Radiological protection issues arising during and after the Fukushima nuclear reactor accident.
Following the Fukushima accident, the International Commission on Radiological Protection (ICRP) convened a task group to compile lessons learned from the nuclear reactor accident at the Fukushima Daiichi nuclear power plant in Japan, with respect to the ICRP system of radiological protection. In this memorandum the members of the task group express their personal views on issues arising during and after the accident, without explicit endorsement of or approval by the ICRP. While the affected people were largely protected against radiation exposure and no one incurred a lethal dose of radiation (or a dose sufficiently large to cause radiation sickness), many radiological protection questions were raised. The following issues were identified: inferring radiation risks (and the misunderstanding of nominal risk coefficients); attributing radiation effects from low dose exposures; quantifying radiation exposure; assessing the importance of internal exposures; managing emergency crises; protecting rescuers and volunteers; responding with medical aid; justifying necessary but disruptive protective actions; transiting from an emergency to an existing situation; rehabilitating evacuated areas; restricting individual doses of members of the public; caring for infants and children; categorising public exposures due to an accident; considering pregnant women and their foetuses and embryos; monitoring public protection; dealing with 'contamination' of territories, rubble and residues and consumer products; recognising the importance of psychological consequences; and fostering the sharing of information. Relevant ICRP Recommendations were scrutinised, lessons were collected and suggestions were compiled. It was concluded that the radiological protection community has an ethical duty to learn from the lessons of Fukushima and resolve any identified challenges. Before another large accident occurs, it should be ensured that inter alia: radiation risk coefficients of potential health effects are properly interpreted; the limitations of epidemiological studies for attributing radiation effects following low exposures are understood; any confusion on protection quantities and units is resolved; the potential hazard from the intake of radionuclides into the body is elucidated; rescuers and volunteers are protected with an ad hoc system; clear recommendations on crisis management and medical care and on recovery and rehabilitation are available; recommendations on public protection levels (including infant, children and pregnant women and their expected offspring) and associated issues are consistent and understandable; updated recommendations on public monitoring policy are available; acceptable (or tolerable) 'contamination' levels are clearly stated and defined; strategies for mitigating the serious psychological consequences arising from radiological accidents are sought; and, last but not least, failures in fostering information sharing on radiological protection policy after an accident need to be addressed with recommendations to minimise such lapses in communication.


Fish distribution in watersheds of the eastern part of the Serra da Mantiqueira (state of São Paulo).
The present work aims to analyse jointly four contiguous watersheds in the eastern part of the Serra da Mantiqueira with respect to the distribution of fish fauna and physical structure. The watersheds of Piracuama river, Ribeirão Grande, Buenos and Guaratinguetá are located in Pindamonhangaba, Campos do Jordão and Guaratinguetá municipalities, in the state of São Paulo. Data were collected between the years 2001 and 2010, with collections distributed throughout the seasons, including sites located on the slope and piedmont. The limnological parameters analysed were different between watersheds and habitat structure was different only for the slope segments between Ribeirão Grande and Buenos watersheds, and between Ribeirão Grande and Piracuama watersheds. Thirty-five species of fish were caught, with the highest species richness found in the Ribeirão Grande watershed (30 species), followed by the Piracuama (23 species) and Buenos and Guaratinguetá (21 species each). The most abundant species in both the segments (slope and piedmont) was Trichomycterus itatiayae. The highest degree of species dominance occurred in the Guaratinguetá watershed and in the segment slope, being T. itatiayae the dominant species. Species diversity was lower at the slope than the piedmont, indicating variability in species abundance. Again T. itatiayae was the most abundant species in both segments, showing to be a well adapted species to these streams systems by presenting, as well as other species, morphological adaptations to the stream environment.


[Calmodulin inhibitors suppress a calcium signal from serotonin receptors in smooth muscle cells and remove the vasoconstrictive response upon intravenous introduction of serotonin].
Comparative study of the effect of calmodulin inhibitors (trifluoperazine, W-12, and W-13) and the TRPVI channel blocker (capsazepine) on receptor-dependent calcium exchange in smooth muscle cells of the rat aorta and on the contractility of the isolated aorta was conducted. It was determined that trifluoperazine almost completely removes an increase in the concentration of calcium ions in the cytoplasm of smooth muscle cells (isolated from the rat aorta) and smooth muscle cells of the A7r5 line in response to serotonin and does not influence the cell response to vasopressin and angiotensin II. W-12 and W-13 also do not reduce calcium ion concentration increase (induced by vasopressin and angiotensin II) but reduces by two times its rise in response to serotonin. It was found that the efficiency of calcium exchange suppression by calmodulin inhibitors correlates with the intensity at which they inhibit the contractile response of the aorta on the effect of serotonin. It was detected that the inhibiting effect of calmodulin blockers on calcium exchange in smooth muscle cells and the contractility of the rat isolated aorta during the activation of serotonin vasoconstrictive receptors are realized by a TRPV1-independent mechanism. It was demonstrated in experiments in vivo that trifluoperazine does not influence hypotensive reaction in rats (normally observed in response to intravenous serotonin introduction), but removes the hypertensive effect of this neurotransmitter in rats after chronic introduction of dexamethasone. The results obtained confirm the hypothesis (that we previously stated) about the direct involvement of calmodulin in signal transmission from vasoconstrictive serotonin receptors.


Pentagastrin and gastric mucosal blood flow.
The effect of pentagastrin on mucosal microcirculation was studied in rats by use of intravital microscopy. The superficial mucosal vessels were videorecorded for off-line analysis of red cell velocities (VRBC) and vessel diameters, from which blood flow (QRBC) was calculated. Resting mucosal blood flow calculated from single microvascular flow data, and vessel distribution was 40 ml X min-1 X 100 g-1. Pentagastrin infused intravenously in a dose of 20 micrograms X kg-1 X h-1 resulted in submaximal acid secretion (approximately 60%) and a significant increase in QRBC by 47 +/- 14%. When given in a dose of 96 micrograms X kg-1 X h-1 iv, it resulted in maximal acid secretion and an increase in QRBC by 36 +/- 14%. In another series of experiments the results of QRBC measurements during infusion of pentagastrin (20 micrograms X kg-1 X h-1 iv) were compared with those of aminopyrine (AP) clearance or laser-Doppler flowmetry (LDF) in the same animals. Gastric mucosal blood flow determined by [14C]AP clearance increased by 309 +/- 115%, whereas QRBC increased by 34 +/- 11%. When determined by LDF, blood flow increased by 41 +/- 22%, a value similar to the increase in QRBC (50 +/- 19%). Thus, the percent increase in blood flow during pentagastrin infusion estimated by AP clearance was considerably higher than that observed by either direct microvascular measurements or by LDF.


Incorporating behavioral variables into crash count prediction by severity: A multivariate multiple risk source approach.
The frequency and severity of traffic crashes have commonly been used as indicators of crash risk on transport networks. Comprehensive modeling of crash risk should account for both frequency and injury severity-capturing both the extent and intensity of transport risk for designing effective safety improvement programs. Previous research has revealed that crashes are correlated across severity categories because of the combined influence of risk factors, observed or unobserved. Moreover, crashes are the outcomes of a multitude of factors related to roadway design, traffic operations, pavement conditions, driver behavior, human factors, and environmental characteristics, or in more general terms: factors reflect both engineering and non-engineering risk sources. Perhaps not surprisingly, engineering risk sources have dominated the list of variables in the mainstream modeling of crashes whereas non-engineering sources, in particular, behavioral factors, are crucially omitted. It is plausible to assume that crash contributing factors from the same risk source affect crashes in a similar manner, but their influences vary across different risk sources. Conventional crash frequency modeling hypothesizes that the total crash count at any roadway site is well-approximated by a single risk source to which several explanatory variables contribute collaboratively. The conventional formulation is not capable of accounting for variations between risk sources; therefore, is unable to discriminate distinct impacts between engineering variables and non-engineering variables. To address this shortcoming, this study contributes to the development of multivariate multiple risk source regression, a robust modeling technique to model crash frequency and severity simultaneously. The multivariate multiple risk source regression method applied in this study can effectively capture the correlation between severity levels of crash counts while identifyinging the varying effects of crash contributing factors originated from distinct sources. Using crashes on Wisconsin rural two-lane highways, two risk sources - engineering and behavioral - were employed to develop proposed models. The modeling results were compared with a single equation negative binomial (NB) model, and a univariate multiple risk source model. The results show that the multivariate multiple risk source model significantly outperforms the other models in terms of statistical fit across several measures. The study demonstrates a unique approach to explicitly incorporating behavioral factors into crash prediction models while taking crash severity into consideration. More importantly, the parameter estimates provide more insight into the distinct sources of crash risk, which can be used to further inform safety practitioners and guide roadway improvement programs.


Cell surface localization of tissue transglutaminase is dependent on a fibronectin-binding site in its N-terminal beta-sandwich domain.
Increasing evidence indicates that tissue transglutaminase (tTG) plays a role in the assembly and remodeling of extracellular matrices and promotes cell adhesion. Using an inducible system we have previously shown that tTG associates with the extracellular matrix deposited by stably transfected 3T3 fibroblasts overexpressing the enzyme. We now show by confocal microscopy that tTG colocalizes with pericellular fibronectin in these cells, and by immunogold electron microscopy that the two proteins are found in clusters at the cell surface. Expression vectors encoding the full-length tTG or a N-terminal truncated tTG lacking the proposed fibronectin-binding site (fused to the bacterial reporter enzyme beta-galactosidase) were generated to characterize the role of fibronectin in sequestration of tTG in the pericellular matrix. Enzyme-linked immunosorbent assay style procedures using extracts of transiently transfected COS-7 cells and immobilized fibronectin showed that the truncation abolished fibronectin binding. Similarly, the association of tTG with the pericellular matrix of cells in suspension or with the extracellular matrix deposited by cell monolayers was prevented by the truncation. These results demonstrate that tTG binds to the pericellular fibronectin coat of cells via its N-terminal beta-sandwich domain and that this interaction is crucial for cell surface association of tTG.


Measurement of serum C reactive protein concentration after bone marrow transplantation for leukaemia.
C reactive protein concentration was measured serially in 19 patients with leukaemia after bone marrow transplantation. Six episodes of graft versus host disease occurred in the presence of fever but with no evidence of infection, and these were associated with C reactive protein concentrations as high as 200 mg/l. C reactive protein values were also increased in 12 febrile episodes associated with infection, in seven of which graft versus host disease was also present. C reactive protein concentrations are of no value in differentiating infection from graft versus host disease, but in both cases they may be useful as an objective index of response to appropriate treatment.


