Vestibular disease in dogs under UK primary veterinary care: Epidemiology and clinical management.
Vestibular disease (VD), central or peripheral, can be a dramatic primary-care presentation. Current literature describes mostly dogs examined in referral centers. Describe the prevalence, presentation, clinical management, and outcomes of VD in dogs under primary veterinary care at UK practices participating in VetCompass. Seven hundred and fifty-nine vestibular cases identified out of 905 544 study dogs. Retrospective cohort study. Potential VD cases clinically examined during 2016 were verified by reviewing clinical records for signalment, presenting clinical signs, treatments, and outcomes. Multivariable logistic regression was used to evaluate factors associated with VD. The overall prevalence of VD was 8 per 10 000 dogs (95% CI = 7-9). Median age at first diagnosis was 12.68 years (interquartile range [IQR], 11.28-14.64). Compared with crossbreeds, breeds with the highest odds of VD diagnosis included French Bulldogs (odds ratio [OR] = 9.25, 95% CI = 4.81-17.76, P < .001), Bulldogs (OR = 6.53, 95% CI = 2.66-16.15, P < .001), King Charles Spaniels (OR = 4.96, 95% CI = 2.52-9.78, P < .001), Cavalier King Charles Spaniels (OR = 3.56, 95% CI = 2.50-5.06, P < .001), and Springer Spaniels (OR = 3.37, 95% CI = 2.52-4.52, P < .001). The most common presenting signs were head tilt (69.8%), nystagmus (68.1%), and ataxia (64.5%). The most frequently used treatments were antiemetics (43.2%), systemic glucocorticoids (33.1%), antimicrobials (25%), and propentofylline (23.25%). There were 3.6% of cases referred. Improvement was recorded in 41.8% cases after a median of 4 days (IQR, 2-10.25). Our study identifies strong breed predispositions for VD. The low referral rates suggest that primary-care data sources offer more generalizable information for benchmarking to help clinicians review their own clinical activities.


A review of attention-deficit/hyperactivity disorder from the perspective of brain networks.
Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed neurodevelopmental disorder in childhood, which affects more than 5% of the population worldwide. ADHD is characterized by developmentally inappropriate behaviors of inattention, and/or impulsivity and hyperactivity. These behavioral manifestations contribute to diminished academic, occupational and social functioning, and have neurobiological bases. Neuronal deficits, especially in the attention and executive function processing networks, have been implicated in both children and adults with ADHD by using sophisticated structural and functional neuroimaging approaches. These structural and functional abnormalities in the brain networks have been associated with the impaired cognitive, affective, and motor behaviors seen in the disorder. The goal of this review is to summarize and integrate emerging themes from the existing neuroimaging connectivity studies based on advanced imaging techniques, applied in data of structural magnetic resonance imaging (MRI), functional MRI (fMRI), diffusion tensor imaging, electroencephalography and event related potential; and to discuss the results of these studies when considering future directions for understanding pathophysiological mechanisms and developmental trajectories of the behavioral manifestations in ADHD. We conclude this review by suggesting that future research should put more effort on understanding the roles of the subcortical structures and their structural/functional pathways in ADHD.


Cryptococcosis in patients with hematologic malignancies. A report from GIMEMA-infection.
Cryptococcosis is an important cause of morbidity and death in immunocompromised patients. The aim of this study was to evaluate clinical and laboratory characteristics, and outcome of patients with cryptococcosis complicating hematologic diseases. This was a retrospective study, conducted over a ten-year period (1993-2002) in 21 hematology divisions, in tertiary care or university hospitals. This study evaluated 17 patients with hematologic diseases who developed cryptococcosis. Possible risk factors recognized before the onset of the infection were: administration of steroids for the underlying malignancy (6 patients), diabetes mellitus (4 patients), cutaneous lesions (2 patients) and autoimmune disease, hepatic cirrhosis, chronic renal failure and exposure to pigeons (1 patient each). Five patients received prophylaxis, consisting of fluconazole in 2 cases. Fever, neurological and respiratory signs developed according to the primary sites of infection (5 blood, 5 central nervous system, 4 lung, and 1 each in gut, skin and mouth). Diagnosis was made by positive microbiological culture, antigen detection in serum or cerebrospinal fluid, or polymerase chain reaction. All patients started specific treatment (fluconazole, 7 patients; amphotericin-B deoxycolate or liposomal amphotericin-B, 10 patients). Two patients died from cryptococcosis within 30 days after diagnosis. Cryptococcosis in patients with hematologic malignancies is a rare complication. In neutropenic patients, it is less fatal than other fungal infections (i.e. aspergillosis or candidemia). Specific treatment, started promptly, positively influences the outcome.


Preliminary assignments of the aromatic and some methyl group resonances of the 1H-NMR spectrum of the oxidized form of uteroglobin. Application to the interaction of oxidized uteroglobin with progesterone.
Two-dimensional NMR methods have been used to assign aromatic and methyl group resonances in the 1H-NMR spectrum of oxidized uteroglobin. Assignments to specific amino acids are based on X-ray-determined structures of two crystal forms (C222(1) and P2(1] and on an energy-minimized X-ray structure of the C222(1) form of uteroglobin. These preliminary assignments are sufficient to probe the interaction of oxidized uteroglobin with progesterone in solution. The protein global structure is unmodified but some direct or indirect conformational changes are induced in the H1H4(H1'H4') pockets and close to Phe28 by progesterone.


Using VAAST to identify an X-linked disorder resulting in lethality in male infants due to N-terminal acetyltransferase deficiency.
We have identified two families with a previously undescribed lethal X-linked disorder of infancy; the disorder comprises a distinct combination of an aged appearance, craniofacial anomalies, hypotonia, global developmental delays, cryptorchidism, and cardiac arrhythmias. Using X chromosome exon sequencing and a recently developed probabilistic algorithm aimed at discovering disease-causing variants, we identified in one family a c.109T>C (p.Ser37Pro) variant in NAA10, a gene encoding the catalytic subunit of the major human N-terminal acetyltransferase (NAT). A parallel effort on a second unrelated family converged on the same variant. The absence of this variant in controls, the amino acid conservation of this region of the protein, the predicted disruptive change, and the co-occurrence in two unrelated families with the same rare disorder suggest that this is the pathogenic mutation. We confirmed this by demonstrating a significantly impaired biochemical activity of the mutant hNaa10p, and from this we conclude that a reduction in acetylation by hNaa10p causes this disease. Here we provide evidence of a human genetic disorder resulting from direct impairment of N-terminal acetylation, one of the most common protein modifications in humans.


Tianma modulates blood vessel tonicity.
Tianma is a traditional Chinese medicine (TCM) often used for the treatment of hypertension and heart diseases. To elucidate the function of tianma at the molecular level, we investigated the effect of tianma on vascular functions and aortic protein metabolism. We found that long-term treatment with tianma (~2.5g/kg/day for three months) in one-year-old rats could enhance acetylcholine (ACh)-induced vasorelaxation in endothelium-intact thoracic aortic rings against both KCl (80 mM)- and phenylephrine (PE)-induced contraction. By using the iTRAQ (isobaric tag for relative and absolute quantification) technique, we confirmed from the functional data at the proteome level that tianma treatment down-regulated the expressions of contractile proteins (e.g. Acta2) and other related structural proteins (e.g. desmin), and up-regulated the expressions of extracellular matrix (ECM) glycoproteins (e.g. Fbln5) and anti-thrombotic proteins (e.g. Anxa2) in aortic tissue. By inductive reasoning, tianma could perform its vasodilatory effect not only by inhibiting vascular smooth muscle contraction, but also by enhancing blood vessel elasticity and stabilizing the arterial structure. Thus, tianma might become a novel therapeutic herbal medicine for cardiovascular diseases by regulating the aortic proteome metabolism.


Detection of Bisphenol A and Nonylphenol in Rat's Blood Serum, Tissue and Impact on Reproductive System.
Bisphenol A (BPA) and Nonylphenol (NP) have estrogen-like activity, and some of their adverse biological effects have been demonstrated. This study was designed to determine the association of plasma and tissue concentrations of BPA and NP and changes in the parameters of the reproductive system in rats. Male Wistar rats were administered three doses of BPA and NP (5, 25, and 125 μg/kg) by gavage for 35 consecutive days in 2014-2015, and a 2-ml blood sample was taken from each treated rat. Concentrations of BPA and NP in the blood were determined using the HPLC-fluorescence detection method. The sperm are produced in the epididymis and vas deferens, and they swim up in Ham's F10 solution, and, then, various parameters were evaluated using an invert microscope, and they included the count, motility, and morphology of the sperm. The weight of the testes and prostate in the rats receiving BPA and NP treatment showed significant decreases compared to the control group. Similarly, NP created higher concentration than BPA in the serum (e.g., 5.48 ± 0.65 vs. 1.36 ± 0.25, at 125 μg/kg). Compared to the control group, dose-dependent significant decreases in count and motility in the sperm were observed following the administration of BPA (25 and 125 μg/kg) and NP (all three doses). Morphologic aspects of the rats' sperm were changed in various doses of BPA and NP. According to our findings, BPA and NP induced dose-dependent toxic effects on various parameters, i.e., sperm toxicity, weight of the testes, and weight of the prostate gland.


Antimicrobial resistance profile of Staphylococcus aureus isolates obtained from skin and soft tissue infections of outpatients from a university hospital in Recife -PE, Brazil.
Staphylococcus aureus has a notable ability to acquire resistance to antibiotics, and methicillin resistance represents a growing public health problem. Methicillin-resistant S. aureus (MRSA) has also become important outside the hospital environment, particularly in the United States. In Brazil, since 2005, cases of community skin infections caused by MRSA have been reported, but resistance studies involving outpatients are scarce. To know the resistance profile of S. aureus involved in skin and soft tissue infections of patients seen at the Dermatology outpatient clinic of a university hospital in Recife, Pernambuco State, northeastern Brazil. Prospective study involving 30 patients with skin and soft tissue infections, seen at the Dermatology outpatient clinic from May until November 2011. To evaluate the susceptibility of S. aureus to antibiotics, the disk diffusion method and oxacillin screening agar were used. From a total of 30 samples of skin lesions, 19 (63%) had positive culture for S. aureus. The following resistance patterns of S. aureus were observed: penicillin, 95%; tetracycline, 32%; erythromycin, 21%; gentamicin, 16%; cefoxitin, 11%; oxacillin, 11%; trimethoprim-sulfamethoxazole, 11%; chloramphenicol, 11%; clindamycin, 5% ; and ciprofloxacin, 0%. One of the identified MRSA was obtained from a patient without risk factors for its acquisition, and was resistant, beyond to the beta-lactams, only to tetracycline. With regard to the resistance patterns of S. aureus, resistances to tetracycline, erythromycin and gentamicin were the highest. It was documented, for the first time in Pernambuco, a case of skin infection caused by community-associated MRSA.


