C. grandiflora subgenome may be reflective of the differential genetic load.


Biology and toxicology of tellurium explored by speciation analysis.
Tellurium (Te) is widely used in industry because it has unique physicochemical properties. Although Te is a non-essential element in animals and plants, it is expected to be metabolized to organometallic compounds having a carbon-Te bond in living organisms exposed to inorganic Te compounds. Thus, the speciation and identification of tellurometabolites are expected to contribute to the depiction of the metabolic chart of Te. Speciation by elemental mass spectrometry and identification by molecular mass spectrometry coupled with separation techniques have significantly contributed to the discovery of tellurometabolites in animals and plants. The aim of this mini review is to present recent advances in the biology and toxicology of tellurium as revealed by speciation and identification by molecular mass spectrometry.


Endogenous IL-33 and Its Autoamplification of IL-33/ST2 Pathway Play an Important Role in Asthma.
IL-33 and its receptor ST2 are contributing factors to airway inflammation and asthma exacerbation. The IL-33/ST2 signaling pathway is involved in both the onset and the acute exacerbations of asthma. In this study, we address the role of endogenous IL-33 and its autoamplification of the IL-33/ST2 pathway in Ag-dependent and Ag-independent asthma-like models. Wild-type, IL-33 knockout, ST2 knockout mice were either intratracheally administrated with 500 ng of rIL-33 per day for four consecutive days or were sensitized and challenged with OVA over 21 d. In wild-type mice, IL-33 or OVA induced similar airway hyperresponsiveness and eosinophilic airway inflammation. IL-33 induced its own mRNA and ST2L mRNA expression in the lung. IL-33 autoamplified itself and ST2 protein expression in airway epithelial cells. OVA also induced IL-33 and ST2 protein expression. In IL-33 knockout mice, the IL-33- and OVA-induced airway hyperresponsiveness and eosinophilic airway inflammation were both significantly attenuated, whereas IL-33-induced ST2L mRNA expression was preserved, although no autoamplification of IL-33/ST2 pathway was observed. In ST2 knockout mice, IL-33 and OVA induced airway hyperresponsiveness and eosinophilic airway inflammation were both completely diminished, and no IL-33/ST2 autoamplification was observed. These results suggest that endogenous IL-33 and its autoamplification of IL-33/ST2 pathway play an important role in the induction of asthma-like phenotype. Thus an intact IL-33/ST2 pathway is necessary for both Ag-dependent and Ag-independent asthma-like mouse models.


Longitudinal effects of lesions on functional networks after stroke.
While ischemic stroke reflects focal damage determined by the affected vascular territory, clinical symptoms are often more complex and may be better explained by additional indirect effects of the focal lesion. Assumed to be structurally underpinned by anatomical connections, supporting evidence has been found using alterations in the functional connectivity of resting-state functional magnetic resonance imaging (fMRI) data in both sensorimotor and attention networks. To assess the generalizability of this phenomenon in a stroke population with heterogeneous lesions, we investigated the distal effects of lesions on a global level. Longitudinal resting-state fMRI scans were acquired at three consecutive time points, beginning during the acute phase (days 1, 7, and 90 post-stroke) in 12 patients after ischemic stroke. We found a preferential functional change in affected networks (i.e., networks containing lesions changed more during recovery when compared with unaffected networks). This change in connectivity was significantly correlated with clinical changes assessed with the National Institute of Health Stroke Scale. Our results provide evidence that the functional architecture of large-scale networks is critical to understanding the clinical effect and trajectory of post-stroke recovery.