Levator-Urethra Gap: Normative Data in a Nonpregnant Nulliparous Population.
This study aimed to establish a normative range of the levator-urethra gap (LUG) measurement in nonpregnant, nulliparous women to be used as a standard against which assessments of injury or avulsion of the levator ani could be made. Nulliparous women in the Pacific Northwest who were planning pregnancy within the ensuing 12 months underwent high-resolution magnetic resonance imaging (MRI) and 3-dimensional transperineal ultrasonography. In the plane of minimal hiatal dimensions, the LUG was measured on both the right and left sides for 3 contiguous image slices. One hundred thirty-five participants underwent examinations, of which 134 had evaluable MRIs and 70 had evaluable ultrasounds. Mean (SD) age was 30.8 (4.0) years, and mean (SD) body mass index was 25.9 (6.4). The majority of the participants self-identified as White (80%) and non-Hispanic (89%). The 99th percentile was no greater than 2.39 cm on any slice for either MRI or US-based measurements. In the MRI set, the lowest LUG values at which all 3 measurements on a side were found to have exceeded a putative threshold value (for injury) were 2.1 cm for the right side and 2.05 cm for the left side. The corresponding LUG values in the ultrasound set were 2.2 cm on the right and 2.25 cm on the left. The LUG threshold in 3 successive slices in the minimal hiatal dimension suggestive of levator ani injury could be as low as 2.1 cm when using MRI and 2.25 cm when using ultrasound in a similar population.


Statistical mapping of the effect of knee extension on thigh muscle viscoelastic properties using magnetic resonance elastography.
Skeletal muscle viscoelastic properties reflect muscle microstructure and neuromuscular activation. Elastographic methods, including magnetic resonance elastography, have been used to characterize muscle viscoelastic properties in terms of region of interest (ROI) measurements. The present study extended this approach to create thresholded pixel-by-pixel maps of viscoelastic properties of skeletal muscle during rest and knee extension in eleven subjects. ROI measurements were taken for individual quadricep muscles and the quadriceps region as a whole, and the viscoelastic parameter map pixels were statistically tested at positive false discovery rate q ≤ 0.25. ROI measurements showed significant (p ≤ 0.05) increase in storage modulus (G') and loss modulus (G″), with G″ increasing more than G', in agreement with previous findings. The q-value maps further identified the vastus intermedius as the primary driver of this change, with greater G″/G' increase than surrounding regions. Additionally, a cluster of significant decrease in G″/G' was found in the region of vastus lateralis below the fulcrum point of the lift. Viscoelastic parameter mapping of contracted muscle allows new insight into the relationship between physiology, neuromuscular activation, and human performance.


Construction of a clinical prediction model for the impact of acupuncture on pregnancy outcomes in poor ovarian response (POR) patients based on a patient registry research platform.
To construct a clinical prediction model for the impact of acupuncture on pregnancy outcomes in poor ovarian response (POR) patients, providing insights and methods for predicting pregnancy outcomes in POR patients undergoing acupuncture treatment. Clinical data of 268 POR patients (2 cases were eliminated) primarily treated with "thirteen needle acupuncture for Tiaojing Cuyun (regulating menstruation and promoting pregnancy)" was collected from the international patient registry platform of acupuncture moxibustion (IPRPAM) from September 19, 2017 to April 30, 2023, involving 24 clinical centers including Acupuncture-Moxibustion Hospital of China Academy of Chinese Medical Sciences. LASSO and univariate Cox regression were used to screen factors influencing pregnancy outcomes, and a multivariate Cox regression model was established based on the screening results. The best model was selected using the Akaike information criterion (AIC), and a nomogram for clinical pregnancy prediction was constructed. The prediction model was evaluated using receiver operating characteristic (ROC) curves and calibration curves, and internal validation was performed using the Bootstrap method. (1) Age, level of anti-Müllerian hormone (AMH), and total treatment numbers of acupuncture were independent predictors of pregnancy outcomes in POR patients receiving acupuncture (P<0.05). (2) The AIC value of the best subset-Cox multivariate model (560.6) was the smallest, indicating it as the optimal model. (3) The areas under curve (AUCs) of the clinical prediction model after 6, 12, 24, and 36 months treatment were 0.627, 0.719, 0.770, and 0.766, respectively, and in the validation group, they were 0.620, 0.704, 0.759, and 0.765, indicating good discrimination and repeatability of the prediction model. (4) The calibration curve showed that the prediction curve of the clinical prediction model was close to the ideal model's prediction curve, indicating good calibration of the prediction model. The clinical prediction model for the impact of acupuncture on pregnancy outcomes in POR patients based on the IPRPAM platform has good clinical application value and provides insights into predicting pregnancy outcomes in POR patients undergoing acupuncture treatment.


West nile virus antibody prevalence in horses of Ukraine.
West Nile virus (WNV) is a mosquito-borne virus of global importance. Over the last two decades, it has been responsible for significant numbers of cases of illness in humans and animals in many parts of the world. In Ukraine, WNV infections in humans and birds were first reported more than 25 years ago, yet the current epidemiological status is quite unclear. In this study, serum samples from over 300 equines were collected and screened in order to detect current WNV activity in Ukraine with the goal to estimate the risk of infection for humans and horses. Sera were tested by enzyme-linked immunosorbent assay (ELISA) and virus neutralization assay (NT) to detect WNV-specific antibodies. The results clearly revealed that WNV circulates in most of the regions from which samples were obtained, shown by a WNV seroprevalence rate of 13.5% of examined horses. This is the first topical report indicating the presence of WNV infections in horses in Ukraine, and the results of this study provide evidence of a widespread WNV circulation in this country.


Selective serotonin reuptake inhibitors in human pregnancy: to treat or not to treat?
Selective serotonin reuptake inhibitors (SSRIs) are increasingly prescribed during pregnancy. The purpose of the present paper is to summarize and evaluate the current evidence for the risk/benefit analysis of SSRI use in human pregnancy. The literature has been inconsistent. Although most studies have not shown an increase in the overall risk of major malformations, several studies have suggested that SSRIs may be associated with a small increased risk for cardiovascular malformations. Others have noted associations between SSRIs and specific types of rare major malformations. In some studies, there appears to be a small increased risk for miscarriages, which may be associated with the underlying maternal condition. Neonatal effects have been described in up to 30% of neonates exposed to SSRIs late in pregnancy. Persistent pulmonary hypertension of the newborn has also been described with an absolute risk of <1%. The risk associated with treatment discontinuation, for example, higher frequency of relapse and increased risk of preterm delivery, should also be considered. The overall benefit of treatment seems to outweigh the potential risks.


An HSP90 cochaperone Ids2 maintains the stability of mitochondrial DNA and ATP synthase.
Proteostasis unbalance and mitochondrial dysfunction are two hallmarks of aging. While the chaperone folds and activates its clients, it is the cochaperone that determines the specificity of the clients. Ids2 is an HSP90's cochaperone controlling mitochondrial functions, but no in vivo clients of Ids2 have been reported yet. We performed a screen of the databases of HSP90 physical interactors, mitochondrial components, and mutants with respiratory defect, and identified Atp3, a subunit of the complex V ATP synthase, as a client of Ids2. Deletion of IDS2 destabilizes Atp3, and an α-helix at the middle region of Ids2 recruits Atp3 to the folding system. Shortage of Ids2 or Atp3 leads to the loss of mitochondrial DNA. The intermembrane space protease Yme1 is critical to maintaining the Atp3 protein level. Moreover, Ids2 is highly induced when cells carry out oxidative respiration. These findings discover a cochaperone essentially for maintaining the stability of mitochondrial DNA and the proteostasis of the electron transport chain-crosstalk between two hallmarks of aging.


Cell-Penetrating Streptavidin: A General Tool for Bifunctional Delivery with Spatiotemporal Control, Mediated by Transport Systems Such as Adaptive Benzopolysulfane Networks.
In this report, cell-penetrating streptavidin (CPS) is introduced to exploit the full power of streptavidin-biotin biotechnology in cellular uptake. For this purpose, transporters, here cyclic oligochalcogenides (COCs), are covalently attached to lysines of wild-type streptavidin. This leaves all four biotin binding sites free for at least bifunctional delivery. To maximize the standards of the quantitative evaluation of cytosolic delivery, the recent chloroalkane penetration assay (CAPA) is coupled with automated high content (HC) imaging, a technique that combines the advantages of fluorescence microscopy and flow cytometry. According to the resulting HC-CAPA, cytosolic delivery of CPS equipped with four benzopolysulfanes was the best among all tested CPSs, also better than the much smaller TAT peptide, the original cell-penetrating peptide from HIV. HaloTag-GFP fusion proteins expressed on mitochondria were successfully targeted using CPS carrying two different biotinylated ligands, HaloTag substrates or anti-GFP nanobodies, interfaced with peptide nucleic acids, flipper force probes, or fluorescent substrates. The delivered substrates could be released from CPS into the cytosol through desthiobiotin-biotin exchange. These results validate CPS as a general tool which enables unrestricted use of streptavidin-biotin biotechnology in cellular uptake.


Root Cause Analysis and Actions for the Prevention of Medical Errors: Quality Improvement and Resident Education.
The quality of care delivered by orthopedic surgeons continues to grow in importance. Multiple orthopedic programs, organizations, and committees have been created to measure the quality of surgical care and reduce the incidence of medical adverse events. Structured root cause analysis and actions (RCA2) has become an area of interest. If performed thoroughly, RCA2 has been shown to reduce surgical errors across many subspecialties. The Accreditation Council for Graduate Medical Education has a new mandate for programs to involve residents in quality improvement processes. Resident engagement in the RCA2 process has the dual benefit of educating trainees in patient safety and producing meaningful changes to patient care that may not occur with traditional quality improvement initiatives. The RCA2 process described in this article can provide a model for the development of quality improvement programs. In this article, the authors discuss the history and methods of the RCA2 process, provide a stepwise approach, and give a case example. [Orthopedics. 2017; 40(4):e628-e635.].


