Evaluation of recombinant dense granule antigen 7 (GRA7) of Toxoplasma gondii for detection of immunoglobulin G antibodies and analysis of a major antigenic domain.
Dense granule protein 7 (GRA7) of Toxoplasma gondii was expressed in Escherichia coli as a fusion protein. The leader peptide contained a 25-amino-acid mouse tumor necrosis factor fragment and six histidyl residues. After purification by metal chelate affinity chromatography, the antigen was evaluated in an enzyme-linked immunosorbent assay for detection of immunoglobulin G (IgG). For two sets of IgG-positive human serum samples, obtained from routine screening, an overall sensitivity of 81% was obtained. For chronic-phase sera, the sensitivity of detection was 79%, but chronic-phase sera with low titers were more difficult to detect (65% sensitivity for sera with immunofluorescence titer of 1/64). When GRA7 was combined with Tg34AR (rhoptry protein 2 C-terminal fragment), the sensitivity rose to 96%. For a set of acute-phase serum samples tested on GRA7, the sensitivity of detection was 94%, and high-titer IgM-positive sera were detected at an especially high rate. In contrast, when Tg34AR was used, the sensitivity was only 85% for this latter set of serum samples. Three truncated GRA7 fragments containing the same leader peptide as that of recombinant GRA7 were produced. The shortest fragment (97 N-terminal amino acids) was not reactive with human sera or with a specific anti-GRA7 monoclonal antibody, while the two larger fragments were reactive. The most important antigenic domain of GRA7 for human sera was localized between residues 97 and 146. The epitope for the specific monoclonal antibody could be further narrowed down by the use of synthetic peptides, but this epitope is not recognized by sera from T. gondii-infected humans. These results indicate that GRA7 may be considered as an additional tool for studying the immune response to T. gondii.


[Assessment of blood volume in children by means of different prediction formulas].
To assess the blood volume (BV) of children by using different prediction formulas (PF) and to confirm the value of these in providing reference estimates. The results of BV measurements in 19 children, performed at the Department of Physiology of the Haematology and Immunology Institute, were studied. The children had been sent to this centre to define the diagnosis of anaemia (11 cases) or polycythaemia (8 cases). Four adult and 2 children formulas based on body measurements were applied in order to estimate the reference BV. The relationship between the measured red cell volume (RCV) and plasma volume (PV) and the reference values was calculated for each formula, and the results were evaluated by establishing the normality criteria. The PF used provided reference estimates of the different BV for a given patient. It was found that most adult formulas gave RCV and PV estimates which differ from those of children. PV was commonly decreased with all the formulas. The different PF provide distinct BV estimates in most patients, and coincidentally the results differ in any given child. The formulas applied to adults, based on weight and height or body surface, should not be applied to estimate the BV in children. The use of equations based on height is recommended, correlating the BV assessment with the results of other studies.


Effect of ramipril on blood pressure and protein excretion rate in normotensive nondiabetic patients with proteinuria.
Angiotensin-converting enzyme inhibitors reduce proteinuria in both normotensive and hypertensive patients with proteinuric renal disease. However, the mechanism of the antiproteinuric effect has not been clarified. We performed a prospective, double-blind, placebo-controlled, randomized crossover trial to test the hypothesis that the antiproteinuric effect of ramipril was due to an improvement in glomerular permselectivity independent of blood pressure and glomerular filtration rate. The effect of low-dose (1.25 mg/d) and high-dose (5 mg/d) ramipril was assessed in 15 normotensive nondiabetic patients with proteinuria (> 150 mg/d). The study was divided into four 12-week periods: placebo, high- or low-dose ramipril, crossover to low- or high-dose ramipril, and placebo. Blood pressure, glomerular filtration rate, renal plasma flow rate, urinary protein excretion rate, and plasma angiotensin II levels were measured at the end of each period. Mean arterial pressure, urine protein to creatinine ratio, and albumin excretion rate decreased significantly during low- and high-dose ramipril. Glomerular filtration rate and renal plasma flow rate were not changed significantly. Plasma angiotensin II levels decreased with both low- and high-dose ramipril. There were no episodes of hypotension and only one subject developed cough during ramipril that did not require discontinuation of the study drug. In conclusion, administration of ramipril in both low and high doses lowered blood pressure and reduced proteinuria in this cohort of normotensive patients with a variety of proteinuric renal diseases. The antiproteinuric effect of ramipril is probably mediated by a reduction in glomerular capillary pressure.


Inbred mouse strains reveal biomarkers that are pro-longevity, antilongevity or role switching.
Traditionally, biomarkers of aging are classified as either pro-longevity or antilongevity. Using longitudinal data sets from the large-scale inbred mouse strain study at the Jackson Laboratory Nathan Shock Center, we describe a protocol to identify two kinds of biomarkers: those with prognostic implication for lifespan and those with longitudinal evidence. Our protocol also identifies biomarkers for which, at first sight, there is conflicting evidence. Conflict resolution is possible by postulating a role switch. In these cases, high biomarker values are, for example, antilongevity in early life and pro-longevity in later life. Role-switching biomarkers correspond to features that must, for example, be minimized early, but maximized later, for optimal longevity. The clear-cut pro-longevity biomarkers we found reflect anti-inflammatory, anti-immunosenescent or anti-anaemic mechanisms, whereas clear-cut antilongevity biomarkers reflect inflammatory mechanisms. Many highly significant blood biomarkers relate to immune system features, indicating a shift from adaptive to innate processes, whereas most role-switching biomarkers relate to blood serum features and whole-body phenotypes. Our biomarker classification approach is applicable to any combination of longitudinal studies with life expectancy data, and it provides insights beyond a simplified scheme of biomarkers for long or short lifespan.


Modeling and optimization of Q-switched double-clad fiber lasers.
The numerical modeling of actively Q-switched fiber lasers is systematically presented. On the basis of typical Q-switched ytterbium-doped double-clad fiber lasers under forward and backward pump, the dynamic characteristics of pulse energy, pulse width, population inversion, and stored energy at tens-of-kilohertz repetition rates are studied by using the traveling-wave method. The laser performance is further investigated for different fiber core diameters, doping rates, cavity lengths, fiber losses, signal and pump wavelengths, reflectivities of output coupler, and switching speed of an acousto-optic modulator; the laser optimization is also quantitatively discussed. Some simulation results are also compared with previous experimental results.


Using a cyclocarbon additive as a cyclone separator to achieve fast lithiation and delithiation without dendrite growth in lithium-ion batteries.
Carbon materials are widely used for reversible lithium uptake in the anode of lithium-ion batteries. Nevertheless, the challenge of uncontrollable dendrite deposition during fast charge-discharge cycles remains a grand hurdle. Various strategies have been explored to prevent detrimental heterogeneous dendrite metal deposits, such as interface engineering and electrolyte modification, but they often compromise the reverse diffusion freedom of Li+ ions during discharging and are incompatible with the most mainstream use of graphite as an anode material. Here, we propose the incorporation of a novel carbon allotrope of cyclocarbon as a potential additive in the anode. In contrast to conventional carbon materials, density functional theory calculations reveal that cyclocarbon has a much higher affinity for Li atoms than Li+ ions, even surpassing the inherent cohesion of Li atoms, due to the charge transfer from the 2s orbital of Li atoms to the unique in-plane π orbital of cyclocarbon. Furthermore, ab initio molecular dynamics simulations show that Li+ ions can shuttle freely back and forth across cyclocarbon, whereas the lithiation process for Li atoms occurs rapidly within picoseconds. The delithiation of Li atoms within cyclocarbon follows a voltage-gated mechanism that is effectively controlled by an external electric field of 3 V nm-1. Remarkably, cyclocarbon exhibits potential compatibility with commercialized graphite electrodes via the π-π interaction and also can be extended to sodium-ion and potassium-ion batteries. These distinct compatibility, scalability and electrochemical properties of cyclocarbon provide a new avenue to realize both safety and ultrafast rechargeable performance of ion batteries.


Improving global environmental management with standard corporate reporting.
Multinational corporations play a prominent role in shaping the environmental trajectory of the planet. The integration of environmental costs and benefits into corporate decision-making has enormous, but as yet unfulfilled, potential to promote sustainable development. To help steer business decisions toward better environmental outcomes, corporate reporting frameworks need to develop scientifically informed standards that consistently consider land use and land conversion, clean air (including greenhouse gas emissions), availability and quality of freshwater, degradation of coastal and marine habitats, and sustainable use of renewable resources such as soil, timber, and fisheries. Standardization by itself will not be enough--also required are advances in ecosystem modeling and in our understanding of critical ecological thresholds. With improving ecosystem science, the opportunity for realizing a major breakthrough in reporting corporate environmental impacts and dependencies has never been greater. Now is the time for ecologists to take advantage of an explosion of sustainability commitments from business leaders and expanding pressure for sustainable practices from shareholders, financial institutions, and consumers.


[Changes in the receptive field of pigeon tectum neurons subjected to vestibular and acoustic stimulation].
The changes in the receptive fields of neurons in the deep layers of the tectum opticum were studied as induced by labyrinthine and sound stimulation. Variations in the size of the receptive field, the particular direction of sensitive cells movement, duration of the reaction and amount of impulses in it were found. The results obtained and data from the literature allow one to suggest an active role of tectum opticum in the transformation of signals from the retina depending on the kind of information from other sensory systems.


Adsorption and dissociation of H2O on the (001) surface of uranium mononitride: energetics and mechanism from first-principles investigation.
The interfacial interaction of uranium mononitride (UN) with water from the environment unavoidably leads to corrosion of nuclear fuels, which affects a lot of processes in the nuclear fuel cycle. In this work, the microscopic adsorption behaviors of water on the UN(001) surface as well as water dissociation and accompanying H2 formation mechanisms have been investigated on the basis of DFT+U calculations and ab initio atomistic thermodynamics. For adsorption of one H2O monomer, the predicted adsorption energies are -0.88, -2.07, and -2.07 eV for the most stable molecular, partially dissociative, and completely dissociative adsorption, respectively. According to our calculations, a water molecule dissociates into OH and H species via three pathways with small energy barriers of 0.78, 0.72, and 0.85 eV, respectively. With the aid of the neighboring H atom, H2 formation through the reaction of H* + OH* can easily occur via two pathways with energy barriers of 0.61 and 0.36 eV, respectively. The molecular adsorption of water shows a slight coverage dependence on the surface while this dependence becomes obvious for partially dissociative adsorption as the water coverage increases from 1/4 to 1 ML. In addition, based on the "ab initio atomistic thermodynamic" simulations, increasing H2O partial pressure will enhance the stability of the adsorbed system and water coverage, while increasing temperature will decrease the H2O coverage. We found that the UN(001) surface reacts easily with H2O at room temperature, leading to dissolution and corrosion of the UN fuel materials.


