Thalidomide prolongs disease stabilization after conventional therapy in patients with recurrent glioblastoma.
Thalidomide shows antiangiogenic activity and it has been successfully employed in various tumors. Considering the poor therapeutic options for glioblastoma and the role of angiogenesis in malignant glioma cells growth, we investigated the therapeutic activity of thalidomide in patients affected by recurrent glioblastoma. Inclusion criteria were: recurrent glioblastoma pretreated with surgery and radiotherapy, age >/=18 years, adequate performance status, hematological, renal, and hepatic functions. Exclusion criteria included severe underlying diseases, neuropathy or concurrent radiotherapy. Eighteen patients entered the study, 17 of whom were assessable for toxicity and response. Most of patients were pretreated with chemotherapy (77.8%). Thalidomide was well tolerated: the most common side effects were constipation (76.5% of patients), somnolence (47%), and peripheral neuropathy (11.8%). One minimal response (MR) and 8 stable disease (SD) were observed, with an overall clinical benefit of 52.9%. Median time to progression and median overall survival (OS) for responders was 25 weeks (range 12-40) and 36 weeks (range 16-64), respectively. In conclusion, thalidomide induces modest side effects and it may be considered a valid therapeutic option for patients with recurrent glioblastoma.


Proton pump inhibitor failure in gastro-oesophageal reflux disease: a perspective aided by the Gartner hype cycle.
Some patients with gastro-oesophageal reflux disease (GORD) experience symptoms despite proton pump inhibitor (PPI) treatment. In the early years of their availability, these drugs were thought to be a highly effective treatment for GORD and realisation that symptom relief was often incomplete came as a disappointment. This review considers the evolution of thinking with the aid of the Gartner hype cycle - a graphical depiction of the process of innovation, evolution and adoption of new technologies. Acknowledging that over-simplistic concepts of GORD have been largely responsible for inflated expectations of PPI therapy is an important step forward in establishing how patients with persistent symptoms, despite PPIs, should be assessed and treated.


Hypersensitive response-related death.
The hypersensitive response (HR) of plants resistant to microbial pathogens involves a complex form of programmed cell death (PCD) that differs from developmental PCD in its consistent association with the induction of local and systemic defence responses. Hypersensitive cell death is commonly controlled by direct or indirect interactions between pathogen avirulence gene products and those of plant resistance genes and it can be the result of multiple signalling pathways. Ion fluxes and the generation of reactive oxygen species commonly precede cell death, but a direct involvement of the latter seems to vary with the plant-pathogen combination. Protein synthesis, an intact actin cytoskeleton and salicylic acid also seem necessary for cell death induction. Cytological studies suggest that the actual mode and sequence of dismantling the cell contents varies among plant-parasite systems although there may be a universal involvement of cysteine proteases. It seems likely that cell death within the HR acts more as a signal to the rest of the plant rather than as a direct defence mechanism.


Assessment of potential impacts of municipal solid waste treatment alternatives by using life cycle approach: a case study in Vietnam.
In Vietnam, most of municipal solid waste (MSW) is disposed of at open dumping and landfill sites, and the methane gas from waste is the un-ignorable source of greenhouse gas (GHG) emission. It is indispensable to explore the possibility for GHG mitigation in MSW management. The objective of this study was to estimate alternative waste treatment practices towards the GHG emission mitigation, energy consumption and generation, reduction of landfill volume, and various benefits for proposing the appropriate selection by scenario analyses for representative Vietnam's cities. Impacts were calculated by utilizing life cycle assessment (LCA) method. A literature review survey on the current applicability of LCA database for assessing impacts from waste sector in developing countries, especially for Vietnam, was carried out. This study assessed the contribution of alternative solid waste treatment practices. The result showed that, except investment and operation costs, incineration with energy recovery seems the suitable alternative for treating waste from representative cities of Vietnam according to reduction of GHG emission and waste burden to landfill sites and energy recovery and generation. Besides, MSW composition was identified as an important factor directly influencing to impacts as well as other products and benefits of waste treatment alternatives. Reliable data on waste composition are indispensable for assessing to choose, improve, or plan the waste treatment practices towards sustainable development.


Cytotoxic auranofin analogues bearing phosphine, arsine and stibine ligands: A study on the possible role of the ligand on the biological activity.
Three gold(I) linear compounds, sharing the general formula [AuI(LPh3)], have been synthesized and characterized. The nature of the ligand has been modified by moving down among some of the elements of group 15, i.e. phosphorus, arsenic and antimony. The structures of derived compounds have been solved through XRD and the reactivity behaviour towards selected biomolecules has been investigated through a multi-technique approach involving NMR, high-resolution mass spectrometry and IR. Moreover, the biological activity of the investigated compounds has been comparatively analyzed through classical methodologies and the disclosed differences are discussed in detail.


Point-of-care haemostasis and coagulation monitoring in cardiac surgery at IRCCS Policlinico San Donato.
A rational management of perioperative and postoperative bleeding in modern cardiac surgery requires a thorough application of point-of-care (POC) monitoring in order to prevent and readily treat alterations of the haemostatic process. Preoperative platelet dysfunction, residual heparin after extracorporeal circulation, coagulation factors, and/or fibrinogen deficiency could be ruled out and specifically addressed with an appropriate treatment. Our approach includes preoperative platelet function testing of patients administered with thienopyridines or ticagrelor within 7-10 days before planned surgery and platelet function testing-based surgery timing. In the case of postoperative bleeding, residual heparin is tested and additional protamine is eventually administered. Simultaneously, an overall activity of coagulation factors (except fibrinogen) is assessed and, if significantly reduced, correction with prothrombotic complex concentrate is considered. If fibrinogen deficiency is suspected, a specific test is run, and in the case of severe reduction, the deficiency is compensated by fibrinogen concentrate or appropriate volume of fresh-frozen plasma. If both coagulation factors and fibrinogen activity are reduced, fibrinogen is usually considered for correction as first line, followed by prothrombin complex concentrate in the case of further bleeding. It is our clinical practice not to test nor to treat patients until postoperative bleeding appears clinically relevant. At IRCCS Policlinico San Donato, we firmly believe in the importance of the POC-based strategy for haemostatic treatment and constantly update our knowledge through research projects targeted in answering clinically relevant questions.


Whole-course care in photodynamic therapy of colorectal cancer: A short communication.
Photodynamic therapy is now widely used in different oncologic fields. It is feasible for the treatment of early, non-surgical and non-obstructive cancers. Also, in gastroenterology, where it was a few attempts to treat both the premalignant lesion and advanced colorectal cancer. Photodynamic therapy provides a new treatment option for advanced colon cancer patients with severe obstruction and elderly patients whose cardiopulmonary function cannot tolerate surgery, and effective nursing support throughout the treatment is the key to ensure successful treatment. This study reported the effect of whole-course care for colorectal cancer patients undergoing photodynamic therapy in the Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.


Representing fine-wire EMG with surface EMG in three thigh muscles during high knee flexion movements.
Activation waveforms of vastus intermedius, adductor magnus, and semimembranosus have not been reported for high knee flexion activities such as kneeling or squatting, likely due to the invasive procedures required for their measurement. Their relatively large physiological cross sectional areas would suggest their contributions to knee joint loading could be considerable. Therefore, the purpose of this study was to quantify the activities of these muscles using fine-wire EMG and to assess easy to measure surface sites (vastus lateralis, rectus femoris, vastus medialis, semitendinosus, and biceps femoris) for their potential as proxy measures using <10 %MVC RMS and >0.85 R2 as criteria for successful representation of deep muscle activity by that measured at a surface site. Overall, no surface and fine-wire site pair met both criteria for these movements. When fine-wire measurement of muscle activity is infeasible or impractical, the waveforms presented in supplementary material could be used as a guide for the activity of these deep muscles. Although select muscles for some participants satisfied our criteria, inter-participant variability was considerable. Therefore, future muscle models may benefit from fine-wire measurement of these muscles, but researchers should be cautious of electrode site specificity.


Three-dimensional changes in head shape after extended sagittal strip craniectomy with wedge ostectomies and helmet therapy.
OBJECTIVE Outcome studies for sagittal strip craniectomy have largely relied on the 2D measure of the cephalic index (CI) as the primary indicator of head shape. The goal of this study was to measure the 2D and 3D changes in head shape that occur after sagittal strip craniectomy and postoperative helmet therapy. METHODS The authors performed a retrospective review of patients treated with sagittal strip craniectomy at their institution between January 2012 and October 2015. Inclusion criteria were as follows: 1) isolated sagittal synostosis; 2) age at surgery < 200 days; and 3) helmet management by a single orthotist. The CI was calculated from 3D images. Color maps and dot maps were generated from 3D images to demonstrate the regional differences in the magnitude of change in head shape over time. RESULTS Twenty-one patients met the study inclusion criteria. The mean CI was 71.9 (range 63.0-77.9) preoperatively and 81.1 (range 73.0-89.8) at the end of treatment. The mean time to stabilization of the CI after surgery was 57.2 ± 32.7 days. The mean maximum distances between the surfaces of the preoperative and 1-week postoperative and between the surfaces of the preoperative and end-of-treatment 3D images were 13.0 ± 4.1 mm and 24.71 ± 6.83 mm, respectively. The zone of maximum change was distributed equally in the transverse and vertical dimensions of the posterior vault. CONCLUSIONS The CI normalizes rapidly after sagittal strip craniectomy (57.2 days), with equal distribution of the change in CI occurring before and during helmet therapy. Three-dimensional analysis revealed significant vertical and transverse expansion of the posterior cranial vault. Further studies are needed to assess the 3D changes that occur after other sagittal strip craniectomy techniques.