Roles and functions of enrolled nurses in Australia: Perspectives of enrolled nurses and registered nurses.
To determine, from the perspectives of enrolled nurses and registered nurses, the current scope of enrolled nurse practice and to identify the activities that most enrolled nurses frequently performed in their workplace. Enrolled nurse scope of practice in Australia has evolved and expanded over the past decade. However, the unclear role, function and competency differentiation between enrolled nurse and registered nurse leads to role confusion and ongoing professional debate. Exploratory Descriptive Study. A cross-sectional online survey of enrolled nurses and registered nurses across Australia was conducted examining their levels of agreement on statements related to the scope of practice and the clinical and nonclinical activities that enrolled nurses were required to perform in their workplace. Valid responses were received from 892 enrolled nurses and 1,198 registered nurses. Enrolled nurses mostly agreed that they understood their scope of practice; did not undertake roles for which they were unprepared; sometimes undertook activities other than direct patient care; and believed that they operated equally to many registered nurses. The majority of enrolled nurses reported that they performed tasks mostly related to basic patient care in their workplace. There were a number of significant differences between perspectives of registered nurses and enrolled nurses. Clarifying the roles and scope of practice between the registered nurse and the enrolled nurse is important, and explicit differences in responsibility and accountability between their roles must be clearly articulated to harmonise perceptions about role and capability. Health service providers, policymakers and education providers need to work collaboratively to ensure that facets of enrolled nurse education and scope of practice in line with regulation are affirmed by all concerned. Health service providers, policymakers and education providers need to work collaboratively to ensure that facets of enrolled nurse education and scope of practice in line with regulation are affirmed by all concerned.


The mediator of cellular immunity. IX. The relationship between cellular hypersensitivity and acquired cellular resistance in rats infected with Listeria monocytogenes.
Acquired resistance to the intracellular bacterial parasite, Listeria monocytogenes can be transferred to normal recipients by thoracic duct lymphocytes or peritoneal exudate cells obtained from rats infected with this organism; The appearance of protective cells in thoracic duct lymph coincides with the development in the donors of delayed-type hypersensitivity to Listeria antigens and accumulation in induced peritoneal exudates of cells which are responsive to these antigens in the migration inhibitory factor (MIF) assay. The cells in exudates that confer protection, and those that release MIF, arise at sites remote from their final destination. From their point of origin in the caudal lymph nodes of infected rats, cells with these properties are delivered to the thoracic duct and hence to the blood from where they are drawn into the peritoneal cavity in response to inflammation. The parallel observed in the appearance, increase and subsequent decline of protective lymphocytes and MIF-producing cells in exudates suggest that the two activities are mediated by a single line of T cells. However this may be, the development and deployment of the cells concerned encourages the belief that MIF has a meaningful role in the expression of cellular resistance to infection.


Vitamin/mineral supplementation among cancer survivors: 1987 and 1992 National Health Interview Surveys.
The number of cancer survivors in the United States is increasing, but little is known about this population, including its use of vitamin/mineral supplements. We combined data on vitamin/mineral use from the 1987 and 1992 National Health Interview Survey Cancer Epidemiology Supplement (CES) for cancer survivors: persons reporting a diagnosis of cancer other than nonmelanoma skin cancer > 5 yr before their interviews [n = 461 (1987) and 228 (1992)] and persons reporting no history of cancer [n = 20,851 (1987) and 11,186 (1992)]. For both groups, we calculated gender-specific proportions (adjusted for age, race/ethnicity, education, smoking status, and poverty index) for use of multivitamins, vitamins A, C, and E, and calcium during the year before each survey. Supplement use was similar in survivors and persons reporting no history of cancer. Among survivors, calcium use was significantly higher among women (34.9%) than men (13.8%), and vitamin A use was higher among men than women (P < 0.05). Over three-fourths of both groups used multivitamins, and about one-half used vitamin C. No differences were found in vitamin/mineral use between male survivors and men with no cancer history or between female survivors and women with no cancer history. These first nationally representative estimates suggest that persons who have survived cancer and those who report that they never had the disease do not differ appreciably in their use of vitamin/mineral supplements. Results were based on small numbers of survivors, however, and require replication.


Modulation of DNA fragmentation factor 40 nuclease activity by poly(ADP-ribose) polymerase-1.
Poly(ADP-ribose) polymerase-1 (PARP-1) influences numerous cellular processes, including DNA repair, transcriptional regulation, and caspase-independent cell death, by utilizing NAD(+) to synthesize long chains of poly(ADP-ribose) (PAR) on target proteins, including itself. During the apoptotic response, caspases-3 and -7 cleave PARP-1, thereby inhibiting its activity. Here, we have examined the role of PARP-1 activation and cleavage in the latter stages of apoptosis in response to DNA fragmentation. PARP-1 poly(ADP-ribosyl)ation correlated directly with induction of apoptosis by the lipid peroxidation product, 4-hydroxy-2-nonenal. A significant decrease in PAR accumulation was observed upon caspase or DNA fragmentation factor 40 (DFF40) inhibition. Because DNA fragmentation mediated by DFF40 augmented PARP-1 modification status in apoptotic cells, we hypothesized that PARP-1 alters DFF40 function following PAR accumulation. Indeed, PARP-1, in the presence of NAD(+), significantly decreased DFF40 activity on plasmid substrates. Conversely, PARP-1 enhanced the DNase activity of DFF40 in the absence of NAD(+). The inhibition of DFF40 activity in the presence of NAD(+) was reduced by co-incubation with poly(ADP-ribose) glycohydrolase and a PARP inhibitor. Additionally, caspase-cleaved PARP-1, in the presence of NAD(+), did not inhibit DFF40 activity significantly. Our results suggest that PARP-1 poly(ADP-ribosyl)ation is a terminal event in the apoptotic response that occurs in response to DNA fragmentation and directly influences DFF40 activity.


Carbidopa is an activator of aryl hydrocarbon receptor with potential for cancer therapy.
Carbidopa is used with l-DOPA (l-3,4-dihydroxyphenylalanine) to treat Parkinson's disease (PD). PD patients exhibit lower incidence of most cancers including pancreatic cancer, but with the notable exception of melanoma. The decreased cancer incidence is not due to l-DOPA; however, the relevance of Carbidopa to this phenomenon has not been investigated. Here, we tested the hypothesis that Carbidopa, independent of l-DOPA, might elicit an anticancer effect. Carbidopa inhibited pancreatic cancer cell proliferation both in vitro and in vivo Based on structural similarity with phenylhydrazine, an inhibitor of indoleamine-2,3-dioxygenase-1 (IDO1), we predicted that Carbidopa might also inhibit IDO1, thus providing a molecular basis for its anticancer effect. The inhibitory effect was confirmed using human recombinant IDO1. To demonstrate the inhibition in intact cells, AhR (aryl hydrocarbon receptor) activity was monitored as readout for IDO1-mediated generation of the endogenous AhR agonist kynurenine in pancreatic and liver cancer cells. Surprisingly, Carbidopa did not inhibit but instead potentiated AhR signaling, evident from increased CYP1A1 (cytochrome P450 family 1 subfamily A member 1), CYP1A2, and CYP1B1 expression. In pancreatic and liver cancer cells, Carbidopa promoted AhR nuclear localization. AhR antagonists blocked Carbidopa-dependent activation of AhR signaling. The inhibitory effect on pancreatic cancer cells in vitro and in vivo and the activation of AhR occurred at therapeutic concentrations of Carbidopa. Chromatin immunoprecipitation assay further confirmed that Carbidopa promoted AhR binding to its target gene CYP1A1 leading to its induction. We conclude that Carbidopa is an AhR agonist and suppresses pancreatic cancer. Hence, Carbidopa could potentially be re-purposed to treat pancreatic cancer and possibly other cancers as well.


[A neonate with anaemia of prematurity: zinc protoporphyrin identifies iron deficiency anaemia without iron deficiency].
Anaemia is a common problem in premature infants and is generally easy to treat with iron supplementation. If the anaemia persists despite appropriate correction of deficiencies, more extensive evaluation is required. We describe a case of a premature male infant with a production-deficient anaemia without metabolic deficiencies, eventually identified as anaemia of prematurity. This type of anaemia is commonly diagnosed but its highly variable and complex aetiology and phenotype are often poorly understood. A probable explanation for the anaemia of prematurity in this case was a transient iron incorporation defect, identifiable by high levels of zinc protoporphyrin.


Mucuna pruriens and its major constituent L-DOPA recover spermatogenic loss by combating ROS, loss of mitochondrial membrane potential and apoptosis.
The Ayurvedic medicinal system claims Mucuna pruriens (MP) to possess pro-male fertility, aphrodisiac and adaptogenic properties. Some scientific evidence also supports its pro-male fertility properties; however, the mechanism of its action is not yet clear. The present study aimed at demonstrating spermatogenic restorative efficacy of MP and its major constituent L-DOPA (LD), and finding the possible mechanism of action thereof in a rat model. Ethinyl estradiol (EE) was administered at a rate of 3 mg/kg body weight (BW)/day for a period of 14 days to generate a rat model with compromised spermatogenesis. MP and LD were administered in two separate groups of these animals starting 15(th) day for a period of 56 days, and the results were compared with an auto-recovery (AR) group. Sperm count and motility, testis histo-architecture, level of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), apoptosis, peripheral hormone levels and testicular germ cell populations were analysed, in all experimental groups. We observed efficient and quick recovery of spermatogenesis in MP and LD groups in comparison to the auto-recovery group. The treatment regulated ROS level, apoptosis, and mitochondrial membrane potential (MMP), recovered the hypothalamic-pituitary-gonadal axis and the number of testicular germ cells, ultimately leading to increased sperm count and motility. M. pruriens efficiently recovers the spermatogenic loss induced due to EE administration. The recovery is mediated by reduction in ROS level, restoration of MMP, regulation of apoptosis and eventual increase in the number of germ cells and regulation of apoptosis. The present study simplified the complexity of mechanism involved and provided meaningful insights into MP/LD mediated correction of spermatogenic impairment caused by estrogens exposure. This is the first study demonstrating that L-DOPA largely accounts for pro-spermatogenic properties of M. pruriens. The manuscript bears CDRI communication number 8374.