Vitamin E plasma kinetics in swine show low bioavailability and short half-life of -α-tocopheryl acetate.
Vitamin E is important for animal production because of its effects on health and product quality, but the amount and form required remains controversial. Our objective was to quantify the absolute bioavailability of oral -α-tocopheryl acetate (α-TAc) in swine (22 ± 1 kg and 8 wk old, fitted with jugular catheters) adapted to a diet supplemented with 75 mg/kg -α-TAc; 75 mg/kg was chosen because this level represents the nonweighted average inclusion level in piglet diets across Western key swine-producing countries. For this, a 350-g test meal (6% fat) was supplied at time 0 containing 75 mg deuterated (D9) -α-TAc to 9 animals, and 8 animals received an intravenous () dose containing deuterated (D6) RRR-α-tocopherol (α-T) at one-eighth the oral dose and a test meal without supplemental vitamin E. Plasma samples (12 to 13 per animal) were obtained at incremental intervals over 75 h for analysis of deuterated α-T using liquid chromatography-tandem mass spectrometry. Surprisingly, the i.v. dose rapidly disappeared from plasma and then reappeared. The half-life for this first peak was only 1.7 ± 0.3 min. The second peak had an appearance rate (Ka) of 0.10 ± 0.06 d and a half-life of 5.9 ± 1.2 h. Oral dosing resulted, after a lag of 56 min, in a Ka of 0.91 ± 0.21 d and a half-life of 2.6 ± 0.8 h. The bioavailability for oral α-TAc was 12.5%, whereas the area under the curve was only 5.4%. This low bioavailability, small area under the curve, and short half-life are likely because of various factors, that is, the use of only 6% fat in the diet, the use of the acetate ester and , and the high dose relative to requirements. In conclusion, i.v. dosed vitamin E shows both a rapid and a very slow pool, whereas orally dosed vitamin E shows a single slow pool. The oral material has a very short half-live (44% of i.v. or 2.6 h), low bioavailability (12.5%), and a very small area under the curve (5.4%), bringing into question the efficacy of typical doses of vitamin E in swine diets for alleviating oxidative stress.


Observer-Based Event-Triggered Predictive Control for Networked Control Systems under DoS Attacks.
This paper studies the problem of DoS attack defense based on static observer-based event-triggered predictive control in networked control systems (NCSs). First, under the conditions of limited network bandwidth resources and the incomplete observability of the state of the system, we introduce the event-triggered function to provide a discrete event-triggered transmission scheme for the observer. Then, we analyze denial-of-service (DoS) attacks that occur on the network transmission channel. Using the above-mentioned event-triggered scheme, a novel class of predictive control algorithms is designed on the control node to proactively save network bandwidth and compensate for DoS attacks, which ensures the stability of NCSs. Meanwhile, a closed-loop system with an observer-based event-triggered predictive control scheme for analysis is created. Through linear matrix inequality (LMI) and the Lyapunov function method, the design of the controller, observer and event-triggered matrices is established, and the stability of the scheme is analyzed. The results show that the proposed solution can effectively compensate DoS attacks and save network bandwidth resources by combining event-triggered mechanisms. Finally, a smart grid simulation example is employed to verify the feasibility and effectiveness of the scheme's defense against DoS attacks.


Inhibitory effect of TIMP influences the morphology of varicose veins.
Imbalance of matrix metalloproteinase enzymes (MMP) and their inhibitors (TIMPs) may contribute to the development of varicose veins. We hypothesised that, histological changes in varicose vein wall correlate with alterations in expression of MMP/TIMP. Varicose veins (n=26) were compared with great saphenous vein (GSV) segments (n=11) from arterial bypass, and with arm and neck veins from fistula and carotid operations (n=13). Varicose vein wall thickness was measured, enabling categorisation as atrophic and hypertrophic. MMP-2, MT1-MMP, TIMP-2, and TIMP-3 expression were quantitatively analysed by immunohistochemistry. There was significantly higher expression of TIMP-2 (immunopositive area 4.34% versus 0.26%), linked with connective tissue accumulation in the tunica media of varicose veins as compared with arm and neck vein controls. TIMP-2 and TIMP-3 expression was higher in hypertrophic than atrophic segments (3.2% versus 0.99% for TIMP-2, 1.7% versus 0.08% for TIMP-3). Similarly, TIMP-2 and TIMP-3 had elevated expression in the thicker proximal varicose vein segments compared to distal (4.3% versus 1.3% for TIMP-2 and 0.94% versus 0.41% for TIMP-3). This study linked morphological changes in varicose vein walls with MMP/TIMP balance. A higher TIMP expression favours deposition of connective tissue and thus thicker vein wall, reducing matrix turnover by suppression of protease activity.


SEN1, a positive effector of tRNA-splicing endonuclease in Saccharomyces cerevisiae.
The SEN1 gene, which is essential for growth in the yeast Saccharomyces cerevisiae, is required for endonucleolytic cleavage of introns from all 10 families of precursor tRNAs. A mutation in SEN1 conferring temperature-sensitive lethality also causes in vivo accumulation of pre-tRNAs and a deficiency of in vitro endonuclease activity. Biochemical evidence suggests that the gene product may be one of several components of a nuclear-localized splicing complex. We have cloned the SEN1 gene and characterized the SEN1 mRNA, the SEN1 gene product, the temperature-sensitive sen1-1 mutation, and three SEN1 null alleles. The SEN1 gene corresponds to a 6,336-bp open reading frame coding for a 2,112-amino-acid protein (molecular mass, 239 kDa). Using antisera directed against the C-terminal end of SEN1, we detect a protein corresponding to the predicted molecular weight of SEN1. The SEN1 protein contains a leucine zipper motif, consensus elements for nucleoside triphosphate binding, and a potential nuclear localization signal sequence. The carboxy-terminal 1,214 amino acids of the SEN1 protein are essential for growth, whereas the amino-terminal 898 amino acids are dispensable. A sequence of approximately 500 amino acids located in the essential region of SEN1 has significant similarity to the yeast UPF1 gene product, which is involved in mRNA turnover, and the mouse Mov-10 gene product, whose function is unknown. The mutation that creates the temperature-sensitive sen1-1 allele is located within this 500-amino-acid region, and it causes a substitution for an amino acid that is conserved in all three proteins.


Variety in vegetable and fruit consumption and risk of bladder cancer in the European Prospective Investigation into Cancer and Nutrition.
Recent research does not show an association between fruit and vegetable consumption and bladder cancer risk. None of these studies investigated variety in fruit and vegetable consumption, which may capture different aspects of consumption. We investigated whether a varied consumption of vegetables and fruits is associated with bladder cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Detailed data on food consumption and complete follow-up for cancer incidence were available for 452,185 participants, who were recruited from ten European countries. After a mean follow-up of 8.7 years, 874 participants were diagnosed with bladder cancer. Diet diversity scores (DDSs) were used to quantify the variety in fruit and vegetable consumption. Multivariable Cox proportional hazard models were used to assess the effect of the DDSs on bladder cancer risk. There was no evidence of a statistically significant association between bladder cancer risk and any of the DDSs when these scores were considered as continuous covariates. However, the hazard ratio (HR) for the highest tertile of the DDS for combined fruit and vegetable consumption was marginally significant compared to the lowest (HR = 1.30, 95% confidence interval: 1.00-1.69, p-trend = 0.05). In EPIC, there is no clear association between a varied fruit and vegetable consumption and bladder cancer risk. This finding provides further evidence for the absence of any strong association between fruit and vegetable consumption as measured by a food frequency questionnaire and bladder cancer risk.


Reciprocal relationship between pain and depression: a 12-month longitudinal analysis in primary care.
Pain and depression are the most prevalent physical and psychological symptom-based disorders, respectively, and co-occur 30 to 50% of the time. However, their reciprocal relationship and potentially causative effects on one another have been inadequately studied. Longitudinal data analysis involving 500 primary care patients with persistent back, hip, or knee pain were enrolled in the Stepped Care for Affective Disorders and Musculoskeletal Pain (SCAMP) study. Half of the participants had comorbid depression and were randomized to a stepped care intervention (n = 123) or treatment as usual (n = 127). Another 250 nondepressed patients with similar pain were followed in a parallel cohort. Outcomes were assessed at baseline, 3, 6, and 12 months. Mixed effects model repeated measures (MMRM) multivariable analyses were conducted to determine if change in pain severity predicted subsequent depression severity, and vice versa. Change in pain was a strong predictor of subsequent depression severity (t-value = 6.63, P < .0001). Likewise, change in depression severity was an equally strong predictor of subsequent pain severity (t-value = 7.28, P < .0001). Results from the full cohort were similar in the clinical trial subgroup. In summary, pain and depression have strong and similar effects on one another when assessed longitudinally over 12 months. This study strengthens the evidence for a bidirectional and potentially causative influence of pain and depression on one another. A change in severity of either symptom predicts subsequent severity of the other symptom. Thus, recognition and management of both conditions may be warranted, particularly when treatment focused on 1 condition is not leading to an optimal response.


