The effect of two publicly funded insurance programs on use of dental services for young children.
The purpose of this study is to compare the use of dental services for preschool aged children enrolled in North Carolina Medicaid, a traditional program based on a fee-for-service schedule, and North Carolina Health Choice (NCHC), an State Children's Health Insurance Program (S-CHIP) dental insurance program structured similarly to private insurance. All children (165,858) 1-5 years of age enrolled in Medicaid and S-CHIP (NCHC) at some time during one study year (October 1, 1999-September 30, 2000). DATA SOURCES/EXTRACTION METHODS: Medicaid and NCHC enrollment and dental claims files were obtained for individual children. An observational study with a retrospective cohort design. Use of dental services for each child was measured as having at least one dental claim during the outcome period (October 1, 1999-September 30, 2000). Multivariable logistic regression models were developed to compare the effect of two differently administered insurance programs on the use of dental services, controlling for demographic, enrollment, and county characteristics. Children enrolled solely in S-CHIP (NCHC) were 1.6 times more likely (95 percent confidence intervals (CI)=1.50-1.79) to have a dental visit than those enrolled solely in Medicaid. Prediction models for children enrolled for 12 months indicated that those enrolled in S-CHIP (NCHC) had a significantly higher probability of having a dental visit (50 percent) than those enrolled in both plans (44 percent) or Medicaid only (39 percent), a trend found in all age groups. The S-CHIP (NCHC) program appears to provide children with increased access to dental care compared to children in the Medicaid program.


Implementation of a Massive Transfusion Protocol: Evaluation of Its Use and Efficacy.
Massive transfusion protocols (MTPs) allow practitioners to follow a prescribed algorithm for the rapid replacement of blood products during a massive hemorrhage. They function as an established protocol to provide consistent treatment. Once implemented, the MTP must be evaluated to ensure best practice. The purpose of this clinical improvement project was to formally evaluate the use and efficacy of an MTP during its first year of implementation. The specific aims were to (1) determine whether MTP activations were missed; (2) compare outcomes between those patients managed by the MTP and those who were not; and (3) provide recommendations to the institution's stakeholders. A retrospective medical record review was conducted with 101 electronic medical records of adult trauma patients treated over 1 year. Patients were identified to have experienced massive bleeding if their medical record contained 1 of 4 indicators: (1) transfusion of uncrossmatched blood; (2) tranexamic acid administration; (3) transfusion of 4 or more units of packed red blood cells (PRBCs) in 1 hr; and/or (4) transfusion of 10 or more units of PRBCs in 24 hr. While 58 patients experienced massive bleeding, only 16 (28%) were managed using the MTP. Although the non-MTP group received fewer transfused blood products due to higher initial and 24-hr hemoglobin levels, more deaths occurred in this group than in the MTP group. The recommendations were to (1) establish well-defined criteria for MTP activation based on the 4 indicators of massive bleeding and (2) regularly evaluate the use and efficacy of the MTP to ensure positive patient outcomes.


Effects of livestock grazing on grassland carbon storage and release override impacts associated with global climate change.
Predicting future carbon (C) dynamics in grassland ecosystems requires knowledge of how grazing and global climate change (e.g., warming, elevated CO2 , increased precipitation, drought, and N fertilization) interact to influence C storage and release. Here, we synthesized data from 223 grassland studies to quantify the individual and interactive effects of herbivores and climate change on ecosystem C pools and soil respiration (Rs). Our results showed that grazing overrode global climate change factors in regulating grassland C storage and release (i.e., Rs). Specifically, grazing significantly decreased aboveground plant C pool (APCP), belowground plant C pool (BPCP), soil C pool (SCP), and Rs by 19.1%, 6.4%, 3.1%, and 4.6%, respectively, while overall effects of all global climate change factors increased APCP, BPCP, and Rs by 6.5%, 15.3%, and 3.4% but had no significant effect on SCP. However, the combined effects of grazing with global climate change factors also significantly decreased APCP, SCP, and Rs by 4.0%, 4.7%, and 2.7%, respectively but had no effect on BPCP. Most of the interactions between grazing and global climate change factors on APCP, BPCP, SCP, and Rs were additive instead of synergistic or antagonistic. Our findings highlight the dominant effects of grazing on C storage and Rs when compared with the suite of global climate change factors. Therefore, incorporating the dominant effect of herbivore grazing into Earth System Models is necessary to accurately predict climate-grassland feedbacks in the Anthropocene.


Benzyl-2-Acetamido-2-Deoxy-α-d-Galactopyranoside Increases Human Immunodeficiency Virus Replication and Viral Outgrowth Efficacy In Vitro.
Glycosylation of host and viral proteins is an important posttranslational modification needed to ensure correct function of glycoproteins. For this reason, we asked whether inhibition of O-glycosylation during human immunodeficiency virus (HIV) in vitro replication could affect HIV infectivity and replication rates. We used benzyl-2-acetamido-2-deoxy-α-d-galactopyranoside (BAGN), a compound that has been widely used to inhibit O-glycosylation in several cell lines. Pretreatment and culture of PHA-blast target cells with BAGN increased the percentage of HIV-infected cells (7.6-fold, p = 0.0115), the per-cell amount of HIV p24 protein (1.3-fold, p = 0.2475), and the viral particles in culture supernatants (7.1-fold, p = 0.0029) compared to BAGN-free cultures. Initiating infection with virus previously grown in the presence of BAGN further increased percentage of infected cells (30-fold, p < 0.0001), intracellular p24 (1.5-fold, p = 0.0433), and secreted viral particles (74-fold, p < 0.0001). BAGN-treated target cells showed less CD25 and CCR5 expression, but increased HLA-DR surface expression, which positively correlated with the number of infected cells. Importantly, BAGN improved viral outgrowth kinetics in 66% of the samples tested, including samples from HIV controllers and subjects in whom no virus could be expanded in the absence of BAGN. Sequencing of the isolated virus indicated no skewing of viral quasi-species populations when compared to BAGN-free culture conditions. BAGN also increased virus production in the ACH2 latency model when used together with latency-reversing agents. Taken together, our results identify BAGN treatment as a simple strategy to improve viral outgrowth in vitro and may provide novel insights into host restriction mechanisms and O-glycosylation-related therapeutic targets for HIV control strategies.


Molecular Phylogenetic Relationships of the Brown Leaf Rust Fungi on Wheat, Rye, and Other Grasses.
The classification of brown leaf rust fungi (Puccinia recondita complex and allied species) on wheat (Triticum aestivum), rye (Secale cereale), and other grasses in the family Poaceae has experienced a long history of controversy and uncertainty due to the reduced morphological characteristics available for taxonomy and difficulty of conducting interfertility experiments. However, because these are pathogens on important crops, it is important to clarify the species delimitations reflecting the natural lineages. In this study, phylogenetic analyses were conducted with DNA sequence data from the ribosomal DNA internal transcribed spacer region and elongation factor 1-α to elucidate this species complex. Three phylogenetic lineages were recovered within the complex of rye leaf rust fungi, P. recondita sensu stricto, which is congruent with existing classifications based on DNA content, sexual compatibility, and morphological studies. The brown leaf rust fungus on wheat (P. triticina) grouped with the related species P. persistens on Elymus repens and E. intermedia as a strongly supported clade. Collections on other Elymus spp. were separated into six clades. Based on the phylogenetic affinities of nine type specimens and aecial host associations, potential taxonomic names were evaluated for selected lineages.


Evidence for the presence of two bovine lentiviruses in the cattle population of Bali.
Antibodies directed against two bovine lentiviruses, Jembrana disease virus (JDV) and bovine immunodeficiency virus (BIV), were detected in Balinese cattle sera using two new enzyme-linked immunosorbent assays (ELISAs) based on the combination of capsid (CA) protein and transmembrane (TM) peptides derived from JDV or BIV sequences. Twenty eight of the 77 sera tested on the JDV ELISA showed anti-JDV antibodies with an unequal distribution of seropositive animals throughout the different districts of Bali. Furthermore, when 17 of the JDV positive sera were tested on Western blot, using the same JDV CA antigen, only 13 were judged positive confirming that the ELISA was a more sensitive technique for the detection of seropositive animals. Finally, 9 of the 49 JDV seronegative animals showed anti-BIV antibodies when tested on BIV-specific ELISA. These two ELISAs appeared to be highly sensitive for the detection of anti-JDV and anti-BIV antibodies. Moreover, for the first time, animals showing antibodies against BIV were identified on the main island of Bali and on the JDV-free Nusa Penida island.


Retrospective Analysis on the Feasibility and Efficacy of Docetaxel-Cisplatin Therapy for Recurrent Endometrial Cancer.
There is poor evidence regarding effective treatment for recurrent endometrial cancer. We treated patients with recurrent endometrial cancer with docetaxel-cisplatin (DP) therapy as second-line or third-line chemotherapy. We aimed to evaluate the feasibility and efficacy of DP therapy for patients with recurrent endometrial cancer. We included 26 patients diagnosed with recurrent endometrial cancer, who underwent DP chemotherapy at our Institution. Docetaxel at 70 mg/m(2)and cisplatin at 60 mg/m(2)were administered by intravenous injection every 3 weeks. We retrospectively analyzed the clinicopathological factors associated with the response rate (RR) and prognosis. We also analyzed the adverse effects of DP therapy. Median follow-up was 33.8 months and the median number of therapy cycles was six. Grade 3 or 4 adverse effects included leukopenia (66%), neutropenia (81%), anemia (9%), diarrhea (12%), general fatigue (12%), liver dysfunction (4%), peripheral neuropathy (4%), and hyponatremia (4%). RR was 58% and the median progression-free survival (PFS) was 7.5 months. The group with a treatment-free interval of 6 months or more tended to have better PFS than that with less than 6 months (p=0.01). The group with a platinum-free interval of 6 months or more had significantly better PFS than that with less than 6 months (p=0.09). Although the history of taxane usage was not relevant to prognosis, a taxane-free interval of 12 months or more was associated with a tendency for better PFS (p=0.06). DP therapy was fully feasible and demonstrated efficacy for patients with recurrent endometrial cancer.