Dopamine transporter imaging for the diagnosis of dementia with Lewy bodies.
Dementia with Lewy bodies (DLB) is a common cause of neurodegenerative dementia of old age. Its accurate recognition can be important in clinical management and is essential for the development of disease-modifying treatments. The current clinical diagnostic criteria are limited particularly by relatively poor sensitivity. Dopamine transporter (DAT) imaging using single-photon emission computed tomography (SPECT) is the most highly developed supplementary test for DLB, and is now incorporated as a suggestive feature in the consensus diagnostic criteria. However, there is uncertainty about its accuracy and its place in clinical practice. It is most commonly used in people who are already suspected of having DLB. We had two objectives in this review: (A) to estimate the accuracy of DAT imaging for the diagnosis of DLB in people with dementia in secondary care (specialist dementia services), and (B) to estimate the accuracy of DAT imaging for the diagnosis of DLB in people with dementia in secondary care who are already suspected of having DLB on the basis of a prior clinical work-up. We searched MEDLINE (1946 to February 2013), Embase (1980 to February 2013), BIOSIS Previews (1926 to February 2013), PsycINFO (1806 to February 2013), CINAHL (1982 to February 2013), LILACS (February 2013) and Web of Science and Conference Proceedings (ISI Web of Science) (1945 to February 2013). Several of these sources contain conference abstracts. We also searched four specialised databases containing diagnostic reviews: Meta-analyses van Diagnostisch Onderzoek (MEDION; February 2013), Database of Abstracts of Reviews of Effects (DARE; February 2013), Health Technology Assessment Database (HTA; February 2013), and Aggressive Research Intelligence Facility (ARIF; February 2013). We checked reference lists of relevant studies and reviews for potential additional studies. Terms for electronic database searching were devised in conjunction with the team at the Cochrane Dementia and Cognitive Improvement Group. We included test accuracy studies with delayed verification, diagnostic case-control studies, and two-gate studies with alternative diagnosis controls. (A) participants with dementia in secondary care, (B) participants in secondary care meeting consensus clinical criteria (other than the DAT imaging criterion) for possible or probable DLB, or both. SPECT or positron emission tomography (PET) imaging of brain dopamine transporters. Reference standard: Neuropathological diagnosis at autopsy. Two review authors independently selected studies for inclusion and extracted data. We extracted results into a 2x2 table, showing the binary test results cross-classified with the binary reference standard. We used this data to calculate sensitivities, specificities, and their 95% confidence intervals. We used the QUADAS-2 tool plus some additional items to assess methodological quality. We included one study that was applicable to our first objective (A). It reported data on 22 participants who met consensus clinical criteria for DLB or National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for Alzheimer's disease, or both (a two-gate design with alternative diagnosis controls). The index test was SPECT scanning using the ligand (123)I-FP-CIT. We considered the study to be at high risk of bias in the participant selection and index test domains (QUADAS-2). (123)I-FP-CIT SPECT analysed semiquantitatively had a sensitivity of 1.00 (95% confidence interval (CI) 0.66 to 1.00) and a specificity of 0.92 (95% CI 0.64 to 1.00) for the diagnosis of DLB (n = 22, 1 study). Analysed visually, the sensitivity was 0.86 (95% CI 0.42 to 1.00) and the specificity was 0.83 (95% CI 0.52 to 0.98) (n = 19, 1 study).We considered that the study also provided the best available data to address our second objective (B). At baseline, 15 participants were clinically suspected of having DLB. In this group, (123)I-FP-CIT SPECT scanning analysed semiquantitatively had a sensitivity of 1.00 (95% CI 0.63 to 1.00) and a specificity of 1.00 (95% CI 0.59 to 1.00) for the diagnosis of DLB (n = 15, 1 study). Analysed visually, accuracy in this group was lower with a sensitivity of 0.83 (95% CI 0.36 to 1.00) and a specificity of 0.71 (95% CI 0.29 to 0.96) (n = 13, 1 study). Only one study has used a neuropathological reference standard to assess the accuracy of DAT imaging for the diagnosis of DLB. The small size of the included study means that sensitivity and specificity estimates are imprecise. However, data from this study suggest that DAT imaging is more accurate than clinical diagnosis. Clinical diagnosis is therefore unsuitable to use as a reference standard for assessing the accuracy of DAT imaging.No studies using a neuropathological reference standard have directly addressed the common clinical scenario where the use of DAT imaging is considered as a diagnostic test in a person with possible DLB, or assessed the accuracy of DAT imaging in people with mild dementia. However, the data from the included study suggest that, where there is moderately severe dementia and a strong pre-existing suspicion of DLB (probable DLB), then a normal (123)I-FP-CIT SPECT scan may be an accurate means of excluding the diagnosis.Semiquantitative ratings of (123)I-FP-CIT SPECT scans appeared to be more accurate than visual ratings in all analyses.


A vitamin B-12 supplement of 500 μg/d for eight weeks does not normalize urinary methylmalonic acid or other biomarkers of vitamin B-12 status in elderly people with moderately poor vitamin B-12 status.
Plasma vitamin B-12 is the most commonly used biomarker of vitamin B-12 status, but the predictive value for low vitamin B-12 status is poor. The urinary methylmalonic acid (uMMA) concentration has potential as a functional biomarker of vitamin B-12 status, but the response to supplemental vitamin B-12 is uncertain. A study was conducted to investigate the responsiveness of uMMA to supplemental vitamin B-12 in comparison with other biomarkers of vitamin B-12 status [plasma vitamin B-12, serum holotranscobalamin (holoTC), plasma MMA] in elderly people with moderately poor vitamin B-12 status. A double-blind, placebo-controlled, randomized 8-wk intervention study was carried out using vitamin B-12 supplements (500 μg/d, 100 μg/d, and 10 μg/d cyanocobalamin) in 100 elderly people with a combined plasma vitamin B-12 <250 pmol/L and uMMA ratio (μmol MMA/mmol creatinine) >1.5. All biomarkers had a dose response to supplemental vitamin B-12. Improvements in plasma vitamin B-12 and serum holoTC were achieved at cobalamin supplements of 10 μg/d, but even 500 μg/d for 8 wk did not normalize plasma vitamin B-12 in 8% and serum holoTC in 12% of people. The response in uMMA was comparable with plasma MMA; 15-25% of people still showed evidence of metabolic deficiency after 500 μg/d cobalamin for 8 wk. There was a differential response in urinary and plasma MMA according to smoking behavior; the response was enhanced in ex-smokers compared with never-smokers. uMMA offers an alternative marker of metabolic vitamin-B12 status, obviating the need for blood sampling.


[Regulation of T-type Ca(2+) channel in lysophosphatidylcholine-stimulated cardiomyocytes].
To study the effect of lysophosphatidylcholine (LPC) on T-type calcium channel currents (I(Ca.T)) in cardiomyocytes, and identify the mechanism by which LPC accumulation in intracellular and/or interstitial space may uptake tachycardia and various arrhythmias during cardiac ischemia. Neonatal rat cardiomyocytes from 1 to 3-day-old Wistar rats and hypertrophied ventricular myocytes from Wistar rats were prepared. Human cardiac T-type calcium channel α1 subunits, Ca(V3.1) and Ca(V3.2), were stably expressed in HEK293 cells. In this study, cardiomyocytes and heterologous expression of human Ca(V3.1) and Ca(V3.2) components were measureed by whole-cell patch clamp to study the up-regulation of I(Ca.T) by LPC. LPC markedly accelerated the spontaneous beating rates of neonatal rat cardiomyocytes from (42±8) beats/min in control to (64 ±8) beats/min after LPC application for 5 min at the physiological [Ca(2+)](i) concentration (pCa=7.2). In neonatal cardiomyocytes, I(Ca.T) was significantly increased by 10 μmol/L LPC by 21.5% when [Ca(2+)](i) was high (pCa=7). Intracellular Ca(2+)-dependent augmentation of I(Ca.T) by LPC was confirmed not only in neonatal cardiomyocytes but also in adult ventricular myocytes from the hypertrophied hearts. In this experiment, I(Ca.T) was significantly increased by 10 μmol/L LPC by 23.5% when [Ca(2+)](i) was high (pCa=7), although it was unchanged when [Ca(2+)](i) was low (pCa=11), control: (3.8±0.2) pA/pF, n=16; LPC: (3.7±0.4) pA/pF, n=10. LPC exerted no effect on the Ca(V3.1) T-type Ca(2+) channel current (I(Ca(V)3.1)) regardless of the [Ca(2+)](i) concentration at a pCa of 7 or at a pCa of 11. In contrast, LPC up-regulated the Ca(V3.2) T-type Ca(2+) channel current (I(Ca(V)3.2)), which was much larger at a pCa of 7 [LPC=10 μmol/L: (68.8±2.1) pA/pF, n=10; LPC=50 μmol/L: (78.4±4.8) pA/pF, n=9)] than that at a pCa of 11 [(38.5±2.1) pA/pF, n=11]. The present study indicates that LPC up-regulates the cardiac I(Ca.T) in physiological or higher [Ca(2+)](i) concentration, which may accelerate the pathophysiological cardiac automaticity and trigger tachyarrhythmias as novel ischemia-related mechanism.


Synthesis of magnetic bentonite-gelatin hydrogel beads and their applications in Cu2+ capturing.
Heavy metal ions that exist in groundwater and farmland jeopardize the ecological environment and are very difficult to remove because of the complicated actual environment. Raw bentonite-gelatin beads (RB-GT) and magnetic bentonite-gelatin beads (MB-GT) synthesized in this work would be an appropriate tool to solve this problem. Those beads are synthesized by a facile hybrid injection method. Their adsorption behaviors on Cu(II) ions were systematically investigated using the batch adsorption method. The beads were characterized by scan electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectra (FTIR), and X-ray photoelectron spectroscopy (XPS). The adsorption isotherm and adsorption kinetic study showed that the Cu2+ adsorption by MB-GT beads fitted the Langmuir model and the pseudo-second model. The adsorption maximum capacities reached 192.5 mg/g and 236.5 mg/g with Cu concentration of 1000 mg/L for RB-GT and MB-GT beads, respectively. The competitive adsorption with other heavy metal ions (Ni(II), Pd(II) and Cd(II)) were compared. The adsorption of Cu(II) mechanisms is also further discussed.


