ent-Kaurane-based regio- and stereoselective inverse electron demand hetero-Diels-Alder reactions: synthesis of dihydropyran-fused diterpenoids.
A mild and concise approach for the construction of a 3,4-dihydro-2H-pyran ring integrated into the A-ring of the natural product oridonin using an optimized inverse electron demand hetero-Diels-Alder (IED HDA) reaction is reported herein. A self-dimerization of the exocyclic enone installed in the A-ring through a homo-HDA reaction was identified to exclusively give a dimeric ent-kaurane diterpenoid with the spirochroman core. Moreover, efficient cross-HDA cycloadditions of this enone with various vinyl ethers or vinyl sulfides, instead of its own homo-HDA dimerization, were achieved in a regio- and stereoselective manner, thus providing access to novel dihydropyran-fused diterpenoids as potential anticancer agents to overcome chemoresistance.


Targeting Plasmodium with constrained peptides and peptidomimetics.
Malaria remains a worldwide health concern with an estimated quarter of a billion people infected and nearly half a million deaths annually. Malaria is caused by a parasite infection from Plasmodium strains which are transmitted from mosquitoes into the human host. Although several small molecule inhibitors have been found to target the early stages of transmission and prevent parasite proliferation, multiple drug resistant parasite strains have emerged and drug resistance remains a major hurdle. As an alternative to small molecule inhibition, several peptide-based therapeutics have been explored for their potential as antimalarial compounds. Chemically constrained peptides or peptidomimetics were developed to target large binding interfaces of parasite-based proteins that have historically been difficult to selectively inhibit using small molecules. Here, we review ongoing research aimed at developing constrained peptides targeting protein-protein interactions pertinent to malaria pathogenesis. These targets include Falcipain-2, the J domain of CDPK1, myosin A tail domain interacting protein, the PKA signaling pathway, and an unclear signaling pathway involving angiotensin-derived peptides. Diverse synthetic methods were also used for each target. Merging parasite biology with synthetic strategies may provide new opportunities to develop alternative methods for uncovering novel antimalarials and may offer an alternate source for targeting drug-resistant parasite strains.


Psychopharmacological treatment of patients with borderline personality disorder: comparing data from routine clinical care with recommended guidelines.
Objectives: Borderline personality disorder (BPD) is a life-threatening mental disorder. Guideline recommendations for pharmacological treatment of patients with BPD vary widely. The objective of the present study was to investigate pharmacotherapy of BPD patients in a routine clinical care setting. Methods: Data on the pharmacological treatment of 110 patients (90% female) with BPD (F- 60.3), treated in an inpatient psychiatric-psychosomatic clinic in Austria were assessed. Results: Results show that clinicians frequently prescribe psychotropic medications to patients with BPD, in many cases multiple medications. The most commonly prescribed substance groups were antipsychotics, mood stabilisers and antidepressants. The most commonly prescribed individual drugs were Quetiapine, Lamotrigine and Setraline. There was no significant difference in the different types or overall number of medications prescribed to BPD patients with vs. without comorbid diagnoses. Pharmacotherapy was not related to comorbidity. Conclusions: The present study shows that in routine clinical care settings psychotropic medications are frequently prescribed to patients with BPD, very often resulting in polypharmacy. A positive association between the number of medications and the effectiveness of the inpatient treatment program, as well as the absence of a relationship between number of medications and comorbidity contradicts the often suggested iatrogenic effect of polypharmacy. Key points Guidelines for pharmacotherapy of borderline personality disorders lack consensus Yet, clinicians frequently prescribe psychotropic medications to BPD patients Types/number of medications prescribed to patients with vs. without comorbidities are similar Larger treatment effects are observed for patients with greater numbers of medications Further knowledge is needed about how and why clinicians prescribe medications.


Mutations of the serine protease inhibitor, Kazal type 1 gene, in patients with idiopathic chronic pancreatitis.
The pathogenesis of chronic pancreatitis (CP) is poorly understood. Genetic studies revealed mutations in the cationic trypsinogen gene and an increased frequency of cystic fibrosis gene mutations in patients with CP. Recently, a point mutation (N34S) in the gene encoding the serine protease inhibitor, Kazal type 1 (SPINK1), was found in approximately 20% of patients with CP. The aim of our study was to determine the frequency of the N34S SPINKI gene mutation in a well-defined patient cohort with idiopathic CP (ICP) and to compare the incidence with healthy controls. In addition, we investigated the impact of this mutation on the long-term course of CP. Fourteen patients with early-onset and four patients with late-onset CP of our well-defined pancreatitis cohort were enrolled in the present study, and 397 healthy individuals served as a control population. Coding exonic and the flanking intronic sequences of SPINK1 were investigated by direct DNA sequencing. The mutations found were confirmed by melting curve analysis. In addition, the N34S mutation was detected by analyzing the DNA fragments generated by digestion with restriction enzyme TspR I. Clinical data of patients with the N34S mutation were compared with those without mutations. The N34S mutation was detected in six of 14 (43%) patients with early-onset ICP. One patient was homozygous, and five patients were heterozygous for this mutation. The N34S mutation in a heterozygous state was found in four of 397 healthy controls (1.0%). The different allele frequency observed (seven of 28 vs four of 794) was significant (odds ratio = 66, 95% CI = 18-242, p < 0.0001). The clinical course was similar in patients with a mutation compared with those without a mutation. No other SPINKI mutations were detected. The N34S mutation was not found in patients with late-onset ICP. Our results indicate that the N34S mutation in the SPINKI gene is strongly associated with ICP, especially with the early-onset type. The natural course is similar in patients with mutations compared with SPINK1 mutation-negative patients. The N34S mutation may easily be screened for by restriction digestion with TspR I.


pH-mediated fluorescence and G-quadruplex binding of amido phthalocyanines.
A new family of G-quadruplex ligands termed "amido phthalocyanines" (APcs) was synthesized by reacting variable amino acids with tetraamino zinc phthalocyanine. Variation in the number of methylene units separating the APc scaffold from terminal ammonium groups systematically modulated ammonium pK(a) values that, in turn, mediated APc aggregation and DNA binding. Certain APcs exhibited nearly 1000-fold enhancements in fluorescence quantum yield upon binding G-quadruplex DNA under physiological conditions of pH and ionic strength. G-quadruplexes derived from the c-myc and c-kit promoters and the human telomeric repeat were evaluated for APc affinity and specificity using two complementary and direct fluorescence binding assays that revealed apparent dissociation constants ranging from 20 to 200 nM. Approximately 500-fold lower affinities for duplex and single-stranded DNAs were observed. Interestingly, APc-quadruplex binding was relatively insensitive to ionic strength (0.03-1 M KCl) but highly dependent on the pH of the solution. Our results provide a mechanism for the "turn-on" fluorescence properties exhibited by these compounds that will assist in future rational design of new G-quadruplex-specific fluorescent probes and drug candidates.


Relationship between changes in body fat and a decline of renal function in the elderly.
Obesity is a risk factor for chronic kidney disease, and its prevalence among the elderly is increasing. We investigated the effects of changes in body fat percentage (BFP) on the longitudinal changes in the estimated glomerular filtration rate (eGFR) in the elderly. This prospective cohort study included 390 participants aged >65 years who underwent bioelectrical impedance analysis at baseline and follow-up as a part of the Korean Longitudinal Study on Health and Aging. After a median follow-up period of 5.3 years, BFP was significantly higher than that at the start point (P<0.05). Participants who had the largest increase in BFP had the highest BMI and waist circumference (WC) (P<0.001). The highest tertile had the highest white blood cell count and erythrocyte sedimentation rate, incidence of rapid progression, and decline in eGFR >25% (P≤0.017, P = 0.025, P = 0.005, respectively). The lowest tertile had the lowest triglyceride and highest high-density lipoprotein levels (P<0.05). The adjusted decline rate in eGFR was correlated with a change in BFP (P = 0.039), but not with that in BMI or WC. The highest tertile had a 4.875-fold increase in the risk for rapid progression to a decline in eGFR (95% CI: 1.366-17.397) and a 4.931-fold decrease in the risk to a decline in eGFR>25% (95% CI: 1.617-15.037), when compared with the lowest tertile. In subgroup analysis, the incidence of renal outcomes was significantly increased according to the increase in BFP in patients with lower eGFR (P≤0.010). A change in BFP may be associated with inflammation and dyslipidemia development, and longitudinal changes in body fat are related to a decrease in eGFR in the elderly.


Muscle activity in the spinal cord-injured during wheelchair ambulation.
Right shoulder complex muscles of nondisabled, paraplegic, and quadriplegic subjects were monitored with electromyography (EMG) during standardized wheelchair ambulation. It was shown that wheelchair ambulation required the recruitment of large amounts of available motor units in spinal cord-injured persons. Motor unit recruitments differed for the groups: recruitment was minimal for the nondisabled subjects, moderate for paraplegics, and often maximal for quadriplegics. In addition, large intra- and intergroup variabilities were found in the pattern of muscle recruitment during the standardized wheelchair ambulation movement. The high variability shown in the muscle recruitment patterns of the normal individuals was unexpected, because the ambulation movement had been standardized as much as possible. The technique used to monitor muscle activity in this study reflects an example of how EMG can be employed to analyze activity during a movement. Using this technique one can objectively determine if assumptions about what is occurring in a muscle group during activity are correct.


Management of hepatocellular carcinoma with portal vein thrombosis.
Management of hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT) is complex and requires an understanding of multiple therapeutic options. PVT is present in 10%-40% of HCC at the time of diagnosis, and is an adverse prognostic factor. Management options are limited, as transplantation is generally contraindicated, and surgical resection is only rarely performed in select centers. Systemic medical therapy with sorafenib has been shown to modestly prolong survival. Transarterial chemoembolization has been performed in select cases but has shown a high incidence of complications. Emerging data on treatment of PVT with Y-90 radioembolization suggest that this modality is well-tolerated and associated with favorable overall survival. Current society guidelines do not yet specifically recommend radioembolization for patients with PVT, but this may change with the development of newer staging systems and treatment algorithms. In this comprehensive literature review, we present current and available management options with the relative advantages, disadvantages and contraindications of these treatment options with summarized data on overall survival.