Sequential accumulation of K-ras mutations and p53 overexpression in the progression of pancreatic mucinous cystic neoplasms to malignancy.
Pancreatic mucinous cystic neoplasms (MCNs) provide a spectrum of neoplastic changes ranging from benign to malignant. The authors have correlated K-ras mutations and p53 overexpression with the evolution of these tumors. Areas of mild, moderate, or severe dysplasia were microdissected from paraffin-embedded tissue sections of 28 different MCNs (10 benign, 9 borderline, 9 malignant). Nonneoplastic pancreatic ducts were also microdissected from tissues adjacent to the tumors. Ten serous cystadenomas served as negative controls. K-ras codon 12 mutations were identified by a mutant-enriched nested polymerase chain reaction-restriction fragment length polymorphism assay and confirmed by sequencing. p53 overexpression was demonstrated by immunohistochemistry. K-ras mutations were detected in 20% of benign, 33% of borderline, and 89% of malignant MCNs. Histologically, mutations were found in 26% (7/27) of MCN epithelia with mild dysplasia, 38% (5/13) of MCN epithelia with moderate dysplasia, and 89% (8/9) of MCN epithelia with severe dysplasia or carcinoma. Ten percent (4/39) of nonneoplastic pancreatic ducts at the margins of MCN harbored mutations, all associated with borderline or malignant tumors. Overexpression of p53 occurred in none of the benign or borderline MCNs but in 44% (4/9) of the malignant tumors (p = 0.006 benign/borderline vs. malignant). p53 immunoreactivity was concentrated in areas of severe dysplasia/carcinoma or invasion, where K-ras mutation had been detected. These findings demonstrate a sequential accumulation of genetic changes in the carcinogenesis of MCN. K-ras mutations appear early and increase in proportion with increasing dysplasia. Overexpression of p53 is a late finding observed only in carcinomas, and in combination with mutated K-ras genes. The presence of K-ras mutations in nonneoplastic ducts supports formal pancreatic resection over enucleation for treatment. Mucinous cystic neoplasms may be a useful model to study the evolution of pancreatic ductal adenocarcinomas, in which precursor lesions remain unknown.


Congenital heart block and immune mediated sensorineural hearing loss: possible cross reactivity of immune response.
Immune-mediated sensorineural hearing loss may complicate systemic autoimmune diseases. We have previously reported the presence of antibodies directed against inner ear antigens in patients with Cogan syndrome, a disease characterized by sudden hearing loss and interstitial keratitis. Such autoantibodies cross-react with an epitope of SSA/Ro60 protein. Anti-Ro/SSA antibodies in pregnant women cross the placenta and reach the fetal tissues inducing an immune-mediated damage of the cardiac conduction system. We wanted to evaluate whether mothers with anti-Ro/SSA antibodies who gave birth to children with congenital heart block have antibodies directed against inner ear antigens and whether these antibodies are connected with the presence of immune-mediated sensorineural hearing loss. We did not find anti-inner ear antibodies in the majority of the mothers. On the contrary a 13-year-old boy with congenital heart block and sensorineural hearing loss was positive for the presence of anti-inner ear antigens antibodies. Moreover his serum was positive for the presence of anti-Ro60 peptide antibodies but did not recognize the entire protein Ro60 (TROVE2), a behaviour similar to that of sera from patients with Cogan syndrome. In conclusion the data obtained so far show that anti-inner ear antibodies do not recognize the entire protein TROVE2 and do not support the hypothesis that such antibodies may be involved in the pathogenesis of congenital heart block.


Peptide inhibitors of HIV-1 protease and viral infection of peripheral blood lymphocytes based on HIV-1 Vif.
We recently reported that HIV-1 Vif (virion infectivity factor) inhibits HIV-1 protease in vitro and in bacteria, suggesting that it may serve as the basis for the design of new protease inhibitors and treatment for HIV-1 infection. To evaluate this possibility, we synthesized peptide derivatives from the region of Vif, which inhibits protease, and tested their activity on protease. In an assay of cleavage of virion-like particles composed of HIV-1 Gag precursor polyprotein, full-length recombinant Vif, and a peptide consisting of residues 21-65 of Vif, but not a control peptide or BSA, inhibited protease activity. Vif21-65 blocked protease at a molar ratio of two to one. We then tested this peptide and a smaller peptide, Vif41-65, for their effects on HIV-1 infection of peripheral blood lymphocytes. Both Vif peptides inhibited virus expression below the limit of detection, but control peptides had no effect. To investigate its site of action, Vif21-65 was tested for its effect on Gag cleavage by protease during HIV-1 infection. We found that commensurate with its reduction of virus expression, Vif21-65 inhibited the cleavage of the polyprotein p55 to mature p24. These results are similar to those obtained by using Ro 31-8959, a protease inhibitor in clinical use. We conclude that Vif-derived peptides inhibit protease during HIV-1 infection and may be useful for the development of new protease inhibitors.


Treatment of fulminant hepatic failure in rats using a bioartificial liver device containing porcine hepatocytes producing interleukin-1 receptor antagonist.
Fulminant hepatic failure (FHF) is a serious clinical condition that is associated with high mortality. There is evidence that FHF is an inflammatory disease, which is supported clinically by elevated serum levels of cytokines. In an effort to develop hepatocytes with additional functions for use in our bioartificial liver (BAL) device, we focused on interleukin-1 (IL-1) blockade as a therapeutic modality. Primary porcine hepatocytes were isolated from the livers of miniature swine and then transfected with an adenoviral vector encoding human interleukin-1 receptor antagonist (AdIL-1Ra). The transfected hepatocytes secreted human IL-1Ra. These transfected hepatocytes were incorporated into a flat-plate BAL device to evaluate their efficacy in treating D-galactosamine (GalN)- induced FHF in a rat model. After extracorporeal perfusion with the BAL device containing the transfected hepatocytes, there were significant reductions in the plasma levels of hepatic enzymes (aspartate aminotransferase and alanine aminotransferase) and cytokines (IL-1 and IL-6), indicating a beneficial effect. Animal survival was significantly improved in the treated group compared to the control group. These experiments demonstrate that combining inflammatory cytokine blockade with a functional BAL device may be an effective therapeutic option in the treatment of FHF.


Passive quasi-monochromatic depth discrimination using a coherence imager with volume holographic pupil.
We present a new passive depth detection method for quasi-monochromatic and spatially incoherent objects. We utilize the wavefront discrimination properties of a volume holographic pupil combined with a measurement of the degree of coherence of the diffracted field. Depth detection is posed as the Bayesian hypothesis testing on the outcome of the coherence measurement. We present the analysis of our proposed optical system and experimental results confirming binary depth discrimination with high confidence for featureless objects.


From patients to partners: participant-centric initiatives in biomedical research.
Advances in computing technology and bioinformatics mean that medical research is increasingly characterized by large international consortia of researchers that are reliant on large data sets and biobanks. These trends raise a number of challenges for obtaining consent, protecting participant privacy concerns and maintaining public trust. Participant-centred initiatives (PCIs) use social media technologies to address these immediate concerns, but they also provide the basis for long-term interactive partnerships. Here, we give an overview of this rapidly moving field by providing an analysis of the different PCI approaches, as well as the benefits and challenges of implementing PCIs.


The development of a monolith-based purification process for Orthopoxvirus vaccinia virus Lister strain.
The purification of large viruses remains an important field of research and development. The development of efficient purification trains is restricted by limited analytical methods, as well as by the complexity of large viruses, as well as the high variability in starting material from cell culture. Vaccinia virus holds great potential as an oncolytic and immunotherapeutic vaccine against a broad spectrum of cancers. In this work, monolith-based capture and polishing chromatographic steps for vaccinia virus Lister strain has been developed. Virus produced in CV-1 cells was harvested and passed through a 0.8μm pre-filter before loading onto CIEX, AIEX and HIC CIM monoliths. Without the need for nuclease treatment, up to 99% of the total DNA loaded can be removed from the vaccinia feed stream by the CIM OH monolith, which also reduces the total protein concentration in the product pool to LLOQ levels, and achieves infectious virus recoveries of 90%. Binding capacities of greater than 1×109pfu of vaccinia per mL of matrix were obtained on both CIM SO3 and CIM OH monoliths. Multiple orthogonal analytical methods have been used to develop process knowledge and understanding.


Mothers After Gestational Diabetes in Australia Diabetes Prevention Program (MAGDA-DPP) post-natal intervention: study protocol for a randomized controlled trial.
Gestational diabetes mellitus (GDM) is defined as glucose intolerance with its onset or first recognition during pregnancy. Post-GDM women have a life-time risk exceeding 70% of developing type 2 diabetes mellitus (T2DM). Lifestyle modifications reduce the incidence of T2DM by up to 58% for high-risk individuals. The Mothers After Gestational Diabetes in Australia Diabetes Prevention Program (MAGDA-DPP) is a randomized controlled trial aiming to assess the effectiveness of a structured diabetes prevention intervention for post-GDM women. This trial has an intervention group participating in a diabetes prevention program (DPP), and a control group receiving usual care from their general practitioners during the same time period. The 12-month intervention comprises an individual session followed by five group sessions at two-week intervals, and two follow-up telephone calls. A total of 574 women will be recruited, with 287 in each arm. The women will undergo blood tests, anthropometric measurements, and self-reported health status, diet, physical activity, quality of life, depression, risk perception and healthcare service usage, at baseline and 12 months. At completion, primary outcome (changes in diabetes risk) and secondary outcome (changes in psychosocial and quality of life measurements and in cardiovascular disease risk factors) will be assessed in both groups. This study aims to show whether MAGDA-DPP leads to a reduction in diabetes risk for post-GDM women. The characteristics that predict intervention completion and improvement in clinical and behavioral measures will be useful for further development of DPPs for this population. Australian New Zealand Clinical Trials Registry ANZCTRN 12610000338066.


Possible risk of invasive pulmonary aspergillosis with marijuana use during chemotherapy for small cell lung cancer.
Bacterial and fungal contaminants have been identified in marijuana samples and thus are a potential risk factor in the immunocompromised patient using it as an antiemetic. We describe the development of an invasive pulmonary aspergillosis in a patient using illicitly obtained marijuana as an antiemetic during combination antitumor therapy for small cell lung cancer. Although this patient had multiple risk factors implicated in the development of invasive pulmonary aspergillosis, the infectious potential of inhaled marijuana must be recognized. Further study of this potential health risk in needed.