[Pre- and postoperative irradiation in the treatment of resectable Klatskin tumours].
Proximal bile duct carcinoma (Klatskin tumour) is infrequent and difficult to treat. In principle, surgery is indicated. The usefulness of irradiation after resection is controversial in the literature. This article describes the experiences gained in the Academic Medical Centre of Amsterdam with pre- and postoperative irradiation of resectable Klatskin tumours. Preoperative irradiation (10.5 Gy) is administered to devitalize detached tumour cells in the bile, to prevent implantation metastases after resection. Postoperative irradiation has been administered since 1986 according to protocol. An analysis of 71 patients, of whom 48 had been irradiated after resection while 23 had not, showed a statistically significant prolongation of survival in the group irradiated postoperatively. Radiotherapy was administered externally (55 Gy) or in combination with internal radiotherapy (45 Gy external, 10 Gy internal). For internal irradiation, the source of radiation (Iridium-192) was introduced along the bile duct anastomoses via the soma formed by the blind end of the Roux-Y jejunal loop used for bile duct reconstruction. Since internal irradiation in combination with external irradiation caused more complications, while there was no difference of survival from patients only irradiated externally, the complete postoperative irradiation is currently being given from the outside. Pre- and postoperative irradiation may contribute to the success of the treatment of the resectable Klatskin tumour.


Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection.
Long-acting injectable regimens may simplify therapy for patients with human immunodeficiency virus type 1 (HIV-1) infection. We conducted a phase 3, randomized, open-label trial in which adults with HIV-1 infection who had not previously received antiretroviral therapy were given 20 weeks of daily oral induction therapy with dolutegravir-abacavir-lamivudine. Participants who had an HIV-1 RNA level of less than 50 copies per milliliter after 16 weeks were randomly assigned (1:1) to continue the current oral therapy or switch to oral cabotegravir plus rilpivirine for 1 month followed by monthly injections of long-acting cabotegravir plus rilpivirine. The primary end point was the percentage of participants who had an HIV-1 RNA level of 50 copies per milliliter or higher at week 48 (Food and Drug Administration snapshot algorithm). At week 48, an HIV-1 RNA level of 50 copies per milliliter or higher was found in 6 of 283 participants (2.1%) who received long-acting therapy and in 7 of 283 (2.5%) who received oral therapy (adjusted difference, -0.4 percentage points; 95% confidence interval [CI], -2.8 to 2.1), a result that met the criterion for noninferiority for the primary end point (margin, 6 percentage points). An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 93.6% who received long-acting therapy and in 93.3% who received oral therapy (adjusted difference, 0.4 percentage points; 95% CI, -3.7 to 4.5), a result that met the criterion for noninferiority for this end point (margin, -10 percentage points). Of the participants who received long-acting therapy, 86% reported injection-site reactions (median duration, 3 days; mild or moderate severity, 99% of cases); 4 participants withdrew from the trial for injection-related reasons. Grade 3 or higher adverse events and events that met liver-related stopping criteria occurred in 11% and 2%, respectively, who received long-acting therapy and in 4% and 1% who received oral therapy. Treatment satisfaction increased after participants switched to long-acting therapy; 91% preferred long-acting therapy at week 48. Therapy with long-acting cabotegravir plus rilpivirine was noninferior to oral therapy with dolutegravir-abacavir-lamivudine with regard to maintaining HIV-1 suppression. Injection-site reactions were common. (Funded by ViiV Healthcare and Janssen; FLAIR ClinicalTrials.gov number, NCT02938520.).


Stigma towards mental illness and substance use issues in primary health care: Challenges and opportunities for Latin America.
Stigma towards mental illness and addictive disorders is a global problem and one of the main obstacles in tackling this issue remains the effective integration of mental health services into primary health care (PHC). In Latin America, information has significantly increased on the existence of stigma; however, little is known about effective interventions to prevent stigma and promote recovery-oriented practices in PHC. The aim of this study is to understand the existing evidence regarding mental health stigma in PHC with a special focus on the Latin American region. A scoping review of the literature related to mental health stigma in PHC was conducted. Two hundred and seventeen articles were evaluated; 74 met inclusion criteria and 14 additional articles were selected from references of search results. Results were subdivided into five different perspectives: users, family members and significant others, health professionals, contextual factors, and potential effective interventions. Only nine studies were based in Latin America, and only one described an intervention to reduce stigma in mental health services, not specifically in PHC. We found an urgent need to develop interventions to understand and reduce stigma in PHC settings, especially in Latin America.


Early age conductive hearing loss causes audiogenic seizure and hyperacusis behavior.
Recent clinical reports found a high incidence of recurrent otitis media in children suffering hyperacusis, a marked intolerance to an otherwise ordinary environmental sound. However, it is unclear whether the conductive hearing loss caused by otitis media in early age will affect sound tolerance later in life. Thus, we have tested the effects of tympanic membrane (TM) damage at an early age on sound perception development in rats. Two weeks after the TM perforation, more than 80% of the rats showed audiogenic seizure (AGS) when exposed to loud sound (120 dB SPL white noise, < 1 min). The susceptibility of AGS lasted at least sixteen weeks after the TM damage, even the hearing loss recovered. The TM damaged rats also showed significantly enhanced acoustic startle responses compared to the rats without TM damage. These results suggest that early age conductive hearing loss may cause an impaired sound tolerance during development. In addition, the AGS can be suppressed by the treatment of vigabatrin, acute injections (250 mg/kg) or oral intakes (60 mg/kg/day for 7 days), an antiepileptic drug that inhibits the catabolism of GABA. c-Fos staining showed a strong staining in the inferior colliculus (IC) in the TM damaged rats, not in the control rats, after exposed to loud sound, indicating a hyper-excitability in the IC during AGS. These results indicate that early age conductive hearing loss can impair sound tolerance by reducing GABA inhibition in the IC, which may be related to hyperacusis seen in children with otitis media.


Alterations in gut microbiota composition and metabolic parameters after dietary intervention with barley beta glucans in patients with high risk for metabolic syndrome development.
Metabolic syndrome is a complex disease that is exponentially increasing in the western world, and diet is one of the possible ways to improve the metabolic status of patients. Barley beta glucans are dietary fibres that show promise for improvement cholesterol levels and postprandial glucose response, but they have been rarely investigated in human trials with concurrent focus on gut microbiota. A double-blind, placebo-controlled, randomised clinical trial was conducted with 43 volunteers with high risk for metabolic syndrome development or with diagnosed metabolic syndrome. During a four-week intervention study, participants consumed experimental bread containing 6 g of barley beta glucans or equal bread but without beta glucans. After dietary intervention, total plasma cholesterol decreased in the test group (-0.26 ± 0.54, p = 0.019), but not in the control group. Short chain fatty acids (SCFA) composition in faeces significantly changed with increase of propionic acid in test group (43.2%, p = 0.045) and with decrease of acetic acid in control group (41.8%, p = 0.011). The microbiome analysis based on Illumina paired end sequencing of 16S rRNA genes showed a decrease in microbial diversity and richness in the test group. The pre-intervention gut microbiota composition showed higher abundance of health associated Bifidobacterium spp. and Akkermansia municiphila within cholesterol-responsive group, showing that diet-induced metabolic response is possibly dependent on individual gut microbiota composition.


Monitoring the changes to the nutrient composition of fast foods following the introduction of menu labelling in New South Wales, Australia: an observational study.
The present study examined the energy (kilojoule) content of Australian fast-food menu items over seven years, before and after introduction of menu board labelling, to determine the impact of the introduction of the legislation. Analysis of the median energy contents per serving and per 100g of fast-food menu items. Change in energy content of menu items across the years surveyed and differences in energy content of standard and limited-time only menu items were analysed. Five of Australia's largest fast food chains: Hungry Jack's, KFC, McDonald's, Oporto and Red Rooster. All standard and limited-time only menu items available at each fast-food chain, collected annually for seven years, 2009-2015. Although some fast-food chains/menu item categories had significant increases in the energy contents of their menus at some time points during the 7-year period, overall there were no significant or systematic decreases in energy following the introduction of menu labelling (P=0·19 by +17 kJ/100 g, P=0·83 by +8 kJ/serving). Limited-time only items were significantly higher in median energy content per 100 g than standard menu items (+74 kJ/100 g, P=0·002). While reformulation across the entire Australian fast-food supply has the potential to positively influence population nutrient intake, the introduction of menu labelling legislation in New South Wales, Australia did not lead to reduced energy contents across the five fast-food chains. To encourage widespread reformulation by the fast-food industry and enhance the impact of labelling legislation, the government should work with industry to set targets for reformulation of nutrient content.


Association between Smoking Status and the Risk of Hip Fracture in Patients with Type 2 Diabetes: A Nationwide Population-Based Study.
Limited longitudinal evidence exists regarding the potential association between smoking status and hip fracture among individuals with type 2 diabetes. We investigated this association using large-scale, nationwide cohort data for the Korean population. This nationwide cohort study included 1,414,635 adults aged 40 and older who received Korean National Health Insurance Service health examinations between 2009 and 2012. Subjects with type 2 diabetes were categorized according to their smoking status, amount smoked (pack-years), number of cigarettes smoked per day, and duration of smoking. The results are presented as hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between smoking status parameters and risk of hip fracture in multivariable Cox proportional hazard regression analysis. Compared with never-smokers, an increased adjusted HR (aHR) for hip fracture was observed in current smokers (1.681; 95% CI, 1.578 to 1.791), and a comparable aHR for hip fracture was found in former smokers (1.065; 95% CI, 0.999 to 1.136). For former smokers who had smoked 20 pack-years or more, the risk was slightly higher than that for never-smokers (aHR, 1.107; 95% CI, 1.024 to 1.196). The hip fracture risk of female former smokers was similar to that of female current smokers, but the hip fracture risk in male former smokers was similar to that of male never-smokers. Smoking is associated with an increased risk of hip fracture in patients with type 2 diabetes. Current smokers with diabetes should be encouraged to quit smoking because the risk of hip fracture is greatly reduced in former smokers.