Leisure-Time Physical Activity, Falls, and Fall Injuries in Middle-Aged Adults.
Although exercise and strength training have been shown to be protective against falls in older adults (aged 65 years and older), evidence for the role of leisure-time physical activity (LTPA) in the prevention of falls and resulting injuries in middle-aged adults (aged 45-64 years) is lacking. In the present study, we investigate the association between self-reported engagement in LTPA and the frequency of falls and fall-related injuries among middle-aged and older adults, while controlling for key sociodemographic and health characteristics. Nationally representative data from the 2010 U.S. Behavioral Risk Factor Surveillance Survey were analyzed in April 2014 to examine the number of adults aged ≥45 years who self-reported their fall experience in the previous 3 months and any injuries that resulted from those falls. We then evaluated the association between LTPA and self-reported falls and injuries across three age strata (45-54, 55-64, and ≥65 years). The two main self-reported outcome measures were (1) frequency of falls in the 3 months prior to the survey interview date and (2) the number of injuries resulting from these falls. Prevalence ratios (PRs) and 95% CIs were calculated using Poisson regression models with robust SEs. Of 340,680 survey participants aged ≥45 years, 70.7% reported engaging in LTPA, and 17% reported one or more falls. Among those reporting a fall within 3 months, 25.6% experienced one injurious fall (fall resulting in an injury) and 8.4% reported two or more injurious falls. Controlling for sociodemographic and health characteristics, among adults aged 45-54 years, those who engaged in LTPA were significantly less likely to report one fall (PR=0.90, 95% CI=0.81, 0.99); two or more falls (PR=0.84, 95% CI=0.77, 0.93); one injurious fall (PR=0.88, 95% CI=0.78, 0.99); and two or more injurious falls (PR=0.69, 95% CI=0.58, 0.83) than those who did not exercise. A similar protective effect of LTPA on reporting falls and injuries was noted for adults aged 55-64 and ≥65 years. Similar to older adults, middle-aged adults who engage in LTPA report fewer falls and fall-related injuries. Upon further confirmation of the relationship between LTPA and falls among middle-aged adults, fall prevention interventions could be developed for this population.


The influence of hygroscopic expansion of resin-based restorative materials on artificial gap reduction.
This study compared the effect of water sorption on the extent of marginal gap reduction in two resin-modified glass-ionomer cements (RMGICs), two giomers, two compomers, and two resin composites over a twelve-week storage period. Artificial gaps were created in 160 borosilicate glass cylinders. One-half of the internal surface of each cylinder was blocked out with wax and the other half was sandblasted. The bonding surface was further treated with 4% hydrofluoric acid, rinsed, and then coated with silane. After removal of the wax, one coat of dentin adhesive was applied to the silane-treated surface of the cylinder, briefly air dried and light cured. Eight light-cured restorative materials were placed incrementally: Vitremer (V), Fuji II LC (FJ), Beautifil (B), Reactmer Paste (R), Compoglass F (C), F2000 (F), Filtek Z250 (Z), and Tetric-Ceram (T). For each material, ten specimens were stored in deionized water (W), and ten (control) in nonaqueous silicone fluid (O) at 37 degrees C. The dimension of the same maximum gap created in each specimen was repeatedly measured at 0, 1, 2, 4, 6, 8, 10, and 12 weeks. R-W exhibited extensive hygroscopic expansion that resulted in cracking of 40% of glass cylinders after the 2nd week and 70% after the 4th week. One-way ANOVA of the other seven water groups showed significant differences (p < 0.001) among gap widths measured at different time intervals in V-W, FJ-W, C-W, F-W. Both RMGICs had the most significant gap reduction during the first week (p < 0.001). Both compomers exhibited delayed water-sorption characteristics, with more significant gap reduction observed in C-W. B-W was similar to the two resin composites Z-W and T-W and exhibited the least gap reduction. After the first week, there were no significant differences in the percentage reduction in marginal gaps for any of the groups (p > 0.05). Marginal gap reduction that results from water sorption is more extensive and rapid in RMG-ICs, followed by compomers, whereas composites are relatively stable. Reactmer Paste exhibits rapid and extensive expansion and should probably be avoided in tooth preparations that involve thin unsupported enamel.


Public understanding of medical terminology: non-English speakers may not receive optimal care.
Many systems of telephone triage are being developed (including NHS Direct, general practitioner out of hours centres, ambulance services). These rely on the ability to determine key facts from the caller. Level of consciousness is an important indicator after head injury but also an indicator of severe illness. To determine the general public's understanding of the term unconscious. A total of 700 people were asked one of seven questions relating to their understanding of the term unconscious. All participants were adults who could speak sufficient English to give a history to a nurse. Correct understanding of the term unconscious varied from 46.5% to 87.0% for varying parameters. Those with English as their first language had a better understanding (p<0.01) and there was a significant variation with ethnicity (p<0.05). Understanding of the term unconscious is poor and worse in those for whom English is not a first language. Decision making should not rely on the interpretation of questions using technical terms such as unconscious, which may have a different meaning between professional and lay people.


Emerging Electrochemical Sensors for Real-Time Detection of Tetracyclines in Milk.
Antimicrobial drug residues in food are strictly controlled and monitored by national laws in most territories. Tetracyclines are a major broad-spectrum antibiotic class, active against a wide range of Gram-positive and Gram-negative bacteria, and they are the leading choice for the treatment of many conditions in veterinary medicine in recent years. In dairy farms, milk from cows being treated with antibiotic drugs, such as tetracyclines, is considered unfit for human consumption. Contamination of the farm bulk tank with milk containing these residues presents a threat to confidence of supply and results in financial losses to farmers and dairy. Real-time monitoring of milk production for antimicrobial residues could reduce this risk and help to minimise the release of residues into the environment where they can cause reservoirs of antimicrobial resistance. In this article, we review the existing literature for the detection of tetracyclines in cow's milk. Firstly, the complex nature of the milk matrix is described, and the test strategies in commercial use are outlined. Following this, emerging biosensors in the low-cost biosensors field are contrasted against each other, focusing upon electrochemical biosensors. Existing commercial tests that identify antimicrobial residues within milk are largely limited to beta-lactam detection, or non-specific detection of microbial inhibition, with tests specific to tetracycline residues less prevalent. Herein, we review a number of emerging electrochemical biosensor detection strategies for tetracyclines, which have the potential to close this gap and address the industry challenges associated with existing tests.


Small Molecule, Big Prospects: MicroRNA in Pregnancy and Its Complications.
MicroRNAs are small, noncoding RNA molecules that regulate target gene expression in the posttranscriptional level. Unlike siRNA, microRNAs are "fine-tuners" rather than "switches" in the regulation of gene expression; thus they play key roles in maintaining tissue homeostasis. The aberrant microRNA expression is implicated in the disease process. To date, numerous studies have demonstrated the regulatory roles of microRNAs in various pathophysiological conditions. In contrast, the study of microRNA in pregnancy and its associated complications, such as preeclampsia (PE), fetal growth restriction (FGR), and preterm labor, is a young field. Over the last decade, the knowledge of pregnancy-related microRNAs has increased and the molecular mechanisms by which microRNAs regulate pregnancy or its associated complications are emerging. In this review, we focus on the recent advances in the research of pregnancy-related microRNAs, especially their function in pregnancy-associated complications and the potential clinical applications. Here microRNAs that associate with pregnancy are classified as placenta-specific, placenta-associated, placenta-derived circulating, and uterine microRNA according to their localization and origin. MicroRNAs offer a great potential for developing diagnostic and therapeutic targets in pregnancy-related disorders.


A prediction model for live birth and multiple births within the first three cycles of assisted reproductive technology.
To develop a model predictive of live-birth rates (LBR) and multiple birth rates (MBR) for an individual considering assisted reproduction technology (ART) using linked cycles from Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) for 2004-2011. Longitudinal cohort. Clinic-based data. 288,161 women with an initial autologous cycle, of whom 89,855 did not become pregnant and had a second autologous cycle and 39,334 did not become pregnant in the first and second cycles and had a third autologous cycle, with an additional 33,598 women who had a cycle using donor oocytes (first donor cycle). None. LBRs and MBRs modeled by woman's age, body mass index, gravidity, prior full-term births, infertility diagnoses by oocyte source, fresh embryos transferred, and cycle, using backward-stepping logistic regression with results presented as adjusted odds ratios (AORs) and 95% confidence intervals. The LBRs increased in all models with prior full-term births, number of embryos transferred; in autologous cycles also with gravidity, diagnoses of male factor, and ovulation disorders; and in donor cycles also with the diagnosis of diminished ovarian reserve. The MBR increased in all models with number of embryos transferred and in donor cycles also with prior full-term births. For both autologous and donor cycles, transferring two versus one embryo greatly increased the probability of a multiple birth (AOR 27.25 and 38.90, respectively). This validated predictive model will be implemented on the Society for Assisted Reproductive Technology Web site (www.sart.org) so that patients considering initiating a course of ART can input their data on the Web site to generate their expected outcomes.


LSE-Sign: A lexical database for Spanish Sign Language.
The LSE-Sign database is a free online tool for selecting Spanish Sign Language stimulus materials to be used in experiments. It contains 2,400 individual signs taken from a recent standardized LSE dictionary, and a further 2,700 related nonsigns. Each entry is coded for a wide range of grammatical, phonological, and articulatory information, including handshape, location, movement, and non-manual elements. The database is accessible via a graphically based search facility which is highly flexible both in terms of the search options available and the way the results are displayed. LSE-Sign is available at the following website: http://www.bcbl.eu/databases/lse/.


Selaginella tamariscina water extract inhibits receptor activator for the nuclear factor-κB ligand-induced osteoclast differentiation by blocking mitogen-activated protein kinase and NF-κB signaling.
Selaginella tamariscina has been traditionally used in Korea for treating hematochezia, hematuria, and prolapse of the anus. The aim of this study was to evaluate the inhibitory effect of Selaginella tamariscina water extract (ST-WE) on osteoclast differentiation, and to determine the underlying molecular mechanism. RAW264.7 cells were used as a model to examine receptor activator for the nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation. Expression of osteoclastic genes and transcription factors was evaluated by real-time quantitative polymerase chain reaction (QPCR). Activation of the mitogen-activated protein kinases, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38, and NF-κB were determined by Western blot analysis. ST-WE significantly inhibited RANKL-induced tartrate-resistant acid phosphatase (TRAP) activity and formation of multinucleated osteoclasts in RAW264.7 cells. ST-WE also significantly inhibited the RANKL-induced mRNA expression of TRAP, cathepsin K, and the d2 isoform of vacuolar ATPase V(0) domain (ATPv0d2) gene. In addition, ST-WE inhibited the RANKL-induced phosphorylation of ERK, JNK, and p38, phosphorylation of I-κB(α) and NF-κB p65, and the expression of transcription factors c-fos, Fra-2, and nuclear factor of activated T cells 1. Furthermore, ST inhibited the bone resorptive activity of osteoclasts. ST-WE might have beneficial effects on bonedisease by inhibiting osteoclastogenesis and osteoclastic activity.