Phase Noise of SAW Delay Line Magnetic Field Sensors.
Surface acoustic wave (SAW) sensors for the detection of magnetic fields are currently being studied scientifically in many ways, especially since both their sensitivity as well as their detectivity could be significantly improved by the utilization of shear horizontal surface acoustic waves, i.e., Love waves, instead of Rayleigh waves. By now, low-frequency limits of detection (LOD) below 100 pT/Hz can be achieved. However, the LOD can only be further improved by gaining a deep understanding of the existing sensor-intrinsic noise sources and their impact on the sensor's overall performance. This paper reports on a comprehensive study of the inherent noise of SAW delay line magnetic field sensors. In addition to the noise, however, the sensitivity is of importance, since both quantities are equally important for the LOD. Following the necessary explanations of the electrical and magnetic sensor properties, a further focus is on the losses within the sensor, since these are closely linked to the noise. The considered parameters are in particular the ambient magnetic bias field and the input power of the sensor. Depending on the sensor's operating point, various noise mechanisms contribute to f0 white phase noise, f-1 flicker phase noise, and f-2 random walk of phase. Flicker phase noise due to magnetic hysteresis losses, i.e. random fluctuations of the magnetization, is usually dominant under typical operating conditions. Noise characteristics are related to the overall magnetic and magnetic domain behavior. Both calculations and measurements show that the LOD cannot be further improved by increasing the sensitivity. Instead, the losses occurring in the magnetic material need to be decreased.


Social competence intervention for youth with Asperger Syndrome and high-functioning autism: an initial investigation.
Individuals with high functioning autism (HFA) or Asperger Syndrome (AS) exhibit difficulties in the knowledge or correct performance of social skills. This subgroup's social difficulties appear to be associated with deficits in three social cognition processes: theory of mind, emotion recognition and executive functioning. The current study outlines the development and initial administration of the group-based Social Competence Intervention (SCI), which targeted these deficits using cognitive behavioral principles. Across 27 students age 11-14 with a HFA/AS diagnosis, results indicated significant improvement on parent reports of social skills and executive functioning. Participants evidenced significant growth on direct assessments measuring facial expression recognition, theory of mind and problem solving. SCI appears promising, however, larger samples and application in naturalistic settings are warranted.


Cardiac echinococcosis with intra-atrial localization.
Echinococcosis is a frequently encountered parasitic disease in the Mediterranean region, including Turkey. Cardiac disease is seen in 0.5-2% of patients. Usually the cysts are located within the pericardium or intramyocardially; intracavitary localization of the cyst is rarely seen. We herein report a patient who initially presented with hemoptysis and was echocardiographically diagnosed to have an intra-atrial hydatid cyst. Although patients with cardiac hydatid cysts may present with cardiac symptoms, symptoms typically involve other organ systems, following dissemination of the organism. Therefore, echocardiographic screening of patients who are diagnosed with echinococcosis, even if they have no cardiac symptoms, may ensure early diagnosis and prevent development of lethal complications, such as cyst rupture or embolization.


Onchocerciasis: the burden of disease.
The greatest burdens related to human onchocerciasis are the result of the eye and skin lesions and severe itching produced by the microfilariae. Although the major manifestations of the disease do show geographical variation (e.g. onchocercal blindness is not a common complication in all endemic countries), they are often sufficiently severe to prevent human use of the often very fertile land close to the rivers in which the vectors breed. Though for many years thought to be of relatively minor importance compared with onchocercal eye disease, the skin lesions of onchocerciasis have recently been shown to be a major socio-economic burden, in terms of disability-adjusted life-years. The demonstration of an excellent correlation between the prevalence of palpable nodules in a community and the community microfilarial load has led to the development of rapid, safe and non-invasive methods to assess and map the levels of endemicity across whole countries. This has enabled mass treatment with Mectizan (ivermectin, MSD) to be targeted first at hyperendemic communities. Estimates of the burden of onchocerciasis will continue to change as better means of measurement become available. It seems possible, however, that use of Mectizan will eliminate the disease before its true burden can be estimated accurately.


Expressional Analysis of MSX1 (Human) Revealed its Role in Sagittal Jaw Relationship.
Abnormal skeletal jaw relationships is an important factor causing difficulty in speech, mastication, sleep and social interaction, thus affect the overall well being of an individual. The present study was an attempt to decipher the role of human MSX1 in terms of sagittal jaw relationship by employing Polymerase Chain Reaction (PCR) based analysis. Ninety-eight case subjects belonging to North India with skeletal Class II and Class III jaw relationships were selected. Further, thirty-five control subjects of the same region having Class I skeletal and dental relationships (normal Jaw relationships) with good alignment of all teeth were enrolled. MSX1 gene sequencing was performed using the subjects' blood samples. Multiple sequence alignment was performed to find Single Nucleotide Polymorphisms (SNP's). Nine SNP's were obtained of which seven were reported and two novels. Statistical analysis was performed using Chi square test to compare genotype differences between case and control groups. SNP rs186861426 was found to be significantly associated in Class I subjects (p-value=0.02). The sequencing results suggested that individuals having changes from G (guanosine) with A (adenine) genotype had approximately seven times low risk for developing Class II division 1 malocclusion as compared to those alleles having GG genotype and therefore, allele 'A' position on chromosome 4 (rs186861426) seems to have a protective role. The study unfolds an important relationship between MSX1 gene and Class II division 1 malocclusion and Class I normal skeletal relationships. The study tried to interpret the role of human MSX1 and extend the gene pool responsible for the skeletal anomalies related to development of abnormal upper and lower jaws.


Psychological interventions for individuals with cystic fibrosis and their families.
With increasing survival estimates for individuals with cystic fibrosis, long-term management has become an important focus. Psychological interventions are largely concerned with adherence to treatment, emotional and social adaptation and health-related quality of life. We are unaware of any relevant systematic reviews. To determine whether psychological interventions for people with cystic fibrosis provide significant psychosocial and physical benefits in addition to standard medical care. Studies were identified from two Cochrane trials registers (Cystic Fibrosis and Genetic Disorders Group; Depression, Anxiety and Neurosis Group), Ovid MEDLINE and PsychINFO; unpublished trials were located through professional networks and Listserves. Most recent search of the Cystic Fibrosis and Genetic Disorders Group's register: 19 December 2013.Most recent search of the Depression, Anxiety and Neurosis Group's register: 12 November 2013. Randomised controlled studies of a broad range of psychological interventions evaluating subjective and objective health outcomes, such as quality of life or pulmonary function, in individuals of all ages with cystic fibrosis and their immediate family. We were interested in psychological interventions, including psychological methods within the scope of psychotherapeutic or psychosomatic mechanism of action (e.g. cognitive behavioural, cognitive, family systems or systemic, psycho-dynamic, or other, e.g. supportive, relaxation, or biofeedback), which were aimed at improving psychological and psychosocial outcomes (e.g. quality of life, levels of stress or distress, psychopathology, etc.), adaptation to disease management and physiological outcomes. Three authors were involved in selecting the eligible studies and two of these authors assessed their risk of bias. The review includes 16 studies (eight new studies included in this update) representing data from 556 participants. Studies are diverse in their design and their methods. They cover interventions with generic approaches, as well as interventions developed specifically to target disease-specific symptoms and problems in people with cystic fibrosis. These include cognitive behavioural interventions to improve adherence to nutrition or psychosocial adjustment, cognitive interventions to improve adherence or those associated with decision making in lung transplantation, a community-based support intervention and other interventions, such as self-hypnosis, respiratory muscle biofeedback, music therapy, dance and movement therapy, and a tele-medicine intervention to support patients awaiting transplantation.A substantial proportion of outcomes relate to adherence, changes in physical status or other specific treatment concerns during the chronic phase of the disease.There is some evidence that behavioural interventions targeting nutrition and growth in children (4 to 12 years) with cystic fibrosis are effective in the short term. Evidence was found that providing a structured decision-making tool for patients considering lung transplantation improves patients' knowledge of and expectations about the transplant, and reduces decisional conflict in the short term. One study about training in biofeedback-assisted breathing demonstrated some evidence that it improved some lung function measurements. Currently there is insufficient evidence for interventions aimed at other aspects of the disease process. Currently, insufficient evidence exists on psychological interventions or approaches to support people with cystic fibrosis and their caregivers, although some of the studies were promising. Due to the heterogeneity between studies, more of each type of intervention are needed to support preliminary evidence. Multicentre studies, with consequent funding implications, are needed to increase the sample size of these studies and enhance the statistical power and precision to detect important findings. In addition, multicentre studies could improve the generalisation of results by minimizing centre or therapist effects. Psychological interventions should be targeted to illness-specific symptoms or behaviours to demonstrate efficacy.


Increased Resistance of Pseudomonas aeruginosa to Carbenicillin After Reversion from Spheroplast to Rod Form.
Five of six strains of Pseudomonas aeruginosa had at least fourfold increase in resistance to carbenicillian after they reverted from carbenicillin-induced spheroplasts to rod forms. The most susceptible laboratory strain showed the greatest increase in resistance. There was a marked inoculum effect on the minimal inhibitory concentration of carbenicillin when high inocula (10(7) colony-forming units) or very low inocula (10(2) or 10(3) colony-forming units) were used. Population analysis of this reverted strain revealed increase in resistance of the entire population of cells to carbenicillin. However, the degree of resistance was not homogenous. Only a few cells were highly resistant. Comparison of the effect of carbenicillin on the growth of the parent and reverted strains confirmed the increase in resistance of the reverted strain. The resistance remained stable after 42 passages.


A hospital-based study on seroprevalence of leptospirosis among febrile cases in northeastern Malaysia.
To determine the seroprevalence of leptospirosis among febrile inpatient cases in northeastern Malaysia. A hospital-based cross-sectional study was conducted among 999 febrile cases admitted to 10 hospitals in northeastern Malaysia. A survey using a proforma sheet was used to obtain sociodemographic and occupational information. Serum samples were screened for leptospirosis by IgM enzyme-linked immunosorbent assay test (IgM ELISA) and confirmed by microscopic agglutination test (MAT). There was an equivalent distribution of males and females in the 999 respondents enrolled in the study. The majority were Malay (94.7%) and their mean age was 39.4 (standard deviation 17.6) years. The overall seroprevalence of leptospirosis was 8.4% (95% confidence interval (CI) 6.8-10.3) (n=84). The high-risk occupational group was found to have a higher seroprevalence, which was 56% (95% CI 45.3-66.1) (n=47). The predominant serogroup was Sejroe (82.1%, 95% CI 72.6-88.8) (n=69). This study revealed a possible high seroprevalence of leptospirosis among febrile cases, indicating the need to review the importance of adding leptospirosis to the case investigation of febrile illness, especially among high-risk occupational groups in Malaysia, as well as in other endemic countries.