Long noncoding RNA LCTS5 inhibits non-small cell lung cancer by interacting with INO80.
To investigate the effect of lncRNA LCTS5 in the non-small cell lung cancer (NSCLC). LncRNA profiling was used to identify the novel lncRNA LCTS5. Viability and migration assays were implemented to evaluate the in vitro effect of LCTS5. Transplantation study was designed to investigate the in vivo role. Short hairpin RNA (shRNA) and lentiviral vector were used to alter LCTS5 expression. We identified a novel lncRNA named LCTS5 whose abundance is dramatically decreased in NSCLC. Overexpressing LCTS5 effectively inhibits viability and migration. Meanwhile, LCTS5 overexpression retards xenograft tumor growth and proliferation. LCTS5 interacts with INO80 to reduce INO80 occupancy at enhancer regions of multiple lung cancer related genes without affecting INO80 decay. The newly identified lncRNA LCTS5 impairs NSCLC progression and provides a compelling target for therapeutic intervention during NSCLC treatments.


Isolation of Specific Neuron Populations from Roundworm Caenorhabditis elegans.
During the aging process, many cells accumulate high levels of damage leading to cellular dysfunction, which underlies many geriatric and pathological conditions. Post-mitotic neurons represent a major cell type affected by aging. Although multiple mammalian models of neuronal aging exist, they are challenging and expensive to establish. The roundworm Caenorhabditis elegans is a powerful model to study neuronal aging, as these animals have short lifespan, an available robust genetic toolbox, and well-cataloged nervous system. The method presented herein allows for seamless isolation of specific cells based on the expression of a transgenic green fluorescent protein (GFP). Transgenic animal lines expressing GFP under distinct, cell type-specific promoters are digested to remove the outer cuticle and gently mechanically disrupted to produce slurry containing various cell types. The cells of interest are then separated from non-target cells through fluorescence-activated cell sorting, or by anti-GFP-coupled magnetic beads. The isolated cells can then be cultured for a limited time or immediately used for cell-specific ex vivo analyses such as transcriptional analysis by real time quantitative PCR. Thus, this protocol allows for rapid and robust analysis of cell-specific responses within different neuronal populations in C. elegans.


Esthetic Smile Perception Among Dental Students at Different Educational Levels.
To evaluate the perception of six esthetic components of the smile among dental students and whether such a perception was influenced by different education levels and gender. This was an analytical cross-sectional study. A self-administered questionnaire was applied to all students (n=182) at clinical levels (year four and five) to evaluate a total of 6 ideal images (smile arc [SA], buccal corridor [BC], gingival display [GD], midline diastema [MD], crown length [CL] and width [CW]). In addition, students were asked to evaluate 20 altered images of these ideal images. A 10-point visual analogue scale was used to assess the ideal images, with the right end of the scale labeled "attractive smile" and represented by the number 10 and the left end of the scale labeled "unattractive smile" and represented by the number 0. The opposite scoring was applied for the altered esthetics smile images. Descriptive statistics was run to report sample characteristics, and the Mann-Whitney U-tests were performed to compare clinical levels and gender on aspects of esthetic smile. The response rate was 80% (77 females and 68 males). Students at level five scored statistically significantly (p<0.001) higher towered attractive esthetic smile in ideal SA, while students at level four scored statistically significantly (p=0.016 and 0.006, respectively) higher towered attractive esthetic smile in ideal GD and CL. At altered smile esthetics images evaluation, fifth year dental students scored statistically significantly (p=0.030, 0.026 and 0.028, respectively) higher towered unattractive esthetic smile in two altered images of SA and one of BC. In contrast, fourth year dental students scored statistically significantly (p=0.022, 0.048, 0.027, respectively) higher towered unattractive esthetic smile in one altered image of GD, midline diastema and crown width. Males in year four were more likely to score higher than females for ideal images meanwhile females in year five scored higher than males towards attractive smile in ideal images. Males and females differences in scoring ideal images on both levels were generally non-significant (P>0.05) although males were statistically significantly to score higher than females towards unattractive images in both levels (p<0.05). Dental students at the fifth-year level of study had higher perception of esthetic components of smile than those at the fourth-year level. At each level of study, female dental students apparently had higher perceptions of smile esthetics than males.


Antioxidant and redox regulation of cellular signaling: introduction.
Oxidation-reduction (redox) based regulation of gene expression appears to be a fundamental regulatory mechanism in cell biology. This basic information has been exploited to develop novel strategies in clinical therapeutics. In contrast to the conventional idea that reactive species mostly serve as a trigger for oxidative damage of biological structures, we now know that low physiologically relevant concentration of reactive oxygen species can regulate a variety of key molecular mechanisms. Physical exercise causes redox changes in various cells and tissues. The molecular implications of such change are yet uncharacterized. The five component articles of this symposium discuss skeletal muscle contraction, cell adhesion, heat shock proteins, programmed cell death, and carbohydrate metabolism as they relate to physical exercise.


Anti-inflammaging effects of human alpha-1 antitrypsin.
Inflammaging plays an important role in most age-related diseases. However, the mechanism of inflammaging is largely unknown, and therapeutic control of inflammaging is challenging. Human alpha-1 antitrypsin (hAAT) has immune-regulatory, anti-inflammatory, and cytoprotective properties as demonstrated in several disease models including type 1 diabetes, arthritis, lupus, osteoporosis, and stroke. To test the potential anti-inflammaging effect of hAAT, we generated transgenic Drosophila lines expressing hAAT. Surprisingly, the lifespan of hAAT-expressing lines was significantly longer than that of genetically matched controls. To understand the mechanism underlying the anti-aging effect of hAAT, we monitored the expression of aging-associated genes and found that aging-induced expressions of Relish (NF-ĸB orthologue) and Diptericin were significantly lower in hAAT lines than in control lines. RNA-seq analysis revealed that innate immunity genes regulated by NF-kB were significantly and specifically inhibited in hAAT transgenic Drosophila lines. To confirm this anti-inflammaging effect in human cells, we treated X-ray-induced senescence cells with hAAT and showed that hAAT treatment significantly decreased the expression and maturation of IL-6 and IL-8, two major factors of senescence-associated secretory phenotype. Consistent with results from Drosophila,RNA-seq analysis also showed that hAAT treatment significantly inhibited inflammation related genes and pathways. Together, our results demonstrated that hAAT significantly inhibited inflammaging in both Drosophila and human cell models. As hAAT is a FDA-approved drug with a confirmed safety profile, this novel therapeutic potential may make hAAT a promising candidate to combat aging and aging-related diseases.


Assessment and perceptions of intensive care data quality, reporting and use: a survey of ICU directors.
It is becoming increasingly common for government bodies, healthcare providers, funders and consumers to seek measures of the quality of critical care. It is important to ensure the quality of intensive care unit (ICU) data is high so these stakeholders can confidently use quality of care measures in decision-making. This paper aims to evaluate the quality of data collected for and submitted to the Australian and New Zealand Intensive Care Society Adult Patient Database, and to investigate the perceptions of NSW ICU directors in relation to ICU data quality, reporting and usage. A survey tool was developed based on an existing framework that consisted of procedures for assessing data quality in medical registries. The survey was distributed to the directors of all NSW ICUs that submitted data in the 2007/2008 financial year. Overall, completeness of the data and its quality was perceived to be good. Participants were less likely to engage in activities involving the detection and correction of data errors, feedback of data or use of data for local purposes. A number of barriers and enablers to good quality ICU data as well as strategies to improve data quality were identified. Inadequate staff, training and resources for data collection were widespread concerns. NSW ICU directors believe more work is required to achieve high quality data and appropriate use of the data collected. Strategies targeting increased resources including updated technology and improved staffing and training, as well as low-cost solutions such as audit, feedback and clinician engagement, have been highlighted.


The cortical actin cytoskeleton of lactotropes as an intracellular target for the control of prolactin secretion.
We investigated the role of cortical actin filaments (F-actin) in the regulation of PRL secretion in cultured normal anterior pituitary cells. F-actin dynamics were evaluated by fluorescence microscopy, and PRL secretion from attached cells was measured by the reverse hemolytic plaque assay. F-actin localized to the periphery of lactotropes. PRL-releasing factors such as TRH, vasoactive intestinal peptide (VIP), and forskolin, or removal of the PRL-inhibiting factor dopamine (DA) from cultures chronically exposed to DA, caused fragmentation, i.e. focal disassembly of cortical F-actin. Basal, VIP-, and DA withdrawal-induced cortical F-actin disassembly were dependent on extracellular Ca2+ whereas TRH- and forskolin-induced disassembly were not. Short-term (5 min) treatment of cells with the F-actin-disrupting agent cytochalasin D (CD) enhanced basal PRL secretion but did not further stimulate TRH- or VIP-induced PRL secretion. The results support the existence of a causal link between F-actin disassembly and increased PRL secretion. On the other hand, exposure of cultures to DA decreased the percentage of cells showing cortical F-actin disassembly within minutes. Longer treatments (2-4 h) caused stabilization of cortical actin filaments as revealed by the protection vis-a-vis the depolymerizing effect of CD. The protective effect was specific for lactotropes and was evident with DA concentrations as low as 50 nM. Chronic exposure of the cells to DA blocked CD- and TRH-evoked actin disassembly and PRL secretion while VIP-induced effects were partially inhibited. Stabilization of F-actin with the marine sponge venom, jasplakinolide, also decreased basal and stimulated PRL secretion. In conclusion, our results suggest that, first, the cortical actin cytoskeleton of lactotropes is an integrator of the multiple factors regulating PRL secretion directly on the lactotrope, and second, the tonic inhibition of PRL secretion is mediated, at least in part, by DA-induced stabilization of cortical F-actin.