Olfactory receptor pseudo-pseudogenes.
Pseudogenes are generally considered to be non-functional DNA sequences that arise through nonsense or frame-shift mutations of protein-coding genes. Although certain pseudogene-derived RNAs have regulatory roles, and some pseudogene fragments are translated, no clear functions for pseudogene-derived proteins are known. Olfactory receptor families contain many pseudogenes, which reflect low selection pressures on loci no longer relevant to the fitness of a species. Here we report the characterization of a pseudogene in the chemosensory variant ionotropic glutamate receptor repertoire of Drosophila sechellia, an insect endemic to the Seychelles that feeds almost exclusively on the ripe fruit of Morinda citrifolia. This locus, D. sechellia Ir75a, bears a premature termination codon (PTC) that appears to be fixed in the population. However, D. sechellia Ir75a encodes a functional receptor, owing to efficient translational read-through of the PTC. Read-through is detected only in neurons and is independent of the type of termination codon, but depends on the sequence downstream of the PTC. Furthermore, although the intact Drosophila melanogaster Ir75a orthologue detects acetic acid-a chemical cue important for locating fermenting food found only at trace levels in Morinda fruit-D. sechellia Ir75a has evolved distinct odour-tuning properties through amino-acid changes in its ligand-binding domain. We identify functional PTC-containing loci within different olfactory receptor repertoires and species, suggesting that such 'pseudo-pseudogenes' could represent a widespread phenomenon.


The Endofullerene HF@C60: Inelastic Neutron Scattering Spectra from Quantum Simulations and Experiment, Validity of the Selection Rule, and Symmetry Breaking.
Accurate quantum simulations of the low-temperature inelastic neutron scattering (INS) spectra of HF@C60 are reported for two incident neutron wavelengths. They are distinguished by the rigorous inclusion of symmetry-breaking effects in the treatment and having the spectra computed with HF as the guest, rather than H2 or HD, as in the past work. The results demonstrate that the precedent-setting INS selection rule, originally derived for H2 and HD in near-spherical nanocavities, applies also to HF@C60, despite the large mass asymmetry of HF and the strongly mixed character of its translation-rotation eigenstates. This lends crucial support to the theoretical prediction made earlier that the INS selection rule is valid for any diatomic molecule in near-spherical nanoconfinement. The selection rule remains valid in the presence of symmetry breaking but is modified slightly in an interesting way. Comparison is made with the recently published experimental INS spectrum of HF@C60. The agreement is very good, apart from one peak for which our calculations suggest a reassignment. This reassignment is consistent with the measured INS spectrum presented in this work, which covers an extended energy range.


Non-invasive chemically specific measurement of subsurface temperature in biological tissues using surface-enhanced spatially offset Raman spectroscopy.
Here we demonstrate for the first time the viability of characterising non-invasively the subsurface temperature of SERS nanoparticles embedded within biological tissues using spatially offset Raman spectroscopy (SORS). The proposed analytical method (T-SESORS) is applicable in general to diffusely scattering (turbid) media and features high sensitivity and high chemical selectivity. The method relies on monitoring the Stokes and anti-Stokes bands of SERS nanoparticles in depth using SORS. The approach has been conceptually demonstrated using a SORS variant, transmission Raman spectroscopy (TRS), by measuring subsurface temperatures within a slab of porcine tissue (5 mm thick). Root-mean-square errors (RMSEs) of 0.20 °C were achieved when measuring temperatures over ranges between 25 and 44 °C. This unique capability complements the array of existing, predominantly surface-based, temperature monitoring techniques. It expands on a previously demonstrated SORS temperature monitoring capability by adding extra sensitivity stemming from SERS to low concentration analytes. The technique paves the way for a wide range of applications including subsurface, chemical-specific, non-invasive temperature analysis within turbid translucent media including: the human body, subsurface monitoring of chemical (e.g. catalytic) processes in manufacture quality and process control and research. Additionally, the method opens prospects for control of thermal treatment of cancer in vivo with direct non-invasive feedback on the temperature of mediating plasmonic nanoparticles.


Improved anti-tumor efficiency against prostate cancer by docetaxel-loaded PEG-PCL micelles.
This study primarily focused on the systematic assessment of both in vitro and in vivo anti-tumor effects of docetaxel-loaded polyethylene glycol (PEG)2000-polycaprolactone (PCL)2600 micelles on hormone-refractory prostate cancer (HRPC). By using solvent evaporation method, PEG-PCL was chosen to prepare doxetaxel (DTX)-loaded mPEG-PCL micelles (DTX-PMs), with the purpose of eliminating side effects of the commercial formulation (Tween 80) and prolonging the blood circulation time. The prepared DTX-PMs had an average particle size of 25.19±2.36 nm, a zeta potential of 0.64±0.15 mV, a polydispersity index of 0.56±0.03, a drug loading of (8.72±1.05)%, and an encapsulation efficiency of (98.1±8.4)%. In vitro cytotoxicity studies indicated that DTX-PMs could effectively kill LNCap-C4-2B cells and show a dose- and time-dependent efficacy. The hemolysis test showed that DTX-PMs had less hemocytolysis than the commercial product of Duopafei®. A sustained in vitro release behavior and prolonged circulation time in blood vessels were observed in the DTX-PMs. Furthermore, when compared with Duopafei®, the DTX-PMs dramatically reduced the prostate specific antigen (PSA) level and tumor growth of prostate tumor-bearing nude mice in vivo. In conclusion, the DTX-PMs can lower systemic side effects, improve anti-tumor activity with prolonged blood circulation time, and will bring an alternative to patients with HRPC.


Transgenerational transmission of trauma and resilience: a qualitative study with Brazilian offspring of Holocaust survivors.
Over the past five decades, clinicians and researchers have debated the impact of the Holocaust on the children of its survivors. The transgenerational transmission of trauma has been explored in more than 500 articles, which have failed to reach reliable conclusions that could be generalized. The psychiatric literature shows mixed findings regarding this subject: many clinical studies reported psychopathological findings related to transgenerational transmission of trauma and some empirical research has found no evidence of this phenomenon in offspring of Holocaust survivors. This qualitative study aims to detect how the second generation perceives transgenerational transmission of their parents' experiences in the Holocaust. In-depth individual interviews were conducted with fifteen offspring of Holocaust survivors and sought to analyze experiences, meanings and subjective processes of the participants. A Grounded Theory approach was employed, and constant comparative method was used for analysis of textual data. The development of conceptual categories led to the emergence of distinct patterns of communication from parents to their descendants. The qualitative methodology also allowed systematization of the different ways in which offspring can deal with parental trauma, which determine the development of specific mechanisms of traumatic experience or resilience in the second generation. The conceptual categories constructed by the Grounded Theory approach were used to present a possible model of the transgenerational transmission of trauma, showing that not only traumatic experiences, but also resilience patterns can be transmitted to and developed by the second generation. As in all qualitative studies, these conclusions cannot be generalized, but the findings can be tested in other contexts.


The mitochondrial external NADPH dehydrogenase modulates the leaf NADPH/NADP+ ratio in transgenic Nicotiana sylvestris.
Plant mitochondria contain alternative external NAD(P)H dehydrogenases, which oxidize cytosolic NADH or NADPH and reduce ubiquinone without inherent linkage to proton pumping and ATP production. In potato, St-NDB1 is an external Ca2+-dependent NADPH dehydrogenase. The physiological function of this enzyme was investigated in homozygous Nicotiana sylvestris lines overexpressing St-ndb1 and co-suppressing St-ndb1 and an N. sylvestris ndb1. In leaf mitochondria isolated from the overexpressor lines, higher activity of alternative oxidase (AOX) was detected. However, the AOX induction was substantially weaker than in the complex I-deficient CMSII mutant, previously shown to contain elevated amounts of NAD(P)H dehydrogenases and AOX. An aox1b and an aox2 gene were up-regulated in CMSII, but only aox1b showed a response, albeit smaller, in the transgenic lines, indicating differences in AOX activation between the genotypes. As in CMSII, the increase of AOX in the overexpressing lines was not due to a general oxidative stress. The lines overexpressing St-ndb1 had consistently lowered leaf NADPH/NADP+ ratios in the light and variably decreased levels in darkness, but unchanged NADH/NAD+ ratios. CMSII instead had similar NADPH/NADP+ and lower NADH/NAD+ ratios than the wild type. These results demonstrate that St-NDB1 is able to modulate the cellular balance of NADPH and NADP+ at least in the day and that reduction of NADP(H) and NAD(H) is independently controlled. Similar growth rates, chloroplast malate dehydrogenase activation and xanthophyll ratios indicate that the change in reduction does not communicate to the chloroplast, and that the cell tolerates significant changes in NADP(H) reduction without deleterious effects.


Automated beam placement for breast radiotherapy using a support vector machine based algorithm.
To develop an automated beam placement technique for whole breast radiotherapy using tangential beams. We seek to find optimal parameters for tangential beams to cover the whole ipsilateral breast (WB) and minimize the dose to the organs at risk (OARs). A support vector machine (SVM) based method is proposed to determine the optimal posterior plane of the tangential beams. Relative significances of including/avoiding the volumes of interests are incorporated into the cost function of the SVM. After finding the optimal 3-D plane that separates the whole breast (WB) and the included clinical target volumes (CTVs) from the OARs, the gantry angle, collimator angle, and posterior jaw size of the tangential beams are derived from the separating plane equation. Dosimetric measures of the treatment plans determined by the automated method are compared with those obtained by applying manual beam placement by the physicians. The method can be further extended to use multileaf collimator (MLC) blocking by optimizing posterior MLC positions. The plans for 36 patients (23 prone- and 13 supine-treated) with left breast cancer were analyzed. Our algorithm reduced the volume of the heart that receives >500 cGy dose (V5) from 2.7 to 1.7 cm(3) (p = 0.058) on average and the volume of the ipsilateral lung that receives >1000 cGy dose (V10) from 55.2 to 40.7 cm(3) (p = 0.0013). The dose coverage as measured by volume receiving >95% of the prescription dose (V95%) of the WB without a 5 mm superficial layer decreases by only 0.74% (p = 0.0002) and the V95% for the tumor bed with 1.5 cm margin remains unchanged. This study has demonstrated the feasibility of using a SVM-based algorithm to determine optimal beam placement without a physician's intervention. The proposed method reduced the dose to OARs, especially for supine treated patients, without any relevant degradation of dose homogeneity and coverage in general.


