A systems level, functional genomics analysis of chronic epilepsy.
Neither the molecular basis of the pathologic tendency of neuronal circuits to generate spontaneous seizures (epileptogenicity) nor anti-epileptogenic mechanisms that maintain a seizure-free state are well understood. Here, we performed transcriptomic analysis in the intrahippocampal kainate model of temporal lobe epilepsy in rats using both Agilent and Codelink microarray platforms to characterize the epileptic processes. The experimental design allowed subtraction of the confounding effects of the lesion, identification of expression changes associated with epileptogenicity, and genes upregulated by seizures with potential homeostatic anti-epileptogenic effects. Using differential expression analysis, we identified several hundred expression changes in chronic epilepsy, including candidate genes associated with epileptogenicity such as Bdnf and Kcnj13. To analyze these data from a systems perspective, we applied weighted gene co-expression network analysis (WGCNA) to identify groups of co-expressed genes (modules) and their central (hub) genes. One such module contained genes upregulated in the epileptogenic region, including multiple epileptogenicity candidate genes, and was found to be involved the protection of glial cells against oxidative stress, implicating glial oxidative stress in epileptogenicity. Another distinct module corresponded to the effects of chronic seizures and represented changes in neuronal synaptic vesicle trafficking. We found that the network structure and connectivity of one hub gene, Sv2a, showed significant changes between normal and epileptogenic tissue, becoming more highly connected in epileptic brain. Since Sv2a is a target of the antiepileptic levetiracetam, this module may be important in controlling seizure activity. Bioinformatic analysis of this module also revealed a potential mechanism for the observed transcriptional changes via generation of longer alternatively polyadenlyated transcripts through the upregulation of the RNA binding protein HuD. In summary, combining conventional statistical methods and network analysis allowed us to interpret the differentially regulated genes from a systems perspective, yielding new insight into several biological pathways underlying homeostatic anti-epileptogenic effects and epileptogenicity.


A case study of global health at the university: implications for research and action.
Global health is increasingly a major focus of institutions in high-income countries. However, little work has been done to date to study the inner workings of global health at the university level. Academics may have competing objectives, with few mechanisms to coordinate efforts and pool resources. To conduct a case study of global health at Canada's largest health sciences university and to examine how its internal organization influences research and action. We drew on existing inventories, annual reports, and websites to create an institutional map, identifying centers and departments using the terms 'global health' or 'international health' to describe their activities. We compiled a list of academics who self-identified as working in global or international health. We purposively sampled persons in leadership positions as key informants. One investigator carried out confidential, semi-structured interviews with 20 key informants. Interview notes were returned to participants for verification and then analyzed thematically by pairs of coders. Synthesis was conducted jointly. More than 100 academics were identified as working in global health, situated in numerous institutions, centers, and departments. Global health academics interviewed shared a common sense of what global health means and the values that underpin such work. Most academics interviewed expressed frustration at the existing fragmentation and the lack of strategic direction, financial support, and recognition from the university. This hampered collaborative work and projects to tackle global health problems. The University of Toronto is not exceptional in facing such challenges, and our findings align with existing literature that describes factors that inhibit collaboration in global health work at universities. Global health academics based at universities may work in institutional siloes and this limits both internal and external collaboration. A number of solutions to address these challenges are proposed.


The clustered protocadherin endolysosomal trafficking motif mediates cytoplasmic association.
Clustered protocadherins (Pcdhs) are a large family of neural cadherin-like proteins encoded by individual exons located within three gene clusters. Each exon codes an extracellular, transmembrane, and proximal cytoplasmic domain. These "variable" regions may be spliced to a constant cytoplasmic moiety encoded at the end of a cluster. Pcdh extracellular domains mediate homophilic cell-cell binding but their cytoplasmic domains cause intracellular retention and may negatively regulate Pcdh cell-cell binding. Pcdhs can be found at the cell surface in neurons and other cells but are also, unlike classical cadherins, prominently trafficked to the endolysosome system. It was previously found that a segment within the variable portion of the Pcdh-γA3 cytoplasmic domain (VCD) was shown to be necessary for endolysosomal trafficking. Here it is shown that this same VCD segment can mediate cytoplasmic association among Pcdhs from the different clusters. Internal deletions within this VCD region (termed here the VCD motif) that disrupt the association altered trafficking of Pcdh-γA3 in the endolysosomal system while deletions outside VCD motif did not affect trafficking. The results show that Pcdhs associate cytoplasmically via a motif within the VCD and that this is critical for Pcdh trafficking. Given that truncation at the VCD motif alters endolysosomal trafficking of Pcdhs, the VCD interaction described here may provide new insights into the dynamic nature of Pcdh mediated cell-cell interactions.


Mast cells and eosinophils in the jejunal mucosa of patients with intestinal cow's milk allergy and celiac disease of childhood.
We counted the number of granulated mast cells with high iron diamine staining, and the number of eosinophils with hematoxyline-eosin staining, in the lamina propria of the jejunum in 12 untreated patients with intestinal cow's milk allergy (CMA), 47 with celiac disease (CD), and 14 controls. A decreased number of mast cells and an increased number of eosinophils were found in 58% of patients with CMA, and in 60% of those with CD. The number of mast cells showed a significant positive correlation with the villous height, and the number of eosinophils a negative correlation with both the villous height, and the number of mast cells. Appropriate dietary treatment resulted in a rise in the number of granulated mast cells and a decrease in the number of eosinophils in both patient groups.


Artesunate versus artemether for the treatment of recrudescent multidrug-resistant falciparum malaria.
The therapeutic efficacy and toxicity of artesunate (2mg/kg/day for five days, then 1 mg/kg/day for two days: total=12 mg/kg) was compared with that of artemether (4 mg/kg followed by 2 mg/kg/day for two days, then 1 mg/kg/day for four days: total=12 mg/kg) for the treatment of recrudescent multidrug-resistant falciparum malaria in an open randomized trial in 443 patients living on the western border of Thailand. Parasite and fever clearance times were similar in both groups; within 48 hr 94% (95% confidence interval [CI]=91-96%]) of the treated patients were aparasitemic and 93% (95% CI=89-96%) were afebrile. Symptom resolution and resolution of hepatomegaly were slightly slower in the artesunate group; adjusted hazards ratio=1.5 (95% CI=1-2.0, P < 0.01) and 2.2 (95% CI=1.4-8, P=0.04), respectively. There was no significant difference in times to resolution or development of anemia or splenomegaly between treatment groups. By day 28, 3% (95% CI=0.3-5%) of the patients treated with artesunate and 6% of those treated with artemether (95% CI = 2-9%) had recurrent infections (P=0.3). Both regimens were very well tolerated, with no significant adverse effects attributable to either derivative. Overall, these data suggest that the two oral artemisinin derivatives are safe, highly effective, and result in equivalent therapeutic responses in the treatment of drug-resistant falciparum malaria.


Efficacy and safety results from CheckMate 140, a phase 2 study of nivolumab for relapsed/refractory follicular lymphoma.
Nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody, showed promising activity in relapsed or refractory (R/R) follicular lymphoma (FL) in a phase 1 study. We conducted a phase 2 trial to further evaluate its efficacy and safety in patients with R/R FL and to explore biomarkers of response. Patients with R/R FL and at least 2 prior lines of therapy, each containing a CD20 antibody or an alkylating agent, were treated with nivolumab 3 mg/kg every 2 weeks. The primary end point was objective response rate (ORR) assessed by an independent radiologic review committee. Biomarker analyses included gene expression profiling and multiplex immunofluorescence studies of pretreatment tumor samples. A total of 92 patients were treated. After a minimum follow-up of 12 months, ORR was 4% (4 of 92 patients). Median progression-free survival (PFS) was 2.2 months (95% confidence interval [CI], 1.9-3.6 months). Median duration of response was 11 months (95% CI, 8-14 months). Exploratory analyses suggested that responders had significantly higher proportion of CD3+ T cells in the tumor microenvironment than nonresponders, but no significant differences in PD-1 or programmed death-ligand 1 expression were observed. High expression of a set of tumor-associated macrophage genes was associated with reduced PFS (hazard ratio, 3.28; 95% CI, 1.76-6.11; P = .001). The safety profile was consistent with previous reports of nivolumab. In conclusion, nivolumab monotherapy was associated with very limited activity in patients with R/R FL. Better understanding of the immune biology of this disease may facilitate the development of effective checkpoint-based strategies. This trial was registered at www.clinicaltrials.gov as #NCT02038946.


Mesoderm induction and the control of gastrulation in Xenopus laevis: the roles of fibronectin and integrins.
Exposure of isolated Xenopus animal pole ectoderm to the XTC mesoderm-inducing factor (XTC-MIF) causes the tissue to undergo gastrulation-like movements. In this paper, we take advantage of this observation to investigate the control of various aspects of gastrulation in Xenopus. Blastomeres derived from induced animal pole regions are able, like marginal zone cells, but unlike control animal pole blastomeres, to spread and migrate on a fibronectin-coated surface. Dispersed animal pole cells are also able to respond to XTC-MIF in this way; this is one of the few mesoderm-specific responses to induction that has been observed in single cells. The ability of induced animal pole cells to spread on fibronectin is abolished by the peptide GRGDSP. However, the elongation of intact explants is unaffected by this peptide. This may indicate that fibronectin-mediated cell migration is not required for convergent extension. We have investigated the molecular basis of XTC-MIF-induced gastrulation-like movements by measuring rates of synthesis of fibronectin and of the integrin beta 1 chain in induced and control explants. No significant differences were observed, and this suggests that gastrulation is not initiated simply by control of synthesis of these molecules. In future work, we intend to investigate synthesis of other integrin subunits and to examine possible post-translational modifications to fibronectin and the integrins.


Job characteristics and leisure physical activity.
This study employs a sample population of older workers to estimate an empirical model of leisure exercise activity. Alternative theories relating work and leisure attitudes relevant for understanding the exercise behavior of older workers are tested empirically. Responses of 6,433 full-time older workers (51 to 61 years old) from the 1992 Health and Retirement Study (HRS) are grouped into two white-collar and blue-collar worker categories and are analyzed to test whether self-reported levels of regular physical activity are associated with the physical demands and stress associated with one's job. Although the white-collar workers, whose jobs involve more physical efforts, are more likely to do light physical activity, the blue-collar workers, whose jobs are more physically demanding, tend to engage in more vigorous exercise. The empirical results are most supportive of the generalization theory, and they also illustrate the complexity of relationships between work and leisure physical activity.