Differentiation between subpopulations of a polychromatic damselfly with respect to morph frequencies, but not neutral genetic markers.
The damselfly, Nehalennia irene (Hagen), has two distinct female colour morphs. Individuals of one morph have male-like colouration and pattern (androchromes), whereas gynochromes are different from males and androchromes in these respects. In several damselflies, such female-limited polychromatism is attributable to a single genetic locus. We developed six polymorphic genetic markers, which were codominant, to test for genetic differentiation in N. irene, collected from two sites located 8 km from one another in eastern Ontario, Canada. Based on three censuses spanning a 10 year period (1992-2001), morph ratios differed consistently and significantly between these two sites. However, subpopulations at these sites were not genetically differentiated with respect to the putatively neutral markers. Our results suggest that site differences in morph ratios of female N. irene cannot be explained by genetic drift, but are consistent with spatially variable selection operating on different morphs, perhaps mediated by male density. Alternatively, morph type may be a plastic trait and cues for induction may differ between sites.


Modelling prognostic factors in advanced pancreatic cancer.
Pancreatic cancer is the fifth most common cause of cancer death. Identification of defined patient groups based on a prognostic index may improve the prediction of survival and selection of therapy. Many prognostic factors have been identified often based on retrospective, underpowered studies with unclear analyses. Data from 653 patients were analysed. Continuous variables are often simplified assuming a linear relationship with log hazard or introducing a step function (dichotomising). Misspecification may lead to inappropriate conclusions but has not been previously investigated in pancreatic cancer studies. Models based on standard assumptions were compared with a novel approach using nonlinear fractional polynomial (FP) transformations. The model based on FP-transformed covariates was most appropriate and confirmed five previously reported prognostic factors: albumin, CA 19-9, alkaline phosphatase, LDH and metastases, and identified three additional factors not previously reported: WBC, AST and BUN. The effects of CA 19-9, alkaline phosphatase, AST and BUN may go unrecognised due to simplistic assumptions made in statistical modelling. We advocate a multivariable approach that uses information contained within continuous variables appropriately. The functional form of the relationship between continuous covariates and survival should always be assessed. Our model should aid individual patient risk stratification and the design and analysis of future trials in pancreatic cancer.


Genetic polymorphisms in cell cycle regulatory genes MDM2 and TP53 are associated with susceptibility to lung cancer.
The tumor suppressor TP53 pathway plays a crucial role in preventing carcinogenesis through its ability to impose cell cycle arrest and apoptosis following DNA damage and oncogene activation. MDM2 is a key negative regulator of the TP53 pathway and is overexpressed in many cancers as oncoprotein. We investigated the association between genetic variation in the promoter region of MDM2 (c.-5+309G>T, rs2279744:g.G>T) and the coding region of TP53 (c.215G>C, rs1042522:g.G>C, designated Arg72Pro) and the risk of developing lung cancer. The genotypes of 1,106 patients and 1,420 controls were determined by tetra-primer amplification refractory mutation system (ARMS)-PCR or PCR-based restriction fragment length polymorphism (RFLP). Associations with risk of lung cancer were estimated by logistic regression. We observed an increased lung cancer risk associated with the MDM2 GG (odds ratio [OR] = 1.83, 95% confidence interval [CI] = 1.45-2.32) and TG (OR = 1.33, 95% CI = 1.09-1.63) genotypes. An increased risk was also associated with the TP53 Pro/Pro genotype (OR = 1.47, 95% CI = 1.17-1.85, P = 0.003) compared to the Arg/Arg genotype. The gene-gene interaction of MDM2 and TP53 polymorphisms increased lung cancer risk in a supermultiplicative manner (OR for the presence of both MDM2 GG and TP53 Pro/Pro genotypes = 4.56, 95% CI = 2.76-7.54). Significant interactions were observed between these polymorphisms (respectively and jointly) and smoking (OR = 10.41, 95% CI = 5.26-20.58) for smokers with both the MDM2 GG and TP53 Pro/Pro genotypes. In conclusion, genetic polymorphisms in cell cycle regulatory genes MDM2 and TP53 contribute to the risk of developing lung cancer.


Silver nanoparticle-embedded polymersome nanocarriers for the treatment of antibiotic-resistant infections.
The rapidly diminishing number of effective antibiotics that can be used to treat infectious diseases and associated complications in a physician's arsenal is having a drastic impact on human health today. This study explored the development and optimization of a polymersome nanocarrier formed from a biodegradable diblock copolymer to overcome bacterial antibiotic resistance. Here, polymersomes were synthesized containing silver nanoparticles embedded in the hydrophobic compartment, and ampicillin in the hydrophilic compartment. Results showed for the first time that these silver nanoparticle-embedded polymersomes (AgPs) inhibited the growth of Escherichia coli transformed with a gene for ampicillin resistance (bla) in a dose-dependent fashion. Free ampicillin, AgPs without ampicillin, and ampicillin polymersomes without silver nanoparticles had no effect on bacterial growth. The relationship between the silver nanoparticles and ampicillin was determined to be synergistic and produced complete growth inhibition at a silver-to-ampicillin ratio of 1 : 0.64. In this manner, this study introduces a novel nanomaterial that can effectively treat problematic, antibiotic-resistant infections in an improved capacity which should be further examined for a wide range of medical applications.


Patients' experiences with the advanced practice nurse role in Swiss family practices: a qualitative study.
Considering shortages of general practitioners (GP) and strategies for improving the quality of health care provision, many countries have implemented interprofessional care models with advanced practice nurses (APN). International evidence suggests that APN care results in high patient satisfaction. In Switzerland, the role is still new, and the patient perspective has not yet been researched. Our aim was therefore to explore patients' experiences with the APN role in Swiss family practices. We conducted 22 semi-structured interviews in four different family practices with patients aged 18 to 97 suffering from minor acute to multiple chronic diseases, and who had at least one consultation with an APN. All interviews were audiotaped, transcribed verbatim, and analysed using qualitative content analysis. The analysis resulted in five themes: Despite the unfamiliarity, all patients were willing to be consulted by an APN because it was recommended by their GP (1); after several encounters, most participants perceived differences between the APN and the GP consultation in terms of the length and style of the consultations as well as the complexity of their tasks (2); the interviewees emphasised coaching, guidance, care coordination, and GP-assisting tasks as APN core competencies and attributed the characteristics empathetic, trustworthy, and competent to the APN role (3); most patients especially valued home visits and the holistic approach of the APNs, but they also noticed that in certain cases GP supervision was required (4); and due to the close collaboration between the APN and the GP, patients felt safe, well cared for and experienced improvements in physical and psychological well-being as well as in daily activities (5). Our results suggested that patients value the APNs' competencies, despite their initial lack of role knowledge. Trust in the GP seemed to be the most important factor for patients' receptiveness toward the APN role. Overall, patients perceived an added value due to the enlargement of the scope of practice offered by APNs. The patient perspective might provide valuable insights for further APN role implementation in Swiss family practices.


Vocal behavior of the elusive purple frog of India (Nasikabatrachus sahyadrensis), a fossorial species endemic to the Western Ghats.
Quantitative descriptions of animal vocalizations can inform an understanding of their evolutionary functions, the mechanisms for their production and perception, and their potential utility in taxonomy, population monitoring, and conservation. The goal of this study was to provide the first acoustical and statistical analysis of the advertisement calls of Nasikabatrachus sahyadrensis. Commonly known as the Indian purple frog, N. sahyadrensis is an endangered species endemic to the Western Ghats of India. As the only known species in its family (Nasikabatrachidae), it has ancient evolutionary ties to frogs restricted to the Seychelles archipelago (Sooglossidae). The role of vocalizations in the behavior of this unique species poses interesting questions, as the animal is fossorial and potentially earless and it breeds explosively above the soil for only about two weeks a year. In this study, we quantified 19 acoustic properties of 208 calls recorded from 10 males. Vocalizations were organized into distinct call groups typically composed of two to six short (59 ms), pulsatile calls, each consisting of about five to seven pulses produced at a rate of about 106 pulses/s. The frequency content of the call consisted of a single dominant peak between 1200-1300 Hz and there was no frequency modulation. The patterns of variation within and among individuals were typical of those seen in other frogs. Few of the properties we measured were related to temperature, body size, or condition, though there was little variation in temperature. Field observations and recordings of captive individuals indicated that males engaged in both antiphonal calling and call overlap with nearby calling neighbors. We discuss our findings in relation to previous work on vocal behavior in other fossorial frogs and in sooglossid frogs.


Development of two morphological types of retinopetal fibers in chick embryos, as shown by the diffusion along axons of a carbocyanine dye in the fixed retina.
Centrifugal fibers to the retinas of chick embryos and hatched chicks have been examined and traced following staining by diffusion along their axonal membranes of the carbocyanine dye DiI in fixed tissue. In the older embryos and hatched chicks, the report of Dogiel (Arch. Mikrosk. Anat. 44:622-648, 1895) has been confirmed that there are two very different morphological types of centrifugal fiber. The restricted type ends as a relatively thick fiber, lacking varicosities, that runs for a short distance in the most sclerad level of the inner plexiform layer before terminating in a pericellular nest overlying the flask-shaped body of a single amacrine cell. Thin filaments occasionally leave the pericellular net, apparently to terminate on adjacent cells. The widespread type also runs in the most sclerad level of the inner plexiform layer, but it is thin, varicose, and highly branched, and its terminal arbor may span more than 1 mm, remaining at the same level. Both types of terminal arbor issue from parent axons in the optic fiber layer of the retina. A single parent axon gives either a single terminal fiber of the restricted type or several terminals of the widespread type, but never a mixture of the two. It is argued that the restricted and widespread types originate respectively from the neurons of the contralateral isthmo-optic nucleus and from the "ectopic" neurons scattered outside the isthmo-optic nucleus. In development, the centrifugal fibers reach the retina between E9 and E10 and initially run radially in the optic fiber layer, parallel to the retinofugal fibers but avoiding the dorsal retina. They dive into the inner plexiform layer at about E12. By E13, the terminal arbors are forming, and the widespread and restricted types can already be distinguished. The widespread type continues to increase its territory until about E18, and then appears to remain stable, whereas the restricted type attains its maximum ramification between E13 and E15 and then contracts. Prior to the retraction, the terminal territories of the restricted type fibers overlap, which may provide the anatomical basis for the interaxonal competition that apparently contributes to neuronal death in the isthmo-optic nucleus between E13 and E16. Axons of ganglion cells exhibit transient side branches between E11 and E13; these never reach as deep as the level where the centrifugal fibers run.