Heat shock alters nuclear ribonucleoprotein assembly in Drosophila cells.
Heterogeneous nuclear RNA is normally complexed with a specific set of proteins, forming ribonucleoprotein particles termed hnRNP. These particles are likely to be involved in mRNA processing. We have found that the structure of hnRNP is profoundly altered during the heat shock response in Drosophila cultured cells. Although hnRNA continues to be synthesized at a near-normal rate during heat shock, its assembly into hnRNP is incomplete, as evidenced by a greatly decreased protein content of the particles in Cs2SO4 density gradients. RNA-protein cross-linking conducted in vivo (Mayrand and Pederson, Proc. Natl. Acad. Sci. U.S.A. 78:2208-2212, 1981) also reveals that hnRNA made during heat shock is complexed with greatly reduced amounts of protein. The block of hnRNP assembly occurs immediately upon heat shock, even before the onset of heat shock protein synthesis. Additional experiments reveal that hnRNP assembled normally at 25 degrees C subsequently disassembles during heat shock. The capacity for normal hnRNP assembly is gradually restored after heat-shocked cells are returned to 25 degrees C. Heat-shocked mammalian cells also show a similar block in hnRNP assembly. We suggest that incomplete assembly of hnRNP during heat shock leads to abortive processing of most mRNA precursors and favors the processing or export (or both) of others whose pathway of nuclear maturation is less dependent on, or even independent of, normal hnRNP particle structure. This hypothesis is compatible with a large number of previous observations.


Osteochondral defect repair using a polyvinyl alcohol-polyacrylic acid (PVA-PAAc) hydrogel.
Poly(vinyl alcohol) (PVA) hydrogels can be candidates for articular cartilage repair due to their high water content. We synthesized a PVA-poly(acrylic acid) (PAAc) hydrogel formulation and determined its ability to function as a treatment option for condylar osteochondral (OC) defects in a New Zealand white rabbit (NZWR) model for 12 weeks and 24 weeks. In addition to hydrogel OC implants, tensile bar-shaped hydrogels were also implanted subcutaneously to evaluate changes in mechanical properties as a function of in vivo duration. There were no statistically significant differences (p > 0.05) in the water content measured in the OC hydrogel implant that was harvested after 12 weeks and 24 weeks, and non-implanted controls. There were no statistically significant differences (p > 0.05) in the break stress, strain at break or modulus of the tensile bars either between groups. Histological analysis of the OC defect, synovial capsule and fibrous tissue around the tensile bars determined hydrogel biocompatibility. Twelve-week hydrogels were found to be in situ flush with the articular cartilage; meniscal tissue demonstrated an intact surface. Twenty-four week hydrogels protruded from the defect site due to lack of integration with subchondral tissue, causing fibrillation to the meniscal surface. Condylar micro-CT scans ruled out osteolysis and bone cysts of the subchondral bone, and no PVA-PAAc hydrogel contents were found in the synovial fluid. The PVA-PAAc hydrogel was determined to be fully biocompatible, maintained its properties over time, and performed well at the 12 week time point. Physical fixation of the PVA-PAAc hydrogel to the subchondral bone is required to ensure long-term performance of hydrogel plugs for OC defect repair.


Does nebulized epinephrine improve the efficacy of hypertonic saline solution in the treatment of hospitalized moderate acute bronchiolitis? A double blind, randomized clinical trial.
Nebulized 3% hypertonic saline solution (HSS 3%) has proven to reduce hospital stay in infants with acute bronchiolitis, as compared with nebulized physiological saline solutions. There are no studies assessing the effectiveness of nebulized epinephrine in patients treated with HSS 3%. The aim of this study was to compare the length of stay (LOS) in hospitalized patients treated with HSS 3% with placebo vs. HSS 3% with epinephrine. Secondarily we aimed to assess the effectiveness and safety of both treatments. We performed a prospective, randomized, double-blind, parallel-group study, including infants hospitalized for moderate acute bronchiolitis. Both groups received standard life support and were randomly treated with nebulized HSS 3% (7 mL) with either placebo 3 mL or epinephrine 3 mL. Nebulizations were initially administered every four hours and this interval was modified according to the patient's response. Sixty-four infants were included, 32 patients in each group. No statistically significant differences were found between the two groups (P=0.948) in length of stay, disease severity, SatO2, respiratory rate or heart rate. On the third day of hospitalization, severity and respiratory rate in the HSS 3%+E presented a non statistically significant trend to an earlier improvement, (P=0.063 and P=0.096 repectively). No adverse events occurred. Four patients (two from each group) required transfer to the pediatric intensive care unit. With a third of the final estimated sample, we find a trend to an earlier clinical recovery in the epinephrine group, even though no statistical significant differences in LOS were found. The study needs to be continued until the total sample is recruited.


Fluid dynamics of a pediatric ventricular assist device.
The number of pediatric patients requiring some form of mechanical circulatory assistance is growing throughout the world because of new surgical procedures and the success of pediatric cardiac transplantation. However, the salvage rate for those patients requiring circulatory support may be as low as 25%. Despite the fact that Penn State's 70 cc pneumatic ventricular assist device has been used with a success rate of over 90% in more than 250 patients worldwide, efforts to scale down the pump have encountered difficulties. Animal experiments with a 15 cc version were unsuccessful, with explanted pumps showing extensive thrombus deposition within the pumping chamber. The materials used to fabricate the smaller pump as well as the basic operating principles are identical to the successful adult-sized version. It is therefore believed that reducing the size of the pump altered the internal flow field, and that fluid dynamic factors were responsible for the high degree of thrombus observed with the implanted devices. A dimensional analysis was conducted that revealed significant differences in both Reynolds (Re) and Strouhal (St) numbers between the successful and unsuccessful pumps. Two component laser Doppler velocimetry was then used to characterize the internal flow field quantitatively. Comparison with data from the 70 cc pump showed a reduction in wall shear stress and turbulence levels in the 15 cc pump that would yield an environment conducive to clot formation.


A Multiscale Model for Solute Diffusion in Hydrogels.
The number of biomedical applications of hydrogels is increasing rapidly on account of their unique physical, structural, and mechanical properties. The utility of hydrogels as drug delivery systems or tissue engineering scaffolds critically depends on the control of diffusion of solutes through the hydrogel matrix. Predicting or even modeling this diffusion is challenging due to the complex structure of hydrogels. Currently, the diffusivity of solutes in hydrogels is typically modeled by one of three main theories proceeding from distinct diffusion mechanisms: (i) hydrodynamic, (ii) free volume, and (iii) obstruction theory. Yet, a comprehensive predictive model is lacking. Thus, time and capital-intensive trial-and-error procedures are used to test the viability of hydrogel applications. In this work, we have developed a model for the diffusivity of solutes in hydrogels combining the three main theoretical frameworks, which we call the multiscale diffusion model (MSDM). We verified the MSDM by analyzing the diffusivity of dextran of different sizes in a series of poly(ethylene glycol) (PEG) hydrogels with distinct mesh sizes. We measured the subnanoscopic free volume by positron annihilation lifetime spectroscopy (PALS) to characterize the physical hierarchy of these materials. In addition, we performed a meta-analysis of literature data from previous studies on the diffusion of solutes in hydrogels. The model presented outperforms traditional models in predicting solute diffusivity in hydrogels and provides a practical approach to predicting the transport properties of solutes such as drugs through hydrogels used in many biomedical applications.


[The theoretical analysis of Fick's equation. On the centennial of the use of Fick's principle in physiology].
In the first section Adolf Fick's outstanding scientific performances are pointed out in their historical sequence, particularly the derivation of the laws of diffusion (1855) and the basic equation for determining the heart-minute-volume (Fm) by O2-absorption per time (V02) and arteriovenous O2-difference (AVD), known as Fick's Principle. The latter was derived theoretically in 1870 by Fick, but it found it practical employment by other investigators, in dog not before 1886 and in man not earlier than 1930. In the following two sections the universality of Fick's Principle is shown by explaining its internal relation 1. to Fick's first law of diffusion and 2. to the general law of solution. This is done by mathematical transformation of the relations (formulas)of the physical resp. the physiological standards (parameters). By analyzing the diffusion of a substance into a streaming fluid according to the first diffusion law, perfectly isomorphic equations to Fick's Principle (No. 7 and No. 9) are obtained by what Fick's formula as a determinant of the heart-minute-volume is just proved to be derivable from Fick's first diffusion law. Furthermore by transforming the trivial formula for the determination of substance concentration in a fluid provement is given, that Fick's Principle may be considered a variant of the solution theory. By this the internal relation of the so-called dilution respectively indicating methods depending on the Stewart-Hamilton-Principle to the original Fick's Principle is made visible. In the last section an attempt is made to produce a relation to 1. the so-called physical methods determining the minute volume which primarily are known as a measurement for stroke volume and frequency, and, besides that, 2. to Vierordt's equation, by which the heart-minute-volume is determinable from circulating blood volume and circulation time. This trial is made by equating the value of the minute volume given by Fick's Principle (VO2/AVD) with the product from stroke volume and beating frequency, and on the other hand by equating it with the quotient from circulating blood volume Qc and complete circulation time Tc (Qc/Tc). Finally, physiological arguments are derived from these relations, allowing an evaluation of the relative proportions in circulation adaption during muscular work of the magnitudes of changes in stroke volume, beating frequencies, or the O2-pulse.


Prophylactic mastectomy and reconstruction: clinical outcomes and patient satisfaction.
The purpose of this study was to evaluate both clinical outcomes and satisfaction in patients who have undergone prophylactic mastectomy and breast reconstruction. A 5-year retrospective analysis of the senior author's (S.L.S.) experience with breast reconstruction following prophylactic mastectomy was performed. Timing, type of mastectomy and reconstruction, complications, and cancer occurrence/recurrence were examined. Patients reported their level of satisfaction and willingness to undergo the procedure again. Aesthetic outcomes were graded by an independent and blinded group of surgeons. There were 101 breast reconstructions performed in 74 patients following prophylactic mastectomy. With a mean follow-up of 31 months, there were three breast-site complications in this group (3 percent). Forty-seven patients in the study had a unilateral prophylactic mastectomy; on the contralateral side with cancer, there were five breast-site complications in reconstructions following therapeutic mastectomy (10 percent). Aesthetic outcome ratings by surgeons were higher in the bilateral prophylactic mastectomy and reconstruction patients compared with the cancer patients who had undergone a therapeutic mastectomy and reconstruction along with a contralateral prophylactic mastectomy; however, this difference did not reach statistical significance. Patient satisfaction was higher in the bilateral prophylactic group, with all of the patients completing the survey stating they would undergo the procedure again. Breast reconstruction following prophylactic mastectomy was as safe as or more safe than that following therapeutic mastectomy, which has been shown in other studies to result in a high percentage of patient satisfaction. Although not statistically significant, the results from reconstruction after prophylactic mastectomy trended toward improved aesthetic outcome with a lower complication rate compared with reconstruction after therapeutic mastectomy.