Pathologic roles of prorenin and (pro)renin receptor in the eye.
Recent reports indicated that tissue renin-angiotensin system (RAS) was upregulated and angiotensin II type 1 receptor signaling plays crucial roles in ocular inflammation and neovascularization; however, the precise mechanism for activating tissue RAS had not been defined until recently. (Pro)renin receptor, a recently identified molecule existing in the major organs but not in the circulation, has attracted growing attention as an activator of tissue RAS. When the handle region of the prorenin prosegment binds to (pro)renin receptor, prorenin undergoes a conformational change to its enzymatically active state without the conventional proteolysis of the prorenin prosegment. Systemic treatment with a peptide with the structure of the handle region (handle region peptide; HRP), which competitively binds to (pro)renin receptor as a decoy peptide and inhibit the nonproteolytic activation of prorenin, resulted in the suppression of retinal inflammation and neovascularizaion in the rodent models. Retinal expression of RAS-related inflammatory and angiogenic molecules, such as intercellular adhesion molecule-1, monocyte chemotactic protein-1, and vascular endothelial growth factor, was also suppressed with application of HRP. These findings demonstrate that nonproteolytically activated prorenin plays a significant role in the ocular inflammation and neovascularization.


Amelioration of experimental autoimmune encephalomyelitis by β-elemene treatment is associated with Th17 and Treg cell balance.
Experimental autoimmune encephalomyelitis (EAE), an animal mode of multiple sclerosis (MS), was previously considered that is mediated by Th1 cells. However, a number of recent studies provided strong evidence that T helper cells that produce interleukin (IL)-17 (Th17) and anti-inflammatory CD4+ Foxp3+ regulatory T cells (Tregs) play a dominant role in the pathogenesis of EAE. β-elemene is a natural antitumor plant drug with the role of multiple target, and it has been found to pass through the blood-brain barrier easily. It also has been strongly implicated as an immune modulatory agent, but the precise mechanisms of its action are largely unknown. In the present study, we mainly investigated the efficacy and mechanism of β-elemene against EAE in vivo and vitro. The treatment of C57 mice with β-elemene significantly delayed the onset of EAE, markedly suppressed MOG-specific T cell proliferation in a dose-dependent manner, dramatically reduced the IL-17, IL-6, IL-23, and RORγt production and induced the Foxp3 expression in both the periphery and the inflamed spinal cord. These findings indicated that β-elemene amelioration EAE was, to a large extent, due to inhibit differentiation and development of Th17 cells depends on down-regulating expression of IL-6, IL-23, RORγt signaling, and promoting expansion in Treg cells. Suggesting it is useful in the control of MS and other Th17 cell-mediated inflammatory diseases.


Dielectric properties of human red blood cells in suspension at radio frequencies.
Dielectric properties of human red blood cells (RBCs) in suspension (hematocrit 50%) from 243 healthy persons (120 males, 123 females) were measured at 25 degrees C in a frequency range of 1-500 MHz, with a coaxial transmission line reflection method (one-side measurement). The measuring system, controlled by an IBM-PC computer, was composed of a network analyzer (HP4195A), an impedance test adapter (HP41951-61001), a coaxial line sensor, and a temperature-controlling set. The data measured revealed a statistically significant age dependence, with a critical age of about 49 years, above which permittivity and conductivity of human RBCs in suspension decreased significantly.


Suitability of electronic mini-boluses for early identification of lambs.
Three types of ceramic mini-boluses, B1 [13.8 g; 10.5 x 51.0 mm (o.d. x length)], B2 (16.2 g; 12.2 x 42.2 mm), and B3 (20.1 g; 11.2 x 56.4 mm), were used to electronically identify as soon as possible after birth a total of 545 lambs of 3 breeds: Ripollesa (meat breed, n = 274), Manchega (dairy breed, n = 129), and Lacaune (dairy breed, n = 142). Boluses were administered by a trained operator using a balling gun or directly by hand. Lambs were also identified with 2 types of plastic ear tags in the left (temporary, 1.5 g) and the right (permanent, 4.1 g) ears. Lamb and identification device performances were checked during suckling (to wk 5 or 7) and fattening. At 24 kg of BW, lambs were slaughtered (n = 385) or kept for breeding (n = 144). No differences in performance were observed between the 2 dairy breeds, and their data were pooled. Minimum BW for bolus administration was lower in dairy than in meat lambs (P < 0.001). Across breeds, B1 and B3 did not differ in lamb age (27 d) and weight (9.2 kg) at administration, but B2 required older and heavier lambs (33 d and 11.1 kg; P < 0.01). Boluses did not affect lamb performance, but final readability at slaughter differed between B1 and B2 (97.7 and 95.2%, respectively) and B3 (100%), and between ear tags (temporary, 98.1; permanent, 100%). Bolus recovery was 100% in all cases, but the proportion of boluses found in the reticulum varied among bolus type (83.3 to 93.8%; P < 0.05). Three B1 (2%) were recovered from the abomasum. In a second experiment, effects of the intermediate mini-bolus (B2) on diet digestibility were evaluated. Digestibility of control and bolus-administered, Manchega ram lambs (14.9 kg of BW; n = 8) fed ad libitum with 2 pelleted concentrates and barley straw was assessed in digestibility crates. Feed intake and nutrient digestibility were measured in four 21-d periods, during which lambs received the 2 diets consecutively. No differences in intake, growth performance, or nutrient digestibility were observed between control and bolused lambs. In conclusion, the B3 mini-bolus proved to be an efficient device for identification of lambs before weaning (recommended age, >4 wk; recommended BW, >10 kg), allowing a reliable traceability of dairy and meat lambs until slaughter.


Sequential continuous infusion of fludarabine and cytarabine associated with liposomal daunorubicin (DaunoXome) (FLAD) in primary refractory or relapsed adult acute myeloid leukemia patients.
A large proportion of adult patients with acute myeloid leukemia (AML) relapse after treatment, and some of them are resistant to primary induction chemotherapy. Sixty-one patients from seven hematological centers with poor-risk AML, primary refractory (n = 16), or relapsed (n = 45) were treated with a salvage regimen, including fludarabine (2 days) and cytarabine (3 days) in a sequential continuous infusion, associated with liposomal daunorubicin (3 days) (FLAD). Complete response rate was 44% and 56% for refractory and relapsed patients, respectively, with an overall response rate of 52% (32 of 61). Twenty-two patients (36%) were resistant to the salvage therapy. Seven patients (12%) died early during chemotherapy, four of them because of sepsis. Nineteen patients in complete remission (CR) underwent a stem-cell transplant (SCT) procedure: five autologous, nine from a HL-A identical sibling, and five from HL-A matched unrelated donors. Post-treatment aplasia and mucositis were major toxicities. Twenty patients (62.5%) relapsed after this treatment in a median of 7.3 months; ten patients relapsed after a SCT procedure. Nine patients are alive and disease free; three of them were rescued after a further cytotoxic treatment. The FLAD regimen proved to be an effective and well-tolerated treatment, with acceptable toxicity in this group of high-risk patients. A better response rate was obtained in the subgroup of relapsed patients, compared to patients treated for refractory disease. More then half (five of nine) of long-surviving patients are those who were submitted to a transplant procedure; thus, the main indication for FLAD seems to be to try to induce a rapid CR with minimum toxicity in order to perform a transplant as soon as possible.


Comparison of the prognostic potential of hyaluronic acid, hyaluronidase (HYAL-1), CD44v6 and microvessel density for prostate cancer.
Despite the development of nomograms designed to evaluate a prostate cancer (PCa) patient's prognosis, the information has been limited to PSA, clinical stage, Gleason score and tumor volume estimates. We compared the prognostic potential of 4 histologic markers, hyaluronic acid (HA), HYAL-1-type hyaluronidase (HAase), CD44v6 and microvessel density (MVD) using immunohistochemistry. HA is a glycosaminoglycan that promotes tumor metastasis. CD44 glycoproteins serve as cell surface receptors for HA, and the CD44v6 isoform is associated with tumor metastasis. HYAL-1-type HAase is expressed in tumor cells and, like other HAases, degrades HA into angiogenic fragments. Archival PCa specimens (n=66) were obtained from patients who underwent radical prostatectomy for clinically localized PCa and had a minimum follow-up of 72 months (range 72-131 months, mean 103 months). For HA, HYAL-1 and CD44v6 staining and MVD determination, a biotinylated HA-binding protein, an anti-HYAL-1 IgG, an anti-CD44v6 IgG and an anti-CD34 IgG were used, respectively. HA and HYAL-1 staining was classified as either low- or high-grade. CD44v6 staining and MVD were evaluated quantitatively and then grouped as either low- or high-grade. Using 72 months as the cut-off limit for evaluating biochemical recurrence, HA, HYAL-1, combined HA-HYAL-1, CD44v6 and MVD staining predicted progression with 96%, 84%, 84%, 68% and 76% sensitivity, respectively. Specificity was, 61% (HA), 80.5% (HYAL-1), 87.8% (HA-HYAL-1), 56.1% (CD44v6) and 61% (MVD). Sensitivity and specificity values for each marker did not change significantly in a subset of 45 patients for whom follow-up of longer than 112 months was available. In univariate analysis using the Cox proportional hazards model, preoperative PSA, Gleason sum, margin status, seminal vesicle, extraprostatic extension (EPE), HA, HYAL-1, HA-HYAL-1 and MVD, but not CD44v6, age and clinical stage, were significant in predicting biochemical recurrence (p < 0.05). In multivariate analysis using stepwise selection, only preoperative PSA (hazard ratio/unit PSA change=1.086, p < 0.0001), EPE (hazard ratio=6.22, p=0.0016) and HYAL-1 (hazard ratio=8.196, p=0.0009)/HA-HYAL-1 (hazard ratio=5.191, p=0.0021) were independent predictors of biochemical recurrence. HA was an independent predictor of prognosis if HYAL-1 staining inference was not included in the multivariate model. In our retrospective study with 72- to 131-month follow-up, EPE, preoperative PSA and HYAL-1 either alone or together with HA (i.e., combined HA-HYAL-1) were independent prognostic indicators for PCa.