The enhancement effect: evidence for adaptation of inhibition using a binaural centering task.
The enhancement effect is consistently shown when simultaneously masked stimuli are preceded by the masker alone, with a reduction in the amount of masking relative to when that precursor is absent. One explanation for this effect proposed by Viemeister and Bacon [(1982). J. Acoust. Soc. Am. 71, 1502-1507] is the adaptation of inhibition, which predicts that an enhanced component (the "target") will be effectively more intense within the auditory system than one that has not been enhanced. Forward masking studies have indicated this effect of increased gain; however, other explanations of the enhancement effect have also been suggested. In order to provide an alternative measure of the amount of effective gain for an enhanced target, a subjective binaural centering task was used in which listeners matched the intensities of enhanced and unenhanced 2-kHz tones presented to opposite ears to produce a centered stimulus. The results showed that the enhancement effect produces an effective 4-5 dB increase in the level of the enhanced target. The enhancement effect was also measured using other enhancement paradigms which yielded similar results over a range of levels for the target, supporting an account based on adaptation of inhibition.


Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis.
During treatment of brain tumors, some head and neck tumors, and other diseases, like arteriovenous malformations, the normal brain is exposed to ionizing radiation. While high radiation doses can cause severe tissue destruction, lower doses can induce cognitive impairments without signs of overt tissue damage. The underlying pathogenesis of these impairments is not well understood but may involve the neural precursor cells in the dentate gyrus of the hippocampus. To assess the effects of radiation on cognitive function, 2-month-old mice received either sham treatment (controls) or localized X irradiation (10 Gy) to the hippocampus/cortex and were tested behaviorally 3 months later. Compared to controls, X-irradiated mice showed hippocampal-dependent spatial learning and memory impairments in the Barnes maze but not the Morris water maze. No nonspatial learning and memory impairments were detected. The cognitive impairments were associated with reductions in proliferating Ki-67-positive cells and Doublecortin-positive immature neurons in the subgranular zone (SGZ) of the dentate gyrus. This study shows significant cognitive impairments after a modest dose of radiation and demonstrates that the Barnes maze is particularly sensitive for the detection of radiation-induced cognitive deficits in young adult mice. The significant loss of proliferating SGZ cells and their progeny suggests a contributory role of reduced neurogenesis in the pathogenesis of radiation-induced cognitive impairments.


A novel mechanism of proton transfer in protonated peptides.
The study presents quantum-chemical calculations on proton transfer in protonated N-acetylglycyl-N1-methylglycinamide (AGA) as a short oligopeptide model. All calculations employ the B3LYP functional and the 6-31++G** basis set. Two different mechanisms of proton transfer are discussed. The rate-determining step of the first mechanism exhibits an energy barrier of about 17.7 kcal mol-1, and it is represented by an isomerization of the proton around the double bond of the carbonyl group. The second mechanism is based on the large conformational flexibility of AGA, where all carbonyl oxygens cooperate. The rate-determining step of this mechanism exhibits an energy barrier of only 8.3 kcal mol-1.


Lipid storage metabolism is limited by the prevailing low oxygen concentrations within developing seeds of oilseed rape.
The aim of this study was to investigate whether endogenous restrictions in oxygen supply are limiting for storage metabolism in developing oilseed rape (Brassica napus) seeds. Siliques were studied 30 d after flowering, when rapid lipid accumulation is occurring in the seeds. (a). By using microsensors, oxygen concentrations were measured within seeds and in the silique space between seeds. At ambient external oxygen (21% [v/v]) in the light, oxygen fell to 17% (v/v) between and 0.8% (v/v) within seeds. A step-wise reduction of the external oxygen concentration led within 2 h to a further decrease of internal oxygen concentrations, and a step-wise increase of the external oxygen concentration up to 60% (v/v) resulted in an increase in internal oxygen that rose to 30% (v/v) between and 8% (v/v) within seeds. (b). The increase in oxygen levels in the seeds was accompanied by a progressive increase in the levels of ATP, UTP, and the ATP to ADP and UTP to UDP ratios over the entire range from 0% to 60% (v/v) external oxygen. (c). To investigate metabolic fluxes in planta, 14C-sucrose was injected into seeds, which remained otherwise intact within their siliques. The increase in oxygen in the seeds was accompanied by a progressive increase in the rate of lipid (including triacylglycerol), protein and cell wall synthesis, and an increase in glycolytic flux over a range from sub- to superambient oxygen concentrations. In contrast to lipid synthesis, starch synthesis was not significantly increased at superambient oxygen levels. The levels of fermentation products such as lactate and glycerol-3P increased only at very low (0%-4% [v/v]) external oxygen concentrations. (d). When 14C-acetate or 14C-acetyl-coenzyme A (CoA) was injected into seeds, label incorporation into triacylglycerol progressively increased over the whole range of external oxygen concentrations from 0% to 60% (v/v). (e). Stimulation of lipid synthesis was accompanied by an increase in sugar levels and a decrease in the levels of hexose-phosphates and acetyl-CoA, indicating sucrose unloading and the use of acetyl-CoA as possible regulatory sites. (f). Increased lipid synthesis was also accompanied by an increase in the maximal activities of invertase and diacylglycerol acyltransferase. (g). The developmental shift from starch to lipid storage between 15 and 45 d after flowering was accompanied by an increase in the seed energy state. (h). The results show that at ambient oxygen levels, the oxygen supply is strongly limiting for energy metabolism and biosynthetic fluxes in growing rape seeds, affecting lipid synthesis more strongly than starch synthesis. The underlying mechanisms and implications for strategies to increase yield and storage product composition in oilseed crops are discussed.


Characterization of beta-adrenergic receptors on human cerebral microvessels.
Cerebral microvessels were separated and prepared from human brain cortex by albumin floatation and glass bead filtration. The binding of a specific beta-adrenergic antagonist, (125I) iodohydroxybenzylpindolol, to the microvessel preparation was characterized by high affinity, saturability, and stereospecificity. The presence of specific beta-adrenergic receptor sites in human cerebral microvessels supports the hypothesis of adrenergic regulation of the function of cerebral microvessels.


Current challenges: the ups and downs of tACS.
The non-invasive delivery of electric currents through the scalp (transcranial electrical stimulation) is a popular tool for neuromodulation, mostly due to its highly adaptable nature (waveform, montage) and tolerability at low intensities (< 2 mA). Applied rhythmically, transcranial alternating current stimulation (tACS) may entrain neural oscillations in a frequency- and phase-specific manner, providing a causal perspective on brain-behaviour relationships. While the past decade has seen many behavioural and electrophysiological effects of tACS that suggest entrainment-mediated effects in the brain, it has been difficult to reconcile such reports with the weak intracranial field strengths (< 1 V/m) achievable at conventional intensities. In this review, we first describe the ongoing challenges faced by users of tACS. We outline the biophysics of electrical brain stimulation and the factors that contribute to the weak field intensities achievable in the brain. Since the applied current predominantly shunts through the scalp-stimulating the nerves that innervate it-the plausibility of transcutaneous (rather than transcranial) effects of tACS is also discussed. In examining the effects of tACS on brain activity, the complex problem of salvaging electrophysiological recordings from artefacts of tACS is described. Nevertheless, these challenges by no means mark the rise and fall of tACS: the second part of this review outlines the recent advancements in the field. We describe some ways in which artefacts of tACS may be better managed using high-frequency protocols, and describe innovative methods for current interactions within the brain that offer either dynamic or more focal current distributions while also minimising transcutaneous effects.


Towards Zero-Shot Sign Language Recognition.
This paper tackles the problem of zero-shot sign language recognition (ZSSLR), where the goal is to leverage models learned over the seen sign classes to recognize the instances of unseen sign classes. In this context, readily available textual sign descriptions and attributes collected from sign language dictionaries are utilized as semantic class representations for knowledge transfer. For this novel problem setup, we introduce three benchmark datasets with their accompanying textual and attribute descriptions to analyze the problem in detail. Our proposed approach builds spatiotemporal models of body and hand regions. By leveraging the descriptive text and attribute embeddings along with these visual representations within a zero-shot learning framework, we show that textual and attribute based class definitions can provide effective knowledge for the recognition of previously unseen sign classes. We additionally introduce techniques to analyze the influence of binary attributes in correct and incorrect zero-shot predictions. We anticipate that the introduced approaches and the accompanying datasets will provide a basis for further exploration of zero-shot learning in sign language recognition.


Morphometric analysis of atrophic changes in human lingual epithelium in iron deficiency anaemia.
A stereological analysis of epithelial structure at the lateral surface of the tongue showed that iron deficiency anaemia was associated with reduced epithelial thickness despite the absence of overt mucosal abnormalities. The epithelial atrophy was entirely due to a reduction in the size and number of cells in the maturation compartment. By contrast, the progenitor cell compartment was increased in thickness due to an increase in the number of cells. This hyperplastic reaction may be a trophic response to the overall loss of epithelium in this condition.


Examination of Risk for Sleep-Disordered Breathing Among College Football Players.
Professional football linemen are at risk for sleep-disordered breathing (SDB) compared with other types of athletes. It is currently unknown whether college football linemen display a similar risk profile. (1) To determine for the first time whether college football linemen show risk for SDB and (2) test the hypothesis that SDB risk is higher in college football linemen compared with an athletic comparison group. Descriptive laboratory study. The Health Risk Assessment Laboratory. Male football linemen (n = 21) and track (n = 19) Division I athletes between the ages of 18 and 22 years. Participants completed the Multivariable Apnea Prediction Index and Epworth Sleepiness Scale surveys, validated measures of symptoms of sleep apnea and daytime sleepiness, respectively. Neck and waist circumferences, blood pressure, Modified Mallampati Index (MMPI), and tonsil size were determined, followed by body composition assessment using dual-energy X-ray absorptiometry. Scores from surveys, anthropometric data, MMPI, and body composition. Survey data demonstrated a deficiency in sleep quality and efficiency, coinciding with increased self-reported symptoms of apnea (Multivariable Apnea Prediction Index = 0.78) in college linemen relative to track athletes. Neck circumference (44.36 cm), waist circumference (107.07 cm), body mass index (35.87 kg/m2), and percent body fat (29.20%), all of which exceeded the clinical predictors of risk for obstructive sleep apnea, were significantly greater in linemen compared with track athletes. Multivariable Apnea Prediction variables were significantly correlated with MMPI, neck circumference, percent body fat, body mass index, and systolic blood pressure (r ≥ .31, P < .05), indicating that college football linemen are at increased risk for SDB. Risk factors for SDB recognized in professional football linemen are also present at the college level. Screening may minimize present or future risk for SDB, as well as the downstream risk of SDB-associated metabolic and cardiovascular disease.