Shortened rehabilitation period using a modified surgical technique for reconstruction of lost elbow extension in tetraplegia.
Our aim was to evaluate the functional outcome of reconstruction of elbow extension in tetraplegia using a new technique for improving the attachment sites of posterior deltoid-to-triceps transfer in conjunction with an active rehabilitation programme. Ten tetraplegic patients (15 arms) had modified deltoid-to-triceps transfer using a tibialis anterior tendon graft. The operation included large overlaps between the tendon attachments, and additional security by anchoring the distal stump of the tendon graft to the olecranon. During the first 3 weeks of immobilisation, isometric contractions were made and during the following 4 weeks the flexion angle of the elbow was increased by 15 degrees a week; weights were also used to reinforce muscle strength. The mean follow up was 10 months (range 5-19). The elbow extension strength after posterior deltoid-to-triceps transfer was measured in horizontal and vertical planes. After rehabilitation the active range of motion and strength of elbow extension had improved substantially. The mean active elbow extension range of motion was 132 degrees (range 120 degrees -145 degrees ) and the elbow could be extended actively in all planes. Elbow extension strength was restored to well above the counteraction of the weight of the arm. Mean (SEM) elbow extension was significantly greater in the horizontal shoulder plane compared with the vertical plane (10.4 (1.0) compared with 6.5 (1.2) Nm, p < 0.001) and strength increased roughly linearly as the degree of flexion of the elbow increased. The most dramatic increase was in the range between 120 degrees and 135 degrees of flexion, regardless of the plane of action of the shoulder. We have shown good functional results and a shorter rehabilitation period using a rigorous suturing technique that allows for active strength and mobility training without additional adverse effects.


Pre-Erythrocytic Vaccines against Malaria.
Malaria, caused by the protozoan Plasmodium, is a devastating disease with over 200 million new cases reported globally every year. Although immunization is arguably the best strategy to eliminate malaria, despite decades of research in this area we do not have an effective, clinically approved antimalarial vaccine. The current impetus in the field is to develop vaccines directed at the pre-erythrocytic developmental stages of Plasmodium, utilizing novel vaccination platforms. We here review the most promising pre-erythrocytic stage antimalarial vaccine candidates.


Geographies of an Online Social Network.
How is online social media activity structured in the geographical space? Recent studies have shown that in spite of earlier visions about the "death of distance", physical proximity is still a major factor in social tie formation and maintenance in virtual social networks. Yet, it is unclear, what are the characteristics of the distance dependence in online social networks. In order to explore this issue the complete network of the former major Hungarian online social network is analyzed. We find that the distance dependence is weaker for the online social network ties than what was found earlier for phone communication networks. For a further analysis we introduced a coarser granularity: We identified the settlements with the nodes of a network and assigned two kinds of weights to the links between them. When the weights are proportional to the number of contacts we observed weakly formed, but spatially based modules resemble to the borders of macro-regions, the highest level of regional administration in the country. If the weights are defined relative to an uncorrelated null model, the next level of administrative regions, counties are reflected.


Particle size distribution and polycyclic aromatic hydrocarbons emissions from agricultural crop residue burning.
Laboratory measurements were conducted to determine particle size distribution and polycyclic aromatic hydrocarbons (PAHs) emissions from the burning of rice, wheat, and corn straws, three major agricultural crop residues in China. Particle size distributions were determined by a wide-range particle spectrometer (WPS). PAHs in both the particulate and gaseous phases were simultaneously collected and analyzed by GC-MS. Particle number size distributions showed a prominent accumulation mode with peaks at 0.10, 0.15, and 0.15 μm for rice, wheat, and corn-burned aerosols, respectively. PAHs emission factors of rice, wheat, and corn straws were 5.26, 1.37, and 1.74 mg kg(-1), respectively. It was suggested that combustion with higher efficiency was characterized by smaller particle size and lower PAHs emission factors. The total PAHs emissions from the burning of three agricultural crop residues in China were estimated to be 1.09 Gg for the year 2004.


Differential gene expression profile of retinoblastoma compared to normal retina.
The retinoblastoma gene (RB1) is a tumor suppressor gene that was first discovered in a rare ocular pediatric tumor called retinoblastoma (RB). The RB1 gene is essential for normal progression through the cell cycle and exerts part of its function through the family of transcription factors (E2F) and many other intermediaries. In the absence of normal RB1, genomic instability and chromosomal aberrations accumulate, leading to tumor initiation, progression, and ultimately metastasis. The purpose of this report was to identify the molecular pathways that are deregulated in retinoblastoma. We compared gene expression signatures of matched normal retinal tissue and retinoblastoma (RB) tumor tissue from six individuals, using microarray analysis followed by statistical and bioinformatic analyses. We identified 1,116 genes with increased expression and 837 with decreased expression in RB tumor tissue compared to matched normal retinal tissue. Functional categories of the cognate genes with the greatest statistical support were cell cycle (309 genes), cell death (437 genes), DNA replication, recombination and repair (270 genes), cellular growth and proliferation (464 genes), and cellular assembly and organization (110 genes). The list included differentially expressed retinal cone-cell-specific markers. These data indicated the predominance of cone cells in RB and support the idea that the latter group of cells may be the cells of origin for RB. The genes differentially expressed in RB as compared to normal retina belong mainly to DNA damage-response pathways, including, but not limited to, breast cancer associated genes (BRCA1, BRCA2), ataxia telangiectasia mutated gene (ATM), ataxia telangiectasia and Rad3 related gene(ATR), E2F, checkpoint kinase 1 (CHK1) genes. In addition, novel pathways, such as aryl hydrocarbon receptor (AHR) signaling, polo-like kinase and mitosis, purine metabolism pathways were involved. The molecules AHR, CHK1, and polo-like kinases are of particular interest because there are several currently available drugs that target these molecules. Further studies are needed to determine if targeting these pathways in RB will have therapeutic value. It is also important to evaluate the relative importance of these pathways in different cells that make up the normal retina.