Do Pain-related Beliefs Influence Adherence to Multidisciplinary Rehabilitation?: A Systematic Review.
To understand how pain-related cognitions predict and influence treatment retention and adherence during and after a multidisciplinary rehabilitation program. Electronic databases including Medline, CINAHL, PsycINFO, Academic Search Complete, and Scopus were used to search 3 combinations of key words: chronic pain, beliefs, and treatment adherence. The search strategy yielded 591 results, with an additional 12 studies identified through reference screening. Eighty-one full-text papers were assessed for eligibility and 10 papers met the inclusion and exclusion criteria for this review. The pain-related beliefs that have been measured in relation to treatment adherence include: pain-specific self-efficacy, perceived disability, catastrophizing, control beliefs, fear-avoidance beliefs, perceived benefits and barriers, and other less commonly measured beliefs. The most common pain-related belief investigated in relation to treatment adherence was pain-related self-efficacy. Findings for the pain-related beliefs investigated among the studies were mixed. Collectively, all of the aforementioned pain-related beliefs, excluding control beliefs, were found to influence treatment adherence behaviors. The findings suggest that treatment adherence is determined by a combination of pain-related beliefs either supporting or inhibiting chronic pain patients' ability to adhere to treatment recommendations over time. In the studies reviewed, self-efficacy appears to be the most commonly researched predictor of treatment adherence, its effects also influencing other pain-related beliefs. More refined and standardized methodologies, consistent descriptions of pain-related beliefs, and methods of measurement will improve our understanding of adherence behaviors.


The effects of pelvic diagonal movements and resistance on the lumbar multifidus.
[Purpose] The purpose of this study was to compare the effects of pelvic diagonal movements, made with and without resistance, on the thickness of lumbar multifidus muscles. [Subjects and Methods] Participants in this study were healthy subjects who had no musculoskeletal disorders or lumbar-related pain. Participants were positioned on their side and instructed to lie with their hip flexor at 40 degrees. Ultrasonography was used for measurement, and the values of two calculations were averaged. [Results] The thickness of ipsilateral lumbar multifidus muscles showed a significant difference following the exercise of pelvic diagonal movements. The results of anterior elevation movements and posterior depression movements also demonstrated significant difference. There was no significant difference in lumbar multifidus muscles thickness between movements made with and without resistance. [Conclusion] These findings suggest that pelvic diagonal movements can be an effective method to promote muscular activation of the ipsilateral multifidus. Furthermore, researchers have concluded that resistance is not required during pelvic diagonal movements to selectively activate the core muscles.


A design thinking approach to effective vaccine safety communication.
The highly complex and controversial topic of vaccine safety communication warrants innovative, user-centered solutions that would start with gaining mutual respect while taking into account the needs, concerns and underlying motives of patients, parents and physicians. To this end, a non-profit collaborative project was conducted by The Vienna Vaccine Safety Initiative, an international think tank aiming to promote vaccine safety research and communication, and the School of Design Thinking in Potsdam, Germany, the first school for innovation in Europe. The revolutionary concept of the Design Thinking approach is to group students in small multi-disciplinary teams. As a result they can generate ground-breaking ideas by combining their expertise and different points of view. The team agreed to address the following design challenge question: "How might we enable physicians to encourage parents and children to prevent infectious diseases?" The current article describes, step-by step, the ideation and innovation process as well as first tangible outcomes of the project.


Homograft rejection delayed by treatment of donor tissue in vitro with antilymphocyte serum.
Treatment of rabbit corneal tissue in vitro with pooled rabbit serum delays the onset of corneal homograft rejection in the host. Addition of antilymphocyte serum results in a further significant delay in the onlset of rejection. The mechanisms by which such treatment of donor tissues may modify the antigenic content of the material are discussed.


Does postexercise modelled capillary blood flow accurately reflect cardiovascular effects by different exercise intensities?
Blood flow (BF) in exercising muscles is an important factor for exercise capacity. Recently, a non-invasive method to estimate capillary BF (Qcap ) was introduced. Using this method, the Fick principle is re-arranged by using relative differences in deoxygenated haemoglobin (ΔHHb) as a surrogate for arteriovenous O2 difference and pulmonary oxygen uptake (VO2 ) instead of muscular oxygen uptake. The aim of this study was to examine (I) the relationship between Qcap and exercise intensity during and following exercise, and (II) to critically reflect the Qcap approach. Seventeen male subjects completed six bouts of cycling exercise with different exercise intensities (40-90% peak oxygen uptake, VO2peak ) in randomized order. VO2 and ΔHHb were monitored continuously during the trail. Qcap was modelled bi-exponentially, and mean response time (MRT) was calculated during recovery as well as the dissociation of modelled VO2 and Qcap recovery kinetics (MRT/τVO2 ). End-exercise Qcap increased continuously with exercise intensity. This also applied to MRT. Postexercise MRT/τVO2 increased from 40 to 60% VO2peak but remained stable thereafter. The results show that Qcap response to exercise is linearly related to exercise intensity. This is presumably due to vasoactive factors like shear-stress or endothelial-mediated vasodilation. MRT/τVO2 shows that postexercise Qcap is elevated for a longer period than VO2 , which is representative for metabolic demand following exercise ≥70% VO2peak . This is a hint for prolonged local vasodilation. According to previous studies, Qcap could not be modelled properly in some cases, which is a limitation to the method and therefore has to be interpreted with caution.


Perioperative Interstitial Fluid Expansion Predicts Major Morbidity Following Pancreatic Surgery: Appraisal by Bioimpedance Vector Analysis.
To evaluate whether perioperative bioimpedance vector analysis (BIVA) predicts the occurrence of surgery-related morbidity. BIVA is a reliable tool to assess hydration status and compartimentalized fluid distribution. The BIVA of patients undergoing resection for pancreatic malignancies was prospectively measured on the day prior to surgery and on postoperative day (POD)1. Postoperative morbidity was scored per the Clavien-Dindo classification (CDC), and the Comprehensive Complication Index (CCI). Out of 249 patients, the overall and major complication rates were 61% and 16.5% respectively. The median CCI was 24 (IQR 0.0-24.2), and 24 patients (9.6%) had a complication burden with CCI≥40. At baseline the impedance vectors of severe complicated patients were shorter compared to the vectors of uncomplicated patients only for the female subgroup (P=0.016). The preoperative extracellular water (ECW) was significantly higher in patients who experienced severe morbidity according to the CDC or not [19.4L (17.5-22.0) vs. 18.2L (15.6-20.6), P=0.009, respectively] and CCI≥40, or not [20.3L (18.5-22.7) vs. 18.3L (15.6-20.6), P=0.002, respectively]. The hydration index on POD1 was significantly higher in patients who experienced major complications than in uncomplicated patients (P=0.020 and P=0.025 for CDC and CCI, respectively).At a linear regression model, age (β=0.14, P=0.035), sex female (β=0.40, P<0.001), BMI (β=0.30, P<0.001), and malnutrition (β=0.14, P=0.037) were independent predictors of postoperative ECW. The amount of extracellular fluid accumulation predicts major morbidity after pancreatic surgery. Female, obese and malnourished patients were at high risk of extracellular fluid accumulation.


Studies on the effect of chronic consumption of moderate amounts of ethanol on male rat hepatic microsomal drug-metabolizing activity.
Weanling, male Sprague-Dawley rats given 10% ethanol in the drinking water and food ad lib. for up to 8 weeks consumed 17% of their calories as ethanol. The alanine aminotransferase (ALT), aspartate aminotransferase (AST), and liver histology by light microscopy were unaffected by this treatment. Similarly, hepatic microsomal NADPH-cytochrome c reductase, ethylmorphine N-demethylase and benzphetamine N-demethylase activities were also not affected by ethanol consumption. On the other hand, cytochrome P-450 content, aniline hydroxylase activity and acetaminophen metabolism as measured by both the cysteine conjugate and the [3H]acetaminophen covalently-bound to microsomal protein were increased significantly by ethanol consumption. The maximal effect was seen by 6 weeks. The 2- to 3-fold increase in aniline and acetaminophen metabolism, the absence of liver damage, and the similarity in weight gains and caloric intakes for controls and treated animals suggest that the rat on 10% ethanol in the drinking water is a reasonable model for studies of the effect of moderate alcohol consumption on specific biochemical pathways.


Eosinophils in Health and Disease: A State-of-the-Art Review.
Eosinophils play a homeostatic role in the body's immune responses. These cells are involved in combating some parasitic, bacterial, and viral infections and certain cancers and have pathologic roles in diseases including asthma, chronic rhinosinusitis with nasal polyps, eosinophilic gastrointestinal disorders, and hypereosinophilic syndromes. Treatment of eosinophilic diseases has traditionally been through nonspecific eosinophil attenuation by use of glucocorticoids. However, several novel biologic therapies targeting eosinophil maturation factors, such as interleukin (IL)-5 and the IL-5 receptor or IL-4/IL-13, have recently been approved for clinical use. Despite the success of biologic therapies, some patients with eosinophilic inflammatory disease may not achieve adequate symptom control, underlining the need to further investigate the contribution of patient characteristics, such as comorbidities and other processes, in driving ongoing disease activity. New research has shown that eosinophils are also involved in several homeostatic processes, including metabolism, tissue remodeling and development, neuronal regulation, epithelial and microbiome regulation, and immunoregulation, indicating that these cells may play a crucial role in metabolic regulation and organ function in healthy humans. Consequently, further investigation is needed into the homeostatic roles of eosinophils and eosinophil-mediated processes across different tissues and their varied microenvironments. Such work may provide important insights into the role of eosinophils not only under disease conditions but also in health. This narrative review synthesizes relevant publications retrieved from PubMed informed by author expertise to provide new insights into the diverse roles of eosinophils in health and disease, with particular emphasis on the implications for current and future development of eosinophil-targeted therapies.


Aetiologies and outcomes of diffuse alveolar haemorrhage presenting as acute respiratory failure of uncertain cause.
Connective tissue diseases are the most common disorders causing diffuse alveolar haemorrhage (DAH) confirmed by open lung biopsy. However, it is not known whether these diseases are also the most common causes of DAH in patients presenting with the features of ARDS/acute lung injury (ALI). This study evaluated the frequency of concomitant disease in patients with ARDS/ALI and DAH. The sampling frame comprised all patients in a tertiary referral hospital diagnosed with ARDS/ALI and who underwent BAL between January 2000 and July 2006. The medical records of those patients who had BAL fluid findings compatible with DAH were reviewed. Of the 97 patients diagnosed with ARDS/ALI and who underwent BAL, 27 had BAL fluid findings compatible with DAH. Sixteen of the 27 patients did not have connective tissue diseases (59%); of these 12 patients had concomitant haematological malignancies or solid tumours. Of the seven patients who presented with DAH and no known underlying disease, only two were subsequently diagnosed with a connective tissue disorder. The in-hospital mortality rate was 55% and 63% for patients with DAH with and without connective tissue diseases, respectively (P = 0.710). The majority of patients with DAH presenting with the features of ARDS/ALI did not have underlying connective tissue diseases. Concomitant malignancies were found frequently in these patients. The outcome did not differ between patients with DAH with or without connective tissue diseases.