Financial hardship among rural cancer survivors: An analysis of the Medical Expenditure Panel Survey.
Some cancer survivors report spending 20% of their annual income on medical care. Undue financial burden that patients face related to the cost of care is referred to as financial hardship, which may be more prevalent among rural cancer survivors. This study examined contrasts in financial hardship among 1419 rural and urban cancer survivors using the 2011 Medical Expenditure Panel Survey supplement - The Effects of Cancer and Its Treatment on Finances. We combined four questions, creating a measure of material financial hardship, and examined one question on financial worry. We conducted multivariable logistic regression analyses, which produced odds ratios (OR) for factors associated with financial hardship and worry, and then generated average adjusted predicted probabilities. We focused on rural and urban differences classified by metropolitan statistical area (MSA) designation, controlling for age, education, race, marital status, health insurance, family income, and time since last cancer treatment. More rural cancer survivors reported financial hardship than urban survivors (23.9% versus 17.1%). However, our adjusted models revealed no significant impact of survivors' MSA designation on financial hardship or worry. Average adjusted predicted probabilities of financial hardship were 18.6% for urban survivors (Confidence Interval [CI]: 11.9%-27.5%) and 24.2% for rural survivors (CI: 15.0%-36.2%). For financial worry, average adjusted predicted probabilities were 19.9% for urban survivors (CI: 12.0%-31.0%) and 18.8% for rural survivors (CI: 12.1%-28.0%). Improving patient-provider communication through decision aids and/or patient navigators may be helpful to reduce financial hardship and worry regardless of rural-urban status.


Opioid dependence treatment: options in pharmacotherapy.
The development of effective treatments for opioid dependence is of great importance given the devastating consequences of the disease. Pharmacotherapies for opioid addiction include opioid agonists, partial agonists, opioid antagonists, and alpha-2-adrenergic agonists, which are targeted toward either detoxification or long-term agonist maintenance. Agonist maintenance therapy is currently the recommended treatment for opioid dependence due to its superior outcomes relative to detoxification. Detoxification protocols have limited long-term efficacy, and patient discomfort remains a significant therapy challenge. Buprenorphine's effectiveness relative to methadone remains a controversy and may be most appropriate for patients in need of low doses of agonist treatment. Buprenorphine appears superior to alpha-2 agonists, however, and office-based treatment with buprenorphine in the USA is gaining support. Studies of sustained-release formulations of naltrexone suggest improved effectiveness for retention and sustained abstinence; however, randomized clinical trials are needed.


David Hunter Hubel, the 'Circe effect', and SARS-CoV-2 infection of the human visual system.
David Hunter Hubel (1926-2013) was an internationally recognized neurophysiologist and vision neuroscientist noted for his life-long studies on the columnar structure and highly integrated function of the brain's primary and secondary visual cortex. He was co-recipient with the American neuropsychologist and neurobiologist Roger Wolcott Sperry (1913-1994) and the Swedish neurophysiologist Torsten Nils Wiesel (1924-present) of the 1981 Nobel Prize in Physiology or Medicine, for their significant discoveries concerning the functional specialization of the cerebral hemispheres, the layered structure of the human cerebral visual cortex and information processing in the visual system, how the human visual cortex is organized into columns, and how this remarkable cellular organization and connectivity for the human visual system can be modified by lifestyle, experience, aging and disease. This commentary integrates these significant findings with current observations on SARS-CoV-2, the causative agent of COVID-19, and its invasion of the human visual system via the angiotensin converting enzyme 2 (ACE2) receptor.


Non-invasive tumor detection in small animals using novel functional Pluronic nanomicelles conjugated with anti-mesothelin antibody.
In this study QDs were encapsulated in carboxylated PluronicF127 (F127COOH) triblock polymeric micelles and conjugated with anti-mesothelin antibody for the purpose of alleviating potential toxicity, enhancing the stability and improving targeting efficiency of CdTe/ZnS quantum dots (QDs) in tumors. The amphiphilic triblock polymer of F127COOH contains hydrophilic carboxylated poly(ethylene oxide) (PEO) and hydrophobic poly(propylene oxide) (PPO) units. After encapsulating QDs into carboxylated F127 (F127COOH-QD) micelles, the particles were conjugated with anti-mesothelin antibodies to allow targeting of cancerous areas. The size of the monodispersed spherical QD-containing micelles was determined to be ∼120 nm by dynamic light scattering (DLS). The critical micelle concentration (CMC) was estimated to be 4.7 × 10(-7) M. In an in vitro study, the anti-methoselin antibody conjugated F127COOH (Me-F127COOH-QD) nanomicelles showed negligible cytotoxicity to pancreatic cancer cells (Panc-1). Confocal microscopy demonstrated that the Me-F127COOH-QD nanomicelles were taken up more efficiently by Panc-1 cells, due to antibody mediated targeting. An in vivo imaging study showed that Me-F127COOH-QD nanomicelles accumulated at the pancreatic tumor site 15 min after intravenous injection. In addition, the low in vivo toxicity of the nanomicellar formulation was evaluated by pathological assays. These results suggest that anti-mesothein antibody conjugated carboxylated F127 nanomicelles may serve as a promising nanoscale platform for early human pancreatic cancer detection and targeted drug delivery.


IGF-1 concentrations after weaning in young sows fed different pre-mating diets are positively associated with piglet mean birth weight at subsequent farrowing.
Pre-mating diets can influence piglet birth weight and within-litter birth weight variation and thereby piglet survival and development. The major objective of this study was to evaluate the litter characteristics of young sows whose pre-mating diets received different supplementation. The supplements included a top-dressing of 200 g, consisting of either wheat (CON) or wheat plus microfibrillated cellulose, L-carnitine or L-arginine at one of two supplementation levels (low and high) in late lactation and during the weaning-to-oestrus interval (WEI). The second objective was to investigate the role of body condition loss and IGF-1 concentration during the WEI for subsequent litter characteristics. In total, sows after their first (N =41) and second (N =15) lactation were used. One week before weaning, the sows were allocated to the seven treatments based on the number of piglets and BW loss from farrowing until 1 week before weaning. Pre-mating diets did not affect litter characteristics at subsequent farrowing. However, at subsequent farrowing, sows after their first lactation had a lower total number of piglets born per litter (18.3 v. 20.3), higher mean piglet birth weight (1365 v. 1253 g), lower CV of birth weight (20.0 v. 26.1%) and lower percentage of piglets <1000 g (11.5 v. 24.4%) than sows after their second lactation. Litter weight at second parturition was positively related to IGF-1 during the WEI after first lactation (P <0.04). Within parity, piglet mean birth weight was positively related to IGF-1 at oestrus (P <0.02). Surprisingly, within parity, a higher relative loin muscle depth loss during previous lactation was related to lower CV and SD of birth weight (P <0.05, for both). In conclusion, pre-mating diets did not affect litter characteristics at subsequent birth. However, a higher IGF-1 concentration during the WEI was positively associated with subsequent litter weight and piglet mean birth weight. Further studies should elucidate the role of IGF-1 during the WEI for subsequent litter characteristics and dietary interventions to stimulate IGF-1.


Enlarging multiplexing capacity with reduced radial cross talk in volume holographic discs.
A novel design for a volume holographic optical disc to reduce radial cross talk is proposed. By adopting a proper spatial filter, the radial cross talk can be reduced and the radial selectivity increases so that the multiplexing capacity can increase effectively. The theory and the corresponding experiment are demonstrated.


Development of the Neurochemical Architecture of the Central Complex.
The central complex represents one of the most conspicuous neuroarchitectures to be found in the insect brain and regulates a wide repertoire of behaviors including locomotion, stridulation, spatial orientation and spatial memory. In this review article, we show that in the grasshopper, a model insect system, the intricate wiring of the fan-shaped body (FB) begins early in embryogenesis when axons from the first progeny of four protocerebral stem cells (called W, X, Y, Z, respectively) in each brain hemisphere establish a set of tracts to the primary commissural system. Decussation of subsets of commissural neurons at stereotypic locations across the brain midline then establishes a columnar neuroarchitecture in the FB which is completed during embryogenesis. Examination of the expression patterns of various neurochemicals in the central complex including neuropeptides, a neurotransmitter and the gas nitric oxide (NO), show that these appear progressively and in a substance-specific manner during embryogenesis. Each neuroactive substance is expressed by neurons located at stereotypic locations in a given central complex lineage, confirming that the stem cells are biochemically multipotent. The organization of axons expressing the various neurochemicals within the central complex is topologically related to the location, and hence birthdate, of the neurons within the lineages. The neurochemical expression patterns within the FB are layered, and so reflect the temporal topology present in the lineages. This principle relates the neuroanatomical to the neurochemical architecture of the central complex and so may provide insights into the development of adaptive behaviors.


Isometric hip abduction using a Thera-Band alters gluteus maximus muscle activity and the anterior pelvic tilt angle during bridging exercise.
The purpose of this study was to investigate the effects of bridging with isometric hip abduction (IHA) using the Thera-Band on gluteus maximus (GM), hamstring (HAM), and erector spinae (ES) muscle activity; GM/HAM and GM/ES ratios; and the anterior pelvic tilt angle in healthy subjects. Twenty-one subjects participated in this study. Surface EMG was used to collect EMG data of GM, HAM, and ES muscle activities, and Image J software was used to measure anterior pelvic tilt angle. A paired t-test was used to compare GM, HAM, and ES muscle activity; the GM/HAM and GM/ES ratios; and the anterior pelvic tilt angle with and without IHA during the bridging exercise. GM muscle activity increased significantly and the anterior pelvic tilt angle decreased significantly during bridging with IHA using the Thera-Band (p < 0.05). However, there were no significant differences in the activity of the HAM and ES and the GM/HAM and GM/ES ratios between bridging with and without IHA (p > 0.05). The results of this study suggest that bridging with IHA using the Thera-Band can be implemented as an effective method to facilitate GM muscle activity and reduce the anterior pelvic tilt angle.