Procalcitonin-guided antibiotic therapy algorithms for different types of acute respiratory infections based on previous trials.
Although evidence indicates that use of procalcitonin to guide antibiotic decisions for the treatment of acute respiratory infections (ARI) decreases antibiotic consumption and improves clinical outcomes, algorithms used within studies had differences in PCT cut-off points and frequency of testing. We therefore analyzed studies evaluating procalcitonin-guided antibiotic therapy and propose consensus algorithms for different respiratory infection types. Areas covered: We systematically searched randomized-controlled trials (search strategy updated on February 2018) on procalcitonin-guided antibiotic therapy of ARI in adults using a pre-specified Cochrane protocol and analyzed algorithms from 32 trials that included 10,285 patients treated in primary care settings, emergency departments (ED), and intensive care units (ICU). We derived consensus algorithms for use of procalcitonin by the type of ARI including community-acquired pneumonia, bronchitis, chronic obstructive pulmonary disease or asthma exacerbation, sepsis, and post-operative sepsis due to respiratory infection. Consensus algorithm recommendations differ with regard to timing of treatment (i.e. timing of initiation in low-risk patients or discontinuation in high-risk patients) and procalcitonin cut-off points for the recommendation/strong recommendation to discontinue antibiotics (≤ 0.25/≤ 0.1 µg/L in ED and inpatients, ≤ 0.5/≤ 0.25 µg/L in ICU patients, and reduction by ≥ 80% from peak levels in sepsis patients). Expert commentary: Our proposed algorithms may facilitate safe and efficient implementation of procalcitonin-guided antibiotic protocols in diverse healthcare settings. Still, the decision about initiation and cessation of antibiotic treatment remains a clinical decision based on the patient assessment and the severity of illness and use of procalcitonin should not delay empirical treatment in high risk situations.


Adsorption mechanism and valency of catechol-functionalized hyperbranched polyglycerols.
Nature often serves as a model system for developing new adhesives. In aqueous environments, mussel-inspired adhesives are promising candidates. Understanding the mechanism of the extraordinarily strong adhesive bonds of the catechol group will likely aid in the development of adhesives. With this aim, we study the adhesion of catechol-based adhesives to metal oxides on the molecular level using atomic force microscopy (AFM). The comparison of single catechols (dopamine) with multiple catechols on hyperbranched polyglycerols (hPG) at various pH and dwell times allowed us to further increase our understanding. In particular, we were able to elucidate how to achieve strong bonds of different valency. It was concluded that hyperbranched polyglycerols with added catechol end groups are promising candidates for durable surface coatings.


Perceived acceptability of home-based couples voluntary HIV counseling and testing in Northern Tanzania.
It is estimated that 5.6% of the Tanzanian population ages 15-49 are infected with HIV, but only 30% of adults have ever had an HIV test. Couples' testing has proven to increase testing coverage and introduce HIV prevention, but barriers include access to testing services and unequal gender dynamics in relationships. Innovative approaches are needed to address barriers to couple's testing and increase uptake of HIV testing. Using qualitative data collection methods, a formative study was conducted to assess the acceptability of a home-based couples counseling and testing (HBCCT) approach. Eligible study participants included married men and women, HIV-infected individuals, health care and home-based care providers, voluntary counseling and testing counselors, and community leaders. A total of 91 individuals participated in focus group discussions (FGDs) and in-depth interviews conducted between September 2009 and January 2010 in rural settings in Northern Tanzania. An HBCCT intervention appears to be broadly acceptable among participants. Benefits of HBCCT were identified in terms of access, confidentiality, and strengthening the relationship. Fears of negative consequences from knowing one's HIV status, including stigma, blame, physical abuse, or divorce, remain a concern and a potential barrier to the successful provision of the intervention. Lessons for implementation highlighted the importance of appointments for home visits, building relationships of confidence and trust between counselors and clients, and assessing and responding to a couple's readiness to undergo HIV testing. HBCCT should addresses HIV stigma, emphasize confidentiality, and improve communication skills for disclosure and decision-making among couples.


Catalytic hydrolysis of vasoactive intestinal peptide by human autoantibody.
Vasoactive intestinal peptide (VIP) labeled with 125I, [Tyr10-125I]VIP, can be hydrolyzed by immunoglobulin G (IgG) purified from a human subject, as judged by trichloroacetic acid precipitation and reversed-phase high-performance liquid chromatography (HPLC). The hydrolytic activity was precipitated by antibody to human IgG, it was bound by immobilized protein G and showed a molecular mass close to 150 kilodaltons by gel filtration chromatography, properties similar to those of authentic IgG. The Fab fragment, prepared from IgG by papain treatment, retained the VIP hydrolytic activity of the IgG. Peptide fragments produced by treatment of VIP with the antibody fraction were purified by reversed-phase HPLC and identified by fast atom bombardment-mass spectrometry and peptide sequencing. The scissile bond in VIP deduced from these experiments was Gln16-Met17. The antibody concentration (73.4 fmol per milligram of IgG) and the Kd (0.4 nM) were computed from analysis of VIP binding under conditions that did not result in peptide hydrolysis. Analysis of the antibody-mediated VIP hydrolysis at varying concentrations of substrate suggested conformity with Michaelis-Menton kinetics (Km). The values for Km (37.9 X 10(-9) M) and the turnover number kcat (15.6 min-1) suggested relatively tight VIP binding and a moderate catalytic efficiency of the antibody.


Cardiac sympathetic rejuvenation: a link between nerve function and cardiac hypertrophy.
Neuronal function and innervation density is regulated by target organ-derived neurotrophic factors. Although cardiac hypertrophy drastically alternates the expression of various growth factors such as endothelin-1, angiotensin II, and leukemia inhibitory factor, little is known about nerve growth factor expression and its effect on the cardiac sympathetic nerves. This study investigated the impact of pressure overload-induced cardiac hypertrophy on the innervation density and cellular function of cardiac sympathetic nerves, including kinetics of norepinephrine synthesis and reuptake, and neuronal gene expression. Right ventricular hypertrophy was induced by monocrotaline treatment in Wistar rats. Newly developed cardiac sympathetic nerves expressing beta(3)-tubulin (axonal marker), GAP43 (growth-associated cone marker), and tyrosine hydroxylase were markedly increased only in the right ventricle, in parallel with nerve growth factor upregulation. However, norepinephrine and dopamine content was paradoxically attenuated, and the protein and kinase activity of tyrosine hydroxylase were markedly downregulated in the right ventricle. The reuptake of [(125)I]-metaiodobenzylguanidine and [(3)H]-norepinephrine were also significantly diminished in the right ventricle, indicating functional downregulation in cardiac sympathetic nerves. Interestingly, we found cardiac sympathetic nerves in hypertrophic right ventricles strongly expressed highly polysialylated neural cell adhesion molecule (PSA-NCAM) (an immature neuron marker) as well as neonatal heart. Taken together, pressure overload induced anatomical sympathetic hyperinnervation but simultaneously caused deterioration of neuronal cellular function. This phenomenon was explained by the rejuvenation of cardiac sympathetic nerves as well as the hypertrophic cardiomyocytes, which also showed the fetal form gene expression.


alpha-Lipoic acid prevents the increase in atherosclerosis induced by diabetes in apolipoprotein E-deficient mice fed high-fat/low-cholesterol diet.
Considerable evidence indicates that hyperglycemia increases oxidative stress and contributes to the increased incidence of atherosclerosis and cardiovascular complications in diabetic patients. To examine the effect of alpha-lipoic acid, a potent natural antioxidant, on atherosclerosis in diabetic mice, 3-month-old apolipoprotein (apo) E-deficient (apoE(-/-)) mice were made diabetic by administering streptozotocin (STZ). At 4 weeks after starting the STZ administration, a high-fat diet with or without alpha-lipoic acid (1.65 g/kg) was given to the mice and to nondiabetic apoE(-/-) controls. At 20 weeks, markers of oxidative stress were significantly lower in both the diabetic apoE(-/-) mice and their nondiabetic apoE(-/-) controls with alpha-lipoic acid supplement than in those without it. Remarkably, alpha-lipoic acid completely prevented the increase in plasma total cholesterol, atherosclerotic lesions, and the general deterioration of health caused by diabetes. These protective effects of alpha-lipoic acid were accompanied by a reduction of plasma glucose and an accelerated recovery of insulin-producing cells in the pancreas, suggesting that part of its effects are attributable to protecting pancreatic beta-cells from damage. Our results suggest that dietary alpha-lipoic acid is a promising protective agent for reducing cardiovascular complications of diabetes.


Burnout and Mental Health Problems in Biomedical Doctoral Students.
Although burnout and mental health problems may adversely impact quality of scientific research, academic productivity, and attrition in biomedical doctoral training programs, very little research has been done on this topic. Recent studies have used brief survey methods to begin to explore burnout and mental health problems in biomedical doctoral students. In this pilot study, biomedical doctoral students (N = 69; 12% of enrolled biomedical doctoral students at a large research institution's school of medicine in the United States) were administered standardized psychiatric interviews and self-report questionnaires focused on dimensions of burnout, mental health symptoms, and academic outcomes. We discovered high levels of burnout, depression, and anxiety. Additionally, we identified that burnout was significantly associated with thoughts related to dropping out, subjective appraisal of employment opportunities, functional impairment due to a mental health problem, and having at least one current psychiatric disorder. These findings extend prior research indicating the presence of significant emotional health challenges doctoral students in biomedical graduate programs face involving high burnout and difficulties with the training environment. We outline several recommendations and next steps to programmatically understand and address these emerging emotional wellness concerns in biomedical doctoral students.


Mechanisms of inhibition of lipolysis by insulin, vanadate and peroxovanadate in rat adipocytes.
Vanadate and peroxovanadate (pV), potent inhibitors of tyrosine phosphatases, mimic several of the metabolic actions of insulin. Here we compare the mechanisms for the anti-lipolytic action of insulin, vanadate and pV in rat adipocytes. Vanadate (5 mM) and pV (0.01 mM) inhibited lipolysis induced by 0.01-1 microM isoprenaline, vanadate being more and pV less efficient than insulin (1 nM). A loss of anti-lipolytic effect of pV was observed by increasing the concentration of isoprenaline and/or pV. pV induced tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 to a greater extent than insulin, whereas vanadate affected these components little if at all. In addition, only a higher concentration (0.1 mM) of pV induced the tyrosine phosphorylation of p85, the 85 kDa regulatory subunit of phosphoinositide 3-kinase (PI-3K). Vanadate activated PI-3K-independent (in the presence of 10 nM isoprenaline) and PI-3K-dependent (in the presence of 100 nM isoprenaline) anti-lipolytic pathways, both of which were found to be independent of phosphodiesterase type 3B (PDE3B). pV (0.01 mM), like insulin, activated PI-3K- and PDE3B-dependent pathways. However, the anti-lipolytic pathway of 0.1 mM pV did not seem to require insulin receptor substrate-1-associated PI-3K and was found to be partly independent of PDE3B. Vanadate and pV (only at 0.01 mM), like insulin, decreased the isoprenaline-induced activation of cAMP-dependent protein kinase. Overall, these results underline the complexity and the diversity in the mechanisms that regulate lipolysis.