Anomeric effect, hyperconjugation and electrostatics: lessons from complexity in a classic stereoelectronic phenomenon.
Understanding the interplay of multiple components (steric, electrostatic, stereoelectronic, dispersive, etc.) that define the overall energy, structure, and reactivity of organic molecules can be a daunting task. The task becomes even more difficult when multiple approaches based on different physical premises disagree in their analysis of a multicomponent molecular system. Herein, we will use a classic conformational "oddity", the anomeric effect, to discuss the value of identifying the key contributors to reactivity that can guide chemical predictions. After providing the background related to the relevant types of hyperconjugation and a brief historic outline of the origins of the anomeric effect, we outline variations of its patterns and provide illustrative examples for the role of the anomeric effect in structure, stability, and spectroscopic properties. We show that the complete hyperconjugative model remains superior in explaining the interplay between structure and reactivity. We will use recent controversies regarding the origin of the anomeric effect to start a deeper discussion relevant to any electronic effect. Why are such questions inherently controversial? How to describe a complex quantum system using a model that is "as simple as possible, but no simpler"? What is a fair test for such a model? Perhaps, instead of asking "who is right and who is wrong?" one should ask "why do we disagree?". Stereoelectronic thinking can reconcile quantum complexity with chemical intuition and build the conceptual bridge between structure and reactivity. Even when many factors contribute to the observed structural and conformational trends, electron delocalization is a dominating force when the electronic demand is high (i.e., bonds are breaking as molecules distort from their equilibrium geometries). In these situations, the role of orbital interactions increases to the extent where they can define reactivity. For example, negative hyperconjugation can unleash the "underutilized" stereoelectronic power of unshared electrons (i.e., the lone pairs) to stabilize a developing positive charge at an anomeric carbon. This analysis paves the way for the broader discussion of the omnipresent importance of negative hyperconjugation in oxygen-containing functional groups. From that point of view, the stereoelectronic component of the anomeric effect plays a unique role in guiding reaction design.


Plasma protein carbonylation in chronic uremia.
Carbonylation is an irreversible modification caused by the introduction into proteins of carbonyl derivatives (aldehydes and ketones), which can alter protein structure and function and lead to cellular dysfunction and tissue damage. Chronic uremia may be associated with an increased carbonyl overload ("carbonyl stress"), though carbonyl formation has been proposed so far for major plasma proteins only. In this study we looked for evidence and for the targets of plasma protein carbonylation in patients on hemodialysis. We also examined the effect of in vitro carbonylated albumin on mRNA levels of endothelial cell adhesion molecules involved in early atherogenesis. Carbonylated proteins in uremic plasma were detected by a covalent hydrazine bait strategy and identified by combining electrophoretic separation with mass spectrometry analysis of tryptic digests. Some plasma samples were first depleted of albumin and immunoglobulins to improve detection of lower abundance proteins. The functional impact of carbonylation was assessed in human vein endothelial cells by studying models of modified human serum albumin. Post-dialysis plasma carbonylated protein levels were significantly increased compared to pre-dialysis levels. Susceptibility to carbonyl formation was described on a open-platform investigation for a number of plasma proteins, albumin being the main scavenger of carbonyl reactive species. Incubation of endothelial cells with low doses of carbonylated albumin caused a significant increase in intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 mRNA levels. Chronic uremia appears as a state of "carbonyl stress" targeting several different plasma proteins. Carbonylated albumin displayed biological effects that may be relevant to uremic atherosclerosis.


The role of carbohydrate in the antigenic and immunogenic structure of bovine herpesvirus type 1 glycoproteins gI and gIV.
The role of carbohydrate in the antigenic and immunogenic structure of bovine herpesvirus type 1 (BHV-1) glycoproteins gI and gIV was investigated. Deglycosylated proteins induced a significantly lower antibody response in rabbits than native glycoproteins suggesting that the immunogenicity of several epitopes on gI and gIV is carbohydrate-dependent. Loss of carbohydrate from gI also resulted in a significantly decreased ability to induce a serum neutralizing antibody response to BHV-1, due to modifications in three distinct carbohydrate-containing continuous epitopes. Similarly, in vitro lysis of BHV-1-infected cells was significantly reduced when antibodies raised against deglycosylated gI were employed; this was attributed to changes in two of the three carbohydrate-dependent neutralizing epitopes on gI. The oligosaccharides may be directly involved as actual components of these continuous epitopes, rather than in stabilization of the conformation of the protein. In contrast, carbohydrate removal from gIV did not have a significant effect on the capacity to stimulate a neutralizing antibody response. Accordingly, none of the neutralizing epitopes on gIV appeared to be carbohydrate-dependent. Similarly, lysis of virus-infected cells was not significantly reduced when antibodies specific for deglycosylated rather than native gIV were used. In contrast to the humoral response, the delayed-type hypersensitivity response was stronger in rabbits immunized with deglycosylated proteins than in those inoculated with native glycoproteins gI or gIV. Consequently, the carbohydrates on gI and gIV may play a dual role in the host's immune recognition and response by contributing to certain epitopes, but masking others. The implications for the development of a subunit vaccine against BHV-1 are discussed.


The influence of cognitive tasks on vestibular-induced eye movements in young and older adults.
The purpose of this study was to further investigate the mechanism of the influence of concurrent cognitive tasks on eye movements induced by earth-vertical axis rotation (EVAR) in young and older participants. Ten young (ages 21-34), ten young-old (ages 65-74) and nine older participants (ages 75-84) each performed five different cognitive tasks during sinusoidal EVAR in darkness at 0.02 Hz for three cycles, 0.05 Hz for four cycles, and 0.1 Hz for five cycles, all at a peak velocity of 50 degrees per second. The five tasks differed from one another in terms of their inherent sensory and motor components and were designed to provide insight into the effect of cognitive processing on VOR dynamics. Tasks included auditory frequency and lateralization disjunctive reaction time (DRT) tasks, silent and audible backward counting, and a question-response clinical standard task. For the DRT trials, tones were presented to the participant through earphones. Participants were instructed to respond as accurately and as quickly as possible. Eye movements were recorded with electro-oculography and calibrations were performed before and after every five rotations in all subjects. Participants had an increase in VOR phase lead while performing DRT tasks as compared to the clinical standard and counting tasks. The effect was most noticeable at the 0.02 Hz frequency and was present in all age groups. In addition, we observed a decrease in VOR gain while subjects performed auditory DRT tasks during EVAR at 0.02 Hz, 0.05 Hz and 0.1 Hz as compared to the clinical standard and counting tasks. These results suggest cognitive task-dependent interference between central auditory processing and vestibular processing primarily at the sensory rather than at the motor level.


Minor neurological dysfunction and behaviour in 9-year-old children born at term: evidence for sex dimorphism.
The aim of the study was to assess associations between minor neurological dysfunction (MND) and behaviour, with specific attention to sex differences. This was an observational cohort study in which 341 9-year-old children (177 male, 164 female) without perinatal risk were neurologically assessed, with attention to severity and type of MND. Eight domains of dysfunction were distinguished, including posture and muscle tone, fine manipulative ability and coordination. Severity of MND was based on the number of dysfunctional domains. Behaviour was assessed by parents and teachers using the Child Behavior Checklist and Teacher's Report Form (TRF); outcomes were internalizing and externalizing behaviour and total score of behavioural problems. Females with complex MND or dysfunctional posture and muscle tone had increased risk for externalizing behavioural problems (OR 4.52, 95% CI 1.01-20.2, and OR 4.05, 95% CI 1.06-15.5, respectively). In males, these associations were absent. However, males with simple MND had an increased risk for behavioural problems indicated by the total TRF-score (OR 7.52, 95% CI 1.36-41.4). In children without perinatal risk, associations between MND and behaviour are sex-specific. In females, dysfunction of complex neural networks, including the cerebellum, is associated with externalizing behaviour. In males, neurobehavioural relationships are limited, suggesting a larger role of psychosocial factors in the genesis of behavioural problems.


Ecotoxicological profiling of selected cyanobacterial strains using multi-endpoint effect-directed analysis.
The main goal of this study was to perform an ecotoxicological profiling of terrestrial and aquatic cyanobacterial strains found in different soils or in toxic cyanobacterial blooms in Vojvodina region, Serbia, using the effect-directed analysis (EDA) approach. The applied procedure was based on a series of in vitro or small-scale bioassays covering multiple endpoints in combination with advanced chemical analytical protocols. Non-selective and non-target preparation techniques were used for the extraction of a broad range of chemical compounds present in three terrestrial (Anabaena Č2, Anabaena Č5, Nostoc S8) and three aquatic (Nostoc Z1, Phormidium Z2, Oscillatoria K3) strains. Ecotoxicological endpoints addressed included evaluation of the fish cytotoxicity in vitro (acute toxicity), algal growth inhibition (chronic toxicity), and interaction with cellular detoxification mechanisms. All cyanobacterial strains tested in the 1st tier EDA showed significant effects in terms of chronic toxicity and interaction with cellular detoxification. Three major fractions of different polarities were further tested in the 2nd tier, using bioassays which showed the strongest response: induction of CYP1A1 biotransformation enzyme and inhibition of zebrafish organic anion (Oatp1d1) and cation (Oct1) uptake transporters. Oscillatoria K3 strain was selected for a more detailed 3rd tier EDA, and the obtained results revealed that positive sub-fractions possess polar anion and cation compounds that are reactive to both uptake transporters, and compounds responsible for the strongest effects have a pronounced lipophilic character. Apart from lipophilic non-polar compounds that represent typical phase I substrates, sub-fractions that contained polar substances are also shown to significantly induce CYP1A1.