Hedgehog-stimulated phosphorylation of the kinesin-related protein Costal2 is mediated by the serine/threonine kinase fused.
The Hedgehog (Hh) signaling molecule is required for the development of numerous tissues in Drosophila. Within the cell, Hh signal transduction utilizes a large protein complex consisting of the Fused (Fu), Costal2 (Cos2), and Cubitis interruptus (Ci) proteins, but the functional interactions between these proteins are still largely uncharacterized. Using a baculovirus system, we demonstrate that the serine/threonine kinase Fu phosphorylates the kinesin-like protein Cos2 when coexpressed with Cos2. Coexpression of Cos2 and a kinase-inactive version of Fu eliminates the majority of Cos2 phosphorylation. We then show that the primary Fu-induced phosphorylation site of Cos2 is serine 572, whereas serine 931 is phosphorylated to a lesser extent. Mutation of serine 572 to alanine eliminates most, but not all, specific phosphopeptides of Cos2 when coexpressed with Fu. We also demonstrate that the phosphorylation pattern of Cos2 produced by baculovirus coexpression with kinase-dead Fu is almost identical to the phosphorylation pattern of Cos2 isolated from unstimulated S2 cells. Finally, the phosphorylation pattern of Cos2 produced by baculovirus coinfection with wild-type Fu is almost identical to that of Cos2 isolated from S2 cells stimulated by Hh, indicating that phosphorylation of serines 572 and 931 is a genuine Hh signaling event. This study clarifies the unique functions of Fu and Cos2 in Hh signal transduction and identifies only the second known phosphorylation site of a kinesin-like molecule.


Poroelastic behaviour of the degenerating human intervertebral disc: a ten-day study in a loaded disc culture system.
The intervertebral disc (IVD) allows flexibility to the vertebral column, and transfers the predominant axial loads during daily activities. Its axial biomechanical behaviour is poroelastic, due to the water-binding and releasing capacity of the nucleus pulposus. Degeneration of the intervertebral disc presumably affects both the instantaneous elastic response to the load on the IVD and the subsequent interstitial flow of fluid. This study aims to quantify the poroelastic behaviour of the IVD and its change with degeneration, as defined by the magnetic resonance imaging-based Pfirrmann Score (PS). For a period of ten days, 36 human lumbar IVDs were loaded with a simulated physiological axial loading regime, while deformation was monitored. The IVDs responded to the loads with instantaneous elastic and slow poroelastic axial deformation. Several mechanical parameters changed throughout the first five days of the experiment, until the IVDs settled into a dynamic equilibrium. In this equilibrium, degeneration was significantly related to a decrease in disc height loss during the daytime high load phase (ρ = -0.49), and to a decrease in the rate of this deformation during the final half hour of each day (ρ = -0.53). These properties were related to the nucleus glycosaminoglycan/hydroxyproline (GAG/HYP) ratio, rather than GAG content alone, indicating that remodelling of the extracellular matrix reduces poroelastic properties of the IVD. This implies that the degenerated discs have a reduced capacity to bind water and/or a reduced resistance against fluid flow. The resulting loss in hydrostatic pressure may further change cell behaviour in the nucleus pulposus.


Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in adult psychiatry. A 20-year register study.
Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are increasingly recognized in adults. This study aimed to assess trends in diagnostic practice, diagnostic delay and comorbidity regarding ADHD and ASD in adult psychiatric patients. Individuals with diagnosed ADHD or ASD were identified in an adult psychiatry register comprising 56,462 patients. ADHD was diagnosed in up to 2.7% and ASD in 1.3% of the patients. Most cases were diagnosed within 2 years of first contact with adult psychiatry, but some patients were treated for 10 years or more before being diagnosed with ADHD or ASD. Seventy per cent of ADHD and 56% of ASD patients were treated as outpatients only. Other psychiatric diagnoses were registered in about 60%. Affective disorders were common in patients with ADHD. Psychoses and intellectual disability were more common in ASD patients. Psychoactive substance use-related disorders were considerably more common in those with ADHD. Concomitant ADHD and ASD were seldom diagnosed in this clinical material. ADHD and ASD were probably much underdiagnosed in the studied group of psychiatric patients. Other psychiatric diagnoses were common, but not ADHD with concomitant ASD.


A study of the beam-specific interplay effect in proton pencil beam scanning delivery in lung cancer.
For lung tumors with large motion amplitudes, the use of proton pencil beam scanning (PBS) can produce large dose errors. In this study, we assess under what circumstances PBS can be used to treat lung cancer patients who exhibit large tumor motion, based on the quantification of tumor motion and the dose interplay. PBS plans were optimized on average 4DCT datasets using a beam-specific PTV method for 10 consecutive patients with locally advanced non-small-cell-lung-cancer (NSCLC) treated with proton therapy to 6660/180 cGy. End inhalation (CT0) and end exhalation (CT50) were selected as the two extreme scenarios to acquire the relative stopping power ratio difference (Δrsp) for a respiration cycle. The water equivalent difference (ΔWET) per radiological path was calculated from the surface of patient to the iCTV by integrating the Δrsp of each voxel. The magnitude of motion of voxels within the target follows a quasi-Gaussian distribution. A motion index (MI (>5mm WET)), defined as the percentage of target voxels with an absolute integral ΔWET larger than 5 mm, was adopted as a metric to characterize interplay. To simulate the treatment process, 4D dose was calculated by accumulating the spot dose on the corresponding respiration phase to the reference phase CT50 by deformable image registration based on spot timing and patient breathing phase. The study indicated that the magnitude of target underdose in a single fraction plan is proportional to the MI (p < .001), with larger motion equating to greater dose degradation and standard deviations. The target homogeneity, minimum, maximum and mean dose in the 4D dose accumulations of 37 fractions varied as a function of MI. This study demonstrated that MI can predict the level of dose degradation, which potentially serves as a clinical decision tool to assess whether lung cancer patients are potentially suitable to receive PBS treatment.


The development of the dementia concept in 19th century.
The dementia concept has been reformulated through its history and the 19th century was remarkable in the construction of this concept as we understand it today. Like other syndromes, much of the history of the dementia concept comes from the attempt to separate it from other nosological conditions, giving it a unique identity. The fundamental elements for the arising of the dementia modern concept were: a) correlation of the observed syndrome with organic-cerebral lesions; b) understanding of the irreversibility of the dementia evolution; c) its relation with human ageing; and d) the choice of the cognitive dysfunction as a clinical marker of the dementia concept.


Restoring Value to the World's Degraded Lands.
Roughly 43 percent of Earth's terrestrial vegetated surface has diminished capacity to supply benefits to humanity because of recent, direct impacts of land use. This represents an approximately 10 percent reduction in potential direct instrumental value (PDIV), defined as the potential to yield direct benefits such as agricultural, forestry, industrial, and medicinal products. If present trends continue, the global loss of PDIV could reach approximately 20 percent by 2020. From a biophysical perspective, recovery of approximately 5 percent of PDIV is feasible over the next 25 years. Capitalizing on natural recovery mechanisms is urgently needed to prevent further irreversible degradation and to retain the multiple values of productive land.


Hemodynamic and cardiac adaptation in essential hypertension. Consequences for therapy.
In so-called essential hypertension, at least three different subsets of pathophysiologic findings can be identified: mild hypertension in nonobese juvenile subjects characterized by elevated cardiac output, normal peripheral resistance, increased sympathetic activity as measured by norepinephrine and plasma renin activity; hypertension in the elderly with a low cardiac output, often with left ventricular hypertrophy, elevated total peripheral resistance, nephrosclerosis contracted intravascular volume, and low plasma renin activity; and obese hypertensive patients with a high cardiac output, expanded intravascular volume, and a normal total peripheral resistance. Although there is often an overlap among these three entities, antihypertensive treatment can easily be adapted accordingly. A beta-adrenoreceptor blocker is the step-one drug to be used in mild hypertension with an elevated cardiac output. The drug's negative inotropic and chronotropic properties will bring the elevated cardiac output and heart rate back to normal. In the elderly hypertensive patient, an arteriolar and venous vasodilator, such as an antiadrenergic agent, slow channel calcium blocker, or a converting enzyme inhibitor, will lower total peripheral resistance and unburden the left ventricle. In the obese patient and also in most black subjects, the first-step antihypertensive agent remains a thiazide diuretic. Labetalol, an agent with both beta- and alpha-adrenoreceptor properties, shows promise for the treatment of hypertension in the young as well as in the older patient. It seems to be the agent of choice in patients with established essential hypertension who are concomitantly suffering from coronary artery disease.


Activation and control of CNS innate immune responses in health and diseases: a balancing act finely tuned by neuroimmune regulators (NIReg).
Innate immunity is an arsenal of molecules and receptors expressed by professional phagocytes, glial cells and neurons and involved in host defence and clearance of toxic and dangerous cell debris. However, any uncontrolled innate immune responses within the central nervous system (CNS) are widely recognized as playing a major role in the development of autoimmune disorders and neurodegeneration, with multiple sclerosis (MS) and Alzheimer's diseases (AD) being primary examples. Critically, neuroimmune regulatory proteins (NIReg) may control the adverse immune responses in health and diseases. NIRegs are found mainly on neurons, glia, endothelia and ependymal cells and include GPI-anchored molecules (CD24, CD90, complement regulators CD55 and CD59), molecules of the immunoglobulin superfamily (siglec CD22, Siglec 10, CD200, ICAM-5) and others (CD47, fractalkine, TAM receptor tyrosine kinase and complement C3a and factor H). These regulators modulate the innate immune response in the CNS and for instance critically control the level of phagocytosis and inflammation engaged by resident microglia and infiltrating immune cells. Others will sequester and neutralize proinflammatory molecules such as HMGB1 and DNA. Moreover, some NIRegs can instigate the recruitment of stem cells to mediate tissue repair. In the absence of these regulators, when neurons die by apoptosis, become infected or damaged, microglia and infiltrating immune cells are free to cause injury and an adverse inflammatory response in acute and chronic settings. The therapeutic applications of NIRegs should be exploited given their natural and selective healing properties.