Novel and recurrent germline LEMD3 mutations causing Buschke-Ollendorff syndrome and osteopoikilosis but not isolated melorheostosis.
Mutations in the LEMD3 gene were recently incriminated in Buschke-Ollendorff syndrome (BOS) and osteopoikilosis, with or without melorheostosis. The relationship of this gene with isolated sporadic melorheostosis is less clear. We investigated LEMD3 in a two-generation BOS family showing an extremely variable expression of the disease, in a sporadic patient with skin features of BOS, and in an additional subject with isolated melorheostosis. We identified two different mutations, both resulting in a premature stop codon, in the two cases of BOS. The mutation (c.2564G>A) reported in the familial case is novel, while that observed in the sporadic case (c.1963C>T) has been previously reported in an American woman with osteopoikilosis and melorheostosis who had a family history of isolated osteopoikilosis. The search for mutations in DNA extracted from the peripheral blood, as well as skin and bone biopsies of the patient with melorheostosis failed to identify any pathogenic change. Our results further expand the LEMD3 mutation repertoire, corroborate the extreme interfamilial and intrafamilial clinical variability of LEMD3 mutations, and underline the lack of a clear phenotype-genotype correlation in BOS. The present study supports the general conclusion that LEMD3 mutations do not contribute to isolated sporadic melorheostosis. The genetic or epigenetic influences that are responsible for the development of melorheostosis require further investigation.


A framework for supervising lifestyle diseases using long-term activity monitoring.
Activity monitoring of a person for a long-term would be helpful for controlling lifestyle associated diseases. Such diseases are often linked with the way a person lives. An unhealthy and irregular standard of living influences the risk of such diseases in the later part of one's life. The symptoms and the initial signs of these diseases are common to the people with irregular lifestyle. In this paper, we propose a novel healthcare framework to manage lifestyle diseases using long-term activity monitoring. The framework recognizes the user's activities with the help of the sensed data in runtime and reports the irregular and unhealthy activity patterns to a doctor and a caregiver. The proposed framework is a hierarchical structure that consists of three modules: activity recognition, activity pattern generation and lifestyle disease prediction. We show that it is possible to assess the possibility of lifestyle diseases from the sensor data. We also show the viability of the proposed framework.


Ultrafast all-optical implementation of a leaky integrate-and-fire neuron.
In this paper, we demonstrate for the first time an ultrafast fully functional photonic spiking neuron. Our experimental setup constitutes a complete all-optical implementation of a leaky integrate-and-fire neuron, a computational primitive that provides a basis for general purpose analog optical computation. Unlike purely analog computational models, spiking operation eliminates noise accumulation and results in robust and efficient processing. Operating at gigahertz speed, which corresponds to at least 108 speed-up compared with biological neurons, the demonstrated neuron provides all functionality required by the spiking neuron model. The two demonstrated prototypes and a demonstrated feedback operation mode prove the feasibility and stability of our approach and show the obtained performance characteristics.


The rise of computational biology.
The year 2001 saw a remarkable burst of interest in biological simulation, with several international meetings on the subject, and the inclusion, by journals, of web site references from which published models can be downloaded. So, why has all this happened so suddenly?


Highly efficient perturbative + variational strategy based on orthogonal valence bond theory for the evaluation of magnetic coupling constants. Application to the trinuclear Cu(ii) site of multicopper oxidases.
A new strategy based on orthogonal valence-bond analysis of the wave function combined with intermediate Hamiltonian theory has been applied to the evaluation of the magnetic coupling constants in two AF systems. This approach provides both a quantitative estimate of the J value and a detailed analysis of the main physical mechanisms controlling the coupling, using a combined perturbative + variational scheme. The procedure requires a selection of the dominant excitations to be treated variationally. Two methods have been employed: a brute-force selection, using a logic similar to that of the CIPSI approach, or entanglement measures, which identify the most interacting orbitals in the system. Once a reduced set of excitations (about 300 determinants) is established, the interaction matrix is dressed at the second-order of perturbation by the remaining excitations of the CI space. The diagonalization of the dressed matrix provides J values in good agreement with experimental ones, at a very low-cost. This approach demonstrates the key role of d → d* excitations in the quantitative description of the magnetic coupling, as well as the importance of using an extended active space, including the bridging ligand orbitals, for the binuclear model of the intermediates of multicopper oxidases. The method is a promising tool for dealing with complex systems containing several active centers, as an alternative to both pure variational and DFT approaches.


Race and Sex Differences in Modifiable Risk Factors and Incident Heart Failure.
The purpose of this study was to examine race- and sex-based variation in the associations between modifiable risk factors and incident heart failure (HF) among the SCCS (Southern Community Cohort Study) participants. Low-income individuals in the southeastern United States have high HF incidence rates, but relative contributions of risk factors to HF are understudied in this population. We studied 27,078 black or white SCCS participants (mean age: 56 years, 69% black, 63% women) enrolled between 2002 and 2009, without prevalent HF, receiving Centers for Medicare and Medicaid Services. The presence of hypertension, diabetes mellitus, physical underactivity, high body mass index, smoking, high cholesterol, and poor diet was assessed at enrollment. Incident HF was ascertained using International Classification of Diseases-9th revision, codes 428.x in Centers for Medicare and Medicaid Services data through December 31, 2010. Individual risk and population attributable risk for HF for each risk factor were quantified using multivariable Cox models. During a median (25th, 75th percentile) 5.2 (3.1, 6.7) years, 4,341 (16%) participants developed HF. Hypertension and diabetes were associated with greatest HF risk, whereas hypertension contributed the greatest population attributable risk, 31.8% (95% confidence interval: 27.3 to 36.0). In black participants, only hypertension and diabetes associated with HF risk; in white participants, smoking and high body mass index also associated with HF risk. Physical underactivity was a risk factor only in white women. In this high-risk, low-income cohort, contributions of risk factors to HF varied, particularly by race. To reduce the population burden of HF, interventions tailored for specific race and sex groups may be warranted.


Lyophilized plasma with ascorbic acid decreases inflammation in hemorrhagic shock.
Delivery of a high ratio of plasma to packed red blood cells to patients who require massive transfusion is associated with improved survival. Hemorrhagic shock causes increased production of pro-inflammatory cytokines. These are associated with late morbidity and mortality. The use of fresh frozen plasma makes high ratio resuscitation logistically difficult and does not address dysfunctional inflammation. Lyophilized plasma (LP) is a stable powdered form of plasma that is both safe and easily reconstituted. Previous work demonstrated that LP reconstituted with ascorbic acid (AA) decreased inflammation. Whether the reduction of inflammation was associated with LP or the AA is unknown. Thirty female swine were anesthetized and subjected to a multisystem combat relevant model consisting of femur fracture, controlled hemorrhage, and hypothermia. A standardized grade V liver injury was made and the animals were randomly assigned to receive LP reconstituted with AA, citric acid (CA), or hydrochloric acid (HCl). Blood was drawn at baseline and at 2 hours and 4 hours for interleukin (IL)-6, IL-8, and tumor necrosis factor-α serum concentrations measured by enzyme-linked immunosorbent assay. Lung tissue was harvested and processed for gene expression before euthanizing the animals. No differences were observed in mortality, baseline cytokine serum concentration, or gene expression. Enzyme-linked immunosorbent assay demonstrated that IL-6 concentration increased over time for all groups (p < 0.05), but less so at 2 hours in the AA group compared with CA and HCl. In this animal model of trauma, hemorrhage and resuscitation, AA decreases IL-6 expression relative to CA and HCl. These findings confirm previous work from our laboratory and suggest that AA is responsible for suppression of dysfunctional inflammation in this model.


Predictors of syphilis seroreactivity and prevalence of HIV among street recruited injection drug users in Los Angeles County, 1994-6.
To describe HIV prevalence and the association between syphilis incidence and sexual and drug injection risk behaviours in a cohort of street recruited injecting drug users (IDUs) in Los Angeles County, between 1994 and 1996. During the study period, 513 street recruited African-American and Latino IDUs were screened for syphilis and antibodies to HIV. Subjects were administered a risk behaviour survey at baseline and followed up at 6 month intervals for 18 months with repeated interviews and serological screening. Rate ratios were used to examine associations between syphilis incidence and demographic characteristics and risk behaviours. A proportional hazard model was used to identify predictors of syphilis incidence independent of demographic characteristics. 74% of the sample were male, 70% African-American, 30% Latino; and the median age was 43 years. Overall baseline serological prevalence of HIV was 2.5% and of syphilis 5.7%. None of the participants were co-infected for HIV and syphilis at baseline or at any of the 6 month follow ups. Among 390 eligible IDUs retained for analysis of incidence data, the overall syphilis incidence was 26.0 per 1000 person years. Higher syphilis incidence was found for women compared with men (RR = 2.70; 95% CI 1.60, 4.55), and for those 44 years of age or younger compared with those 45 years of age and older (RR = 2.26; 95% CI 1.25, 4.08). African-Americans were more likely to be syphilis incident cases when compared with Latinos, although the difference did not reach statistical significance (RR = 1.27; 95% CI 0.72, 2.23). In bivariate analysis, risk behaviours significantly associated with higher syphilis incidence included injection of cocaine, "speedball" and heroin, "crack" smoking, recency of first injection event, backloading of syringes, injecting with others, exchanging drugs or money for sex, multiple sex partners, and non-heterosexual sexual preference. Variables that significantly predicted syphilis infection at follow up in the multivariate analysis included multiple sex partners (RR = 7.8; 95% CI 2.4, 25.0), exchanging money for sex (RR = 3.0; 95% CI 0.9, 9.6), and recent initiation to injection drug use (RR = 4.6; 95% CI 1.1, 18.8). Syphilis transmission among IDUs in Los Angeles County remains a serious public health concern, particularly among IDUs who engage in trading of sex for money or drugs. Although low, the prevalence of HIV observed in this study constitutes a serious concern because of the potential for expanded HIV transmission in this susceptible population of IDUs with high syphilis incidence. Enhanced case finding screening efforts and prevention of transmission of sexually transmitted infections should specifically target hard to reach IDUs and their sexual partners.