SAG-UPS attenuates proapoptotic SARM and Noxa to confer survival advantage to early hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a deadly cancer because of its commonly late diagnosis and limited treatment options. SAG (sensitive to apoptosis gene)-dependent UPS (ubiquitin-proteasome system) is a key switch between immune-mediated apoptosis and overactivation-mediated protumorigenesis, prompting us to hypothesize that SAG-UPS modulates chronic inflammation-induced tumorigenesis. Here, we investigated the molecular mechanism by which SAG-UPS regulates death/survival of liver cancer cells. By retrospective studies, we found reciprocal expressions of anti-/proapoptotic factors: SAG/SARM and SAG/Noxa in human primary HCC tissues - the antiapoptotic SAG was significantly upregulated whereas the proapoptotic SARM and Noxa were markedly downregulated, suggesting their involvement in hepatocarcinogenesis. Upregulated SAG-UPS effectively manipulates the levels of high-molecular-weight ubiquitinated SARM and Noxa in carcinoma tissues compared with corresponding normal tissues. SAG-overexpressing HCC cell lines display reduced SARM and Noxa (but not Bcl-2, Bax and Bcl-xL), suggesting that SARM and Noxa are specific substrates of SAG-dependent ubiquitination. SARM overexpression activated caspase-3 and caspase-9, reducing cell viability. SAG knockdown significantly elevated apoptosis with increased cytosolic cytochrome c, confirming SAG-mediated antiapoptosis in HCC. SAG overexpression stimulated protumorigenic cytokines, IL-1β, IL-6 and TNF, but not antitumorigenic IL-12p40 and anti-inflammatory IL-10. This is consistent with higher proinflammatory cytokines (IL-1β, IL-6 and TNF) in hepatoma compared with healthy tissues. Altogether, early stage-upregulated SAG-UPS exacerbates hepatocarcinogenesis progression, through: (1) ubiquitination-mediated degradation of proapoptotic SARM and Noxa; and (2) production of protumorigenic cytokines that induce a protumorigenic microenvironment, conferring survival advantage to HCC cells. Thus, we propose SAG-UPS to be an early diagnostic marker for HCC, and a potential target for therapeutics development.


Voiding patterns in patients with post-prostatectomy incontinence: urodynamic and demographic analysis.
A significant percentage of patients with post-prostatectomy incontinence have been reported to void by Valsalva's maneuver, which is our observation as well. We determine the mechanism of voiding in patients with post-prostatectomy incontinence and correlate this to demographic data, urodynamic parameters and outcome after artificial urinary sphincter implantation, and identify possible risk factors. Videourodynamic data from 61 consecutive patients with post-prostatectomy incontinence were reviewed to determine voiding patterns. The causes of incontinence were radical prostatectomy in 58 patients and transurethral resection of the prostate followed by radiation therapy in 3. The relationship between voiding patterns and demographic data (age, diabetes mellitus, degree and duration of incontinence, history of radiation therapy or treated bladder neck contracture) as well as urodynamic parameters (bladder capacity, compliance, instability, sensation, leak point pressure and residual urine) were studied. After artificial urinary sphincter implantation outcome was assessed in relation to the voiding patterns. Stress incontinence was present in all patients while concomitant urgency/urge incontinence was present in 48%. Of the patients 43 (70.5%) voided by detrusor contraction (group 1) while the remaining 18 (29.5%) voided by straining (group 2). Mean patient age +/- SD was 70.8 +/- 6.9 and 69.2 +/- 7.2 years, and duration of incontinence was 48 +/- 33 and 46 +/- 30 months in groups 1 and 2, respectively (p >0.05). Also, no significant differences were found between the groups with regard to other demographic data. Delayed first sensation (at volume greater than 140 ml.) was seen in 42.5% and 29.4%, capacity less than 300 ml. in 41.9% and 39%, impaired/poor compliance in 25.6% and 22.2%, bladder instability in 16.3% and 5.6%, abdominal leak point pressure 60 cm. H(2)O or less in 59.4% and 60% and residual urine greater than 50 ml. in 11.6% and 17.6% in groups 1 and 2, respectively (p >0.05). After artificial urinary sphincter implantation 35% and 22.2% of patients used greater than 1 pad a day in groups 1 and 2, respectively. One patient in each group reported difficulty during urination and both patients had no residual urine. No identifiable demographic or urodynamic risk factors could be detected in association with the strain pattern of voiding in patients with post-prostatectomy incontinence. The absence of a difference in bladder compliance, residual urine volume and outcome after artificial urinary sphincter implantation between detrusor and strain voiders would suggest no increased risk for complications in the strain voiding group.


In vitro demonstration of anaerobic oxidation of methane coupled to sulphate reduction in sediment from a marine gas hydrate area.
Anaerobic oxidation of methane (AOM) and sulphate reduction were examined in sediment samples from a marine gas hydrate area (Hydrate Ridge, NE Pacific). The sediment contained high numbers of microbial consortia consisting of organisms that affiliate with methanogenic archaea and with sulphate-reducing bacteria. Sediment samples incubated under strictly anoxic conditions in defined mineral medium (salinity as in seawater) produced sulphide from sulphate if methane was added as the sole organic substrate. No sulphide production occurred in control experiments without methane. Methane-dependent sulphide production was fastest between 4 degree C and 16 degree C, the average rate with 0.1 MPa (approximately 1 atm) methane being 2.5 micro mol sulphide day(-1) and (g dry mass sediment)(-1). An increase of the methane pressure to 1.1 MPa (approximately 11 atm) resulted in a four to fivefold increase of the sulphide production rate. Quantitative measurements using a special anoxic incubation device without gas phase revealed continuous consumption of dissolved methane (from initially 3.2 to 0.7 mM) with simultaneous production of sulphide at a molar ratio of nearly 1:1. To test the response of the indigenous community to possible intermediates of AOM, molecular hydrogen, formate, acetate or methanol were added in the absence of methane; however, sulphide production from sulphate with any of these compounds was much slower than with methane. In the presence of methane, such additions neither stimulated nor inhibited sulphate reduction. Hence, the experiments did not provide evidence for one of these compounds acting as a free extracellular intermediate (intercellular shuttle) during AOM by the presently investigated consortia.


Kolmogorov's spline network.
In this paper, an innovative neural-network architecture is proposed and elucidated. This architecture, based on the Kolmogorov's superposition theorem (1957) and called the Kolmogorov's spline network (KSN), utilizes more degrees of adaptation to data than currently used neural-network architectures (NNAs). By using cubic spline technique of approximation, both for activation and internal functions, more efficient approximation of multivariate functions can be achieved. The bound on approximation error and number of adjustable parameters, derived in this paper, favorably compares KSN with other one-hidden layer feedforward NNAs. The training of KSN, using the ensemble approach and the ensemble multinet, is described. A new explicit algorithm for constructing cubic splines is presented.


Sex difference in insulin-stimulated glucose transport in rat and human adipocytes.
In an effort to determine whether differences in basal and maximum insulin-stimulated glucose transport by isolated adipocytes are a function of donor sex, we measured glucose transport rates in the absence and presence of 8 nM insulin in adipocytes isolated from the abdominal subcutaneous fat tissue of nine male and ten female subjects with varying degrees of obesity and in adipocytes isolated from the abdominal subcutaneous and retroperitoneal fat tissue of (180-220 g) male and female rats. Because maximal insulin-stimulated glucose transport rate per cell of adipocytes isolated from subcutaneous abdominal tissue of male and female subjects was constant in each sex, the data have been normalized on the basis of transport per cell. The results demonstrated that basal and maximal insulin-stimulated glucose transport per cell was 53-75% higher per cell in the females versus males in adipocytes from human subcutaneous abdominal adipose tissue (P less than 0.01). A similar difference in glucose transport rate between males and females (P less than 0.001) was also found in rat abdominal subcutaneous adipose tissue. Adipocytes isolated from rat retroperitoneal adipose tissue had higher transport rates (approximately three-fold) and smaller sex differences (35% higher in females) than found in adipocytes from rat and human subcutaneous tissue. These results indicate that basal and maximum insulin-stimulated glucose transport is higher by adipocytes isolated from females and that this difference is independent of adipose cell size and species.


The Search for Herbal Antibiotics: An In-Silico Investigation of Antibacterial Phytochemicals.
Recently, the emergence and spread of pathogenic bacterial resistance to many antibiotics (multidrug-resistant strains) have been increasing throughout the world. This phenomenon is of great concern and there is a need to find alternative chemotherapeutic agents to combat these antibiotic-resistant microorganisms. Higher plants may serve as a resource for new antimicrobials to replace or augment current therapeutic options. In this work, we have carried out a molecular docking study of a total of 561 antibacterial phytochemicals listed in the Dictionary of Natural Products, including 77 alkaloids (17 indole alkaloids, 27 isoquinoline alkaloids, 4 steroidal alkaloids, and 28 miscellaneous alkaloids), 99 terpenoids (5 monoterpenoids, 31 sesquiterpenoids, 52 diterpenoids, and 11 triterpenoids), 309 polyphenolics (87 flavonoids, 25 chalcones, 41 isoflavonoids, 5 neoflavonoids, 12 pterocarpans, 10 chromones, 7 condensed tannins, 11 coumarins, 30 stilbenoids, 2 lignans, 5 phenylpropanoids, 13 xanthones, 5 hydrolyzable tannins, and 56 miscellaneous phenolics), 30 quinones, and 46 miscellaneous phytochemicals, with six bacterial protein targets (peptide deformylase, DNA gyrase/topoisomerase IV, UDP-galactose mutase, protein tyrosine phosphatase, cytochrome P450 CYP121, and NAD⁺-dependent DNA ligase). In addition, 35 known inhibitors were docked with their respective targets for comparison purposes. Prenylated polyphenolics showed the best docking profiles, while terpenoids had the poorest. The most susceptible protein targets were peptide deformylases and NAD⁺-dependent DNA ligases.