High-dose weekly intravenous immunoglobulin to prevent infections in patients undergoing autologous bone marrow transplantation or severe myelosuppressive therapy. A study of the American Bone Marrow Transplant Group.
To determine whether intravenous immunoglobulin (IVIG) prevents severe infections during autologous bone marrow transplantation or equivalent high-dose myelosuppressive therapy. Randomized, stratified, nonblinded study. Three tertiary care university hospitals. One hundred seventy patients entered the study; 82 received IVIG and 88 were untreated controls. The study groups were similar for parameters capable of influencing the likelihood of infection. Intravenous immunoglobulin was given weekly at a dose of 500 mg/kg body weight from the initiation of cytotoxic therapy to the resolution of neutropenia. The development of bloodstream or other clinically proven infection, platelet use, and the development of alloimmunity to platelet transfusion. Clinical infection, bacteremia, and fungemia occurred in 43%, 35%, and 6% of the IVIG-treated patients and in 44%, 34%, and 9% of the control patients. Gram-positive bacteremia and gram-negative bacteremia occurred in 28% and 11% of the IVIG group and in 23% and 13% of the control group. Death due to infection occurred in 4.9% of IVIG recipients and in 2.3% of controls. None of these observations was statistically significant (P > 0.2). Survival to hospital discharge was achieved in 86.6% of the IVIG group and in 96.6% of the control group. The survival difference (10%; 95% CI, 1.7% to 18.3%; P = 0.02) was due to a higher incidence of regimen-related toxic death in the IVIG-treated group. The use of IVIG did not prevent infection. Fewer deaths occurred among controls due to a higher incidence of fatal hepatic veno-occlusive disease in patients receiving IVIG.


Effect of wing scalloping mutations on cut expression and sense organ differentiation in the Drosophila wing margin.
A number of wing scalloping mutations have been examined to determine their effects on the mutant phenotype of cut mutations and on the expression of the Cut protein. The mutations fall into two broad classes, those which interact synergistically with weak cut wing mutations to produce a more extreme wing phenotype than either mutation alone and those that have a simple additive effect with weak cut wing mutations. The synergistically interacting mutations are alleles of the Notch, Serrate and scalloped genes. These mutations affect development of the wing margin in a manner similar to the cut wing mutations. The mutations inactivate the cut transcriptional enhancer for the wing margin mechanoreceptors and noninnervated bristles and prevent differentiation of the organs. Surprisingly, reduction of Notch activity in the wing margin does not have the effect of converting epidermal cells to a neural fate as it does in other tissues of ectodermal origin. Rather, it prevents the differentiation of the wing margin mechanoreceptors and noninnervated bristles.


Family analysis of immunoglobulin classes and subclasses in children with autistic disorder.
Autistic disorder is a severe neurodevelopment disorder characterized by a triad of impairments in reciprocal social interaction, verbal and nonverbal communication, and a pattern of repetitive stereotyped activities, behaviours and interests. There are strong lines of evidence to suggest that the immune system plays an important role in the pathogenesis of autistic disorder. The aim of this study was to analyze quantitative plasma concentration of immunoglobulin classes, and subclasses in autistic patients and their families. The investigation was performed retrospectively in 50 persons with autistic disorder in the Republic of Macedonia. Infantile autistic disorder was diagnosed by DSM-IV and ICD-10 criteria. Plasma immunoglobulin classes (IgM, IgA, and IgG) and subclasses (IgG1, IgG2, IgG3, and IgG4) were determined using Nephelometer Analyzer BN-100. Multiple comparisons for the IgA variable have shown statistically significant differences between three pairs: male autistic from the fathers (p = 0,001), female autistic from the mothers (p = 0,008), as well as healthy sisters from the fathers (p = 0,011). Statistically significant differences found between three groups regarding autistic disorder (person with autistic disorder, father/mother of a person with autistic disorder, and brother/sister) independent of sex belongs to IgA, IgG2, and IgG3 variables. Multiple comparisons for the IgA variable have shown statistically significant differences between children with autistic disorder from the fathers and mothers (p < 0,001), and healthy brothers and sisters from the fathers and mothers (p < 0,001). Comparison between healthy children and children with autistic disorder from the same family should be tested for immunoglobulin classes and subclasses in order to avoid differences between generations.