Electrical stimulation of post-irradiated head and neck squamous cell carcinoma to improve xerostomia.
We observed a significant improvement in the complaints of dysphagia in patients with head and neck cancer who had received noninvasive neuromuscular electrical stimulation (E-stim) of their pharyngeal muscles. We wanted to determine if the improvement in dysphagia was a result of decreased complaints of xerostomia and increased saliva production, since one of our first patients being treated with E-stim noticed a significant improvement in xerostomia. Prospective trial to determine the effects of E-stim by evaluating saliva production and dysphagia questionnaires instituted by our speech pathologists on head and neck cancer patients that had received radiotherapy (XRT) and were to undergo E-stim for dysphagia. Prior to the initiation of E-stim and one to two months after E-stim, saliva samples were collected and patients were asked to answer a Dysphagia and Xerostomia Index Questionnaire. All patients received E-stim two to four months after completing XRT. Patients received three E-stim treatments per week for a total of one to two months. Four electrodes were placed along anterior neck over pharyngeal muscles. E-stim was initiated using four to 30mA at 80-100 pulse-widths. Five patients that received either postoperative radiation therapy or concomitant chemoradiotherapy had been treated with E-stim. All five patients noticed a significant improvement in dysphagia. Five out of five patients noticed a definite increase in saliva production with symptoms of decreased intake of water with meals, sleeping longer hours at night, and increased moistness of lips. E-stim therapy appears to be an effective and approved treatment for dysphagia. Our study shows that it may also be beneficial for xerostomia in the post-irradiated head and neck cancer patients. To determine if E-stim will benefit the previously irradiated patient with dysphagia and xerostomia.


Pertussis vaccination: use of acellular pertussis vaccines among infants and young children. Recommendations of the Advisory Committee on Immunization Practices (ACIP)
Concerns about the safety of whole-cell pertussis vaccines prompted development of acellular vaccines that are less likely to provoke adverse events because they contain purified antigenic components of Bordetella pertussis. Two diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccines--ACEL-IMUNE and Tripedia--have been licensed for several years, but (until recently) only for administration of the fourth and fifth doses in the series to children aged 15 months-6 years who previously had received three or more doses of diphtheria and tetanus toxoids and whole-cell pertussis (DTP) vaccine. Published reports indicate that, when administered to infants aged 2, 4, and 6 months, acellular pertussis vaccines are effective in preventing pertussis disease and associated with fewer local, systemic, and certain more serious adverse events than whole-cell pertussis vaccines. On the basis of these data, the Food and Drug Administration (FDA) has licensed three DTaP vaccines for use among children aged 6 weeks-6 years. Tripedia is now licensed for the initial four doses, and ACEL-IMUNE for all five doses of the diphtheria, tetanus and pertussis vaccination series. A third DtaP vaccine (Infanix) was licensed in January 1997 for the initial four doses of the series. Tripedia, ACEL-IMUNE, and Infanix are now recommended for routine vaccination of infants and young children, although whole-cell pertussis vaccines remain acceptable alternatives. Tripedia, ACEL-IMUNE, and Infanix are recommended for all remaining doses in the schedule for children who have started the vaccination series with one, two, three, or four doses of whole-cell pertussis vaccines. In September 1996, FDA licensed the use of TriHIBit (ActHIB reconstituted with Tripedia) for the fourth dose in the series of vaccinations against diphtheria, tetanus, pertussis, and Haemophilus influenzae type b disease.


Alternative splicing in human cancer cells is modulated by the amiloride derivative 3,5-diamino-6-chloro-N-(N-(2,6-dichlorobenzoyl)carbamimidoyl)pyrazine-2-carboxide.
Alternative splicing (AS) is a process that enables the generation of multiple protein isoforms with different biological properties from a single mRNA. Cancer cells often use the maneuverability conferred by AS to produce proteins that contribute to growth and survival. In our previous studies, we identified that amiloride modulates AS in cancer cells. However, the effective concentration of amiloride required to modulate AS is too high for use in cancer treatment. In this study, we used computational algorithms to screen potential amiloride derivatives for their ability to regulate AS in cancer cells. We found that 3,5-diamino-6-chloro-N-(N-(2,6-dichlorobenzoyl)carbamimidoyl)pyrazine-2-carboxamide (BS008) can regulate AS of apoptotic gene transcripts, including HIPK3, SMAC, and BCL-X, at a lower concentration than amiloride. This splicing regulation involved various splicing factors, and it was accompanied by a change in the phosphorylation state of serine/arginine-rich proteins (SR proteins). RNA sequencing was performed to reveal that AS of many other apoptotic gene transcripts, such as AATF, ATM, AIFM1, NFKB1, and API5, was also modulated by BS008. In vivo experiments further indicated that treatment of tumor-bearing mice with BS008 resulted in a marked decrease in tumor size. BS008 also had inhibitory effects in vitro, either alone or in a synergistic combination with the cytotoxic chemotherapeutic agents sorafenib and nilotinib. BS008 enabled sorafenib dose reduction without compromising antitumor activity. These findings suggest that BS008 may possess therapeutic potential for cancer treatment.


Bactericidal activity of daptomycin, vancomycin, teicoplanin and linezolid against Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium using human peak free serum drug concentrations.
The bactericidal activities of daptomycin, vancomycin, teicoplanin and linezolid at human peak free serum concentrations (C(max,free)) were determined against Staphylococcus aureus (one methicillin-susceptible and two methicillin-resistant strains), Enterococcus faecalis and Enterococcus faecium (one vancomycin-susceptible and one vancomycin-resistant strain of each). Daptomycin was rapidly bactericidal against 7/7 strains at C(max,free) of 22.0 mg/L (corresponding to 63% protein binding) and against 3/7 strains at 4.8 mg/L (corresponding to 92% protein binding). Vancomycin (18.0 mg/L) was bactericidal against only two strains. Both teicoplanin (4.5 mg/L) and linezolid (10.4 mg/L) were consistently bacteriostatic. Daptomycin is a useful option for the treatment of Gram-positive infections owing to its strong bactericidal activity.


Using stated preference valuation in the offshore environment to support marine planning.
This study presents valuations of components of marine natural capital that have hitherto been overlooked by the valuation literature. Using a discrete choice experiment, it values a set of ecosystem services linked to seabed natural capital in the UK section of the North Sea. The study focuses on offshore seabed habitats, using Good Environmental Status as a measure of seabed health, thus linking directly to management targets under the EU Marine Strategy Framework Directive. It considers how changing pressures on seabed habitats could affect marine industries and other ecosystems through trade-offs with (1) the contribution that exploitation of these habitats makes to the maritime cultural heritage; and (2) changes to the health of seabird populations. For seabed habitats and seabirds, the elicited values mainly represent non-use values for changes in the condition of natural capital assets. For maritime cultural heritage the valuation refers to the changed provision of this cultural ecosystem service. Results show that the public in England hold significant, strongly correlated, values for changes in the condition of offshore seabeds and seabird populations. Projected losses in maritime cultural heritage are found to lead to expected welfare decreases. Implications of these findings for marine planning and decision-making are discussed.


Peptidyl-Prolyl Isomerase ppiB Is Essential for Proteome Homeostasis and Virulence in Burkholderia pseudomallei.
Burkholderia pseudomallei is the causative agent of melioidosis, a disease endemic to Southeast Asia and northern Australia. Mortality rates in these areas are high even with antimicrobial treatment, and there are few options for effective therapy. Therefore, there is a need to identify antibacterial targets for the development of novel treatments. Cyclophilins are a family of highly conserved enzymes important in multiple cellular processes. Cyclophilins catalyze the cis-trans isomerization of xaa-proline bonds, a rate-limiting step in protein folding which has been shown to be important for bacterial virulence. B. pseudomallei carries a putative cyclophilin B gene, ppiB, the role of which was investigated. A B. pseudomalleiΔppiB (BpsΔppiB) mutant strain demonstrates impaired biofilm formation and reduced motility. Macrophage invasion and survival assays showed that although the BpsΔppiB strain retained the ability to infect macrophages, it had reduced survival and lacked the ability to spread cell to cell, indicating ppiB is essential for B. pseudomallei virulence. This is reflected in the BALB/c mouse infection model, demonstrating the requirement of ppiB for in vivo disease dissemination and progression. Proteomic analysis demonstrates that the loss of PpiB leads to pleiotropic effects, supporting the role of PpiB in maintaining proteome homeostasis. The loss of PpiB leads to decreased abundance of multiple virulence determinants, including flagellar machinery and alterations in type VI secretion system proteins. In addition, the loss of ppiB leads to increased sensitivity toward multiple antibiotics, including meropenem and doxycycline, highlighting ppiB inhibition as a promising antivirulence target to both treat B. pseudomallei infections and increase antibiotic efficacy.


Electrochemical formation protocols for maximising the life-time of a sodium ion battery.
Electrochemical protocols for reducing formation time and maximising cycle life in a sodium ion battery are proposed. The formation protocols comprise low current cycles within a targeted voltage window. After accelerated cell aging tests, the impedance and cycle life are evaluated. Maximum life time is obtained for formation within the 3.6-3.8 V window. 250 cycles are observed to 80% of initial capacity with accelerated ageing, compared to 90 cycles with no formation.


Effects of spa therapy on serum leptin and adiponectin levels in patients with knee osteoarthritis.
Adipocytokine, including leptin and adiponectin, may play an important role in the pathophysiology of osteoarthritis (OA). Spa therapy is one of the most commonly used non-pharmacological approaches for OA, but its mechanisms of action are not completely known. The aim of the present study was to assess whether spa therapy modified plasma levels of leptin and adiponectin in thirty patients with knee OA treated with a cycle of a combination of daily locally applied mud-packs and bicarbonate-sulphate mineral bath water. Leptin and adiponectin plasma levels were assessed at baseline and after 2 weeks, upon completion of the spa treatment period. The concentrations of leptin and adiponectin were measured by ELISA. At basal time, plasma leptin levels were significantly correlated with body mass index (BMI) and gender, but no significant correlation was found with patient age, duration of disease, radiographic severity of knee OA, VAS score or Lequesne index. There was no correlation between plasma adiponectin level and BMI, gender and age, duration of the disease, radiographic severity of knee OA and VAS score. A significant correlation of plasma adiponectin levels was found only with the Lequesne index. At the end of the mud-bath therapy cycle, serum leptin levels showed a slight but not significant increase, while a significant decrease (P < 0.05) in serum adiponectin levels was found. However, leptin and adiponectin concentrations after treatment were not correlated with other clinical parameters. In conclusion, our data show that spa therapy can modify plasma levels of the adipocytokines leptin and adiponectin, important mediators of cartilage metabolism. Whether this effect may play a potential role in OA needs further investigations.