Camptothecin and its analog SN-38, the active metabolite of irinotecan, inhibit binding of the transcriptional regulator and oncoprotein FUBP1 to its DNA target sequence FUSE.
The transcriptional regulator FUSE Binding Protein 1 (FUBP1) is overexpressed in more than 80% of all human hepatocellular carcinomas (HCCs) and other solid tumor entities including prostate and colorectal carcinoma. FUBP1 expression is required for HCC tumor cell expansion, and it functions as an important pro-proliferative and anti-apoptotic oncoprotein that binds to the single-stranded DNA sequence FUSE to regulate the transcription of a variety of target genes. In this study, we screened an FDA-approved drug library and discovered that the Topoisomerase I (TOP1) inhibitor camptothecin (CPT) and its derivative 7-ethyl-10-hydroxycamptothecin (SN-38), the active irinotecan metabolite that is used in the clinics in combination with other chemotherapeutics to treat carcinoma, inhibit FUBP1 activity. Both molecules prevent in vitro the binding of FUBP1 to its single-stranded target DNA FUSE, and they induce deregulation of FUBP1 target genes in HCC cells. Our results suggest the interference with the FUBP1/FUSE interaction as a further molecular mechanism that, in addition to the inactivation of TOP1, may contribute to the therapeutic potential of CPT/SN-38. Targeting of FUBP1 in HCC therapy with SN-38/irinotecan could be a particularly interesting option because of the high FUBP1 levels in HCC cells and their dependency on FUBP1 expression.


PBA Preferentially Impairs Cell Survival of Glioblastomas Carrying mutp53 by Reducing Its Expression Level, Stabilizing wtp53, Downregulating the Mevalonate Kinase and Dysregulating UPR.
Phenylbutyrate (PBA) is a derivative of Butyric Acid (BA), which has the characteristics of being a histone deacetylase (HDAC) inhibitor and acting as a chemical chaperone. It has the potential to counteract a variety of different diseases, from neurodegeneration to cancer. In this study, we investigated the cytotoxic effect of PBA against glioblastoma cells carrying wt or mutant (mut) p53 and found that it exerted a higher cytotoxic effect against the latter in comparison with the former. This could be due to the downregulation of mutp53, to whose pro-survival effects cancer cells become addicted. In correlation with mutp53 reduction and wtp53 activation, PBA downregulated the expression level of mevalonate kinase (MVK), a key kinase of the mevalonate pathway strongly involved in cancer cell survival. Here we differentiated the chaperoning function of PBA from the others anti-cancer potentiality by comparing its effects to those exerted by NaB, another HDACi that derives from BA but, lacking the phenyl group, cannot act as a chemical chaperone. Interestingly, we observed that PBA induced a stronger cytotoxic effect compared to NaB against U373 cells as it skewed the Unfolded Protein Response (UPR) towards cell death induction, upregulating CHOP and downregulating BIP, and was more efficient in downregulating MVK. The findings of this study suggest that PBA represents a promising molecule against glioblastomas, especially those carrying mutp53, and its use, approved by FDA for urea cycle disorders, should be extended to the glioblastoma anticancer therapy.


Training nonspecialists in clinical evaluation for telepsychiatry using videoconferencing: A feasibility and effectiveness study.
Videoconferencing-based telepsychiatry has been used successfully for the assessment and management of psychiatric disorders. However, training mental health professionals through videoconferencing has seldom been attempted. Online decision support systems for diagnosing psychiatric disorders had been developed earlier at the Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, as a part of a project for delivering telepsychiatric services to remote areas. The feasibility of videoconferencing for training nonspecialist staff in the use of the online tool to diagnose psychiatric disorders was examined. The effectiveness of training was evaluated using ratings of diagnostic agreement between trainees and trainers and estimations of training costs. The Skype platform was used for videoconferences (VCs). Broadband internet connections had bandwidths of 4 mbps and speeds of 512 kbps. A total of 62 training sessions were conducted by the PGIMER team for remote-site teams using role-play techniques and actual patient interviews. Videoconferencing-based training was considered to be convenient, satisfactory, and useful by all the participants. Diagnostic agreement between trainees and trainers was 89%-100%. Such training also appeared to be cost-effective. The main problems encountered were poor connectivity and poor audiovisual quality of the VCs. Videoconferencing can be feasible and effective for training nonspecialists to diagnose psychiatric disorders.


Venous leg ulcers - the search for a prognostic indicator.
Disordered cell function within chronic wounds generates many parameters that can be measured to differentiate between healing and non healing status. Theoretically, these may form the basis of a wound assessment system to define disease severity and response to treatment. In a review of tissue, wound exudate and microbiology studies of venous leg ulcers, we identify many such parameters that are associated with healing status. These include cytokines, proteases and their inhibitors, senescence markers, oxidative stress markers and microbiological status defined by culture. Some of these, such as protease level in wound exudate, have been proposed as prognostic indicators of healing status and many more could be considered potential markers to incorporate into a wound assessment system. However, no published data are available that validate known wound components to accurately reflect wound progression on a single patient basis. Rather than further characterisation of the expression of known wound biomarkers, the development of an accurate and objective test for prediction of chronic wound outcome requires identification of an appropriate combination of novel molecules that vary coordinately with healing status.


Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen.
The androgen receptor (AR) is highly expressed in androgen-dependent and recurrent prostate cancer (CaP) suggesting it has a role in the growth and progression of CaP. Previously proposed mechanisms for AR reactivation in recurrent CaP include altered growth factor signaling leading to protein phosphorylation and AR mutations that broaden ligand specificity. To further establish a role for AR in recurrent CaP, we compared several properties of AR in relation to the growth response to low levels of androgens in model systems of androgen-dependent and recurrent CaP. AR from all of the tumors and cell lines bound [3H]R1881 with similar high affinity (mean Kd, 0.12 nM). In the absence of androgen, AR in androgen-dependent LNCaP cells was unstable with a degradation half-time (t(1/2)) of 3 h at 37 degrees C. In contrast, AR was 2-4 times more stable in recurrent CWR22 tumors (t(1/2), >12 h) and CWR-R1 or LNCaP-C4-2 cell lines (t(1/2), 6-7 h) derived from recurrent prostate tumors. In the recurrent CWR22 tumor and its CWR-R1 cell line grown in the absence of androgen, AR immunostaining was entirely nuclear, whereas under the same conditions AR in LNCaP-C4-2 and LNCaP cells was predominantly nuclear but was also detected in the cytoplasm. High level expression, increased stability, and nuclear localization of AR in recurrent tumor cells were associated with an increased sensitivity to the growth-promoting effects of dihydrotestosterone in the femtomolar range. The concentration of dihydrotestosterone required for growth stimulation in CWR-R1 and LNCaP-C4-2 cells was four orders of magnitude lower than that required for androgen-dependent LNCaP cells. The results suggest that AR is transcriptionally active in recurrent CaP and can increase cell proliferation at the low circulating levels of androgen reported in castrated men.


Assisting upon entry: Helping type and approach as moderators of how role conflict affects newcomer resource drain.
We extend recent research on the costs and benefits of helping to help providers by asking whether and under what conditions newcomer help giving may amplify or mitigate the role-conflict-based resource drain such individuals may experience in the context of their initial socialization. Drawing from conservation of resources (COR) theory, we propose that whether providing assistance to peers enhances or weakens newcomer help providers' resilience to such conflict-based resource drain (i.e., exhaustion) depends on both the type of help given (instrumental vs. emotional) and the orientation (more vs. less empowering) that newcomers adopt when providing it. We test our propositions on the basis of time-lagged data collected from newly hired call center representatives at the end of their first and sixth months on the job. Results largely support our predictions, with instrumental assistance mitigating, and emotional assistance exacerbating, the role-conflict-based resource drain experienced by newcomer help providers. Moreover, these amplifying effects of emotional help provision on the conflict-exhaustion relationship are largely eliminated among those newcomer help providers reporting a more empowering approach to help provision. (PsycINFO Database Record


The development and piloting of a patient held record with adult mental health users.
This article reports on the development and piloting of a patient held record for adult mental health users. Development of the format and content of the record was determined in consultation with a user group. Piloting and subsequent evaluation of the record with users revealed a number of issues which need to be addressed in the promotion of a patient held record.


Facile synthesis of β-Ga2O3 based high-performance electronic devices via direct oxidation of solution-processed transition metal dichalcogenides.
Gallium oxide (Ga2O3) is a promising wide bandgap semiconductor that is viewed as a contender for the next generation of high-power electronics due to its high theoretical breakdown electric field and large Baliga's figure of merit. Here, we report a facile route of synthesizing β-Ga2O3via direct oxidation conversion using solution-processed two-dimensional (2D) GaS semiconducting nanomaterial. Higher order of crystallinity in X-ray diffraction (XRD) patterns and full surface coverage formation in scanning electron microscopy (SEM) images after annealing were achieved. A direct and wide bandgap of 5 eV was calculated, and the synthesized β-Ga2O3was fabricated as thin film transistors (TFT). The β-Ga2O3TFT fabricated exhibits remarkable electron mobility (1.28 cm2/Vs) and a good current ratio (Ion/Ioff) of 2.06×105. To further boost the electrical performance and solve the structural imperfections resulting from the exfoliation process of the 2D nanoflakes, we also introduced and doped graphene in β-Ga2O3TFT devices, increasing the electrical device mobility by ~8-fold and thereby promoting percolation pathways for the charge transport. We found that electron mobility and conductivity increase directly with the graphene doping concentration. From these results, it can be proved that the β-Ga2O3networks have excellent carrier transport properties. The facile and convenient synthesis method successfully developed in this paper makes an outstanding contribution to applying 2D oxide materials in different and emerging optoelectronic applications.