Physiologic and molecular consequences of endothelial Bmpr2 mutation.
Pulmonary arterial hypertension (PAH) is thought to be driven by dysfunction of pulmonary vascular microendothelial cells (PMVEC). Most hereditary PAH is associated with BMPR2 mutations. However, the physiologic and molecular consequences of expression of BMPR2 mutations in PMVEC are unknown. In vivo experiments were performed on adult mice with conditional endothelial-specific expression of the truncation mutation Bmpr2delx4+, with age-matched transactivator-only mice as controls. Phenotype was assessed by RVSP, counts of muscularized vessels and proliferating cells, and staining for thromboses, inflammatory cells, and apoptotic cells. The effects of BMPR2 knockdown in PMVEC by siRNA on rates of apoptosis were assessed. Affymetrix expression arrays were performed on PMVEC isolated and cultured from triple transgenic mice carrying the immortomouse gene, a transactivator, and either control, Bmpr2delx4+ or Bmpr2R899X mutation. Transgenic mice showed increased RVSP and corresponding muscularization of small vessels, with histologic alterations including thrombosis, increased inflammatory cells, increased proliferating cells, and a moderate increase in apoptotic cells. Expression arrays showed alterations in specific pathways consistent with the histologic changes. Bmpr2delx4+ and Bmpr2R899X mutations resulted in very similar alterations in proliferation, apoptosis, metabolism, and adhesion; Bmpr2delx4+ cells showed upregulation of platelet adhesion genes and cytokines not seen in Bmpr2R899X PMVEC. Bmpr2 mutation in PMVEC does not cause a loss of differentiation markers as was seen with Bmpr2 mutation in smooth muscle cells. Bmpr2 mutation in PMVEC in vivo may drive PAH through multiple, potentially independent, downstream mechanisms, including proliferation, apoptosis, inflammation, and thrombosis.


The PDI genes of wheat and their syntenic relationship to the esp2 locus of rice.
The storage protein polymers in the endosperm, stabilised by disulphide bonds, determine a number of processing qualities of wheat dough. The enzyme protein disulphide isomerase (PDI), involved in the formation of disulphide bonds, is strongly suggested to play a role in the formation of wheat storage protein bodies. Reports of the rice mutant esp2 exhibiting aberrant storage protein deposition in conjunction with a lack of PDI expression provided strong indications of a direct role for PDI in storage protein deposition. The potential significance of wheat PDI prompted the present studies into exploring any orthology between wheat PDI genes and rice PDI and esp2 loci. By designing allele-specific (AS)-polymerase chain reaction (PCR) markers, two of the three wheat PDI genes could be genetically mapped to group 4 chromosomes and showed close association with GERMIN genes. Physical mapping led to localisation of wheat PDI genes to chromosomal "bins" on the proximal section of chromosome 4AL and distal sections of 4BS and 4DS. Identification of the putative PDI gene of rice and its comparison to the esp2 locus revealed that they were present at similar positions on the short arm of chromosome 11. Analysis of a large section of the PDI-containing section of rice chromosome 11S revealed a number of putative orthologues from The Institute for Genomic Research Triticum aestivum Gene Index database, of which five had been mapped, each localising to group 4 chromosomes, many in good agreement with our mapping results. The results strongly suggest a close linkage between the esp2 marker and the PDI gene of rice and an orthology between the PDI loci of rice and wheat and predict quantitative-trait loci involved in storage protein deposition at the PDI loci.


Associations of genetic variations of the endothelial nitric oxide synthase gene and environmental carcinogens with oral cancer susceptibility and development.
Oral cancer is a major head and neck cancer that is reported to be causally associated with genetic factors and environmental carcinogens. Endothelial nitric oxide synthase (eNOS) was reported to modulate carcinogenesis and progression through nitric oxide (NO) production. Genetic polymorphisms in the eNOS gene can regulate its transcription and further mediate NO production. The purpose of this study was to explore the influences of eNOS gene polymorphisms combined with environmental carcinogens on the predisposition for oral cancer. Two single-nucleotide polymorphisms (SNPs) of the eNOS gene, -786 T > C (rs2070744) and 894G > T (rs1799983), were genotyped in 1200 controls and 1044 patients with oral cancer using a TaqMan-based real-time polymerase chain reaction (PCR). We found that patients who carried the -786 T > C TC genotype were at higher risk for developing an advanced clinical stage (stage III/IV) compared to those with the -786 T > C TT genotype; however, there was no significant association of the two individual SNPs with oral cancer between patients and the control group. According to behavioral exposure to environmental carcinogens, the presence of these two eNOS SNPs combined with tobacco use and/or betel quid chewing profoundly enhanced the risk of oral cancer. Moreover, carriers with the betel quid-chewing habit who had haplotypes of the two eNOS SNPs more easily developed oral cancer. These results indicated an involvement of -786 T > C polymorphisms in the progression of oral cancer and support the interaction between eNOS gene polymorphisms and environmental carcinogens as a predisposing factor of oral carcinogenesis.


Effect of saccade automaticity on perisaccadic space compression.
Briefly presented stimuli occurring just before or during a saccadic eye movement are mislocalized, leading to a compression of visual space toward the target of the saccade. In most cases this has been measured in subjects over-trained to perform a stereotyped and unnatural task where saccades are repeatedly driven to the same location, marked by a highly salient abrupt onset. Here, we asked to what extent the pattern of perisaccadic mislocalization depends on this specific context. We addressed this question by studying perisaccadic localization in a set of participants with no prior experience in eye-movement research, measuring localization performance as they practiced the saccade task. Localization was marginally affected by practice over the course of the experiment and it was indistinguishable from the performance of expert observers. The mislocalization also remained similar when the expert observers were tested in a condition leading to less stereotypical saccadic behavior-with no abrupt onset marking the saccade target location. These results indicate that perisaccadic compression is a robust behavior, insensitive to the specific paradigm used to drive saccades and to the level of practice with the saccade task.


[Benefits of an add-on treatment with the synthetic cannabinomimetic nabilone on patients with chronic pain--a randomized controlled trial].
The aim of this study was to investigate the efficacy and efficiency of an add-on treatment with the synthetic cannabinomimetic nabilone on patients with chronic pain. Of major interest were the evaluation of the influence the treatment had on pain and on quality of life as well as the subjective assessment of positive effects and side effects by the study participants. The placebo-controlled double-blinded pilot study was divided into a 14 week cross-over period (two 4 week medication phases plus wash-out phases) followed by a 16 week medication switch period with free choice of the study drugs (drug A and drug B) by the study participants. The principal inclusion criterion was chronic therapy-resistant pain in causal relationship with a pathologic status of the skeletal and locomotor system. The study participants chose the dosage of the study drug themselves (between 1 und 4 capsules/day, in the case of nabilone this corresponds to (1/4)-1 mg/day). Pain intensity was assessed by a visual analogue scale (VAS), quality of life by the Mezzich and Cohen QOL-score. Altogether, 30 patients were included and analyzed. From the results, it is obvious that throughout the cross-over periods the nabilone treatment was superior (medians [25%-; 75%-percentiles]: nabilone/placebo): decrease of the average spinal pain intensity within the last 4 weeks (DeltaVAS) 0.9 [0.0; 2.0] / 0.5 [0.0; 1.7], decrease of the current spinal pain intensity (DeltaVAS) 0.6 [0.0; 2.5] / 0.0 [-1.0, 1.0] (p = .006), decrease of the average headache intensity within the last 4 weeks (DeltaVAS) 1.0 [-1.0; 2.4] / 0.2 [-0.9; 1.0], increase of the number of days without headache within the last 4 weeks 2.0 [0.0; 6.5] / 0.0 [-5.0; 4.0], increase of the quality of life (DeltaQOL-Score) 5.0 [0.8; 10.8] / 2.0 [-2.3; 8.0]. In the medication switch period, the number of study participants who favoured nabilone (nabilone intake > or =85% of all medication days) was more than 4 times higher than those who favoured placebo. The number of days with nabilone intake was clearly higher than the number with placebo intake (medians: 89% vs. 11% of all medication days, p = .003). In summary, the study results allow the conclusion that a majority of patients with chronic pain classify nabilone intake in addition to the standard treatment as a measure with a positive individual benefit-riskratio. Thus, this kind of treatment may be an interesting and attractive enrichment of analgetic therapy concepts.


In-gel activity-based protein profiling of a clickable covalent ERK1/2 inhibitor.
In-gel activity-based protein profiling (ABPP) offers rapid assessment of the proteome-wide selectivity and target engagement of a chemical tool. Here we demonstrate the use of the inverse electron demand Diels Alder (IEDDA) click reaction for in-gel ABPP by evaluating the selectivity profile and target engagement of a covalent ERK1/2 probe tagged with a trans-cyclooctene group. The chemical probe was shown to bind covalently to Cys166 of ERK2 using protein MS and X-ray crystallography, and displayed submicromolar GI50s in A375 and HCT116 cells. In both cell lines, the probe demonstrated target engagement and a good selectivity profile at low concentrations, which was lost at higher concentrations. The IEDDA cycloaddition enabled fast and quantitative fluorescent tagging for readout with a high background-to-noise ratio and thereby provides a promising alternative to the commonly used copper catalysed alkyne-azide cycloaddition.