Proteomic insights on the metabolism in inflammatory bowel disease.
Inflammatory bowel diseases (IBD) are chronic and relapsing inflammatory conditions of the gut that include Crohn's disease and ulcerative colitis. The pathogenesis of IBD is not completely unraveled, IBD are multi-factorial diseases with reported alterations in the gut microbiota, activation of different immune cell types, changes in the vascular endothelium, and alterations in the tight junctions' structure of the colonic epithelial cells. Proteomics represents a useful tool to enhance our biological understanding and to discover biomarkers in blood and intestinal specimens. It is expected to provide reproducible and quantitative data that can support clinical assessments and help clinicians in the diagnosis and treatment of IBD. Sometimes a differential diagnosis of Crohn's disease and ulcerative colitis and the prediction of treatment response can be deducted by finding meaningful biomarkers. Although some non-invasive biomarkers have been described, none can be considered as the "gold standard" for IBD diagnosis, disease activity and therapy outcome. For these reason new studies have proposed an "IBD signature", which consists in a panel of biomarkers used to assess IBD. The above described approach characterizes "omics" and in this review we will focus on proteomics.


Mixed methods implementation research of cognitive stimulation therapy (CST) for dementia in low and middle-income countries: study protocol for Brazil, India and Tanzania (CST-International).
In low/middle-income countries (LMICs), the prevalence of people diagnosed with dementia is expected to increase substantially and treatment options are limited, with acetylcholinesterase inhibitors not used as frequently as in high-income countries (HICs). Cognitive stimulation therapy (CST) is a group-based, brief, non-pharmacological intervention for people with dementia that significantly improves cognition and quality of life in clinical trials and is cost-effective in HIC. However, its implementation in other countries is less researched. This protocol describes CST-International; an implementation research study of CST. The aim of this research is to develop, test, refine and disseminate implementation strategies for CST for people with mild to moderate dementia in three LMICs: Brazil (upper middle-income), India (lower middle-income) and Tanzania (low-income). Four overlapping phases: (1) exploration of barriers to implementation in each country using meetings with stakeholders, including clinicians, policymakers, people with dementia and their families; (2) development of implementation plans for each country; (3) evaluation of implementation plans using a study of CST in each country (n=50, total n=150). Outcomes will include adherence, attendance, acceptability and attrition, agreed parameters of success, outcomes (cognition, quality of life, activities of daily living) and cost/affordability; (4) refinement and dissemination of implementation strategies, enabling ongoing pathways to practice which address barriers and facilitators to implementation. Ethical approval has been granted for each country. There are no documented adverse effects associated with CST and data held will be in accordance with relevant legislation. Train the trainer models will be developed to increase CST provision in each country and policymakers/governmental bodies will be continually engaged with to aid successful implementation. Findings will be disseminated at conferences, in peer-reviewed articles and newsletters, in collaboration with Alzheimer's Disease International, and via ongoing engagement with key policymakers.


Separation of Americium in High Oxidation States from Curium Utilizing Sodium Bismuthate.
A simple separation of americium from curium would support closure of the nuclear fuel cycle, assist in nuclear forensic analysis, and allow for more accurate measurement of neutron capture properties of (241)Am. Methods for the separation of americium from curium are however complicated and time-consuming due to the similar chemical properties of these elements. In this work a novel method for the separation of americium from curium in nitric acid media was developed using sodium bismuthate to perform both the oxidation and separation. Sodium bismuthate is shown to be a promising material for performing a simple and rapid separation. Curium is more strongly retained than americium on the undissolved sodium bismuthate at nitric acid concentrations below 1.0 M. A separation factor of ∼90 was obtained in 0.1 M nitric acid. This separation factor is achieved within the first minute of contact and is maintained for at least 2 h of contact. Separations using sodium bismuthate were performed using solid-liquid extraction as well as column chromatography.


Three-dimensional reconstruction of colon carcinoma metastases in liver.
Resection of liver metastases in patients with colon cancer increases survival but success depends on removal of all tumour tissue. For this purpose, understanding of spatial relationships between metastases and liver architecture is essential. Because metastatic cancer growth is essentially a three-dimensional (3D) event, we decided to apply 3D reconstruction techniques to study these spatial relationships between metastases and liver structures such as blood vessels, stroma and the liver capsule (Glisson's capsule). Colon carcinoma metastases were experimentally induced in rat liver by injection of colon cancer cells (CC531) into the portal vein. Three weeks later, livers from these animals and control livers were removed and immediately frozen in liquid nitrogen. Thirty-seven to 110 consecutive sections were used for each 3D reconstruction of 26 metastases in eight livers. Contours of different structures were stained by (immuno)histochemical means, traced in each section and stored in a database. From the contour model, a volume model was generated. Among the 26 metastases, seven were found to grow distantly from the liver capsule. They were small and consisted of well-differentiated cancer cells that were totally surrounded by a basement membrane and stroma which was always connected with adjacent blood vessels of a portal tract. The remaining 19 metastases showed a more advanced pattern of development. Infiltration of poorly differentiated colon cancer cells progressed through the stroma at various sites and areas of direct contact between cancer cells and hepatocytes were frequently found. This type of outgrowth of cancer cells was only found when metastases had made contact with the liver capsule. However, some areas in sections of these advanced stages still resembled small metastases. On the basis of these findings, we conclude that stroma-affects the differentiation pattern of cancer cells and has at least a dual role in tumour growth. On the one hand it limits invasion of cancer cells in the surrounding host tissue. On the other hand, stroma formation at the capsule, which consists mainly of granulation tissue, facilitates outgrowth of the tumours. Furthermore, our 3D reconstructions demonstrate the spatial heterogeneity of larger metastases and the importance of a 3D approach to understand growth and development of metastases in general and colon cancer metastases in the liver in particular.


The effects of disinfection with Er, Cr:YSGG laser, application of CPP-ACP and sodium hypochlorite on shear bond strength.
The effects of commonly used antimicrobial and anticariogenic agents on the adhesion of pit and fissure sealants were investigated in this study. The aim of this study is to evaluate the effects of erbium, chromium: yttrium-scandium-gallium-garnet (Er, Cr:YSGG) laser disinfection, casein phosphopeptides-amorphous calcium phosphate (CPP-ACP) containing paste and sodium hypochlorite application before the placement of a resin-based pit and fissure sealant on the shear bond strength of primary tooth enamel. The shear bond strength test evaluated the bond strength of sealants on the buccal enamel surfaces of primary molar teeth. The study groups were pit and fissure sealant without any preapplication, pre application of disinfection with Er, Cr:YSGG laser, disinfection with Er, Cr:YSGG laser and CPP-ACP containing paste, sodium hypochlorite, sodium hypochlorite and CPP-ACP containing paste and CPP-ACP containing paste. The pit and fissure sealants were placed using 4 mm diameter, 2 mm height cylindrical plastic tubes. Shear force was applied to each sample. The surfaces of the broken samples were detected under stereomicroscope and were grouped as adhesive, cohesive, and mixed. The results of the study were evaluated using the SPSS 16.0 package program for statistical analysis. The groups where sodium hypochlorite and sodium hypochlorite with CPP-ACP were applied showed the lowest bond strength (p < 0.05). It was observed that most of the failures in these groups were adhesive-type failures. No significant difference was observed between the shear bond strengths of the other groups (p < 0.05). Er, Cr: YSGG laser and CPP-ACP containing paste are alternative methods for pre-application of fissure sealants.


Cholesterol screening by primary care pediatricians: a study of attitudes and practices in the Minneapolis-St Paul metropolitan area.
A telephone survey of the 197 board-certified pediatricians actively engaged in primary care in the Minneapolis-St Paul metropolitan area was conducted to assess their cholesterol screening practices and hypercholesterolemia management. The response rate was 95%. Nearly all the pediatricians (90%) do some cholesterol screening, with the majority (58%) screening only children with a strong family history of coronary heart disease. Though only 33% screen all their patients, 66% advocate universal pediatric screening. Most of the pediatricians indicated they would manage hypercholesterolemia patients themselves, nearly always with dietary means. Despite their strong support for screening, the pediatricians expressed skepticism about the significance of childhood cholesterol level as a predictor of adult cardiovascular disease and doubted their effectiveness in getting patients to adopt a cholesterol-reducing diet. Their definition of elevated total cholesterol level in childhood was consistent with published recommendations, but only 29% could define elevated low-density lipoprotein cholesterol level. The pediatricians expressed strong opposition to pediatric cholesterol screening in schools or in any setting other than clinics and hospitals.


Identification of a novel mutation in the paired domain of PAX3 in an Iranian family with waardenburg syndrome type I.
Waardenburg syndrome Type I (WS1) is an autosomal dominant disorder that has previously been associated with mutations in the PAX3 gene on the 2q35 region. In this study, we used an Iranian WS1 family with seven affected individuals in three generations. The phenotypic characteristics of the family include sensorineural deafness, dystopia canthorum, hypopigmented skin patches of the upper limbs, congenital white forelock, confluent white eyebrows, nonpigmented iris, poliosis, and hypopigmentation of the retina. Herein, we report a previously unidentified single-base substitution in exon II (C-->T at position 218) that results in a change of serine to leucine (S73L) in this family. This change was not observed in 100 chromosomes of healthy unrelated individuals. This mutation is within the PAX3 paired domain region, a structure that is highly conserved and implicated in DNA binding. This is the first identification of a PAX3 mutation for this phenotype in the Iranian population. This also provides additional confirmation for the involvement of this gene in the etiology of WS1.