Proteomics analysis reveals protein expression differences for hypopharyngeal gland activity in the honeybee, Apis mellifera carnica Pollmann.
Most of the proteins contained in royal jelly (RJ) are secreted from the hypopharyngeal glands (HG) of young bees. Although generic protein composition of RJ has been investigated, little is known about how age-dependent changes on HG secretion affect RJ composition and their biological consequences. In this study, we identified differentially expressed proteins (DEPs) during HG development by using the isobaric tag for relative and absolute quantification (iTRAQ) labeling technique. This proteomic method increases the potential for new protein discovery by improving the identification of low quantity proteins. A total of 1282 proteins were identified from five age groups of worker bees, 284 of which were differentially expressed. 43 (15.1%) of the DEPs were identified for the first time. Comparison of samples at day 6, 9, 12, and 16 of development relative to day 3 led to the unambiguous identification of 112, 117, 127, and 127 DEPs, respectively. The majority of these DEPs were up-regulated in the older worker groups, indicating a substantial change in the pattern of proteins expressed after 3 days. DEPs were identified among all the age groups, suggesting that changes in protein expression during HG ontogeny are concomitant with different states of worker development. A total of 649 proteins were mapped to canonical signaling pathways found in the Kyoto Encyclopedia of Genes and Genomes (KEGG), which were preferentially associated with metabolism and biosynthesis of secondary metabolites. More than 10 key high-abundance proteins were involved in signaling pathways related to ribosome function and protein processing in the endoplasmic reticulum. The results were validated by qPCR. Our approach demonstrates that HG experienced important changes in protein expression during its ontogenic development, which supports the secretion of proteins involved in diverse functions in adult workers beyond its traditional role in royal jelly production.


Cerebral activations related to audition-driven performance imagery in professional musicians.
Functional Magnetic Resonance Imaging (fMRI) was used to study the activation of cerebral motor networks during auditory perception of music in professional keyboard musicians (n = 12). The activation paradigm implied that subjects listened to two-part polyphonic music, while either critically appraising the performance or imagining they were performing themselves. Two-part polyphonic audition and bimanual motor imagery circumvented a hemisphere bias associated with the convention of playing the melody with the right hand. Both tasks activated ventral premotor and auditory cortices, bilaterally, and the right anterior parietal cortex, when contrasted to 12 musically unskilled controls. Although left ventral premotor activation was increased during imagery (compared to judgment), bilateral dorsal premotor and right posterior-superior parietal activations were quite unique to motor imagery. The latter suggests that musicians not only recruited their manual motor repertoire but also performed a spatial transformation from the vertically perceived pitch axis (high and low sound) to the horizontal axis of the keyboard. Imagery-specific activations in controls were seen in left dorsal parietal-premotor and supplementary motor cortices. Although these activations were less strong compared to musicians, this overlapping distribution indicated the recruitment of a general 'mirror-neuron' circuitry. These two levels of sensori-motor transformations point towards common principles by which the brain organizes audition-driven music performance and visually guided task performance.


Cohesion between sister chromatids must be established during DNA replication.
Cohesion between sister chromatids, which opposes the splitting force exerted by the mitotic spindle during metaphase, is essential for their segregation to opposite poles of the cell during anaphase. In Saccharomyces cerevisiae, cohesion depends on a set of chromosomal proteins called cohesins, which include structural maintenance of chromosomes 1p (Smc1p), Smc3p and sister chromatid cohesion 1p (Scc1p). Strains with mutations in the genes encoding these proteins separate sister chromatids prematurely and fail to align them in metaphase. This leads to missegregation of chromosomes in the following anaphase. In a normal cell cycle, Scc1p was synthesized and recruited to chromosomes at the onset of S phase. Using cells that expressed Scc1p exclusively from a galactose-inducible promoter, we showed that if Scc1p was synthesised only after completion of S phase, it still bound to chromosomes but failed to promote sister chromatid cohesion. Cohesion between sister chromatids must be established during DNA replication, possibly following the passage of a replication fork. Furthermore, Scc1p (and other cohesins) are needed both for maintaining cohesion during mitosis and for establishing it during S phase. Establishment of sister chromatid cohesion is therefore an essential but hitherto neglected aspect of S phase.


Apparent digestibility, nitrogen balance, and ruminal constituents in ram lambs fed high-concentrate diets containing soybean hulls.
Corn often constitutes the main portion of high-concentrate diets fed to feedlot lambs. However, soybean hulls (SH) may be used to replace corn, and may reduce feed costs and the risk of acidosis. The objective of this experiment was to determine the effect of SH inclusion rate in high-concentrate diets on DMI, apparent digestibility of nutrients, N balance, and some rumen constituents. Sixteen ruminally fistulated Santa Inês ram lambs (44.3 ± 5 kg of BW and 6 mo old) were housed in suspended metabolism crates. A randomized complete block design experiment with 4 diets and 4 blocks was used. Blocks were defined by BW, and diets were allotted randomly within block. The control diet contained 70% corn and 0% SH. In the remaining diets, SH replaced corn at the rate of 15, 30, or 45% of the original corn concentration, which resulted in 0, 10.5, 21.0, and 31.4% of SH in the dietary DM. The DMI (kg/d) increased linearly (P < 0.01) with increasing dietary SH inclusion. A trend was observed for linear decreases (P = 0.10) in apparent DM, OM, and nonfiber carbohydrate digestibility, and a trend was observed for an increase (P = 0.08) in NDF digestibility with increasing dietary SH addition. Apparent digestibilities of CP and ether extract and ADF digestibility were not affected by SH inclusion rate. Total ruminal concentration of short-chain fatty acids was affected quadratically (P = 0.03) by diet; acetate concentration increased linearly (P < 0.01), whereas quadratic effects were observed on propionate concentration (P = 0.03) and acetate-to-propionate ratio (P < 0.01) with increasing dietary SH. Ruminal pH increased linearly (P < 0.01) as corn was replaced by SH. Nitrogen retention was not affected by the addition of SH, in spite of a linear increase in urinary N (P < 0.01). The replacement of corn grain with up to 45% SH (31.4% of SH in the dietary DM) resulted in a trend to decrease apparent digestibility of DM and to increase NDF digestibility, presenting a fermentation pattern that would reduce the risk of acidosis.


Correlation between extent of sinus surgery, radiographic disease, and postoperative outcomes.
The extent of endoscopic sinus surgery (ESS) required for optimal outcomes in chronic rhinosinusitis (CRS) is undefined. We evaluated whether concordance between the extent of surgery and degree of radiographic disease influences postoperative outcomes. 247 CRS patients who underwent ESS were retrospectively assigned a concordance score reflecting the similarity between the extent of surgery and degree of radiographic disease. 0 points were assigned when sinusotomy was performed on a diseased sinus, or no sinusotomy was performed on a nondiseased sinus; plus 1 for sinusotomy on a nondiseased sinus; and -1 for a diseased sinus left unopened. The total possible score ranged from minus 10 to plus 10. Patients were divided into 5 subgroups according to variance from complete concordance. SNOT-22 scores and revision rates were compared at 6 and 24 months. All five subgroups had similar preoperative SNOT-22 scores and improved at 6 months postoperatively. At 6 months postoperatively, the most conservatively operated and most extensively operated subgroups each achieved equivalent improvements in SNOT-22 as the completely concordant subgroup. At 24 months, the most extensively operated subgroup had a 12.5-point smaller improvement in SNOT-22 scores compared to the completely concordant subgroup. Multivariate analysis showed no association between concordance score and revision rate. Symptom improvement and revision rates after ESS do not appear to correlate with the degree of concordance between extent of surgery and radiographic disease. More extensive surgery than indicated by CT confers neither greater symptomatic improvement nor long-term detriment.


Individual variation in the production of a 'bystander signal' following irradiation of primary cultures of normal human urothelium.
The existence of a bystander effect following both alpha and gamma irradiation of many cell lines is not now in dispute. The significance of this effect for cancer risk assessment and radiotherapy treatment planning requires demonstration of its relevance in vivo. The problem in demonstrating the existence of the effect in vivo is that other systemic effects may mask or confound the effect being investigated and it is practically impossible to attribute an effect in a particular cell to a signal produced in another irradiated cell. To approach this problem, we have developed an assay where fragments of human tissue can be irradiated ex vivo and the media harvested and added to unirradiated, allogenic explants or to a clonogenic cell line which has a well characterized and stable response to the bystander signal. The variation in production of the signal from patient to patient can thus be assessed using molecular and cellular endpoints. A study using tissue from over 100 patients and from mouse strains with well characterized responses to low level radiation exposure shows that there is variation in the effect of the signal produced by irradiated tissue from different patients. Gender, smoking status and the existence of a bladder malignancy influence the expression of the signal by normal urothelium. The effects of exposure to medium containing the signal are transmitted to distant progeny of the exposed cell population. The results may be important not only for understanding radiation risk mechanisms for protection but also for radiotherapy treatment planning where they may open new avenues for development of drugs for combined therapy.