Identification of genetic polymorphisms modulating nausea and vomiting in two series of opioid-treated cancer patients.
Nausea and vomiting are often associated with opioid analgesia in cancer patients; however, only a subset of patients develop such side effects. Here, we tested the hypothesis that the occurrence of nausea and vomiting is modulated by the genetic background of the patients. Whole exome sequencing of DNA pools from patients with either low (n = 937) or high (n = 557) nausea and vomiting intensity, recruited in the European Pharmacogenetic Opioid Study, revealed a preliminary association of 53 polymorphisms. PCR-based genotyping of 45 of these polymorphisms in the individual patients of the same series confirmed the association for six SNPs in AIM1L, CLCC1, MUC16, PDE3A, POM121L2, and ZNF165 genes. Genotyping of the same 45 polymorphisms in 264 patients of the Italian CERP study, also treated with opioids for cancer pain, instead confirmed the association for two SNPs in ZNF568 and PDE3A genes. Only one SNP, rs12305038 in PDE3A, was confirmed in both series, although with opposite effects of the minor allele on the investigated phenotype. Overall, our findings suggest that genetic factors are indeed associated with nausea and vomiting in opioid-treated cancer patients, but the role of individual polymorphisms may be weak.


Vaccinia virus infection induces a stress response that leads to association of Hsp70 with viral proteins.
We studied the impact of vaccinia virus infection on stress protein gene expression in human cells and investigated the possibility that eukaryotic heat shock proteins interact with viral components during assembly. Infection of human monocyte-macrophages by vaccinia virus caused a dramatic decrease in levels of cellular mRNAs such as those encoding actin and tubulin. In contrast, infection did not cause a significant reduction in the levels of Hsp90 and Hsp60 mRNAs and led to substantially increased levels of Hsp70 mRNAs. The accumulation of these stress protein mRNAs was due both to increases in their transcription rate and to their stability relative to other cellular mRNAs. The relative levels of the heat shock proteins and the other cellular proteins reflected the relative levels of their mRNAs. These results indicate that stress protein gene expression is relatively refractory to the generally deleterious effects of vaccinia virus infection on host cell gene expression. The continued expression of some of these stress proteins may be beneficial to the virus; the observations that the levels of Hsp70 are greatest at the peak of viral gene expression and that a large fraction of cellular Hsp70 is associated with vaccinia virus proteins suggest that Hsp70 is involved in vaccinia virus assembly.


Severe anaphylactic reactions in patients receiving oxaliplatin therapy: a rare but potentially fatal complication.
The most well-known adverse events of oxaliplatin are hematologic toxicity, gastrointestinal tract toxicity, and sensory neuropathy. However, hypersensitivity reaction of oxaliplatin, especially severe anaphylactic reactions (SAR), was less often reported. Three hundred and three patients with colon cancer treated by oxaliplatin-containing chemotherapy in one institution were analyzed. Patients were considered to have oxaliplatin-induced SAR if they suffered from at least one of the following symptoms after oxaliplatin infusion: symptomatic bronchospasm, allergy-related edema/angioedema, unstable blood pressure, or anaphylaxis. The reported cases in published literatures that met our definition were also reviewed. There were 4 out of 303 patients suffering from SAR after receiving oxaliplatin infusion, with an estimated incidence of 1.32%. Two of them became unconscious and had hypertensive crisis, and one patient had consciousness loss with hypotension. All four patients needed various level of oxygen support. Twenty-seven cases of oxaliplatin-induced SAR were found from Medline. Among the 31 reported cases, the most frequent SAR symptom was hypotension. However, we reported two unique SAR cases with hypertension crisis. In only four out of ten cases, patients could tolerate rechallenge of oxaliplatin. There is no association between the occurrence of oxaliplatin-induced SAR and metastatic sites. Oxaliplatin-induced SAR is a rare but potentially fatal complication. Hypertension crisis can be one of the oxaliplatin anaphylactic reactions. Only few patients suffering this complication could tolerate subsequent treatment of oxaliplatin by prolonged infusion time or using a desensitization schedule, thus changing regimen might be a better alternative for them.


Functional outcomes after shoulder resection: the patient's perspective.
Resection arthroplasty is a salvage procedure used for the treatment of deep-seated infections after total shoulder arthroplasty, hemiarthroplasty, and reverse total shoulder arthroplasty. Previous studies have reported a 50% to 66% rate of pain relief after resection arthroplasty but with significant functional limitations. Our study aimed to qualify the perspective of the patients on their limitations and satisfaction with resection arthroplasty. A retrospective record review of resection arthroplasties performed between September 2003 and December 2012 yielded 14 patients, and 7 completed the survey. The patients completed surveys with the focus on the "patient perspective." Functional scores, including American Shoulder and Elbow Surgeons, Simple Shoulder Test, Disabilities of the Arm, Shoulder, and Hand (DASH), DASH work, and DASH sports, were determined. Pain reduction and functional outcomes were similar to past reports of resection arthroplasty. Five of the 7 patients (71%) reported satisfaction with their resection arthroplasty, and 6 of the 7 patients (86%) would undergo the procedure again if given the choice. Five of the 7 patients (71%) were able to most of activities of daily living. Patients in our study were generally satisfied with their resection arthroplasty. Resection arthroplasty is a reasonable option for treatment of deep-seated periprosthetic infections or for patients with multiple previous failed procedures for total shoulder arthroplasty, hemiarthroplasty. and reverse shoulder arthroplasty.


Defective membrane repair in dysferlin-deficient muscular dystrophy.
Muscular dystrophy includes a diverse group of inherited muscle diseases characterized by wasting and weakness of skeletal muscle. Mutations in dysferlin are linked to two clinically distinct muscle diseases, limb-girdle muscular dystrophy type 2B and Miyoshi myopathy, but the mechanism that leads to muscle degeneration is unknown. Dysferlin is a homologue of the Caenorhabditis elegans fer-1 gene, which mediates vesicle fusion to the plasma membrane in spermatids. Here we show that dysferlin-null mice maintain a functional dystrophin-glycoprotein complex but nevertheless develop a progressive muscular dystrophy. In normal muscle, membrane patches enriched in dysferlin can be detected in response to sarcolemma injuries. In contrast, there are sub-sarcolemmal accumulations of vesicles in dysferlin-null muscle. Membrane repair assays with a two-photon laser-scanning microscope demonstrated that wild-type muscle fibres efficiently reseal their sarcolemma in the presence of Ca2+. Interestingly, dysferlin-deficient muscle fibres are defective in Ca2+-dependent sarcolemma resealing. Membrane repair is therefore an active process in skeletal muscle fibres, and dysferlin has an essential role in this process. Our findings show that disruption of the muscle membrane repair machinery is responsible for dysferlin-deficient muscle degeneration, and highlight the importance of this basic cellular mechanism of membrane resealing in human disease.


Surveillance for highly pathogenic avian influenza in wild birds in the USA.
As part of the USA's National Strategy for Pandemic Influenza, an Interagency Strategic Plan for the Early Detection of Highly Pathogenic H5N1 Avian Influenza in Wild Migratory Birds was developed and implemented. From 1 April 2006 through 31 March 2009, 261,946 samples from wild birds and 101,457 wild bird fecal samples were collected in the USA; no highly pathogenic avian influenza was detected. The United States Department of Agriculture, and state and tribal cooperators accounted for 213,115 (81%) of the wild bird samples collected; 31, 27, 21 and 21% of the samples were collected from the Atlantic, Pacific, Central and Mississippi flyways, respectively. More than 250 species of wild birds in all 50 states were sampled. The majority of wild birds (86%) were dabbling ducks, geese, swans and shorebirds. The apparent prevalence of low pathogenic avian influenza viruses during biological years 2007 and 2008 was 9.7 and 11.0%, respectively. The apparent prevalence of H5 and H7 subtypes across all species sampled were 0.5 and 0.06%, respectively. The pooled fecal samples (n= 101,539) positive for low pathogenic avian influenza were 4.0, 6.7 and 4.7% for biological years 2006, 2007 and 2008, respectively. The highly pathogenic early detection system for wild birds developed and implemented in the USA represents the largest coordinated wildlife disease surveillance system ever conducted. This effort provided evidence that wild birds in the USA were free of highly pathogenic avian influenza virus (given the expected minimum prevalence of 0.001%) at the 99.9% confidence level during the surveillance period.


A data management and publication workflow for a large-scale, heterogeneous sensor network.
It is common for hydrology researchers to collect data using in situ sensors at high frequencies, for extended durations, and with spatial distributions that produce data volumes requiring infrastructure for data storage, management, and sharing. The availability and utility of these data in addressing scientific questions related to water availability, water quality, and natural disasters relies on effective cyberinfrastructure that facilitates transformation of raw sensor data into usable data products. It also depends on the ability of researchers to share and access the data in useable formats. In this paper, we describe a data management and publication workflow and software tools for research groups and sites conducting long-term monitoring using in situ sensors. Functionality includes the ability to track monitoring equipment inventory and events related to field maintenance. Linking this information to the observational data is imperative in ensuring the quality of sensor-based data products. We present these tools in the context of a case study for the innovative Urban Transitions and Aridregion Hydrosustainability (iUTAH) sensor network. The iUTAH monitoring network includes sensors at aquatic and terrestrial sites for continuous monitoring of common meteorological variables, snow accumulation and melt, soil moisture, surface water flow, and surface water quality. We present the overall workflow we have developed for effectively transferring data from field monitoring sites to ultimate end-users and describe the software tools we have deployed for storing, managing, and sharing the sensor data. These tools are all open source and available for others to use.


Ni3TeO6--a collinear antiferromagnet with ferromagnetic honeycomb planes.
We report a comprehensive study of magnetic properties of Ni(3)TeO(6). The system crystallizes in a noncentrosymmetric rhombohedral lattice, space group R3. There are three differently coordinated Ni atoms in the unit cell. Two of them form an almost planar honeycomb lattice, while the third one is placed between the layers. Magnetization and specific heat measurements revealed a single magnetic ordering at T(N) = 52 K. Below T(N) the susceptibility with the magnetic field parallel to the c axis drops towards zero while the perpendicular susceptibility remains constant, a characteristic of antiferromagnetic materials. Neutron diffraction confirmed that the system is antiferromagnet below T(N) with ferromagnetic ab planes stacked antiferromagnetically along the c axis. All Ni moments are in the S = 1 spin state and point along the c axis.