Can the Mixed Virtual Reality Simulator Into D'mentia Enhance Empathy and Understanding and Decrease Burden in Informal Dementia Caregivers?
To evaluate whether the mixed virtual reality dementia simulator training Into D'mentia increased informal caregivers' understanding for people with dementia, their empathy, sense of competence, relationship quality with the care receiver, and/or decreased burden, depression, and anxiety. A quasi-experimental longitudinal study with an intervention group (n = 145) and a control group (n = 56) was conducted. All participants were informal caregivers of people with dementia. They completed six questionnaires and semi-structured interviews 1 week before as well as 1 week, 2.5 months, and 15 months after the training. Data were analyzed on both group and individual level using linear mixed model analyses and Reliable Change Indices. Eighty-five percent of the participants in the intervention group found the intervention useful; 76% said they had changed their approach to caregiving, and 61% stressed that the intervention had increased their understanding of dementia. No significant differences were found between the two groups over time regarding empathy, sense of competence, relationship quality with the care receiver, burden, depression, and anxiety, at either group or individual level. Caregivers indicated that the Into D'mentia intervention improved their understanding of dementia, that they had learned to be more patient, to take things more slowly, and to focus on positive aspects of caregiving. However, no significant change was found on the variables assessed via the questionnaires. Future research can consider enriching this intervention with other aspects such as more educational material, more simulations, and group sessions, tailored to the individual caregiver and his/her situation, and examine whether these new interventions yield change on questionnaires. These new, more personalized interventions for dementia caregivers could help caregivers to better understand the persons with dementia they care for and to ultimately enhance the well-being of both caregivers and persons with dementia.


Coordinated rates of evolution between interacting plastid and nuclear genes in Geraniaceae.
Although gene coevolution has been widely observed within individuals and between different organisms, rarely has this phenomenon been investigated within a phylogenetic framework. The Geraniaceae is an attractive system in which to study plastid-nuclear genome coevolution due to the highly elevated evolutionary rates in plastid genomes. In plants, the plastid-encoded RNA polymerase (PEP) is a protein complex composed of subunits encoded by both plastid (rpoA, rpoB, rpoC1, and rpoC2) and nuclear genes (sig1-6). We used transcriptome and genomic data for 27 species of Geraniales in a systematic evaluation of coevolution between genes encoding subunits of the PEP holoenzyme. We detected strong correlations of dN (nonsynonymous substitutions) but not dS (synonymous substitutions) within rpoB/sig1 and rpoC2/sig2, but not for other plastid/nuclear gene pairs, and identified the correlation of dN/dS ratio between rpoB/C1/C2 and sig1/5/6, rpoC1/C2 and sig2, and rpoB/C2 and sig3 genes. Correlated rates between interacting plastid and nuclear sequences across the Geraniales could result from plastid-nuclear genome coevolution. Analyses of coevolved amino acid positions suggest that structurally mediated coevolution is not the major driver of plastid-nuclear coevolution. The detection of strong correlation of evolutionary rates between SIG and RNAP genes suggests a plausible explanation for plastome-genome incompatibility in Geraniaceae.


A Case of Fetal Familial Hemophagocytic Lymphohistiocytosis Type 5 caused by STXBP2 Gene Mutation.
Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is a rare hyper-inflammatory syndrome caused by mutations in STXBP2. Most cases present at 2 - 6 months of age, and FHL-5 is extremely rare in neonates. Appropriate laboratory tests, abdominal ultrasonography and whole exome sequencing were carried out. Respiratory support, antibiotics, and transfusion of blood products were done. Laboratory tests revealed metabolic acidosis, thrombocytopenia, mild anemia, and low fibrinogen level. Blood culture, metagenomics, and TORCH screening were negative. Liver and spleen enlargements were confirmed by abdominal ultrasonography. Whole exome sequencing identified a homozygous mutation in STXBP2 c. 1432del G (p. V478Sfs*5). The heterozygous STXBP2 mutation was identified in the paternal grandfather, maternal grandfather, and parents. Here we report a case with a novel homozygous deletion in exon 16 of STXBP2, which caused the earliest reported case of FHL-5 in a neonate. Our results identify a new pathogenic variant for the early identification and clinical consultation of FHL-5.


Endogenous Extracellular Vesicles Participate in Brain Remodeling after Ischemic Stroke.
Brain remodeling after an ischemic stroke represents a promising avenue for exploring the cellular mechanisms of endogenous brain repair. A deeper understanding of these mechanisms is crucial for optimizing the safety and efficacy of neuroprotective treatments for stroke patients. Here, we interrogated the role of extracellular vesicles, particularly exosomes, as potential mediators of endogenous repair within the neurovascular unit (NVU). We hypothesized that these extracellular vesicles may play a role in achieving transient stroke neuroprotection. Using the established ischemic stroke model of middle cerebral artery occlusion in adult rats, we detected a surged in the extracellular vesicle marker CD63 in the peri-infarct area that either juxtaposed or co-localized with GFAP-positive glial cells, MAP2-labeled young neurons, and VEGF-marked angiogenic cells. This novel observation that CD63 exosomes spatially and temporally approximated glial activation, neurogenesis, and angiogenesis suggests that extracellular vesicles, especially exosomes, contribute to the endogenous repair of the NVU, warranting exploration of extracellular vesicle-based stroke therapeutics.


Post-Operative Magnetic Resonance Evaluation of Anterior Talofibular Ligament following Arthroscopic Brostrom Procedure: Analysis and Outcomes of 40 Repairs at 12 Months.
Lateral ankle sprains are one of the most common orthopedic injuries. When conservative treatment fails, surgical correction is often performed using either open or arthroscopic techniques. We hypothesize that MRI evaluation of the arthroscopic brostrom repair will show intact repair and decrease in thickness of the anterior talofibular ligament (ATFL) at 1 year, with statistically significant improvement of patient function and pain scores. Post-operative MRI was utilized at minimum 1-year follow-up to evaluate the integrity of the arthroscopic brostrom repair, as well as comparison of ATFL thickness to literature validated average thickness. A musculoskeletal fellowship trained radiologist performed all MRI reads. In addition, three fellowship trained foot and ankle specialists from a single institution all performed measurements of the ATFL. Surgical satisfaction using 1-100 scale, and Karlsson-Peterson (KP) were measured at 1 year post-operatively. In addition, pre and post-operative Foot Function Index (FFI), American Orthopedic Foot and Ankle (AOFAS) hindfoot scores, and Visual Analog Scale (VAS) were measured using unpaired t-tests. All repairs were shown to be intact at minimum 1-year follow-up via MRI evaluation, with ATFL thickness of 2.21mm. Pre-operative FFI, AOFAS, and VAS were 54.9, 46.4, and 7.1 respectively. Post-Operative scores were 11.0, 91.7, and 1.3 respectively. Surgical satisfaction was 88.2, KP was 75.3. Comparison of pre- and post-operative scores (VAS, FFI, AOFAS) were shown to be statistically significant, p<0.05. No significant difference in demographic data was observed at 1 year. The data from this study offers evidence that the arthroscopic brostrom repair provides patients with good outcomes as well as an intact ATFL with normal morphology at 1 year post-operatively.


Endometrial biopsy technique and uterine pathologic findings in llamas.
Uterine tissue specimens from 90 llamas with history of infertility were examined and graded microscopically; 83 specimens were obtained by endometrial biopsy and 7 specimens were obtained at necropsy. Fifteen llamas (16.7%) had a normal uterus, which was graded 1A. Twenty-three llamas (25.6%) had minor uterine abnormalities that were graded 1B. Forty-five llamas (50.0%) had appreciable endometritis that was graded 2A. Three llamas (3.3%) had endometritis with gland fibrosis that was graded 2B. Two llamas (2.2%) had notable uterine gland fibrosis that was graded 3A. Two llamas (2.2%) had uterine neoplasia that was graded 3B. Thirty-six llamas had follow-up evaluation; 22 became pregnant, most after some form of treatment. Uterine biopsy in llamas was readily performed without complications and was valuable in identifying a wide range of uterine diseases, most of which were amenable to treatment.


Laboratory analyses for Lyme disease.
Numerous techniques are available for the laboratory diagnosis of Lyme disease. Assays for the detection of antibodies to Borrelia burgdorferi are the most practical means of confirming infection. False positive reactions can occur, but the more serious disadvantages are low sensitivity and lengthy processing time. Nonetheless, serologic tests are being improved and remain valuable research and diagnostic tools. Serologic test results for antibodies to B. burgdorferi should be considered along with clinical data and epidemiological information when evaluating a patient for Lyme disease.


SEMA6A drives GnRH neuron-dependent puberty onset by tuning median eminence vascular permeability.
Innervation of the hypothalamic median eminence by Gonadotropin-Releasing Hormone (GnRH) neurons is vital to ensure puberty onset and successful reproduction. However, the molecular and cellular mechanisms underlying median eminence development and pubertal timing are incompletely understood. Here we show that Semaphorin-6A is strongly expressed by median eminence-resident oligodendrocytes positioned adjacent to GnRH neuron projections and fenestrated capillaries, and that Semaphorin-6A is required for GnRH neuron innervation and puberty onset. In vitro and in vivo experiments reveal an unexpected function for Semaphorin-6A, via its receptor Plexin-A2, in the control of median eminence vascular permeability to maintain neuroendocrine homeostasis. To support the significance of these findings in humans, we identify patients with delayed puberty carrying a novel pathogenic variant of SEMA6A. In all, our data reveal a role for Semaphorin-6A in regulating GnRH neuron patterning by tuning the median eminence vascular barrier and thereby controlling puberty onset.


Expression of Sailx suchowensis SsIRT9 enhances cadmium accumulation and alters metal homeostasis in tobacco.
Cadmium (Cd) contamination in soils is of great concern for plant growth and human health. Willow (Salix spp.) is a promising phytoextractor because of its high biomass production. However, as a non-hyperaccumulator, willow has a low competitive ability in extraction of Cd. Thus, improving Cd concentrations in developing tissues is one of the primary tasks. Here, our study uncovers a novel SsIRT9 gene from Sailx suchowensis which manipulates plant Cd accumulation. SsIRT9 was more highly expressed in willow roots than other SsIRT genes. As a plasma membrane-localized protein, when expressed in yeast, SsIRT9 retarded cell growth more severely than other SsIRT proteins in the presence of Cd. Furthermore, SsIRT9 was cloned and expressed in tobacco and SsIRT9 did not affect plant growth. In hydroponic experiments, SsIRT9 lines displayed higher Cd in the shoots than the wild type. When grown in Cd-contaminated soils, Cd levels in transgenic tobacco increased by 152-364% in roots and by 135-444% in shoots, demonstrating significant superiority in Cd accumulation over other functional IRT/ZIP transporters. Moreover, expressing SsIRT9 in tobacco altered metal homeostasis, especially manganese and zinc. Taken together, we envision that SsIRT9 expression in plants is a promising strategy for upgrading extraction of Cd from soils.