Chloroplast stromal proteins, CRR6 and CRR7, are required for assembly of the NAD(P)H dehydrogenase subcomplex A in Arabidopsis.
In higher plants, the chloroplast NAD(P)H dehydrogenase (NDH) complex mediates chlororespiration and photosystem I (PSI) cyclic electron transport in thylakoid membranes. Because of its low abundance and fragility, our knowledge on the assembly of chloroplast NDH is very limited, and some nuclear-encoded factors may be involved in this process. We show here that two Arabidopsis proteins, CHLORORESPIRATORY REDUCTION 6 (CRR6) and CRR7, which were previously identified in mutants specifically defective in NDH accumulation, are present in the stroma, and their stability is independent of the NDH complex, suggesting that they are unlikely to be NDH subunits. Blue native PAGE analysis showed that the accumulation of NDH subcomplex A, which is a core part of NDH that is conserved in divergent species, was specifically impaired in the crr6 and crr7-1 mutants. However, the expression of plastid-encoded genes encoding the subcomplex A subunits was not affected, suggesting that CRR6 and CRR7 are involved in post-translational steps during the biogenesis of subcomplex A. We also discovered that a substantial quantity of NdhH is present in several protein complexes in the chloroplast stroma, possibly as early assembly intermediates of subcomplex A. Although the accumulation of these stromal complexes was not affected in crr6 or crr7-1, CRR6 was co-purified with NdhH, implying that CRR6 functions in the later step of subcomplex-A biogenesis. Accumulation of CRR7 was independent of that of CRR6; we propose that CRR7 functions in a different step in subcomplex-A biogenesis from CRR6.


Beetroot juice protects against N-nitrosodiethylamine-induced liver injury in rats.
Red beetroot, a common ingredient of diet, is a rich source of a specific class of antioxidants, betalains. Our previous studies have shown the protective role of beetroot juice against carcinogen induced oxidative stress in rats. The aim of this study was to examine the effect of long term feeding (28 days) with beetroot juice on phase I and phase II enzymes, DNA damage and liver injury induced by hepatocarcinogenic N-nitrosodiethylamine (NDEA). Long term feeding with beetroot juice decreased the activities of enzymatic markers of cytochrome P450, CYP1A1/1A2 and CYP2E1. NDEA treatment also reduced the activities of these enzymes, but increased the activity of CYP2B. Moreover, combined treatment with beetroot juice and NDEA enhanced significantly CYP2B only. Modulation of P450 enzyme activities was accompanied by changes in the relevant proteins levels. Increased level and activity of NQO1 was the most significant change among phase II enzymes. Beetroot juice reduced the DNA damage increased as the result of NDEA treatment, as well as the biomarkers of liver injury. Collectively, these results confirm the protective effect of beetroot juice against oxidative damage shown in our previous studies and indicate that metabolic alterations induced by beetroot feeding may protect against liver damage.


Design, synthesis, and biological evaluation of 4-phenoxybenzenesulfonyl pyrrolidine derivatives as matrix metalloproteinase inhibitors.
A series of 4-phenoxybenzenesulfonyl pyrrolidine derivatives were designed, synthesized, and evaluated as matrix metalloproteinases (MMPs) inhibitors. All of the synthesized compounds displayed inhibitory activity against MMP-2 and MMP-9. Compounds 4a, 4e, and 4i displayed more potent activity than the other compounds. While the three compounds mildly or moderately inhibited the proliferation of cancer cells, they significantly suppressed the migration and invasion of cancer cells at relatively low concentrations as determined by a wound healing assay and transwell assay. In addition, compound 4e suppressed vascular endothelial cell tube formation and sprouting of microvessels from aortic rings in vitro in a dose-dependent manner. Compound 4e markedly suppressed the pulmonary metastasis of H22 cells in mice. These findings along with molecular docking results suggested that compound 4e might be a promising candidate for further structural optimization to develop MMP inhibitors as potential anticancer agents.


Congenital hypothyroidism detected by neonatal screening: relationship between biochemical severity and early clinical features.
The relationships between biochemical severity of hypothyroidism (as judged by plasma thyroxine) and the clinical and radiographic findings at diagnosis were evaluated in 449 infants born in 1982-4 with congenital hypothyroidism identified by neonatal screening. Details of pregnancy, delivery, and the neonatal period were also examined and compared with the findings in a normal population of 36,727 infants born in 1988. Infants with plasma thyroxine values of 30 nmol/l or less had a significantly higher incidence of prolonged jaundice, feeding difficulties, lethargy, umbilical hernia and macroglossia, showed more severe delay of bone maturation on a knee radiograph, and had a higher proportion of thyroid agenesis on isotope scan. In contrast, an ectopic or hypoplastic gland was more common in infants with plasma thyroxine values above 30 nmol/l. Prevalence of illness in pregnancy and mode of delivery was not related to severity of hypothyroidism and were similar to figures for the normal population. Induction of labour, gestation over 40 weeks, and birth weight above 3500 g were significantly more common in the hypothyroid infants. Perinatal illness and congenital malformations were more common in the infants with low plasma thyroxine values at diagnosis.


Rare Primary Central Nervous System Tumors in Adults: An Overview.
Overall, tumors of primary central nervous system (CNS) are quite common in adults with an incidence rate close to 30 new cases/100,000 inhabitants per year. Significant clinical and biological advances have been accomplished in the most common adult primary CNS tumors (i.e., diffuse gliomas). However, most CNS tumor subtypes are rare with an incidence rate below the threshold defining rare disease of 6.0 new cases/100,000 inhabitants per year. Close to 150 entities of primary CNS tumors have now been identified by the novel integrated histomolecular classification published by the World Health Organization (WHO) and its updates by the c-IMPACT NOW consortium (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy). While these entities can be better classified into smaller groups either by their histomolecular features and/or by their location, assessing their treatment by clinical trials and improving the survival of patients remain challenging. Despite these tumors are rare, research, and advances remain slower compared to diffuse gliomas for instance. In some cases (i.e., ependymoma, medulloblastoma) the understanding is high because single or few driver mutations have been defined. The European Union has launched European Reference Networks (ERNs) dedicated to support advances on the clinical side of rare diseases including rare cancers. The ERN for rare solid adult tumors is termed EURACAN. Within EURACAN, Domain 10 brings together the European patient advocacy groups (ePAGs) and physicians dedicated to improving outcomes in rare primary CNS tumors and also aims at supporting research, care and teaching in the field. In this review, we discuss the relevant biological and clinical characteristics, clinical management of patients, and research directions for the following types of rare primary CNS tumors: medulloblastoma, pineal region tumors, glioneuronal and rare glial tumors, ependymal tumors, grade III meningioma and mesenchymal tumors, primary central nervous system lymphoma, germ cell tumors, spinal cord tumors and rare pituitary tumors.


One-pot conjugated linoleic acid production from castor oil by Rhizopus oryzae lipase and resting cells of Lactobacillus plantarum.
Conjugated linoleic acid (CLA) has attracted as novel type of fatty acids having unusual health-promoting properties such as anticarcinogenic and antiobesitic effects. The present work employed castor oil as substrate for one-pot production of CLA using washed cells of Lactobacillus plantarum (L. plantarum) and lipases as catalysts. Among the screened lipases, the lipase Rhizopus oryzae (ROL) greatly assisted resting cells to produce CLA. Mass spectral analysis of the product showed that two major isomers of CLA were produced in the reaction mixture i.e. cis-9, trans-11 56.55% and trans-10, cis-12 43.45%. Optimum factors for CLA synthesis were found as substrate concentration (8 mg/mL), pH (6.5), washed cell concentration (12% w/v), and incubation time of 20 h. Hence, the combination of ROL with L. plantarum offers one pot production of CLA selectively using castor oil as a cost-effective substrate.


Living with uncertainty and hope: A qualitative study exploring parents' experiences of living with childhood multiple sclerosis.
Background There is growing recognition that multiple sclerosis is a possible, albeit uncommon, diagnosis in childhood. However, very little is known about the experiences of families living with childhood multiple sclerosis and this is the first study to explore this in depth. Objective Our objective was to explore the experiences of parents of children with multiple sclerosis. Methods Qualitative in-depth interviews with 31 parents using a grounded theory approach were conducted. Parents were sampled and recruited via health service and voluntary sector organisations in the United Kingdom. Results Parents' accounts of life with childhood multiple sclerosis were dominated by feelings of uncertainty associated with four sources; diagnostic uncertainty, daily uncertainty, interaction uncertainty and future uncertainty. Parents attempted to manage these uncertainties using specific strategies, which could in turn create further uncertainties about their child's illness. However, over time, ongoing uncertainty appeared to give parents hope for their child's future with multiple sclerosis. Conclusion Illness-related uncertainties appear to play a role in generating hope among parents of a child with multiple sclerosis. However, this may lead parents to avoid sources of information and support that threatens their fragile optimism. Professionals need to be sensitive to the role hope plays in supporting parental coping with childhood multiple sclerosis.


Monitoring brain temperature by time-resolved near-infrared spectroscopy: pilot study.
Mild hypothermia (HT(32°C-33°C)) is an effective neuroprotective strategy for a variety of acute brain injuries. However, the wide clinical adaptation of HT(32-33°C) has been hampered by the lack of a reliable noninvasive method for measuring brain temperature, since core measurements have been shown to not always reflect brain temperature. The goal of this work was to develop a noninvasive optical technique for measuring brain temperature that exploits both the temperature dependency of water absorption and the high concentration of water in brain (80%-90%). Specifically, we demonstrate the potential of time-resolved near-infrared spectroscopy (TR-NIRS) to measure temperature in tissue-mimicking phantoms (in vitro) and deep brain tissue (in vivo) during heating and cooling, respectively. For deep brain tissue temperature monitoring, experiments were conducted on newborn piglets wherein hypothermia was induced by gradual whole body cooling. Brain temperature was concomitantly measured by TR-NIRS and a thermocouple probe implanted in the brain. Our proposed TR-NIRS method was able to measure the temperature of tissue-mimicking phantoms and brain tissues with a correlation of 0.82 and 0.66 to temperature measured with a thermometer, respectively. The mean difference between the TR-NIRS and thermometer measurements was 0.15°C ± 1.1°C for the in vitro experiments and 0.5°C ± 1.6°C for the in vivo measurements.