An efficient Ugi-3CR/aza Diels-Alder/Pomeranz-Fritsch protocol towards novel aza-analogues of (±)-nuevamine, (±)-lennoxamine and magallanesine: a diversity oriented synthesis approach.
A rapid and efficient synthesis of a series of (±)-nuevamine, (±)-lennoxamine and magallanesine aza analogues is described. The synthetic strategy involves Ugi-3CR and two further condensation processes, aza-Diels-Alder cycloaddition and the Pomeranz-Fritsch reaction. The variation of the chain-size in aldehyde moieties provided structural diversity in only two operational reaction steps.


Biomechanical pressures and upper extremity asymmetry: a study on young laborers.
The purpose of this study is to reveal the impacts of biomechanical pressures of heavy working conditions on the upper extremities of young laborers. The study covers the examination of the upper extremities of 104 young laborers in the industrial workshops of Ankara, Turkey regarding bilateral asymmetry. The average age of the laborers was 18.48 +/- 0.61 years. The control group consisted of 102 non-laborers with an average age of 18.39 +/- 0.58 years. The laborers were measured with regard to width of elbows, wrists, and hands, and the length of hands. No significant difference between the groups was observed with the exception of average wrist width. However, while the labor group showed directional asymmetry in all measurements, the non-laborers exhibited directional asymmetry only in hand width and length. Consequently, the study revealed that biomechanical pressures tend to increase directional asymmetry in the upper extremities.


The corpus callosum in monozygotic twins concordant and discordant for handedness and language dominance.
We used diffusion tensor imaging to assess callosal morphology in 35 pairs of monozygotic twins, of which 17 pairs were concordant for handedness and 18 pairs were discordant for handedness. Functional hemispheric language dominance was established for each twin member using fMRI, resulting in 26 twin pairs concordant and 9 twin pairs discordant for language dominance. On the basis of genetic models of handedness and language dominance, which assume one "right shift" (RS) gene with two alleles, an RS+ allele biasing toward right-handedness and left cerebral language dominance and an RS- allele leaving both asymmetries to chance, all twins were classified according to their putative genotypes, and the possible effects of the gene on callosal morphology was assessed. Whereas callosal size was under a high genetic control that was independent of handedness and language dominance, twin pairs with a high probability of carrying the putative RS+ allele showed a connectivity pattern characterized by a genetically controlled, low anisotropic diffusion over the whole corpus callosum. In contrast, the high connectivity pattern exhibited by twin pairs more likely to lack the RS+ allele was under significantly less genetic influence. The data suggest that handedness and hemispheric dominance for speech production might be at least partly dependent on genetically controlled processes of axonal pruning in the corpus callosum.


Simulated electronic health record (Sim-EHR) curriculum: teaching EHR skills and use of the EHR for disease management and prevention.
Electronic health records (EHRs) can improve many aspects of patient care, yet few formal EHR curricula exist to teach optimal use to students and other trainees. The Simulated EHR (Sim-EHR) curriculum was introduced in January 2011 at Oregon Health & Science University (OHSU) to provide learners with a safe hands-on environment in which to apply evidence-based guidelines while learning EHR skills. Using an EHR training platform identical to the OHSU EHR system, learners review and correct a simulated medical chart for a complex virtual patient with chronic diseases and years of fragmented care. They write orders and prescriptions, create an evidence-based plan of care for indicated disease prevention and management, and review their work in a small-group setting. Third-year students complete the Sim-EHR curriculum as part of the required family medicine clerkship; their chart work is assessed using a rubric tied to the curriculum's general and specific objectives. As of January 2014, 406 third-year OHSU medical students, on campus or at remote clerkship sites, and 21 OHSU internal medicine interns had completed simulated charts.In this article, the authors describe the development and implementation of the Sim-EHR curriculum, with a focus on use of the curriculum in the family medicine clerkship. They also share preliminary findings and lessons learned. They suggest that the Sim-EHR curriculum is an effective, interactive method for providing learners with EHR skills education while demonstrating how a well-organized chart helps ensure safe, efficient, and quality patient care.