Positive symptoms are associated with clinicians' global impression in treatment-resistant schizophrenia.
Previous investigations on the relationship between global rating measures and symptoms have not considered the additional role of functioning. In this naturalistic study, we examined the relationship between symptom domains and functioning on Clinical Global Impression scales for severity (CGI-S) and improvement (CGI-I) in a sample of patients with schizophrenia assessed to be treatment resistant. Participants were patients with a diagnosis of schizophrenia or schizoaffective disorder who failed 2 prior antipsychotic trials and were considered candidates for clozapine. They were assessed on the 18-item Brief Psychiatric rating Scale (BPRS), Social Occupational Functioning Assessment Scale (SOFAS), and CGI-S at baseline. A subset of patients was followed up at 6 weeks after initiation of clozapine and assessed on the CGI-I. The independent effects of symptom domains and functioning on the CGI scales were examined via multivariate regression models. Brief Psychiatric rating Scale positive factor (P < 0.001) and SOFAS (P < 0.001) scores were significant determinants of CGI-S at baseline. Multivariate models suggested that relative change measures had a better fit for the CGI-I compared to absolute change measures (R = 0.72 vs R = 0.61, respectively). Improvements in BPRS positive (P < 0.001) and affect (P = 0.002) factors and SOFAS (P = 0.030) scores were significant determinants of CGI-I. Ratings of 1 and 2 on the CGI-I corresponded to a mean relative change in the BPRS total of 65% and 41%, respectively. Positive symptoms were a key determinant of clinicians' impression of severity and improvement in this study. Although psychosocial functioning played a large part in determining severity, it was not as significant in the assessment of improvement.


Continuous Versus Bolus Gastric Feeding in Children Receiving Mechanical Ventilation: A Systematic Review.
Nutrition guidelines recommend enteral nutrition in the form of gastric feedings for critically ill children and acknowledge a lack of evidence describing an optimal method for providing these feedings. To determine the state of the science regarding the efficacy of bolus (intermittent) or continuous gastric feedings to improve nutrition delivery in critically ill children receiving mechanical ventilation. Five hundred seventy-nine abstracts met the inclusion criteria and were screened by 2 reviewers according to prespecified criteria. Full-text reviews were performed on 28 articles; 11 studies were selected for detailed analysis. Because of the small number of eligible studies, broader searches were conducted. Only 5 studies with a collective enrollment of fewer than 200 children closely addressed the specific research question. These 5 studies did not report any similarity in feeding regimens, nor did they report nutritional outcomes. Two of the articles described findings from the same study population. Although 4 of the 5 studies randomized children to bolus versus continuous feedings, only 3 studies described attainment of nutrient delivery goals in both the intervention and the control groups; the remaining study did not report this outcome. The heterogeneity in methodology and outcomes among the 5 studies did not allow for a meta-analysis. The dearth of evidence regarding best practices and outcomes related to bolus versus continuous gastric feedings in critically ill children receiving mechanical ventilation requires additional rigorous investigation.


Assessing the distribution of volatile organic compounds using land use regression in Sarnia, "Chemical Valley", Ontario, Canada.
Land use regression (LUR) modelling is proposed as a promising approach to meet some of the challenges of assessing the intra-urban spatial variability of ambient air pollutants in urban and industrial settings. However, most of the LUR models to date have focused on nitrogen oxides and particulate matter. This study aimed at developing LUR models to predict BTEX (benzene, toluene, ethylbenzene, m/p-xylene and o-xylene) concentrations in Sarnia, 'Chemical Valley', Ontario, and model the intra-urban variability of BTEX compounds in the city for a community health study. Using Organic Vapour Monitors, pollutants were monitored at 39 locations across the city of Sarnia for 2 weeks in October 2005. LUR models were developed to generate predictor variables that best estimate BTEX concentrations. Industrial area, dwelling counts, and highways adequately explained most of the variability of BTEX concentrations (R2: 0.78 - 0.81). Correlations between measured BTEX compounds were high (> 0.75). Although most of the predictor variables (e.g. land use) were similar in all the models, their individual contributions to the models were different. Yielding potentially different health effects than nitrogen oxides and particulate matter, modelling other air pollutants is essential for a better understanding of the link between air pollution and health. The LUR models developed in these analyses will be used for estimating outdoor exposure to BTEX for a larger community health study aimed at examining the determinants of health in Sarnia.


Quantitative evaluation of collagen crosslinks and corresponding tensile mechanical properties in mouse cervical tissue during normal pregnancy.
The changes in the mechanical integrity of the cervix during pregnancy have implications for a successful delivery. Cervical collagens are known to remodel extensively in mice with progressing gestation leading to a soft cervix at term. During this process, mature crosslinked collagens are hypothesized to be replaced with immature less crosslinked collagens to facilitate cervical softening and ripening. To determine the mechanical role of collagen crosslinks during normal mouse cervical remodeling, tensile load-to-break tests were conducted for the following time points: nonpregnant (NP), gestation day (d) 6, 12, 15, 18 and 24 hr postpartum (PP) of the 19-day gestation period. Immature crosslinks (HLNL and DHLNL) and mature crosslinks (DPD and PYD) were measured using ultra performance liquid chromatography-electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS). There were no significant changes in the total immature crosslink density (HLNL+DHLNL mol per collagen mol) throughout normal mouse gestation (range: 0.31-0.49). Total mature crosslink density (PYD+DPD mol per collagen mol) decreased significantly in early softening from d6 to d15 (d6: 0.17, d12: 0.097, d15: 0.026) and did not decrease with further gestation. The maturity ratio (total mature to total immature crosslinks) significantly decreased in early softening from d6 to d15 (d6: 0.2, d15: 0.074). All of the measured crosslinks correlated significantly with a measure of tissue stiffness and strength, with the exception of the immature crosslink HLNL. This data provides quantitative evidence to support the hypothesis that as mature crosslinked collagens decline, they are replaced by immature collagens to facilitate increased tissue compliance in the early softening period from d6 to d15.


Intraoperative changes in transcranial motor evoked potentials and somatosensory evoked potentials predicting outcome in children with intramedullary spinal cord tumors.
Intraoperative dorsal column mapping, transcranial motor evoked potentials (TcMEPs), and somatosensory evoked potentials (SSEPs) have been used in adults to assist with the resection of intramedullary spinal cord tumors (IMSCTs) and to predict postoperative motor deficits. The authors sought to determine whether changes in MEP and SSEP waveforms would similarly predict postoperative motor deficits in children. The authors reviewed charts and intraoperative records for children who had undergone resection for IMSCTs as well as dorsal column mapping and TcMEP and SSEP monitoring. Motor evoked potential data were supplemented with electromyography data obtained using a Kartush microstimulator (Medtronic Inc.). Motor strength was graded using the Medical Research Council (MRC) scale during the preoperative, immediate postoperative, and follow-up periods. Reductions in SSEPs were documented after mechanical traction, in response to maneuvers with the cavitational ultrasonic surgical aspirator (CUSA), or both. Data from 12 patients were analyzed. Three lesions were encountered in the cervical and 7 in the thoracic spinal cord. Two patients had lesions of the cervicomedullary junction and upper spinal cord. Intraoperative MEP changes were noted in half of the patients. In these cases, normal polyphasic signals converted to biphasic signals, and these changes correlated with a loss of 1-2 grades in motor strength. One patient lost MEP signals completely and recovered strength to MRC Grade 4/5. The 2 patients with high cervical lesions showed neither intraoperative MEP changes nor motor deficits postoperatively. Dorsal columns were mapped in 7 patients, and the midline was determined accurately in all 7. Somatosensory evoked potentials were decreased in 7 patients. Two patients each had 2 SSEP decreases in response to traction intraoperatively but had no new sensory findings postoperatively. Another 2 patients had 3 traction-related SSEP decreases intraoperatively, and both had new postoperative sensory deficits that resolved. One additional patient had a CUSA-related SSEP decrease intraoperatively, which resolved postoperatively, and the last patient had 3 traction-related sensory deficits and a CUSA-related sensory deficit postoperatively, none of which resolved. Intraoperative TcMEPs and SSEPs can predict the degree of postoperative motor deficit in pediatric patients undergoing IMSCT resection. This technique, combined with dorsal column mapping, is particularly useful in resecting lesions of the upper cervical cord, which are generally considered to be high risk in this population. Furthermore, the spinal cord appears to be less tolerant of repeated intraoperative SSEP decreases, with 3 successive insults most likely to yield postoperative sensory deficits. Changes in TcMEPs and SSEP waveforms can signal the need to guard against excessive manipulation thereby increasing the safety of tumor resection.


What You Do Not Know Could Hurt You: What Women Wish Their Doctors Had Told Them About Chemotherapy Side Effects on Memory and Response to Alcohol.
For many patients, a cancer diagnosis is followed by chemotherapy treatment, which works by attacking cells that are growing and dividing throughout the body. Although cancer cells grow and divide more quickly than healthy cells, both are targets. The loss of healthy cells is associated with side effects, such as memory loss and altered response to a variety of food and drugs. In this pilot study, we use the "Survey of female cancer treatments, effects on memory and alcohol awareness" to explore trends in female experience and awareness of side effects associated with chemotherapy. We examined 79 female cancer patients, 46 Spanish-speaking women in Puerto Rico and 33 English-speaking women in the continental United States, and compared the rates of a reported memory loss or an altered ethanol response following chemotherapy, whether or not potential side effects were discussed with a medical professional, and whether they experienced changes in alcohol consumption after treatment. A majority of participants reported having experienced short-term memory loss postchemotherapy. Changes in response to alcohol and an altered sensitivity to alcohol were also reported by 25%-47% of the respondents. Additionally, more than half of all female cancer patients reported that they wished they would have received information on the side effects of chemotherapy and secondary medications prior to treatment. The survey results suggest that medical professionals are not adequately informing women of common, potentially harmful side effects of chemotherapy. Women do wish to be more educated about potential side effects related to memory and alcohol and be given the opportunity to discuss potential outcomes with a medical professional prior to treatment to reduce the negative impact of treatment-related side effects on posttreatment quality of life.