Predicting the relative impacts of maternal and neonatal respiratory syncytial virus (RSV) vaccine target product profiles: A consensus modelling approach.
Respiratory syncytial virus (RSV) is the major viral cause of infant and childhood lower respiratory tract disease worldwide. Defining the optimal target product profile (TPP) is complicated due to a wide range of possible vaccine properties, modalities and an incomplete understanding of the mechanism of natural immunity. We report consensus population level impact projections based on two mathematical models applied to a low income setting. Two structurally distinct age-specific deterministic compartmental models reflecting uncertainty associated with the natural history of infection and the mechanism by which immunity is acquired and lost were constructed. A wide range of vaccine TPPs were explored including dosing regime and uptake, and effects in the vaccinated individual on infectiousness, susceptibility, duration of protection, disease severity and interaction with maternal antibodies and natural induced immunity. These were combined with a range of vaccine implementation strategies, targeting the highest priority age group and calibrated using hospitalization data from Kilifi County Hospital, Kenya. Both models were able to reproduce the data. The impact predicted by the two models was qualitatively similar across the range of TPPs, although one model consistently predicted higher impact than the other. For a proposed realistic range of scenarios of TPP combinations, the models predicted up to 70% reduction in hospitalizations in children under five years old. Vaccine designs which reduced the duration and infectiousness of infection were predicted to have higher impacts. The models were sensitive to the coverage and rate of loss of vaccine protection but not to the interaction between vaccine and maternal/naturally acquired immunity. The results suggest that vaccine properties leading to reduced virus circulation by lessening the duration and infectiousness of infection upon challenge are of major importance in population RSV disease control. These features should be a focus for vaccine development.


Plant, fungal, bacterial, and nitrogen interactions in the litter layer of a native Patagonian forest.
Plant-microbial interactions in the litter layer represent one of the most relevant interactions for biogeochemical cycling as litter decomposition is a key first step in carbon and nitrogen turnover. However, our understanding of these interactions in the litter layer remains elusive. In an old-growth mixed Nothofagus forest in Patagonia, we studied the effects of single tree species identity and the mixture of three tree species on the fungal and bacterial composition in the litter layer. We also evaluated the effects of nitrogen (N) addition on these plant-microbial interactions. In addition, we compared the magnitude of stimulation of litter decomposition due to home field advantage (HFA, decomposition occurs more rapidly when litter is placed beneath the plant species from which it had been derived than beneath a different plant species) and N addition that we previously demonstrated in this same forest, and used microbial information to interpret these results. Tree species identity had a strong and significant effect on the composition of fungal communities but not on the bacterial community of the litter layer. The microbial composition of the litter layer under the tree species mixture show an averaged contribution of each single tree species. N addition did not erase the plant species footprint on the fungal community, and neither altered the bacterial community. N addition stimulated litter decomposition as much as HFA for certain tree species, but the mechanisms behind N and HFA stimulation may have differed. Our results suggest that stimulation of decomposition from N addition might have occurred due to increased microbial activity without large changes in microbial community composition, while HFA may have resulted principally from plant species' effects on the litter fungal community. Together, our results suggest that plant-microbial interactions can be an unconsidered driver of litter decomposition in temperate forests.


Menaquinone biosynthesis potentiates haem toxicity in Staphylococcus aureus.
Staphylococcus aureus is a pathogen that infects multiple anatomical sites leading to a diverse array of diseases. Although vertebrates can restrict the growth of invading pathogens by sequestering iron within haem, S. aureus surmounts this challenge by employing high-affinity haem uptake systems. However, the presence of excess haem is highly toxic, necessitating tight regulation of haem levels. To overcome haem stress, S. aureus expresses the detoxification system HrtAB. In this work, a transposon screen was performed in the background of a haem-susceptible, HrtAB-deficient S. aureus strain to identify the substrate transported by this putative pump and the source of haem toxicity. While a recent report indicates that HrtAB exports haem itself, the haem-resistant mutants uncovered by the transposon selection enabled us to elucidate the cellular factors contributing to haem toxicity. All mutants identified in this screen inactivated the menaquinone (MK) biosynthesis pathway. Deletion of the final steps of this pathway revealed that quinone molecules localizing to the cell membrane potentiate haem-associated superoxide production and subsequent oxidative damage. These data suggest a model in which membrane-associated haem and quinone molecules form a redox cycle that continuously generates semiquinones and reduced haem, both of which react with atmospheric oxygen to produce superoxide.


Comparison of the anti-inflammatory activity of Commiphora mukul (an indigenous drug) with those of phenylbutazone and ibuprofen in experimental arthritis induced by mycobacterial adjuvant.
In the present investigation a method of induction of experimental arthritis in animals was modified to provide a better model replica of human arthritis. Inflammatory syndrome, resembling rheumatoid arthritis in man, was induced in the right hock joint of albino rabbits by intra-articular injection of the killed mycobacterial adjuvant in liquid paraffin. Development of this arthritic syndrome was studied from a period of five months with and without drugs. Anti-inflammatory agents such as phenylbutazone, ibuprofen and fraction "A" of gum-guggual from Commiphora mukkul were administered orally at a daily dose of 100, 100 and 500 mg/kg, respectively, for a period of five months. All three drugs decreased the thickness of the joint swelling during the course of drug treatment. These results indicate the beneficial role of phenylbutazone, ibuprofen and fraction "A" of gum-guggul in experimental arthritis.


Clinical characteristics of 304 kindreds evaluated for familial dilated cardiomyopathy.
Familial dilated cardiomyopathy (FDC) is dilated cardiomyopathy of unknown cause occurring in 2 or more closely related family members. Members of 304 families suspected to have FDC were evaluated by family history (FH) and medical record review and were categorized as affected with idiopathic dilated cardiomyopathy (IDC), unaffected, unknown, or no data. Pedigrees were categorized with confirmed FDC, probable FDC, possible FDC or IDC based on strength of evidence. Of the 304 pedigrees, 125 were categorized as confirmed FDC, 48 were probable FDC, 72 were possible FDC, and 59 had sporadic, nonfamilial IDC. Numbers of living first- and second-degree family members, and median number of relatives available for FH was greatest with confirmed FDC, and diminished for probable and possible FDC, and IDC categories. LV dimensions increased and LV function worsened in index patients along the spectrum from confirmed FDC, probable FDC, possible FDC and IDC, and a greater proportion of IDC patients underwent heart transplant. However, the age of onset, duration of disease, the time to death or heart transplant, and most other findings were similar among the 4 categories. Clinical characteristics of IDC and FDC are similar, precluding an FDC diagnosis from clinical features only.


Gustafson's method for age determination from teeth--a modification for the use of dentists in identification teams.
Gustafson's method for age determination from teeth is based on the evaluation of ground sections of teeth. Six age-associated parameters are evaluated in the ground section and are compared to a regression curve of age versus the age-associated changes. Two of these changes, transparency of radicular dentin and secondary dentin, have the highest correlation with age. The evaluation of these parameters only from thin (0.25-mm) ground sections may lead to an artificially high "secondary dentin value." These artifacts may be caused by the attempt to include the whole pulp chamber and root canal in a 0.25-mm-thick ground section and by an accidental overgrinding of the apical area of the root, respectively. These artifacts were encountered occasionally even in ground sections prepared by highly trained personnel and became more frequent in ground sections prepared by a person who, though trained, did not use this technique daily. A modification of the data-collecting method is suggested to make possible the use of thick (1.0-mm) ground sections for the evaluation of most of the aging criteria, thereby eliminating the possible inaccuracies in the preparation and evaluation of the thin (0.25-mm) ground sections.


Genome organization is a major component of gene expression control in response to stress and during the cell division cycle in trypanosomes.
The trypanosome genome is characterized by RNA polymerase II-driven polycistronic transcription of protein-coding genes. Ten to hundreds of genes are co-transcribed from a single promoter; thus, selective regulation of individual genes via initiation is impossible. However, selective responses to external stimuli occur and post-transcriptional mechanisms are thought to account for all temporal gene expression patterns. We show that genes encoding mRNAs that are differentially regulated during the heat-shock response are selectively positioned in polycistronic transcription units; downregulated genes are close to transcription initiation sites and upregulated genes are distant. We demonstrate that the position of a reporter gene within a transcription unit is sufficient to reproduce this effect. Analysis of gene ontology annotations reveals that positional bias is not restricted to stress-response genes and that there is a genome-wide organization based on proximity to transcription initiation sites. Furthermore, we show that the relative abundance of mRNAs at different time points in the cell division cycle is dependent on the location of the corresponding genes to transcription initiation sites. This work provides evidence that the genome in trypanosomes is organized to facilitate co-coordinated temporal control of gene expression in the absence of selective promoters.


Association between pruritus and serum concentrations of parathormone, calcium and phosphorus in hemodialysis patients.
Chronic renal disorders have a progressive course in most cases, and finally result in end-stage renal disease (ESRD). Hemodialysis (HD) is one of the mainstays in the treatment of these patients. Disturbance in calcium (Ca) and phosphorus (P) metabolism and alteration of serum levels of parathormone (PTH) are observed in these patients. One of the most common cutaneous manifestations in patients on HD is pruritus. The aim of this study is to evaluate the association between pruritus and serum concentrations of Ca, P and PTH in patients with chronic renal disease. This analytic, descriptive, cross-sectional study was performed on 120 patients on HD at the Fifth-Azar Hospital in Gorgan, Iran, in 2010. Information related to the patients, including age, gender, pruritus, time of pruritus and duration on dialysis, was extracted from questionnaires. Serum concentrations of intact PTH, Ca and P were measured. Data were analyzed by the chi-square test and SPSS-16 software. A P-value less than 0.05 was considered statistically significant. Among the 120 study patients, 50% were male and the mean age (±SD) was 49 ± 12.3 years. Sixty percent of the patients had pruritus, of whom 33.3% had PTH levels above the normal range. Among the 40% of the patients who did not have pruritus, 39.6% had PTH levels higher than the normal levels. The mean serum Ca and P levels were 8.44 ± 1.65 mg/dL and 5.48 ± 1.81 mg/dL, respectively. The mean (±SD) Ca-P product was 55.46 ± 47.16 and the mean PTH concentration was 274.34 ± 286.53 pg/mL. No significant association was found between pruritus and age, sex, serum PTH and P levels as well as Ca-P product. However, the association between serum Ca levels and pruritus was significant (P = 0.03). Our study showed that most patients with pruritus had serum Ca levels in the abnormal range (lower or higher), and there was no significant correlation between serum iPTH level and pruritis. Thus, good control of serum Ca levels is important to reduce pruritus in these patients.


Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group.
Over 11 million Americans have both diabetes and hypertension-comorbid diseases that strongly predispose people to both renal as well as cardiovascular (CV) injury. Hypertension substantially contributes to CV morbidity and mortality in people with diabetes. Diabetes is the most common cause of end-stage renal disease in the United States. Furthermore, hypertension and diabetes are particularly prevalent in certain populations, such as African-Americans and Native Americans. Since the 1994 Working Group Report on Hypertension and Diabetes, a large body of clinical trial data has affirmed the original blood pressure goal of less than 130/85 mmHg recommended to preserve renal function and reduce CV events in people with hypertension and diabetes. Data that are more recent have emerged, however, to support an even lower diastolic blood pressure goal, ie, 80 mmHg, in order to optimally preserve renal function and reduce CV events in people with diabetic nephropathy. A review of clinical trials indicates that more than 65% of people with diabetes and hypertension will require two or more different antihypertensive medications to achieve the new suggested target blood pressure of 130/80 mmHg. The purpose of this report is to update the previous recommendations with a focus on level of blood pressure control, proteinuria reduction, and therapeutic approaches to achieve these goals. We provide an evidence-based approach, integrating data from the major clinical trials that were designed as randomized prospective, long-term studies that had as a primary endpoint either progression of diabetic nephropathy or reduction in CV events. This report also addresses socioeconomic and cultural barriers that hinder achievement of blood pressure goals. Lastly, the report discusses approaches to resolve cultural barriers, both physician- and patient-derived, that interfere with achievement of lower blood pressure goals.


Differential RNA packaging into small extracellular vesicles by neurons and astrocytes.
Small extracellular vesicles (sEVs) mediate intercellular communication by transferring RNA, proteins, and lipids to recipient cells. These cargo molecules are selectively loaded into sEVs and mirror the physiological state of the donor cells. Given that sEVs can cross the blood-brain barrier and their composition can change in neurological disorders, the molecular signatures of sEVs in circulation can be potential disease biomarkers. Characterizing the molecular composition of sEVs from different cell types is an important first step in determining which donor cells contribute to the circulating sEVs. Cell culture supernatants from primary mouse cortical neurons and astrocytes were used to purify sEVs by differential ultracentrifugation and sEVs were characterized using nanoparticle tracking analysis, transmission electron microscopy and western blot. RNA sequencing was used to determine differential expression and loading patterns of miRNAs in sEVs released by primary neurons and astrocytes. Motif analysis was conducted on enriched miRNAs in sEVs and their respective donor cells. Sequencing total cellular RNA, and miRNAs from sEVs isolated from culture media of postnatal mouse cortical neurons and astrocytes revealed a distinct profile between sEVs and their corresponding cells. Though the total number of detected miRNAs in astrocytes was greater than neurons, neurons expressed more sEV-associated miRNAs than astrocytes. Only 20.7% of astrocytic miRNAs were loaded into sEVs, while 41.0% of neuronal miRNAs were loaded into sEVs, suggesting differences in the cellular sorting mechanisms. We identified short RNA sequence motifs, or EXOmotifs, on the miRNAs that were differentially loaded or excluded from sEVs. A sequence motif GUAC was enriched in astrocytic sEVs. miRNAs preferably retained in neurons or astrocytes had a similar RNA motif CACACA, suggesting a cell-type-independent mechanism to maintain cellular miRNAs. mRNAs of five RNA-binding proteins associated with passive or active RNA sorting into sEVs were differentially expressed between neurons and astrocytes, one of which, major vault protein was higher in astrocytes than in neurons and detected in astrocytic sEVs. Our studies suggest differences in RNA sorting into sEVs. These differences in miRNA signatures can be used for determining the cellular sources of sEVs altered in neurological disorders. Video abstract.


Prevalence of avian-pathogenic Escherichia coli strain O1 genomic islands among extraintestinal and commensal E. coli isolates.
Escherichia coli strains that cause disease outside the intestine are known as extraintestinal pathogenic E. coli (ExPEC) and include pathogens of humans and animals. Previously, the genome of avian-pathogenic E. coli (APEC) O1:K1:H7 strain O1, from ST95, was sequenced and compared to those of several other E. coli strains, identifying 43 genomic islands. Here, the genomic islands of APEC O1 were compared to those of other sequenced E. coli strains, and the distribution of 81 genes belonging to 12 APEC O1 genomic islands among 828 human and avian ExPEC and commensal E. coli isolates was determined. Multiple islands were highly prevalent among isolates belonging to the O1 and O18 serogroups within phylogenetic group B2, which are implicated in human neonatal meningitis. Because of the extensive genomic similarities between APEC O1 and other human ExPEC strains belonging to the ST95 phylogenetic lineage, its ability to cause disease in a rat model of sepsis and meningitis was assessed. Unlike other ST95 lineage strains, APEC O1 was unable to cause bacteremia or meningitis in the neonatal rat model and was significantly less virulent than uropathogenic E. coli (UPEC) CFT073 in a mouse sepsis model, despite carrying multiple neonatal meningitis E. coli (NMEC) virulence factors and belonging to the ST95 phylogenetic lineage. These results suggest that host adaptation or genome modifications have occurred either in APEC O1 or in highly virulent ExPEC isolates, resulting in differences in pathogenicity. Overall, the genomic islands examined provide targets for further discrimination of the different ExPEC subpathotypes, serogroups, phylogenetic types, and sequence types.


Care Delivery for Children With Epilepsy During the COVID-19 Pandemic: An International Survey of Clinicians.
To evaluate the effect of the COVID-19 pandemic on global access to care and practice patterns for children with epilepsy. We conducted a cross-sectional, online survey of pediatric neurologists across the world affiliated with the International Child Neurology Association, the Chinese Child Neurology Society, the Child Neurology Society, and the Pediatric Epilepsy Research Consortium. Results were analyzed in relation to regional burden of COVID-19 disease. From April 10 to 24, 2020, a sample of 212 respondents from 49 countries indicated that the COVID-19 pandemic has dramatically changed many aspects of pediatric epilepsy care, with 91.5% reporting changes to outpatient care, 90.6% with reduced access to electroencephalography (EEG), 37.4% with altered management of infantile spasms, 92.3% with restrictions in ketogenic diet initiation, 93.4% with closed or severely limited epilepsy monitoring units, and 91.3% with canceled or limited epilepsy surgery. Telehealth use had increased, with 24.7% seeing patients exclusively via telehealth. Changes in practice were related both to COVID-19 burden and location. In response to COVID-19, pediatric epilepsy programs have implemented crisis standards of care that include increased telemedicine, decreased EEG use, changes in treatments of infantile spasms, and cessation of epilepsy surgery. The long-term impact of these abrupt changes merit careful study.


Epistasis among HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci determines multiple sclerosis susceptibility.
Multiple sclerosis (MS), a common central nervous system inflammatory disease, has a major heritable component. Susceptibility is associated with the MHC class II region, especially HLA-DRB5*0101-HLA-DRB1*1501-HLA-DQA1*0102-HLA-DQB1*0602 haplotypes(hereafter DR2), which dominate genetic contribution to MS risk. Marked linkage disequilibrium (LD) among these loci makes identification of a specific locus difficult. The once-leading candidate, HLA-DRB1*15, localizes to risk, neutral, and protective haplotypes. HLA-DRB1*15 and HLA-DQB1*0602, nearly always located together on a small ancestral chromosome segment, are strongly MS-associated. One intervening allele on this haplotype, viz. HLA-DQA1*0102, shows no primary MS association. Two Canadian cohorts (n = 830 and n = 438 trios) genotyped for HLA-DRB1, HLA-DQA1 and HLA-DQB1 alleles were tested for association using TDT. To evaluate epistasis involving HLA-DRB1*15, transmissions from HLA-DRB1*15-negative parents were stratified by the presence/absence of HLA-DRB1*15 in affected offspring. All 3 alleles contribute to MS susceptibility through novel epistatic interactions. HLA-DQA1*0102 increased disease risk when combined with HLA-DRB1*1501 in trans, thereby unambiguously implicating HLA-DQ in MS susceptibility. Three-locus haplotypes demonstrated that HLA-DRB1*1501 and HLA-DQB1*0602 each influence risk. Transmissions of rare morcellated DR2 haplotypes showed no interaction with HLA-DQA1*0102. Incomplete haplotypes bearing only HLA-DRB1*1501 or HLA-DQB1*0602 did not predispose to MS. Balanced reciprocal transmission distortion can mask epistatic allelic association. These findings implicate epistasis among HLA class II alleles in human immune responses generally, provide partial explanation for intense linkage disequilibrium in the MHC, have relevance to animal models, and demonstrate key roles for DR2-specific interactions in MS susceptibility. MHC disease associations may be more generally haplotypic or diplotypic.


To accurately estimate implicit influences on health behavior, accurately estimate explicit influences.
This project considered how inattention to left-out variable error and measurement correspondence in the assessment of explicit measures can result in upwardly biased estimates of the predictive utility of implicit measures designed to predict health behaviors. A pilot study (n = 96) used a cross-sectional design to predict beer consumption and a main study (n = 132) used a longitudinal design to predict binge drinking. In each study, a battery of 4 implicit inventories (implicit association test, personalized implicit association test, evaluative priming, and attribution misattribution paradigm) and a battery of correspondent explicit measures (based on the Reasoned Action Model and the Prototype Willingness Model) were administered to college youth. The Implicit Association Test and evaluative priming measures were not predictive of alcohol consumption in either study, but the personalized implicit association test (PIAT) and affective misattribution paradigm (AMP) accounted for between 5% and 12% in behavioral criteria, when analyzed in isolation or after explicit measures were statistically controlled following measurement conventions in this research domain. When implicit measures were folded into a structural equation model derived from the Reasoned Action and Prototype Willingness Models, The PIAT was no longer a significant predictor of behavior and the AMP resulted in a 1%-2% incremental increase in accounted for variance. Left-out variable error and measurement correspondence are core principles that need to be considered when modeling the relative contributions of implicit and explicit constructs in the prediction of health behaviors. (PsycINFO Database Record


The association between cigarette smoking and multiple sclerosis.
Genetic factors partially explain the susceptibility of multiple sclerosis (MS) and might even relate to the clinical course. Still, many epidemiological studies point at an important role for environmental factors in MS. Smoking is one of the major candidates. In this review we provide an overview of the epidemiological studies on cigarette smoking and the association on MS risk and MS clinical course. In addition, we discuss the possible biological pathways that may influence neurological damage in MS. Moreover, the relation of smoking with other environmental MS risk factors will be addressed.