International Association for the Study of Pain Presidential Task Force on Cannabis and Cannabinoid Analgesia: research agenda on the use of cannabinoids, cannabis, and cannabis-based medicines for pain management.
The President of the International Association for the Study of Pain established a task force on cannabis and cannabinoid analgesia to systematically examine the evidence on (1) analgesic pharmacology of cannabinoids and preclinical evidence on their efficacy in animal models of injury-related or pathological persistent pain; (2) the clinical efficacy of cannabis, cannabinoids, and cannabis-based medicines for pain; (3) harms related to long-term use of cannabinoids; as well as (4) societal issues and policy implications related to the use of these compounds for pain management. Here, we summarize key knowledge gaps identified in the task force outputs and propose a research agenda for generating high-quality evidence on the topic. The systematic assessment of preclinical and clinical literature identified gaps in rigor of study design and reporting across the translational spectrum. We provide recommendations to improve the quality, rigor, transparency, and reproducibility of preclinical and clinical research on cannabis and cannabinoids for pain, as well as for the conduct of systematic reviews on the topic. Gaps related to comprehensive understanding of the endocannabinoid system and cannabinoid pharmacology, including pharmacokinetics and drug formulation aspects, are discussed. We outline key areas where high-quality clinical trials with cannabinoids are needed. Remaining important questions about long-term and short-term safety of cannabis and cannabinoids are emphasized. Finally, regulatory, societal, and policy challenges associated with medicinal and nonmedicinal use of cannabis are highlighted, with recommendations for improving patient safety and reducing societal harms in the context of pain management.


End-stage renal disease risk equations for Hong Kong Chinese patients with type 2 diabetes: Hong Kong Diabetes Registry.
The objective of the study was to investigate risk factors and develop risk equations for end-stage renal disease (ESRD) in Chinese patients with type 2 diabetes. A prospective cohort of 4,438 patients with type 2 diabetes mellitus and without ESRD (median observation period 2.9 years, interquartile range 1.6-4.1 years) was included in the analysis. The end-point (ESRD) was defined by: (1) death due to diabetes with renal manifestations or renal failure; (2) hospitalisation due to renal failure; (3) estimated GFR (eGFR) <15 ml min(-1) 1.73 m(-2). Cox proportional hazards regression was used to develop risk equations. The data were randomly and evenly divided into the training data for development of the risk equations and the test data for validation. The validation was performed using the area under the receiver operating characteristic curve (aROC), which takes into account follow-up time and censoring. During the observation period, 159 patients or 12.45 per 1,000 person-years (95% CI 10.52-14.37 per 1,000 person-years) developed ESRD. Known duration of diabetes, systolic blood pressure, log(10) total cholesterol:HDL cholesterol ratio and retinopathy were significant predictors of ESRD. After further adjusting for eGFR, log(10) spot albumin:creatinine ratio (ACR) and haematocrit, only eGFR, haematocrit and log(10) ACR remained as independent predictors of ESRD. The risk equation derived from these three independent predictors had good discrimination, with an aROC of 0.97. Estimated GFR, haematocrit and ACR were independent predictors of ESRD and the derived risk equation performed well in Chinese patients with type 2 diabetes.


Systematic review of the literature on characteristics of late-talking toddlers.
Research has investigated late-talking toddlers because they are at great risk of continuing to experience language-learning difficulties once they enter school and hence are candidates for early intervention. It is also important to consider this group of children with regards to the immediate characteristics which are detrimental to their development and for which early intervention has become increasingly available. To review the literature on late-talking toddlers in order to identify the characteristics of this population whose importance has been clearly demonstrated, identify sources of incongruence in findings, and to underscore aspects of language delay at 2 years of age and characteristics about which additional knowledge is needed. The review highlights the need to define the language difficulties found in late-talking toddlers based on clinical profiles that go beyond the criterion of an expressive vocabulary delay. It also underscores the association between vocabulary delay and characteristics of the child such as social-emotional development and characteristics of the socio-familial environment such as language stimulation. Future research should take into account the lack of homogeneity observed within the population of children with a vocabulary delay at 2 years of age and attempt to identify subgroups within late-talking toddlers. It should also consider a multifactorial perspective of child development to further the understanding of this phenomenon.