Latency characteristics of the short-wavelength-sensitive cones and their associated pathways.
There are many distinct types of retinal ganglion and LGN cells that have opponent cone inputs and which may carry chromatic information. Of interest are the asymmetries in those LGN cells that carry S-cone signals: in S-ON cells, S+ signals are opposed by (L + M) whereas, in many S-OFF cells, L+ signals are opposed by (S + M), giving -S + L - M (C. Tailby, S. G. Solomon, & P. Lennie, 2008). However, the S-opponent pathway is traditionally modeled as +/-[S - (L + M)]. A phase lag of the S-cone signal has been inferred from psychophysical thresholds for discriminating combinations of simultaneous sinusoidal modulations along +/-[L - M] and +/-[S - (L + M)] directions (C. F. Stromeyer, R. T. Eskew, R. E. Kronauer, & L. Spillmann, 1991). We extend this experiment, measuring discrimination thresholds as a function of the phase delay between pairs of orthogonal component modulations. When one of the components isolates the tritan axis, there are phase delays at which discrimination is impossible; when neither component is aligned with the tritan axis, discrimination is possible at all delays. The data imply that the S-cone signal is delayed by approximately 12 ms relative to (L - M) responses. Given that post-receptoral mechanisms show diverse tuning around the tritan axis, we suggest that the delay arises before the S-opponent channels are constructed, possibly in the S-cones themselves.


Improved light-transmission method for the study of LNAPL migration and distribution rule.
In this study, diesel was selected as a pollutant to study the migration and distribution rule of light non-aqueous phase liquid (LNAPL) in the simulated vadose zone. Saturation was regarded as a critical parameter to reflect the LNAPL migration and distribution rule. To get LNAPL saturation distribution figures, an image processing method of saturation was established to improve light-transmission technology, which can deal with digital camera images. Results showed that the vadose zone contains three areas from top to bottom, named dry media, transition zone and capillary zone. The system has two interfaces at which moisture content increased significantly. The significant increase in moisture content induced two apparent horizontal LNAPL diffusions in the two interfaces. Furthermore, the highly saturated LNAPL was mostly distributed near the wet interface, which lay between the dry media and the transition zone. Moreover, the downstream expansion of LNAPL in the capillary zone was promoted by groundwater flow, yet cutting off LNAPL supply could stop the downstream expansion after a period of time. The accuracy of this image processing method of saturation was verified by mass balance theory and reported a relative error of 4.38%.


Estimation of genetic parameters and detection of quantitative trait loci for metabolites in Danish Holstein milk.
Small components and metabolites in milk are significant for the utilization of milk, not only in dairy food production but also as disease predictors in dairy cattle. This study focused on estimation of genetic parameters and detection of quantitative trait loci for metabolites in bovine milk. For this purpose, milk samples were collected in mid lactation from 371 Danish Holstein cows in first to third parity. A total of 31 metabolites were detected and identified in bovine milk by using (1)H nuclear magnetic resonance (NMR) spectroscopy. Cows were genotyped using a bovine high-density single nucleotide polymorphism (SNP) chip. Based on the SNP data, a genomic relationship matrix was calculated and used as a random factor in a model together with 2 fixed factors (herd and lactation stage) to estimate the heritability and breeding value for individual metabolites in the milk. Heritability was in the range of 0 for lactic acid to >0.8 for orotic acid and β-hydroxybutyrate. A single SNP association analysis revealed 7 genome-wide significant quantitative trait loci [malonate: Bos taurus autosome (BTA)2 and BTA7; galactose-1-phosphate: BTA2; cis-aconitate: BTA11; urea: BTA12; carnitine: BTA25; and glycerophosphocholine: BTA25]. These results demonstrate that selection for metabolites in bovine milk may be possible.


[Dance therapeutic workshop for elderly people living in a home].
Elderly persons are often depressive; thus they are in loss of desire and motivation. They don't take care anymore of themselves and seem disembodied. It is exactly on this loss of desire that arts therapies have an impact. This involvement of the body facilitates the awareness of one's often unexploited capacities but also allows the emergence of pleasure and finally desire. Arts therapies are based on the conscience of here and now, with the perspective to become a creative being. It is the matter of helping people to recognize their own creativity that was underestimated by themselves up to here. These sessions allow the patients to go out of their room while bringing them a sensation of relaxation and well-being. They are proud to produce something by themselves and recover thus a certain self-esteem. And, through this activity, they are able to express what they feel. The statistical computations are made with the data of 10 elderly persons aged 77 to 95 years. We analyze the rating scales for self-expression through movement during 10 sessions. The subjects also filled in the Campbell's Index of Well-being in T1 and T2. Arts therapies improve in a significant way the cognitive functioning and the psychological well-being of elderly persons, as well as their quality of life.


Structural determinants driving homoserine lactone ligand selection in the Pseudomonas aeruginosa LasR quorum-sensing receptor.
Quorum sensing is a cell-cell communication process that bacteria use to orchestrate group behaviors. Quorum sensing is mediated by signal molecules called autoinducers. Autoinducers are often structurally similar, raising questions concerning how bacteria distinguish among them. Here, we use the Pseudomonas aeruginosa LasR quorum-sensing receptor to explore signal discrimination. The cognate autoinducer, 3OC12 homoserine lactone (3OC12HSL), is a more potent activator of LasR than other homoserine lactones. However, other homoserine lactones can elicit LasR-dependent quorum-sensing responses, showing that LasR displays ligand promiscuity. We identify mutants that alter which homoserine lactones LasR detects. Substitution at residue S129 decreases the LasR response to 3OC12HSL, while enhancing discrimination against noncognate autoinducers. Conversely, the LasR L130F mutation increases the potency of 3OC12HSL and other homoserine lactones. We solve crystal structures of LasR ligand-binding domains complexed with noncognate autoinducers. Comparison with existing structures reveals that ligand selectivity/sensitivity is mediated by a flexible loop near the ligand-binding site. We show that LasR variants with modified ligand preferences exhibit altered quorum-sensing responses to autoinducers in vivo. We suggest that possessing some ligand promiscuity endows LasR with the ability to optimally regulate quorum-sensing traits.


Association of serum carotenoid, retinol, and tocopherol concentrations with the progression of Parkinson's Disease.
A pivotal role of oxidative stress has been emphasized in the pathogenesis as well as in the disease progression of Parkinson's disease (PD). We aimed at investigating serum levels of antioxidant vitamins and elucidating whether they could be associated with the pathogenesis and progression of PD. Serum levels of retinol, α- and γ-tocopherols, α- and β-carotenes, lutein, lycopene, zeaxanthin and β-cryptoxanthin were measured and compared between 104 patients with idiopathic PD and 52 healthy controls matched for age and gender. In order to examine the relationship between antioxidant vitamins and the disease progression, multiple group comparisons were performed among the early PD (Hoehn and Yahr stage I and II, N = 47), advanced PD (stage III and IV, N = 57) and control groups. Separate correlation analyses were performed between the measured antioxidant vitamins and clinical variables, such as Hoehn and Yahr stage and Unified Parkinson's Disease Rating Scale (UPDRS) motor score. Compared to controls, PD patients had lower levels of α- and β-carotenes and lycopene. α-carotene, β-carotene and lycopene levels were significantly reduced in advanced PD patients relative to early PD patients and were negatively correlated with Hoehn and Yahr stage and UPDRS motor score in PD patients. No significant differences were found in serum levels of retinol, α- and γ-tocopherols, and other carotenoids between PD patients and controls. No significant correlations were found between these vitamin levels and clinical variables in PD patients. We found that serum levels of some carotenoids, α-carotene, β-carotene and lycopene, were lower in PD patients, and that these carotenoids inversely correlated with clinical variables representing disease progression. Our findings suggest that decreases in serum α-carotene, β-carotene and lycopene may be associated with the pathogenesis as well as progression of PD.


Two-level motor nerve transfer for the treatment of long thoracic nerve palsy.
The authors report a case of long thoracic nerve (LTN) palsy treated with two-level motor nerve transfers of a pectoral fascicle of the middle trunk, and a branch of the thoracodorsal nerve. This procedure resulted in near-total improvement of the winged scapula deformity, and a return of excellent shoulder function. A detailed account of the postoperative physical therapy regimen is included, as this critical component of the favorable result cannot be overlooked. This case establishes the two-level motor nerve transfer as a new option for treating LTN palsy, and demonstrates that nerve transfers should be considered in the therapeutic algorithm of an idiopathic mononeuritis.


Cytotoxic effects of N-hydroxyparacetamol in suspsensions of isolated rat hepatocytes.
The cytotoxicity of N-hydroxyparacetamol (N-OH-pHAA), a postulated proximate metabolite of the hepatotoxic and nephrotoxic analgesic paracetamol, was studied in suspensions of hepatocytes isolated by collagen-perfusion of livers of male rats. Incubation of cells with 0.25-2.0 mM N-OH-pHAA led after 3-5 hours to increased cell permeability measured by increased trypan blue uptake, increased NADH penetration or leakage of prelabelled 51Cr. N-OH-pHAA rapidly depleted cellular glutathione, 16% of initial levels were seen after 30 min. incubation. 3H-N-OH-pHAA bound covalently to cellular proteins in a time- and concentration-dependent manner, considerably higher binding rates were seen with boiled cells compared to intact cells. Pretreatment of animals with the cytochrome P-450 inducer phenobarbital did not affect N-OH-pHAA cytotoxicity or covalent binding, whereas the cytochrome P-450 inhibitor metyrapone inhibited both cytotoxicity and binding. Lipid peroxidation in hepatocytes could be seen as a limited range of N-OH-pHAA concentrations. In contrast, lipid peroxidation was an early event in cells exposed to carbon tetrachloride. A minimal exposure time of 30 min. of the hepatocytes to N-OH-pHAA was sufficient to elicit cellular damage occurring after 3-5 hours.