Genomic insights into host adaptation between the wheat stripe rust pathogen (Puccinia striiformis f. sp. tritici) and the barley stripe rust pathogen (Puccinia striiformis f. sp. hordei).
Plant fungal pathogens can rapidly evolve and adapt to new environmental conditions in response to sudden changes of host populations in agro-ecosystems. However, the genomic basis of their host adaptation, especially at the forma specialis level, remains unclear. We sequenced two isolates each representing Puccinia striiformis f. sp. tritici (Pst) and P. striiformis f. sp. hordei (Psh), different formae speciales of the stripe rust fungus P. striiformis highly adapted to wheat and barley, respectively. The divergence of Pst and Psh, estimated to start 8.12 million years ago, has been driven by high nucleotide mutation rates. The high genomic variation within dikaryotic urediniospores of P. striiformis has provided raw genetic materials for genome evolution. No specific gene families have enriched in either isolate, but extensive gene loss events have occurred in both Pst and Psh after the divergence from their most recent common ancestor. A large number of isolate-specific genes were identified, with unique genomic features compared to the conserved genes, including 1) significantly shorter in length; 2) significantly less expressed; 3) significantly closer to transposable elements; and 4) redundant in pathways. The presence of specific genes in one isolate (or forma specialis) was resulted from the loss of the homologues in the other isolate (or forma specialis) by the replacements of transposable elements or losses of genomic fragments. In addition, different patterns and numbers of telomeric repeats were observed between the isolates. Host adaptation of P. striiformis at the forma specialis level is a complex pathogenic trait, involving not only virulence-related genes but also other genes. Gene loss, which might be adaptive and driven by transposable element activities, provides genomic basis for host adaptation of different formae speciales of P. striiformis.


Exclusion of metal oxide by an RF sputtered Ti layer in flexible perovskite solar cells: energetic interface between a Ti layer and an organic charge transporting layer.
In this work, the effects of a titanium (Ti) layer on the charge transport and recombination rates of flexible perovskite solar cells were studied. Ti as an efficient barrier layer was deposited directly on PET-ITO flexible substrates through RF magnetic sputtering using a Ti-source and a pressure of ∼5 mTorr. A Ti coated PET-ITO was used for the fabrication of a flexible perovskite solar cell without using any metal oxide layer. The fabricated flexible perovskite solar cell was composed of a PET-ITO/Ti/perovskite (CH3NH3PbI3)/organic hole transport layer of 2,2',7,7'-tetrakis [N,N'-di-p-methoxyphenylamine]-9,9'-spirobifluorene (spiro-OMeTAD)-Li-TFSI/Ag. A high conversion efficiency of ∼8.39% along with a high short circuit current (JSC) of ∼15.24 mA cm(-2), an open circuit voltage (VOC) of ∼0.830 V and a high fill factor (FF) of ∼0.66 was accomplished by the fabricated flexible perovskite solar cell under a light illumination of ∼100 mW cm(-2) (1.5 AM). Intensity-modulated photocurrent (IMPS)/photovoltage spectroscopy (IMVS) studies demonstrated that the fabricated flexible perovskite solar cell considerably reduced the recombination rate.


Children with disabilities in the context of disaster: a social vulnerability perspective.
An estimated 200 million children worldwide experience various forms of disability. This critical review extrapolates from existing literature in 2 distinct areas of scholarship: one on individuals with disabilities in disaster, and the other on children in disaster. The extant literature suggests that various factors may contribute to the physical, psychological, and educational vulnerability of children with disabilities in disaster, including higher poverty rates, elevated risk exposure, greater vulnerability to traumatic loss or separation from caregivers, more strain on parents, and poor postdisaster outcomes, unless medical, familial, social, and educational protections are in place and vital social networks are quickly reestablished. Future research needs are outlined in the conclusion.


Cost of using a patient tracer to reduce loss to follow-up and ascertain patient status in a large antiretroviral therapy program in Johannesburg, South Africa.
To evaluate a pilot intervention to engage a patient tracer to follow up lost patients at a large public clinic in South Africa. A social worker spent 4 months contacting by telephone a random sample of patients who had initiated antiretroviral therapy (ART) at least 6 months earlier and were >or=1 month late for a scheduled visit. The tracer was authorized to assist patients to return to care if needed. Cost was calculated from the perspective of the clinic. The tracer was able to determine the final status of 260 of a sample of 493 lost patients. Of the 260, 55 (21%) had died, 56 (21%) were still on ART at the same site, 79 (30%) reported transferring to another site and 70 (27%) had discontinued treatment. Among those discontinuing, commonly cited reasons were relocation (n = 18, 26%), traditional medicine or religious beliefs (n = 11, 16%), fear of disclosure or other family barriers (n = 9, 13%), and employment obstacles (n = 7, 10%). Twenty patients returned to care at the original site as a result of the intervention, at an average cost of $432 per patient returned. A patient tracer was an effective way to determine the final status of lost patients and succeeded in returning some to care, but the cost per patient returned was high. Better information systems allowing sites to track deaths and transfers would greatly improve the efficiency of loss to follow-up interventions.


Life crisis as a precursor to child abuse.
A number of theories have been proposed on the causation of child abuse, and many of these theories assign some role to stress. Stress is variously conceptualized as a continuous state resulting from poverty, poor housing, and the like, or as an immediate crisis such as an argument or the breakdown of an appliance. An alternate perspective on stress identifies it with life change events which require readjustment in the lifestyle of a person. When an excessive number or magnitude of such life change events occur, the person affected may be said to be in a state of life crisis. Such states of life crisis have been found to be associated with the onset of physical illness and with the occurrence of accidents and injuries. In this study, a questionnaire was administered to 35 abusing parents and 35 matched controls who had experienced problems with their children but had not been abusive. The two groups were compared for their life change scores on the Social Readjustment Rating Scale for the year before their abuse or problems began with their children. The mean score of the nonabusers was 124, which does not indicate a life crisis. For the abusers, the mean score was 234, which indicates a moderate life crisis. These means are significantly different at the .001 level by the t test. The role of symbiosis, an emotiontional attachment in which a person seeks to be taken care of by another person, was also explored. It is argued that abusive parents are competing with each other and with their children for the role of being cared for. This kind of behavior seems to make the person particularly vulnerable to life changes, which in turn produce stress. Support for this view was found in the responses to the questionnaire. Prevention strategies aimed at reducing change and stress might include better provision of crisis-intervention services, measures aimed at reducing unemployment or lack of opportunity, effective health maintenance services, and greater provision of counseling and mental health services. Use of the Social Readjustment Rating Scale in a preventive program of early intervention is also possible.


Mystery solved: Trehalose kickstarts autophagy by blocking glucose transport.
Although vertebrates cannot synthesize the natural disaccharide trehalose, exogenous administration of trehalose to mammalian cells may be beneficial for protein misfolding disorders. In this issue, DeBosch et al. show that trehalose may also be useful in treating nonalcoholic fatty liver disease and identify inhibition of cellular glucose import through SLC2A (also known as GLUT) transporters as a mechanism by which trehalose stimulates autophagy through the adenosine monophosphate-activated protein kinase (AMPK).


Petroleum and hazardous material releases from industrial facilities associated with Hurricane Katrina.
Hurricane Katrina struck an area dense with industry, causing numerous releases of petroleum and hazardous materials. This study integrates information from a number of sources to describe the frequency, causes, and effects of these releases in order to inform analysis of risk from future hurricanes. Over 200 onshore releases of hazardous chemicals, petroleum, or natural gas were reported. Storm surge was responsible for the majority of petroleum releases and failure of storage tanks was the most common mechanism of release. Of the smaller number of hazardous chemical releases reported, many were associated with flaring from plant startup, shutdown, or process upset. In areas impacted by storm surge, 10% of the facilities within the Risk Management Plan (RMP) and Toxic Release Inventory (TRI) databases and 28% of SIC 1311 facilities experienced accidental releases. In areas subject only to hurricane strength winds, a lower fraction (1% of RMP and TRI and 10% of SIC 1311 facilities) experienced a release while 1% of all facility types reported a release in areas that experienced tropical storm strength winds. Of industrial facilities surveyed, more experienced indirect disruptions such as displacement of workers, loss of electricity and communication systems, and difficulty acquiring supplies and contractors for operations or reconstruction (55%), than experienced releases. To reduce the risk of hazardous material releases and speed the return to normal operations under these difficult conditions, greater attention should be devoted to risk-based facility design and improved prevention and response planning.


The ABC of health care team dynamics: understanding complex affective, behavioral, and cognitive dynamics in interprofessional teams.
Interprofessional teams form the basis of many health care problem-solving and decision-making mechanisms. However, more than 70% of medical errors are attributable to dysfunctional team dynamics. The recent suggestion that health care teams are more complex than nonmedical teams suggests that we require more sophisticated knowledge of team dynamics and processes. The mechanisms of dysfunctional interprofessional teams focusing on affective, behavioral, and cognitive effects are explored. We argue that interprofessional composition impacts team dynamics by increasing the likelihood of affective conflict, which mediates a decrease in elaborative behaviors and open-mindedness. The hypotheses are investigated using a cross-sectional, correlational design. Survey data received from 218 members of 47 interprofessional teams employed in an acute care setting, representing a 39% response rate, is used to investigate two moderated mediation pathways. Analysis supports a significant relationship between interprofessional composition and affective conflict but only when team rate highly for professional identification. Results also support a dual moderated mediation pathway through which professional diversity has a dysfunctional effect on debate and open-mindedness. A range of strategies emerge from the findings to minimize dysfunctional interprofessional team dynamics. These include the use of leadership strategies, such as transformational styles, reinforcement of shared values such as patient-centeredness, and development of a shared group identity.


Behavior of identified Edinger-Westphal neurons during ocular accommodation.
1. The present study used single-unit recording and antidromic activation techniques in alert rhesus monkeys to examine the static and dynamic behavior of 21 parasympathetic, preganglionic neurons of the Edinger-Westphal nucleus (EW) during ocular accommodation. 2. All identified EW neurons were active when viewing at optical infinity with an average firing rate of 11.6 spikes/s. During near viewing, there was a linear relationship between firing rate and accommodation with an overall gain for the population of preganglionic EW neurons of 3.3 (spikes/s)/diopter. 3. The activity of eight identified EW neurons was studied during viewing of targets with conflicting vergence and accommodative demands to dissociate their vergence and accommodation responses. With normal viewing these responses are so closely matched that it cannot be determined if the activity of a cell is related to vergence or to accommodation, but with dissociated viewing these relationships can be determined. Under this viewing condition, six preganglionic EW neurons showed the same relationship to accommodation as they did during normal viewing. However, the activity of two cells could not be explained solely by accommodation, and they showed some activity related to vergence. 4. Microstimulation at the sites of identified EW neurons produced accommodation in the ipsilateral eye. Repeated measures of the effect of microstimulation yielded a value of 75 ms for the latency of the response. This latency was essentially the same in both animals tested. 5. The activity of identified EW neurons is related to the velocity of accommodation as well as to static accommodation. The relationship between accommodation velocity and firing rate was studied for 15 identified EW neurons during sine-wave tracking of targets moving in depth. All of these cells showed a clear relationship between firing rate and accommodation velocity. Overall, this group of identified EW neurons showed a velocity sensitivity of 1.2 (spikes/s)/(diopter/s) and an estimated neural time constant of 380 ms. 6. Eleven neurons encountered near to preganglionic EW neurons could not be antidromically activated by stimulation of the oculomotor nerve. These neurons had statistically higher gains with respect to the near response; indeed, there was no overlap between the gains of these neurons and the gains of preganglionic EW neurons. Upon dissociation of vergence from accommodation, they were found to be related to either vergence or to vergence and accommodation but not solely to accommodation.