Identification of novel graded polarity actin filament bundles in locomoting heart fibroblasts: implications for the generation of motile force.
We have determined the structural organization and dynamic behavior of actin filaments in entire primary locomoting heart fibroblasts by S1 decoration, serial section EM, and photoactivation of fluorescence. As expected, actin filaments in the lamellipodium of these cells have uniform polarity with barbed ends facing forward. In the lamella, cell body, and tail there are two observable types of actin filament organization. A less abundant type is located on the inner surface of the plasma membrane and is composed of short, overlapping actin bundles (0.25-2.5 microm) that repeatedly alternate in polarity from uniform barbed ends forward to uniform pointed ends forward. This type of organization is similar to the organization we show for actin filament bundles (stress fibers) in nonlocomoting cells (PtK2 cells) and to the known organization of muscle sarcomeres. The more abundant type of actin filament organization in locomoting heart fibroblasts is mostly ventrally located and is composed of long, overlapping bundles (average 13 microm, but can reach up to about 30 microm) which span the length of the cell. This more abundant type has a novel graded polarity organization. In each actin bundle, polarity gradually changes along the length of the bundle. Actual actin filament polarity at any given point in the bundle is determined by position in the cell; the closer to the front of the cell the more barbed ends of actin filaments face forward. By photoactivation marking in locomoting heart fibroblasts, as expected in the lamellipodium, actin filaments flow rearward with respect to substrate. In the lamella, all marked and observed actin filaments remain stationary with respect to substrate as the fibroblast locomotes. In the cell body of locomoting fibroblasts there are two dynamic populations of actin filaments: one remains stationary and the other moves forward with respect to substrate at the rate of the cell body. This is the first time that the structural organization and dynamics of actin filaments have been determined in an entire locomoting cell. The organization, dynamics, and relative abundance of graded polarity actin filament bundles have important implications for the generation of motile force during primary heart fibroblast locomotion.


Prioritizing congenital syphilis control in south China: a decision analytic model to inform policy implementation.
Syphilis is a major public health problem in many regions of China, with increases in congenital syphilis (CS) cases causing concern. The Chinese Ministry of Health recently announced a comprehensive 10-y national syphilis control plan focusing on averting CS. The decision analytic model presented here quantifies the impact of the planned strategies to determine whether they are likely to meet the goals laid out in the control plan. Our model incorporated data on age-stratified fertility, female adult syphilis cases, and empirical syphilis transmission rates to estimate the number of CS cases associated with prenatal syphilis infection on a yearly basis. Guangdong Province was the focus of this analysis because of the availability of high-quality demographic and public health data. Each model outcome was simulated 1,000 times to incorporate uncertainty in model inputs. The model was validated using data from a CS intervention program among 477,656 women in China. Sensitivity analyses were performed to identify which variables are likely to be most influential in achieving Chinese and international policy goals. Increasing prenatal screening coverage was the single most effective strategy for reducing CS cases. An incremental increase in prenatal screening from the base case of 57% coverage to 95% coverage was associated with 106 (95% CI: 101, 111) CS cases averted per 100,000 live births (58% decrease). The policy strategies laid out in the national plan led to an outcome that fell short of the target, while a four-pronged comprehensive syphilis control strategy consisting of increased prenatal screening coverage, increased treatment completion, earlier prenatal screening, and improved syphilis test characteristics was associated with 157 (95% CI: 154, 160) CS cases averted per 100,000 live births (85% decrease). The Chinese national plan provides a strong foundation for syphilis control, but more comprehensive measures that include earlier and more extensive screening are necessary for reaching policy goals.


Recent advances in combretastatin based derivatives and prodrugs as antimitotic agents.
The dynamic and crucial role of tubulin in different cellular functions rendered it a promising target in anticancer drug development. Combretastatin A-4 (CA-4), an inhibitor of tubulin polymerization isolated from natural sources, is a lead molecule with significant cytotoxicity against tumour cells. Owing to its non polar nature it exhibits low solubility in natural biological fluids, thereby prompting the development of new CA-4 based derivatives. The modification of this lead molecule was mostly carried out by keeping the crucial cis-orientation of the double bond intact, along with a trimethoxyphenyl aromatic ring, by employing different approaches. The issue of solubility was also addressed by the development of water soluble prodrugs of CA-4. The present review highlights the investigations into the parallel development of both new CA-4 based derivatives and prodrugs in the past few years.


CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide.
CUSP9 treatment protocol for recurrent glioblastoma was published one year ago. We now present a slight modification, designated CUSP9*. CUSP9* drugs--aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, sertraline, ritonavir, are all widely approved by regulatory authorities, marketed for non-cancer indications. Each drug inhibits one or more important growth-enhancing pathways used by glioblastoma. By blocking survival paths, the aim is to render temozolomide, the current standard cytotoxic drug used in primary glioblastoma treatment, more effective. Although esthetically unpleasing to use so many drugs at once, the closely similar drugs of the original CUSP9 used together have been well-tolerated when given on a compassionate-use basis in the cases that have come to our attention so far. We expect similarly good tolerability for CUSP9*. The combined action of this suite of drugs blocks signaling at, or the activity of, AKT phosphorylation, aldehyde dehydrogenase, angiotensin converting enzyme, carbonic anhydrase -2,- 9, -12, cyclooxygenase-1 and -2, cathepsin B, Hedgehog, interleukin-6, 5-lipoxygenase, matrix metalloproteinase -2 and -9, mammalian target of rapamycin, neurokinin-1, p-gp efflux pump, thioredoxin reductase, tissue factor, 20 kDa translationally controlled tumor protein, and vascular endothelial growth factor. We believe that given the current prognosis after a glioblastoma has recurred, a trial of CUSP9* is warranted.


Genome to kinome: species-specific peptide arrays for kinome analysis.
Tools for conducting high-throughput kinome analysis do not exist for many species. For example, two commonly used techniques for monitoring phosphorylation events are phosphorylation-specific antibodies and peptide arrays. The majority of phosphorylation-specific antibodies are for human or mouse targets, and the construction of peptide arrays relies on information from phosphorylation databases, which are similarly biased toward human and mouse data. This is a substantial obstacle because many species other than mouse represent important biological models. On the basis of the observation that phosphorylation events are often conserved across species with respect to their relative positioning within proteins and their biological function, we demonstrate that it is possible to predict the sequence contexts of phosphorylation events in other species for the production of peptide arrays for kinome analysis. Through this approach, genomic information can be rapidly used to create inexpensive, customizable, species-specific peptide arrays for high-throughput kinome analysis. We anticipate that these arrays will be valuable for investigating the conservation of biological responses across species, validating animal models of disease, and translating research to clinical applications.


Evidence for canalization of Distal-less function in the leg of Drosophila melanogaster.
A considerable body of theory pertaining to the evolution of canalization has emerged recently, yet there have been few empirical investigations of their predictions. To address this, patterns of canalization and trait correlation were investigated under the individual and joint effects of the introgression of a loss-of-function allele of the Distal-less gene and high-temperature stress on a panel of iso-female lines. Variation was examined for number of sex comb teeth and the length of the basi-tarsus on the pro-thoracic leg of male Drosophila melanogaster. I demonstrate that whereas there is evidence for trait canalization, there is no evidence to support the hypothesis of the evolution of genetic canalization as a response to microenvironmental canalization. Furthermore, I demonstrate that although there are genetic correlations between these traits, there is no association between their measures of canalization. I discuss the prospects of the evolutionary lability of the Distal-less gene within the context of changes in genetic variation and covariation.


Behavioral economics-A framework for donor organ decision-making in pediatric heart transplantation.
The high discard rate of pediatric donor hearts presents a major challenge for children awaiting heart transplantation. Recent literature identifies several factors that contribute to the disparities in pediatric donor heart usage, including regulatory oversight, the absence of guidelines on pediatric donor heart acceptance, and variation among transplant programs. However, a likely additional contributor to this issue are the behavioral factors influencing transplant team decisions in donor offer scenarios, a topic that has not yet been studied in detail. Behavioral economics and decision psychology provide an excellent foundation for investigating decision-making in the pediatric transplant setting, offering key insights into the behavior of transplant professionals. We conducted a systematic review of published literature in pediatric heart transplant related to behavioral economics and the psychology of decision-making. In this review, we draw on paradigms from these two domains in order to examine how existing aspects of the transplant environment, including regulatory oversight, programmatic variation, and allocation systems, may precipitate potential biases surrounding donor offer decisions. Recognizing how human decision behavior influences donor acceptance is a first step toward improving utilization of potentially viable pediatric donor hearts.


Propofol Suppresses Esophageal Squamous Cell Carcinoma Cell Migration and Invasion by Down-Regulation of Sex-Determining Region Y-box 4 (SOX4).
BACKGROUND This study was done to verify whether propofol could inhibit esophageal squamous cell carcinoma (ESCC) cell line EC9706 cell migration and invasion by targeting SOX4. MATERIAL AND METHODS Different concentrations of propofol were co-incubated with EC9706 cells. The pcDNA-SOX4 or SOX4 siRNA plasmid was transfected into cells before the treatment with propofol 5 µg/L. The migratory and invasion ability of EC9706 cells were tested by wound-healing assay and Transwell chambers. Western blotting was used to investigate the expressions of MMP-2, MMP-9, TIMP-1, TIMP-2, and SOX4. Gelatin zymography was employed to detect the activity of MMP2 and MMP-9. RESULTS Compared with the control, the migration and invasion activity of EC9706 cells were decreased after incubation with different concentrations of propofol (P<0.01). The expression of MMP-2, MMP-9, and SOX4 was decreased and that of TIMP-1 was increased in the propofol-treated EC9706 cells (P<0.01). Down-regulation of SOX4 by SOX4-siRNA had the same effect as propofol on EC9706 cells, including suppressing cell migration and invasion, inhibiting the expression and activity of MMP-2/9, and increasing the expression TIMP-1. Over-expression of SOX4 could partly abrogated propofol-mediated inhibition of EC9706 cell migration and invasion. CONCLUSIONS Propofol inhibits EC9706 cell migration and invasion by down-regulation of SOX4.


Misoprostol as a labor induction agent.
The objective of this investigation was to compare the efficacy, safety, and cost of intravaginal misoprostol as a labor induction agent to a standard protocol using prostaglandin E2 (Prepidil) and intravenous oxytocin. Thirty-eight patients requiring induction of labor with an unfavorable cervix (Bishop score < or = 5) were prospectively randomized to receive either 50 mcg misoprostol every 4 hours until delivery, or a single dose of PGE2 gel (0.5 mg) followed by intravenous oxytocin infusion. Changes in Bishop scores were recorded in a blinded fashion. Clinical outcomes were compared in the two groups, including induction-to-delivery times and cesarean section rates. Seventeen women were treated with misoprostol, 19 patients received PGE2/oxytocin, and two patients dropped out of the study. The groups did not differ significantly with respect to age, parity, gestational age, weight, height, reason for induction, or initial Bishop score. There was a significant difference in the median change of the Bishop score among those treated with misoprostol (4) and those of the control group (1) (P < 0.001). Fifteen (88%) receiving misoprostol delivered within 36 hours compared with 9 (47%) of controls (P = 0.01). Significantly more women in the misoprostol arm (8) experienced tachysystole when compared with the control group (0) (P < 0.01). There were no perinatal morbidities in either group. These data support misoprostol as an effective and economical cervical-ripening and labor-inducing agent.