Burden and epidemiology of rotavirus diarrhea in selected African countries: preliminary results from the African Rotavirus Surveillance Network.
Severe rotavirus diarrhea in children <5 years of age is a major public health problem; however, limited regional and country specific data on rotavirus disease burden are available from sub-Saharan Africa. In June 2006, the World Health Organization Regional Office for Africa initiated rotavirus surveillance in selected African countries. With use of standardized methodology developed by the World Health Organization, children <5 years of age who were hospitalized with severe diarrhea were enrolled, and stool specimens were collected for detection of rotavirus strains with use of a commercial enzyme immunoassay. Rotavirus strains were further characterized for G and P types with use of a reverse-transcriptase polymerase chain reaction. From June 2006 through December 2008, rotavirus surveillance was established at 14 sites in 11 African countries. Of 5461 stool samples collected from children enrolled in 8 countries with 1 or 2 complete years of data, 2200 (40%) were positive for rotavirus. Ninety percent of all rotavirus hospitalizations occurred among children aged 3-12 months. Predominant types included G1P[8] (21%), G2P[4] (7%), and P [8] (29%); however, unusual types were also detected, including G8P[6] (5%), G8P[8] (1%), G12P[6] (1%), and G12P[6] (1%). A high percentage of mixed rotavirus infections was also detected. These preliminary results indicate that rotavirus is a major cause of severe diarrheal disease in African children.


Outcome evaluation following subarachnoid hemorrhage.
Seventy-eight individuals among a population of 1.46 million suffered aneurysmal subarachnoid hemorrhage (SAH) during 1983. Within 24 hours after the bleed, 32 of the 78 patients were in Hunt and Hess neurological Grades I to II, 13 were in Grade III, 21 were in Grades IV to V, and 12 were dead on admission to a hospital or forensic department. When the amount of blood visualized on computerized tomography (CT) scanning was integrated with the Hunt and Hess neurological classification in order to improve prediction of prognosis, only 16 patients were considered to have a good prognosis (CT-modified Grades I to II), 21 had a less favorable prognosis (CT-modified Grade III), and 29 had a poor prognosis (CT-modified Grades IV to V). Assessment at 1 year revealed that only 32 patients (41%) had a good physical recovery. The physical morbidity rate was 22%, and the overall mortality rate was 37%. Twenty-six individuals with a good neurological outcome and five with a fair outcome also underwent reexamination 1 year or more post-SAH, which included a comprehensive evaluation of the quality of life, assessment of cognitive dysfunction, and determination of general adjustment. Five of the patients with a good neurological outcome and all five with a fair outcome (four of whom had had a poor prognosis in the acute stage) showed severe psychosocial and cognitive incapacitation. When functional morbidity, based upon persistent severe cognitive and psychosocial impairment, was included in the outcome assessment, only 33% of the total series was considered to have a favorable outcome. Approximately 60% of the initially good-risk patients (Grades I and II) showed a good physical outcome without concomitant indications of severe cognitive dysfunction and/or psychosocial impairment. Among the good-risk patients with a CT-modified grade, the figure was 70%. It is suggested that in any outcome grading system, persistent cognitive and psychosocial disturbances be taken into account.


A fine-needle aspirate-based vulnerability assay identifies polo-like kinase 1 as a mediator of gemcitabine resistance in pancreatic cancer.
This work aimed to discover targets for combination treatment with gemcitabine in pancreatic cancer. We selected 11 tumors from our live collection of freshly generated pancreatic cancer xenografts with known degrees of varying gemcitabine sensitivity. We briefly (6 h) exposed fine-needle aspiration material to control vehicle or gemcitabine (1 mumol/L) and compared the gene expression of the treated and untreated samples using a reverse transcription-PCR-based, customized low-density array with 45 target genes of therapeutic interest. The gene expression of the untreated sample (which can be considered a baseline/static readout) was not predictive of gemcitabine efficacy in these tumors. Altogether, the only gene that differentiated sensitive versus resistant cases was polo-like kinase 1 (Plk1), showing >50% downregulation in sensitive cases and no change in the resistant cases. Inhibition of Plk1 by either small interfering RNA gene knockdown or with the Plk1 pathway modulator (ON 01910.Na) synergized with gemcitabine in gemcitabine-refractory in vitro models providing mechanistic proof of concept. In vivo experiments in gemcitabine-resistant xenografts showed synergistic activity decreasing cell proliferation and tumor regressions. A quantitative gene expression-based vulnerability assay identified Plk1 as a relevant target dictating the susceptibility of pancreatic cancer to gemcitabine. Dynamic interrogation of cancer has the potential to provide key information about mechanisms of resistance and to enhance individualization of treatment.


Multi-channel current electro-optic isolated measurement and discharge current characteristics in a parallel plate transmission line driver.
In this paper, a 96 kJ compact synchronous discharge driver is designed. The issue of the current measurement of the six parallel gas spark switches is resolved by a multi-channel isolated current measuring system, and the driver's circuit simulation model is constructed. Then, the discharge current characteristics of each branch and load are investigated, and the results show that when the operating voltage is at least 50 kV, the parallel switches are conducted synchronously. The designed multi-channel isolated current measuring system meets the use requirements at a maximum operating voltage of 80 kV, the peak current measured by a single channel is 500 kA at this time, which corresponds to the load current of 3 MA, and the current rise time (0%-100% rise time) is about 1.15 µs. However, the asynchronous conduction of these switches will increase the branch circuit's peak current by a maximum of 25%, and the maximum value of the inverse peak current ratio of the branch will increase to 1.16, which will threaten the safe operation of the components. At this time, there is a redistribution of charge between the already conducting branches, so the impact of the load current is less than that of the basic branch current. When the conduction dispersion of the switchers is less than 452 ns, the peak current of the load reduction is less than 3%, and the current waveform meets the application requirements. The research is essential for understanding the operating status of the driver and assessing the through-current capability of the device's components, such as gas switches and capacitors.


Building Negative-Thermal-Expansion Protective Layers on the Grain Boundary of Ni-rich Cathodes Enables Safe and Durable High Voltage Lithium-Ion Batteries.
Ni-rich layered oxide cathode materials demonstrate high energy densities for Li-ion batteries, but the electrochemically driven thermal runaway and mechanical degradation remain their long-standing challenges in practical applications. Herein, it presents a novel ZrV2 O7 (ZVO) coating with negative thermal expansion properties along the secondary particles and primary particle grain boundaries (GBs), to simultaneously enhance the structural and thermal stability of LiNi0.8 Co0.1 Mn0.1 O2 (NCM811). It unveils that, such an architecture can significantly enhance the electronic conductivity, suppress the microcracks of GBs, alleviate the layered to spinel/rock-salt phase transformation, and meanwhile relieve the lattice oxygen loss by increasing the oxygen vacancy formation energy increased (1.43 vs 1.90 eV). Consequently, the ZVO-coated NCM811 material demonstrates a remarkable cyclability with 86.5% capacity retention after 100 cycles, and an outstanding rate performance of 30 C under a high-voltage of 4.6 V, outperforming the state-of-the-art literature. More importantly, the Li+ transportation can be readily blocked at 120 °C by the negative-thermal-expansion ZVO coating, thus avoiding the high-temperature thermal runaway.


Intraperitoneal dissemination of endometrial cancer cells after hysteroscopy: a systematic review and meta-analysis.
Hysteroscopy is a diagnostic procedure with a high accuracy in diagnosing endometrial cancer. Because of the increase of intrauterine pressure during distention media inflation, several retrospective studies postulated that it may result in cancer cell dissemination within the peritoneal cavity through the fallopian tubes. We therefore set to estimate whether hysteroscopy increases the risk for intraperitoneal cancer cell dissemination in patients with endometrial cancer and the risk of disease upstaging in patients with clinically early-stage disease. We searched the PubMed, the ISI Web of Science, and the Cochrane Library through July 2009. Eligible trials were all controlled clinical trials in which patients were allocated to hysteroscopy (alone or after other diagnostic procedure, eg, dilation and curettage and biopsy) versus any other diagnostic procedure except hysteroscopy or no procedure before surgery for endometrial carcinoma. Nine trials were included in our analysis. One thousand fifteen patients with histologically proven endometrial carcinoma were allocated to hysteroscopy or no hysteroscopy before surgery. Hysteroscopy resulted in a significantly higher rate of malignant peritoneal cytology (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.13-2.79; P = 0.013) and significantly higher disease upstaging owing solely to the presence of malignant cells in the peritoneal cavity (OR, 2.61; 95% CI, 1.47-4.63; P = 0.001) compared with no hysteroscopy. When isotonic sodium chloride was used as distention medium, hysteroscopy resulted in a statistically significant higher rate of malignant peritoneal cytology (OR, 2.89; 95% CI, 1.48-5.64; P = 0.002), whereas a nonsignificant trend for higher malignant cells was observed in patients allocated to the hysteroscopy group (OR, 3.23; 95% CI, 0.94-11.09; P = 0.062) when inflated media pressure reached or exceeded 100 mm Hg. Hysteroscopy in patients with endometrial cancer hints a risk for cancer cell dissemination within the peritoneal cavity. Prospective and sufficiently powered trials are needed to clarify whether the risk of cancer cell spreading is correlated with worse prognosis.


cDNA cloning and transcriptional regulation of the vitellogenin receptor from the imported fire ant, Solenopsis invicta Buren (Hymenoptera: Formicidae).
We describe the cloning of the first hymenopteran vitellogenin receptor (VgR) cDNA from the imported fire ant, Solenopsis invicta, an invasive pest. Using reverse transcription polymerase chain reaction and rapid amplification of cDNA ends, fragments encompassing the entire coding region of a putative VgR were cloned and sequenced. The complete 5764 bp cDNA encodes a 1782 residue protein with a predicted molecular mass of 201.3 kDa (=SiVgR). Northern blot analysis demonstrated that the 7.4 kb SiVgR transcript was present only in ovaries of reproductive females (virgin alates and queens). The temporal profile of transcriptional expression showed that SiVgR mRNA increased with age in virgin alate females and that this was up-regulated by methoprene, a juvenile hormone (JH) analogue. This suggests that the SiVgR gene is JH regulated.