Cholesterol and violence: is there a connection?
To determine whether the seeming relation between low or lowered cholesterol levels and violence is consistent with causality according to Hill's criteria and whether construct validity is supported by convergence of findings across different types of studies. Search of the MEDLINE database for English-language articles published between 1965 and 1995 was supplemented by searches of the PsycINFO and Current Contents databases and bibliographies of relevant articles. Peer-reviewed observational and experimental articles and meta-analyses that presented original research; related cholesterol levels to behaviorally defined violence; and, if experimental, had single-factor (lipid-only) intervention. Studies were grouped according to type. Data on the relation of violence to cholesterol levels from each study were recorded. Observational studies (including cohort, case-control, and cross-sectional studies) consistently showed increased violent death and violent behaviors in persons with low cholesterol levels. Some meta-analyses of randomized trials found excess violent deaths in men without heart disease who were randomly assigned to receive cholesterol-lowering therapy. Experimental studies showed increased violent behaviors in monkeys assigned to low-cholesterol diets. Human and animal research indicates that low or lowered cholesterol levels may reduce central serotonin activity, which in turn is causally linked to violent behaviors. Many trials support a significant relation between low or lowered cholesterol levels and violence (P < 0.001). A significant association between low or lowered cholesterol levels and violence is found across many types of studies. Data on this association conform to Hill's criteria for a causal association. Concerns about increased risk for violent outcomes should figure in risk-benefit analyses for cholesterol screening and treatment.


Risk management in clinical practice. Part 6b. Identifying and avoiding medico-legal risks in removable dentures.
The most likely cause of complaint with prosthodontics is a denture that in some way fails to be accepted. A denture that does not perform as the patient expects can give rise to great disappointment and anger. The problem is that acceptance of a denture is not just a technical issue. Success depends on the individual's ability to tolerate and adapt to the denture. It is therefore essential to make the right assessment for the patient from the outset. This includes discovering the patient's priorities and establishing realistic expectations. With the aim of assisting the dental profession in identifying and avoiding medico-legal risks in removable dentures, this article sets out a systematic, diagnostic and collaborative approach to complete and partial denture assessment and treatment.


Sunlight robbery: a critique of public health policy on vitamin D in the UK.
The British Isles have a very cloudy climate and as a result receive fewer hours of clear sunlight than most other industrial regions. The majority of people in these islands have low blood levels of vitamin D [25(OH)D] all year round. Few food products are fortified with vitamin D in the UK and the government does not recommend any vitamin D supplement for most adults in the UK. Diseases associated with vitamin D insufficiency such as cancer, heart disease, diabetes (types 1 and 2) and multiple sclerosis are more frequent in the UK, and particularly in Scotland, than in many other European countries and some, such as multiple sclerosis and diabetes (types 1 and 2), are increasing in incidence. Present knowledge suggests that the risk of some chronic diseases could be reduced if vitamin D intake or sun exposure of the population were increased. Yet policy and public health recommendations of the UK government and its agencies (e.g. the Health Protection Agency, the Food Standards Agency) and of Cancer Research UK have failed to take full account of established and putative benefits of vitamin D and/or sunshine. The epidemic of chronic disease in the UK, which is associated with and caused at least in part by vitamin D insufficiency, has not been adequately recognized by these agencies, and too often measures taken by them have been misguided, inappropriate or ineffective.


A randomized crossover, pilot study examining the effects of a normal protein vs. high protein breakfast on food cravings and reward signals in overweight/obese "breakfast skipping", late-adolescent girls.
This pilot study examined whether the addition of a normal protein (NP) vs. high protein (HP) breakfast leads to alterations in food cravings and plasma homovanillic acid (HVA), which is an index of central dopamine production, in overweight/obese 'breakfast skipping' late-adolescent young women. A randomized crossover design was incorporated in which 20 girls (age 19 ± 1 y; BMI 28.6 ± 0.7 kg/m2) consumed 350 kcal NP (13 g protein) breakfast meals, 350 kcal HP (35 g protein) breakfast meals, or continued breakfast skipping (BS) for 6 consecutive days/pattern. On day 7 of each pattern, a 4 h testing day was completed including the consumption of breakfast (or no breakfast) followed by food craving questionnaires and blood sampling for HVA concentrations throughout the morning. Both breakfast meals reduced post-meal cravings for sweet and savory foods and increased HVA concentrations vs. BS (all, p < 0.05). Between breakfast meals, the HP breakfast tended to elicit greater reductions in post-meal savory cravings vs. NP (p = 0.08) and tended to elicit sustained increases in HVA concentrations prior to lunch vs. NP (p = 0.09). Lastly, HVA concentrations were positively correlated with the protein content at breakfast (r: 0.340; p < 0.03). Collectively, these findings suggest that the addition of breakfast reduces post-meal food cravings and increases homovanillic acid concentrations in overweight/obese young people with higher protein versions eliciting greater responses.


The Participation of Senior Citizens in Policy-Making: Patterning Initiatives in Europe.
Worldwide, active aging policy calls for greater participation of senior citizens in the social, economic, and political realms. Despite emerging evidence of initiatives engaging senior citizens in social activities, little is known about the use of participatory approaches in the design and/or implementation of policies that matter to older citizens. This article identifies initiatives facilitating the civic participation of older people in policy-making in European Union member and associate states, drawing on a review of the literature, consultation of national policy experts, and exemplary case studies. Four main patterns of senior civic participation are identified: adopting consultative or co-decisional participatory approaches in policy design or policy implementation. The four are represented to varying degrees at different geographical levels (national, regional, local), with different actor configurations (appointed, elected/nominated, corporate representation), and with varying degree of institutionalization (temporary/permanent). Case studies illustrate approaches taken to enhance the quality and effectiveness of public services for senior citizens. Future research should strengthen this line of enquiry to cast further light on conditions facilitating the civic participation of senior citizens.


Pre- and post-processing for tomographic reconstruction of terahertz time-domain spectroscopy.
Reflection-type terahertz tomography is obtained using time-domain spectroscopy. Due to different velocities of the terahertz ray in free space and inside a sample, the tomographic transverse plane is not obtained by a simple reconstruction using time index. A pre-processing method is proposed to compensate for the different velocities of the terahertz ray for tomographic reconstruction. Maximum intensity projection, averaging, and short-time Fourier transform are proposed as post-processing methods along the depth direction for the terahertz tomography. Log-scale display is also suggested for a better visualization. Some experimental results with the pre- and post-processing are demonstrated.


Strigolactones suppress adventitious rooting in Arabidopsis and pea.
Adventitious root formation is essential for the propagation of many commercially important plant species and involves the formation of roots from nonroot tissues such as stems or leaves. Here, we demonstrate that the plant hormone strigolactone suppresses adventitious root formation in Arabidopsis (Arabidopsis thaliana) and pea (Pisum sativum). Strigolactone-deficient and response mutants of both species have enhanced adventitious rooting. CYCLIN B1 expression, an early marker for the initiation of adventitious root primordia in Arabidopsis, is enhanced in more axillary growth2 (max2), a strigolactone response mutant, suggesting that strigolactones restrain the number of adventitious roots by inhibiting the very first formative divisions of the founder cells. Strigolactones and cytokinins appear to act independently to suppress adventitious rooting, as cytokinin mutants are strigolactone responsive and strigolactone mutants are cytokinin responsive. In contrast, the interaction between the strigolactone and auxin signaling pathways in regulating adventitious rooting appears to be more complex. Strigolactone can at least partially revert the stimulatory effect of auxin on adventitious rooting, and auxin can further increase the number of adventitious roots in max mutants. We present a model depicting the interaction of strigolactones, cytokinins, and auxin in regulating adventitious root formation.


[A Retrospective Series of 77 Pediatric Patients with Vertigo at a National Center for Child Health and Development].
The evaluation and management of vertigo in children varies among institutional and medical specialties. The aim of this study was to describe the characteristics of vertigo in children presenting at a national pediatric center. Patients < 16 years old presenting with vertigo to the department of otolaryngology at a national center for child health and development from April 2004 to October 2009 were included (N = 77; 42 males and 35 females; average age, 8.7 ± 3.4 years) in this study. The most common diagnoses were vestibular migraine (VM; N = 21), benign paroxysmal vertigo (BPV; N =16), unilateral vestibulopathy (N = 12), and psychogenic vertigo (N = 8). Significant differences were observed in the frequency of the diagnoses between children aged older and younger than 7 years: BPV was most common in children < 7 years of age (p < 0.01) and VM was most common in ≥ 27 years of age (p < 0.05). Because obtaining adequate information from children for making a correct diagnosis is sometimes difficult, acquiring sufficient information from the parents is important. In addition, getting the parents to record the nystagmus during a vertigo attack with a digital camera or cellular phone can be useful because observing the nystagmus recorded on the video is helpful for making a diagnosis. Furthermore, the parents are participating in their child's care by attempting to record the attack, strengthening the relationship between the parents and the child. The incidence of psychogenic vertigo is low (less than 10%). Therefore, although physicians have recently tended to define the disorder as psychogenic when no objective abnormality is found in a patient, making a diagnosis of psychogenic vertigo is not recommended. Because vertigo can sometimes make a child anxious, delivering the correct diagnosis and treatment at the early stage is important for preventing anxiety in affected children.


Alterations in IQGAP1 expression and localization in colorectal carcinoma and liver metastases following oxaliplatin-based chemotherapy.
IQGAP1 is a scaffolding protein that serves a key role in cell dynamics by integrating internal and external stimuli to distinct signal outputs. Previous studies have identified several genes that are significantly up- or downregulated in the peripheral white cells (PWCs) of patients with colorectal adenocarcinoma (CRC), who underwent oxaliplatin-based chemotherapy (CT). In addition, screening studies have reported that IQ-motif containing GTPase activating protein 1 (IQGAP1) transcriptional expression levels varied from 'off' to 'on' following oxaliplatin CT. In order to determine if variations previously described in PWCs are able to be observed at the protein level in tumors and in metastases following CT, the present study performed an immunohistochemical analysis of IQGAP1 in CRC and primary metastases. IQGAP1 expression was observed in the nuclear envelope and in lateral cell membranes and cytoplasm in normal colon tissue. However, in tumor tissue, cells exhibited a diffuse pattern, with variable expression levels of staining in the nuclear membrane and cytoplasm, with the highest expression intensity observed at the invasive front. In healthy and metastasized liver tissue and in the metastases themselves, expression levels varied from cell to cell from no expression to a high level. In the majority of cells, IQGAP1 co-localized with microtubules at the cytoplasmic face of the nuclear envelope. Strong positive expression was observed in areas of the lesion where cells were detaching from the lesion into the lumen. Despite the homogeneous IQGAP1 staining pattern observed in healthy colon tissue sections, CRC demonstrated heterogeneity in staining, which was more marked in metastasized liver tissue resected following CT. However, the most notable findings were the observed effects on the cellular and subcellular distribution and its implications for cancer biology. These results suggest that IQGAP1 may be a putative biomarker, a candidate for clinical diagnostics and a potential novel target for anti-cancer therapeutics.