Free energy surface of the Michaelis complex of lactate dehydrogenase: a network analysis of microsecond simulations.
It has long been recognized that the structure of a protein creates a hierarchy of conformations interconverting on multiple time scales. The conformational heterogeneity of the Michaelis complex is of particular interest in the context of enzymatic catalysis in which the reactant is usually represented by a single conformation of the enzyme/substrate complex. Lactate dehydrogenase (LDH) catalyzes the interconversion of pyruvate and lactate with concomitant interconversion of two forms of the cofactor nicotinamide adenine dinucleotide (NADH and NAD(+)). Recent experimental results suggest that multiple substates exist within the Michaelis complex of LDH, and they show a strong variance in their propensity toward the on-enzyme chemical step. In this study, microsecond-scale all-atom molecular dynamics simulations were performed on LDH to explore the free energy landscape of the Michaelis complex, and network analysis was used to characterize the distribution of the conformations. Our results provide a detailed view of the kinetic network of the Michaelis complex and the structures of the substates at atomistic scales. They also shed light on the complete picture of the catalytic mechanism of LDH.


Transitions from reproductive systems governed by two self-incompatible loci to one in fungi.
Self-incompatibility (SI), a reproductive system broadly present in plants, chordates, fungi, and protists, might be controlled by one or several multiallelic loci. How a transition in the number of SI loci can occur and the consequences of such events for the population's genetics and dynamics have not been studied theoretically. Here, we provide analytical descriptions of two transition mechanisms: linkage of the two SI loci (scenario 1) and the loss of function of one incompatibility gene within a mating type of a population with two SI loci (scenario 2). We show that invasion of populations by the new mating type form depends on whether the fitness of the new type is lowered, and on the allelic diversity of the SI loci and the recombination between the two SI loci in the starting population. Moreover, under scenario 1, it also depends on the frequency of the SI alleles that became linked. We demonstrate that, following invasion, complete transitions in the reproductive system occurs under scenario 2 and is predicted only for small populations under scenario 1. Interestingly, such events are associated with a drastic reduction in mating type number.


Implementing the Affordable Care Act: choosing an essential health benefits benchmark plan.
To improve the adequacy of private health insurance, the Affordable Care Act requires insurers to cover a minimum set of medical benefits, known as "essential health benefits." In implementing this requirement, states were asked to select a "benchmark plan" to serve as a reference point. This issue brief examines state action to select an essential health benefits benchmark plan and finds that 24 states and the District of Columbia selected a plan. All but five states will have a small-group plan as their benchmark. Each state, whether or not it made a benchmark selection, will have a set of essential health benefits that reflects local, employer-based health insurance coverage currently sold in the state. States adopted a variety of approaches to selecting a benchmark, including intergovernmental collaboration, stakeholder engagement, and research on benchmark options.


Nanoparticle encapsidation of Flock house virus by auto assembly of Tobacco mosaic virus coat protein.
Tobacco Mosaic virus (TMV) coat protein is well known for its ability to self-assemble into supramolecular nanoparticles, either as protein discs or as rods originating from the ~300 bp genomic RNA origin-of-assembly (OA). We have utilized TMV self-assembly characteristics to create a novel Flock House virus (FHV) RNA nanoparticle. FHV encodes a viral polymerase supporting autonomous replication of the FHV genome, which makes it an attractive candidate for viral transgene expression studies and targeted RNA delivery into host cells. However, FHV viral genome size is strictly limited by native FHV capsid. To determine if this packaging restriction could be eliminated, FHV was adapted to express enhanced green fluorescent protein (GFP), to allow for monitoring of functional FHV RNA activity. Then TMV OA was introduced in six 3' insertion sites, with only site one supporting functional FHV GFP expression. To create nanoparticles, FHV GFP-OA modified genomic RNA was mixed in vitro with TMV coat protein and monitored for encapsidation by agarose electrophoresis and electron microscopy. The production of TMV-like rod shaped nanoparticles indicated that modified FHV RNA can be encapsidated by purified TMV coat protein by self-assembly. This is the first demonstration of replication-independent packaging of the FHV genome by protein self-assembly.


Evaluation of in vitro anti-genotoxic potential of melatonin against arsenic and fluoride in human blood cultures.
Melatonin has been known for its anti-oxidant potential but not much studied for the anti-genotoxic potential. The current study elucidate the role of melatonin against in vitro genotoxicity by arsenic (As) and fluoride (F). Human peripheral blood cultures were exposed to As (1.4 microM) and F (34 microM), alone and in combination, with and without melatonin (0.2 mM). Ethyl methane sulphonate (EMS; 1.9 mM) was selected as the positive control to analyze the genotoxic parameters like sister chromatid exchanges (SCEs), cell cycle proliferative index (CCPI) and primary DNA damage. The frequency of SCE/cell, SCE/chromosome and primary DNA damage reduced significantly (p<0.001) accompanied with a marked increase in CCPI upon addition of melatonin. Similarly marked recovery was attained by melatonin from As and F induced primary DNA damage as studied using comet assay. The results clearly indicate towards the protection of lymphocytes from toxic effects af As and F by melatonin in vitro.


Soliton shedding from Airy pulses in Kerr media.
We simulate and analyze the propagation of truncated temporal Airy pulses in a single mode fiber in the presence of self-phase modulation and anomalous dispersion as a function of the launched Airy power and truncation coefficient. Soliton pulse shedding is observed, where the emergent soliton parameters depend on the launched Airy pulse characteristics. The Soliton temporal position shifts to earlier times with higher launched powers due to an earlier shedding event and with greater energy in the Airy tail due to collisions with the accelerating lobes. In spite of the Airy energy loss to the shed Soliton, the Airy pulse continues to exhibit the unique property of acceleration in time and the main lobe recovers from the energy loss (healing property of Airy waveforms).


Role of the small RNA RyhB in the Fur regulon in mediating the capsular polysaccharide biosynthesis and iron acquisition systems in Klebsiella pneumoniae.
The capsular polysaccharide (CPS) and iron acquisition systems are important determinants of Klebsiella pneumoniae infections, and we have previously reported that the ferric uptake repressor (Fur) can play dual role in iron acquisition and CPS biosynthesis. In many bacteria, Fur negatively controls the transcription of the small non-coding RNA RyhB to modulate cellular functions and virulence. However, in K. pneumoniae, the role played by RyhB in the Fur regulon has not been characterised. This study investigated Fur regulation of ryhB transcription and the functional role of RyhB in K. pneumoniae. Deletion of fur from K. pneumoniae increased the transcription of ryhB; the electric mobility shift assay and the Fur-titration assay revealed that Fur could bind to the promoter region of ryhB, suggesting that Fur directly represses ryhB transcription. Additionally, in a Δfur strain with elevated CPS production, deletion of ryhB obviously reduced CPS production. The following promoter-reporter assay and quantitative real-time PCR of cps genes verified that RyhB activated orf1 and orf16 transcription to elevate CPS production. However, deletion of ryhB did not affect the mRNA levels of rcsA, rmpA, or rmpA2. These results imply that Fur represses the transcription of ryhB to mediate the biosynthesis of CPS, which is independent of RcsA, RmpA, and RmpA2. In addition, the Δfur strain's high level of serum resistance was attenuated by the deletion of ryhB, indicating that RyhB plays a positive role in protecting the bacterium from serum killing. Finally, deletion of ryhB in Δfur reduced the expression of several genes corresponding to 3 iron acquisition systems in K. pneumoniae, and resulted in reduced siderophore production. The regulation and functional role of RyhB in K. pneumoniae is characterized in this study. RyhB participates in Fur regulon to modulate the bacterial CPS biosynthesis and iron acquisition systems in K. pneumoniae.


Relationships between free radical scavenging and antioxidant activity in foods.
Numerous attempts have been made to relate the free radical scavenging capacity of compounds to their antioxidant activity in foods even though antioxidant activity is dependent on both physical and chemical properties. The objective of this study was to compare the free radical scavenging activity of various compounds to their ability to inhibit lipid oxidation in foods. The order of free radical scavenging activity of polar compounds was ferulic acid > coumaric acid > propyl gallate > gallic acid > ascorbic acid as determined by a modified oxygen radical absorbance capacity, while the order of nonpolar compounds was rosmarinic acid > butylated hydroxytoluene >or= tert-butylhydroquinone (TBHQ) > alpha-tocopherol as determined by the 2,2-diphenyl-1-picrylhydrazyl assay. Of these compounds, only propyl gallate and TBHQ were found to inhibit lipid oxidation in cooked ground beef as determined by thiobarbituric acid reactive substances, while only propyl gallate, TBHQ, gallic acid, and rosmarinic acid inhibited lipid oxidation in an oil-in-water emulsion as determined by lipid hydroperoxides and headspace hexanal. These data indicate that the free radical scavenging assays tested have limited value in predicting the antioxidant activity in complex foods.