Lymphoid enhancer factor 1 directs hair follicle patterning and epithelial cell fate.
T cell-specific transcription factor (TCF-1) and lymphoid enhancer factor 1 (LEF-1) have been implicated exclusively in the regulation of T cell-specific genes. The only adult tissue other than thymus known to express these factors is spleen and lymph node, which contain low levels of LEF-1 and no TCF-1. We noticed that genes involved in hair-specific gene expression possess LEF-1/TCF-1 consensus motifs located in similar positions relative to their TATA box. We show that of the two factors only LEF-1 is expressed in hair follicles; it can be cloned in both splice forms from human skin keratinocytes and it can bind to these sites in the hair promoters. We show that LEF-1 mRNA is present in pluripotent ectoderm, and it is up-regulated in a highly restricted pattern just before the formation of underlying mesenchymal condensates and commitment of overlying ectodermal cells to invaginate and become hair follicles. New waves of ectodermal LEF-1 spots appear concomitant with new waves of follicle morphogenesis. To test whether LEF-1 patterning might be functionally important for hair patterning and morphogenesis, we used transgenic technology to alter the patterning and timing of LEF-1 over the surface ectoderm. Striking abnormalities arose in the positioning and orientation of hair follicles, leaving a marked disruption of this normally uniform patterning. This provides the first direct evidence that ectodermal cues are critical in establishing these developmental processes, which at later stages are known to be influenced by underlying mesenchyme. Remarkably, elevated LEF-1 in the lip furrow epithelium of developing transgenic animals triggered these cells to invaginate, sometimes leading to the inappropriate adoption of hair follicle and tooth cell fates. Collectively, our findings demonstrate that ectodermal expression of LEF-1 plays a central role in gene expression, pattern formation, and other developmental processes involving epithelial-mesenchymal associations.


Incidence of deep vein thrombosis in erysipelas or cellulitis of the lower extremities.
The incidence of deep vein thrombosis (DVT) in patients with erysipelas and cellulitis of the lower extremities is unknown. As such, the indication and efficacy of prophylactic anticoagulation for prevention of DVT in these patients is unclear. The main goal of this review is to provide an estimate of the incidence of DVT in erysipelas and cellulitis based on existing literature. A comprehensive search of the electronic sources: MEDLINE, EMBASE, CINAHL, LILAC and Cochrane without any language limitation was performed from 1950 to April 2011 for articles focused on the occurrence of DVT in cellulitis or erysipelas of the lower extremities. The selected studies were divided into two groups according to presence or absence of systematic investigation for DVT. Those studies in which the patients received prophylactic or therapeutic anticoagulants before a diagnosis of DVT were excluded. The reported incidence rate of DVT in patients with erysipelas or cellulitis of the lower extremities is highly variable, ranging from 0 to 15%. In this review, the overall incidence rates of DVT in studies with and without systematic investigation for thromboembolism were 2.72% (95% CI: 1.71-3.75%) and 0.68% (95% CI: 0.27-1.07%), respectively. Given the low reported overall incidence of DVT, neither routine prophylactic anticoagulation nor systematic paraclinical investigation for DVT is indicated in low risk patients with erysipelas or cellulitis of the lower extremities. DVT should still be considered in patients with high pretest probability or other thromboembolic risk factors.