Molecular structures and interactions in the yeast kinetochore.
Kinetochores are the elaborate protein assemblies that attach chromosomes to spindle microtubules in mitosis and meiosis. The kinetochores of point-centromere yeast appear to represent an elementary module, which repeats a number of times in kinetochores assembled on regional centromeres. Structural analyses of the discrete protein subcomplexes that make up the budding-yeast kinetochore have begun to reveal principles of kinetochore architecture and to uncover molecular mechanisms underlying functions such as transmission of tension and establishment and maintenance of bipolar attachment. The centromeric DNA is probably wrapped into a compact organization, not only by a conserved, centromeric nucleosome, but also by interactions among various other DNA-bound kinetochore components. The rod-like, heterotetrameric Ndc80 complex, roughly 600 Å long, appears to extend from the DNA-proximal assembly to the plus end of a microtubule, to which one end of the complex is known to bind. Ongoing structural studies will clarify the roles of a number of other well-defined complexes.


Sensitivity of the lidar solution to errors of the aerosol backscatter-to-extinction ratio: influence of a monotonic change in the aerosol extinction coefficient.
Unlike other errors in the lidar equation solution for the two-component atmosphere, the error of the measured aerosol extinction coefficient caused by inaccuracies in the assumed aerosol backscatter-to-extinction ratios significantly depends on the aerosol spatial inhomogeneity. In a slightly nonhomogeneous atmosphere, an incorrect value in the assumed aerosol backscatter-to-extinction ratio does not significantly corrupt the measurement result, whereas in an atmosphere with a large monotonic change of the aerosol extinction [e.g., in the lower troposphere], the incorrect value yields a large distortion of the retrieved extinction-coefficient profile. In the latter case, even the far-end solution can produce a large error in the retrieved extinction coefficient. The analytical formulas for the determination of the range errors, obtained for the Klett and the optical-depth solutions, show that these errors significantly depend on the method of the boundary-condition determination. Distortions of the retrieved aerosol extinction profiles are, in general, larger if the assumed aerosol backscatter-to-extinction ratio is underestimated in relation to the real value.


Differentiation of mouse induced pluripotent stem cells (iPSCs) into nucleus pulposus-like cells in vitro.
A large percentage of the population may be expected to experience painful symptoms or disability associated with intervertebral disc (IVD) degeneration - a condition characterized by diminished integrity of tissue components. Great interest exists in the use of autologous or allogeneic cells delivered to the degenerated IVD to promote matrix regeneration. Induced pluripotent stem cells (iPSCs), derived from a patient's own somatic cells, have demonstrated their capacity to differentiate into various cell types although their potential to differentiate into an IVD cell has not yet been demonstrated. The overall objective of this study was to assess the possibility of generating iPSC-derived nucleus pulposus (NP) cells in a mouse model, a cell population that is entirely derived from notochord. This study employed magnetic activated cell sorting (MACS) to isolate a CD24(+) iPSC subpopulation. Notochordal cell-related gene expression was analyzed in this CD24(+) cell fraction via real time RT-PCR. CD24(+) iPSCs were then cultured in a laminin-rich culture system for up to 28 days, and the mouse NP phenotype was assessed by immunostaining. This study also focused on producing a more conducive environment for NP differentiation of mouse iPSCs with addition of low oxygen tension and notochordal cell conditioned medium (NCCM) to the culture platform. iPSCs were evaluated for an ability to adopt an NP-like phenotype through a combination of immunostaining and biochemical assays. Results demonstrated that a CD24(+) fraction of mouse iPSCs could be retrieved and differentiated into a population that could synthesize matrix components similar to that in native NP. Likewise, the addition of a hypoxic environment and NCCM induced a similar phenotypic result. In conclusion, this study suggests that mouse iPSCs have the potential to differentiate into NP-like cells and suggests the possibility that they may be used as a novel cell source for cellular therapy in the IVD.


Interplay of clamp loader subunits in opening the beta sliding clamp of Escherichia coli DNA polymerase III holoenzyme.
The Escherichia coli beta dimer is a ring-shaped protein that encircles DNA and acts as a sliding clamp to tether the replicase, DNA polymerase III holoenzyme, to DNA. The gamma complex (gammadeltadelta'chipsi) clamp loader couples ATP to the opening and closing of beta in assembly of the ring onto DNA. These proteins are functionally and structurally conserved in all cells. The eukaryotic equivalents are the replication factor C (RFC) clamp loader and the proliferating cell nuclear antigen (PCNA) clamp. The delta subunit of the E. coli gamma complex clamp loader is known to bind beta and open it by parting one of the dimer interfaces. This study demonstrates that other subunits of gamma complex also bind beta, although weaker than delta. The gamma subunit like delta, affects the opening of beta, but with a lower efficiency than delta. The delta' subunit regulates both gamma and delta ring opening activities in a fashion that is modulated by ATP interaction with gamma. The implications of these actions for the workings of the E. coli clamp loading machinery and for eukaryotic RFC and PCNA are discussed.


Low anticoagulant heparin targets multiple sites of inflammation, suppresses heparin-induced thrombocytopenia, and inhibits interaction of RAGE with its ligands.
While heparin has been used almost exclusively as a blood anticoagulant, important literature demonstrates that it also has broad anti-inflammatory activity. Herein, using low anti-coagulant 2-O,3-O-desulfated heparin (ODSH), we demonstrate that most of the anti-inflammatory pharmacology of heparin is unrelated to anticoagulant activity. ODSH has low affinity for anti-thrombin III, low anti-Xa, and anti-IIa anticoagulant activities and does not activate Hageman factor (factor XII). Unlike heparin, ODSH does not interact with heparin-platelet factor-4 antibodies present in patients with heparin-induced thrombocytopenia and even suppresses platelet activation in the presence of activating concentrations of heparin. Like heparin, ODSH inhibits complement activation, binding to the leukocyte adhesion molecule P-selectin, and the leukocyte cationic granular proteins azurocidin, human leukocyte elastase, and cathepsin G. In addition, ODSH and heparin disrupt Mac-1 (CD11b/CD18)-mediated leukocyte adhesion to the receptor for advanced glycation end products (RAGE) and inhibit ligation of RAGE by its many proinflammatory ligands, including the advanced glycation end-product carboxymethyl lysine-bovine serum albumin, the nuclear protein high mobility group box protein-1 (HMGB-1), and S100 calgranulins. In mice, ODSH is more effective than heparin in reducing selectin-mediated lung metastasis from melanoma and inhibits RAGE-mediated airway inflammation from intratracheal HMGB-1. In humans, 50% inhibitory concentrations of ODSH for these anti-inflammatory activities can be achieved in the blood without anticoagulation. These results demonstrate that the anticoagulant activity of heparin is distinct from its anti-inflammatory actions and indicate that 2-O and 3-O sulfate groups can be removed to reduce anticoagulant activity of heparin without impairing its anti-inflammatory pharmacology.


A Src-like inactive conformation in the abl tyrosine kinase domain.
The improper activation of the Abl tyrosine kinase results in chronic myeloid leukemia (CML). The recognition of an inactive conformation of Abl, in which a catalytically important Asp-Phe-Gly (DFG) motif is flipped by approximately 180 degrees with respect to the active conformation, underlies the specificity of the cancer drug imatinib, which is used to treat CML. The DFG motif is not flipped in crystal structures of inactive forms of the closely related Src kinases, and imatinib does not inhibit c-Src. We present a structure of the kinase domain of Abl, determined in complex with an ATP-peptide conjugate, in which the protein adopts an inactive conformation that resembles closely that of the Src kinases. An interesting aspect of the Src-like inactive structure, suggested by molecular dynamics simulations and additional crystal structures, is the presence of features that might facilitate the flip of the DFG motif by providing room for the phenylalanine to move and by coordinating the aspartate side chain as it leaves the active site. One class of mutations in BCR-Abl that confers resistance to imatinib appears more likely to destabilize the inactive Src-like conformation than the active or imatinib-bound conformations. Our results suggest that interconversion between distinctly different inactive conformations is a characteristic feature of the Abl kinase domain.


Nanoshell-mediated laser surgery simulation for prostate cancer treatment.
Laser surgery, or laser-induced thermal therapy, is a minimally invasive alternative or adjuvant to surgical resection in treating tumors embedded in vital organs with poorly defined boundaries. Its use, however, is limited due to the lack of precise control of heating and slow rate of thermal diffusion in the tissue. Nanoparticles, such as nanoshells, can act as intense heat absorbers when they are injected into tumors. These nanoshells can enhance thermal energy deposition into target regions to improve the ability for destroying larger cancerous tissue volumes with lower thermal doses. The goal of this paper is to present an integrated computer model using a so-called nested-block optimization algorithm to simulate laser surgery and provide transient temperature field predictions. In particular, this algorithm aims to capture changes in optical and thermal properties due to nanoshell inclusion and tissue property variation during laser surgery. Numerical results show that this model is able to characterize variation of tissue properties for laser surgical procedures and predict transient temperature fields comparable to those measured by in vivo magnetic resonance temperature imaging techniques. Note that the computational approach presented in the study is quite general and can be applied to other types of nanoparticle inclusions.