Bio-solid-State processes for synthesis of Li-Fe-phosphate.
Lithium-Fe-phosphates have become of great interest as storage cathodes for rechargeable Li-batteries because of their high density, environmental friendliness, and safety. The objective of this study was to examine bio-solid-state synthesis of LiFePO4 by microbial processes at room temperature. The microbial reduction of Fe(III)-citrate using an organic carbon, glucose, as an electron donor in the presence of NaHPO4 and lithium that resulted in the formation of Li-substituted iron phosphate. Our studies showed that bacteria enriched from inter-tidal flat sediments, designated as Haejae-1, synthesized Li-substituted iron phosphate. Characterization by X-ray diffraction showed the reduction of Fe(III)-citrate in the presence of NaHPO4 and LiCl2 resulted in the precipitation of Li-substituted vivianite [Li(x)Fe(3-x)(PO4)2 x 8H2O]. SEM-EDX, FTIR, and ESCA analyses showed the chemical composition of the synthesized phases was Li, Fe, P, C, and O. Based on the chemical and physical structure of the mineral, the novel bio-nano-material may be potentially useful to the development of energy storage materials.


Lethal combat and sex ratio evolution in a parasitoid wasp.
Sex allocation theory provides excellent opportunities for testing how behavior and life histories are adjusted in response to environmental variation. One of the most successful areas from this respect is Hamilton's local mate competition theory. As predicted by theory, a large number of animal species have been shown to adjust their offspring sex ratios (proportion male) conditionally, laying less female-biased sex ratios as the number of females that lay eggs on a patch increases. However, recent studies have shown that this predicted pattern is not followed by 2 parasitoid species in the genus Melittobia, which always produce extremely female-biased sex ratios. A possible explanation for this is that males fight fatally and that males produced by the first female to lay eggs on a patch have a competitive advantage over later emerging males. This scenario would negate the advantage of later females producing a less female-biased sex ratio. Here we examine fatal fighting and sex ratio evolution in another species, Melittobia acasta. We show that females of this species also fail to adjust their offspring sex ratio in response to the number of females laying eggs on a patch. We then show that although earlier emerging males do have an advantage in winning fights, this advantage 1) can be reduced by an interaction with body size, with larger males more likely to win fights and 2) only holds for a brief period around the time at which the younger males emerge from their pupae. This suggests that lethal male combat cannot fully explain the lack of sex ratio shift observed in Melittobia species. We discuss alternative explanations.


Influenza A Virus Infection Predisposes Hosts to Secondary Infection with Different Streptococcus pneumoniae Serotypes with Similar Outcome but Serotype-Specific Manifestation.
Influenza A virus (IAV) and Streptococcus pneumoniae are major causes of respiratory tract infections, particularly during coinfection. The synergism between these two pathogens is characterized by a complex network of dysregulated immune responses, some of which last until recovery following IAV infection. Despite the high serotype diversity of S. pneumoniae and the serotype replacement observed since the introduction of conjugate vaccines, little is known about pneumococcal strain dependency in the enhanced susceptibility to severe secondary S. pneumoniae infection following IAV infection. Thus, we studied how preinfection with IAV alters host susceptibility to different S. pneumoniae strains with various degrees of invasiveness using a highly invasive serotype 4 strain, an invasive serotype 7F strain, and a carrier serotype 19F strain. A murine model of pneumococcal coinfection during the acute phase of IAV infection showed a significantly increased degree of pneumonia and mortality for all tested pneumococcal strains at otherwise sublethal doses. The incidence and kinetics of systemic dissemination, however, remained bacterial strain dependent. Furthermore, we observed strain-specific alterations in the pulmonary levels of alveolar macrophages, neutrophils, and inflammatory mediators ultimately affecting immunopathology. During the recovery phase following IAV infection, bacterial growth in the lungs and systemic dissemination were enhanced in a strain-dependent manner. Altogether, this study shows that acute IAV infection predisposes the host to lethal S. pneumoniae infection irrespective of the pneumococcal serotype, while the long-lasting synergism between IAV and S. pneumoniae is bacterial strain dependent. These results hold implications for developing tailored therapeutic treatment regimens for dual infections during future IAV outbreaks.


[Use of a transplant from the iliac crest with axial blood supply for anterior spondylodesis of the lower lumbar and lumbosacral segments of the spine].
The method of anterior osseoplasic stabilization of inferiolumbar and lumbosacral parts of spine by means of non-free vascularized transplant from the anterior part of the iliac crest has been developed. In the anatomical experiment at 100 objects there have been studied alternative surgical anatomy of vascular transplant pedicle from deep vessels, surrounding the iliac bone, ascertained the possibility of its lengthening at the cost of the muscular-periosteal "cuff". 9 patients have been operated on with positive results. There have been achieved an acceleration of the osseous stabilization of the spine by 1.5-2 times as compared with the traditional methods without essential restructuring of resolution of transplants with vascular connections.


CD28-independent induction of experimental autoimmune encephalomyelitis.
Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated disease initiated by antigen-specific CD4(+) T cells. Signaling through CD28 is a critical second signal for activation of T cells, and CD28 knockout (CD28KO) mice have been reported to be resistant to induction of EAE. We now report that CD28KO mice have no intrinsic defect in mediating disease, because they developed EAE after passive transfer of primed T cells. After immunization, peripheral T cells from CD28KO mice were primed and developed memory phenotype, but had decreased antigen-specific IFN-gamma production as compared with cells from wild-type (WT) animals. Reimmunization of CD28KO mice brought out clinical disease and increased IFN-gamma production in vitro. Pathologically, there were cellular infiltrates in the central nervous system, in contrast to single-immunized mice. We show furthermore that blocking B7-1 or CTLA4, but not B7-2, in CD28KO mice induces disease after a single immunization. Thus, EAE can be induced in animals lacking CD28-dependent costimulation, suggesting that alternative costimulatory pathways were used. Blocking the OX40-OX40L costimulatory pathway differentially affected disease induction in CD28KO mice as compared with WT controls. Our data show that EAE may develop in the absence of CD28 T-cell costimulation. These findings have implications for therapies aimed at blocking costimulatory signals in autoimmune diseases.


Elliptical broken line method for calculating capillary density in nailfold capillaroscopy: Proposal and evaluation.
Nailfold capillaroscopy is a practical method for identifying and obtaining morphological changes in capillaries which might reveal relevant information about diseases and health. Capillaroscopy is harmless, and seems simple and repeatable. However, there is lack of established guidelines and instructions for acquisition as well as the interpretation of the obtained images; which might lead to various ambiguities. In addition, assessment and interpretation of the acquired images are very subjective. In an attempt to overcome some of these problems, in this study a new modified technique for assessment of nailfold capillary density is introduced. The new method is named elliptic broken line (EBL) which is an extension of the two previously known methods by defining clear criteria for finding the apex of capillaries in different scenarios by using a fitted elliptic. A graphical user interface (GUI) is developed for pre-processing, manual assessment of capillary apexes and automatic correction of selected apexes based on 90° rule. Intra- and inter-observer reliability of EBL and corrected EBL is evaluated in this study. Four independent observers familiar with capillaroscopy performed the assessment for 200 nailfold videocapillaroscopy images, form healthy subject and systemic lupus erythematosus patients, in two different sessions. The results show elevation from moderate (ICC=0.691) and good (ICC=0.753) agreements to good (ICC=0.750) and good (ICC=0.801) for intra- and inter-observer reliability after automatic correction of EBL. This clearly shows the potential of this method to improve the reliability and repeatability of assessment which motivates us for further development of automatic tool for EBL method.


Protease inhibitors as models for the study of oxidative folding.
The correct balance between proteases and their natural protein inhibitors is of great importance in living systems. Protease inhibitors usually comprise small folds that are crosslinked by a high number of disulfide bonds, making them perfect models for the study of oxidative folding. To date, the oxidative folding of numerous protease inhibitors has been analyzed, revealing a great diversity of folding pathways that differ mainly in the heterogeneity and native disulfide-bond content of their intermediates. The two extremes of this diversity are represented by bovine pancreatic trypsin inhibitor and hirudin, which fold, respectively, via few native intermediates and heterogeneous scrambled isomers. Other proteins, such as leech carboxypeptidase inhibitor, share characteristics of both models displaying mixed folding pathways. The study of the oxidative folding of two-domain inhibitors, such as secretory leukocyte protease inhibitor, tick carboxypeptidase inhibitor, and Ascaris carboxypeptidase inhibitor, has provided some clues about how two-domain protease inhibitors may fold, that is, either by folding each domain autonomously or with one domain assisting in the folding of the other. Finally, the recent determination of the structures of the major intermediates of protease inhibitors has shed light on the molecular mechanisms guiding the oxidative folding of small disulfide-rich proteins.


Racial and Ethnic Variability in the Prevalence and Incidence of Comorbidities Associated with Gastric Cancer in the United States.
Comorbidities are known to impact quality of life, treatment choices, and survival. Our objectives were to characterize comorbid conditions in a cohort of elderly gastric cancer patients and to determine if there is variability in the prevalence or incidence of the comorbid conditions across racial/ethnic groups. A total of 12,612 individuals, ≥66 years of age, diagnosed with gastric cancer between 2000 and 2007, and an equal number of gender- and region-matched cancer-free individuals, were identified using the National Cancer Institute's Surveillance, Epidemiology, and End Results registry linked to Medicare claims in the United States. The prevalence (%) in the year before diagnosis and the 12-month incidence rates after diagnosis were estimated for 32 chronic and ten acute comorbid conditions for the entire cohort and by race/ethnicity (Asian, Black, Hispanic, White, and other) and Asian subgroups (e.g., Chinese, Filipino, Japanese, Pacific Islander). White and Black cases exhibited the highest prevalence of most comorbid conditions. Asian and Pacific Islander cases exhibited the lowest. There was substantial variability in the 12-month incidence of the comorbidities across the racial/ethnic groups. Electrolyte disorder was the most common incident condition among Whites and Blacks. With the exception of Whites, anemia was the most common incident condition in all racial and ethnic groups 180 days following chemotherapy. There is variability in the prevalence and incidence in comorbidities across racial/ethnic groups.