Efficacy of FEIBA for acute bleeding and surgical haemostasis in haemophilia A patients with inhibitors: a multicentre registry in Turkey.
Long used in established industrialized nations to treat patients with haemophilia and inhibitors, factor eight inhibitor bypassing activity (FEIBA) has, in recent years, been introduced into more geographically diverse settings. Data are needed on how successfully FEIBA therapy has been implemented in new regions. To determine the efficacy and safety of FEIBA for the treatment of acute bleeding and surgical haemostasis in a newly industrialized country. A multicentre registry of haemophilia A patients with inhibitors receiving FEIBA treatment was established in Turkey. With a standardized case report form, data were collected retrospectively on: patient demographics; characteristics of acute bleeding episodes and surgical interventions; FEIBA regimen; and treatment outcomes. Thirty-seven patients received a total of 112 FEIBA treatment courses, 90 for acute bleeding and 22 for surgical haemostasis. The median FEIBA dose per infusion for acute bleeding was 50 IU kg(-1), and for surgery was 100 IU kg(-1). For both acute joint and muscle/soft tissue bleeding and in surgery, haemostasis was attained in a median of two FEIBA infusions. FEIBA was judged effective in 92% of treatment courses for acute bleeding, with a 95% confidence interval (CI) of 85-97%. Rates of haemostatic efficacy did not differ significantly between anatomical sites of acute bleeding. The haemostatic efficacy rate of FEIBA in surgery was 86% (CI, 65-97%). No thromboembolic complications or other adverse events occurred during any treatment course. FEIBA has been successfully integrated into clinical practice in Turkey, with rates of haemostatic efficacy comparable to those reported in countries with a longer history of FEIBA usage.


Prevalence and risk factors of diabetic retinopathy in non-Hispanic whites and Hispanics with NIDDM. San Luis Valley Diabetes Study.
Diabetic retinopathy (DR) is the leading cause of blindness in adults in the United States. Because photocoagulation can reduce the incidence of blindness from severe DR by approximately 50%, it is important to identify people at increased risk for DR so that appropriate treatment can be accomplished. Use of populations at increased risk for diabetes may identify groups at increased risk for complications. A recent report from the San Antonio Heart Study showed that Mexican Americans were at greater risk for servere DR than non-Hispanic Whites. To compare the prevalence of DR between non-Hispanics and Hispanics in southern Colorado, 279 people with non-insulin-dependent diabetes mellitus (NIDDM) were identified, and retinal photographs identified the presence and severity of retinopathy. The worse eye was used to classify the severity of DR for each patient. Ninety percent of the subjects (166 Hispanics and 85 non-Hispanic Whites) were classified by retinopathy level. The duration-adjusted prevalence of any DR was 41.8% in Hispanics and 54.1% in non-Hispanic Whites. Severe DR (preproliferative and proliferative) occurred in 18.5% of the Hispanics and in 21.3% of the non-Hispanic Whites. The odds ratio for any DR, comparing Hispanics with non-Hispanic Whites adjusted for other risk factors, was 0.40 (95% confidence interval = 0.21, 0.76). Other risk factors for the presence of any retinopathy included use of exogenous insulin, increased duration of diabetes, younger age at diagnosis, increased glycosylated hemoglobin level, and increased systolic blood pressure. These data suggest that, compared with non-Hispanic Whites, Hispanics in Colorado may be at decreased risk for diabetic retinopathy.


Grey and white matter correlates of recent and remote autobiographical memory retrieval--insights from the dementias.
The capacity to remember self-referential past events relies on the integrity of a distributed neural network. Controversy exists, however, regarding the involvement of specific brain structures for the retrieval of recently experienced versus more distant events. Here, we explored how characteristic patterns of atrophy in neurodegenerative disorders differentially disrupt remote versus recent autobiographical memory. Eleven behavioural-variant frontotemporal dementia, 10 semantic dementia, 15 Alzheimer's disease patients and 14 healthy older Controls completed the Autobiographical Interview. All patient groups displayed significant remote memory impairments relative to Controls. Similarly, recent period retrieval was significantly compromised in behavioural-variant frontotemporal dementia and Alzheimer's disease, yet semantic dementia patients scored in line with Controls. Voxel-based morphometry and diffusion tensor imaging analyses, for all participants combined, were conducted to investigate grey and white matter correlates of remote and recent autobiographical memory retrieval. Neural correlates common to both recent and remote time periods were identified, including the hippocampus, medial prefrontal, and frontopolar cortices, and the forceps minor and left hippocampal portion of the cingulum bundle. Regions exclusively implicated in each time period were also identified. The integrity of the anterior temporal cortices was related to the retrieval of remote memories, whereas the posterior cingulate cortex emerged as a structure significantly associated with recent autobiographical memory retrieval. This study represents the first investigation of the grey and white matter correlates of remote and recent autobiographical memory retrieval in neurodegenerative disorders. Our findings demonstrate the importance of core brain structures, including the medial prefrontal cortex and hippocampus, irrespective of time period, and point towards the contribution of discrete regions in mediating successful retrieval of distant versus recently experienced events.