Genomic (in)stability of the breast tumor microenvironment.
The breast tumor microenvironment plays an active role in tumorigenesis. Molecular alterations have been identified in tumor-associated stroma; however, there is considerable debate as to whether the stroma is characterized by genomic instability or whether detection of chromosomal alterations reflects technological artifact rather than the true genomic content of the tumor microenvironment. Thus, breast stroma specimens from 112 women undergoing reductive mammoplasty (n = 7), prophylactic mastectomy (n = 6), or mastectomy for a breast disease (n = 99) were frozen in optimal cutting temperature medium. Allelic imbalance (AI) analysis was conducted using a panel of 52 microsatellite markers in 484 stromal specimens from 98 women, of which 92% had no detectable AI events. When compared with previously generated AI data from 77 formalin-fixed, paraffin-embedded (FFPE) stroma specimens, 42% of which harbored at least one detectable AI event, the frequency of AI in the FFPE specimens (4.62%) was significantly higher (P < 0.001) than that found in frozen specimens (0.45%). This comparison of AI between FFPE and research-grade specimens suggests that past reports of AI in breast stroma reflect artifact in the archival specimens caused by formalin-fixation, paraffin-embedding and tissue storage. Furthermore, SNP data were generated from a subset of 86 stromal specimens using SNP arrays and copy number alterations were identified using Partek Genomics Suite. For 95% of the specimens, no detectable copy number alterations were found and the 11 changes that were detected were small and not shared between specimens. These data, therefore, support a model in which the tumor microenvironment is genetically stable.


Quantitative dynamics of Salmonella and E. coli in feces of feedlot cattle treated with ceftiofur and chlortetracycline.
Antibiotic use in beef cattle is a risk factor for the expansion of antimicrobial-resistant Salmonella populations. However, actual changes in the quantity of Salmonella in cattle feces following antibiotic use have not been investigated. Previously, we observed an overall reduction in Salmonella prevalence in cattle feces associated with both ceftiofur crystalline-free acid (CCFA) and chlortetracycline (CTC) use; however, during the same time frame the prevalence of multidrug-resistant Salmonella increased. The purpose of this analysis was to quantify the dynamics of Salmonella using colony counting (via a spiral-plating method) and hydrolysis probe-based qPCR (TaqMan® qPCR). Additionally, we quantified antibiotic-resistant Salmonella by plating to agar containing antibiotics at Clinical & Laboratory Standards Institute breakpoint concentrations. Cattle were randomly assigned to 4 treatment groups across 16 pens in 2 replicates consisting of 88 cattle each. Fecal samples from Days 0, 4, 8, 14, 20, and 26 were subjected to quantification assays. Duplicate qPCR assays targeting the Salmonella invA gene were performed on total community DNA for 1,040 samples. Diluted fecal samples were spiral plated on plain Brilliant Green Agar (BGA) and BGA with ceftriaxone (4 μg/ml) or tetracycline (16 μg/ml). For comparison purposes, indicator non-type-specific (NTS) E. coli were also quantified by direct spiral plating. Quantity of NTS E. coli and Salmonella significantly decreased immediately following CCFA treatment. CTC treatment further decreased the quantity of Salmonella but not NTS E. coli. Effects of antibiotics on the imputed log10 quantity of Salmonella were analyzed via a multi-level mixed linear regression model. The invA gene copies decreased with CCFA treatment by approximately 2 log10 gene copies/g feces and remained low following additional CTC treatment. The quantities of tetracycline or ceftriaxone-resistant Salmonella were approximately 4 log10 CFU/g feces; however, most of the samples were under the quantification limit. The results of this study demonstrate that antibiotic use decreases the overall quantity of Salmonella in cattle feces in the short term; however, the overall quantities of antimicrobial-resistant NTS E. coli and Salmonella tend to remain at a constant level throughout.


Investigating the association between strategic and pathological gambling behaviors and substance use in youth: could religious faith play a differential role?
This study investigated the link between gambling behaviors and the use of alcohol, drugs, and nonprescribed prescription medications, while exploring the moderating role of distinct religious faiths. In 2010, 570 students from the American University of Beirut completed a self-reported, anonymous English questionnaire, which included lifetime gambling and past-year substance use measures. Half (55%) were lifetime gamblers, of whom, 12% were probable pathological gamblers. About 60% were strategic gamblers. Lifetime gamblers were more than twice as likely as nongamblers to report past-year illegal drug use and alcohol abuse. Probable pathological gamblers were also more than four times as likely as nongamblers to report nonmedical prescription drug use, illegal drug use, and alcohol abuse. Compared to nonstrategic gamblers, strategic gamblers had more than three times the odds of illegal drug and cigarette use. The link between alcohol abuse and gambling was stronger among Christians than Muslims. Conversely, Muslims were more likely to report the co-occurrence of various gambling behaviors (lifetime, probable pathological, and strategic gambling) with both illegal drug use and cigarette use. Gambling and substance use behaviors were strongly linked in this sample of youth from Lebanon, corroborating the evidence from North America. Particularly novel are the co-occurrence of pathological gambling and nonmedical prescription drug use and the potential differential role of religion. (Am J Addict 2014;23:280-287).


Innervation patterns of thumb trapeziometacarpal joint ligaments.
The human thumb trapeziometacarpal (TM) joint is a unique articulation that allows stability during pinch and grip and great degrees of mobility. Because the saddle-shaped articulating surfaces of the TM joint are inherently unstable, joint congruity depends on the action of restraining ligaments and periarticular muscles. From other joints, it is known that proprioceptive and neuromuscular joint stability depend on afferent information from nerve endings within ligaments. We hypothesize that the TM joint ligaments may similarly be innervated, indicating a possible proprioceptive function of the joint. We harvested 5 TM joint ligaments in entirety from 10 fresh-frozen cadaver hands with no or only minor signs of osteoarthritis and suture-marked them for proximal-distal orientation. The ligaments harvested were the dorsal radial, dorsal central, posterior oblique, ulnar collateral, and anterior oblique ligaments. After paraffin-sectioning, we stained the ligaments using a triple-antibody immunofluorescent technique and analyzed them using immunofluorescence microscopy. Using the triple-stain technique, mechanoreceptors could be classified as Pacinian corpuscles, Ruffini endings, or Golgi-like endings. The 3 dorsal ligaments had significantly more nerve endings than the 2 volar ligaments. Most of the nerve endings were close to the bony attachments and significantly closer (P = .010) to the metacarpal insertion of each ligament. The anterior oblique ligament had little to no innervation in any of the specimens analyzed. The TM joint ligaments had an abundance of nerve endings in the dorsal ligaments but little to no innervation in the anterior oblique ligament. The Ruffini ending was the predominant mechanoreceptor type, with a greater density in the mobile metacarpal portion of each ligament. Presence of mechanoreceptors in the dorsal TM joint ligaments infers a proprioceptive function of these ligaments in addition to their biomechanical importance in TM joint stability.


High frequency laser Doppler measurements using multiaxial-mode lasers.
Generally applicable laser Doppler anemometers have become commercially available and are now widely used for fluid flow studies. When used for high velocity measurements, e.g., in excess of 100 m/sec, laser Doppler anemometers usually comprise a high power argon-ion laser and a counter signal processor. A literature survey showed that most high speed LDA measurements have been carried out at Doppler frequencies much below the frequency capabilities of modern LDA frequency counters. This paper suggests that this might be due to the multiaxial-mode output of cw lasers employed for high speed velocity measurements. The theory is discussed and experimental investigations are described that verify the theoretical results. These results suggest the use of single-mode lasers for high speed velocity measurements. The multiaxial-mode output of cw lasers is also claimed to be responsible for signal-to-noise ratio differences between LDA signals obtained with the blue and green lines of argon-ion lasers. The differences are only observed, however, when broadband detection systems are employed. Consideration is also given to the use of photodetectors for high frequency LDA systems. It is shown that photomultipliers that permit high anode currents are advantageous in laser Doppler anemometry; they are essential when measurements are made at high Doppler frequencies. Their use permits available high power lasers to be employed for LDA measurements and the high and basically noise-free gain of photomultipliers still to be used.


Adjustable Data Cleaning Towards Extracting Statistical Information.
Each device, organization, or human, is affected by the effects of Big Data. Analysing these vast amounts of data can be considered of vital importance, surrounded by many challenges. To address a portion of these challenges, a Data Cleaning approach is being proposed, designed to filter the non-important data. The functionality of the Data Cleaning is evaluated on top of Global Terrorism Data, to furtherly create policies on how terrorism is affecting national healthcare.


Signal processing in the TGF-beta superfamily ligand-receptor network.
The TGF-beta pathway plays a central role in tissue homeostasis and morphogenesis. It transduces a variety of extracellular signals into intracellular transcriptional responses that control a plethora of cellular processes, including cell growth, apoptosis, and differentiation. We use computational modeling to show that coupling of signaling with receptor trafficking results in a highly versatile signal-processing unit, able to sense by itself absolute levels of ligand, temporal changes in ligand concentration, and ratios of multiple ligands. This coupling controls whether the response of the receptor module is transient or permanent and whether or not different signaling channels behave independently of each other. Our computational approach unifies seemingly disparate experimental observations and suggests specific changes in receptor trafficking patterns that can lead to phenotypes that favor tumor progression.


Evaluation of portable microscopic devices for the diagnosis of Schistosoma and soil-transmitted helminth infection.
The diagnosis of parasitic worm (helminth) infections requires specialized laboratory settings, but most affected individuals reside in locations without access to such facilities. We tested two portable microscopic devices for the diagnosis of helminth infections in a cross-sectional survey in rural Côte d'Ivoire. We examined 164 stool samples under a light microscope and then re-examined with a commercial portable light microscope and an experimental mobile phone microscope for the diagnosis of Schistosoma mansoni and soil-transmitted helminths. Additionally, 180 filtered urine samples were examined by standard microscopy and compared with the portable light microscope for detection of Schistosoma haematobium eggs. Conventional microscopy was considered the diagnostic reference standard. For S. mansoni, S. haematobium and Trichuris trichiura, the portable light microscope showed sensitivities of 84.8%, 78.6% and 81.5%, respectively, and specificities of 85.7%, 91.0% and 93.0%, respectively. For S. mansoni and T. trichiura, we found sensitivities for the mobile phone microscope of 68.2% and 30.8%, respectively, and specificities of 64.3% and 71.0%, respectively. We conclude that the portable light microscope has sufficient diagnostic yield for Schistosoma and T. trichiura infections, while the mobile phone microscope has only modest sensitivity in its current experimental set-up. Development of portable diagnostic technologies that can be used at point-of-sample collection will enhance diagnostic coverage in clinical and epidemiological settings.