Previous induced abortions and the risk of very preterm delivery: results of the EPIPAGE study.
To evaluate the risk of very preterm birth (22-32 weeks of gestation) associated with previous induced abortion according to the complications leading to very preterm delivery in singletons. Multicentre, case-control study (the French EPIPAGE study). Regionally defined population of births in France. The sample consisted of 1943 very preterm live-born singletons (< 33 weeks of gestation), 276 moderate preterm live-born singletons (33-34 weeks) and 618 unmatched full-term controls (39-40 weeks). Data from the EPIPAGE study were analysed using polytomous logistic regression models to control for social and demographic characteristics, lifestyle habits during pregnancy and obstetric history. The main mechanisms of preterm delivery were classified as gestational hypertension, antepartum haemorrhage, fetal growth restriction, premature rupture of membranes, idiopathic preterm labor and other causes. Odds ratios for very preterm birth by gestational age and by pregnancy complications leading to preterm delivery associated with a history of induced abortion. Women with a history of induced abortion were at higher risk of very preterm delivery than those with no such history (OR + 1.5, 95% CI 1.1-2.0); the risk was even higher for extremely preterm deliveries (< 28 weeks). The association between previous induced abortion and very preterm delivery varied according to the main complications leading to very preterm delivery. A history of induced abortion was associated with an increased risk of premature rupture of the membranes, antepartum haemorrhage (not in association with hypertension) and idiopathic spontaneous preterm labour that occur at very small gestational ages (< 28 weeks). Conversely, no association was found between induced abortion and very preterm delivery due to hypertension. Previous induced abortion was associated with an increased risk of very preterm delivery. The strength of the association increased with decreasing gestational age.


Camouflaged Nanoreactors Mediated Radiotherapy-Adjuvant Chemodynamic Synergistic Therapy.
Chemodynamic therapy based on the Fenton-like catalysis ability of Fe3O4 has the advantages of no involvement of chemical drugs and minimal adverse effects as well as the limitation of depletable efficacy. Radiotherapy based on high-energy radiation offers the convenience of treatment and cost-effectiveness but lacks precision and cellular adaptation of tumor cells. Approaching such dilemmas from a nanoscale materials perspective, we aim to bridge the weaknesses of both treatment methods by combining the principles of two therapeutics reciprocally. We have designed a camouflaged Fe3O4@HfO2 composite nanoreactor (FHCM), which combines a chemodynamic therapeutic agent Fe3O4 and a radiosensitizer HfO2 that both has passed clinical trials and was inspired by a cell membrane biomimetic technique. FHCM is employed as conceived radiotherapy-adjuvant chemodynamic synergistic therapy of malignant tumors, which has undergone dual scrutiny from both the physical and biological aspects. Experimental results obtained at different levels, including theory, material characterizations, and in vitro and in vivo verifications, suggest that FHCM effectively impaired tumor cells through physical and molecular biological mechanisms involving a HfO2-Fe3O4 photoelectron-electron transfer chain and DNA damage-ferroptosis-immunity chain. It is worth noting that compared to single therapies such as only chemodynamic therapy or radiotherapy, FHCM-mediated radiotherapy-adjuvant chemodynamic synergistic therapy exhibits stronger tumor inhibition efficacy. It significantly addresses the inherent limitations of chemodynamic therapy and radiotherapy and underscores the feasibility and importance of using existing clinical weapons, such as radiotherapy, as auxiliary strategies to overcome certain flaws of emerging antitumor therapeutics like chemodynamic therapy.


Habitat-mediated foraging limitations drive survival bottlenecks for juvenile salmon.
Realistic population models and effective conservation strategies require a thorough understanding of mechanisms driving stage-specific mortality. Mortality bottlenecks for many species occur in the juvenile stage and are thought to result from limitation on food or foraging habitat during a "critical period" for growth and survival. Without a way to account for maternal effects or to measure integrated consumption rates in the field, it has been virtually impossible to test these relationships directly. Hence uncertainties about mechanisms underlying such bottlenecks remain. In this study we randomize maternal effects across sites and apply a new method for measuring consumption integrated over weeks to months to test the hypothesis that food limitation drives early-season juvenile mortality bottlenecks in Atlantic salmon (Salmo salar). Using natural signatures of geologically derived cesium (133Cs), we estimated consumption rates of >400 fry stocked into six streams. Two to four weeks after stocking, consumption was extremely low across sites (0.005 g x g(-1) x d(-1)) and was predicted to be below maintenance rations (i.e., yielding negative energy balances) for the majority of individuals from five of six sites. However, consumption during this time was positively correlated with growth rates and survival (measured at the end of the growing season). In contrast, consumption rates increased in mid- (0.030 g x g(-1) x d(-1)) and late (0.035 g x g(-1) x d(-1)) seasons, but juvenile survival and consumption were not correlated, and correlations between growth and consumption were weak. These findings are consistent with predictions of a habitat-based bioenergetic model constructed using the actual stream positions of the individual fish in the present study, which indicates that habitat-based models capture important environmental determinants of juvenile growth and survival. Hence, by combining approaches, reducing maternal effects and controlling initial conditions, we offer a general framework for linking foraging with juvenile survival and present the first direct consumption-based evidence for the early season bottleneck hypothesis.


The effect of maras powder on DNA methylation and micronucleus formation in human buccal tissue.
The plant powder "maras powder" (MP) has been used widely instead of cigarettes in the southeastern region of Turkey. The aim of this study was to assess the impacts of MP and cigarette smoking on the methylation and micronuclei (MN) formation in buccal cells of humans with a comparison to blood lymphocytes. DNA samples from 80 subjects (40 MP users, 20 tobacco smokers, 20 healthy volunteers) were analyzed for their genomic methylation status using Hpa II and Msp I digestions followed by a simple gel electrophoresis and ethidium bromide staining. A densitometric method was developed to measure the methylation in genomic DNA samples and the results were evaluated using a software program designed for this purpose. Buccal epithelial cells were collected from the same groups and examined for MN formation. The results indicated that a general genomic hypomethylation was present in almost all of the samples that were obtained from MP users and tobacco smokers. This hypomethylation was significant in MP users compared to smokers and healthy volunteers. The percentage of cells containing MN was 1.93 in MP users, 0.95 in healthy volunteers, and 1.82 in smokers. The MN frequency was significantly higher in MP users and smokers than in healthy volunteers. There was no statistical difference between smokers and MP users. Evidence indicates that MP usage induces DNA hypomethylation and increase frequency of MN formation.


Evidence that a herbivore tolerance response affects selection on floral traits and inflorescence architecture in purple loosestrife (Lythrum salicaria).
The study of the evolution of floral traits has generally focused on pollination as the primary driver of selection. However, herbivores can also impose selection on floral traits through a variety of mechanisms, including florivory and parasitism. Less well understood is whether floral and inflorescence architecture traits that influence a plant's tolerance to herbivory, such as compensatory regrowth, alter pollinator-mediated selection. Because herbivore damage to Lythrum salicaria meristems typically leads to an increase in the number of inflorescences and the size of the floral display, an experiment was conducted to test whether simulated herbivory (i.e. clipping the developing meristem) could alter the magnitude or direction of pollinator-mediated selection on a suite of floral and inflorescence architecture traits. Using a pollen supplementation protocol, pollen limitation was compared in the presence and absence of meristem damage in order to quantify any interaction between pollinator and herbivore-mediated selection on floral traits. Surprisingly, in spite of an obvious impact on floral display and architecture, with clipped plants producing more inflorescences and more flowers, there was no difference in pollen limitation between clipped and unclipped plants. Correspondingly, there was no evidence that imposing herbivore damage altered pollinator-mediated selection in this system. Rather, the herbivory treatment alone was found to alter direct selection on floral display, with clipped plants experiencing greater selection for earlier flowering and weaker selection for number of inflorescences when compared with unclipped plants. These findings imply that herbivory on its own can drive selection on plant floral traits and inflorescence architecture in this species, even more so than pollinators. Specifically, herbivory can impose selection on floral traits if such traits influence a plant's tolerance to herbivory, such as through the timing of flowering and/or the compensatory regrowth response.


Estimation of tissue resistivities from multiple-electrode impedance measurements.
In order to measure in vivo resistivity of tissues in the thorax, the possibility of combining anatomical data extracted from high-resolution images with multiple-electrode impedance measurements, a priori knowledge of the range of tissue resistivities, and a priori data on the instrumentation noise is assessed in this study. A statistically constrained minimum-mean-square error estimator (MIMSEE) that minimizes the effects of linearization errors and instrumentation noise is developed and compared to the conventional least-squares error estimator (LSEE). The MIMSEE requires a priori signal and noise information. The statistical constraint signal information was obtained from a priori knowledge of the physiologically allowed range of regional resistivities. The noise constraint information was obtained from a priori knowledge of the linearization error and the instrumentation noise. The torso potentials were simulated by employing a three-dimensional canine torso model. The model consists of four different conductivity regions: heart, right lung, left lung, and body. It is demonstrated that the statistically constrained MIMSEE performs significantly better than the LSEE in determining resistivities. The results based on the torso model indicate that regional resistivities can be estimated to within 40% accuracy of their true values by utilizing a statistically constrained MIMSEE, even if the instrumentation noise is comparable to the measured torso potentials. The errors obtained using the LSEE with the same linearized transfer function and level of instrumentation noise were about five times larger than those obtained using the MIMSEE. For larger measurement errors the MIMSEE performs even better when compared to the LSEE.


A phase II study of S-1 chemotherapy with concurrent thoracic radiotherapy in elderly patients with locally advanced non-small-cell lung cancer: the Okayama Lung Cancer Study Group Trial 0801.
Although thoracic irradiation (TRT) is a standard treatment for elderly patients with locally advanced non-small-cell lung cancer (LA-NSCLC), treatment outcomes are poor. We previously reported a phase I trial combining S-1, an oral 5-fluorouracil derivative, and thoracic radiation, which yielded safe and effective outcomes. In this phase II trial, 30 patients aged 76 years or older with LA-NSCLC received S-1 (80 mg/m(2) on days 1-14 and 29-42) and TRT (60Gy). The primary end-point was the response rate. The median age and pre-treatment Charlson score were 79 years and 1, respectively. The mean proportions of the actual doses of S-1 and TRT delivered relative to the planned doses were 95% and 98%, respectively. Partial responses were observed in 19 patients (63%; 95% confidence interval: 45-82%), which did not attain the end-point. At a median follow-up time of 23.7 months, the median progression-free survival and median survival times were 13.0 months and 27.9 months, respectively. No difference in efficacy was observed upon stratification by tumour histology. Toxicities were generally mild, except for grade 3 or greater febrile neutropenia and pneumonitis in 7% and 10% of patients, respectively. No patient developed severe oesophagitis. Although the primary end-point was not met, concurrent S-1 chemotherapy and radiotherapy yielded favourable survival data. Also, the combined treatment was well-tolerated in elderly patients with LA-NSCLC.