Elg1, a central player in genome stability.
ELG1 is a conserved gene uncovered in a number of genetic screens in yeast aimed at identifying factors important in the maintenance of genome stability. Elg1's activity prevents gross chromosomal rearrangements, maintains proper telomere length regulation, helps repairing DNA damage created by a number of genotoxins and participates in sister chromatid cohesion. Elg1 is evolutionarily conserved, and its mammalian ortholog (also known as ATAD5) is embryonic lethal when lost in mice, acts as a tumor suppressor in mice and humans, exhibits physical interactions with components of the human Fanconi Anemia pathway and may be responsible for some of the phenotypes associated with neurofibromatosis. In this review, we summarize the information available on Elg1-related activities in yeast and mammals, and present models to explain how the different phenotypes observed in the absence of Elg1 activity are related.


Formulation and characterization of nanoencapsulated curcumin using sodium caseinate and its incorporation in ice cream.
In the present investigation, the preparation and characterization of a curcumin nanoemulsion with milk protein (sodium caseinate) and its incorporation into ice cream were undertaken. Among the different combinations, the most stable formulation was observed using milk fat (8%), medium chain triglycerides (2%), curcumin (0.24%) and sodium caseinate (6%) with a mean particle size of 333.8 ± 7.18 nm, a zeta potential of -44.1 ± 0.72 mV and an encapsulation efficiency of 96.9 ± 0.28%. The effect of different processing conditions (heating, pH and ionic strength) on the particle size distribution and zeta potential of the nanoemulsion was evaluated. During heat treatment, the particle size of the nanoemulsion was increased from 333.8 ± 7.18 to 351.1 ± 4.04 nm. The nanoemulsion was destabilized at pH 4.6 and the particle size increased above and below pH 5.0. However, there was a slight increase in the particle size with a change in the ionic concentration. The release kinetics data suggested that in simulated gastro-intestinal digestion, the nanoemulsion was stable against pepsin digestion (a 5.25% release of curcumin), while pancreatic action led to a 16.12% release of curcumin from the nanoemulsion. Finally, our formulation was successfully incorporated into ice cream and the sensory attributes were evaluated. No significant difference was observed in the scores of the sensory attributes between the control and ice cream prepared with a curcumin nanoemulsion. Moreover, the encapsulation efficiency of the curcumin incorporated into the ice cream was 93.7%, which indicates that it can withstand the processing conditions. The findings suggest that ice cream is a suitable dairy product for the delivery of lipophilic bioactive components (curcumin) which can be used for therapeutic purposes.


Isometric force generated by locust skeletal muscle: responses to single stimuli.
A mathematical model of the locust hind leg extensor muscle is described. The model accounts for the force response of the muscle to well-separated input stimuli under isometric conditions. Experimental data was collected by stimulating the extensor muscle and measuring the force generated at the tibia. In developing a model it was assumed that the response to a single isolated stimulus was linear. A linear model was found to fit well to the response to an isolated stimulus. No assumptions were made about the model order and models of various order were fitted to data in the frequency domain, using a least squares fit. The stimulus can be approximated as an impulse, with the response to each stimulus well described by a linear second-order system. Using a third-order model provided a better fit to data, but the improvement in fit was marginal and the model uses one extra parameter. A fourth-order model, which is often used to describe the behaviour of isometric muscle was found to overfit the data. Using a second-order model provides a simpler way of describing the behaviour of an isometric twitch.


Looking for trees in the forest: summary tree from posterior samples.
Bayesian phylogenetic analysis generates a set of trees which are often condensed into a single tree representing the whole set. Many methods exist for selecting a representative topology for a set of unrooted trees, few exist for assigning branch lengths to a fixed topology, and even fewer for simultaneously setting the topology and branch lengths. However, there is very little research into locating a good representative for a set of rooted time trees like the ones obtained from a BEAST analysis. We empirically compare new and known methods for generating a summary tree. Some new methods are motivated by mathematical constructions such as tree metrics, while the rest employ tree concepts which work well in practice. These use more of the posterior than existing methods, which discard information not directly mapped to the chosen topology. Using results from a large number of simulations we assess the quality of a summary tree, measuring (a) how well it explains the sequence data under the model and (b) how close it is to the "truth", i.e to the tree used to generate the sequences. Our simulations indicate that no single method is "best". Methods producing good divergence time estimates have poor branch lengths and lower model fit, and vice versa. Using the results presented here, a user can choose the appropriate method based on the purpose of the summary tree.


A Randomized Controlled Trial of an Optimized Smoking Treatment Delivered in Primary Care.
The effectiveness of smoking cessation treatment is limited in real-world use, perhaps because we have not selected the components of such treatments optimally nor have treatments typically been developed for and evaluated in real-world clinical settings. To validate an optimized smoking cessation treatment package that comprises intervention components identified as effective in factorial screening experiments conducted as per the Multiphase Optimization Strategy (MOST). Adult smokers motivated to quit were recruited from primary care clinics (N = 623). Participants were randomized to receive either recommended usual care (R-UC; 10 min of in-person counseling, 8 weeks of nicotine patch, and referral to quitline services) or abstinence-optimized treatment (A-OT; 3 weeks of prequit mini-lozenges, 26 weeks of nicotine patch + mini-lozenges, three in-person and eight phone counseling sessions, and 7-11 automated calls to prompt medication use). The key outcomes were self-reported and biochemically confirmed (carbon monoxide, CO <6 ppm) 7-day point-prevalence abstinence. A-OT participants had significantly higher self-reported abstinence rates than R-UC participants at 4, 8, 16, and 26 weeks (ORs: 1.91-3.05; p <. 001). The biochemically confirmed 26-week abstinence rates were lower than the self-reported 26-week rates, but revealed a similar treatment effect size (OR = 2.94, p < .001). There was no moderation of treatment effects on 26-week abstinence by demographic, psychiatric, or nicotine dependence variables. A-OT had an incremental cost-effectiveness ratio for 26-week CO-confirmed abstinence of $7,800. A smoking cessation treatment that is optimized via MOST development meaningfully enhances cessation rates beyond R-UC smoking treatment in smokers seen in primary care. NCT02301403.


Long-lasting (fatiguing) activity of isolated muscle fibres influenced by microwave electromagnetic field.
The study aims to clarify the effect of exposure to microwave electromagnetic field (MMW) on muscle fibre fatigue. Repetitive stimulation with interstimulus interval of 200 ms was applied on isolated frog muscle fibre to evoke intracellular action potentials and twitch contractions. After their recording muscle fibre preparation was moved in a Petri dish with radius of 28 mm on open air for one hour exposure to continuous MMW with frequency of 2.45 GHz and power density of 20 mW/cm2. Then it was again moved in the chamber with non irradiated Ringer's solution at controlled temperature for the repeated records. After MMW exposure the changes in amplitude and time parameters characterizing fatigue were attenuated and delayed vs. controls. The twitch amplitude curve described an drastic fall in the first 5 sec followed by an increase and next decrease. MMW (2.45 GHz) have a specific, non-thermal influence on muscle fibre activity resulting in some resistance to fatigue.


Engineering Transport in Manganites by Tuning Local Nonstoichiometry in Grain Boundaries.
Interface-dominated materials such as nanocrystalline thin films have emerged as an enthralling class of materials able to engineer functional properties of transition metal oxides widely used in energy and information technologies. In particular, it has been proven that strain-induced defects in grain boundaries of manganites deeply impact their functional properties by boosting their oxygen mass transport while abating their electronic and magnetic order. In this work, the origin of these dramatic changes is correlated for the first time with strong modifications of the anionic and cationic composition in the vicinity of strained grain boundary regions. We are also able to alter the grain boundary composition by tuning the overall cationic content in the films, which represents a new and powerful tool, beyond the classical space charge layer effect, for engineering electronic and mass transport properties of metal oxide thin films useful for a collection of relevant solid-state devices.


Practical guidelines for the comprehensive analysis of ChIP-seq data.
Mapping the chromosomal locations of transcription factors, nucleosomes, histone modifications, chromatin remodeling enzymes, chaperones, and polymerases is one of the key tasks of modern biology, as evidenced by the Encyclopedia of DNA Elements (ENCODE) Project. To this end, chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) is the standard methodology. Mapping such protein-DNA interactions in vivo using ChIP-seq presents multiple challenges not only in sample preparation and sequencing but also for computational analysis. Here, we present step-by-step guidelines for the computational analysis of ChIP-seq data. We address all the major steps in the analysis of ChIP-seq data: sequencing depth selection, quality checking, mapping, data normalization, assessment of reproducibility, peak calling, differential binding analysis, controlling the false discovery rate, peak annotation, visualization, and motif analysis. At each step in our guidelines we discuss some of the software tools most frequently used. We also highlight the challenges and problems associated with each step in ChIP-seq data analysis. We present a concise workflow for the analysis of ChIP-seq data in Figure 1 that complements and expands on the recommendations of the ENCODE and modENCODE projects. Each step in the workflow is described in detail in the following sections.


Depression in the elderly: pathological study of raphe and locus ceruleus.
Depressive symptoms in the elderly are common and disabling and constitute a risk factor for the development of Alzheimer's disease (AD). One hypothesis worth exploring is that depression in the elderly is related to development of AD pathology at subcortical sites before such pathology develops in the hippocampus and neocortex. We describe here an autopsy study of the locus ceruleus (LC) and raphe nuclei (RN) in nine subjects with depression and 18 age and sex matched controls that were included in a community-based study of cognitive function and ageing (MRC-CFAS). We found no relationship between depression and (1) mean counts of serotonergic or total RN neuronal profiles (2) noradrenergic or total LC neuronal profiles (3) counts of neurofibrillary tangles in these nuclei, or (4) size of neurones in the RN. Nor were these parameters related to age or sex of the subjects. We conclude that depression in the elderly is unlikely to be related to RN or LC neurone counts or RN cell size or to AD-type pathology in these nuclei. However, because of the small numbers of cases studied and our inability to carry out a full stereological study because of tissue limitations the findings are preliminary.