Influences of hippocampal place cell firing in the awake state on the activity of these cells during subsequent sleep episodes.
Rat hippocampal (CA1) complex spike "place cells" of freely behaving rats were recorded in pairs continuously during a series of waking (exploration and still-alert), drowsy (quiet-awake), and sleeping (slow-wave, pre-rapid-eye-movement and rapid-eye-movement sleep) behaviors. Pairs of units were selected that had nonoverlapping place fields. The rats were restricted from entering the place field of either cell overnight, and on the day of recording cells were exposed to their individual place fields independently and in a counterbalanced manner. Following exposure, recordings were made in the subsequent sleep episodes and the firing characteristics of both cells were analyzed. Following exposure, significant increases in the spiking activity of the exposed cell were observed in the subsequent sleeping states that were not evident in the unexposed cell. The increased activity was observed in the rate of firing (spikes/sec), the rate of occurrence of bursts with multiple spikes, as well as the number of bursts displaying short (2-4 msec) interspike intervals. The findings suggest that neuronal activity of hippocampal place cells in the awake states may influence the firing characteristics of these cells in subsequent sleep episodes. The increased firing rates along with the greater number of multiple spike bursts and the shorter interspike intervals within the burst, following exposure to a cell's place field, may represent possible information processing during sleep.


Effect of stress on structural brain asymmetry.
There is a growing body of evidence that stressful events may affect the brain not only as a whole, but also in multiple laterality aspects. The present review is aimed at discussing the effect of stress and stress hormones on structural brain asymmetry. Differences and crossroads of functional and structural asymmetry are briefly mentioned throughout the document. The first part of this review summarizes major findings in the field of structural brain asymmetries in animals and humans from the evolutionary perspective. Additionally, effect of stress on animals is discussed generally. The second part then explores asymmetrical effects of stress on structural changes of principal brain areas - amygdala, hippocampus, neocortex, diencephalon, basal forebrain and basal ganglia from the point of normal lateralization, steroids, trauma and genetic factors. At the end we present hypothesis why stress appears to have asymmetrical effects on lateralized brain structures.


Two structural motifs within canonical EF-hand calcium-binding domains identify five different classes of calcium buffers and sensors.
Proteins with EF-hand calcium-binding motifs are essential for many cellular processes, but are also associated with cancer, autism, cardiac arrhythmias, and Alzheimer's, skeletal muscle and neuronal diseases. Functionally, all EF-hand proteins are divided into two groups: (1) calcium sensors, which function to translate the signal to various responses; and (2) calcium buffers, which control the level of free Ca2+ ions in the cytoplasm. The borderline between the two groups is not clear, and many proteins cannot be described as definitive buffers or sensors. Here, we describe two highly-conserved structural motifs found in all known different families of the EF-hand proteins. The two motifs provide a supporting scaffold for the DxDxDG calcium binding loop and contribute to the hydrophobic core of the EF hand domain. The motifs allow more precise identification of calcium buffers and calcium sensors. Based on the characteristics of the two motifs, we could classify individual EF-hand domains into five groups: (1) Open static; (2) Closed static; (3) Local dynamic; (4) Dynamic; and (5) Local static EF-hand domains.


Lysosomal storage diseases.
Lysosomal storage diseases (LSDs) are a group of over 70 diseases that are characterized by lysosomal dysfunction, most of which are inherited as autosomal recessive traits. These disorders are individually rare but collectively affect 1 in 5,000 live births. LSDs typically present in infancy and childhood, although adult-onset forms also occur. Most LSDs have a progressive neurodegenerative clinical course, although symptoms in other organ systems are frequent. LSD-associated genes encode different lysosomal proteins, including lysosomal enzymes and lysosomal membrane proteins. The lysosome is the key cellular hub for macromolecule catabolism, recycling and signalling, and defects that impair any of these functions cause the accumulation of undigested or partially digested macromolecules in lysosomes (that is, 'storage') or impair the transport of molecules, which can result in cellular damage. Consequently, the cellular pathogenesis of these diseases is complex and is currently incompletely understood. Several LSDs can be treated with approved, disease-specific therapies that are mostly based on enzyme replacement. However, small-molecule therapies, including substrate reduction and chaperone therapies, have also been developed and are approved for some LSDs, whereas gene therapy and genome editing are at advanced preclinical stages and, for a few disorders, have already progressed to the clinic.