Molecular mechanisms involved in the protective effect of pituitary adenylate cyclase-activating polypeptide in an in vitro model of amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. Based on transcriptional profiles of motor cortex samples, in a previous work, we were able to classify two subgroups of sporadic ALS (SALS) patients, named SALS1 and SALS2. A further meta-analysis study has revealed sixteen drug targets commonly deregulated in SALS2 and superoxide dismutase 1 (SOD1) G93A mice. The identified candidate drug targets included pituitary adenylate cyclase-activating polypeptide (PACAP), epidermal growth factor receptor (EGFR) and matrix metallopeptidase-2 (MMP-2). By using a motor neuron-like hybrid cell line (NSC-34) expressing human SOD1 G93A as an in vitro model of ALS, here we investigated the functional correlation among these three genes. Our results have shown that PACAP increases cell viability following serum deprivation. This effect is induced through EGFR transactivation mediated by protein kinase A stimulation. Furthermore, EGFR phosphorylation activates mitogen-activated protein kinases/extracellular signal-regulated kinases 1 and 2 survival signaling pathway and increases MMP-2 expression, significantly reduced by serum starvation. These results suggest that a deeper characterization of mechanisms involved in PACAP/EGFR/MMP-2 axis activation in G93A SOD1 mutated neurons may allow identifying new targets for ALS therapy.


Epidemiology of NMOSD in Catalonia: Influence of the new 2015 criteria in incidence and prevalence estimates.
Population-based studies on neuromyelitis optica spectrum disorders (NMOSD) are limited, and it is unclear whether the rates have changed with the implementation of the new 2015 criteria. To estimate the incidence and prevalence of NMOSD in Catalonia (Spain), using both the 2006 and the 2015 criteria. In this clinic-based retrospective study, patients diagnosed with NMOSD between 2006 and 2015 were identified using multiple sources, including direct contact to all Catalan hospitals, identification of cases through the Catalan Health Surveillance System, and registry of antibodies to aquaporin-4 (AQP4-IgG) and myelin oligodendrocyte glycoprotein (MOG-IgG) in a reference laboratory. The incidence rate was calculated for the period 1 January 2006-1 January 2016 and prevalence for the date 1 January 2016. We identified 74 patients (by the 2015 criteria). Most patients were Caucasian (81%), and female (76%) with a median age at disease onset of 42 years (range, 10-76 years). In total, 54 (73%) patients were positive for AQP4-IgG, 11 (15%) double-seronegative, and 9 (12%) MOG-IgG-positive. Rates of incidence and prevalence (0.63/1,000,000 person-years and 0.89/100,000, respectively) were 1.5-fold higher than those reported by the 2006 criteria. Lowest rates were seen in children and elder people and highest in women and middle-aged people (40-59 years). The female predominance was lost in incident AQP4-IgG-seronegative children and AQP4-IgG-positive elder people. MOG-IgG and double-seronegativity contributed similarly but did not influence the long-term outcome. The new criteria increase the estimates, but NMOSD remains as a rare disease. The differences in age- and sex-specific estimates highlight the importance of the serologic classification.


Myocardial motion estimation of tagged cardiac magnetic resonance images using tag motion constraints and multi-level b-splines interpolation.
Myocardial motion estimation of tagged cardiac magnetic resonance (TCMR) images is of great significance in clinical diagnosis and the treatment of heart disease. Currently, the harmonic phase analysis method (HARP) and the local sine-wave modeling method (SinMod) have been proven as two state-of-the-art motion estimation methods for TCMR images, since they can directly obtain the inter-frame motion displacement vector field (MDVF) with high accuracy and fast speed. By comparison, SinMod has better performance over HARP in terms of displacement detection, noise and artifacts reduction. However, the SinMod method has some drawbacks: 1) it is unable to estimate local displacements larger than half of the tag spacing; 2) it has observable errors in tracking of tag motion; and 3) the estimated MDVF usually has large local errors. To overcome these problems, we present a novel motion estimation method in this study. The proposed method tracks the motion of tags and then estimates the dense MDVF by using the interpolation. In this new method, a parameter estimation procedure for global motion is applied to match tag intersections between different frames, ensuring specific kinds of large displacements being correctly estimated. In addition, a strategy of tag motion constraints is applied to eliminate most of errors produced by inter-frame tracking of tags and the multi-level b-splines approximation algorithm is utilized, so as to enhance the local continuity and accuracy of the final MDVF. In the estimation of the motion displacement, our proposed method can obtain a more accurate MDVF compared with the SinMod method and our method can overcome the drawbacks of the SinMod method. However, the motion estimation accuracy of our method depends on the accuracy of tag lines detection and our method has a higher time complexity.


Critical Analysis of Thrombocytopenia Associated With Glycoprotein IIb/IIIa Inhibitors and Potential Role of Zalunfiban, a Novel Small Molecule Glycoprotein Inhibitor, in Understanding the Mechanism(s).
Thrombocytopenia is a rare but serious complication of the intravenous glycoprotein IIb/IIIa (GPIIb/IIIa; integrin αIIbβ3) receptor inhibitors (GPIs), abciximab, eptifibatide, and tirofiban. The thrombocytopenia ranges from mild (50 000-100 000 platelets/μL), to severe (20 000 to <50 000/μL), to profound (<20 000/μL). Profound thrombocytopenia appears to occur in <1% of patients receiving their first course of therapy. Thrombocytopenia can be either acute (<24 hours) or delayed (up to ~14 days). Both hemorrhagic and thrombotic complications have been reported in association with thrombocytopenia. Diagnosis requires exclusion of pseudothrombocytopenia and heparin-induced thrombocytopenia. Therapy based on the severity of thrombocytopenia and symptoms may include drug withdrawals and treatment with steroids, intravenous IgG, and platelet transfusions. Abciximab-associated thrombocytopenia is most common and due to either preformed antibodies or antibodies induced in response to abciximab (delayed). Readministration of abciximab is associated with increased risk of thrombocytopenia. Evidence also supports an immune basis for thrombocytopenia associated with the 2 small molecule GPIs. The latter bind αIIbβ3 like the natural ligands and thus induce the receptor to undergo major conformational changes that potentially create neoepitopes. Thrombocytopenia associated with these drugs is also immune-mediated, with antibodies recognizing the αIIbβ3 receptor only in the presence of the drug. It is unclear whether the antibody binding depends on the conformational change and whether the drug contributes directly to the epitope. Zalunfiban, a second-generation subcutaneous small molecule GPI, does not induce the conformational changes; therefore, data from studies of zalunfiban will provide information on the contribution of the conformational changes to the development of GPI-associated thrombocytopenia.


Rational Basis for the Use of Bergamot Essential Oil in Complementary Medicine to Treat Chronic Pain.
In complementary medicine, aromatherapy uses essential oils to improve agitation and aggression observed in dementia, mood, depression, anxiety and chronic pain. Preclinical research studies have reported that the essential oil obtained from bergamot (BEO) fruit (Citrus bergamia, Risso) modifies normal and pathological synaptic plasticity implicated, for instance, in nociceptive and neuropathic pain. Interestingly, recent results indicated that BEO modulates sensitive perception of pain in different models of nociceptive, inflammatory and neuropathic pain modulating endogenous systems. Thus, local administration of BEO inhibited the nociceptive behavioral effect induced by intraplantar injection of capsaicin or formalin in mice. Similar effects were observed with linalool and linalyl acetate, major volatile components of the phytocomplex, Pharmacological studies showed that the latter effects are reversed by local or systemic pretreatment with the opioid antagonist naloxone hydrochloride alike with naloxone methiodide, high affinity peripheral μ-opioid receptor antagonist. These results and the synergistic effect observed following systemic or intrathecal injection of an inactive dose of morphine with BEO or linalool indicated an activation of peripheral opioid system. Recently, in neuropathic pain models systemic or local administration of BEO or linalool induced antiallodynic effects. In particular, in partial sciatic nerve ligation (PSNL) model, intraplantar injection of the phytocomplex or linalool in the ipsilateral hindpaw, but not in the contralateral, reduced PSNL-induced extracellularsignal- regulated kinase (ERK) activation and mechanical allodynia. In neuropathic pain high doses of morphine are needed to reduce pain. Interestingly, combination of inactive doses of BEO or linalool with a low dose of morphine induced antiallodynic effects in mice. Peripheral cannabinoid and opioid systems appear to be involved in the antinociception produced by intraplantar injection of β -caryophyllene, present in different essential oils including BEO. The data gathered so far indicate that the essential oil of bergamot is endowed with antinociceptive and antiallodynic effects and contribute to form the rational basis for rigorous testing of its efficacy in complementary medicine.


Influence of the target tissue size on the shape of ex vivo microwave ablation zones.
The aim of this study was to numerically and experimentally characterise the influence of tissues dimensions on the size and shape of microwave-induced ablation zones. A 2.45 GHz interstitial antenna was introduced into ex vivo bovine liver samples, delivering 60 W for 10 min; then the dimensions of the coagulated area were measured. Ablations were performed both in large samples (termed unrestricted tissue) for characterising the tissue response, and in thin samples, whose dimensions in the plane perpendicular to the antenna were smaller than the short axis of the ablated area obtained in unrestricted samples. In the numerical study the electromagnetic field emitted from the antenna and the corresponding temperature increase were evaluated in both unrestricted and thin tissue samples. When the height of the tissue was smaller than the ablation diameter measured in unrestricted samples, a 7.5% increase in length of the ablated zone was experimentally observed. When both the height and width were lower than the diameter measured in unrestricted samples, an elongation of about 23.4% was experimentally obtained. The numerical study showed that the boundary conditions between the target tissue and the surrounding materials are critical. The ex vivo performances of microwave ablation devices are notably influenced by the shape and dimension of the tissues where the procedure takes place. Accordingly, dedicated interventional protocols should be developed for treatment planning on targets of different shape and size.


Variability in schizophrenia. Reflection of a regulatory disease.
The clinical course, body weight, biological measurements, and responses to neuroleptic agents were examined in 92 chronic schizophrenics over a period of ten years. The individual occurrence of periodic exacerbations, shifts in symptoms, changes in drug responses, unusual fluctuations in body weight, and transient biological abnormalities led me to conclude that schizophrenia is characterized by an independent variability of clinical and biological features. This variability indicates that schizophrenia is a disease of regulation.


The molecular defect in type IIB von Willebrand disease. Identification of four potential missense mutations within the putative GpIb binding domain.
Type IIB von Willebrand Disease (vWD) is characterized by the selective loss of large von Willebrand Factor (vWF) multimers from plasma, presumably due to their increased reactivity with platelets and subsequent clearance from the circulation. Using the PCR, one of a panel of four potential missense mutations was identified in each of the 14 patients studied from 11 unrelated families. None of these substitutions was encountered in a large panel of normal DNAs. These changes all represent C----T transitions at CpG dinucleotides, proposed "hot spots" for mutation in the human genome. The four resulting amino acid substitutions, Arg543----Trp, Arg545----Cys, Val553----Met, and Arg578----Gln, are all clustered within the GpIb binding domain of vWF. Disruption of this latter functional domain may explain the pathogenesis of Type IIB vWD. By sequence polymorphism analysis, the Arg543----Trp substitution was shown to have occurred as at least two independent mutational events. This latter observation, along with the identification of mutations in all 14 patients studied and their localization to the GpIb binding domain, all strongly suggest that these substitutions represent the authentic defects responsible for Type IIB vWD. This panel of mutations may provide a useful diagnostic tool for the majority of patients with Type IIB vWD.