Haplotypes spanning the complement factor H gene are protective against age-related macular degeneration.
Age-related macular degeneration (AMD) is a devastating disorder that adversely affects the quality of life of nearly 2 million Americans who have advanced forms of the disease. Besides the well-known risk imparted by carrying the Y402H variant in the complement factor H (CFH) gene on chromosome 1, recent evidence of the existence of protective haplotypes spanning CFH has been reported. The haplo.stats program was used to test for association of the protective haplotypes after adjusting for age in the dataset of 584 sporadic cases and 248 control samples. Logistic regression modeling and likelihood ratio tests were used to investigate an interaction between a particular haplotype and smoking status. The HBAT option of FBAT was used to confirm the associations in an independent dataset of 201 families. Two protective (P) haplotypes in a family-based dataset (P1 = CAATTTAG, P = 0.021; and P2 = CGGCTTAG, P = 0.018) were identified for the first time. Age-adjusted score statistics provided support for these protective haplotypes in the case-control dataset (P1 frequency in cases approximately 13%, in controls approximately 20%, P = 0.001; P2 frequency in cases approximately 5%, in controls approximately 8%, P = 0.077). There was also tentative evidence of an interaction between one of the protective haplotypes and cigarette smoking (P = 0.04 likelihood ratio test for P2-smoking interaction). Replication of the association between the protective haplotypes and decreased AMD susceptibility provides increased evidence that these associations have biological meaning. The suggestion of a haplotype-smoking interaction adds to the growing body of evidence that smoking is an important environmental covariate in AMD that should be considered in genetic studies. Identification of the protective variant(s) carried within these haplotypes is critical for understanding the etiology of AMD.


Loss of the Intellectual Disability and Autism Gene Cc2d1a and Its Homolog Cc2d1b Differentially Affect Spatial Memory, Anxiety, and Hyperactivity.
Hundreds of genes are mutated in non-syndromic intellectual disability (ID) and autism spectrum disorder (ASD), with each gene often involved in only a handful of cases. Such heterogeneity can be daunting, but rare recessive loss of function (LOF) mutations can be a good starting point to provide insight into the mechanisms of neurodevelopmental disease. Biallelic LOF mutations in the signaling scaffold CC2D1A cause a rare form of autosomal recessive ID, sometimes associated with ASD and seizures. In parallel, we recently reported that Cc2d1a-deficient mice present with cognitive and social deficits, hyperactivity and anxiety. In Drosophila, loss of the only ortholog of Cc2d1a, lgd, is embryonically lethal, while in vertebrates, Cc2d1a has a homolog Cc2d1b which appears to be compensating, indicating that Cc2d1a and Cc2d1b have a redundant function in humans and mice. Here, we generate an allelic series of Cc2d1a and Cc2d1b LOF to determine the relative role of these genes during behavioral development. We generated Cc2d1b knockout (KO), Cc2d1a/1b double heterozygous and double KO mice, then performed behavioral studies to analyze learning and memory, social interactions, anxiety, and hyperactivity. We found that Cc2d1a and Cc2d1b have partially overlapping roles. Overall, loss of Cc2d1b is less severe than loss of Cc2d1a, only leading to cognitive deficits, while Cc2d1a/1b double heterozygous animals are similar to Cc2d1a-deficient mice. These results will help us better understand the deficits in individuals with CC2D1A mutations, suggesting that recessive CC2D1B mutations and trans-heterozygous CC2D1A and CC2D1B mutations could also contribute to the genetics of ID.


Endocan expression is correlated with poor progression-free survival in patients with pancreatic neuroendocrine tumors.
Endocan expression has been reported to be associated with aggressive tumor progression and poor outcomes in various cancers, such as breast cancer, renal cell cancer, lung cancer, gastric cancer, and pituitary adenomas. However, the prognostic significance of endocan in neuroendocrine tumors remains unknown. Thus, the aim of this study was to determine the correlation between endocan expression in pancreatic neuroendocrine tumor (PNET) tissues and progression-free survival. This study included 73 patients with confirmed PNETs who were treated in a single tertiary center in north Taiwan between 1992 and 2015. Immunohistochemical endocan expression and microvessel density (MVD) were examined, and the relationships between these parameters and other clinicopathological characteristics were analyzed. The abovementioned patients were divided into groups according to their endocan expression levels (≥1% or <1%) and median MVDs. Negative endocan expression (P = .002) and a high MVD (P < .001) were significant and favorable prognostic factors for progression-free survival. However, positive endocan expression was significantly associated with a low MVD (P = .037) and tumor mitosis (Ki-67 index) (P = .028). Multivariate Cox regression analysis showed that positive endocan expression (hazard ratio: 4.778, P = .018) and lymph node involvement (hazard ratio: 5.121, P = .005) were independent prognostic factors for tumor recurrence.In conclusion, endocan expression was correlated with poor clinical outcomes in PNETs. Our data indicated that endocan expression may be a reliable marker for predicting tumor recurrence in patients with PNETs.


Perspectives on exercise intensity, volume, step characteristics and health outcomes in walking for transport.
Quantification of movement intensity and energy utilization, together with frequency of trips, duration, distance, step counts and cadence, is essential for interpreting the character of habitual walking for transport, and its potential support of health. The purpose of the study is to illuminate this with valid methods and novel perspectives, and to thereby provide a new basis for characterizing and interpreting walking in relation to health outcomes. Habitual middle-aged commuting pedestrians (males = 10, females = 10) were investigated in the laboratory at rest and with maximal treadmill and cycle ergometer tests. Thereafter, levels of oxygen uptake, energy expenditure, ventilation, heart rate, blood lactate, rated perceived exertion, cadence, number of steps, duration, distance, and speed were recorded during the normal walking commute of each participant in Greater Stockholm, Sweden. The number of commutes per week over the year was self-reported. Walking in the field demanded about 30% more energy per km compared to level treadmill walking. For both sexes, the walking intensity in field was about 46% of maximal oxygen uptake, and energy expenditure amounted to 0.96 kcal · kg- 1 · km- 1. The MET values (males: 6.2; females: 6.5) mirrored similar levels of walking speed (males: 5.7; females: 5.9 km · h- 1) and levels of oxygen uptake (males: 18.6; females: 19.5 mL · kg- 1 · min- 1). The average number of MET-hours per week in a typical month was 22 for males and 20 for females. This resulted in a total weekly energy expenditure of ~1,570 and 1,040 kcal for males and females, respectively. Over the year, the number of walking commutes and their accumulated distance was ~385 trips and 800 km for both sexes. Walking in naturalistic field settings demands its own studies. When males and females walk to work, their relative aerobic intensities and absolute energy demands for a given distance are similar. It is equivalent to the lower part of the moderate relative intensity domain. The combination of oxygen uptake, trip duration and frequency leads to high and sustained levels of MET-hours as well as energy expenditure per week over the year, with a clear health enhancing potential. Based on this study we recommend 6000 transport steps per day, or equivalent, during five weekdays, over the year, in order to reach optimal health gains.


Potential of Carboxymethylated Polyallylamine as a Functional Group on Chelating Resin for Solid-Phase Extraction of Trace Elements.
New chelating resins immobilizing carboxymethylated polyallylamine (CM-PAA) were prepared by immobilizing PAAs with some molecular weights on methacrylate resins and then carboxymethylating a part of amino groups in the PAAs using various amounts of sodium monochloroacetate. The molecular weight of PAA barely affected both the amount of PAA immobilized on the resin and the relationship between the carboxymethylation (CM) rate and the ratio of the amount of monochloroacetate used in the CM step. The selectivity of CM-PAA resin for solid-phase extraction of trace elements was almost the same as that of a resin immobilizing carboxylymethylated polyethyleneimine; 10 elements, namely Cd, Co, Cu, Fe, Mo, Ni, Pb, Ti, V, and Zn, could be quantitatively recovered over a wide pH range and alkali and alkaline earth elements were scarcely extracted under acidic and neutral conditions. The CM-PAA resin was applicable to the separation and preconcentration of the elements in a certified reference material (Waste Water, EU-L-1) and a real environmental water sample (ground water).


The Role of Hemostatic Factors in Atherosclerosis in Patients with Chronic Renal Disease.
Atherosclerotic cardiovascular disease remains the leading cause of increased morbidity and mortality observed in chronic kidney disease (CKD) patients. Endothelial dysfunction (ED) is thought to be a key initial event in the development of atherosclerosis. The aim of this study was to evaluate the potential role of hemostatic factors in atherosclerosis, thrombosis and cardiovascular complications in patients suffering from chronic renal disease. The study was conducted on 50 renal patients divided into two groups of equal size. Group 1 consisted of 25 patients with end-stage renal disease (ESRD) on regular hemodialysis. Group 2 consisted of 25 chronic renal disease patients on conservative treatment. Twenty age- and sex-matched healthy subjects were included in the study to serve as a control group. Thrombomodulin (TM), von Willebrand factor (vWF), tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1) and hsCRP were assessed. High-resolution B-mode ultrasonography of both the common and internal carotid arteries to measure carotid intima media thickness (CIMT) was performed on all subjects. There were highly significant increases in hsCRP, TM, vWF, tPA and PAI-1 in both patient groups compared to the control group (P<0.01 for all except for TM between group 2 and 3 P<0.05) with significant increase in group 1 compared to group 2 (P<0.01). In addition, there was a highly significant increase in CIMT in both patient groups compared to the control group (P<0.01) with a significant increase in group 1 compared to group 2 (P<0.05). The study revealed significant positive correlation of hemostatic factors (TM, vWf, PAI-1 & t-PA) with creatinine, urea, hsCRP & CIMT. CKD patients have increased risk of atherosclerosis as measured by CIMT, which is used as a surrogate marker of early atherosclerosis and has been shown to be a strong predictor of future myocardial infarction and stroke. They have high levels of TM, vWF, tPA, PAI-1 that correlate with kidney function, hsCRP and CIMT. Therefore, these abnormalities in hemostasis may account for the increased risk of atherothrombosis in these patients. The elevated hsCRP levels and their correlation to hemostatic factors and CIMT might provide an important clue to link a systemic marker of inflammation to atherosclerosis. Further research is required to better understand the procoagulant state in patients with CKD.