The p57 CDKi integrates stress signals into cell-cycle progression to promote cell survival upon stress.
The p57(Kip2) cyclin-dependent kinase inhibitor (CDKi) has been implicated in embryogenesis, stem-cell senescence and pathologies, but little is known of its role in cell cycle control. Here, we show that p57(Kip2) is targeted by the p38 stress-activated protein kinase (SAPK). Phosphorylation of p57(Kip2) at T143 by p38 enhances its association with and inhibition of Cdk2, which results in cell-cycle delay upon stress. Genetic inactivation of the SAPK or the CDKi abolishes cell-cycle delay upon osmostress and results in decreased cell viability. Oxidative stress and ionomycin also induce p38-mediated phosphorylation of p57 and cells lacking p38 or p57 display reduced viability to these stresses. Therefore, cell survival to various stresses depends on p57 phosphorylation by p38 that inhibits CDK activity. Together, these findings provide a novel molecular mechanism by which cells can delay cell cycle progression to maximize cell survival upon stress.


Iron-overload-related disease in HFE hereditary hemochromatosis.
Most persons who are homozygous for C282Y, the HFE allele most commonly asssociated with hereditary hemochromatosis, have elevated levels of serum ferritin and transferrin saturation. Diseases related to iron overload develop in some C282Y homozygotes, but the extent of the risk is controversial. We assessed HFE mutations in 31,192 persons of northern European descent between the ages of 40 and 69 years who participated in the Melbourne Collaborative Cohort Study and were followed for an average of 12 years. In a random sample of 1438 subjects stratified according to HFE genotype, including all 203 C282Y homozygotes (of whom 108 were women and 95 were men), we obtained clinical and biochemical data, including two sets of iron measurements performed 12 years apart. Disease related to iron overload was defined as documented iron overload and one or more of the following conditions: cirrhosis, liver fibrosis, hepatocellular carcinoma, elevated aminotransferase levels, physician-diagnosed symptomatic hemochromatosis, and arthropathy of the second and third metacarpophalangeal joints. The proportion of C282Y homozygotes with documented iron-overload-related disease was 28.4% (95% confidence interval [CI], 18.8 to 40.2) for men and 1.2% (95% CI, 0.03 to 6.5) for women. Only one non-C282Y homozygote (a compound heterozygote) had documented iron-overload-related disease. Male C282Y homozygotes with a serum ferritin level of 1000 mug per liter or more were more likely to report fatigue, use of arthritis medicine, and a history of liver disease than were men who had the wild-type gene. In persons who are homozygous for the C282Y mutation, iron-overload-related disease developed in a substantial proportion of men but in a small proportion of women.


The active and passive components of glucose absorption in rat jejunum under low and high perfusion stress.
In order to determine how perfusion design affects the relationship of the apparent "active" and "passive" components of glucose absorption, rat jejunum was perfused with 50 mM glucose under conditions of low and high mechanical stress. Phloretin or cytochalasin B was used to inhibit GLUT2 and phloridzin to inhibit SGLT1. In low stress perfusions, the ratios of the "passive" to the "active" components determined using phloretin and phloridzin were 2.2 and 0.43, respectively. This discrepancy was explained by the fact that phloridzin inhibits not only SGLT1 but also indirectly that part of the GLUT2-mediated component controlled by SGLT1 through the glucose-induced activation and recruitment of GLUT2 to the brush-border membrane. In high stress perfusions, the ratios of the "passive" to the "active" components determined using phloretin and phloridzin were 0.94 and 0.95, respectively; cytochalasin B gave 0.95. The identity of these results was explained by the observation that the passive component is not dependent on the active component, because glucose-induced activation and recruitment of GLUT2 does not occur in high stress perfusions. Simultaneous inhibition of SGLT1 and GLUT2 in high stress perfusions with phloridzin and cytochalasin B inhibited absorption by 92 +/- 7 %; non-carrier-mediated transport is therefore minimal. Our data provide support for the view that the term "facilitated" should be used to replace the term "passive" in describing the component now known to be mediated by GLUT2. The study of the mechanism and regulation of this facilitated component depends crucially on the design of the perfusion system.


Inter Organizational Practice Committee Recommendations/Guidance for Teleneuropsychology in Response to the COVID-19 Pandemic†.
The Inter Organizational Practice Committee convened a workgroup to provide rapid guidance about teleneuropsychology (TeleNP) in response to the COVID-19 pandemic. A collaborative panel of experts from major professional organizations developed provisional guidance for neuropsychological practice during the pandemic. The stakeholders included the American Academy of Clinical Neuropsychology/American Board of Clinical Neuropsychology, the National Academy of Neuropsychology, Division 40 of the American Psychological Association, the American Board of Professional Neuropsychology, and the American Psychological Association Services, Inc. The group reviewed literature; collated federal, regional, and state regulations and information from insurers; and surveyed practitioners to identify best practices. Literature indicates that TeleNP may offer reliable and valid assessments, but clinicians need to consider limitations, develop new informed consent procedures, report modifications of standard procedures, and state limitations to diagnostic conclusions and recommendations. Specific limitations affect TeleNP assessments of older adults, younger children, individuals with limited access to technology, and individuals with other individual, cultural, and/or linguistic differences. TeleNP may be contraindicated or infeasible given specific patient characteristics, circumstances, and referral questions. Considerations for billing TeleNP services are offered with reservations that clinicians must verify procedures independently. Guidance about technical issues and "tips" for TeleNP procedures are provided. This document provides provisional guidance with links to resources and established guidelines for telepsychology. Specific recommendations extend these practices to TeleNP. These recommendations may be revised as circumstances evolve, with updates posted continuously at IOPC.online.


A model for effective planning of SME support services.
This paper presents a model for effective planning of support services for small and medium-sized enterprises (SMEs). The idea is to scrutinize and measure the suitability of support services in order to give recommendations for the improvement of a support planning process. We examined the applied support services and matched them with the problems and needs of SMEs, based on the survey conducted in 2013 on a sample of 336 SMEs in Serbia. We defined and analysed the five research questions that refer to support services, their consistency with the SMEs' problems and needs, and the relation between the given support and SMEs' success. The survey results have shown a statistically significant connection between them. Based on this result, we proposed an eight-phase model as a method for the improvement of support service planning for SMEs. This model helps SMEs to plan better their requirements in terms of support; government and administration bodies at all levels and organizations that provide support services to understand better SMEs' problems and needs for support.


The efficacy and safety of Jian-Wei-Qu-Tong Pills for the treatment of chronic non-atrophic gastritis (spleen and stomach qi deficiency with damp-heat stasis syndrome): study protocol for a phase II, randomized controlled trial.
Chronic gastritis (CG), a poorly understood entity, is a very common disease of the digestive tract and is difficult to cure. Chronic non-atrophic gastritis (CNG) is the most common type of CG. Even if treated with current standard chemotherapy, some patients will not be freed from this confusing disease. Many studies have shown traditional Chinese medicine (TCM) is more effective compared to chemotherapy in the treatment of chronic gastritis and no serious side effects have been identified. However, the studies that have been carried out were not scientifically rigorous trials. Our aim is to design a high-quality trial for a new TCM drug, the Jian-Wei-Qu-Tong Pills (JWQTP), to investigate the efficacy and safety of this new drug in treating chronic non-atrophic gastritis patients with spleen and stomach qi deficiency with damp-heat stasis syndrome (SSQDDSS). This is a phase II, multicenter, parallel-group, double-blind, randomized and placebo-controlled trial. A total of 240 participants will be assigned to a high-dose group, a low-dose group or a placebo control group with a 1:1:1 ratio at five sites. Then, one dose (six 1-g pills), with a variable ratio between real drug and dummy drug according to the intervention protocol, will be taken three times a day before each meal for 8 weeks. The primary outcome is the eradication rate of epigastric pain. The secondary outcome includes the changes of endoscopic examination, histopathological examination, traditional Chinese medicine symptom scores and patient-reported outcome instrument scores for chronic gastrointestinal diseases and the eradication rate of Helicobacter pylori (HP). Many CNG patients suffer from frequent, recurrent bouts of dyspeptic symptoms. This is the first clinical trial to evaluate the safety and efficacy of JWQTP in treating CNG with SSQDDSS in a multicenter, parallel-group, double-blind, randomized and placebo-controlled manner. This trial may not only provide evidence for a phase III clinical trial, but also a vision of an alternative option for CNG treatment. The registration number, ChiCTR-TRC-14004088, was assigned by the Chinese Clinical Trial Registry on 7 January 2014.


TRPM8 ion channel is aberrantly expressed and required for preventing replicative senescence in pancreatic adenocarcinoma: potential role of TRPM8 as a biomarker and target.
Pancreatic adenocarcinoma is mostly fatal and generally resistant to conventional treatments, such that effective therapies with tolerable side effects are desperately needed. Ion channels including the transient receptor potential (TRP) channels have been implicated in human malignancies, but their roles in pancreatic cancer were mostly unknown. Recent identification of the melastatin-subfamily members of the TRP family of ion channels, and their functions in pancreatic epithelia and adenocarcinoma, is expected to provide a new perspective to understanding the mechanism underlying pancreatic tumorigenesis. In this report, we present the clinical and pathological features of a mini-series of patients with pancreatic adenocarcinoma, which aberrantly exhibits immunoreactivity against the TRPM8 channel. We have recently demonstrated the proliferative role of TRPM8 channel in pancreatic cancer cells. Here, we present evidence that RNA interference-mediated silencing of TRPM8 induces replicative senescence in pancreatic adenocarcinoma cells. This suggests that the aberrantly expressed TRPM8 channel may contribute to pancreatic tumorigenesis by preventing oncogene-induced senescence, and targeted inhibition of TRPM8 may enhance tumor sensitivity to therapeutics. Based on these observations, we hypothesize that the TRPM8 ion channel plays a crucial role in the growth and progression of pancreatic neoplasia during tumorigenesis. We propose that TRPM8 can be exploited as a clinical biomarker and as a therapeutic target for developing personalized therapy in pancreatic adenocarcinoma.