Evaluating the applied use of a mental health screener: Structural validity of the Social, Academic, and Emotional Behavior Risk Screener.
Universal screening for mental health has gained prominence in schools with the adoption of multitiered systems of support. However, there is a general lack of brief, psychometrically defensible instruments that assess emotional and behavioral risk. This study employed a multilevel, confirmatory bifactor analysis to evaluate the factor structure of a novel screening instrument-the Social, Academic, and Emotional Behavioral Risk Screener (SAEBRS; Kilgus & von der Embse, 2014)-examining the structure at the student (within) and teacher or rater (between) levels. Item response theory (IRT) analyses were then used to examine the functioning of 2 existing factors, social risk and academic risk, in addition to a newly introduced third factor, emotional risk, within a sample of 834 elementary and middle school students. Results indicated good fit of a bifactor model including the addition of the new Emotional Behavior subscale. IRT analyses suggested strong item-level discriminative properties (a > 1.0) for 17 of the 19 SAEBRS items and indicated that scale precision was greatest within the low to moderate range of each respective dimension (social, academic, and behavioral risk). Overall, the findings provide support for the use of the SAEBRS as a screener for mental health-related concerns. Implications for model interpretation and model use are discussed. (PsycINFO Database Record


Oncolytic viral therapy for human prostate cancer by conditionally replicating herpes simplex virus 1 vector G207.
Over the last few years, a conditionally replicating herpes simplex virus 1 (HSV-1) vector, G207 has been used for the treatment of several malignant tumors. In this article we evaluate the anti-tumoral effect of G207 against prostate cancer in vitro and in vivo. The susceptibility of the human prostate cancer cell lines, DU145 and PC3 to G207 at a multiplicity of infection (MOI) of 0.1 was examined. In addition, the growth characteristics of G207 were assessed. Athymic mice with s.c. tumors were inoculated in vivo intraneoplastically with 1 x 10(7) plaque-forming units (PFU) of G207. For the pathological analyses, s.c. tumors were stained with X-gal. DU145 and PC3 were efficiently destroyed by G207 within 7 days. The viral yields of G207 increased time-dependently. In vivo, the intraneoplastic inoculation of G207 induced a significant inhibition of the tumor growth. The mean tumor growth ratio was significantly inhibited in the G207-treated tumors (DU145, P < 0.0001; PC3, P < 0.001 versus controls). In a pathological study, many lacZ-positive cells were diffusely present in the G207-treated tumors. G207 showed a significant antitumoral effect against human prostate cancer cell lines, and thus may be considered a useful agent for the treatment of prostate cancer.


Fibrocartilaginous embolism of the spinal cord diagnosed by characteristic clinical findings and magnetic resonance imaging in 26 dogs.
Fibrocartilaginous embolism (FCE) is a disorder of acute onset that presents with nonprogressive ataxia. We performed a retrospective examination of FCE of the spinal cord diagnosed by characteristic clinical findings and magnetic resonance imaging (MRI) in 26 dogs. In the present study, treatment consisting of physiotherapy alone, or this in combination with corticosteroid administration, was initiated immediately following diagnosis of FCE. Age at onset and the gender ratio in the present study closely correlated with those previously reported. In the present study, 88% of the dogs that developed FCE were small- to medium-sized, which is different from previously reported studies. There is a possibility that FCE also develops relatively frequently in small- to medium-sized dogs. No significant difference was observed between the physiotherapy alone and the physiotherapy and corticosteroids groups of dogs. FCE development has been reported predominantly at the vertebral levels C6-T2 and L4-S3 and less frequently at C1-5 and T3-L3. However, in the present study, FCE developed predominantly at T3-L3. FCE developed at T3-L3 or C1-5 in 69% of the cases in the present study, suggesting that there is relatively frequent development of FCE at these vertebral levels. The recovery time of T3-L3 was the shortest (10.2 +/- 7.4 days), and that of C1-5 was next-shortest (15.8 +/- 5.4) in this study. This suggested the possibility that the detection ratio of cases was low, because the symptoms in cases of FCE that has developed in C1-5 and T3-L3 would have improved before inspection in the secondary institution, where the MRI and diagnosis were performed.


An ecophysiologically informed model of seed dispersal by orangutans: linking animal movement with gut passage across time and space.
Fauna-mediated ecosystem service provision (e.g. seed dispersal) can be difficult to quantify and predict because it is underpinned by the shifting niches of multiple interacting organisms. Such interactions are especially complex in tropical ecosystems, including endangered peat forests of Central Borneo, a biodiversity hot spot and home to the critically endangered orangutan (Pongo pygmaeus wurmbii). We combined studies of the digestive physiology of captive orangutans in Australia with detailed field studies of wild orangutans in the Natural Laboratory of Peat-Swamp Forest of Sabangau, Central Kalimantan, Indonesia. By measuring the gut transit time (TT) of indigestible seed mimics (beads) in captivity and applying this as a temporal constraint to movement data of wild orangutans, we developed a mechanistic, time-explicit spatial model to project the seed dispersal patterns by these large-bodied, arboreal frugivores. We followed seven orangutans and established home range kernels using Time Local Convex Hull (T-LoCoH) modelling. This allowed us to model individual orangutan movements and to adjust these models according to gut transit times to estimate seed dispersal kernels. Female movements were conservative (core ranges of 55 and 52 ha in the wet and dry seasons, respectively) and revisitation rates to the same location of n = 4 in each 24-h block. Male movements were more unpredictable, yielding fragmented core ranges and revisitation rates to the same location of only 1.2 times each 24 h; males also demonstrated large disjunctions where they moved rapidly over long distances and were frequently lost from view. Seed dispersal kernels were nested predictably within the core ranges of females, but not males. We used the T-LoCoH approach to analyse movement ecology, which offered a powerful tool to predict the primary deposition of seeds by orangutans, thereby providing a reliable method for making a priori predictions of seed dispersal dynamics by other frugivores in novel ecosystems.


Qualifications, Demographics, Satisfaction, and Future Capacity of the HIV Care Provider Workforce in the United States, 2013-2014.
The human immunodeficiency virus (HIV)-infected population in the United States is increasing by about 30 000 annually (new infections minus deaths). With improvements in diagnosis and engagement in care, additional qualified HIV care providers may be needed. We surveyed a probability sample of 2023 US HIV care providers in 2013-2014, including those at Ryan White HIV/AIDS Program (RWHAP)-funded facilities and in private practices. We estimated future patient care capacity by comparing counts of providers entering and planning to leave practice within 5 years, and the number of patients under their care. Of surveyed providers, 1234 responded (adjusted response rate, 64%): 63% were white, 11% black, 11% Hispanic, and 16% other race/ethnicity; 37% were satisfied/very satisfied with salary/reimbursement, and 33% were satisfied/very satisfied with administrative time. Compared with providers in private practice, more providers at RWHAP-funded facilities were HIV specialists (71% vs 43%; P < .0001) and planned to leave HIV practice within 5 years (11% vs 4%; P = .0004). An estimated 190 more full-time equivalent providers (defined as 40 HIV clinical care hours per week) entered practice in the past 5 years than are expected to leave in the next 5 years. If these rates continue, by 2019 patient care capacity will increase by 65 000, compared with an increased requirement of at least 100 000. Projected workforce growth by 2019 will not accommodate the increased number of HIV-infected persons requiring care. RWHAP-funded facilities may face attrition of highly qualified providers. Dissatisfaction with salary/reimbursement and administrative burden is substantial, and black and Hispanic providers are underrepresented relative to HIV patients.


Retinoblastoma: clues to human oncogenesis.
The retinoblastoma gene can be considered a model for a class of recessive human cancer genes that have a "suppressor" or "regulatory" function. The loss or inactivation of both alleles of this gene appears to be a primary mechanism in the development of retinoblastoma. Such a mechanism is in direct contrast to that of putative human oncogenes which are thought to induce tumorigenesis following activation or alteration. The high incidence of second primary tumors among patients who inherit one inactive retinoblastoma allele also suggests that this cancer gene plays a key role in the etiology of several other primary malignancies. Finally, the observation that extra nonrandom copies of specific chromosomal regions occur in some of these tumors provides circumstantial evidence that an "expressor" gene (possibly an oncogene) may be involved in retinoblastoma development.


Functional cooperativity of enzymes of phosphoinositide conversion according to synergistic effects on pectin secretion in tobacco pollen tubes.
The Arabidopsis phosphoinositide kinases PI4Kβ1 and PIP5K5 have been implicated in the control of directional vesicle trafficking underlying polar tip growth in pollen tubes. PI4Kβ1 and PIP5K5 catalyze key consecutive steps of phosphoinositide conversion, and it appears obvious that phosphatidylinositol-4-phosphate formed by PI4Kβ1 might act as a substrate for phosphatidylinositol-4,5-bisphosphate formation by PIP5K5. However, this hypothesis has not been experimentally addressed and distinct localization patterns of PI4Kβ1, PIP5K5, and also PI-synthases (PIS) generating phosphatidylinositol suggest additional complexity. Here, the synergistic functionality of enzymes of phosphoinositide conversion was assessed. In tobacco and Arabidopsis pollen tubes, phosphoinositides influence the apical secretion of pectin, and increased pectin deposition results in characteristic morphological alterations. Catalytically active and dominant negative variants of PI4Kβ1 and PIP5K5 were systematically co-expressed in tobacco pollen tubes and the incidence of morphologies related to enhanced pectin secretion was evaluated. The data support a proposed functional interplay of PI4Kβ1 and PIP5K5 at the trans-Golgi network, mediating directional vesicle trafficking. Co-expression experiments additionally including PIS isoforms, PIS1 or PIS2, indicate that pectin secretion is synergistically mediated by PI4Kβ1 and PIP5K5 acting on PtdIns formed by PIS2 rather than PIS1. Possible ramifications for the preferential channeling of phosphoinositide intermediates between particular isoforms of PI pathway enzymes are discussed.


Feasibility of a tiny centrifugal blood pump (TinyPump) for pediatric extracorporeal circulatory support.
In this study, the performances of the TinyPump (priming volume 5 mL) system including the pediatric cannulae (Stöckert Pediatric Arterial Cannulae 2.6, 3.0, and 4.0 mm, Stöckert Instruments GmbH, Munich, Germany; Polystan 20-Fr Venous Catheter, MAQUET GmbH, Rastatt, Germany) and an oxygenator (Terumo Capiox RX05 Baby-RX, Terumo Cardiovascular Systems Co., Tokyo, Japan) were studied in vitro followed with preliminary ex vivo studies in 20-kg piglets. In vitro results revealed that the TinyPump system met the requirements for pump speed, pump flow, and pressure drop as extracorporeal circulatory support during open heart surgery and extracorporeal membrane oxygenation (ECMO) in pediatric patients. In 2-h ex vivo studies using 20-kg piglets where the blood contacting surface of the TinyPump was coated with a biocompatible phospholipid polymer, the plasma-free hemoglobin levels remained less than 5.0 mg/dL and no thrombus formation was observed inside the pump. The TinyPump system including the oxygenator and connecting circuits resulted in an overall priming volume of 68 mL, the smallest ever reported. The TinyPump can be a safe option for pediatric circulatory support during open heart surgery and ECMO without requiring blood transfusion.