RhoA/Rho-kinase suppresses endothelial nitric oxide synthase in the penis: a mechanism for diabetes-associated erectile dysfunction.
Significant impairment in endothelial-derived nitric oxide is present in the diabetic corpus cavernosum. RhoA/Rho-kinase may suppress endothelial nitric oxide synthase (eNOS). Here, we tested the hypothesis that RhoA/Rho-kinase contributes to diabetes-related erectile dysfunction and down-regulation of eNOS in the streptozotocin (STZ)-diabetic rat penis. Colocalization of Rho-kinase and eNOS protein was present in the endothelium of the corpus cavernosum. RhoA/Rho-kinase protein abundance and MYPT-1 phosphorylation at Thr-696 were elevated in the STZ-diabetic rat penis. In addition, eNOS protein expression, cavernosal constitutive NOS activity, and cGMP levels were reduced in the STZ-diabetic penis. To assess the functional role of RhoA/Rho-kinase in the penis, we evaluated the effects of an adeno-associated virus encoding the dominant-negative RhoA mutant (AAVTCMV19NRhoA) on RhoA/Rho-kinase and eNOS and erectile function in vivo in the STZ-diabetic rat. STZ-diabetic rats transfected with AAVCMVT19NRhoA had a reduction in RhoA/Rho-kinase and MYPT-1 phosphorylation at a time when cavernosal eNOS protein, constitutive NOS activity, and cGMP levels were restored to levels found in the control rats. There was a significant decrease in erectile response to cavernosal nerve stimulation in the STZ-diabetic rat. AAVT19NRhoA gene transfer improved erectile responses in the STZ-diabetic rat to values similar to control. These data demonstrate a previously undescribed mechanism for the down-regulation of penile eNOS in diabetes mediated by activation of the RhoA/Rho-kinase pathway. Importantly, these data imply that inhibition of RhoA/Rho-kinase improves eNOS protein content and activity thus restoring erectile function in diabetes.


The argos gene encodes a diffusible factor that regulates cell fate decisions in the Drosophila eye.
The argos gene encodes a protein that is required for viability and that regulates the determination of cells in the Drosophila eye. A developmental analysis of argos mutant eyes indicates that the mystery cells, which are usually nonneuronal, are transformed into extra photoreceptors, and that supernumerary cone cells and pigment cells are also recruited. Clonal analysis indicates that argos acts nonautonomously and can diffuse over the range of several cell diameters. Conceptual translation of the argos gene suggests that it encodes a secreted protein.


Neonatal hepatoblastoma: two cases posing a diagnostic dilemma, with a review of the literature.
Hepatoblastoma accounts for less than 1% of all pediatric malignancies. However, it remains the most common malignant tumor of the liver in newborns. Less than 10% of hepatoblastoma cases are diagnosed in the neonatal period. The diagnosis can be very difficult due to the wide spectrum of presentation and differences in the size of the lesion at the time of detection either antenatally or during an infant's neonatal course. In this review, we describe the current investigations used to establish the diagnosis of congenital hepatoblastoma and the role of a nuclear red cell scan as an additional strategy in the evaluation of this malignant condition. The report uses two cases of neonatal hepatoblastoma to highlight both the clinical and pathologic findings, and the problems encountered in the evaluation of this disorder.


The toxicity of Roundup® 360 SL formulation and its main constituents: glyphosate and isopropylamine towards non-target water photoautotrophs.
The toxicity of commercial formulation of Roundup® 360 SL, widely used, nonselective herbicide and its main constituents, glyphosate (PMG), equimolar (1:1) isopropylamine salt of glyphosate (GIPA) and isopropylamine (IPA) was examined towards eight aquatic microphotoautotrophs; seven cyanobacterial strains representing either saline or freshwater communities, and common eukaryotic algae Chlorella vulgaris Beijerinck. Autotrophs were cultured 21 days in their appropriate standard media supplemented with various amounts of Roundup®, glyphosate, GIPA and IPA. The determination of the growth of examined photoautotrophs was performed by time-course measurements of total chlorophyll content in experimental cultures. The growth rates related to corresponding concentrations of chemicals, the EC(50) values and generation doubling time were determined in order to present the toxicity Roundup® 360 SL formulation and its main constituents. Market available formulation of Roundup® was found to possess toxicity significantly higher than this, attributed to its main constituents; however both these compounds, isopropylamine and glyphosate, also inhibited the growth of examined strains in a dose-dependent manner. Notably, the interpretation of toxicity of the examined substances was found to be significantly dependent on the method of EC(50) calculation. The choice of molar or weight concentration of substances tested separately and in specific formulation was found to be essential in this matter. Due to these findings the EC(50) values were calculated based either on molar or on weight concentrations. Considering Roundup® 360 SL formulation, these values ranged from 10(-3) up to 10(-1) mM and they were one order of magnitude lower than those found for isopropylamine. Quite surprisingly the minimum EC(50) values found for glyphosate did not reach micromolar concentrations, whereas most of the EC(50) values revealed to IPA did not exceed this range. Notably, in all the cases except for Synechocystis aquatilis Sauvageau, isopropylamine alone was indicated as more toxic than glyphosate.


An unexpected surfactant role of immiscible nitrogen in the structural development of silver nanoparticles: an experimental and numerical investigation.
Artificially designing the crystal orientation and facets of noble metal nanoparticles is important to realize unique chemical and physical features that are very different from those of noble metals in bulk geometries. However, relative to their counterparts synthesized in wet-chemical processes, vapor-depositing noble metal nanoparticles with the desired crystallographic features while avoiding any notable impurities is quite challenging because this task requires breaking away from the thermodynamically favorable geometry of nanoparticles. We used plasma-generated N atoms as a surface-active agent, a so-called surfactant, to control the structural development of Ag nanoparticles supported on a chemically heterogeneous ZnO substrate. The N-surfactant-facilitated sputter deposition provided strong selectivity for crystalline orientation and facets, leading to a highly flattened nanoparticle shape that clearly deviated from the energetically favorable spherical polyhedra, due to the drastic decreases in the surface free energies of Ag nanoparticles in the presence of the N surfactant. The Ag nanoparticles successively developed a nearly unidirectional (111) orientation aligned by stimulating the crystalline coupling of Ag along the orientation of the ZnO substrate. The experimental and simulation results not only offer new insights into the advantages of N as a surfactant for the orientation and shape-controlled synthesis of Ag nanoparticles via sputter deposition but also provide the first solid evidence validating that immiscible, nonresidual gaseous surfactants can be used in the vapor deposition processes of noble metal nanoparticles to manipulate their surface free energies.


A catalyst-free intermolecular trans-iodoalkylation of alkynes.
We report the first catalyst-free and trans-selective iodoalkylation reaction of alkynes with a series of α-carbonyl compounds. This unprecedented three-component iodoalkylation reaction is enabled by using (iodoethynyl)trimethylsilane as a radical initiator and iodide source. The 1,2-difunctionalization affords alkenyl iodides, which are versatile building blocks for the construction of tri-substituted alkene derivatives.


Decision Making Influences Tibial Impact Accelerations During Lateral Cutting.
Lower-extremity musculoskeletal injuries are common in sports such as basketball and soccer. Athletes competing in sports of this nature must maneuver in response to the actions of their teammates, opponents, etc. This limits their ability to preplan movements. The purpose of this study was to compare impact accelerations during preplanned versus unplanned lateral cutting. A total of 30 subjects (15 males and 15 females) performed preplanned and unplanned cuts while the authors analyzed impact accelerations using an accelerometer secured to their tibia. For the preplanned condition, subjects were aware of the movement to perform before initiating a trial. For the unplanned condition, subjects initiated their movement and then reacted to the illumination of one of 3 visual stimuli which dictated whether they would cut, land, or land-and-jump. A mixed-model analysis of variance with a between factor of sex (male and female) and a within factor of condition (preplanned and unplanned) was used to analyze the magnitude and variability of the impact accelerations for the cutting trials. Both males and females demonstrated higher impact accelerations (P = .01) and a trend toward greater intertrial variability (P = .07) for the unplanned cutting trials (vs preplanned cuts). Unplanned cutting may place greater demands on the musculoskeletal system.


Martensitic organic crystals as soft actuators.
Being capable of rapid and complete structure switching, the martensitic phase transitions in molecular crystals are thought to hold a tremendous potential as thermally driven organic actuators. However, the mechanical engineering parlance in the assessment of their performance is not immediately legible to the chemistry research community that starts to explore these materials, and the unavailability of performance indices has precluded molecular crystals from being considered in the device design process. Here, we demonstrate that an organic martensite, hexamethylbenzene, can be used to perform work that is comparable to that of most actuator classes. Millimeter-size single crystals of this material undergo a transition between two forms by uniaxial expansion at a rate of 6.36(2) mm s-1, exerting force in the range 10-100 mN. The force-to-weight ratio of the crystals is on the order of 104 and is superior to that of some living creatures. An actuator performance chart reveals that the performance of this material is close to that of nanomuscles, electrostatic actuators and voice coils, with a strain higher than that of electro/magnetostrictive actuators and ceramic piezoelectrics and stress higher than that of the electroactive polymers, MEMS devices, nanomuscles, voice coils, and some solenoids. Moreover, the crystals of this material are mechanically compliant and can be reversibly bent and shaped to fit the desired application. Altogether, the results point to the untapped potential of molecular crystals as rapid and efficient soft, organic actuators.


Pseudoaccountability.
The public has long entrusted the medical profession to regulate its own practices, but our efforts to do so have been uneven. In place of rigorous, enforceable standards, we have sometimes reverted to pseudoaccountability: weak regulations that only give the appearance that we have been responsible in setting and enforcing high standards. We have failed to deal effectively with substandard practitioners, lagged in preventing medical errors, inadequately documented patient care in the medical record, slipped up in protecting patients in clinical research projects, and accepted financial arrangements with industry that may affect our judgment. In response, government has intervened, and threatens to intervene further with regulations that sometimes are excessively intrusive and cumbersome. To preserve our remaining autonomy, we must show that we are serious about protecting the public. Professional membership organizations must stop promulgating weak guidelines and offering evaluative methods to assess and regulate their own coveted members. Instead, they must turn over assessment of their members to arm's-length, disinterested groups. Regulatory programs must have provisions with impeccable standards, surveillance processes, and methods to deal with infractions. In planning new self-regulatory approaches, we should invite open discussion and genuine involvement by independent members of the public or the government to help ensure that our decisions about standard setting are not self-serving. Our profession has already lost much authority. We can ill afford to lose more.