Testing for mean and correlation changes in microarray experiments: an application for pathway analysis.
Microarray experiments examine the change in transcript levels of tens of thousands of genes simultaneously. To derive meaningful data, biologists investigate the response of genes within specific pathways. Pathways are comprised of genes that interact to carry out a particular biological function. Existing methods for analyzing pathways focus on detecting changes in the mean or over-representation of the number of differentially expressed genes relative to the total of genes within the pathway. The issue of how to incorporate the influence of correlation among the genes is not generally addressed. In this paper, we propose a non-parametric rank test for analyzing pathways that takes into account the correlation among the genes and compared two existing methods, Global and Gene Set Enrichment Analysis (GSEA), using two publicly available data sets. A simulation study was conducted to demonstrate the advantage of the rank test method. The data indicate the advantages of the rank test. The method can distinguish significant changes in pathways due to either correlations or changes in the mean or both. From the simulation study the rank test out performed Global and GSEA. The greatest gain in performance was for the sample size case which makes the application of the rank test ideal for microarray experiments.


CULTIVATION OF LEPTOSPIRAE. II. GROWTH AND LYSIS IN SYNTHETIC MEDIUM.
Stalheim, O. H. V. (University of Wisconsin, Madison), and J. B. Wilson. Cultivation of leptospirae. II. Growth and lysis in synthetic medium. J. Bacteriol. 88:55-59. 1964.-Differences were found in the ability of leptospirae to grow in a synthetic medium; 43 strains, consisting of 16 serotypes, were tested and designated as either type I or type II. Type I leptospirae did not grow; type II grew and could be subcultured. The lytic effect of several lipids was measured with Leptospira pomona and L. canicola as representatives of type I and II leptospirae, respectively. L. pomona organisms were rapidly lysed by the monoolein of the synthetic medium and by other lipids as well; L. canicola cells were consistently more resistant. Although both organisms incorporated similar amounts of label when incubated in the presence of oleic-1-C(14) acid, only L. canicola grew in a modified, nonlytic synthetic medium. No differences were found in susceptibility to lysis between virulent and avirulent L. canicola organisms. Mutant type I leptospirae grown in synthetic medium had increased resistance to lysis by surface-active agents; they were poorly agglutinated by antiserum. The role of protein in the growth and antigenicity of type I leptospirae is discussed.


Longitude Position in a Time Zone and Cancer Risk in the United States.
Background: Circadian disruption is a probable human carcinogen. From the eastern to western border of a time zone, social time is equal, whereas solar time is progressively delayed, producing increased discrepancies between individuals' social and biological circadian time. Accordingly, western time zone residents experience greater circadian disruption and may be at an increased risk of cancer.Methods: We examined associations between the position in a time zone and age-standardized county-level incidence rates for total cancers combined and 23 specific cancers by gender using the data of the Surveillance, Epidemiology, and End Results Program (2000-2012), including four million cancer diagnoses in white residents of 607 counties in 11 U.S. states. Log-linear regression was conducted, adjusting for latitude, poverty, cigarette smoking, and state. Bonferroni-corrected P values were used as the significance criteria.Results: Risk increased from east to west within a time zone for total and for many specific cancers, including chronic lymphocytic leukemia (both genders) and cancers of the stomach, liver, prostate, and non-Hodgkin lymphoma in men and cancers of the esophagus, colorectum, lung, breast, and corpus uteri in women.Conclusions: Risk increased from the east to the west in a time zone for total and many specific cancers, in accord with the circadian disruption hypothesis. Replications in analytic epidemiologic studies are warranted.Impact: Our findings suggest that circadian disruption may not be a rare phenomenon affecting only shift workers, but is widespread in the general population with broader implications for public health than generally appreciated. Cancer Epidemiol Biomarkers Prev; 26(8); 1306-11. ©2017 AACR.


Prenatal Exposure to Air Toxics and Malignant Germ Cell Tumors in Young Children.
To assess prenatal air toxics exposure and risk for childhood germ cell tumors (GCTs) by histological subtype (yolk sac tumor and teratoma). In this case-control study, GCT cases less than 6 years (n = 243) identified from California Cancer Registry records were matched by birth year to cancer-free population controls (n = 147,100), 1984 to 2013. Routinely monitored air toxic exposures were linked to subjects' birth address. Logistic regression estimated GCT risks per interquartile range increase in exposure. Prenatal exposure to various highly-correlated, traffic-related air toxics during the second trimester increased GCT risk, particularly 1,3-butadiene (odds ratio [OR] = 1.51; 95% confidence interval [CI] = 1.01, 2.26) and meta/para-xylene (OR = 1.56; 95% CI = 1.10, 2.21). Analyses by subtype indicated elevated ORs for yolk sac tumors but not teratomas. Our estimated ORs are consistent with positive associations between some prenatal traffic-related air toxics and GCT risk, notably yolk sac tumors.


[Guideline for diagnosis and treatment of urinary incontinence in elderly].
Urinary incontinence is a frequent geriatric syndrome, characterized by involuntary urine losses that have a negatively influence on the health, their functionality and social relationships in whom suffered it. Nevertheless, most of these patients are not diagnosed and they do not receive treatment. The objective of this clinical guideline is to provide recommendations based on the best scientific evidence available for diagnosis and treatment of the urinary incontinence in the elderly, at primary care attention. Articles of clinical relevance were selected based on clinical evidence and analyzed by two family physicians, one geriatrician, one gerontologist and two experts in methods for elaboration of clinical guidelines. To verify comprehension and clinical applicability, 4 workshops including 35 family physicians were carried out, and the corresponding adjustments were made. The clinical guideline can be a tool for physicians at primary care attention to classify urinary incontinence and to provide pharmacologic and nonpharmacologic treatment. Additionally, the guideline presents recommendations for identification of patients who need specialized care.


Structural studies of TcO2 by neutron powder diffraction and first-principles calculations.
Crystalline technetium dioxide was prepared and for the first time its crystal structure determined by neutron powder diffraction. In addition, electronic structure calculations using density functional theory were performed to further elucidate the bonding mechanisms in TcO2. The crystal structure determined by Rietveld analysis with the NPD data is of a distorted rutile type, similar to that of MoO2; space group P21/c, a = 5.6891(1), b = 4.7546(1), c = 5.5195(1) A, and beta = 121.453(1) degrees . The NPD analysis also establishes a new neutron scattering length of 6.00(3) fm for 99Tc. Our results clearly show metal-metal bonding between Tc pairs along the edge-sharing chains of TcO6 octahedra. The Tc-Tc bond was found to be 2.622(1) A from NPD profile analysis and 2.59 A from first-principles DFT calculations. The bond is somewhat longer than expected from earlier predictions, suggesting that the nature of the Tc-Tc interaction is weaker than anticipated for the Tc(IV) cation with three outer electrons. The NPD results supported by the DFT calculations suggest that the filling of antibonding orbitals and the influence of the crystal field stabilization of the d3 Tc cations lead to more regular TcO6 octahedra and diminish the metal-metal bond strength compared with closely related oxides such MoO2 and WO2.


Mechanisms of hypoxic and aerobic cytotoxicity of mitomycin C in Chinese hamster V79 cells.
Mitomycin C (MMC) induced aerobic and hypoxic cytotoxicity in Chinese hamster V79 cells was studied to evaluate the role of the 1-electron versus 2-electron reductive bioactivation. Superoxide dismutase, catalase, and desferal had no protective effects on the aerobic or hypoxic cytotoxicity of MMC, whereas Tempol and Tempol-H, which are known to interrupt and terminate radical reactions, provided partial protection under aerobic conditions. However, under hypoxic conditions, Tempol provided complete protection whereas Tempol-H was ineffective. Electron paramagnetic resonance and spin-trapping investigations, designed to study the mechanisms of such protective effects, confirmed that MMC is activated by the human NADPH:cytochrome P-450 oxidoreductase to its semiquinone radical and that, under aerobic conditions, the semiquinone radical reduces molecular oxygen. Under hypoxic conditions, the semiquinone of MMC reduces H2O2 to produce OH radicals as detected by electron paramagnetic resonance-spin trapping with 5,5-dimethyl-1-pyrroline N-oxide. The 1-electron reduced product of MMC was also found to reduce Tempol to the hydroxylamine, Tempol-H, whereas oxidation of Tempol-H by MMC-. was negligible. Cell survival studies and electron paramagnetic resonance observations indicate that the hypoxic cytotoxicity of MMC is mediated by 1-electron activation to its semiquinone intermediate. Under aerobic conditions, the steady state concentration of this intermediate is low due to the facile autooxidation of the semiquinone producing O2-. and H2O2 which are capable of causing oxidative cytotoxicity. Tempol, which can accept an electron from reducing radical species, completely inhibited the hypoxic cytotoxicity of MMC indicating MMC-., the semiquinone of MMC as the species responsible for DNA alkylation and selective hypoxic cytotoxicity of MMC. Our results also indicate that the aerobic cytotoxicity is mediated by other processes in addition to the 1-electron mediated activation.


Fluctuations in Sustained Attention Explain Moment-to-Moment Shifts in Children's Memory Formation.
Why do children's memories often differ from adults' after the same experience? Whereas prior work has focused on children's immature memory mechanisms to answer this question, here we focus on the costs of attentional lapses for learning. We track sustained attention and memory formation across time in 7- to 10-year-old children and adults (n = 120) to show that sustained attention causally shapes the fate of children's individual memories. Moreover, children's attention lapsed twice as frequently as adults', and attention fluctuated with memory formation more closely in children than adults. In addition, although attentional lapses impaired memory for expected events in both children and adults, they impaired memory for unexpected events in children only. Our work reveals that sustained attention is an important cognitive factor that controls access to children's long-term memory stores. Our work also raises the possibility that developmental differences in cognitive performance stem from developmental shifts in the ability to sustain attention.